Regulators of integrated stress pathways

Abstract

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

Description

[0001] This application is a divisional application based on a patent application filed on May 5, 2017, with application number 201780042069.2 (PCT / US2017 / 031360), and the invention name is: "Regulators of integrated stress pathways".

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Application No. 62 / 332,278, filed May 5, 2016, which is incorporated herein by reference in its entirety. Background Art

[0004] In metazoans, various stress signals gather at a single phosphorylation event at serine 51 of a common effector (translation initiation factor eIF2α). This step is implemented in mammalian cells by 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 UV light, PKR in response to viral infection and metabolic stress, and HRI in response to heme deficiency. This collection of signal transduction pathways is referred to as "integrated stress response" (ISR) because they gather on the same molecular event. eIF2α phosphorylation causes a weakening of translation, which results in a stress that allows cells to cope with changes (Wek, RC et al., Biochem Soc Trans (2006) 34 (Pt 1): 7-11).

[0005] eIF2 (which consists of three subunits, α, β, and γ) binds GTP and the initiator Met-tRNA to form a ternary complex (eIF2-GTP-Met-tRNA i ), which in turn associates with the 40S ribosomal subunit, thereby scanning the 5'UTR of mRNA to select the start AUG codon. After phosphorylation of its α subunit, eIF2 becomes a competitive inhibitor of its GTP exchange factor (GEF) eIF2B (Hinnebusch, AG and Lorsch, JRCold Spring Harbor Perspect Biol (2012) 4 (10)). The tight and non-productive binding of phosphorylated eIF2 to eIF2B prevents the loading of the eIF2 complex with 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). Because eIF2B is less abundant than eIF2, phosphorylation of only a small portion of total eIF2 has a significant effect on eIF2B activity in cells.

[0006] eIF2B is a complex molecular machine, composed of five different subunits, eIF2B1 to eIF2B5. eIF2B5 catalyzes the GDP / GTP exchange reaction and, together with the partially homologous subunit eIF2B3, 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 to each other and form a "regulatory subcomplex" (Dev, K. et al., Mol Cell Biol (2010) 30: 5218-5233) that provides a binding site for the substrate eIF2 of eIF2B. The exchange of GDP with the GTP in eIF2 is catalyzed by its dedicated guanine nucleotide exchange factor (GEF) eIF2B. eIF2B exists in cells as a decamer (B12B22B32B42B52) or a dimer of two pentamers (Gordiyenko, Y. et al., Nat Commun (2014) 5:3902; Wortham, NC et al., FASEB J (2014) 28:2225-2237). Molecules such as ISRIB interact with eIF2B dimers and stabilize the conformation of eIF2B dimers, thereby enhancing intrinsic GEF activity and making cells less sensitive to the cellular effects of phosphorylation of eIF2α (Sidrauski, C. et al., eLife (2015) e07314; Sekine, Y. et al., Science (2015) 348:1027-1030). Thus, small molecule therapeutics that can modulate eIF2B activity may have the potential to attenuate the PERK branch of the UPR and the overall ISR, and thus be useful in preventing and / or treating various diseases, such as neurodegenerative diseases, leukodystrophies, cancer, inflammatory diseases, musculoskeletal diseases, or metabolic diseases. Summary of the Invention

[0007] The present invention features compounds, compositions, and methods for modulating eIF2B (e.g., activation of eIF2B) and attenuating ISR signaling pathways. In some embodiments, the present invention features an eIF2B modulator (e.g., an eIF2B activator) comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In other embodiments, the present invention features methods of using a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, for treating a disease or condition, such as a neurodegenerative disease, a leukodystrophy, cancer, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or condition associated with impaired function of a component in eIF2B or an ISR pathway (e.g., an eIF2 pathway).

[0008] In one aspect, the invention features a compound of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl or a cubic alkyl, wherein each bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl or a cubic alkyl is optionally substituted by 1-4 R X Group substitution; L 1 and L 2 Each is independently C1-C6 alkylene, C2-C6 alkenylene, 2-7 membered heteroalkylene, O or NR C , wherein each C1-C6 alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene is optionally substituted by 1-5 R X Replacement; R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, siloxy-C1-C6 alkyl; A and W are each independently aryl or 5-6 membered heteroaryl, wherein each phenyl or 5-6 membered heteroaryl is optionally substituted by 1-5 R Y Replace; each R X Independently selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, oxo, halo, cyano, –OR A ,–NR B R C ,–NR B C(O)R D,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–SR E ,–S(O)R D ,–S(O)2R D 、-OS(O)R D 、–OS(O)2R D and G 2 ; Each R Y are independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, –OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)R D 、–S(O)2R D and G 1 ; or two R on adjacent atoms Y The groups together with the atoms to which they are attached form an optionally substituted group consisting of 1 to 5 R X Substituted 3-7 membered fused cycloalkyl, heterocyclyl, aryl or heteroaryl ring; each G 1 and G 2 is independently a C3-C6 cycloalkyl, a 4-7 membered heterocyclyl, an aryl or a 5-6 membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4-7 membered heterocyclyl, an aryl or a 5-6 membered heteroaryl is optionally substituted by 1-3 R Z Replace; each R Z are independently selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR Dand –S(O)2R D ; Each R A are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, –C(O)NR B R C ,–C(O)R D , –C(O)OH or –C(O)OR D ; R B and R C Each of R is independently hydrogen or C1-C6 alkyl; or B and R C Together with the atoms to which they are attached, they form a Z substituted 3-7 membered heterocyclyl ring; each R D is independently C1-C6 alkyl, 2-7 membered heteroalkyl or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2-7 membered heteroalkyl or halo-C1-C6 alkyl is optionally substituted by 1-5 R G Replace; each R E are independently hydrogen, C1-C6 alkyl or halo-C1-C6 alkyl; each R F are independently hydrogen, C1-C6 alkyl or halo; each R G is independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted by 1-5 R H Replace; each R H are independently C1-C6 alkyl or haloC1-C6 alkyl; m is 1, 3 or 5; and t is 0 or 1.

[0011] In some embodiments, D is a bridged monocyclic cycloalkyl or cubic alkyl, each of which is optionally substituted by 1-4 R X In some embodiments, D is a bridged 4-6 membered monocyclic cycloalkyl or cubic alkyl, each of which is optionally substituted by 1-4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1-4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1-4 R X In some embodiments, D is selected from: In some embodiments, D is selected from: In some embodiments, D is selected from: In some embodiments, D is selected from: In some embodiments, D is replaced by 1 R X In some embodiments, R X It is C1-C6 alkyl, oxo, halo, cyano, –OR A 、–OS(O)2R D 、–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3). In some embodiments, R X is an oxo group, –OR A or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D ). In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl or tetrazolyl).

[0012] In some embodiments, D is replaced by 0 R X In some embodiments, D is

[0013] In some embodiments, L 1 and L 2 At least one of which is independently 2-7 membered heteroalkylene, O or NR C , wherein heteroalkylene is optionally substituted with 1-5 R X In some embodiments, L 1 and L 2 At least one of which is independently optionally replaced by 1-5 R XIn some embodiments, L 1 and L 2 Both are independently optionally substituted with 1-5 R X In some embodiments, L 1 and L 2 One of them is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 The other of the groups is independently 2-7 membered heteroalkylene, and wherein C1-C6 alkylene, C2-C6 alkenylene and 2-7 membered heteroalkylene are each optionally substituted by 1-5 R X In some embodiments, L 1 and L 2 Both are C1-C6 alkylene or C2-C6 alkenylene, and wherein C1-C6 alkylene and C2-C6 alkenylene are each optionally substituted by 1-5 R X In some embodiments, L 1 and L 2 Both are optionally replaced by 1-5 R X Substituted C2-C6 alkenylene.

[0014] In some embodiments, R X It is C1-C6 alkyl, oxo, halo, cyano, –OR A 、–OS(O)2R D ,–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3). In some embodiments, R X is an oxo group, –OR A or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D ). In some embodiments, G2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl or tetrazolyl).

[0015] In some embodiments, L 1 and L 2 Each of the following is independently selected from the group consisting of CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(O)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(O)-*, C H2N(C(O)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, NHC(O)OCH2-*, O-*, NH-*, S(O)2CH-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-*, or CH2C(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 and L 2 Each of is independently selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 independently selected from CH2O-* and CH=CH-*, L 2independently selected from CHO-*, CHCH-*, CH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHCHCHO-*, CHCHOCH-*, NHCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)C H3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, -NHC(O)OCH2-*, O-*, NH-*, S(O)2CH2-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-*, or CH2C(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 is CH2O-*, L 2 are independently selected from CHO-*, CHCH-*, CHC(O)-*, CH═CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to A and W, respectively.

[0016] In some embodiments, t is 1. In some embodiments, t is 0.

[0017] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, or siloxy-C1-C6 alkyl. 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl. In some embodiments, R 1 and R 2 Each is independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, *-CH3, *-CH2CH2OH or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0018] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y In some embodiments, A is phenyl and W is independently phenyl or heteroaryl. In some embodiments, A and W are each independently phenyl. In some embodiments, A is phenyl and W is heteroaryl (e.g., monocyclic heteroaryl or bicyclic heteroaryl).

[0019] In some embodiments, W is a monocyclic heteroaryl. In some embodiments, W is a bicyclic heteroaryl. In some embodiments, W is a 10-membered heteroaryl, a 9-membered heteroaryl, a 6-membered heteroaryl, or a 5-membered heteroaryl. In some embodiments, W is a nitrogen-containing heteroaryl, an oxygen-containing heteroaryl, or a sulfur-containing heteroaryl.

[0020] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y substituted phenyl or 5-6 membered heteroaryl, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m 、–S(O)2R D or G 1 In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 R Y In some embodiments, each of A and W is independently selected from:

[0021]

[0022]

[0023] In some embodiments, each of A and W is independently selected from:

[0024] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl, each of A and W is optionally substituted by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y replace.

[0025] In some embodiments, A is selected from:

[0026] In some embodiments, W is selected from:

[0027] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, each of A and W is optionally replaced by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 .

[0028] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0029] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0030] In some embodiments, A and W are each independently replaced by two R Y Replace, and 2 R Y Together with the atoms to which they are attached, they form a X In some embodiments, 2 R Y Together with the atoms to which they are attached, they form a pyrazolyl, pyrrolyl, isoxazolyl, phenylthio, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (eg, CH3 or fluoro).

[0031] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, G 1is cyclopropyl, isoxazolyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). Z is independently C1-C6 alkyl (eg, CH3).

[0032] In one aspect, the invention features a compound of formula (Ia):

[0033]

[0034] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl or a cubic alkyl, wherein each bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl or a cubic alkyl is optionally substituted by 1-4 R X Group substitution; L 1 and L 2 are each independently C1-C6 alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene, wherein each C1-C6 alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene is optionally substituted by 1-5 R X Replacement; R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, siloxy-C1-C6 alkyl; A and W are each independently phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6 membered heteroaryl is optionally substituted by 1-5 R Y Replace; each R X Independently selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, –OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–SR E ,–S(O)R D and –S(O)2R D ; Each R Yare independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, –OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)R D ,–S(O)2R D and G 1 ; or two R on adjacent atoms Y The groups together with the atoms to which they are attached form an optionally substituted group consisting of 1 to 5 R X Substituted 3-7 membered fused cycloalkyl, heterocyclyl, aryl or heteroaryl ring; each G 1 is independently a C3-C6 cycloalkyl, a 4-7 membered heterocyclyl, an aryl or a 5-6 membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4-7 membered heterocyclyl, an aryl or a 5-6 membered heteroaryl is optionally substituted by 1-3 R Z Replace; each R Z are independently selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D and –S(O)2R D ; Each R A are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, –C(O)NR B R C ,–C(O)R D , –C(O)OH or –C(O)OR D ; R B and R C Each of R is independently hydrogen or C1-C6 alkyl; or B and R CTogether with the atoms to which they are attached, they form a Z substituted 3-7 membered heterocyclyl ring; each R D is independently C1-C6 alkyl, 2-7 membered heteroalkyl or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2-7 membered heteroalkyl or halo-C1-C6 alkyl is optionally substituted by 1-5 R G Replace; each R E are independently hydrogen, C1-C6 alkyl or halo-C1-C6 alkyl; each R F are independently hydrogen, C1-C6 alkyl or halo; each R G is independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted by 1-5 R H Replace; each R H are independently C1-C6 alkyl or haloC1-C6 alkyl; m is 1, 3 or 5; and t is 0 or 1.

[0035] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0036]

[0037] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof,

[0038] wherein D is (1,2,3,4,6,7)-cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane or bicyclo[3.1.1]heptane, each of which is optionally replaced by 1-4 R X Group substitution; L 1 and L 2 Each is independently CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(O)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(O)-*, CH2 N(C(O)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, NHC(O)OCH2-*, O-*, NH-*, S(O)2CH-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-*, or CH2C(O)-*, and “-*” indicates the point of attachment to A and W, respectively; R1 and R 2 are each independently hydrogen, CH3, CH2CH2OH or CH2CH2OSi(CH3)2C(CH3)3; A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinone, triazinyl, thiazolyl, triazolyl, oxadiazolyl or oxadiazolone, each of which is optionally substituted by 1-5 R Y Replace; each R X independently selected from CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D 、-C(O)CH3、-SCH3 or G 2 ; Each R Y is independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 ; or two R on adjacent atoms Y The groups, together with the atoms to which they are attached, form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-2 R X Replacement; G 1 and G 2 is cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl or tetrazolyl or pyrazolyl, each of which is optionally substituted by 1-2 R Z Replace; each R D is optionally replaced by 1-5 R G Substituted CH2O; each R G are independently optionally replaced by 1-5 R H Substituted pyridyl; each R H is independently CF3; each R Z are independently CH3; and t is 0 or 1.

[0039] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0040]

[0041] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 1 , L 2 、R 1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0042] In some embodiments, the compound of formula (I) is a compound of formula (Id):

[0043]

[0044] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 1 , L 2 Each of A and W is as defined for Formula (I).

[0045] In some embodiments, the compound of formula (I) is a compound of formula (Ie):

[0046]

[0047] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 , A, W, R 1 、R 2 Each of and t is as defined for Formula (I).

[0048] In some embodiments, the compound of formula (I) is a compound of formula (If):

[0049]

[0050] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 , W, R Y 、R 1 、R 2 Each of and t is as defined for Formula (I).

[0051] In some embodiments, the compound of formula (I) is a compound of formula (Ig):

[0052]

[0053] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 1 , L 2 、R1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0054] In some embodiments, the compound of formula (I) is a compound of formula (Ih):

[0055]

[0056] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 、R 1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0057] In some embodiments, the compound of formula (I) is a compound of formula (Ii):

[0058]

[0059] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 、R 1 、R 2 , W, R X 、R Y Each of and t is as defined for Formula (I).

[0060] In some embodiments, the compound of formula (I) is a compound of formula (Ij):

[0061]

[0062] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 1 , L 2 、R 1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0063] In some embodiments, the compound of formula (I) is a compound of formula (Ik):

[0064]

[0065] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 、R 1 、R 2 , A, W, RX Each of and t is as defined for Formula (I).

[0066] In some embodiments, the compound of formula (I) is a compound of formula (II):

[0067]

[0068] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 、R 1 、R 2 , W, R X 、R Y Each of and t is as defined for Formula (I).

[0069] In some embodiments, the compound is selected from any compound listed in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0070] In some embodiments, a compound of Formula (I) (e.g., a compound of Formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il)), or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutically acceptable composition comprising a compound as described in any one of the preceding claims and a pharmaceutically acceptable carrier.

[0071] In another aspect, the invention features a method of treating a neurodegenerative disease, leukodystrophy, cancer, inflammatory disease, musculoskeletal disease, metabolic disease, or a disease or condition associated with impaired function of a component in the eIF2B or ISR pathway (e.g., the eIF2 pathway) in a subject, wherein the method comprises administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a combination thereof.

[0072] In some embodiments, the method includes treating neurodegenerative diseases. In some embodiments, the neurodegenerative diseases include white matter ablative leukoencephalopathy, childhood ataxia with CNS myelin deficiency, leukodystrophy, leukoencephalopathy, myelin deficiency or demyelinating disease, intellectual disability syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease (Creutzfeldt-Jakob disease), frontotemporal dementia, Gerstmann-Straussler-Scheinker disease (Gerstmann-Straussler-Scheinker disease), Huntington's disease (Huntington's disease), dementia (e.g., HIV-associated dementia or Lewy body dementia), kuru, Parkinson's disease, progressive nuclear palsy, tau disease or prion disease. In some embodiments, the neurodegenerative diseases include white matter ablative leukoencephalopathy. In some embodiments, the neurodegenerative disease comprises a psychiatric disorder such as agoraphobia, Alzheimer's disease, anorexia nervosa, amnesia, anxiety disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, claustrophobia, depression, paranoia, Diogenes syndrome, movement disorders, insomnia, Munchausen syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, psychosis, phobia, schizophrenia, seasonal affective disorder, schizophreniform personality disorder, sleepwalking, social phobia, substance abuse, tardive dyskinesia, Tourette syndrome, or trichotillomania. In some embodiments, the neurodegenerative disease includes diseases or conditions with symptoms of cognitive impairment or cognitive decline such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, autism, frontotemporal dementia, dementia (e.g., HIV-associated dementia or Lewy body dementia), age-related dementia, chronic traumatic encephalopathy, HIV-induced neurocognitive disorder, HIV-associated neurocognitive disorder, anoxic injury (e.g., premature brain injury, chronic perinatal hypoxia), traumatic brain injury, or postoperative cognitive dysfunction. In some embodiments, the neurodegenerative disease includes intellectual disability syndrome. In some embodiments, the neurodegenerative disease includes mild cognitive impairment.

[0073] In some embodiments, the method comprises treating cancer. In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or secretory cell cancer. In some embodiments, the method comprises treating cancer in combination with a chemotherapeutic agent for enhancing memory (e.g., long-term memory).

[0074] In some embodiments, the method comprises treating an inflammatory disease. In some embodiments, the inflammatory disease comprises postoperative cognitive dysfunction, traumatic brain injury, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, or atopic dermatitis.

[0075] In some embodiments, the method comprises treating a musculoskeletal disease. In some embodiments, the musculoskeletal disease comprises muscular dystrophy, multiple sclerosis, Mali ataxia, muscle wasting disorders (e.g., muscle dystrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscular atrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendonitis, back pain, muscle pain, muscle aches, repetitive strain injury, or paralysis.

[0076] In some embodiments, the method includes treating a metabolic disease. In some embodiments, the metabolic disease includes nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy or Kaplan-Meier disease.

[0077] In another aspect, the invention features a method of treating a disease or condition in a subject associated with modulation (e.g., reduction) of eIF2B activity or level, modulation (e.g., reduction) of eIF2α activity or level, modulation (e.g., increase) of eIF2α phosphorylation, modulation (e.g., increase) of phosphorylated eIF2α pathway activity, or modulation (e.g., increase) of ISR activity, wherein the method comprises administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a combination thereof. In some embodiments, the disease may be caused by a mutation in a gene or protein sequence associated with a member of the eIF2 pathway (e.g., the eIF2α signaling pathway or the ISR pathway).

[0078] In another aspect, the invention features a method of treating leukodystrophy such as vulvovaginal leukoencephalopathy (VWMD) or ataxia in children with insufficient central nervous system myelination. In some embodiments, the leukodystrophy is characterized by an amino acid mutation (e.g., an amino acid deletion, an amino acid addition, or an amino acid substitution) in a tRNA synthetase. In some embodiments, administration of a compound of Formula (I) enhances eIF2B activity in a subject suffering from a leukodystrophy such as vulvovaginal leukoencephalopathy (VWMD) or ataxia in children with insufficient central nervous system myelination.

[0079] In another aspect, the invention features a method of treating a disease or condition associated with an amino acid mutation (e.g., an amino acid deletion, an amino acid addition, or an amino acid substitution) in a gene or gene product (e.g., RNA or protein) that regulates (e.g., reduces) protein synthesis. In some embodiments, administration of a compound of Formula (I) enhances the residual GEF activity of a mutant GEF complex in a subject.

[0080] In another aspect, the invention features a composition for treating a neurodegenerative disease, leukodystrophy, cancer, inflammatory disease, musculoskeletal disease, or metabolic disease in a subject, wherein the composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0081] In some embodiments, the neurodegenerative disease comprises a leukoencephalopathy with white matter ablative effect, a childhood ataxia with CNS hypomyelination, a leukodystrophy, a leukoencephalopathy, a hypomyelination or demyelinating disease, a mental retardation syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Strauss-Schönlein disease, Huntington's disease, dementia (e.g., HIV-associated dementia or Lewy body dementia), kuru, Parkinson's disease, progressive nuclear palsy, tauopathy, or a prion disease. In some embodiments, the neurodegenerative disease comprises a leukoencephalopathy with white matter ablative effect. In some embodiments, the neurodegenerative disease comprises a psychiatric disorder such as agoraphobia, Alzheimer's disease, anorexia nervosa, amnesia, anxiety disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, claustrophobia, depression, paranoia, Diogenes syndrome, movement disorders, insomnia, Munchausen syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, psychosis, phobia, schizophrenia, seasonal affective disorder, schizophreniform personality disorder, sleepwalking, social phobia, substance abuse, tardive dyskinesia, Tourette syndrome, or trichotillomania. In some embodiments, the neurodegenerative disease includes diseases or conditions with symptoms of cognitive impairment or cognitive decline such as Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, autism, frontotemporal dementia, dementia (e.g., HIV-associated dementia or Lewy body dementia), age-related dementia, chronic traumatic encephalopathy, HIV-induced neurocognitive disorder, HIV-associated neurocognitive disorder, anoxic injury (e.g., premature brain injury, chronic perinatal hypoxia), traumatic brain injury, or postoperative cognitive dysfunction. In some embodiments, the neurodegenerative disease includes intellectual disability syndrome. In some embodiments, the neurodegenerative disease includes mild cognitive impairment.

[0082] In some embodiments, the cancer comprises pancreatic cancer, breast cancer, multiple myeloma, or secretory cell cancer.In some embodiments, the method comprises treating the cancer in combination with a chemotherapeutic agent for enhancing memory (e.g., long-term memory).

[0083] In some embodiments, the inflammatory disease comprises postoperative cognitive dysfunction, traumatic brain injury, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, or atopic dermatitis.

[0084] In some embodiments, the musculoskeletal disease comprises muscular dystrophy, multiple sclerosis, Mali ataxia, muscle wasting disorders (e.g., muscle dystrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscular dystrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendonitis, back pain, muscle pain, muscle aches, repetitive strain injury, or paralysis.

[0085] In some embodiments, the metabolic disease comprises nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, or Karnofsky disease.

