Methods for Treating Neurogenic Diseases

Abstract

The present specification relates to methods of treating neurodegenerative diseases characterized by the accumulation of abnormal microtubule-associated protein tau (MAPT) using substituted thieno[3,2-d]pyrimidine compounds, forms thereof, and pharmaceutical compositions.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 260,944, filed September 7, 2021, the contents of which are incorporated by reference herein in their entirety for all purposes. The present specification relates to methods of treating neurodegenerative diseases characterized by the accumulation of abnormal microtubule-associated protein tau (MAPT) using substituted thieno[3,2-d]pyrimidine compounds, forms thereof, and pharmaceutical compositions. [Background technology]

[0002] Tauopathies are a group of neurodegenerative diseases characterized by the accumulation and aggregation of abnormal forms of the microtubule-associated protein tau (MAPT), leading to the formation of neurofibrillary tangles (NFTs) and paired helical filaments (PHFs) in neurons and glia in affected brain regions. Tau accumulation and aggregation are the primary pathological feature of more than 18 irreversible neurodegenerative disorders, collectively referred to as tauopathies. These diseases include frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD), which can be sporadic or hereditary when caused by mutations in the MAPT gene1. Tauopathies account for 10-20% of all dementia cases and are estimated to affect approximately 55,000 people in the United States. Currently, there are no effective disease-modifying therapies, and few experimental drugs focused on tau have undergone clinical trials.

[0003] Tau protein is encoded by the MAPT gene located on chromosome 17q21 and is necessary for the stabilization and assembly of microtubules. Microtubules are important for axonal transport and maintaining the structural integrity of cells. In the adult brain, tau is found in neurons, mostly in axons. Tau is also found in oligodendrocytes and astrocytes, and its function is similar to that in neurons. Binding of tau to microtubules can induce conformational changes in the protein. In its normal form, tau is unfolded and phosphorylated. In the brains of patients with primary tauopathy, tau is hyperphosphorylated, has a folded beta-pleated sheet structure, and undergoes aggregation. Binding of tau to microtubules is regulated by the phosphorylation / dephosphorylation ratio. Hyperphosphorylation of tau results in loss of microtubule interactions, leading to microtubule dysfunction and impaired axonal transport as well as fibrillization of tau. Recently, it has been suggested that the proportion of tau sequences that are phosphorylated, rather than the number of phosphorylated epitopes on each tau sequence, predicts the extent of NFT aggregation and formation.

[0004] There are six isoforms of tau expressed in the adult brain. These six isoforms result from alternative splicing of three N-terminal exons in the tau gene: exon 2, exon 3, and exon 10. Three of the six isoforms result from splicing in of exon 10, whereas the other three are the result of splicing out of exon 10. Splicing in of exon 10 results in an isoform with four repeated microtubule-binding domains (4R tau), whereas splicing out of exon 10 results in an isoform with three repeated microtubule-binding domains (3R tau). This is important because healthy human brain consists of equal amounts of tau with three and four repeat microtubule-binding domains, whereas some primary tauopathies are characterized by a predominance of isoforms with four repeat microtubule-binding domains (4R tauopathies), some by a predominance of isoforms with three repeat microtubule-binding domains (3R tauopathies), and some by a roughly equal mixture of isoforms with three and four repeat microtubule-binding domains (3R+4R tauopathies). Tau neurofibrillary tangles in disease have distinct isoform compositions, suggesting that splicing is an important target for potential therapeutics.

[0005] MAPT mutations affecting the splicing of exons 2 and 3 are very rare, whereas pathogenic mutations in exon 10 and the exon 10-intron 10 boundary region are more common, representing approximately 27% of all known tau mutations. Most pathogenic mutations result in missplicing, which in most cases results in inclusion of exon 10 and increases 4R tau expression. The present disclosure relates to the use of compounds of formula (I) or forms or compositions thereof for treating tauopathy. These sets of compounds induce exon 10 skipping in MAPT pre-mRNA during the splicing process. Exon 10 skipping of MAPT mRNA changes the open reading frame (ORF) and creates a premature stop codon (PTC) in the exon 10-skipped mRNA (ΔE4 mRNA) of MAPT4R. It has been shown that such exon skipping splicing events can function to reduce gene expression by creating mRNA with a premature stop codon, thereby signaling the mRNA to be degraded instead of being translated into protein. Similarly, MAPT ΔE4 mRNA produced in the presence of these compounds undergoes mRNA degradation, resulting in a decrease in the level of MAPT 4R mRNA, resulting in MAPT4R protein reduction.

[0006] International Publication No. WO2016 / 115434 discloses kinetin derivatives useful for improving mRNA splicing in cells, particularly for improving mRNA splicing in genes with at least one exon end in nucleotide sequence CAA, such as IKBKAP gene.The disclosed compounds can be used to treat diseases of the central nervous system, such as familial dysautonomia. To date, there are no disease-modifying therapies available for tauopathies, and improved methods and compositions for treating tauopathies and their associated symptoms are needed. International Publication No. WO2020 / 167624 discloses substituted pyrrolo[2,3-d]pyrimidine compounds useful for therapeutic targeting of the pre-mRNA splicing mechanism in the IKBKAP gene and for treating familial dysautonomia. Neither application discloses compounds that induce exon 10 skipping in MAPT pre-mRNA splicing. In addition, neither application discloses compounds that cause MAPT protein reduction, particularly MAPT protein reduction due to mRNA degradation of MAPT 4R mRNA produced in the presence of the compound. Furthermore, neither application discloses compounds that are useful for treating tauopathies.

[0007] The compounds described herein are potential MAPT pre-mRNA splicing compounds that can be used as disease-modifying treatments for a variety of tauopathies. All other documents referenced herein are incorporated by reference into this application as if fully set forth herein. Summary of the Invention

[0008] The present specification relates to a method or use of a compound for treating a neurodegenerative disease characterized by the accumulation of abnormal microtubule-associated protein tau (MAPT) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

[0009] [ka] (I) (wherein R1, R2, R3, and R4 are defined herein). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] One aspect of the present specification relates to a method or use of a compound for treating a neurodegenerative disease characterized by accumulation of abnormal microtubule associated protein tau (MAPT) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof, wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof.

[0011] [ka] (I) (In the formula, R1 is selected from the group consisting of phenyl and heteroaryl; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Phenyl or heteroaryl can be selected from 1, 2, 3, or 4 independently selected R 1a may be substituted with a substituent; R 1a Cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, and C 1-6 independently selected from the group consisting of alkoxy; R2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6Alkynyl may contain a chiral carbon having either the (R) or (S) configuration; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, phenyl, heterocyclyl, or heteroaryl can be one, two, three, or four independently selected R 2a may be substituted with a substituent; R 2a is cyano, halo, hydroxy, oxo, C 1-6 Alkyl, halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, Halo-C 1-6 Alkoxy, carboxyl, amino, C 1-6 Alkyl-amino, halo-C 1-6 Alkyl-amino, deutero-C 1-6 Alkyl-amino, (C 1-6 Alkyl)2-amino, C 3-10 Cycloalkyl-amino, phenyl-amino, heterocyclyl-amino, heteroaryl-amino, C 1-6 Alkyl-thio, C 1-6 Alkyl-sulfonyl, C 3-10 independently selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; C 3-10 Each occurrence of cycloalkyl, phenyl, heterocyclyl, or heteroaryl is selected from 1, 2, 3, or 4 independently selected R 2a’ may be substituted with a substituent; R 2a’ is cyano, halo, hydroxy, oxo, C 1-6Alkyl, halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, and C 1-6 independently selected from the group consisting of alkoxy; R3 is hydrogen, cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy, Amino, C 1-6 Alkyl-amino, (C 1-6 Alkyl)2-amino, C 3-10 selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, heterocyclyl, or heteroaryl can be one, two, three, or four independently selected R 3a may be substituted with a substituent; R 3a Cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, and C 1-6 independently selected from the group consisting of alkoxy; R4 is hydrogen, cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy, carbamoyl, C 3-10 selected from the group consisting of cycloalkyl, phenyl, and heterocyclyl; Heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S.

[0012] One embodiment of the method or use is wherein R1 is selected from the group consisting of phenyl and heteroaryl; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Phenyl or heteroaryl is one, two, three, or four independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0013] Another embodiment of the method or use is wherein R1 is selected from the group consisting of phenyl and heteroaryl; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Phenyl or heteroaryl is one or two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R is phenyl, and the phenyl is selected from 1, 2, 3, or 4 independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0014] Another embodiment of the method or use is wherein R is phenyl, which is substituted with one R 1a This includes compounds of formula (I) which are substituted with a substituent.

[0015] Another embodiment of the method or use is wherein R1 is heteroaryl; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is one, two, three, or four independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R1 is heteroaryl; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is one or two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-tetrazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, and quinolinyl; Heteroaryl is one, two, three, or four independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0016] Another embodiment of the method or use is wherein R1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-tetrazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, and quinolinyl; Heteroaryl is one or two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0017] Another embodiment of the method or use is wherein R1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-tetrazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, and quinolinyl; Heteroaryl is one R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0018] Another embodiment of the method or use is wherein R1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-tetrazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, and quinolinyl; Heteroaryl is selected from two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0019] Another embodiment of the method or use is wherein R1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 2H-1,2,3-triazolyl, 1H-tetrazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl; Heteroaryl is one, two, three, or four independently selected R 1aThis includes compounds of formula (I) which may be substituted with substituents.

