Compounds for treatment of spinal cerebellar ataxia type 3

Abstract

One aspect of the present specification relates to a compound for improving pre-mRNA splicing in a cell. In particular, another aspect of the present specification relates to substituted heteroaryl compounds, forms and pharmaceutical compositions thereof, and methods for treating or ameliorating spinal cerebellar ataxia type 3 (SCA3) (also referred to as Mahade-Joseph Disease (MJD)).

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is an international application claiming the benefit of U.S. Provisional Patent Application No. 63 / 354,339, filed on June 22, 2022, entitled “Compounds for the Treatment of Spinocerebellar Ataxia Type 3,” the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] One aspect of the present specification relates to compounds for improving pre-mRNA (pre mRNA) splicing in cells. Specifically, another aspect of the present specification relates to substituted heteroaryl compounds, forms thereof and pharmaceutical compositions, and methods for treating or improving spinocerebellar ataxia type 3 (SCA3) (also known as Machado-Joseph disease (MJD)). Background Art

[0004] Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a rare autosomal dominant disorder characterized by progressive ataxia. SCA3 is the most common dominant ataxia worldwide. Although the exact number of patients is unknown, it is estimated that the average prevalence is 1-5 / 100,000, with higher incidence in China, Portugal, Brazil, the Netherlands, Germany, and Japan. It is also significant in the United States, where SCA3 accounts for approximately 21% of dominant ataxias. SCA3 has three subtypes based on age of onset: subtype 1 (early onset, 10-30 years), subtype 2 (mid-onset, 30-50 years), and subtype 3 (late onset, 50-70 years). People with SCA3 usually survive 10 to 20 years after the onset of symptoms. Symptoms include slowly progressive loss of coordination of the arms and legs, a staggering gait that may be mistaken for intoxication, difficulty speaking and swallowing, impaired eye movements, sometimes with double vision or proptosis, and leg spasticity. Some people experience persistent muscle contractions that cause twisting of the body and limbs, repetitive movements, and abnormal postures. Others may develop facial or tongue twitches, neuropathy, or problems with urination and the autonomic nervous system.

[0005] SCA3 is caused by an unstable expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat sequence in the ATXN3 gene, which is transcribed into mutant ATXN3 (mATXN3) mRNA. This expansion of mATXN3 mRNA leads to the production of mutant ataxia-3 (ATXN3) containing a polyglutamine (polyQ) region. Both mATXN3 mRNA and mutant ATXN3 protein disrupt several cellular processes, leading to neurodegeneration in the cerebellum, brainstem, and other related brain regions.

[0006] In healthy people, the number of CAG repeats in ATXN3 mRNA ranges from 10 to 45, while in SCA3 patients it can vary between 61 and 87. CAG repeat numbers between 45 and 60 are associated with incomplete penetrance of the disease. As demonstrated in other polyQ diseases, the number of repeats in SCA3 patients is inversely correlated with the age of onset.

[0007] In several preclinical models of SCA3, reduction in ATXN3 protein levels improved SCA3 pathology, confirming the importance of reducing ATNX3 as a therapeutic target for improving downstream pathogenic effects. The present specification relates to the use of a compound of formula (I) or a form or composition thereof for treating SCA3. These compounds induce exon 4 skipping of ATXN3 pre-mRNA during splicing. Exon 4 skipping of ATXN3 mRNA changes the open reading frame (ORF) and produces a premature stop codon (PTC) in the ATXN3 exon 4 skipped mRNA (ΔE4 mRNA). It has been shown that this exon skipping splicing event can reduce gene expression by producing mRNA with a premature stop codon, thereby signaling that the mRNA is degraded rather than translated into protein. Similarly, the ATXN3ΔE4 mRNA produced in the presence of these compounds will undergo mRNA degradation, resulting in reduced ATXN3 mRNA levels, thereby resulting in reduced ATXN3 protein.

[0008] To date, there are no disease-modifying therapies available for SCA3, and there is a need for improved methods and compositions for treating SCA3 and its associated symptoms. The compounds described herein represent potential ATXN3 pre-mRNA splicing compounds that may be used as disease-modifying therapies for SCA3.

[0009] All other documents mentioned herein are incorporated by reference into this application as if fully set forth herein. Summary of the invention

[0010] One aspect of the present disclosure includes compounds of formula (I) or forms thereof:

[0011]

[0012] Among them, A, A′, L, R B , R 1 , R 2 , R 3 and Ring Q are as defined herein.

[0013] One aspect of the disclosure includes a method of using a compound of formula (I) or a form or composition thereof to treat or improve SCA3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form or composition thereof.

[0014] One aspect of the disclosure includes use of a compound of formula (I) or a form thereof for treating or improving SCA3 in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof to the subject.