[0086] In another aspect, the invention features a composition for treating a disease or condition associated with modulation (e.g., reduction) of eIF2B activity or level, modulation (e.g., reduction) of eIF2α activity or level, modulation (e.g., increase) of eIF2α phosphorylation, modulation (e.g., increase) of phosphorylated eIF2α pathway activity, or modulation (e.g., increase) of ISR activity in a subject, wherein the composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the disease may be caused by a mutation in a gene or protein sequence associated with a member of the eIF2 pathway (e.g., the eIF2α signaling pathway or the ISR pathway).

[0087] In another aspect, the invention features a composition for treating leukodystrophy such as vulvovaginal leukoencephalopathy (VWMD) or ataxia in children with insufficient myelination of the central nervous system. In some embodiments, the leukodystrophy is characterized by an amino acid mutation (e.g., an amino acid deletion, an amino acid addition, or an amino acid substitution) in a tRNA synthetase. In some embodiments, a composition comprising a compound of formula (I) enhances eIF2B activity in a subject suffering from leukodystrophy such as vulvovaginal leukoencephalopathy (VWMD) or ataxia in children with insufficient myelination of the central nervous system.

[0088] In another aspect, the invention features a composition for treating a disease or condition associated with an amino acid mutation (e.g., an amino acid deletion, an amino acid addition, or an amino acid substitution) in a gene or gene product (e.g., RNA or protein) that regulates (e.g., reduces) protein synthesis. In some embodiments, a composition comprising a compound of formula (I) enhances the residual GEF activity of a mutant GEF complex in a subject. DETAILED DESCRIPTION

[0089] The invention features compounds, compositions, and methods comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof for use, for example, in the modulation (e.g., activation) of eIF2B and attenuation of ISR signaling pathways.

[0090] definition

[0091] Chemical definition

[0092] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the Periodic Table of the Elements on the inside cover of Handbook of Chemistry and Physics, 75th edition, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0093] Abbreviations used herein have their conventional meanings in chemistry and biology.The chemical structures and formulas listed herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0094] The compounds described herein may include one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers and, alternatively, as mixtures of various isomers.

[0095] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the compound in the "S" form is substantially free of the compound in the "R" form, and is therefore in the "R" form in enantiomeric excess. The term "enantiomerically pure" or "pure enantiomer" means that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight of the enantiomer. In certain embodiments, weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0096] In the compositions provided herein, the enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound can comprise, for example, about 90% of an excipient and about 10% of an enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition can, for example, comprise at least about 95% by weight of an R compound and up to about 5% by weight of an S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound can comprise, for example, about 90% of an excipient and about 10% of an enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition can, for example, comprise at least about 95% by weight of an S compound and up to about 5% by weight of an R compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0097] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O etc.

[0098] The articles "a" and "an" may be used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article. By way of example, "analog" means one analog or more than one analog.

[0099] When a range of values ​​is listed, it is intended to encompass every value and subrange within the range. For example, "C1-C6 alkyl" is intended to encompass 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.

[0100] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention.

[0101] "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-C 20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6 alkyl”). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Each example of an alkyl group can be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; such as substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, an alkyl group is an unsubstituted C1-C6 alkyl group. 1–10 In certain embodiments, an alkyl group is a substituted C 1–6 Alkyl. Common alkyl abbreviations include Me(–CH3), Et(–CH2CH3), iPr(–CH(CH3)2), nPr(–CH2CH2CH3), n–Bu(–CH2CH2CH2CH3), or i–Bu(–CH2CH(CH3)2).

[0102] The term "alkylene," by itself or as part of another substituent, unless otherwise stated, means a divalent radical derived from an alkyl group, as exemplified by, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred in the present invention. The term "alkenylene," by itself or as part of another substituent, unless otherwise stated, means a divalent radical derived from an alkene group. Alkylene groups may be described, for example, as C1-C6-membered alkylene, where the term "membered" refers to non-hydrogen atoms within the moiety.

[0103] "Alkenyl" refers to a straight or branched chain hydrocarbon radical having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C 20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-C 10 In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C 2–4 In some embodiments, the alkenyl group is an unsubstituted C 1-4, C 1-6, C 1-8, C 1-17, C 1-19, C 2-30, C 3-41, C 3-50, C 3-6, C 3-7, C 3-8, C 3-9, C 4-10, C 4-11, C 4-12, C 4-13, C 4-14, C 4-15, C 4-16, C 4-17, C 4-18, C 4-19, C 4-20, C 4-21, C 4-22, C 4-23, C 4-24, C 4-25, C 4-26, C 4-27, C 4-28, C 4-29, C 4-30, C 4-31, C 4-32, C 4-33, C 4-34, C 4-35, C 4-36, C 4-37, C 4-38, C 4-44, C 4-45, C 4-46, C 4-47, C 4-48, C 4-50, C 4-51, C 4-6, C 4-7, C 4-8, C 4-9, C 4-10, C 4-11, C 4-12, C 4-13, C 4-14, C 4-26, C 4-37, C 4-38, C 4-39, C 4-44, C 4-52, C 4-45, C 4-46, C 4-47, C 4-48, C 4-49, C 4-53, C 4-54, C 4-55, C 4-56, C 4-5 2–10 In certain embodiments, an alkenyl group is a substituted C 2–6 Alkenyl.

[0104] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons in total in the ring array) ("C6-C 14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "aryl"; for example, anthracenyl). Aryl groups can be described as, for example, C6-C 10In some embodiments, an aryl group is an unsubstituted C6-C8 aryl group, wherein the term "membered" refers to a non-hydrogen ring atom within the moiety. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C6-C8 aryl group. 14 In certain embodiments, the aryl group is a substituted C6-C 14 Aryl.

[0105] In certain embodiments, the aryl group is substituted with one or more groups selected from the group consisting of halo, C1-C8 alkyl, halo-C1-C8 alkyl, halooxy-C1-C8 alkyl, cyano, hydroxy, alkoxy C1-C8 alkyl, and amino.

[0106] Representative examples of substituted aryl groups include the following

[0107]

[0108] where R 56 and R 57 One of the may be hydrogen and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, halo-C1-C8 alkyl, 4-10 membered heterocyclyl, alkanoyl, alkoxy-C1-C8 alkyl, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 、C(O)O alkyl、C(O)O aryl、CONR 58 R 59 、CONR 58 OR 59 NR 58 R 59 、SO2NR 58 R 59 , S-alkyl, S(O)-alkyl, S(O)2-alkyl, S-aryl, S(O)-aryl, S(O2)-aryl; or R 56 and R 57 They may be linked to form cyclic rings (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from N, O or S groups.

[0109] Other representative aryl groups having fused heterocyclyl groups include the following:

[0110]

[0111] wherein each W' is selected from C(R 66 )2、NR 66 , O and S; and each Y 'is selected from carbonyl, NR 66 , O and S; and R 66 are independently hydrogen, C1–C8 alkyl, C3–C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 membered heteroaryl.

[0112] "Arylene" and "heteroarylene" by themselves or as part of another substituent mean a divalent radical derived from an aryl and heteroaryl radical, respectively. Non-limiting examples of heteroaryl groups include pyridyl, pyrimidinyl, phenylthio, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodiazyl, thiodecalinyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothiophenyl, phenyl, naphthyl substituted or unsubstituted, and the divalent radical of each heteroaryl example is a non-limiting example of a substituent heteroaryl.

[0113] "Halo" or "halogen," by itself or as part of another substituent, means, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide," by itself or as part of another substituent, means a fluoride, chloride, bromide, or iodide atom. In certain embodiments, a halo group is fluorine or chlorine.

[0114] In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-C1-C6 alkyl" includes but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0115] The term "heteroalkyl," by itself or in combination with another term, unless otherwise stated, means a non-cyclic, stable straight or branched chain, or combinations thereof, comprising at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the 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. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. When reciting "heteroalkyl", the specific heteroalkyl group is followed such as -CH2O, -NR B R C In the case of the description of the like, it will be understood that the term heteroalkyl and -CH2O or -NR B R C are not redundant or mutually exclusive. Instead, specific heteroalkyl groups are recited to increase clarity. Therefore, the term "heteroalkyl" should not be interpreted herein to exclude specific heteroalkyl groups such as -CH2O, -NR B R C wait.

[0116] Similarly, the term "heteroalkylene," by itself or as part of another substituent, unless otherwise specified, refers to a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CHO- and -CHCHO-. A heteroalkylene group may be described, for example, as a 2- to 7-membered heteroalkylene group, where the term "membered" refers to a non-hydrogen atom within the moiety. For heteroalkylene groups, heteroatoms may also occupy one or both chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- may represent both -C(O)R'- and -R'C(O)-.

[0117] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons in common in the ring array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups, where one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). Heteroaryl groups can be described, for example, as 6-10 membered heteroaryls, where the term "membered" refers to non-hydrogen ring atoms within the moiety.

[0118] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, a 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Each instance of a heteroaryl group can be independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0119] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. 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 tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, aza-, oxa-, and thia-. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0120] Examples of representative heteroaryl groups include the following:

[0121]

[0122] wherein each Y is selected from carbonyl, N, NR 65 , O and S; and R 65 are independently hydrogen, C1–C8 alkyl, C3–C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 membered heteroaryl.

[0123] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C3-C 10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C8 cycloalkyl”). 10Cycloalkyl"). Cycloalkyl groups can be described, for example, as C4-C7 membered cycloalkyl, where the term "membered" refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. The groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octyl (C8), bicyclo[2.1.1]hexyl (C6), bicyclo[3.1.1]heptyl (C7), and the like. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octyl (C8), bicyclo[2.1.1]hexyl (C6), bicyclo[3.1.1]heptyl (C7), and the like. 10 The cycloalkyl groups include, but are not limited to, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9), 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As shown in the foregoing examples, in certain embodiments, the cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic cycloalkyl"), and may be saturated or may be partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C3-C 10 In certain embodiments, a cycloalkyl group is a substituted C3-C 10 Cycloalkyl.

[0124] In some embodiments, "cycloalkyl" is a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C3-C 10In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, cycloalkyl groups have 5 to 6 ring carbon atoms (“C5-C6 cycloalkyl”). In some embodiments, cycloalkyl groups have 5 to 10 ring carbon atoms (“C5-C 10 Examples of C5-C6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl groups include the aforementioned C5-C6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl groups include the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 cycloalkyl group. 10 In certain embodiments, a cycloalkyl group is a substituted C3-C 10 Cycloalkyl.

[0125] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, where valence permits. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. A heterocyclyl bicyclic ring system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl or heterocyclyl ring; or includes ring systems in which the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl groups can be described as, for example, 3-7 membered heterocyclyls, where the term "member" refers to the non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of a heterocyclyl group can be independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In certain embodiments, a heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0126] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, a 5-6 membered heterocyclyl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0127] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thioranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiecanyl. Exemplary 5-membered heterocyclyl 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, dihydrobenzothienyl, benzoxazolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0128] Specific examples of heterocyclyl groups are shown in the following illustrative examples:

[0129]

[0130] Where each W is selected from CR 67 、C(R 67 )2、NR 67 , O and S; and each Y is selected from NR 67 , O and S; and R 67 are independently hydrogen, C1–C8 alkyl, C3–C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 membered heteroaryl. These heterocyclic rings may be optionally substituted by one or more groups selected from the group consisting of: aryl, amide, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., acylamino), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxyl, keto, nitro, sulfhydryl, –S-alkyl, –S-aryl, –S(O)-alkyl, –S(O)-aryl, –S(O)2-alkyl and –S(O)2-aryl. Substituted groups include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

[0131] "Nitrogen-containing heterocyclic group" means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazinone.

[0132] "Amino" refers to the group -NR 70 R 71 , where R 70 and R 71 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 In some embodiments, amino refers to NH2.

[0133] "Cyano" refers to the radical -CN.

[0134] "Hydroxyl" refers to the group -OH.

[0135] As defined herein, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether or not preceded by "optionally," means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an available substituent, such as a substituent that, upon substitution, results in a stable compound, such as a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. It is contemplated that the term "substituted" includes substitution with all available substituents of an organic compound, such as any substituent described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations to yield stable compounds. For purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatoms and result in the formation of a stable moiety.

[0136] Two or more substituents may optionally be linked to form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group. It has been found that such so-called ring-forming substituents are typically, but not necessarily, attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents are attached to adjacent members of the cyclic base structure to form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents are attached to a single member of the cyclic base structure to form a spiro ring structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0137] "Counter ions" or "anionic counter ions" are negatively charged groups associated with cationic quaternary amino groups to maintain electronic neutrality. Exemplary counter ions include halides (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-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0138] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. The example of pharmaceutically acceptable acid addition salt includes those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid, etc. (see, e.g., Berge et al., Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionality, which allows the compound to be converted into base addition salts or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the present invention. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. In other cases, the formulation can be a lyophilized powder in a first buffer, e.g., 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, which is combined with a second buffer prior to use.

[0139] Thus, the compounds of the present invention may exist as salts, such as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0140] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0141] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted to the compounds of the present invention.

[0142] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polymorphic or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes contemplated by the present invention and are intended to fall within the scope of the present invention.

[0143] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present invention. Illustrative examples of acceptable salts are salts of mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (methyl iodide, ethyl iodide, etc.).

[0144] Certain compounds of the present invention have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms of amino acids defined according to absolute stereochemistry as (R)- or (S)- or (D)- or (L)-, and each isomer is encompassed within the scope of the present invention. The compounds of the present invention do not include those known in the art that are too unstable to synthesize and / or separate. The present invention is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-isomers or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, it is expected that the compounds include both E and Z geometric isomers.

[0145] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

[0146] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0147] It will be apparent to those skilled in the art that certain compounds of the present invention may exist in tautomeric forms and all such tautomeric forms of the compounds are within the scope of the present invention.

[0148] The term "treating" or "treatment" refers to any successful manifestation of treating or ameliorating an injury, disease, disorder, or condition, including any objective or subjective parameter, such as alleviation; remission; attenuation of symptoms or making the injury, disorder, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the degenerative endpoint less debilitating; or improving the patient's physical or mental health. Treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric testing, and / or psychiatric evaluation. For example, certain methods herein treat cancer (e.g., pancreatic cancer, breast cancer, multiple myeloma, secretory cell cancers), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, frontotemporal dementia), leukodystrophies (e.g., white matter ablative leukoencephalopathy, childhood ataxia with CNS hypomyelination), postoperative cognitive dysfunction, traumatic brain injury, intellectual disability syndromes, inflammatory diseases, musculoskeletal diseases, inflammatory diseases, or diseases or conditions associated with impaired function of eIF2B or components of signaling or signaling pathways including the ISR and decreased eIF2 pathway activity). For example, certain methods herein treat cancer by reducing or decreasing or preventing the development, growth, metastasis or progression of cancer or reducing symptoms of cancer; treat neurodegeneration by improving mental health, increasing mental function, slowing the decline in mental function, reducing dementia, delaying the onset of dementia, improving cognitive skills, reducing the loss of cognitive skills, improving memory, reducing memory deterioration, reducing symptoms of neurodegeneration or prolonging survival; treat white matter ablative leukoencephalopathy by reducing the symptoms of white matter ablative leukoencephalopathy or reducing the loss of white matter or reducing the loss of myelin or increasing the amount of myelin or increasing the amount of white matter; treat pediatric ataxia with CNS hypomyelination by reducing the symptoms of pediatric ataxia with CNS hypomyelination or increasing the level of myelin or reducing the loss of myelin; treat intellectual disability syndrome by reducing the symptoms of intellectual disability syndrome, treat inflammatory diseases by treating the symptoms of inflammatory diseases; treat musculoskeletal diseases by treating the symptoms of musculoskeletal diseases; or treat metabolic diseases by treating the symptoms of metabolic diseases. Symptoms of the diseases, disorders, or conditions described herein (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or conditions or diseases associated with impaired function of eIF2B or a component of a signal transduction pathway, including the eIF2 pathway, eIF2α phosphorylation, or the ISR pathway) are known or can be determined by one of ordinary skill in the art. The term "treating," "treating," "treating," and its conjugations include preventing an injury, pathology, condition, or disease (e.g., preventing the development of one or more symptoms of a disease, disorder, or condition described herein).

[0149] "Effective amount" is an amount sufficient to achieve the purpose of the description (e.g., to achieve the effect of its 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). An example of an "effective amount" is an amount sufficient to promote the treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount." A "prophylactic effective amount" of a drug is an amount that will have an expected preventive effect when administered to a subject, 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 complete preventive effect does not necessarily occur by administering a single dose, but may only occur after administering a series of doses. Therefore, a prophylactic effective amount may be administered in one or more administrations. The exact amount will depend on the purpose of the treatment, and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, Gennaro, ed., Lippincott, Williams & Wilkins).

[0150] "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means a decrease in the severity or frequency of one or more symptoms, or the elimination of one or more symptoms.

[0151] The term "associated" or "associated with" in the context of a substance or substance activity or function associated with a disease (e.g., a disease or condition described herein, such as cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or a disease or condition associated with an impaired function of a component in an eIF2B or signal transduction pathway, including an eIF2 pathway, eIF2α phosphorylation, or an ISR pathway) means that the disease (completely or partially) or the symptoms of the disease (completely or partially) are caused by the substance or substance activity or function. For example, a symptom of a disease or condition associated with an impaired function of eIF2B can be a symptom caused (completely or partially) by a decrease in eIF2B activity (e.g., a decrease in eIF2B activity or level, an increase in eIF2α phosphorylation or activity of phosphorylated eIF2α, or a decrease in eIF2 activity or an increase in the activity of a phosphorylated eIF2α signal transduction or ISR signaling pathway). As used herein, an object described as being associated with a disease can be a target for treatment of the disease if it is a pathogenic substance. For example, a disease associated with eIF2 activity or eIF2 pathway activity can be treated with an agent (e.g., a compound as described herein) that is effective in increasing the level or activity of eIF2 or the eIF2 pathway or reducing phosphorylated eIF2α activity or the ISR pathway. For example, a disease associated with phosphorylated eIF2α can be treated with an agent (e.g., a compound as described herein) that is effective in reducing the level of activity of phosphorylated eIF2α or a downstream component or effector of phosphorylated eIF2α. For example, a disease associated with eIF2α can be treated with an agent (e.g., a compound as described herein) that is effective in increasing the level of activity of eIF2 or a downstream component or effector of eIF2.

[0152] "Control" or "controlled experiment" is used according to its plain and ordinary meaning and refers to an experiment in which the experimental subjects or reagents are treated as in parallel experiments, except that the experimental procedures, reagents, or variables are ignored. In some cases, a control serves as a standard of comparison when evaluating the effects of an experiment.

[0153] "Contacting" is used according to its plain ordinary meaning and refers to the process of allowing at least two different substances (e.g., chemical compounds or cells including biomolecules) to become close enough to react, interact, or physically touch. However, it should be recognized that the resulting reaction product can be produced directly by the reaction between the added reagents, or by intermediates from one or more added reagents, which can be produced in the reaction mixture. The term "contacting" can include allowing two substances to react, interact, or physically touch, wherein the two substances can be a compound as described herein and a protein or enzyme (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway). In some embodiments, contacting includes allowing a compound as described herein to interact with a protein or enzyme involved in a signaling pathway (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway).

[0154] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like with respect to protein-inhibitor (e.g., antagonist) interactions mean negatively affecting (e.g., reducing) the activity or function of a protein relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to a reduction in a disease or a symptom of a disease. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or a signaling pathway. Thus, inhibition includes, at least in part, partially or completely blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzyme activity or the amount of a protein. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or a signaling pathway (e.g., a component of an eIF2B, eIF2α, or eIF2 pathway, a pathway activated by phosphorylation of eIF2α, or an ISR pathway). Thus, inhibition can include, at least in part, partially or completely reducing stimulation, reducing or decreasing activation or inactivation, desensitizing or downregulating the amount of a signal transduction or enzyme activity or a protein that is increased in a disease (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway, each of which is associated with cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, or a metabolic disease). Inhibition can include, at least in part, partially or completely reducing stimulation, reducing or decreasing activation or inactivation, desensitizing or downregulating the amount of a signal transduction or enzyme activity or a protein (e.g., eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway) that can modulate the level of another protein or increase cell survival (e.g., reducing phosphorylated eIF2α pathway activity can increase cell survival of cells that may or may not have increased phosphorylated eIF2α pathway activity compared to a non-disease control, or reducing eIF2α pathway activity can increase cell survival of cells that may or may not have increased eIF2α pathway activity compared to a non-disease control).

[0155] As defined herein, the terms "activation," "activate," "activating," and the like with respect to protein-activator (e.g., agonist) interactions mean actively affecting (e.g., increasing) the activity or function of a protein (e.g., eIF2B, eIF2α, or a component of an eIF2 pathway or an ISR pathway) relative to the activity or function of the protein in the absence of the activator (e.g., a compound described herein). In some embodiments, activation refers to an increase in the activity of a signal transduction pathway or a signaling pathway (e.g., eIF2B, eIF2α, or a component of an eIF2 pathway or an ISR pathway). Thus, activation can include, at least in part, partially or completely increasing the amount of a protein (e.g., the level of eIF2B, eIF2α, or a component of an eIF2 pathway or an ISR pathway associated with cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, or a metabolic disease) that stimulates, increases, or allows activation or activation, sensitizes, or upregulates signal transduction or enzyme activity, or that is decreased in a disease. Activation can include, at least in part, partially or completely increasing stimulation, increasing or allowing activation or activating, sensitizing or upregulating the amount of a signal transduction or enzymatic activity or protein (e.g., eIF2B, eIF2α or a component of the eIF2 pathway or ISR pathway) that can modulate the level of another protein or increase cell survival (e.g., increasing eIF2α activity can increase cell survival of cells that may or may not have decreased eIF2α activity compared to non-disease controls).

[0156] The term "modulate" refers to an increase or decrease in the level of a target molecule or the function of a target molecule. In some embodiments, modulation of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway can result in a decrease in the severity of one or more symptoms of a disease associated with a component of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, or metabolic diseases) or a disease that is not caused by a component of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway but that would benefit from modulation of a component of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway (e.g., reducing the level or activity level of a component of the eIF2B, eIF2α, or eIF2 pathway).

[0157] As used herein, the term "modulator" refers to the function of regulating (for example, increasing or decreasing) the level of a target molecule or a target molecule. In embodiments, the modulator of a component of eIF2B, eIF2α or eIF2 pathway or ISR pathway is an anticancer agent. In embodiments, the modulator of a component of eIF2B, eIF2α or eIF2 pathway or ISR pathway is a neuroprotectant. In embodiments, the modulator of a component of eIF2B, eIF2α or eIF2 pathway or ISR pathway is a memory enhancer. In embodiments, the modulator of a component of eIF2B, eIF2α or eIF2 pathway or ISR pathway is a memory enhancer (for example, a long-term memory enhancer). In embodiments, the modulator of a component of eIF2B, eIF2α or eIF2 pathway or ISR pathway is an anti-inflammatory agent. In some embodiments, the modulator of a component of eIF2B, eIF2α or eIF2 pathway or ISR pathway is a pain reliever.