[0020] Another embodiment of the method or use is wherein R1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 2H-1,2,3-triazolyl, 1H-tetrazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl; Heteroaryl is one or two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0021] Another embodiment of the method or use is wherein R1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 2H-1,2,3-triazolyl, 1H-tetrazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl; Heteroaryl is one R 1a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrrolyl, 1H-pyrazolyl, 1H-imidazolyl, 2H-1,2,3-triazolyl, 1H-tetrazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl; Heteroaryl is selected from two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0022] Another embodiment of the method or use is where R1 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazo 1H-1,2,3-triazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 1,2-thiazol-3-yl, 1,2-thiazol-4-yl, 1,2-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol- 4-yl, 1,3-thiazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, tetrazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3- heteroaryl selected from the group consisting of triazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, benzofuran-2-yl, benzofuran-5-yl, and quinolin-4-yl; Heteroaryl is one, two, three, or four independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0023] Another embodiment of the method or use is where R1 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazo 1H-1,2,3-triazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 1,2-thiazol-3-yl, 1,2-thiazol-4-yl, 1,2-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol- 4-yl, 1,3-thiazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, tetrazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3- heteroaryl selected from the group consisting of triazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, benzofuran-2-yl, benzofuran-5-yl, and quinolin-4-yl; Heteroaryl is one or two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0024] Another embodiment of the method or use is where R1 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazo 1H-1,2,3-triazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 1,2-thiazol-3-yl, 1,2-thiazol-4-yl, 1,2-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol- 4-yl, 1,3-thiazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, tetrazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3- heteroaryl selected from the group consisting of triazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, benzofuran-2-yl, benzofuran-5-yl, and quinolin-4-yl; Heteroaryl is one R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0025] Another embodiment of the method or use is where R1 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazo 1H-1,2,3-triazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 1,2-thiazol-3-yl, 1,2-thiazol-4-yl, 1,2-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol- 4-yl, 1,3-thiazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, tetrazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3- heteroaryl selected from the group consisting of triazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, benzofuran-2-yl, benzofuran-5-yl, and quinolin-4-yl; Heteroaryl is selected from two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0026] Another embodiment of the method or use is where R1 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 2H-1,2,3-triazol-4-yl, 1H-tetrazol-5-yl, 1,2-thiazol-4-yl, 1,2-thiazol- heteroaryl selected from the group consisting of 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, and pyrazin-2-yl; Heteroaryl is one, two, three, or four independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0027] Another embodiment of the method or use is where R1 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 2H-1,2,3-triazol-4-yl, 1H-tetrazol-5-yl, 1,2-thiazol-4-yl, 1,2-thiazol- heteroaryl selected from the group consisting of 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, and pyrazin-2-yl; Heteroaryl is one or two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0028] Another embodiment of the method or use is where R1 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 2H-1,2,3-triazol-4-yl, 1H-tetrazol-5-yl, 1,2-thiazol-4-yl, 1,2-thiazol- heteroaryl selected from the group consisting of 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, and pyrazin-2-yl; Heteroaryl is one R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0029] Another embodiment of the method or use is where R1 is furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 2H-1,2,3-triazol-4-yl, 1H-tetrazol-5-yl, 1,2-thiazol-4-yl, 1,2-thiazol- heteroaryl selected from the group consisting of 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, and pyrazin-2-yl; Heteroaryl is selected from two independently selected R 1a This includes compounds of formula (I) which may be substituted with substituents.

[0030] One embodiment of the method or use comprises R 1a But cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, and C 1-6 The compounds of formula (I) include those compounds independently selected from the group consisting of alkoxy. Another embodiment of the method or use comprises R 1a But halo and C 1-6 The compounds of formula (I) include those compounds in which the aryl group is independently selected from the group consisting of alkyl. Another embodiment of the method or use comprises R 1a is halo, wherein halo is selected from the group consisting of fluoro, chloro, bromo, and iodo. Another embodiment of the method or use comprises R 1a is fluoro. Another embodiment of the method or use comprises R 1a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl; 1-6 This includes compounds of formula (I) wherein:

[0031] Another embodiment of the method or use comprises R 1a is methyl. In one embodiment of the method or use, R2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl may contain a chiral carbon having either the (R) or (S) configuration; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, phenyl, heterocyclyl, and heteroaryl are each independently selected from 1, 2, 3, or 4 R 2a This includes compounds of formula (I) which may be substituted with substituents.

[0032] Another embodiment of the method or use includes a compound of formula (I) wherein R2 is hydrogen. Another embodiment of the method or use is wherein R2 is C 1-6 is alkyl, C 1-6 The alkyl may contain a chiral carbon having an (R) or (S) configuration; C 1-6alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R2 is C 1-6 is alkyl, C 1-6 The alkyl contains a chiral carbon having the (R) configuration; C 1-6 alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R2 is C 1-6 is alkyl, C 1-6 The alkyl contains a chiral carbon having an (S) configuration; C 1-6 alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents.

[0033] Another embodiment of the method or use is C 2 , wherein R is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl. 1-6 is alkyl, C 1-6 The alkyl may contain a chiral carbon having an (R) or (S) configuration; C 1-6 alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is C 2 , wherein R is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl. 1-6 is alkyl, C 1-6 The alkyl contains a chiral carbon having the (R) configuration; C 1-6 alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is C 2 , wherein R is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl. 1-6 is alkyl, C 1-6 The alkyl contains a chiral carbon having an (S) configuration; C 1-6 alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents.

[0034] Another embodiment of the method or use is a C 1 , wherein R is selected from the group consisting of methyl, ethyl, propyl, butyl, and pentyl. 1-6 is alkyl, C 1-6 The alkyl may contain a chiral carbon having an (R) or (S) configuration; C 1-6 alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents.

[0035] Another embodiment of the method or use is a C 1 , wherein R is selected from the group consisting of methyl, ethyl, propyl, butyl, and pentyl. 1-6 is alkyl, C 1-6 The alkyl contains a chiral carbon having the (R) configuration; C 1-6 alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is a C 1 , wherein R is selected from the group consisting of methyl, ethyl, propyl, butyl, and pentyl. 1-6 is alkyl, C 1-6 The alkyl contains a chiral carbon having an (S) configuration; C 1-6 alkyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents.

[0036] Another embodiment of the method or use is wherein R2 is heterocyclyl; heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heterocyclyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R2 is heterocyclyl; heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heterocyclyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R2 is heterocyclyl; heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heterocyclyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents.

[0037] Another embodiment of the method or use is wherein R2 is a heterocyclyl selected from the group consisting of azetidinyl, oxetanyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2H-pyranyl, tetrahydropyranyl, morpholinyl, 1,3-oxazinanyl, 1,3-oxazinan-2-on-yl, and azepanyl; Heterocyclyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is wherein R2 is a heterocyclyl selected from the group consisting of azetidinyl and pyrrolidinyl; Heterocyclyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents.

[0038] Another embodiment of the method or use is where R2 is selected from the group consisting of azetidin-2-yl, azetidin-3-yl, oxetan-2-yl, oxetan-3-yl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, tetrahydrofuran-1-yl, tetrahydrofuran-2-yl, oxazolidin-2-yl, oxazolidin-4-yl, oxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, heterocyclyl selected from the group consisting of tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 1,3-oxazinan-2-yl, 1,3-oxazinan-3-yl, 1,3-oxazinan-4-yl, 1,3-oxazinan-2-on-6-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, and azepan-4-yl; Heterocyclyl is one, two, three, or four independently selected R 2a This includes compounds of formula (I) which may be substituted with substituents.

[0039] Another embodiment of the method or use is wherein R2 is a heterocyclyl selected from the group consisting of azetidin-3-yl and pyrrolidin-3-yl; Heterocyclyl is one, two, three, or four independently selected R 2aThis includes compounds of formula (I) which may be substituted with substituents. One embodiment of the method or use comprises R 2a But cyano, halo, hydroxy, oxo, C 1-6 Alkyl, halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, Halo-C 1-6 Alkoxy, carboxyl, amino, C 1-6 Alkyl-amino, halo-C 1-6 Alkyl-amino, deutero-C 1-6 Alkyl-amino, (C 1-6 Alkyl)2-amino, C 3-10 Cycloalkyl-amino, phenyl-amino, heterocyclyl-amino, heteroaryl-amino, C 1-6 Alkyl-thio, C 1-6 Alkyl-sulfonyl, C 3-10 independently selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; C 3-10 Each occurrence of cycloalkyl, phenyl, heterocyclyl, or heteroaryl is selected from 1, 2, 3, or 4 independently selected R 2a’ This includes compounds of formula (I) which may be substituted with substituents.

[0040] Another embodiment of the method or use comprises R 2a But halo, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, Amino, C 1-6 Alkyl-amino, C 3-10 Cycloalkyl-amino, C 3-10cycloalkyl, or heterocyclyl; C 3-10 Each occurrence of cycloalkyl or heterocyclyl is selected from 1, 2, 3, or 4 independently selected R 2a’ This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use comprises R 2a is a halo selected from the group consisting of fluoro, chloro, bromo, and iodo. Another embodiment of the method or use comprises R 2a is fluoro. Another embodiment of the method or use comprises R 2a is hydroxy. Another embodiment of the method or use comprises R 2a is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl; 1-6 This includes compounds of formula (I) wherein: Another embodiment of the method or use comprises R 2a is methyl. Another embodiment of the method or use comprises R 2a is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-6 Includes compounds of formula (I) which are alkoxy. Another embodiment of the method or use comprises R 2a is methoxy. Another embodiment of the method or use comprises R 2a is amino.

[0041] Another embodiment of the method or use comprises R 2a But, C 1-6 Alkyl-amino, C 1-6 Includes compounds of formula (I) where alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl.

[0042] Another embodiment of the method or use comprises R 2a is methyl-amino. Another embodiment of the method or use comprises R 2a But, C 3-10 Cycloalkyl-amino, C 3-10 Cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; 3-10 Cycloalkyl is one, two, three or four independently selected R 2a’ This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use comprises R 2a is cyclobutyl-amino.

[0043] Another embodiment of the method or use comprises R 2a But, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; 3-10 Cycloalkyl is one, two, three or four independently selected R 2a’ This includes compounds of formula (I) which may be substituted with substituents. Another aspect is R 2a is 1, 2, 3, or 4 independently selected R 2a’ This includes compounds of formula (I) which are optionally substituted cyclopropyl. Another embodiment of the method or use comprises R 2a is a heterocyclyl selected from the group consisting of azetidinyl, oxetanyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2H-pyranyl, tetrahydropyranyl, morpholinyl, 1,3-oxazinanyl, 1,3-oxazinan-2-on-yl, and azepanyl; Heterocyclyl is one, two, three, or four independently selected R 2a’This includes compounds of formula (I) which may be substituted with substituents.