[0015] One aspect of the present specification includes the use of a compound of formula (I) or a form thereof in the preparation of a medicament for treating or ameliorating SCA3 in a subject in need thereof, comprising administering an effective amount of the medicament to the subject. DETAILED DESCRIPTION

[0016] One aspect of the present disclosure relates to compounds of formula (I) or forms thereof:

[0017]

[0018] in:

[0019] A is selected from CR A and N;

[0020] A' is selected from S and NR A’ The group composed of;

[0021] L is selected from the group consisting of CH2 and CD2;

[0022] R A Selected from hydrogen, halogen, C 1-6 Alkyl and C 3-8 A group consisting of cycloalkyl groups;

[0023] R A’ Selected from hydrogen, C 1-4 Alkyl and halo-C 1-4 A group consisting of alkyl groups;

[0024] R B Selected from hydrogen and C 1-6 A group consisting of alkyl groups;

[0025] R 1 Selected from phenyl, heteroaryl, C 3-8 Cycloalkyl, CO2C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 The group consisting of alkynyl groups;

[0026] Wherein heteroaryl is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S;

[0027] Among them C 3-8 Cycloalkyl is a saturated or partially unsaturated monocyclic or bicyclic ring system;

[0028] Among them, phenyl, heteroaryl and C 3-8 The cycloalkyl group is replaced by 0, 1, 2, 3 or 4 independently selected R 1a Substituent substitution,

[0029] R 1a Selected from cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, deuterated-C 1-6 Alkyl and C 1-6 A group consisting of alkoxy groups;

[0030] R 2 Selected from hydrogen, cyano, halogen, C 2-6 -Alkynyl, C 1-6 -alkoxy-C 2-6 -Alkynyl and hydroxy-C 2-6 - a group consisting of alkynyl;

[0031] R 3 Selected from hydrogen, cyano, halogen, hydroxyl, SH, C 1-6 Alkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, C 1-6 Alkoxy, halo-C 1-6 Alkoxy, thio-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy-C 2-6 Alkynyl, Hydroxyl-C 2-6 Alkynyl, (CH3)3Si-C 2-6 Alkynyl, Heteroaryl-C 2-6 Alkynyl, C 3-8 The group consisting of cycloalkyl, phenyl and heteroaryl,

[0032] wherein heteroaryl is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S, and

[0033] Among them C 3-8 Cycloalkyl, phenyl and heteroaryl are each independently substituted with 0, 1, 2, 3 or 4 independently selected R 3a Substituent substitution;

[0034] R 3a Selected from cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, deuterated-C 1-6 Alkyl and C 1-6 A group consisting of alkoxy groups;

[0035] Ring Q is

[0036]

[0037] R 4 Selected from hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy and halo-C 1-6 A group consisting of alkoxy groups;

[0038] R 5 Selected from amino, C 1-4 Alkyl-amino and (C 1-4 alkyl)2-amino group;

[0039] W is selected from CH2, CD2, CH-R W , CD-R W , C(R W )2 and C(O);

[0040] X is selected from CH2, CD2, CH-R X , CD-R X , C(R X )2. CH, CD, CR X , C=CH2, C=CD2, C=C(R X )2、C(O), NH, NC 1-4 the group consisting of alkyl, N-phenyl, O, S, S(O) and SO2;

[0041] Y is selected from CH2, CD2, CH-R Y , CD-R Y , C(R Y )2. CH, CD, CR Y , C=CH2, C=CD2, C=C(R Y )2, N-phenyl, O, S, S(O) and SO2;

[0042] Z is selected from CH2, CD2, CH-R Z , CD-R Z , C(R Z )2. CH, CD, CR Z , NH, NC 1-4 the group consisting of alkyl, N-phenyl, O, S, S(O) and SO2;

[0043] Each R W , R X , R Y , R Z Independently selected from halogen, hydroxyl, C 1-6 Alkyl, halo-C1-6 Alkyl, C 1-6 Alkoxy, halo-C 1-6 Alkoxy, amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, CO2H, CO2C 1-6 Alkyl, C(O)NH2, C(O)N(C 1-6 alkyl)2, C(O)-heterocyclyl and C(O)NH-phenyl, and each R W , R X , R Y , R Z may combine to form a carbocyclic or heterocyclic ring;

[0044] n is selected from the group consisting of 0, 1, 2, and 3; and

[0045] When the valence permits, independently represent a single bond or a double bond;

[0046] The compound is in the form of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form thereof.

[0047] One aspect includes compounds of formula (I), wherein the compound is a compound of formula (Ia) or a form thereof

[0048]

[0049] Another aspect includes compounds of formula (Ia) or forms thereof, wherein

[0050] L is CH2 or CD2;

[0051] R A It is hydrogen;

[0052] R B is hydrogen or CH3; and

[0053] R 2 It is Cl or CN.

[0054] One aspect includes compounds of formula (I), wherein the compound is a compound of formula (Ib) or a form thereof

[0055]

[0056] Another aspect includes compounds of formula (Ib) or forms thereof, wherein

[0057] L is CH2;

[0058] R B is hydrogen; and

[0059] R 2 It is Cl.

[0060] One aspect includes compounds of formula (I), wherein the compound is a compound of formula (Ic) or a form thereof

[0061]

[0062] Another aspect includes compounds of formula (Ic) or forms thereof, wherein

[0063] L is CH2;

[0064] R A It is hydrogen;

[0065] R A’ is CH3 or CHF2;

[0066] R B is hydrogen; and

[0067] R 2 It is Cl.

[0068] One aspect includes compounds of formula (I), wherein the compound is a compound of formula (Id) or a form thereof

[0069]

[0070] Another aspect includes compounds of formula (Id) or forms thereof, wherein

[0071] L is CH2;

[0072] R A’ It is CHF2;

[0073] R B is hydrogen; and

[0074] R 2 It is Cl.

[0075] One aspect includes compounds of formula (I), wherein A is selected from CR A and N groups.

[0076] Another aspect includes compounds of formula (I) wherein A is CR A .

[0077] Another aspect includes compounds of formula (I) wherein A is N.

[0078] One aspect includes compounds of formula (I), wherein A' is selected from S and NR A’ Composed of groups.

[0079] Another aspect includes compounds of formula (I) wherein A' is S.