[0158] A "patient" or "subject in need thereof" refers to a living organism having or susceptible to a disease or condition that can be treated by administering a compound or pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the patient is a domesticated animal. In some embodiments, the patient is a dog. In some embodiments, the patient is a parrot. In some embodiments, the patient is a livestock animal. In some embodiments, the patient is a mammal. In some embodiments, the patient is a cat. In some embodiments, the patient is a horse. In some embodiments, the patient is a cow. In some embodiments, the patient In some embodiments, the patient is a canine. In some embodiments, the patient is a feline. In some embodiments, the patient is an ape. In some embodiments, the patient is a monkey. In some embodiments, the patient is a mouse. In some embodiments, the patient is a laboratory animal. In some embodiments, the patient is a rat. In some embodiments, the patient is a hamster. In some embodiments, the patient is a test animal. In some embodiments, the patient is a newborn animal. In some embodiments, the patient is a newborn human. In some embodiments, the patient is a newborn mammal. In some embodiments, the patient is an elderly animal. In some embodiments, the patient is an elderly human. In some embodiments, the patient is an elderly mammal. In some embodiments, the patient is an elderly patient.

[0159] "Disease," "disorder," or "condition" refers to a state or condition in a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the compounds and methods described herein include reducing or eliminating one or more symptoms of a disease, disorder, or condition, for example, by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0160] As used herein, the term "signaling pathway" refers to a series of interactions between a cell and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which in turn can transmit changes to additional components, with the event optionally propagating to other signaling pathway components.

[0161] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration of an active agent to a subject and in its absorption and that may be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, regular saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, spices, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments. Such formulations may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring substances, and / or aromatic substances that do not react adversely with the compounds of the present invention. One of ordinary skill in the art will recognize that other pharmaceutical excipients may also be used in the present invention.

[0162] The term "preparing" is intended to include formulating the active compound with encapsulating material as a carrier, the encapsulating material providing a capsule in which the active component, with or without other carriers, is surrounded by the carrier, which is thereby associated with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0163] As used herein, the term "administering" means oral administration to a subject, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or implantation of a sustained-release device, for example, a small osmotic pump. Administered by any route, including parenteral and transmucosal (for example, buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of delivery include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, etc. "Total administration" means administering at the same time of one or more other therapies (for example, anticancer agents, chemotherapeutics or the treatment of neurodegenerative diseases), just before or just after the administration of the compositions described herein. The compounds of the present invention can be administered alone or can be administered to the patient in total. Co-administration is intended to include administration of the compounds singly or in combination (more than one compound or agent), simultaneously or sequentially. Thus, the formulations may also be combined with other active substances, if desired (e.g., to reduce metabolic degradation).

[0164] As used herein, the term "eIF2B" refers to the heteropentameric eukaryotic translation initiation factor 2B. eIF2B is composed of five subunits: eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. eIF2B1 refers to a protein associated with Entrez gene 1967, OMIM 606686, Uniprot Q14232, and / or RefSeq (protein) NP_001405. eIF2B2 refers to a protein associated with Entrez gene 8892, OMIM 606454, Uniprot P49770, and / or RefSeq (protein) NP_055054. eIF2B3 refers to a protein associated with Entrez gene 8891, OMIM 606273, Uniprot Q9NR50, and / or RefSeq (protein) NP_065098. eIF2B4 refers to a protein associated with Entrez gene 8890, OMIM 606687, Uniprot Q9UI10, and / or RefSeq (protein) NP_751945. eIF2B5 refers to a protein associated with Entrez gene 8893, OMIM 603945, Uniprot Q13144, and / or RefSeq (protein) NP_003898.

[0165] The terms "eIF2alpha", "eIF2a" or "eIF2α" are interchangeable and refer to the protein "eukaryotic translation initiation factor 2 alpha subunit eIF2S1". In embodiments, "eIF2alpha", "eIF2a" or "eIF2α" refer to the human protein. Included within the terms eIF2alpha", "eIF2a" or "eIF2α" are wild-type and mutant forms of the protein. In embodiments, "eIF2alpha", "eIF2a" or "eIF2α" refer to the protein associated with Entrez gene 1965, OMIM 603907, UniProt P05198 and / or RefSeq (protein) NP_004085. In embodiments, the reference numbers immediately above refer to the protein and related nucleic acids known as of the filing date of this application.

[0166] Compound

[0167] In one aspect, the invention features a compound of formula (I):

[0168]

[0169] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl or a cubic alkyl, wherein each bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl or a cubic alkyl is optionally substituted by 1-4 R X Group substitution; L 1 and L 2 Each is independently C1-C6 alkylene, C2-C6 alkenylene, 2-7 membered heteroalkylene, O or NR C , wherein each C1-C6 alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene is optionally substituted by 1-5 R X Replacement; R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, siloxy-C1-C6 alkyl; A and W are each independently aryl or 5-6 membered heteroaryl, wherein each phenyl or 5-6 membered heteroaryl is optionally substituted by 1-5 R Y Replace; each R X Independently selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, –OR A ,–NR B R C ,–NR B C(O)RD ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–SR E ,–S(O)R D ,–S(O)2R D 、–OS(O)R D 、–OS(O)2R D and phenyl, 5-6 membered heteroaryl; each R Y are independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, –OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)R D ,–S(O)2R D and G 1 ; or two R on adjacent atoms Y The groups together with the atoms to which they are attached form an optionally substituted group consisting of 1 to 5 R X Substituted 3-7 membered fused cycloalkyl, heterocyclyl, aryl or heteroaryl ring; each G 1 is independently a C3-C6 cycloalkyl, a 4-7 membered heterocyclyl, an aryl or a 5-6 membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4-7 membered heterocyclyl, an aryl or a 5-6 membered heteroaryl is optionally substituted by 1-3 R Z Replace; each R Z are independently selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR Dand –S(O)2R D ; Each R A are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, –C(O)NR B R C ,–C(O)R D , –C(O)OH or –C(O)OR D ; R B and R C Each of R is independently hydrogen or C1-C6 alkyl; or B and R C Together with the atoms to which they are attached, they form a Z substituted 3-7 membered heterocyclyl ring; each R D is independently C1-C6 alkyl, 2-7 membered heteroalkyl or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2-7 membered heteroalkyl or halo-C1-C6 alkyl is optionally substituted by 1-5 R G Replace; each R E are independently hydrogen, C1-C6 alkyl or halo-C1-C6 alkyl; each R F are independently hydrogen, C1-C6 alkyl or halo; each R G is independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted by 1-5 R H Replace; each R H are independently C1-C6 alkyl or halo-C1-C6 alkyl; m is 1, 3 or 5; and t is 0 or 1.

[0170] In some embodiments, D is a bridged monocyclic cycloalkyl or cubic alkyl, each of which is optionally substituted by 1-4 R X In some embodiments, D is a bridged 4-6 membered monocyclic cycloalkyl or cubic alkyl, each of which is optionally substituted by 1-4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1-4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1-4 R X In some embodiments, D is selected from: In some embodiments, D is selected from: In some embodiments, D is selected from: In some embodiments, D is selected from: In some embodiments, D is replaced by 1 R X In some embodiments, R X It is C1-C6 alkyl, oxo, halo, cyano, –OR A 、–OS(O)2R D ,–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3). In some embodiments, R X is an oxo group, –OR A or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D ). In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl or tetrazolyl).

[0171] In some embodiments, D is replaced by 0 R X In some embodiments, D is

[0172] In some embodiments, L 1 and L 2 At least one of which is independently 2-7 membered heteroalkylene, O or NR C , wherein heteroalkylene is optionally substituted with 1-5 R X In some embodiments, L 1 and L 2 At least one of which is independently optionally replaced by 1-5 R XIn some embodiments, L 1 and L 2 Both are independently optionally substituted with 1-5 R X In some embodiments, L 1 and L 2 One of them is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 The other of the group is independently a 2-7 membered heteroalkylene, and wherein each of the C1-C6 alkylene, C2-C6 alkenylene and 2-7 membered heteroalkylene is optionally substituted by 1-5 R X In some embodiments, L 1 and L 2 Both are C1-C6 alkylene or C2-C6 alkenylene, and wherein C1-C6 alkylene and C2-C6 alkenylene are each optionally substituted by 1-5 R X In some embodiments, L 1 and L 2 Both are optionally replaced by 1-5 R X Substituted C2-C6 alkenylene.

[0173] In some embodiments, each R X are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, oxo or –C(O)R D (e.g., CH3, OH, oxo, CH2OH, CH2OCH3, or C(O)CH3). In some embodiments, each R X are independently C1-C6 alkyl, oxo or –C(O)R D (e.g., CH3, oxo, or C(O)CH3).

[0174] In some embodiments, L 1 and L 2Each of the following is independently selected from the group consisting of CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(O)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(O)-*, C H2N(C(O)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, NHC(O)OCH2-*, O-*, NH-*, S(O)2CH-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-*, or CH2C(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 and L 2 Each of is independently selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 independently selected from CH2O-* and CH=CH-*, L 2 independently selected from CHO-*, CHCH-*, CH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHCHCHO-*, CHCHOCH-*, NHCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)C H3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, -NHC(O)OCH2-*, O-*, NH-*, S(O)2CH2-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-*, or CH2C(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 is CH2O-*, L 2are independently selected from CHO-*, CHCH-*, CHC(O)-*, CH═CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to A and W, respectively.

[0175] In some embodiments, t is 1. In some embodiments, t is 0.

[0176] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, or siloxy-C1-C6 alkyl. 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl. In some embodiments, R 1 and R 2 Each is independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, *-CH3, *-CH2CH2OH or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0177] In some embodiments, A is phenyl and W is independently phenyl or 5-6 membered heteroaryl. In some embodiments, A and W are each independently phenyl. In some embodiments, A is phenyl and W is 5-6 membered heteroaryl.

[0178] In some embodiments, W is a monocyclic 5-6 membered heteroaryl. In some embodiments, two R on adjacent atoms of W are Y The groups together with the atoms to which they are attached form an optionally substituted group consisting of 1 to 5 RX In some embodiments, W is a 3-7 membered fused cycloalkyl or heterocyclyl group, thereby forming a bicyclic heteroaryl group. In some embodiments, W is a 10-membered heteroaryl group, a 9-membered heteroaryl group, a 6-membered heteroaryl group, or a 5-membered heteroaryl group. In some embodiments, W is a heteroaryl group containing nitrogen, oxygen, or sulfur as allowed by valence.

[0179] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y substituted phenyl or 5-6 membered heteroaryl, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 R Y In some embodiments, each of A and W is independently selected from:

[0180]

[0181] In some embodiments, each of A and W is independently selected from:

[0182] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl, each of A and W is optionally substituted by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D、–C(O)OH、–C(O)OR D ,–S(R F ) m 、–S(O)2R D or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y replace.

[0183] In some embodiments, A is selected from:

[0184] In some embodiments, W is selected from:

[0185] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, each of A and W is optionally replaced by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m 、–S(O)2R D or G 1 .

[0186] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0187] In some embodiments, each R Yis independently chlorine, fluorine, iodine, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0188] In some embodiments, A and W are each independently replaced by two R Y Replace, and 2 R Y Together with the atoms to which they are attached, they form a X In some embodiments, 2 R Y Together with the atoms to which they are attached, they form a pyrazolyl, pyrrolyl, isoxazolyl, phenylthio, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (eg, CH3 or fluoro).

[0189] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, G 1 is cyclopropyl, isoxazolyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). Z is independently C1-C6 alkyl (eg, CH3).

[0190] In another aspect, the invention features a compound of formula (Ia):

[0191]

[0192] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein D is a bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl or a cubic alkyl, wherein each bridged monocyclic cycloalkyl, a bridged monocyclic heterocyclyl or a cubic alkyl is optionally substituted by 1-4 R X Group substitution; L 1 and L 2are each independently C1-C6 alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene, wherein each C1-C6 alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene is optionally substituted by 1-5 R X Replacement; R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl, siloxy-C1-C6 alkyl; A and W are each independently phenyl or 5-6 membered heteroaryl, wherein each phenyl or 5-6 membered heteroaryl is optionally substituted by 1-5 R Y Replace; each R X Independently selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, –OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–SR E ,–S(O)R D and –S(O)2R D ; Each R Y are independently selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, –OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)R D ,–S(O)2R D and G 1 ; or two R on adjacent atoms Y The groups together with the atoms to which they are attached form an optionally substituted group consisting of 1 to 5 R XSubstituted 3-7 membered fused cycloalkyl, heterocyclyl, aryl or heteroaryl ring; each G 1 is independently a C3-C6 cycloalkyl, a 4-7 membered heterocyclyl, an aryl or a 5-6 membered heteroaryl, wherein each C3-C6 cycloalkyl, a 4-7 membered heterocyclyl, an aryl or a 5-6 membered heteroaryl is optionally substituted by 1-3 R Z Replace; each R Z are independently selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A ,–NR B R C ,–NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D and –S(O)2R D ; Each R A are independently hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, –C(O)NR B R C ,–C(O)R D , –C(O)OH and –C(O)OR D ; R B and R C Each of R is independently hydrogen or C1-C6 alkyl; or B and R C Together with the atoms to which they are attached, they form a Z substituted 3-7 membered heterocyclyl ring; each R D is independently C1-C6 alkyl, 2-7 membered heteroalkyl or halo-C1-C6 alkyl, wherein each C1-C6 alkyl, 2-7 membered heteroalkyl or halo-C1-C6 alkyl is optionally substituted by 1-5 R G Replace; each R E are independently hydrogen, C1-C6 alkyl or halo-C1-C6 alkyl; each R F are independently hydrogen, C1-C6 alkyl or halo; each R G is independently aryl or 5-6 membered heteroaryl, wherein each aryl or 5-6 membered heteroaryl is optionally substituted by 1-5 R H Replace; each R H are independently C1-C6 alkyl or haloC1-C6 alkyl; m is 1, 3 or 5; and t is 0 or 1.

[0193] In some embodiments, D is a bridged monocyclic cycloalkyl or cubic alkyl, each of which is optionally substituted by 1-4 R X In some embodiments, D is a bridged 4-6 membered monocyclic cycloalkyl or cubic alkyl, each of which is optionally substituted by 1-4 R X In some embodiments, D is selected from cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, or bicyclo[3.1.1]heptane, each of which is optionally substituted with 1-4 R X In some embodiments, D is selected from: In some embodiments, D is selected from: In some embodiments, D is replaced by 1 R X In some embodiments, R X is an oxo group, –OR A or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D In some embodiments, D is replaced by 0 R X In some embodiments, D is

[0194] In some embodiments, L 1 and L 2 At least one of which is independently optionally replaced by 1-5 R X In some embodiments, L 1 and L 2 Both are independently optionally substituted with 1-5 R X In some embodiments, L 1 and L 2 One of them is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 The other of the group is independently a 2-7 membered heteroalkylene, and wherein each of the C1-C6 alkylene, C2-C6 alkenylene and 2-7 membered heteroalkylene is optionally substituted by 1-5 R X In some embodiments, each R X are independently C1-C6 alkyl, oxo or –C(O)R D (e.g., CH3, oxo, or C(O)CH3). In some embodiments, L 1 and L 2Each of is independently selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 is CH2O-*, L 2 are independently selected from CHO-*, CHCH-*, CHC(O)-*, CH═CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to A and W, respectively.

[0195] In some embodiments, t is 1. In some embodiments, t is 0.

[0196] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, or siloxy-C1-C6 alkyl. 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl. In some embodiments, R 1 and R 2 Each is independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 One of is independently hydrogen, and R 1 and R 2The other of R is independently hydrogen, *-CH3, *-CH2CH2OH or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0197] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y substituted phenyl or 5-6 membered heteroaryl, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, each of A and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y In some embodiments, each of A and W is independently selected from:

[0198] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl, each of A and W is optionally substituted by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 RY replace.

[0199] In some embodiments, A is selected from:

[0200] In some embodiments, in some embodiments, W is selected from:

[0201] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0202] In some embodiments, A and W are each independently replaced by two R Y Replace, and 2 R Y Together with the atoms to which they are attached, they form a X In some embodiments, 2 R Y Together with the atoms to which they are attached, they form a pyrazolyl, pyrrolyl, isoxazolyl, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (eg, CH3 or fluoro).

[0203] In some embodiments, G 1 is cyclopropyl, isoxazolyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (eg, CH3).

[0204] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0205]

[0206] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof,

[0207] wherein D is (1,2,3,4,6,7)-cubane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane or bicyclo[3.1.1]heptane, each of which is optionally replaced by 1-4 R X Group substitution; L 1 and L 2 Each is independently CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(O)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(O)-*, CH2 N(C(O)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, NHC(O)OCH2-*, O-*, NH-*, S(O)2CH-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-*, or CH2C(O)-*, and “-*” indicates the point of attachment to A and W, respectively; R 1 and R 2 are each independently hydrogen, CH3, CH2CH2OH or CH2CH2OSi(CH3)2C(CH3)3; A and W are each independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinone, triazinyl, thiazolyl, triazolyl, oxadiazolyl or oxadiazolone, each of which is optionally substituted by 1-5 R Y Replace; each R X independently selected from CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D 、-C(O)CH3、-SCH3 or G 2 ; Each R Yis independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 ; or two R on adjacent atoms Y The groups, together with the atoms to which they are attached, form a pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-2 R X Replacement; G 1 and G 2 is cyclopropyl, isoxazolyl, phenyl, piperidinyl, oxadiazolyl or tetrazolyl or pyrazolyl, each of which is optionally substituted by 1-2 R Z Replace; each R D is optionally replaced by 1-5 R G Substituted CH2O; each R G are independently optionally replaced by 1-5 R H Substituted pyridyl; each R H is independently CF3; each R Z are independently CH3; and t is 0 or 1.

[0208] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0209]

[0210] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 1 , L 2 、R 1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0211] In some embodiments, R X It is C1-C6 alkyl, oxo, halo, cyano, –OR A 、–OS(O)2R D ,–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NRB R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3). In some embodiments, R X is an oxo group, –OR A or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D ). In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl or tetrazolyl).

[0212] In some embodiments, L 1 and L 2 At least one of which is independently 2-7 membered heteroalkylene, O or NR C , wherein heteroalkylene is optionally substituted with 1-5 R X In some embodiments, L 1 and L 2 At least one of which is independently optionally replaced by 1-5 R X In some embodiments, L 1 and L 2 Both are independently optionally substituted with 1-5 R X In some embodiments, L 1 and L 2 One of them is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 The other of the groups is independently 2-7 membered heteroalkylene, and wherein C1-C6 alkylene, C2-C6 alkenylene and 2-7 membered heteroalkylene are each optionally substituted by 1-5 R X In some embodiments, L 1 and L 2 Both are C1-C6 alkylene or C2-C6 alkenylene, and wherein C1-C6 alkylene and C2-C6 alkenylene are each optionally substituted by 1-5 R X In some embodiments, L 1 and L2 Both are optionally replaced by 1-5 R X Substituted C2-C6 alkenylene.

[0213] In some embodiments, R X It is C1-C6 alkyl, oxo, halo, cyano, –OR A 、–OS(O)2R D ,–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3). In some embodiments, R X is an oxo group, –OR A or NR B R C (e.g., oxo, OH, OCH3, N(CH3)2, or OC(O)R D ). In some embodiments, G 2 is aryl or 5-6 membered heteroaryl (eg, oxadiazolyl or tetrazolyl).

[0214] In some embodiments, L 1 and L 2Each of the following is independently selected from the group consisting of CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(O)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OCH2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(O)-*, C H2N(C(O)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, NHC(O)OCH2-*, O-*, NH-*, S(O)2CH-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-*, or CH2C(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 and L 2 Each of is independently selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 independently selected from CH2O-* and CH=CH-*, L 2 independently selected from CHO-*, CHCH-*, CH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHCHCHO-*, CHCHOCH-*, NHCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)C H3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, -NHC(O)OCH2-*, O-*, NH-*, S(O)2CH2-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-*, or CH2C(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 is CH2O-*, L 2are independently selected from CHO-*, CHCH-*, CHC(O)-*, CH═CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to A and W, respectively.

[0215] In some embodiments, t is 1. In some embodiments, t is 0.

[0216] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, or siloxy-C1-C6 alkyl. 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl. In some embodiments, R 1 and R 2 Each is independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, *-CH3, *-CH2CH2OH or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0217] In some embodiments, A is phenyl and W is independently phenyl or 5-6 membered heteroaryl. In some embodiments, A and W are each independently phenyl. In some embodiments, A is phenyl and W is 5-6 membered heteroaryl.

[0218] In some embodiments, W is a monocyclic 5-6 membered heteroaryl. In some embodiments, two R on adjacent atoms of W are Y The groups together with the atoms to which they are attached form an optionally substituted group consisting of 1 to 5 RX In some embodiments, W is a 3-7 membered fused cycloalkyl or heterocyclyl group, thereby forming a bicyclic heteroaryl group. In some embodiments, W is a 10-membered heteroaryl group, a 9-membered heteroaryl group, a 6-membered heteroaryl group, or a 5-membered heteroaryl group. In some embodiments, W is a heteroaryl group containing nitrogen, oxygen, or sulfur as allowed by valence.

[0219] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y substituted phenyl or 5-6 membered heteroaryl, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m 、–S(O)2R D or G 1 In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 R Y In some embodiments, each of A and W is independently selected from:

[0220]

[0221]

[0222] In some embodiments, each of A and W is independently selected from:

[0223] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl, each of A and W is optionally substituted by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NRB R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y replace.

[0224] In some embodiments, A is selected from:

[0225] In some embodiments, W is selected from:

[0226] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, each of A and W is optionally replaced by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 .

[0227] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0228] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0229] In some embodiments, A and W are each independently replaced by two R Y Replace, and 2 R Y Together with the atoms to which they are attached, they form a X In some embodiments, 2 R Y Together with the atoms to which they are attached, they form a pyrazolyl, pyrrolyl, isoxazolyl, phenylthio, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (eg, CH3 or fluoro).

[0230] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, G 1 is cyclopropyl, isoxazolyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). Z is independently C1-C6 alkyl (eg, CH3).

[0231] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0232]

[0233] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 1 , L 2 Each of A and W is as defined for Formula (I).

[0234] In some embodiments, the compound of formula (I) is a compound of formula (Ie):

[0235]

[0236] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 , A, W, R 1 、R 2 Each of and t is as defined for Formula (I).

