BR122024013729A2 - THIENO[3,2-B]PYRIDIN-7-AMINE COMPOUNDS, THEIR USES IN THE TREATMENT OF FAMILIAL DYSAUTONOMIA AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME - Google Patents

Abstract

"THIENO[3,2-B]PYRIDIN-7-AMINE COMPOUNDS, THEIR USES IN THE TREATMENT OF FAMILIAL DYSAUTONOMIA AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME". The present invention relates to compounds of Formula (I) useful for improving pre-mRNA splicing in a cell. In particular, another aspect of the present invention relates to substituted thieno[3,2-b]pyridine compounds, pharmaceutical forms and compositions thereof and methods of use for the treatment or amelioration of familial dysautonomia.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS Split from BR112021015853-7, filed 2/10/2020.

[001] This application claims priority to Provisional Application No. US 62/805,283, filed on February 13, 2019. JOINT RESEARCH AGREEMENT STATEMENT

[002] The subject matter described was developed and the claimed invention was made by, or on behalf of, one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention. The claimed invention was made as a result of activities carried out 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.

TECHNICAL FIELD

[003] One aspect of the present invention relates to compounds useful for enhancing pre-mRNA splicing in a cell. In particular, another aspect of the present invention relates to substituted thieno[3,2-b]pyridine compounds, pharmaceutical forms and compositions of methods of use for the treatment or amelioration of familial dysautonomia.

BACKGROUND

[004] Familial dysautonomia (FD) is a congenital sensory and autonomic neuropathy (HSAN) of the central and peripheral nervous system characterized by widespread variable sensory and autonomic dysfunction. FD affects neuronal development and is associated with progressive neuronal degeneration. Multiple systems are affected, resulting in a marked reduction in quality of life and premature death. FD is caused by mutations in the IKBKAP gene (also known as ELP1) and in all cases described to date, there is at least one allele carrying a T to C mutation at position 6 in intron 20 that results in a unique tissue-specific exon skipping pattern.

[005] Kinetin derivatives useful for therapeutically targeting pre-mRNA splicing mechanisms and treating FD have been described in International Patent Application No. WO2016/115434, the disclosure of which is incorporated by reference in its entirety.

[006] All other documents referred to herein are incorporated by reference into this application as if fully set forth herein.

SUMMARY

[007] One aspect of the present invention includes compounds comprising a compound of Formula (I):

[008] or a form thereof, wherein R1, R3, R4, R5, and R6 are defined herein.

[009] One aspect of the present invention includes a method for using a compound of Formula (I) or a form or composition thereof for treating or ameliorating FD in a subject in need thereof comprising administering to the subject an effective amount of the compound of Formula (I) or a form or composition thereof.

[0010] One aspect of the present invention includes a use for a compound of Formula (I) or a form thereof for the treatment or amelioration of FD in a subject in need thereof comprising administering to the subject an effective amount of the compound of Formula (I) or a form thereof.

[0011] One aspect of the present invention includes a use for a compound of Formula (I) or a form thereof in the manufacture of a medicament for the treatment or amelioration of FD in a subject in need thereof comprising administering to the subject an effective amount of the medicament.

DETAILED DESCRIPTION

[0012] One aspect of the present invention relates to compounds comprising a compound of Formula (I):

[0013] or a form thereof, wherein:

[0014] R1 is phenyl or heteroaryl, optionally substituted with one, two, three or four independently selected R1a substituents,

[0015] wherein heteroaryl is a 5 to 8 membered aromatic monocyclic or bicyclic carbon atom ring radical having 1 to 3 heteroatoms selected from N, O and S;

[0016] R1a is cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, or C1-6alkoxy;

[0017] R3 is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and C1-6alkylamino,

[0018] wherein C1-6alkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted with one, two, three or four independently selected R3a substituents, and

[0019] wherein each case of C1-6alkyl, C2-6alkenyl and C2-6alkynyl may optionally contain a chiral carbon having an (R) or (S) configuration;

[0020] R3a is cyano, halo, hydroxy, oxo, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, halo-C1-6alkoxy, carboxyl, amino, C1-6alkoxycarbonyl, C1-6alkylamino, halo-C1-6alkylamino, (C1-6alkyl)2-amino, phenylamino, heterocyclylamino, heteroarylamino, phenyl-(C1-6alkyl)-amino, heterocyclyl-(C1-6alkyl)-amino, heteroaryl-(C1-6alkyl)-amino, C1-6alkylthio, C1-6alkylsulfoxyl and C1-6alkylsulfonyl,

[0021] wherein heterocyclyl is a 3- to 7-membered monocyclic carbon atom ring radical having 1 to 3 heteroatoms selected from N, O and S,

[0022] wherein heteroaryl is a 5 to 8 membered aromatic monocyclic or bicyclic carbon atom ring radical having 1 to 3 heteroatoms selected from N, O and S;

[0023] wherein each case of phenyl, heterocyclyl and heteroaryl is optionally substituted with one, two, three or four independently selected R3a’ substituents;

[0024] R3a' is cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, or amino;

[0025] R4 is hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, halo-C1-6alkoxy, amino, C1-6alkyl-amino, (C1-6alkyl)2-amino, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl,

[0026] wherein heterocyclyl is a 3- to 7-membered monocyclic carbon atom ring radical having 1 to 3 heteroatoms selected from N, O and S,

[0027] wherein heteroaryl is a 5- to 8-membered aromatic monocyclic or bicyclic carbon atom ring radical having 1 to 3 heteroatoms selected from N, O and S, and

[0028] wherein each case of C1-6alkyl, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one, two, three, or four independently selected R4a substituents;

[0029] R4a is cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, or C1-6alkoxy;

[0030] R5 is hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, carbamoyl, C3-10cycloalkyl, or heterocyclyl,

[0031] wherein heterocyclyl is a 3- to 7-membered monocyclic carbon atom ring radical having 1 to 3 heteroatoms selected from N, O and S; and

[0032] R6 is hydrogen, halo, or C1-6alkyl;

[0033] wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate and tautomeric form thereof.

[0034] One aspect includes a compound of Formula (I), wherein R1 is phenyl or heteroaryl, optionally substituted with one, two, three or four independently selected R1a substituents, wherein heteroaryl is a 5- to 8-membered aromatic monocyclic or bicyclic carbon atom ring structure radical having 1 to 3 heteroatoms selected from N, O and S.

[0035] Another aspect includes a compound of Formula (I), wherein R1 is phenyl, optionally substituted with one, two, three, or four independently selected R1a substituents.

[0036] Another aspect includes a compound of Formula (I), wherein R1 is phenyl, optionally substituted with a substituent of R1a.

[0037] Another aspect includes a compound of Formula (I), wherein R1 is heteroaryl, optionally substituted with one, two, three or four independently selected R1a substituents, wherein heteroaryl is a 5 to 8 membered aromatic monocyclic or bicyclic carbon atom ring structure radical having from 1 to 3 heteroatoms selected from N, O and S.

[0038] Another aspect includes a compound of Formula (I), wherein R1 is heteroaryl, optionally substituted with a substituent of R1a, wherein heteroaryl is a 5- to 8-membered aromatic monocyclic or bicyclic carbon atom ring structure radical having 1 to 3 heteroatoms selected from N, O and S.

[0039] Another aspect includes a compound of Formula (I), wherein R1 is heteroaryl selected from furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,3-thiazolyl, 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 heteroaryl is optionally substituted with one, two, three, or four, independently of R1a substituents.

[0040] Another aspect includes a compound of Formula (I), wherein R1 is heteroaryl selected from furanyl, thiophenyl, 1,3-thiazolyl, and pyridinyl, wherein heteroaryl is optionally substituted with one, two, three, or four, independently of R1a substituents.

[0041] Another aspect includes a compound of Formula (I), wherein R1 is heteroaryl selected from furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrazol-1 -yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, isoxazol-3-yl, isoxazole -4-yl, isoxazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-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- 4-yl, 1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin- 3-yl, pyridazin-4-yl, benzofuran-2-yl, benzofuran-5-yl and quinoline-4-yl, wherein, heteroaryl is optionally substituted with one, two, three or four, independently of R1a substituents.

[0042] Another aspect includes a compound of Formula (I), wherein R1 is heteroaryl selected from furan-2-yl, thiophen-2-yl, 1,3-thiazol-2-yl, and pyridin-4-yl, wherein heteroaryl is optionally substituted with one, two, three, or four, independently of R1a substituents.

[0043] One aspect includes a compound of Formula (I), wherein R1a is cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, or C1-6alkoxy.

[0044] Another aspect includes a compound of Formula (I), wherein R1a is halo.

[0045] Another aspect includes a compound of Formula (I), wherein R1a is halo selected from fluorine, chlorine, bromine and iodine.

[0046] Another aspect includes a compound of Formula (I), wherein R1a is fluorine.

[0047] One aspect includes a compound of Formula (I), wherein R3 is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C1-6alkylamino,

[0048] wherein each case of C1-6alkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted with one, two, three or four independently selected R3a substituents, and

[0049] wherein each case of C1-6alkyl, C2-6alkenyl and C2-6alkynyl may optionally contain a chiral carbon having an (R) or (S) configuration.

[0050] Another aspect includes a compound of Formula (I), wherein R3 is hydrogen, C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, optionally substituted with one, two, three, or four independently selected R3a substituents, wherein the C1-6alkyl, C2-6alkenyl, or C2-6alkynyl may optionally contain a chiral carbon having an (R) or (S) configuration.

[0051] Another aspect includes a compound of Formula (I), wherein R3 is hydrogen.

[0052] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein the C1-6alkyl optionally contains a chiral carbon having an (R) or (S) configuration.

[0053] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0054] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl selected from methyl, ethyl, propyl, butyl, pentyl and hexyl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0055] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl selected from methyl, ethyl, propyl, butyl, and pentyl, optionally substituted with one, two, three, or four independently selected R3a substituents.

[0056] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C1-6alkyl optionally contains a chiral carbon having an (R) configuration.

[0057] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl selected from methyl, ethyl, propyl, butyl, pentyl and hexyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein the C1-6alkyl optionally contains a chiral carbon having an (R) configuration.

[0058] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl selected from methyl, ethyl, propyl, butyl, and pentyl, optionally substituted with one, two, three, or four independently selected R3a substituents, and wherein the C1-6alkyl optionally contains a chiral carbon having an (R) configuration.

[0059] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C1-6alkyl optionally contains a chiral carbon having an (S) configuration.

[0060] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl selected from methyl, ethyl, propyl, butyl, pentyl and hexyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C1-6alkyl optionally contains a chiral carbon having an (S) configuration.

[0061] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkyl selected from methyl, ethyl, propyl, butyl, and pentyl, optionally substituted with one, two, three, or four independently selected R3a substituents, and wherein the C1-6alkyl optionally contains a chiral carbon having an (S) configuration.

[0062] Another aspect includes a compound of Formula (I), wherein R3 is C2-6alkenyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein the C2-6alkenyl optionally contains a chiral carbon having an (R) or (S) configuration.

[0063] Another aspect includes a compound of Formula (I), wherein R3 is C2-6alkenyl selected from ethenyl, propenyl, butenyl, pentenyl, hexenyl and heptenyl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0064] Another aspect includes a compound of Formula (I), wherein R3 is butenyl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0065] Another aspect includes a compound of Formula (I), wherein R3 is C2-6alkenyl selected from ethenyl, propenyl, butenyl, pentenyl, hexenyl and heptenyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C2-6alkenyl optionally contains a chiral carbon having an (R) configuration.

[0066] Another aspect includes a compound of Formula (I), wherein R3 is butenyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C2-6alkenyl optionally contains a chiral carbon having an (R) configuration.

[0067] Another aspect includes a compound of Formula (I), wherein R3 is C2-6alkynyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein the C2-6alkynyl optionally contains a chiral carbon having an (R) or (S) configuration.

[0068] Another aspect includes a compound of Formula (I), wherein R3 is C2-6alkenyl selected from ethenyl, propenyl, butenyl, pentenyl, hexenyl and heptenyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C2-6alkenyl optionally contains a chiral carbon having an (S) configuration.

[0069] Another aspect includes a compound of Formula (I), wherein R3 is butenyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C2-6alkenyl optionally contains a chiral carbon having an (S) configuration.

[0070] Another aspect includes a compound of Formula (I), wherein R3 is C2-6alkynyl selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl, optionally substituted with one, two, three, or four independently selected R3a substituents.

[0071] Another aspect includes a compound of Formula (I), wherein R3 is butynyl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0072] Another aspect includes a compound of Formula (I), wherein R3 is C2-6alkynyl selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl and heptynyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein the C2-6alkynyl optionally contains a chiral carbon having an (R) configuration.

[0073] Another aspect includes a compound of Formula (I), wherein R3 is butynyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C2-6alkynyl optionally contains a chiral carbon having an (R) configuration.

[0074] Another aspect includes a compound of Formula (I), wherein R3 is C2-6alkynyl selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl and heptynyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein the C2-6alkynyl optionally contains a chiral carbon having an (S) configuration.

[0075] Another aspect includes a compound of Formula (I), wherein R3 is butynyl, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C2-6alkynyl optionally contains a chiral carbon having an (S) configuration.

[0076] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, optionally substituted with one, two, three or four independently selected R3a substituents and wherein the C1-6alkyl optionally contains a chiral carbon having an (R) or (S) configuration.

[0077] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, optionally substituted with one, two, three or four independently selected R3a substituents.

[0078] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl, optionally substituted with one, two, three, or four independently selected R3a substituents.

[0079] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, wherein C1-6alkyl is propyl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0080] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, optionally substituted with one, two, three or four independently selected R3a substituents and wherein the C1-6alkyl optionally contains a chiral carbon having an (R) configuration.

[0081] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl, optionally substituted with one, two, three, or four independently selected R3a substituents, and wherein C1-6alkyl optionally contains a chiral carbon having an (R) configuration.

[0082] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, wherein C1-6alkyl is propyl, optionally substituted with one, two, three or four independently selected R3a substituents, and wherein C1-6alkyl optionally contains a chiral carbon having an (R) configuration.

[0083] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, optionally substituted with one, two, three or four independently selected R3a substituents and wherein C1-6alkyl optionally contains a chiral carbon having an (S) configuration.

[0084] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl, optionally substituted with one, two, three, or four independently selected R3a substituents, and wherein C1-6alkyl optionally contains a chiral carbon having an (S) configuration.

[0085] Another aspect includes a compound of Formula (I), wherein R3 is C1-6alkylamino, wherein C1-6alkyl is propyl, optionally substituted with one, two, three or four independently selected R3a substituents, and wherein C1-6alkyl optionally contains a chiral carbon having an (S) configuration.

[0086] Another aspect includes a compound of Formula (I), wherein R3 is C3-10cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted with one, two, three, or four independently selected R3a substituents.

[0087] Another aspect includes a compound of Formula (I), wherein R3 is cyclopropyl or cyclopentyl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0088] Another aspect includes a compound of Formula (I), wherein R3 is heterocyclyl, optionally substituted with one, two, three or four independently selected R3a substituents, wherein heterocyclyl is a 3 to 7 membered monocyclic carbon atom ring structure radical having from 1 to 3 heteroatoms selected from N, O and S and wherein heterocyclyl optionally contains a chiral carbon having an (R) or (S) configuration.

[0089] Another aspect includes a compound of Formula (I), wherein R3 is heterocyclyl selected from azetidinyl, oxetanyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2H-pyranyl, tetrahydropyranyl, morpholinyl, 1,3-oxazinanyl, and azepanyl, optionally substituted with one, two, three, or four independently selected R3a substituents.

[0090] Another aspect includes a compound of Formula (I), wherein R3 is azetidinyl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0091] Another aspect includes a compound of Formula (I), wherein R3 is heterocyclyl selected from azetidin-2-yl, azetidin-3-yl, oxetan-2-yl, oxetan-3-yl, pyrazolidine-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, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H- pyran- 4-yl, 2H-pyran-5-yl, 2H-pyran-6-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 1,3-oxazinan-2-yl, 1,3-oxazinan-3-yl, 1,3-oxazinan-4-yl, azepan-1-yl, azepan- 2-yl, azepan-3-yl and azepan-4-yl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0092] Another aspect includes a compound of Formula (I), wherein R3 is azetidin-3-yl, optionally substituted with one, two, three or four independently selected R3a substituents.

[0093] One aspect includes a compound of Formula (I), wherein R3a is cyano, halo, hydroxy, oxo, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, halo-C1-6alkoxy, carboxyl, amino, C1-6alkoxycarbonyl, C1-6alkylamino, halo-C1-6alkylamino, (C1-6alkyl)2-amino, phenyl-amino, heterocyclyl-amino, heteroaryl-amino, phenyl-(C1-6alkyl)-amino, heterocyclyl-(C1-6alkyl)-amino, heteroaryl-(C1-6alkyl)-amino, C1-6alkyl-thio, C1-6alkyl-sulfoxyl, or C1-6alkyl-sulfonyl, wherein each case of C3-10cycloalkyl, phenyl, heterocyclyl, and heteroaryl are optionally substituted with one, two, three or four independently selected substituents of R3a’.

[0094] Another aspect includes a compound of Formula (I), wherein R3a is cyano, halo, hydroxy, oxo, C1-6alkyl, C1-6alkoxy, halo-C1-6alkoxy, carboxyl, amino, C1-6alkoxycarbonyl, C1-6alkylamino, halo-C1-6alkylamino, (C1-6alkyl)2-amino, phenylamino, heteroarylamino, phenyl-(C1-6alkyl)-amino, heterocyclyl-(C1-6alkyl)-amino, heteroaryl-(C1-6alkyl)-amino, C1-6alkylthio, C1-6alkylsulfoxyl, or C1-6alkylsulfonyl, wherein heterocyclyl is a 3- to 7-membered monocyclic, carbon atom ring structure radical having from 1 to 3 heteroatoms selected from N, O and S, wherein heteroaryl is a 5- to 8-membered aromatic monocyclic or bicyclic carbon atom ring radical having 1 to 3 heteroatoms selected from N, O and S and in which each case of C3-10cycloalkyl, phenyl, heterocyclyl and heteroaryl is optionally substituted with one, two, three or four independently selected R3a' substituents.

[0095] Another aspect includes a compound of Formula (I), wherein R3a is cyano.

[0096] Another aspect includes a compound of Formula (I), wherein R3a is halo selected from fluorine, chlorine, bromine and iodine.

[0097] Another aspect includes a compound of Formula (I), wherein R3a is fluorine.

[0098] Another aspect includes a compound of Formula (I), wherein R3a is hydroxy.

[0099] Another aspect includes a compound of Formula (I), wherein R3a is oxo.

[00100] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkyl selected from C1-6alkyl selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[00101] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkyl selected from methyl and isopropyl.

[00102] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, iso-butoxy, tert-butoxy, pentoxy and hexyloxy.

[00103] Another aspect includes a compound of Formula (I), wherein R3a is methoxy.

[00104] Another aspect includes a compound of Formula (I), wherein R3a is halo-C1-6alkoxy, wherein the C1-6alkoxy is selected from methoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, iso-butoxy, tert-butoxy, pentoxy and hexyloxy partially or completely substituted with one or more halogen atoms, where permitted by available valences.

[00105] Another aspect includes a compound of Formula (I), wherein R3a is halo-C1-6alkoxy, wherein the C1-6alkoxy is methoxy substituted with three fluorine atoms.

[00106] Another aspect includes a compound of Formula (I), wherein R3a is carboxyl.

[00107] Another aspect includes a compound of Formula (I), wherein R3a is amino.

[00108] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkoxycarbonyl, wherein C1-6alkoxy is selected from methoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, iso-butoxy, tert-butoxy, pentoxy, and hexyloxy.

[00109] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkoxycarbonyl, wherein the C1-6alkoxy is methoxy.

[00110] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkyl-amino, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[00111] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkylamino, wherein C1-6alkyl is methyl.

[00112] Another aspect includes a compound of Formula (I), wherein R3a is halo-C1-6alkyl-amino, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl partially or completely substituted with one or more halogen atoms, where permitted by available valences.

[00113] Another aspect includes a compound of Formula (I), wherein R3a is halo-C1-6alkyl-amino, wherein C1-6alkyl is methyl substituted with three fluorine atoms.

[00114] Another aspect includes a compound of Formula (I), wherein R3a is (C1-6alkyl)2-amino, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[00115] Another aspect includes a compound of Formula (I), wherein R3a is (C1-6alkyl)2-amino, wherein C1-6alkyl is methyl.

[00116] Another aspect includes a compound of Formula (I), wherein R3a is phenylamino, wherein phenyl is optionally substituted with one, two, three or four independently selected R3a’ substituents.

[00117] Another aspect includes a compound of Formula (I), wherein R3a is phenylamino wherein phenyl is optionally substituted with one independently selected R3a’ substituent.

[00118] Another aspect includes a compound of Formula (I), wherein R3a is heteroaryl-amino, wherein heteroaryl is a 5- to 8-membered aromatic monocyclic or bicyclic carbon atom ring structure radical having from 1 to 3 heteroatoms selected from N, O and S, wherein heteroaryl is optionally substituted with one, two, three or four independently selected R3a' substituents.

[00119] Another aspect includes a compound of Formula (I), wherein R3a is heteroaryl-amino, wherein heteroaryl is selected from furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,3-thiazolyl, 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 heteroaryl is optionally substituted with one, two, three, or four independently selected R3a' substituents.

[00120] Another aspect includes a compound of Formula (I), wherein R3a is heteroaryl-amino, wherein heteroaryl is selected from 1H-pyrazolyl, pyridinyl, and pyrazinyl, wherein each instance is optionally substituted with one, two, three, or four independently selected R3a’ substituents.

[00121] Another aspect includes a compound of Formula (I), wherein R3a is phenyl-(C1-6alkyl)-amino, wherein C1-6alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl, wherein phenyl is phenyl is optionally substituted with one, two, three, or four independently selected substituents of R3a'.

[00122] Another aspect includes a compound of Formula (I), wherein R3a is phenyl-(C1-6alkyl)-amino, wherein C1-6alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl, wherein phenyl is phenyl is optionally substituted with an independently selected substituent of R3a’.

[00123] Another aspect includes a compound of Formula (I), wherein R3a is phenyl-(C1-6alkyl)-amino, wherein C1-6alkyl is methyl.

[00124] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkylthio, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[00125] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkylthio, wherein C1-6alkyl is methyl.

[00126] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkyl-sulfoxy, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[00127] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkyl-sulfoxy, wherein C1-6alkyl is methyl.

[00128] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkylsulfonyl, wherein C1-6alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[00129] Another aspect includes a compound of Formula (I), wherein R3a is C1-6alkylsulfonyl, wherein C1-6alkyl is methyl.

[00130] One aspect includes a compound of Formula (I), wherein R3a' is cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, or amino.

[00131] Another aspect includes a compound of Formula (I), wherein R3a' is halo or C1-6alkyl.

[00132] Another aspect includes a compound of Formula (I), wherein R3a' is cyano.

[00133] Another aspect includes a compound of Formula (I), wherein R3a' is halo selected from fluorine, chlorine, bromine and iodine.

[00134] Another aspect includes a compound of Formula (I), wherein R3a' is fluorine or chlorine.

[00135] Another aspect includes a compound of Formula (I), wherein R3a' is C1-6alkyl selected from methyl, ethyl, propyl, butyl, pentyl and hexyl.

[00136] Another aspect includes a compound of Formula (I), wherein R3a' is methyl.

[00137] Another aspect includes a compound of Formula (I), wherein R3a' is C1-6 alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, iso-butoxy, tert-butoxy, pentoxy and hexyloxy.

[00138] Another aspect includes a compound of Formula (I), wherein R3a' is methoxy.

[00139] Another aspect includes a compound of Formula (I), wherein R3a' is amino.

[00140] One aspect includes a compound of Formula (I), wherein R4 is hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, halo-C1-6alkoxy, amino, C1-6alkyl-amino, (C1-6alkyl)2-amino, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl, wherein heterocyclyl is a 3- to 7-membered monocyclic, carbon atom, ring structure radical having from 1 to 3 heteroatoms selected from N, O, and S, wherein heteroaryl is a 5- to 8-membered aromatic, monocyclic or bicyclic carbon atom ring structure radical having from 1 to 3 heteroatoms selected from N, O, and S, and wherein each case of C1-6alkyl, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl are optionally substituted with one, two, three, or four independently selected R4a substituents.

[00141] Another aspect includes a compound of Formula (I), wherein R4 is hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkoxy, or C3-10cycloalkyl, wherein the C1-6alkyl or C3-10cycloalkyl is optionally substituted with one, two, three or pending selected.

[00142] Another aspect includes an R4 is hydrogen.

[00143] Another aspect includes an R4 that is cyan.

[00144] Another aspect includes an R4 is halo selected from fluorine, chlorine

[00145] Another aspect includes an R4 is halo selected from chlorine and bromine.

[00146] Another aspect includes a compound of Formula (I), wherein R4 is hydroxy.

[00147] Another aspect includes a compound of Formula (I), wherein R4 is C1-6alkyl selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl, wherein the C1-6alkyl is optionally substituted with one, two, three, or four independently selected R4a substituents.

[00148] Another aspect includes a compound of Formula (I), wherein R4 is methyl optionally substituted with one, two, three or four independently selected R4a substituents.

[00149] Another aspect includes a compound of Formula (I), wherein R4 is halo-C1-6alkoxy, wherein C1-6alkoxy is selected from methoxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, iso-butoxy, tert-butoxy, pentoxy and hexyloxy partially or completely substituted with one or more halogen atoms, where permitted by available valences.

[00150] Another aspect includes a compound of Formula (I), wherein R3a is halo-C1-6alkoxy, wherein the C1-6alkoxy is methoxy substituted with two fluorine atoms.

[00151] Another aspect includes a compound of Formula (I), wherein R4 is C3-10cycloalkyl, wherein the C3-10cycloalkyl is optionally substituted with one, two, three or four independently selected R4a substituents.

[00152] Another aspect includes a compound of Formula (I), wherein R4 is C3-10cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted with one, two, three, or four independently selected R4a substituents.

[00153] Another aspect includes a compound of Formula (I), wherein R4 is cyclopropyl, optionally substituted with one, two, three or four independently selected R4a substituents.

[00154] One aspect includes a compound of Formula (I), wherein R4a is cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, or C1-6alkoxy.

[00155] One aspect includes a compound of Formula (I), wherein R5 is hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, carbamoyl, C3-10cycloalkyl, or heterocyclyl, wherein heterocyclyl is a 3- to 7-membered monocyclic, carbon atom ring structure radical having 1 to 3 heteroatoms selected from N, O, and S.

[00156] Another aspect includes a compound of Formula (I), wherein R5 is hydrogen, cyano, halo, or C1-6alkyl.

[00157] Another aspect includes a compound of Formula (I), wherein R5 is hydrogen.

[00158] Another aspect includes a compound of Formula (I), wherein R5 is cyano.

[00159] Another aspect includes a compound of Formula (I), wherein R5 is halo selected from fluorine, chlorine, bromine and iodine.

[00160] Another aspect includes a compound of Formula (I), wherein R5 is chlorine.

[00161] Another aspect includes a compound of Formula (I), wherein R5 is C1-6alkyl selected from methyl, ethyl, propyl, butyl, pentyl and hexyl.

[00162] Another aspect includes a compound of Formula (I), wherein R5 is methyl.

[00163] One aspect includes a compound of Formula (I), wherein R6 is hydrogen, halo, or C1-6alkyl.