[0080] Another aspect includes compounds of formula (I) wherein A' is NR A’ .

[0081] One aspect includes compounds of formula (I), wherein L is selected from the group consisting of CH2 and CD2.

[0082] One aspect includes compounds of formula (I) wherein R A Selected from hydrogen, halogen, C 1-6 Alkyl and C 3-8 A group consisting of cycloalkyl.

[0083] Another aspect includes compounds of formula (I) wherein R A It's hydrogen.

[0084] One aspect includes compounds of formula (I) wherein R A’ Selected from hydrogen, C 1-4 Alkyl and halo-C 1-4 Alkyl group.

[0085] Another aspect includes compounds of formula (I) wherein R A’ Selected from the group consisting of CH3 and CHF2.

[0086] One aspect includes compounds of formula (I) wherein R B Selected from hydrogen and C 1-6 Alkyl group.

[0087] Another aspect includes compounds of formula (I) wherein R B Selected from the group consisting of hydrogen and CH3.

[0088] One aspect includes compounds of formula (I) wherein R 1 Selected from phenyl, heteroaryl, C 3-8 Cycloalkyl, CO2C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 The group consisting of alkynyl groups;

[0089] Wherein heteroaryl is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S;

[0090] Among them C 3-8 Cycloalkyl is a saturated or partially unsaturated monocyclic or bicyclic ring system;

[0091] Among them, phenyl, heteroaryl and C 3-8 The cycloalkyl group is replaced by 0, 1, 2, 3 or 4 independently selected R 1a Substituent substitution.

[0092] Another aspect includes compounds of formula (I) wherein R 1 is 0, 1, 2, 3 or 4 independently selected R 1a Substituents: phenyl substituted.

[0093] Another aspect includes compounds of formula (I) wherein R 1 It is an unsubstituted phenyl group.

[0094] Another aspect includes compounds of formula (I) wherein R 1 is an R 1a Substituents: phenyl substituted.

[0095] Another aspect includes compounds of formula (I) wherein R 1 is 0, 1, 2, 3 or 4 independently selected R 1a Substituent-substituted heteroaryl,

[0096] Wherein heteroaryl is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S;

[0097] Another aspect includes compounds of formula (I) wherein R 1 is an unsubstituted heteroaryl group,

[0098] The heteroaryl group is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S.

[0099] Another aspect includes compounds of formula (I) wherein R 1 is a heteroaryl group selected from the group consisting of 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 the heteroaryl group is replaced by 0, 1, 2, 3, or 4 independently selected R 1a Substituent substitution.

[0100] Another aspect includes compounds of formula (I) wherein R 1 is a heteroaryl group selected from furanyl and thienyl, wherein the heteroaryl group is substituted by 0, 1, 2, 3 or 4 independently selected R 1a Substituent substitution.

[0101] Another aspect includes compounds of formula (I) wherein R 1is an unsubstituted heteroaryl selected from the group consisting of furanyl, thienyl, 1,3-thiazolyl, 1,3-oxazolyl and pyridinyl.

[0102] Another aspect includes compounds of formula (I) wherein R 1 is a heteroaryl radical selected from the group consisting of 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, isoxazol-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, 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 quinolin-4-yl, wherein the heteroaryl is replaced by 0, 1, 2, 3 or 4 independently selected R 1a Substituent substitution.

[0103] Another aspect includes compounds of formula (I) wherein R 1 is a heteroaryl group selected from furan-2-yl, thiophen-2-yl, thiophen-3-yl, 1,3-thiazol-2-yl, 1,3-oxazol-2-yl and pyridin-4-yl, wherein the heteroaryl group is substituted by 0, 1, 2, 3 or 4 independently selected R 1a Substituent substitution.

[0104] Another aspect includes compounds of formula (I) wherein R 1 is an unsubstituted heteroaryl selected from the group consisting of furan-2-yl, thien-2-yl, thien-3-yl, 1,3-thiazol-2-yl, 1,3-oxazol-2-yl and pyridin-4-yl.

[0105] One aspect includes compounds of formula (I) wherein R 1 It is CO2C 1-6 alkyl.

[0106] Another aspect includes compounds of formula (I) wherein R 1 It is CO2CH3.

[0107] One aspect includes compounds of formula (I) wherein R 1It is C 3-8 Cycloalkyl, wherein C 3-8 Cycloalkyl is composed of 0, 1, 2, 3 or 4 independently selected R 1a Substituents are substituted saturated or partially unsaturated monocyclic or bicyclic ring systems.

[0108] Another aspect includes compounds of formula (I) wherein R 1 yes

[0109] One aspect includes compounds of formula (I) wherein R 1 It is C 2-6 Alkenyl.

[0110] Another aspect includes compounds of formula (I) wherein R 1 yes

[0111] One aspect includes compounds of formula (I) wherein R 1 It is C 2-6 Alkynyl.

[0112] Another aspect includes compounds of formula (I) wherein R 1 yes

[0113] Another aspect includes compounds of formula (I) wherein R 1 It is phenyl, CO2CH3,

[0114] One aspect includes compounds of formula (I) wherein R 1a Selected from cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, deuterated-C 1-6 Alkyl and C 1-6 A group consisting of alkoxy groups.

[0115] Another aspect includes compounds of formula (I) wherein R 1a It's a halogen.

[0116] Another aspect includes compounds of formula (I) wherein R 1a is a halogen selected from fluorine, chlorine, bromine and iodine.

[0117] Another aspect includes compounds of formula (I) wherein R 1a It's fluorine.