[0237] In some embodiments, L 2 is optionally replaced by 1-5 R X substituted C1-C6 membered alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene. In some embodiments, L 2 is selected from CHO-*, CHCH-*, CHCHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH2-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH3)-*, CHCH(OH)-*, NHC(O)OCH-*, NH-*, S(O)CH-* or CHC(O)-*, and “-*” indicates the point of attachment to W.

[0238] C1-C6 alkyl, oxo, halo, cyano, –OR A 、–OS(O)2R D ,–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3).

[0239] In some embodiments, L 2is selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to W. In some embodiments, L 2 is selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to W.

[0240] In some embodiments, t is 1. In some embodiments, t is 0.

[0241] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, or siloxy-C1-C6 alkyl. 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl. In some embodiments, R 1 and R 2 Each is independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, *-CH3, *-CH2CH2OH or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2are each independently hydrogen.

[0242] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y In some embodiments, A and W are each independently substituted with 1-5 R Y substituted phenyl or 5-6 membered heteroaryl, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, each of A and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y In some embodiments, each of A and W is independently selected from:

[0243]

[0244]

[0245] In some embodiments, each of A and W is independently selected from:

[0246] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl, each of A and W is optionally substituted by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y replace.

[0247] In some embodiments, A is selected from:

[0248] In some embodiments, in some embodiments, W is selected from:

[0249] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0250] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0251] In some embodiments, A and W are each independently replaced by two R Y Replace, and 2 R Y Together with the atoms to which they are attached, they form a X In some embodiments, 2 R Y Together with the atoms to which they are attached, they form a pyrazolyl, pyrrolyl, isoxazolyl, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (eg, CH3 or fluoro).

[0252] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (eg, CH3) or halo (eg, chloro).

[0253] In some embodiments, the compound of formula (I) is a compound of formula (If):

[0254]

[0255] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 , W, R Y 、R 1 、R 2 Each of and t is as defined for Formula (I).

[0256] In some embodiments, L 2 is optionally replaced by 1-5 R X substituted C1-C6 membered alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene. In some embodiments, L 2 is optionally replaced by 1-5 R X Substituted 2-7 membered heteroalkylene, O or NR C In some embodiments, L 2 Selected from CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(O)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OC H2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(O)-*, CH 2N(C(O)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, NHC(O)OCH2-*, O-*, NH-*, S(O)2CH-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-* or CH2C(O)-*, and “-*” indicates the point of attachment to W.

[0257] In some embodiments, each R X are independently C1-C6 alkyl, oxo, halo, cyano, -OR A 、–OS(O)2RD ,–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3).

[0258] In some embodiments, L 2 is selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to W. In some embodiments, L 2 is selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to W.

[0259] In some embodiments, t is 1. In some embodiments, t is 0.

[0260] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, or siloxy-C1-C6 alkyl. 1 and R 2One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl. In some embodiments, R 1 and R 2 Each is independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, *-CH3, *-CH2CH2OH or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0261] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y substituted phenyl or 5-6 membered heteroaryl, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 R Y In some embodiments, each of A and W is independently selected from:

[0262]

[0263]

[0264] In some embodiments, each of A and W is independently selected from:

[0265] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl, each of A and W is optionally substituted by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y replace.

[0266] In some embodiments, A is selected from:

[0267] In some embodiments, W is selected from:

[0268] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, each of A and W is optionally replaced by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G1 .

[0269] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0270] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0271] In some embodiments, A and W are each independently replaced by two R Y Replace, and 2 R Y Together with the atoms to which they are attached, they form a X In some embodiments, 2 R Y Together with the atoms to which they are attached, they form a pyrazolyl, pyrrolyl, isoxazolyl, phenylthio, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (eg, CH3 or fluoro).

[0272] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, G 1 is cyclopropyl, isoxazolyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, each R Zis independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). Z is independently C1-C6 alkyl (eg, CH3).

[0273] In some embodiments, the compound of formula (I) is a compound of formula (Ig):

[0274]

[0275] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 1 , L 2 、R 1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0276] In some embodiments, the compound of formula (I) is a compound of formula (Ih):

[0277]

[0278] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 、R 1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0279] In some embodiments, the compound of formula (I) is a compound of formula (Ii):

[0280]

[0281] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 、R 1 、R 2 , W, R X 、R Y Each of and t is as defined for Formula (I).

[0282] In some embodiments, L 2 is optionally replaced by 1-5 R X substituted C1-C6 membered alkylene, C2-C6 alkenylene or 2-7 membered heteroalkylene. In some embodiments, L 2 is optionally replaced by 1-5 R X Substituted 2-7 membered heteroalkylene, O or NRC In some embodiments, L 2 Selected from CH2O-*, CH2CH2-*, CH2CH2CH2-*, CH2-*, CH2C(O)-*, CH=CH-*, CH2CH2O-*, CH2OCH2-*, CH2OC H2CH2-*, CH2CH2CH2O-*, CH2CH2OCH2-*, NHCH2-*, CH2NH-*, CH2N(CH3)-*, CH2N(CH3)C(O)-*, CH 2N(C(O)CH3)-*, CH2CH(OH)-*, CH(OH)-*, CH(OH)CH2CH2-*, CH2CH(OH)-*, CH2NHC(O)-*, NHC(O)OCH2-*, O-*, NH-*, S(O)2CH-*, S(O)2CH2CH2-*, S(O)2CH2CH2O-* or CH2C(O)-*, and “-*” indicates the point of attachment to W.

[0283] In some embodiments, each R X are independently C1-C6 alkyl, oxo, halo, cyano, -OR A 、–OS(O)2R D 、–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3).

[0284] In some embodiments, L 2is selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to W. In some embodiments, L 2 is selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to W.

[0285] In some embodiments, t is 1. In some embodiments, t is 0.

[0286] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, or siloxy-C1-C6 alkyl. 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl. In some embodiments, R 1 and R 2 Each is independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, *-CH3, *-CH2CH2OH or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2are each independently hydrogen.

[0287] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y substituted phenyl or 5-6 membered heteroaryl, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 R Y In some embodiments, each of A and W is independently selected from:

[0288]

[0289]

[0290] In some embodiments, each of A and W is independently selected from:

[0291] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl, each of A and W is optionally substituted by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(RF ) m ,–S(O)2R D or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y replace.

[0292] In some embodiments, A is selected from:

[0293] In some embodiments, W is selected from:

[0294] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, each of A and W is optionally replaced by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m ,–S(O)2R D or G 1 .

[0295] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0296] In some embodiments, each R Yis independently chlorine, fluorine, iodine, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0297] In some embodiments, A and W are each independently replaced by two R Y Replace, and 2 R Y Together with the atoms to which they are attached, they form a X In some embodiments, 2 R Y Together with the atoms to which they are attached, they form a pyrazolyl, pyrrolyl, isoxazolyl, phenylthio, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (eg, CH3 or fluoro).

[0298] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, G 1 is cyclopropyl, isoxazolyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). Z is independently C1-C6 alkyl (eg, CH3).

[0299] In some embodiments, the compound of formula (I) is a compound of formula (Ij):

[0300]

[0301] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 1 , L 2 、R 1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0302] In some embodiments, the compound of formula (I) is a compound of formula (Ik):

[0303]

[0304] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 、R 1 、R 2 , A, W, R X Each of and t is as defined for Formula (I).

[0305] In some embodiments, the compound of formula (I) is a compound of formula (II):

[0306]

[0307] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein L 2 、R 1 、R 2 , W, R X 、R Y Each of and t is as defined for Formula (I).

[0308] In some embodiments, L 1 and L 2 At least one of which is independently optionally replaced by 1-5 R X In some embodiments, L 1 and L 2 Both are independently optionally substituted with 1-5 R X In some embodiments, L 1 and L 2 One of them is independently C1-C6 alkylene or C2-C6 alkenylene, and L 1 and L 2 The other of the groups is independently 2-7 membered heteroalkylene, and wherein C1-C6 alkylene, C2-C6 alkenylene and 2-7 membered heteroalkylene are each optionally substituted by 1-5 R X In some embodiments, each R X are independently C1-C6 alkyl, oxo or –C(O)R D (e.g., CH3, oxo, or C(O)CH3). In some embodiments, L 1 and L 2Each of is independently selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to A and W, respectively. In some embodiments, L 1 is CH2O-*, L 2 are independently selected from CHO-*, CHCH-*, CHC(O)-*, CH═CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to A and W, respectively.

[0309] In some embodiments, L 2 is selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-*, or CHC(O)-*, and "-*" indicates the point of attachment to W. In some embodiments, L 2 is selected from CHO-*, CHCH-*, CHC(O)-*, CH=CH-*, CHCHO-*, CHOCH-*, CHOCHCH-*, CHCHCHO-*, CHCHOCH2-*, CHNH-*, CHN(CH)-*, CHN(CH)C(O)-*, CHN(C(O)CH)-*, CHCH(OH)-*, NHC(O)OCH-* or CHC(O)-*, and “-*” indicates the point of attachment to W.

[0310] In some embodiments, each R X are independently C1-C6 alkyl, oxo, halo, cyano, -ORA 、–OS(O)2R D 、–S(O)2R D ,–SR E NR B C(O)R D ,–C(O)NR B R C ,–C(O)R D 、–C(O)OH、NR B R C or G 2 (e.g., CH3, oxo, fluorine, OH, cyano, OCH3, NH2, N(CH3)2, NHC(O)CH3, OC(O)CH3, C(O)NH2, OS(O)2CH3, -S(O)2CH3, -S(O)2CH2CH3, C(O)OH, OC(O)R D , -C(O)CH3 or -SCH3).

[0311] In some embodiments, t is 1. In some embodiments, t is 0.

[0312] In some embodiments, R 1 and R 2 are each independently hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, or siloxy-C1-C6 alkyl. 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl. In some embodiments, R 1 and R 2 Each is independently hydrogen, *-CH3, *-CH2CH2OH, or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 One of is independently hydrogen, and R 1 and R 2 The other of R is independently hydrogen, *-CH3, *-CH2CH2OH or *-CH2CH2OSi(CH3)2C(CH3)3, and "*-" indicates the point of attachment to the nitrogen atom. In some embodiments, R 1 and R 2 are each independently hydrogen.

[0313] In some embodiments, A is phenyl and W is independently phenyl or 5-6 membered heteroaryl. In some embodiments, A and W are each independently phenyl. In some embodiments, A is phenyl and W is 5-6 membered heteroaryl.

[0314] In some embodiments, W is a monocyclic 5-6 membered heteroaryl. In some embodiments, two R on adjacent atoms of W are Y The groups together with the atoms to which they are attached form an optionally substituted group consisting of 1 to 5 R X In some embodiments, W is a 3-7 membered fused cycloalkyl or heterocyclyl group, thereby forming a bicyclic heteroaryl group. In some embodiments, W is a 10-membered heteroaryl group, a 9-membered heteroaryl group, a 6-membered heteroaryl group, or a 5-membered heteroaryl group. In some embodiments, W is a heteroaryl group containing nitrogen, oxygen, or sulfur as allowed by valence.

[0315] In some embodiments, A and W are each independently optionally replaced by 1-5 R Y substituted phenyl or 5-6 membered heteroaryl, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m 、–S(O)2R D or G 1 In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, triazinyl, triazolyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y In some embodiments, each of A and W is independently phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted with 1-5 R Y In some embodiments, each of A and W is independently selected from:

[0316]

[0317]

[0318] In some embodiments, each of A and W is independently selected from:

[0319] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl, each of A and W is optionally substituted by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m 、–S(O)2R D or G 1 In some embodiments, A is phenyl and W is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyridazinonyl, oxadiazolyl, or oxadiazolonyl, each of which is optionally substituted by 1-5 R Y replace.

[0320] In some embodiments, A is selected from:

[0321] In some embodiments, W is selected from:

[0322] In some embodiments, A is phenyl and W is phenyl or 5-6 membered heteroaryl. In some embodiments, each of A and W is optionally replaced by 1-5 R Y Replace, and each R Y are independently C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, halo, cyano, –OR A ,–NR B R C ,–C(O)R D 、–C(O)OH、–C(O)OR D ,–S(R F ) m 、–S(O)2R D or G 1 .

[0323] In some embodiments, each R Yis independently chlorine, fluorine, iodine, CF3, CHF2, CH2CF3, CH3, CH2CH3, C(CH3)2OH, OCH3, OCH2CH3, OCF3, S(O)2CH3, S(O)2CH2CH2CH3, CN, N(CH3)2, SF5, SCH3, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(OH)(CH3)CF3, S(O)2CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0324] In some embodiments, each R Y is independently chlorine, fluorine, iodine, CF3, CH3, CH2CH3, OCH3, S(O)2CH3, CN, N(CH3)2, SF5, NH2, C(CH)3, CH(CH3)2, CH2CN, CH2NH2, CH(OH)CH3, C(O)CH3, C(O)OCH3, C(O)OH, OCHF2 or G 1 .

[0325] In some embodiments, A and W are each independently replaced by two R Y Replace, and 2 R Y Together with the atoms to which they are attached, they form a X In some embodiments, 2 R Y Together with the atoms to which they are attached, they form a pyrazolyl, pyrrolyl, isoxazolyl, phenylthio, furanyl, or dioxolanyl ring, each of which is optionally substituted by 1-5 R X In some embodiments, each R X is independently C1-C6 alkyl or halo (eg, CH3 or fluoro).

[0326] In some embodiments, G 1 is cyclopropyl, isoxazolyl, piperidinyl, phenyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, G 1 is cyclopropyl, isoxazolyl or pyrazolyl, each of which is optionally substituted by 1-5 R Z In some embodiments, each R Z is independently C1-C6 alkyl (e.g., CH3) or halo (e.g., chloro). Z is independently C1-C6 alkyl (eg, CH3).

[0327] In some embodiments, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il)) or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutically acceptable composition comprising a compound as described in any one of the preceding claims and a pharmaceutically acceptable carrier.

[0328] In some embodiments, the compound is selected from any compound listed in Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0329] Table 1: Exemplary compounds of the present invention

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394] Methods of Preparing Exemplary Compounds

[0395] The compounds of the present invention may be better understood in conjunction with the following synthetic schemes and methods illustrating how the compounds may be prepared. The compounds of the present invention may be prepared by various synthetic procedures. Representative synthetic procedures are shown in, but not limited to, Schemes 1-24. Variables A, D, W, L 1 , L 2 、R 1 and R 2For example, in the Summary of the Invention as defined in detail herein

[0396] Scheme 1: Representative scheme for the synthesis of exemplary compounds of the invention.

[0397]

[0398] As shown in Scheme 1, when A and W are the same and L 1 and L 2 When the compounds of formula (1) are the same and represent compounds of formula (2A), compounds of formula (3) can be prepared from compounds of formula (1). Carboxylic acids of formula (2A) can be coupled with amines of formula (1) under amide bond forming conditions to obtain compounds of formula (3). Examples of conditions known to form amides from mixtures of carboxylic acids and amines include, but are not limited to, the addition of coupling agents such as, but not limited to, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI) or the corresponding hydrochlorides, 1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (BOPCl), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanamine hexafluorophosphate N-oxide or 2-(7 -azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HBTU), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,4,6-trioxide The coupling agent can be added as a solid, a solution, or as a reagent bound to a solid support resin.

[0399] In addition to the coupling agent, an auxiliary coupling agent can promote the coupling reaction. Auxiliary coupling agents often used in coupling reactions include but are not limited to (dimethylamino) pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole (HOBT). The reaction can be optionally carried out in the presence of a base (such as but not limited to triethylamine, N, N-diisopropylethylamine or pyridine). The coupling reaction can be carried out in a solvent such as but not limited to tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, dichloromethane and ethyl acetate. The reaction can be carried out at ambient temperature or by heating. Heating can be conventionally or by microwave radiation.

[0400] Alternatively, the acid chloride of formula (2B) can be reacted with an amine of formula (1) in the presence of a base (such as a tertiary amine base such as, but not limited to, triethylamine or N,N-diisopropylethylamine or an aromatic base such as pyridine) at room temperature or with heating in a solvent (such as, but not limited to, dichloromethane) to obtain an amide of formula (3). The amine of formula (1) can also be coupled with the acid chloride of formula (2B) in the presence of a base (such as, but not limited to, sodium hydroxide) in a mixture of water and dichloromethane.

[0401] Scheme 2: Representative scheme for the synthesis of exemplary compounds of the invention.

[0402]

[0403] As shown in Scheme 2, when A and W are the same or different and L 1 and L 2 When the compounds of formula (1) are the same or different and represent compounds of formula (2), compounds of formula (3) can be prepared from compounds of formula (1). The amine of formula (1) can be protected with a suitable protecting group (PG) to obtain a compound of formula (4). For example, the amine of formula (1) can be treated with di-tert-butyl dicarbonate in a solvent such as, but not limited to, tetrahydrofuran at ambient temperature to obtain a compound of formula (4), wherein PG is C(O)OC(CH3)3. A carboxylic acid of formula (2A) or an acyl chloride of formula (2B) can be coupled with an amine of formula (4) under the amide bond forming conditions described in Scheme 1 to obtain a compound of formula (5). The protecting group (PG) in formula (5) can be removed to obtain a compound of formula (6). For example, the BOC protecting group can be removed using an acid such as, but not limited to, trifluoroacetic acid or hydrochloric acid in a solvent such as, but not limited to, methanol, 1,4-dioxane or dichloromethane or a mixture thereof. The reaction can be performed at ambient temperature or at elevated temperature. Carboxylic acids of formula (7A) or acid chlorides of formula (7B) can be coupled with amines of formula (6) under the amide bond forming conditions described in Scheme 1 to afford compounds of formula (3), which represent compounds of formula (I).

[0404] Scheme 3: Representative scheme for the synthesis of exemplary compounds of the invention.

[0405]

[0406] As shown in Scheme 3, compounds of formula (9) (when t is 0, which represents a compound of formula (I)) can be prepared from compounds of formula (6). Compounds of formula (6) (which can be prepared as described in Scheme 2) can be reacted with an aldehyde of formula (8) (wherein R 100The reaction is typically carried out at ambient temperature in a solvent such as, but not limited to, 1,2-dichloroethane, dichloromethane, methanol, ethanol, tetrahydrofuran, acetonitrile, or a mixture thereof.

[0407] Scheme 4: Representative scheme for the synthesis of exemplary compounds of the invention.

[0408]

[0409] Alternatively, compounds of formula (9) (when t is 0, which represents compounds of formula (I)) can be prepared from compounds of formula (6) as shown in Scheme 4. Amines of formula (6) can be reacted with bromides of formula (10) in the presence of a base (such as, but not limited to, potassium carbonate) to obtain compounds of formula (9). The reaction is typically performed at elevated temperature in a solvent (such as, but not limited to, N,N-dimethylformamide or dimethyl sulfoxide).

[0410] Scheme 5: Representative scheme for the synthesis of exemplary compounds of the invention.

[0411]

[0412] Compounds of formula (13) and compounds of formula (14), which represent compounds of formula (I) wherein t is 1, can be prepared as shown in Scheme 5. Amines of formula (6), which can be prepared as described in Scheme 2, can be treated with 2-chloroacetyl chloride in the presence of a base such as, but not limited to, potassium carbonate to obtain compounds of formula (11). The addition is typically performed at low temperatures in a solvent such as, but not limited to, tetrahydrofuran, water, or a mixture thereof, and then warmed to ambient temperature. An alcohol of formula (12A) can be reacted with a compound of formula (11) in the presence of a strong base such as, but not limited to, sodium hydride to obtain a compound of formula (13). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, N,N-dimethylformamide. Alternatively, an alcohol of formula (12A) can be reacted with a compound of formula (11) in the presence of a base such as, but not limited to, potassium carbonate, optionally with the addition of a catalytic amount of potassium iodide, to obtain a compound of formula (13). The reaction is typically performed at elevated temperature, optionally in a microwave, and in a solvent such as, but not limited to, acetonitrile, acetone, or a mixture thereof. An alcohol of formula (12B) wherein n is 1-6 can be reacted with a compound of formula (11) in the presence of a strong base such as, but not limited to, sodium hydride to obtain a compound of formula (14). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, N,N-dimethylformamide.

[0413] Scheme 6: Representative scheme for the synthesis of exemplary compounds of the invention.

[0414]

[0415] As shown in Scheme 6, a compound of formula (15) (which represents a compound of formula (I) wherein t is 1 and L 2 is a C2-C7 heteroalkylene) can be prepared from compounds of formula (6). Amines of formula (6) can be treated with bis(trichloromethyl)carbonate followed by an alcohol of formula (12B) to obtain compounds of formula (15). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran.

[0416] Scheme 7: Representative scheme for the synthesis of exemplary compounds of the invention.

[0417]

[0418] Compounds of formula (18) (which represent compounds of formula (I) wherein t is 1 and R 2 is C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl or siloxy-C1-C6 alkyl) can be prepared from compounds of formula (6) as shown in Scheme 7. Amines of formula (6) can be alkylated with alkylating agents of formula (16) (wherein X is a halide) in the presence of a base (such as, but not limited to, potassium carbonate) to obtain compounds of formula (17). The reaction is typically performed at elevated temperature in a solvent (such as, but not limited to, N,N-dimethylformamide). Carboxylic acids of formula (7A) or acid chlorides of formula (7B) can be coupled with amines of formula (17) under the amide bond forming conditions described in Scheme 1 to obtain compounds of formula (18).

[0419] Scheme 8: Representative scheme for the synthesis of exemplary compounds of the invention.

[0420]

[0421] As shown in Scheme 8, compounds of formula (20) (which represent compounds of formula (I) where t is 1) can be prepared from amines of formula (6). Amines of formula (6) can be reacted with chloroformates of formula (19) in the presence of a base (such as, but not limited to, N,N-diisopropylethylamine) to obtain compounds of formula (20). The reaction is typically performed at ambient temperature in a solvent (such as, but not limited to, toluene, dichloromethane, or a mixture thereof).

[0422] Scheme 9: Representative scheme for the synthesis of exemplary compounds of the invention.

[0423]

[0424] The compound of formula (I) (wherein R 1is C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, hydroxy-C1-C6 alkyl or silyloxy-C1-C6 alkyl) can be prepared from a compound of formula (5) as shown in Scheme 9. Amines of formula (5), which can be prepared as described in Scheme 2, can be alkylated with an alkylating agent of formula (21) (wherein X is a halide) in the presence of a base (such as, but not limited to, sodium hydride) to obtain compounds of formula (22). The reaction is typically performed at ambient temperature in a solvent (such as, but not limited to, tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, or a mixture thereof). After removal of the protecting group (PG), the compound of formula (22) can be reacted with a carboxylic acid of formula (7A) or an acid chloride of formula (7B) under the amide bond forming conditions described in Scheme 2 to obtain a compound of formula (I).

[0425] Scheme 10: Representative scheme for the synthesis of exemplary compounds of the invention.

