Compounds that disintegrate tau protein aggregates and uses thereof

Abstract

Disclosed herein are novel compounds, pharmaceutically acceptable salts, enantiomers, non-enantiomers, tautomers, racemates, solvates, metabolic precursors, or prodrugs thereof, that degrade tau protein aggregates. Also disclosed herein are uses of the compounds, pharmaceutically acceptable salts, enantiomers, non-enantiomers, tautomers, racemates, solvates, metabolic precursors, or prodrugs thereof, in the manufacture of a medicament for treating a tauopathy, and methods of aiding in the treatment of or treating a tauopathy in a subject.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 935,017, filed November 13, 2019, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Neurodegenerative diseases affect an estimated 50 million Americans each year and impose a tremendous human toll and economic costs of hundreds of billions of dollars annually in medical expenses and lost productivity. Tauopathies are a class of neurodegenerative diseases associated with pathological aggregation of tau protein (microtubule-associated protein tau, MAPT) in the human brain and include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), Pick's disease (PiD), and progressive supranuclear palsy (PSD). In tauopathies, tau aggregates spread throughout the brain like prions, as seen, for example, in AD brains where tau pathology appears in consistent spatiotemporal patterns (H. Braak et al., Neurobiol Aging (1995), 16(3):271-78; H. Braak et al., Acta Neuropathol (2006) 112(4):389-404). Tau-propagating factors, consisting mainly of short filaments, have been found to be significantly enriched in synaptic compartments in brain regions lacking widespread cellular tau pathology, indicating that tau factors can spread throughout the human brain along synaptically connected neuronal networks.

[0003] Despite many therapeutic approaches aimed at removing aggregated tau species that have been or are currently being investigated, to date there are no effective treatments that halt, prevent or reverse the progression of such neurodegenerative diseases. Thus, new drugs that can slow the progression and / or prevent the occurrence of these neurodegenerative diseases are needed. Furthermore, there is a need for drugs that can distinguish between pathological forms of tau and normal functional configurations of tau such that normal intracellular functions are not disrupted. Summary of the Invention [Problem to be solved by the invention]

[0004] The present disclosure relates to novel bispecific conjugate compounds that bind to tau aggregates and recruit ubiquitin E3 ligase to mark the aggregates for proteomic degradation and clearance. These compounds specifically bind to tau aggregates and distinguish between tau aggregates and monomeric (normal) tau. These results suggest that the compounds have the potential to promote clearance of pathogenic tau with minimal effects on normal / physiological tau species in the brains of human tauopathy patients, making them suitable for clinical use.

[0005] The present disclosure provides compositions and methods for the treatment of a group of disorders and conditions associated with tau aggregates. The methods of the invention include administering to a subject a bispecific conjugate or pharmaceutical composition described herein comprising a therapeutically effective amount of a compound of the invention effective to treat, alleviate or prevent a disorder or condition associated with tau aggregates. In certain embodiments, a therapeutically effective amount of a compound described herein is effective to halt, prevent or reverse the progression of a neurodegenerative disease.

[0006] In some embodiments, a pharmaceutical composition of a compound for the treatment of a tau-associated neurodegenerative disease is provided. The composition provided comprises an effective amount of a compound described herein and a pharma- ceutical acceptable excipient. [Means for solving the problem]

[0007] One aspect of the present disclosure is a compound represented by formula (I) to (VI):

[0008] [ka] TIFF0007605504000002.tif137140

[0009] or a pharma- ceutically acceptable salt, solvate, hydrate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein L1, L2, L3, X, Y, J, Q, K, T, U, V, Z, Y1, R', R'', R''', R 2' , R 3' , n, m, k and m6 are as defined herein.

[0010] Another aspect of the present disclosure is a composition comprising a compound of the present disclosure and a pharma- ceutically acceptable excipient.

[0011] Another aspect of the present disclosure is a method of aiding in the treatment of a tauopathy in a subject, comprising administering an effective amount of a compound of the present disclosure or a composition of the present disclosure, where the compound or composition treats or aids in the treatment of the subject.

[0012] Another aspect of the present disclosure is the use of the compounds of the present disclosure in the treatment of a tauopathy or a tau-associated disease or disorder.

[0013] Another aspect of the present disclosure is the use of a compound of the present disclosure in the manufacture of a medicament for the treatment of a tauopathy or a tau-associated disease or disorder.

[0014] Another aspect of the present disclosure is the use of the compounds of the present disclosure in diagnosing a tauopathy or a tau-related disease or disorder.

[0015] Another aspect of the present disclosure is a kit comprising a compound of the present disclosure or a composition of the present disclosure and printed instructions for its use.

[0016] Another aspect of the present disclosure is a method of synthesizing the compounds of the present disclosure.

[0017] The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the exemplary embodiments and features described herein, further aspects, embodiments, objects and features of the present disclosure will become more fully apparent from the drawings and detailed description, and the appended claims. [Brief description of the drawings]

[0018] [Figure 1] Figure 1 shows the degradation of tau aggregates measured by APNmAb005 ELISA assay. Treatment with 1 μM compound 162842 reduced the optical density (OD)450 value by 20% compared to vehicle, reflecting a reduction in tau aggregates. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present disclosure provides compounds that specifically bind to tau protein in aggregate form and also bind to ubiquitin E3 ligase, an intracellular enzyme that transfers activated ubiquitin to a specific site on a target protein.

[0020] Ubiquitin is a highly conserved small protein (8 kDa, 76 amino acids) that is ubiquitously expressed in cells. Once expressed, ubiquitin is activated by a ubiquitin-activating enzyme ("E1") and then transferred to a ubiquitin-conjugating enzyme ("E2"). An E3 ligase transfers ubiquitin from the E2 enzyme to the target substrate. There are estimated to be over 600 different E3 ligases that recognize a variety of different protein substrates. Once ubiquitinated, the substrate is transferred to the proteasome, which breaks down the protein into oligopeptides and ultimately into single amino acids. The ubiquitin-proteasome system is responsible for regulating the concentration of some proteins and for degrading and recycling damaged or misfolded proteins.

[0021] The present disclosure provides compositions and methods for the treatment of a group of disorders and conditions associated with tau aggregates. The methods of the invention include administering to a subject a compound or pharmaceutical composition described herein that includes a therapeutically effective amount of a compound of the invention that is effective to treat, reduce or prevent a disorder or condition associated with tau aggregates. In certain embodiments, a therapeutically effective amount of a compound described herein is effective to halt, prevent or reverse the progression of a neurodegenerative disease.

[0022] One aspect of the present disclosure is a compound represented by formula (I) to (VI):

[0023] [ka] TIFF0007605504000004.tif44141

[0024] wherein in formula I, R 3' is H or C 1~6 alkyl, Y1 is CH2 or

[0025] [ka]

[0026] L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L3 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain, Z is C or N, U is O, S or CH, V is N, where Z and U are not both heteroatoms, K is CH or N, Q is CH or N, where K and Q are not both N, and each occurrence of R''' is H, OH, NH, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkylamino, C 3~6 Cycloalkyl and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and J is CR 6 or N, where X is CR 6 or N, Y is CR 6 or N, where at least one of J, X, and Y is N, but J and Y are not simultaneously N, and X and Y are not simultaneously N; R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy, wherein NH, C 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula II, each occurrence of R 2' is H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 m6 is 0, 1, 2, 3 or 4; Y1 is CH2 or

[0027] [ka]

[0028] L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group, and L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain, Z is C or N, U is O, S or CH, V is N, where Z and U are not both heteroatoms, K is CH or N, Q is CH or N, where K and Q are not both N, and each occurrence of R''' is H, OH, NH, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and J is CR 6 or N, where X is CR 6 or N, Y is CR 6 or N, where at least one of J, X, and Y is N, but J and Y are not simultaneously N, and X and Y are not simultaneously N; R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy, wherein NH, C 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula III, L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group, and L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain, Z is C or N, U is O, S or CH, V is N, where Z and U are not both heteroatoms, K is CH or N, Q is CH or N, where K and Q are not both N, and each occurrence of R''' is H, OH, NH, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and J is CR 6 or N, where X is CR 6 or N, Y is CR 6 or N, where at least one of J, X, and Y is N, but J and Y are not simultaneously N, and X and Y are not simultaneously N; R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy, wherein NH, C 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula IV, R 3'is H or C 1~6 alkyl, Y1 is CH2 or

[0029] [ka]

[0030] L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L3 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain; Z is C or N; U is O, S or CH; V is N or NH; T is CH or N, where up to two of U, Z, V and T contain heteroatoms; K is CH or N; Q is CH or N, where K and Q are not both N; and each occurrence of R''' is H, OH, NH2, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and J is CR 6 or N, where X is CR 6 or N, Y is CR 6or N, where at least one of J, X, and Y is N, but J and Y are not simultaneously N, and X and Y are not simultaneously N; R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy, wherein NH, C 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula V, each occurrence of R 2' is H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 m6 is 0, 1, 2, 3 or 4; Y1 is CH2 or

[0031] [ka]

[0032] L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group, and L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain; Z is C or N; U is O, S or CH; V is N or NH; T is CH or N, where up to two of U, Z, V and T contain heteroatoms; K is CH or N; Q is CH or N, where K and Q are not both N; and each occurrence of R''' is H, OH, NH2, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and J is CR 6 or N, where X is CR 6 or N, Y is CR 6 or N, where at least one of J, X, and Y is N, but J and Y are not simultaneously N, and X and Y are not simultaneously N; R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy, wherein NH, C 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula VI, L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group, and L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain; Z is C or N; U is O, S or CH; V is N; T is CH or N, where up to two of U, Z, V and T contain heteroatoms; K is CH or N; Q is CH or N, where K and Q are not both N; and each occurrence of R''' is H, OH, NH2, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and J is CR 6 or N, where X is CR 6 or N, Y is CR 6 or N, where at least one of J, X, and Y is N, but J and Y are not simultaneously N, and X and Y are not simultaneously N; R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy, wherein NH, C 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 Optionally substituted with 1 to 3 of cycloalkyl and / or halo.

[0033] In certain embodiments, the compound is a compound of formula I.

[0034] In certain embodiments, the compound is of the structure of formula II.

[0035] In certain embodiments, the compound is of the structure of formula III.

[0036] In certain embodiments, the compound is of the structure of formula IV.

[0037] In certain embodiments, the compound is of the structure of Formula V.

[0038] In certain embodiments, the compound is of the structure of formula VI.

[0039] In certain embodiments, the moieties of formulas (I), (II) and (III):

[0040] [ka]

[0041] teeth,

[0042] [ka]

[0043] It is.

[0044] In certain embodiments, the moieties of formula (IV), (V) and (VI):

[0045] [ka]

[0046] teeth,

[0047] [ka]

[0048] It is.

[0049] In certain embodiments, the moieties of formulas (I)-(VI):

[0050] [ka]

[0051] teeth,

[0052] [ka]

[0053] It is.

[0054] In certain embodiments, the moieties of formula (I) and (IV):

[0055] [ka]

[0056] teeth,

[0057] [ka]

[0058] It is.

[0059] In certain embodiments, the moieties of formula (II) and (V):

[0060] [ka]

[0061] teeth,

[0062] [ka]

[0063] It is.

[0064] In one embodiment of the present disclosure, L1 is a bond.

[0065] In one embodiment of the present disclosure, L1 is -NH-, -O-, or -S-.

[0066] In one embodiment of the present disclosure, L3 is a bond.

[0067] In one embodiment of the present disclosure, L3 is -NH-, -O-, or -S-.

[0068] In one embodiment of the present disclosure, L2 is a substituted or unsubstituted C 1~30 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 It is an alkyl or nitrogen protecting group.

[0069] In certain embodiments, L2 is an unsubstituted C 1~30 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 It is an alkyl or nitrogen protecting group.

[0070] In certain embodiments, L2 is a substituted or unsubstituted C 1~24 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 It is an alkyl or nitrogen protecting group.

[0071] In certain embodiments, L2 is an unsubstituted C 1~24 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 It is an alkyl or nitrogen protecting group.

[0072] In certain embodiments, L2 is a substituted or unsubstituted C 1~20 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1-, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 It is an alkyl or nitrogen protecting group.

[0073] In certain embodiments, L2 is an unsubstituted C 1~20 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 It is an alkyl or nitrogen protecting group.

[0074] In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with -O-.

[0075] In certain embodiments, the chain of L2 comprises a length of up to 50 contiguous covalently bonded atoms, excluding hydrogen atoms and substituents.

[0076] In certain embodiments, L2 comprises a length of, for example, up to 46, 45, 40, 35, 32, 30, 25, 23, 20, 15, 14, 12, 11, 10, 9, 8, 7, 6, 5, 3 contiguous covalently bonded atoms, excluding hydrogen atoms and substituents.

[0077] In certain embodiments, any atom of L2 may be substituted. In certain embodiments, none of the atoms in the linker L2 are substituted. In certain embodiments, none of the carbon atoms of the linker are substituted.

[0078] In certain embodiments, L2 is a linker that contains an asymmetric carbon / stereocenter, i.e., contains an sp3 hybridized carbon atom with four different groups attached. In certain embodiments, a compound that contains such an L2 group is enantiomerically enriched or substantially enantiomerically enriched. In certain embodiments, a compound that contains such an L2 group is enantiomerically pure. In certain embodiments, a compound that contains such an L2 group is a racemate.

[0079] In certain embodiments, L2 comprises substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene, or a combination thereof. In certain embodiments, L2 is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene. In certain embodiments, L2 is a linker selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof.

[0080] Reference to L2, which is a combination of at least two examples of a divalent moiety described herein, refers to a linker consisting of at least one example of a first divalent moiety and at least one example of a second divalent moiety, where the first and second divalent moieties are the same or different and are within the scope of the divalent moieties described herein, and where the first and second divalent moiety examples are contiguous covalently linked to each other. For example, when L2 is a combination of alkylene and heteroalkylene linkers, -alkylene-heteroalkylene-, -alkylene-(heteroalkylene)2-, and -heteroalkylene-alkylene-heteroalkylene- are all within the scope of L2, where the alkylene in each instance in any one of the linkers can be the same or different, and the heteroalkylene in each instance in any one of the linkers can be the same or different.

[0081] In certain embodiments, L2 is a substituted or unsubstituted alkylene, e.g., a substituted or unsubstituted C 1~6 Alkylene, substituted or unsubstituted C 1~2 Alkylene, substituted or unsubstituted C 1~3 Alkylene, substituted or unsubstituted C 3~4 Alkylene, substituted or unsubstituted C 4~5 Alkylene, substituted or unsubstituted C 5~6 Alkylene, substituted or unsubstituted C 3~6 Alkylene, or substituted or unsubstituted C 4~6 Representative alkylene groups include unsubstituted alkylene groups, such as methylene (-CH-), ethylene (-(CH)-), n-propylene (-(CH)-), n-butylene (-(CH)-), n-pentylene (-(CH)-), and n-hexylene (-(CH)-).

[0082] In certain embodiments, L2 is a substituted or unsubstituted alkenylene, e.g., a substituted or unsubstituted C 2~6 Alkenylene, substituted or unsubstituted C 1~3 Alkenylene, substituted or unsubstituted C 3~4 Alkenylene, substituted or unsubstituted C4~5 Alkenylene, or substituted or unsubstituted C 5~6 At least one example of alkenylene is included.

[0083] In certain embodiments, L2 is a substituted or unsubstituted alkynylene, e.g., a substituted or unsubstituted C 2~6 Alkynylene, substituted or unsubstituted C 2~3 Alkynylene, substituted or unsubstituted C 3~4 Alkynylene, substituted or unsubstituted C 4~5 Alkynylene, or substituted or unsubstituted C 5~6 Contains at least one example of alkynylene.

[0084] In certain embodiments, L2 is a substituted or unsubstituted heteroalkylene, e.g., a substituted or unsubstituted heteroC 1~6 Alkylene, substituted or unsubstituted hetero C 1~2 Alkylene, substituted or unsubstituted hetero C 2~3 Alkylene, substituted or unsubstituted hetero C 3~4 Alkylene, substituted or unsubstituted hetero C 4~5 Alkylene, or substituted or unsubstituted hetero C 5~6 Representative heteroalkylene groups include unsubstituted heteroalkylene groups, such as, -(CH2)2-O(CH2)2-, -OCH2-, -CHO-, -O(CH2)2-, -(CH2)2O-, -O(CH2)3-, -(CH2)3O-, -O(CH2)4-, -(CH2)4O-, -O(CH2)5-, -(CH2)5O-, -O(CH2)6-, and -O(CH2)6O-, as well as amide groups (e.g., -NH-C(=O)- and -C(=O)NH-).

[0085] In certain embodiments, L2 is a substituted or unsubstituted heteroalkenylene, e.g., a substituted or unsubstituted heteroC 2~6 Alkenylene, substituted or unsubstituted hetero C 1~3 Alkenylene, substituted or unsubstituted hetero C 3~4 Alkenylene, substituted or unsubstituted hetero C 4~5Alkenylene, or substituted or unsubstituted hetero C 5~6 At least one example of alkenylene is included.

[0086] In certain embodiments, L2 is a substituted or unsubstituted heteroalkynylene, e.g., a substituted or unsubstituted heteroC 2~6 Alkynylene, substituted or unsubstituted hetero C 2~3 Alkynylene, substituted or unsubstituted hetero C 3~4 Alkynylene, substituted or unsubstituted hetero C 4~5 Alkynylene, or substituted or unsubstituted hetero C 5~6 Contains at least one example of alkynylene.

[0087] In certain embodiments, L2 is a substituted or unsubstituted carbocyclylene, e.g., a substituted or unsubstituted C 3~6 Carbocyclylene, substituted or unsubstituted C 3~4 Carbocyclylene, substituted or unsubstituted C 4~5 Carbocyclylene, or substituted or unsubstituted C 5~6 Contains at least one example of carbocyclylene.

[0088] In certain embodiments, L2 includes at least one example of a substituted or unsubstituted heterocyclylene, such as a substituted or unsubstituted 3- to 6-membered heterocyclylene, a substituted or unsubstituted 3- to 4-membered heterocyclylene, a substituted or unsubstituted 4- to 5-membered heterocyclylene, or a substituted or unsubstituted 5- to 6-membered heterocyclylene. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 5- to 8-membered heterocyclyl group in which one to four ring heteroatoms are selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 6-membered heterocyclyl group in which one to three ring heteroatoms are selected from the group consisting of nitrogen and oxygen. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with piperidine, piperazine, or morpholine.

[0089] In certain embodiments, L2 includes at least one example of a substituted or unsubstituted arylene, such as a substituted or unsubstituted phenylene. In certain embodiments, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with an optionally substituted phenyl group.

[0090] In certain embodiments, L2 includes at least one example of substituted or unsubstituted heteroarylene, for example, substituted or unsubstituted 5-6 membered heteroarylene.

[0091] In certain embodiments, L2 is an unsubstituted hydrocarbon chain, and optionally one or more chain atoms of the hydrocarbon chain are -NR a1 -R in each example is replaced independently by a1 are independently hydrogen, substituted or unsubstituted C 1~6 alkyl or nitrogen protecting group, or optionally two examples of R a1 taken together with the intervening atoms form a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring. In certain embodiments, at least one instance of R a1 is hydrogen. In certain embodiments, at least one instance of R a1 is substituted or unsubstituted C 1~6 In certain embodiments, at least one instance of R a1 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Tts)).

[0092] In certain embodiments, L2 is an optionally substituted C 1~45 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L2 is an unsubstituted C 1~45 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L2 is an optionally substituted C 1~24 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L2 is an unsubstituted C 1~24 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L2 is an optionally substituted C 1~20 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L2 is an unsubstituted C 1~20 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L2 is an optionally substituted C 1~30a hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -O- or -NR a1 In certain embodiments, L2 is independently replaced by an unsubstituted C 1~30 a hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -O- or -NR a1 -. In certain embodiments, L2 is independently replaced by an unsubstituted C 1~30 In certain embodiments, L2 is an unsubstituted C 1~26 A hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -C(=O)-, -O-, or -NR a1 -. In certain embodiments, L2 is independently replaced by an unsubstituted C 1~20 In certain embodiments, L2 is an unsubstituted C 5~26 A hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -C(=O)-, -O-, or -NR a1 -. In certain embodiments, L2 is independently replaced by an unsubstituted C 5~26 In certain embodiments, L2 is an unsubstituted C 5~20 A hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -C(=O)-, -O-, or -NR a1 -. In certain embodiments, L2 is independently replaced by an unsubstituted C 5~20 a hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -O- or -NR a1 -. In certain embodiments, L2 is independently replaced by an unsubstituted C 5~15 A hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -C(=O)-, -O-, or -NR a1 -. In certain embodiments, L2 is independently replaced by an unsubstituted C 15~20 A hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -C(=O)-, -O-, or -NR a1-. In certain embodiments, L2 is independently replaced by an unsubstituted C 20~25 A hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain are -C(=O)-, -O-, or -NR a1 -. In certain embodiments, L2 is independently replaced by substituted or unsubstituted C 1~45 In certain embodiments, L2 is a substituted or unsubstituted C 5~40 In certain embodiments, one or more chain atoms of the hydrocarbon chain of L2 are -C(=O)-, -O-, -S-, -NR a1 In certain embodiments, one or more chain atoms of the hydrocarbon chain of L2 is independently replaced with -, -N=, or =N-. a1 - is independently replaced by R a1 are independently hydrogen, substituted or unsubstituted C 1~6 In certain embodiments, L2 is an unsubstituted C 1~26 A cyclic moiety herein refers to a cycloalkylene or heterocycloalkylene, for example:

[0093] [ka] TIFF0007605504000020.tif18130

[0094] It is.

