Compounds for treating familial dysautonomia

Abstract

To provide compounds useful for improving pre-mRNA splicing in a cell.SOLUTION: Specifically, another aspect of the present description relates to substituted thieno[3,2-d]pyrimidine compounds, forms and pharmaceutical compositions thereof, and methods of use for treating or ameliorating familial dysautonomia.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 947,049, filed December 12, 2019. Joint Research Agreement Statement The disclosed subject matter was developed, and the claimed invention was created, by or on behalf of one or more parties to a joint research agreement executed on or before the effective filing date of the claimed invention. The claimed invention was created as a result of activities undertaken within the scope of the joint research agreement. The parties to the joint research agreement are PTC Therapeutics, Inc. and The General Hospital Corporation, d / b / a Massachusetts General Hospital. An embodiment of the present specification relates to a compound useful for improving pre-mRNA splicing in cells. In particular, another embodiment of the present specification relates to a substituted thieno[3,2-d]pyrimidine compound, its formulation and pharmaceutical composition, and a method of use for treating or ameliorating familial dysautonomia. [Background technology]

[0002] Familial dysautonomia (FD) is a hereditary sensory and autonomic neuropathy (HSAN) of the central and peripheral nervous systems characterized by widespread sensory and fluctuating autonomic dysfunction. FD affects neural development and is associated with progressive neuronal degeneration. Multiple systems are affected, resulting in a significant decrease in quality of life and premature death. FD is caused by mutations in the IKBKAP (also known as ELP1) gene; all cases described to date have at least one allele carrying a T to C mutation at position 6 of intron 20, resulting in a unique pattern of tissue-specific exon skipping. Kinetin derivatives useful for therapeutic targeting of the pre-mRNA splicing machinery and for treating FD are described in International Patent Application No. WO2016 / 115434, the disclosure of which is incorporated by reference in its entirety. All other documents referred to herein are incorporated by reference into this application as if fully set forth herein. Summary of the Invention

[0003] Embodiments herein include compounds comprising a compound of formula (I), or a form thereof: [ka] (wherein R1, R2, R3, and R4 are defined herein). Embodiments herein include methods of using a compound of formula (I), or a form or composition thereof, to treat or ameliorate FD in a subject in need thereof, said method comprising administering to the subject an effective amount of a compound of formula (I), or a form or composition thereof. Embodiments herein include the use of a compound of Formula (I), or a form thereof, to treat or ameliorate FD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a form thereof. Embodiments herein include the use of a compound of formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating FD in a subject in need thereof, comprising administering to the subject an effective amount of the medicament. DETAILED DESCRIPTION OF THE INVENTION

[0004] An aspect of the present specification relates to a compound comprising 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, racemates, enantiomers, diastereoisomers, stereoisomers, and tautomeric forms thereof. [ka] (In the formula, R1 is 1, 2, 3, or 4 independently selected R 1a optionally substituted aryl or heteroaryl; R 1a are cyano, halo, hydroxy, C 1-6 Alkyl, Halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, or C 1-6 is an alkoxy; R2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, aryl, heterocyclyl, or heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Each instance of cycloalkyl, aryl, heterocyclyl, and heteroaryl may be selected from 1, 2, 3, or 4 independently selected R 2a may be substituted with a substituent; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Each example of alkynyl and heterocyclyl may contain a chiral carbon having an (R) or (S) configuration; 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 3-10Cycloalkyl-amino, aryl-amino, heterocyclyl-amino, heteroaryl-amino, C 1-6 Alkyl-thio, C 1-6 Alkyl-sulfonyl, C 3-10 cycloalkyl, aryl, heterocyclyl, or heteroaryl; C 3-10 Each instance of cycloalkyl, aryl, heterocyclyl, and heteroaryl may 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, or C 1-6 is an 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 cycloalkyl, aryl, heterocyclyl, or heteroaryl; C 1-6 Alkyl, C 3-10 Each instance of cycloalkyl, aryl, heterocyclyl, or heteroaryl may be selected from 1, 2, 3, or 4 independently selected R 3a may be substituted with a substituent; R 3a are cyano, halo, hydroxy, C 1-6 Alkyl, Halo-C 1-6 Alkyl, or C 1-6 is an alkoxy; R4 is hydrogen, cyano, halo, hydroxy, C 1-6 Alkyl, Halo-C 1-6 Alkyl, C 1-6 Alkoxy, carbamoyl, C 3-10 cycloalkyl, aryl, or heterocyclyl)

[0005] In one embodiment, R is selected from 1, 2, 3, or 4 independently selected R 1a This includes compounds of formula (I) that are optionally substituted aryl or heteroaryl.

[0006] Another embodiment is where R is one or two independently selected R 1a This includes compounds of formula (I) that are optionally substituted aryl or heteroaryl. Another embodiment is where R is 1, 2, 3, or 4 independently selected R 1a This includes compounds of formula (I) which are aryl optionally substituted with substituents. Another embodiment is where R is one R 1a This includes compounds of formula (I) which are aryl optionally substituted with substituents. Another embodiment is where R is 1, 2, 3, or 4 independently selected R 1a This includes compounds of formula (I) wherein the aryl is selected from optionally substituted phenyl and naphthyl. Another embodiment is where R is 1, 2, 3, or 4 independently selected R 1a This includes compounds of formula (I) which are optionally substituted phenyl. Another embodiment is where R is one R 1a This includes compounds of formula (I) which are optionally substituted phenyl. Another embodiment is where R is 1, 2, 3, or 4 independently selected R 1a Included are compounds of formula (I) that are heteroaryl, optionally substituted with substituents. Another embodiment is where R is one or two independently selected R 1a Included are compounds of formula (I) that are heteroaryl, optionally substituted with substituents.

[0007] Another embodiment is heteroaryl selected from 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, wherein each instance of heteroaryl is selected from 1, 2, 3, or 4 independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0008] Another embodiment is heteroaryl selected from 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, wherein each instance of heteroaryl is selected from one or two independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents. Another embodiment is heteroaryl selected from 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, and each instance of heteroaryl is selected from one R 1a This includes compounds of formula (I) that are optionally substituted with substituents. Another embodiment is heteroaryl selected from 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, wherein each instance of heteroaryl is selected from two independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0009] Another embodiment is where R is heteroaryl selected from 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, pyridinyl, pyrimidinyl, and pyrazinyl, and each instance of heteroaryl is selected from 1, 2, 3, or 4 independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents. Another embodiment is where R is heteroaryl selected from 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, pyridinyl, pyrimidinyl, and pyrazinyl, and each instance of heteroaryl is selected from one or two independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents. Another embodiment is heteroaryl selected from 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, pyridinyl, pyrimidinyl, and pyrazinyl, and each instance of heteroaryl is selected from one R 1aThis includes compounds of formula (I) that are optionally substituted with substituents. Another embodiment is where R is heteroaryl selected from 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, pyridinyl, pyrimidinyl, and pyrazinyl, and each instance of heteroaryl is selected from two independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0010] Another embodiment 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-imidazol-5-yl, 1H-imidazol-5-yl, 1H-imidazol-6-yl, 1H-imidazol-7-yl, 1H-imidazol-8-yl, 1H-imidazol-9-yl, 1H-imidazol-10-yl, 1H-imidazol-11-yl, 1H-imidazol-12-yl, 1H-imidazol-13-yl, 1H-imidazol-14-yl, 1H-imidazol-15-yl, 1H-imidazol-16-yl, 1H-imidazol-17-yl, 1H-imidazol-18-yl, 1H-imidazol-19 ... ,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 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-triazol-5-yl, 1,2,3-thiadiazol heteroaryl selected from pyridin-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, wherein each instance of heteroaryl is selected from one, two, three, or four independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0011] Another embodiment is when 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-imidazol-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-triazol-5-yl, 1,2,3-thiazol- heteroaryl selected from diazol-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, wherein each instance of heteroaryl is selected from one or two independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0012] Another embodiment is when 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-imidazol-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-triazol-5-yl heteroaryl selected from 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; each instance of heteroaryl is selected from one R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0013] Another embodiment 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-imidazol-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 1,2-oxazol-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-triazol-5-yl, 1,2,3 heteroaryl selected from -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; each instance of heteroaryl is selected from two independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0014] Another embodiment is when 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-5-yl, 1,3-thiazol-2-yl, 1H-thiazol-5-yl, 1H-thiazol-2-yl, 1H-thiazol-5-yl, 1H-thiazol-2-yl, 1H-thiazol-5-yl, 1H-thiazol-4-yl, 1H-thiazol-5-yl, 1H-thiazol-5-yl, 1H-thiazol-2 ... heteroaryl selected from 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, wherein each instance of heteroaryl is selected from 1, 2, 3, or 4 independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0015] Another embodiment is when 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-5-yl, 1,3-thiazol- heteroaryl selected from 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, wherein each instance of heteroaryl is selected from one or two independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0016] Another embodiment is when 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-5-yl, 1,3- heteroaryl selected from 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, wherein each instance of heteroaryl is selected from one R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0017] Another embodiment 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-5-yl, 1,3 ... heteroaryl selected from 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, and each instance of heteroaryl is selected from two independently selected R 1a This includes compounds of formula (I) that are optionally substituted with substituents.

[0018] One aspect is R 1a But cyano, halo, hydroxy, C 1-6 Alkyl, Halo-C 1-6 Alkyl, deutero-C 1-6 Alkyl, or C 1-6 Includes compounds of formula (I) which are alkoxy. Another aspect is R 1a Halo or C 1-6 This includes compounds of formula (I) wherein: Another aspect is R 1a is halo selected from fluoro, chloro, bromo, and iodo. Another aspect is R 1a is fluoro. Another aspect is R 1a is selected from methyl, ethyl, propyl, butyl, pentyl and hexyl 1-6 This includes compounds of formula (I) wherein: Another aspect is R 1a is methyl.

[0019] In one embodiment, R2 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 is a cycloalkyl, aryl, heterocyclyl, or heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Each instance of cycloalkyl, aryl, heterocyclyl, and heteroaryl may be selected from 1, 2, 3, or 4 independently selected R 2a may be substituted with a substituent, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Each example of alkynyl and heterocyclyl includes compounds of formula (I) that may contain a chiral carbon having either the (R) or the (S) configuration. Another embodiment includes compounds of Formula (I) where R2 is hydrogen. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C which may be substituted 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) that may contain chiral carbons having either the (R) or the (S) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C which may be substituted 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) that contain a chiral carbon having the (R) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C which may be substituted 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) that contain a chiral carbon having the (S) configuration.

[0020] Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C selected from optionally substituted methyl, ethyl, propyl, butyl, pentyl, and hexyl 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) that may contain chiral carbons having either the (R) or the (S) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C selected from optionally substituted methyl, ethyl, propyl, butyl, pentyl, and hexyl 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) that contain a chiral carbon having the (R) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C selected from optionally substituted methyl, ethyl, propyl, butyl, pentyl, and hexyl 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) that contain a chiral carbon having the (S) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C selected from optionally substituted methyl, ethyl, propyl, butyl, and pentyl 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) that may contain chiral carbons having either the (R) or the (S) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C selected from optionally substituted methyl, ethyl, propyl, butyl, and pentyl 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) that contain a chiral carbon having the (R) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a C selected from optionally substituted methyl, ethyl, propyl, butyl, and pentyl 1-6alkyl, C 1-6 Alkyl includes compounds of formula (I) that contain a chiral carbon having the (S) configuration.

[0021] Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a Heterocyclyl is optionally substituted, and includes compounds of formula (I) that may contain a chiral carbon having either the (R) or the (S) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a Heterocyclyl is optionally substituted, and includes compounds of formula (I) that contain a chiral carbon atom having the (R) configuration. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a Heterocyclyl is optionally substituted, and includes compounds of formula (I) that contain a chiral carbon having the (S) configuration.

[0022] Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a Included are compounds of formula (I) that are heterocyclyls selected from optionally substituted 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. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a Includes compounds of formula (I) that are heterocyclyl selected from optionally substituted azetidinyl and pyrrolidinyl.

[0023] Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2aAzetidin-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-4-yl, and azepan-1-yl, azepan-2-yl, azepan-3-yl, and azepan-4-yl. Another embodiment is where R2 is 1, 2, 3, or 4 independently selected R 2a This includes compounds of formula (I) which are heterocyclyl selected from optionally substituted azetidin-3-yl and pyrrolidin-3-yl.

[0024] One aspect is 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, C1-6 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, aryl-amino, heterocyclyl-amino, heteroaryl-amino, C 1-6 Alkyl-thio, C 1-6 Alkyl-sulfonyl, C 3-10 is a cycloalkyl, aryl, heterocyclyl, or heteroaryl; C 3-10 Each instance of cycloalkyl, aryl, heterocyclyl, and heteroaryl may be selected from 1, 2, 3, or 4 independently selected R 2a´ This includes compounds of formula (I) that are optionally substituted with substituents. Another aspect is 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 3-10 cycloalkyl, or heterocyclyl, and C 3-10 Each instance of cycloalkyl or heterocyclyl may be selected from 1, 2, 3, or 4 independently selected R 2a´ This includes compounds of formula (I) that are optionally substituted with substituents.

[0025] Another aspect is R 2a is halo selected from fluoro, chloro, bromo, and iodo. Another aspect is R 2a is fluoro. Another aspect is R 2a is hydroxy.

[0026] Another aspect is R 2a is selected from methyl, ethyl, propyl, butyl, pentyl and hexyl 1-6 This includes compounds of formula (I) wherein: Another aspect is R2a is methyl. Another aspect is R 2a is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy 1-6 Includes compounds of formula (I) which are alkoxy. Another aspect is R 2a is methoxy. Another aspect is R 2a is amino. Another aspect is R 2a C 1-6 alkyl-amino, C 1-6 Includes compounds of formula (I) where alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. Another aspect is R 2a is methyl-amino. Another aspect is R 2a C 3-10 cycloalkyl-amino, C 3-10 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; 3-10 Each instance of cycloalkyl may be selected from 1, 2, 3, or 4 independently selected R 2a´ This includes compounds of formula (I) that are optionally substituted with substituents. Another aspect is R 2a is cyclobutyl-amino. Another aspect is R 2a C 3-10 is cycloalkyl, C 3-10 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; 3-10 Each instance of cycloalkyl may be selected from 1, 2, 3, or 4 independently selected R 2a´ This includes compounds of formula (I) that are optionally substituted with substituents. Another aspect is R 2ais cyclopropyl, and C 3-10 Each instance of cycloalkyl may be selected from 1, 2, 3, or 4 independently selected R 2a´ This includes compounds of formula (I) that are optionally substituted with substituents.

[0027] Another aspect is R 2a is a heterocyclyl selected from 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, and each instance of heterocyclyl is selected from one, two, three, or four independently selected R 2a´ This includes compounds of formula (I) that are optionally substituted with substituents. Another aspect is R 2a is 1,3-oxazinan-2-on-yl.

[0028] Another aspect is R 2aazetidin-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-4-yl, piperazine- heterocyclyl selected from 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-one-6-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, and azepan-4-yl, wherein each instance of heterocyclyl is selected from 1, 2, 3, or 4 independently selected R 2a´ This includes compounds of formula (I) that are optionally substituted with substituents. Another aspect is R 2a is 1,3-oxazinan-2-on-6-yl.

[0029] 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 is a cycloalkyl, aryl, heterocyclyl, or heteroaryl; C 1-6Alkyl, C 3-10 Each instance of cycloalkyl, aryl, heterocyclyl, or heteroaryl may be selected from 1, 2, 3, or 4 independently selected R 3a This includes compounds of formula (I) that are optionally substituted with substituents. Another embodiment is where R3 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, or aryl, and C 1-6 Alkyl, C 3-10 Each instance of cycloalkyl, or aryl may be selected from 1, 2, 3, or 4 independently selected R 3a This includes compounds of formula (I) that are optionally substituted with substituents. Another embodiment includes compounds of Formula (I) where R3 is hydrogen. Another embodiment includes compounds of Formula (I) where R3 is cyano. Another embodiment includes compounds of Formula (I) where R3 is halo selected from fluoro, chloro, bromo, and iodo. Another embodiment includes compounds of Formula (I) where R3 is bromo. Another embodiment includes compounds of Formula (I) where R3 is hydroxy.

[0030] Another embodiment is where R3 is 1, 2, 3, or 4 independently selected R 3a C selected from optionally substituted methyl, ethyl, propyl, butyl, pentyl, and hexyl 1-6 This includes compounds of formula (I) wherein: Another embodiment is where R3 is 1, 2, 3, or 4 independently selected R 3a C selected from optionally substituted methyl and ethyl 1-6 This includes compounds of formula (I) wherein: Another embodiment is a C 1111111 wherein R is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-6 Includes compounds of formula (I) which are alkoxy. Another embodiment includes compounds of Formula (I) where R3 is methoxy. Another embodiment is where R3 is 1, 2, 3, or 4 independently selected R 3a C selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl 3-10 Includes compounds of formula (I) which are cycloalkyl. Another embodiment is where R3 is 1, 2, 3, or 4 independently selected R 3a Includes compounds of formula (I) which are optionally substituted cyclopropyl. Another embodiment is where R3 is 1, 2, 3, or 4 independently selected R 3a This includes compounds of formula (I) wherein the aryl is selected from optionally substituted phenyl and naphthyl. Another embodiment is where R3 is 1, 2, 3, or 4 independently selected R 3a This includes compounds of formula (I) which are optionally substituted phenyl.

[0031] One aspect is R 3a But cyano, halo, hydroxy, C 1-6 Alkyl, Halo-C 1-6 Alkyl, or C 1-6 Includes compounds of formula (I) which are alkoxy. Another aspect is R 3a Halo or C 1-6 Includes compounds of formula (I) which are alkoxy. Another aspect is R 3a is halo selected from fluoro, chloro, bromo, and iodo. Another aspect is R 3a is chloro. Another aspect is R 3a is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy 1-6 Includes compounds of formula (I) which are alkoxy. Another aspect is R 3a is methoxy.

[0032] In one embodiment, R4 is hydrogen, cyano, halo, hydroxy, C 1-6 Alkyl, Halo-C 1-6 Alkyl, C 1-6 Alkoxy, carbamoyl, C 3-10 Includes compounds of formula (I) that are cycloalkyl, aryl, or heterocyclyl. Another embodiment is where R4 is hydrogen, cyano, halo, C 1-6 Alkyl, Halo-C 1-6 Alkyl, carbamoyl, C 3-10 cycloalkyl, or aryl.

[0033] Another embodiment includes compounds of Formula (I) where R4 is hydrogen. Another embodiment includes compounds of Formula (I) where R4 is cyano. Another embodiment includes compounds of Formula (I) where R4 is halo selected from fluoro, chloro, bromo, and iodo. Another embodiment includes compounds of Formula (I) where R4 is halo selected from chloro and bromo.

[0034] Another embodiment is a C 1 ... 1-6 This includes compounds of formula (I) wherein: Another embodiment is a C 1 ... 1-6 This includes compounds of formula (I) wherein: Another embodiment is where R4 is halo-C 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl, which are partially or fully substituted, where available valences allow, with one or more halogen atoms. Another embodiment is where R4 is halo-C 1-6 alkyl, C 1-6 Alkyl includes compounds of formula (I) where it is methyl substituted with three fluorine atoms. Another embodiment includes compounds of Formula (I) where R4 is carbamoyl. Another embodiment is a C 1 ... 3-10 Includes compounds of formula (I) which are cycloalkyl. Another embodiment includes compounds of Formula (I) where R4 is cyclopropyl. Another embodiment includes compounds of Formula (I) where R4 is aryl selected from phenyl and naphthyl. Another embodiment includes compounds of Formula (I) where R4 is phenyl.

[0035] In one embodiment, the compound of formula (I) or a form thereof is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereoisomer, a stereoisomer, and a tautomeric form thereof.

[0036] Compounds of formula (I) or embodiments thereof (compound no. 1 ) indicates that the salt form is isolated [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereoisomer, a stereoisomer, and a tautomeric form thereof.

[0037] Another embodiment of the compound of formula (I) or a form thereof is [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] wherein the compound is in a form selected from the group consisting of a hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomeric form thereof.

[0038] The present application further provides pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The present application further provides a method of treating familial dysautonomia, a disease of the central and peripheral nervous system associated with one or more pre-mRNA splicing defects, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0039] 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.

[0040] chemical definition The chemical terms used above and throughout the description herein shall be understood by those skilled in the art to have the meanings indicated below, unless specifically defined otherwise.

[0041] As used herein, "C 1-6The term "alkyl" generally refers to a saturated hydrocarbon radical having from 1 to 8 carbon atoms in a straight or branched chain arrangement, including, but not limited to, methyl, ethyl, n-propyl (also called propyl or propanyl), isopropyl, n-butyl (also called butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also called pentyl or pentanyl), n-hexyl (also called hexyl or hexanyl), and the like. In some embodiments, C 1-6 Alkyl is C 1-6 Alkyl, C 1-4 C includes, but is not limited to, alkyl, etc. 1-6 Alkyl radicals may be substituted, where available valences allow, with substituent types described herein. As used herein, "deutero" or "deutero-C 1-6 The term "alkyl" generally refers to a saturated hydrocarbon radical having from 1 to 6 carbon atoms in a straight or branched chain arrangement, in which one or more carbon atom members are replaced, where structural stability permits, with one or more deuterium atoms, including, but not limited to, deutero-methyl, deutero-ethyl, deutero-propyl, deutero-butyl, deutero-pentyl, deutero-hexyl, and the like. In certain embodiments, deutero-C 1-6 Alkyl is deutero-C 1-4 Alkyl, deutero-C, and the like. 1-6 Alkyl radicals may be substituted, where available valences allow, with substituent types described herein.