[0044] Another embodiment of the method or use comprises R 2a is 1,3-oxazinan-2-one-yl. Another embodiment of the method or use comprises R 2a azetidin-2-yl, azetidin-3-yl, oxetan-2-yl, oxetan-3-yl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, tetrahydrofuran-1-yl, tetrahydrofuran-2-yl, oxazolidin-2-yl, oxazolidin-4-yl, oxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin heterocyclyl selected from the group consisting of azinin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 1,3-oxazinan-2-yl, 1,3-oxazinan-3-yl, 1,3-oxazinan-4-yl, 1,3-oxazinan-2-on-6-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, and azepan-4-yl; Heterocyclyl is one, two, three, or four independently selected R 2a’ This includes compounds of formula (I) which may be substituted with substituents.

[0045] Another embodiment of the method or use comprises R 2a is 1,3-oxazinan-2-one-6-yl. In one embodiment, R3 is hydrogen, cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy, Amino, C 1-6 Alkyl-amino, (C 1-6 Alkyl)2-amino, C 3-10 selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; heterocyclyl is a 3-7 membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S; C 1-6 Alkyl, C 3-10 Each occurrence of cycloalkyl, phenyl, heterocyclyl, or heteroaryl is selected from 1, 2, 3, or 4 independently selected R 3a This includes compounds of formula (I) which may be substituted with substituents.

[0046] Another embodiment is where R3 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, and phenyl; C 1-6 Alkyl, C 3-10 cycloalkyl, or phenyl, each of which is 1, 2, 3, or 4 independently selected R 3a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use includes a compound of formula (I) wherein R3 is hydrogen. Another embodiment of the method or use includes a compound of formula (I) wherein R3 is cyano. Another embodiment of the method or use includes a compound of formula (I) wherein R3 is halo selected from the group consisting of fluoro, chloro, bromo, and iodo. Another embodiment of the method or use includes a compound of formula (I) wherein R3 is bromo. Another embodiment of the method or use includes a compound of formula (I) wherein R3 is hydroxy.

[0047] Another embodiment of the method or use is wherein R3 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl; C 1-6 alkyl is one, two, three, or four independently selected R 3a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is a C 1-6 is alkyl, C 1-6 alkyl is one, two, three, or four independently selected R 3a This includes compounds of formula (I) which may be substituted with substituents. Another embodiment of the method or use is a C 1111111, wherein R is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-6 Includes compounds of formula (I) which are alkoxy. Another embodiment of the method or use includes a compound of formula (I) wherein R3 is methoxy. Another embodiment of the method or use is wherein R3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-10 is cycloalkyl, C 3-10 Cycloalkyl is one, two, three, or four independently selected R 3a This includes compounds of formula (I) which may be substituted with substituents.

[0048] Another embodiment of the method or use is wherein R3 is 1, 2, 3, or 4 independently selected R 3a This includes compounds of formula (I) which are optionally substituted cyclopropyl. Another embodiment of the method or use is wherein R3 is 1, 2, 3, or 4 independently selected R 3a This includes compounds of formula (I) which are phenyl which may be substituted. One embodiment of the method or use comprises R 3a But cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, and C 1-6 The compounds of formula (I) include those selected from the group consisting of alkoxy.

[0049] Another embodiment of the method or use comprises R 3a But halo and C 1-6 The compounds of formula (I) include those selected from the group consisting of alkoxy.

[0050] Another embodiment of the method or use comprises R 3a is a halo selected from the group consisting of fluoro, chloro, bromo, and iodo. Another embodiment of the method or use comprises R 3a is chloro. Another embodiment of the method or use comprises R 3a is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-6 Includes compounds of formula (I) which are alkoxy. Another embodiment of the method or use comprises R 3a is methoxy. In one embodiment of the method or use, R4 is hydrogen, cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy, carbamoyl, C 3-10 selected from the group consisting of cycloalkyl, phenyl, and heterocyclyl; Includes compounds of formula (I) where heterocyclyl is a radical of a 3- to 7-membered monocyclic carbon atom ring structure containing 1-3 heteroatoms selected from N, O, and S.

[0051] Another embodiment of the method or use is wherein R4 is hydrogen, cyano, halo, C 1-6 Alkyl, halo-C 1-6 Alkyl, Carbamoyl, C 3-10The compounds of formula (I) include those in which the aryl group is selected from the group consisting of cycloalkyl, cycloalkyl, and phenyl. Another embodiment of the method or use includes a compound of formula (I) wherein R4 is hydrogen. Another embodiment of the method or use includes a compound of formula (I) wherein R4 is cyano. Another embodiment of the method or use includes a compound of formula (I) wherein R4 is halo selected from the group consisting of fluoro, chloro, bromo, and iodo. Another embodiment of the method or use includes a compound of formula (I) wherein R4 is halo selected from the group consisting of chloro and bromo. Another embodiment of the method or use is C 4 , wherein R is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl. 1-6 This includes compounds of formula (I) wherein:

[0052] Another embodiment of the method or use is a C 1-6 This includes compounds of formula (I) wherein: Another embodiment of the method or use is wherein R4 is halo-C 1-6 Alkyl, C 1-6 alkyl is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl; C 1-6 Includes compounds of formula (I) where alkyl is partially or fully substituted with one or more halogen atoms, where available valences permit. Another embodiment of the method or use is wherein R4 is halo-C 1-6 Alkyl, C 1-6 Includes compounds of formula (I) where alkyl is methyl substituted with 3 fluorine atoms. Another embodiment of the method or use includes a compound of formula (I) wherein R4 is carbamoyl. Another embodiment of the method or use is wherein R4 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-10 Includes compounds of formula (I) which are cycloalkyl. Another embodiment of the method or use includes a compound of formula (I) wherein R4 is cyclopropyl. Another embodiment of the method or use includes a compound of formula (I) wherein R4 is phenyl. One aspect of the method or use comprises:

[0053] [ka] JPEG2024533264000004.jpg254154 JPEG2024533264000005.jpg250157 JPEG2024533264000006.jpg219165 JPEG2024533264000007.jpg241163 JPEG2024533264000008.jpg249157 JPEG2024533264000009.jpg229164 JPEG2024533264000010.jpg250158 The present invention includes compounds of formula (I) or forms thereof, including compounds selected from the group consisting of JPEG2024533264000011.jpg253170, wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof.

[0054] Another embodiment of the method or use comprises: JPEG2024533264000012.jpg218166 TIFF2024533264000013.tif213159 TIFF2024533264000014.tif213163 TIFF2024533264000015.tif213155 TIFF2024533264000016.tif208159 TIFF2024533264000017.tif213155 TIFF2024533264000018.tif47153 Compounds of formula (I) or forms thereof (compound no. (#) 1 ) indicates that the salt form has been isolated, and the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof.

[0055] Another embodiment of the method or use comprises: TIFF2024533264000019.tif203151 TIFF2024533264000020.tif213151 TIFF2024533264000021.tif187147 TIFF2024533264000022.tif223154 TIFF2024533264000023.tif125157 or a form thereof, wherein the form of the compound is selected from the group consisting of a hydrate, solvate, and tautomeric form thereof.

[0056] One embodiment of the method or use comprises a compound of formula (I) or a form thereof for treating a neurodegenerative disease characterized by the accumulation and aggregation of aberrant MAPT in a subject.

[0057] One embodiment of the method or use comprises a compound of formula (I) or a form thereof for treating a neurodegenerative disease in a subject characterized by the formation of neurofibrillary tangles and paired helical filaments in neurons and glia of affected brain regions.

[0058] One embodiment of the method or use includes a compound of formula (I) or a form thereof, wherein the neurogenerative disease is selected from the group consisting of Alzheimer's disease, dementia pugilistica, Amyotrophic lateral sclerosis-parkinsonism-dementia of Guam (ALS / PD), Pick's disease, argyrophilic grain dementia, Niemann-Pick disease type C, Subacute sclerosing panencephalitis (SSPE), Progressive supranuclear palsy (PSP), Multiple system atrophy (MSA), Corticobasoganlionic degeneration, Frontotemporal dementia with parkinsonism-17 (FTDP-17), Postencephalitic parkinsonism (PEP), Autosomal recessive parkinsonism, Frontotemporal dementia, and Progressive supranuclear palsy. One embodiment includes a method for inducing exon 10 skipping in MAPT pre-mRNA, comprising contacting a human cell with a compound of formula (I) or a form thereof.

[0059] One embodiment includes a method for producing MAPT ΔE4 mRNA, the method comprising contacting a human cell with a compound of formula (I) or a form thereof. One embodiment includes a method for reducing MAPT4R protein, comprising contacting a human cell with a compound of formula (I) or a form thereof. One aspect of the present specification relates to a pharmaceutical composition comprising a compound of formula (I) or a form thereof and at least one pharma- ceutically acceptable excipient for administration to a subject to treat a neurodegenerative disease characterized by the accumulation and aggregation of aberrant MAPT. One aspect of the present specification relates to the manufacture of a medicament for treating a neurodegenerative disease characterized by accumulation and aggregation of abnormal MAPT in a subject, comprising a compound of formula (I) or a form thereof and at least one pharma- ceutically acceptable excipient. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0060] chemical definition The chemical terms used above and throughout the description herein shall be understood by those of ordinary skill in the art to have the following indicated meanings, unless expressly defined otherwise. As used herein, "C 1-6 The term "alkyl" generally refers to a saturated hydrocarbon group having from 1 to 8 carbon atoms in a straight or branched arrangement, including, but not limited to, methyl, ethyl, n-propyl (also referred to as propyl or propanyl), isopropyl, n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also referred to as pentyl or pentanyl), n-hexyl (also referred to as hexyl or hexanyl), and the like. 1-6 Alkyl is C 1-6 Alkyl, C 1-4 Alkyl, etc., but are not limited to these. 1-6 Alkyl groups, where available valences allow, can be substituted with the types of substituents described herein.

[0061] As used herein, "hetero-C 1-6 The term "alkyl" generally refers to a saturated hydrocarbon group having from 1 to 6 carbon atoms in a straight or branched arrangement, in which one or more heteroatoms, such as O, S or N atoms, are members in the chain, and includes, but is not limited to, hetero-methyl, hetero-ethyl, hetero-propyl, hetero-butyl, hetero-pentyl, hetero-hexyl, and the like. In certain embodiments, hetero-C 1-6 Alkyl is hetero-C 2-6 Alkyl, Hetero-C 1-4 Alkyl, Hetero-C 2-4Hetero-C 1-6 Alkyl groups, where available valences allow, can be substituted with the types of substituents described herein.