[0095] In certain embodiments, L2 is an all-carbon substituted or unsubstituted C 1~45 In certain embodiments, L2 is an all-carbon substituted or unsubstituted C 1~30 In certain embodiments, L2 is an all-carbon substituted or unsubstituted C 1~26 In certain embodiments, L2 is an all-carbon substituted or unsubstituted C 1~24In certain embodiments, L2 is an all-carbon substituted or unsubstituted C 1~20 In certain embodiments, L2 is an all-carbon substituted or unsubstituted C 1~20 It is a hydrocarbon chain.

[0096] In certain embodiments, L2 is

[0097] [ka]

[0098] In certain embodiments, L2 comprises this moiety and g is 1, 2, 3, 4, 5 or 6. In certain embodiments, g is 1. In certain embodiments, g is 2. In certain embodiments, g is 3. In certain embodiments, g is 4. In certain embodiments, g is 5. In certain embodiments, g is 6.

[0099] In certain embodiments, L2 comprises the moiety -NHC(=O)-.

[0100] In certain embodiments, L2 comprises the moiety -NH-.

[0101] Examples of L2 in this disclosure are

[0102] [ka] TIFF0007605504000023.tif103160

[0103] Including, but not limited to:

[0104] In certain embodiments, L2 has the formula:

[0105] [ka]

[0106] It is of the following.

[0107] In certain embodiments, L2 has the formula:

[0108] [ka]

[0109] It is of the following.

[0110] In certain embodiments, L2 has the formula:

[0111] [ka] TIFF0007605504000027.tif14129

[0112] wherein g is 1, 2, 3, 4 or 5; h is 0, 1, 2, 3, 4 or 5; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

[0113] In certain embodiments, L2 has the formula:

[0114] [ka]

[0115] wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

[0116] In certain embodiments, L2 has the formula:

[0117] [ka]

[0118] where g is 1, 2, 3, 4, 5, 6, 7 or 8.

[0119] In certain embodiments, L2 has the formula:

[0120] [ka]

[0121] wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

[0122] In certain embodiments, L2 has the formula:

[0123] [ka]

[0124] wherein g is 1, 2, 3, 4, 5, 6, 7 or 8; and f is 1, 2, 3, 4, 5, 6, 7 or 8.

[0125] In certain embodiments, L2 has the formula:

[0126] [ka]

[0127] wherein g is 1, 2, 3, 4, 5, 6, 7 or 8.

[0128] In certain embodiments, the compounds of the present disclosure have the following structure:

[0129] [ka]

[0130] wherein in formula I-1, R 3' is H or C 1~6 alkyl, Y1 is CH2 or

[0131] [ka]

[0132] L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L3 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain, Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, Q is CH or N, K is CH or N, where Q and K are not both N, and each occurrence of R''' is H, OH, NH, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, where n is 0, 1 or 2; In formula II-1, each occurrence of R 2' is H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 m6 is 0, 1, 2, 3 or 4; Y1 is CH2 or

[0133] [ka]

[0134] L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L3 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain, Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, Q is CH or N, K is CH or N, where Q and K are not both N, and each occurrence of R''' is H, OH, NH, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, where n is 0, 1 or 2; In formula III-1, L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, an optionally substituted acyl, an optionally substituted alkyl or a nitrogen protecting group, L3 is a bond, -NR-, -O- or -S-, where R is hydrogen, an optionally substituted acyl, an optionally substituted alkyl or a nitrogen protecting group, and L2 is a substituted or unsubstituted C 1~50is a hydrocarbon chain, Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, Q is CH or N, K is CH or N, where Q and K are not both N, and each occurrence of R''' is H, OH, NH, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, where n is 0, 1 or 2; In formula IV-1, R 3' is H or C 1~6 alkyl, Y1 is CH2 or

[0135] [ka]

[0136] L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L3 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L2 is a substituted or unsubstituted C 1~50is a hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N, where only one of U, Z and T is a heteroatom; Q is CH or N; K is CH or N, where Q and K are not both N; and each occurrence of R''' is H, OH, NH2, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and X is CR 6 or N, Y is CR 6 or N, where one of X and Y is N and the other is CR 6 and R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy, wherein NH, C 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula V-1, each occurrence of R 2' is H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 m6 is 0, 1, 2, 3 or 4; Y1 is CH2 or

[0137] [ka]

[0138] L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L3 is a bond, -NR-, -O- or -S-, where R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N, where only one of U, Z and T is a heteroatom; Q is CH or N; K is CH or N, where Q and K are not both N; and each occurrence of R''' is H, OH, NH2, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and X is CR 6 or N, Y is CR 6 or N, where one of X and Y is N and the other is CR 6 and R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy, wherein NH, C1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula VI-1, L1 is a bond, -NR-, -O- or -S-, where R is hydrogen, an optionally substituted acyl, an optionally substituted alkyl or a nitrogen protecting group, L3 is a bond, -NR-, -O- or -S-, where R is hydrogen, an optionally substituted acyl, an optionally substituted alkyl or a nitrogen protecting group, and L2 is a substituted or unsubstituted C 1~50 is a hydrocarbon chain; Z is C or N; U is O, S or CH; T is CH or N, where only one of U, Z and T is a heteroatom; Q is CH or N; K is CH or N, where Q and K are not both N; and each occurrence of R''' is H, OH, NH2, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 R' is independently selected from the group consisting of alkoxy and halogen, k is 0, 1, 2 or 3, and each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, m is 0, 1, 2, 3 or 4, and each occurrence of R″ is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkyl, C 3~6 Cycloalkylamino and C 3~6 heterocycloalkyl, n is 0, 1 or 2, and X is CR 6 or N, Y is CR 6 or N, where one of X and Y is N and the other is CR 6 and R 6 H, NH2, C 1~6 Alkyl and C 1~6alkoxy, wherein NH, C 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 Optionally substituted with 1 to 3 of cycloalkyl and / or halo.

[0139] In certain embodiments, the compound of formula I-1 has the following formula 1, 5, 6, 8, 10 or 13:

[0140] [ka]

[0141] It is a compound of the formula:

[0142] One embodiment of the present disclosure is a compound in which R′ is H, C 1~3 Haloalkyl or C 1~3 A compound of formula 1 which is alkoxy, preferably H, CF3, CCl3, methoxy or ethoxy, more preferably H, CF3 or methoxy.

[0143] One embodiment of the present disclosure is a compound of formula 1, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

[0144] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkoxy, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino and C 3~5 Heterocycloalkyl is a compound of formula 1, preferably H, F, Cl, NH2, methoxy, ethoxy, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropyl, cyclobutyl or cyclopentyl, more preferably H, F, dimethylamino or cyclopropyl.

[0145] One embodiment of the present disclosure is a compound of formula 1, wherein n is 0, 1 or 2, preferably 0 or 1.

[0146] One embodiment of the present disclosure is a compound of formula 1, wherein R''' is H, OH or halogen, preferably H, OH, F or Cl, more preferably H.

[0147] One embodiment of the present disclosure is a compound of formula 1, wherein k is 0, 1, 2 or 3, preferably 0 or 1.

[0148] One embodiment of the present disclosure is 1' O, NH,

[0149] [ka]

[0150] is a compound of formula 1,

[0151] In one embodiment of the present disclosure, A is O, NH,

[0152] [ka]

[0153] , preferably O or

[0154] [ka]

[0155] is a compound of formula 1,

[0156] One embodiment of the present disclosure is a compound of formula 1, wherein m2 is 2, 3, 4 or 6, preferably 2 or 6.

[0157] One embodiment of the present disclosure is 3' is H or C 1~3 is an alkyl, preferably H or methyl, more preferably H.

[0158] One embodiment of the present disclosure is a compound represented by formula 1-1:

[0159] [ka]

[0160] The compound is of formula 1 having the structure shown in

[0161] In Formula 1-1, R 3' is H or C 1~3 alkyl, Y1 is CH2 or

[0162] [ka]

[0163] where A is O, NH,

[0164] [ka]

[0165] m2 is 1, 2, 3, 4, 5, 6, and 7; R 1' is O, NH,

[0166] [ka]

[0167] where U is O, S or CH, Z is C or N, and U and Z are not both heteroatoms, and R' is H, C 1~3 Haloalkyl or C 1~3 Alkoxy, R'' is H, F, Cl, OH, NH2, C 1~3 alkoxy, methylamino, dimethylamino, diethylamino or cyclopropylamino, and n is 0, 1 or 2.

[0168] One embodiment of the present disclosure is a compound of formula 1-1, wherein m2 is 2, 3, 4 or 6, preferably 2 or 6.

[0169] One embodiment of the present disclosure is 3' is H or methyl.

[0170] In one embodiment of the present disclosure, A is O or

[0171] [ka]

[0172] is a compound of formula 1-1,

[0173] One embodiment of the present disclosure is 1' is O, NH or

[0174] [ka]

[0175] is a compound of formula 1-1,

[0176] One embodiment of the disclosure is a compound of formula 1-1 where Z is N and U is CH.

[0177] One embodiment of the disclosure is a compound of formula 1-1, wherein Z is C and U is S or O.

[0178] One embodiment of the present disclosure is a compound of formula 1-1, where R″ is H, F, Cl, OH, NH2, methoxy, methylamino, dimethylamino, diethylamino, cyclopropyl or cyclopropylamino, preferably H, F, methylamino, dimethylamino or cyclopropylamino.

[0179] One embodiment of the present disclosure is a compound in which R′ is H, C 1~3 fluoroalkyl, methoxy or ethoxy, preferably compounds of formula 1-1 where R' is H, methoxy or CF3.

[0180] One embodiment of the present disclosure is3' is H or C 1~3 In the compound of formula 5, R is alkyl, preferably H or methyl.

[0181] In one embodiment of the present disclosure, A is O, NH or

[0182] [ka]

[0183] , preferably O.

[0184] One embodiment of the present disclosure is a compound of formula 5, wherein m4 is 0, 1, 2 or 3, preferably 0 or 3.

[0185] One embodiment of the present disclosure is a compound of formula 5, wherein m5 is 0, 1, 2 or 3, preferably 0 or 1.

[0186] One embodiment of the present disclosure is a compound of formula 5, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 3 or 5.

[0187] One embodiment of the present disclosure is 1' is O, NH or

[0188] [ka]

[0189] is a compound of formula 5,

[0190] One embodiment of the present disclosure is a compound in which R′″ is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

[0191] One embodiment of the present disclosure is a compound of formula 5, wherein k is 0, 1, 2 or 3, preferably 0 or 1.

[0192] One embodiment of the present disclosure is a compound of formula 5, wherein Z is C and U is O or S.

[0193] One embodiment of the present disclosure is a compound of formula 5 where Z is N and U is CH.

[0194] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0195] One embodiment of the present disclosure is a compound of formula 5, wherein m is 0, 1, 2 or 3, preferably 0 or 1.

[0196] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 Heterocycloalkyl is preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, cyclopropyl or dimethylamino, more preferably H, F, CF3, cyclopropyl, cyclopropylamino or dimethylamino.

[0197] One embodiment of the present disclosure is a compound of formula 5, wherein n is 0, 1 or 2, preferably 0 or 1.

[0198] One embodiment of the present disclosure is a compound represented by formula 5-1:

[0199] [ka]

[0200] The compound is of formula 5 having the structure shown in

[0201] In formula 5-1, R 3' is H or C 1~3 alkyl, Y1 is CH2 or

[0202] [ka]

[0203] where A is O, NH,

[0204] [ka] TIFF0007605504000053.tif15134

[0205] m5 is 0 or 1, m4 is 0, 1, 2, 3 or 4, m3 is 1, 2, 3, 4, 5 or 6, R 1' is O, NH,

[0206] [ka]

[0207] Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, and R''' is H, OH, C 1~3 Alkyl, C 1~3 Alkoxy or halogen, R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, where R'' is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino and C 3~5heterocycloalkyl, where n is 0, 1 or 2.

[0208] One embodiment of the present disclosure is a compound of formula 5-1, where A is O.

[0209] One embodiment of the disclosure is a compound of formula 5-1, wherein m5 is 0 or 1.

[0210] One embodiment of the disclosure is a compound of formula 5-1, wherein m4 is 0 or 3.

[0211] One embodiment of the present disclosure is a compound of formula 5-1, wherein m3 is 3, 5.

[0212] One embodiment of the present disclosure is 1' is O, NH or

[0213] [ka]

[0214] is a compound of formula 5-1,

[0215] One embodiment of the disclosure is a compound of formula 5-1, where Z is C and U is O or S.

[0216] One embodiment of the disclosure is a compound of formula 5-1 where Z is N and U is CH.

[0217] One embodiment of the present disclosure is a compound in which R′ is H, halogen, C 1~3 Alkyl, C 1~3 Fluoroalkyl or C 1~3 Alkoxy is preferably H, methyl, CF3, methyl or methoxy, more preferably H or CF3.

[0218] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 Compounds of formula 5-1 which are heterocycloalkyl, preferably H, F, CF3, amino, methylamino, dimethylamino, cyclopropyl, or cyclopropylamino, more preferably H, F, CF3, dimethylamino, cyclopropylamino, or cyclopropyl.

[0219] One embodiment of the present disclosure is 3' is H or C 1~3 The compound of formula 6 is alkyl, preferably H or methyl.

[0220] In one embodiment of the present disclosure, A is O, NH or

[0221] [ka]

[0222] , preferably O or NH.

[0223] One embodiment of the present disclosure is a compound of formula 6, wherein m2 is 1, 2, 3, 4, 5, 6 or 7, preferably 2 or 6.

[0224] One embodiment of the present disclosure is 1' is O, NH or

[0225] [ka]

[0226] , preferably O or NH.

[0227] One embodiment of the present disclosure is a compound of formula 6, wherein Z is C or N and U is O, S or CH, where Z and U are not both heteroatoms, preferably Z is C and U is S.

[0228] One embodiment of the present disclosure is a compound in which R′″ is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

[0229] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0230] One embodiment of the present disclosure is a compound of formula 6, wherein m is 0, 1, 2 or 3, preferably 0 or 1.

[0231] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 A compound of formula 6 which is heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F, CF3, dimethylamino, cyclopropyl or cyclopropylamino.

[0232] One embodiment of the present disclosure is a compound of formula 6, where n is 0 or 1.

[0233] One embodiment of the present disclosure is a compound represented by formula 6-1:

[0234] [ka]

[0235] The compound is of formula 6 having the structure shown in

[0236] In Equation 6-1, R 3' is H or C 1~3 alkyl, Y1 is CH2 or

[0237] [ka]

[0238] where A is O, NH,

[0239] [ka] TIFF0007605504000061.tif15134

[0240] m2 is 1, 2, 3, 4, 5, 6 or 7; R 1' is O, NH,

[0241] [ka]

[0242] and R''' is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, k is 0, 1, 2 or 3, Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, m is 0, 1, 2 or 3, and R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 heterocycloalkyl, where n is 0, 1 or 2.

[0243] One embodiment of the present disclosure is 3' is H or methyl.

[0244] One embodiment of the disclosure is a compound of formula 6-1, where A is O or NH.

[0245] One embodiment of the disclosure is a compound of formula 6-1, where m2 is 2 or 6.

[0246] One embodiment of the present disclosure is 1' is a compound of formula 6-1, where

[0247] One embodiment of the present disclosure is a compound of formula 6-1, where R' is H or CF3.

[0248] One embodiment of the present disclosure is a compound of formula 6-1, where m is 0, 1, 2 or 3, preferably 0 or 1.

[0249] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 Heterocycloalkyl is preferably H, F, CF, methoxy, methyl, dimethylamino, cyclopropyl, cyclopropylamino or methylamino, more preferably H, CF, F, dimethylamino, cyclopropyl or cyclopropylamino, most preferably H, dimethylamino, cyclopropyl or cyclopropylamino.

[0250] One embodiment of the disclosure is a compound of formula 6-1, where n is 0 or 1.

[0251] One embodiment of the disclosure is a compound of formula 6-1 where R″ is substituted adjacent to the N atom.

[0252] One embodiment of the present disclosure is 3' is H or C 1~3 The compound of formula 8 is alkyl, preferably H or methyl.

[0253] In one embodiment of the present disclosure, Y1 is CH2 or

[0254] [ka]

[0255] , preferably a compound of formula 8, where CH2.

[0256] In one embodiment of the present disclosure, A is O, NH,

[0257] [ka]

[0258] , preferably O.

[0259] One embodiment of the present disclosure is a compound of formula 8, wherein m2 is 1, 2, 3 or 4, preferably 2.

[0260] One embodiment of the present disclosure is 1' O, NH,

[0261] [ka]

[0262] , preferably O.

[0263] One embodiment of the present disclosure is a compound in which R′″ is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

[0264] One embodiment of the present disclosure is a compound of formula 8, wherein k is 0 or 1.

[0265] One embodiment of the present disclosure is a compound of formula 8, wherein Z is C or N and U is O, S or CH, where Z and U are not both heteroatoms, preferably Z is N and U is CH, preferably Z is C and U is S.

[0266] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 The compound of formula 8 is alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0267] One embodiment of the present disclosure is a compound of formula 8, wherein m is 0, 1, or 2.

[0268] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 A compound of formula 8 which is heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, cyclopropyl or cyclopropylamino.

[0269] One embodiment of the present disclosure is a compound of formula 8, where n is 0, 1 or 2.

[0270] One embodiment of the present disclosure comprises:

[0271] [ka]

[0272] is a compound of formula 8,

[0273] One embodiment of the present disclosure is 3' is H or C 1~3 The compound of formula 10 is alkyl, preferably H or methyl.

[0274] In one embodiment of the present disclosure, Y1 is CH2 or

[0275] [ka]

[0276] , preferably CH2.

[0277] In one embodiment of the present disclosure, A is O, NH,

[0278] [ka]

[0279] , preferably

[0280] [ka]

[0281] is a compound of formula 10,

[0282] An embodiment of the present disclosure is a compound of formula 10, wherein m5 is 0 or 1.

[0283] An embodiment of the present disclosure is a compound of formula 10, wherein m4 is 0 or 1.

[0284] One embodiment of the present disclosure is a compound of formula 10, wherein m3 is 1, 2, 3, 4 or 5, preferably 4.

[0285] One embodiment of the present disclosure is 1'O, NH,

[0286] [ka]

[0287] , preferably O.

[0288] One embodiment of the present disclosure is a compound in which R′″ is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

[0289] One embodiment of the present disclosure is a compound of formula 10, wherein k is 0 or 1.

[0290] One embodiment of the present disclosure is a compound of formula 10, wherein Z is C and U is S or O.

[0291] One embodiment of the present disclosure is a compound of formula 10 where Z is N and U is CH.

[0292] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 The compound of formula 10 is alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0293] One embodiment of the present disclosure is a compound of formula 10, wherein m is 0 or 1.

[0294] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5Compounds of formula 10 which are heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F or CF3.

[0295] One embodiment of the present disclosure is a compound of formula 10, wherein n is 0 or 1.

[0296] One embodiment of the present disclosure is 3' is H or C 1~3 The compound of formula 13 is alkyl, preferably H or methyl.

[0297] In one embodiment of the present disclosure, Y1 is CH2 or

[0298] [ka]

[0299] , preferably a compound of formula 13, where CH2 is

[0300] In one embodiment of the present disclosure, A is O, NH,

[0301] [ka]

[0302] , preferably

[0303] [ka]

[0304] is a compound of formula 13,

[0305] One embodiment of the present disclosure is a compound of formula 13, wherein m2 is 1, 2, 3 or 4, preferably 1.

[0306] One embodiment of the present disclosure is 1' O, NH,

[0307] [ka]

[0308] , preferably NH.