[0042] As used herein, "hetero-C" refers to 1-6The term "alkyl" generally refers to a saturated hydrocarbon radical having from 1 to 6 carbon atoms in a straight or branched chain arrangement, in which one or more heteroatoms, e.g., 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 2-4 Including, but not limited to, alkyl, etc. Hetero-C 1-6 Alkyl radicals may be substituted, where available valences allow, with substituent types described herein. As used herein, "C 2-6 The term "alkenyl" generally refers to a partially unsaturated hydrocarbon radical having from 2 to 8 carbon atoms in a straight or branched chain arrangement and having one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also called vinyl), allyl, propenyl, and the like. In some embodiments, C 2-6 Alkenyl is C 2-6 Alkenyl, C 2-4 Alkenyl and the like are included, but are not limited to. 2-6 Alkenyl radicals may be substituted, where available valences allow, with the types of substituents described herein. As used herein, "C 2-6 The term "alkynyl" generally refers to a partially unsaturated hydrocarbon radical having from 2 to 8 carbon atoms in a straight or branched chain arrangement and having one or more carbon-carbon triple bonds therein, including, but not limited to, ethynyl (also called acetylenyl), propynyl, butynyl, and the like. In some embodiments, C 2-6 Alkynyl is C 2-6 Alkynyl, C 2-4 Alkynyl and the like are included, but are not limited to. 2-6Alkynyl radicals may be substituted, where available valences allow, with the types of substituents described herein.

[0043] 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 radical having from 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 radicals may be substituted, where available valences allow, with substituent types described herein.

[0044] As used herein, the term "oxo" refers to a radical of the formula: =O. As used herein, the term "carboxyl" refers to a radical of the formula: -COOH, -C(O)OH, or -CO2H. As used herein, the term "carbamoyl" refers to a radical of the formula: -C(O)NH2. As used herein, "C 3-10 The term "cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon radical, 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 Including, but not limited to, cycloalkyl, etc. C 3-10Cycloalkyl radicals may be substituted, where available valences allow, with the types of substituents described herein.

[0045] The term "aryl," as used herein, generally refers to a radical of a monocyclic, bicyclic, or polycyclic aromatic ring structure of carbon atoms, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. Aryl radicals may be substituted, where available valences allow, with the types of substituents described herein. The term "heteroaryl," as used herein, generally refers to a monocyclic, bicyclic, or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members, where structural stability permits, are replaced 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 radicals may be substituted on carbon or nitrogen atom ring members, where available valences allow, with the types of substituents described herein.

[0046] In some embodiments, the nomenclature of heteroaryl radicals may vary, such as, by way of non-limiting example, furanyl may also be called furyl, thiophenyl may also be called thienyl, pyridinyl may also be called pyridyl, benzothiophenyl may also be called benzothienyl, and 1,3-benzoxazolyl may also be called 1,3-benzooxazolyl. In certain other aspects, terms relating to heteroaryl radicals may also include other positional isomers, for example, by way of non-limiting example, the term pyrrolyl may include 2H-pyrrolyl, 3H-pyrrolyl, etc., the term pyrazolyl may include 1H-pyrazolyl, etc., the term imidazolyl may include 1H-imidazolyl, etc., the term triazolyl may include 1H-1,2,3-triazolyl, etc., the term oxadiazolyl may include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc., the term tetrazolyl may include 1H-tetrazolyl, 2H-tetrazolyl, etc., the term indolyl may include 1H-indolyl, etc., the term indazolyl may include 1H-indazolyl, 2H-indazolyl, etc., the term benzimidazolyl may also include 1H-benzimidazolyl, the term purinyl may include 9H-purinyl, etc.

[0047] The term "heterocyclyl" as used herein generally refers to a radical of a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic carbon atom ring structure 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 oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazoline, and the like. Heterocyclyl radicals include, but are not limited to, lysinyl, thiazolinyl, 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 radicals may be substituted on carbon or nitrogen atom ring members, where available valences allow, with substituent types described herein.

[0048] As used herein, "C 1-6 The term "alkyl-amino" refers to a radical 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 C 1-6 Alkyl refers to a radical of which, where available valences allow, is partially or fully substituted with one or more halogen atoms. As used herein, "deutero-C" 1-6 The term "alkyl-amino" refers to a group of the formula: -NH-C 1-6 Alkyl (wherein C 1-6Alkyl refers to a radical of 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 radical (alkyl)2. As used herein, "C 1-6 The term "alkyl-carboxyl-amino" refers to a radical of the formula: --NH--C(O)--. As used herein, the term "aryl-amino" refers to a radical of the formula: --NH-aryl. As used herein, the term "heterocyclyl-amino" refers to a radical of the formula: --NH-heterocyclyl. As used herein, the term "heteroaryl-amino" refers to a radical of the formula: --NH-heteroaryl. As used herein, "C 1-6 The term "alkyl-thio" refers to a group of the formula: -SC 1-6 Refers to an alkyl radical. 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 radical.

[0049] The terms "halo" or "halogen" as used herein generally refer to halogen atom radicals and include 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 C 1-6 Alkyl refers to a radical of which, where available valences allow, 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: -C 1-6 Alkyl-halo (wherein C 1-6Alkyl refers to a radical of which, where available valences allow, 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: -C 1-6 Alkyl-deutero (wherein C 1-6 Alkyl refers to a radical of which, where available valences permit, is partially or fully substituted with one or more deuterium atoms. As used herein, the term "hydroxy" refers to a radical of the formula: --OH. As used herein, "hydroxy-C 1-6 The term "alkyl" refers to a group of the formula: -C 1-6 Alkyl-OH (wherein C 1-6 Alkyl refers to a radical of which, where available valences allow, is partially or fully substituted with one or more hydroxy radicals.

[0050] As used herein, the term "substituent" refers to a positional variable on an atom of a core molecule that replaces or substitutes one or more hydrogens on the designated atom at the designated atomic position, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Those of skill in the art should note that any carbon and heteroatom that appears to have an unsatisfied valence, as described or depicted herein, is presumed to have a sufficient number of hydrogen atoms to satisfy the described or depicted valence. In certain instances, one or more substituents having a double bond as a point of attachment (e.g., "oxo" or "=O") may be described, depicted, or listed within a substituent herein, and a structure may show only a single bond as a point of attachment to the core structure of Formula (I). Those of skill in the art will understand that a double bond is intended for such substituents, even if only a single bond is depicted. As used herein, with respect to the definitions of chemical terms provided herein, the term "such as" means that variations in chemical structure that one of ordinary skill in the art would expect 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 allow.

[0051] For purposes of this description, when one or more substitute variables of a compound of formula (I) or a form thereof encompasses functional groups incorporated into a compound of formula (I), each functional group appearing anywhere within the disclosed compound can be independently selected and, where appropriate, independently and / or optionally substituted.

[0052] As used herein, the term "independently selected" or "each selected" refers to a functional 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 for the compounds described herein includes replacement of the generic substituent with a species of substituent included within the particular genus, for example, aryl can be replaced with phenyl or naphthalenyl, etc., and it is understood that the resulting compound would be within the scope of the compounds described herein.

[0053] As used herein, the terms "in each instance" or "in each instance, if present" are used interchangeably with "...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 the term "alkyl," each, when present alone or as a substituent, is a C3-10 It is intended to refer to cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems. The term "optionally substituted," as used herein, means optional substitution with the specified substituted variable, groups, radicals or moieties.

[0054] Compound form The term "form" as used herein 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, enantiomer, diastereoisomer, stereoisomer, polymorph, and tautomeric form.

[0055] 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 diastereoisomer thereof. In certain embodiments described herein, the form of the compound of formula (I) is its tautomer. In certain embodiments described herein, the compound of formula (I) is in a pharmaceutically acceptable form. In certain embodiments described herein, the compound of Formula (I), or a form thereof, is isolated for use.

[0056] As used herein, the term "isolated" refers to the physical state of a compound of formula (I) or a form thereof after being 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 an isolation or purification process or processes described herein or known to those of skill in the art (e.g., chromatography, recrystallization, etc.), or by standard analytical techniques described herein or known to those of skill in the art.

[0057] The term "protected" as used herein means that a functional group in a compound of formula (I) or a form thereof is in a modified form so as to prevent 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 T.W. 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 a Wang resin or a 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 the pharmacologically active compounds described herein. Thus, such derivatives may be described as "prodrugs." All prodrugs of the compounds described herein are within the scope of the uses described herein.

[0058] As used herein, the term "prodrug" refers to a form of the compound (e.g., a drug precursor) that is converted in vivo to yield the active compound of Formula (I) or a form thereof. The conversion may occur by various mechanisms (e.g., by metabolic and / or non-metabolic chemical processes), for example, by hydrolysis and / or metabolism in the blood, liver, and / or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Prodrugs 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.

[0059] In one example, when a compound of formula (I) or a form thereof contains a carboxylic acid functional group, prodrugs can include esters 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, prodrug forms 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, prodrug forms can be prepared by replacing one or more 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, as appropriate: carboxylic acid ester, sulfonic acid ester, amino acid ester, phosphonic acid ester, and mono-, di-, or triphosphate ester, or alkyl substituent. It will be appreciated by those skilled in the art that one or more of such substituents can be used to obtain a compound of formula (I), or a form thereof, as a prodrug, as described herein.

[0060] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically 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 certain instances, a solvate can be isolated, 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 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.

[0061] The compound of formula (I) can form salts, which are intended to be included within the scope of the present specification. Reference herein to a compound of formula (I) or a form thereof is understood to include reference to its salt forms, unless otherwise indicated. As used herein, the term "salt(s)" refers to acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Furthermore, when a 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") may be formed and may be included within the term "salt(s)" as used herein.

[0062] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of the compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of formula (I) can be formed, for example, by reacting the 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., in which the salt precipitates or in an aqueous medium, followed by lyophilization. Pharmaceutically acceptable salts include salts of one or more 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, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucuronate, 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 detailed embodiments of acid addition salts include chlorides or dichlorides.

[0063] Additionally, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by 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 in The Orange Book (Food & Drug Administration, Washington, DC on their website), the disclosures of which are incorporated herein by reference.

[0064] 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 pharmaceutically acceptable salts described herein and, furthermore, all such acid and base salts are considered equivalent to the free form of the corresponding compound for the purposes of this description.

[0065] Compounds of formula (I) and forms thereof may further exist in tautomeric forms, and all such tautomeric forms are assumed 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 a form thereof may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. This specification is intended to include all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof, including racemic mixtures. The compounds described herein may contain one or more chiral centers and, as such, 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 aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another particular aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of ordinary skill in the art will appreciate, when more than one chiral center is 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.

[0066] As used herein, the term "chiral" refers to a carbon atom bonded to four non-identical substituents. Stereochemical definitions and conventions used herein generally follow those of S.P. 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 denote the absolute configuration of the molecule around its chiral center(s). The substituents attached to a given chiral center are ranked according to the Cahn-Ingold-Prelog ranking rules (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511).

[0067] 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 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 greater, in an amount of 92% or greater, in an amount of 95% or greater, in an amount of 98% or greater, in an amount of 99% or greater, or in an amount equal to 100%. In one aspect herein, the compound of formula (I) or a form thereof is a substantially pure (R) enantiomer form present in an amount of 90% or greater, in an amount of 92% or greater, in an amount of 95% or greater, in an amount of 98% or greater, in an amount of 99% or greater, 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.

[0068] Furthermore, all geometric and positional isomers are encompassed herein. For example, if 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 encompassed within the scope of this description. Diastereoisomeric mixtures can be separated into their individual diastereoisomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated using chiral HPLC columns or other chromatographic methods well known to those skilled in the art. Enantiomers can also be separated by converting an enantiomeric mixture into a diastereoisomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Additionally, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered part of this description.

[0069] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of the prodrugs), including enantiomeric forms (which may exist even without asymmetric carbons), rotamer forms, atropisomers, and diastereoisomeric forms, including those that may exist due to asymmetric carbons on various substituents, are contemplated within the scope of this description, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers or may exist as racemic mixtures as described above. Use of the terms "salts," "solvates," "esters," "prodrugs," and the like is intended to apply equally to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or isotopologues of the present compounds.

[0070] The term "isotopologue" refers to an isotopically enriched compound described herein identical to that listed herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from that usually found in nature. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 35 Cl and 36 Cl, each of which is also within the scope of this description. Certain isotopically enriched compounds described herein (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 isotopes (i.e., 14 C) are particularly preferred due to their ease of preparation and detectability. Additionally, heavier isotopes such as deuterium (i.e., 2 H) may be preferred in some circumstances because it may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability.

[0071] Crystalline polymorphs and amorphous forms of the compounds of formula (I), and of the salts, solvates, hydrates, esters and prodrugs of the compounds of formula (I), are further intended to be included in this description.

[0072] Use of the compound Provided herein are methods for treating a disease in a subject in need thereof. As used herein, the term "subject" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof. In certain embodiments, the disease is familial dysautonomia, a disease of the central and peripheral nervous system associated with one or more pre-mRNA splicing defects. The present application further provides a method of treating familial dysautonomia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula (I)).

[0073] In some embodiments of the methods provided herein, the compound is selected from the group of compounds of formula (I): or a pharmaceutically acceptable salt thereof. In some embodiments, a method for improving pre-mRNA splicing of the IKBKAP gene includes contacting the gene (e.g., in a cell or subject expressing the gene) with a compound provided herein (e.g., a compound of Formula (I)).

[0074] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a desired biological or medicinal response in a tissue, system, animal, individual, or human, as determined by a researcher, veterinarian, physician, or other clinician. In some embodiments, the dosage of the compound, or a pharmaceutically acceptable salt thereof, administered to a subject or individual is about 1 mg to about 2 g, about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 1 mg to 50 mg, or about 50 mg to about 500 mg. 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 predisposed to the disease, condition, or disorder but who has not yet developed or exhibits the lesions or symptomology of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder (i.e., arresting further development of the lesions and / or symptomology) in an individual who has or exhibits the lesions or symptomology of the disease, condition, or disorder; and (3) ameliorating a disease; e.g., ameliorating a disease, condition, or disorder (i.e., abrogating the lesions and / or symptomology) in an individual who has or exhibits the lesions or symptomology of the disease, condition, or disorder, e.g., reducing the severity of the disease or alleviating or alleviating one or more symptoms of the disease.

[0075] Also provided herein is a method for increasing IKBKAP (also known as ELP1) protein expression in a patient in need thereof, comprising administering to the patient an effective amount of a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). For example, such a method comprises increasing IKBKAP protein expression in a serum sample from the patient. Further provided herein is a method for increasing the mean percentage of IKBKAP protein expression in a patient in need thereof, comprising administering to the patient an effective amount of a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Also provided herein are methods for increasing IKBKAP protein expression in a cell (e.g., ex vivo or in vivo), comprising contacting the cell with a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt 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 IKBKAP protein expression is increased in a cell selected from the group consisting of a lung cell, a muscle cell, a liver cell, a heart cell, a brain cell, a kidney cell, and a nerve cell (e.g., a sciatic nerve cell or a trigeminal nerve cell), or any combination thereof. In some embodiments thereof, the amount of IKBKAP protein expression is increased in plasma. Also provided herein is a method for increasing IKBKAP protein levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). For example, such a method comprises increasing IKBKAP protein levels in a serum sample from the patient. Further provided herein is a method for increasing the mean percentage of IKBKAP protein levels in a patient in need thereof, comprising administering to the patient an effective amount of a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Also provided herein is a method for increasing IKBKAP protein levels in a cell (e.g., ex vivo or in vivo), the method comprising contacting the cell with a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof).

[0076] In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method. In some embodiments, the level of IKBKAP protein abundance is increased in cells selected from the group consisting of lung cells, muscle cells, liver cells, heart cells, brain cells, kidney cells, and nerve cells (e.g., sciatic nerve cells or trigeminal nerve cells), or any combination thereof. In some embodiments thereof, the level of IKBKAP protein abundance is increased in plasma.

[0077] Also provided herein is a method for increasing full-length IKBKAP mRNA in a patient in need thereof, comprising administering to the patient an effective amount of a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). For example, such a method comprises increasing the concentration of full-length IKBKAP mRNA in a serum sample from the patient. Further provided herein is a method for increasing the average percentage of exon inclusion (i.e., the percentage of correctly spliced ​​or full-length IKBKAP mRNA) in a patient in need thereof, comprising administering to the patient an effective amount of a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). In some embodiments, full-length IKBKAP mRNA can be measured in serum, e.g., blood samples obtained from a patient before administration of a compound provided herein, and in blood samples obtained from a patient after administration of a compound provided herein. In some embodiments, post-administration blood samples from a patient 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, e.g., 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 entireties.

[0078] Further provided herein is a method for increasing full-length IKBKAP mRNA in a cell, the method comprising contacting the cell with a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula (I)). The amount of full-length IKBKAP mRNA in the treated cell is increased compared to cells in a subject not treated with a compound provided herein. The method for increasing the amount of full-length IKBKAP mRNA in a cell can be carried out by contacting the cell in vitro with a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt form thereof), thereby increasing the amount of full-length IKBKAP mRNA in the cell in vitro. The use of such an in vitro method for increasing the amount of full-length IKBKAP mRNA includes, but is not limited to, use in screening assays (e.g., a compound provided herein is used as a positive control or standard for compound(s) of unknown activity or efficacy in increasing the amount of full-length IKBKAP mRNA). In some embodiments, the amount of full-length IKBKAP mRNA is increased in cells selected from the group consisting of lung cells, muscle cells, liver cells, heart cells, brain cells, kidney cells, and nerve cells (e.g., sciatic nerve cells or trigeminal nerve cells), or any combination thereof, hi some embodiments, the amount of full-length IKBKAP mRNA is increased in plasma.

[0079] A method for increasing full-length IKBKAP mRNA in a cell can be carried out, for example, by contacting a cell (e.g., a lung cell, a muscle cell, a liver cell, a heart cell, a brain cell, a kidney cell, or a nerve cell) in vivo with a compound provided herein (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), thereby increasing the amount of full-length IKBKAP mRNA in the subject in vivo. The contact is achieved by having a compound provided herein or a pharmaceutically acceptable salt form thereof present in the subject in an amount effective to achieve an increase in the amount of full-length IKBKAP mRNA. This can be achieved, for example, by administering an effective amount of a compound provided herein or a pharmaceutically acceptable salt form thereof to the subject. Uses of such in vivo methods for increasing the amount of full-length IKBKAP mRNA include, but are not limited to, use in methods for treating diseases or conditions in which an increase in the amount of full-length IKBKAP mRNA is beneficial. In some embodiments thereof, the amount of full-length IKBKAP mRNA is increased in cells selected from the group consisting of lung cells, muscle cells, liver cells, heart cells, brain cells, kidney cells, and nerve cells (e.g., sciatic nerve cells or trigeminal nerve cells), or any combination thereof, in a patient suffering from, for example, a disease or disorder provided herein (e.g., familial dysautonomia). The method is preferably carried out by administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt form thereof, to a subject suffering from familial dysautonomia.

[0080] In some aspects, one or more of the compounds provided herein can be administered to a subject in need thereof in combination with at least one additional pharmaceutical agent, hi some embodiments, the additional pharmaceutical agent is a compound provided herein (e.g., a compound of Formula (I)). Additional examples of suitable additional pharmaceutical agents that can be used in combination with the compounds of the present application for the treatment of diseases described herein include, but are not limited to, antioxidants, anti-inflammatory agents, steroids, immunosuppressants, or other agents, such as therapeutic antibodies.In some aspects, the compounds provided herein can be administered to a subject in need thereof in combination with at least one additional pharmaceutical agent for treating familial dysautonomia.In some embodiments, the additional pharmaceutical agent is phosphatidylserine.

[0081] When used as therapeutic agents, the compounds provided herein can be administered in the form of pharmaceutical compositions, and the methods described herein can include administering the 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 area to be treated. Administration can be intrapulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration can include, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular infusion or injection; 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 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 embodiments, the compounds provided herein are suitable for oral administration. In some embodiments, the compounds provided herein are suitable for parenteral administration. In some embodiments, the compounds provided herein are suitable for intravenous administration. In some embodiments, the compounds provided herein are suitable for transdermal administration (e.g., administration using a patch or microneedle). Pharmaceutical compositions for topical administration can include transdermal patches (e.g., conventional or electrostimulation), 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.

[0082] Pharmaceutical compositions containing a compound provided herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients) are also provided. In making the compositions provided herein, the active ingredient is typically mixed with or 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 compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Some examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. Formulations can further include, but are not limited to, lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; flavoring agents, or combinations thereof.

[0083] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood that the amount of compound administered and the administration schedule will usually be determined by a physician depending on the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0084] Also provided herein are kits comprising the compounds provided herein, more particularly, compounds of Formula (I) or pharmaceutically acceptable salts thereof. In some embodiments, the kits can include, for example, one or more delivery systems for the compounds provided herein or pharmaceutically acceptable salts thereof, and kit instructions (e.g., instructions for treating a subject). In some embodiments, the kits can include the compounds provided herein or pharmaceutically acceptable salts thereof, and one or more additional agents as set forth herein. In some embodiments, the kit may include one or more compounds provided herein or additional pharmaceutical agents, or pharmaceutically acceptable salts thereof, and a label indicating that the contents should be administered to a subject who is resistant to standard care agents or adjuvants used in the treatment of familial dysautonomia. In some embodiments, the additional pharmaceutical agent is phosphatidylserine. In another embodiment, the kit may include one or more compounds provided herein or additional pharmaceutical agents, or pharmaceutically acceptable salts thereof, and a label indicating that the contents should be administered to a subject having cells expressing abnormal IKBKAP pre-mRNA splicing. In another embodiment, the kit may include one or more compounds provided herein or additional pharmaceutical agents, or pharmaceutically acceptable salts thereof, and a label indicating that the contents should be administered to a subject having a central or peripheral nervous system disease caused by abnormal pre-mRNA splicing. In another embodiment, the kit can include one or more compounds provided herein or additional pharmaceutical agents, or pharmaceutically acceptable salts thereof, and a label indicating that the contents should be administered to a subject with familial dysautonomia. In some embodiments, the kit can include one or more compounds provided herein or pharmaceutically acceptable salts thereof, and a label indicating that the contents should be administered together with one or more additional pharmaceutical agents provided herein.