[0062] As used herein, "C 2-6 The term "alkenyl" generally refers to a partially unsaturated hydrocarbon group having from 2 to 8 carbon atoms in a linear or branched arrangement and having one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also known as vinyl), allyl, propenyl, and the like. In certain embodiments, C 2-6 Alkenyl is C 2-6 Alkenyl, C 2-4 Alkenyl, but not limited to alkenyl. 2-6 Alkenyl groups may be optionally substituted, where available valences permit, with the types of substituents described herein. As used herein, "C 2-6 The term "alkynyl" generally refers to a partially unsaturated hydrocarbon group having from 2 to 8 carbon atoms in a linear or branched arrangement and having one or more carbon-carbon triple bonds therein, and includes, but is not limited to, ethynyl (also called acetylenyl), propynyl, butynyl, and the like. In certain embodiments, C 2-6 Alkynyl is C 2-6 Alkynyl, C 2-4 Alkynyl and the like. 2-6 Alkynyl groups may be optionally substituted, where available valences permit, with the types of substituents described herein.

[0063] As used herein, "C 1-6 The term "alkoxy" generally refers to a group of the formula: -OC 1-6 Alkyl refers to a saturated hydrocarbon group having 1 to 8 carbon atoms in a straight or branched chain arrangement, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like.1-6 Alkoxy is C 1-6 Alkoxy, C 1-4 Alkoxy and the like. 1-6 Alkoxy groups may be optionally substituted, where available valences permit, with the types of substituents described herein. As used herein, the term "oxo" refers to a group of the formula: =O. As used herein, the term "carboxyl" refers to a group of the formula: -COOH, -C(O)OH or -COH. As used herein, the term "carbamoyl" refers to a group of the formula: -C(O)NH2.

[0064] As used herein, "C 3-10 The term "cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon group, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl, and the like. 3-10 Cycloalkyl is C 3-8 Cycloalkyl, C 5-8 Cycloalkyl, C 3-10 cycloalkyl, etc. 3-10 Cycloalkyl groups may be optionally substituted, where available valences permit, with the types of substituents described herein.

[0065] As used herein, the term "aryl" generally refers to a radical of a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. Aryl groups may be optionally substituted, where available valences permit, with the types of substituents described herein.

[0066] As used herein, the term "heteroaryl" generally refers to a radical of a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure in which one or more carbon atom ring members are replaced, where structural stability permits, by one or more heteroatoms, such as O, S or N atoms, including, but not limited to, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and the like. Heteroaryl groups may be optionally substituted on either carbon or nitrogen ring atoms, where available valences permit, with the types of substituents described herein.

[0067] In certain aspects, the nomenclature of heteroaryl groups may vary, for example and without limitation, furanyl may also be referred to as furyl, thiophenyl may also be referred to as thienyl, pyridinyl may also be referred to as pyridyl, benzothiphenyl may also be referred to as benzothienyl, and 1,3-benzoxazolyl may also be referred to as 1,3-benzooxazolyl.

[0068] In certain other aspects, the heteroaryl group terms may also include other regioisomers, such as, for example and without limitation, the term pyrrolyl may include 2H-pyrrolyl, 3H-pyrrolyl, the term pyrazolyl may include 1H-pyrazolyl, the term imidazolyl may include 1H-imidazolyl, the term triazolyl may include 1H-1,2,3-triazolyl, the term oxadiazolyl may include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, the term tetrazolyl may include 1H-tetrazolyl, 2H-tetrazolyl, the term indolyl may include 1H-indolyl, the term indazolyl may include 1H-indazolyl, 2H-indazolyl, the term benzimidazolyl may include 1H-benzimidazolyl, the term purinyl may include 9H-purinyl, and the like. As used herein, the term "heterocyclyl" generally refers to a group of saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structures in which one or more carbon atom ring members have been replaced, where structural stability permits, by a heteroatom, such as an O, S or N atom, and includes, for example, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolin ... Heterocyclyl groups include, but are not limited to, zolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, tetrahydropyranyl, thiopyranyl, 1,3-dioxanyl, 1,3-oxazinanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, etc. Heterocyclyl groups may be substituted on either carbon or nitrogen ring atom members, where available valences permit, with the types of substituents described herein.

[0069] As used herein, the term "cyano" refers to a group of the formula: --CN. As used herein, the term "amino" refers to a group of the formula: --NH. As used herein, "C 1-6 The term "alkyl-amino" refers to a group of the formula: -NH-C1-6 alkyl. As used herein, "halo-C 1-6 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-6 Alkyl (wherein 1-6 Alkyl refers to a group which, where available valences permit, is partially or fully substituted with one or more halogen atoms.

[0070] As used herein, "deutero-C 1-6 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-6 Alkyl (wherein 1-6 Alkyl refers to the group (which, where available valences permit, is partially or fully substituted with one or more deuterium atoms). As used herein, "(C 1-6 The term "amino" refers to a group of the formula: -N(C 1-6 It refers to the group (alkyl). As used herein, the term "phenyl-amino" refers to a group of the formula: --NH-phenyl. As used herein, the term "heterocyclyl-amino" refers to a group of the formula: --NH-heterocyclyl. As used herein, the term "heteroaryl-amino" refers to a group of the formula: --NH-heteroaryl.

[0071] As used herein, "C 1-6 The term "alkyl-thio" refers to a group of the formula: -SC 1-6 Refers to an alkyl group. As used herein, "C 1-6 The term "alkyl-sulfonyl" refers to a group of the formula: -SO2-C 1-6 Refers to an alkyl group. As used herein, the term "halo" or "halogen" refers generally to a halogen atom radical and includes fluoro, chloro, bromo and iodo. As used herein, "halo-C 1-6 The term "alkoxy" means a group of the formula: -OC 1-6 Alkyl-halo (wherein 1-6 Alkyl refers to a group which, where available valences permit, is partially or fully substituted with one or more halogen atoms. As used herein, "halo-C 1-6 The term "alkyl" refers to a group of the formula: 1-6 Alkyl-halo (wherein 1-6Alkyl refers to a group which, where available valences permit, is partially or fully substituted with one or more halogen atoms. As used herein, "deutero-C 1-6 The term "alkyl" refers to a group of the formula: 1-6 Alkyl-deutero (wherein 1-6 Alkyl refers to the group (which, where available valences permit, is partially or fully substituted with one or more deuterium atoms).

[0072] As used herein, the term "hydroxy" refers to a group of the formula: --OH. As used herein, "hydroxy-C 1-6 The term "alkyl" refers to a group of the formula: 1-6 Alkyl-OH (wherein 1-6 Alkyl refers to the group which, where available valences permit, is partially or fully substituted with one or more hydroxy groups.

[0073] As used herein, the term "substituent" refers to a position variable on an atom of a core molecule that is substituted at a designated atomic position, replacing one or more hydrogens on the designated atom, provided that the normal valence of the designated atom is not exceeded, and the substitution results in a stable compound. Combinations of substituents and / or variables are permitted only if such combinations result in stable compounds. Those skilled in the art should note that any carbon and heteroatom with an apparently unsatisfied valence described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the described or shown valence. In some instances, one or more substituents having a double bond (e.g., "oxo" or "=O") as a point of attachment may be described, shown, or listed in the substituents herein, and the structure may show only a single bond as a point of attachment to the core structure of formula (I). Those skilled in the art will understand that although only a single bond is shown, a double bond is intended for those substituents.

[0074] As used herein, the term "such as" in relation to the definitions of chemical terms provided herein means that variations in the chemical structure that may be expected by one of ordinary skill in the art include, but are not limited to, isomers (including chain, branched or positional structural isomers), hydration of ring systems (including saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring structures), and all other variations that result in stable compounds, where available valences permit. For purposes herein, when one or more substituent variables of a compound of formula (I) or a form thereof includes a functional group that is incorporated in a compound of formula (I), each functional group appearing anywhere within the disclosed compounds may be independently selected and, where appropriate, independently and / or optionally substituted. As used herein, the term "independently selected" or "each selected" refers to a functional group variable in a list of substituents that may occur more than once on the structure of formula (I), and the substitution pattern at each occurrence is independent of the pattern at any other occurrence. Furthermore, the use of a generic substituent variable in any formula or structure of the compounds described herein includes the replacement of the generic substituent with a species substituent included within the particular genus, for example, aryl may be replaced with phenyl or naphthalenyl, etc., and it is understood that the resulting compound is included within the scope of the compounds described herein.

[0075] As used herein, the term "each occurrence" or "if present, at each occurrence" means "...C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, heterocyclyl and heterocyclyl-C 1-4 When used following a phrase such as "alkyl", each of the C's when present alone or as a substituent is 3-10 It is intended to refer to cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems. As used herein, the term "optionally substituted" means optional substitution with the specified substituent variable, group, radical or moiety.

[0076] Compound Form As used herein, the term "form" means a compound of formula (I) having a form selected from the group consisting of its free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomeric, diastereomeric, stereoisomeric, polymorphic and tautomeric forms. In certain embodiments described herein, the compound of formula (I) is in the form of a free acid, a free base, or a salt thereof. In certain embodiments described herein, the compound of formula (I) is in the form of a salt thereof. In certain embodiments described herein, the forms of the compounds of formula (I) are isotopologues thereof. In certain embodiments described herein, the compound of formula (I) may be in the form of a stereoisomer, racemate, enantiomer, or diastereomer thereof. In certain embodiments described herein, the compounds of formula (I) may be in the form of a tautomer thereof. In certain embodiments described herein, the compound of formula (I) is in a pharma- ceutically acceptable form.

[0077] In certain aspects described herein, the compound of formula (I) or a form thereof is isolated for use.

[0078] As used herein, the term "isolated" refers to the physical state of a compound of formula (I) or a form thereof after it has been isolated and / or purified from a synthetic process (e.g., from a reaction mixture) or from a natural source, or a combination thereof, in sufficient purity to be characterized by standard analytical techniques described herein or known to one of skill in the art, following an isolation or purification process (e.g., chromatography, recrystallization, etc.) described herein or known to one of skill in the art.