[0309] One embodiment of the present disclosure is a compound in which R′″ is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, preferably H, methyl, methoxy or F, more preferably H.

[0310] One embodiment of the present disclosure is a compound of formula 13, wherein k is 0, 1, 2 or 3, preferably 0 or 1.

[0311] An embodiment of the present disclosure is a compound of formula 13, wherein Z is C and U is S or O.

[0312] One embodiment of the present disclosure is a compound of formula 13 where Z is N and U is CH.

[0313] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0314] One embodiment of the present disclosure is a compound of formula 13, wherein m is 0, 1, 2 or 3, preferably 0 or 1.

[0315] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C3~5 A compound of formula 13 which is heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, cyclopropyl, cyclopropylamino or dimethylamino, more preferably H, F, CF3, dimethylamino, cyclopropyl or cyclopropylamino, most preferably dimethylamino.

[0316] One embodiment of the present disclosure is a compound of formula 13, wherein n is 0, 1 or 2, preferably 0 or 1.

[0317] One embodiment of the compound of formula II-1 is represented by the following formula 3:

[0318] [ka]

[0319] It is a compound of the formula:

[0320] One embodiment of the present disclosure is 2' H, OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 The compound of formula 3 is alkylamino or NH2, preferably H, OH or NH2.

[0321] One embodiment of the present disclosure is a compound of formula 3, wherein m6 is 0, 1, 2 or 3, preferably 0 or 1.

[0322] One embodiment of the present disclosure is 1' is a compound of formula 3, wherein

[0323] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, preferably H, halogen or C 1~3 Fluoroalkyl, more preferably H or F.

[0324] One embodiment of the present disclosure is a compound of formula 3, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

[0325] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 Compounds of formula 3 which are alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

[0326] One embodiment of the present disclosure is a compound of formula 3, wherein n is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0327] One embodiment of the present disclosure is a compound of formula 3 where Z is C and U is O or S.

[0328] One embodiment of the present disclosure is a compound of formula 3 where Z is N and U is CH.

[0329] One embodiment of the present disclosure is a compound in which R′″ is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, preferably H, F, methyl or methoxy, more preferably H.

[0330] One embodiment of the present disclosure is a compound represented by formula 3-1:

[0331] [ka]

[0332] In formula 3-1, R 2' is H, OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 alkylamino or NH2, m6 is 0, 1, 2 or 3, Y1 is CH2 or

[0333] [ka]

[0334] and R 1' is O, NH,

[0335] [ka]

[0336] Z is C or N, U is O, S or CH, where Z and U are not both heteroatoms, and R″ is H, halo, OH, NH, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 alkylamino, where n is 0, 1 or 2.

[0337] One embodiment of the present disclosure is 2' is a compound of formula 3-1, where is H, NH2 or OH.

[0338] One embodiment of the present disclosure is a compound of formula 3-1 where m6 is 0 or 1.

[0339] In one embodiment of the present disclosure, when m6 is 1, R 2' At the following positions of phenyl:

[0340] [ka] TIFF0007605504000080.tif16129

[0341] is a compound of formula 3-1, wherein

[0342] One embodiment of the present disclosure is 1' is a compound of formula 3-1, wherein

[0343] One embodiment of the disclosure is a compound of formula 3-1, where R″ is F, dimethylamino, methylamino, cyclopropyl, or cyclopropylamino.

[0344] One embodiment of the disclosure is a compound of formula 3-1, where n is 0, 1, or 2.

[0345] One embodiment of the compound of III-1 has the following formula 15:

[0346] [ka]

[0347] It is a compound of the formula:

[0348] One embodiment of the present disclosure is a compound of formula 15, wherein m2 is 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2, 3, 4, 5 or 6, more preferably 2 or 5.

[0349] One embodiment of the present disclosure is 1' O, NH,

[0350] [ka]

[0351] , preferably O or NH.

[0352] One embodiment of the present disclosure is a compound in which R′″ is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, preferably H, F, methyl or methoxy, more preferably H.

[0353] One embodiment of the present disclosure is a compound of formula 15, wherein Z is C and U is O or S.

[0354] One embodiment of the present disclosure is a compound of formula 15, where Z is N and U is CH.

[0355] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, preferably H, halogen or C 1~3 Fluoroalkyl, more preferably H, CF3 or F.

[0356] One embodiment of the present disclosure is a compound of formula 15, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0357] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 Compounds of formula 15 which are alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F, methylamino, cyclopropylamino or dimethylamino, most preferably H or dimethylamino.

[0358] One embodiment of the present disclosure is a compound of formula 15, wherein n is 0, 1 or 2, preferably 0 or 1.

[0359] One embodiment of the compound of formula IV-1 is represented by the following formula 2, 7, 9, 11, 12 or 14:

[0360] [ka] TIFF0007605504000084.tif114129

[0361] It is a compound of the formula:

[0362] One embodiment of the present disclosure is 3' is H or C1~3 In the compound of formula 2, R is alkyl, preferably H or methyl.

[0363] In one embodiment of the present disclosure, Y1 is CH2 or

[0364] [ka]

[0365] is a compound of formula 2,

[0366] In one embodiment of the present disclosure, A is O, NH,

[0367] [ka]

[0368] , preferably O.

[0369] One embodiment of the present disclosure is a compound of formula 2, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 6.

[0370] One embodiment of the present disclosure is 1' O, NH,

[0371] [ka]

[0372] , preferably NH.

[0373] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5Heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, cyclopropyl or cyclopropylamino.

[0374] One embodiment of the present disclosure is a compound of formula 2, wherein n is 0, 1 or 2, preferably 0 or 1.

[0375] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 The compound of formula 2 is alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0376] One embodiment of the present disclosure is a compound of formula 2, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0377] One embodiment of the present disclosure is a compound of formula 2 where Z is C, U is O or S, and W is CH.

[0378] One embodiment of the present disclosure is a compound of formula 2 where Z is N, U is CH, and W is CH.

[0379] One embodiment of the present disclosure is a compound of formula 2 where Z is C, W is N, and U is CH.

[0380] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 The compound of formula 2 is alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0381] One embodiment of the present disclosure is a compound of formula 2, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0382] One embodiment of the present disclosure is 3' is H or C 1~3 In the compound of formula 7, R is alkyl, preferably H or methyl.

[0383] In one embodiment of the present disclosure, Y1 is CH2 or

[0384] [ka]

[0385] is a compound of formula 7,

[0386] In one embodiment of the present disclosure, A is O, NH,

[0387] [ka]

[0388] , preferably O.

[0389] One embodiment of the present disclosure is a compound of formula 7, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

[0390] One embodiment of the present disclosure is 1' O, NH,

[0391] [ka]

[0392] , preferably NH.

[0393] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C3~5 Cycloalkylamino or C 3~5 Heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, cyclopropyl or cyclopropylamino.

[0394] One embodiment of the present disclosure is a compound of formula 7, wherein n is 0, 1 or 2, preferably 0 or 1.

[0395] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 The compound of formula 7 is alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0396] One embodiment of the present disclosure is a compound of formula 7, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0397] One embodiment of the present disclosure is a compound of formula 7 where Z is C, U is O or S, and W is CH.

[0398] One embodiment of the present disclosure is a compound of formula 7 where Z is N, U is CH, and W is CH.

[0399] One embodiment of the present disclosure is a compound of formula 7 where Z is C, W is N, and U is CH.

[0400] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 The compound of formula 7 is alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0401] One embodiment of the present disclosure is a compound of formula 7, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0402] One embodiment of the present disclosure is 3' is H or C 1~3 In the compound of formula 9, R is alkyl, preferably H or methyl.

[0403] In one embodiment of the present disclosure, Y1 is CH2 or

[0404] [ka]

[0405] is a compound of formula 9,

[0406] In one embodiment of the present disclosure, A is O, NH,

[0407] [ka]

[0408] , preferably O.

[0409] One embodiment of the present disclosure is a compound of formula 9, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

[0410] One embodiment of the present disclosure is 1' O, NH,

[0411] [ka]

[0412] , preferably NH.

[0413] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 A compound of formula 9 which is heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, cyclopropyl or cyclopropylamino.

[0414] One embodiment of the present disclosure is a compound of formula 9, wherein n is 0, 1 or 2, preferably 0 or 1.

[0415] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 The compound of formula 9 is alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0416] One embodiment of the present disclosure is a compound of formula 9, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0417] One embodiment of the present disclosure is a compound of formula 9 where Z is C, U is O or S, and W is CH.

[0418] One embodiment of the present disclosure is a compound of formula 9 where Z is N, U is CH, and W is CH.

[0419] One embodiment of the present disclosure is a compound of formula 9 where Z is C, W is N, and U is CH.

[0420] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 The compound of formula 9 is alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0421] One embodiment of the present disclosure is a compound of formula 9, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0422] One embodiment of the present disclosure is 3' is H or C 1~3 The compound of formula 11 is alkyl, preferably H or methyl.

[0423] In one embodiment of the present disclosure, Y1 is CH2 or

[0424] [ka]

[0425] is a compound of formula 11,

[0426] In one embodiment of the present disclosure, A is O, NH,

[0427] [ka]

[0428] , preferably O.

[0429] One embodiment of the present disclosure is a compound of formula 11, wherein m2 is 2, 3, 4, 5 or 6, preferably 2 or 3.

[0430] One embodiment of the present disclosure is 1' O, NH,

[0431] [ka]

[0432] , preferably NH.

[0433] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 Heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, cyclopropyl or cyclopropylamino.

[0434] One embodiment of the present disclosure is a compound of formula 11, wherein n is 0, 1 or 2, preferably 0 or 1.

[0435] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 The compound of formula 11 is alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0436] One embodiment of the present disclosure is a compound of formula 11, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0437] One embodiment of the present disclosure is a compound of formula 11, where Z is C, U is O or S, and W is CH.

[0438] One embodiment of the present disclosure is a compound of formula 11, where Z is N, U is CH, and W is CH.

[0439] One embodiment of the present disclosure is a compound of formula 11, where Z is C, W is N, and U is CH.

[0440] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3Alkylamino, C 1~3 Compounds of formula 11 which are alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0441] One embodiment of the present disclosure is a compound of formula 11, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0442] One embodiment of the present disclosure is 3' is H or C 1~3 The compound of formula 12 is alkyl, preferably H or methyl.

[0443] In one embodiment of the present disclosure, Y1 is CH2 or

[0444] [ka]

[0445] , preferably CH2.

[0446] In one embodiment of the present disclosure, A is O, NH,

[0447] [ka]

[0448] , preferably O.

[0449] One embodiment of the present disclosure is a compound of formula 12, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 2 or 3.

[0450] One embodiment of the present disclosure is a compound of formula 12, wherein m4 is 0 or 1, 2 or 3, preferably 0 or 3.

[0451] One embodiment of the present disclosure is a compound of formula 12, wherein m5 is 0 or 1, 2 or 3, preferably 0 or 1.

[0452] One embodiment of the present disclosure is 1' O, NH,

[0453] [ka]

[0454] , preferably NH.

[0455] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 Heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, cyclopropyl or cyclopropylamino.

[0456] One embodiment of the present disclosure is a compound of formula 12, where n is 0, 1 or 2, preferably 0 or 1.

[0457] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 The compound of formula 12 is alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0458] One embodiment of the present disclosure is a compound of formula 12, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0459] One embodiment of the present disclosure is a compound of formula 12, where Z is C, U is O or S, and W is CH.

[0460] One embodiment of the disclosure is a compound of formula 12 where Z is N, U is CH, and W is CH.

[0461] One embodiment of the present disclosure is a compound of formula 12, where Z is C, W is N, and U is CH.

[0462] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 The compound of formula 12 is alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0463] One embodiment of the present disclosure is a compound of formula 12, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0464] One embodiment of the present disclosure is 3' is H or C 1~3 The compound of formula 14 is alkyl, preferably H or methyl.

[0465] In one embodiment of the present disclosure, Y1 is CH2 or

[0466] [ka]

[0467] , preferably a compound of formula 14, where CH2.

[0468] In one embodiment of the present disclosure, A is O, NH,

[0469] [ka]

[0470] , preferably O.

[0471] One embodiment of the present disclosure is a compound of formula 14, wherein m3 is 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.

[0472] An embodiment of the present disclosure is a compound of formula 14, wherein m4 is 0, 1, 2, 3 or 4, preferably 0 or 3.

[0473] One embodiment of the present disclosure is a compound of formula 14, wherein m5 is 0 or 1, 2 or 3, preferably 0 or 1.

[0474] One embodiment of the present disclosure is 1' O, NH,

[0475] [ka]

[0476] , preferably

[0477] [ka]

[0478] is a compound of formula 14,

[0479] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 A compound of formula 14 which is heterocycloalkyl, preferably H, F, OH, NH2, methyl, methoxy, CF3, CCl3, methylamino, dimethylamino, cyclopropyl or cyclopropylamino, more preferably H, F, CF3, cyclopropyl or cyclopropylamino.

[0480] One embodiment of the present disclosure is a compound of formula 14, wherein n is 0, 1 or 2, preferably 0 or 1.

[0481] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 The compound of formula 14 is alkoxy, preferably H, F, CF3, CCl3, methyl or methoxy, more preferably H or CF3.

[0482] One embodiment of the present disclosure is a compound of formula 14, wherein m is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0483] One embodiment of the present disclosure is a compound of formula 14, where Z is C, U is O or S, and W is CH.

[0484] One embodiment of the present disclosure is a compound of formula 14 where Z is N, U is CH, and W is CH.

[0485] One embodiment of the present disclosure is a compound of formula 14 where Z is C, W is N, and U is CH.

[0486] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 The compound of formula 14 is alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0487] One embodiment of the present disclosure is a compound of formula 14, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0488] One embodiment of the compound of V-1 is represented by the following formula 4:

[0489] [ka]

[0490] It is a compound of the formula:

[0491] One embodiment of the present disclosure is 2' H, OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 The compound of formula 4 is alkylamino or NH2, preferably H, OH or NH2.

[0492] One embodiment of the present disclosure is a compound of formula 4, wherein m6 is 0, 1, 2 or 3, preferably 0 or 1.

[0493] One embodiment of the present disclosure is 1' O, NH,

[0494] [ka]

[0495] , preferably O or NH.

[0496] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, preferably H, halogen or C 1~3 Fluoroalkyl, more preferably H or F.

[0497] One embodiment of the present disclosure is a compound of formula 4, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

[0498] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3Compounds of formula 4 which are alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

[0499] One embodiment of the present disclosure is a compound of formula 4, wherein n is 0, 1 or 2, preferably 0 or 1.

[0500] One embodiment of the present disclosure is a compound of formula 4 where Z is C, U is O or S, and W is CH.

[0501] One embodiment of the present disclosure is a compound of formula 4 where Z is N, U is CH, and W is CH.

[0502] One embodiment of the present disclosure is a compound of formula 4 where Z is C, U is CH, and W is N.

[0503] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 The compound of formula 4 is alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0504] One embodiment of the present disclosure is a compound of formula 4, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0505] One embodiment of the present disclosure is a compound represented by formula 4-1:

[0506] [ka]

[0507] The compound is of formula 4 having the structure shown in

[0508] In formula 4-1, R 2' is H, OH, C 1~3 Alkyl, C 1~3Alkoxy, C 1~3 alkylamino or NH2, Y1 is CH2 or

[0509] [ka]

[0510] and R 1' is O, NH,

[0511] [ka]

[0512] and R'' is H, halo, OH, NH2, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino or C 3~5 heterocycloalkyl, n is 0, 1 or 2, and R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, m is 0, 1 or 2, n is 0, 1 or 2, U is O or S, and R''' is H, OH, NH2, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 alkoxy or halogen; and k is 0, 1, 2, 3 or 4.

[0513] One embodiment of the present disclosure is 1' is a compound of formula 4-1, where

[0514] One embodiment of the present disclosure is a compound of formula 4-1, where R″ is H.

[0515] One embodiment of the present disclosure is a compound of formula 4-1, where R′ is H.

[0516] One embodiment of the present disclosure is 2' is a compound of formula 4-1, where

[0517] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 Compounds of formula 4-1 which are alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0518] One embodiment of the present disclosure is a compound of formula 4, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0519] An embodiment of the present disclosure is a compound of formula 4 where U is S.

[0520] One embodiment of the compound of VI-1 is represented by the following formula 16 or 17:

[0521] [ka]

[0522] It is a compound of the formula:

[0523] One embodiment of the present disclosure is a compound of formula 16, wherein m2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.

[0524] One embodiment of the present disclosure is 1' O, NH,

[0525] [ka]

[0526] , preferably NH.

[0527] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, preferably H, halogen or C 1~3Fluoroalkyl, more preferably H or F.

[0528] One embodiment of the present disclosure is a compound of formula 16, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

[0529] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 Compounds of formula 16 which are alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

[0530] One embodiment of the present disclosure is a compound of formula 16, where n is 0, 1 or 2, preferably 0 or 1.

[0531] One embodiment of the present disclosure is a compound of formula 16 where Z is C, U is O or S, and W is CH.

[0532] One embodiment of the disclosure is a compound of formula 16 where Z is N, U is CH, and W is CH.

[0533] One embodiment of the present disclosure is a compound of formula 16 where Z is C, U is CH, and W is N.

[0534] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 The compound of formula 16 is alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0535] One embodiment of the present disclosure is a compound of formula 16, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0536] One embodiment of the present disclosure is a compound of formula 17, wherein m2 is 1, 2, 3, 4, 5 or 6, preferably 2 or 5.

[0537] One embodiment of the present disclosure is 1' O, NH,

[0538] [ka]

[0539] , preferably NH.

[0540] In one embodiment of the present disclosure, R′ is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, preferably H, halogen or C 1~3 Fluoroalkyl, more preferably H or F.

[0541] One embodiment of the present disclosure is a compound of formula 17, wherein m is 0, 1, 2, 3 or 4, preferably 0 or 1.

[0542] One embodiment of the present disclosure is a compound in which R″ is H, halo, OH, NH, C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 Compounds of formula 17 which are alkylamino, preferably H, halo, methylamino, dimethylamino, cyclopropylamino or cyclopropyl, more preferably H, F or dimethylamino.

[0543] One embodiment of the present disclosure is a compound of formula 17, where n is 0, 1 or 2, preferably 0 or 1.

[0544] One embodiment of the present disclosure is a compound of formula 17, where Z is C, U is O or S, and W is CH.

[0545] One embodiment of the present disclosure is a compound of formula 17, where Z is N, U is CH, and W is CH.

[0546] One embodiment of the disclosure is a compound of formula 17 where Z is C, U is CH, and W is N.

[0547] In one embodiment of the present disclosure, R′″ is H, OH, NH, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 The compound of formula 17 is alkoxy or halogen, preferably H, F, methoxy, methylamino or dimethylamino.

[0548] One embodiment of the present disclosure is a compound of formula 17, wherein k is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

[0549] Some embodiments of the present disclosure are compounds having the structures depicted in Table 1.

[0550] [Table 1] TIFF0007605504000113.tif254145TIFF0007605504000114.tif253146TIFF0007605504000115.tif254144TIFF0007605504000116.t if246145TIFF0007605504000117.tif255138TIFF0007605504000118.tif254141TIFF0007605504000119.tif254140TIFF0007605504 000120.tif254136TIFF0007605504000121.tif253136TIFF0007605504000122.tif253138TIFF0007605504000123.tif253143TIFF00 07605504000124.tif254137TIFF0007605504000125.tif255139TIFF0007605504000126.tif254144TIFF0007605504000127.tif98145

[0551] In the following detailed description, reference is made to the accompanying drawings, which form a part of this application. In the drawings, like numerals generally identify like components unless otherwise indicated by context. The exemplary alternatives described in the detailed description, drawings, and claims are not intended to be limiting. Other alternatives may be used and other changes may be made without departing from the spirit or scope of the subject matter presented herein. It is readily understood that the aspects generally described herein and illustrated in the figures can be arranged, substituted, combined and designed in a wide variety of different configurations, all of which are expressly contemplated and made a part of this application.

[0552] One embodiment is a compound, which is isotopically or radiolabeled.One embodiment is a solvate, hydrate, salt or ester of a compound of the present disclosure.

[0553] One aspect of the disclosure is a composition comprising a compound of the disclosure and a pharma- ceutically acceptable excipient.

[0554] One aspect of the disclosure is a method of aiding in the treatment of a tauopathy in a subject, comprising administering an effective amount of a compound of the disclosure or a composition of the disclosure, where the compound or composition treats the subject.