[0118] One aspect includes compounds of formula (I) wherein R 2 Selected from hydrogen, cyano, halogen, C 2-6 Alkynyl, C 1-6 Alkoxy-C 2-6Alkynyl and Hydroxyl-C 2-6 Alkyne group.

[0119] Another aspect includes compounds of formula (I) wherein R 2 It's cyano.

[0120] Another aspect includes compounds of formula (I) wherein R 2 It's a halogen.

[0121] Another aspect includes compounds of formula (I) wherein R 2 is a halogen selected from fluorine, chlorine, bromine and iodine.

[0122] Another aspect includes compounds of formula (I) wherein R 2 It's chlorine.

[0123] One aspect includes compounds of formula (I) wherein R 3 Selected from hydrogen, cyano, halogen, hydroxyl, SH, C 1-6 Alkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, C 1-6 Alkoxy, halo-C 1-6 Alkoxy, thio-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy-C 2-6 Alkynyl, Hydroxyl-C 2-6 Alkynyl, (CH3)3Si-C 2-6 Alkynyl, Heteroaryl-C 2-6 Alkynyl, C 3-8 The group consisting of cycloalkyl, phenyl and heteroaryl,

[0124] wherein the heteroaryl group is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S, and

[0125] Among them C 3-8 Cycloalkyl, phenyl and heteroaryl are each independently substituted with 0, 1, 2, 3 or 4 independently selected R 3a Substituent substitution.

[0126] Another aspect includes compounds of formula (I) wherein R 3 Selected from hydrogen, cyano, halogen, C 1-6 Alkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, halo-C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy-C2-6 Alkynyl, Hydroxyl-C 2-6 Alkynyl, (CH3)3Si-C 2-6 Alkynyl, Heteroaryl-C 2-6 Alkynyl, C 3-8 A group consisting of a cycloalkyl group and a phenyl group,

[0127] wherein the heteroaryl group is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S, and

[0128] Among them C 3-8 Cycloalkyl, phenyl and heteroaryl are independently substituted by 0, 1, 2, 3 or 4 independently selected R 3a Substituent substitution.

[0129] Another aspect includes compounds of formula (I) wherein R 3 It's hydrogen.

[0130] Another aspect includes compounds of formula (I) wherein R 3 It's cyano.

[0131] Another aspect includes compounds of formula (I) wherein R 3 It's a halogen.

[0132] Another aspect includes compounds of formula (I) wherein R 3 is a halogen selected from fluorine, chlorine, bromine and iodine.

[0133] Another aspect includes compounds of formula (I) wherein R 3 It's chlorine.

[0134] Another aspect includes compounds of formula (I) wherein R 3 It's bromine.

[0135] Another aspect includes compounds of formula (I) wherein R 3 It's iodine.

[0136] Another aspect includes compounds of formula (I) wherein R 3 is a C selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl 1-6 alkyl.

[0137] Another aspect includes compounds of formula (I) wherein R 3 It's methyl.

[0138] Another aspect includes compounds of formula (I) wherein R 3 It is ethyl.

[0139] Another aspect includes compounds of formula (I) wherein R 3is a halogenated-C selected from the group consisting of CH2F, CHF2, CF3 and CH2CH2F 1-6 alkyl.

[0140] Another aspect includes compounds of formula (I) wherein R 3 is a hydroxyl-C selected from CH2OH 1-6 alkyl.

[0141] Another aspect includes compounds of formula (I) wherein R 3 is a halogenated-C selected from CH2OCHF2 1-6 Alkoxy.

[0142] Another aspect includes compounds of formula (I) wherein R 3 is selected from CH=CH2 and CH=C=CH2 2-6 Alkenyl.

[0143] Another aspect includes compounds of formula (I) wherein R 3 It is freedom to choose Composed of group C 2-6 Alkynyl.

[0144] Another aspect includes compounds of formula (I) wherein R 3 It is freedom to choose Composed of the group hydroxy-C 2-6 Alkynyl.

[0145] Another aspect includes formula (I), wherein R 3 Is selected from (CH3)3Si-C 2-6 Alkynyl.

[0146] Another aspect includes formula (I), wherein R 3 Is selected from Heteroaryl-C 2-6 Alkynyl, wherein the heteroaryl ring is replaced by 0, 1, 2, 3 or 4 independently selected R 3a Substituent substitution.

[0147] Another aspect includes compounds of formula (I) wherein R 3 is a C selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl 3-8 Cycloalkyl, which is composed of 0, 1, 2, 3 or 4 independently selected R 3a Substituent substitution.

[0148] Another aspect includes compounds of formula (I) wherein R 3 is 0, 1, 2, 3 or 4 independently selected R 3a The substituent is substituted cyclopropyl.

[0149] Another aspect includes compounds of formula (I) wherein R 3 is an unsubstituted cyclopropyl group.

[0150] Another aspect includes compounds of formula (I) wherein R 3 is 0, 1, 2, 3 or 4 independently selected R 3a Substituents: phenyl substituted.

[0151] Another aspect includes compounds of formula (I) wherein R 3 It is an unsubstituted phenyl group.

[0152] One aspect includes compounds of formula (I) wherein R 3a Selected from cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, deuterated-C 1-6 Alkyl and C 1-6 A group consisting of alkoxy groups.

[0153] Another aspect includes compounds of formula (I) wherein R 3a Selected from the group consisting of Cl and OCH3.