[0079] As used herein, the term "protected" means that the functional group in the compound of formula (I) or in its form is in a modified form so as not to cause undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups are known by those skilled in the art and by reference to standard textbooks such as, for example, TW Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. In some instances, the protecting group may also be a polymer resin, such as Wang resin or 2-chlorotrityl-chloride resin. Protecting groups may be added or removed according to standard techniques well known to those skilled in the art and described herein. It will also be recognized by those skilled in the art that such protected derivatives of the compounds described herein may not possess pharmacological activity themselves, but may be administered to a subject and subsequently metabolized in the body to form a compound described herein that is pharmacologically active. Thus, such derivatives may be described as "prodrugs". All prodrugs of the compounds described herein are included within the scope of the uses described herein.

[0080] As used herein, the term "prodrug" refers to a form of the compound (e.g., a drug precursor) that is converted in vivo to produce an active compound of formula (I) or a form thereof. Conversion can occur by various mechanisms (e.g., by metabolic and / or non-metabolic chemical processes), such as by hydrolysis and / or metabolism in blood, liver and / or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0081] In one example, when a compound of formula (I) or a form thereof contains a carboxylic acid functional group, the prodrug can include an ester formed by replacing the hydrogen atom of the acidic group with a functional group, such as an alkyl. In another example, when a compound of formula (I) or a form thereof contains a hydroxyl functional group, the prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group, such as an alkyl, alkylcarbonyl, or phosphonate ester. In another example, when a compound of formula (I) or a form thereof contains an amine functional group, the prodrug form can be prepared by replacing one or more of the amine hydrogen atoms with a functional group, such as an alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of a compound of formula (I) or a form thereof include compounds substituted with one or more of the following groups: carboxylate esters, sulfonate esters, amino acid esters, phosphonate esters, and mono-, di-, or triphosphate esters, or alkyl substituents, as appropriate. It will be appreciated by those skilled in the art that one or more of such substituents, as described herein, may be used to provide a compound of formula (I) or a form thereof as a prodrug.

[0082] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to encompass both solvated and unsolvated forms. As used herein, the term "solvate" refers to a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some instances, a solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both solution-phase solvates and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. As used herein, the term "hydrate" refers to a solvate where the solvent molecule is water.

[0083] The compound of formula (I) can form salts, which are intended to be included within the scope of the present specification. Reference herein to the compound of formula (I) or a form thereof is understood to include reference to its salt form, unless otherwise indicated. The term "salt" as used herein refers to acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. In addition, when the compound of formula (I) or a form thereof contains both a basic moiety, such as, but not limited to, an amine moiety, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") can be formed, which are included within the term "salt" as used herein. As used herein, the term "pharmaceutically acceptable salts" refers to salts of the compounds described herein that are safe and effective for use in mammals (i.e., non-toxic and physiologically acceptable) and that possess biological activity, although other salts are also useful. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) or a form thereof with an amount, e.g., an equivalent amount, of an acid or base in a medium, e.g., a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0084] Pharmaceutically acceptable salts include salts of one or more of the acidic or basic groups present in the compounds described herein. Specific embodiments of acid addition salts include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, hydrogen sulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, and the like. Certain embodiments of acid addition salts include chlorides or dichlorides.

[0085] In addition, acids generally considered suitable for forming pharma- ceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC on their website), the disclosures of which are incorporated herein by reference.

[0086] Suitable base salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts. All such acid and base salts are intended to be included within the scope of pharma- ceutically acceptable salts described herein, and all such acid and base salts are considered equivalent for purposes herein to the free forms of the corresponding compounds. Compounds of formula (I) and forms thereof may further exist in tautomeric forms, and all such tautomeric forms are contemplated and intended to be included within the scope of the compounds of formula (I) or forms thereof described herein. The compounds of formula (I) or forms thereof may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. This specification is intended to include all stereoisomeric forms of the compounds of formula (I) and mixtures thereof, including racemic mixtures. The compounds described herein may contain one or more chiral centers and therefore may exist as racemic mixtures (R / S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (if one chiral center is present). In one particular embodiment, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions that substantially contain only the (S) isomer. In another particular embodiment, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions that substantially contain only the (R) isomer. As one of ordinary skill in the art will appreciate, if two or more chiral centers are present, the compounds described herein may also exist as (R,R), (R,S), (S,R) or (S,S) isomers as defined by the IUPAC nomenclature recommendations.

[0087] As used herein, the term "chiral" refers to a carbon atom that is bonded to four non-identical substituents. Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. In describing optically active compounds, the prefixes D and L, or R and S, are used to represent the absolute configuration of the molecule around its chiral center. The substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold and Prelog ranking rules. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511).

[0088] As used herein, the term "substantially pure" refers to a compound that consists essentially of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100% of a single isomer. In one aspect herein, the compound of formula (I) or a form thereof is a substantially pure (S) enantiomeric form present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or an amount equal to 100%. In one aspect herein, the compound of formula (I) or a form thereof is a substantially pure (R) enantiomeric form present in an amount of 90% or more, in an amount of 92% or more, in an amount of 95% or more, in an amount of 98% or more, in an amount of 99% or more, or in an amount equal to 100%. As used herein, a "racemate" is any mixture of isometric forms that is not "enantiomerically pure," including, but not limited to, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20.

[0089] In addition, the present specification embraces all geometric and positional isomers. For example, when a compound of formula (I) or a form thereof incorporates a double bond or a fused ring, both cis and trans forms, as well as mixtures, are embraced within the scope of the present specification. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by using chiral HPLC columns or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., hydrolyzing). Some of the compounds of formula (I) may also be atropisomers (e.g., substituted biaryls) and are considered as part of the present specification.

[0090] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds (including salts, solvates, esters and prodrugs, and salts, solvates and esters of the prodrugs), such as those that may exist due to asymmetric carbons on the various substituents, are contemplated within the scope of this specification, including enantiomeric forms (which may also exist in the absence of asymmetric carbons), rotamer forms, atropisomers, and diastereomeric forms, as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl, etc.). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers or may exist in racemic mixtures as described above.

[0091] Use of the compound Provided herein is a method for treating a disease in a subject in need thereof. As used herein, the term "subject" or "patient" refers to any animal, including mammals. For example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human. As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response sought in a tissue, system, animal, individual, or human by a researcher, veterinarian, physician, or other clinician. In some embodiments, the dosage of the compound, or a pharma- ceutically acceptable salt thereof, administered to a subject or individual is from about 1 mg to about 2 g, from about 1 mg to about 1000 mg, from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, or from about 50 mg to about 500 mg.

[0092] As used herein, the term "treating" or "treatment" refers to one or more of: (1) preventing a disease; e.g., preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but has not yet experienced or exhibited the symptoms or symptomology of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder (i.e., preventing further development of the symptoms and / or symptomology); and (3) ameliorating a disease; e.g., ameliorating a disease, condition, or disorder (i.e., reversing the symptoms and / or symptomology) in an individual who is experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder, e.g., reducing the severity of the disease or reducing or alleviating one or more symptoms of the disease.

[0093] The present application provides a method for treating a neurodegenerative disease characterized by accumulation and aggregation of aberrant MAPT in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula (I)). Also provided herein is a method for treating neurofibrillary tangle and paired helical filament formation in neurons and glia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula (I)).

[0094] Also provided herein is a method for lowering MAPT4R protein in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula (I)). In some aspects of the methods provided herein, the compound is selected from the group of compounds of formula (I): or a pharma- ceutically acceptable salt thereof. Also provided herein is a method of inducing exon 10 skipping in MAPT pre-mRNA in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Also provided herein is a method of inducing exon 10 skipping in MAPT pre-mRNA in a cell, the method comprising contacting the cell (e.g., ex vivo or in vivo) with a compound of formula (I) or a form thereof.

[0095] Also provided herein is a method of inducing exon 10 skipping in MAPT pre-mRNA in a gene, the method comprising contacting the gene (e.g., in a cell or subject expressing the gene) with a compound of formula (I) or a form thereof. Also provided herein is a method for producing MAPT ΔE4 mRNA in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Also provided herein is a method of producing MAPT ΔE4 mRNA in a cell, comprising contacting the cell (eg, ex vivo or in vivo) with a compound of formula (I) or a form thereof in a subject. Also provided herein is a method of producing MAPT ΔE4 mRNA in a gene, comprising contacting the gene (e.g., in a cell or subject expressing the gene) with a compound of formula (I) or a form thereof. Also provided herein is a method for reducing MAPT 4R mRNA in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.For example, such a method comprises reducing MAPT 4R mRNA concentration in a serum sample from the subject.

[0096] In some embodiments, MAPT 4R mRNA can be measured in serum, for example, in blood samples obtained from a subject before administration of a compound of formula (I) or a form thereof and in blood samples obtained from a subject after administration of a compound provided herein. In some embodiments, blood samples obtained from a subject after administration are obtained 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, and / or 30 days after administration of a compound provided herein. See, for example, FB Axelrod et al., Pediatr Res (2011) 70(5): 480-483; and RS Shetty et al., Human Molecular Genetics (2011) 20(21): 4093-4101, both of which are incorporated by reference in their entirety.

[0097] Further provided herein is a method for reducing MAPT 4R mRNA in a cell, comprising contacting the cell (e.g., ex vivo or in vivo) with a therapeutically effective amount of a compound of formula (I) or a salt form thereof. The amount of MAPT 4R mRNA in the treated cell is reduced compared to the cell in a subject in the absence of a compound provided herein. The method for reducing the amount of MAPT 4R mRNA in a cell can be carried out by contacting the cell with a compound of formula (I) or a form thereof in vitro, thereby reducing the amount of MAPT 4R mRNA in the cell in vitro. The use of such an in vitro method for reducing the amount of MAPT 4R mRNA includes, but is not limited to, use in screening assays (e.g., a compound of formula (I) or a form thereof is used as a positive control or standard to be compared with a compound of unknown activity or efficacy in reducing the amount of MAPT 4R mRNA).