[0555] In some embodiments, the tauopathy is a neurodegenerative tauopathy. In some embodiments, the tauopathy is selected from the group consisting of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), Creutzfeldt-Jakob disease, dementia pugilistica, Down's syndrome, Gerstmann-Straussler-Scheinker disease, British dementia, Danish dementia, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Parkinsonism dementia complex of Guam, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcifications, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, Pallidoponto-nigral degeneration ... The tauopathy is selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, tangle-only dementia, white matter tauopathy with globular glial inclusions, frontotemporal dementia, postencephalitic parkinsonism, parkinsonism linked to chromosome 17, and myotonic dystrophy. In some embodiments, the tauopathy is Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or Pick's disease (PiD).

[0556] In some embodiments, according to any of the methods described above, the method further comprises administering to the subject at least one additional therapeutic agent, in some embodiments, the at least one additional therapeutic agent is selected from a neurological agent, an anti-tau antibody, a tau inhibitor, an anti-amyloid beta antibody, a beta-amyloid aggregation inhibitor, an anti-BACE1 antibody, and a BACE1 inhibitor.

[0557] In some embodiments, the subject is diagnosed with or at risk of developing a tau protein-related disease by any of the methods described above, hi some embodiments, the subject is diagnosed with or at risk of developing a tauopathy selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD).

[0558] In another aspect, provided herein is a method of reducing pathological human tau in a sample. The method comprises contacting the sample with a bispecific conjugate according to any of the embodiments described above. In some embodiments, the pathological human tau is from a tauopathy selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD). In some embodiments, the pathological human tau is tau type 1A, IB, 11A or MB, misordered tau, mis-disordered tau, sarkosyl-insoluble tau, extracellular tau deposits, tau aggregates, paired helical fibrils, neurofibrillary pathology, or hyperphosphorylated forms of truncated tau or full-length tau. In some embodiments, the pathological human tau is hyperphosphorylated sarkosyl-insoluble tau. In some embodiments, the sample is a brain sample, a cerebrospinal fluid sample or a blood sample. In some embodiments, detecting comprises generating a readout comprising information about the presence of pathological human tau in the sample, hi some embodiments, the sample is from a subject and the method further comprises diagnosing whether the subject has or is likely to develop a tauopathy based on the readout.

[0559] In another aspect, provided herein is a method of reducing tau protein levels in a subject having or at risk of developing a tau protein-related disease, comprising administering to the subject a compound according to any of the embodiments described above or a pharmaceutical composition according to any of the embodiments described above, wherein: a) the level of non-phosphorylated tau protein, phosphorylated tau protein and / or hyperphosphorylated tau protein is reduced in the subject compared to the level in the subject prior to administration of the compound, and / or the level of pathological tau species is reduced in the subject compared to the level in the subject prior to administration of the compound.

[0560] In another aspect, provided herein is a method of preserving or increasing cognitive memory ability or slowing memory loss in a subject having or at risk of developing a tau protein-related disease, comprising administering to the subject a compound according to any of the embodiments described above or a pharmaceutical composition according to any of the embodiments described above.

[0561] In another aspect, provided herein is a method of inhibiting and / or reversing the propagation of tau aggregation in a subject having or at risk of developing a tau protein-related disease, comprising administering to the subject a compound according to any of the embodiments described above or a pharmaceutical composition according to any of the embodiments described above.

[0562] In another aspect, provided herein is a method of inhibiting and / or reversing tau seeding in a subject having or at risk of developing a tau protein-associated disease, comprising administering to the subject a compound according to any of the embodiments described above or a pharmaceutical composition according to any of the embodiments described above.

[0563] definition Unless otherwise defined, all terms, designations and other scientific or technical terms of the art used herein have the meaning commonly understood by those skilled in the art to which this application pertains. In some cases, commonly understood terms are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantially different meaning than that commonly understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methods by those skilled in the art.

[0564] Where a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, to one-tenth of the unit of the lower limit unless otherwise clearly dictated by context, as well as any other stated or intervening values ​​in that stated range, are encompassed within the scope of the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are encompassed within the scope of the disclosure, subject to any specific excluded limits in the stated ranges. Where the stated range includes one or both limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0565] Certain ranges are presented herein with numerical values ​​preceded by the term "about." The term "about" is used herein to provide literal support for the exact number it precedes, as well as a number that is near or approximately the number preceded by the term. In determining whether a number is near or approximately a specifically stated number, the near or approximately unstated number may be a number that provides the substantial equivalence of the specifically stated number in the context in which it is presented.

[0566] It is understood that certain features of the present disclosure, which are described for clarity in the context of separate embodiments, may also be provided in combination with a single embodiment. Conversely, various features of the present disclosure, which are described for simplicity in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments of the present disclosure are specifically encompassed in the present disclosure and disclosed herein as if each and every combination were individually and explicitly disclosed herein. In addition, all subcombinations of the various embodiments and elements thereof are specifically encompassed in the present disclosure and disclosed herein as if each and every subcombination were individually and explicitly disclosed herein. When ranges of values ​​are listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 ” is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 is intended to encompass.

[0567] "Alkyl" refers to a radical of a straight or branched chain saturated hydrocarbon group having the indicated number of carbon atoms. In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tertiary amyl (C5), and n-hexyl (C6).

[0568] "Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds at any position in the chain, which may be mono- or polysubstituted and mono-, di- or polyvalent. Examples of alkenyl groups include vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

[0569] "Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds at any position in the chain, which can be mono- or polysubstituted and mono-, di- or polyvalent. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and the like.

[0570] "Cycloalkyl" refers to any stable cyclic or polycyclic hydrocarbon group and may be saturated with any carbon atom, may be mono- or polysubstituted, and may be mono-, di- or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.

[0571] "Optionally" means that the subsequently described event or circumstance may occur, but need not occur, and the description includes the occurrence of the above described event or circumstance as well as the absence of the described event or circumstance.

[0572] "Substituted" means that any one or more hydrogen atoms at a particular atom are replaced with a substituent, including deuterium and hydrogen variants, so long as the valence of the particular atom is normal and the substituted compound is stable. If the substituent is keto (i.e., =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur in aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless specified, the type and number of substituents can be any based on chemical feasibility.

[0573] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 2 R, said group may be optionally substituted with up to two R groups, and R is selected independently of the definition of R at each occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0574] When the number of bonding groups is zero, for example -(A)0-, the bonding group is a single bond.

[0575] "Alkoxy" refers to any of the above alkyl groups having the specified number of carbon atoms attached through an oxygen bridge. 1~6 Alkoxy includes C1, C2, C3, C4, C5 and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentyloxy.

[0576] "Aryl" refers to a polyvalent unsaturated aromatic hydrocarbon substituent which may be mono- or polysubstituted, mono-, di- or polyvalent, and monocyclic or polycyclic (e.g., 1 to 3 rings, at least one of which is aromatic), which are fused together or covalently linked.

[0577] "Halo" or "halogen," by itself or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom.

[0578] "Haloalkyl" includes both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1~4)Alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Unless specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

[0579] "Heterocyclo" refers to a 3- to 10-membered non-aromatic ring or aromatic ring system having the indicated ring carbon atoms (e.g., 2-6 ring carbon atoms) and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("C 2~6 In heterocyclo groups containing one or more nitrogen atoms, the point of attachment may be at carbon or at the nitrogen atom, where valence permits. Heterocyclo groups are either monocyclic ("monocyclic heterocyclo"), or fused, bridged, or spiro ring systems, e.g., bicyclic systems (bicyclic heterocyclo"), and may be saturated or partially unsaturated. Heterocyclobicyclic ring systems contain one or more heteroatoms in one or both rings. "Heterocyclo" also includes ring systems in which a heterocyclic ring as defined above is fused to one or more carbocyclic groups, with the point of attachment being at either the carbocyclic or heterocyclic ring, or in which a heterocyclic ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being at the heterocyclic ring, in such cases the number of ring members continues to specify the number of ring members of the heterocyclic ring system.

[0580] "Nitrogen protecting group" refers to a protecting group that prevents side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0581] In some embodiments, a heterocyclo group is a 5-10 membered non-aromatic or aromatic ring system having the indicated ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclo group is a 5-6 membered non-aromatic or aromatic ring system having the indicated ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclo"). In some embodiments, a 5-6 membered heterocyclo has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclo has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclo has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0582] Representative 3-membered heterocyclo groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Representative 4-membered heterocyclo groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Representative 5-membered heterocyclo groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Representative 5-membered heterocyclo groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Representative 5-membered heterocyclo groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Representative 6-membered heterocyclo groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Representative 6-membered heterocyclo groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Representative 6-membered heterocyclo groups containing two heteroatoms include, but are not limited to, triazinanyl. Representative 7-membered heterocyclo groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Representative 8-membered heterocyclo groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Representative 5-membered heterocyclo groups (also referred to as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Representative 6-membered heterocyclo groups (also referred to as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0583] The term "pharmaceutically acceptable salt" means a salt that is not harmful to mammals, especially humans. Pharmaceutically acceptable salts can be formed using non-toxic acids or bases, including mineral acids or inorganic bases, or organic acids or bases. Examples of pharmaceutically acceptable salts include metal salts formed with aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc., and organic salts formed with lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, etc. Pharmaceutically acceptable salts also include acid addition salts and base addition salts.

[0584] The term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable substance, composition or vehicle, such as saline, liquid or solid fillers, diluents, solvents or encapsulating materials. Examples of pharmaceutically acceptable excipients include water, saline, normal saline or phosphate buffered saline (PBS), Sodium Chloride Injection, Ringer's Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringer's Injection.

[0585] "Effective amount" means a sufficient amount of a drug or agent to achieve the desired effect without toxicity. In the oral formulation of the present invention, an "effective amount" of one active agent in the composition means the amount necessary to achieve the desired effect when combined with another active agent in the composition. The effective amount varies for each individual and depends on the age and general condition of the recipient, as well as the specific active agent.

[0586] The term "solvate" refers to a solvent-containing compound formed by the association of one or more solvent molecules with the compound of the present invention. Solvates include, for example, monosolvates, disolvates, trisolvates and tetrasolvates. Solvates also include hydrates. The term "hydrate" refers to a compound or its salt that further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. Hydrates include monohydrates, dihydrates, trihydrates, tetrahydrates, etc.

[0587] The term "effective dose" refers to an amount of a compound or composition that has a target effect. For example, in some embodiments, an effective dose can refer to an amount of a compound or composition that enables tau imaging.

[0588] The term "tau imaging" refers to imaging of tau protein accumulation in the brain, which can be performed by positron emission tomography (PET), fluorescence microscopy, multiphoton imaging, two-photon imaging, near-infrared fluorescence imaging, autoradiography, and single-photon emission computed tomography (SPECT).

[0589] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting progression of a disease. In some embodiments, treatment is administered after one or more signs or symptoms of a disease have occurred or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject before symptoms develop (e.g., in light of a history of the condition or in light of a known genetic predisposition). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0590] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the embodiments listed below, their combination with other chemical synthetic methods, and equivalent alternatives known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0591] Compound synthesis: The following synthetic procedures are provided as examples that will enable one of ordinary skill in the art to synthesize compounds of the present disclosure.

[0592] Compounds of formula (I)

[0593] [ka]

[0594] Compounds of general formula (I) are prepared as described in the following scheme:

[0595] [ka]

[0596] Compound of formula (II)

[0597] [ka]

[0598] Compounds of general formula (II) are prepared as described in the following scheme:

[0599] [ka]

[0600] Compound of formula (III)

[0601] [ka]

[0602] Compounds of general formula (III) are prepared as described in the following scheme:

[0603] [ka]

[0604] Compound of formula (IV)

[0605] [ka]

[0606] Compounds of general formula (IV) are prepared as described in the following scheme:

[0607] [ka]

[0608] Compound of formula (V)

[0609] [ka]

[0610] Compounds of general formula (V) are prepared as described in the following scheme:

[0611] [ka]

[0612] Compound of formula (VI)

[0613] [ka]

[0614] Compounds of general formula (VI) are prepared as described in the following scheme:

[0615] [ka]

[0616] Other compounds within the scope of the disclosure are synthesized by methods such as these and by analogy with the methods described in the Examples below. Additional synthetic methods can be found in WO2019214681, WO2018102067, and WO2019014429, all of which are incorporated herein by reference in their entirety.

[0617] Treatment Method The compounds of the present disclosure are administered to a subject to treat a disorder or disease associated with tauopathy, accumulation of tau protein aggregates and / or neurofibrillary tangles. Tauopathy includes Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Parkinson's disease (PD), Creutzfeldt-Jakob disease, dementia pugilistica, Down's syndrome, Gerstmann-Straussler-Scheinker disease, British dementia, Danish dementia, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Parkinsonism dementia complex of Guam, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, calcification, and the like. The tauopathy may include diffuse neurofibrillary tangle disease with glaucoma, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallidopontonigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle-predominant dementia, white matter tauopathy with globular glial inclusions, frontotemporal dementia, postencephalitic parkinsonism, parkinsonism linked to chromosome 17, and myotonic dystrophy. In some embodiments, the tauopathy is Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD).

[0618] A. Administration The pharmaceutical compositions of the present invention can be formulated in a desired dosage with appropriate pharma- ceutically acceptable excipients and then administered orally, parenterally, intracisternally, intraperitoneally, intrathecally, intraventricularly, topically, bucally, etc., to humans and other animals, depending on the disease or condition to be treated.

[0619] In certain embodiments, pharmaceutical compositions comprising compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg in one or more administrations over a period of one or more days. In some embodiments, the effective amount per administration ranges from about 0.001 mg / kg to about 200 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, one or more times per day to achieve the desired treatment and / or prophylactic effect. In some embodiments, the compounds described herein are in a dosage sufficient to deliver from about 0.001 mg / kg to about 200 mg / kg, from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, from about 0.1 mg / kg to about 40 mg / kg, from about 0.5 mg / kg to about 30 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 25 mg / kg of subject body weight per day, one or more times per day, to obtain the desired treatment and / or prophylactic effect. The desired dosage may be delivered three times per day, twice per day, once per day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In some embodiments, the dosage is delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations). In some embodiments, the compositions described herein are administered at a dose below the dose at which the agent causes non-specific effects.

[0620] In some embodiments, at least one additional therapeutic agent is administered to the subject, hi some embodiments, the additional therapeutic agent is a neurological drug, an anti-tau antibody, a tau inhibitor, an anti-amyloid beta antibody, a beta-amyloid aggregation inhibitor, an anti-BACE1 antibody, or a BACE1 inhibitor.

[0621] In some embodiments, the subject is diagnosed with or at risk of developing a tau protein-related disease, hi some embodiments, the subject is diagnosed with or at risk of developing a tauopathy selected from the group consisting of Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD).

[0622] B. Composition The pharmaceutical compositions described herein can be prepared by methods generally known in the art of pharmacology.In general, such methods include combining the compounds disclosed herein with carriers and / or one or more other accessory ingredients, and then shaping and / or packaging the product into the desired single or multiple dose units.

[0623] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as single unit doses and / or as multiple single unit doses.As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[0624] Pharmaceutically acceptable excipients used in the preparation of pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, stabilizers, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may also be present in the composition.

[0625] Suitable diluents include calcium carbonate, sodium carbonate, calcium phosphate, calcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0626] Suitable granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0627] C. Kit In some embodiments, the kits described herein further include instructions for using the kit. The kits described herein may also include information as required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kits and instructions provide treatment of a disease (e.g., a neurological disorder, a neurodegenerative disease, or a tauopathy) in a subject in need thereof. In some embodiments, the kits and instructions provide prevention of a disease (e.g., a neurological disorder, a neurodegenerative disease, or a tauopathy) in a subject in need thereof. In certain embodiments, the kits and instructions provide reduction of risk of onset of a disease (e.g., a neurological disorder, a neurodegenerative disease, or a tauopathy) in a subject in need thereof. In some embodiments, the kits and instructions provide promotion of degradation of tau protein in a subject or cell. In some embodiments, the kits and instructions provide diagnosis of a neurological disorder in the central nervous system (e.g., through the use of a radiolabeled compound of the present disclosure). In some embodiments, the kits and instructions provide for imaging and / or detection of neurological disorders in the central nervous system (e.g., through the use of radiolabeled compounds of the present disclosure). In some embodiments, the kits and instructions provide for imaging and / or detection of pathological aggregation of tau protein in the central nervous system (e.g., through the use of radiolabeled compounds of the present disclosure). The kits described herein may also include one or more additional pharmaceutical agents described herein as separate compositions.

[0628] D. Diagnosis The compounds of the present disclosure provide a method for detecting and imaging tau aggregates. This imaging can be performed by molecular imaging methods such as positron emission tomography (PET), fluorescence microscopy, multiphoton imaging, two-photon imaging, near-infrared fluorescence imaging, autoradiography, and single-photon emission computed tomography (SPECT). This imaging also includes in vitro, ex vivo, and in vivo imaging.

[0629] The imaging method includes administering a radiolabeled compound of the present disclosure to a subject and detecting the radiolabeled compound of the present invention in the subject. The present invention further provides a method for detecting tau aggregates in vitro or in vivo using a radiolabeled compound of the present disclosure as described herein. Thus, the present invention provides a tool useful for early detection and diagnosis of Alzheimer's disease. The present invention also provides a tool useful for monitoring the progression of Alzheimer's disease and the effectiveness of treatment.

[0630] Generally, the imaging method includes the steps of: (a) administering a radiolabeled compound of the present disclosure to a subject; (b) allowing the radiolabeled compound to bind to tau in the subject; (c) detecting a signal emitted by a radioisotope in the bound radiolabeled compound; (d) generating an image representative of the location and / or amount of the signal; and (e) determining the distribution and extent of tau aggregates in the subject.

[0631] The step of "administering" the radiolabeled compound of the present invention is often performed parenterally, such as intravenously. The intravenous route provides an efficient way to deliver the compound to the whole body of the subject. Intravenous administration does not result in substantial physical intervention or substantial health risks to the subject. The radiolabeled compound can be administered as a radiopharmaceutical composition. The administration step is not required for the complete definition of the imaging method of the present invention. Thus, the imaging method of the present invention can also be understood to include the above-defined steps (b) to (e) performed on a subject to whom the radiolabeled compound of the present invention has previously been administered.

[0632] The "detecting" step of the method includes detecting the signal emitted by the radioisotope in the radiolabeled compound of the present invention with the aid of a detector sensitive to that signal, such as a PET camera. This detecting step can also be understood as acquiring signal data.

[0633] The "generating" step of the method of the invention is performed by a computer which applies a reconstruction algorithm to the acquired signal data to obtain a data set. This data set is then manipulated to generate an image showing the location and / or amount of signal emitted by the radioisotope. The "determining" step can be performed by evaluating the generated image, since the signal emitted directly correlates with the amount of enzyme or neoplastic tissue.

[0634] The amount of isotopically labeled and radiolabeled derivatives of the Compound for administration to a 70 kg adult human one or more times per day may contain about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg of the Compound per unit dosage form.

[0635] All publications and patent applications mentioned in this disclosure are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0636] None of the references cited herein are admitted to constitute prior art. The discussion of the references states what their authors assert, and the inventors reserve the right to challenge the accuracy and pertinence of the cited documents. Although a number of sources of information, including scientific journal articles, patent documents, and textbooks, are referred to herein, it will be expressly understood that such references do not constitute an admission that any of these documents form part of the common general knowledge in the art.

[0637] The discussion of general methods presented herein is intended for illustrative purposes only. Other alternative methods and substitutes will be apparent to those of skill in the art upon review of this disclosure. They are intended to be included within the spirit and scope of this application.

[0638] [Example] The following examples are provided as further guidance to one of ordinary skill in the art and are not intended to limit the scope of the claimed invention in any way.

[0639] Generally, in the following examples, chemicals were purchased from Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other suppliers. 1 H NMR and 19 F NMR spectra were recorded on a Bruker AVIII 400 or Bruker AVIII 500 spectrometer.

[0640] LCMS measurements were performed on an Agilent 1200 HPLC / 6100 SQ System using the following conditions: Method A: Mobile phase: A: Water (0.01% TFA) B: CAN (0.01% TFA); Gradient phase: 5% B increasing to 95% B within 1.4 min, 1.6 min at 95% B (total runtime: 3 min); Flow rate: 2.3 mL / min; Column: SunFire C18, 4.6×50 mm, 3.5 μm; Column temperature: 50° C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API. Method B: Mobile phase: A: Water (10 mM NH4HCO3) B: Acetonitrile; Gradient phase: 5% B to 95% B in 1.5 min, 1.5 min at 95% B (total runtime: 3 min); Flow rate: 2.0 mL / min; Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Column temperature: 40 °C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API). Method C: Mobile phase: A: Water (10 mM NH4HCO3) B: Acetonitrile; Gradient phase: 5% B to 95% B in 1.5 min, 1.5 min at 95% B (total runtime: 3 min); Flow rate: 2.0 mL / min; Column: XBridge C18, 4.6 x 50 mm, 3.5 μm; Column temperature: 40 °C. Detectors: ADC ELSD, DAD (214nm and 254nm), MSD (ES-API).