[00164] Another aspect includes a compound of Formula (I), wherein R6 is hydrogen.

[00165] An aspect of the compound of Formula (I) or a form thereof includes a compound selected from the group consisting of:

[00166] wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate and tautomeric form thereof.

[00167] An aspect of the compound of Formula (I) or a form thereof (wherein the compound number (#1) indicates that the salt form has been isolated) includes a compound selected from the group consisting of:

[00168] wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate and tautomeric form thereof.

[00169] Another aspect of the compound of Formula (I) or a form thereof is a salt of the compound selected from the group consisting of:

[00170] wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, and tautomer.

[00171] The present application also provides a pharmaceutical composition, characterized in that it comprises a compound provided herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[00172] The present application also 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, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[00173] 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 are described herein for use in the present invention; other suitable methods and materials known in the art may also be used.

[00174] 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 the event of a conflict, this specification, including definitions, will control.

CHEMICAL DEFINITIONS

[00175] The chemical terms used above and throughout the present invention, unless specifically defined otherwise, should be understood by one of ordinary skill in the art as having the following indicated meanings.

[00176] As used herein, the term "C1-6alkyl" generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration, including, but not limited to, methyl, ethyl, n-propyl (also referred to as propyl or propanyl), isopropyl, n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also referred to as pentyl or pentanyl), n-hexyl (also referred to as hexyl or hexanyl), and the like. In certain aspects, C1-6alkyl includes, but is not limited to, C1-6alkyl, C1-4alkyl, and the like. A C1-6alkyl radical is optionally substituted with substituent species, as described herein, when permitted by the available valences.

[00177] As used herein, the term "heteroC1-6alkyl" generally refers to saturated hydrocarbon radicals having from one to six carbon atoms in a straight or branched chain configuration, in which one or more heteroatoms, such as an O, S or N atom are members of the chain, including, but not limited to, hetero-methyl, hetero-ethyl, hetero-propyl, hetero-butyl, hetero-pentyl, hetero-hexyl and the like. In certain aspects, heteroC1-6alkyl includes, but is not limited to, heteroC2-6alkyl, heteroC1-4alkyl, heteroC2-4alkyl and the like. A heteroC1-6alkyl radical is optionally substituted with substituent species as described herein, where permitted by available valencies.

[00178] As used herein, the term "C2-6alkenyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also referred to as vinyl), allyl, propenyl, and the like. In certain aspects, C2-6alkenyl includes, but is not limited to, C2-6alkenyl, C2-4alkenyl, and the like. A C2-6alkenyl radical is optionally substituted with substituent species, as described herein, when permitted by the available valencies.

[00179] As used herein, the term "C2-6alkynyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including, but not limited to, ethynyl (also referred to as acetylenyl), propynyl, butynyl, and the like. In certain aspects, C2-6alkynyl includes, but is limited to, C2-6alkynyl, C2-4alkynyl, and the like. A C2-6alkynyl radical is optionally substituted with substituent species, as described herein, when permitted by the available valencies.

[00180] As used herein, the term "C1-6alkoxy" generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the Formula: -O-C1-6alkyl, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like. In certain aspects, C1-6alkoxy includes, but is not limited to, C1-6alkoxy, C1-4alkoxy, and the like. A C1-6alkoxy radical is optionally substituted with substituent species as described herein when permitted by available valencies.

[00181] As used herein, the term "oxo" refers to a radical of the Formula: =O.

[00182] As used herein, the term "carboxyl" refers to a radical of the Formula: -COOH, -C(O)OH or -CO2H.

[00183] As used herein, the term "C1-6alkoxycarbonyl" refers to a radical of the Formula: -COO-C1-6alkyl, -C(O)O-C1-6alkyl or -CO2-C1-6alkyl.

[00184] As used here, the term "carbamoyl" refers to a radical of the Formula: -C(O)NH2.

[00185] As used herein, the term "C3-10cycloalkyl" 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, tetrahydronaphthalenyl and the like. In certain aspects, C3-10cycloalkyl includes, but is not limited to, C3-8cycloalkyl, C5-8cycloalkyl, C3-10cycloalkyl and the like. A C3-10cycloalkyl radical is optionally substituted with substituent species as described herein when permitted by available valencies.

[00186] As used herein, the term "aryl" generally refers to an aromatic, monocyclic, bicyclic or polycyclic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical is optionally substituted with substituent species, as described herein, when permitted by the available valencies.

[00187] As used herein, the term "heteroaryl" generally refers to an aromatic, monocyclic, bicyclic, or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where structural stability permits, with one or more heteroatoms, such as an O, S, or N atom, 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, benzoimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and the like. A heteroaryl radical is optionally substituted on a nitrogen or carbon atom ring member with substituent species as described herein, when permitted by the available valences.

[00188] In certain aspects, the nomenclature for a heteroaryl radical may differ, such as, in non-limiting examples where furanyl may also be referred to as furyl, thiophenyl may also be referred to as thienyl, pyridinyl may also be referred to as pyridyl, benzothiophenyl may also be referred to as benzothienyl, and 1,3-benzoxazolyl may also be referred to as 1,3-benzooxazolyl.

[00189] In certain other aspects, the term for a heteroaryl radical may also include other regioisomers, such as, in non-limiting examples wherein the term pyrrolyl may also include 2H-pyrrolyl, 3H-pyrrolyl, and the like, the term pyrazolyl may also include 1H-pyrazolyl and the like, the term imidazolyl may also include 1H-imidazolyl and the like, the term triazolyl may also include 1H-1,2,3-triazolyl and the like, the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like, the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl and the like, the term indolyl may also include 1H-indolyl and the like, the term indazolyl may also include 1H-indazolyl, 2H-indazolyl and the like, the term benzoimidazolyl may also include 1H-benzoimidazolyl and the term purinyl may also include 9H-purinyl and the like.

[00190] As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where structural stability permits, with a heteroatom such as an O, S or N atom, including, but not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazol ... azolidinyl, 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 and the like. A heterocyclyl radical is optionally substituted on a nitrogen or carbon atom ring member with substituent species as described herein, when allowed by the available valences.

[00191] As used herein, the term "C1-6alkylamino" refers to a radical of the Formula: -NH-C1-6alkyl.

[00192] As used herein, the term "halo-C1-6alkyl-amino" refers to a radical of the Formula: -NH-C1-6alkyl, wherein C1-6alkyl is partially or completely substituted with one or more halogen atoms when allowed by the available valences.

[00193] As used herein, the term "(C1-6alkyl)2-amino" refers to a radical of the Formula: -N(C1-6alkyl)2.

[00194] As used herein, the term "C1-6alkyl-carboxyl-amino" refers to a radical of the Formula: -NH-C(O)-.

[00195] As used herein, the term "aryl-amino" refers to a radical of the Formula: -NH-aryl.

[00196] As used herein, the term "heterocyclyl-amino" refers to a radical of the Formula: -NH-heterocyclyl.

[00197] As used herein, the term "heteroaryl-amino" refers to a radical of the Formula: -NH-heteroaryl.

[00198] As used herein, the term "aryl-(C1-6alkyl)-amino" refers to a radical of the Formula: -N(C1-6alkyl)-aryl.

[00199] As used herein, the term "heterocyclyl-(C1-6alkyl)-amino" refers to a radical of the Formula: -N(C1-6alkyl)-heterocyclyl.

[00200] As used herein, the term "heteroaryl-(C1-6alkyl)-amino" refers to a radical of the Formula: -N(C1-6alkyl)-heteroaryl.

[00201] As used herein, the term "C1-6alkylthio" refers to a radical of the Formula: -S-C1-6alkyl.

[00202] As used herein, the term "C1-6alkylsulfoxy" refers to a radical of the Formula: -S(O)-C1-6alkyl.

[00203] As used herein, the term "C1-6alkylsulfonyl" refers to a radical of the Formula: -SO2-C1-6alkyl.

[00204] As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluorine, chlorine, bromine, and iodine.

[00205] As used herein, the term "halo-C1-6alkoxy" refers to a radical of the Formula: -O-C1-6alkyl-halo, wherein the C1-6alkyl is partially or completely substituted with one or more halogen atoms when allowed by the available valences.

[00206] As used herein, the term "halo-C1-6alkyl" refers to a radical of the Formula: -C1-6alkyl-halo, wherein C1-6alkyl is partially or completely substituted with one or more halogen atoms when allowed by the available valences.

[00207] As used herein, the term "hydroxy" refers to a radical of the Formula: -OH.

[00208] As used herein, the term "hydroxy-C1-6alkyl" refers to a radical of the Formula: -C1-6alkyl-OH, wherein C1-6alkyl is partially or completely substituted with one or more hydroxy radicals when allowed by the available valences.

[00209] As used herein, the term "substituent" means positional variables on the atoms of a nucleus molecule that are substituted into a designated atom position by replacing one or more hydrogens on the designated atom, provided that the normal valency of the designated atom is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds. One skilled in the art should note that any carbon, as well as heteroatom, with valencies that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valencies described or shown. In certain cases, one or more substituents having a double bond (e.g., "oxo" or "=O") as the point of attachment may be depicted, shown or listed herein within a substituent group, wherein the structure may show only a single bond as the point of attachment to the central structure of Formula (I). One of skill in the art would understand that although only a single bond is shown, a double bond is intended for such substituents.

[00210] As used herein, the term "and the like", with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that would be expected by one of skill in the art include, without limitation, isomers (including structural, chain or branch isomers), hydration of ring systems (including partial saturation or unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations when permitted by the available valences that result in a stable compound.

[00211] For purposes of this invention, where one or more substituent variables for a compound of Formula (I) or a form thereof encompass functionalities incorporated into a compound of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.

[00212] As used herein, the terms "independently selected" or "each selected" refer to functional variables in a list of substituents that may occur more than once in the structure of Formula (I), the substitution pattern in each occurrence being independent of the pattern in any other occurrence. Furthermore, the use of a generic substituent variable in any Formula or structure for a compound described herein is understood to include replacement of the generic substituent with substituents of species that are included in the particular genus, for example, aryl may be substituted with phenyl or naphthalenyl and the like, and that the resulting compound is to be included in the scope of the compounds described herein.

[00213] As used herein, the terms "each case of" or "in each case, when present," when used before a phrase such as, "C3-10cycloalkyl, C3-10cycloalkyl-C1-4alkyl, aryl, aryl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocyclyl, and heterocyclyl-C1-4alkyl," are intended to refer to C3-10cycloalkyl, aryl, heteroaryl, and heterocyclyl ring systems when each is present alone or as a substituent.

[00214] As used herein, the term "optionally substituted" means optional substitution with specific substituent variables, groups, radicals or moieties.

COMPOUND FORMS

[00215] As used herein, the term "form" means a compound of Formula (I) having a form selected from the group consisting of a free acid, free base, salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.

[00216] In certain aspects described herein, the form of the compound of Formula (I) is a free acid, free base, or salt thereof.

[00217] In certain aspects described herein, the form of the compound of Formula (I) is a salt thereof.

[00218] In certain aspects described herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer, or diastereomer thereof.

[00219] In certain aspects described herein, the form of the compound of Formula (I) is a tautomer thereof.

[00220] In certain aspects described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.

[00221] In certain aspects described herein, the compound of Formula (I) or a form thereof is isolated for use.

[00222] As used herein, the term "isolated" means 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 natural source or combination thereof according to an isolation or purification process or processes described herein or that are well known to the skilled artisan (e.g., chromatography, recrystallization, and the like) in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.

[00223] As used herein, the term "protected" means that a functional group in a compound of Formula (I) or a form thereof is in a modified form to prevent unwanted side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art, as well as by reference to standard textbooks, such as, for example, 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 certain cases, 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, which are well known to those skilled in the art and as described herein. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds described herein may not possess pharmacological activity as such, that they may be administered to an individual and subsequently metabolized in the body to form compounds described herein that are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds described herein are included within the scope of use described herein.

[00224] As used herein, the term "prodrug" means a form of a present compound (e.g., a drug precursor) that is transformed in vivo to produce an active compound of Formula (I) or a form thereof. Transformation may occur by various mechanisms (e.g., by metabolic and/or nonmetabolic chemical processes), such as, 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, "Pro-drug as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[00225] In one example, when a compound of Formula (I) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by replacing the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like. In another example, when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of the compounds of Formula (I) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters, and mono-, di-, or triphosphate esters or alkyl substituents, where appropriate. As described herein, it is understood by one of skill in the art that one or more of these substituents may be used to provide a compound of Formula (I) or a form thereof as a prodrug.

[00226] 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 invention herein is intended to encompass both solvated and unsolvated forms.

[00227] As used herein, the term "solvate" means a physical association of a compound described herein with one or more solvent molecules. Such physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

[00228] As used herein, the term "hydrate" means a solvate in which the solvent molecule is water.

[00229] The compounds of Formula (I) can form salts, which are intended to be included within the scope of this invention. Reference to a compound of Formula (I) or a form thereof herein is understood to include reference to salt forms thereof, unless otherwise indicated. The term "salt(s)" as used herein denotes acidic 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 ("inner salts") can be formed and are included within the term "salt(s)" as used herein.

[00230] The term "pharmaceutically acceptable salt(s)", as used herein, means those salts of 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 compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[00231] Pharmaceutically acceptable salts include one or more salts of basic or acidic groups present in compounds described herein. Particular aspects of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, and the like. Certain particular aspects of acid addition salts include chloride or dichloride.

[00232] Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts of 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, D.C. on its website). These disclosures are incorporated herein by reference thereto.

[00233] Suitable base salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, and zinc salts.

[00234] All such acid salts and base salts are intended to be included within the scope of the pharmaceutically acceptable salts as described herein. Furthermore, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this invention.

[00235] Compounds of Formula (I) and forms thereof may further exist in a tautomeric form. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or a form thereof as described herein.

[00236] Compounds of Formula (I) or a form thereof may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. The present invention is intended to include all stereoisomeric forms of compounds of Formula (I) as well as mixtures thereof, including racemic mixtures.

[00237] The compounds described herein may include one or more chiral centers, and as such may exist as racemic (R/S) mixtures or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when a chiral center is present). In one particular aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions comprising substantially only the (S) isomer. In another particular aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions comprising substantially only the (R) isomer. As one skilled in the art will recognize, when more than one chiral center is present, the compounds described herein may also exist as an (R,R), (R,S), (S,R), or (S,S) isomer, as defined by the IUPAC nomenclature recommendations.

[00238] As used herein, the term "chiral" refers to a carbon atom bonded to four non-identical substituents. The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Ste-reochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. When describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The substituents bonded to the chiral center under consideration are classified according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; erratum 511).

[00239] As used herein, the term "substantially pure" refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.

[00240] In one aspect of the invention, a compound of Formula (I) or a form thereof is a substantially pure (S) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

[00241] In one aspect of the invention, a compound of Formula (I) or a form thereof is a substantially pure (R) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

[00242] As used herein, a "racemate" is any mixture of isometric forms that are not "enantiomerically pure", including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.

[00243] Furthermore, the present invention encompasses all geometric and positional isomers. 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 the invention. Diastereomeric mixtures may be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers may be separated by the use of a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers may also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. In addition, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered to be part of this invention.

[00244] All stereoisomers (e.g., geometric isomers, optical isomers, and the like) of the present compounds (including those of the salts, solvates, esters, and prodrugs of the compounds, as well as the salts, solvates, and esters of the prodrugs), such as those that may exist due to asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). The individual stereoisomers of compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture as described above.

[00245] The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the present compounds.

[00246] The term "isotopologue" refers to isotopically enriched compounds described herein that are identical to those recited herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number generally found in nature. Examples of isotopes that may be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 35Cl, and 36Cl, respectively, each of which is also within the scope of this invention.

[00247] Certain isotopically enriched compounds described herein (e.g., those labeled with 3H and 14C) are useful in substrate and/or compound tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, substitution with heavier isotopes, such as deuterium (i.e., 2H) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosing requirements) and therefore may be preferred in some circumstances.

COMPOST USES

[00248] Provided herein are methods of treating a disease in a subject in need thereof. As used herein, the term "subject" refers to any animal, including mammals. For example, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some aspects, the subject is a human. In some aspects, 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 a particular aspect, the disease is familial dysautonomia, a disease of the central and peripheral nervous system associated with one or more pre-mRNA splicing defects.

[00249] The present application further provides a method of treating familial dysautonomia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula (I)).

[00250] In some aspects of the methods provided herein, the compound is selected from the group of compounds of Formula (I), or a pharmaceutically acceptable salt thereof.

[00251] In some aspects, the method of improving splicing of the pre-mRNA of the IKBKAP gene comprises 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)).

[00252] As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response being sought in a tissue, system, animal, subject, or human by a researcher, veterinarian, physician, or other clinician. In some aspects, 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.

[00253] As used herein, the term "treat" or "treatment" refers to one or more of (1) preventing disease; e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but does not yet exhibit or show the pathology or symptomatology of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual who is exhibiting or showing the pathology or symptomatology of the disease, condition, or disorder (i.e., stopping the further development of the pathology and/or symptomatology); and (3) ameliorating a disease; e.g., ameliorating a disease, condition, or disorder in an individual who is exhibiting or showing the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and/or symptomatology), such as by decreasing the severity of the disease or reducing or alleviating one or more symptoms of the disease.

[00254] Also provided herein are methods for increasing the expression of the IKBKAP protein (also referred to as ELP1) in a patient in need thereof, the method comprising administering an effective amount of a compound provided herein, (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), to the patient. For example, such methods include increasing the expression of the IKBKAP protein in serum samples from the patient. Further provided are methods for increasing the mean percentage of expression of the IKBKAP protein in a patient in need thereof, the method comprising administering an effective amount of a compound provided herein (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), to the patient.

[00255] Also provided herein are methods for increasing the expression of the IKBKAP protein 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). In some aspects, the method is an in vitro method. In some aspects, the method is an in vivo method. In some aspects, the amount of expression of the IKBKAP protein 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, a nerve cell (e.g., a sciatic nerve cell or a trigeminal nerve cell), or any combination thereof. In some aspects thereof, the amount of expression of the IKBKAP protein is increased in plasma.

[00256] Also provided herein are methods for increasing the level of IKBKAP protein in a patient in need thereof, the method comprising administering an effective amount of a compound provided herein, (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), to the patient. For example, such methods include increasing the level of IKBKAP protein in serum samples from the patient. Further provided are methods for increasing the average percentage level of IKBKAP protein in a patient in need thereof, the method comprising administering an effective amount of a compound provided herein (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), to the patient.

[00257] Also provided herein are methods for increasing the level of IKBKAP protein 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).

[00258] In some aspects, the method is an in vitro method. In some aspects, the method is an in vivo method. In some aspects, the amount of the IKBKAP protein level 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, a nerve cell (e.g., a sciatic nerve cell or a trigeminal nerve cell), or any combination thereof. In some aspects thereof, the amount of the IKBKAP protein level is increased in plasma.

[00259] Also provided herein are methods for increasing full-length IKBKAP mRNA in a patient in need thereof, the method comprising administering an effective amount of a compound provided herein, (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), to the patient. For example, such methods include increasing the concentration of full-length IKBKAP mRNA in serum samples from the patient. Also provided herein are methods for increasing the mean percentage of exon inclusion (i.e., the percentage of full-length or correctly excised IKBKAP mRNA) in a patient in need thereof, the method comprising administering an effective amount of a compound provided herein (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), to the patient.

[00260] In some aspects, full-length IKBKAP mRNA can be measured in serum, e.g., in blood samples obtained from the patient prior to administration of a compound as provided herein and in blood samples obtained from the patient after administration of a compound as provided herein. In some aspects, blood samples obtained from the patient after administration are obtained after one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, fourteen days, twenty-one days, twenty-eight days, and/or thirty days of administration of the compound as provided herein. See, e.g., F.B. Axelrod et al., Pediatr Res (2011) 70(5):480-483; and R.S. Shetty et al., Human Molecular Genetics (2011) 20 (21): 4093–4101, both incorporated by reference in their entirety.

[00261] Further provided herein is a method of 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 relative to a cell in a subject in the absence of a compound provided herein. The method of increasing the amount of full-length IKBKAP mRNA in a cell can be carried out by contacting the cell with a compound provided herein (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt form thereof), in vitro, thereby increasing the amount of full-length IKBKAP mRNA in a cell in vitro. Uses of this in vitro method for increasing the amount of full-length IKBKAP mRNA include, but are not limited to, use in a screening assay (e.g., wherein a compound provided herein is used as a positive control or standard in comparison to a compound or compounds of unknown activity or potency in increasing the amount of full-length IKBKAP mRNA).

[00262] In some aspects, the amount of full-length IKBKAP mRNA 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, a nerve cell (e.g., a sciatic nerve cell or a trigeminal nerve cell), or any combination thereof. In some aspects thereof, the amount of full-length IKBKAP mRNA is increased in plasma.

[00263] The method of increasing full-length IKBKAP mRNA in a cell can be accomplished, 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), with a compound provided herein (i.e., a compound of Formula (I), or a pharmaceutically acceptable salt thereof), in vivo, thereby increasing the amount of full-length IKBKAP mRNA in a subject in vivo. Contacting is accomplished by causing a compound provided herein, or a pharmaceutically acceptable salt form thereof, to be present in a 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 a subject. Uses of an in vivo method for increasing the amount of full-length IKBKAP mRNA include, but are not limited to, use in methods of treating a disease or condition where an increase in the amount of full-length IKBKAP mRNA is beneficial.

[00264] In some aspects thereof, the amount of full-length IKBKAP mRNA 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, a nerve cell (e.g., a sciatic nerve cell or a trigeminal nerve cell), or any combination thereof, for example, in a subject suffering from 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.

[00265] 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. In some embodiments, the additional pharmaceutical agent is a compound provided herein (e.g., a compound of Formula (I)).

[00266] Additional examples of additional pharmaceutical agents suitable for use in combination with the compounds of the present application for the treatment of the diseases provided 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 the treatment of familial dysautonomia. In some embodiments, the additional pharmaceutical agent is phosphatidylserine.

[00267] When employed as a therapeutic agent, the compounds provided herein may be administered in the form of a pharmaceutical composition; thus, the methods described herein may include administration of a pharmaceutical composition. Such compositions may be prepared as described herein or elsewhere, and may be administered by a variety of routines, depending on whether local or systemic treatment is desired and the area to be treated. Administration may be pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration may include, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial (e.g., intrathecal, intraocular, or intraventricular) administration. Parenteral administration may be in the form of a single bolus dose, or may be, for example, by a continuous infusion pump. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be required or desirable. In some aspects, the compounds provided herein are suitable for both oral and parenteral administration. In some aspects, the compounds provided herein are suitable for oral administration. In some aspects, the compounds provided herein are suitable for parenteral administration. In some aspects, the compounds provided herein are suitable for intravenous administration. In some aspects, the compounds provided herein are suitable for transdermal administration (e.g., administration using a patch or microneedle). Pharmaceutical compositions for topical administration may include transdermal patches (e.g., regular or electrostimulated), ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be required or desirable.

[00268] Also provided are pharmaceutical compositions having, as an active ingredient, a compound provided herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient acts as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[00269] Some examples of suitable excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may additionally include, without limitation, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; flavoring agents, or combinations thereof.

[00270] The active compound may 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 to be administered and the schedule of administration will generally be determined by a physician in accordance with the relevant circumstances, including the condition to be treated, the administration routine chosen, the actual compound administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, and the like.

[00271] Also provided herein are kits including a compound provided herein, more particularly, a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a kit can include one or more delivery systems, e.g., for a compound provided herein, or a pharmaceutically acceptable salt thereof, and instructions for use of the kit (e.g., instructions for treating a subject). In some embodiments, a kit can include a compound provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional agents, as provided herein.

[00272] In some aspects, the kit can include one or more additional pharmaceutical compounds or agents as provided herein, or a pharmaceutically acceptable salt thereof, and a label indicating that the contents are to be administered to a subject resistant to a standard or adjunctive treatment agent used in the treatment of familial dysautonomia. In some aspects, the additional pharmaceutical agent is phosphatidylserine. In another aspect, the kit can include a compound provided herein, or a pharmaceutically acceptable salt thereof, and a label indicating that the contents are to be administered to a subject with cells expressing abnormal IKBKAP pre-mRNA splicing. In another aspect, the kit can include one or more additional pharmaceutical compounds or agents as provided herein, or a pharmaceutically acceptable salt thereof, and a label indicating that the contents are to be administered to a subject with a disease of the central nervous system or peripheral nervous system resulting from abnormal pre-mRNA splicing.

[00273] In another aspect, the kit may include one or more additional compounds or pharmaceutical agents as provided herein, or a pharmaceutically acceptable salt thereof, and a label indicating that the contents are to be administered to a subject having familial dysautonomia. In some aspects, a kit may include one or more compounds as provided herein, or a pharmaceutically acceptable salt thereof, and a label indicating that the contents are to be administered with one or more additional pharmaceutical agents as provided herein.

[00274] In another aspect, the observed concentration-biological effect relationship with respect to a compound of Formula (I) or a form thereof indicates a target plasma concentration ranging from approximately 0.001 μgΦr/mL to approximately 50 μg^hr/mL, from approximately 0.01 μgΦr/mL to approximately 20 μgΦr/mL, from approximately 0.05 μgΦr/mL to approximately 10 μgΦr/mL, or from approximately 0.1 μgΦr/mL to approximately 5 μgΦr/mL. To achieve such plasma concentrations, the compounds described herein can be administered in doses ranging, such as, for example, without limitation, from 1.0 ng to 10,000 mg.

[00275] In one aspect, the dose administered to achieve an effective target plasma concentration can be administered based on individual or patient-specific factors, wherein doses administered on a weight-by-weight basis can be in the range of about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.001 mg/kg/day to about 3000 mg/kg/day, or about 0.001 mg/kg/day to about 2500 mg/kg/day, or about 0.001 mg/kg/day to about 2000 mg/kg/day, or about 0.001 mg/kg/day to about 1500 mg/kg/day, or about 0.001 mg/kg/day to about 1000 mg/kg/day, or about 0.001 mg/kg/day to about from 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 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 250 mg/kg/day, or about 0.01 mg/kg/day to about 200 mg/kg/day, or about 0.01 mg/kg/day to about 150 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day, or about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 50 mg/kg/day, or about 0.01 mg/kg/day to about 25 mg/kg/day, or about 0.01 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 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.

[00276] Effective amounts for a given individual can be determined by routine experimentation that is within the skill and judgment of a skilled artisan or practitioner in light of factors related to the individual. Dosage and administration can be adjusted to provide sufficient levels of the active agents or maintain the desired effect. Factors that can be taken into consideration include genetic screening, severity of the disease state, stage of disease progression, general health of the individual, ethnicity, age, weight, sex, diet, time of day and frequency of administration, drug combination, reaction sensitivities, experience with other therapies, and tolerance/response to therapy.

[00277] The dose administered to achieve an effective target plasma concentration may be administered orally (once in approximately a 24 hour period; i.e., "q.d."), twice (once in approximately a 12 hour period; i.e., "b.i.d." or "q.12h"), three times (once in approximately a 8 hour period; i.e., "t.i.d." or "q.8h"), or four times (once in approximately a 6 hour period; i.e., "q.d.s.", "q.i.d." or "q.6h") daily.

[00278] In certain aspects, the dose administered to achieve an effective target plasma concentration may also be administered in a single, divided or continuous dose to a patient or subject having a weight in a range of about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). The typical adult subject is expected to have an average weight in a range of about 70 kg. Long-acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.