[0098] In some embodiments, the amount of MAPT 4R mRNA is decreased in central nervous system cells, hi some embodiments thereof, the amount of MAPT 4R mRNA is decreased in plasma. The method of reducing mutant MAPT 4R mRNA in central nervous system cells can be carried out, for example, by contacting the cells with a compound of formula (I) or a form thereof in vivo, thereby reducing the amount of MAPT 4R mRNA in a subject in vivo. The contacting is achieved by having the compound of formula (I) or a form thereof present in the subject in an amount effective to achieve a reduction in the amount of MAPT 4R mRNA. This can be achieved, for example, by administering an effective amount of a compound of formula (I) or a form thereof to the subject. The use of such in vivo methods of reducing the amount of MAPT 4R mRNA includes, but is not limited to, use in methods of treating diseases or conditions in which a reduction in the amount of MAPT 4R mRNA is beneficial. In some embodiments thereof, the amount of MAPT 4R mRNA is decreased in central nervous system cells in subjects suffering from a neurodegenerative disease characterized by the accumulation and aggregation of abnormal MAPT.The method is preferably carried out by administering an effective amount of a compound of formula (I) or a form thereof to a subject suffering from a neurodegenerative disease characterized by the accumulation and aggregation of abnormal MAPT.

[0099] Also provided herein is a method for reducing MAPT4R protein expression in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.For example, such a method comprises reducing MAPT4R protein expression in a serum sample from the subject.Further provided herein is a method for reducing the average percentage of MAPT4R protein expression in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Also provided herein is a method for decreasing MAPT4R protein levels in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Further provided herein is a method for decreasing the average percentage of MAPT4R protein levels in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

[0100] Also provided herein is a method for reducing MAPT4R protein levels in a cell (e.g., ex vivo or in vivo), comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) or a form thereof. In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method. In some embodiments, the amount of MAPT4R protein level is decreased in a cell. In some embodiments, the cell is a central nervous system cell. In some embodiments, one or more of the compounds of formula (I) or its forms can be administered to a subject in need thereof in combination with at least one additional pharmaceutical agent.

[0101] Additional examples of suitable additional pharmaceutical agents for use in combination with the compounds of the present application to treat the diseases presented herein include, but are not limited to, antioxidants, anti-inflammatory agents, steroids, immunosuppressants, or other agents, such as therapeutic antibodies. In some embodiments, the compound of formula (I) or a form thereof can be administered to a subject in need thereof in combination with at least one additional pharmaceutical agent to treat a neurodegenerative disease characterized by the accumulation and aggregation of aberrant MAPT.

[0102] When used as therapeutic agents, the compounds provided herein can be administered in the form of pharmaceutical compositions, and thus the methods described herein can include administering pharmaceutical compositions. These compositions can be prepared as described herein or elsewhere, and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the site to be treated. Administration can be pulmonary (e.g., by inhalation or insufflation of powders or aerosols, e.g., by a nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration can include, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial, (e.g., intrathecal, intraocular, or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners, and the like may be necessary or desirable. In some embodiments, the compounds provided herein are suitable for oral and parenteral administration. In some aspects, the compounds provided herein are suitable for oral administration. In some aspects, the compounds provided herein are suitable for parenteral administration. In some aspects, the compounds provided herein are suitable for intravenous administration. In some aspects, the compounds provided herein are suitable for transdermal administration (e.g., administration using a patch or microneedle). Pharmaceutical compositions for topical administration may include transdermal patches (e.g., conventional or electrostimulation type), ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0103] Also provided are pharmaceutical compositions that contain the compound of formula (I) or a form thereof as an active ingredient in combination with one or more pharma- ceutically acceptable carriers (excipients). In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft and hard gelatin capsules, suppositories, sterile injectable liquids, and sterile packaged powders.

[0104] Some examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. In addition, the formulation can include, but is not limited to, lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propylhydroxybenzoates; sweetening agents; flavoring agents, or combinations thereof. The active compound can be effective over a wide dosage range and is generally administered in a pharma- ceutical effective amount. It is understood that the amount of compound to be administered and the administration schedule will usually be determined by the physician depending on the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound to be administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.

[0105] In another embodiment, the concentration-biological effect relationship observed for the compound of formula (I) or a form thereof exhibits a target plasma concentration in the range of about 0.001 μg·hr / mL to about 50 μg·hr / mL, about 0.01 μg·hr / mL to about 20 μg·hr / mL, about 0.05 μg·hr / mL to about 10 μg·hr / mL, or about 0.1 μg·hr / mL to about 5 μg·hr / mL. To achieve such plasma concentrations, the compounds described herein may be administered at varying doses, such as, but not limited to, 1.0 ng to 10,000 mg.

[0106] In one aspect, the dose administered to achieve an effective target plasma concentration can be administered based on subject or patient specific factors, and the dose administered on a weight basis can be from about 0.001 mg / kg / day to about 3500 mg / kg / day, or from about 0.001 mg / kg / day to about 3000 mg / kg / day, or from about 0.001 mg / kg / day to about 2500 mg / kg / day, or from about 0.001 mg / kg / day to about 2000 mg / kg / day, or from about 0.001 mg / kg / day to about 1500 mg / kg / day, or from about 0.001 mg / kg / day to about 1000 mg / kg / day, or from about 0.001 mg / kg / day to about 500 mg / kg / day, or about 0.001 mg / kg / day to about 250 mg / kg / day, or about 0.001 mg / kg / day to about 200 mg / kg / day, or about 0.001 mg / kg / day to about 150 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day, or about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 50 mg / kg / day, or about 0.001 mg / kg / day to about 25 mg / kg / day, or about 0.001 mg / kg / day to about 10 mg / kg / day, or is from about 0.001 mg / kg / day to about 5 mg / kg / day, or from about 0.001 mg / kg / day to about 1 mg / kg / day, or from about 0.001 mg / kg / day to about 0.5 mg / kg / day, or from about 0.001 mg / kg / day to about 0.1 mg / kg / day, or from about 0.01 mg / kg / day to about 3500 mg / kg / day, or from about 0.01 mg / kg / day to about 3000 mg / kg / day, or from about 0.01 mg / kg / day to about 2500 mg / kg / day, or from about 0.01 mg / kg / day to about 2000 mg / kg / day, or from about 0.01 mg / kg / day to about 1500 mg / kg / day , or about 0.01 mg / kg / day to about 1000 mg / kg / day, or about 0.01 mg / kg / day to about 500 mg / kg / day, or about 0.01 mg / kg / day to about 250 mg / kg / day, or about 0.01 mg / kg / day to about 200 mg / kg / day, or about 0.01 mg / kg / day to about 150 mg / kg / day, or about 0.01 mg / kg / day to about 100 mg / kg / day, or about 0.01 mg / kg / day to about 75 mg / kg / day, or about 0.01 mg / kg / day to about 50 mg / kg / day, or about 0.01 mg / kg / day to about 25 mg / kg / day, or about 0.0.01 mg / kg / day to about 10 mg / kg / day, or about 0.01 mg / kg / day to about 5 mg / kg / day, or about 0.01 mg / kg / day to about 1 mg / kg / day, or about 0.01 mg / kg / day to about 0.5 mg / kg / day, or about 0.01 mg / kg / day to about 0.1 mg / kg / day, or about 0.1 mg / kg / day to about 3500 mg / kg / day, or about 0.1 mg / kg / day to about 3000 mg / kg / day, or about 0.1 mg / kg / day to about 2500 mg / kg / day, or about 0.1 mg / kg / day to about 2000 mg / kg / day, or about 0.1 mg / kg / day to about 1500 mg / kg / day, or about 0.1 mg / kg / day to about 1 ...000 mg / kg / day, The dose may range from about 0.1 mg / kg / day to about 500 mg / kg / day, or from about 0.1 mg / kg / day to about 250 mg / kg / day, or from about 0.1 mg / kg / day to about 200 mg / kg / day, or from about 0.1 mg / kg / day to about 150 mg / kg / day, or from about 0.1 mg / kg / day to about 100 mg / kg / day, or from about 0.1 mg / kg / day to about 75 mg / kg / day, or from about 0.1 mg / kg / day to about 50 mg / kg / day, or from about 0.1 mg / kg / day to about 25 mg / kg / day, or from about 0.1 mg / kg / day to about 10 mg / kg / day, or from about 0.1 mg / kg / day to about 5 mg / kg / day, or from about 0.1 mg / kg / day to about 1 mg / kg / day, or from about 0.1 mg / kg / day to about 0.5 mg / kg / day.

[0107] The effective amount for a given subject can be determined by routine experimentation within the skill and judgment of the clinician or person skilled in the art, taking into account factors related to the subject.Dosage and administration can be adjusted to provide sufficient levels of active agent or to maintain the desired effect.Factors that can be taken into account include genetic screening, severity of disease state, status of disease progression, general health of the subject, ethnicity, age, weight, sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, experience with other therapies, and tolerability / response to the therapy.

[0108] Doses administered to achieve effective target plasma concentrations may be administered orally once (once in an approximately 24 hour period; i.e., "qd"), twice (once in an approximately 12 hour period; i.e., "bid" or "q.12h"), three times (once in an approximately 8 hour period; i.e., "tid" or "q.8h"), or four times (once in an approximately 6 hour period; i.e., "qds", "qid" or "q.6h") daily.

[0109] In certain embodiments, the dose administered to achieve an effective target plasma concentration may also be administered in single, divided, or continuous doses for patients or subjects having a body weight ranging from about 40 to about 200 kg (the dose may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). A typical adult subject is expected to have a median body weight in the range of about 70 kg. Long-acting pharmaceutical compositions may be administered every 2, 3, or 4 days, once per week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation. The compounds and compositions described herein may be administered to a subject via any drug delivery route known in the art, non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, and pulmonary routes of administration.

[0110] In another embodiment, the administered dose may be adjusted based on the dosage forms described herein formulated to deliver about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000 or 4000 mg / day. For any compound, the effective amount can be estimated initially in cell culture assays or in relevant animal models, such as mouse, guinea pig, chimpanzee, marmoset, or tamarin animal models. Relevant animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and the LD 50 / ED 50 In certain embodiments, the effective amount is such that a large therapeutic index is achieved. In further particular embodiments, the dosage is within the ED 50 The dosage may vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0111] Another aspect included within the scope of the present specification is the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily resulting from enzymatic processes. Thus, the present specification includes the use of compounds produced by a process comprising contacting a compound described herein with mammalian tissue or a mammal for a period of time sufficient to produce a metabolic product thereof. Such products typically comprise a radiolabel of formula (I), e.g. 14 C or 3H) compounds, administering a detectable dose (e.g., greater than about 0.5 mg / kg) of the radiolabeled compound to a mammal, such as a rat, mouse, guinea pig, dog, monkey, or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood, or other biological samples. The conversion products are "radiolabeled" by being isotopically enriched and therefore easily isolated (some are isolated by the use of antibodies capable of binding to epitopes remaining in the metabolite). The structures of the metabolites are determined in a conventional manner, for example, by MS or NMR analysis. In general, the analysis of the metabolites can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products are useful in diagnostic assays for therapeutic dosing of the compounds described herein, even if they do not possess biological activity of their own unless otherwise found in vivo.