[0641] Abbreviations: THF-tetrahydrofuran; DMF-N,N-dimethylformamide; EtOAc-ethyl acetate; DCM-dichloromethane; MeOH-methanol; EtOH-ethanol; TEA-triethanolamine; TFA-trifluoroacetic acid; RT-room temperature.

[0642] Further embodiments are disclosed in more detail in the following examples, which are provided as examples and are not intended to limit the scope of the disclosure or claims in any way. Although specific options of the disclosure have been disclosed, it should be understood that various modifications and combinations are possible and are contemplated to be within the true spirit and scope of the appended claims. Therefore, it is not intended to limit the precise summary and disclosure presented herein.

[0643] [Example 1] Synthesis of compound 159985

[0644] [ka]

[0645] (A) 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107.49 mg, 4.48 mmol) at 0° C. and stirred at RT for 1 h. 2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (2.65 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at RT for 14 h. The mixture was quenched by adding water at 0° C. and then extracted with EtOAc (200 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over Na2SO4, concentrated and purified by column chromatography (DCM:MeOH=10:1, Rf=0.7) to give 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (compound 159835, 603 mg, 0.70 mmol, 62% yield) as a pale yellow solid.

[0646] (B) tert-Butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate: A mixture of 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (200 mg, 0.23 mmol) and NaI (42 mg, 0.28 mmol) in CHCN (5 mL) was heated at 80 °C for 20 h. The residue was dissolved in DCM (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na2SO4, and concentrated to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (compound 159890, 185.1 mg, 0.23 mmol, 98% yield) as a yellow solid.

[0647] (C) tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate: A mixture of 2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (67 mg, 0.24 mmol), K2CO3 (51 mg, 0.37 mmol), and tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (100 mg, 0.12 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. The mixture was quenched with water and then extracted with DCM (200 mL). The organic layer was dried over Na2SO4, concentrated and purified by column chromatography on silica gel (DCM:MeOH=20:1, Rf=0.52) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (53 mg, 0.05 mmol, 45% yield) as a pale yellow solid.

[0648] (D) 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (52 mg, 0.05 mmol) in DCM (5 mL) was added TFA (0.08 mL, 1.08 mmol) and stirred at RT for 20 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (compound 159985, 41 mg, 0.05 mmol, 83% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6). MS (ESI) m / z 867 (M+H) + .

[0649] [Example 2] Synthesis of compound 160219

[0650] [ka]

[0651] (A) Compound 160087: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at 0° C. and stirred at room temperature for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1.86 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at room temperature for 14 h. The mixture was cooled to 0° C. and quenched with water. The precipitate was collected by filtration, washed with water and purified by column chromatography (DCM:MeOH=20:1, Rf=0.68) to give 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (595 mg, 0.86 mmol, 77% yield) as a yellow solid.

[0652] (B) Compound 160150: A mixture of 2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (595 mg, 0.86 mmol), NaI (156 mg, 1.04 mmol) in MeCN (15 mL) was heated at 80° C. for 17 h. The residue was dissolved in DCM (50 mL) and water (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (449 mg, 0.70 mmol, 81% yield) as a yellow solid.

[0653] (C) Compound 160159: A mixture of 2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (96 mg, 0.35 mmol), K2CO3 (96 mg, 0.70 mmol), tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (150 mg, 0.23 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. Water (10 mL) was added to the mixture and the resulting precipitate was collected by filtration. The residue was purified by column chromatography (DCM: EtOAc = 5: 2, Rf = 0.32) to give tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (121 mg, 0.15 mmol, 66% yield) as a yellow solid.

[0654] (D) Compound 160219: tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (120 mg, 0.15 mmol) in DCM (5 mL) was added with TFA (0.23 mL, 3.03 mmol) and the mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO3. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (21 mg, 0.03 mmol, 18% yield) as a yellow solid.

[0655] [Example 3] Synthesis of compound 160939

[0656] [ka]

[0657] (A) Compound 160812: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at 0° C. and stirred at RT for 1 h. 2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (1125 mg, 2.24 mmol) in DMF (5 mL) was added to the reaction mixture and stirred at RT for 22 h. The mixture was dissolved in water (50 mL) and DCM (50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na2SO4, concentrated and purified by column chromatography on silica gel (EtOAc:DCM=1:5, Rf=0.13) to give 2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (733 mg, 0.94 mmol, 84% yield) as a yellow solid.

[0658] (B) Compound 160829: A mixture of 2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (333 mg, 0.43 mmol) and NaI (109 mg, 0.73 mmol) in CH3CN (10 mL) was heated at 80° C. for 15 h. The solvent was removed under reduced pressure and the residue was redissolved in EtOAc. The mixture was washed with water (50 mL), brine (50 mL), dried over MgSO4, and concentrated to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethyl]carbamate (112 mg, 0.15 mmol, 36% yield) as a yellow solid.

[0659] (C) Compound 160889: A mixture of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-3a,7a-dihydro-1,3-benzothiazol-6-yl]-N-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethyl]carbamate (112 mg, 0.15 mmol), Cs2CO3 (149.09 mg, 0.46 mmol), and dimethyl 4-hydroxybenzene-1,2-dicarboxylate (64 mg, 0.30 mmol) in DMF (2 mL) was stirred at 50° C. for 1 h. The mixture was cooled to RT and water was added. The precipitate was collected by filtration and then purified by column chromatography (EtOAc:DCM=1:1, Rf=0.33) to give dimethyl 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (102 mg, 0.13 mmol, 82% yield) as a yellow solid.

[0660] (D) Compound 160901: To a solution of dimethyl 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (102 mg, 0.13 mmol) in EtOH (2 mL) was added NaOH (40 mg, 1 mmol) in water (2 mL). The resulting mixture was stirred at RT for 40 h. The reaction was diluted with EtOAc (10 mL) and acidified to pH 1 with 1N HCl solution. The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 4-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (86 mg, 0.13 mmol, 99.9% yield) as an orange solid.

[0661] (E) Compound 160939: A mixture of 4-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (122 mg, 0.18 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (32 mg, 0.20 mmol) in pyridine (5 mL) was heated at 120° C. for 19 h. The mixture was cooled to RT, diluted with DCM (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was collected, dried over Na2SO4, concentrated and purified by column chromatography (MeOH:DCM=1:10, Rf=0.73) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (49 mg, 0.06 mmol, 35% yield) as a yellow solid.

[0662] [Example 4] Synthesis of compound 161103

[0663] [ka]

[0664] (A) Compound 160891: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (500 mg, 1.12 mmol) in DMF (10 mL) was added NaH (107 mg, 4.48 mmol) at 0° C. and stirred at RT for 1 h. 5-(4-methylphenyl)sulfonyloxypentyl 4-methylbenzenesulfonate (1.85 g, 4.48 mmol) in DMF (10 mL) was added to the reaction mixture and stirred at RT for 17 h. The mixture was cooled to 0° C. and quenched with water. The resulting precipitate was collected by filtration and purified by column chromatography (DCM:EtOAc=4:1, Rf=0.7) to give 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl 4-methylbenzenesulfonate (604 mg, 0.88 mmol, 79% yield) as a yellow solid.

[0665] (B) Compound 160938: A mixture of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (122 mg, 0.58 mmol), Cs2CO3 (285 mg, 0.87 mmol), KI (5 mg, 0.03 mmol), and 5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentyl 4-methylbenzenesulfonate (200 mg, 0.29 mmol) in DMF (2 mL) was heated at 50° C. for 2 h. The reaction was quenched with water. The resulting solid was collected by filtration and washed with water to give dimethyl 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]benzene-1,2-dicarboxylate (206 mg, 0.28 mmol, 98% yield) as a yellow solid.

[0666] (C) Compound 160999: To a solution of dimethyl 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]benzene-1,2-dicarboxylate (100 mg, 0.14 mmol) in EtOH (2 mL) was added NaOH (110 mg, 2.76 mmol) in water (2 mL) and stirred at RT for 40 h. The reaction was neutralized to pH 1 with 1N HCl solution. The precipitate was collected by filtration and washed with water to give 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]phthalic acid (93 mg, 0.13 mmol, 97% yield) as a yellow solid.

[0667] (D) Compound 161054: A mixture of 4-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentoxy]phthalic acid (93 mg, 0.13 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (48 mg, 0.29 mmol) in pyridine (3 mL) was heated at 120° C. for 40 hours. Water was then added to the mixture. The precipitate was collected by filtration and purified by column chromatography (DCM:EtOAc=4:1, Rf=0.28) to give tert-butyl N-[5-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxypentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (61 mg, 0.08 mmol, 58% yield) as a yellow solid.

[0668] (E) Compound 161103: To a solution of tert-butyl N-[5-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxypentyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (61 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.12 mL, 1.55 mmol) and stirred at RT for 6 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[5-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]pentoxy]isoindole-1,3-dione (44 mg, 0.06 mmol, 80% yield) as a yellow solid.

[0669] [Example 5] Synthesis of compound 160273

[0670] [ka]

[0671] (A) Compound 160210: A mixture of 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (95 mg, 0.37 mmol), K2CO3 (101 mg, 0.73 mmol), tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 0.24 mmol) in DMF (5 mL) was heated at 50° C. for 5 h. The mixture was quenched with water and extracted with DCM (200 mL). The organic layer was collected, dried over Na2SO4, concentrated and purified by column chromatography (DCM:MeOH=20:1, Rf=0.48) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (83 mg, 0.09 mmol, 36% yield) as a pale yellow solid.

[0672] (B) Compound 160273: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (83 mg, 0.09 mmol) in DCM (5 mL) was added TFA (0.13 mL, 1.74 mmol) and stirred at RT for 7 h. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 3-[6-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (73 mg, 0.08 mmol, 92% yield) as a yellow solid.

[0673] [Example 6] Synthesis of compound 160313

[0674] [ka]

[0675] (A) Compound 160284: A mixture of 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (58 mg, 0.22 mmol), K2CO3 (61 mg, 0.44 mmol), tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (95 mg, 0.15 mmol) in DMF (2 mL) was heated at 50° C. for 5 h. Water (10 mL) was added to the mixture. The resulting precipitate was collected by filtration and then purified by column chromatography (DCM:MeOH=20:1, Rf=0.52) to afford tert-butyl N-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (57 mg, 0.07 mmol, 50% yield) as a yellow solid.

[0676] (B) Compound 160313: To a solution of tert-butyl N-[2-[2-[[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (54 mg, 0.07 mmol) in DCM (5 mL), TFA (0.11 mL, 1.39 mmol) was added and the mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and neutralized to pH 8 with saturated NaHCO3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 3-[6-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (39 mg, 0.05 mmol, 77% yield) as a yellow solid.

[0677] [Example 7] Synthesis of compound 162640

[0678] [ka]

[0679] Compound 162640 was synthesized according to a similar method to Example 6. 1H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.01-8.05 (m, 4H), 7.72 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 9.7 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 7.05-7.09 (m, 2H), 6.81-6.85 (m, 2H), 6.61 (t, J = 5.8 Hz, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.19-4.27 (m, 4H), 3.79-3.85 (m, 7H), 3.66 (t, J = 5.8 Hz, 3H), 3.48-3.54 (m, 3H), 2.85-2.93 (m, 1H), 1.92-1.99 (m, 1H).

[0680] [Example 8] Synthesis of compound 162842

[0681] [ka]

[0682] Compound 162842 was synthesized according to a similar method to Example 6. 1H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.40 (s, 1H), 8.13 (d, J = 6.6 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.89 (dd, J = 8.9, 2.5 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 5.06 (dd, J = 13.2, 5.1 Hz, 1H), 4.35-4.38 (m, 2H), 4.32 (d, J = 17.2 Hz, 1H), 4.28 (dd, J = 8.2, 4.5 Hz, 2H), 4.20 (d, J = 17.2 Hz, 1H), 3.96-3.99 (m, 2H), 3.92-3.95 (m, 2H), 3.08 (s, 7H), 2.85-2.93 (m, 1H), 2.26-2.37 (m, 2H), 1.91-1.98 (m, 2H).

[0683] [Example 9] Synthesis of compound 162903

[0684]

change

[0685] Compound 162903 was synthesized by the same method as in Example 6. 1H NMR (600 MHz, DMS-d6) δ 10.97 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.9, 2.6 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.18-7.21 (m, 1H), 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.08 (dd, J = 13.4, 5.1 Hz, 1H), 4.38 (d, J = 17.2 Hz, 1H), 4.22-4.29 (m, 4H), 3.89 (dd, J = 9.2, 5.0 Hz, 3H), 3.11 (s, 3H), 2.56-2.63 (m, 1H), 2.33-2.40 (m, 1H).

[0686] [Example 10] Synthesis of compound 163123

[0687] [ka]

[0688] Compound 163123 was synthesized according to a similar method to Example 6. 1H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.92-7.96 (m, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.13-7.18 (m, 2H), 7.07 (dd, J = 8.4, 2.1 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 5.07 (dd, J = 13.4, 5.2 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 4.22-4.27 (m, 6H), 3.85-3.91 (m, 5H), 3.10 (s, 7H), 2.85-2.96 (m, 1H), 2.55-2.63 (m, 2H), 2.31-2.42 (m, 2H).

[0689] [Example 11] Synthesis of compound 163365

[0690] [ka]

[0691] Compound 163365 was synthesized according to a similar method to Example 6. 1H NMR (600 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.09 (s, 1H), 7.96 (dd, J = 8.9, 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.7, 2.2 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 5.07 (dd, J = 13.3, 5.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.22-4.28 (m, 5H), 3.86-3.91 (m, 3H), 3.10 (s, 5H), 2.84-2.94 (m, 2H). [Example 12] Synthesis of compound 161247

[0692]

change

[0693] (A) Compound 161084: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (200 mg, 0.45 mmol) in DMF (3 mL) was added NaH (32 mg, 1.34 mmol) at 0° C. The resulting mixture was stirred at RT for 1 h. 2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (454 mg, 0.90 mmol) was added to the reaction mixture and stirred at RT for 22 h. The mixture was quenched with water. The precipitate was collected by filtration and purified by column chromatography (EtOAC:DCM=2:3, Rf=0.48) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (235 mg, 0.30 mmol, 67% yield) as a yellow solid.

[0694] (B) Compound 161112: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[tert-butyl-(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (235 mg, 0.30 mmol) in THF (5 mL) was added dropwise a 1M solution of TBAF in THF (1.81 mL, 1.81 mmol). The reaction mixture was stirred at RT for 7 h. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (100 mL). The mixture was washed with water (100 mL) and brine (100 mL). The organic layer was collected, dried over Na2SO4, and concentrated to give tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 0.30 mmol, 99.7% yield) as a yellow solid.

[0695] (C) Compound 161181: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (120 mg, 0.18 mmol) in THF (3 mL) was added NaH (9 mg, 0.36 mmol) at 0° C. and stirred for 30 min. Then tert-butyl 2-bromoethanoate (0.08 mL, 0.54 mmol) was added and the mixture was heated at 50° C. for 8 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography (EtOAc:DCM=2:3, Rf=0.35) to give tert-butyl 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate (84 mg, 0.11 mmol, 60% yield) as a yellow solid.

[0696] (D) Compound 161218: A mixture of tert-butyl 2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate (84 mg, 0.11 mmol) and TFA (0.12 mL, 1.61 mmol) in DCM (2 mL) was stirred at RT for 23 h. The mixture was acidified to pH 1 with 1N HCl solution. The mixture was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give 2-[2-[2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoic acid (60 mg, 0.10 mmol, 89% yield) as a yellow solid.

[0697] (E) Compound 161247: A mixture of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-hydroxy-pyrrolidine-2-carboxamide (45 mg, 0.11 mmol), 2-[2-[2-[2-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy ... The mixture was diluted with DCM, washed with water and brine, dried over Na2SO4, concentrated and purified by column chromatography on NH silica gel (MeOH:DCM=97:3, Rf=0.48) to give rac-(2R,4S)-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-hydroxy-1-[rac-(2R)-2-[2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxamide (16 mg, 0.01 mmol, 14% yield) as a yellow solid.

[0698] [Example 13] Synthesis of compound 160275

[0699] [ka]

[0700] (A) Compound 160161: To a solution of NaH (81 mg, 2.02 mmol) in DMF (1 mL) was added tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (300 mg, 0.67 mmol) in DMF (6 mL) at 0° C. and stirred at 25° C. for 30 min. 2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (794 mg, 1.34 mmol) in DMF (3 mL) was added to the reaction mixture and heated at 50° C. for 2 h. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by column chromatography (MeOH:DCM=3:97, Rf=0.3) to give 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (273 mg, 0.32 mmol, 47% yield) as a yellow oil.

[0701] (B) Compound 160244: A mixture of 2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (270 mg, 0.31 mmol) and NaI (56.18 mg, 0.37 mmol) in CH3CN (5 mL) was heated at 80° C. for 19 h. The mixture was diluted with DCM and extracted with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated to dryness to give tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (256 mg, 0.31 mmol, 99.9% yield) as an orange oil.

[0702] (C) Compound 160252: A mixture of 2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (102 mg, 0.37 mmol), K2CO3 (77 mg, 0.56 mmol) and tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (153 mg, 0.19 mmol) in DMF (4 mL) was heated at 50° C. for 18 h. The mixture was diluted with DCM (200 mL) and extracted with water. The organic layer was collected, dried over MgSO4, concentrated and purified by column chromatography (MeOH:DCM=5:95, Rf=0.3) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (61 mg, 0.06 mmol, 34% yield) as a yellow solid.

[0703] (D) Compound 160275: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (61 mg, 0.06 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.53 mmol) at 0° C. The resulting mixture was stirred at RT for 5 h. The solution was neutralized with saturated NaHCO3 solution at 0° C. and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by column chromatography on NH silica gel (MeOH:DCM=99:1, Rf=0.3) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (51 mg, 0.05 mmol, 86% yield) as a yellow solid.

[0704] [Example 14] Synthesis of compound 161177

[0705] [ka]

[0706] (A) Compound 161026: A mixture of dimethyl 4-hydroxyphthalate (139 mg, 0.62 mmol), Cs2CO3 (303 mg, 0.93 mmol), tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (200 mg, 0.31 mmol) in DMF (5 mL) was heated at 50° C. for 1 h. The mixture was quenched with water and extracted with DCM. The organic layer was dried over MgSO4, concentrated and purified by column chromatography (EtOAc:Hex=1:1, Rf=0.4) to give dimethyl 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (148 mg, 0.20 mmol, 66% yield) as a yellow solid.

[0707] (B) Compound 161083: To a solution of dimethyl 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (148 mg, 0.20 mmol) in MeOH (1 mL) and water (1 mL) was added LiOH (39 mg, 1.63 mmol). The reaction mixture was stirred at RT for 5 days. The solution was acidified to pH 4-5 with 1 N HCl. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (119 mg, 0.17 mmol, 84% yield) as a yellow solid.

[0708] (C) Compound 161115: A mixture of 4-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (119 mg, 0.17 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (31 mg, 0.19 mmol) in pyridine (2 mL) was heated at 120 °C for 2 days. The mixture was concentrated to dryness and purified by column chromatography (MeOH:DCM=5:95, Rf=0.3) to give tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (39 mg, 0.05 mmol, 29% yield) as a yellow solid.

[0709] (D) Compound 161177: To a solution of tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (39 mg, 0.05 mmol) in DCM (1 mL) was added TFA (1 mL, 13.06 mmol) at 0° C. The resulting mixture was stirred at RT for 2 h. The solution was neutralized with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by chromatography (MeOH:DCM=1:99, Rf=0.1) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (11 mg, 0.02 mmol, 31% yield) as a yellow solid.

[0710] [Example 15] Synthesis of compound 160383

[0711] [ka]

[0712] (A) Compound 160366: A mixture of 3-(6-hydroxy-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione (63 mg, 0.24 mmol), K2CO3 (51 mg, 0.37 mmol), tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (100 mg, 0.12 mmol) in DMF (2 mL) was heated at 50 °C for 3 h. The mixture was quenched with water, extracted with DCM (200 mL), dried over MgSO4, concentrated and purified by chromatography (MeOH:DCM=5:95, Rf=0.3) to give tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (26 mg, 0.03 mmol, 22% yield) as a yellow solid.

[0713] (B) Compound 160383: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1-oxo-3H-isoindol-5-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (26 mg, 0.03 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.53 mmol) at 0° C., and the mixture was stirred at RT for 3 h. The solution was neutralized with saturated NaHCO3 solution at 0° C., then extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by chromatography (MeOH:DCM=5:95, Rf=0.2) to give 3-[6-[2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione (9 mg, 0.01 mmol, 33% yield) as a yellow solid.