[0085] In another embodiment, the concentration-biological effect relationship observed for the compound of Formula (I) or a form thereof indicates a target plasma concentration ranging from about 0.001 μg·hr / mL to about 50 μg·hr / mL, from about 0.01 μg·hr / mL to about 20 μg·hr / mL, from about 0.05 μg·hr / mL to about 10 μg·hr / mL, or from 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 doses ranging, for example, but not limited to, from 1.0 ng to 10,000 mg.

[0086] In one embodiment, the dose administered to achieve an effective target plasma concentration may be administered based on subject or patient-specific factors, and may be administered on a weight basis 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 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 about 0.001 mg / kg / day to about 5 mg / kg / day, or about 0.001 mg / kg / day to about 1 mg / kg / day, or about 0.001 mg / kg / day to about 0.5 mg / kg / day, or about 0.001 mg / kg / day to about 0.1 mg / kg / day, or about 0.01 mg / kg / day to about 3500 mg / kg / day, or about 0.01 mg / kg / day to about 3000 mg / kg / day, or about 0.01 mg / kg / day to about 2500 mg / kg / day, or about 0.01 mg / kg / day to about 2000 mg / kg / day, or about 0.01 mg / kg / day to about 1500mg / kg / day, or about 0.01mg / kg / day to about 1000mg / kg / day, or about 0.01mg / kg / day to about 500mg / kg / day, or about 0.01mg / kg / day to about 250mg / kg / day, or about 0.01mg / kg / day to about 200mg / kg / day, or about 0.01mg / kg / day to about 150mg / kg / day, or about 0.01mg / kg / day to about 100mg / kg / day, or about 0.01mg / kg / day to about 75mg / kg / day, or about 0.01mg / kg / day to about 50mg / kg / day, or about 0.0.01 mg / kg / day to about 25 mg / kg / day, or about 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 1000 mg / kg / day, or about 0.1 mg / kg / day to about 500 mg / kg / day, or about 0.1 mg / kg / day to about 250 mg / kg / day, or about 0.1 mg / kg / day to about 200 mg / kg / day, or about 0.1 mg / kg / day to about 150 mg / kg / day, or about 0.1 mg / kg / day to about 100 mg / kg / day, or about 0.1 mg / kg / day to about 75 mg / kg / day, or Or it may be in the range of about 0.1 mg / kg / day to about 50 mg / kg / day, or about 0.1 mg / kg / day to about 25 mg / kg / day, or about 0.1 mg / kg / day to about 10 mg / kg / day, or about 0.1 mg / kg / day to about 5 mg / kg / day, or about 0.1 mg / kg / day to about 1 mg / kg / day, or about 0.1 mg / kg / day to about 0.5 mg / kg / day.

[0087] The effective amount for a given subject can be determined by routine experimentation within the skill and judgment of a clinician or person skilled in the art, taking into account factors related to the subject. Dosage regimens can be adjusted to provide sufficient levels of active agent(s) or to maintain a desired effect. Factors to be considered include genetic screening, severity of the disease state, disease progression status, the subject's overall health, ethnicity, age, weight, sex, diet, time and frequency of administration, drug combination(s), reaction sensitivities, experience with other therapies, and tolerability / response to treatment. The dose administered to achieve an effective target plasma concentration may be orally administered once daily (approximately once every 24 hours, i.e., "qd"), twice daily (approximately once every 12 hours, i.e., "bid" or "q.12h"), three times daily (approximately once every 8 hours, i.e., "tid" or "q.8h"), or four times daily (approximately once every 6 hours, i.e., "qds", "qid" or "q.6h"). In certain embodiments, the dose administered to achieve an effective target plasma concentration may be administered as a single, divided, or continuous infusion to patients or subjects having a body weight in the range of about 40 to about 200 kg (doses 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.

[0088] The compounds and compositions described herein can be administered to a subject via any drug delivery route known in the art, including, but not limited to, oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and injection), intracerebral, and intrapulmonary routes of administration.

[0089] In another embodiment, the administered dose may be adjusted based on a dosage form 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.

[0090] For any compound, the effective amount can be initially evaluated in cell culture assays or relevant animal models, such as mice, guinea pigs, chimpanzees, marmosets, or tamarins. 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 that is lethal in 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, an effective amount provides a large therapeutic index. In further specific 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.

[0091] Another aspect included within the scope of this 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, or esterification of the administered compound, primarily through enzymatic processes. Thus, this description 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 yield a metabolic product thereof.

[0092] Such products typically include radiolabeled isotopologues of the compounds described herein (e.g., 14 C or 3Identification of metabolic transformation products is accomplished by preparing a radioactively labeled compound (H), 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 metabolic transformation products in urine, bile, blood, or other biological samples. Because the transformation products are "radiolabeled" by being isotopically enriched, they are readily isolated (some are isolated using antibodies capable of binding to antigenic determinants remaining in the metabolite). The structures of the metabolites are determined by conventional techniques, such as MS or NMR analysis. In general, analysis of metabolites can be performed similarly to conventional drug metabolism studies well known to those skilled in the art. The transformation products are useful in diagnostic assays for therapeutic administration of the compounds described herein, even if they themselves possess no biological activity unless otherwise found in vivo.

[0093] Preparation of compounds General synthesis example As disclosed herein, methods for preparing the compounds of formula (I) described herein, or a form thereof, generally employ standard, well-known synthetic methodologies. Many of the starting materials are commercially available or can be prepared in the specific synthetic examples below using techniques known to those skilled in the art. Functional transformations to modify substituents, where chemically feasible, may also be performed and are considered to be within the scope of the general schemes and the knowledge of one skilled in the art. Compounds of formula (I) or a form thereof can be prepared as described in the following schemes.

[0094] Scheme A: Compounds of formula (I) may be prepared as described in Scheme A below. [ka]

[0095] Compound A1 (X=halogen) is treated with an optionally substituted aryl / heteroarylmethylamine in the presence of a base (e.g., TEA) using a suitable solvent (e.g., DMSO) at a suitable temperature to give compound A2. Protection of A2 with BocO in the presence of DMAP as a catalyst gives A3. Alternatively, compound A1 can be treated with ammonia to give compound A4, which can then be protected with BocO in the presence of DMAP as a catalyst to give A5. Reaction of A5 with an optionally substituted aryl / heteroaryl methyl alcohol under typical Mitsunobu reaction conditions (e.g., DEAD / PPh) in a suitable solvent (e.g., THF) gives A3. Compound A3 can be reacted with an optionally substituted cyclic sulfamidate prepared from the corresponding amino alcohol in the presence of a strong base (e.g., LDA) in a suitable solvent (e.g., THF) at a suitable temperature (e.g., −78° C.) to give A6. Deprotection can be completed by treatment with an acid (e.g., HCl in dioxane or TFA) to give compound A7.

[0096] Scheme B: Compounds of formula (I) may be prepared as described in Scheme B below. [ka]

[0097] Compound B1 is reacted with iodine in the presence of a strong base (e.g., LDA) in a suitable solvent (e.g., THF) at a suitable temperature (e.g., −78° C.) to give compound B2. Compound B2 can be converted to compound B3 by a Negishi reaction using an optionally substituted and appropriately protected amino-containing alkyl / cycloalkylzinc reagent in the presence of a catalyst (e.g., Pd(dppf)Cl) in a suitable solvent (e.g., THF) at a suitable temperature. Treatment of B3 with an acid (e.g., HCl in dioxane or TFA) gives compound B4. Alternatively, compound B2 can be converted to compound B5 by the Negishi reaction using an optionally substituted and appropriately protected ester-containing alkyl / cycloalkylzinc reagent in a suitable solvent (e.g., THF) in the presence of a catalyst (e.g., Pd(dppf)Cl2) at a suitable temperature. Compound B5 can be further converted to the corresponding alcohol B6 with a reducing agent (e.g., LAH) in a suitable solvent (e.g., THF). Further conversion of alcohol B6 to azide B7 can be achieved by reacting it with mesyl chloride in the presence of a base (e.g., TEA) in a suitable solvent (e.g., DCM), followed by reaction with sodium azide in a suitable solvent (e.g., DMF). Subjecting azide B7 to typical Staudinger reaction conditions (PPh3 in water and THF) gives the corresponding amine B8, which can be deprotected with an acid (e.g., HCl in dioxane or TFA) to give compound B9.

[0098] Scheme C: Compounds of formula (I) may be prepared as described in Scheme C below. [ka]

[0099] Compound C1 can be converted to the corresponding aldehyde C2 by treatment with a strong base (e.g., LDA) at a suitable temperature (e.g., −78° C.), followed by treatment with DMF in a suitable solvent (e.g., THF). Compound C2 can be condensed with Ellman's sulfinamide in the presence of a Lewis acid (e.g., CuSO) in a suitable solvent (e.g., DCE) at a suitable temperature to give compound C3. Reaction of C3 with a Grignard reagent in a suitable solvent (e.g., THF) gives compound C4, which can be further deprotected with an acid (e.g., HCl in dioxane or TFA) to give compound C5.

[0100] Scheme D: Compounds of formula (I) may be prepared as described in Scheme D below. [ka]

[0101] Compound D1 (X = halogen) is converted to D2 by reacting with sodium thiomethoxide in a suitable solvent (e.g., THF) at a suitable temperature. Compound D2 is reacted with an optionally substituted cyclic sulfamidate prepared from the corresponding amino alcohol in a suitable solvent (e.g., THF) in the presence of a strong base (e.g., LDA) at a suitable temperature (e.g., -78 ° C.) to give D3. Compound D3 is then oxidized to D4 with an oxidizing agent (e.g., mCPBA) in a suitable solvent (e.g., DCM). D4 is reacted with an optionally substituted aryl / heteroarylmethylamine in the presence of a base (e.g., TEA) using a suitable solvent (e.g., DMSO) at a suitable temperature to give compound D5. D5 can be deprotected by treating with an acid (e.g., HCl in dioxane or TFA) to give compound D6. Alternatively, compound D4 may be treated with ammonia in a solvent such as dioxane, followed by protection with BocO in the presence of DMAP as a catalyst to give compound D7. Reaction of D7 with an optionally substituted aryl / heteroaryl methyl alcohol under typical Mitsunobu reaction conditions (e.g., DEAD / PPh) in a suitable solvent (e.g., THF) gives compound D8, which can be deprotected using an acid (e.g., HCl in dioxane or TFA) to give compound D6.

[0102] Preparation of compounds Specific Synthesis Examples For the purpose of more detailed description and to aid in understanding, the following non-limiting examples are provided to more fully illustrate the scope of the compounds described herein, but should not be construed as specifically limiting that scope. Similar variations of the compounds described herein, which may now be known or may later be developed and which would be within the purview of one skilled in the art, are considered to be within the scope of the compounds described herein and are claimed. These examples illustrate the preparation of certain compounds. Those skilled in the art will understand that the techniques described in these examples represent techniques that function well in synthetic practice as described by those skilled in the art and therefore constitute preferred modes in that practice. However, it should be understood that those skilled in the art should recognize, in light of the present disclosure, that many modifications can be made in the specific methods disclosed and still obtain the same or similar results without departing from the spirit and scope of the present specification.

[0103] Except for the following examples of embodied compounds, unless otherwise indicated, all numbers expressing amounts of raw materials, reaction conditions, experimental data, and the like used in the specification and claims should be understood to be modified by the term "about." Accordingly, all such numbers represent approximations that may vary depending on the desired properties sought to be obtained by the reaction or as a result of various experimental conditions. Thus, within the range of expected experimental reproducibility, the term "about" with respect to resulting data refers to the range of the data, provided that it may vary according to the standard deviation from the mean. Similarly, with respect to experimental results obtained, resulting data may be consistently rounded up or down without loss of significant digits. At the very least, and without intending to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and rounding techniques employed by those of ordinary skill in the art.

[0104] Notwithstanding that the numerical ranges and parameters setting forth the broad ranges herein are approximations, the numerical values ​​set forth in the examples set forth below are reported as precisely as possible, however, any numerical values ​​inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0105] Compound example As used above, and throughout the specification, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: [Table 3-1] [Table 3-2] [Table 3-3]

[0106] Intermediate 1 tert-Butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide [ka]

[0107] A solution of imidazole (3108 g, 45.66 mol, 8.0 eq.) in i-PrOAc (10 L) in a 30 L round-bottom flask was cooled to -20 to -25 °C in a dry ice / acetone bath. SOCl (2040 g, 17.13 mol, 3.0 eq.) was added dropwise over 15 min, followed by tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate (1000 g, 5.71 mol, 1.0 eq.) in i-PrOAc (10 L) over 20 min. The temperature was raised to 15-25 °C, and the mixture was stirred at that temperature for 15 h. The mixture was then poured into 7.5 kg of ice and 1.5 kg of water. The organic phase was separated and washed with brine (5 L × 2). The resulting organic phase was transferred to a 50 L jacketed reactor and MeCN (17 L) and HO (3 L) were added. The mixture was cooled to 4 °C, and RuCl3·3HO (29.8 g, 0.11 mol, 0.02 eq.) was added, followed by NaIO4 (1342 g, 6.2 mol, 1.1 eq.), in portions over 1 h while maintaining the temperature at 8–10 °C. The mixture was poured into water (10 L). The organic phase was separated, washed with 20% Na2SO3 (aq.) and brine (5 L × 2), dried over Na2SO4, and then filtered through a silica gel pad. The filtrate was evaporated to give a residual solid, which was triturated with MTBE / petroleum ether (v / v = 1:1, 1.2 L) for 30 min and filtered through a Buchner funnel. The solid cake was washed with petroleum ether (1 L), redissolved in CHCl (5.4 L), and the solution was filtered through a silica gel pad. The filtrate was evaporated, followed by azeotropic evaporation with MTBE (1000 mL × 2) at 43 °C to give tert-butyl (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1040 g, 76.8% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 4.69 (dd, J= 9.2, 6.0 Hz, 1 H), 4.47 - 4.40 (m, 1 H), 4.22 (dd, J= 8.8, 2.8 Hz, 1 H), 1.57 (s, 9 H), 1.53 (s, J= 6.4Hz, 3H).

[0108] Intermediate 2 tert-Butyl (S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide [ka]

[0109] Step 1: N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serinate To a solution of methyl (tert-butoxycarbonyl)-L-serinate (25 g, 114.0 mmol) in CHCl (250 mL) was added imidazole (62.1 g, 912 mmol) and TBSCl (32 g, 205.9 mmol) at 0° C. The mixture was stirred for 2 h and then poured into a mixture of CHCl (300 mL) and water (200 mL). The organic phase was separated, washed with water (2×100 mL) and brine (1×100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give methyl N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serine (35.5 g, 93.3% yield) as an oil. LC-MS: m / z: 356.2 [M+Na] + .

[0110] Step 2: tert-Butyl (R)-(1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate To a solution of methyl N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serine (35.5 g, 106 mmol) in THF (200 mL) and EtOH (100 mL) was added CaCl (23.6 g, 213 mmol) followed by NaBH (16.1 g, 426 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, allowed to warm to room temperature for 16 h, and then poured into a mixture of EtOAc (200 mL) and water (150 mL). The organic phase was separated, washed with water (2 × 200 mL) and brine (1 × 150 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (R)-(1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate (30 g, 92.3% yield) as a white solid. LC-MS: m / z: 328.2 [M+Na] + ;RT=1.93 min.

[0111] Step 3: tert-butyl (4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide To a solution of imidazole (54 g, 785.3 mmol) in CHCl (300 mL) was added SOCl (12.9 mL, 176.0 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, and (R)-(1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)tert-butylcarbamate (30 g, 98.2 mmol) was added. The mixture was stirred at 0° C. for an additional 1 h and then poured into a mixture of EtOAc (500 mL) and water (400 mL). The organic layer was separated and washed with water (2×800 mL) and brine (800 mL), then dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (32.6 g, 94.4% yield) as a white solid. LC-MS: m / z: 374.1 [M+Na] + ;RT=2.08 min.

[0112] Step 4: tert-Butyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylate To a solution of tert-butyl (4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (32.6 g, 92.7 mmol) in water (300 mL) and CHCl (300 mL) were added NaIO (31.8 g, 148.0 mmol) and RuCl (1.94 g, 9.3 mmol) at room temperature. The mixture was stirred overnight and then extracted with CHCl (3 × 500 mL). The combined organic phases were washed with saturated NaHSO (aq. 500 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica) eluting with CHCl / hexane (50-100%) to give tert-butyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylate (18 g, 52.8% yield) as a white solid. LC-MS: m / z: 390.2 [M+Na] + ;RT=2.05 min; 1 H NMR (400 MHz, CDCl3) δ ppm 4.53-4.51 (m, 2 H), 4.2 (s, 1 H), 3.76-3.69 (m, 2 H), 1.46 (s, 9 H), 0.81 (s, 9 H), 0.00 (s, 6 H).

[0113] Intermediate 3 tert-Butyl (S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide [ka]

[0114] Step 1: N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-homoserine To a solution of (tert-butoxycarbonyl)-L-homoserine (21 g, 96.0 mmol) and imidazole (52 g, 770 mmol) in CHCl (210 mL) was added TBSCl (23 g, 153 mmol). The mixture was stirred at room temperature for 5 hours. Water (100 mL) was then added, and the organic phase was separated, washed with brine (80 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-homoserine (31.9 g, 99% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.85 (d, 1H), 4.22 (m, 1H), 3.69-3.75 (m, 2H), 1.93-2.01 (m, 2H), 1.36 (s, 9H), 0.83 (s, 9H), 0.00 (s, 6H); no COOH observed.

[0115] Step 2: tert-Butyl (S)-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)carbamate To a solution of N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-homoserine (31.9 g, 96 mmol) and N-methylmorpholine (10.7 g, 105 mmol) in THF (300 mL) was added isopropyl chloroformate (12.8 g, 105 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour and then filtered. The filtrate was cooled to 0° C., and a solution of NaBH (4 g, 105.0 mmol) in water was slowly added thereto. The mixture was stirred at 0° C. for 2 hours and then diluted with water (100 mL). The organic phase was separated, washed with brine (2×100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (S)-(4-((tertbutyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)carbamate (20 g, 57% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.41 (s, 1 H), 3.75-3.79 (m, 1 H), 3.66 (t, 1H), 3.55-3.58 (m, 2 H), 1.69-1.99 (m, 2 H), 1.85-1.66 (m, 2 H), 1.36 (s, 9 H), 0.83 (s, 9 H), 0.00 (s, 6 H).

[0116] Step 3: tert-butyl (4S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide To a solution of imidazole (22 g, 313 mmol) in CHCl (200 mL) was added SOCl (13.5 g, 113 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h, cooled to 0 °C, and a solution of tert-butyl (S)-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)carbamate (20 g, 62.7 mmol) in CHCl (100 mL) was added. The mixture was stirred at room temperature for 2 h and diluted with water (100 mL). The organic phase was separated, washed with brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (4S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide as a colorless oil (23 g, 99% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 3.83-4.05 (m, 1 H), 3.62-3.69 (m, 2 H), 3.53-3.59 (m, 2 H), 1.60-1.78 (m, 2 H), 1.36 (d, 9 H), 0.81 (d, 9 H), 0.02 (d, 6 H).

[0117] Step 4: tert-Butyl (S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide To a mixture of tert-butyl (4S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (23 g, 62.7 mmol) and NaIO (31 g, 144 mmol) in CHCl (300 mL) and water (310 mL) was added RuCl (0.83 g, 4 mmol). The reaction was stirred at room temperature for 5 h. The organic phase was separated, washed with 10% NaHSO (4 × 150 mL) and brine (150 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (20:1) to give tert-butyl (S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide as a white solid (5 g, 21% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 4.95 (q, 2 H), 4.30-3.35 (m, 1 H), 3.64-3.77 (m, 2 H), 1.96-2.11 (m, 2 H), 1.52 (s, 9 H), 0.83 (s, 9 H), 0.00 (s, 6 H).

[0118] Intermediate 4 7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine [ka]

[0119] Step 1: 7-Bromothieno[3,2-d]pyrimidine-2,4-diol Thieno[3,2-d]pyrimidine-2,4-diol (250.0 g; 1.48 mol, 1.00 eq.) and AcOH (3.0 L) were added to a 5 L round-bottom flask under N2 gas at 16–20 °C. The mixture was heated to 75 °C, and Br2 (594.0 g, 3.71 mol, 2.5 eq.) was added dropwise over 60 min. The reaction was continued at this temperature for 6 h, after which it was cooled to 16 °C. The mixture was poured into a stirred solution of Na2SO3 (856.8 g, 6.8 mol, 5.00 eq.) in water (8 L). The mixture was filtered, and the filter cake was washed with water and then dried in an air blast dryer for 12 h at 90 °C to give 7-bromothieno[3,2-d]pyrimidine-2,4-diol (328 g, 89% yield) as an off-white solid. LC-MS: m / z = 248.9 [M+H] + (Purity 83.6% (UV 214 nm, 1.64 min); 1 H NMR (DMSO-d6) δ: 11.54 (s, 1H), 11.44 (s, 1H), 8.37 (s, 1H). Step 2: 7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine To a mixture of 7-bromothieno[3,2-d]pyrimidine-2,4-diol (297.0 g, 1.20 mol, 1.00 eq.) in MeCN (2.7 L) was added N,N-dimethylaniline (98.00 g, 0.82 mol, 0.68 eq.) and POCl (1836.6 g, 5.95 mol, 5.5 eq.) dropwise over 30 min at 20 °C. The mixture was then heated to 85 °C and stirred at that temperature for 36 h, then cooled and poured into ice chips (4 kg) for stirring over 20 min. After stirring at 10 °C for an additional 30 min, the mixture was filtered, and the filter cake was washed with water and dried in an air blast dryer for 12 h at 60 °C to give 7-bromo-2,4-dichlorothieno[3,2-d]pyrimidine (272 g, 80% yield) as an off-white solid. LC-MS: m / z 284.9 [M+H] + (purity 88.0%, RT=3.66 min); 1 H NMR (DMSO-d6) δ: 8.85 (s, 1H).