[0112] Preparation of compounds Compounds of formula (I) can be prepared using reagents and methods known in the art, including those provided in International Application No. PCT / US2020 / 063612, the entire contents of which are incorporated herein by reference. EXAMPLES

[0113] Biological Examples The following in vitro biological examples demonstrate the utility of the compounds herein for the treatment of neurodegenerative diseases characterized by the accumulation of aberrant forms of MAPT. To more fully describe and aid in the understanding of the present specification, the following non-limiting biological examples are provided to more fully illustrate the scope of the present specification, and should not be construed as explicitly limiting the scope thereof. Variations of the present specification, whether now known or that may later be developed, that are within the scope of ascertainment by one of ordinary skill in the art, are deemed to be within the scope of the present specification and of the following claims.

[0114] Example 1 RT-qPCR assay to quantify MAPT 3R mRNA in cells Test compounds were serially diluted 3.16-fold in 100% DMSO to generate 7-point concentration curves. Aliquots of 0.5 μL of diluted compounds were transferred to a 96-well flat-bottom plate by a liquid handler. Aliquots of 0.5 μL of DMSO were also transferred to separate wells to serve as controls. Duplicate samples were prepared for each compound concentration and DMSO control. Cells were thawed and incubated in cell culture medium (DMEM, 10% FBS, and 1% antibiotic cocktail) for 72 hours. Cells were trypsinized, counted, and resuspended in cell culture medium to a concentration of 200,000 cells / mL. 100 μL aliquots of cell suspension were plated into compound-containing 96-well microtiter plates at 20,000 cells per well and incubated in a cell culture incubator (37° C., 5% CO2, 100% relative humidity). After 24 hours, the medium was aspirated from the cells and 20 μL of RCL2 lysis buffer (10 mM Tris-HCL pH 7.4, 150 mM NaCl, 0.33% IGEPAL® CA-630) was added to each well and incubated at room temperature for 1 minute. Chilled nuclease-free water (140 μL per well) was added and the plate was immediately transferred to ice. After 1 minute on ice, the plate was frozen at -80°C overnight.

[0115] Preparation of RT-qPCR reaction mixture: TIFF2024533264000024.tif104146

[0116] Aliquots of 4 μL / well of cell lysate were transferred using a liquid handler to Armadillo 384-well PCR plates containing 6 μL / well of RT-qPCR reaction mix prepared as detailed above. The plates were then sealed with MicroAmp™ Optical Adhesive Film, followed by spinning down for 1 minute and placing into a CFX384 thermocycler (BioRad).

[0117] RT-qPCR was performed at the following temperatures for the indicated times: Step 1: 48℃ (30 minutes) Step 2: 95℃ (10 minutes) Step 3: 95℃ (15 seconds) Step 4: 60℃ (1 min) Steps 3 and 4 were then repeated for a total of 40 cycles.

[0118] For each dose of compound treatment, the percent exon 4 skipping was calculated using Equations 1 and 2. Formula 1

number

number

[0119] The data were fitted to a dose-response curve using the XLfit® statistical and curve fitting package to obtain EC 2X The EC values ​​obtained for representative compounds tested were 2X Values ​​(μM) are shown in Table 1.

[0120] EC 2X Values ​​≧3000 nM are designated as “inactive”. EC 2X Values ​​>1500nM to ≦3000nM are indicated by a single asterisk (*). EC 2X Values ​​>1000nM to ≦1500nM are indicated by two asterisks (**). EC 2X Values ​​>500nM to ≦1000nM are indicated by three asterisks (***). EC 2X Values ​​>50nM to ≦500nM are indicated by four asterisks (****). EC 2X Values ​​≦50 nM are indicated by five asterisks (*****).

[0121] [Table 1]

[0122] All documents referenced in this specification, whether or not they are specifically and individually indicated as incorporated by reference, are incorporated by reference into this application for any and all purposes to the same extent as if each individual reference was fully indicated herein.

[0123] Although the claimed subject matter has been fully described above, it will be understood by those skilled in the art that it can be practiced under a wide range of equivalents without affecting the scope of the subject matter or specific embodiments described herein, and it is intended that the appended claims be construed to include all such equivalents.

Claims

1. 1. A pharmaceutical composition for use in a method for treating a neurodegenerative disease characterized by the accumulation of abnormal microtubule-associated protein tau (MAPT) in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of formula (I) or a form thereof, wherein the form of the compound is selected from the group consisting of salts, hydrates, solvates, and tautomeric forms thereof. 【Chemical 1】 (I) (In the formula, R 1 is selected from the group consisting of phenyl and heteroaryl; Heteroaryl is a group of 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; The phenyl or heteroaryl may be selected from 1, 2, 3, or 4 independently selected R 1a may be substituted with a substituent, R 1a is cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, and C 1-6 independently selected from the group consisting of alkoxy; R 2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a group of 3-7 membered monocyclic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a group of 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl may contain a chiral carbon having either the (R) or the (S) configuration; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, phenyl, heterocyclyl, or heteroaryl can be selected from 1, 2, 3, or 4 independently selected R 2a may be substituted with a substituent, R 2a is cyano, halo, hydroxy, oxo, C 1-6 Alkyl, halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halo-C 1-6 Alkoxy, carboxyl, amino, C 1-6 Alkyl-amino, halo-C 1-6 Alkyl-amino, deutero-C 1-6 Alkyl-amino, (C 1-6 alkyl) 2 - Amino, C 3-10 cycloalkyl-amino, phenyl-amino, heterocyclyl-amino, heteroaryl-amino, C 1-6 Alkyl-thio, C 1-6 Alkyl-sulfonyl, C 3-10 independently selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a group of 3-7 membered monocyclic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a group of 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; C 3-10 Each occurrence of cycloalkyl, phenyl, heterocyclyl, or heteroaryl is selected from 1, 2, 3, or 4 independently selected R 2a’ may be substituted with a substituent, R 2a’ is cyano, halo, hydroxy, oxo, C 1-6 Alkyl, halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, and C 1-6 independently selected from the group consisting of alkoxy; R 3 is hydrogen, cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy, amino, C 1-6 Alkyl-amino, (C 1-6 alkyl) 2 - Amino, C 3-10 selected from the group consisting of cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a group of 3-7 membered monocyclic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a group of 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; C 1-6 Alkyl, C 3-10 Cycloalkyl, phenyl, heterocyclyl, or heteroaryl can be selected from 1, 2, 3, or 4 independently selected R 3a may be substituted with a substituent, R 3a is cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, and C 1-6 independently selected from the group consisting of alkoxy; R 4 is hydrogen, cyano, halo, hydroxy, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy, carbamoyl, C 3-10 selected from the group consisting of cycloalkyl, phenyl, and heterocyclyl; Heterocyclyl is a group of 3-7 membered monocyclic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S.

2. R 1 is one, two, three, or four independently selected R 1a The pharmaceutical composition according to claim 1, wherein the phenyl is optionally substituted with a substituent.

3. R 1 is heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, tetrazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, and quinolinyl, and the heteroaryl is selected from the group consisting of 1, 2, 3, or 4 independently selected R 1a The pharmaceutical composition according to claim 1, which is optionally substituted with a substituent.

4. R 1 2. The pharmaceutical composition of claim 1, wherein is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl.

5. R 1a But halo and C 1-6 2. The pharmaceutical composition of claim 1, wherein the aryl group is selected from the group consisting of alkyl.

6. R 2 But hydrogen, C 1-6 2. The pharmaceutical composition of claim 1, wherein the aryl group is selected from the group consisting of alkyl and heterocyclyl.

7. R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, and pentyl 1-6 The pharmaceutical composition of claim 1, wherein the aryl group is alkyl.

8. R 2 But C 1-6 alkyl, C 1-6 10. The pharmaceutical composition of claim 1, wherein the alkyl contains a chiral carbon having the (R) configuration.

9. R 2 But C 1-6 alkyl, C 1-6 10. The pharmaceutical composition of claim 1, wherein the alkyl contains a chiral carbon having the (S) configuration.

10. 1. A pharmaceutical composition for use in a method for treating a neurodegenerative disease characterized by accumulation of abnormal microtubule-associated protein tau (MAPT) in a subject in need thereof, said method comprising administering to a subject an effective amount of: 2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R,3S)-2-amino-3-methylpentyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R)-2-amino-3,3-dimethylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-ethyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-cyclopropyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; (2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carboxamide; 6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carbonitrile; (2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(3-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrazin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-(azetidin-3-yl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 7-bromo-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluorophenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminoethyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1R)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; (4S)-4-[(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)methyl]-1,3-oxazinan-2-one; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; (2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-(pyrrolidin-3-yl)thieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-phenylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminoethyl]-N-[(furan-2-yl)methyl]-2,7-diphenylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine; (2S)-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol; 6-(3-aminopropyl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-oxazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; (2R)-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol; 6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(1H-imidazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R)-2-amino-3-methoxypropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-[(2S)-2-(methylamino)propyl]thieno[3,2-d]pyrimidin-4-amine; 7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2-carbonitrile; 2-chloro-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-7-carbonitrile; 6-[(2S)-2-aminopropyl]-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2,7-dicarbonitrile; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-phenyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-(4-chlorophenyl)-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1R)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; (3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoropyrimidin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine, and (2R)-2-amino-3-(2-chloro-7-methoxy-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol or a form thereof selected from the group consisting of:

11. The compound or its form is 6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; (2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; and (3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol and the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof.