[0714] [Example 16] Synthesis of compound 160744

[0715] [ka]

[0716] (A) Compound 160690: To a solution of 2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-ol (400 mg, 1.15 mmol) in DMF (10 mL) was added NaH (184 mg, 4.59 mmol) at 0° C. and stirred at RT for 1 h. 2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (2 mL, 4.13 mmol) was added to the mixture and stirred at RT for 14 h under argon. The mixture was diluted with DCM (10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was collected, dried over Na2SO4, concentrated and purified by column chromatography (DCM:MeOH=50:1, Rf=0.29) to give 2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (520 mg, 0.68 mmol, 59% yield) as a pale yellow solid.

[0717] (B) Compound 160707: A mixture of 2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (520 mg, 0.68 mmol) and NaI (122 mg, 0.81 mmol) in CH3CN (6 mL) was heated at 80° C. for 5 h. Water was added to the mixture and it was extracted with DCM. The organic layer was washed with water (20 mL), brine (20 mL), dried over Na2SO4, concentrated and purified by chromatography (MeOH:DCM=1:50, Rf=0.39) to give 6-fluoro-5-[4-[6-[2-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]imidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (427 mg, 0.59 mmol, 87% yield) as a pale yellow solid.

[0718] (C) Compound 160744: A mixture of 2-[2,6-bis(oxo)piperidin-3-yl]-5-hydroxy-isoindole-1,3-dione (114 mg, 0.41 mmol), Cs2CO3 (202 mg, 0.62 mmol), and 6-fluoro-5-[4-[6-[2-[2-[2-[2-[2-(2-iodoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3,8a-dihydroimidazo[1,2-a]pyridin-2-yl]phenyl]-N,N-dimethyl-pyridin-2-amine (150 mg, 0.21 mmol) in DMF (3 mL) was heated at 50° C. for 20 h. The mixture was quenched with water and the resulting precipitate was collected by filtration. The residue was purified by column chromatography (MeOH:DCM=1:20, Rf=0.34) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (28 mg, 0.03 mmol, 15% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.28 (s, 1H), 8.23 ​​(d, J = 2.3Hz, 1H), 7.97 (d, J = 7.8, 2H), 7.87 (dd, J = 10.8, 8.4Hz, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.57 (d, J = 7.8Hz, 2H), 7.50 (d, J = 9.7 Hz, 1H), 7.43 (d, J = 2.3Hz, 1H), 7.34 (dd, J = 8.4, 2.3 Hz, 1H), 7.05 (dd, J = 9.7, 2.3 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 5.11 (dd, J = 12.9, 5.5 Hz, 1H), 4.25-4.32 (m, 2H), 4.06-4.14 (m, 2H), 3.74-3.79 (m, 4H), 3.47-3.63 (m, 18H), 3.06 (s, 6H), 2.80-2.96 (m, 2H).

[0719] [Example 17] Synthesis of compound 161111

[0720]

change

[0721] (A) Compound 160947: To a solution of 2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-ol (400 mg, 1.15 mmol) in dry DMF (8 mL), NaH (0.14 g, 3.44 mmol) was added at 0° C. and stirred at RT for 1 h. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (1.43 g, 3.44 mmol) was added to the mixture and stirred at the same temperature for 16 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, concentrated and purified by column chromatography on silica gel (EtOAc:DCM=1:5, Rf=0.33) to give 2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate (227 mg, 0.38 mmol, 33% yield) as an orange solid.

[0722] (B) Compound 160997: A mixture of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (161 mg, 0.77 mmol), Cs2CO3 (374.2 mg, 1.15 mmol), KI (6 mg, 0.04 mmol), and 2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate (226 mg, 0.38 mmol) in DMF (4 mL) was heated at 50 °C for 4 h. The mixture was quenched with water and the resulting precipitate was collected by filtration and washed with water to give dimethyl 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]benzene-1,2-dicarboxylate (212 mg, 0.34 mmol, 88% yield) as an orange solid.

[0723] (C) Compound 161006: To a solution of dimethyl 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoropyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]benzene-1,2-dicarboxylate (211 mg, 0.34 mmol) in MeOH (2 mL) was added NaOH (443 mg, 11.08 mmol) in water (2 mL) and stirred at RT for 5 days. The reaction was diluted with EtOAc (50 mL) and acidified to pH 1 with 1N HCl solution. The organic layer was washed with water (50 mL), brine (50 mL), dried over Na2SO4 and concentrated to give 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]phthalic acid (185 mg, 0.31 mmol, 92% yield) as a yellow solid.

[0724] (D) Compound 161111: A mixture of 4-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]phthalic acid (67 mg, 0.11 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (20 mg, 0.15 mmol) in pyridine (3 mL) was heated at 120° C. for 14 h. The solvent was removed under reduced pressure. The residue was redissolved in DCM and water was added. The resulting precipitate was collected by filtration and purified by column chromatography (MeOH:DCM=1:100, Rf=0.19) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[4-[6-(dimethylamino)-2-fluoro-pyridin-3-yl]phenyl]imidazo[1,2-a]pyridin-6-yl]oxyethoxy]ethoxy]isoindole-1,3-dione (18 mg, 0.02 mmol, 22% yield) as a yellow solid.

[0725] [Example 18] Synthesis of compound 161215

[0726] [ka]

[0727] (A) Compound 160806: To a solution of NaH (138 mg, 3.45 mmol) in DMF (2 mL) was added tert-butyl N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (500 mg, 1.15 mmol) in DMF (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 30 min. 2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethyl 4-methylbenzenesulfonate (954 mg, 2.30 mmol) in DMF (3 mL) was added to the reaction mixture and stirred at room temperature for 21 h. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by column chromatography (EtOAc:DCM=3:17, Rf=0.3) to give 2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (339 mg, 0.50 mmol, 44% yield) as a yellow solid.

[0728] (B) Compound 160814: A mixture of 2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethyl 4-methylbenzenesulfonate (339 mg, 0.50 mmol) and NaI (90 mg, 0.60 mmol) in MeCN (10 mL) was heated at 80° C. for 19 h. The mixture was added to water and extracted with EtOAc. The organic layer was washed with water (50 mL), brine (50 mL), dried over MgSO4, concentrated and purified by column chromatography (EtOAc:DCM=1:9, Rf=0.3) to give tert-butyl N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (197 mg, 0.31 mmol, 62% yield) as a yellow solid.

[0729] (C) Compound 161091: A mixture of dimethyl 4-oxobenzene-1,2-dicarboxylate (131 mg, 0.62 mmol), Cs2CO3 (305 mg, 0.93 mmol), tert-butyl N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-N-[2-(2-iodoethoxy)ethyl]carbamate (197 mg, 0.31 mmol) in DMF (5 mL) was heated at 50 °C for 1 h. The mixture was quenched with water and extracted with DCM. , dried over MgSO4, concentrated and purified by column chromatography (EtOAc:Hexanes=1:1, Rf=0.3) to give dimethyl 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (147 mg, 0.21 mmol, 66% yield) as a yellow solid.

[0730] (D) Compound 161105: To a solution of dimethyl 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]benzene-1,2-dicarboxylate (147 mg, 0.21 mmol) in MeOH (2 mL), NaOH (66 mg, 1.65 mmol) in water (2 mL) was added and the mixture was stirred at room temperature for 3 days. The reaction was neutralized to pH 1 with 1N HCl solution. The precipitate was collected by filtration and washed with water to give 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (135 mg, 0.20 mmol, 96% yield) as a white solid.

[0731] (E) Compound 161183: A mixture of 4-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]phthalic acid (135 mg, 0.20 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (49 mg, 0.29 mmol) in pyridine (2 mL) was heated at 120 °C for 20 h. The mixture was concentrated to dryness and purified by column chromatography on NH silica gel (MeOH:DCM=1:99, Rf=0.1) to give tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (47 mg, 0.06 mmol, 30% yield) as a yellow solid.

[0732] (F) Compound 161215: tert-butyl N-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethyl]-N-[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]carbamate (47 mg, 0.06 mmol) in DCM (1 mL) was added with TFA (1 mL, 13 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. The solution was neutralized with saturated NaHCO3 solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by chromatography on NH silica gel (MeOH:DCM=1:99, Rf=0.1) to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[[6-fluoro-5-[4-(6-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]isoindole-1,3-dione (17 mg, 0.02 mmol, 38% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.28 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.70 (dd, J = 10.3, 8.2 Hz, 1H), 7.46-7.52 (m, 3H), 7.43 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.2, 2.3 Hz, 1H), 7.14 (t, J = 5.7 Hz, 1H), 7.01 (dd, J = 10.3, 2.2 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 5.08 (dd, J = 13.1, 5.3 Hz, 1H), 4.34-4.28 (m, 2H), 3.75-3.83 (m, 5H), 3.62 (t, J = 5.5 Hz, 2H), 3.39-3.44 (m, 2H), 2.77-2.91 (m, 1H), 2.49-2.66 (m, 2).

[0733] [Example 19] Synthesis of compound 161409

[0734] [ka] Compound 161409 could be synthesized according to a similar method to Example 19. 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.27 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.71 (dd, J = 10.2, 8.6 Hz, 1H), 7.45-7.53 (m, 3H), 7.41 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.6, 2.1 Hz, 1H), 7.13 (t, J = 5.3 Hz, 1H), 7.00 (dd, J = 9.7, 1.6 Hz, 1H), 6.49 (d, J = 9.2 Hz, 1H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.24-4.29 (m, 2H), 3.77 (s, 3H), 3.72-3.76 (m, 2H), 3.44-3.58 (m, 20H), 3.34-3.41 (m, 3H), 2.77-2.91 (m, 2H).

[0735] [Example 20] Synthesis of compound 161104

[0736] [ka]

[0737] (A) Compound 160937: To a solution of tert-butyl 2-[4-[6-[(2-methylpropan-2-yl)oxycarbonylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]-pyridine-1-carboxylate (500 mg, 1.03 mmol) in DMF (10 mL) was added NaH (49 mg, 1.23 mmol) at 0° C. and stirred at RT for 30 min. 2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (789 mg, 1.34 mmol) was added to the reaction mixture and stirred at RT for 6 h. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The organic layer was washed with brine, dried over MgSO4, concentrated and purified by column chromatography (EtOAc:DCM=1:4, Rf=0.33) to give tert-butyl 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (280 mg, 0.31 mmol, 30% yield) as a pale yellow oil.

[0738] (B) Compound 160987: A solution of dimethyl 4-hydroxybenzene-1,2-dicarboxylate (130.05 mg, 0.62 mmol), Cs2CO3 (303 mg, 0.93 mmol), and tert-butyl 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (280 mg, 0.31 mmol) in DMF (3 mL) was heated at 50° C. for 3 h. The mixture was quenched with water and the resulting precipitate was collected by filtration. The solid was then purified by column chromatography (EtOAc:DCM=4:1, Rf=0.32) to give dimethyl 4-[2-[2-[2-[2-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (98 mg, 0.10 mmol, 34% yield) as a pale yellow oil.

[0739] (C) Compound 161004: To a solution of dimethyl 4-[2-[2-[2-[2-[2-[2-[2-[(2-methylpropan-2-yl)oxycarbonyl-[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]benzene-1,2-dicarboxylate (98 mg, 0.10 mmol) in EtOH (5 mL) was added NaOH (33 mg, 0.83 mmol) in water (5 mL) and stirred at RT for 4 days. The reaction was diluted with DCM (10 mL) and acidified to pH 1 with 1N HCl solution. The organic layer was washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to dryness to give 4-[2-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (79 mg, 0.10 mmol, 93% yield) as a pale yellow solid.

[0740] (D) Compound 161045: A mixture of 4-[2-[2-[2-[2-[2-[2-[2-[[5-[4-[1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolo[2,3-c]pyridin-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phthalic acid (79 mg, 0.10 mmol) and 3-aminopiperidine-2,6-dione HCl (18 mg, 0.11 mmol) in pyridine (3 mL) was heated at 120° C. for 42 hours. The solvent was removed under reduced pressure. The residue was redissolved in DCM (10 mL), washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (MeOH:DCM=1:19, Rf=0.3) to give tert-butyl 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (22 mg, 0.02 mmol, 25% yield) as a yellow solid.

[0741] (E) Compound 161104: To a solution of tert-butyl 2-[4-[6-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2,6-bis(oxo)piperidin-3-yl]-1,3-bis(oxo)isoindol-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]pyridin-3-yl]phenyl]pyrrolo[2,3-c]pyridine-1-carboxylate (22 mg, 0.02 mmol) in DCM (3 mL) was added TFA (0.03 mL, 0.36 mmol) and the mixture was stirred at RT for 42 h. The mixture was neutralized to pH 8 with saturated NaHCO3 and extracted with DCM (10 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give 2-[2,6-bis(oxo)piperidin-3-yl]-5-[2-[2-[2-[2-[2-[2-[2-[[5-[4-(1H-pyrrolo[2,3-c]pyridin-2-yl)phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindole-1,3-dione (15 mg, 0.02 mmol, 73% yield) as a yellow solid.

[0742] [Example 21] Synthesis of compound 160624

[0743] [ka]

[0744] Compound 160557: A mixture of 3-(6-oxidanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (169 mg, 0.65 mmol), Cs2CO3 (317 mg, 0.97 mmol), tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (209 mg, 0.32 mmol) in DMF (5 mL) was heated at 50 °C for 1 h. The mixture was quenched with water, extracted with DCM, dried over MgSO4, concentrated and purified by column chromatography (solvent gradient 0% to 3% MeOH in DCM, Rf=0.2) to give tert-butyl (5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)(2-(2-(3-(5-hydroxy-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)ethoxy)ethyl)carbamate (68 mg, 0.09 mmol, 27% yield) as a yellow solid.

[0745] Compound 160624: To a solution of tert-butyl (5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)(2-(2-(3-(5-hydroxy-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)ethoxy)ethyl)carbamate (68 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL, 13.06 mmol) at 0° C. and stirred at room temperature for 6 h. The solution was neutralized with saturated NaHCO3 solution at 0° C. and the solution was extracted with DCM. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness to give 1-(2-(2-((5-(4-(6-(dimethylamino)benzo[d]thiazol-2-yl)phenyl)pyridin-2-yl)amino)ethoxy)ethyl)-3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (51 mg, 0.07 mmol, 85% yield) as a yellow solid.

[0746] [Example 22] Synthesis of compound 162641

[0747] [ka]

[0748] Compound 162586: To a solution of tert-butyl N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]-N-[2-(2-iodanylethoxy)ethyl]carbamate (100 mg, 0.16 mmol) in DMF (5 mL) was added 3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)piperidine-2,6-dione (48 mg, 0.19 mmol) and KCO (101 mg, 0.31 mmol) and heated at 80 °C for 3 h. The mixture was diluted with DCM, washed with water and brine, dried over Na2SO4, concentrated and purified by column chromatography (MeOH:DCM=1:20, Rf=0.3) to give tert-butyl N-[2-[2-[3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-2,6-bis(oxidanylidene)piperidin-1-yl]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (70 mg, 0.09 mmol, 58% yield) as a yellow solid.

[0749] Compound 162641: tert-Butyl N-[2-[2-[3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-2,6-bis(oxidanylidene)piperidin-1-yl]ethoxy]ethyl]-N-[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]carbamate (70 mg, 0.09 mmol) in DCM (2 mL) was added with TFA (0.1 mL, 1.35 mmol) and stirred at room temperature for 20 hours. The mixture was neutralized to pH 8 with saturated NaHCO3 solution. The residue was dissolved in DCM (20 mL) and water (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated to give 3-(7-azanyl-3-oxidanylidene-1H-isoindol-2-yl)-1-[2-[2-[[2-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]-1,3-benzothiazol-6-yl]amino]ethoxy]ethyl]piperidine-2,6-dione (30 mg, 0.04 mmol, 46% yield) as a yellow solid.

[0750] [Example 23] Synthesis of compound 161598

[0751] [ka]

[0752] Compound 161444: To a solution of tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (200 mg, 0.45 mmol) in DMF (5 mL) was added NaH (43 mg, 1.79 mmol) at 0° C. and stirred at room temperature for 1 h. To the mixture was added 2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (681 mg, 1.34 mmol) and stirred at the same temperature for 24 h. The reaction was quenched by adding water. The resulting solid was collected by filtration and purified by column chromatography (EtOAc:DCM=7:3, Rf=0.4) to afford tert-butyl N-[2-[2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (252 mg, 0.32 mmol, 72% yield) as a yellow oil.

[0753] Compound 161467: To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl]-N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]carbamate (252 mg, 0.32 mmol) in THF (5 mL), TBAF (1 M in THF, 1.94 mL, 1.94 mmol) was added dropwise and stirred at room temperature for 19 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (50 mL). The mixture was washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. Concentration to dryness afforded tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (214 mg, 0.32 mmol, 99% yield) as a yellow oil.

[0754] Compound 161530: To a mixture of tert-butyl N-[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-N-[2-[2-[2-[2-(2-hydroxyethyloxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (214 mg, 0.32 mmol) and tert-butyl 2-bromanyl ethanoate (0.14 mL, 0.96 mmol) in THF (3 mL) was added NaH (19 mg, 0.80 mmol) at 0° C. and stirred at room temperature for 42 hours. The reaction was quenched by adding water. The mixture was diluted with DCM (50 mL), washed with water (50 mL) and brine (50 mL), dried over Na2SO4, concentrated to dryness and purified by column chromatography (EtOAc:Hex=1:1, Rf=0.35) to give tert-butyl 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate (130 mg, 0.17 mmol, 52% yield) as a yellow oil.

[0755] Compound 161586: To a solution of tert-butyl 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]-[(2-methylpropan-2-yl)oxycarbonyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoate (130 mg, 0.17 mmol) in DCM (2 mL) was added TFA (0.38 mL, 4.99 mmol) and stirred at room temperature for 22 h. The mixture was concentrated to dryness to give the TFA salt of 2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoic acid (179 mg, 0.29 mmol, >99% yield) as an orange oil.

[0756] Compound 161598: A mixture of (2S,4R)-1-[(2S)-2-azanyl-3,3-dimethyl-butanoyl]-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide (79 mg, 0.18 mmol), 2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy ... The mixture was dissolved in DCM, washed with water and brine, dried over anhydrous Na2SO4, concentrated and purified by column chromatography (MeOH:DCM=3:100, Rf=0.32) to give rac-(2R,4S)-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-1-[rac-(2R)-2-[2-[2-[2-[2-[2-[2-[[5-[4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]phenyl]pyridin-2-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxamide (16 mg, 0.01 mmol, 8% yield) as a yellow solid.

[0757] [Example 24] In vitro fluorescence-based recombinant tau binding assay (A) Expression and purification of human tau: 1 mM IPTG (Sangon Biotech, Cat. No. A100487) was used to induce the production of tau by bacteria (BL21, Invitrogen, Cat. No. C600003) transformed with full-length 2N4R tau expression plasmid. After 3 hours, the cell pellet was resuspended in lysis buffer (100 mM PIPES, 1 mM EGTA, 1 mM MgSO4, pH 6.8) and lysed by sonication followed by centrifugation (15,000 rpm, 15 min, 4°C). The supernatant was then placed in a boiling water bath for 20 min followed by centrifugation (15,000 rpm, 15 min, 4°C). The supernatant was applied to a Q-Sepharose® Fast Flow column (GE healthcare, Catalog No. 17-0510-01), the flow-through was applied to a SP-Sepharose® Fast Flow column (GE healthcare, Catalog No. 17-0729-01), and tau protein was eluted with elution buffer (100 mM PIPES, 1 M NaCl, 1 mM EGTA, 1 mM MgSO4, 0.2 M NaCl, pH 6.8). The collected tau-containing eluate fractions were pooled, concentrated, dialyzed against HEPES buffer (25 mM HEPES, 0.1 mM EDTA, 0.5 mM DTT, 100 mM NaCl, pH 7.2), and stored in small aliquots at -80°C until use. Protein concentration was determined by UV absorption.

[0758] (B) Preparation of heparin-induced aggregated tau (aTau): 2 μM tau prepared in 30 mM Tris-HCl, pH 7.5 buffer was incubated in a tube with 15 μM heparin (Sigma, Cat. No. H3149) at 37° C. for 24 hours.

[0759] (C) Fluorescence spectrum scanning assay of compounds: Compounds were dissolved in 100% DMSO, and 40 nM aTau was incubated with 10 μM of each compound in 2% DMSO in a 96-well plate (Corning, Cat. No. 3573) at 37° C. for 1 h. Compound emission and excitation were scanned by a microplate spectrometer (EnSpire 2300, PerkinElmer).