[00279] The compounds and compositions described herein may be administered to the subject via any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, and pulmonary routes of administration.

[00280] In another aspect, the administered dose may be adjusted based on a pharmaceutical form formulated herein for release at 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.

[00281] For any compound, the effective amount can be estimated initially in cell culture assays or in relevant animal models, such as mouse, guinea pig, chimpanzee, marmoset or tamarin animal models. Relevant animal models can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine useful doses and routes of administration in humans. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the therapeutically effective dose in 50% of the population) and LD50 (the lethal dose for 50% of the population). The dose relationship between therapeutic and toxic effects is the therapeutic index and can be expressed as the ratio, LD50/ED50. In certain aspects, the effective amount is such that a large therapeutic index is achieved. In other particular aspects, the dosage is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range, depending on the dosage form used, the sensitivity of the patient and the route of administration.

[00282] Another aspect included within the scope of the present invention is the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes the use of compounds produced by a process comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to produce a metabolic product thereof.

[00283] Such products are typically identified by preparing a radiolabeled isotopologue (e.g., 14C or 3H) of a compound described herein, administering the radiolabeled compound at a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal, such as a rat, mouse, guinea pig, dog, monkey, or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood, or other biological samples. The conversion products are readily isolated since they are "radiolabeled" by virtue of being isotopically enriched (others are isolated by the use of antibodies capable of binding to the epitopes that survive on the metabolite). Metabolite structures are determined in conventional manner, for example, by MS or NMR analysis. In general, metabolite analysis can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products, provided they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein, even if they have no biological activity of their own.

PREPARATION OF COMPOUNDS General Synthetic Methods

[00284] As described herein, general methods for preparing the compounds of Formula (I) or a form thereof as described herein are available via standard, well-known synthetic methodology. Many of the starting materials are commercially available or, when not available, can be prepared using the routes described below using techniques known to those skilled in the art. The synthetic schemes provided herein comprise several reaction steps, each of which is intended to be independent and may be carried out with or without any prior or subsequent steps. In other words, each of the individual reaction steps of the synthetic schemes provided herein in isolation is contemplated. Scheme A:

[00285] Compounds of Formula (I) may be prepared as described in Scheme A below.

Captions: where - base - unprotection

[00286] Compound A1 with an optional R4 substituent was treated with an optionally substituted 3-chloro-3-oxopropanoate in the presence of a base (such as triethyl amine and the like) in a suitable solvent (such as DCM and the like) at an appropriate temperature (such as room temperature and the like) to afford compound A2. Compound A2 was cyclized to compound A3 in the presence of a base (such as sodium ethoxide and the like) in a suitable solvent (such as ethanol and the like) at an appropriate temperature (such as reflux temperature and the like). Hydrolysis of A3 in an aqueous solution of a base (such as NaOH and the like) afforded compound A4, which was treated with a chlorinating reagent (such as POCl3 and the like) at an appropriate temperature to afford compound A5.

[00287] Compound A5 was treated with an optionally substituted aryl/heteroarylmethyl amine in the presence of a base (such as TEA and the like) using a suitable solvent (such as DMSO and the like) at an appropriate temperature to afford compound A6. Protection of A6 with Boc2O in the presence of DMAP as a catalyst afforded A7. Compound A7 can be reacted with a substituted cyclic sulfamidate, prepared from the corresponding starch alcohol, in the presence of a strong base (such as LDA and the like) in a suitable solvent (such as THF and the like) at an appropriate temperature such as -78 °C to afford A8. Deprotection can be accomplished by treatment with an acid (such as HCl in dioxane or TFA and the like) to afford compound A8.

Scheme B:

[00288] Compounds of Formula (I) may be prepared as described in Scheme B below.

[00289] Compound B1 is reacted with iodine in the presence of a strong base (such as LDA and the like) in a suitable solvent (such as THF and the like) at a suitable temperature such as -78 °C to provide B2. Compound B2 can be converted to compound B3 by a Negeshi reaction with an alkyl/cycloalkyl zinc reagent having optionally substituted and appropriately protected amino in the presence of a catalyst (such as Pd(dppf)Cl2 and the like) in a suitable solvent (such as THF and the like) at a suitable temperature. Treatment of B3 with an acid (such as HCl in dioxane or TFA and the like) to provide compound B4.

Scheme C:

[00290] Compounds of Formula (I) may be prepared as described in Scheme C below.

Caption: unprotected

[00291] Compound C1 can be converted to the corresponding aldehyde C2 by treatment with a strong base (such as LDA and the like) at a suitable temperature such as -78 °C followed by DMF in a suitable solvent (such as THF and the like). Compound C2 can be condensed with Ellman sulfinamide in the presence of a Lewis acid (such as CuSO4 and the like) in a suitable solvent (such as DCE and the like) at a suitable temperature to afford compound C3. Reaction of C3 with a Grignard reagent in a suitable solvent (such as THF and the like) affords compound C4, which can be further deprotected with an acid (such as HCl in dioxane or TFA and the like) to afford compound C5.

SPECIFIC SYNTHETIC EXAMPLES

[00292] To describe in greater detail and aid in understanding, the following non-limiting examples are offered to more fully illustrate the scope of the compounds described herein and are not to be construed as specifically limiting the scope thereof. Such variations of the compounds described herein, which may now be known or later developed, that would be within the competence of one skilled in the art to discover, are considered to be within the scope of the compounds as described herein and claimed herein below. These examples illustrate the preparation of certain compounds. Those skilled in the art will understand that the techniques described in these examples represent techniques, as described by those skilled in the art, that function well in synthetic practice and, as such, constitute the preferred modes for practicing the same. However, it should be appreciated that those skilled in the art should, in light of the present invention, appreciate that many changes can be made to the specific methods that are described and still obtain a similar or similar result, without departing from the spirit and scope of the present invention.

[00293] Except in the following examples of the compounds shown, unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, experimental data, and so on, used in the specification and claims are to be understood as being modified by the term "about". Accordingly, all such numbers represent approximations that may vary depending on the desired properties sought to be obtained by a reaction or as a result of varying experimental conditions. Therefore, within an expected range of experimental reproducibility, the term "about" in the context of the resulting data refers to a range of data provided that may vary by one standard deviation from the mean. Likewise, for the experimental results provided, the resulting data may be rounded up or down to present the data consistently without loss of significant figures. At a minimum and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be interpreted in light of the number of significant digits and rounding techniques used by those skilled in the art.

[00294] Although the numerical ranges and parameters that establish the broad scope of the present invention are approximations, the numerical values set forth in the examples presented below are reported with the greatest possible precision. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective test measurements. EXAMPLES OF COMPOUNDS

[00295] As used above and throughout the present invention, the following abbreviations, unless otherwise indicated, should be understood to have the following meanings:

Intermediate 1

[00296] (S)-4-(((tert-butyldimethylsilyl)oxy)methyl 2,2-dioxide)-1,2,3-oxathiazolidine-3-tert-butylcarboxylate Captions: imidazole Step 1: N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serinate

[00297] To a solution of methyl (tert-butoxycarbonyl)-L-serinate (25 g, 114.0 mmol) in DCM (250 mL) were 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 DCM (300 mL) and water (200 mL). The organic phase was separated, washed with water (2 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give methyl N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serinate (35.5 g, 93.3% yield) as an oil. LC-MS: m/z: 356.2 [M+Na]+. Step 2: (R)-(1-((tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)tert-butyl carbmate

[00298] To a solution of methyl N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serinate (35.5 g, 106 mmol) in THF (200 mL) and EtOH (100 mL) was added CaCl2 (23.6 g, 213 mmol) followed by NaBH4 (16.1 g, 426 mmol) at 0 °C. The mixture was stirred for 0.5 h at 0 °C and at room temperature for 16 h, then poured into a mixture of EtOAc (200 mL) and water (150 mL). The organic phase was separated and washed with water (2 x 200 mL) and brine (1 x 150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo 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. Step 3: tert-butyl (4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidin-3-carboxylate 2-oxide

[00299] To a solution of imidazole (54 g, 785.3 mmol) in DCM (300 mL) at 0 °C was added SOCl2 (12.9 mL, 176.0 mmol). The mixture was stirred at 0 °C for 1 h and tert-butyl (R)-(1-(( tert-butyldimethylsilyl)oxy)-3-hydroxypropan-2-yl)carbamate (30 g, 98.2 mmol) was added. The mixture was stirred for an additional 1 h at 0 °C, then poured into a mixture of EtOAc (500 mL) and water (400 mL). The organic layer was separated and washed with water (2 x 800 mL) and brine (800 mL), then dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give (4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidin-3-carboxylate tert-butyl 2-oxide (32.6 g, 94.4% yield) as a white solid. LC-MS: m/z: 374.1 [M+Na]+ ; RT=2.08 min. Step 4: (4S)-4-[[ tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidin-3-carboxylate tert-butyl

[00300] To a solution of (4S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3-oxathiazolidin-3-carboxylate 2-oxide (32.6 g, 92.7 mmol) in water (300 mL) and DCM (300 mL) were added NaIO4 (31.8 g, 148.0 mmol) and RuCl3 (1.94 g, 9.3 mmol) at room temperature. The mixture was stirred overnight and then extracted with DCM (3 x 500 mL). The combined organic phases were washed with saturated NaHSO3 (aq., 500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica), eluted with DCM/hexane (50-100%) to afford tert-butyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidin-3-carboxylate (18 g, 52.8% yield) as a white solid. LC-MS: m/z: 390.2 [M+Na]+; RT=2.05 min; 1H 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).

Intermediate 2

[00301] (S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidin-3-carboxylate-2,2-dioxide tert-butyl Legend: Imidazole - isopropyl chloroformate Step 1: N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-homoserine

[00302] To a solution of (tert-butoxycarbonyl)-L-homoserine (21 g, 96.0 mmol) and imidazole (52 g, 770 mmol) in DCM (210 mL) was added TBSCl (23 g, 153 mmol). The mixture was stirred at room temperature for 5 h. Water (100 mL) was then added, and the organic phase was separated and washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-homoserine (31.9 g, 99% yield) as a colorless oil. 1H 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). Step 2: Tert-butyl (S)-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)carbamate

[00303] To a solution of N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)-L-homoserine (31.9 g, 96 mmol) and N-methyl morpholine (10.7 g, 105 mmol) in THF (300 mL) at 0 °C was added isopropyl chloroformate (12.8 g, 105 mmol). The mixture was stirred at 0 °C for 1 h and then filtered. The filtrate was cooled to 0 °C, at which temperature a solution of NaBH4 (4 g, 105.0 mmol) in water was slowly added. The mixture was stirred for 2 h at 0 °C, then diluted with water (100 mL). The organic phase was separated and washed with brine (2 × 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give tert-butyl (S)-(4-((tert-butyldimethylsilyl)oxy)-1-hydroxybutan-2-yl)carbamate (20 g, 57% yield) as a colorless oil.

[00304] 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). Step 3: (4S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidine-3-carboxylate tert-butyl 2-oxide

[00305] To a solution of imidazole (22 g, 313 mmol) in DCM (200 mL) at 0 °C was added SOCl2 (13.5 g, 113 mmol). 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 DCM (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 and washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give (4S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidin-3-carboxylate tert-butyl 2-oxide as a colorless oil (23 g, 99% yield). 1H 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). Step 4: (S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-tert-butyl dioxide

[00306] To a mixture of (4S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidin-3-carboxylate tert-butyl 2-oxide (23 g, 62.7 mmol) and NaIO4 (31 g, 144 mmol) in DCM (300 mL) and water (310 mL) was added RuCl3 (0.83 g, 4 mmol). The reaction was stirred at room temperature for 5 h. The organic phase was separated and washed with 10% NaHSOs (4 x 150 mL) and brine (150 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with petroleum ether and ethyl acetate (20:1) to afford (S)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,2,3-oxathiazolidin-3-carboxylate 2,2-dioxide as a white solid (5 g, 21% yield). 1H 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).

Intermediate 3

[00307] (R)-4-(fluoromethyl)-1,2,3-oxathiazolidin-3-carboxylate 2,2-tert-butyl dioxide Step 1: tert-butyl (4R)-4-(benzyloxymethyl)-2-oxo-oxathiazolidine-3-carboxylate

[00308] To a solution of imidazole (4.5 g, 4.37 mL, 66.1 mmol, 3.80 eq.) in DCM (160 mL) at -78 °C was added thionyl chloride (2.290 g, 1.40 mL, 19.2 mmol, 1.10 eq.) followed by N,N-diisopropylethylamine (4.450 g, 6.00 mL, 34.1 mmol, 1.96 eq.). After 30 min, a solution of tert-butyl N-[(1S)-1-(benzyloxymethyl)-2-hydroxyethyl]carbamate (4.894 g, 17.39 mmol, 1.00 eq.) in DCM (20 mL) was added over 30 min at -78 °C. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by water (50 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (100 mL), dried over sodium sulfate, then concentrated to give tert-butyl (4R)-4-(benzyloxymethyl)-2-oxo-oxathiazoline-3-carboxylate (5.9 g, 18.0 mmol, 1.04 eq.) as an oil that was used without purification. Step 2: tert-butyl (4R)-4-(benzyloxymethyl)-2,2-dioxo-oxathiazoline-3-carboxylate

[00309] To a solution of tert-butyl (4R)-4-(benzyloxymethyl)-2-oxo-oxathiazolidin-3-carboxylate (5.9 g, 18.0 mmol, 1.00 eq.) in CH3CN (160 mL) and water (100 mL) at 0 °C was added NaIO4 (6.0 g, 28.0 mmol, 1.55 eq.) followed by RuCl3 (16 mg, 0.077 mmol, 0.0043 eq.). The mixture was stirred at 0 °C for 45 min, and then diluted with water (50 mL). The mixture was extracted with diethyl ether (2 x 80 mL). The combined organic extracts were washed with water (50 mL) followed by brine (100 mL) and dried over sodium sulfate. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (120 g, 0 to 100% DCM/hexanes) to give tert-butyl (4R)-4-(benzyloxymethyl)-2,2-dioxo-oxathiazoidine-3-carboxylate (5.228 g, 85% yield) as a colorless oil that solidified on standing at room temperature after trituration with hexanes. Step 3: tert-butyl N-[(1R )-1-(benzyloxymethyl)-2-fluoro-ethyl]carbamate

[00310] To a solution of tert-butyl (4R)-4-(benzyloxymethyl)-2,2-dioxo-oxathiazolidin-3-carboxylate (5.228 g, 15.22 mmol, 1.00 eq.) in THF (70 mL) was added TBAF (1 M) in THF (18.0 mL, 18.0 mmol, 1.18 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 h, and then at room temperature overnight. The reaction was quenched with aqueous citric acid (1N, ~20 mL). The mixture was extracted with EtOAc (2 x 80 mL). The combined organic phases were washed with water followed by ketone (~50 mL). The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (0-30% EtOAc in hexanes with 10% DCM) to afford tert-butyl N-[(1R)-1-(benzyloxymethyl)-2-fluoroethyl]carbamate (3.250 g, 75% yield) as a colorless oil. Step 4: tert-butyl N-[(1R)-1-(fluoromethyl)-2-hydroxyethyl]carbamate

[00311] To a solution of tert-butyl N-[(1R)-1-(benzyloxymethyl)-2-fluoroethyl]carbamate (2.505 g, 8.84 mmol, 1.00 eq.) in EtOAc (30 mL) was added 10% palladium on carbon (Degussa type) 128 mg (~5 mass %) at room temperature. The flask was evacuated and refilled with a hydrogen balloon (1 atm) in three cycles. The mixture was stirred at room temperature for 3 h then filtered and evaporated. The filtrate was concentrated to give tert-butyl N-[(1R)-1-(fluoromethyl)-2-hydroxyethyl]carbamate (1.725 g, quantitative). Step 5: tert-butyl (4R)-4-(fluoromethyl)-2-oxo-oxathiazolidin-3-carboxylate

[00312] To a solution of imidazole (3.0 g, 2.91 mL, 44.07 mmol, 3.73 eq.) in DCM (110 mL) at -78 °C was added thionyl chloride (1.00 mL, 13.73 mmol, 1.16 eq.) followed by N,N-diisopropylethylamine (3.90 mL, 22.2 mmol, 1.87 eq.). The reaction was stirred at -78 °C for 30 min, and a solution of tert-butyl N-[(1R)-1-(fluoromethyl)-2-hydroxyethyl]carbamate (2.285 g, 11.83 mmol, 1.00 eq.) in DCM (15 mL) was added over 30 min at -78 °C. The mixture was warmed to room temperature and stirred at room temperature overnight. The reaction was quenched with water (50 mL). The organic layer was separated and washed with water (50 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to give tert-butyl (4R)-4-(fluoromethyl)-2-oxo-oxathiazolidin-3-carboxylate (2.830 g) as an oil which was taken to the next step without further purification. Step 6: tert-butyl (4R)-4-(fluoromethyl)-2,2-dioxo-oxathiazolidin-3-carboxylate

[00313] To a solution of tert-butyl (4R)-4-(fluoromethyl)-2-oxo-oxathiazolidin-3-carboxylate (2.830 g, 11.8 mmol, 1.00 eq.) in a mixed solvent of CH3CN (100 mL) and water (60 mL) was added NaIO4 (3.940 g, 18.4 mmol, 1.55 eq.) followed by RuCl3 (20 mg, 0.096 mmol, 0.0081 eq.) at 0 °C. The mixture was stirred at 0 °C for 45 min, then diluted with water (50 mL) and extracted with diethyl ether (2 x 80 mL). The combined organic phases were washed with water (50 mL) and brine (100 mL), dried over sodium sulfate, and evaporated. The residue was purified by flash column chromatography (120 g, 0-100% DCM/hexanes) to afford tert-butyl (4R)-4-(fluoromethyl)-2,2-dioxo-oxathiazolidine-3-carboxylate (2384 mg, 78.9% yield). 1H NMR (400 MHz, CDCl3) δ ppm 4.47-4.74 (m, 5 H), 1.56 (s, 9 H).

Intermediate 4

[00314] 3-bromo-5,7-dichlorothieno[3,2-b]pyridine Captions: Ethyl 3-chloro-3-oxopropanoate - reflux, overnight Step 1: Methyl 3-amino-4-bromothiophene-2-carboxylate

[00315] To a solution of methyl 3-aminothiophene-2-carboxylate (40.0 g, 255.0 mmol) in AcOH (1000 mL) was added Br2 (80.2 g, 510.0 mmol) at 25 °C. The mixture was stirred at 65 °C for 12 h, then cooled to room temperature. The mixture was then poured into water (2000 mL), and the suspension was filtered. The filter cake was collected and dried in vacuo, then purified by column chromatography on silica gel eluting with 10% EtOAc in petroleum ether to afford methyl 3-amino-4-bromothiophene-2-carboxylate as a yellow solid (30.0 g, 50.0% yield). 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1 H), 5.64 (m, 2 H), 3.84 (s, 3 H). Step 2: methyl 4-bromo-3-(3-ethoxy-3-oxopropanamido)thiophene-2-carboxylate

[00316] To a solution of methyl 3-amino-4-bromothiophene-2-carboxylate (30.0 g, 128 mmol) in DCM (500 mL) were added triethylamine (16.8 g, 166 mmol) and ethyl 3-chloro-3-oxopropanoate (25.0 g, 166 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h. The mixture was quenched with ice-cold water (1.5 L) and extracted with DCM (3 x 500 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated to give methyl 4-bromo-3-(3-ethoxy-3-oxopropane)thiophene-2-carboxylate as a brown solid (40.0 g, 90.0% yield), which was used in the next step without further purification. LC-MS: m/z: 350.0 [M+H]+; RT=1.59 min. Step 3: Ethyl 3-bromo-5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate

[00317] To a solution of methyl 4-bromo-3-(3-ethoxy-3-oxopropanamido)thiophene-2-carboxylate (35.0 g, 100 mmol) in ethanol (500 mL) was added sodium ethanoate (10.0 g, 166 mmol) at 0 °C. The mixture was stirred at 100 °C for 12 h, then cooled to room temperature. The mixture was filtered. The filter cake was washed with ethyl acetate (100 mL) and dried in vacuo to afford ethyl 3-bromo-5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate as a brown solid (33.0 g, 95.0% yield), which was used in the next step without further purification. LC-MS: m/z: 317.6 [M+H]+; RT=1.53 min. Step 4: 3-bromothieno[3,2-b]pyridine-5,7(4H,6H)-dione

[00318] To a solution of ethyl 3-bromo-5,7-dioxo-4,5,6,7-tetrahydrotieno[3,2-b]pyridine-6-carboxylate (30.0 g, 94.6 mmol) in water (1000 mL) was added sodium hydroxide (7.60 g, 189 mmol) at

[00319] 0 °C. The mixture was stirred at 110 °C for 12 h, then cooled to room temperature. The pH was adjusted to pH=6 by HCl (10 N), and the mixture was filtered. The filter cake was collected and dried in vacuo to afford 3-bromothieno[3,2-b]pyridine-5,7(4H,6H)-dione as a brown solid (20.0 g, 86.0% yield), which was used in the next step without further purification. LC-MS: m/z: 245.9 [M+H]+; RT=1.35 min. Step 5: 3-bromo-5,7-dichlorothieno[3,2-b]pyridine

[00320] To POCl3 (60 mL) was added 3-bromothieno[3,2- b]pyridine-5,7(4H,6H)-dione (20.0 g, 81.6 mmol). The mixture was stirred and refluxed for 12 h, then cooled to room temperature, quenched with ice-cold water (1.5 L), and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica using petroleum ether and ethyl acetate (5:1) to give 3-bromo-5,7-dichlorothieno[3,2- b ]pyridine as a white solid (20.0 g, 87.0% yield). 1H NMR 400 MHz (DMSO-d6) δ ppm 8.58 (s, 1H), 7.99 (s, 1H). Intermediate 5

[00321] 3,5,7-trichloro-thieno[3,2-b]pyridine Captions: reflux, overnight - 3-chloro-3-oxopropanoate - N,N- dimethylaniline Step 1: methyl 3-acetamidothiophene-2-carboxylate

[00322] To Ac2O (300 mL) at room temperature was added methyl 3-aminothiophene-2-carboxylate (80 g, 508.9 mmol), and the mixture was stirred at room temperature overnight. The reaction was quenched with MeOH (800 mL), and the mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo, and the residue was taken up to pH=9~10 with saturated aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate (3 × 400 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give methyl 3-acetamidothiophene-2-carboxylate (96 g, 94.7% yield) as an off-white solid. LC-MS: m/z: 200.1 [M+H]+; RT=1.63 min. Step 2: methyl 3-acetamido-4,5-dichlorothiophene-2-carboxylate

[00323] To a solution of methyl 3-acetamidothiophene-2-carboxylate (96 g, 482.6 mmol) in CHCl3 (500 mL), SO2Cl2 (96 mL, 1206.1 mmol) was added dropwise. The mixture was stirred at 75 °C overnight, cooled to room temperature, and concentrated in vacuo to give a solid, which was triturated with diethyl ether to give methyl 3-acetamido-4,5-dichlorothiophene-2-carboxylate (103.6 g, 80.2% yield) as an off-white solid. 1H NMR 400 MHz (CDCl3) δ ppm 8.24 (s, 1H), 3.87-3.90 (m, 3H), 2.23 (s, 3H). Step 3: Methyl 3-acetamido-4-chlorothiophene-2-carboxylate

[00324] To a solution of methyl 3-acetamido-4,5-dichlorothiophene-2-carboxylate (103.5 g, 386.0 mmol) in H2O and HOAc (3:1 (v/v), 800 mL) was added Zn powder (100.9 g, 1544.2 mmol). The mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered. The filtrate was extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and evaporated in vacuo to afford methyl 3-acetamido-4-chlorothiophene-2-carboxylate (72.2 g, 80.1% yield) as an off-white solid. 1H NMR 400 MHz (CDCl3) δ ppm 7.36 (s, 1H), 7.26 (s, 1H), 3.87-3.88 (m, 3H), 2.23 (s, 3H). Step 4: Methyl 3-amino-4-chlorothiophene-2-carboxylate

[00325] A mixture of methyl 3-acetamido-4-chlorothiophene-2-carboxylate (70.0 g, 299.5 mmol) in MeOH and concentrated HCl (1:1 (v/v), 300 mL) was stirred at 110 °C overnight, then cooled to room temperature and concentrated in vacuo. The resulting solid was dissolved in water (200 mL) and neutralized with aqueous NaHCO3. The mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (8:1) as eluent to afford methyl 3-amino-4-chlorothiophene-2-carboxylate (47.1 g, 82.2% yield) as an off-white solid. LC-MS: m/z: 192.0 [M+H]+; RT=1.70 min. Step 5: methyl 4-chloro-3-(3-ethoxy-3-oxopropanamido)thiophene-2-carboxylate

[00326] To a solution of methyl 3-amino-4-chlorothiophene-2-carboxylate (45.0 g, 234.8 mmol) in DCM (300 mL) at 0 °C was added Et3N (47.5 g, 469.7 mmol) followed by ethyl 3-chloro-3-oxopropanoate (53.1 g, 352.3 mmol) dropwise. The mixture was stirred at room temperature overnight and then washed with water (2 x 300 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (1:1) as eluent to furnish methyl 4-chloro-3-(3-ethoxy-3-oxopropanamido)thiophene-2-carboxylate (41.8 g, 58.3% yield) as an off-white solid. LC-MS: m/z: 306.0 [M+H]+; RT=1.55 min; 1H NMR 400 MHz (CDCl3) δ ppm 10.12 (s, 1H), 8.01 (s, 1H), 4.11-4.13 (m, 2H), 3.79 (s, 3H), 3.48 (s, 2H), 1.19-1.22 (m, 3H). Step 6: 3-chloro-5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-ethyl carboxylate

[00327] To a solution of methyl 4-chloro-3-(3-ethoxy-3-oxopropanamido)thiophene-2-carboxylate (40.0 g, 130.8 mmol) in EtOH (300 mL) was added NaOEt (9.0 g, 130.8 mmol). The mixture was stirred at 85 °C overnight, then cooled to room temperature. The product was obtained by filtration to afford ethyl 3-chloro-5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate (34.3 g, 95.8% yield) as an off-white solid. LC-MS: m/z: 274.0 [M+H]+; RT=1.56 min; 1H NMR 400 MHz (CDCl3) δ ppm 7.55 (s, 1H), 4.07-4.09 (m, 2H), 3.44-3.46 (m, 1H), 1.18-1.21 (m, 3H), 1.06-1.08 (m, 1H). Step 7: 3-ethyl chlorothieno[3,2-b]pyridine-5,7(4H,6H)-dione

[00328] Ethyl 3-chloro-5,7-dioxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate (34.3 g, 125.2 mmol) was added to a solution of NaOH (10.0 g, 250.4 mmol) in H2O (200 mL). The mixture was stirred at 105 °C overnight, then cooled to room temperature. The pH was adjusted to ~6-7 with concentrated HCl. The filter cake was collected by filtration and dried in vacuo to afford 3-chlorothieno[3,2-b]pyridine-5,7(4H,6H)-dione (22.3 g, 88.3% yield) as an off-white solid. LC-MS: m/z: 202.0 [M+H]+; RT=1.34 min. Step 8: 3,5,7-Trichlorothieno[3,2-b]pyridine

[00329] 3-Chlorothieno[3,2-b]pyridine-5,7(4H,6H)-dione (22.0 g, 109.1 mmol) and N,N-dimethylaniline (6.6 g, 0.5 eq, 54.5 mmol) were added to POCl3 (150 mL). The mixture was stirred at 110 °C overnight, then cooled to room temperature. Excess POCl3 was removed in vacuo, and the solid was poured into ice-cold water (100 mL). A white solid was obtained by filtration, dried in vacuo, and further purified by column chromatography on silica using petroleum ether and ethyl acetate (5:1) to afford 3,5,7-trichlorothieno[3,2-b]pyridine (18.7 g, 72.1% yield) as an off-white solid. LC-MS: m/z: 237.9, 239.9, 241.9 [M+H]+; RT=2.01 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.49 (s, 1H), 7.99 (s, 1H).