[0120] Example 1 (Compound 2) 2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine [ka]

[0121] Step 1: 2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine A mixture of 2,4-dichlorothieno[3,2-d]pyrimidine (59 mg, 0.28 mmol, 1.0 eq.), 2-furylmethanamine (33 mg, 0.030 mL, 0.33 mmol, 1.2 eq.), and NEt (85 mg, 0.12 mL, 0.84 mmol, 3.0 eq.) in acetonitrile (0.5 mL) was stirred at room temperature for 1 h, then diluted with ethyl acetate, washed with water and brine, dried, and evaporated. The residue was purified on silica gel with ethyl acetate in dichloromethane (0-10% gradient) to give 2-chloro-N-(2-furylmethyl)thieno[3,2-d]pyrimidin-4-amine (71 mg, 96% yield). MS m / z 266.0, 268.0 [M+H] + ; 1 H NMR (CDCl3) δ : 7.77 (d, J= 5.4 Hz, 1H), 7.43 (dd, J= 1.6, 0.9 Hz, 1H), 7.39 (d, J= 5.4 Hz, 1H), 6.40 (qd, J= 3.4, 1.3 Hz, 2H), 5.43 (br s, 1H), 4.88 (d, J= 5.4 Hz, 2H).

[0122] The following compounds were prepared according to the procedure of Example 1 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 4]

[0123] Example 2 (Compound 25) N-[(furan-2-yl)methyl]-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine [ka]

[0124] Step 1: 7-Methyl-2-(trifluoromethyl)-3H-thieno[3,2-d]pyrimidin-4-one A mixture of methyl 3-amino-4-methylthiophene-2-carboxylate (1770 mg, 10.0 mmol, 1.0 eq.), 2,2,2-trifluoroacetamidine (2640 mg, 20.0 mmol, 2.0 eq.), and TFA (2280 mg, 1.53 mL, 20.0 mmol, 2.0 eq.) in ethanol (12 mL) was stirred at 150° C. for 4 hours and then cooled. The mixture was evaporated, and the residue was treated with ethyl acetate and water. The organic layer was separated, washed with water and brine, and then evaporated. The residue was purified on silica gel with methanol in dichloromethane (0-10% gradient) to give 7-methyl-2-(trifluoromethyl)-3H-thieno[3,2-d]pyrimidin-4-one (830 mg, 35% yield). MS m / z: 235.1 [M+H] + . Step 2: 4-chloro-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidine A mixture of 7-methyl-2-(trifluoromethyl)-3H-thieno[3,2-d]pyrimidin-4-one (560 mg, 2.4 mmol, 1.0 eq.) and POCl3 (4900 mg, 3.0 mL, 32 mmol, 13 eq.) was stirred at 105 °C for 8 h and then evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate (aq.). The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was purified on silica gel with ethyl acetate in hexane (3-15% gradient) to give 4-chloro-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidine (170 mg, 28% yield). MS: m / z: 253.1, 255.1 [M+H] + ;1 H NMR (CDCl3) δ: 7.85 (d, J= 1.1 Hz, 1H), 2.59 (d, J= 0.9 Hz, 3H). Step 3: N-(2-Furylmethyl)-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine To a solution of 4-chloro-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidine (170 mg, 0.67 mmol, 1.0 eq.) in acetonitrile (2.0 mL) was added furfurylamine (330 mg, 0.30 mL, 3.4 mmol, 5.0 eq.). The mixture was then stirred at 60 °C for 1 h, then cooled, diluted with ethyl acetate, washed with water and brine, then dried and evaporated. The residue was purified on silica gel with ethyl acetate in hexane (5-30% gradient) to give N-(2-furylmethyl)-7-methyl-2-(trifluoromethyl)thieno[3,2-d]pyrimidin-4-amine. MS: m / z: 314.1 [M+H] + . 1 H NMR (CDCl3) δ: 7.46 (d, J= 1.1 Hz, 1H), 7.42 (d, J= 1.1 Hz, 1H), 6.41 (d, J= 3.2 Hz, 1H), 6.38 (dd, J= 3.2, 1.8 Hz, 1H), 5.41 (br s, 1H), 4.91 (d, J= 5.5 Hz, 2H), 2.51 (d, J= 1.1 Hz, 3H).

[0125] Example 3 (Compound 3) 6-[(2S)-2-Aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine [ka]

[0126] Step 1: tert-Butyl (2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate A mixture of 2-chloro-N-(2-furylmethyl)thieno[3,2-d]pyrimidin-4-amine (0.265 g, 1.0 mmol, 1.0 eq.), prepared according to the procedure in Example 1, was dissolved in dichloromethane (3.0 mL), followed by the addition of di-tert-butyl dicarbonate (0.467 g, 2.12 mmol, 2.0 eq.) and 4-dimethylaminopyridine (13 mg, 0.11 mmol, 0.1 eq.), and allowed to stir for 1.5 hours until completion. The reaction was then diluted with ethyl acetate, washed with water and brine, dried, and evaporated. The material was purified by silica gel column chromatography using ethyl acetate in hexanes (5-25% gradient) to give tert-butyl (2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (0.374 g, 96.6% yield). MS m / z 366.2, 368.6 [M+H] + ; 1 H NMR (CDCl3) δ : 7.98 (d, J= 5.5 Hz, 1H), 7.43 (d, J= 5.6 Hz, 1H), 6.30 (ddd, J= 14.0, 3.2, 1.2 Hz, 2H), 5.24 (s, 2H), 1.54 (s, 9H).

[0127] Step 2: tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate To a solution of tert-butyl (2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (128 mg, 0.35 mmol, 1.0 eq.) in THF (1.0 mL) was added LDA (2.0 M, 0.24 mL, 0.49 mmol, 1.4 eq.) dropwise at −78° C. After 15 min, a solution of tert-butyl (4S)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (103 mg, 0.42 mmol, 1.2 eq.) in THF (0.5 mL) was added, and the temperature was allowed to rise to 0° C. over 1 h. The reaction was quenched with 1.0 M citric acid. The mixture was stirred at room temperature for 30 min and then extracted with ethyl acetate. The organic layer was washed with water, saturated NaHCO solution, and brine, then dried and evaporated. The residue was purified on silica gel with ethyl acetate in dichloromethane (0-10% gradient) to give tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (51 mg, 28% yield). MS m / z 545.2, 547.1 [M+Na] + ; 1 H NMR (CDCl3) δ : 7.30 (dd, J= 1.8, 0.8 Hz, 1H), 7.15 (s, 1H), 6.28 - 6.33 (m, 2H), 5.21 (s, 2H), 4.32 - 4.56 (m, 1H), 3.95 - 4.10 (m, 1H), 3.14 (d, J= 5.0 Hz, 2H), 1.54 (s, 9H), 1.43 - 1.47 (m, 9H), 1.19 (d, J= 6.7 Hz, 3H).

[0128] Step 3: tert-butyl N-[(1S)-2-(2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate General Boc removal procedure using HCl in dioxane. A mixture of tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (21 mg, 0.040 mmol), anisole (0.25 mL), and HCl in dioxane (4.0 N, 1.0 mL) was stirred at room temperature for 1 hour, then diluted with ether and filtered. The solid was collected and dried to give tert-butyl N-[(1S)-2-(2,4-dichlorothieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (15 mg, 94% yield). MS m / z 323.2, 325.2 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.46–7.50 (m, 1H), 7.29–7.31 (m, 1H), 6.38–6.43 (m, 2H), 4.85 (s, 2H), 3.69–3.75 (m, 1H), 3.35–3.41 (m, 1H), 3.27–3.31 (m, 1H), 1.40 (d, J = 6.6 Hz, 3H); no 3NH observed.

[0129] The following compounds were prepared according to the procedure of Example 3 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 5-1] [Table 5-2] [Table 5-3]

[0130] Example 4 (Compound 19) (2R)-2-Amino-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)propan-1-ol dihydrochloride [ka]

[0131] Step 1: tert-butyl N-[(1R)-1-[[2-chloro-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]methyl]-2-hydroxy-ethyl]carbamate To a solution of tert-butyl N-[(1R)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-[2-chloro-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]ethyl]carbamate (50 mg, 0.088 mmol, 1.0 eq., prepared according to the procedure of Example 3, Step 2) in THF (0.5 mL) was added TBAF (1.0 M in THF) (0.18 mL, 0.18 mmol, 2.0 eq.) at 0° C. After 2 h at room temperature, the mixture was diluted with ether, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was purified on silica gel with ethyl acetate in hexanes (5-50% gradient) to give tert-butyl N-[(1R)-1-[[2-chloro-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]methyl]-2-hydroxy-ethyl]carbamate (31 mg, 78% yield). MS m / z 575.5, 577.5 [M+Na] + ; 1 H NMR (CDCl3) δ: 7.29 (s, 1H), 6.26 - 6.31 (m, 2H), 5.20 (s, 2H), 4.86 - 5.00 (m, 1H), 3.88 - 3.99 (m, 1H), 3.70 - 3.77 (m, 1H), 3.60 - 3.69 (m, 1H), 3.22 (d, J = 7.3 Hz, 2H), 2.42 (s, 3H), 1.53 (s, 9H), 1.44 (s, 9H), no 1OH was observed.

[0132] Step 2: (2R)-2-Amino-3-[2-chloro-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]propan-1-ol dihydrochloride Following the general Boc deprotection procedure using HCl in dioxane, (2R)-2-amino-3-[2-chloro-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]propan-1-ol dihydrochloride (10 mg, 34% yield) was obtained. MS m / z 353.3, 355.3 [M+H] + ; 1 H NMR (methanol-d4) δ: 7.23–7.37 (m, 1H), 6.17–6.27 (m, 2H), 4.63 (s, 2H), 3.60–3.69 (m, 1H), 3.49 (s, 1H), 3.40–3.45 (m, 1H), 3.21–3.26 (m, 1H), 3.09–3.15 (m, 1H), 2.21 (s, 3H); 3NH and 1OH not observed.

[0133] The following compounds were prepared according to the procedure of Example 4 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 6]

[0134] Example 5 (Compound 79) 6-[(2S)-2-Aminopropyl]-2-chloro-N-[(3-fluoropyridin-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride [ka]

[0135] Step 1: (S)-(tert-butyl 6-(2-((tert-butoxycarbonyl)(methyl)amino)propyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of tert-butyl (S)-(6-(2-((tert-butoxycarbonyl)amino)propyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (111 mg, 0.21 mmol, 1.0 eq., prepared according to the procedure of Example 3, Step 2) in THF (1 mL) was added LiHMDS (1.0 M in THF, 0.23 mL, 1.1 eq.) dropwise at −50° C. After 30 min, MeI (35 mg, 0.25 mmol, 1.2 eq.) in THF (1 mL) was added and the mixture was allowed to warm to room temperature gradually over 1 h. The mixture was stirred at room temperature for an additional 1 h, then cooled to −50° C. and quenched with a few drops of citric acid (1.0 M, aq.). After warming to room temperature, the reaction was diluted with water and EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated. The crude material was purified by flash column chromatography on silica gel eluting with 0-10% EtOAc in CHCl to give a mixture of unreacted starting material and the desired product, which was further purified by preparative HPLC eluting with 20-100% CHCN in water containing 0.1% formic acid to give tert-butyl (S)-(6-(2-((tert-butoxycarbonyl)(methyl)amino)propyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (67 mg, 59% yield) as a white solid. MS m / z 573.3, 575.3 [M+Na] + .

[0136] Step 2: (S)-2-chloro-N-(furan-2-ylmethyl)-7-methyl-6-(2-(methylamino)propyl)thieno[3,2-d]pyrimidin-4-amine (S)-(6-(2-((tert-butoxycarbonyl)(methyl)amino)propyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (67 mg, 0.12 mmol) in HCl solution (4 M in dioxane, 1 mL) was stirred at room temperature for 1 hour, and then the volatile organics were removed. The crude solid was triturated with diethyl ether and filtered to give (S)-2-chloro-N-(furan-2-ylmethyl)-7-methyl-6-(2-(methylamino)propyl)thieno[3,2-d]pyrimidin-4-amine (33 mg, 50% yield) as the hydrochloride salt. MS m / z 351.1, 353.1 [M+H] + ; 1 H NMR (methanol-d4) δ: 7.46 (dd, J=1.8, 0.9 Hz, 1H), 6.32-6.45 (m, 2H), 4.80 (s, 2H), 3.55-3.63 (m, 1H), 3.42-3.48 (m, 1H), 3.17-3.23 (m, 1H), 2.80 (s, 3H), 2.38 (s, 3H), 1.27-1.38 (d, J=6.6 Hz, 3H); 2NH not observed.

[0137] Example 6 (Compound 28) 6-[(2S)-2-Aminopropyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine [ka]

[0138] Step 1: 2-chloro-7-methyl-4-methylsulfanyl-thieno[3,2-d]pyrimidine A round-bottom flask was charged with 2,4-dichloro-7-methyl-thieno[3,2-d]pyrimidine (3.0 g, 14 mmol, 1.0 eq.) and sodium methanethiolate (1.1 g, 14 mmol, 1.05 eq.) under vacuum and then filled with nitrogen. THF (55 mL) was then added to the round-bottom flask and stirred at 35° C. for 5.5 hours. The mixture was then filtered. The filtrate was evaporated and dried under vacuum to give 2-chloro-7-methyl-4-methylsulfanyl-thieno[3,2-d]pyrimidine (2.8 g, 84% yield), which was used in the next step without further purification. MS m / z 231.0, 233.0 [M+H] + ; 1 H NMR (CDCl3) δ: 7.52 (d, J=0.92 Hz, 1 H) 2.77 (s, 3 H) 2.48 (d, J=1.07 Hz, 3 H).

[0139] Step 2: tert-butyl N-[(1S)-2-(2-chloro-7-methyl-4-methylsulfanyl-thieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate To a solution of 2-chloro-7-methyl-4-methylsulfanyl-thieno[3,2-d]pyrimidine (500 mg, 2.16 mmol, 1.0 eq.) in THF (9.0 mL), LDA (2.0 M in THF / heptane / ethylbenzene) (1.3 mL, 2.60 mmol, 1.2 eq.) was added dropwise at −78° C. After 15 min, a solution of tert-butyl (4S)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (617.1 mg, 2.60 mmol, 1.2 eq.) in THF (9.0 mL) was added dropwise. The mixture was stirred at −78° C. for 10 min, then quenched with 1.0 M citric acid, followed by stirring at room temperature for 15 min. The mixture was diluted with ethyl acetate and washed with water, sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate in hexanes (2-25%) to give tert-butyl N-[(1S)-2-(2-chloro-7-methyl-4-methylsulfanyl-thieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (605 mg, 72% yield) as a white solid. MS m / z 388.4, 390.4 [M+H] + ; 1 H NMR (CDCl3) δ: 4.42 - 4.50 (m, 1 H), 3.98 - 4.08 (m, 1 H), 3.05 - 3.21 (m, 2 H), 2.75 (s, 3 H), 2.40 (s, 3 H), 1.44 (s, 9 H), 1.19 (d, J=6.87 Hz, 3 H).

[0140] Step 3: tert-butyl N-[(1S)-2-(2-chloro-7-methyl-4-methylsulfonyl-thieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate A solution of tert-butyl N-[(1S)-2-(2-chloro-7-methyl-4-methylsulfanyl-thieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (605 mg, 1.6 mmol, 1.0 eq.) and mCPBA (1435 mg, 6.2 mmol, 4.0 eq.) in CHCl (25 mL) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed with sodium thiosulfate (aq.), sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate in dichloromethane (0-10%) to give tert-butyl N-[(1S)-2-(2-chloro-7-methyl-4-methylsulfonyl-thieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (286 mg, 44% yield) as an off-white solid. MS m / z 442.1, 444.1 [M+Na] + ; 1 H NMR (CDCl3) δ: 4.44 - 4.61 (m, 1 H), 4.05 (br d, J=5.65 Hz, 1 H), 3.38 (s, 3 H), 3.22 - 3.29 (m, 1 H), 3.15 - 3.22 (m, 1 H), 2.48 (s, 3 H), 1.42 - 1.45 (m, 9 H), 1.23 (d, J=6.87 Hz, 3 H).

[0141] Step 4: tert-butyl N-[(1S)-2-[2-chloro-7-methyl-4-(2-thienylmethylamino)thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate To a solution of tert-butyl N-[(1S)-2-(2-chloro-7-methyl-4-methylsulfonyl-thieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (147 mg, 0.35 mmol, 1.0 eq.) in DMF (1.5 mL), 2-thienylmethanamine (79 mg, 0.70 mmol, 2.0 eq.) was added and stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and washed with NH4Cl, water, and brine. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate in hexanes (10-50%) to give tert-butyl N-[(1S)-2-[2-chloro-7-methyl-4-(2-thienylmethylamino)thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (120 mg, 76% yield) as a yellow solid. MS m / z 453.2, 455.2 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.26 (dd, J=5.11, 1.14 Hz, 1 H), 7.07 (d, J=2.90 Hz, 1 H), 6.94 (dd, J=5.11, 3.43 Hz, 1 H), 4.90 (d, J=5.49 Hz, 2 H), 3.85–3.94 (m, 1 H), 2.99–3.07 (m, 2 H), 2.30 (s, 3 H), 1.34 (s, 9 H), 1.17 (d, J=7.20 Hz, 3 H); no 2NH observed.

[0142] Step 5: 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-(2-thienylmethyl)thieno[3,2-d]pyrimidin-4-amine To a reaction tube containing tert-butyl N-[(1S)-2-[2-chloro-7-methyl-4-(2-thienylmethylamino)thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (120 mg, 0.26 mmol, 1.0 eq.) was added HCl in dioxane (4.0 M, 2.5 mL). The reaction mixture was stirred for 30 minutes, then diluted with diethyl ether, filtered, and rinsed with additional diethyl ether. The solid was placed under vacuum for 24 hours to give 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-(2-thienylmethyl)thieno[3,2-d]pyrimidin-4-amine (90 mg, 96% yield) as a white solid. MS m / z 353.1, 355.1 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.32 (dd, J=5.11, 1.14 Hz, 1 H), 7.14 (d, J=2.59 Hz, 1 H), 6.97 (dd, J=5.04, 3.51 Hz, 1 H), 5.01 (s, 2 H), 3.61 - 3.65 (m, 1 H), 3.33 - 3.39 (m, 1 H), 3.20 - 3.27 (m, 1 H), 2.40 (s, 3 H), 1.36 (d, J=6.56 Hz, 3 H); no 3NH observed.

[0143] The following compounds were prepared according to the procedure of Example 6 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6]

[0144] Example 7 (Compound 92) 6-[(2S)-2-Aminopropyl]-2-chloro-N-[(4-fluoro-1,3-thiazol-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine [ka]

[0145] Step 1: tert-butyl N-[(1S)-2-[4-(tert-butoxycarbonylamino)-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate tert-Butyl N-[(1S)-2-(2-chloro-7-methyl-4-methylsulfonyl-thieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (500 mg, 1.2 mmol, 1.0 eq., prepared according to the procedure of Example 6) and ammonia (0.5 mol / L) in dioxane (10 mL, 4.8 mmol, 4.0 eq.) were placed in a round-bottom flask and stirred at room temperature for 2 hours. Volatile organics were removed by a stream of nitrogen. The crude residue was then dissolved in CHCl (10 mL), and di-tert-butyl dicarbonate (660 mg, 3.0 mmol, 2.5 eq.) and 4-(dimethylamino)pyridine (15 mg, 0.12 mmol, 0.10 eq.) were added. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and potassium carbonate (1700 mg, 12 mmol, 10 eq.) was added. The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, and evaporated. The residue was purified on silica gel with ethyl acetate and dichloromethane (0-10%) to give tert-butyl N-[(1S)-2-[4-(tert-butoxycarbonylamino)-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (170 mg, 31% yield) as a white solid. 1 H NMR (CDCl3) δ: 7.66 (br s, 1H), 4.51 (d, J=7.6 Hz, 1H), 4.03 (br s, 1H), 3.02-3.19 (m, 2H), 2.38 (s, 3H), 1.55 (s, 9H), 1.43 (s, 9H), 1.18 (d, J=6.7 Hz, 3H).

[0146] Step 2: tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-[(4-fluorothiazol-2-yl)methyl]carbamate To a solution of tert-butyl N-[(1S)-2-[4-(tert-butoxycarbonylamino)-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (170 mg, 0.37 mmol, 1.0 eq.), (4-fluorothiazol-2-yl)methanol (74 mg, 0.56 mmol, 1.5 eq.), and PPh3 (157 mg, 0.59 mmol, 1.6 eq.) in THF (1 mL) was added DEAD (40% in toluene) (0.25 mL, 0.59 mmol, 1.5 eq.). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified on silica gel with ethyl acetate in dichloromethane (0-20%) to give tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-[(4-fluorothiazol-2-yl)methyl]carbamate (180 mg, 84% yield). MS m / z 572.2, 574.2 [M+H] + ; 1 H NMR (CDCl3) δ: 6.49 (d, J=4.7 Hz, 1H), 5.35 (s, 2H), 4.49 (br d, J=2.3 Hz, 1H), 3.99-4.08 (m, 1H), 3.20 (br dd, J=14.0, 4.6 Hz, 1H), 3.04-3.11 (m, 1H), 2.40 (s, 3H), 1.50 (s, 9H), 1.44 (s, 9H), 1.18 (d, J=6.7 Hz, 3H).