[0154] Another aspect includes compounds of formula (I) wherein R 3 Selected from hydrogen, cyano, Cl, Br, I, CH3, CH2CH3, CHF2, CF3, CH2CH2F, CH2OH, CH2OCHF2, CH=CH2, CH=C=CH2, cyclopropyl, phenyl,

[0155] The group composed of.

[0156] One aspect includes compounds of formula (I) wherein ring Q is

[0157]

[0158] and any stereoisomers thereof.

[0159] One aspect includes compounds of formula (I) wherein R 4 Selected from hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy and halo-C 1-6 A group consisting of alkoxy groups.

[0160] Another aspect includes compounds of formula (I) wherein R 4 Selected from the group consisting of hydrogen, halogen and hydroxyl.

[0161] Another aspect includes compounds of formula (I) wherein R 4 Selected from hydrogen.

[0162] Another aspect includes compounds of formula (I) wherein R 4 It's a halogen.

[0163] Another aspect includes compounds of formula (I) wherein R 4 is a halogen selected from fluorine, chlorine, bromine and iodine.

[0164] Another aspect includes compounds of formula (I) wherein R 4 It's fluorine.

[0165] Another aspect includes compounds of formula (I) wherein R 4 It's hydroxyl.

[0166] One aspect includes compounds of formula (I) wherein R 5 Selected from amino, C 1-4 Alkyl-amino and (C 1-4 The group consisting of alkyl) 2-amino.

[0167] Another aspect includes compounds of formula (I) wherein R 5 It's amino.

[0168] Another aspect includes compounds of formula (I) wherein R 5 Yes (C 1-4 Alkyl) 2-amino.

[0169] Another aspect includes compounds of formula (I) wherein R 5 It is N2(CH3).

[0170] Another aspect includes compounds of formula (I) wherein R 5 It is C 1-4 Alkyl-amino.

[0171] Another aspect includes compounds of formula (I) wherein R 5 It is NH(CH3).

[0172] One aspect includes compounds of formula (I), wherein W is selected from CH2, CD2, CH-R W , CD-R W , C(R W )2 and C(O) group.

[0173] Another aspect includes compounds of formula (I) wherein W is CH2.

[0174] Another aspect includes compounds of formula (I) wherein W is CD2.

[0175] Another aspect includes compounds of formula (I) wherein W is C(O).

[0176] One aspect includes compounds of formula (I), wherein X is selected from CH2, CD2, CH-R X , CD-R X , C(R X )2. CH, CD, CR X , C=CH2, C=CD2, C=C(R X )2、C(O), NH, NC 1-4 The group consisting of alkyl, N-phenyl, O, S, S(O) and SO2.

[0177] Another aspect includes compounds of formula (I) wherein X is CH2.

[0178] Another aspect includes compounds of formula (I) wherein X is CH-R X .

[0179] Another aspect includes compounds of formula (I) wherein X is C(R X )2.

[0180] Another aspect includes compounds of formula (I) wherein X is CH.

[0181] Another aspect includes compounds of formula (I) wherein X is CD.

[0182] Another aspect includes compounds of formula (I) wherein X is CR X .

[0183] Another aspect includes compounds of formula (I) wherein X is C(O).

[0184] Another aspect includes compounds of formula (I) wherein X is NH.

[0185] Another aspect includes compounds of formula (I) wherein X is O.

[0186] One aspect includes compounds of formula (I), wherein Y is selected from CH2, CD2, CH-R Y , CD-R Y , C(R Y )2. CH, CD, CR Y , C=CH2, C=CD2, C=C(R Y )2, N-phenyl, O, S, S(O) and SO2.

[0187] Another aspect includes compounds of formula (I) wherein Y is CH2.

[0188] Another aspect includes compounds of formula (I) wherein Y is CD2.

[0189] Another aspect includes compounds of formula (I) wherein Y is CH-R Y .

[0190] Another aspect includes compounds of formula (I) wherein Y is C(R Y )2.

[0191] Another aspect includes compounds of formula (I) wherein Y is CH.

[0192] Another aspect includes compounds of formula (I) wherein Y is CD.

[0193] Another aspect includes compounds of formula (I) wherein Y is CR Y .

[0194] Another aspect includes compounds of formula (I) wherein Y is C=CH2.

[0195] Another aspect includes compounds of formula (I) wherein Y is O.

[0196] Another aspect includes compounds of formula (I) wherein Y is NC 1-4 Alkyl, where C 1-4 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

[0197] Another aspect includes compounds of formula (I) wherein Y is N-CH3.

[0198] One aspect includes compounds of formula (I) wherein Z is selected from CH2, CD2, CH-R Z , CD-R Z , C(R Z )2. CH, CD, CR Z , NH, NC 1-4 The group consisting of alkyl, N-phenyl, O, S, S(O) and SO2.

[0199] Another aspect includes compounds of formula (I) wherein Z is CH2.

[0200] Another aspect includes compounds of formula (I) wherein Z is CD2.

[0201] Another aspect includes compounds of formula (I) wherein Z is CH-R Z .

[0202] Another aspect includes compounds of formula (I) wherein Z is C(R Z )2.

[0203] Another aspect includes compounds of formula (I) wherein Z is NH.

[0204] Another aspect includes compounds of formula (I) wherein Z is N-phenyl.

[0205] Another aspect includes compounds of formula (I) wherein Z is O.

[0206] One aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z Independently selected from halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy, halo-C 1-6 Alkoxy, amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, CO2H, CO2C 1-6 Alkyl, C(O)NH2, C(O)N(C 1-6 alkyl)2, C(O)-heterocyclyl and C(O)NH-phenyl, and each R W , R X , R Y , R Z They may be combined to form a carbocyclic or heterocyclic ring.