Intermediate 6

[00330] tert-butyl (5-chloro-2-iodo-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[00331] To a solution of tert-butyl (5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (410 mg, 1.08 mmol, 1.0 eq.), prepared according to the procedure in Example 2, in THF (3 mL) was added LDA (2.0M in THF, 0.60 mL, 1.1 eq.) at -78 °C. After stirring for 15 min, a solution of iodine (288 mg, 1.14 mmol, 1.05 eq.) in THF (2 mL) was added dropwise and stirring was continued for 1 h. The reaction was quenched by the addition of EtOAc and NH4Cl (saturated aqueous) and warmed to room temperature. The organic layers were washed with sodium thiosulfate solution, water, and brine, dried over sodium sulfate, and evaporated. The residue was purified by flash column chromatography on silica gel eluting with 0 to 15% EtOAc in hexane to give tert-butyl (5-chloro-2-iodo-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (436 mg, 80% yield). MS m/z 505.5, 507.5 [M+H]+ . Example 1 (Compound 2)

[00332] 5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine

[00333] A mixture of 5,7-dichloro-3-methyl-thieno[3,2-b]pyridine (201 mg, 0.922 mmol, 1.00 eq.) and 2-furylmethanamine (895 mg, 0.81 mL, 9.22 mmol, 10.0 eq.) in DMSO (0.8 mL) was stirred at 100 °C for 24 h. The mixture was cooled, diluted with ethyl acetate, washed with water and brine, dried, and evaporated. The residue was purified on silica gel with ethyl acetate and hexanes to afford 5-chloro-N-(2-furylmethyl)-3-methyl-thieno[3,2-b]pyridin-7-amine (230 mg, 90% yield). EM m/z 279.1, 281.1 [M+H]+, 1H NMR (400 MHz, CDCl3) δ ppm 7.44 (d, J= 1.2 Hz, 1 H), 7.26 (d, J= 1.1 Hz, 1 H), 6.58 (s, 1 H), 6.39 (dd, J= 3.2, 1.8 Hz, 1 H), 6.35 (d, J= 3.2 Hz, 1 H), 4.70 (br s, 1 H), 4.54 (d, J= 5.3 Hz, 2 H), 2.49 (d, J= 1.1 Hz, 3 H).

[00334] The compounds below were prepared according to the procedure of Example 1, substituting the appropriate starting materials, reagents and reaction conditions. Example 2 (Compound 28)

[00335] 2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride Caption: Dioxane Step 1: tert-butyl N-(5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate

[00336] To a solution of 5-chloro-3-methyl-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (3.90 g, 13.0 mmol, 1.0 eq.), prepared according to the procedure in Example 1, in CH2Cl2 (53 mL) was added di-tert-butyl dicarbonate (5.8 g, 26.0 mmol, 2.0 eq.) followed by 4-(dimethylamino)pyridine (1.6 g, 13.0 mmol, 1.0 eq.). The mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate in hexanes (5 to 35% gradient) to give tert-butyl N-(5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (4.77 g, 91% yield). MS m/z 395.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41 (s, 1 H), 7.24 (dd, J=1.00 Hz, 1 H), 7.06 (s, 1 H), 6.89 (dd, J=1.00 Hz, 1 H), 6.81 (d, J=1.00 Hz, 1 H), 5.07 (s, 2 H), 2.51 (d, J=1.07 Hz, 3 H), 1.47 (s, 9 H). Step 2: tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate

[00337] To a solution of tert-butyl N-(5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (4.77 g, 12.1 mmol, 1.0 eq.) in THF (24 mL) at -78 °C was added lithium diisopropylamide (2.0 M) in THF/heptane/ethylbenzene (7.2 mL, 14.5 mmol, 1.2 eq.). After 15 min, a solution of tert-butyl (4S)-4-methyl-2,2-dioxo-oxathiazolidin-3-carboxylate (3.44 g, 14.5 mmol, 1.2 eq.) in THF (24 mL) was added to the reaction solution, and the mixture was stirred at -78 °C for 20 min. The reaction was quenched with 1.0 M citric acid, then stirred for 30 min. The mixture was diluted with ethyl acetate and washed with water and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate in CH2Cl2 (0 to 25% gradient) to give tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (4.10 g, 61% yield). EM m/z 553.0, 555.0 [M+H]+, 1H NMR (400 MHz, CDCl3) δ ppm 7.22 (d, J=5.33 Hz, 1 H), 6.99 (s, H), 6.86 (dd, J=5.04, 3.51 Hz, 1 H), 6.78 (d, J=2.90 Hz, 1 H), 5.02 (dd, J=1.00 Hz, 2 H), 4.46 (br s, 1 H), 4.01 (br s, 1 H), 3.07 - 3.16 (m, 1 H), 2.93 - 3.07 (m, 1 H), 2.41 (s, 3 H), 1.45 (s, 18 H), 1.14 (d, J=6.71 Hz, 3 H). Step 3 2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine

[00338] General Boc deprotection procedure: A mixture of tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (4.10 g, 7.4 mmol, 1.0 eq.) and HCl (4 M) in dioxane (35 mL) was stirred at room temperature for 1 h. The mixture was diluted with diethyl ether (2x) and filtered. The filter cake was washed with ether, collected, and dried to give 2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine dihydrochloride (2.5 g, 96% yield). EM m/z 352.1, 354.1 [M+H]+, 1H NMR (methanol-d4) δ ppm 7.38 (dd, J= 5.19, 1.07 Hz, 1 H), 7.18 (d, J= 2.75 Hz, 1 H), 7.10 (s, 1 H), 7.01 (dd, J= 5.04, 3.51 Hz, 1 H), 4.97 (s, 2 H), 3.60 - 3.72 (m, 1 H), 3.37 - 3.44 (m, 1 H), 3.24 - 3.30 (m, 1 H), 2.47 (s, 3 H), 1.39 (d, J= 6.56 Hz, 3 H).

[00339] The compounds below were prepared according to the procedure of Example 2, substituting the appropriate starting materials, reagents and reaction conditions. Example 3 (Compound 17)

[00340] (2R)-2-amino-3-(5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)propan dihydrochloride -1-ol Step 1: N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propyl]-5-chloro-thieno[3,2-b]pyridin-7-yl]-N- tert-butyl (2-furylmethyl)carbamate

[00341] To a solution of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-[tert-butyl(dimethyl)silyl]oxy-propyl]-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (41 mg, 0.063 mmol, 1.0 eq.), prepared according to the procedure in Example 2, in THF (0.5 mL) at 0 °C was added TBAF (1.0 M in THF) (0.25 mL, 0.25 mmol, 4.0 eq.). After 1 h at room temperature, the mixture was diluted with ether, washed with water and brine, dried, and evaporated. The residue was purified on silica gel with ethyl acetate and hexanes (5 to 65% gradient) to afford tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropyl]-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (33 mg, 98% yield). MS m/z 538.3, 540.1 [M+H] + . Step 2: (2 R )-2-amino-3-[5-chloro-7-(2-furylmethylamino)thieno[3,2-b]pyridin-2-yl]propan-1-ol

[00342] A mixture of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propyl]-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (33 mg, 0.061 mmol, 1.0 eq.), anisole (0.1 mL), and HCl (4 M in dioxane) (1.0 mL) was stirred at room temperature for 30 min, then 3 drops of MeOH were added, and the mixture was stirred for an additional 30 min. The mixture was diluted with ether and filtered. The solid was collected and dried to give (2R)-2-amino-3-[5-chloro-7-(2-furylmethylamino)thieno[3,2-b]pyridin-2-yl]propan-1-ol dihydrochloride (21 mg, 83% yield). MS m/z 338.3, 340.2 [M+H]+. 1H NMR (methanol-d4) δ ppm 7.52 (d, J= 1.2 Hz, 1 H), 7.42 (s, 1 H), 7.16 (s, 1 H), 6.49 (s, 1 H), 6.41 - 6.45 (m, 1 H), 4.77 (s, 2 H), 3.79 - 3.86 (m, 1 H), 3.64 - 3.71 (m, 2 H), 3.44 - 3.50 (m, 1 H), 3.36 - 3.42 (m, 1 H).

[00343] The compounds below were prepared according to the procedure of Example 3, substituting the appropriate starting materials, reagents and reaction conditions. Example 4 (Compound 42)

[00344] 5-Chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(2S)-2- hydrochloride Legends: for - dioxane Step^^S2-{2-{2-{{tert-butoxycarbonyl}{methyl}amino}propy^z5-chloroz3- methylthieno[3,2-b]pyridin-7-yl)(furan- tert-butyl 2-ylmethyl)carbamate

[00345] To a solution of tert-butyl (S)-(2-(2-((tert-butoxycarbonyl)amino)propyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (120 mg, 0.22 mmol, 1.0 eq.) in THF (1 mL) was added LHMDS (1.0 M in THF, 0.27 mL, 1.1 eq.) at -50 °C. After 30 min, Mel (42 mg, 1.2 eq.) in THF (1 mL) was added. The mixture was gradually warmed to room temperature over 1 h, stirred at room temperature for 1 h, cooled to -50 °C, then quenched with a few drops of citric acid. 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 evaporated. The residue was purified by flash column chromatography on silica gel eluting with 0 to 10% EtOAc in DCM followed by purification by preparative HPLC eluting with 20 to 100% ACN in water (with 0.1% formic acid) to afford tert-butyl (S)-(2-(2-((tert-butoxycarbonyl)(methyl)amino)propyl)-5-chloro-3-methylthieno[3,2- b ]pyridin-7-yl)(furan-2-ylmethyl)carbamate (35 mg, 28% yield) as a white solid. MS m/z 550.2, 552.2 [M+H] + . Step 2: £S2-5-chloro-N-(furan-2-ylmethyl}-3-methyl-2-(2-(methylamino}propyl) thieno[3,2-b]pyridin-7-amine

[00346] Tert-butyl (S)-(2-(2-((tert-butoxycarbonyl)(methyl)amino)propyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (35 mg, 0.064 mmol) was stirred in a solution of HCl (4 M in dioxane, 1 mL) at room temperature for 1 h. The mixture was concentrated in vacuo. The solid was triturated with diethyl ether and filtered to give (S)-5-chloro-N-(furan-2-ylmethyl)-3-methyl-2-(2-(methylamino)propyl)thieno[3,2-b]pyridin-7-amine dihydrochloride (12 mg, 49% yield). MS m/z 350.1, 352.1 [M+H]+; 1H NMR (methanol-d4) δ ppm 7.49 (t, J= 1.2 Hz, 1 H), 6.90 (s, 1 H), 6.41 (d, J= 1.3 Hz, 2 H), 4.66 (s, 2 H), 3.57 - 3.60 (m, 1 H), 3.44 - 3.47 (m, 1 H), 3.18 - 3.23 (m, 1 H), 2.80 (s, 3 H), 2.43 (s, 3 H), 1.35 (d, J= 6.6 Hz, 3 H). Example 5 (Compound 104)

[00347] 2-[(2R)-2-amino-3-(methylsulfanyl)propyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b] dihydrochloride ]pyridin-7-amine Figure Caption: dioxane Step 1: [(2R)-2-( tert-butoxycarbonylamino)-3-[7-[ tert-butoxycarbonyl(2-furylmethyl)amino]-5-chloro-3-methyl-thieno[3 ,2-b]pyridin-2-yl]propyl]methanesulfonate

[00348] To a solution of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (217.0 mg, 0.393 mmol, 1.0 eq.), prepared according to the procedure in Example 3, in DCM (2.5 mL) was added a solution of methanesulfonyl chloride (592 mg, 0.40 mL, 5.17 mmol, 13.1 eq.) in DCM (9.60 mL) followed by N,N-diisopropylethylamine (75.5 mg, 0.10 mL, 0.57 mmol, 1.46 eq.) at 0 °C. The reaction was stirred at 0 °C for 1 h, then quenched by sodium bicarbonate (~5 mL) and extracted with DCM (5 × 10 mL) using a phase separator. Volatiles were removed under reduced pressure to afford [(2R)-2-(tert-butoxycarbonylamino)-3-[7-[tert-butoxycarbonyl(2-furylmethyl)amino]-5-chloro-3-methyl-thieno[3,2-b]pyridin-2-yl]propyl]methanesulfonate (262.2 mg, 0.42 mmol, 1.06 eq.) as a light yellow foam that was washed to the next step without further purification. MS m/z 630.4, 632.3 [M+H]+ Step 2: tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfanyl-propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate

[00349] To a solution of [(2R)-2-(tert-butoxycarbonylamino)-3-[7-[tert-butoxycarbonyl(2-furylmethyl)amino]-5-chloro-3-methyl-thieno[3,2-b]pyridin-2-yl]propyl]methanesulfonate (262.2 mg, 0.42 mmol, 1.0 eq.) in DMF (2.5 mL) was added sodium methanethiolate (45.0 mg, 0.58 mmol, 1.39 eq.) at room temperature. The mixture was stirred at room temperature overnight then quenched with water (2 mL). The mixture was extracted with EtOAc (2x30 mL). The combined organic layers were washed with water followed by ketone (30 mL) and dried over sodium sulfate. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (12 g, 0 to 20% EtOAc in hexanes with 10% DCM) to afford tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfanyl-propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (202.3 mg, 84% yield) as a light yellow foam. MS m/z 582.3, 584.3 [M+H]+. Step 3: (R)-2-(2-amino-3-(methylthio)propyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine

[00350] Removal of the Boc group following the general procedure described in Step 3 for Example 2 afforded (R)-2-(2-amino-3-(methylthio)propyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride MS m/z 382.3, 384.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.31 - 8.48 (m, 3 H), 7.68 (br s, 1 H), 7.59 (d, J=0.92 Hz, 1 H), 6.60 (s, 1 H), 6.40 (dd, J=3.05, 1.83 Hz, 1 H), 6.35 (d, J=3.05 Hz, 1 H), 4.51 (s, 2 H), 3.46 - 3.54 (m, 1 H), 3.36 (dd, J=14.84, 6.15 Hz, 1 H), 3.29 (dd, J=14.92, 7.57 Hz, 1 H), 2.83 (dd, J=14.21, 6.37 Hz, 1 H), 2.76 (dd, J=14.14, 5.93 Hz, 1 H), 2.28 (s, 3 H), 2.11 (s, 3 H).

[00351] The compounds below were prepared according to the procedure of Example 5, substituting the appropriate starting materials, reagents and reaction conditions. Example 6 (Compound 111)

[00352] (3S)-3-Amino-4-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2- dihydrochloride il)butanenitrile Step 1: N-[2-[(2S)-2-(tert-butoxycarbonylamino)-3-cyano-propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl tert-butyl ]-N-(2-furylmethyl)carbamate

[00353] To a solution of [(2R)-2-(tert-butoxycarbonylamino)-3-[7-[tert-butoxycarbonyl(2-furylmethyl)amino]-5-chloro-3-methyl-thieno[3,2-b]pyridin-2-yl]propyl]methanesulfonate (216 mg, 0.34 mmol, 1.0 eq.), prepared according to the procedure in Example 5, in DMF (2.5 mL) was added sodium cyanide (30 mg, 0.58 mmol, 1.7 eq.) at room temperature. The reaction was stirred at 60 °C for 3 h. The reaction was quenched with water (2.0 mL) and then extracted with EtOAc (2x40 mL). The combined organic phases were washed with water followed by ketone (30 mL) then dried over sodium sulfate. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (12 g, 0 to 20% EtOAc in hexanes with 10% DCM) to afford tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-3-cyanopropyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (134.2 mg, 70% yield) as an off-white foam. MS m/z 561.3, 563.3 [M+H] + . Step 2 (S)-3-amino-4-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)butanenitrile

[00354] Removal of the Boc group following the general procedure described in Step 3 for Example 2 afforded (S)-3-amino-4-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)butanenitrile hydrochloride. MS m/z 361.3, 363.3 [M+H]+, 359.2, 361.2 [M-H]-; 1H NMR 500 MHz (DMSO-d6) δ ppm 8.61 (br s, 3 H), 7.66 (br s, 1 H), 7.59 (s, 1 H), 6.60 (s, 1 H), 6.40 (br s, 1 H), 6.35 (br s, 1 H), 4.51 (br s, 2 H), 3.33 - 3.45 (m, 2 H), 3.24 (br dd, J=14.95, 8.24 Hz, 1 H), 2.91 - 3.06 (m, 2 H), 2.28 (s, 3 H).

[00355] The compounds below were prepared according to the procedure of Example 6, substituting the appropriate starting materials, reagents and reaction conditions. Example 7 (Compound 64 and Compound 65)

[00356] 2-[(2R)-2-amino-3-(trifluoromethoxy)propyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[ formate 3,2-b]pyridin-7-amine and

[00357] (2R)-3-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-2 formate -yl)-2-[(trifluoromethyl)amino]propan-1-ol Step 1 N-[3-bromo-2-[(2R)-2-(tert-butoxycarbonylamino)-3-(trifluoromethoxy)propyl]-5-chloro-thieno[3,2-b]pyridin-7-yl tert-butyl ]-N-(thiazol-2-ylmethyl)carbamate and N-[(1R )-1-[[3-bromo-7-[ tert-butoxycarbonyl(thiazol-2-ylmethyl)amino]-5- tert -butyl chloro-thieno[3,2-b]pyridin-2-yl]methyl]-2-hydroxyethyl]-N-(trifluoromethyl)carbamate

[00358] A mixture of tert-butyl N-[3-bromo-2-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propyl]-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(thiazol-2-ylmethyl)carbamate (64 mg, 0.10 mmol, 1.0 eq.), prepared according to the procedure in Example 3, silver trifluoromethanesulfonate (78 mg, 0.30 mmol, 3.0 eq.), Selectfluor® (56 mg, 0.15 mmol, 1.5 eq.), potassium fluotene (23 mg, 0.40 mmol, 4.0 eq.), and 2,6-di-tert-butylphenol (11 mg, 0.050 mmol, 0.50 eq.) was a solution of 2-fluoropyridine (30 mg, 0.027 mL, 0.30 mmol, 3.0 eq.) and (trifluoromethyl)trimethylsilane (43 mg, 0.046 mL, 0.30 mmol, 3.0 eq.) in EtOAc (0.5 mL) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM and purified on silica gel with ethyl acetate in dichloromethane (0 to 25 to 75% gradient) to afford, as the less polar fraction, tert-butyl N-[3-bromo-2-[(2R)-2-(tert-butoxycarbonylamino)-3-(trifluoromethoxy)propyl]-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(thiazol-2-ylmethyl)carbamate (3.5 mg, 4.9% yield), 1H NMR (CDCl3) δ ppm 7.52-7.77 (m, 1 H), 7.40-7.25 (m, 2 H), 5.08 (br s, 2 H), 4.68-4.82 (m, 1 H), 4.11 - 4.23 (m, 1 H), 3.98 (dd, J= 17.3, 3.6 Hz, 2 H), 3.23 (d, J= 6.3 Hz, 2 H), 1.29 - 1.42 (m, 18 H), and N-[(1R)-1-[[3-bromo-7-[tert-butoxycarbonyl(thiazol-2- tert-butyl ylmethyl)amino]-5-chloro-thieno[3,2-b]pyridin-2-yl]methyl]-2-hydroxyethyl]-N-(trifluoromethyl)carbamate (35 mg, 49% yield), 1H NMR (chloroform-d) δ ppm 7.77 (br s, 1 H), 7.44 (br s, 1 H), 7.35 (s, 1 H), 5.22 (d, J= 6.6 Hz, 2 H), 4.86 (br s, 1 H), 4.26 (br s,, 1 H), 4.02 - 4.12 (m, 2 H), 3.32 (d, J= 6.0 Hz, 2 H), 1.36 - 1.49 (m, 18 H). Step 2: 2-[(2R)-2-amino-3-(trifluoromethoxy)propyl]-3-bromo-5-chloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[00359] Removing the Boc group following the general procedure described in Step 3 for Example 2, tert-butyl N-[3-bromo-2-[(2R)-2-(tert-butoxycarbonylamino)-3-(trifluoromethoxy)propyl]-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(thiazol-2-ylmethyl)carbamate (3.5 mg) was treated with HCl in dioxane, then purified by HPLC to afford 2-[(2R)-2-amino-3-(trifluoromethoxy)propyl]-3-bromo-5-chloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, formic acid salt, MS m/z 501.2, 503.1, 505.1 [M+H]+; 1H NMR (methanol-d4) δ ppm 8.39 (s, 1 H), 7.74 - 7.82 (m, 1 H), 7.51 - 7.58 (m, 1 H), 6.57 (s, 1 H), 4.90 (s, 2 H), 4.04 - 4.22 (m, 2 H), 3.62 - 3.79 (m, 1 H), 3.33 - 3.41 (m, 1 H), 3.19 - 3.27 (m, 1 H). (2R)-3-[3-bromo-5-chloro-7-(thiazol-2-ylmethylamino)thieno[3,2-b]pyridin-2-yl]-2-(trifluoromethylamino)propan-1-ol formate

[00360] Deprotection of tert-butyl N-[(1R)-1-[[3-bromo-7-[tert-butoxycarbonyl(thiazol-2-ylmethyl)amino]-5-chloro-thieno[3,2-b]pyridin-2-yl]methyl]-2-hydroxy-ethyl]-N-(trifluoromethyl)carbamate afforded (2R)-3-[3-bromo-5-chloro-7-(thiazol-2-ylmethylamino)thieno[3,2-b]pyridin-2-yl]-2-(trifluoromethylamino)propan-1-ol, formic acid salt, MS m/z 501.2, 503.1, 505.1 [M+H]+; 1H NMR (methanol-d4) δ ppm 8.37 (s, 1 H), 7.80 (d, J= 3.1 Hz, 1 H), 7.56 (d, J= 3.2 Hz, 1 H), 6.59 (s, 1 H), 4.92 (s, 2 H), 4.26 (br s, 1 H), 4.14 - 4.22 (m, 1 H), 3.80 - 3.94 (m, 1 H), 3.35 - 3.47 (m, 2 H). Example 8 (Compound 113)

[00361] 2-[(2R)-2-amino-3-(methanesulfonyl)propyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b] dihydrochloride pyridin-7-amine Caption: dioxane Step 1: N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfonyl-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7- tert-butyl yl]-N-(2-furylmethyl)carbamate

[00362] To a solution of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfanyl-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (256.0 mg, 0.42 mmol, 1.0 eq.), prepared according to the procedure in Example 5, in DCM (3.0 mL) was added 3-chloroperoxybenzoic acid (189.4 mg, 0.82 mmol, 1.9 eq.) at 0 °C. The reaction was stirred at 0 °C for 1 h, then quenched with sodium bicarbonate (3.0 mL). The mixture was extracted with DCM (5x10 mL) using a phase separator. The combined organic phases were dried over sodium sulfate then concentrated. The residue was purified by flash column chromatography (24 g, 0 to 40% EtOAc in hexanes with 10% DCM) to give tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfonyl-propyl]-3,5-dichlorothieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (232.8 mg, 86% yield) as an off-white foam. MS m/z 634.3 [M+H]+ , 656.4 [M+Na]+. Step 2: (R)-2-(2-amino-3-(methylsulfonyl)propyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[00363] Removal of the Boc group following the general procedure described in Step 3 for Example 2 afforded (R)-2-(2-amino-3-(methylsulfonyl)propyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine dihydrochloride MS m/z 434.3, 436.3 [M+H]+, 432.2 [M-H]-; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.47 (br s, 3 H), 7.98 (br t, J=5.49 Hz, 1 H), 7.60 (s, 1 H), 6.71 (s, 1 H), 6.37 - 6.43 (m, 2 H), 4.54 (br d, J=5.19 Hz, 2 H), 3.95 - 4.06 (m, 1 H), 3.45 - 3.66 (m, 4 H), 3.17 (s, 3 H).

[00364] The compounds below were prepared according to the procedure of Example 8, substituting the appropriate starting materials, reagents and reaction conditions. Example 9 (Compound 47)

[00365] 2-[(2S)-2-amino-4-fluorobutyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] dihydrochloride ]pyridin-7-amine Step 1: N-[2-[(2S)-2-(tert-butoxycarbonylamino)-4-fluoro-butyl]-3,5-dichlorothieno[3,2-b]pyridin-7-yl]-N tert-butyl-(thiazol-2-ylmethyl)carbamate

[00366] To a mixture of tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-4-hydroxy-butyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(thiazol-2-ylmethyl)carbamate (35 mg, 0.058 mmol, 1.0 eq.), prepared according to the procedure in Example 3, and pyridine-2-sulfonyl fluoride (11 mg, 0.064 mmol, 1.1 eq.) in toluene (0.2 mL) was added 7-methyl-1,5,7-triazabicyclo[4,4,0]dec-5-ene (18 mg, 0.017 mL, 0.12 mmol, 2.0 eq.). The mixture was stirred at room temperature for 3 d, then diluted with DCM and purified on silica gel with ethyl acetate in hexanes (5 to 50% gradient) to afford tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-4-fluoro-butyl]-3,5-dichloro-thieno[3,2- b ]pyridin-7-yl]-N-(thiazol-2-ylmethyl)carbamate (30 mg, 85% yield). MS m/z 627.2, 629.1 [M+Na]+ . Step 2: (3S)-3-amino-4-[3,5-dichloro-7-(thiazol-2-ylmethylamino)thieno[3,2- b ]pyridin-2-yl]butan-1-ol

[00367] The general Boc deprotection procedure described in Step 3 for Example 2 using HCl in dioxane was followed to afford (3S)-3-amino-4-[3,5-dichloro-7-(thiazol-2-ylmethylamino)thieno[3,2-b]pyridin-2-yl]butan-1-ol dihydrochloride (14 mg, 99% yield). MS m/z 405.1, 407.2, 409.1 [M+H]+; 1H NMR (methanol-d4) δ: 8.08 (d, J= 3.5 Hz, 1 H), 7.91 (d, J= 3.5 Hz, 1 H), 6.99 (s, 1 H), 5.23 (s, 2 H), 4.61 - 4.81 (m, 2 H), 3.85 - 3.95 (m, 1 H), 3.51 (qd, J= 14.9, 7.2 Hz, 2 H),

[00368] 2.12 - 2.26 (m, 2 H).