[0147] Step 3: 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluorothiazol-2-yl)methyl]-7-methyl-thieno[3,2-d]pyrimidin-4-amine To a reaction tube containing tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-[(4-fluorothiazol-2-yl)methyl]carbamate (180 mg, 0.31 mmol, 1.0 eq.), hydrochloric acid (4 mol / L) in dioxane (3 mL) was added. The mixture was stirred at room temperature for 1 hour, then diluted with diethyl ether, filtered, and rinsed with diethyl ether. The solid was dried under vacuum to give 6-[(2S)-2-aminopropyl]-2-chloro-N-[(4-fluorothiazol-2-yl)methyl]-7-methyl-thieno[3,2-d]pyrimidin-4-amine (60 mg, 51% yield) as a white solid. MS m / z 372.1, 374.1 [M+H] + ; 1 H NMR (CDCl3) δ: 6.82 (d, J=4.7 Hz, 1H), 5.02 (s, 2H), 3.66-3.68 (m, 1H), 3.36-3.39 (m, J=6.7 Hz, 1H), 3.26-3.29 (m, J=8.2 Hz, 1H), 2.41 (s, 3H), 1.41 (d, J=6.6 Hz, 3H); no 3NH observed.

[0148] The following compounds were prepared according to the procedure of Example 7 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 8]

[0149] Example 8 (Compound 64) 6-[(2S)-2-Aminopropyl]-2-chloro-N-[(3,5-difluoropyridin-4-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride [ka]

[0150] Step 1: tert-butyl N-[(1S)-2-[4-(tert-butoxycarbonylamino)-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate A mixture of tert-butyl N-[(1S)-2-(2-chloro-7-methyl-4-methylsulfonyl-thieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (500 mg, 1.2 mmol, 1.0 eq.) prepared according to the procedure of Example 6 and ammonia (0.5 mol / L) in dioxane (10 mL, 4.8 mmol, 4.0 eq.) was stirred at room temperature for 2 hours. The volatile organics were removed by a stream of nitrogen. The residue was suspended in CHCl (10 mL), and BocO (660 mg, 0.69 mL, 3.0 mmol, 2.5 eq.) and DMAP (15 mg, 0.12 mmol, 0.10 eq.) were added. After 2 hours at room temperature, the mixture was concentrated. The residue was redissolved in MeOH (10 mL) and K2CO3 (1.7 g, 12 mmol, 10 eq.) was added. The mixture was stirred at room temperature for 1 h. The organic solvent was then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, and evaporated. The residue was purified on silica gel with ethyl acetate and dichloromethane (0-10% gradient) to give tert-butyl N-[(1S)-2-[4-(tert-butoxycarbonylamino)-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (180 mg, 33% yield). MS m / z 457.3, 455.4 [MH] - ; 1 H NMR (CDCl3) δ : 7.56 (br s, 1H), 4.44 - 4.58 (m, 1H), 3.95 - 4.11 (m, 1H), 2.99 - 3.23 (m, 2H), 2.40 (s, 3H), 1.57 (s, 9H), 1.45 (s, 9H), 1.20 (d, J= 6.7 Hz, 3H).

[0151] Step 2: tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-[(3,5-difluoro-4-pyridyl)methyl]carbamate To a mixture of tert-butyl N-[(1S)-2-[4-(tert-butoxycarbonylamino)-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (40 mg, 0.088 mmol, 1.0 eq.), (3,5-difluoro-4-pyridyl)methanol (19 mg, 0.13 mmol, 1.5 eq.), and PPh3 (37 mg, 0.14 mmol, 1.6 eq.) in THF (1.0 mL) was added DEAD (40% in toluene) (0.060 mL, 0.13 mmol, 1.5 eq.). After 2 h at room temperature, complete reaction was observed by LC / MS, and the mixture was concentrated. The residue was purified on silica gel with ethyl acetate in dichloromethane (0-20% gradient) to give tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-[(3,5-difluoro-4-pyridyl)methyl]carbamate (51 mg, 100% yield). MS m / z 606.2, 608.3 [M+Na] + ; 1 H NMR (CDCl3) δ : 8.28 (s, 2H), 5.38 (s, 2H), 4.41 - 4.57 (m, 1H), 3.93 - 4.10 (m, 1H), 3.18 (d, J= 4.4 Hz, 1H), 2.99 - 3.12 (m, 1H), 2.41 (s, 3H), 1.51 (s, 9H), 1.45 (s, 9H), 1.18 (d, J= 6.7 Hz, 3H).

[0152] Step 3: 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoro-4-pyridyl)methyl]-7-methyl-thieno[3,2-d]pyrimidin-4-amine dihydrochloride N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-[(3,5-difluoro-4-pyridyl)methyl]carbamate tert-butyl (51 mg, 0.087 mmol) was treated with HCl (1.0 mL) in dioxane at room temperature for 2 hours, then diluted with ether and filtered. The solid was collected and dried to give 6-[(2S)-2-aminopropyl]-2-chloro-N-[(3,5-difluoro-4-pyridyl)methyl]-7-methyl-thieno[3,2-d]pyrimidin-4-amine dihydrochloride (40 mg, 100% yield). MS m / z 384.1, 386.1 [M+H] + ; 1 H NMR (methanol-d₄) δ: 8.57 (br s, 2H), 5.02 (s, 2H), 3.63–3.67 (m, 1H), 3.36–3.45 (m, 1H), 3.30 (s, 1H), 2.41 (s, 3H), 1.38 (d, J = 6.3 Hz, 3H); no 3NH observed.

[0153] The following compounds were prepared according to the procedure of Example 8 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 9]

[0154] Example 9 (Compound 8) 6-[(2S)-2-Aminopropyl]-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride [ka]

[0155] Step 1: tert-butyl N-[(1S)-2-(4-chlorothieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate To a solution of 4-chlorothieno[3,2-d]pyrimidine (340 mg, 2.0 mmol, 1.0 eq.) in THF (8.0 mL) was added LDA (2.0 M) (970 mg, 1.2 mL, 2.4 mmol, 1.2 eq.) at −78° C. After 30 min, a solution of tert-butyl (4S)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (620 mg, 2.6 mmol, 1.3 eq.) in THF (8.0 mL) was added dropwise. The mixture was stirred for 1 h while the temperature was slowly warmed to −20° C. The reaction was quenched by the addition of 1.0 N citric acid. The mixture was stirred at room temperature for 90 min, then diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, water, and brine, then dried over sodium sulfate, and evaporated. The residue was purified on silica gel with ethyl acetate in dichloromethane (0-15% gradient) to give tert-butyl N-[(1S)-2-(4-chlorothieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (160 mg, 24% yield). MS m / z 328.2, 330.2 [M+H] + ; 1 H NMR (CDCl3) δ : 8.86 (s, 1H), 7.26 (s, 1H), 4.36 - 4.53 (m, 1H), 3.90 - 4.06 (m, 1H), 3.12 (d, J= 6.0 Hz, 2H), 1.37 (s, 9H), 1.15 (d, J= 6.7 Hz, 3H).

[0156] Step 2: tert-butyl N-[(1S)-2-[4-(2-furylmethylamino)thieno[3,2-d]pyrimidin-6-yl]-1-methylethyl]carbamate A mixture of tert-butyl N-[(1S)-2-(4-chlorothieno[3,2-d]pyrimidin-6-yl)-1-methyl-ethyl]carbamate (50 mg, 0.15 mmol, 1.0 eq.) and 2-furylmethanamine (74 mg, 0.067 mL, 0.76 mmol, 5.0 eq.) in acetonitrile (0.5 mL) was stirred at room temperature overnight. LC / MS showed that the reaction was proceeding slowly. The mixture was then heated at 70° C. for 4 h, then cooled and evaporated. The mixture was treated with water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was purified on silica gel with ethyl acetate in dichloromethane (0-100% gradient) to give tert-butyl N-[(1S)-2-[4-(2-furylmethylamino)thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate. MS m / z 389.4, 390.4 [M+H] + ; 1 H NMR (CDCl3) δ : 8.65 (s, 1H), 7.41 (dd, J= 1.7, 0.8 Hz, 1H), 7.25 (s, 1H), 6.33 - 6.40 (m, 2H), 5.42 - 5.73 (m, 1H), 4.89 (d, J= 5.3 Hz, 2H), 4.43 - 4.59 (m, 1H), 3.90 - 4.08 (m, 1H), 3.12 (d, J= 5.2 Hz, 2H), 1.43 (s, 9H), 1.19 (d, J= 6.7 Hz, 3H).

[0157] Step 3: 6-[(2S)-2-Aminopropyl]-N-(2-furylmethyl)thieno[3,2-d]pyrimidin-4-amine dihydrochloride The tert-butyl N-[(1S)-2-[4-(2-furylmethylamino)thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate obtained above was treated with anisole (0.2 mL) and HCl (4 M in dioxane) (2.0 mL). The mixture was stirred at room temperature for 2 hours, then diluted with a large amount of ether and filtered. The solid was collected and dried to give 6-[(2S)-2-aminopropyl]-N-(2-furylmethyl)thieno[3,2-d]pyrimidin-4-amine dihydrochloride (36 mg, 65% yield over two steps). MS m / z 289.3, 290.3 [M+H] + ; 1 H NMR (methanol-d₄) δ: 8.75 (s, 1H), 7.36–7.49 (m, 2H), 6.29–6.45 (m, 2H), 4.92 (s, 2H), 3.65–3.72 (m, 1H), 3.36–3.44 (m, 1H), 3.29–3.35 (m, 1H), 1.35 (d, J = 6.6 Hz, 3H); 3NH not observed.

[0158] The following compounds were prepared according to the procedure of Example 9 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 10]

[0159] Example 10 (Compound 15) 6-[(2S)-2-Aminopropyl]-N-[(furan-2-yl)methyl]-2,7-dimethylthieno[3,2-d]pyrimidin-4-amine dihydrochloride [ka]

[0160] Step 1: tert-butyl N-[(1S)-2-[4-(2-furylmethylamino)-2,7-dimethyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate A mixture of tert-butyl N-[(1S)-2-[2-chloro-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (60 mg, 0.14 mmol, 1.0 eq., prepared according to the procedure in Example 3), trimethylboroxine (35 mg, 0.039 mL, 0.27 mmol, 2.0 eq.), CsCO (130 mg, 0.41 mmol, 3.0 eq.), and PdCldppf CHCl complex (11 mg, 0.014 mmol, 0.10 eq.) in dioxane (1.0 mL) and water (0.1 mL) was stirred at 120 °C under Ar for 2 h. After cooling, the reaction was diluted with ethyl acetate, washed with brine, and then dried and concentrated. The residue was purified on silica gel with ethyl acetate in hexanes (5-50% gradient) to give tert-butyl N-[(1S)-2-[4-(2-furylmethylamino)-2,7-dimethyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (60 mg, 100% yield). MS m / z 417.5 [M+H-Boc] + ; 1 H NMR (CDCl3) δ : 7.26 (d, 1H), 6.23 - 6.27 (m, 1H), 6.20 (d, J= 3.1 Hz, 1H), 5.17 (s, 2H), 4.40 - 4.58 (m, 1H), 3.94 - 4.11 (m, 1H), 3.17 (br s, 1H), 2.99 - 3.11 (m, 1H), 2.81 (s, 3H), 2.41 (s, 3H), 1.49 (s, 9H), 1.46 (s, 9H), 1.16 (d, J= 6.9 Hz, 3H).

[0161] Step 2: 6-[(2S)-2-Aminopropyl]-N-(2-furylmethyl)-2,7-dimethyl-thieno[3,2-d]pyrimidin-4-amine dihydrochloride A mixture of N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2,7-dimethyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (60 mg, 0.12 mmol, 1.0 eq.), anisole (0.2 mL), and HCl (4 M in dioxane) (1.0 mL) was stirred at room temperature for 2 hours. A few drops of methanol were added to homogenize the mixture, and the mixture was stirred for an additional hour before diluting it with a large amount of ether. The mixture was filtered, washed with ether, and dried to give 6-[(2S)-2-aminopropyl]-N-(2-furylmethyl)-2,7-dimethyl-thieno[3,2-d]pyrimidin-4-amine dihydrochloride (38 mg, 84% yield). MS m / z 317.3 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.36 (s, 1H), 6.26 - 6.37 (m, 2H), 4.84 (s, 2H), 3.51 - 3.62 (m, 1H), 3.27 - 3.34 (m, 1H), 3.14 - 3.19 (m, 1H), 2.68 (s, 3H), 2.36 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H); 3NH not observed.

[0162] The following compounds were prepared according to the procedure of Example 10 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 11]

[0163] Example 11 (Compounds 20 and 21) 6-[(2S)-2-Aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carboxamide trifluoroacetic acid and 6-[(2S)-2-Aminopropyl]-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidine-2-carbonitrile trifluoroacetic acid [ka]

[0164] Step 1: tert-butyl N-[(1S)-2-[2-cyano-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate A mixture of tert-butyl N-[(1S)-2-[2-chloro-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (60 mg, 0.14 mmol, 1.0 eq., prepared according to the procedure of Example 3), 1,4-diazabicyclo[2.2.2]octane (16 mg, 0.14 mmol, 1.0 eq.), and sodium cyanide (10 mg, 0.21 mmol, 1.5 eq.) in DMSO (1.0 mL) and water (0.1 mL) was stirred at 80° C. for 2 hours, then at 100° C. for 4 hours, then cooled, diluted with ethyl acetate, washed with brine, dried, and evaporated. The residue was purified on silica gel with ethyl acetate in hexane to give tert-butyl N-[(1S)-2-[2-cyano-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (29 mg, 49% yield). MS m / z 428.5 [M+H-Boc] + .

[0165] Step 2: 6-[(2S)-2-aminopropyl]-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidine-2-carboxamide 2,2,2-trifluoroacetic acid and 6-[(2S)-2-aminopropyl]-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidine-2-carbonitrile 2,2,2-trifluoroacetic acid N-[(1S)-2-[2-cyano-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate tert-butyl was stirred with HCl in dioxane (1.0 mL) for 2 hours, then diluted with ether and filtered. The solid was collected and purified by preparative HPLC to give 6-[(2S)-2-aminopropyl]-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidine-2-carboxamide 2,2,2-trifluoroacetate (4.8 mg, 15% yield). [MS m / z 346.3 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.38 - 7.44 (m, 1H), 6.33 - 6.40 (m, 2H), 4.91 (s, 2H), 3.57 - 3.67 (m, 1H), 3.16 - 3.25 (m, 1H), 2.46 (s, 3H), 1.36 (d, J = 6.6 Hz, 3H), 1H equivocal due to MeOD; 5NH not observed] and 6-[(2S)-2-aminopropyl]-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidine-2-carbonitrile 2,2,2-trifluoroacetic acid (10.0 mg, 33% yield). MS m / z 328.3 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.38–7.44 (m, 1H), 6.31–6.38 (m, 2H), 4.78 (s, 2H), 3.54–3.64 (m, 1H), 3.28–3.31 (m, 1H), 3.14–3.22 (m, 1H), 2.39 (s, 3H), 1.35 (d, J = 6.6 Hz, 3H); 3NH not observed.

[0166] Example 12 (Compound 68) 6-[(2S)-2-Aminopropyl]-7-bromo-2-chloro-N-[(3-fluoropyridin-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride [ka]

[0167] Step 1: tert-butyl N-[(1S)-2-[7-bromo-2-chloro-4-[(3-fluoro-4-pyridyl)methylamino]thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate A mixture of tert-butyl N-[(1S)-2-[2-chloro-4-[(3-fluoro-4-pyridyl)methylamino]thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (29 mg, 0.064 mmol, 1.0 eq., prepared according to the procedure of Example 6) and NBS (14 mg, 0.077 mmol, 1.2 eq.) in acetonitrile (0.1 mL) was stirred at 80° C. for 8 h, then cooled, diluted with ethyl acetate, washed with brine, dried and evaporated. The residue was purified on silica gel with ethyl acetate in dichloromethane (0-75% gradient) to give tert-butyl N-[(1S)-2-[7-bromo-2-chloro-4-[(3-fluoro-4-pyridyl)methylamino]thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (7 mg, 20% yield). MS m / z 530.0, 531.9, 533.9 [M+H] + .

[0168] Step 2: 6-[(2S)-2-Aminopropyl]-7-bromo-2-chloro-N-[(3-fluoro-4-pyridyl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride A mixture of tert-butyl N-[(1S)-2-[7-bromo-2-chloro-4-[(3-fluoro-4-pyridyl)methylamino]thieno[3,2-d]pyrimidin-6-yl]-1-methyl-ethyl]carbamate (7.0 mg, 0.01 mmol, 1.0 eq.) and HCl (4 M in dioxane) (0.5 mL, 2 mmol, 200 eq.) was stirred at room temperature for 2 hours, then diluted with ether and filtered. The solid was collected and dried to give 6-[(2S)-2-aminopropyl]-7-bromo-2-chloro-N-[(3-fluoro-4-pyridyl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride (6.0 mg, 90% yield). 1 H NMR (methanol-d₄) δ: 9.00-9.14 (m, 1H), 8.66-8.78 (m, 1H), 8.08-8.22 (m, 1H), 5.11 (s, 2H), 3.76-3.84 (m, 1H), 3.43-3.49 (m, 1H), 3.35-3.41 (m, 1H), 1.41 (d, J=6.4 Hz, 3H); 3NH not observed.

[0169] Example 13 (Compound 77) 6-[(2S)-2-Aminopropyl]-2-chloro-7-ethyl-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine [ka]

[0170] Step 1: 2-chloro-7-ethyl-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine 7-Bromo-2-chloro-N-(2-furylmethyl)thieno[3,2-d]pyrimidin-4-amine (400 mg, 1.2 mmol, 1.0 eq., prepared according to the procedure of Example 1), tri-tert-butylphosphonium tetrafluoroborate (15 mg, 0.05 mmol, 0.03 eq.), and tris(dibenzylideneacetone)dipalladium (24 mg, 0.03 mmol, 0.015 eq.) were weighed into a 20 mL scintillation vial. THF (5 mL) was added, followed by diethylzinc (1.0 mol / L) in hexane (1.3 mL, 1.3 mmol, 1.1 eq.). After stirring at room temperature for 1 h, the reaction was quenched with saturated NaHCO3 and poured into HO. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified on silica gel eluting with EtOAc in hexanes (0-30%) to give 2-chloro-7-ethyl-N-(2-furylmethyl)thieno[3,2-d]pyrimidin-4-amine (210 mg, 62% yield) as a white solid. MS m / z 293.9, 295.9 [M+H] + ; 1 H NMR (CDCl3) δ: 7.40-7.42 (m, 1H), 7.38-7.39 (m, 1H), 6.38 (s, 2H), 4.83-4.89 (m, 2H), 2.90 (dd, J=7.5, 1.1 Hz, 2H), 1.34 (t, J=7.5 Hz, 3H); 1NH not observed.

[0171] Step 2: tert-Butyl (2-chloro-7-ethylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate A solution of 2-chloro-7-ethyl-N-(2-furylmethyl)thieno[3,2-d]pyrimidin-4-amine (210 mg, 0.7 mmol, 1.0 eq.), di-tert-butyl dicarbonate (200 mg, 0.9 mmol, 1.1 eq.), 4-dimethylaminopyridine (25 mg, 0.2 mmol, 0.2 eq.), and dichloromethane (2 mL) was stirred at room temperature for 30 min. After concentration under reduced pressure, the crude residue was purified on silica gel eluting with 0-10% EtOAc in hexane to give tert-butyl N-(2-chloro-7-ethyl-thieno[3,2-d]pyrimidin-4-yl)-N-(2-furylmethyl)carbamate (260 mg, 92% yield) as a white solid. MS m / z 393.9, 395.9 [M+H] + ; 1 H NMR (CDCl3) δ: 7.59 (t, J=1.1 Hz, 1H), 7.27-7.31 (m, 1H), 6.19-6.36 (m, 2H), 5.21 (s, 2H), 2.93 (qd, J=7.5, 0.9 Hz, 2H), 1.52 (s, 9H), 1.35 (t, J=7.5 Hz, 3H).

[0172] Step 3: tert-butyl (S)-(6-(2-((tert-butoxycarbonyl)amino)propyl)-2-chloro-7-ethylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of tert-butyl N-(2-chloro-7-ethyl-thieno[3,2-d]pyrimidin-4-yl)-N-(2-furylmethyl)carbamate (260 mg, 0.7 mmol, 1.0 eq.) in THF (4 mL) was added lithium diisopropylamide (2.0 mol / L) (0.36 mL, 0.72 mmol, 1.1 eq.) in THF / heptane / ethylbenzene at −78° C. After stirring at −78° C. for 1 h, a solution of tert-butyl (4S)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (216 mg, 9.1 mmol, 1.3 eq.) in THF (4 mL) was added dropwise. The bath was removed and the reaction mixture was stirred at room temperature for 1 h, at which point it was quenched with 1 M citric acid (4 mL) and allowed to stir at room temperature for 0.5 h. The reaction mixture was diluted with EtOAc and washed with HO. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified on silica gel eluting with EtOAc (0-10%) in dichloromethane to give tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-ethyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (226 mg, 62% yield) as a pale yellow oil. MS m / z 573.3, 575.2 [M+Na] + ; 1 H NMR (CDCl3) δ: 7.28 (s, 1H), 6.26-6.29 (m, 2H), 5.17 (s, 2H), 3.95-4.07 (m, 1H), 3.18 (dd, J=14.3, 5.5 Hz, 1H), 3.00-3.10 (m, 1H), 2.87 (q, J=7.5 Hz, 2H), 1.51 (s, 9H), 1.43 (s, 9H), 1.22 (t, J=7.5 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H); 1NH not observed.