[0426]

[0427] As shown in Scheme 10, compounds of formula (25) (which represent compounds of formula (I) wherein t is 1) can be prepared from compounds of formula (6). Amines of formula (6) (which can be prepared as described in Scheme 2) can be reacted with 2-hydroxyacetic acid under the amide bond forming conditions described in Scheme 2 to obtain compounds of formula (23). Compounds of formula (23) can be alkylated with alkylating agents of formula (24) (wherein X is a halide and n is 0-5) in the presence of a base (such as, but not limited to, sodium hydride) to obtain compounds of formula (25). The reaction is typically performed at elevated temperature in a solvent (such as, but not limited to, tetrahydrofuran, N,N-dimethylformamide, or a mixture thereof).

[0428] Scheme 11: Representative scheme for the synthesis of exemplary compounds of the invention.

[0429]

[0430] Compounds of formula (28), which represent compounds of formula (I), wherein t is 1, can be prepared from compounds of formula (23) as shown in Scheme 11. Compounds of formula (23), which can be prepared as described in Scheme 10, can be reacted with methyl 2-bromoacetate in the presence of a base, such as, but not limited to, cesium carbonate, to obtain compounds of formula (26). The reaction is typically performed at ambient temperature in a solvent, such as, but not limited to, tetrahydrofuran. Compounds of formula (26) can be treated with aqueous lithium hydroxide to obtain compounds of formula (27). The reaction is typically performed at ambient temperature in a solvent, such as, but not limited to, tetrahydrofuran, methanol, or a mixture thereof. Compounds of formula (27) can be treated with N-hydroxyacetimidate in the presence of a coupling agent, such as, but not limited to, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU), and a base, such as, but not limited to, triethylamine, to obtain compounds of formula (28). The reaction is typically performed at elevated temperature in a solvent such as, but not limited to, acetonitrile.

[0431] Scheme 12: Representative scheme for the synthesis of exemplary compounds of the invention.

[0432]

[0433] As shown in Scheme 12, compounds of formula (30), which represent compounds of formula (I), can be prepared from compounds of formula (26). Compounds of formula (26), which can be prepared as described in Scheme 11, can be treated with hydrazine monohydrate to obtain compounds of formula (29). The reaction is typically performed at elevated temperatures in a solvent such as, but not limited to, ethanol. Compounds of formula (29) can be treated with 1,1'-carbonyldiimidazole to obtain compounds of formula (30). The reaction is typically performed at elevated temperatures in a solvent such as, but not limited to, 1,4-dioxane.

[0434] Scheme 13: Representative scheme for the synthesis of exemplary compounds of the invention.

[0435]

[0436] Scheme 13 describes the synthesis of compounds of formula (I), wherein D is a 2-oxobicyclo[2.2.2]octan-1-yl core. 4-Amino-2-oxobicyclo[2.2.2]octane-1-carboxylic acid ethyl ester (which can be prepared as described herein) can be reacted with a carboxylic acid of formula (2A) or an acid chloride of formula (2B) under the amide bond forming conditions described in Scheme 1 to obtain a compound of formula (31). The compound of formula (31) can be treated with a methanolic solution of sodium hydroxide at ambient temperature to obtain a compound of formula (32). The acid of formula (32) can be treated with diphenylphosphoryl azide in the presence of a base such as, but not limited to, triethylamine, followed by treatment with tert-butanol to obtain a compound of formula (33). The reaction is typically performed at elevated temperature in a solvent such as, but not limited to, toluene. The compound of formula (33) can be treated with an acid such as, but not limited to, hydrochloric acid in a solvent such as, but not limited to, 1,4-dioxane at ambient temperature to obtain a compound of formula (34). Compounds of formula (34) can be reacted with carboxylic acids of formula (7A) or acid chlorides of formula (7B) under the amide bond forming conditions described in Scheme 2 to provide compounds of formula (I).

[0437] Scheme 14: Representative scheme for the synthesis of exemplary compounds of the invention.

[0438]

[0439] Scheme 14 describes the synthesis of carboxylic acids (37), (42), and (45), which represent acids of formula (2A) and formula (7A).

[0440] The compound of formula (35) can be reacted with ethyl 2-hydroxyacetate in the presence of a strong base (such as, but not limited to, potassium tert-butoxide) to obtain a compound of formula (36). The reaction is typically performed at ambient temperature in a solvent (such as, but not limited to, tetrahydrofuran). The compound of formula (36) can be treated with aqueous lithium hydroxide to obtain a compound of formula (37). The reaction is typically performed at ambient temperature in a solvent (such as, but not limited to, tetrahydrofuran).

[0441] The alcohol of formula (38) can be reacted with tert-butyl 2-bromoacetate in the presence of a base (such as, but not limited to, potassium carbonate) to obtain a compound of formula (39). The reaction is typically performed at elevated temperature in a solvent (such as, but not limited to, N,N-dimethylformamide). The compound of formula (39) can be treated with an acid (such as, but not limited to, hydrochloric acid) to obtain a compound of formula (37). The reaction is typically performed at ambient temperature in a solvent (such as, but not limited to, 1,4-dioxane).

[0442] The compound of formula (40) can be reacted with ethyl 3-bromopropionate in the presence of a strong base (such as, but not limited to, sodium hydride) to obtain a compound of formula (41). The addition is typically performed at low temperatures in a solvent (such as, but not limited to, tetrahydrofuran) and then warmed to ambient temperature. The compound of formula (41) can be treated with aqueous sodium hydroxide to obtain a compound of formula (42). The reaction is typically performed at ambient temperature in a solvent (such as, but not limited to, tetrahydrofuran).

[0443] Carboxylic acids of formula (43) can be reacted with sarcosine methyl ester under the amide bond forming conditions described in Scheme 1 to obtain compounds of formula (44). Compounds of formula (44) can be treated with aqueous sodium hydroxide to obtain compounds of formula (45). The reaction is typically performed at ambient temperature in a solvent such as, but not limited to, ethanol.

[0444] Scheme 15: Representative scheme for the synthesis of exemplary compounds of the invention.

[0445]

[0446] As shown in Scheme 15, bromides of formula (47), which represent compounds of formula (10) and formula (24), can be prepared from alcohols of formula (46). Compounds of formula (46) can be reacted with 1,2-dibromoethane in the presence of a base (such as, but not limited to, potassium carbonate) to obtain compounds of formula (47). The reaction is typically performed at elevated temperature in a solvent (such as, but not limited to, acetonitrile).

[0447] Scheme 16: Representative scheme for the synthesis of exemplary compounds of the invention.

[0448]

[0449] As shown in Scheme 16, the compound of formula (49) (wherein A and W are the same or different and L 1 and L 2The same or different compounds representing formula (I) can be prepared from compounds of formula (48). Carboxylic acids of formula (7A) or acid chlorides of formula (7B) can be coupled with amines of formula (48) under amide bond forming conditions as described in Scheme 1 to obtain compounds of formula (49). Ketones of formula (48) can also be reduced in the presence of a reducing agent such as, but not limited to, sodium borohydride in a solvent such as a mixture of methanol and dichloromethane to obtain alcohols of formula (50). Carboxylic acids of formula (7A) or acid chlorides of formula (7B) can be coupled with amines of formula (50) under amide bond forming conditions as described in Scheme 1 to obtain compounds of formula (51). Ketones of formula (49) can also be reduced in the presence of a reducing agent such as, but not limited to, sodium borohydride in a solvent such as a mixture of methanol and dichloromethane to obtain alcohols of formula (51). Compounds of formula (48), formula (49), formula (50), and formula (51) can be further derivatized as shown in the following examples.

[0450] Scheme 17: Representative scheme for the synthesis of exemplary compounds of the invention.

[0451]

[0452] As shown in Scheme 17, compounds of formula (52) can be converted to compounds of formula (6), which in turn can be converted to compounds of formula (I) by the methods described in Schemes 2-8 and Scheme 10. Thus, a carboxylic acid of formula (2A) or an acid chloride of formula (2B) can be coupled with an amine of formula (50) under the amide bond forming conditions described in Scheme 1, followed by ester hydrolysis using conditions known to those skilled in the art to obtain compounds of formula (53). Compounds of formula (53) can be reacted under Curtius reaction conditions such as treatment with diphenylphosphoryl azide and triethylamine in heated toluene, followed by acid hydrolysis to obtain compounds of formula (6).

[0453] Scheme 18: Representative scheme for the synthesis of exemplary compounds of the invention.

[0454]

[0455] As shown in Scheme 18, the compound of formula (6) can be converted to the compound of formula (57), which represents the compound of formula (I). Thus, the compound of formula (6) can be coupled with a protected amino acid of formula (54) (wherein PG is a suitable amine protecting group) using the amide bond coupling conditions described in Scheme 1 to provide the compound of formula (55). The protecting group PG in the compound of formula (55) can be removed under conditions known to those skilled in the art to expose the primary amine, which can be coupled with a carboxylic acid of formula (56) using the amide bond coupling conditions described in Scheme 1 to provide the compound of formula (57).

[0456] Scheme 19: Representative scheme for the synthesis of exemplary compounds of the invention.

[0457]

[0458] As shown in Scheme 19, a compound of formula (6) can be converted to a compound of formula (59), which represents a compound of formula (I). The compound of formula (6) can be reacted with a sulfonyl chloride of formula (58) in the presence of a base such as triethylamine in an optionally warm solvent such as, but not limited to, N,N-dimethylformamide to provide a compound of formula (59).

[0459] Scheme 20: Representative scheme for the synthesis of exemplary compounds of the invention.

[0460]

[0461] As shown in Scheme 20, a compound of formula (6) can be converted to a compound of formula (61), which represents a compound of formula (I). A compound of formula (6) can be reacted with an isocyanate of formula (60) in the presence of pyridine to provide a compound of formula (61).

[0462] Scheme 21: Representative scheme for the synthesis of exemplary compounds of the invention.

[0463]

[0464] As shown in Scheme 21, a compound of formula (6) can be converted to a compound of formula (63), which represents a compound of formula (I). The compound of formula (6) can be reacted with a carbonyl chloride salt of formula (62) in the presence of a base such as N,N-diisopropylethylamine in a solvent such as tetrahydrofuran to provide a compound of formula (63).

[0465] Scheme 22: Representative scheme for the synthesis of exemplary compounds of the invention.

[0466]

[0467] As shown in Scheme 22, compounds of formula (64) can be converted to compounds of formula (65), which represent compounds of formula (I). Compounds of formula (64) can be reduced with indium(III) bromide and triethylsilane (Et3SiH) in warm dichloromethane to provide compounds of formula (65).

[0468] Scheme 23: Representative scheme for the synthesis of exemplary compounds of the invention.

[0469]

[0470] As shown in Scheme 23, the compound of formula (66) can be converted into the compound of formula (1). Therefore, the ester portion of the compound of formula (66) can be hydrolyzed under conditions known to those skilled in the art to obtain the corresponding carboxylic acid. The carboxylic acid can be treated under Curtius reaction conditions to complete the conversion of the compound of formula (67). The compound of formula (67) can be reacted with di-tert-butyl dicarbonate in the presence of a base to obtain an orthogonally protected diamine (68). The compound of formula (68) can be converted into the compound of formula (1) under catalytic hydrogenation conditions in the presence of an acid (such as 4M hydrochloric acid) in a solvent (such as warm dioxane). The compound of formula (1) can be used as described in Scheme 1 or Scheme 2.

[0471] Scheme 24: Representative scheme for the synthesis of exemplary compounds of the invention.

[0472]

[0473] As shown in Scheme 24, the compound of formula (68) can be converted to the compound of formula (71). The compound of formula (68) can be reductively aminated to the compound of formula (69), wherein R 2b is an optionally substituted C1-C6 alkyl group. Compounds of formula (69) can be treated under acidic conditions known to those skilled in the art to selectively remove the tert-butoxycarbonyl protecting group, and the exposed amine can then be coupled with a compound of formula (2A) using the amide bond forming reaction conditions described in Scheme 1 to obtain a compound of formula (70). Alternatively, an acid chloride of formula (2B) can also be coupled with an amine as described in Scheme 1. The benzyl protecting group of the compound of formula (70) can be removed under catalytic hydrogenation conditions, and the exposed amine can then be coupled with a carboxylic acid of formula (7A) to obtain a compound of formula (71). Compounds of formula (71) can also be obtained by reacting the corresponding acid chloride with the previously mentioned exposed amine using the conditions also described in Scheme 1. Compounds of formula (71) represent compounds of formula (I).

[0474] Pharmaceutical composition

[0475] The present invention is characterized in that the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof is provided in a pharmaceutical composition in an effective amount. In some embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic effective amount.

[0476] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparation methods comprise the following steps: the compound of formula (I) ("active ingredient") is associated with a carrier and / or one or more other auxiliary ingredients, and then, if necessary and / or desired, the product is shaped and / or packaged into a desired single dose or multiple dose unit. The pharmaceutical composition can be prepared, packaged and / or sold in large quantities as a single unit dose and / or as multiple single unit doses. As used herein, a "unit dose" is an individual amount of a pharmaceutical composition comprising a predetermined amount of active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient to be administered to the subject and / or a suitable fraction of such a dosage, such as half or one-third of such a dosage.

[0477] The relative amounts of the compound of formula (I), pharmaceutically acceptable excipients and / or any additional ingredients in the pharmaceutical compositions of the present invention will vary depending on the identity, size and / or condition of the subject being treated and further depending on the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) of the compound of formula (I).

[0478] The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients that can be used in the manufacture of the pharmaceutical compositions of the present invention are any of those well known in the art of pharmaceutical formulation and include inert diluents, dispersants and / or granulating agents, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Pharmaceutically acceptable excipients that can be used in the manufacture of the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0479] The compositions of the present invention can be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions can be administered intravenously and / or orally.

[0480] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, subcutaneously, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in parenterally acceptable non-toxic diluents or solvents, for example, as a solution in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are commonly used as solvents or suspending media.

[0481] The pharmaceutically acceptable compositions of the present invention can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are usually also added. For oral administration in capsule form, available diluents include lactose and dry corn starch. When aqueous suspensions for oral use are needed, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavorings or coloring agents may also be added. In some embodiments, the oral formulations provided are formulated for immediate release or sustained release / delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. The compound of formula (I) may also be in microencapsulated form.

[0482] The compositions of the present invention can be delivered transdermally, topically, or formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, paints, powders, and aerosols. Oral formulations include tablets, pills, powders, lozenges, capsules, liquids, troches, cachets, gels, syrups, slurries, suspensions, and the like suitable for ingestion by the patient. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present invention may further include components to provide sustained release and / or comfort. Such components include high molecular weight anionic permeable polymers, curdlan, and a finely dispersed drug carrier matrix. These components are discussed in more detail in U.S. Patent Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be administered via intradermal injection of microspheres containing the drug, which are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995; administered as a biodegradable and injectable gel formulation (see, e.g., Gao Pharm. Res. 12: 857-863, 1995); or administered as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997). In another embodiment, the formulation of the composition of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, that is, by using a liposome attached to a lipid The liposomes bind to the cell's surface membrane protein receptors, leading to endocytosis. By using liposomes, especially when the liposomes carry receptor ligands specific for target cells on their surface or are otherwise targeted to specific organs, the delivery of the compositions of the present invention can be concentrated to target cells in vivo. (See, for example, Al-Muhammed, J. Microencapsul. 13: 293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6: 698-708, 1995; Ostro, J. Hosp. Pharm. 46: 1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.

[0483] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the therapeutic target includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations for each of these areas or organs can be readily prepared.

[0484] In some embodiments, in order to prolong the effect of the drug, it is often desirable to slow down the absorption of the drug for subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline form or amorphous material with poor water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenteral drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0485] Although the descriptions of pharmaceutical compositions provided herein relate primarily to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to various animals are well known, and the ordinary veterinary pharmacologist can design and / or perform such modifications through ordinary experimentation.

[0486] The compounds provided herein (e.g., compounds of Formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof) are typically formulated in dosage unit form, such as a single unit dosage form, for ease of administration and uniformity of dosage. However, it will be understood that the total daily dosage of the compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend on various factors, including the condition being treated and the severity of the condition; the activity of the specific active ingredient being employed; the specific composition being employed; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and excretion rate of the specific active ingredient being employed; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient being employed; and similar factors well known in the medical field.

[0487] The precise amount of compound required to achieve an effective amount will vary from subject to subject depending on, for example, the species, age, and general condition of the subject, the severity of the side effects or symptoms, the identity of the specific compound(s), the mode of administration, and the like. The desired dose may be delivered three times a day, twice a day, once a day, every other day, every three days, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations) may be used to deliver the desired dose.

[0488] In certain embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, for administration one or more times a day may comprise about 0.0001 mg to about 5000 mg, e.g., about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg of compound per unit dosage form.

[0489] In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, may be administered one or more times a day at a dosage level sufficient to deliver from about 0.001 mg / kg to about 1000 mg / kg, e.g., from about 0.001 mg / kg to about 500 mg / kg, from about 0.01 mg / kg to about 250 mg / kg, from about 0.1 mg / kg to about 100 mg / kg, from about 0.1 mg / kg to about 50 mg / kg, from about 0.1 mg / kg to about 40 mg / kg, from about 0.1 mg / kg to about 25 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, or from about 1 mg / kg to about 50 mg / kg of the subject's body weight per day to achieve the desired therapeutic effect.

[0490] It should be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to children or adolescents can be determined by a medical practitioner or person skilled in the art and can be lower than or the same as that administered to adults.

[0491] It should also be understood that compounds or compositions as described herein, such as compounds of formula (I) or pharmaceutically acceptable salts thereof, solvates, hydrates, tautomers or stereoisomers, can be administered in combination with one or more additional pharmaceutical agents. The compound or composition can be administered in combination with additional pharmaceutical agents that improve its bioavailability, reduce and / or change its metabolism, inhibit its excretion and / or change its distribution in the body. It should also be understood that the therapy employed can achieve the desired effect for the same condition, and / or it can achieve different effects.

[0492] The compound or composition can be used simultaneously with one or more other pharmaceutical agents, before or after one or more other pharmaceutical agents, which can be used as, for example, combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include preventive active agents. Each other pharmaceutical agent can be used at a dosage determined for this pharmaceutical agent and / or according to a schedule determined for this pharmaceutical agent. Other pharmaceutical agents can also be used with each other and / or with compounds or compositions as described herein in a single dose or separately at different doses. The specific combination used in the scheme will take into account the compatibility of the inventive compound with the other pharmaceutical agent and / or the desired treatment and / or preventive effect to be achieved. In general, it is contemplated that the other pharmaceutical agents used in combination are used at a level not exceeding that used alone. In some embodiments, the level used in combination will be lower than those used alone.

[0493] Exemplary additional 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 U.S. Food and Drug Administration as provided in the Code of Federal Regulations (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.

[0494] The pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient (e.g., a compound as described herein, including embodiments or examples) is included in a therapeutically effective amount (i.e., an amount effective for achieving its intended purpose). The actual amount effective for a specific application will depend in particular on the condition being treated. When applied in a method to treat a disease, such compositions will include an active ingredient effective in achieving the desired result, such as a component of a target molecule (e.g., a component of a eIF2B, eIF2 or eIF2α signal transduction pathway or a component of a phosphorylated eIF2α pathway or an ISR pathway) and / or reduce, eliminate or slow down the progression of disease symptoms (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or symptoms associated with the impaired function of a component of an eIF2B, eIF2α or eIF2 pathway or an ISR pathway). The determination of the therapeutically effective amount of the compound of the present invention is fully within the capabilities of those skilled in the art, especially in the context of the detailed disclosure herein.

[0495] The dosage and frequency (single or multiple doses) of administration to a mammal may vary depending on various factors, such as whether the mammal has another disease, and its route of administration; the size, age, sex, health, weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated (e.g., cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or symptoms of a disease or condition associated with impaired function of a component of the eIF2B, eIF2α, or eIF2 pathway or ISR pathway), the type of concurrent treatment, complications from the disease being treated, or other health-related problems. Other treatment regimens or agents may be used in conjunction with the methods and compounds of the applicant's invention. Adjustment and manipulation of the established dosage (e.g., frequency and duration) are well within the capabilities of those skilled in the art.

[0496] For any compound described herein, a therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of one or more active compounds that are capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0497] As is well known in the art, therapeutically effective amounts for humans can also be determined from animal models. For example, dosages for humans can be formulated to achieve concentrations found to be effective in animals. Dosages for humans can be adjusted by monitoring compound effectiveness and adjusting the dosage upward or downward, as described above. Adjusting the dosage to achieve maximum efficacy in humans based on the methods described above and other methods is well within the capabilities of those of ordinary skill.

[0498] The dosage may vary depending on the patient's needs and the compound employed. The dosage administered to a patient in the context of the present invention should be sufficient to achieve a beneficial therapeutic response in the patient over time. The magnitude of the dosage will also be determined by the presence, nature, and extent of any adverse side effects. Determination of the appropriate dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect is achieved under the circumstances. The amount and interval of the dosage can be gradually adjusted to provide a level of the administered compound that is effective for the specific clinical indication being treated. This will provide a treatment regimen that is commensurate with the severity of the individual's disease state.

[0499] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not result in significant toxicity and is still effective in treating the clinical symptoms presented by a particular patient. Such planning should involve careful selection of the active compound by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, the preferred mode of administration and toxicity profile of the selected agent.

[0500] The present invention also encompasses kits (e.g., pharmaceutical packs). The inventive kits can be used to prevent and / or treat a disease (e.g., cancer, a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, a metabolic disease, or other diseases or conditions described herein).

[0501] The provided kits may include an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampoule, bottle, syringe, and / or dispenser packaging or other suitable container). In some embodiments, the provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of the inventive pharmaceutical composition or compound. In some embodiments, the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form a unit dosage form.

[0502] Therefore, on the one hand, there is provided a kit including a first container, wherein the first container comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, solvate, hydrate, tautomer or stereoisomer or a pharmaceutical composition thereof. In certain embodiments, the kit can be used to prevent and / or treat a proliferative disease in a subject. In certain embodiments, the kit includes instructions for administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, solvate, hydrate, tautomer or stereoisomer or a pharmaceutical composition thereof to a subject to prevent and / or treat a disease as described herein.

[0503] Treatment

[0504] The present invention is characterized in that the compound, composition and method of comprising the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer.In some embodiments, the compound, composition and method are used to prevent or treat disease, disorder or condition.Exemplary disease, disorder or condition include but are not limited to neurodegenerative disease, leukodystrophy, cancer, inflammatory disease, musculoskeletal disease or metabolic disease.