[0760] (D) In ​​vitro fluorometric aTau binding assay: 2 μM aTau was diluted to 0.04 μM in 30 mM Tris-HCl (pH 6.8) and then incubated with serially diluted compounds (three-fold serial dilutions, 10 μM to 0.00017 μM) in a 96-well plate (Corning, Cat. No. 3573) for 1 h at 37°C. The fluorescence intensity (excitation / emission = 370 / 500 nm) of APN-0729 was read on a microplate spectrometer (EnSpire 2300, PerkinElmer). The Kd values ​​of the compounds were calculated using the following equation: Y=B max ×X / (Kd+X), where X is the concentration of the compound; Y is the fluorescence signal of (compound+aTau)-(compound+DMSO); B max is the maximum signal. The results are shown in Table 2 below.

[0761] [Table 2]

[0762] (E) PBB5 competition assay: 2 μM aTau was diluted to 0.12 μM in mM Tris-HCl (pH 6.8) and then incubated with 0.1 μM 2-(4-(2-(methylamino)pyridin-5-yl)-1,3-butadien-1-yl)benzothiazol-6-ol (PBB5) and serially diluted compounds (three-fold serial dilutions, 10 μM to 0.00017 μM) in a 96-well plate (Corning, Cat. No. 3573) for 1 h at 37° C. The fluorescence intensity of PBB5 (excitation / emission=530 / 690 nm) was read on a microplate spectrometer (EnSpire 2300, PerkinElmer). The percentage of competition was calculated using the following equation: (Max-compound alone wells) / (Max-Min) x 100%, where Max = (Tau+PBB5) signal - (buffer+PBB5) signal; and Min = (buffer+PBB5) signal - (buffer+PBB5) signal.

[0763] IC of each compound 50 Values ​​were calculated using GraphPad Prism software using the "4 Parameter Logistic Model or Sigmoidal Dose-Response Model": Y=Bottom+(Top-Bottom) / (1+(IC50 / X)^HillSlope)

[0764] To investigate the tau-binding ability of the compounds, a fluorescence-based in vitro tau-binding assay was performed. All compounds retained tau-binding ability and competed with PBB5.

[0765] [Example 25] Cell-based tau binding assay (A) Preparation of mouse brain lysates as a source of tau seeds: Three-month-old WT and rTg4510 mice were sacrificed by cervical dislocation. Brains were rapidly removed from the skull, weighed, the cerebellum was discarded, and the remaining brain was dissected along the midline on ice. Half of each cerebrum was placed in a homogenization tube (MP Biomedicals) and kept on ice. Ice-cold homogenization buffer was added to a volume of 5 times the weight of the brain. The homogenate was vortexed for 40 seconds at a speed of 6 m / s using a FastPrep-24TM 5G (MP biomedicals), then centrifuged at 13,000×g for 15 minutes at 4°C (Eppendorf). The supernatant of the brain lysate was transferred to a new microcentrifuge tube and stored at -80°C.

[0766] Brain lysates were buffer exchanged from Tris-based buffer to PBS because the homogenization buffer caused minor toxicity to HEK cells. Brain lysates were thawed on ice. Sterile PBS was added to 2 ml centrifugal filter tubes (10K cutoff, Amicon) and then centrifuged at 4500×g for 2 min at 4°C to rinse the tubes. Thawed lysates were added into the filter tubes and filled up to 2 mL with sterile 1× PBS. The tubes were centrifuged at 4500×g for 60 min at 4°C. The PBS washing step was repeated. After the centrifugation step, 300 μL of supernatant at the bottom of the centrifuged tubes was collected and kept on ice. The remainder of the supernatant was repeatedly filled with buffer and centrifuged again for 20 min. The second collected supernatant was combined with the previous one. Protein concentration was measured by Bradford assay (Bio-Red). Buffer exchanged mouse brain lysates were diluted to 3mg / mL in sterile 1X PBS, aliquoted into 90μL and 180μL microcentrifuge tubes and stored at -80°C.

[0767] (B) Cell culture: Tau RD(LM)-eGFP HEK293 cells were cultured in two types of culture media. For cell maintenance, cells were cultured in DMEM / F-12 (Gibco) supplemented with 10% FBS (Gibco), 1% PS (Gibco), and 6 μg / mL puromycin (Gibco), and 1 × 10 cells were cultured in 6-well plates (Greiner). 6 Cells were cultured in DMEM / F-12 supplemented with 1.25% FBS, 1% PS, and 6 μg / mL puromycin (binding medium) and plated at 1.5 × 10 cells / well in poly-D-lysine precoated 96-well plates (BD Biosciences). Cells were passaged twice a week. For tau binding studies, cells were cultured in DMEM / F-12 supplemented with 1.25% FBS, 1% PS, and 6 μg / mL puromycin (binding medium) and plated at 1.5 × 10 cells / well in poly-D-lysine precoated 96-well plates (BD Biosciences). 4 Cells were plated per well.

[0768] (C) Compound treatment: Frozen mouse brain lysates were thawed on ice and diluted to 1 μg / μL in 1X PBS. The diluted brain lysates or 1X PBS were added into each well of the 96-well plate containing the cells cultured for 24 hours. After 24 hours of incubation, the culture medium was replaced with fresh binding medium. Three days after tau seeding, 10 mM compound stock solutions were serially diluted in half from 1000 nM to 500, 250, 125, 62.5, 31.25, 15.63, 7.8 nM in fresh binding medium, and the DMSO (Sigma) concentration was maintained at 0.1% in all wells. The medium in the 96-well plate was then replaced with medium containing various concentrations of compound. The plate was returned to the incubator for 2 hours and the medium was replaced with binding medium containing 8% NucRed 647 (Thermo Fisher) to stain nuclei for 30 minutes. Cells were fixed with 4% PFA (Electron Microscopy Sciences) for 20 min at RT and then exchanged into 1X PBS for imaging.

[0769] (D) Image acquisition and analysis: All images were taken with ImageXpress Micro Confocal (Molecular devices) using a 20X objective, and excitation / emission settings were set by DAPI, FITC20 & Cy5 channels for APN-0729, Tau-eGFP & Nucleus, respectively. All images were processed for tau binding analysis using a customized module of MetaXpress software (Molecular devices). This module allows to measure: (1) total cell number (= number of nuclei); (2) number of tau aggregates; (3) number of tau positive cells; (4) tau aggregate average area; (5) number of tau and compound double positive aggregates; (6) number of tau and compound double positive cells; (7) compound average intensity in tau aggregates; (8) tau and compound double positive area in tau aggregates.

[0770] [Example 26] Tau degradation assay (A). Cell-based model of tau inclusion formation: Brain lysates from 6-month-old rTg4510 mice were prepared as described in Example 26 above and used as a source of tau seeds. P301L-Tau-FL-GFP HEK293 cells are GFP-tagged HEK293 cells expressing full-length human tau T40 (2N4R) with the P301L mutation (P301L-Tau-FL-GFP). 1×10 6P301L-Tau-FL-GFP HEK293 cells were cultured in culture medium containing DMEM / F-12 (Gibco) supplemented with 10% fetal bovine serum (FBS) (Gibco), 1% penicillin-streptomycin (Gibco), and 0.5 mg / ml Geneticin (Thermo Fisher Scientific) for 24 h on 6-well plates to reach 70-90% confluency, indicating that the cells were ready for transfection. 50 μg of brain lysate from 6-month-old rTg4510 mice was diluted in 400 μL serum-free medium and mixed with 16 μL Lipofectamine 3000 reagent (Thermo Fisher Scientific) diluted in 400 μl serum-free medium. The mixture of rTg4510 brain lysate and Lipofectamine 3000 was incubated at room temperature for 25 min. The culture medium was removed, and then the mixed solution of rTg4510 lysate and Lipofectamine 3000 was added to the cells for transfection. The mixed solution was incubated at room temperature for 5 hours, and then the medium was replaced with 10% fetal bovine serum (FBS). After 2 days of incubation, tau aggregates (tau spots) were induced and images were acquired by ImageXpress Micro Confocal high content imaging system (Molecular Devices) as described in Example 52 above. Analysis was performed by two modules of MetaXpress software (Molecular Devices) customized for the analysis of aggregated tau. Output included cell number, number of tau spots, average intensity of tau spots, and average size of tau spots.

[0771] (B) Compound treatment: 100 μL of 3 × 10 tau aggregates prepared as described in step (A) above. 4The cells were plated on a 96-well plate (BD Biosciences) coated with poly-D-lysine and cultured for 24 hours. The compounds to be tested were dissolved in culture medium containing 0.1% DMSO. Each of the test compounds at concentrations of 1, 0.2, and 0.04 μM was added to the cells containing tau aggregates and incubated at 37° C. for 24 hours. After that, the culture medium was removed, the cells were washed with PBS solution, and then lysed using 30 μL of lysis buffer (PBS containing 0.3% Triton X-100 and 400 mM NaCl) at 4° C. for 1 hour, and then the cell lysate was diluted with 170 μl of PBS containing 400 mM NaCl. The cell lysate was filtered through a 0.45 μM filter plate (Pall) and applied to the tau aggregation assay.

[0772] (C). Control cell lysate: Control cell lysate was collected from non-seeded cells.

[0773] (D). ELISA-Based Tau Aggregation Assay: APNmAb005 ELISA kit for tau aggregation assay was designed and developed to detect abnormal tau aggregates in buffer solutions or cell lysates by using anti-tau APNmab005 as the capture and detection antibody. This antibody is a highly specific antibody that binds to human tau aggregates accumulated in mammalian cells. APNmAb005 is described in PCT Patent Application No. PCT / IB2020 / 057415, filed August 5, 2020, which is incorporated herein by reference.

[0774] 0.15 μg of APNmAb005 in 100 mM sodium carbonate buffer (pH 9.6) was coated on a high-binding polystyrene 96-well microplate (Greiner Bio-One) overnight at 4°C. The microplate was washed with PBS and then treated with Intercept (PBS) blocking buffer (LI-COR) for 2 hours at room temperature. The microplate was then washed with PBS, and then compound-treated cell lysates, prepared as described in step (C) above, were added into each well of the microplate and incubated for 2 hours at room temperature. The microplate was washed with PBS and then incubated with secondary antibody APNmAb005 conjugated to HRP for 3 hours at room temperature. The secondary antibody APNmAb005 conjugated to HRP was prepared using an HRP conjugation kit (Abcam, ab102890). The microplate was then washed with PBS and incubated with 100 μL of horseradish peroxidase (HRP) substrate at room temperature. After 20 min of incubation, the reaction was terminated by adding 100 μL of stop solution (Cell Signaling Technology). The optical density (OD) at 450 nm was measured using an EnVision microplate reader (PerkinElmer).

[0775] Figure 1 shows the degradation of tau aggregates measured by APNmAb005 ELISA assay. Treatment with 1 μM compound 162842 reduced the optical density (OD)450 value by 20% compared to vehicle, reflecting a reduction in tau aggregates.

[0776] Some embodiments of the compounds were evaluated in the tau degradation assay, and the results are summarized in Table 3.

[0777] [Table 3]

[0778] [Example 27] In vivo pharmacokinetic studies To determine whether compounds of the present disclosure can cross the blood-brain barrier (BBB), example compound 160313 was administered to mice (1 mg / kg, intravenously) in plasma and brain tissue pharmacokinetic studies.

[0779] Animal Care: Mice were housed in an animal room environment with 15 air changes / hour, 12 hours of light / day, 20°C-24°C temperature, and 40%-70% humidity. The test room was disinfected and cleaned before the start of the study, and the operating area was cleaned after each dosing or sampling during the study. All animals had free access to food and water during the study. Animals were provided with a Certified Rodent Diet and water ad libitum. The nutritional composition and contaminant levels of the food, as well as impurities and contaminants in the water, were monitored by a third party. The health status of the animals was assessed according to accepted animal care procedures and deemed suitable for experimental use.

[0780] Sample collection and processing: Approximately 110 μL of whole blood was collected from all animals by facial or cardiac puncture under isoflurane anesthesia at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing and placed into tubes containing potassium ethylenediaminetetraacetate (K2EDTA). Brain samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. Perfusion with pre-chilled saline was performed by cardiac puncture before collecting the brains. Plasma samples were obtained by centrifuging the blood samples at 2000 g for 5 minutes at 4° C. and transferring the supernatant to a new tube. All plasma and brain samples were stored at approximately −70° C. until analysis.

[0781] Bioanalytical method development: Compound concentrations in plasma and brain samples were determined using a method based on liquid chromatography with tandem mass spectrometry (LC-MS / MS).

[0782] Results: The PK parameters are summarized in Table 4. Compound 160313 could penetrate the BBB in a short time. The brain / plasma ratio is about 0.31.