[0173] Step 4: (S)-6-(2-aminopropyl)-2-chloro-7-ethyl-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine A solution of tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-ethyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (200 mg, 0.4 mmol, 1.0 eq.) in HCl (4 M in dioxane) (2 mL) was stirred at room temperature for 4 hours. The precipitate was filtered and rinsed with diethyl ether to give 6-[(2S)-2-aminopropyl]-2-chloro-7-ethyl-N-(2-furylmethyl)thieno[3,2-d]pyrimidin-4-amine hydrochloride (137 mg, 97% yield) as an off-white solid. MS m / z 351.1, 353.1 [M+H] + ; 1 H NMR (DMSO-d6) δ: 8.80 (br t, J=5.6 Hz, 1H), 8.31 (br s, 3H), 7.59 (d, J=0.9 Hz, 1H), 6.40 (dd, J=3.1, 1.8 Hz, 1H), 6.32 (d, J=3.1 Hz, 1H), 4.65 (d, J=5.5 Hz, 2H), 3.36-3.43 (m, 1H), 3.31-3.35 (m, 1H), 3.03-3.19 (m, 1H), 2.63-2.82 (m, 2H), 1.22 (d, J=6.4 Hz, 3H), 1.12 (t, J=7.5 Hz, 3H).

[0174] Example 14 (Compound 87) 6-[(2S)-2-Aminopropyl]-2-chloro-7-phenyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine [ka]

[0175] Step 1: (S)-(tert-butyl 6-(2-((tert-butoxycarbonyl)amino)propyl)-2-chloro-7-phenylthieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate A mixture of tert-butyl N-[7-bromo-6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (100 mg, 0.2 mmol, 1.0 eq., prepared according to the procedure of Example 3), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium dichloromethane complex (7 mg, 0.008 mmol, 0.04 eq.), phenylboronic acid (23 mg, 0.2 mmol, 1.0 eq.), 1,4-dioxane (1 mL) and aqueous potassium carbonate (2 M) (0.25 mL, 0.50 mmol, 2.5 eq.) was heated at 80° C. for 2 h, cooled, then diluted with ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified on silica eluting with EtOAc in hexanes (0-20%) to give tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-phenyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (75 mg, 75% yield) as an off-white solid. MS m / z 615.3, 617.4 [M+H] + .

[0176] Step 2: (S)-6-(2-aminopropyl)-2-chloro-7-phenyl-N-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine A solution of tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-phenyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (75 mg, 0.12 mmol, 1.0 eq.) in HCl (4 M in dioxane) (1 mL) was stirred at room temperature for 2 h. The reaction was concentrated, and the crude residue was purified on silica gel eluting with MeOH (0-10%) in dichloromethane to give 6-[(2S)-2-aminopropyl]-2-chloro-7-phenyl-N-(2-thienylmethyl)thieno[3,2-d]pyrimidin-4-amine hydrochloride (18 mg, 25% yield) as a pale yellow solid. MS m / z 415.3, 417.4 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.54 (m, 2H), 7.45-7.50 (m, 1H), 7.39-7.45 (m, 2H), 7.28-7.33 (m, 1H), 7.09-7.15 (m, 1H), 6.95-7.00 (m, 1H), 4.96 (s, 2H), 3.44-3.54 (m, 1H), 3.34-3.37 (m, 1H), 3.21-3.28 (m, 1H), 1.19 (d, J=6.7 Hz, 3H); 3NH not observed.

[0177] The following compounds were prepared according to the procedure of Example 14 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 12]

[0178] Example 15 (Compounds 51 and 52) 6-[(2S)-2-Amino-4-fluorobutyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride and (4S)-4-[(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)methyl]-1,3-oxazinan-2-one [ka]

[0179] Step 1: [(3S)-3-(tert-butoxycarbonylamino)-4-[4-[tert-butoxycarbonyl(2-furylmethyl)amino]-2-chloro-7-methylthieno[3,2-d]pyrimidin-6-yl]butyl]methanesulfonate To a solution of tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)-4-hydroxybutyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (125 mg, 0.220 mmol, 1.0 eq., prepared according to the procedure of Example 4) and DIPEA (58.1 mg, 0.0770 mL, 0.441 mmol, 2.0 eq.) in CHCl (2.0 mL) cooled to 0 ° C., methanesulfonyl chloride (1.0 M in CHCl) (490 mg, 0.33 mL, 0.331 mmol, 1.50 eq.) was added. LC / MS showed that the reaction was immediately complete. The mixture was diluted with cold water and CHCl, washed with 1.0 M KHSO, sodium bicarbonate, and brine, dried over sodium sulfate, and evaporated to give [(3S)-3-(tert-butoxycarbonylamino)-4-[4-[tert-butoxycarbonyl(2-furylmethyl)amino]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]butyl]methanesulfonate (148 mg, 104% yield), which was used in the next step without further purification. MS m / z 646.0, 648.0 [M+H] + .

[0180] Step 2: tert-butyl (S)-(6-(2-((tert-butoxycarbonyl)amino)-4-fluorobutyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate and tert-butyl (S)-(2-chloro-7-methyl-6-((2-oxo-1,3-oxazinan-4-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate A mixture of [(3S)-3-(tert-butoxycarbonylamino)-4-[4-[tert-butoxycarbonyl(2-furylmethyl)amino]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]butyl]methanesulfonate (88.0 mg, 0.14 mmol) and TBAF (1.0 M, 1.0 mL) was stirred at 65 °C for 1 h, then cooled and concentrated. The residue was purified on silica gel eluting with ethyl acetate in dichloromethane (0 to 10% gradient) to give tert-butyl (S)-(6-(2-((tert-butoxycarbonyl)amino)-4-fluorobutyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (20 mg, 26% yield). MS m / z 569.1, 571.1 [M+H] + ; 1 H NMR (CDCl3) δ : 7.29-7.32 (m, 1H), 6.24-6.34 (m, 2H), 5.20 (s, 2H), 4.45-4.68 (m, 3H), 3.99-4.09 (m, 1H), 3.22-3.33 (m, 1H), 3.10-3.21 (m, 1H), 2.41 (s, 3H), 1.95-2.05 (m, 1H), 1.79-1.94 (m, 1H), 1.53 (s, 9H), 1.43 (s, 9H); and (S)-(2-chloro-7-methyl-6-((2-oxo-1,3-oxazinan-4-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate tert-butyl (20 mg, 30% yield). [MS m / z 515.1, 517.1 [M+Na] + ; 1H NMR (CDCl3) δ : 7.30-7.34 (m, 1H), 6.25-6.35 (m, 2H), 5.55-5.69 (m, 1H), 5.22 (s, 2H), 4.35-4.44 (m, 1H), 4.22-4.31 (m, 1H), 3.83-3.93 (m, 1H), 3.08-3.21 (m, 2H), 2.36-2.44 (m, 3H), 2.07-2.14 (m, 1H), 1.79-1.91 (m, 1H), 1.55 (s, 9H).

[0181] Step 3: (S)-6-(2-amino-4-fluorobutyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride The general Boc deprotection procedure using HCl in dioxane was applied to tert-butyl (S)-(6-(2-((tert-butoxycarbonyl)amino)-4-fluorobutyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate to give (S)-6-(2-amino-4-fluorobutyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine dihydrochloride (16 mg, 90% yield). MS m / z 369.1, 371.1 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.45 (s, 1H), 6.36 (s, 2H), 4.78 (s, 2H), 4.57-4.76 (m, 2H), 3.71-3.82 (m, 1H), 3.34-3.42 (m, 2H), 2.37 (s, 3H), 2.07-2.19 (m, 2H); no 3NH observed.

[0182] Step 4: (S)-4-((2-chloro-4-((furan-2-ylmethyl)amino)-7-methylthieno[3,2-d]pyrimidin-6-yl)methyl)-1,3-oxazinan-2-one The general Boc deprotection procedure using HCl in dioxane was applied to tert-butyl (S)-(2-chloro-7-methyl-6-((2-oxo-1,3-oxazinan-4-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate to give (S)-4-((2-chloro-4-((furan-2-ylmethyl)amino)-7-methylthieno[3,2-d]pyrimidin-6-yl)methyl)-1,3-oxazinan-2-one (10 mg, 63% yield). MS m / z 393.1, 395.1 [M+H] + ; 1 H NMR (CDCl3) d: 7.41 (s, 1H), 6.38 (s, 2H), 5.64 (br s, 1H), 5.39 (br s, 1H), 4.79 - 4.93 (m, 2H), 4.32 - 4.41 (m, 1H), 4.21 - 4.30 (m, 1H), 3.79 - 3.91 (m, 1H), 3.13 (d, J= 6.7 Hz, 2H), 2.38 (s, 3H), 2.03 - 2.13 (m, 1H), 1.78 - 1.89 (m, 1H).

[0183] Example 16 (Compound 76) 6-[(2R)-2-amino-3-methoxypropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine [ka]

[0184] Step 1: tert-butyl (R)-(6-(2-((tert-butoxycarbonyl)amino)-3-methoxypropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a stirred solution of tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (100.0 mg, 0.2 mmol, 1.0 eq., prepared according to the procedure of Example 4) in a mixture of DMF (0.5 mL) and THF (1.5 mL) was added sodium hydride (60% by weight) in mineral oil (10 mg, 0.25 mmol, 1.3 eq.) at 0° C. After stirring for 30 minutes at 0° C., a solution of iodomethane (2.0 M) in tert-butyl methyl ether (100 μL, 0.20 mmol, 1.1 eq.) was added. The reaction was allowed to warm to room temperature and stirred for an additional 12 hours. The reaction was quenched with HO (approximately 5 mL) and then extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified on silica gel eluting with 10% dichloromethane-doped EtOAc (0-30%) to afford tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-propyl]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (49.0 mg, 43% yield) as an off-white foam. MS m / z 567.2, 569.2 [M+H] + ; 1 H NMR (acetone-d6) δ: 7.36-7.45 (m, 1H), 6.27-6.36 (m, 2H), 5.17-5.24 (m, 2H), 3.99-4.05 (m, 1H), 3.41-3.47 (m, 2H), 3.33-3.37 (m, 3H), 3.27-3.33 (m, 1H), 3.11-3.19 (m, 1H), 2.76 (s, 3H), 1.53 (s, 9H), 1.32-1.37 (m, 9H); 1NH not observed.

[0185] Step 2: (R)-6-(2-amino-3-methoxypropyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine A mixture of tert-butyl N-[(1R)-1-[[2-chloro-4-(2-furylmethylamino)-7-methyl-thieno[3,2-d]pyrimidin-6-yl]methyl]-2-methoxy-ethyl]carbamate (30.0 mg, 0.06 mmol, 1.0 eq.) in anisole (0.40 mL, 3.6 mmol, 57 eq.) and hydrochloric acid (4 M) in 1,4-dioxane (3.0 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with ether (approximately 10 mL), and the resulting heterogeneous mixture was stirred at room temperature for 15 min. The precipitate was filtered and washed with diethyl ether to give an off-white solid, which was dried under high vacuum to give 6-[(2R)-2-amino-3-methoxy-propyl]-2-chloro-N-(2-furylmethyl)-7-methyl-thieno[3,2-d]pyrimidin-4-amine dihydrochloride (16.0 mg, 57% yield) as an off-white solid. MS m / z 367.2, 369.2 [M+H] + ; 1 H NMR (DMSO-d6) δ: 8.72-8.84 (m, 1H), 8.19-8.24 (m, 2H), 7.59-7.62 (m, 1H), 6.40-6.44 (m, 1H), 6.32-6.35 (m, 1H), 4.67 (d, J=5.5 Hz, 2H), 3.51-3.55 (m, 1H), 3.47-3.51 (m, 1H), 3.36-3.41 (m, 1H), 3.33 (s, 3H), 3.18-3.25 (m, 2H), 2.24 (s, 3H).

[0186] Example 17 (Compound 78) 2-chloro-6-[(2S)-2-(cyclobutylamino)propyl]-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine [ka]

[0187] A mixture of (S)-6-(2-aminopropyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine (HCl salt, 63 mg, 0.17 mmol, 1.0 eq., prepared according to the procedure of Example 3), cyclobutanone (24 mg, 0.34 mmol, 2.0 eq.), triethylamine (34 mg, 2.0 eq.), and acetic acid (31 mg, 3.0 eq.) in dichloroethane (0.3 mL) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (111 mg, 0.51 mmol, 3.0 eq.) was added, and the mixture was stirred at 50° C. for 16 hours. After cooling, the reaction was quenched by adding a few drops of water. The crude product was filtered, washed with methanol, and the filtrate was concentrated and purified by preparative HPLC eluting with CHCN (5-60%) in water containing 0.1% formic acid to give (S)-2-chloro-6-(2-(cyclobutylamino)propyl)-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine (36 mg, 55% yield) as the formate salt. MS m / z 391.2, 393.2 [M+H] + ; 1 H NMR (methanol-d4) δ: 8.43 (s, 1H), 7.32 (d, J=1.2 Hz, 1H), 6.18-6.30 (m, 2H), 4.63 (s, 2H), 3.50-3.60 (m, 1H), 3.06-3.15 (m, 2H), 2.78-2.85 (m, 1H), 2.12-2.25 (m, 5H), 1.78-1.93 (m, 2H), 1.63-1.73 (m, 2H), 1.04 (d, J=6.1 Hz, 3H), no 2NH observed.

[0188] Example 18 (Compound 65) 6-[(2S)-2-Aminopropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine [ka]

[0189] Step 1: tert-butyl N-[2-chloro-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate To a mixture of tert-butyl N-(7-bromo-2-chloro-thieno[3,2-d]pyrimidin-4-yl)-N-(2-furylmethyl)carbamate (500 mg, 1.1 mmol, 1.0 eq.), 4-methoxyphenylboronic acid (193 mg, 1.2 mmol, 1.1 eq.), potassium carbonate (3.0 eq.), and 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (94 mg, 0.11 mmol, 0.1 eq.), prepared according to the procedure of Example 3, dioxane (5 mL) was added, and the reaction was stirred at 100° C. for 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water, sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was then purified on silica gel with ethyl acetate in hexanes (0-20%) to give tert-butyl N-[2-chloro-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (306 mg, 57% yield). MS m / z 472.4, 474.4 [M+H] + .

[0190] Step 2: tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate To a solution of tert-butyl N-[2-chloro-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (93 mg, 0.19 mmol, 1.0 eq.) in THF (0.4 mL) was added n-butyllithium (2.5 mol / L) in hexane (0.08 mL, 0.21 mmol, 1.1 eq.) dropwise at −78° C. After 15 min, a solution of tert-butyl (4S)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (51 mg, 0.21 mmol, 1.1 eq.) in THF (0.4 mL) was added dropwise. The mixture was stirred at −78° C. for 10 min, then quenched with 1.0 M citric acid, followed by stirring at room temperature for 15 min. The mixture was diluted with ethyl acetate and washed with water, sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate in hexanes (2-30%) to give tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (55 mg, 44% yield). MS m / z 629.6, 631.6 [M+H] + ; 1 H NMR (CDCl3) δ: 7.32 (d, J=8.7 Hz, 2H), 7.30-7.31 (m, J=0.9 Hz, 1H), 7.02 (d, J=8.7 Hz, 2H), 6.28-6.32 (m, 2H), 5.20 (s, 2H), 4.39 (br s, 1H), 3.97 (br s, 1H), 3.88 (s, 3H), 3.07-3.20 (m, 2H), 1.54 (s, 9H), 1.41 (s, 9H), 1.03 (d, J=6.7 Hz, 3H).

[0191] Step 3: 6-[(2S)-2-aminopropyl]-2-chloro-N-(2-furylmethyl)-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine To a reaction tube containing tert-butyl N-[6-[(2S)-2-(tert-butoxycarbonylamino)propyl]-2-chloro-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (55 mg, 0.31 mmol, 1.0 eq.), hydrochloric acid (4 M) in dioxane (3 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with diethyl ether, filtered, and rinsed with diethyl ether. The solid was placed under vacuum for 24 hours to give 6-[(2S)-2-aminopropyl]-2-chloro-N-(2-furylmethyl)-7-(4-methoxyphenyl)thieno[3,2-d]pyrimidin-4-amine (18 mg, 48% yield) as an off-white solid. MS m / z 429.4, 431.4 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.44 (d, J=0.9 Hz, 1H), 7.33 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.33-6.37 (m, 2H), 4.77 (s, 2H), 3.86 (s, 3H), 3.43-3.49 (m, 1H), 3.28 (br d, J=6.3 Hz, 1H), 3.23 (br d, J=8.5 Hz, 1H), 1.17 (d, J=6.4 Hz, 3H); no 3NH was observed.

[0192] Example 19 (Compound 99) (2R)-2-Amino-3-(2-chloro-7-methoxy-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidin-6-yl)propan-1-ol [ka]

[0193] Step 1: tert-butyl N-(2-chloro-7-hydroxy-thieno[3,2-d]pyrimidin-4-yl)-N-(2-thienylmethyl)carbamate To a mixture of tert-butyl N-(7-bromo-2-chloro-thieno[3,2-d]pyrimidin-4-yl)-N-(2-thienylmethyl)carbamate (1.85 g, 1.12 mmol, 1.0 eq.) prepared according to the procedure in Example 3 and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoboralane (1 mL, 4.82 mmol, 1.2 eq.) in THF (4 mL) was added n-BuLi (2.5 mol / L) in hexane (1.9 mL) dropwise at −78° C. The reaction was stirred at −78° C. for 1 h, then removed from the bath and allowed to warm to room temperature. The reaction was quenched with NH4Cl(sat.) (3 mL), diluted with water, and then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was dissolved in diethyl ether (40 mL), and hydrogen peroxide (35% by weight) in water (1.2 mL, 12.0 mmol, 3.0 eq.) was added. The reaction mixture was stirred for 12 hours, cooled to 0°C, and quenched with Na2SO3. The crude mixture was then poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate in hexanes (0-50%) to give tert-butyl N-(2-chloro-7-hydroxy-thieno[3,2-d]pyrimidin-4-yl)-N-(2-thienylmethyl)carbamate (540 mg, 34% yield). MS m / z 398.1, 400.1 [M+H] + ; 1 H NMR (CDCl3) δ: 7.22 (dd, J = 5.1, 1.1 Hz, 1H), 7.12 (d, J = 2.9 Hz, 1H), 7.02 (s, 1H), 6.93 (dd, J = 5.0, 3.5 Hz, 1H), 5.38 (s, 2H), 1.59 (s, 9H); no 1OH was observed.

[0194] Step 2: tert-butyl N-[7-[tert-butyl(dimethyl)silyl]oxy-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate To a mixture of tert-butyl N-(2-chloro-7-hydroxy-thieno[3,2-d]pyrimidin-4-yl)-N-(2-thienylmethyl)carbamate (540 mg, 1.3 mmol, 1.0 eq.), tert-butyldimethylsilyl chloride (253 mg, 1.6 mmol, 1.2 eq.), and imidazole (0.1 mL, 1.7 mmol, 1.3 eq.) was added CHCl (5.5 mL). The mixture was stirred at room temperature for 1 h, then diluted with CHCl and washed with water, sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate in hexanes (0-20%) to give tert-butyl N-[7-[tert-butyl(dimethyl)silyl]oxy-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (590 mg, 84% yield). MS m / z 512.3, 514.3 [M+H] + ; 1 H NMR (CDCl3) δ: 7.20 (dd, J=5.0, 0.9 Hz, 1H), 7.08 (d, J=3.1 Hz, 1H), 6.99 (s, 1H), 6.90 (dd, J=5.0, 3.7 Hz, 1H), 5.35 (s, 2H), 1.56 (s, 9H), 1.03 (s, 9H), 0.27 (s, 6H).

[0195] Step 3: tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-[tert-butyl(dimethyl)silyl]oxy-propyl]-7-[tert-butyl(dimethyl)silyl]oxy-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate To a solution of tert-butyl N-[7-[tert-butyl(dimethyl)silyl]oxy-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (590 mg, 1.1 mmol, 1.0 eq.) in THF (2.0 mL) was added LDA (2.0 M in THF / heptane / ethylbenzene) (0.7 mL, 1.3 mmol, 1.2 eq.) at −78° C. After 15 min, a solution of tert-butyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylate (550 mg, 1.5 mmol, 1.3 eq.) in THF (2.0 mL) was added dropwise. The mixture was stirred at −78° C. for 10 minutes and then quenched with 1.0 M citric acid, followed by stirring at room temperature for 15 minutes. The mixture was diluted with ethyl acetate and washed with water, sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate in hexanes (2–35%) to give tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino-3-[tert-butyl(dimethyl)silyl]oxy-propyl]-7-[tert-butyl(dimethyl)silyl]oxy-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (267 mg, 29% yield). MS m / z 799.6, 801.6 [M+H] + ; 1 H NMR (CDCl3) δ: 7.19 (d, J=5.0 Hz, 1H), 7.08 (s, 1H), 6.89-6.92 (m, J=3.1 Hz, 1H), 5.32 (s, 2H), 4.92 (br s, 1H), 3.91 (br s, 1H), 3.56-3.68 (m, 2H), 3.05-3.17 (m, 2H), 1.55 (s, 9H), 1.37 (s, 9H), 1.06 (s, 9H), 0.91 (s, 9H), 0.31 (s, 6H), 0.06 (s, 6H).