[0207] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z and iodine and fluorine are independently halogens selected from the group consisting of fluorine, chlorine, bromine and iodine.

[0208] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z is independently fluorine.

[0209] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z are independently hydroxyl.

[0210] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z Independently C 1-6 alkyl.

[0211] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z is independently methyl.

[0212] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z Independently C 1-6 Alkoxy.

[0213] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z is independently methoxy.

[0214] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z independently CO2H.

[0215] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z Independently CO2C 1-6 alkyl.

[0216] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z independently CO2CH2CH3.

[0217] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z is independently C(O)NH2.

[0218] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z independently C(O)N(C 1-6 Alkyl)2.

[0219] Another aspect includes compounds of formula (I) wherein each R W , RX , R Y , R Z independently C(O)N(CH3)2.

[0220] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z is independently C(O)-heterocyclyl.

[0221] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z Independently

[0222] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z is independently C(O)NH-phenyl.

[0223] Another aspect includes compounds of formula (I) wherein each R W , R X , R Y , R Z Independently

[0224] One aspect includes compounds of formula (I), wherein n is selected from the group consisting of 0, 1, 2, and 3.

[0225] Another aspect includes compounds of formula (I) wherein n is zero.

[0226] Another aspect includes compounds of formula (I) wherein n is 1.

[0227] Another aspect includes compounds of formula (I) wherein n is 2.

[0228] Another aspect includes compounds of formula (I) wherein n is 3.

[0229] One aspect includes compounds of formula (I) wherein, where valence permits, independently represents a single bond or a double bond.

[0230] Another aspect includes compounds of formula (I) wherein, where valence permits, Represents a single bond.

[0231] Another aspect includes compounds of formula (I) wherein, where valence permits, Represents a double bond.

[0232] One aspect includes compounds of formula (I), wherein ring Q is selected from the group consisting of:

[0233]

[0234]

[0235] and any stereoisomers thereof.

[0236] One aspect includes compounds of formula (I), wherein ring Q is selected from the group consisting of:

[0237]

[0238]

[0239]

[0240]

[0241] One aspect includes compounds of formula (I), wherein ring Q is selected from the group consisting of:

[0242]

[0243]

[0244] and any stereoisomers thereof.

[0245] One aspect includes compounds of formula (I), wherein ring Q is selected from the group consisting of:

[0246]

[0247]

[0248]

[0249] and any stereoisomers thereof.

[0250] One aspect includes compounds of formula (I), wherein ring Q is selected from the group consisting of:

[0251]

[0252]

[0253]

[0254]

[0255] One aspect includes a compound of formula (I) or a form thereof, wherein the compound is selected from the group consisting of the following, wherein "#" indicates that the compound is a racemic mixture of enantiomers, wherein "&" indicates that the compound can exist as opposite enantiomers:

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] The compound is in the form of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form thereof.

[0296] One aspect includes a compound of formula (I) or a form thereof selected from

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331] The compound is in the form of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form thereof.

[0332] One aspect includes a compound of formula (I) or a form thereof selected from

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345] The compound may be in the form of a hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form thereof.

[0346] The present application also provides a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0347] The present application also provides a method for treating spinocerebellar ataxia type 3 (SCA3), which comprises administering to a subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0348] One aspect of the method or use comprises a compound of Formula (I) or a form thereof, wherein exon 4 skipping in ATXN3 pre-mRNA is induced during the splicing process.

[0349] One aspect of the method or use comprises a compound of Formula (I) or a form thereof, wherein the level of ATXN3 mRNA is reduced.

[0350] One aspect of the method or use comprises a compound of Formula (I) or a form thereof, wherein ATXN3 protein is decreased.

[0351] One aspect of the disclosure relates to pharmaceutical compositions comprising a compound of Formula (I) or a form thereof and at least one pharmaceutically acceptable excipient for administration to a subject to treat spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD).

[0352] One aspect of the present specification relates to the preparation of a medicament for treating spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), in a subject, the medicament comprising a compound of formula (I) or a form thereof and at least one pharmaceutically acceptable excipient.

[0353] 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 the invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used.

[0354] Materials, methods and examples are illustrative only and not restrictive. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, this specification (including definitions) shall prevail.

[0355] Chemical Definition

[0356] Unless expressly defined otherwise, one of ordinary skill in the art would understand that the chemical terms used above and throughout the description herein have the following meanings.

[0357] As used herein, the term “C 1-6"Alkyl" generally refers to a saturated hydrocarbon group having 1 to 8 carbon atoms in a straight or branched configuration, including but not limited to methyl, ethyl, n-propyl (also known as propyl or propanyl), isopropyl, n-butyl (also known as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also known as pentyl or pentanyl), n-hexyl (also known as hexyl or hexanyl), and the like. In certain aspects, C 1-6 Alkyl groups include but are not limited to C 1-6 Alkyl, C 1-4 Alkyl, etc. Where available valences permit, C 1-6 Alkyl groups are optionally substituted with substituents described herein.

[0358] As used herein, the term “C 2-6 "Alkenyl" generally refers to partially unsaturated hydrocarbon groups having 2 to 8 carbon atoms and one or more carbon-carbon double bonds in a straight or branched configuration, including but not limited to ethenyl (also known as vinyl), allyl, propenyl, and the like. In certain aspects, C 2-6 Alkenyl includes but is not limited to C 2-6 Alkenyl, C 2-4 Where available valences permit, C 2-6 Alkenyl groups are optionally substituted with substituents described herein.