12. 1. A pharmaceutical composition for use in a method for treating a neurodegenerative disease characterized by accumulation of abnormal microtubule-associated protein tau (MAPT) in a subject in need thereof, said method comprising administering to a subject an effective amount of: 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R,3S)-2-amino-3-methylpentyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R)-2-amino-3,3-dimethylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-ethyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-cyclopropyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; (2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride; 6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carboxamide trifluoroacetate; 6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carbonitrile trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(3-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrazin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-(azetidin-3-yl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluorophenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(1S)-1-aminoethyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(1S)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(1R)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; (2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride; 2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-(pyrrolidin-3-yl)thieno[3,2-d]pyrimidin-4-amine formate; 6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-phenylthieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(1S)-1-aminoethyl]-N-[(furan-2-yl)methyl]-2,7-diphenylthieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine formate; 6-(3-aminopropyl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-oxazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(1H-imidazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R)-2-amino-3-methoxypropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate; 2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-[(2S)-2-(methylamino)propyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-7-bromo-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2-carbonitrile formate; 6-[(2S)-2-aminopropyl]-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2,7-dicarbonitrile hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-7-phenyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-(4-chlorophenyl)-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(1R)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; (3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoropyrimidin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate, and (2R)-2-amino-3-(2-chloro-7-methoxy-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride or a form thereof selected from the group consisting of:

13. The compound salt or form thereof is 6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; (2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; and (3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol dihydrochloride and the salt form of the compound is selected from the group consisting of hydrates, solvates, and tautomeric forms thereof.

14. 10. The pharmaceutical composition of claim 1, wherein an effective amount of the compound or a form thereof induces exon 10 skipping in MAPT mRNA in a subject.

15. 10. The pharmaceutical composition of claim 1, wherein an effective amount of the compound or a form thereof reduces MAPT4R protein in a subject.

16. 2. The pharmaceutical composition of claim 1, wherein the neurogenic disease is selected from the group consisting of Alzheimer's disease, dementia pugilistica, amyotrophic lateral sclerosis-parkinsonism-dementia of Guam (ALS / PD), Pick's disease, argyrophilic grain dementia, Niemann-Pick disease type C, subacute sclerosing panencephalitis (SSPE), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal ganglionic degeneration, frontotemporal dementia with parkinsonism-17 (FTDP-17), postencephalitic parkinsonism (PEP), autosomal recessive parkinsonism, frontotemporal dementia, and progressive supranuclear palsy.

17. 10. The pharmaceutical composition of claim 1, wherein an effective amount of the compound or a form thereof is in admixture with one or more pharmaceutically acceptable excipients.

18. Use of a compound of formula (I) or a form thereof for the manufacture of a medicament for treating a neurodegenerative disease characterized by the accumulation of abnormal microtubule-associated protein tau (MAPT) in a subject in need thereof, wherein the form of the compound is selected from the group consisting of its salts, hydrates, solvates, and tautomeric forms. 【Chemical 1】 (I) (In the formula, R 1 is selected from the group consisting of phenyl and heteroaryl; Heteroaryl is a group of 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; the phenyl or heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R 1a substituents; R 1a is independently selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, deutero-C 1-6 alkyl, and C 1-6 alkoxy; R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a group of 3-7 membered monocyclic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a group of 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl may contain a chiral carbon having an (R) or (S) configuration; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R 2a substituents; R 2a is independently selected from the group consisting of cyano, halo, hydroxy, oxo, C 1-6 alkyl, halo-C 1-6 alkyl, deutero-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, carboxyl, amino, C 1-6 alkyl-amino, halo-C 1-6 alkyl-amino, deutero-C 1-6 alkyl-amino, (C 1-6 alkyl) 2 -amino, C 3-10 cycloalkyl-amino, phenyl-amino, heterocyclyl-amino, heteroaryl-amino, C 1-6 alkyl-thio, C 1-6 alkyl-sulfonyl, C 3-10 cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a group of 3-7 membered monocyclic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a group of 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; each occurrence of C 3-10 cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R 2a′ substituents; R 2a' is independently selected from the group consisting of cyano, halo, hydroxy, oxo, C 1-6 alkyl, halo-C 1-6 alkyl, deutero-C 1-6 alkyl, and C 1-6 alkoxy; R 3 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, amino, C 1-6 alkyl-amino, (C 1-6 alkyl) 2 -amino, C 3-10 cycloalkyl, phenyl, heterocyclyl, and heteroaryl; Heterocyclyl is a group of 3-7 membered monocyclic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; Heteroaryl is a group of 5-8 membered monocyclic or bicyclic aromatic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S; the C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R 3a substituents; R 3a is independently selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, and C 1-6 alkoxy; R 4 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, carbamoyl, C 3-10 cycloalkyl, phenyl, and heterocyclyl; Heterocyclyl is a group of 3-7 membered monocyclic carbon atom ring structures containing 1-3 heteroatoms selected from N, O, and S.

19. The use of claim 18, wherein R 1 is phenyl optionally substituted with 1, 2, 3, or 4 independently selected R 1a substituents.

20. The use of claim 18, wherein R 1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, tetrazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, and quinolinyl, and wherein the heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R 1a substituents.

21. The use according to claim 18, wherein R 1 is a heteroaryl selected from the group consisting of furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2-oxazolyl, 1,3-oxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl.

22. The use of claim 18, wherein R 1a is selected from the group consisting of halo and C 1-6 alkyl.

23. The use of claim 18, wherein R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl, and heterocyclyl.

24. The use according to claim 18, wherein R 2 is a C 1-6 alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, and pentyl.

25. The use of claim 18, wherein R 2 is C 1-6 alkyl, and the C 1-6 alkyl contains a chiral carbon having the (R) configuration.

26. The use of claim 18, wherein R 2 is C 1-6 alkyl, and the C 1-6 alkyl contains a chiral carbon having the (S) configuration.

27. Use of a compound or a form thereof for the manufacture of a medicament for treating a neurodegenerative disease characterized by accumulation of abnormal microtubule-associated protein tau (MAPT) in a subject in need thereof, wherein the compound comprises: 2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R,3S)-2-amino-3-methylpentyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R)-2-amino-3,3-dimethylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-ethyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-cyclopropyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; (2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carboxamide; 6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carbonitrile; (2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(3-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrazin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-(azetidin-3-yl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 7-bromo-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluorophenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminoethyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1R)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; (4S)-4-[(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)methyl]-1,3-oxazinan-2-one; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; (2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-(pyrrolidin-3-yl)thieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-phenylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1S)-1-aminoethyl]-N-[(furan-2-yl)methyl]-2,7-diphenylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine; (2S)-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol; 6-(3-aminopropyl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-oxazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; (2R)-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol; 6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(1H-imidazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R)-2-amino-3-methoxypropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-[(2S)-2-(methylamino)propyl]thieno[3,2-d]pyrimidin-4-amine; 7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2-carbonitrile; 2-chloro-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-7-carbonitrile; 6-[(2S)-2-aminopropyl]-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2,7-dicarbonitrile; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-phenyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-(4-chlorophenyl)-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1R)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 2-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; (3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoropyrimidin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine, and (2R)-2-amino-3-(2-chloro-7-methoxy-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol and the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof.

28. A compound or a form thereof, 6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; (2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine; and (3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol and the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, and a tautomeric form thereof.

29. Use of a compound salt or a form thereof for the manufacture of a medicament for treating a neurodegenerative disease characterized by accumulation of abnormal microtubule-associated protein tau (MAPT) in a subject in need thereof, wherein the compound salt comprises: 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R,3S)-2-amino-3-methylpentyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R)-2-amino-3,3-dimethylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-ethyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-cyclopropyl-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; (2R)-2-amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride; 6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carboxamide trifluoroacetate; 6-[(2S)-2-aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carbonitrile trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(3-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrazin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-(azetidin-3-yl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluorophenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(1S)-1-aminoethyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(1S)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(1R)-1-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(pyrimidin-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; (2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride; 2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-(pyrrolidin-3-yl)thieno[3,2-d]pyrimidin-4-amine formate; 6-[(1S)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-phenylthieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(1S)-1-aminoethyl]-N-[(furan-2-yl)methyl]-2,7-diphenylthieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine formate; 6-(3-aminopropyl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,3-oxazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(1H-imidazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R)-2-amino-3-methoxypropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate; 2-chloro-N-[(furan-2-yl)methyl]-7-methyl-6-[(2S)-2-(methylamino)propyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-7-bromo-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2-carbonitrile formate; 6-[(2S)-2-aminopropyl]-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2,7-dicarbonitrile hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-7-phenyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-(4-chlorophenyl)-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(pyrimidin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(1R)-1-aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; (3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoropyrimidin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate, and (2R)-2-amino-3-(2-chloro-7-methoxy-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride and the compound salt form is selected from the group consisting of salts, hydrates, solvates, and tautomeric forms thereof.

30. A compound salt or a form thereof, 6-[(2R)-2-amino-3-methylbutyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methylfuran-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-bromo-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; (2R)-2-amino-3-(2-chloro-7-methyl-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(2-fluoropyridin-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminobutyl]-2-chloro-7-methyl-N-[(1,2-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2R)-3-amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine hydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-7-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine formate; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3-fluorothiophen-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; 6-[(2S)-2-aminopropyl]-2-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride; and (3S)-3-amino-4-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)butan-1-ol dihydrochloride and the salt form of the compound is selected from the group consisting of hydrates, solvates, and tautomeric forms thereof.

31. The use of claim 18, wherein the compound or a form thereof induces exon 10 skipping in MAPT mRNA in a subject.

32. The use described in claim 18, wherein the compound or a form thereof reduces MAPT4R protein in a subject.

33. The use of claim 18, wherein the neurogenic disease is selected from the group consisting of Alzheimer's disease, dementia pugilistica, amyotrophic lateral sclerosis-parkinsonism-dementia of Guam (Guam ALS / PD), Pick's disease, argyrophilic grain dementia, Niemann-Pick disease type C, subacute sclerosing panencephalitis (SSPE), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal ganglionic degeneration, frontotemporal dementia with parkinsonism-17 (FTDP-17), postencephalitic parkinsonism (PEP), autosomal recessive parkinsonism, frontotemporal dementia, and progressive supranuclear palsy.

34. The use of claim 18, wherein the medicament is an admixture of the compound or a form thereof with one or more pharmaceutically acceptable excipients.

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