[00369] The compounds below were prepared according to the procedure of Example 9, substituting the appropriate starting materials, reagents, and reaction conditions. Compound Spectral Data 74 MS m/z 448.2, 450.2, 452.2 [M+H]+; 1H NMR (DMSO-d6) δ: 8.45 (br s, 3H), 8.14 (br s, 1H), 7.40 (d, J=5.2 Hz, 1H), 7.05-7.18 (m, 1H), 6.99 (s, 1H), 6.65 (s, 1H), 4.52-4.78 (m, 4H), 3.57-3.65 (m, 1H), 3.38 (br d, J=7.0 Hz, 2H), 1.95-2.16 (m, 2H). Example 10 (Compound 107)

[00370] 2-[(2S)-2-amino-4,4-difluorobutyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b] hydrochloride pyridin-7-amine Step 1: (3S)-3-amino-4-[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]butan-1-ol

[00371] To a solution of tert-butyl N-[3-bromo-2-[(2S)-2-(tert-butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy-butyl]-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (300 mg, 0.4 mmol), prepared according to the procedure in Example 2, in CH2Cl2 (3 mL) was added trifluoroacetic acid (0.5 mL, 7 mmol). After stirring at room temperature for 4 h, the reaction was concentrated under reduced pressure. The product was used in the subsequent step without further purification. MS m/z 446.8, 448.2, 450.2 [M+H]+. Step 2: N-[(1S)-1-[[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]methyl]-3-hydroxy-propyl]-2-nitro-benzenesulfonamide

[00372] To a solution of (3S)-3-amino-4-[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]butan-1-ol (100 mg, 0.2 mmol) in CH2Cl2 (1 mL) at room temperature was added 2-nitrobenzenesulfonyl chloride (50 mg, 0.2 mmol, 1.0 eq) followed by N,N-diisopropylethylamine (0.12 mL, 0.69 mmol, 3.5 eq). After stirring at room temperature for 1 h, the mixture was diluted with water (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with 1 M HCl (10 mL) followed by saturated NaHCO 3 (10 mL), then dried over Na 2 SO 4 , filtered, and concentrated. The precipitate was triturated with diethyl ether and filtered to give N-[(1S)-1-[[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]methyl]-3-hydroxy-propyl]-2-nitro-benzenesulfonamide (119 mg, 84% yield) as a light yellow solid. MS m / z 631.2, 633.2, 635.2 [M+H] + ; 1H NMR (DMSO-d6) δ ppm 8.08 (br d, J= 8.5 Hz, 1 H), 7.84 (br t, J= 5.8 Hz, 1 H), 7.65 (t, J= 7.9 Hz, 2 H), 7.30-7.47 (m, 3 H), 7.107.20 (m, 1 H), 7.03 (t, J= 4.1 Hz, 1H), 6.59 (s, 1H), 4.71 (br d, J= 5.8 Hz, 2H), 4.41 (t, J= 4.9 Hz, 1H), 3.78-3.97 (m, 1H), 3.44-3.54 (m, 1H), 3.15 (br dd, J= 14.3, 5.2 Hz, 1H), 2.99 (dd, J= 14.5, 8.7 Hz, 1H), 1,631.81 (m, 2H). Step 3: N-[(1S)-1-[[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]methyl]-3-oxo-propyl]-2-nitro-benzenesulfonamide

[00373] To a suspension of N-[(1S)-1-[[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]methyl]- 3-hydroxypropyl]-2-nitrobenzenesulfonamide (50 mg, 0.08 mmol) in CH2Cl2 (2 mL) periodinane was added from Dess-Martin, 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, (40 mg, 0.09 mmol, 1.1 eq. ). After stirring at room temperature for 4 h, the mixture was concentrated to give N-[(1S)-1-[[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2- b ]pyridin -2-yl]methyl]-3-oxo-propyl]-2-nitro-benzenesulfonamide which was used without further purification. MS m/z 629.2, 631.2, 633.2 [M+H]+. Step 4: S - N-(1 -(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2- b ]pyridin-2-yl)-4,4-difluorobutan -2-yl)-2-nitrobenzenesulfonamide

[00374] To a solution of N-[(1S)-1-[[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]methyl]-3-oxo-propyl]-2-nitro-benzenesulfonamide from step 3 in CH2Cl2 (1 mL) was added dimethylaminosulfur trifluoride (0.25 g, 1 M) at room temperature. After stirring for 30 min, the reaction was quenched with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give (S)-N-(1-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)-4,4-difluorobutan-2-yl)-2-nitrobenzenesulfonamide which was used without further purification. MS m/z 651.1, 653.3 [M+H]+. Step 5: 2-[(2 S )-2-amino-4,4-difluoro-butyl]-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine

[00375] To a solution of N-[(1S)-1-[[3-bromo-5-chloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]methyl]-3,3-difluoro-propyl]-2-nitro-benzenesulfonamide in DMF (1 mL, 12.9 mmol) were added thiophenol (0.02 mL, 0.2 mmol) and K2CO3 (40 mg, 0.29 mmol). After stirring at room temperature for 18 h, the mixture was diluted with MeOH (1 mL), filtered, and purified by preparative HPLC. The collected fractions were concentrated and then treated with 1 M HCl/Et2O (1 mL) to afford 2-[(2S)-2-amino-4,4-difluorobutyl]-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine dihydrochloride (4.0 mg, 9.4% yield) as a white solid. MS m/z 466.1, 468.0, 470.1 [M+H]+; 1H NMR (methanol-d4) δ ppm 7.33 (d, J= 5.2 Hz, 1 H), 7.11 (d, J= 3.1 Hz, 1H), 7.00 (t, J= 4.3 Hz, 1H), 6.66 (s, 1H), 6.04-6.37 (m, 1 H), 4.71-4.83 (m, 2 H), 3.98 (quin, J= 6.8 Hz, 1 H), 3.36-3.51 (m, 2 H), 2.25-2.45 (m, 2 H). Example 11 (Compound 45)

[00376] 2-[(2R)-2-amino-3-methoxypropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin- dihydrochloride 7-amine Step 1: N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl tert-butyl ]-N-(2-furylmethyl)carbamate

[00377] To a solution of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (126.6 mg, 0.23 mmol, 1.0 eq.), prepared according to the procedure in Example 3, in DMF (0.5 mL) and THF (2.0 mL) was added sodium hydride (60 wt %) in mineral oil (15 mg, 0.38 mmol, 1.6 eq.) at 0°C. The mixture was stirred for 5 min at 0 °C, then iodomethane (2.0 M) in tert-butyl methyl ether (112 mg, 0.120 mL, 0.24 mmol, 1.0 eq.) was added. The reaction was warmed to room temperature, then stirred at room temperature overnight. The reaction was quenched with water (~5 mL), then extracted with EtOAc (2 × 40 mL). The combined organic phases were washed with water followed by ketone (~30 mL). The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (12 g, 0-30% EtOAc in hexanes with 10% DCM) to afford tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (88.0 mg, 0.155 mmol, 0.68 eq.) as an off-white solid. MS m/z 566.3 [M+H]+ , 588.2, 590.3 [M+Na]+ . Step 2: (R)-2-(2-amino-3-methoxypropyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine

[00378] Removal of the Boc group following the general procedure described in Step 3 for Example 2 using HCl in dioxane affords (R)-2-(2-amino-3-methoxypropyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride. MS m/z 366.3, 368.2 [M+H]+; 1H NMR 500 MHz (DMSO-d6) δ ppm 8.33 (br s, 3 H), 7.65 (br s, 1 H), 7.56 - 7.62 (m, 1 H), 6.60 (s, 1 H), 6.39 - 6.42 (m, 1 H), 6.36 (d, J=3.05 Hz, 1 H), 4.51 (br s, 2 H), 3.44 - 3.53 (m, 2 H), 3.34 - 3.43 (m, 1 H), 3.31 (s, 3 H), 3.24 (dd, J=14.55, 5.29 Hz, 1 H), 3.18 (dd, J=14.49, 9.25 Hz, 1 H), 2.25 (s, 3 H).

[00379] The compounds below were prepared according to the procedure of Example 11, substituting the appropriate starting materials, reagents, and reaction conditions. Example 12 (Compound 115)

[00380] 3-(5-Chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-D-alanine dihydrochloride Captions: 2-methyl-2-butene - dioxane Step 1: (R)-(2-(2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-3,5-dichlorothieno[3,2-b] tert-butyl pyridin-7-yl)(furan-2-ylmethyl)carbamate

[00381] To tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (614 mg, 1.0 mmol), prepared according to the procedure in Example 3, in CH2Cl2 (3 mL) was added Dess-Martin periodinane, 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, (546 mg, 1.3 mmol, 1.3 eq). After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure, diluted with diethyl ether (3 mL), and stirred with saturated Na2S2O3 (1 mL) and saturated NaHCO3 (1 mL) for 30 min. The organic layer was separated, dried over MgSO4, filtered, and concentrated to give tert-butyl (R)-(2-(2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (510 mg, 83% yield) as a clear oil. MS m/z 569.9 [M+H]+; 1H NMR (DMSO-d6) δ ppm 9.51 (s, 1H), 7.55 (m, 2H), 6.33 (br s, 1H), 6.24 (br s, 1H), 4.90-4.98 (m, 2H), 4.10-4.23 (m, 1H), 3.35-3.41 (m, 1H), 3.13-3.26 (m, 1H), 1.39 (s, 9H), 1.36 (s, 9H). Step 2: (2R)-2-(tert-butoxycarbonylamino)-3-[7-[tert-butoxycarbonyl(2-furylmethyl)amino]-3,5-dichloro-thieno[3,2-b]pyridin-2-yl]propanoic acid

[00382] To a solution of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-oxo-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (510 mg, 0.9 mmol) in tert-butanol (4.0 mL) and water (1.0 mL) was added NaH2PO4 (322 mg, 2.7 mmol, 3 eq.) followed by 2-methyl-2-butene (0.8 mL, 9 mmol, 10 eq.) and finally NaClO2 (162 mg, 1.8 mmol, 2.0 eq.). After stirring at room temperature for 0.5 h, the mixture was diluted with CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give (2R)-2-(tert-butoxycarbonylamino)-3-[7-[tert-butoxycarbonyl(2-furylmethyl)amino]-3,5-dichloro-thieno[3,2-b]pyridin-2-yl]propanoic acid (498 mg, 95% yield) as a white solid. MS m/z 586.1 [M+H]+; 1H NMR (DMSO- d6) δ ppm 12.79-13.13 (m, 1 H), 7.55-7.59 (m, 1 H), 7.51-7.54 (m, 1 H), 7.25-7.33 (m, 1 H), 6.29-6.36 (m, 1 H), 6.20-6.26 (m, 1 H), 4.90-5.01 (m, 2 H), 4.19-4.25 (m, 1 H), 3.50-3.59 (m, 1 H), 3.21-3.29 (m, 1 H), 1.37-1.40 (s, 9 H), 1.33-1.37 (s, 9 H). Step 3: (2R)-2-amino-3-[3,5-dichloro-7-(2-furylmethylamino)thieno[3,2-b]pyridin-2-yl]propanoic acid

[00383] A mixture of (2R)-2-(tert-butoxycarbonylamino)-3-[7-[tert-butoxycarbonyl(2-furylmethyl)amino]-3,5-dichloro-thieno[3,2-b]pyridin-2-yl]propanoic acid (80 mg, 0.14 mmol) in a solution of HCl (4 M in dioxane) (1 mL, 4 mmol) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The solid was triturated with diethyl ether and filtered to afford (2R)-2-amino-3-[3,5-dichloro-7-(2-furylmethylamino)thieno[3,2-b]pyridin-2-yl]propanoic acid dihydrochloride (55 mg, 88% yield). MS m/z 366.1, 368.2 [M+H]+; 1H NMR (DMSO-d6) δ ppm 8.64 (br s, 3 H), 7.93-8.06 (m, 1 H), 7.577.65 (m, 1 H), 6.68-6.75 (m, 1 H), 6.35-6.46 (m, 2 H), 4.48-4.60 (m, 2 H), 4.11-4.23 (m, 1H), 3.48-3.57 (m, 2H), COOH peak not observed.

[00384] The compound below was prepared according to the procedure of Example 12, substituting the appropriate starting materials, reagents, and reaction conditions. Example 13 (Compound 72)

[00385] 2-[(2R)-2-aminobut-3-en-1-yl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thiene dihydrochloride [3,2-b]pyridin-7-amine Figure Caption: dioxane Step 1: (R)-(3-bromo-2-(2-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-5-chlorothieno[3,2-b tert-butylpyridin-7-yl)(thiazol-2-ylmethyl)carbamate

[00386] To a suspension of methyltriphenylphosphonium bromide (260 mg, 0.71 mmol, 2.1 eq.) in THF (3.5 mL) was added KHMDS (1 M) in THF (0.68 mL, 0.68 mmol, 2.0 eq.). The mixture was stirred at room temperature for 2 h, then cooled to -78 °C. (R)-tert-butyl (3-bromo-2-(2-((tert-butoxycarbonyl)amino)-3-oxopropyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiazol-2-ylmethyl)carbamate (215 mg, 0.34 mmol, 1.0 eq.), prepared according to the procedure in Example 12, in THF (2.5 mL), was added, and the temperature was warmed to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl, extracted with ethyl acetate, dried over sodium sulfate, and evaporated. The residue was purified over silica gel with ethyl acetate and hexane (5 to 35% gradient) to give tert-butyl (R)-(3-bromo-2-(2-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiazol-2-ylmethyl)carbamate (86 mg, 40% yield). 1H NMR (CDCl3) δ: 7.71 (d, J= 3.1 Hz, 1 H), 7.30 - 7.39 (m, 2 H), 5.87 (s, 1 H), 5.23 (d, J= 17.1 Hz, 1 H), 5.16 - 5.20 (m, 3 H), 4.50 - 4.75 (m, 2 H), 3.20 - 3.40 (m, 2 H), 1.38 - 1.51 (m, 18 H). Step 2: 2-[(2R)-2-aminobut-3-enyl]-3-bromo-5-chloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[00387] Removal of the Boc group following the general procedure described in Step 3 for Example 2 using HCl in dioxane affords 2-[(2R)-2-aminobut-3-enyl]-3-bromo-5-chloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine dihydrochloride. MS m/z 429.0, 431.1, 433.0 [M+H]+;

[00388] 1H NMR (methanol-d4) δ: 7.82-7.89 (m, 1 H), 7.63-7.69 (m, 1 H), 6.66-6.73 (m, 1 H), 5.81-5.91 (m, 1 H), 5.28-5.37 (m, 2 H), 4.98 (s, 2 H), 4.06-4.17 (m, 1 H), 3.38-3.46 (m, 2 H).

[00389] The compound below was prepared according to the procedure of Example 13, substituting the appropriate starting materials, reagents, and reaction conditions. Example 14 (Compound 123)

[00390] 2-[(2R)-2-aminobut-3-yl-1-yl]-3-methyl-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b ]pyridin-7-amine Step 1: N-[2-[(2R)-2-(tert-butoxycarbonylamino)but-3-ynyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl] tert-butyl -N-(2-furylmethyl)carbamate

[00391] To a stirred suspension of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-oxo-propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (202 mg, 0.37 mmol, 1.0 eq.), prepared according to the procedure in Example 12, and potassium carbonate (100 mg, 0.043 mL, 0.72 mmol, 1.97 eq.) in MeOH (5.0 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (10 wt %) in acetonitrile (800 mg, 1.0 mL, 0.42 mmol, 1.1 eq.) at 0 °C. The reaction was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was subjected to aqueous preparation and purification by flash column chromatography (24 g, 0 to 20% EtOAc/hexanes) to afford tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)but-3-ynyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (136.5 mg, 68% yield) as an off-white foam. MS m/z 546.2, 548.4 [M+H]+. Step 2: (R)-2-(2-aminobut-3-yl-1-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine

[00392] The general deprotection procedure using HCl in dioxane was followed to afford (R)-2-(2-aminobut-3-yl-1-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride MS m/z 346.2, 348.3 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.84 (br d, J= 4.27 Hz, 3 H), 7.67 (br s, 1 H), 7.55 - 7.63 (m, 1 H), 6.60 (s, 1 H), 6.40 (dd, J= 3.05, 1.83 Hz, 1 H), 6.36 (d, J= 2.75 Hz, 1 H), 4.51 (br s, 2 H), 4.23 - 4.36 (m, 1 H), 3.72 (d, J= 2.25 Hz, 1 H), 3.49 (dd, J= 14.19, 4.73 Hz, 1 H), 3.32 (dd, J= 14.19, 10.25 Hz, 1 H), 2.29 (s, 3 H).

[00393] The compound below was prepared according to the procedure of Example 14 by substituting the appropriate starting materials, reagents and reaction conditions. Example 15 (Compound 124)

[00394] 3-(3,5-Dichloro-7-{[(furan-2-yl)methyl]amino}thiene [3,2-b]pyridin-2-yl)-N-(2-fluorophenyl) dihydrochloride )-D-alaninamide Step 1: N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-(4-chloroanilino)-3-oxo-propyl]-3,5-dichloro-thieno[3,2-b] tert-butyl pyridin-7-yl]-N-(2-furylmethyl)carbamate

[00395] To a solution of (2R)-2-(tert-butoxycarbonylamino)-3-[7-[tert-butoxycarbonyl(2-furylmethyl)amino]-3,5-dichloro-thieno[3,2-b]pyridin-2-yl]propanoic acid (100 mg, 0.17 mmol), prepared according to the procedure in Example 12, chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (55 mg, 0.2 mmol, 1.1 eq.), and 4-chloroaniline (30 mg, 0.2 mmol, 1.1 eq.) in acetonitrile (1 mL) was added 1-methylimidazole (0.03 mL, 0.4 mmol, 2 eq.). After stirring at room temperature for 1 h, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over MgSO 4 , filtered, and concentrated. The residue was purified on silica gel eluting with 0 to 30% ethyl acetate in hexanes to afford tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-(4-chloroanilino)-3-oxo-propyl]-3,5-dichlorothieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (52 mg, 44% yield) as a clear foam. MS m/z 695.3, 697.3 [M+H]+; 1H NMR (CDCl3) δ ppm 8.51 (br s, 1 H), 7.46 (d, J= 8.5 Hz, 2 H), 7.26-7.32 (m, 4 H), 7.18 (s, 1 H), 6.27 (br s, 1 H), 6.19 (d, J= 3.1 Hz, 1 H), 4.79-4.86 (m, 2H), 4.65-4.72 (m, 1H), 3.52-3.64 (m, 2H), 1.44 (s, 9H), 1.41 (s, 9H). Step 2(2R)-2-amino-N-(4-chlorophenyl)-3-[3,5-dichloro-7-(2-furylmethylamino)thieno[3,2-b]pyridin-2-yl]propanamide

[00396] A mixture of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-(4-chloroanilino)-3-oxo-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (52 mg, 0.07 mmol) in HCl (4 M in dioxane) (1 mL, 4 mmol) was stirred at room temperature for 4 h. The mixture was concentrated, and the solid was triturated with diethyl ether and filtered to give (2R)-2-amino-N-(4-chlorophenyl)-3-[3,5-dichloro-7-(2-furylmethylamino)thieno[3,2-b]pyridin-2-yl]propanamide hydrochloride (33 mg, 78% yield) as a beige solid. MS m/z 495.0, 497.0 [M+H]+; 1H NMR (DMSO-d6) δ ppm 10.94-11.08 (s, 1 H), 8.70-8.82 (br s, 3 H), 7.90-8.02 (m, 1 H), 7.54-7.66 (m, 3 H), 7.40 (d, J=8.9 Hz, 2 H), 6.68 (s, 1 H), 6.32-6.44 (m, 2 H), 4.47-4.59 (m, 2 H), 4.22-4.32 (m, 1 H), 3.51-3.67 (m, 2 H).

[00397] The compounds below were prepared according to the procedure of Example 15, substituting the appropriate starting materials, reagents, and reaction conditions. Example 16 (Compound 51)

[00398] 2-[(2S)-2-aminopropyl]-5-chloro-3-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride Legends: dioxane - water Step 1: 2Sl-(2∑(2∑((tert-butoxycarbonyl)amino)propyl)∑5∑chloro∑3∑cyclopropyltieno[3,2-b]pyridin-7-yl)(furan-2 tert-butyl-ylmethyl)carbamate

[00399] To a solution of tert-butyl (S)-(3-bromo-2-(2-((tert-butoxycarbonyl)amino)propyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (88 mg, 0.15 mmol, 1.0 eq.), prepared according to the procedure in Example 2, and potassium cyclopropyltrifluoroborate (29 mg, 0.19 mmol, 1.3 eq.) in dioxane (0.8 mL) were added Pd(dppf)Cl2 (12 mg, 0.1000 eq.) and K2CO3 (2M in H2O, 0.22 mL, 3.0 eq.). The sealed tube was heated to 90 °C for 5 h. After cooling, the mixture was diluted with EtOAc and NH4Cl (aq.) and extracted with EtOAc. The combined organic phases were dried and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0 to 10% EtOAc in DCM to afford a mixture of the dry product and unreacted starting material, which was then further purified on preparative HPLC with 25 to 100% CH3CN in water with 0.1% TFA to afford tert-butyl (S)-(2-(2-((tert-butoxycarbonyl)amino)propyl)-5-chloro-3-cyclopropylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (53 mg, 64% yield) as a white solid. MS m/z 562.2, 564.2 [M+H]+. Step 2j{S2-2-(2-aminopropyl)-5-chloro-3-cylpropyl-N:(furanz2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[00400] (S)-(2-(2-((tert-butoxycarbonyl)amino)propyl)-5-chloro-3-cyclopropylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (33 mg, 89% yield) as the hydrochloride salt. MS m/z 362.1, 364.2 [M+H]+; 1H NMR (methanol-d4) δ ppm 7.49 (t, J= 0.9 Hz, 1 H), 7.04 (s, 1H), 6.42 (dd, J= 3.2, 12.5 Hz, 2 H), 4.71 (s, 2 H), 3.75 - 3.78 (m, 1 H), 3.42 - 3.44 (m, 1 H), 3.38 - 3.40 (m, 1 H), 1.84-1.87 (m, 1 H), 1.39 (d, J= 6.6 Hz, 3 H), 1.19-1.21 (m, 2 H), 0.85-0.86 (m, 2 H).

[00401] The compounds below were prepared according to the procedure of Example 16, substituting the appropriate starting materials, reagents, and reaction conditions. Example 17 (Compound 109)

[00402] 2-[(2S)-2-aminopropyl]-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile formate Step 1: S)-(1-(5-chloro-3-cyano-7-((furan-2-ylmethyl)amino)thieno[3,2- b]pyridin-2-yl)propan-2-yl) tert-butyl carbamate

[00403] A mixture of tert-butyl (S)-(3-bromo-2-(2-((tert-butoxycarbonyl)amino)propyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (67 mg, 0.11 mmol, 1.0 eq.), prepared according to the procedure in Example 2, and CuCN (22 mg, 2.2 eq.) in DMF (0.6 mL) was degassed with argon. The sealed tube was heated at 150 °C for 8 h. After cooling, 0.1 mL of NH4Cl (saturated aqueous) and 0.1 mL of NaHCO3 (saturated aqueous) were added. The mixture was stirred for 15 min, filtered, and washed with MeOH (0.5 mL × 3). The combined filtrate was purified by preparative HPLC eluting with 10 to 100% ACN in water with 0.1% formic acid to give tert-butyl (S)-(1-(5-chloro-3-cyano-7-((furan-2-ylmethyl)amino)thieno[3,2- b ]pyridin-2-yl)propan-2-yl)carbamate (15 mg, 30% yield). MS m/z 447.2, 449.2 [M+H] + . Step 2: (S)-2-(2-aminopropyl)-5-chloro-7-((furan-2-ylmethyl)amino)thieno[3,2- b ]pyridine-3-carbonitrile

[00404] tert-Butyl (S)-(1-(5-chloro-3-cyano-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)propan-2-yl)carbamate (15 mg, 0.034 mmol) was stirred in a solution of HCl (4 M in dioxane, 1 mL) at room temperature for 1 h. Organic volatiles were removed. The solid was purified by preparative HPLC eluting with 5 to 50% ACN in water with 0.1% formic acid to afford (S)-2-(2-aminopropyl)-5-chloro-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridine-3-carbonitrile

[00405] (5 mg, 36% yield) as a formic acid salt. MS m/z 347.1, 349.1 [M+H]+; 1H NMR (methanol-d4)

[00406] δ ppm 8.44 (s, 1 H), 7.36 (s, 1 H), 6.61 (s, 1 H), 6.27 (d, J= 1.3 Hz, 2 H ), 4.45 (s, 2 H), 3.48 - 3.51 (m, 1 H), 3.27 - 3.31 (m, 2 H), 1.21 (d, J= 6.6 Hz, 3 H). Example 18 (Compound 50 and Compound 49)

[00407] 2-[(2S)-2-aminopropyl]-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile hydrochloride

[00408] and

[00409] 2-[(2S)-2-aminopropyl]-3-bromo-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile hydrochloride Legend: dioxane Step^^S2∑(2∑(2∑((tertzbutoxycarbonyl)amino)propyl)∑3,5∑dida^0tie^ [3,2-b]pyridin-7-yl)(furan-2-ylmethyl )tert-butyl carbamate and S)-(3-bromo-2-(2-((tert-butoxycarbonyl)amino)propyl)-5-cyanothieno[3,2- b]pyridin-7-yl)(furan- tert-butyl 2-ylmethyl)carbamate

[00410] To a solution of tert-butyl (S)-(3-bromo-2-(2-((tert-butoxycarbonyl)amino)propyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (90 mg, 0.15 mmol, 1.0 eq), prepared according to the procedure in Example 2, in DMF (1 mL) was added zinc cyanide (11 mg, 0.60 eq.), Pd2(dba)3 (7.1 mg, 0.05 eq.), and Xantphos (8.9 mg, 0.10 eq.). The sealed tube was shaken at 120 °C for 1 h. After cooling, the mixture was diluted with EtOAc and NH4Cl (aq.) and extracted with EtOAc. The combined organic phases were dried and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0 to 10% EtOAc in DCM to afford a mixture, which was further purified by preparative HPLC with 25 to 100% ACN in water with 0.1% TFA to afford tert-butyl f)-(2-(2-((tert-butoxycarbonyl)amino)propyl)-3,5-dicyanothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (23 mg, 29% yield) MS m/z 536.3 [M-H] and f)-(3-bromo-2-(2-((tert-butoxycarbonyl)amino)propyl)-5-cyanothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate tert-butyl (35 mg, 40 % yield). MS m/z 591.2, 593.2 [M+H]+. Step 2: (S)-2-(2-aminopropyl)-7-((furan-2-ylmethyl)amino)thieno[3,2- b ]pyridine-3,5-dicarbonitrile

[00411] Deprotection of tert-butyl (fS)-(2-(2-((tert-butoxycarbonyl)amino)propyl)-3,5-dicyanothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate using the general Boc deprotection described in Step 3 of Example 2 affords (fS)-2-(2-aminopropyl)-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridine-3,5-dicarbonitrile (17 mg, 95% yield) as the hydrochloride salt. MS m/z 338.0 [M+H]+; 1H NMR (methanol-d4) δ ppm 7.48 (d, J= 0.9 Hz, 1 H), 7.20 (s, 1 H), 6.40-6.42 (m,

[00412] 2 H), 4.64 (s, 2 H), 3.79 - 3.81 (m, 1 H), 3.55 - 3.59 (m, 1 H), 3.45 - 3 .49 (m, 1 H), 1.42 (d, J= 6.6 Hz, 3 H). S)-2-(2-aminopropyl)-3-bromo-7-((furan-2-ylmethyl)amino)thieno[3,2- b]pyridine-5-carbonitrile

[00413] Deprotection of tert-butyl (S)-(3-bromo-2-(2-((tert-butoxycarbonyl)amino)propyl)-5-cyanothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate using the General Boc deprotection procedure described in Step 3 of Example 2 affords (S)-2-(2-aminopropyl)-3-bromo-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridine-5-carbonitrile (19 mg, 83% yield) as the hydrochloride salt. MS m/z 391.0, 393.0 [M+H]+; 1H NMR (methanol-d4) δ ppm 7.49 (d, J= 0.9 Hz, 1 H), 7.22 (s, 1 H), 6.40-6.42 (m, 2 H), 4.66 (s, 2 H), 3.76 - 3.80 (m, 1 H), 3.41 - 3.45 (m, 1 H), 3.37 - 3 .39 (m, 1 H), 1.42 (d, J= 6.6 Hz, 3 H).