[0359] As used herein, the term “C 2-6 "Alkynyl" generally refers to partially unsaturated hydrocarbon groups having 2 to 8 carbon atoms and one or more carbon-carbon triple bonds in a straight or branched configuration, including but not limited to ethynyl (also known as acetylenyl), propynyl, butynyl, and the like. In certain aspects, C 2-6 Alkynyl groups include, but are not limited to, C 2-6 Alkynyl, C 2-4 Alkynyl, etc. Where available valences permit, C 2-6 Alkynyl groups are optionally substituted with substituents described herein.

[0360] As used herein, the term “C 1-6 "Alkoxy" generally refers to a saturated hydrocarbon group having 1 to 8 carbon atoms in a straight or branched chain configuration of the formula: -OC 1-6 Alkyl, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, etc. In certain aspects, C 1-6 Alkoxy includes but is not limited to C 1-6Alkoxy, C 1-4 Alkoxy, etc. Where available valences permit, C 1-6 Alkoxy groups are optionally substituted with substituents described herein.

[0361] As used herein, the term “C 1-6 Alkoxy-C 2-6 "Alkynyl" refers to a radical of the formula: -C 2-6 Alkynyl-OC 1-6 Alkyl, where available valences permit, C 2-6 Alkynyl is replaced by one or more C 1-6 The alkoxy groups are partially or completely substituted.

[0362] As used herein, the term "oxo" refers to a radical of the formula: =0.

[0363] As used herein, the term "carboxyl" refers to a group of the formula: -COOH, -C(O)OH or -CO2H.

[0364] As used herein, the term “C 1-6 Alkoxy-carbonyl" or "CO2C 1-6 "Alkyl" refers to a group of the formula: -COO-C 1-6 Alkyl, -C(O)OC 1-6 Alkyl or -CO2-C 1-6 alkyl.

[0365] As used herein, the term "carbamoyl" refers to a radical of the formula: -C(O)NH2.

[0366] As used herein, the term “C 3-8 "Cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, etc. In certain aspects, C 3-8 Cycloalkyl includes but is not limited to C 3-8 Cycloalkyl, C 5-8 Cycloalkyl, etc. Where available valences permit, C 3-10 Cycloalkyl groups are optionally substituted with substituents described herein.

[0367] As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure group, including but not limited to phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. Aryl groups are optionally substituted with substituents described herein, where permitted by available valences.

[0368] As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure group, wherein, where structural stability permits, one or more carbon atom ring members are replaced by one or more heteroatoms (e.g., O, S or N atoms). "Heteroaryl" includes, but is not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazine, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl and the like. Heteroaryl groups are optionally substituted on carbon or nitrogen atom ring members with substituents as described herein, where permitted by available valences.

[0369] In some aspects, the naming of heteroaryl groups may be different, for example, in non-limiting embodiments, 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.

[0370] In certain other aspects, the term heteroaryl group may also include other positional isomers, for example, in non-limiting embodiments, the term pyrrolyl may also include 2H-pyrrolyl, 3H-pyrrolyl, etc., the term pyrazolyl may also include 1H-pyrazolyl, etc., the term imidazolyl may also include 1H-imidazolyl, etc., the term triazolyl may also include 1H-1,2,3-triazolyl, etc., the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc., the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl, etc., the term indolyl may also include 1H-indolyl, etc., the term indazolyl may also include 1H-indazolyl, 2H-indazolyl, etc., the term benzimidazolyl may also include 1H-benzimidazolyl, the term purinyl may also include 9H-purinyl, etc.

[0371] As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure group, wherein one or more carbon atom ring members are replaced by heteroatoms (e.g., O, S or N atoms) where structural stability permits. "Heterocyclyl" includes, but is not limited to, oxirane, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, 1,3-dioxanyl, 1,3-oxazinanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, etc. The heterocyclyl group is optionally substituted on a carbon or nitrogen atom ring member with substituents as described herein, where permitted by available valences.

[0372] As used herein, the term “C 1-4 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-4 alkyl.

[0373] As used herein, the term "halo-C 1-4 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-4 Alkyl, where available valences permit, C 1-4 The alkyl group is partially or fully substituted by one or more halogen atoms.

[0374] As used herein, the term “ 1-4 "alkyl)2-amino" refers to a radical of the formula: -N(C 1-4 Alkyl)2.

[0375] As used herein, the term “C 1-6 "Alkyl-thio" refers to a radical of the formula: -SC 1-6 alkyl.

[0376] As used herein, the term “C 1-6 "Alkyl-sulfinyl (sulfoxyl)" refers to a radical of the formula: -S(O)-C 1-6 alkyl.

[0377] As used herein, the term “C 1-6 "Alkyl-sulfonyl" refers to a radical of the formula: -SO2-C 1-6 alkyl.

[0378] As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluorine, chlorine, bromine, and iodine.

[0379] As used herein, the term "halo-C 1-6 "Alkyl" refers to a radical of the formula: -C 1-6 Alkyl-halogen, where available valences permit, C 1-6 The alkyl group is partially or fully substituted by one or more halogen atoms.

[0380] As used herein, the term "halo-C 1-6 "Alkoxy" refers to a radical of the formula: -OC 1-6 Alkyl-halogen, where available valences permit, C 1-6 The alkyl group is partially or fully substituted by one or more halogen atoms.