[0505] In some embodiments, the disease, disorder or condition is associated with (e.g., caused by) regulation of (e.g., reduction) eIF2B activity or level, eIF2α activity or level, or a component of the eIF2 pathway or ISR pathway. In some embodiments, the disease, disorder or condition is associated with regulation of a signaling pathway associated with a component of the eIF2 pathway or ISR pathway (e.g., phosphorylation of a component of the eIF2 pathway or ISR pathway). In some embodiments, the disease, disorder or condition is associated with (e.g., caused by) neurodegeneration. In some embodiments, the disease, disorder or condition is associated with (e.g., caused by) neuronal cell death or dysfunction. In some embodiments, the disease, disorder or condition is associated with (e.g., caused by) glial cell death or dysfunction. In some embodiments, the disease, disorder or condition is associated with (e.g., caused by) an increase in the level or activity of eIF2B, eIF2α, or a component of the eIF2 pathway or ISR pathway. In some embodiments, the disease, disorder, or condition is associated with (e.g., is caused by) decreased levels or activity of eIF2B, eIF2α, or a component of the eIF2 pathway or the ISR pathway.

[0506] In some embodiments, the disease may be caused by a disease or mutation in a protein sequence associated with a member of the eIF2 pathway (e.g., eIF2B, eIF2α, or other components). Exemplary mutations include amino acid mutations in eIF2B1, eIF2B2, eIF2B3, eIF2B4, and eIF2B5 subunits. In some embodiments, amino acid mutations (e.g., amino acid substitutions, additions, or deletions) in a particular protein may result in structural changes that affect protein function, such as conformational or spatial changes. For example, in some embodiments, amino acids in and around the active site or close to a binding site (e.g., a phosphorylation site, a small molecule binding site, or a protein binding site) may mutate so that the activity of the protein is affected. In some cases, amino acid mutations (e.g., amino acid substitutions, additions, or deletions) may be conservative and may not substantially affect the structure and function of the protein. For example, in some cases, replacing a serine residue with a threonine residue may not significantly affect the function of the protein. In other cases, the amino acid mutation may be more drastic, such as replacing a charged amino acid (e.g., aspartic acid or lysine) with a large, non-polar amino acid (e.g., phenylalanine or tryptophan), and thus may have a substantial effect on protein function. The structural nature of the mutation that affects the function of a gene or protein can be readily identified using standard sequencing techniques well known in the art (e.g., deep sequencing techniques). In some embodiments, mutations in members of the eIF2 pathway may affect the binding or activity of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and thus modulate the treatment of a particular disease, disorder, or condition, or a symptom thereof.

[0507] In some embodiments, the eIF2 protein may comprise an amino acid mutation (e.g., an amino acid substitution, addition, or deletion) at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue. In some embodiments, the eIF2 protein may comprise an amino acid substitution at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue. In some embodiments, the eIF2 protein may comprise an amino acid addition at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue. In some embodiments, the eIF2 protein may comprise an amino acid deletion at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue.

[0508] In some embodiments, the eIF2 protein may comprise an amino acid mutation (e.g., amino acid substitution, addition, or deletion) at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue in the eIF2B1, eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. In some embodiments, the eIF2 protein may comprise an amino acid substitution at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue in the eIF2B1, eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. In some embodiments, the eIF2 protein may comprise an amino acid addition at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue in the eIF2Bl, eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. In some embodiments, the eIF2 protein may comprise an amino acid deletion at an alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine residue in the eIF2Bl, eIF2B2, eIF2B3, eIF2B4, eIF2B5 subunits. Exemplary mutations include V183F (eIF2B1 subunit), H341Q (eIF2B3), I346T (eIF2B3), R483W (eIF2B4), R113H (eIF2B5), and R195H (eIF2B5).

[0509] In some embodiments, amino acid mutations (e.g., amino acid substitutions, additions, or deletions) in members of the eIF2 pathway (e.g., the eIF2B protein subunit) may affect the binding or activity of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and thereby modulate the treatment of a particular disease, disorder, or condition, or a symptom thereof.

[0510] neurodegenerative diseases

[0511] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat a neurodegenerative disease. As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the function of the nervous system of a subject 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, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease), kuru, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0512] In some embodiments, the neurodegenerative disease comprises white matter ablative leukoencephalopathy, childhood ataxia with CNS hypomyelination, leukodystrophy, leukoencephalopathy, hypomyelination or demyelinating disease, intellectual disability syndrome, Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Strauss-Schwann disease, Huntington's disease, dementia (e.g., HIV-associated dementia or dementia with Lewy bodies), kuru, multiple sclerosis, Parkinson's disease, or a prion disease.

[0513] In some embodiments, the neurodegenerative disease comprises a white matter ablative leukoencephalopathy, a childhood ataxia with CNS hypomyelination, a leukodystrophy, a leukoencephalopathy, a hypomyelinating or demyelinating disease, or an intellectual disability syndrome.

[0514] In some embodiments, the neurodegenerative disease comprises a psychiatric disorder such as agoraphobia, Alzheimer's disease, anorexia nervosa, amnesia, anxiety disorder, attention deficit disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, claustrophobia, depression, paranoia, Diogenes syndrome, movement disorders, insomnia, Munchausen syndrome, narcolepsy, narcissistic personality disorder, obsessive-compulsive disorder, psychosis, phobia, schizophrenia, seasonal affective disorder, schizophreniform personality disorder, sleepwalking, social phobia, substance abuse, tardive dyskinesia, Tourette syndrome, or trichotillomania.

[0515] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat white matter ablative leukoencephalopathy. Exemplary methods of treating white matter ablative leukoencephalopathy include, but are not limited to, reducing or eliminating the symptoms of white matter ablative leukoencephalopathy, reducing the loss of white matter, reducing the loss of myelin, increasing the amount of myelin, or increasing the amount of white matter in a subject.

[0516] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat ataxia in children with CNS myelin deficiency. Exemplary methods of treating ataxia in children with CNS myelin deficiency include, but are not limited to, reducing or eliminating the symptoms of ataxia in children with CNS myelin deficiency, increasing the level of myelin or reducing the loss of myelin in a subject.

[0517] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat intellectual disability syndrome. Exemplary methods of treating intellectual disability syndrome include, but are not limited to, reducing or eliminating the symptoms of intellectual disability syndrome.

[0518] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat neurodegeneration. Exemplary methods of treating neurodegeneration include, but are not limited to, improving mental health, increasing mental function, slowing the decline of mental function, reducing dementia, delaying the onset of dementia, improving cognitive skills, reducing the loss of cognitive skills, improving memory, reducing memory degradation, or prolonging survival.

[0519] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is used to treat leukoencephalopathy or demyelinating disease.Exemplary leukoencephalopathy includes but is not limited to progressive multifocal leukoencephalopathy, toxic leukoencephalopathy, leukoencephalopathy with ablative white matter, leukoencephalopathy with neuroaxonal spheroids, reversible posterior leukoencephalopathy syndrome, hypertensive leukoencephalopathy, megalencephalic leukoencephalopathy with subcortical cysts, Charcot-Marie-Tooth disorder and Devic's disease.Leukoencephalopathy can include demyelinating disease, which can be hereditary or acquired. In some embodiments, the acquired demyelinating disease can be an inflammatory demyelinating disease (e.g., an infectious inflammatory demyelinating disease or a non-infectious inflammatory demyelinating disease), a toxic demyelinating disease, a metabolic demyelinating disease, an anoxic demyelinating disease, a traumatic demyelinating disease, or an ischemic demyelinating disease (e.g., Binswanger's disease). Exemplary methods of treating white matter diseases or demyelinating diseases include, but are not limited to, reducing or eliminating the symptoms of white matter diseases or demyelinating diseases in a subject, reducing the loss of myelin, increasing the amount of myelin, reducing the loss of white matter, or increasing the amount of white matter in a subject.

[0520] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat traumatic injury or toxin-induced damage to the nervous system (e.g., brain). Exemplary traumatic brain injuries include, but are not limited to, brain abscess, concussion, ischemia, cerebral hemorrhage, skull fracture, diffuse axonal injury, locked-in syndrome, or injuries involving traumatic force or blow to the nervous system or brain that result in organ or tissue damage. Exemplary toxin-induced brain damage include, but are not limited to, toxic encephalopathy, meningitis (e.g., bacterial meningitis or viral meningitis), meningoencephalitis, encephalitis (e.g., Japanese encephalitis, Eastern equine encephalitis, West Nile encephalitis), Guillan-Barre syndrome, Sydenham's chorea, rabies, leprosy, neurosyphilis, prion diseases, or exposure to chemicals (e.g., arsenic, lead, toluene, ethanol, manganese, fluoride, 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).

[0521] In other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is used to treat and improve the memory of the subject. It has been shown that memory induction is promoted by reduced eIF2α phosphorylation and impaired by increased eIF2α phosphorylation. Translation regulators such as compounds disclosed herein (e.g., compounds of formula (I)) can serve as therapeutic agents for improving the memory of human diseases (such as Alzheimer's disease) and activated neurons associated with memory loss (such as Alzheimer's disease) and thus other neurological diseases (such as Parkinson's disease, schizophrenia, amyotrophic lateral sclerosis and prion disease) that may have a negative impact on memory consolidation. In addition, mutations that destroy the integrity of the complex in eIF2γ link intellectual disability (intellectual disability syndrome or ID) in humans to impaired translation initiation. Therefore, two diseases ID and VWM with impaired eIF2 function show different phenotypes, but both mainly affect the brain and damage learning. In some embodiments, the disease or disorder is unsatisfactory memory (e.g., working memory, long-term memory, short-term memory, or memory consolidation).

[0522] In yet other embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is used to improve the subject's memory (e.g., working memory, long-term memory, short-term memory or memory consolidation) method. In some embodiments, the subject is human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domesticated animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a bird. In some embodiments, the subject is a horse. In embodiments, the patient is a cow. In some embodiments, the subject is a primate.

[0523] cancer

[0524] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat cancer. As used herein, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers, 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 liver cancer, lymphomas, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, small cell and large cell lymphomas), Hodgkin's lymphoma, leukemias (including AML, ALL and CML) and / or multiple myeloma. In some additional instances, "cancer" refers to lung cancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma, pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, prostate cancer, metastatic cancer, or carcinoma.

[0525] As used herein, the term "cancer" refers to all types of cancers, neoplasms or malignancies found in mammals, including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions or methods provided herein include lymphomas, sarcomas, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER positive, ER negative, chemotherapy resistance, Herceptin resistance, HER2 positive, doxorubicin resistance, tamoxifen resistance, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, glioma or melanoma. Additional examples include thyroid cancer, endocrine system cancer, 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, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, cancer pancreatic cancer, malignant pancreatic insulinoma, malignant carcinoid tumor, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, hypercalcemia of malignancy, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, 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.

[0526] The term "leukemia" refers to a progressive, malignant disease of the blood-forming organs and is generally characterized by abnormal proliferation and growth of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and characteristics of the disease—acute or chronic; (2) the cell types involved—myeloid (myeloid), lymphoid (lymphoid), or monocytic; and (3) the increase or absence of an increase in the number of abnormal cells in the blood—leukemic or non-leukemic (metaleukemic). 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 leukemias, leukemic leukemias, basophilic leukemias, blast cell leukemias, bovine leukemia, chronic myeloid leukemia, leukemia cutis, stem cell leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hematopoietic leukemia, hematopoietic leukemia, histiocytic leukemia, stem cell leukemia, leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelomonocytic leukemia, Naegelileukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0527] The term "sarcoma" generally refers to a tumor composed of a substance resembling embryonic connective tissue and generally composed of tightly packed cells embedded in a fibrous or homogenous substance. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, chlorosarcoma, 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, spontaneous multiple hemorrhage sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, sarcoma), Kaposi's sarcoma, hepatic stellate cell sarcoma, angiosarcoma, white sarcoma, malignant mesenchymal sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma of bone, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0528] The term "melanoma" is used to refer to tumors of the melanin system that originate in the skin and other organs. Melanomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0529] The term "cancer" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and produce metastases. Exemplary 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 cell carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenocystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, squamous basal cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine corpus carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, carcinoma), epidermoid carcinoma, adenoid epithelial cell carcinoma, explanted carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, matrix carcinoma, hematopoietic carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, clear cell carcinoma, adrenaloid carcinoma, embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, erosive ulcer, Kulczycki cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, carcinoma medullary, medullary carcinoma), melanoma, soft tissue carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinomacarcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthotic cell carcinoma, mucus carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spheroid cell carcinoma, spindle cell carcinoma, medullary carcinoma (carcinoma spongiosum), squamous cell carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectode, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0530] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is used to treat pancreatic cancer, breast cancer, multiple myeloma, secretory cell cancer. For example, some methods herein treat cancer by reducing or 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, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer can be used as a single agent in a composition or in combination with another agent in a composition to treat cancer described herein (e.g., pancreatic cancer, breast cancer, multiple myeloma, secretory cell cancer).

[0531] Inflammatory diseases

[0532] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat an inflammatory disease. As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., increased levels of inflammation compared to a control such as a healthy person not suffering from the disease). Examples of inflammatory diseases include postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes mellitus, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis. Proteins associated with inflammation and inflammatory diseases (e.g., where abnormal expression is a symptom or cause or a marker of the disease) include interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-18 (IL-18), TNF-a (tumor necrosis factor-α), and C-reactive protein (CRP).

[0533] In some embodiments, the inflammatory disease comprises postoperative cognitive dysfunction, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis), systemic lupus erythematosus (SLE), myasthenia gravis, diabetes (e.g., juvenile-onset diabetes or type 1 diabetes), Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma (e.g., allergic asthma), acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, or atopic dermatitis.

[0534] In some embodiments, the inflammatory disease comprises postoperative cognitive dysfunction, which refers to a decline in cognitive function (eg, memory or executive function (eg, working memory, reasoning, task flexibility, processing speed, or problem solving)) following surgery.

[0535] In other embodiments, the method of treatment is a preventive method. For example, a method of treating postoperative cognitive dysfunction may comprise preventing postoperative cognitive dysfunction or symptoms of postoperative cognitive dysfunction or reducing the severity of symptoms of postoperative cognitive dysfunction by administering a compound described herein prior to surgery.

[0536] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is used to treat an inflammatory disease (e.g., an inflammatory disease described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer can be used as a single agent in a composition or in combination with another agent in a composition to treat an inflammatory disease (e.g., an inflammatory disease described herein).

[0537] Musculoskeletal disorders

[0538] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is used to treat musculoskeletal diseases. As used herein, the term "musculoskeletal disease" refers to a disease or condition in which the function of the subject's musculoskeletal system (e.g., muscle, ligament, tendon, cartilage or bone) is impaired. Exemplary musculoskeletal diseases that can be treated with a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof include muscular dystrophy (e.g., Duchenne muscular dystrophy, Becker muscular dystrophy, distal muscular dystrophy, congenital muscular dystrophy, Emery-Dreifuss muscular dystrophy, dystrophy), facioscapulohumeral muscular dystrophy or myotonic dystrophy), multiple sclerosis, amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar palsy, spinal muscular atrophy, progressive spinobulbar muscular atrophy, myelotonic, spinal muscular atrophy, myasthenia gravis, neuralgia, fibromyalgia, Mayo-Joseph disease, spastic fasciculations, Mali ataxia, muscle wasting disorders (e.g., muscular dystrophy, sarcopenia, cachexia), inclusion body myopathy, motor neuron disease, or paralysis.

[0539] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, is used to treat a musculoskeletal disease (e.g., a musculoskeletal disease described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, the treatment method includes treating muscle pain or muscle stiffness associated with a musculoskeletal disease. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, can be used as a single agent in a composition or in combination with another agent in a composition to treat a musculoskeletal disease (e.g., a musculoskeletal disease described herein).

[0540] Metabolic diseases

[0541] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer are used to treat metabolic diseases.As used herein, term " metabolic diseases " refers to the disease or the condition of illness affecting the metabolic process of experimenter. The exemplary metabolic diseases that can be treated with the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (for example, type I diabetes, type II diabetes or gestational diabetes), phenylketonuria, proliferative retinopathy or Ka-Sai disease.

[0542] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is used to treat metabolic diseases (for example, metabolic diseases as described herein) by reducing or eliminating the symptoms of the disease. In some embodiments, the method of treatment includes reducing or eliminating the symptoms including: high blood pressure, high blood sugar levels, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, etc. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer can be used as a single agent in the composition or combined with another agent in the composition to treat metabolic diseases (for example, musculoskeletal diseases as described herein).

[0543] Ways to Increase Protein Production

[0544] In another aspect, the compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof are useful in applications where it is desirable to increase protein production output, such as in vitro cell-free systems for protein production.

[0545] In some embodiments, the invention features a method of increasing protein expression in a cell or in vitro expressing cell, the method comprising administering to the cell or expression system an effective amount of a compound, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the method is a method of increasing protein expression by a cell, and comprises administering to the cell an effective amount of a compound as described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof). In other embodiments, the method is a method of increasing protein expression by an in vitro protein expression system, and comprises administering to the in vitro (e.g., cell-free) protein expression system an effective amount of a compound as described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof).

[0546] In some embodiments, the invention features a method of increasing protein expression in a disease, disorder, or condition characterized by aberrant or decreased levels of protein production (e.g., a leukodystrophy, a leukoencephalopathy, a hypomyelination or demyelinating disease, a muscle wasting disease, or a sarcopenia).

[0547] In some embodiments, the compound listed herein is provided as a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, solvate, hydrate, tautomer or stereoisomer and a pharmaceutically acceptable excipient. In the embodiment of the method, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is co-administered with a second medicament (e.g., therapeutic agent). In other embodiments of the method, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer is co-administered with a second medicament (e.g., therapeutic agent), which is administered in a therapeutically effective amount. In embodiments, the second medicament is a medicament for improving memory.

[0548] Combination therapy

[0549] In one aspect, the present invention features a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof and a second agent (e.g., a second therapeutic agent). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent (e.g., a second therapeutic agent). In some embodiments, the second agent is an agent for treating a disease or condition associated with impaired function of a component of a cancer, neurodegenerative disease, leukodystrophy, inflammatory disease, musculoskeletal disease, metabolic disease, or eIF2B, eIF2α or eIF2 pathway or ISR pathway.

[0550] The compounds described herein can be used in combination with each other, with other active agents known to be useful for treating cancer, neurodegenerative diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, or diseases or conditions associated with impaired function of components of the eIF2B, eIF2α or eIF2 pathway or the ISR pathway, or with adjuvants that may be ineffective alone but may contribute to the efficacy of the active agent.

[0551] In some embodiments, co-administration includes administering an active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20 or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20 or 30 minutes of each other) or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, that is, preparing a pharmaceutical composition comprising two active agents. In other embodiments, the active agent can be formulated separately. In another embodiment, the active agent and / or adjuvant can be connected or conjugated to each other. In some embodiments, the compounds described herein can be combined with the following treatments: cancer, neurodegenerative diseases, leukodystrophy, inflammatory diseases, musculoskeletal diseases, metabolic diseases or diseases or conditions associated with impaired function of components of eIF2B, eIF2α or eIF2 pathways or ISR pathways.

[0552] In embodiments, the second agent is an anticancer agent. In embodiments, the second agent is a chemotherapeutic agent. In embodiments, the second agent is an agent for improving memory. In embodiments, the second agent is an agent for treating a neurodegenerative disease. In embodiments, the second agent is an agent for treating leukodystrophy. In embodiments, the second agent is an agent for treating white matter ablative leukoencephalopathy. In embodiments, the second agent is an agent for treating childhood ataxia with CNS hypomyelination. In embodiments, the second agent is an agent for treating intellectual disability syndrome. In embodiments, the second agent is an agent for treating pancreatic cancer. In embodiments, the second agent is an agent for treating breast cancer. In embodiments, the second agent is an agent for treating multiple myeloma. In embodiments, the second agent is an agent for treating myeloma. In embodiments, the second agent is an agent for treating secretory cell cancer. In embodiments, the second agent is an agent for reducing eIF2α phosphorylation. In an embodiment, the second agent is an agent for inhibiting a pathway activated by phosphorylation of eIF2α. In an embodiment, the second agent is an agent for inhibiting a pathway activated by eIF2α. In an embodiment, the second agent is an agent for inhibiting the integrated stress response. In an embodiment, the second agent is an anti-inflammatory agent. In an embodiment, the second agent is an agent for treating postoperative cognitive dysfunction. In an embodiment, the second agent is an agent for treating traumatic brain injury. In an embodiment, the second agent is an agent for treating musculoskeletal diseases. In an embodiment, the second agent is an agent for treating metabolic diseases. In an embodiment, the second agent is an antidiabetic agent.

[0553] anticancer agents

[0554] U1 1n、 90 Y or 131 I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa TM ), erlotinib (Tarceva TM ), Cetuximab (Erbitux TM ), Lapatinib (Tykerb TM ), panitumumab (Vectibix TM ), Vandetanib (Caprelsa TM ), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethyl erlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, etc.

[0555] "Chemotherapeutic" or "chemotherapeutic agent" are used according to their plain, ordinary meaning and refer to a chemical composition or compound that has anti-tumor properties or the ability to inhibit cell growth or proliferation.

[0556] In addition, the compounds described herein can be co-administered with conventional immunotherapeutic agents, including but not limited to immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., conjugated to m In, 90 Y or 131 I and other anti-CD20 monoclonal antibodies).

[0557] In another embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as 47 Sc, 64 Cu, 67 Cu, 89 Sr. 86 Y. 87 Y. 90 Y. 105 Rh, m Ag, m In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re、 188 Re、 211 At and 212 Bi, optionally conjugated to an antibody against a tumor antigen.

[0558] Other medications

[0559] In some embodiments, the second agent for use in combination with a compound as described herein (e.g., a compound of Formula (I)) or a composition thereof is an agent used to treat a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, or a metabolic disease. In some embodiments, the second agent for use in combination with a compound as described herein (e.g., a compound of Formula (I)) or a composition thereof is an agent approved by the FDA or a similar regulatory agency in a country other than the USA for the treatment of a disease, disorder, or condition described herein.