[00414] The compounds below were prepared according to the procedure of Example 18, substituting the appropriate starting materials, reagents, and reaction conditions. Example 19 (Compound 60)

[00415] 2-[(2S)-2-aminopropyl]-3-chloro-5-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridine dihydrochloride -7-amine Step 1: tert-butyl N-(3-chloro-5-methyl-thieno[3,2-b]pyridin-7-yl)-N-(thiazol-2-ylmethyl)carbamate

[00416] A mixture of tert-butyl N-(3,5-dichlorothieno[3,2-b]pyridin-7-yl)-N-(thiazol-2-ylmethyl)carbamate (100 mg, 0.240 mmol, 1.0 eq.), prepared according to the procedure in Example 2, 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (44 mg, 0.049 mL, 0.35 mmol, 1.5 eq.), Cs2CO3 (171 mg, 0.524 mmol, 2.2 eq.), and PdCl2dppf DCM (14.4 mg, 0.0175 mmol, 0.0727 eq.) in dioxane (1.0 mL) and water (0.1 mL) was stirred at 120 °C. for 2 h, then cooled, diluted with ethyl acetate and washed with brine, dried and evaporated. The residue was purified on silica gel with ethyl acetate and dichloromethane (0 to 50% gradient) to give tert-butyl N-(3-chloro-5-methyl-thieno[3,2-b]pyridin-7-yl)-N-(thiazol-2-ylmethyl)carbamate (71 mg, 75% yield). 1H NMR (CDCl3) δ: 7.69 (d, J= 2.6 Hz, 1 H), 7.34 (d, J= 2.9 Hz, 1 H), 7.07-7.20 (m,

[00417] 1 H), 5.19 (br s, 2 H), 4.40 - 4.63 (m, 1 H), 4.00 - 4.11 (m, 1 H), 3.22 ( br s, 2 H), 2.74 (br s, 3 H), 1.46 (s, 18 H), 1.19 (d, J= 5.8 Hz, 3 H). Step 2j 2-[(2S)-2-Aminopropyl]-3-chloro-5-methyl-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[00418] Deprotection of tert-butyl N-(3-chloro-5-methyl-thieno[3,2-b]pyridin-7-yl)- N-(thiazol-2-ylmethyl)carbamate using the general Boc deprotection procedure with HCl in dioxane afforded 2-[(2S)-2-aminopropyl]-3-chloro-5-methyl-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine dihydrochloride (52 mg, 96% yield). MS m/z 353.1, 355.1 [M+H]+. 1H NMR (methanol-d4) δ: 7.88 - 7.95 (m, 1 H), 7.71 - 7.78 (m, 1 H), 6.97 - 7.05 (m, 1 H), 5.21 (s, 2 H), 3.73 - 3.85 (m,

[00419] 1 H), 3.46 - 3.54 (m, 1 H), 3.37 - 3.44 (m, 1 H), 2.73 (s, 3 H), 1.43 (d , J= 6.6 Hz, 3 H). Example 20 (Compound 21)

[00420] 2-[(1S)-1-Aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride Legends: a - in - dioxane - minor - major Step 1: tert-(5-chloro-2-formyl-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate butyl

[00421] To a solution of tert-butyl N-(5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl)-N-(2-furylmethyl)carbamate (90 mg, 0.24 mmol, 1.0 eq.), prepared according to the procedure in Example 2, in THF (1 mL) at -78 °C was added LDA (2.0 M in THF, 0.14 mL, 1.2 eq.). After 30 min, DMF (0.11 mL, 1.4 mmol, 5.8 eq.) was added dropwise. The temperature was warmed to -50 °C, and the reaction was quenched with saturated aqueous NH4Cl 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 flash column chromatography on silica gel eluting with 0-25% EtOAc in hexane to afford tert-butyl (5-chloro-2-formyl-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (83 mg, 86% yield) as a white solid. 1H NMR (acetone-d6) δ ppm 10.5 (s, 1 H), 7.55 (s, 1 H), 7.45 (s, 1 H), 6.29-6.33 (m, 2 H), 5.03 (s, 2 H), 2.84 (s, 3 H), 1.43 (s, 9 H). Step 2(R,E)-(2-(((tert-butylsulfinyl)imino)methyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)tert-butylcarbamate

[00422] A mixture of tert-butyl (5-chloro-2-formyl-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (151 mg, 0.37 mmol, 1.0 eq.), R-(+)-2-methylpropane-2-sulfinamide (54 mg, 0.45 mmol, 1.2 eq.), and CuSO4 (91 mg, 0.56 mmol, 1.5 eq.) in DCE (0.4 mL) was stirred at 55 °C for 18 h. After cooling, the mixture was purified by flash column chromatography on silica gel eluting with 0 to 50% EtOAc in hexane to afford tert-butyl (R,E)-(2-(((tert-butylsulfinyl)imino)methyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (140 mg, 74% yield). MS m/z 510.4, 512.4 [M+H]+. Step 3: Tert-butyl (2-( (S)-1-(( (R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate and (2-( (R)-1-(( (R) - tert-butylsulfinyl)amino)ethyl)-5-chloro-3-methylthieno[3, tert-butyl 2- b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[00423] To a solution of tert-butyl (R,E)-(2-(((tert-butylsulfinyl)imino)methyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (140 mg, 0.27 mmol, 0.74 eq.) in THF (2.3 mL) was added MeMgBr (3.0 M in Et2O, 0.31 mL, 2.5 eq.) at -78 °C. The mixture was warmed to 0 °C for 1 h, then quenched with a saturated solution of NH4Cl and 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 flash column chromatography on silica gel eluting with 0 to 100% EtOAc in hexanes to afford tert-butyl (2-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (88 mg, 45% yield, the major diastereomer), MS m/z 526.5, 528.5 [M+H]+; 1H NMR (acetone-d6) δ ppm 7.44 (d, J= 0.9 Hz, 1 H), 7.25 (s, 1 H), 6.30-6.32 (m, 1 H), 6.25-6.27 (m, 1 H), 5.07-5.10 (m, 1 H), 4,954.97 (m, 3 H), (t, 3 H), 1.60 (d, J= 6.6 Hz, 3 H), 1.41 (s, 9 H), 1.20 (s, 9 H), and (2-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-3- tert-Butyl methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (26 mg, 13% yield, minor diastereomer), MS m/z 526.5, 528.5 [M+H]+; 1H NMR (acetone-d6) δ ppm 7.43 (s, 1 H), 7.26 (s, 1 H), 6.29-6.31 (m, 1 H), 6.23-6.25 (m, 1 H), 5.10-5.11 (m, 1 H), 4.97 (d, J= 4.9 Hz, 2H), 4.69 (br s , 1 H), 2.43 (t, 3 H), 1.60 (d, J= 6.6 Hz, 3 H), 1.41 (s, 9 H), 1.20 (s, 9 H). Step 4: (S)-2-(1-Aminoethyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2- b]pyridin-7-amine

[00424] A solution of (2-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (20 mg, 0.038 mmol) in HCl (4 M in dioxane, 1 mL) was stirred at room temperature for 1 h. The organic volatiles were removed, and the residue was triturated with diethyl ether and filtered to give (S)-2-(1-aminoethyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine (12 mg, 74% yield) as the dihydrochloride salt. MS m/z 322.1, 324.1 [M+H]+; 1H NMR (DMSO-d6) δ ppm 8.67 (br s, 3 H), 7.80 (br s, 1 H), 7.60 (d, J= 0.9 Hz, 1 H), 6.63 (s, 1 H), 6.40-6.41 (m, 1 H), 6.35-6.37 (m, 1 H), 4.96-4.99 ( m, 1 H), 4.53 (br s, 2 H), 2.36 (s, 3 H), 1.64 (d, J= 6.8 Hz, 3 H). Example 21 (Compound 26)

[00425] 5-Chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(1S)-1-(methylamino)ethyl]thieno[3,2-b]pyridin- hydrochloride 7-amine Caption: dioxane Step 1j(^^S)∑^(£(R)-ierc-b^ylsulfinyl)(methyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7- tert-butyl yl)(furan-2-ylmethyl)carbamate

[00426] To a solution of tert-butyl (2-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (88 mg, 0.17 mmol, 1.0 eq.) in DMF (0.3 mL) was added NaH (60% in oil, 8.7 mg, 1.3 eq.) at 0 °C. After 10 min, a solution of iodomethane (31.0 mg, 1.3 eq.) in DMF (0.3 mL) was added. After 30 min, the reaction was quenched with citric acid (1.0 M) and diluted with EtOAc. The organic phases were washed with water and brine, dried over sodium sulfate, and evaporated. The residue was purified by flash column chromatography on silica gel eluting with 0 to 70% EtOAc in hexane to afford tert-butyl (2-((S)-1-(((R)-tert-butylsulfinyl)(methyl)amino)ethyl)-5-chloro-3-methylthieno[3,2- b ]pyridin-7-yl)(furan-2-ylmethyl)carbamate (79 mg, 87% yield). MS m/z 540.6, 542.6. [M+H]+. Step 2: (S)-2-(1-Aminoethyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2- b ]pyridin-7-amine

[00427] A solution of tert-butyl (2-((S)-1-(((R)-tert-butylsulfinyl)(methyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (79 mg, 0.15 mmol) in HCl (4 M in dioxane, 1 mL) was stirred at room temperature for 1 h. Organic volatiles were removed. The residue was triturated with diethyl ether and filtered to afford (S)-2-(1-aminoethyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine (41 mg, 72% yield) as the hydrochloride salt. MS m/z 336.3, 338.1 [M+H]+; 1H NMR (DMSO-d6) δ ppm 9.38 (br s, 1 H), 9.07 (br s, 1 H), 7.79 (t, J= 6.0 Hz, 1 H), 7.60 (s, 1 H), 6.66 (s, 1 H), 6.37-6.42 (m, 2 H), 4.93-4.98 (m, 1 H ), 4.53 (d, J= 5.8 Hz, 2 H), 2.60 (br s, 3 H), 2.38 (s, 3 H), 1.64 (d, J= 6.8 Hz, 3 H).

[00428] The compound below was prepared according to the procedure of Example 21, substituting the appropriate starting materials, reagents, and reaction conditions. Example 22 (Compound 22 and Compound 3)

[00429] 2-[(1R)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride

[00430] and

[00431] 1-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)ethan-1-ol Captions: in - a - dioxane Step 1: tert-(5-chloro-2-(1-hydroxyethyl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate butyl and (2-( (R) -1-(( (R) - tert-butylsulfinyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan- tert-butyl 2-ylmethyl)carbamate

[00432] A mixture of tert-butyl N-(5-chloro-2-formyl-3-methyl-thieno[3,2-b]pyridin-7-yl)-N-(2-furylmethyl)carbamate (160 mg, 0.39 mmol, 1.0 eq.), prepared according to the procedure in Example 20, S-(+)-2-methylpropane-2-sulfinamide (54 mg, 0.45 mmol, 1.2 eq.) and CuSO4

[00433] (96 mg, 0.59 mmol, 1.5 eq.) in DCE (0.4 mL) was stirred at 55 °C for 18 h. The mixture was filtered through a pad of Celite, washing the solids with DCE. The filtrate was concentrated. To a solution of the residue in THF (2 mL) was added MeMgBr (3.0 M in Et2O, 0.52 mL, 4.0 eq.) at -78 °C. The mixture was gradually warmed to 0 °C over 1 h, then quenched with saturated NH4Cl solution and 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 flash column chromatography on silica gel eluting with 0 to 60% EtOAc in hexane to afford tert-butyl (5-chloro-2-(1-hydroxyethyl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (44 mg, 27%), MS m/z 423.2, 425.2 [M+H] + , then with 100% EtOAc to afford tert-butyl (2-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (40 mg, 27%, the major diastereomer), MS m/z 526.5, 528.5 [M+H]+. Step 2: 1 -(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)ethan-1-ol

[00434] (2-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (20 mg, 0.038 mmol) was stirred in a solution of HCl (4 M in dioxane, 1 mL) at room temperature for 1 h and then the organic volatiles were removed. The residue was triturated with diethyl ether and filtered to give (R)-2-(1-aminoethyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine (12 mg, 74% yield) as the hydrochloride salt. MS m/z 322.1, 324.1 [M+H]+; 1H NMR (DMSO-d6) δ ppm 8.67 (br s, 3 H), 7.80 (br s, 1 H), 7.60 (d, J= 0.9 Hz, 1 H), 6.63 (s, 1 H), 6.40-6.41 (m, 1 H), 6.35-6.37 (m, 1 H), 4.96-4.99 ( m, 1 H), 4.53 (br s, 2 H), 2.36 (s, 3 H), 1.64 (d, J= 6.8 Hz, 3 H). English: t-Butyl (5-chloro-2-(1-hydroxyethyl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (35 mg, 0.083 mmol) was stirred in a solution of HCl (4 M in dioxane, 1 mL) at room temperature for 1 h and then the organic volatiles were removed. The residue was triturated with diethyl ether and filtered to give 1-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)ethan-1-ol (13 mg, 49% yield) as a white solid. MS m/z 323.1, 325.1 [M+H]+; 1H NMR (acetone-d6) δ ppm 7.45 (s, 1 H), 6.58 (s, 1 H), 6.32-6.33 (m, 2 H), 5.31 (q, J= 6.4 Hz, 1 H), 4.59 (d, J= 5.3 Hz, 2 H), 3.50 (br s, 1H), 2.25 (s, 3 H), 1.45 (d, J= 6.4 Hz, 3 H).

[00435] The compounds below were prepared according to the procedure of Example 22 substituting the appropriate starting materials, reagents and reaction conditions. Example 23 (Compound 5 and Compound 25)

[00436] (5-chloro-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)methanol

[00437] and

[00438] 5-chloro-N-(furan-2-ylmethyl)-2-((methylamino)methyl)thieno[3,2-b]pyridin-7-amine hydrochloride Legends: in THF - in dioxane Step 1((7-(( tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)methyl)(methyl) tert-butyl carbamate and tert-butyl (2-(((tert-butoxycarbonyl)oxy)methyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[00439] To a solution of tert-butyl N-(5-chloro-2-formyl-3-methyl-thieno[3,2-b]pyridin-7-yl)-N-(2-furylmethyl)carbamate (40 mg, 0.10 mmol, 1.0 eq.), prepared according to the procedure in Example 20, in DCM was added a solution of methylamine (2.0 M in THF, 0.2 mL, 4 eq.) and sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction mixture was stirred at room temperature overnight, and then quenched by the addition of NaHCO3 (saturated aqueous). The crude product was extracted with DCM, and the combined organic phases were dried and concentrated. This crude material was mixed with 4-DMAP (5 mg) and di-tert-butyl dicarbonate (50 mg) in DCM (1 mL). After stirring at room temperature for 1-2 h, the reaction was concentrated and purified directly by flash column chromatography on silica gel eluting with 0-100% EtOAc in hexane to afford tert-butyl ((7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)methyl)(methyl)carbamate. MS m/z 508.1, 510.1. [M+H]+ and tert-butyl (2-(((tert-butoxycarbonyl)oxy)methyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate. Step 2: 5-chloro-N-(furan-2-ylmethyl)-2-((methylamino)methyl)thieno[3,2-b]pyridin-7-amine and (5-chloro-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)methanol

[00440] The intermediate, tert-butyl ((7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)methyl)(methyl)carbamate, was stirred in a solution of HCl (4 M in dioxane, 0.5 mL) at room temperature for 1 h and then the organic volatiles were removed. The crude solid was triturated with diethyl ether and filtered to afford 5-chloro-N-(furan-2-ylmethyl)-2-((methylamino)methyl)thieno[3,2-b]pyridin-7-amine (1.8 mg, 5.8% yield over 3 steps) as a hydrochloride salt. MS m/z 308.1, 310.1 [M+H]+; 1H NMR (methanol-d4) δ: 7.61 (s, 1H), 7.51 (s, 1H), 7.06 (s, 1H), 6.42-6.46 (m, 2H), 4.73 (s, 2H), 4.63 (s, 2H), 2.83 (s, 3H). (5-chloro-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)methanol

[00441] The intermediate, tert-butyl (2-(((tert-butoxycarbonyl)oxy)methyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate, was stirred in a solution of HCl (4 M in dioxane, 0.5 mL) at room temperature for 1 h and then the organic volatiles were removed. The crude solid was triturated with diethyl ether and filtered to afford (5-chloro-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)methanol (9 mg, 31% yield over 3 steps). MS m/z 295.0, 297.0 [M+H]+; 1H NMR (methanol-d4) δ: 7.35 (s, 1H), 7.29 (s, 1H), 6.66 (s, 1H), 6.26-6.27 (m, 2H), 4.49 (s, 2H), 4.29 (br s, 2H).

[00442] The following compound was prepared according to the reductive amination procedure of Example 23, substituting the appropriate starting materials, reagents, and reaction conditions. Example 24 (Compound 163)

[00443] N2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N7-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridine-2,7-diamine Caption: dioxane Step 1: (S )-(2-((2-((tert-butoxycarbonyl)amino)propyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl) tert-butyl (thiophen-2-ylmethyl)carbamate

[00444] A mixture of tert-butyl (5-chloro-2-iodo-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (100 mg, 0.19 mmol, 1.0 eq), prepared according to Intermediate 6, (S)-(1-aminopropan-2-yl)tert-butylcarbamate (50 mg, 0.29 mmol, 1.5 eq), Cs2CO3 (200 mg, 0.61 mmol, 3.0 eq), Pd2(dba)3 (9 mg, 0.01 mmol, 0.1 eq), Xant-Phos (12 mg, 0.02 mmol, 0.2 eq), and toluene (1 mL) was heated at 100 °C under an argon atmosphere for 3 h. English: The crude reaction mixture was allowed to cool to rt and diluted with EtOAc (20 mL). The organic phase was washed with H2O (20 mL) followed by brine (20 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 30% EtOAc in hexanes to afford tert-butyl (S)-(2-((2-((tert-butoxycarbonyl)amino)propyl)amino)-5-chloro-3-methylthieno[3,2- b ]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (80 mg, 74%) as a white foam. MS m/z 567.2, 569.2 [M+H]+; 1H NMR (DMSO-d6) δ: 7.39-7.43 (m, 1H), 6.71-6.95 (m, 5H), 5.00 (s, 2H), 3.67-3.80 (m, 1H), 3.14-3.23 (m, 1H), 3.03-3.13 (m, 1H), 2.05 (s, 3 H), 1.39 (s, 18H), 1.03-1.10 (d, J= 6.4 Hz, 3H). Step 2: N2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N7-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridine-2,7-diamine

[00445] A mixture of tert-butyl (S)-(2-((2-((tert-butoxycarbonyl)amino)propyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (80 mg, 0.14 mmol) in a solution of HCl (4 M in dioxane, 1 mL) at room temperature for 1 h. The organic volatiles were removed. The residue was triturated with diethyl ether and filtered to afford (S)-N2-(2-aminopropyl)-5-chloro-3-methyl-N7-(thiophen-2-ylmethyl)thieno[3,2-b]pyridine-2,7-diamine (52 mg, 62% yield) as the hydrochloride salt. MS m/z 367.2, 369.2 [M+H]+; 1H NMR (DMSO-d6) δ: 8.34 (br s, 4H), 8.11 (br s, 1H), 7,397.46 (m, 1H), 7.08-7.14 (m, 1H), 6.97-7.02 (m, 1H), 6.58 (s, 1H), 4,714.80 (m, 2H), 3.47-3.55 (m, 1H), 3.41-3.45 (m, 1H), 3.31-3.36 (m, 1H), 2.15 (s, 3H), 1.29 (d, J=6.4 Hz, 3H).

[00446] The compounds below were prepared according to the procedure of Example 24 substituting the appropriate starting materials, reagents and reaction conditions. Example 25 (Compound 131)

[00447] Methyl 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-D-alaninate Step 1: (R )-3-(7-(( tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-2 -methyl(( tert-butoxycarbonyl)amino)propanoate

[00448] To a solution of (R)-3-(7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (45 mg, 0.08 mmol, 1.0 eq.), prepared according to Example 12 step 2, and K2CO3 (35 mg, 0.25 mmol, 3.0 eq.) in DMF (1 mL) was added Mel (25 μL, 0.4 mmol, 5 eq.) and then stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature and diluted with H2O (10 mL). The aqueous phase was extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with 0 to 30% EtOAc in hexanes to afford methyl (R)-3-(7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (28 mg, 60%) as a clear oil. MS m/z 580.2 [M+H]+; 1H NMR (methanol-d4) δ: 7.36-7.48 (m, 1H), 7.12-7.20 (m, 1H), 6.27-6.35 (m, 1H), 6.16-6.26 (m, 1H), 4.88-4.95 (m, 2H), 4.46-4.55 (m, 1H), -4.18 (m, 1H), 3.75 (s, 3H), 3.45-3.57 (m, 1H), 2.38 (s, 3H), 1.44 (s, 9H), 1.42 (s, 9H), 1 NH not observed. Step 2: Methyl 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-D-alaninate

[00449] A mixture of (R)-3-(7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (28 mg, 0.05 mmol) in a solution of HCl (4 M in dioxane) (1 mL, 4 mmol) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The solid was triturated with diethyl ether and filtered to afford methyl (R)-2-amino-3-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)propanoate dihydrochloride (12 mg, 65% yield). MS m/z 380.1, 382.1 [M+H]+; 1H NMR (methanol-d4) δ: 7,497.56 (m, 1H), 7.12-7.18 (m, 1H), 6.45-6.51 (m, 1H), 6.40-6.44 (m, 1H), 4.75 (s, 2H), 4.46-4.53 (m, 1H), 3.90 (s, 3H), 3.67-3.74 (m, 1H), 3,583.66 (m, 1H), 2.46 (s, 3H), 3 NHs not observed. Example 26 (Compound 127 and Compound 130 and Compound 132)

[00450] (2S)-2-amino-1-[3,5-dichloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]propan-1-ol dihydrochloride

[00451] and

[00452] 2-[(2S)-2-amino-1-fluoro-propyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine formate

[00453] and

[00454] 2-[(2S)-2-amino-1,1-difluoro-propyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine Captions: Dess-Martin periodinane - a - dioxane Step 1: N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-hydroxy-propyl]-3,5-dichloro-thieno[3,2 -b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate

[00455] To a solution of tert-butyl N-(3,5-dichlorothieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)-carbamate (110 mg, 0.27 mmol, 2.0 eq.) in THF (1.0 mL) cooled to -78 °C was added LDA (2.0 M, 0.15 mL, 0.30 mmol, 2.2 eq.). After 15 min, a solution of Boc-L-alaninal (25 mg, 0.14 mmol, 1.0 eq.) in THF (0.5 mL) was added dropwise and the temperature warmed to 0 °C over 30 min. The reaction was quenched with saturated NH4Cl, then diluted with ethyl acetate and washed with brine, dried, and then concentrated. The residue was purified on silica gel with ethyl acetate in hexanes (10 to 50% gradient) to provide tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-hydroxy-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (28 mg, 35% production). EM m/z 588.2, 590.2, 592.5 [M+H]+. Step 2: (2S)-2-amino-1-[3,5-dichloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]propan-1-ol dihydrochloride

[00456] The general deprotection procedure using HCl in dioxane was followed to afford (2S)-2-amino-1-[3,5-dichloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]propan-1-ol dihydrochloride (20 mg). MS m/z 388.2, 390.2, 392.2 [M+H]+; 1H NMR (methanol-d4) δ: 7.34 (d, J=5.2 Hz, 1H), 7.07-7.20 (m, 1H), 7.00 (t, J=4.0 Hz, 1H), 6.89 (s, 1H), 5.25 (d, J=7.6 Hz, 1H), 4.87 (s, 2H), 3.70 (m, 1H), 1.33 (d, J=6.7 Hz, 3H), 3 NHs and 1 OH not observed. Step 3: tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-fluoro-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate

[00457] To a solution of tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-hydroxy-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (30.0 mg, 0.0510 mmol, 1.00 eq.) and DIPEA (26.9 mg, 0.036 mL, 0.20 mmol, 4.00 eq.) in DCM (0.5 mL) at -78 °C was added DAST (1.0 M in DCM, 0.20 mL, 0.20 mmol, 4.00 eq.). The temperature was then slowly raised to room temperature and stirred at room temperature overnight. The reaction intermediate was observed by LC/MS. The reaction was quenched with saturated sodium bicarbonate, then diluted with ethyl acetate and washed with brine, dried, and then evaporated. The residue was purified on silica with ethyl acetate and hexanes (10 to 50% gradient) to give tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-fluoro-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]- N -(2-thienylmethyl)carbamate (17 mg, 56% yield). MS m/z 590.3, 592.2, 594.2 [M+H]+. Step 4: 2-[(2S)-2-amino-1-fluoro-propyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine formate

[00458] General deprotection procedure using HCl in dioxane followed by reversed-phase HPLC purification with formic acid used as phase modifier afforded 2-[(2S)-2-amino-1-fluoro-propyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2- b ]pyridin-7-amine formic acid salt (8.0 mg, 64% yield). MS m/z 390.2, 392.2, 394.2 [M+H]+; 1H NMR (methanol-d4) δ: 8.23-8.56 (br s, 1H), 7.33 (d, J=4.3 Hz, 1H), 7.06-7.17 (m, 1H), 7.00 (t, J=4.3 Hz, 1H), 6.68 (s, 1H), 6.34 (d, J=45.3 Hz, 1 H), 4.79 (s, 2H), 3.89-4.07 (m, 1H), 1.39 (d, J=6.4 Hz, 3H), 3 NHs not observed. Step 5: tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propanoyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate

[00459] A mixture of tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-hydroxy-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (28 mg, 0.048 mmol, 1.0 eq.) and Dess-Martin periodinane (31 mg, 0.071 mmol, 1.5 eq.) in DCM (0.5 mL) was stirred at room temperature for 1 h. DCM was removed and the residue was diluted with ether, to which were added 1.0 M Na2S2O3 and saturated sodium bicarbonate. The mixture was separated. The organic layer was washed with 2.0 M K2CO3 and brine, dried over sodium sulfate, and evaporated to give tert-butyl N-[2-[(2S)-2-( tert -butoxycarbonylamino)propanoyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]- N -(2-thienylmethyl)carbamate (32 mg), which was used in the next step without further purification. MS m/z 586.2, 588.3, 590.3 [M+H]+. Step 6: tert-butyl N-[2-[(2 S )-2-( tert -butoxycarbonylamino)-1,1-difluoro-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]- N -(2-thienylmethyl)carbamate

[00460] A mixture of tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propanoyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (32 mg, 0.055 mmol, 1.1 eq.) and DAST (1.0 M in DCM) (1.0 mL, 1.0 mmol, 21 eq.) was stirred at room temperature overnight. LC/MS showed ~13% desired product. The mixture was transferred to an Eppendorf vial, to which Deoxo-Fluor (55 mg, 0.046 mL, 0.24 mmol, 5.0 eq.) was added and the mixture was stirred at room temperature for 6 h, then quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was purified on silica gel with ethyl acetate in hexanes (5 to 50% gradient) to give tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1,1-difluoro-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (3.5 mg, 12% yield). MS m/z 608.2, 610.2, 612.2 [M+H]+. Step 7: 2-[(2S)-2-amino-1,1-difluoro-propyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine

[00461] The general deprotection procedure using HCl in dioxane followed by purification by reversed-phase HPLC with formic acid used as the mobile phase modifier afforded 2-[(2S)-2-amino-1,1-difluoro-propyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (2.3 mg, 98% yield) as the free base. MS m/z 408.3, 410.3, 412.2 [M+H]+; 1H NMR (methanol-d4) δ: 7.28-7.38 (m, 1H), 7.07-7.17 (m, 1H), 6.95-7.05 (m, 1H), 6.73 (s, 1H), 4.79 (s, 2H), 4.47-4.58 (br s, 1H), 1.40 (br d, 0 Hz, 3H), 3 NHs not observed.