[0783] [Table 4] (Appendix 1) Formulas I to VI: [ka] or a pharma- ceutically acceptable salt, enantiomer, non-enantiomer, tautomer, racemate, solvate, metabolic precursor, or prodrug thereof. [In the formula, L1 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L2 is substituted or unsubstituted C 1~50 is a hydrocarbon chain, Z is C or N and U is O, S or CH; K is CH or N, Q is CH or N, and K and Q are not both N; Each occurrence of R''' is H, OH, NH2, C 1~6 Alkyl, C 1~6 Alkylamino, C 1~6 independently selected from the group consisting of alkoxy and halogen, where k is 0, 1, 2 or 3; Each occurrence of R' is H, halogen, OH, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 alkoxy, where m is 0, 1, 2, 3, or 4; Each occurrence of R'' is H, halo, OH, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 3~6 Cycloalkylamino, C 3~6 Cycloalkyl and C 3~6 heterocycloalkyl, where n is 0, 1 or 2; J is for CR 6 or N, where X is CR 6 or N, Y is CR 6or N, and at least one of J, X, and Y is N, but J and Y are not simultaneously N, and X and Y are not simultaneously N; R 6 H, NH2, C 1~6 Alkyl and C 1~6 alkoxy; 1~6 Alkyl or C 1~6 Alkoxy is C 1~3 Alkyl, C 3~6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula I, L3 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R 3' is H or C 1~6 alkyl, Y1 is CH2 or [ka] V is N, and Z and U are not both heteroatoms; In formula II, each occurrence of R 2' is H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 m6 is 0, 1, 2, 3 or 4; Y1 is CH2 or [ka] V is N, and Z and U are not both heteroatoms; In formula III, V is N, and Z and U are not both heteroatoms; In formula IV, L3 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R 3' is H or C 1~6 alkyl, Y1 is CH2 or [ka] wherein V is N or NH, T is CH or N, and up to two of U, Z, V, and T contain heteroatoms; In formula V, each occurrence of R 2' is H, OH, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 m6 is 0, 1, 2, 3 or 4; Y1 is CH2 or [ka] wherein V is N or NH, T is CH or N, and up to two of U, Z, V, and T contain heteroatoms; In formula VI, V is N, T is CH or N, and up to two of U, Z, V and T contain heteroatoms. (Appendix 2) L2 is optionally substituted C 1~45 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 is an alkyl or nitrogen protecting group, Preferably, L2 is a substituted or unsubstituted C 5~40 is a hydrocarbon chain, Preferably, L2 is substituted or unsubstituted C 1~30 , C 1~24 Or C 1~20 A hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety; R a1 are independently hydrogen, substituted or unsubstituted C 1~6 is an alkyl or nitrogen protecting group, Preferably, L2 is unsubstituted C 1~26 , C 5~26 , C 5~20 , C 5~15 , C 15~20 Or C20~25 A hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain is -C(=O)-, -O-, or -NR a1 - is independently replaced by R a1 are independently hydrogen, substituted or unsubstituted C 1~6 is an alkyl or nitrogen protecting group; A compound described in Appendix 1. (Appendix 3) L2 is optionally substituted C 1~30 A hydrocarbon chain, wherein one or more of the chain atoms of the hydrocarbon chain is -O- or -NR a1 are independently replaced by R a1 are independently hydrogen, substituted or unsubstituted C 1~6 is an alkyl or nitrogen protecting group, Preferably, at least one chain atom of the hydrocarbon chain of L2 is -C(=O)-, -O-, -S-, -NR a1 R is independently replaced by -, -N=, or =N-; a1 are independently hydrogen, substituted or unsubstituted C 1~6 an alkyl or nitrogen protecting group, preferably replaced by -O-; A compound described in Appendix 1. (Appendix 4) L2 is selected from the group consisting of substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene, and combinations thereof; Preferably, L2 is selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof; A compound described in Appendix 1. (Appendix 5) Carbocyclylene or heterocyclylene [ka] 5. The compound according to claim 4, (Appendix 6) L2 is substituted or unsubstituted C 1~6 Alkylene, substituted or unsubstituted C 2~6 Alkenylene, substituted or unsubstituted C 2~6 Alkynylene, substituted or unsubstituted hetero C 1~6 Alkylene, substituted or unsubstituted hetero C 2~6 Alkenylene, substituted or unsubstituted hetero C 2~6 Alkynylene, substituted or unsubstituted C 3~6 The compound according to appendix 4, comprising at least one example selected from the group consisting of carbocyclylene, substituted or unsubstituted 3- to 6-membered heterocyclylene, substituted or unsubstituted phenylene, and substituted or unsubstituted 5- to 6-membered heteroarylene. (Appendix 7) The compound of claim 4, wherein L2 comprises at least one example selected from the group consisting of substituted or unsubstituted methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, -(CH2)2-O(CH2)2-, -OCH2-, -CHO-, -O(CH2)2-, -(CH2)2O-, -O(CH2)3-, -(CH2)3O-, -O(CH2)4-, -(CH2)4O-, -O(CH2)5-, -(CH2)5O-, -O(CH2)6-, -O(CH2)6O-, -NH-C(=O)-, and -C(=O)NH-. (Appendix 8) at least one chain atom of the hydrocarbon chain of L2 is independently replaced with a 6-membered heterocyclyl group in which 1 to 3 ring heteroatoms are selected from the group consisting of nitrogen and oxygen; Preferably, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with piperidine, piperazine or morpholine; Preferably, at least one chain atom of the hydrocarbon chain of L2 is independently replaced with an optionally substituted phenyl group. A compound described in Appendix 4. (Appendix 9) L2 is an unsubstituted hydrocarbon chain, optionally with one or more chain atoms of the hydrocarbon chain being -NR a1-R in each example is replaced independently by a1 are independently hydrogen, substituted or unsubstituted C 1~6 alkyl or nitrogen protecting group, or optionally two examples of R a1 The compound of claim 4, wherein, together with intervening atoms, forms a substituted or unsubstituted heterocyclic ring or a substituted or unsubstituted heteroaryl ring. (Appendix 10) At least one example of R a1 is hydrogen, substituted or unsubstituted C 1~6 The compound according to Appendix 9, which is an alkyl (e.g., substituted or unsubstituted methyl or ethyl), a nitrogen protecting group (e.g., benzyl, t-butyl carbonate, benzyl carbamate, 9-fluorenylmethyl carbonate, trifluoroacetyl, triphenylmethyl, acetyl or p-toluenesulfonamide). (Appendix 11) L2 [ka] and g is 1, 2, 3, 4, 5, or 6. (Appendix 12) L2 is the part -O-, [ka] , -NHC(=O)-, or -NH-. (Appendix 13) L2 [ka] wherein g is 1, 2, 3, 4, 5 or 6; f is 1, 2, 3, 4, 5 or 6; and h is 1, 2, 3, 4, 5 or 6. (Appendix 14) The compound of formula I has the formula I-1: [ka] 2. The compound according to claim 1, (Appendix 15) The compound of formula II has formula II-1: [ka] 2. The compound according to claim 1, (Appendix 16) The compound of formula III is represented by formula III-1: [ka] 2. The compound according to claim 1, (Appendix 17) The compound of formula IV has formula IV-1: [ka] 2. The compound according to claim 1, (Appendix 18) The compound of formula V is V-1: [ka] 2. The compound according to claim 1, (Appendix 19) The compound of formula VI is represented by formula VI-1: [ka] 2. The compound according to claim 1, (Appendix 20) The compound of formula I-1 is represented by formula 1, 5, 6, 8, 10 or 13: [ka] The compound according to claim 14, which is compound JPEG0007605504000182.jpg35137. (Appendix 21) The compound is of formula 1, R' is H, C 1~3 Haloalkyl or C 1~3 alkoxy and / or R″ is H, halo, OH, NH2, C 1~3 Alkoxy, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5Cycloalkylamino and C 3~5 heterocycloalkyl, and / or R''' is H, OH or halogen, and / or R 1' O, NH, [ka] and / or A is O, NH, [ka] and / or m2 is 2, 3, 4 or 6, and / or R 3' is H or C 1~3 The compound of claim 20, wherein the aryl group is alkyl. (Appendix 22) The compound is of formula 5, R 3' is H or C 1~3 alkyl and / or A is O, NH or [ka] and / or m4 is 0, 1, 2 or 3, and / or m5 is 0, 1, 2 or 3, and / or m3 is 1, 2, 3, 4, 5 or 6, and / or R 1' is O, NH or [ka] and / or R''' is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C3~5 The compound of claim 20, wherein the compound is a heterocycloalkyl. (Appendix 23) The compound is of formula 6, R 3' is H or C 1~3 alkyl and / or A is O, NH or [ka] and / or m2 is 1, 2, 3, 4, 5, 6 or 7, and / or R 1' is O, NH or [ka] and / or R''' is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 The compound of claim 20, wherein n is 0 or 1 and / or n is heterocycloalkyl. (Appendix 24) The compound is of formula 8, R 3' is H or C 1~3 alkyl and / or A is O, NH, [ka] and / or m2 is 1, 2, 3 or 4, and / or R 1' O, NH, [ka] and / or R''' is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, and / or k is 0 or 1, and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, and / or m is 0, 1 or 2, and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 and / or n is 0, 1, or 2. (Appendix 25) The compound is of formula 10, R 3' is H or C 1~3 alkyl and / or A is O, NH, [ka] and / or m5 is 0 or 1, and / or m4 is 0 or 1, and / or m3 is 1, 2, 3, 4 or 5, and / or R 1' O, NH, [ka] and / or R''' is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, and / or k is 0 or 1, and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, and / or m is 0 or 1, and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 The compound of claim 20, wherein n is 0 or 1 and / or n is heterocycloalkyl. (Appendix 26) The compound is of formula 13, R 3' is H or C 1~3 alkyl and / or A is O, NH, [ka] and / or m2 is 1, 2, 3 or 4, and / or R 1' O, NH, [ka] and / or R''' is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 The compound of claim 20, wherein the compound is a heterocycloalkyl. (Appendix 27) The compound of formula 1 is represented by formula 1-1: [ka] 21. The compound according to claim 20, (Appendix 28) The compound of formula 5 is represented by formula 5-1: [ka] 21. The compound according to claim 20, (Appendix 29) The compound of formula 6 is represented by formula 6-1: [ka] 21. The compound according to claim 20, (Appendix 30) R 3' is H or C 1~3 alkyl, A is O, NH, [ka] m2 is 1, 2, 3, 4, 5, 6, and 7; R 1' O, NH, [ka] and R' is H, C 1~3 Haloalkyl or C 1~3 Alkoxy, where R'' is H, F, Cl, OH, NH2, C 1~3 The compound according to claim 27, which is alkoxy, methylamino, dimethylamino, diethylamino, or cyclopropylamino. (Appendix 31) R 3' is H or C 1~3 alkyl, A is O, NH, [ka] m5 is 0 or 1, m4 is 0, 1, 2, 3 or 4, m3 is 1, 2, 3, 4, 5 or 6, R 1' O, NH, [ka] and R''' is H, OH, or C 1~3 Alkyl, C 1~3 Alkoxy or halogen, R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C1~3 Alkoxy, where R'' is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino and C 3~5 The compound of claim 28, wherein the compound is a heterocycloalkyl. (Appendix 32) R 3' is H or C 1~3 alkyl, A is O, NH, [ka] m2 is 1, 2, 3, 4, 5, 6 or 7; R 1' O, NH, [ka] and R''' is H, OH, or C 1~3 Alkyl, C 1~3 Alkoxy or halogen, R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, m is 0, 1, 2 or 3, and R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 The compound of claim 29, wherein the compound is a heterocycloalkyl. (Appendix 33) The compound of claim 20, wherein the compound is of formula 1, 5, 6, 8, 10, or 13, and K is CH and Q is N, or K is N and Q is CH, or both K and Q are CH. (Appendix 34) Formula 3: [ka] 16. The compound according to claim 15, (Appendix 35) R 2' H, OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 alkylamino or NH2, and / or m6 is 0, 1, 2 or 3, and / or R 1' is O or NH, and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy and / or R″ is H, halo, OH, NH2, C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 alkylamino and / or R''' is H, OH, C 1~3 Alkyl, C 1~3 35. The compound according to claim 34, wherein the aryl group is alkoxy or halogen. (Appendix 36) The compound of claim 34, wherein Z is C and U is O or S, or Z is N and U is CH, and / or K is CH and Q is N, or K is N and Q is CH, or both K and Q are CH. (Appendix 37) Equation 3-1: [ka] 35. The compound according to claim 34, (Appendix 38) R 2' H, OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 alkylamino or NH2, m6 is 0, 1, 2 or 3, R 1' O, NH, [ka] and R'' is H, halo, OH, NH2, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 The compound according to claim 37, which is alkylamino. (Appendix 39) Equation 15: [ka] 17. The compound according to claim 16, (Appendix 40) m2 is 1, 2, 3, 4, 5, 6 or 7, and / or R 1' O, NH, [ka] and / or R''' is H, OH, C 1~3 Alkyl, C 1~3 alkoxy or halogen, and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, m is 0, 1, 2 or 3, and / or R″ is H, halo, OH, NH2, C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 The compound of claim 39, wherein the compound is alkylamino. (Appendix 41) Formula 2, 7, 9, 11, 12 or 14: [ka] 18. The compound according to claim 17, (Appendix 42) The compound is of formula 2, R 3' is H or C 1~3 alkyl and / or A is O, NH, [ka] and / or m2 is 2, 3, 4, 5 or 6, and / or R 1' O, NH, [ka] and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R''' is H, OH, NH2, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 42. The compound according to claim 41, wherein the aryl group is alkoxy or halogen. (Appendix 43) The compound is of formula 7, R 3' is H or C 1~3 alkyl and / or A is O, NH, [ka] and / or m2 is 2, 3, 4, 5 or 6, and / or R 1' O, NH, [ka] and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 and / or m is 0, 1, 2, or 3. (Appendix 44) The compound is of formula 9, R 3' is H or C 1~3 alkyl and / or A is O, NH, [ka] and / or m2 is 2, 3, 4, 5 or 6, and / or R 1' O, NH, [ka] and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R''' is H, OH, NH2, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 42. The compound according to claim 41, wherein the aryl group is alkoxy or halogen. (Appendix 45) The compound is of formula 11, R 3' is H or C 1~3 alkyl and / or A is O, NH, [ka] and / or m2 is 2, 3, 4, 5 or 6, and / or R 1' O, NH, [ka] and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R''' is H, OH, NH2, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 42. The compound according to claim 41, wherein the aryl group is alkoxy or halogen. (Appendix 46) The compound is of formula 12, R 3' is H or C 1~3 alkyl, A is O, NH, [ka] m3 is 1, 2, 3, 4, 5 or 6, m4 is 0, 1, 2 or 3, m5 is 0, 1, 2 or 3, R 1' O, NH, [ka] and R'' is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5Heterocycloalkyl, where R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, m is 0, 1, 2 or 3, and R''' is H, OH, NH2, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 42. The compound according to claim 41, wherein the aryl group is alkoxy or halogen. (Appendix 47) The compound is of formula 14, R 3' is H or C 1~3 alkyl and / or A is O, NH, [ka] and / or m3 is 1, 2, 3, 4, 5 or 6, and / or m4 is 0, 1, 2, 3 or 4, and / or m5 is 0, 1, 2 or 3, and / or R 1' O, NH, [ka] and / or R″ is H, halo, OH, NH2, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Alkylamino, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 3~5 and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 alkoxy, m is 0, 1, 2 or 3, and / or R''' is H, OH, NH2, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 42. The compound according to claim 41, wherein the aryl group is alkoxy or halogen. (Appendix 48) Formula 4: [ka] 19. The compound according to claim 18, (Appendix 49) R 2' H, OH, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 alkylamino or NH2, and / or m6 is 0, 1, 2 or 3, and / or R 1' O, NH, [ka] and / or R' is H, halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl or C 1~3 Alkoxy, where R'' is H, halo, OH, NH2, C 1~3 Alkoxy, C 3~5 Cycloalkyl, C 3~5 Cycloalkylamino or C 1~3 alkylamino and / or R''' is H, OH, NH2, C 1~3 Alkyl, C 1~3 Alkylamino, C 1~3 49. The compound according to claim 48, wherein the aryl group is alkoxy or halogen. (Appendix 50) Equation 4-1: [ka] 49. The compound according to claim 48, (Appendix 51) Equation 16 or 17: [ka] 20. The compound according to claim 19, (Appendix 52) The compound of claim 51, wherein the compound is of formula 16, Z is C, U is O or S, and T is CH, or Z is N, U is CH, T is CH, Z is C, T is N, and U is CH. (Appendix 53) The compound of claim 51, wherein the compound is of formula 17, Z is C, U is O or S, and T is CH, or Z is N, U is CH, T is CH, Z is C, T is N, and U is CH. (Appendix 54) A compound according to Appendix 1, selected from the compounds listed in Table 1. (Appendix 55) A composition comprising a compound according to any one of claims 1 to 54 and a pharma- ceutically acceptable excipient. (Appendix 56) A method for aiding in the treatment of or treating a tauopathy in a subject, comprising administering to the subject an effective amount of a compound described in any one of appendices 1 to 54 or a composition described in appendices 55. (Appendix 57) Use of a compound according to any one of claims 1 to 54 or a composition according to claim 55 in the manufacture of a medicament for treating a tauopathy.

Claims

1. Formulas I to VI: 【Chemistry 1】 or a pharma- ceutically acceptable salt, enantiomer, tautomer, racemate, or solvate thereof. [In the formula, L 1 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; L 2 is substituted or unsubstituted C 1～50 a hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety, and R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group; Z is C or N and U is O, S or CH; K is CH or N, Q is CH or N, and K and Q are not both N; Each occurrence of R''' is H, OH, NH 2 , C 1～6 Alkyl, C 1～6 Alkylamino, C 1～6 independently selected from the group consisting of alkoxy and halogen, where k is 0, 1, 2 or 3; Each occurrence of R' is H, halogen, OH, C 1～6 Alkyl, C 1～6 Haloalkyl and C 1～6 alkoxy, where m is 0, 1, 2, 3, or 4; Each occurrence of R'' is H, halo, OH, NH 2 , C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Haloalkyl, C 1～6 Alkylamino, C 3～6 Cycloalkylamino, C 3～6 Cycloalkyl and C 3～6 heterocycloalkyl, where n is 0, 1 or 2; J is for CR 6 or N, where X is CR 6 or N, Y is CR 6 or N, and at least one of J, X, and Y is N, but J and Y are not simultaneously N, and X and Y are not simultaneously N; R 6 is H, NH 2 , C 1～6 Alkyl and C 1～6 alkoxy, NH 2 , C 1～6 Alkyl or C 1～6 Alkoxy is C 1～3 Alkyl, C 3～6 optionally substituted with 1 to 3 of cycloalkyl and / or halo; In formula I, L 3 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R 3' is H or C 1～6 is alkyl, and Y 1 CH 2 or 【Chemistry 2】 V is N, and Z and U are not simultaneously heteroatoms; In formula II, each occurrence of R 2' is H, OH, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Alkylamino and NH 2 m6 is 0, 1, 2, 3 or 4; Y 1 CH 2 or 【Chemistry 3】 V is N, and Z and U are not simultaneously heteroatoms; In formula III, V is N, and Z and U are not both heteroatoms; In formula IV, L 3 is a bond, -NR-, -O- or -S-; R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R 3' is H or C 1～6 is alkyl, and Y 1 CH 2 or 【Chemistry 4】 wherein V is N or NH, T is CH or N, and up to two of U, Z, V, and T contain heteroatoms; In formula V, each occurrence of R 2' is H, OH, C 1～6 Alkyl, C 1～6 Alkoxy, C 1～6 Alkylamino and NH 2 m6 is 0, 1, 2, 3 or 4; Y 1 CH 2 or 【Chemistry 5】 wherein V is N or NH, T is CH or N, and up to two of U, Z, V, and T contain heteroatoms; In formula VI, V is N, T is CH or N, and up to two of U, Z, V and T contain heteroatoms.

2. L 2 is optionally substituted C 1～45 The compound of claim 1 which is a hydrocarbon chain.

3. L 2 is selected from the group consisting of substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene, and combinations thereof, where one or more chain atoms of the substituents are independently replaced with -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety, and R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group; 2. The compound of claim 1.

4. L 2 is substituted or unsubstituted C 1～6 Alkylene, substituted or unsubstituted C 2～6 Alkenylene, substituted or unsubstituted C 2～6 Alkynylene, substituted or unsubstituted hetero C 1～6 Alkylene, substituted or unsubstituted hetero C 2～6 Alkenylene, substituted or unsubstituted hetero C 2～6 Alkynylene, substituted or unsubstituted C 3～6 The compound of claim 1, comprising at least one member selected from the group consisting of carbocyclylene, substituted or unsubstituted 3- to 6-membered heterocyclylene, substituted or unsubstituted phenylene, and substituted or unsubstituted 5- to 6-membered heteroarylene, where one or more chain atoms of a substituent are independently replaced with -C(=O)-, -O-, -NR a1 -, -S-, or a cyclic moiety, and R a1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group.

5. L 2 is substituted or unsubstituted methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, -(CH 2 ) 2 -O(CH 2 ) 2 -, -OCH 2 -, -O(CH 2 ) 2 -, -O(CH 2 ) 3 -, -O(CH 2 ) 4 -, -O(CH 2 ) 5 -, -O(CH 2 ) 6 2. The compound of claim 1, comprising at least one example selected from the group consisting of -, -NH-C(=O)-, and -NH-C(=O)-.

6. L 2 at least one chain atom of the hydrocarbon chain is independently replaced with a 6-membered heterocyclyl group in which 1 to 3 ring heteroatoms are selected from the group consisting of nitrogen and oxygen; 4. The compound according to claim 3.

7. L 2 but 【Chemistry 6】 and g is 1, 2, 3, 4, 5 or 6.

8. L 2 is the moiety -O-, 【Chemistry 7】 2. The compound of claim 1, comprising: -NHC(=O)- or -NH-.

9. L 2 but 【Chemistry 8】 wherein g is 1, 2, 3, 4, 5 or 6; f is 1, 2, 3, 4, 5 or 6; and h is 1, 2, 3, 4, 5 or 6.

10. The compound of formula I has the formula I-1: 【Chemistry 9】 2. The compound of claim 1,

11. The compound of formula II has formula II-1: 【Chemistry 10】 2. The compound of claim 1,

12. The compound of formula III is represented by formula III-1: 【Chemistry 11】 2. The compound of claim 1,

13. The compound of formula IV has formula IV-1: 【Chemistry 12】 2. The compound of claim 1,

14. The compound of formula V is V-1: 【Chemistry 13】 2. The compound of claim 1,

15. The compound of formula VI is represented by formula VI-1: 【Chemistry 14】 2. The compound of claim 1,

16. Formula 2, 7, 9, 11, 12 or 14: 【Chemistry 15】 14. The compound of claim 13,

17. The compound is of formula 2, R 3' is H or C 1～3 alkyl and / or A is O, NH, 【Chemistry 16】 and / or m2 is 2, 3, 4, 5 or 6, and / or R 1' O, NH, 【Chemistry 17】 and / or R″ is H, halo, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 Alkylamino, C 3～5 Cycloalkyl, C 3～5 Cycloalkylamino or C 3～5 and / or R' is H, halogen, OH, C 1～3 Alkyl, C 1～3 Haloalkyl or C 1～3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R''' is H, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkylamino, C 1～3 17. The compound of claim 16, which is alkoxy or halogen.

18. The compound is of formula 7, R 3' is H or C 1～3 alkyl and / or A is O, NH, 【Chemistry 18】 and / or m2 is 2, 3, 4, 5 or 6, and / or R 1' O, NH, 【Chemistry 19】 and / or R″ is H, halo, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 Alkylamino, C 3～5 Cycloalkyl, C 3～5 Cycloalkylamino or C 3～5 and / or R' is H, halogen, OH, C 1～3 Alkyl, C 1～3 Haloalkyl or C 1～3 17. The compound of claim 16, wherein m is alkoxy and / or m is 0, 1, 2 or 3.

19. The compound is of formula 9, R 3' is H or C 1～3 alkyl and / or A is O, NH, 【Chemistry 20】 and / or m2 is 2, 3, 4, 5 or 6, and / or R 1' O, NH, 【Chemistry 21】 and / or R″ is H, halo, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 Alkylamino, C 3～5 Cycloalkyl, C 3～5 Cycloalkylamino or C 3～5 and / or R' is H, halogen, OH, C 1～3 Alkyl, C 1～3 Haloalkyl or C 1～3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R''' is H, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkylamino, C 1～3 17. The compound of claim 16, which is alkoxy or halogen.

20. The compound is of formula 11, R 3' is H or C 1～3 alkyl and / or A is O, NH, 【Chemical 22】 and / or m2 is 2, 3, 4, 5 or 6, and / or R 1' O, NH, 【Chemistry 23】 and / or R″ is H, halo, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 Alkylamino, C 3～5 Cycloalkyl, C 3～5 Cycloalkylamino or C 3～5 and / or R' is H, halogen, OH, C 1～3 Alkyl, C 1～3 Haloalkyl or C 1～3 alkoxy, and / or m is 0, 1, 2 or 3, and / or R''' is H, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkylamino, C 1～3 17. The compound of claim 16, which is alkoxy or halogen.

21. The compound is of formula 12, R 3' is H or C 1～3 alkyl, A is O, NH, 【Chemistry 24】 m3 is 1, 2, 3, 4, 5 or 6, m4 is 0, 1, 2 or 3, m5 is 0, 1, 2 or 3, R 1' O, NH, 【Chemistry 25】 and R'' is H, halo, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 Alkylamino, C 3～5 Cycloalkyl, C 3～5 Cycloalkylamino or C 3～5 Heterocycloalkyl, where R' is H, halogen, OH, C 1～3 Alkyl, C 1～3 Haloalkyl or C 1～3 Alkoxy, m is 0, 1, 2 or 3, and R''' is H, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkylamino, C 1～3 17. The compound of claim 16, which is alkoxy or halogen.

22. The compound is of formula 14, R 3' is H or C 1～3 alkyl and / or A is O, NH, 【Chemistry 26】 and / or m3 is 1, 2, 3, 4, 5 or 6, and / or m4 is 0, 1, 2, 3 or 4, and / or m5 is 0, 1, 2 or 3, and / or R 1' O, NH, 【Chemistry 27】 and / or R″ is H, halo, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Haloalkyl, C 1～3 Alkylamino, C 3～5 Cycloalkyl, C 3～5 Cycloalkylamino or C 3～5 and / or R' is H, halogen, OH, C 1～3 Alkyl, C 1～3 Haloalkyl or C 1～3 alkoxy, m is 0, 1, 2 or 3, and / or R''' is H, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkylamino, C 1～3 17. The compound of claim 16, which is alkoxy or halogen.

23. Formula 4: 【Chemistry 28】 2. The compound of claim 1,

24. R 2' H, OH, C 1～3 Alkyl, C 1～3 Alkoxy, C 1～3 Alkylamino or NH 2 and / or m6 is 0, 1, 2 or 3, and / or R 1' O, NH, 【Chemical 29】 and / or R' is H, halogen, OH, C 1～3 Alkyl, C 1～3 Haloalkyl or C 1～3 Alkoxy, where R'' is H, halo, OH, NH 2 , C 1～3 Alkoxy, C 3～5 Cycloalkyl, C 3～5 Cycloalkylamino or C 1～3 alkylamino and / or R''' is H, OH, NH 2 , C 1～3 Alkyl, C 1～3 Alkylamino, C 1～3 24. The compound of claim 23, which is alkoxy or halogen.

25. Equation 4-1: 【Chemistry 30】 24. The compound of claim 23,

26. Equation 16 or 17: 【Chemistry 31】 16. The compound of claim 15,

27. 27. The compound of claim 26, wherein the compound is a compound of formula 16, Z is C, U is O or S, and T is CH, or Z is N, U is CH, and T is CH, Z is C, T is N, and U is CH.

28. 27. The compound of claim 26, wherein the compound is a compound of formula 17, Z is C, U is O or S, and T is CH, or Z is N, U is CH, and T is CH, Z is C, T is N, and U is CH.

29. The compound of claim 1, selected from the following group: 【Chemistry 32】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

30. 30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 and a pharma- ceutically acceptable excipient.

31. 31. A medicament for aiding in the treatment of or treating a tauopathy in a subject, comprising an effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutical composition according to claim 30.

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