[0560] In some embodiments, the second agent for treating a neurodegenerative disease, a leukodystrophy, an inflammatory disease, a musculoskeletal disease, or a metabolic disease includes, but is not limited to, an antipsychotic, an antidepressant, an anxiolytic, an analgesic, a stimulant, a sedative, a pain reliever, an anti-inflammatory, a benzodiazepine, a cholinesterase inhibitor, a nonsteroidal anti-inflammatory drug (NSAID), a corticosteroid, a MAO inhibitor, a beta-blocker, a calcium channel blocker, an antacid, or other agent. Exemplary second agents may include donepezil, galantamine, rivastigmine, memantine, levodopa, dopamine, pramipexole, ropinirole, rotigotine, doxapram, oxazepam, quetiapine, selegiline, rasagiline, entacapone, benztropine, trihexyphenidyl, riluzole, diazepam, chlordiazepoxide, lorazepam, alprazolam, buspirone, gepirone, ixapram, oxazepam, selegiline, rasagiline, entacapone, benztropine, trihexyphenidyl, riluzole, diazepam, chlordiazepoxide, lorazepam, alprazolam, buspirone, gepirone, ixapram ... Amoxapine, clomipramine, chlorpromazine ... Imipramine, nortriptyline, protriptyline, trimipramine, maprotiline, bupropion, nefazodone, vortioxetine, lithium, clozapine, fluphenazine, haloperidol, paliperidone, loxapine, thiothixene, pimozide, thioridazine, risperidone, aspirin, ibuprofen, naproxen, acetaminophen, azathioprine, methotrexate, mycophenolic acid, leflunomide, dibenzoylmethane, cilostazol, pentoxifylline, duloxetine, cannabinoids (e.g., nabilone), simethicone, magnesium aluminum hydroxide, aluminum salts, calcium salts, sodium salts, magnesium salts, alginic acid, acarbose, albiglutide, alogliptin, metformin, insulin, lisinopril, atenolol, atorvastatin, fluvastatin, lovastatin, pitavastatin, simvastatin, rosuvastatin, etc.

[0561] Naturally derived medicaments or supplements can also be used in combination with a compound of formula (I) or a composition thereof to treat neurodegenerative diseases, inflammatory diseases, musculoskeletal diseases, or metabolic diseases. Exemplary naturally derived medicaments or supplements include omega-3 fatty acids, carnitine, citicoline, curcumin, ginkgo, vitamin E, vitamin B (e.g., vitamin B5, vitamin B6, or vitamin B12), huperzine A, phosphatidylserine, rosemary, caffeine, melatonin, chamomile, St. John's wort, tryptophan, etc.

[0562] Example

[0563] In order to more fully understand the invention described herein, the following examples are set forth.The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting the scope thereof.

[0564] Synthesis scheme

[0565] Compounds provided herein can be prepared from readily available starting materials using modifications well known to those skilled in the art for the specific synthetic schemes listed below. It will be understood that in the case of given typical or preferred method conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other method conditions may also be used, unless otherwise stated. Optimum reaction conditions may vary according to the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art. The general scheme relating to the method for preparing the exemplary compounds of the present invention is additionally described in the part entitled as the method for preparing compounds.

[0566] In addition, as will be apparent to those skilled in the art, conventional blocking groups may be needed to prevent some functional groups from carrying out undesirable reactions. Suitable blocking groups for specific functional groups and the selection of suitable conditions for protecting and deprotecting are well known in the art. For example, many blocking groups and their introduction and removal are described in Greene et al., Protecting Groups in Organic Synthesis, second edition, Wiley, New York, 1991 and the references cited therein.

[0567] abbreviation

[0568] APCI stands for atmospheric pressure chemical ionization; DCI stands for desorption chemical ionization; DMSO stands for dimethyl sulfoxide; ESI stands for electrospray ionization; HPLC stands for high performance 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; and TLC stands for thin layer chromatography.

[0569] Example 1: N,N'-(bicyclo[2.2.2]octane-1,4-diyl)bis[2-(4-chloro-3-fluorophenoxy)acetamide] (Compound 100)

[0570] A 50 mL round bottom flask equipped with a magnetic stir bar was charged with bicyclo[2.2.2]octane-1,4-diamine dihydrochloride (PharmaBlock, CAS# 2277-93-2, 100 mg, 0.455 mmol), 2-(4-chloro-3-fluorophenoxy)acetic acid (205 mg, 1.001 mmol) and (1-cyano-2-ethoxy-2-oxyethyleneaminooxy)dimethylamino-morpholino-carbon hexafluorophosphate ( 485mg, 1.092mmol). The flask contents were placed under a dry nitrogen atmosphere, and then N, N-dimethylformamide (10mL) was added by syringe. The stirred suspension was frozen to 0 ° C, and then N, N-diisopropylethylamine (0.66mL, 3.78mmol) was introduced dropwise by syringe (the reaction mixture became bright yellow). The reaction mixture was warmed to ambient temperature and stirred for 3 days. The reaction mixture was diluted with water and the white insoluble solid was collected by filtration. The solid was treated with methanol, and then collected by filtration. Thus the title compound (93.5mg, 40% yield) as a white solid was obtained. 1 H NMR (DMSO-d6) δppm 7.51-7.44 (m, 4H), 7.02 (dd, J=11.4, 2.9Hz, 2H), 6.81 (ddd, J=9.0, 2.8, 1.2Hz, 2H), 4.43 (s, 4H), 1.90 (s, 12H). MS(+ESI)m / z 513(M+H) + ,MS(-ESI)m / z 511(MH) - .

[0571] Example 2: 2-(4-chloro-3-fluorophenoxy)-N-[4-(2-{[6-(trifluoromethyl)pyridin-3-yl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide (Compound 101)

[0572] Example 2A: tert-Butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate

[0573] By dicyclo [2.2.2] octane -1,4- diamine dihydrochloride (PharmaBlock, CAS#2277-93-2,200mg, 1.43mmol) is dissolved in methanol (5mL).Solution is alkalized with 50% sodium hydroxide aqueous solution.After stirring for 15 minutes (slightly exothermic), the mixture is diluted with water and salt solution and extracted with dichloromethane (3x150mL).By the organic layer drying (Na2SO4) merged and filter.Filtrate is concentrated under reduced pressure, to obtain the free alkali as white solid.Free alkali, dicyclo [2.2.2] octane -1,4- diamine (176mg, 1.255mmol), di-tert-Butyl dicarbonate (274mg, 1.255mmol) and tetrahydrofuran (100mL) are stirred at ambient temperature for 17 hours.Reactant mixture is concentrated under reduced pressure, and residue is distributed between ethyl acetate and aqueous sodium carbonate. The organic layer was washed with brine, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to afford the title intermediate as an off-white solid (258 mg, 86% yield). 1 H NMR (methanol-d4) δppm1.91-1.85(m,7H),1.65-1.60(m,2H),1.40(s,12H). MS(DCI-NH3)m / z 241(M+H) + .

[0574] Example 2B: tert-Butyl (4-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[2.2.2]octan-1-yl)carbamate

[0575] A 50 mL round bottom flask equipped with a magnetic stir bar was charged with 2-(4-chloro-3-fluorophenoxy)acetic acid (234 mg, 1.144 mmol), tert-butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate (Example 2A, 250 mg, 1.040 mmol) and (535mg, 1.248mmol). The contents of the flask were placed under a dry nitrogen atmosphere and N, N-dimethylformamide (4mL) was introduced by syringe. The reaction mixture was then stirred at ambient temperature while N, N-diisopropylethylamine (0.545mL, 3.12mmol) was added dropwise by syringe. The reaction mixture was stirred at ambient temperature for 19 hours. The reaction mixture was diluted with water (pH=10). Insoluble beige solids were collected by filtration and rinsed thoroughly with water. The substance was washed with water at room temperature. IntelliFlash TM -310(Isco Purify by column chromatography on a 40 g silica gel column, 70:30 to 0:100 heptane / ethyl acetate).Fraction #15-31 were combined and concentrated under reduced pressure to give the title intermediate as a white solid (69.5 mg, 15.65% yield). 1 H NMR(CDCl3)δppm 7.31(t,J=8.6Hz,1H),6.73(dd,J=10.3,2.9Hz,1H),6.64(ddd,J=8.9,2.9,1.2H z,1H),6.07(s,1H),4.32(s,1H),4.31(s,2H),2.05-1.91(m,12H),1.42(s,9H). MS(+ESI)m / z 426(M+H) + ,m / z853(2M+H) + 。MS(-ESI)m / z 425(MH) - .

[0576] Example 2C: N-(4-aminobicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride

[0577] The 4mL bottle being equipped with magnetic stirring bar is filled with (4-(2-(4-chloro-3-fluorophenoxy) acetylamino) bicyclo [2.2.2] octane-1-yl) t-butyl carbamate (embodiment 2B, 69mg, 0.162mmol).Add methyl alcohol (1mL), and stir the solution of gained at ambient temperature, be added into the 4M HCl (1.2mL, 4.80mmol) in dioxane by syringe simultaneously.Reaction mixture was stirred 89 hours at ambient temperature.Volatile matter is removed under reduced pressure to obtain the title intermediate (58.3mg, 99% productive rate) as white solid. 1 H NMR (methanol-d4) δppm 7.36 (t, J=8.7Hz, 1H), 6.89 (dd, J=11.0, 2.9Hz, 1H), 6.79 (ddd, J=9.0, 2.9, 1.3Hz, 1H), 4.43 (s, 2H), 2.15-2.08 (m, 6H), 1.94 1.87(m,6H). MS(+ESI)m / z 327(M+H) + 。MS(-ESI)m / z 325(MH) - .

[0578] Example 2D: 2-(4-chloro-3-fluorophenoxy)-N-[4-(2-{[6-(trifluoromethyl)pyridin-3-yl]oxy}acetamido)bicyclo[2.2.2]octan-1-yl]acetamide

[0579] A 4 mL vial equipped with a magnetic stir bar was charged with N-(4-aminobicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride (Example 2C, 25 mg, 0.069 mmol), 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetic acid (18.26 mg, 0.083 mmol) and 4-[ ... f The main new spot is obvious. LC / MS confirmed that this major new material has the correct mass of the title compound. The reaction mass was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a light yellow solid. This crude solid was IntelliFlash TM -310(Isco The 4-(4-(4-(4-oxo-1-yl)-1-oxo-4-oxo-2-oxo-4-oxo-5-nitropropane)-1-oxo-4-oxo-4-oxo-5-nitropropane-1 ... 1 H NMR(CDCl3)δppm 8.43(d,J=2.9Hz,1H),7.67(d,J=8.7Hz,1H),7.34-7.28(m,2H),6.73(dd,J=10.3,2.9Hz,1H),6 .65(ddd,J=8.9,2.9,1.3Hz,1H),6.10(d,J=2.8Hz,2H),4.45(s,2H),4.33(s,2H),2.08(s,12H). MS(+ESI)m / z530(M+H) + 。MS(-ESI)m / z 528(MH) - .

[0580] Example 3: N-{3-[2-(4-chloro-3-fluorophenoxy)acetylamino]bicyclo[1.1.1]pentan-1-yl}-3-(4-chlorophenyl)propionamide (Compound 102)

[0581] Example 3A: 3-(4-chlorophenyl)propionyl chloride

[0582] The 50mL round-bottom flask equipped with a magnetic stirring bar is filled with white crystals (Aldrich, CAS#2019-34-3, 100mg, 0.542mmol) of 3-(4-chlorophenyl) propionic acid. The flask is closed with the septum attached to a bubbler. Anhydrous dichloromethane (2mL) is introduced by syringe to obtain a solution, and the solution is stirred at ambient temperature. Oxalyl chloride (0.142mL, 1.625mmol) is added by syringe, followed by addition of N, N-dimethylformamide (0.042 μL, 0.542 μmol), and now gas evolution is obvious. Reactant mixture is stirred at ambient temperature for 1 hour. Volatiles are removed under reduced pressure to obtain light yellow oil, which is used in the next step.

[0583] Example 3B: N-{3-[2-(4-chloro-3-fluorophenoxy)acetylamino]bicyclo[1.1.1]pentan-1-yl}-3-(4-chlorophenyl)propionamide

[0584] Embodiment 3A is redissolved in dichloromethane (3mL), and then a suspension of N-(3-aminobicyclo [1.1.1] pentane-1-yl)-2-(4-chloro-3-fluorophenoxy) acetamide hydrochloride (embodiment 112A, 174mg, 0.542mmol) in dichloromethane (10mL) is added to the reaction mixture. This mixture is stirred at ambient temperature under a dry nitrogen atmosphere, and triethylamine (0.302mL, 2.167mmol) is introduced by a syringe. The reaction mixture was stirred for 20.5 hours at ambient temperature. The reaction mixture was processed with citric acid aqueous solution. The organic layer was washed with salt water, then dried (MgSO 4 ) and filtered. The filtrate was concentrated under reduced pressure to obtain a light grey solid, which was processed with tert-butyl methyl ether. Insoluble beige solid was collected by filtration, and IntelliFlash TM -310(Isco Purify by column chromatography on a 24 g silica gel column, 90:10 to 85:15 dichloromethane / acetone, monitored wavelength: 220 nm) to give the title compound (97.9 mg, 40% yield) as a white solid. 1H NMR(DMSO-d6)δppm 8.68(s,1H),8.40(s,1H),7.49(t,J=8.9Hz,1H),7.34-7.30(m,2H),7.23-7.19(m,2H),7.07(dd,J=11.4,2.8Hz,1H), 6.85(ddd,J=9.0,2.9,1.2Hz,1H),4.47(s,2H),2.77(dd,J=8.6,6.9Hz,2H),2.31(dd,J=8.5,7.1Hz,2H),2.20(s,6H). MS(+ESI)m / z 451(M+H) + 。MS(-ESI)m / z 449(MH) - .

[0585] Example 4: N,N'-(pentyl ring [4.2.0.0 2,5 .0 3,8 .0 4,7 ]octane-1,4-diyl)bis[2-(4-chlorophenoxy)-acetamide] (Compound 103)

[0586] Example 4A: Cubane-1,4-diamine dihydrochloride

[0587] The 50mL round-bottom flask equipped with a magnetic stirring bar is filled with cubane-1,4-dicarboxylic acid (Aldrich, CAS#32846-66-5, 800mg, 4.16mmol), triethylamine (1.16mL, 8.32mmol), diphenylphosphoryl azide (1.8mL, 8.35mmol) and tert-butyl alcohol (12.8mL). The flask is equipped with a reflux condenser equipped with a calcium sulfate drying tube, and the reaction mixture is stirred under reflux for 16 hours. The reaction mixture is cooled to ambient temperature and poured into a saturated sodium bicarbonate aqueous solution (50mL). The precipitate is collected by filtration and washed with water. The solid is dissolved in a hot mixture of dichloromethane, tetrahydrofuran, ethyl acetate and ethanol. This warm solution is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure to obtain a light grey solid, which is treated with ether and collected by filtration. The intermediate of thick bis-(tert-butoxy-carbonyl)-protection is suspended in methanol (30mL) and is used in the 4M HCl (30mL, 120mmol, 47.4 equivalent) process in dioxane.Reaction mixture was stirred 4 hours at ambient temperature.Volatile matter is under reduced pressure removed to obtain light brown solid, said light brown solid is washed with diethyl ether and then washed with ethyl acetate.Solid is dissolved in hot methanol and is processed to generate precipitation with acetone.Collect title intermediate solid (125mg, 14.5% productive rate) by filtration. 1HNMR (methanol-d4) δ ppm 4.23 (s, 6H). MS(DCI-NH3)m / z 135(M+H) + ,m / z 152(M+NH4) + ,m / z 169(M+NH4+NH3) + .

[0588] Example 4B: N,N'-(pentyl ring [4.2.0.0 2,5 .0 3,8 .0 4,7 ]octane-1,4-diyl)bis[2-(4-chlorophenoxy)acetamide]

[0589] The 50mL round-bottom flask equipped with a magnetic stirring bar is filled with cubane-1,4-diamine dihydrochloride (Example 4A, 77mg, 0.372mmol). The flask contents are placed under a dry nitrogen atmosphere, and a solution of 2-(4-chlorophenoxy) acetyl chloride (Aldrich, CAS#4122-68-3,160mg, 0.781mmol) in dichloromethane (4mL) is then introduced by a syringe. This stirred suspension is processed with triethylamine (0.4mL, 2.87mmol). The reaction mixture is stirred for 17 hours at ambient temperature under a dry nitrogen atmosphere. Volatiles are removed under reduced pressure, and solid residue is distributed between tert-butyl methyl ether and frozen water. Insoluble material in any layer is suspected to be product and collected by filtration. This thick light grey solid is dissolved in a warm mixture of tetrahydrofuran and ethanol. Silica gel (1.2g) is added, and the solvent is removed in a vacuum. This mixture absorbed onto silica gel was placed on top of a Practichem 4 g silica gel column which removed the top 1.6 g of silica gel. The column was reassembled and connected to an Isco 24g silica gel column and place the assembly on IntelliFlash TM -310 (monitored wavelength: 220 nm) and eluted with 100:0 to 90:10 dichloromethane / acetone to afford the title compound (25.6 mg, 14.6% yield) as a white solid. 1 H NMR (DMSO-d6) δppm 8.82 (s, 2H), 7.40-7.30 (m, 4H), 6.98 (d, J = 8.9Hz, 4H), 4.49 (s, 4H), 3.96 (s, 6H). MS(+ESI)m / z 471(M+H) + 。MS(-ESI)m / z 469(MH) - .

[0590] Example 5: N-{3-[2-(4-chloro-3-fluorophenoxy)acetylamino]bicyclo[1.1.1]pentan-1-yl}-3-(4-chloro-6-oxopyridazin-1(6H)-yl)propionamide (Compound 104)

[0591] Example 5A: Methyl 3-(4-chloro-6-oxopyridazin-1(6H)-yl)propanoate

[0592] The 50mL round-bottom flask equipped with a magnetic stirring bar is filled with 5-chloropyridazine-3 (2H) -one (Maybridge, CAS# 660425-07-0, 350mg, 2.68mmol) and cesium carbonate (1310mg, 4.02mmol). The bottle is sealed with a septum and placed under a dry nitrogen atmosphere, and then N, N- dimethylformamide (7mL) is introduced by a syringe. The reaction mixture is vigorously stirred at ambient temperature, while 3- bromopropionic acid methyl ester (0.351mL, 3.22mmol) is added by a syringe. The reaction mixture is stirred for 22 hours at ambient temperature. The reaction mixture is diluted with water, neutralized with citric acid aqueous solution and extracted with ethyl acetate (twice). The organic layer merged is washed with salt water, then dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure to obtain a yellow oil, which is then added to a column chromatography elution column. IntelliFlash TM -310(Isco Purify by column chromatography on a 40 g silica gel column, 70:30 to 65:35 heptane / ethyl acetate) to give the title intermediate as a clear, colorless oil (479 mg, 82% yield). 1 H NMR (CDCl3) δppm 7.72 (d, J = 2.4Hz, 1H), 6.96 (d, J = 2.4Hz, 1H), 4.42 (t, J = 7.1Hz, 2H), 3.70 (s, 3H), 2.83 (t, J = 7.1Hz, 2H). MS(DCI-NH3)m / z 217(M+H) + ,m / z 234(M+NH4) + .

[0593] Example 5B: 3-(4-chloro-6-oxopyridazin-1(6H)-yl)propanoic acid

[0594] The 50mL round-bottom flask equipped with a magnetic stirring bar is filled with 3-(4-chloro-6-oxopyridazine-1(6H)-yl)methyl propionate (embodiment 5A, 100mg, 0.462mmol). Dioxane (2.3mL) is added, and the solution of gained is stirred at ambient temperature, while adding 5N aqueous sulfuric acid solution (2.3mL, 11.50mmol). Reactant mixture is stirred at 50 ℃ for 17.5 hours. Reactant mixture is concentrated under reduced pressure, and oily residue is dissolved in dichloromethane. By solution drying (Na2SO4) and filter. Filtrate is concentrated under reduced pressure to obtain the title intermediate (33.5mg, 35.8% yield) as white solid. 1 HNMR (CDCl3) δ ppm 7.76 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 4.44 (t, J = 7.0 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H). MS(DCI-NH3)m / z 203(M+H) + ,m / z 220(M+NH4) + .

[0595] Example 5C: 3-(4-chloro-6-oxopyridazin-1(6H)-yl)propanoyl chloride

[0596] The 4mL bottle that is equipped with magnetic stirring bar is filled with 3-(4-chloro-6-oxopyridazine-1 (6H)-yl) propionic acid (embodiment 5B, 47.7mg, 0.235mmol).Bottle is vented to the septum nut seal of bubbler, and bottle contents are placed under dry nitrogen atmosphere.Methylene chloride (1mL) is introduced by syringe, and the reaction mixture oxalyl chloride (0.1mL, 1.142mmol) and catalysis DMF (0.018 μ L, 0.235 μ mol) of stirring are processed.After stirring 45 minutes at ambient temperature, volatile matter is removed under reduced pressure, and the thick acyl chloride intermediate of gained is used in next step.

[0597] Example 5D: N-{3-[2-(4-chloro-3-fluorophenoxy)acetylamino]bicyclo[1.1.1]pentan-1-yl}-3-(4-chloro-6-oxopyridazin-1(6H)-yl)propanamide

[0598] The crude acid chloride intermediate Example 5C was redissolved in dichloromethane (1 mL). Solid N-(3-aminobicyclo[1.1.1]pentane-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride (Example 112A, 76 mg, 0.235 mmol) was added and the vial was resealed with a septum nut vented to a bubbler. Triethylamine (0.2 mL, 1.435 mmol) was added dropwise via a syringe (the reaction mixture became dark). The reaction mixture was vigorously stirred at ambient temperature for 16 hours. The dichloromethane was evaporated and the residue was treated with water at pH=4. The insoluble material was collected by filtration and rinsed with water. The remaining solid was washed with water at room temperature. IntelliFlash TM -310(Isco Purify by column chromatography on a 12 g silica gel column, 95:5 to 70:30 dichloromethane / acetone, monitoring wavelength: 220 nm) to afford 46.9 mg (42.4% yield) of the title compound as a beige solid. 1 H NMR(DMSO-d6)δppm 8.68(s,1H),8.54(s,1H),8.05(d,J=2.4Hz,1H),7.49(t,J=8.9Hz,1H),7.25(d,J=2.4Hz,1H),7.07(dd,J=11.4,2. 9Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2Hz, 1H), 4.47 (s, 2H), 4.19 (t, J = 7.3Hz, 2H), 2.48 (t, J = 7.3Hz, 2H), 2.20 (s, 6H). MS(+ESI)m / z 469(M+H) + 。MS(-ESI)m / z 467(MH) - .

[0599] Example 6: 2-(3,4-dichlorophenoxy)-N-[3-(2-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]acetamide (Compound 105)

[0600] Example 6A: Ethyl 2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)acetate

[0601] To the solution of 2-hydroxyethyl acetic acid (0.167mL, 1.762mmol) in tetrahydrofuran (4mL) at room temperature, potassium tert-butoxide (1.850mL, 1.850mmol) is added. After 10 minutes, the 2-bromo-5-(trifluoromethyl) pyrazine (0.2g, 0.881mmol) added in tetrahydrofuran (4mL) is stirred at room temperature overnight. By adding water (10mL), the reaction mixture is quenched and extracted with ethyl acetate (3x30mL). By organic phase MgSO4 drying, filtration and under reduced pressure concentration. Residue is used in the next step (215mg, 0.859mmol, 98% productive rate) without further purification. 1 H NMR (400MHz, DMSO-d6) δppm 8.76 (dd, J = 1.4, 0.7Hz, 1H), 8.63 (d, J = 1.2Hz, 1H), 5.09 (s, 2H), 4.16 (q, J = 7.1Hz, 2H), 1.19 (t, J = 7.1Hz, 3H). 19 F NMR(376MHz,DMSO-d6)δppm-65.37MS(ESI+)m / z 251(M+H) + .