[00462] The compounds below were prepared according to the procedure of Example 26, substituting the appropriate starting materials, reagents, and reaction conditions. Example 27 (Compound 149)

[00463] 5-chloro-3-(difluoromethoxy)-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine Captions: toluene - ether - dioxane Step 1: tert-butyl N-(5-chloro-3-hydroxy-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate

[00464] To a mixture of tert-butyl N-(3-bromo-5-chloro-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (460 mg, 1.0 mmol, 1.0 eq.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (220 mg, 0.24 mL, 1.2 mmol, 1.2 eq.) in THF (1.0 mL) and toluene (4.0 mL) cooled to -78°C was added n-BuLi (2.5 M in hexane, 0.48 mL, 1.2 mmol, 1.2 eq.) dropwise. The mixture was stirred at -78 °C for 1 h then quenched with saturated ammonium chloride, diluted with ethyl acetate, washed with brine, and then dried and concentrated. To the residue was added Et2O (10 mL), followed by hydrogen peroxide (30 wt % in water, 0.41 mL, 4.0 mmol, 4.0 eq.). The mixture was stirred at room temperature for 16 h then diluted with ether, treated with saturated sodium thiosulfate, and separated. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified on silica with ethyl acetate in hexanes (5 to 40% gradient) to afford tert-butyl N-(5-chloro-3-hydroxy-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (294 mg, 74% yield). MS m/z 397.3, 399.3 [M+H]+. Step 2: tert-butyl N-[5-chloro-3-(difluoromethoxy)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate

[00465] A mixture of tert-butyl N-(5-chloro-3-hydroxy-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (100 mg, 0.252 mmol, 1.00 eq.), sodium chlorodifluoroacetate (91.1 mg, 0.579 mmol, 2.30 eq.) and Cs2CO3 (115 mg, 0.353 mmol, 1.40 eq.) in DMF (240 mg) and water (0.025 mL) was stirred at 100 °C for 16 h, then cooled, diluted with ethyl acetate, and then washed with brine, dried and evaporated. The residue was purified on silica gel with ethyl acetate in hexanes (5 to 25% gradient) to give tert-butyl N-[5-chloro-3-(difluoromethoxy)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (29 mg, 26% yield). MS m/z 447.1, 449.1 [M+H] + . Step 3: 5-chloro-3-(difluoromethoxy)-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine

[00466] The general deprotection procedure using HCl in dioxane was followed to afford 5-chloro-3-(difluoromethoxy)-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine after purification using C18 EZ-Prep with formic acid as the modifier. MS m/z 347.0, 349.0 [M+H]+; 1H NMR (CDCl3) δ: 7.31-7.36 (m, 1H), 7.22-7.26 (m, 1H), 7.10-7.15 (m, 1H), 7.03-7.07 (m, 1H), 6.95-6.98 (t, J=77 Hz, 1H), 6.62 (s, 1H), -5.01 (m, 1H), 4.75 (br s, 2H).

[00467] The compounds below were prepared according to the procedure of Example 27 substituting the appropriate starting materials, reagents and reaction conditions. Example 28 (Compound 167)

[00468] 2-[(2R)-2-amino-3-methylsulfinyl-propyl]-3,5-dichloro-N-(2-furylmethyl)thieno[3,2-b]pyridin-7-amine Step 1: N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfinyl-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N tert-butyl -(2-furylmethyl)carbamate

[00469] To a stirred solution of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfanyl-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (119.6 mg, 0.19 mmol, 1.0 eq.) in a mixed solvent of THF (2.0 mL) and water (1.0 mL) was added sodium periodate (60 mg, 0.28 mmol, 1.4 eq.) at 0 °C. The reaction was stirred at 0 °C for 1 h and then warmed to room temperature and stirred 48 h. The reaction was quenched with water then extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine, dried over sodium sulfate, and then concentrated to give the crude product which was purified by flash column chromatography (0 to 80% EtOAc in DCM) to give tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfinyl-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (103.3 mg, 84% yield) as a light yellow foam. MS m/z 640.1, 642.1. [M+Na]+; 1H NMR (acetone-d6) δ ppm: 7.46 (br d, J=4.4 Hz, 1H), 7.39 (s, 1H), 6.44 (br d, J=8.1 Hz, 1H), 6.30-6.32 (m, 1H), 6.27 (t, J=2.7 Hz, 1H), 4.98 (s, 2H), 4.33-4.46 (m, 1H), 3.49-3.56 (m, 1H), 3.42 (br dd, J=14.0, 7.9 Hz, 1H), 2.91-3.18 (m, 2H), 2.63 (s, 2H), 2.58 (s, 1H), 1.43 (s, 9H), 1.37 (s, 9H). Step 2: tert-2-[(2R)-2-amino-3-methylsulfinyl-propyl]-3,5-dichloro-N-(2-furylmethyl)thieno[3,2-b]pyridin-7-amine

[00470] To a solution of tert-butyl N-[2-[(2R)-2-(tert-butoxycarbonylamino)-3-methylsulfinyl-propyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-furylmethyl)carbamate (103.3 mg, 0.167 mmol, 1.0eq.) in acetonitrile (3.0 mL) and THF (1.0 mL) was added p-toluenesulfonic acid monohydrate (135 mg, 0.672 mmol, 4.0 eq.) and heated to 60 °C and then stirred for 1 h at 60 °C. LC-MS analysis indicated complete consumption of the starting material. The reaction mixture was quenched with sodium carbonate (0.3 M aq., 5 mL) then extracted with EtOAc (2 × 30 mL). The combined organic phases were dried over sodium sulfate and then concentrated to afford the crude product which was dried under high vacuum overnight to afford 2-[(2R)-2-amino-3-methylsulfinyl-propyl]-3,5-dichloro-N-(2-furylmethyl)thieno[3,2-b]pyridin-7-amine (55.8 mg, 80% yield) as an off-white solid. MS m/z 418.4, 420.4. [M+H]+; 1H NMR (DMSO-d6) δ ppm: 7.83-7.91 (m, 1H), 7.60 (s, 1H), 6.65 (d, J=4.0 Hz, 1H), 6.37-6.43 (m, 2H), 4.50-4.55 (m, 2H), 3.39-3.57 (m, 1H), (s, 3H), 3.19 (td, J=14.6, 5.5 Hz, 1H), 3.05 (ddd, J=14.5, 12.4, 7.3 Hz, 1H), 2.72-2.84 (m, 2H), 2 NHs not observed. Example 29 (Compound 129)

[00471] 2-[(2S)-2-Aminopropyl]-5-chloro-N-[(5-fluorothiazol-2-yl)methyl]-3-methyl-thieno[3,2-b]pyridin-7- amine Step 1: N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-( tert-butyl 2-trimethylsilylethoxymethyl)carbamate

[00472] To a two-necked round bottom flask was added tert-butyl N-(5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl)-N-(2-trimethylsilylethoxymethyl)carbamate (1.95 g, 4.55 mmol, 1.0 eq.) dissolved in THF (0.25 M) followed by tert-butyl (4S)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (1.40 g, 5.91 mmol, 1.3 eq.). The mixture was cooled to -78 °C. To the cooled reaction mixture was added lithium diisopropylamide in THF/heptane/ethylbenzene (2.0 M, 2.7 mL, 5.45 mmol, 1.2 eq.) dropwise and the reaction was stirred until completion as monitored by UPLC. Once the reaction was complete (~1.5 h) the reaction was removed from the batch and quenched with 1.0 M citric acid and extracted with ethyl acetate. The combined extracts were washed with water and brine and dried over Na2SO4 and concentrated. The crude mixture was subjected to column chromatography (EtO-Ac/DCM, 0 to 15%) to afford tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-trimethylsilylethoxymethyl)carbamate (1.91 g, 72% yield). MS m/z 586.4, 588.4. [M+H]+;

[00473] 1H NMR (CDCl3) δ ppm: 7.25 (s, 1H), 5.07 (s, 2H), 4.47 (br d, J=1.7 Hz, 1H), 4.02 ( br s, 1H), 3.13-3.19 (m, 1H), 3.05 (br s, 1H), 2.43 (s, 3H), 1.65 (br s, 1H), 1, 44 (s, 18H), 1.17 (d, J=6.7Hz, 3H), 0.98 (s, 1H), 0.95 (s, 1H), 0.03 (s, 9H), 1 NH not observed. Step 2: N-[(1S)-2-[7-(tert-butoxycarbonylamino)-5-chloro-3-methyl-thieno[3,2-b]pyridin-2-yl]-1-methyl-ethyl] tert-butyl carbamate

[00474] To a reaction tube containing tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-(2-trimethylsilylethoxymethyl)carbamate (0.41 g, 0.70 mmol, 1.0 eq.) were added THF (7.0 mL) and tetrabutylammonium fluoride (1 mol/L) in THF (7 mL, 7.0 mmol, 10 eq.) under an argon atmosphere. The reaction was stirred for 12 h at 40 °C. Upon completion, the reaction was cooled to room temperature and diluted with ethyl acetate, washed with water, dried, and concentrated. The crude material was subjected to column chromatography (EtOAc/DCM, 0-15%) to afford tert-butyl N-[(1S)-2-[7-(tert-butoxycarbonylamino)-5-chloro-3-methyl-thieno[3,2-b]pyridin-2-yl]-1-methyl-ethyl]carbamate (19 mg, 6.0% yield). MS m/z 456.4, 458.4. [M+H]+, 1H NMR (CDCl3) δ ppm: 6.61 (s, 1H), 4.47 (br s, 1H), 4.02 (br s, 1H), 3.32-3.32 (m, 1H), 3.09-3.16 (m, 1H), 3.01-3.06 (m, 1H), 2.41 (s, 3H), 1.57 (s, 9H), 1.43 (s, 9H), 1.18 (d, J=6.7 Hz, 3H). Step 3: tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-[(5-fluorothiazol-2-yl)methyl]carbamate

[00475] A solution of tert-butyl N-[(1S)-2-[7-(tert-butoxycarbonylamino)-5-chloro-3-methyl-thieno[3,2-b]pyridin-2-yl]-1-methyl-ethyl]carbamate (19 mg, 0.041 mmol, 1.0 eq.) and (5-fluorothiazol-2-yl)methanol (17 mg, 0.125 mmol, 3.0 eq.) in toluene (0.1 M) was sparged with N2 for 30 min. To this mixture was added 1,1'-(azodicarbonyl)dipiperidine (33 mg, 0.129 mmol, 3.1 eq.) and the mixture was again sparged with N2 and stirred for an additional 10 min. Tri- n -butylphosphine (28 mg, 0.138 mmol, 3.3 eq.) was added and the reaction mixture was stirred at 30 °C for about 17 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give tert -butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2- b ]pyridin-7-yl]-N-[(5-fluorothiazol-2-yl)methyl]carbamate (13 mg, 55% yield). EM m/z 571.3, 573.3 [M+H]+, 1H NMR (CDCl3) δ ppm: 7.20 (d, J=2.4 Hz, 1H), 7.14 (s, 1H), 4.99 (s, 2H), 4.47 (br d, J=1.1 Hz, 1H), 4.01 (br s, 1H), 2-3.17 (m, 1H), 3.05 (br s, 1H), 2.41 (s, 3H), 1.44 (s, 18H), 1.16 (d, J=6.7 Hz, 3H). Step 4: 2-[(2S)-2-Aminopropyl]-5-chloro-N-[(5-fluorothiazol-2-yl)methyl]-3-methyl-thieno[3,2-b]pyridin-7-amine

[00476] To a reaction tube with tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)propyl]-5-chloro-3-methyl-thieno[3,2-b]pyridin-7-yl]-N-[(5-fluorothiazol-2-yl)methyl]carbamate (13 mg, 0.022 mmol, 1.0 eq.) was added hydrochloric acid in dioxane (4.0 M, 1.0 mL, 4.0 mmol) and allowed to stir for 1 h at room temperature. On completion, the reaction was diluted with diethyl ether and filtered to give 2-[(2S)-2-aminopropyl]-5-chloro-N-[(5-fluorothiazol-2-yl)methyl]-3-methyl-thieno[3,2-b]pyridin-7-amine (5.6 mg, 66% yield). MS m/z 371.2, 373.2. [M+H]+, 1H NMR (methanol-d4) δ ppm: 7.41 (d, J=2.0 Hz, 1H), 7.04 (s, 1H), 4.92 (s, 2H), 3.63-3.71 (m, 1H), 3.35-3.42 (m, 1H), 3.23-3.29 (m, 1H), 45 (s, 3H), 1.38 (d, J=6.4 Hz, 3H), 3 NHs not observed. Example 30 (Compound 148)

[00477] 2-(1-aminopropan-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine Captions: dioxane - acetone Step 1: 2-(7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)- ethyl 2-cyanoacetate

[00478] A solution of tert-butyl (5-chloro-2-iodo-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (202 mg, 0.40 mmol, 1.0 eq.), prepared according to the procedure in Intermediate 6, and ethyl 2-cyanoacetate (50 mg, 1.1 eq.) in dioxane (1.6 mL) was added into a suspension of KOtBu (116 mg, 2.5 eq.) in dioxane (0.5 mL) under argon, followed by addition of Pd(OAc)2 (4.5 mg, 0.05 eq.) and dppf (23 mg, 0.100 eq.). After bubbling argon for 2 min, the reaction was sealed and heated to 70 °C for 2 h. After cooling, the reaction was quenched with citric acid (1.0 M) and EtOAc, then extracted with EtOAc. The crude material was purified by flash column chromatography on silica gel eluting with 0 to 60% EtOAc in hexanes to afford ethyl 2-(7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-2-cyanoacetate (145 mg, 74.0% yield) as an orange oil. MS m/z 490.1, 492.1 [M+H]+ Step 2: Ethyl 2-(7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-2-cyanopropanoate

[00479] To a cold mixture of ethyl 2-(7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-2-cyanoacetate (145 mg, 0.30 mmol, 1.0 eq.) and K2CO3 (62 mg, 1.5 eq.) in acetone (0.6 mL) was added Mel (127 mg, 3.0 eq.) under argon. The mixture was stirred at room temperature for 3 h with UPLC analysis indicating completion of the reaction. After cooling to 0 °C, the reaction was quenched with citric acid (1.0 M) and EtOAc. The crude product was applied directly to the next step without further purification. EM m/z 504.1, 506.1 [M+H]+. Step 3: tert-butyl (5-chloro-2-(1-cyanoethyl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[00480] A mixture of ethyl 2-(7-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-2-cyanopropanoate (149 mg, 0.30 mmol, 1.0 eq.) and K2CO3 (62 mg, 1.5 eq.) was stirred in MeOH (0.60 mL) at room temperature for 3 h, then quenched with EtOAc and citric acid (1.0 M, aq.). The crude material was purified by flash column chromatography on silica gel eluting with 0-50% EtOAc in hexane to afford tert-butyl (5-chloro-2-(1-cyanoethyl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (81 mg, 63% yield). MS m/z 432.1, 434.2 [M+H] + . Step 4: tert-butyl (2-(1-aminopropan-2-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[00481] To a cold solution of tert-butyl (5-chloro-2-(1-cyanoethyl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (81 mg, 0.19 mmol, 1.0 eq.) in THF (2.0 mL) was added LAH (1.0 M in THF, 0.28 mL, 1.5 eq.) dropwise at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirring was continued at room temperature for 3 h. The reaction was quenched by the addition of Na2SO4.xH2O (solid) at 0 °C. The mixture was stirred at room temperature for 1 h, filtered, and the solids were washed with MeOH. The combined filtrate was concentrated and purified by HPLC prep eluting with 5 to 100% ACN in water with 0.1% formic acid to give tert-butyl (2-(1-aminopropan-2-yl)-5-chloro-3-methylthieno[3,2- b ]pyridin-7-yl)(furan-2-ylmethyl)carbamate (10 mg, 12% yield). MS m/z 436.2, 438.2 [M+H] + . Step 5: 2-(1-Aminopropan-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2- b ]pyridin-7-amine

[00482] General Boc Deprotection Procedure: A mixture of tert-butyl (2-(1-aminopropan-2-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (10 mg, 0.022 mmol) was stirred in a solution of HCl (4 M in dioxane, 1 mL) at room temperature for 1 h and then the organic volatiles were removed. The crude solid was purified on HPLC prep eluting with 5 to 40% ACN in water with 0.1% formic acid to give 2-(1-aminopropan-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine as the formic acid salt (5.0 mg, 65% yield). MS m/z 335.8, 338.0 [M+H]+; 1H NMR (methanol-d4) δ: 8.44 (s, 1 H), 7.46 (t, J= 1.2 Hz, 1 H), 6.62 (s, 1 H), 6.38 (d, J= 1.3 Hz, 1H), 4.55 (s, 2 H), 3.69 - 3.74 (m, 1 H), 3.23 - (m, 1 H), 3.18 - 3.20 (m, 1 H), 2.39 (s, 3 H), 1.48 (d, J= 6.6 Hz, 3 H), 3 NHs not observed. Formic acid salt. Example 31 (Compound 146)

[00483] 2-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)propan-1-ol Caption: dioxane Step 1: (5-chloro-3-methyl-2-(prop-1-en-2-yl)thieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate tert-butyl

[00484] A mixture of tert-butyl (5-chloro-2-iodo-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (101 mg, 0.20 mmol, 1.0 eq.), prepared according to the procedure in Intermediate 6, and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (46.0 mg, 1.3 eq.) and Pd(dppf)Cl2 (8.3 mg, 0.05 eq.) in dioxane (1 mL) and K2CO3 (2M in H2O, 0.30 mL, 3.0 eq.) was stirred at 75 °C for 3 h. The reaction was quenched with EtOAc and water. The crude material was purified by flash column chromatography on silica gel eluting with 0 to 5% EtOAc in hexanes to afford tert-butyl (5-chloro-3-methyl-2-(prop-1-en-2-yl)thieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (75 mg, 90% yield) as a colorless oil which was used directly in the next step. MS m/z 419.2, 421.2 [M+H] + . Step 2: tert-butyl (5-chloro-2-(1-hydroxypropan-2-yl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[00485] To a cold solution of tert-butyl (5-chloro-3-methyl-2-(prop-1-en-2-yl)thieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (75 mg, 1.0 eq.) in THF (1 mL) was added 9-BBN (0.5 M in THF, 1 mL, 4.0 eq.) dropwise at 0 °C. After stirring at 0 °C for 1 h, the mixture was brought to room temperature, and stirring was continued overnight. The mixture was then cooled to 0 °C. EtOH (0.2 mL) was added followed by the addition of NaOAc (sat., 0.5 mL) and hydrogen peroxide (30 wt % in water, 0.2 mL). The mixture was continued stirring at 0 °C for 1 h and at room temperature for 5 h, then quenched with EtOAc and water. The organic phases were washed with water and brine. The crude material was purified by flash column chromatography on silica gel eluting with 0 to 60% EtOAc in hexanes to afford tert-butyl (5-chloro-2-(1-hydroxypropan-2-yl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (62 mg, 79% yield) as a light yellow solid. MS m/z 437.2, 439.2 [M+H]+. Step 3: 2-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)propan-1-ol

[00486] A mixture of tert-butyl (5-chloro-2-(1-hydroxypropan-2-yl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (16 mg, 0.037 mmol) and HCl (4 M) in dioxane (1.0 mL) was stirred at room temperature for 1 h. The mixture was diluted with diethyl ether (2x) and filtered. The filter cake was washed with ether, collected, and dried to afford 2-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)propan-1-ol (6 mg, 48% yield). MS m/z 337.1, 339.1 [M+H]+; 1H NMR (DMSO-d6) δ: 7.59 (s, 1H), 7.50 (br s, 1 H), 6.52 (s, 1 H), 6.39 (d, J= 1.3 Hz, 1 H), 6.34 (d, J= 1.3 Hz, 1 H), 4.90 (br s, 1 H), 4.49 (s, 2 H), 3.51-3.55 (m, 2 H), 3.43-3.48 (m, 1 H), 2.24 (s, 3 H), 1.27 (d, J= 6.1 Hz, 3 H). Example 32 (Compound 150 and Compound 151)

[00487] 2-[(2R,3S)-3-aminobutan-2-yl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin- 7-amine

[00488] and

[00489] 2-[(2S,3S)-3-aminobutan-2-yl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin- 7-amine Captions: dioxane - Martin's reagent Step 1: (5-chloro-3-methyl-2-(1-oxopropan-2-yl)thieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl ) tert-butyl carbamate

[00490] To a solution of tert-butyl (5-chloro-2-(1-hydroxypropan-2-yl)-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (141 mg, 0.32 mmol, 1.0 eq.), prepared according to the procedure in Example 31, in DCM (1.0 mL) was added Martin's reagent (171 mg, 1.2 eq.) at 0 °C. The light pink solution was stirred at room temperature for 1 h, and UPLC analysis indicated that the reaction was complete. The mixture was filtered and the solid was washed with DCM. The filtrate was combined, washed with NaHCO3 (saturated aqueous), and concentrated. The resulting crude product was applied to the next step without purification. MS m/z 433.3, 435.3 [M-H]+. Step 2: tert-butyl (2-(( E)-1-((( R)-tert-butylsulfinyl)imino)propan-2-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[00491] A mixture of tert-butyl (5-chloro-3-methyl-2-(1-oxopropan-2-yl)thieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (115 mg, 0.26 mmol, 1.0 eq.), R-(+)-2-methylpropane-2-sulfinamide (48 mg, 1.5 eq.) and CuSO4 (215 mg, 5.0 eq.) in DCE (0.5 mL) was stirred at room temperature for 18 h. After cooling, the mixture was purified by flash column chromatography on silica gel eluting with 0 to 30% EtOAc in hexanes to afford tert-butyl (2-((E)-1-(((R)-tert-butylsulfinyl)imino)propan-2-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (79 mg, 49% yield). MS m/z 560.2, 562.2 [M+Na]+. Step 3: (R)-N-((2S,3R/S)-3-(5-chloro-7-((furan-2-ylmethyl)amino)-^methylthieno[3,2-b]pyridin-2-yl)butan-2-yl)-2-methylpropane-2-sulfinamide and (R)-N-((2S,3S/R)-3-(5-chloro-7-((furan-2-ylmethyl )amino)-3-methylthieno[3,2- b]pyridin-2-yl)butan-2-yl)-2-methylpropane-2-sulfinamide

[00492] To a solution of tert-butyl (2-((E)-1-(((R)-tert-butylsulfinyl)imino)propan-2-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate (70 mg, 0.13 mmol, 1.0 eq.) in DCM (0.9 mL) was added MeMgBr (3.0 M in Et2O, 0.11 mL, 2.5 eq.) at -78 °C. The mixture was warmed to -50 °C and kept at -50 °C for 4 h, then warmed to room temperature and continued stirring overnight. The reaction was quenched with saturated NH4Cl solution. The mixture was diluted with EtOAc, then washed with water followed by brine, and the organic layer was dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel eluting with 0 to 100% EtOAc in hexanes to afford a mixture of two diastereomers, which were further purified on prep-HPLC eluting with 10 to 80% CH3CN in water with 0.1% formic acid to afford (R)-N-((2S,3R/S)-3-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2- b ]pyridin-2-yl)butan-2-yl)-2-methylpropane-2-sulfinamide (18 mg, 45% yield), MS m/z 454.3, 456.3 [M+H]+; and (R)-N-((2S,3S/R)-3-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)butan-2-yl)-2-methylpropane-2-sulfinamide (20 mg, 42% production), MS m/z 454.3, 456.3 [M+H]+. Step 4: 2-[(2R,3S)-3-aminobutan-2-yl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine

[00493] A mixture of (R)-N-((2S,3R/S)-3-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)butan-2-yl)-2-methylpropane-2-sulfinamide (18 mg, 0.04 mmol) and HCl (4 M) in dioxane (1.0 mL) was stirred at room temperature for 1 h. The mixture was diluted with diethyl ether (2x) and filtered. The filter cake was washed with ether, collected, and dried to give 2-((2R/S, 3S)-3-aminobutan-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine (5.4 mg, 41% yield) as an HCl salt. MS m/z 350.2, 352.2 [M+H]+;

[00494] 1H NMR (methanol-d4) δ: 7.50 (d, J= 1.1 Hz, 1 H), 7.16 (s, 1 H), 6.48 (d, J= 3.0 Hz, 1 H), 6.42 (dd, J= 3.0, 1.1 Hz, 1 H), 4.77 (s, 2 H), 3.69 - 3.71 (m, 1 H) , 3.58 - 3.61 (m, 1 H), 2.50 (s, 3 H), 1.50 (d, J= 7.0 Hz, 3 H), 1.44 (d, J= 6.56 Hz, 3 H), 3 NHs not observed. 2-[(2S,3S)-3-aminobutan-2-yl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7 -amine

[00495] A mixture of (R)-N-((2S,3S/R)-3-(5-chloro-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridin-2-yl)butan-2-yl)-2-methylpropane-2-sulfinamide (20 mg, 0.04 mmol) and HCl (4 M) in dioxane (1.0 mL) was stirred at room temperature for 1 h. The mixture was diluted with diethyl ether (2x) and filtered. The filter cake was washed with ether, collected, and dried to give 2-((2R/S, 3S)-3-aminobutan-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine (7.4 mg, 53% yield) as an HCl salt. MS m/z 350.2, 352.2 [M+H]+;

[00496] 1H NMR (methanol-d4) δ: 7.50 (d, J= 1.1 Hz, 1 H), 7.10 (s, 1 H), 6.46 (d, J= 3.2 Hz, 1 H), 6.42 (dd, J= 3.0, 1.1 Hz, 1 H), 4.74 (s, 2 H), 3.64 - 3.67 (m, 1 H) , 3.55 - 3.58 (m, 1 H), 2.47 (s, 3 H), 1.54 (d, J= 7.0 Hz, 3 H), 1.27 (d, J= 6.56 Hz, 3 H), 3 NHs not observed. BIOLOGICAL EXAMPLES

[00497] The following in vitro biological examples demonstrate the utility of the compounds of the present invention for the treatment of familial dysautonomia.