[0196] Step 4: tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propyl]-2-chloro-7-hydroxy-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate To a mixture of tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-[tert-butyl(dimethyl)silyl]oxy-propyl]-7-[tert-butyl(dimethyl)silyl]oxy-2-chloro-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (267 mg, 0.3 mmol, 1.0 eq.) in THF (2.7 mL) was added dropwise tetrabutylammonium fluoride (1 M) in THF (0.6 mL, 0.6 mmol, 2 eq.) at 0° C. The reaction mixture was stirred for 24 h and then concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate in hexanes (0-50%) to give tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropyl]-2-chloro-7-hydroxy-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (152 mg, 90% yield). MS m / z 571.3, 573.3 [M+H] + ; 1 H NMR (CDCl3) δ: 7.21 (d, J=5.0 Hz, 1H), 7.11 (s, 1H), 6.93 (d, J=3.2 Hz, 1H), 5.36 (s, 2H), 5.09-5.15 (m, 1H), 3.85-3.91 (m, J=3.7, 1.7, 1.7 Hz, 1H), 3.67 (s, 2H), 3.18-3.26 (m, 1H), 3.10 (dd, J=14.0, 5.3 Hz, 1H), 1.77-2.18 (m, 2H), 1.59 (s, 9H), 1.45 (s, 9H).

[0197] Step 5: tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propyl]-2-chloro-7-methoxy-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate To a mixture of tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropyl]-2-chloro-7-hydroxythieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (152 mg, 0.26 mmol, 1.0 eq.) and triphenylphosphine (77 mg, 0.29 mmol, 1.1 eq.), THF (2.6 mL) was added. The mixture was then cooled to 0° C., and diethyl azodicarboxylate (40% by weight) in toluene (0.1 mL, 0.29 mmol, 1.1 eq.) was added dropwise. After 1 hour, the reaction mixture was concentrated under reduced pressure. The crude residue was purified on silica gel with ethyl acetate and hexanes (0-50%) to give tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropyl]-2-chloro-7-methoxy-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (30 mg, 19% yield). MS m / z 585.1, 587.1 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.22 (br d, J = 5.0 Hz, 1H), 7.02 (br s, 1H), 6.86 (t, J = 3.8 Hz, 1H), 5.27 (br s, 2H), 4.05 (s, 3H), 3.80 (br d, J = 3.5 Hz, 1H), 3.46-3.57 (m, 2H), 3.27 (br d, J = 1.2 Hz, 1H), 2.86 (br dd, J = 14.6, 9.3 Hz, 1H), 1.51 (s, 9H), 1.31 (s, 9H); 1NH and 1OH were not observed.

[0198] Step 6: (2R)-2-amino-3-[2-chloro-7-methoxy-4-(2-thienylmethylamino)thieno[3,2-d]pyrimidin-6-yl]propan-1-ol To a reaction tube containing tert-butyl N-[6-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropyl]-2-chloro-7-methoxy-thieno[3,2-d]pyrimidin-4-yl]-N-(2-thienylmethyl)carbamate (30 mg, 0.05 mmol, 1.0 eq.), hydrochloric acid (4 M) in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, diluted with diethyl ether, and then filtered and rinsed with diethyl ether. The solid was dried under vacuum for 24 hours to give (2R)-2-amino-3-[2-chloro-7-methoxy-4-(2-thienylmethylamino)thieno[3,2-d]pyrimidin-6-yl]propan-1-ol (18 mg, 91% yield) as a yellow solid. MS m / z 385.1, 387.1 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.30 (d, J=5.0 Hz, 1H), 7.11 (br s, 1H), 6.96 (br t, J=3.4 Hz, 1H), 4.96 (s, 2H), 4.07 (s, 3H), 3.78 (br dd, J=11.4, 2.7 Hz, 1H), 3.59-3.65 (m, 1H), 3.57 (br d, J=3.1 Hz, 1H), 3.25-3.27 (m, 1H). 1H is obscured by MeOD peaks; 3NH and 1OH are not observed.

[0199] Example 20 (Compounds 66 and 70) (2S)-3-(2-chloro-4-{[(furan-2-yl)methyl]amino}-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol and 6-[(2S)-3-Amino-2-methylpropyl]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine [ka]

[0200] Step 1: tert-Butyl (2-chloro-6-iodo-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of tert-butyl (2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (890 mg, 2.34 mmol, 1.0 eq.) prepared according to the procedure of Example 3 in THF (8 mL) was added LDA (2.0 M in THF, 1.3 mL, 1.1 eq.) at −78° C. After stirring for 45 min, a solution of iodine (624 mg, 2.46 mmol, 1.05 eq.) in THF (5 mL) was added dropwise, and stirring was continued at −78° C. for 1 h. The reaction was quenched by the addition of EtOAc and NH4Cl (sat. aq.) and allowed to warm to room temperature. The organic layer was washed with sodium thiosulfate solution, water, and brine, dried over sodium sulfate, and evaporated. The residue was purified by silica gel flash column chromatography eluting with EtOAc (0–15%) in hexanes to give tert-butyl (2-chloro-6-iodo-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (1100 mg, 93% yield). 1 H NMR (acetone-d6) δ: 7.40-7.50 (m, 1H), 6.37 (s, 2H), 5.26 (s, 2H), 2.38 (s, 3H), 1.58 (s, 9H).

[0201] Step 2: (S)-3-(4-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-2-chloro-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropanoate methyl ester To a mixture of tert-butyl (2-chloro-6-iodo-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (134 mg, 0.26 mmol, 1.0 eq.) and Pd(PPh3)4 (18 mg, 0.016 mmol, 0.06 eq.) in THF (0.3 mL) was added (R)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide (from Rieke Metals, 0.5 M in THF, 0.7 mL, 1.3 eq.) under Ar. The mixture was heated at 65 °C for 2 h. After cooling, the mixture was quenched by the addition of NH4Cl (sat. aq.) and diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The crude material was purified by silica gel flash column chromatography eluting with EtOAc (0-30%) in hexanes to give (S)-methyl 3-(4-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-2-chloro-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropanoate (72 mg, 57% yield) as a colorless oil. MS m / z 502.3, 504.3 [M+Na] + .

[0202] Step 3: (S)-(2-chloro-6-(3-hydroxy-2-methylpropyl)-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate tert-butyl and (S)-3-(2-chloro-4-((furan-2-ylmethyl)amino)-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol To a solution of methyl (S)-3-(4-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-2-chloro-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropanoate (72 mg, 0.15 mmol, 1.0 eq.) in THF (1.2 mL) was added LAH (1.0 M in THF, 0.18 mL, 1.2 eq.) dropwise at 0° C. The reaction was continued for 1 h at 0° C., then quenched with citric acid (1.0 M, aq., 1 mL) and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel flash column chromatography eluting with EtOAc in hexanes (0-60%) to give tert-butyl (S)-(2-chloro-6-(3-hydroxy-2-methylpropyl)-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (41 mg, 60% yield), MS m / z 452.3, 454.3 [M+H]. + and (S)-3-(2-chloro-4-((furan-2-ylmethyl)amino)-7-methylthieno[3,2-d]pyrimidin-6-yl)-2-methylpropan-1-ol (19 mg, 36% yield). MS m / z 352.3, 354.3 [M+H] + . 1 H NMR (methanol-d) δ: 7.44 (s, 1H), 6.30-6.50 (m, 2H), 4.75 (s, 2H), 3.47-3.52 (m, 2H), 3.08-3.14 (m, 1H), 2.73 (dd, J=14.6, 8.9 Hz, 1H), 2.29 (s, 3H), 1.96-2.08 (m, 1H), 0.97 (d, J=6.7 Hz, 3H); no 1NH or 1OH was observed.

[0203] Step 4: (S)-(6-(3-azido-2-methylpropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate tert-butyl ester To a solution of tert-butyl (S)-(2-chloro-6-(3-hydroxy-2-methylpropyl)-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (80 mg, 0.17 mmol, 1.0 eq.) and DIPEA (47 mg, 2.0 eq.) in CHCl (1 mL) was slowly added a solution of MsCl (30 mg, 0.26 mmol, 1.5 eq.) in CHCl (1 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, then quenched with NaHCO (sat. aq.) and extracted with CHCl. ​​The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The crude product was used directly in the next step without further purification. A mixture of the above crude product (93 mg, 0.17 mmol, 1.0 eq.) and sodium azide (35 mg, 3.0 eq.) in DMSO (0.3 mL) was stirred at room temperature overnight and then quenched with NaHCO (sat. aq.). The mixture was diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The crude material was purified by silica gel flash column chromatography eluting with EtOAc in hexane (0-30%) to give tert-butyl (S)-(6-(3-azido-2-methylpropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (66 mg, 79% yield). 1 H NMR (acetone-d6) δ: 7.42 (dd, J=1.8, 0.9 Hz, 1H), 6.28-6.37 (m, 2H), 5.21 (s, 2H), 3.44 (qd, J=12.4, 6.0 Hz, 2H), 3.14 (dd, J=14.6, 6.4 Hz, 1H), 2.93 (dd, J=14.6, 8.2 Hz, 1H), 2.36 (s, 3H), 2.21 (dt, J=7.9, 6.6 Hz, 1H), 1.53 (s, 9H), 1.06 (d, J=6.7 Hz, 3H).

[0204] Step 5: (S)-(6-(3-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate tert-butyl ester To a solution of tert-butyl (S)-(6-(3-azido-2-methylpropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (66 mg, 0.14 mmol, 1.0 eq.) in THF (1.3 mL) was added triphenylphosphine (110 mg, 0.42 mmol, 3.0 eq.) and water (25 mg, 1.4 mmol, 10 eq.). The mixture was stirred at room temperature overnight. The reaction was quenched with NH4Cl (sat. aq.) and extracted with EtOAc. The organic layer was washed with water and brine and dried over sodium sulfate. After concentration, the crude material was used in the next step without further purification. MS m / z 451.3, 453.3 [M+H] + To a solution of the above crude intermediate (62 mg, 0.14 mmol, 1.0 eq.) in CHCl (1 mL) was added 4-DMAP (12 mg, 0.097 mmol, 0.50 eq.) followed by di-tert-butyl dicarbonate (47 mg, 0.21 mmol, 1.5 eq.). After stirring at room temperature for 1 h, the reaction was quenched with NaHCO (sat. aq.) and then extracted with CHCl. ​​The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The crude material was purified by silica gel flash column chromatography eluting with EtOAc in hexanes (0-30%) to give tert-butyl (S)-(6-(3-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (30 mg, 39% yield). MS m / z 573.2, 574.2 [M+Na] + .

[0205] Step 6: (S)-6-(3-amino-2-methylpropyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine A solution of (S)-(6-(3-((tert-butoxycarbonyl)amino)-2-methylpropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl) tert-butyl carbamate (30 mg, 0.054 mmol, 1.0 eq.) in HCl (4 M in dioxane) (1 mL) was stirred at room temperature for 1 h. The precipitate was filtered and rinsed with diethyl ether to give (S)-6-(3-amino-2-methylpropyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine (6 mg, 32% yield) as the hydrochloride salt. MS m / z 351.2, 353.2 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.46 (dd, J=1.5, 0.9 Hz, 1H), 6.24-6.45 (m, 2H), 4.81 (s, 2H), 3.00-3.14 (m, 2H), 2.84-2.97 (m, 2H), 2.34 (s, 3H), 2.21-2.29 (m, 1H), 1.09 (d, J=6.7 Hz, 3H); no 3NH observed.

[0206] The following compounds were prepared according to the procedure of Example 20 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 13]

[0207] Example 21 (Compound 41) 6-(azetidin-3-yl)-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine [ka]

[0208] Step 1: tert-Butyl 3-(4-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-2-chloro-7-methylthieno[3,2-d]pyrimidin-6-yl)azetidine-1-carboxylate Preparation of (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide: An oven-dried, nitrogen-filled flask was charged with zinc powder (243 mg, 3.7 mmol, 2.0 eq.) and DMA (0.5 mL) under argon. The gray suspension was heated to 40°C, and a solution of 1,2-dibromoethane (113 mg, 0.32 eq.) in DMA (0.5 mL) was added dropwise, followed by a solution of TMSCl (26 mg, 0.13 eq.) in DMAc (0.5 mL). After stirring for 10 min at 40°C, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (520 mg, 1.84 mmol, 1.0 eq.) in DMA (2 mL) was added, and stirring was continued for 30 min at 40°C. After cooling, the organozinc reagent (approximately 0.5 M in DMA) was used immediately in the next step. To a mixture of tert-butyl (2-chloro-6-iodo-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (105 mg, 0.21 mmol, 1.0 eq.), Pd(dppf)Cl (8.6 mg, 0.05 eq.), and CuI (4.0 mg, 0.10 eq.) prepared according to the procedure in Step 1 of Example 20 in DMA (0.5 mL) was added the above organozinc reagent (approximately 0.5 M in DMA, 0.8 mL, 1.5 eq.) under argon. The mixture was then stirred at 90 °C for 1 h. After cooling, the reaction was quenched with NH Cl (sat. aq.), extracted with EtOAc, dried over sodium sulfate, and evaporated. The crude material was purified by silica gel flash column chromatography eluting with EtOAc in hexanes (0-100%) to give tert-butyl 3-(4-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-2-chloro-7-methylthieno[3,2-d]pyrimidin-6-yl)azetidine-1-carboxylate (88 mg, 79% yield). MS m / z 535.2, 537.3 [M+H] + .

[0209] Step 2: 6-(azetidin-3-yl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine Tert-butyl 3-(4-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-2-chloro-7-methylthieno[3,2-d]pyrimidin-6-yl)azetidine-1-carboxylate (88 mg, 0.2 mmol) was stirred in a solution of methanesulfonic acid (422 mg, 20 eq.) in dioxane (2 mL) for 1 h at room temperature, then triturated with diethyl ether and filtered. The crude solid was purified by preparative HPLC eluting with CHCN (5-50%) in water with 0.1% TFA to give 6-(azetidin-3-yl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine (15 mg, 28% yield) as the trifluoroacetate salt. MS m / z 335.3, 337.3, [M+H] + ; 1 H NMR (DMSO-d6) δ: 9.05 (br s, 1H), 8.82 (t, J=5.6 Hz, 1H), 8.73 (br s, 1H), 7.54 (dd, J=1.7, 0.8 Hz, 1H), 6.35 (dd, J=3.1, 1.8 Hz, 1H), 6.26 (d, J=2.7 Hz, 1H), 4.54-4.64 (m, 3H), 4.32 (br s, 2H), 4.02 (br s, 2H), 2.13 (s, 3H).

[0210] The following compounds were prepared according to the procedure of Example 21 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 14]

[0211] Example 22 (Compounds 85 and 83) 6-[(2S)-2-Aminopropyl]-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2,7-dicarbonitrile and 6-[(2S)-2-Aminopropyl]-7-bromo-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-2-carbonitrile [ka]

[0212] Step 1: tert-butyl (S)-(6-(2-((tert-butoxycarbonyl)amino)propyl)-2,7-dicyanothieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate and tert-butyl (S)-(7-bromo-6-(2-((tert-butoxycarbonyl)amino)propyl)-2-cyanothieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate To a degassed solution of tert-butyl (S)-(7-bromo-6-(2-((tert-butoxycarbonyl)amino)propyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate (136 mg, 0.22 mmol, 1.0 eq.), prepared according to the procedure of Example 3, in DMF (1 mL) was added zinc cyanide (15.8 mg, 0.60 eq.), Pd2(dba)3 (10.4 mg, 0.05 eq.), and Xantphos (13.1 mg, 0.10 eq.) under argon. The sealed tube was stirred at 120 °C for 1 h and then cooled. The reaction was quenched with NH4Cl (sat. aq.) and extracted with EtOAc. The combined organic phases were dried and concentrated. The crude material was purified by silica gel flash column chromatography eluting with EtOAc (0-20%) in CHCl to give tert-butyl (S)-(6-(2-((tert-butoxycarbonyl)amino)propyl)-2,7-dicyanothieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate, MS m / z 553.3 [MH], respectively.- and (S)-(7-bromo-6-(2-((tert-butoxycarbonyl)amino)propyl)-2-cyanothieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate tert-butyl, MS m / z 506.1, 508.1 [MH-Boc] - obtained.

[0213] Step 2: (S)-6-(2-aminopropyl)-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidine-2,7-dicarbonylnitrile (S)-tert-Butyl (6-(2-((tert-butoxycarbonyl)amino)propyl)-2,7-dicyanothieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate from Step 1 in HCl (4 M in dioxane, 1 mL) was stirred at room temperature for 1 hour, and then the volatile organics were removed. The crude solid was triturated with diethyl ether and filtered to give (S)-6-(2-aminopropyl)-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidine-2,7-dicarbonitrile (5 mg, 5% overall yield for two steps) as the hydrochloride salt. MS m / z 355.1 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.32 (dd, J=5.2, 1.2 Hz, 1H), 7.06-7.21 (m, 1H), 6.98 (dd, J=5.2, 3.4 Hz, 1H), 4.99 (s, 2H), 3.73-3.89 (m, 1H), 3.56-3.63 (m, 1H), 3.45-3.55 (m, 1H), 1.42 (d, J=6.4 Hz, 3H); no 3NH observed.

[0214] Step 3: (S)-6-(2-aminopropyl)-7-bromo-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidine-2-carbonitrile (S)-tert-Butyl (7-bromo-6-(2-((tert-butoxycarbonyl)amino)propyl)-2-cyanothieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate (from Step 1) in HCl (4 M in dioxane, 1 mL) was stirred at room temperature for 1 h, and then the volatile organics were removed. The crude solid was purified by preparative HPLC with CH3CN (5-40%) in water containing 0.1% formic acid to give (S)-6-(2-aminopropyl)-7-bromo-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidine-2-carbonitrile (10 mg, 11% overall yield for two steps) as the formate salt. MS m / z 408.1, 410.1 [M+H] + ; 1 H NMR (methanol-d₄) δ: 7.31 (dd, J=5.2, 1.2 Hz, 1H), 7.06-7.20 (m, 1H), 6.98 (dd, J=5.0, 3.5 Hz, 1H), 4.99 (s, 2H), 3.71-3.89 (m, 1H), 3.40-3.47 (m, 1H), 3.35-3.39 (m, 1H), 1.40 (d, J=6.7 Hz, 3H); no 3NH observed.

[0215] Example 23 (Compound 84) 2-chloro-4-{[(thiophen-2-yl)methyl]amino}thieno[3,2-d]pyrimidine-7-carbonitrile [ka]

[0216] To a degassed solution of tert-butyl (7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)(thiophen-2-ylmethyl)carbamate (101 mg, 0.22 mmol, 1.0 eq.) in DMF (1 mL) under argon, zinc cyanide (15.8 mg, 0.60 eq.), Pd2(dba)3 (10.4 mg, 0.05 eq.), and Xantphos (13.1 mg, 0.10 eq.) were added, and the sealed tube was then stirred at 120 °C for 1 h. After cooling, the mixture was quenched with NH4Cl (sat. aq.) and then extracted with EtOAc. The combined organic phases were dried and concentrated. The crude material was purified by silica gel flash column chromatography eluting with MeOH (0-10%) in CHCl, followed by further purification by HPLC with CHCN (10-100%) in water containing 0.1% formic acid to give 2-chloro-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidine-7-carbonitrile (5 mg, 7% yield). MS m / z 306.9, 308.9 [M+H] + ; 1 H NMR (DMSO-d6) δ: 9.42 (br t, J=5.2 Hz, 1H), 9.07 (s, 1H), 7.35 (dd, J=5.0, 1.1 Hz, 1H), 7.03 (d, J=2.7 Hz, 1H), 6.91 (dd, J=5.0, 3.5 Hz, 1H), 4.77 (d, J=5.2 Hz, 2H).

[0217] Example 24 (Compound 46) 6-[(1S)-1-Aminoethyl]-7-bromo-2-chloro-N-[(furan-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine [ka]

[0218] Step 1: tert-butyl (7-bromo-2-chloro-6-formylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of tert-butyl (7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (500 mg, 1.12 mmol, 1.0 eq.) prepared according to the procedure of Example 3 in THF (4 mL) was added LDA (2.0 M in THF, 0.67 mL, 1.2 eq.) at −78° C. After 30 min, DMF (823 mg, 11.2 mmol, 10 eq.) was added dropwise. The temperature was raised to −50° C., and the reaction was quenched with saturated aqueous NH4Cl solution and then diluted with EtOAc. The mixture was washed with water followed by brine, and the organic layer was dried over sodium sulfate and evaporated. The residue was purified by silica gel flash column chromatography eluting with EtOAc (0–25%) in hexanes to give tert-butyl (7-bromo-2-chloro-6-formylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (399 mg, 75% yield) as a yellow solid. 1 H NMR (acetone-d6) δ ppm 10.41 (s, 1H), 7.47-7.49 (m, 1H), 6.43-6.44 (m, 1H), 6.39-6.41 (m, 1H), 5.30-5.31 (m, 2H), 1.58-1.62 (m, 9H).

[0219] Step 2: (R,E)-tert-butyl (7-bromo-6-(((tert-butylsulfinyl)imino)methyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate A mixture of tert-butyl (7-bromo-2-chloro-6-formylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (162 mg, 0.34 mmol, 1.0 eq.), R-(+)-2-methylpropane-2-sulfinamide (50 mg, 0.41 mmol, 1.2 eq.) and CuSO (85 mg, 0.51 mmol, 1.5 eq.) in DCE (0.4 mL) was stirred at 55 °C for 18 h. After cooling, the mixture was purified by silica gel flash column chromatography eluting with EtOAc (0-50%) in hexanes to give tert-butyl (R,E)-(7-bromo-6-(((tert-butylsulfinyl)imino)methyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate as a yellow solid (121 mg, 61% yield). MS m / z 577.4, 579.4 [M+H] + .