[0602] Example 6B: 2-((5-(Trifluoromethyl)pyrazin-2-yl)oxy)acetic acid

[0603] To a solution of ethyl 2-((5-(trifluoromethyl)pyrazine-2-yl)oxy)acetate (215 mg, 0.859 mmol) (crude product from a previous reaction) in tetrahydrofuran (4 mL) was added lithium hydroxide (82 mg, 3.44 mmol) and water (1.00 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate. The aqueous layer was separated and acidified to pH=3 with 2NHCl (aqueous solution). The aqueous mixture was extracted with CH2Cl2 (2x20 mL). The combined organic fractions were washed with MgSO4 and concentrated under reduced pressure to obtain the title compound (150 mg, 0.675 mmol, 79% yield). 1 H NMR (400MHz, DMSO-d6) δppm 13.09 (s, 1H), 8.76 (t, J = 1.0 Hz, 1H), 8.60 (d, J = 1.2 Hz, 1H), 5.01 (s, 2H). 19 F NMR (376MHz, DMSO-d6) δppm-64.84. MS(ESI+)m / z223(M+H) + .

[0604] Example 6C: N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(3,4-dichlorophenoxy)acetamide hydrochloride

[0605] To Example 22A (3.45 g, 15 mmol) in dichloromethane (10 mL) / methanol (1 ml) was added 4N HCl in dioxane (53.8 mL, 215 mmol). The mixture was stirred at ambient temperature for 1 hour and then concentrated to give 2.91 g of the title compound as a white solid (100% yield). 1 H NMR (400MHz, DMSO-d6) δppm 8.90 (m, 4H), 7.55 (d, J = 8, 1H), 7.22 (d, J = 2, 1H), 6.98 (dd, J = 8, 2, 1H), 4.50 (s, 2H), 2.23 (s, 6H). MS(ESI+)m / z 301(M+H) + .

[0606] Example 6D: 2-(3,4-dichlorophenoxy)-N-[3-(2-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]acetamide

[0607] To a suspension of N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(3,4-dichlorophenoxy)acetamide hydrochloride (0.05 g, 0.148 mmol, Example 6C) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.078 mL, 0.444 mmol) and 2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)acetic acid (0.036 g, 0.163 mmol, Example 6B), followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.062 g, 0.163 mmol, HATU). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine. The organic layer was dried over MgSO , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (24 g) and eluted with heptane and ethyl acetate (0% to 100%) to give 25 mg of the title compound as a white solid (33.4% yield). 1H NMR(501MHz,DMSO-d6)δppm 8.77(s,1H),8.74(d,J=1.2Hz,1H),8.71(s,1H),8.55(d,J=1.3Hz,1H),7.54(d,J=8.9Hz,1H ), 7.25 (d, J = 2.9Hz, 1H), 6.98 (dd, J = 9.0, 2.9Hz, 1H), 4.85 (s, 2H), 4.48 (s, 2H), 2.24 (s, 6H). 19 F NMR (376MHz, DMSO-d6) δppm-64.74. MS(ESI + )m / z552(M+NH4) + .

[0608] Example 7: N,N'-(Bicyclo[1.1.1]pentane-1,3-diyl)bis[2-(3,4-dichlorophenoxy)acetamide] (Compound 106)

[0609] To a suspension of N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(3,4-dichlorophenoxy)acetamide hydrochloride (50 mg, 0.148 mmol, Example 6C) in tetrahydrofuran (1 mL) / N,N-dimethylformamide (0.1 mL) was added N,N-diisopropylethylamine (0.078 mL, 0.444 mmol) and 2-(3,4-dichlorophenoxy)acetic acid (36.0 mg, 0.163 mmol), followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (61.9 mg, 0.163 mmol, HATU). The reaction mixture was stirred at room temperature for 2 hours. The white solid was filtered and dried to give 40 mg of the title compound as a white solid (53.6% yield). 1 H NMR (400MHz, DMSO-d6) δppm 8.71 (s, 2H), 7.54 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 2.9 Hz, 2H), 6.98 (dd, J = 9.0, 3.0 Hz, 2H), 4.49 (s, 4H), 2.27 (s, 6H). MS(ESI + )m / z 505(M+H) + ,MS(ESI + )m / z 546(M+41) + .

[0610] Example 8: 2-(4-chloro-3-fluorophenoxy)-N-[3-(2-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}acetamido)bicyclo[1.1.1]pentan-1-yl]acetamide (Compound 107)

[0611] To a suspension of Example 112A (30 mg, 0.093 mmol) in N,N-dimethylformamide (0.8 mL) was added N,N-diisopropylethylamine (0.049 mL, 0.280 mmol) and 2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)acetic acid (22.82 mg, 0.103 mmol, Example 6B), followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (39.1 mg, 0.103 mmol, HATU). The reaction mixture was stirred at ambient temperature overnight, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by HPLC (Waters XBridge TM C18 5μm OBD TM Column, 50x100 mm, flow rate 90 mL / min, gradient 5%-95% of CH3CN in buffer (0.1% CF3CO2H / H2O)) to give 30 mg of the title compound as a white solid (65.7% yield). 1 H NMR (400MHz, DMSO-d6) δppm8.78-8.72(m,2H),8.70(s,1H),8.56-8.53(m,1H),7.49(t,J=8.9Hz,1H),7 .06(dd,J=11.4,2.8Hz,1H),6.84(ddd,J=9.0,2.9,1.2Hz,1H),4.85(s,2H),4.47(s,2H),2.24(s,6H). MS(ESI + )m / z 506(M+NH4) + .

[0612] Example 9: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[(1H-indazol-6-yl)oxy]acetylamino}-bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 108)

[0613] Example 9A: tert-Butyl (3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate

[0614] To 2-(4-chloro-3-fluorophenoxy) acetic acid (Aldlab Chemicals, 2.01g, 9.84mmol) solution in DMF (25mL) add N-ethyl-N-isopropylpropane-2-amine (3.96mL, 22.7mmol), then add 2-(3H-[1,2,3] triazolo[4,5-b] pyridine-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (V) (3.02g, 7.94mmol).This mixture is stirred 5 minutes at ambient temperature, and then add (3-aminobicyclo [1.1.1] pentane-1-yl) t-butyl carbamate (PharmaBlock, 1.5g, 7.57mmol).Mixture is stirred 16 hours at ambient temperature.By reaction mixture saturated NH the Cl aqueous solution (20mL) is quenched and uses CH cl (25mL) washing. The aqueous layer was extracted with CH2Cl2 (3x5 mL), and the combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 10% ethyl acetate / heptane to 80% ethyl acetate / heptane) to give the title compound (2.65 g, 6.89 mmol, 91% yield). MS (ESI + )m / z402(M+NH4) + .

[0615] Example 9B: N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide-2-trifluoroacetic acid

[0616] To a solution of the product of Example 9A (0.79 g, 2.05 mmol) in CH2Cl2 (7 mL) at ambient temperature was added trifluoroacetic acid (3.16 mL, 41.1 mmol). The mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (1.06 g, 2.07 mmol, 100% yield), which was used in the next step without purification. MS (ESI + )m / z 285(M+H) + .

[0617] Example 9C: tert-Butyl 2-((1H-indazol-5-yl)oxy)acetate

[0618] To 6-hydroxy-1H-indazole (0.89g, 6.64mmol) and tert-butyl bromoacetate (1.07mL, 7.30mmol) in dioxane (20mL) add bis(trimethylsilyl) amide potassium (1M, in tetrahydrofuran, 7.96mL, 7.96mmol).Then the mixture was stirred at ambient temperature for 14 hours. The mixture was quenched with saturated NH4Cl aqueous solution (5mL) and washed with CH2Cl2 (5mL). Each layer was separated, and the aqueous layer was extracted with CH2Cl2 (3x5mL). The organic fraction merged was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Residue was purified by column chromatography (SiO2, 5% ethyl acetate / heptane to 100% ethyl acetate), to obtain title compound (0.56g, 2.26mmol, 34% yield). MS (ESI + )m / z 249(M+H) + .

[0619] Example 9D: 2-((1H-indazol-6-yl)oxy)acetic acid-trifluoroacetic acid

[0620] To a solution of the product of Example 9C (0.56 g, 2.26 mmol) in CHCl (10 mL) at ambient temperature was added trifluoroacetic acid (3.92 mL, 50.9 mmol). The mixture was stirred at ambient temperature for 3 hours and then concentrated under reduced pressure and azeotroped with toluene to give the title compound (0.85 g, 2.36 mmol, >100% yield), which was used in the next step without purification. MS (ESI + )m / z 193(M+H) + .

[0621] Example 9E: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[(1H-indazol-6-yl)oxy]acetylamino}-bicyclo[1.1.1]pentan-1-yl)acetamide

[0622] To a mixture of the product of Example 9B (0.1 g, 0.195 mmol) and the product of Example 9D (0.090 g, 0.293 mmol) in dimethylacetamide (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.136 mL, 0.780 mmol), followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.078 g, 0.205 mmol). This mixture was stirred at ambient temperature for 16 hours, and then quenched with saturated NaHCO aqueous solution (10 mL) and diluted with CH Cl (10 mL). The layers were separated, and the aqueous layer was extracted with CH Cl (3 x 3 mL). The combined organic fractions were dried over anhydrous Na SO dried, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (Waters XBridge TM C18 5μm OBD TM Column, 50x100 mm, flow rate 90 mL / min, gradient 20%-100% of methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide) to give the title compound (0.04, 0.087 mmol, 45% yield). 1 H NMR(400MHz,DMSO-d6)δppm 12.82(s,1H),8.71(d,J=7.7Hz,2H),7.92(s,1H),7.62(d,J=8.8Hz,1H),7.48(t,J=8.9Hz,1H),7.05(dd ,J=11.4,2.9Hz,1H),6.88(s,1H),6.83(ddt,J=7.5,4.6,1.7Hz,2H),4.46(d,J=3.4Hz,4H),2.26(s,6H). MS(ESI + )m / z 459(M+H) + .

[0623] Example 10: N,N'-(Bicyclo[1.1.1]pentane-1,3-diyl)bis{2-[(1H-indazol-6-yl)oxy]acetamide} (Compound 109)

[0624] Example 10A: tert-Butyl (3-(2-((1H-indazol-6-yl)oxy)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate

[0625] To a solution of the product of Example 9D (0.20 g, 0.56 mmol) in dimethylacetamide (4 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.26 mL, 1.51 mmol), followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.201 g, 0.530 mmol). This mixture was stirred at ambient temperature for 2 minutes, followed by the addition of tert-butyl (3-aminobicyclo[1.1.1]pentane-1-yl)carbamate (PharmaBlock, 0.10 g, 0.504 mmol). The mixture was stirred at ambient temperature for 16 hours, and then quenched with saturated NH4Cl aqueous solution (10 mL), diluted with CH2Cl2 (15 mL), and the layers separated. The aqueous layer was extracted with CH2Cl2 (3 x 5 mL), and the combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (Waters XBridge TM C18 5μm OBD TM Column, 50x100 mm, flow rate 90 mL / min, 20%-100% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) to give the title compound (0.12 g, 0.33 mmol, 65% yield). MS (ESI + )m / z 373(M+H) + .

[0626] Example 10B: 2-((1H-indazol-6-yl)oxy)-N-(3-aminobicyclo[1.1.1]pentan-1-yl)acetamide-3-trifluoroacetic acid

[0627] To a solution of the product of Example 10A (0.12 g, 0.33 mmol) in CH2Cl2 (3 mL) at ambient temperature was added trifluoroacetic acid (0.51 mL, 6.6 mmol). This mixture was stirred at ambient temperature for 3 hours and then concentrated under reduced pressure and azeotroped with toluene to give the title compound (0.22 g, 0.36 mmol, >100% yield), which was used in the next step without purification. MS (ESI + )m / z 273(M+H) + .

[0628] Example 10C: N,N′-(bicyclo[1.1.1]pentane-1,3-diyl)bis{2-[(1H-indazol-6-yl)oxy]acetamide}

[0629] To a mixture of the product of Example 10B (0.10 g, 0.16 mmol) and the product of Example 9D (0.055 g, 0.18 mmol) in dimethylacetamide (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.17 mL, 0.98 mmol) followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.065 g, 0.17 mmol). This mixture was stirred at ambient temperature for 16 hours and directly analyzed by HPLC (Waters XBridge TM C18 5μm OBD TM Column, 50x100 mm, flow rate 90 mL / min, gradient 20%-100% of methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide) to give the title compound (0.055 g, 0.12 mmol, 76% yield). 1 H NMR(501MHz,DMSO-d6)δppm 12.82(s,2H),8.72(s,2H),7.92(t,J=1.3Hz,2H),7.62(d,J=8.8Hz,2H),6. 88(d,J=2.1Hz,2H), 6.82(dd,J=8.8,2.1Hz,2H), 4.47(s,4H), 2.27(s,6H). MS(ESI + )m / z 445(MH) + .

[0630] Example 11: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[(3-methyl-1,2-benzoxazol-6-yl)oxy]acetamido}bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 110)

[0631] Example 11A: tert-Butyl 2-((3-methylbenzo[d]isoxazol-6-yl)oxy)acetate

[0632] By 5-hydroxy-3-methylbenzo [d] isoxazole (Chontech, 1.0g, 6.70mmol), potassium carbonate (1.85g, 13.4mmol) and tert-butyl bromoacetate (1.03mL, 7.04mmol) in N, N-dimethylformamide (20mL) mixture is warmed to 65 DEG C and stirred for 16 hours.Then the mixture is quenched with saturated NaHCO aqueous solution (10mL) and diluted with ethyl acetate (10mL).Separate each layer, and the water layer is extracted with ethyl acetate (3x5mL).The organic fractions merged are through anhydrous NaSODry, filter and concentrate under reduced pressure.The residue is passed through column chromatography (SiO2, 5% ethyl acetate / heptane to 100% ethyl acetate) purified to obtain the title compound (1.45g, 5.51mmol, 82% yield).MS(ESI + )m / z 264(M+H) + .

[0633] Example 11B: 2-((3-methylbenzo[d]isoxazol-6-yl)oxy)acetic acid

[0634] To a solution of the product of Example 11A (1.7 g, 6.46 mmol) in CH Cl (25 mL) at ambient temperature was added trifluoroacetic acid (7.46 mL, 97 mmol). The mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene to give the title compound (1.68 g, 6.49 mmol, 100% yield), which was used in the next step without purification. MS (ESI + )m / z 208(M+H) + .

[0635] Example 11C: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[(3-methyl-1,2-benzoxazol-6-yl)oxy]acetamido}bicyclo[1.1.1]pentan-1-yl)acetamide

[0636] To a mixture of the product of Example 9B (0.20 g, 0.390 mmol) and the product of Example 11B (0.204 g, 0.51 mmol) in dimethylacetamide (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.272 mL, 1.56 mmol), followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.156 g, 0.410 mmol). This mixture was stirred at ambient temperature for 16 hours, then quenched with saturated NaHCO aqueous solution (10 mL) and diluted with CH Cl (10 mL). The layers were separated, and the aqueous layer was extracted with CH Cl (3 x 3 mL). The combined organic fractions were dried over anhydrous Na SO, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (Waters XBridge TM C18 5μm OBD TM Column, 50x100 mm, flow rate 90 mL / min, gradient 20%-100% of methanol in buffer (0.025 M aqueous ammonium bicarbonate adjusted to pH 10 with ammonium hydroxide) to give the title compound (0.18 g, 0.38 mmol, 97% yield). 1 H NMR(400MHz,DMSO-d6)δppm 8.67(d,J=2.0Hz,2H),7.52(d,J=8.9Hz,1H),7.46(t,J=8.9Hz,1H),7.17(d,J=2.6Hz,1H),7.04(dd,J=11.4,2.8Hz, 1H), 6.96 (dd, J=8.8, 2.6Hz, 1H), 6.82 (ddd, J=9.0, 2.9, 1.2Hz, 1H), 4.44 (d, J=6.6Hz, 4H), 2.54 (s, 3H), 2.24 (s, 6H). MS(ESI + )m / z474(M+H) + .

[0637] Example 12: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[(4-fluoro-1H-indazol-6-yl)oxy]acetylamino}-bicyclo[1.1.1]pentan-1-yl)acetamide (Compound 111)

[0638] Example 12A: tert-Butyl 2-((4-fluoro-1H-indazol-6-yl)oxy)acetate

[0639] By 4- fluoro- 1H- indazole -6- alcohol (ArkPharm company, 1.0g, 6.57mmol), potassium carbonate (1.82g, 13.2mmol) and tert-butyl bromoacetate (1.01mL, 6.90mmol) in N, N- dimethylformamide (15mL) mixture is warmed up to 65 ℃ and is stirred for 16 hours. Make the mixture cool to ambient temperature, and use saturated NaHCO The aqueous solution (10mL) is quenched and diluted with ethyl acetate (10mL). Separate each layer, and the water layer is extracted with ethyl acetate (3x5mL). The organic fraction merged is through anhydrous Na SO Dry, filter, concentrate under reduced pressure. Residue is passed through column chromatography (SiO , 5% ethyl acetate / heptane to 100% ethyl acetate) purification, to obtain title compound (0.81g, 3.04mmol, 46% yield). MS (ESI + )m / z267(M+H) + .

[0640] Example 12B: 2-((4-Fluoro-1H-indazol-6-yl)oxy)acetic acid

[0641] To a solution of the product of Example 12A (0.81 g, 3.04 mmol) in CH Cl (5 mL) at ambient temperature was added trifluoroacetic acid (2.34 mL, 30.4 mmol). This mixture was stirred at ambient temperature for 4 hours and then concentrated under reduced pressure. The residue was azeotroped with toluene to give a solid which was reprecipitated from ethyl acetate / heptane to give the title compound (1.31 g, 2.99 mmol, 98% yield). 1 H NMR (400MHz, DMSO-d6) δppm 8.03 (s, 1H), 6.72 (t, J = 1.3Hz, 1H), 6.60 (dd, J = 11.7, 1.8Hz, 1H), 4.75 (s, 2H).

[0642] Example 12C: 2-(4-chloro-3-fluorophenoxy)-N-(3-{2-[(4-fluoro-1H-indazol-6-yl)oxy]acetamido}bicyclo[1.1.1]pentan-1-yl)acetamide

[0643] To the mixture of the product of Example 9B (0.15g, 0.29mmol) and the product of Example 12B (0.14g, 0.32mmol) in DMF (3mL) was added N-ethyl-N-isopropylpropan-2-amine (0.20mL, 1.17mmol), followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (0.18g, 0.31mmol). This mixture was stirred at ambient temperature for 16 hours, then quenched with saturated NaHCO aqueous solution (10mL) and diluted with CH Cl (10mL). The layers were separated and the aqueous layer was extracted with CH Cl (3x3mL). The combined organic fractions were dried over anhydrous Na SO dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 75% ethyl acetate / heptane) to give the title compound (0.11 g, 0.23 mmol, 79% yield). 1 H NMR(500MHz,DMSO-d6)δppm 13.19(s,1H),8.75(d,J=12.0Hz,2H),8.06(s,1H),7.50(t,J=8.9Hz,1H),7.08(dd,J=11.4,2.8Hz,1H),6.86(ddd, J=8.9,2.9,1.2Hz,1H),6.78(t,J=1.4Hz,1H),6.69(dd,J=11.6,1.8Hz,1H),4.52(s,2H),4.49(s,2H),2.28(s,6H). MS(ESI + )m / z 475(M+H) + .

[0644] Example 13: N,N'-(Bicyclo[1.1.1]pentane-1,3-diyl)bis[2-(4-chlorophenoxy)acetamide] (Compound 112)

[0645] Bicyclo[1.1.1]pentane-1,3-diamine dihydrochloride (Pharmablock, 2.588 g, 15.13 mmol) in tetrahydrofuran / water (1 / 1, 60 mL) was treated with potassium carbonate (10.45 g, 76 mmol), cooled to 0°C and then treated with 2-(4-chlorophenoxy)acetyl chloride (4.72 mL, 30.3 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The precipitate was collected by filtration, washed with water and hexane and air-dried to afford 5.635 g (86%) of the title compound. 1H NMR (400MHz, DMSO-d6) δppm 8.66 (s, 2H), 7.42–7.26 (m, 4H), 7.00–6.87 (m, 4H), 4.39 (s, 4H), 2.23 (s, 6H). MS(APCI)m / z436(M+H) + .

[0646] Example 14: 2-(4-chlorophenoxy)-N-(3-{[2-(4-chlorophenoxy)ethyl]amino}bicyclo-[1.1.1]pentan-1-yl)acetamide (Compound 113)

[0647] Example 14A: tert-Butyl (3-(2-(4-chlorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate

[0648] Tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate hydrochloride (Pharmablock, 0.469 g, 2 mmol) in tetrahydrofuran / water (1 / 1, 6 mL) was treated with potassium carbonate (0.732 g, 5.30 mmol), cooled to 0° C. and then treated with 2-(4-chlorophenoxy)acetyl chloride (0.312 mL, 2 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The resulting precipitate was collected by filtration, washed with water and hexanes, and air-dried to afford 0.471 g (57.4%) of the title compound. MS (APCI) m / z 367 (M+H) + .

[0649] Example 14B: N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(4-chlorophenoxy)acetamide

[0650] A solution of Example 14A (0.471 g, 1.148 mmol) in dioxane (3 mL) was treated with 4N HCl in dioxane (3 mL) and stirred at 25° C. for 20 hours. The reaction mixture was concentrated to afford 0.347 g (100%) of the title compound. MS (APCI) m / z 267 (M+H) + .

[0651] Example 14C: 2-(4-chlorophenoxy)-N-(3-{[2-(4-chlorophenoxy)ethyl]amino}bicyclo-[1.1.1]pentan-1-yl)acetamide

[0652] Solution of embodiment 14B (0.1g, 0.33mmol) and 2-(4-chlorophenoxy) acetaldehyde (0.051g, 0.3mmol) in methanol pH 4 buffer solutions (2mL) was stirred at ambient temperature for 1 hour, and then processed with sodium cyanoborohydride (0.062g, 0.99mmol).Reaction mixture was stirred 20 hours, and then distributed between dichloromethane (20mL) and water (20mL).Water layer was extracted with dichloromethane (3x20mL).By the organic layer salt water (2x30mL) merging, washed, dried (Na SO )...

Claims

1. A compound, wherein the compound is selected from or a pharmaceutically acceptable salt thereof.

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