[00498] To describe in greater detail and aid in the understanding of the present invention, the following non-limiting biological examples are offered to more fully illustrate the scope of the invention and are not to be construed as specifically limiting the scope thereof. Such variations of the present invention that may now be known or later developed, which would be within the competence of one skilled in the art to ascertain, are considered to be within the scope of the present invention and as claimed herein below. Example 1 IKBKAP-HTRF Assay

[00499] The assay is used for the quantitative determination of 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 by using a donor-labeled anti-IKAP antibody and an acceptor-labeled anti-IKAP antibody. PROTOCOL

[00500] Cells were thawed and incubated in DMEM-10% FBS for 72 hours. Cells were trypsinized, counted, and resuspended at a concentration of 50,000 cells/mL in DMEM-10% FBS. A 199 μL aliquot of the cell suspensions was seeded at 10,000 cells per well in a 96-well microtiter plate and incubated for 3 to 5 hours. To provide a signal control, three wells received no 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. A 1 μL aliquot of 200× compound solution was transferred to wells containing cells, and the cells were incubated for 48 h in a cell culture incubator (37°C, 5% CO2, 100% relative humidity). Triplicate samples were set up for each compound concentration. After 48 h, 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 h. A 36 μL aliquot of this lysate was subsequently transferred to a 384-well plate containing 4 μL of antibody solution (1:50 dilution of anti-IKAP d2 and anti-IKAP K (9 + 8) in detection buffer). The 384-well plate was then centrifuged for 1 minute to bring the solutions to the bottom of the plate and incubated overnight at 4 °C. The fluorescence of each well of the plate at 665 nm and 620 nm was measured on the EnVision plate reader (Perkin Elmer). The ΔF for each sample is calculated by: Captions: sign - blank

[00501] where Signal is the normalized fluorescence for each sample well and blank (lank) is the normalized mean fluorescence for the blank control wells.

[00502] The maximum increase (MFI) in IK-BKAP protein abundance for compounds of Formula (I) or a form thereof relative to vehicle control are provided in Table 1. MFI was calculated by dividing the ΔF value for each sample well by the sample ΔF for the vehicle control wells.

[00503] An MFI < 1.9 is indicated by one star (*), between > 1.9 and < 2.9 is indicated by two stars (**), between > 2.9 and < 3.9 is indicated by three stars (***), between > 3.9 and < 4.9 is indicated by four stars (****), and > 4.9 is indicated by five stars (*****).

[00504] The EC2x for IKBKAP protein expression obtained from the 7-point concentration curve generated for each test compound according to the protocol in Biological Example 1 is also provided in Table 1. The term "EC2x for IKBKAP protein expression" is defined as the concentration of test compound that is effective in producing twice the amount of IKBKAP protein in a DF patient cell compared to the amount produced from the DMSO vehicle control.

[00505] An EC2x > 1 μM is indicated by one star (*), between > 0.5 μM and < 1 μM is indicated by two stars (**), between > 0.02 μM and < 0.5 μM is indicated by three stars (***), between > 0.005 μM and < 0.02 μM is indicated by four stars (****), and < 0.005 μM is indicated by five stars (*****).

[00506] Regardless of whether a document cited herein has been specifically and individually indicated as being incorporated by reference, all documents referenced herein are incorporated by reference into this application for any and all purposes to the same extent as if each individual reference were fully set forth herein.

[00507] Having now fully described the subject matter of the claims, it will be understood by those skilled in the art that the same may be carried out within a wide range of equivalents without affecting the scope of the subject matter or particular aspects described herein. It is intended that the appended claims be construed to include all equivalents.

Claims (15)

1. Compound, characterized by the fact that it presents the Formula (I): or a form thereof wherein R1 is selected from the group consisting of phenyl and heteroaryl, optionally substituted with one, two, three or four independently selected R1a substituents, wherein heteroaryl is a 5- to 8-membered aromatic monocyclic or bicyclic carbon atom ring structure radical having 1 to 3 heteroatoms selected from N, O, and S; R1a is selected from the group consisting of cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, and C1-6alkoxy; R3 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6alkylamino, wherein each case of C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally substituted with one, two, three, or four independently selected substituents of R3a, and wherein each case of C1-6alkyl, C2-6alkenyl, and C2-6alkynyl may optionally contain a chiral carbon having an (R) or (S) configuration; R3a is selected from the group consisting of cyano, halo, hydroxy, oxo, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, halo-C1-6alkoxy, carboxyl, amino, C1-6alkoxycarbonyl, C1-6alkylamino, halo-C1-6alkylamino, (C1-6alkyl)2-amino, phenylamino, heterocyclylamino, heteroarylamino, phenyl-(C1-6alkyl)-amino, heterocyclyl-(C1-6alkyl)-amino, heteroaryl-(C1-6alkyl)-amino, C1-6alkylthio, C1-6alkylsulfoxyl, and C1-6alkylsulfonyl, wherein heterocyclyl is a 3- to 7-membered monocyclic carbon atom ring structure radical having 1 to 3 heteroatoms selected from N, O, and S, wherein heteroaryl is a 5- to 8-membered aromatic monocyclic or bicyclic carbon atom ring radical having 1 to 3 heteroatoms selected from N, O, and S, and wherein each case of phenyl, heterocyclyl, and heteroaryl is optionally substituted with one, two, three, or four independently selected R3a'substituents;R3a' is selected from the group consisting of cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, and amino; R4 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, halo-C1-6alkoxy, amino, C1-6alkyl-amino, (C1-6alkyl)2-amino, C3-10cycloalkyl, phenyl, heterocyclyl, and heteroaryl, wherein heterocyclyl is a 3- to 7-membered monocyclic, carbon atom, ring structure radical having 1 to 3 heteroatoms selected from N, O, and S, wherein heteroaryl is a 5- to 8-membered monocyclic or bicyclic aromatic, carbon atom, ring structure radical having 1 to 3 heteroatoms selected from N, O, and S, and wherein each case of C1-6alkyl, C3-10cycloalkyl, phenyl, heterocyclyl, or heteroaryl are optionally substituted with one, two, three, or four independently selected R4a substituents; R4a is selected from the group consisting of cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, and C1-6alkoxy; R5 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy, carbamoyl, C3-10cycloalkyl, and heterocyclyl, wherein heterocyclyl is a 3- to 7-membered monocyclic carbon atom ring structure radical having 1 to 3 heteroatoms selected from N, O, and S; R6 is selected from the group consisting of hydrogen, halo, and C1-6alkyl; and wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate, and tautomeric form thereof. 2. The compound of claim 1, wherein R1 is selected from the group consisting of phenyl, furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,3-thiazolyl, 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. 3. Compound according to claim 2, characterized in that R1 is selected from the group consisting of furanyl, thiophenyl, 1,3-thiazolyl and pyridinyl. 4. The compound of claim 1, wherein R3 is selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C1-6alkylamino, wherein each case of C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally substituted with one, two, three, or four independently selected substituents of R3a. 5. Compound according to claim 1, characterized in that R3 is C1-6alkyl having a chiral carbon having the (S) configuration. 6. The compound of claim 1 wherein R3 is C1-6alkyl having a chiral carbon having the (R) configuration. 7. Compound, characterized by the fact that it is selected from the group consisting of: 5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 1-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)ethan-1-ol; 1-(5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)ethan-1-ol; (5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)methanol; 3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 3-chloro-5-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 3-bromo-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile; 7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile; 5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile; 5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile; 7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; (2R)-2-amino-3-(5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)propan-1-ol; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridine-5-carbonitrile; 2-[(1S)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(1R)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(1R)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(1S)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 5-chloro-N-[(furan-2-yl)methyl]-2-[(methylamino)methyl]thieno[3,2-b]pyridin-7-amine; 5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(1S)-1-(methylamino)ethyl]thieno[3,2-b]pyridin-7-amine; 5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(methylamino)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(2-fluorophenyl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(1S)-1-amino-2-methylpropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(1R)-1-amino-2-methylpropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(1S)-2-methyl-1-(methylamino)propyl]thieno[3,2-b]pyridin-7 -amine; 2-[(2S)-2-aminobutyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(3-fluoropyridin-4-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; (2R)-2-amino-3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)propan-1- hello; 2-[(2R)-2-amino-3-methoxypropyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; (2R)-2-amino-3-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)propan- 1-ol; 5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(2S)-2-(methylamino)propyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-methoxypropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-methoxypropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- amine; (3S)-3-amino-4-(3,5-dichloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl) butan-1-ol; 2-[(2S)-2-aminopropyl]-3-bromo-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile; 2-[(2S)-2-aminopropyl]-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile; 2-[(2S)-2-aminopropyl]-5-chloro-3-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-3-methyl-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile; 2-[(1S)-1-aminoethyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(1R)-1-aminoethyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; (2R)-2-amino-3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)propan-1 -ol; 2-[(2S)-2-amino-3-fluoropropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-3-chloro-5-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-methylpentyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-methylpentyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; 2-[(2S)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-(trifluoromethoxy)propyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b ]pyridin-7-amine; (2R)-3-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)-2 -[(trifluoromethyl)amino]propan-1-ol; 2-[(2S)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; 2-[(2S)-2-amino-3-fluoropropyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- amine; 2-[(2S)-2-amino-4-methylpentyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; (2R)-2-amino-3-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-2- il)propan-1-ol; 2-[(2R)-2-aminobut-3-en-1-yl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2- b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-5-chloro-3-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-3-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-methylpentyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- amine; 2-[(2S)-2-amino-4-methylpentyl]-5-chloro-3-cyclopropyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-5-chloro-3-cyclopropyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-3-cyclopropyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; (3S)-3-amino-4-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-2- il)butan-1-ol; 2-[(2R)-2-amino-3-fluoropropyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-5-chloro-3-cyclopropyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; (3S)-3-amino-4-(3-bromo-5-chloro-7-{[(2-fluorophenyl)methyl]amino}thieno[3,2-b]pyridin-2-yl)butan-1- hello; 2-[(2S)-2-aminopropyl]-3-bromo-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile; 2-[(2S)-2-aminopropyl]-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile; (3S)-3-amino-4-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)butanenitrile; 2-[(2R)-2-amino-3-(methylsulfanyl)propyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7- amine; (3S)-3-amino-4-(5-chloro-3-methyl-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)butanenitrile; (3S)-3-amino-4-(3,5-dichloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)butanenitrile; 2-[(2S)-2-amino-4,4-difluorobutyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- amine; 2-[(2R)-2-amino-3-(methanesulfonyl)propyl]-5-chloro-N-[(furan-2-yl)methyl]- 3-methylthieno[3,2-b]pyridin-7- amine; 2-[(2S)-2-aminopropyl]-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile; 2-[(2S)-2-aminopropyl]-5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile; (3S)-3-amino-4-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)butanenitrile; 2-[(2S)-2-aminopropyl]-3-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile; 2-[(2R)-2-amino-3-(methanesulfonyl)propyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine ; 2-[(2R)-2-amino-3-(methylsulfanyl)propyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine ; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-D-alanine; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N,N-dimethyl-D-alaninamide; 2-[(2R)-2-amino-3-(methanesulfonyl)propyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7 -amine; 2-[(2R)-2-amino-3-(methylsulfanyl)propyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7 -amine; 2-[(2R)-2-aminobut-3-en-1-yl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)-N-(2-fluorophenyl)-D-alaninamide ; 3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)-D-alanine; 3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)-N-phenyl-D-alaninamide; 2-[(2R)-2-aminobut-3-yn-1-yl]-3-methyl-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; 3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)-N-(2-fluorophenyl)-D-alaninamide ; 2-[(2R,3S)-2-amino-3-fluorobutyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] pyridin-7-amine; 2-[(2R,3S)-2-amino-3-fluorobutyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- amine; (2S)-2-amino-1-(3,5-dichloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)propan-1- hello; 2-[(2R,3S)-2-amino-3-fluorobutyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] pyridin-7-amine; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7 -amine; 2-[(2S)-2-amino-1-fluoropropyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; methyl 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-D-alaninate; 2-[(2S)-2-amino-1,1-difluoropropyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-(4-cyanophenyl)-D- alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-pyridin-2-yl-D- alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-pyrazin-2-yl-D- alaninamide; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methoxythieno[3,2-b]pyridin-7-amine; 5-chloro-N-[(furan-2-yl)methyl]-3-methoxythieno[3,2-b]pyridin-7-amine; 5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-3-ol; 2-[(2S)-2-aminopropyl]-5-chloro-3-(difluoromethoxy)-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-pyridin-4-yl-D- alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-methyl-N-phenyl-D- alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-(4-methylphenyl)-D- alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-(3-chlorophenyl)-D- alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-(3-methoxyphenyl)-D- alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-(1-methyl-1H-pyrazole -5-yl)-D-alaninamide; 2-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)propan-1-ol; 2-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)propane-1,2-diol; 2-(1-aminopropan-2-yl)-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; 5-chloro-3-(difluoromethoxy)-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; 2-[(2R,3S)-3-aminobutan-2-yl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine ; 2-[(2S,3S)-3-aminobutan-2-yl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine ; 2-(2-aminoethyl)-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)propan- 1-ol; 2-[(2S)-2-amino-1-fluoropropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)propan- 1-ol; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)propan- 1-one; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)propan- 1-one; 2-[(2S)-2-amino-1-fluoropropyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-2- il)propan-1-ol; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-2- il)propan-1-one; 2-[(2S)-2-amino-1-fluoropropyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin- 7-amine; (2R)-2-amino-3-(5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)propan-1-ol; N2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N7-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridine-2,7-diamine; N2-[(2R)-2-aminopropyl]-5-chloro-3-methyl-N7-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridine-2,7-diamine; (2R,3R)-3-amino-4-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) butan-2-ol; 2-[(2R)-2-aminobut-3-yn-1-yl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2- b]pyridin-7- amine; and [(2R)-2-amino-3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2- b]pyridin-2-yl)propyl] (methyl)sulfaniolate; wherein the form of the compound is selected from the group consisting of a salt, hydrate, solvate and tautomeric form thereof. 8. Compound, characterized by the fact that it is selected from the group consisting of: 3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride ; 3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 3-chloro-5-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; (2R)-2-amino-3-(5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)propan-1- dihydrochloride hello; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminobutyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridine-5-carbonitrile trifluoroacetate; 2-[(1S)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(1R)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(1R)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(1S)-1-aminoethyl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 5-chloro-N-[(furan-2-yl)methyl]-2-[(methylamino)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(1S)-1-(methylamino)ethyl]thieno[3,2-b]pyridin-7-amine hydrochloride ; 5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(methylamino)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(2-fluorophenyl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(1S)-1-amino-2-methylpropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride ; 2-[(1R)-1-amino-2-methylpropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride ; 5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(1S)-2-methyl-1-(methylamino)propyl]thieno[3,2-b]pyridin hydrochloride -7-amine; 2-[(2S)-2-aminobutyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(3-fluoropyridin-4-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; (2R)-2-amino-3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)propan-dihydrochloride 1-ol; 2-[(2R)-2-amino-3-methoxypropyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; (2R)-2-amino-3-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) dihydrochloride propan-1-ol; 5-chloro-N-[(furan-2-yl)methyl]-3-methyl-2-[(2S)-2-(methylamino)propyl]thieno[3,2-b]pyridin-7-amine hydrochloride ; 2-[(2S)-2-aminopropyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; 2-[(2R)-2-amino-3-methoxypropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; 2-[(2R)-2-amino-3-methoxypropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride ; 2-[(2R)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7- formate amine; 2-[(2S)-2-amino-4-fluorobutyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-dihydrochloride 7-amine; (3S)-3-amino-4-(3,5-dichloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-2- dihydrochloride il)butan-1-ol; 2-[(2S)-2-aminopropyl]-3-bromo-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile hydrochloride; 2-[(2S)-2-aminopropyl]-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile hydrochloride; 2-[(2S)-2-aminopropyl]-5-chloro-3-cyclopropyl-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(2S)-2-aminopropyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminopropyl]-3-methyl-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile formate; 2-[(1S)-1-aminoethyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(1R)-1-aminoethyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; (2R)-2-amino-3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)propan dihydrochloride -1-ol; 2-[(2S)-2-amino-3-fluoropropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride ; 2-[(2S)-2-aminopropyl]-3-chloro-5-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; 2-[(2S)-2-amino-4-methylpentyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- hydrochloride amine; 2-[(2S)-2-amino-4-methylpentyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] hydrochloride pyridin-7-amine; 2-[(2S)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- hydrochloride amine; 2-[(2R)-2-amino-3-(trifluoromethoxy)propyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2] formate -b]pyridin-7-amine; (2R)-3-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) formate -2-[(trifluoromethyl)amino]propan-1-ol; 2-[(2S)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] dihydrochloride pyridin-7-amine; 2-[(2S)-2-amino-3-fluoropropyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-dihydrochloride 7-amine; 2-[(2S)-2-amino-4-methylpentyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] hydrochloride pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] dihydrochloride pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] dihydrochloride pyridin-7-amine; (2R)-2-amino-3-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-dihydrochloride 2-yl)propan-1-ol; 2-[(2R)-2-aminobut-3-en-1-yl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3 dihydrochloride, 2-b]pyridin-7-amine; 2-[(2S)-2-aminobutyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-amino-4-fluorobutyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- hydrochloride amine; 2-[(2S)-2-aminobutyl]-5-chloro-3-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2R)-2-amino-3-fluoropropyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- hydrochloride amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-3-cyclopropyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- hydrochloride amine; 2-[(2S)-2-aminobutyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- hydrochloride amine; 2-[(2S)-2-amino-4-methylpentyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-hydrochloride 7-amine; 2-[(2S)-2-amino-4-methylpentyl]-5-chloro-3-cyclopropyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] hydrochloride pyridin-7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine dihydrochloride ; 2-[(2S)-2-aminobutyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7-amine hydrochloride; 2-[(2S)-2-aminobutyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-aminobutyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- formate amine; 2-[(2S)-2-aminobutyl]-5-chloro-3-cyclopropyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- hydrochloride amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-3-cyclopropyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] dihydrochloride pyridin-7-amine; 2-[(2S)-2-amino-4-fluorobutyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] dihydrochloride pyridin-7-amine; (3S)-3-amino-4-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-dihydrochloride 2-yl)butan-1-ol; 2-[(2R)-2-amino-3-fluoropropyl]-3,5-dichloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-dihydrochloride 7-amine; 2-[(2R)-2-amino-3-fluoropropyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; 2-[(2S)-2-amino-4-fluorobutyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; 2-[(2S)-2-amino-4-fluorobutyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2R)-2-amino-3-fluoropropyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-amino-4-fluorobutyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride ; 2-[(2S)-2-aminopropyl]-5-chloro-3-cyclopropyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b]pyridin-7- hydrochloride amine; 2-[(2S)-2-amino-4-fluorobutyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; 2-[(2S)-2-amino-4-fluorobutyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine dihydrochloride; 2-[(2S)-2-amino-4-fluorobutyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] formate pyridin-7-amine; (3S)-3-amino-4-(3-bromo-5-chloro-7-{[(2-fluorophenyl)methyl]amino}thieno[3,2-b]pyridin-2-yl)butan-dihydrochloride 1-ol; 2-[(2S)-2-aminopropyl]-3-bromo-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile formate; 2-[(2S)-2-aminopropyl]-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-3,5-dicarbonitrile formate; (3S)-3-amino-4-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) formate butanenitrile; 2-[(2R)-2-amino-3-(methylsulfanyl)propyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-dihydrochloride 7-amine; (3S)-3-amino-4-(5-chloro-3-methyl-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) dihydrochloride butanenitrile; (3S)-3-amino-4-(3,5-dichloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)butanenitrile dihydrochloride; 2-[(2S)-2-amino-4,4-difluorobutyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-dihydrochloride 7-amine; 2-[(2R)-2-amino-3-(methanesulfonyl)propyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-dihydrochloride 7-amine; 2-[(2S)-2-aminopropyl]-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile formate; 2-[(2S)-2-aminopropyl]-5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-3-carbonitrile formate; (3S)-3-amino-4-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)butanenitrile dihydrochloride ; 2-[(2S)-2-aminopropyl]-3-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridine-5-carbonitrile formate; 2-[(2R)-2-amino-3-(methanesulfonyl)propyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7 dihydrochloride -amine; 2-[(2R)-2-amino-3-(methylsulfanyl)propyl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7 hydrochloride -amine; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-D-alanine dihydrochloride; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N,N-dimethyl-D- dihydrochloride alaninamide; 2-[(2R)-2-amino-3-(methanesulfonyl)propyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridine dihydrochloride -7-amine; 2-[(2R)-2-amino-3-(methylsulfanyl)propyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridine dihydrochloride -7-amine; 2-[(2R)-2-aminobut-3-en-1-yl]-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7- formate amine; 3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)-N-(2-fluorophenyl)-D dihydrochloride -alaninamide; 3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)-D-alanine dihydrochloride; 3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)-N-phenyl-D-alaninamide hydrochloride; 2-[(2R)-2-aminobut-3-yn-1-yl]-3-methyl-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b] dihydrochloride pyridin-7-amine; 3-(3,5-dichloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)-N-(2-fluorophenyl)-D dihydrochloride -alaninamide; 2-[(2R,3S)-2-amino-3-fluorobutyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2- dihydrochloride b]pyridin-7-amine; 2-[(2R,3S)-2-amino-3-fluorobutyl]-5-chloro-3-methyl-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-dihydrochloride 7-amine; (2S)-2-amino-1-(3,5-dichloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)propan-dihydrochloride 1-ol; 2-[(2R,3S)-2-amino-3-fluorobutyl]-5-chloro-3-methyl-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2- dihydrochloride b]pyridin-7-amine; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(5-fluoro-1,3-thiazol-2-yl)methyl]-3-methylthieno[3,2-b]pyridine dihydrochloride -7-amine; 2-[(2S)-2-amino-1-fluoropropyl]-3,5-dichloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine formate; methyl 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-D-alaninate dihydrochloride; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N-(4-cyanophenyl)- hydrochloride D-alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N-pyridin-2-yl- hydrochloride D-alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N-pyrazin-2-yl- hydrochloride D-alaninamide; 2-[(2S)-2-aminopropyl]-5-chloro-N-[(furan-2-yl)methyl]-3-methoxythieno[3,2-b]pyridin-7-amine dihydrochloride; 5-chloro-N-[(furan-2-yl)methyl]-3-methoxythieno[3,2-b]pyridin-7-amine hydrochloride; 5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-3-ol hydrochloride; 2-[(2S)-2-aminopropyl]-5-chloro-3-(difluoromethoxy)-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7-amine formate; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N-pyridin-4-yl- hydrochloride D-alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N-methyl-N-phenyl- hydrochloride D-alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N-(4-methylphenyl)- hydrochloride D-alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N-(3-chlorophenyl)- hydrochloride D-alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2- b]pyridin-2-yl)-N-(3-methoxyphenyl)- hydrochloride D-alaninamide; 3-(5-chloro-7-{[(furan-2-yl)methyl]amino}-3-methylthieno[3,2-b]pyridin-2-yl)-N-(1-methyl-1H) hydrochloride -pyrazol-5-yl)-D-alaninamide; 2-(1-aminopropan-2-yl)-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine formate; 2-[(2R,3S)-3-aminobutan-2-yl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7 dihydrochloride -amine; 2-[(2S,3S)-3-aminobutan-2-yl]-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7 dihydrochloride -amine; 2-(2-aminoethyl)-5-chloro-N-[(furan-2-yl)methyl]-3-methylthieno[3,2-b]pyridin-7-amine formate; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) dihydrochloride propan-1-ol; 2-[(2S)-2-amino-1-fluoropropyl]-3-bromo-5-chloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) dihydrochloride propan-1-ol; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) dihydrochloride propan-1-one; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl) dihydrochloride propan-1-one; 2-[(2S)-2-amino-1-fluoropropyl]-3-bromo-5-chloro-N-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridin-7- dihydrochloride amine; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-dihydrochloride 2-yl)propan-1-ol; (2S)-2-amino-1-(3-bromo-5-chloro-7-{[(1,3-thiazol-2-yl)methyl]amino}thieno[3,2-b]pyridin-dihydrochloride 2-yl)propan-1-one; 2-[(2S)-2-amino-1-fluoropropyl]-3-bromo-5-chloro-N-[(1,3-thiazol-2-yl)methyl]thieno[3,2-b] dihydrochloride pyridin-7-amine; (2R)-2-amino-3-(5-chloro-7-{[(thiophen-2-yl)methyl]amino}thieno[3,2-b]pyridin-2-yl)propan-1- formate hello; N2-[(2S)-2-aminopropyl]-5-chloro-3-methyl-N7-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridine-2,7-diamine hydrochloride; N2-[(2R)-2-aminopropyl]-5-chloro-3-methyl-N7-[(thiophen-2-yl)methyl]thieno[3,2-b]pyridine-2,7-diamine hydrochloride; (2R,3R)-3-amino-4-(3-bromo-5-chloro-7-{[(furan-2-yl)methyl]amino}thieno[3,2-b]pyridin-2- hydrochloride il)butan-2-ol; and 2-[(2R)-2-aminobut-3-yn-1-yl]-3,5-dichloro-N-[(furan-2-yl)methyl]thieno[3,2-b]pyridine dihydrochloride -7-amine; wherein the salt form of the compound is selected from the group consisting of a salt, hydrate, solvate and tautomeric form thereof. 9. A method for treating familial dysautonomia, comprising administering to an individual in need thereof an effective amount of a compound as defined in claim 1; Use of the compound as defined in any one of claims 1 to 6 in the preparation of a pharmaceutical composition, medicine or kit for treating familial dysautonomia. 10. A method for treating familial dysautonomia, comprising administering to an individual in need thereof an effective amount of the compound according to claim 7; Use of the compound as defined in any one of claims 1 to 7 in the preparation of a pharmaceutical composition, medicament or kit for treating familial dysautonomia. 11. Method for treating familial dysautonomia, characterized by the fact that it comprises administering to an individual in need thereof an effective amount of compound, as defined in claim 8; Use of the compound, as defined in any one of claims 1 to 6 and 8, in the preparation of a pharmaceutical composition, medicine or kit for treating familial dysautonomia. 12. Pharmaceutical composition, characterized by the fact that it comprises an effective amount of compound, as defined in claim 1, in admixture with a pharmaceutically acceptable excipient. 13. Pharmaceutical composition, characterized by the fact that it comprises an effective amount of compound, as defined in claim 7, in admixture with a pharmaceutically acceptable excipient. 14. Pharmaceutical composition, characterized by the fact that it comprises an effective amount of compound, as defined in claim 8, in admixture with a pharmaceutically acceptable excipient. 15. Invention, which is in any form of its embodiments or in any category of claim that can be claimed, for example, product, or process, or use covered by the object initially described, disclosed, or illustrated in the patent application, Use of the compound, as defined in any one of claims 1 to 8, or of a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition, medicament or kit for treating a disease or a condition in a subject in need thereof and/or to increase the expression of the IKBKAP protein, the level of the IKBKAP protein or the splicing of the pre-mRNA of the IKBKAP gene, Kit, comprising a compound, as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, Ex vivo method for improving the splicing of the pre-mRNA of the IKBKAP gene or increasing the full-length IKBKAP mRNA in a cell, comprising contacting the gene or the cell with a compound, as defined in any one of claims claims 1 to 8, or a pharmaceutically acceptable salt thereof, An ex vivo method for increasing the expression or level of the IKBKAP protein in a cell, comprising contacting the cell with a compound provided herein, that is, a compound as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.