[0220] Step 3: tert-butyl (7-bromo-6-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of tert-butyl (R,E)-(7-bromo-6-(((tert-butylsulfinyl)imino)methyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (110 mg, 0.19 mmol, 1.0 eq.) in THF (1.0 mL) was added MeMgBr (3.0 M in EtO, 0.096 mL, 1.5 eq.) at −78° C. The mixture was gradually warmed to −20° C. over 1 h, quenched with saturated NH4Cl solution, and then diluted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by silica gel flash column chromatography eluting with EtOAc in hexanes (0–100%) to give tert-butyl (7-bromo-6-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (86 mg, 76% yield).1 H NMR (acetone-d6) δ 7.45 (s, 1H), 6.31-6.40 (m, 2H), 5.45-5.49 (m, 1H), 5.26 (s, 2H), 5.13-5.19 (m, 1H), 1.68 (d, J = 6.6 Hz, 3H), 1.56 (s, 9H), 1.23 (s, 9H).

[0221] Step 4: (S)-6-(1-aminoethyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine hydrochloride A solution of tert-butyl (7-bromo-6-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (86 mg, 0.14 mmol) in HCl (4 M in dioxane, 1 mL) was stirred at room temperature for 1 h. The volatile organics were removed, and the residue was triturated with diethyl ether and filtered to give (S)-6-(1-aminoethyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine (12 mg, 74% yield) as the hydrochloride salt. MS m / z 387.2, 389.2 [M+H] + ; 1 H NMR (DMSO-d6) δ: 9.35 (br t, J=5.5 Hz, 1H), 8.87 (br s, 1H), 8.82 (br s, 2H), 7.62 (s, 1H), 6.43 (dd, J=3.1, 1.8 Hz, 1H), 6.37 (d, J=3.1 Hz, 1H), 4.84-5.06 (m, 1H), 4.70 (br t, J=5.2 Hz, 2H), 1.65 (d, J=6.7 Hz, 3H).

[0222] The following compounds were prepared according to the procedure of Example 24 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 15]

[0223] Example 25 (Compounds 58 and 61) 6-[(1S)-1-Aminoethyl]-2-chloro-N-[(furan-2-yl)methyl]-7-phenylthieno[3,2-d]pyrimidin-4-amine and 6-[(1S)-1-Aminoethyl]-N-[(furan-2-yl)methyl]-2,7-diphenylthieno[3,2-d]pyrimidin-4-amine [ka]

[0224] Step 1: tert-butyl (6-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-chloro-7-phenylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate and tert-butyl (6-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2,7-diphenylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate A mixture of tert-butyl (7-bromo-6-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (55 mg, 0.093 mmol, 1.0 eq.), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium dichloromethane complex (3.8 mg, 0.005 mmol, 0.05 eq.), phenylboronic acid (13 mg, 0.1 mmol, 1.1 eq.), 1,4-dioxane (0.8 mL), and aqueous potassium carbonate (2.0 M in water, 0.14 mL, 3.0 eq.) prepared according to the procedure of Example 24 was heated at 75° C. for 3 h. After cooling, the mixture was quenched with saturated NH4Cl solution and then diluted with EtOAc. The combined organic phases were dried and concentrated. The residue was purified by silica gel flash column chromatography eluting with EtOAc in hexanes (0-100%) to give a mixture of two intermediates, tert-butyl (6-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-chloro-7-phenylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (MS m / z 611.5, 613.5 [M+Na]). + ) and tert-butyl (6-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2,7-diphenylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (MS m / z 631.6 [M+H] + ) was obtained, which was used in the next step without further purification.

[0225] Step 2: (S)-6-(1-aminoethyl)-2-chloro-N-(furan-2-ylmethyl)-7-phenylthieno[3,2-d]pyrimidin-4-amine and (S)-6-(1-aminoethyl)-2-chloro-N-(furan-2-ylmethyl)-7-phenylthieno[3,2-d]pyrimidin-4-amine The mixture of the product from Step 1 in HCl (4 M in dioxane, 1 mL) was stirred at room temperature for 1 h, and then the volatile organics were removed. The crude solid was purified by preparative HPLC eluting with ACN (5–50%) in water containing 0.1% formic acid to give (S)-6-(1-aminoethyl)-2-chloro-N-(furan-2-ylmethyl)-7-phenylthieno[3,2-d]pyrimidin-4-amine (10 mg, 28% yield over two steps) and (S)-6-(1-aminoethyl)-2-chloro-N-(furan-2-ylmethyl)-7-phenylthieno[3,2-d]pyrimidin-4-amine (7 mg, 18% yield over two steps), respectively. (S)-6-(1-aminoethyl)-2-chloro-N-(furan-2-ylmethyl)-7-phenylthieno[3,2-d]pyrimidin-4-amine (formate): MS m / z 385.4, 387.4 [M+H] + ; 1 H NMR (methanol-d₄) δ: 8.38 (s, 1H), 7.39-7.43 (m, 2H), 7.29-7.37 (m, 4H), 6.19-6.30 (m, 2H), 4.64-4.69 (m, 2H), 4.58-4.63 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H); no 3NH observed. (S)-6-(1-aminoethyl)-2-chloro-N-(furan-2-ylmethyl)-7-phenylthieno[3,2-d]pyrimidin-4-amine (formate): MS m / z 427.5 [M+H] + ; 1 H NMR (methanol-d₄) δ: 8.44 (s, 1H), 8.26 (dd, J=6.6, 3.2 Hz, 2H), 7.40-7.52 (m, 4H), 7.32-7.39 (m, 2H), 7.25-7.32 (m, 3H), 6.26 (bs, 2H), 4.81-4.85 (m, 2H), 4.62 (q, J=6.5 Hz, 1H), 1.41 (d, J=6.7 Hz, 3H); no 3NH observed.

[0226] Example 26 (Compound 121) 6-[(S)-(1-(1-aminoethyl)cyclopropyl)]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine [ka]

[0227] Step 1: Methyl 1-(4-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-2-chloro-7-methylthieno[3,2-d]pyrimidin-6-yl)cyclopropane-1-carboxylate To a solution of tert-butyl N-(2-chloro-6-iodo-7-methyl-thieno[3,2-d]pyrimidin-4-yl)-N-(2-furylmethyl)carbamate (70 mg, 0.1384 mmol, 1.0 eq., prepared according to the procedure of Example 20, Step 1), tris(dibenzylideneacetone)dipalladium (8 mg, 0.009 mmol), and 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene (8 mg, 0.01 mmol) in THF (1 mL) was added bromo-(1-methoxycarbonylcyclopropyl)zinc (1 mL, 0.4 mmol, 0.4 mol / L) at room temperature. Stirring was continued for 1 h, followed by quenching with NH4Cl (sat. aq.). The reaction mixture was extracted with EtOAc. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by silica gel flash column chromatography eluting with EtOAc in hexanes (0-30%) to afford methyl 1-[4-[tert-butoxycarbonyl(2-furylmethyl)amino]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]cyclopropanecarboxylate (40 mg, 60% yield) as a clear oil. MS m / z 478.3, 480.3 [M+H] + ; 1H NMR (chloroform-d) δ: 7.29 (s, 1H), 6.28-6.33 (m, 2H), 5.19 (s, 2H), 3.68 (s, 3H), 2.39 (s, 3H), 1.82-1.87 (m, 2H), 1.54 (s, 9H), 1.39-1.44 (m, 2H).

[0228] Step 2: tert-Butyl (2-chloro-6-(1-(hydroxymethyl)cyclopropyl)-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of methyl 1-[4-[tert-butoxycarbonyl(2-furylmethyl)amino]-2-chloro-7-methyl-thieno[3,2-d]pyrimidin-6-yl]cyclopropanecarboxylate (600 mg, 1.255 mmol, 1.0 eq.) in THF (10 mL) cooled to 0 °C was added LiAlH (2.0 M in THF, 1 mL, 2 mmol, 1.5 eq.) dropwise. After 5 min of stirring, UPLC showed complete conversion to the product. Quenched with NH Cl (sat. aq.) and diluted with EtOAc. The organics were washed with water and brine, dried over MgSO, filtered, and concentrated. The crude residue was purified by silica gel flash column chromatography eluting with EtOAc in hexanes (0-60%) to afford tert-butyl N-[2-chloro-6-[1-(hydroxymethyl)cyclopropyl]-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (400 mg, 71% yield) as a clear oil. MS m / z 450.3 [M+H] + ; 1 H NMR (chloroform-d) δ: 7.29 (s, 1H), 6.28-6.32 (m, 2H), 5.19 (s, 2H), 3.72 (s, 2H), 2.50 (s, 3H), 1.54 (s, 9H), 1.08-1.14 (m, 4H); no 1OH was observed.

[0229] Step 3: tert-Butyl (2-chloro-6-(1-formylcyclopropyl)-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of tert-butyl N-[2-chloro-6-[1-(hydroxymethyl)cyclopropyl]-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (400 mg, 0.8 mmol, 1.0 eq.) in dichloromethane (6 mL) was added Dess-Martin periodinane (560 mg, 1.3 mmol, 1.3 eq.) at room temperature. After stirring at room temperature for 20 min, the reaction mixture was diluted with dichloromethane (20 mL) and washed with NaHCO3 (sat. aq.). The combined organics were dried over NaSO4, filtered, and concentrated. The crude residue was purified by silica gel flash column chromatography eluting with EtOAc in hexanes (0-40%) to afford tert-butyl N-[2-chloro-6-(1-formylcyclopropyl)-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (340 mg, 85% yield) as a clear oil. MS m / z 448.3 [M+H] + ; 1 H NMR (chloroform-d) δ: 9.17 (s, 1H), 7.29 (s, 1H), 6.28-6.35 (m, 2H), 5.22 (s, 2H), 2.40 (s, 3H), 1.80-1.87 (m, 2H), 1.61-1.67 (m, 2H), 1.55 (s, 9H).

[0230] Step 4: (R,E)-(6-(1-(((tert-butylsulfinyl)imino)methyl)cyclopropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate tert-Butyl To a solution of tert-butyl N-[2-chloro-6-(1-formylcyclopropyl)-7-methyl-thieno[3,2-d]pyrimidin-4-yl]-N-(2-furylmethyl)carbamate (100 mg, 0.2 mmol, 1.0 eq.) and (R)-(+)-2-methyl-2-propanesulfinamide (42 mg, 0.3 mmol, 1.5 eq.) in THF (2 mL) was added titanium(IV) ethoxide (0.1 mL, 0.5 mmol, 2.5 eq.) at room temperature. After stirring at room temperature for 8 h, the reaction was quenched with water (1 mL), filtered through Celite, and concentrated. The crude residue was purified by silica gel flash column chromatography eluting with EtOAc (0-50%) in hexanes to afford tert-butyl (R,E)-(6-(1-(((tert-butylsulfinyl)imino)methyl)cyclopropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (110 mg, 82% yield) as a clear oil. MS m / z 573.2, 575.2 [M+Na] + ; 1 H NMR (chloroform-d) δ: 9.10 (s, 1H), 7.53-7.62 (m, 1H), 6.17-6.27 (m, 2H), 5.12 (s, 2H), 2.30 (s, 3H), 1.54-1.70 (m, 4H), 1.44 (s, 9H), 1.04 (s, 9H).

[0231] Step 5: tert-butyl (6-(1-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)cyclopropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of tert-butyl (R,E)-(6-(1-(((tert-butylsulfinyl)imino)methyl)cyclopropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (122 mg, 0.2 mmol, 1.0 eq.) in dichloromethane (3 mL) cooled to 0° C. was added methylmagnesium bromide (0.1 mL, 3.0 M in diethyl ether, 1.5 eq.). After stirring at 0° C. for 1 h, the reaction was quenched with NH4Cl (sat. aq.) and diluted with EtOAc. The organics were dried over MgSO, filtered, and concentrated to give tert-butyl (6-(1-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)cyclopropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (82 mg, 65% yield) as a clear oil, which was used in the next step without further purification. MS m / z 589.2, 591.2 [M+Na] + .

[0232] Step 6: 6-[(S)-(1-(1-aminoethyl)cyclopropyl)]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine A mixture of tert-butyl (6-(1-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)cyclopropyl)-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (82 mg, 0.15 mmol, 1.0 eq.) in HCl (4 M in dioxane) (1 mL) was stirred at room temperature for 3 h. The mixture was concentrated, and the crude residue was purified by preparative HPLC with CH3CN (5-40%) in water containing 0.1% formic acid to give (S)-6-(1-(1-aminoethyl)cyclopropyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine (46 mg, 80%) as the formate salt. MS m / z 363.2, 365.2 [M+H] + ; 1H NMR (methanol-d₄) δ: 8.41-8.49 (m, 1H), 7.26 (s, 1H), 6.18-6.32 (m, 2H), 4.64 (s, 2H), 2.66-2.77 (m, 1H), 2.30 (s, 3H), 1.16 (br d, J=6.4 Hz, 3H), 1.14-0.99 (br m, 4H); no 3NH observed.

[0233] The following compounds were prepared according to the procedure of Example 26 by substituting the appropriate starting materials, reagents and reaction conditions. [Table 16]

[0234] Biological Examples The following in vitro biological examples demonstrate the utility of the compounds herein for the treatment of familial dysautonomia. 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 specifically limiting its scope. Similar variations of the present specification that may be currently known or that may later be developed and that would be within the purview of one skilled in the art are considered to be within the scope of the present specification and are claimed.

[0235] Example 1 IKBKAP-HTRF assay This assay is used to quantitatively measure the concentration of elongator complex protein 1 (ELP1, also known as IKBKAP) in cell lysates using HTRF® (homogeneous time-resolved fluorescence) technology. IKBKAP is detected in a sandwich HTRF assay using donor-labeled and acceptor-labeled anti-IKAP antibodies. [Table 17]

[0236] protocol Cells were thawed and incubated in DMEM-10% FBS for 72 hours. Cells were trypsinized, counted, and resuspended in DMEM-10% FBS to a concentration of 50,000 cells / mL. Aliquots (199 μL) of the cell suspension were seeded at 10,000 cells per well of a 96-well microtiter plate and incubated for 3–5 hours. To obtain a control signal, three wells were not seeded with cells and served as blank control wells. Test compounds were serially diluted 3.16-fold in 100% DMSO to generate a 7-point concentration curve. Aliquots (1 μL) of 200x compound solution were transferred to the cell-containing wells, and the cells were incubated for 48 hours in a cell culture incubator (37°C, 5% CO2, 100% relative humidity). Triplicate samples were set up for each compound concentration. After 48 hours, the supernatant was removed from the cells, and 50 μL of 1×LB4 lysis buffer containing protease inhibitors was added to the cells and incubated with shaking at room temperature for 1 hour. An aliquot (36 μL) of this lysate was then transferred to a 384-well plate containing 4 μL of antibody solution (anti-IKAP d2 and anti-IKAP K(9+8) diluted 1:50 in detection buffer). The 384-well plate was then centrifuged for 1 minute to collect the solution at the plate bottom, and the plate was incubated overnight at 4°C. Fluorescence at 665 nm and 620 nm in each well of the plate was measured using an EnVision plate reader (Perkin Elmer). δF for each sample was calculated as follows:

number

[0237] The maximum fold increase (MFI) in IKBKAP protein abundance for a compound of formula (I) or a form thereof compared to the vehicle control is shown in Table 1. The MFI was calculated by dividing the δF value in each sample well by the sample δF in the vehicle control wells. MFI≦1.9 is marked with one star ( * ) and >1.9 to ≦2.9 are indicated by an asterisk ( ** ) and >2.9~≦3.9 are indicated by three stars ( *** ), and >3.9 to ≦4.9 is indicated by four stars ( **** ), and >4.9 is indicated by five stars ( ***** )

[0238] EC2 values ​​for IKBKAP protein expression obtained from 7-point concentration curves generated for each test compound according to the protocol in Biological Example 1. 2x The EC2 expression of IKBKAP protein is also shown in Table 1. 2x The term "IKBKAP" is defined as the concentration of test compound effective to produce twice the amount of IKBKAP protein in FD patient cells compared to the amount produced from the DMSO vehicle control. EC 2x >1 μM is indicated by one asterisk ( * ), and >0.5μM to ≦1μM are indicated by an asterisk ( ** ) and >0.02μM to ≦0.5μM are indicated by three asterisks ( *** ), and >0.005μM to ≦0.02μM are indicated by four asterisks ( **** ) and ≦0.005 μM is indicated by five asterisks ( ***** ) [Table 18-1] [Table 18-2]

[0239] All documents referred to in this specification, whether or not the documents cited herein are specifically and individually indicated to be incorporated by reference, are incorporated by reference into this application for all purposes to the same extent as if each individual reference were fully set forth herein.

[0240] The claimed subject matter is now fully described, and it will be understood by those skilled in the art that similar modifications, within a broad range of equivalents, may be made without affecting the scope of the subject matter or specific embodiments described herein. It is intended that the appended claims be construed to include all such equivalents.

Claims

1. A compound of formula (I), or a form thereof, wherein said form of said compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereoisomer, a stereoisomer, and a tautomeric form thereof. 【Chemical 1】 (In the formula, R 1 is one, two, three, or four independently selected R 1a selected from the group consisting of optionally substituted aryl and heteroaryl; R 1a is 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 hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Each example of cycloalkyl, aryl, heterocyclyl, and heteroaryl may be selected from 1, 2, 3, or 4 independently selected R 2a may be substituted with a substituent; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Each example of alkynyl and heterocyclyl may contain a chiral carbon having an (R) or (S) configuration; 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, aryl-amino, heterocyclyl-amino, heteroaryl-amino, C 1-6 Alkyl-thio, C 1-6 Alkyl-sulfonyl, C 3-10 selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl; C 3-10 Each example of cycloalkyl, aryl, heterocyclyl, and heteroaryl may 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, and C 1-6 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, aryl, heterocyclyl, and heteroaryl; C 1-6 Alkyl, C 3-10 Each instance of cycloalkyl, aryl, heterocyclyl, or heteroaryl may 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 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, aryl, and heterocyclyl

2. R 1 is one, two, three, or four independently selected R 1a The compound of claim 1 , which is an optionally substituted phenyl.

3. 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, wherein said heteroaryl is selected from the group consisting of 1, 2, 3, or 4 independently selected R 1a The compound of claim 1 , which is optionally substituted with a substituent.

4. 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, wherein said heteroaryl is selected from the group consisting of 1, 2, 3, or 4 independently selected R 1a The compound of claim 1 , which is optionally substituted with a substituent.

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

6. R 2 is hydrogen, C 1-6 alkyl, and heterocyclyl; 1-6 Each instance of alkyl and heterocyclyl may be selected from 1, 2, 3, or 4 independently selected R 2a may be substituted with a substituent, C 1-6 10. The compound of claim 1, wherein each instance of alkyl and heterocyclyl may contain a chiral carbon having an (R) or (S) configuration.

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

8. R 2 is C 1-6 alkyl, wherein the C 1-6 The compound of claim 1 , wherein the alkyl contains a chiral carbon having the (R) configuration.

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

10. below: 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, wherein said form of said compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomeric form thereof.

11. The compound is: 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(thiophen-3-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1H-pyrazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-imidazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-N-[(furan-3-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1H-pyrrol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-3-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-oxazol-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,2-thiazol-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1H-pyrazol-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-oxazol-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1,3-thiazol-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-N-[(1H-imidazol-5-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-imidazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(2H-1,2,3-triazol-4-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1H-tetrazol-5-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1-methyl-1H-pyrrol-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(2S)-2-aminopropyl]-2-chloro-7-methyl-N-[(1H-pyrrol-3-yl)methyl]thieno[3,2-d]pyrimidin-4-amine 6-[(S)-(1-(1-aminoethyl)cyclopropyl)]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine 6-[(S)-(1-(amino(cyclopropyl)methyl)cyclopropyl)]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine 6-[(2R)-2-amino-2-cyclopropylethyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine, and 6-[(2R)-2-amino-2-cyclopropylethyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine; and said form of said compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomeric form thereof.

12. below: 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, wherein said form of said compound salt is selected from the group consisting of a hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomeric form thereof.

13. The compound salt may be: 6-[(S)-(1-(1-aminoethyl)cyclopropyl)]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate 6-[(S)-(1-(amino(cyclopropyl)methyl)cyclopropyl)]-2-chloro-N-[(furan-2-yl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-amine formate 6-[(2R)-2-amino-2-cyclopropylethyl]-7-bromo-2-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride, and 6-[(2R)-2-amino-2-cyclopropylethyl]-2-chloro-7-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-d]pyrimidin-4-amine dihydrochloride; and said form of said compound salt is selected from the group consisting of a hydrate, solvate, racemate, enantiomer, diastereoisomer, stereoisomer, and tautomeric form thereof.

14. A method for treating familial dysautonomia, comprising administering to a subject in need thereof an effective amount of the compound of claim 1.

15. A method for treating familial dysautonomia, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 10 or 12.

16. 19. A method for treating familial dysautonomia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 11 or 13.

17. 10. A pharmaceutical composition comprising a compound of claim 1 in admixture with a pharmaceutically acceptable excipient.

18. 13. A pharmaceutical composition comprising a compound according to any one of claims 10 or 12 in admixture with a pharmaceutically acceptable excipient.

19. 14. A pharmaceutical composition comprising a compound according to any one of claims 11 or 13 in admixture with a pharmaceutically acceptable excipient.

20. 10. A compound according to claim 1 for use as a pharmaceutical.

21. 13. A compound according to any one of claims 10 or 12 for use as a pharmaceutical.

22. 14. A compound according to any one of claims 11 or 13 for use as a pharmaceutical.

23. 10. A compound according to claim 1 for use in the treatment of familial dysautonomia.

24. 13. A compound according to any one of claims 10 or 12 for use in the treatment of familial dysautonomia.

25. 14. A compound according to any one of claims 11 or 13 for use in the treatment of familial dysautonomia.

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