[0381] As used herein, the term "deuterated-C 1-6 "Alkyl" refers to a radical of the formula: -C 1-6 Alkyl, where available valences permit, C 1-6 The alkyl group is partially or fully substituted with one or more deuterium atoms.

[0382] As used herein, the term "hydroxy" refers to a radical of the formula: -OH.

[0383] As used herein, the term "hydroxy-C 1-6 "Alkyl" refers to a radical of the formula: -C 1-6 Alkyl-OH, where available valences permit, C 1-6 The alkyl group is partially or fully substituted by one or more hydroxy groups.

[0384] As used herein, the term "hydroxy-C 2-6 "Alkynyl" refers to a radical of the formula: -C2-6 Alkynyl -OH, in which, where available valences permit, C 2-6 The alkynyl group is partially or fully substituted by one or more hydroxy groups.

[0385] As used herein, the term "thio-C 1-6 "Alkyl" refers to a radical of the formula: -C 1-6 Alkyl-SH, where available valences permit, C 1-6 The alkyl group is partially or fully substituted by one or more -SH groups.

[0386] As used herein, the term “C 1-6 Alkoxy-C 2-6 "Alkynyl" refers to a radical of the formula: -C 2-6 Alkynyl-C 1-6 Alkoxy groups, in which, where available valences permit, C 2-6 The alkynyl group is partially or fully substituted by one or more hydroxy groups.

[0387] As used herein, the term "(CH3)3Si-C 2-6 "Alkynyl" refers to a radical of the formula: -C 2-6 Alkynyl-Si(CH3)3.

[0388] As used herein, the term "heteroaryl-C 2-6 "-alkynyl" refers to a radical of the formula: C 2-6 Alkynyl-heteroaryl.

[0389] As used herein, the term "substituent" refers to a position variable on an atom of a core molecule substituted at a designated atomic position, replacing one or more hydrogens on the designated atom, provided that the normal valence of the designated atom is not exceeded, and the substitution produces a stable compound. Such a combination is allowed only when the combination of substituents and / or variables produces a stable compound. It should be noted by those of ordinary skill in the art that any carbon and heteroatom that does not seem to satisfy the valence as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the valence described or shown. In some cases, one or more substituents having a double bond (e.g., "oxo" or "=O") as a point of attachment can be described, displayed or listed in the substituent, wherein the structure can only show a single bond as a point of attachment to the core structure of formula (I). It will be understood by those of ordinary skill in the art that, although only a single bond is shown, double bonds are also applicable to those substituents.

[0390] As used herein, the term "etc.", with reference to the definitions of chemical terms provided herein, refers to changes in chemical structure that would be anticipated by one skilled in the art, including but not limited to isomers (including chain, branched or positional structural isomers), hydration of ring systems (including saturated or partially unsaturated monocyclic, bicyclic or polycyclic structures) and all other changes that result in stable compounds as permitted by available valences.

[0391] For purposes of this specification, when one or more substituent variables of a compound of Formula (I) or a form thereof include functional groups that are incorporated into the compound of Formula (I), each functional group occurring at any position in the disclosed compound may be independently selected and, as appropriate, independently and / or optionally substituted.

[0392] As used herein, the term "independently selected" or "individually selected" refers to a functional group variable in a substituent list that may appear more than once on a structure of Formula (I), the substitution pattern at each occurrence being independent of the pattern at any other occurrence. In addition, the use of a generic substituent variable on any formula or structure of a compound described herein should be understood to include replacement of the generic substituent with a substituent of a class included within the specific class, for example, an aryl group can be replaced with a phenyl or naphthyl group, and the resulting compound will be included within the scope of the compounds described herein.

[0393] As used herein, the term "in each case" or "in each case, when present" when used in a phrase such as "... 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, heterocyclyl and heterocyclyl-C 1-4 When it is preceded by "alkyl", it means C 3-10 Cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems, when each occurs alone or as a substituent.

[0394] As used herein, the term "optionally substituted" means optional substitution with the specified substituent variable, group, radical or moiety.

[0395] As used herein, the term "D" refers to a deuterium atom.

[0396] As used herein, the term "isotopically enriched" refers to a compound of Formula I or a form thereof as described herein, but with the exception that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of Formula I or forms thereof described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as H 2 , H3 , C 13 , C 14 、N 15 , O 18 , O 17 , P 31 , P 32 , S 35 、F 18 , Cl 35 and Cl 36 , each of which is also within the scope of this specification.

[0397] Compound form

[0398] As used herein, the term "form" refers to a compound of formula (I) having a form selected from the group consisting of its free acid, free base, salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer and tautomeric forms.

[0399] In certain aspects described herein, the compound of Formula (I) is in the form of a free acid, a free base, or a salt thereof.

[0400] In certain aspects described herein, the compound of Formula (I) is in the form of a salt thereof.

[0401] In certain aspects described herein, the compound of Formula (I) is in the form of a stereoisomer, racemate, enantiomer or diastereomer thereof.

[0402] In certain aspects described herein, the compounds of Formula (I) are in the form of tautomers thereof.

[0403] In certain aspects described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.

[0404] In certain aspects described herein, the compound of Formula (I) or a form thereof is isolated for use.

[0405] As used herein, the term "isolated" refers to the physical state of a compound of Formula (I) or a form thereof after separation and / or purification from a synthetic process (e.g., from a reaction mixture) or a natural source, or a combination thereof, according to one or more separation or purification methods described herein or known to those skilled in the art (e.g., chromatography, recrystallization, etc.), and its purity is sufficient to be characterized by standard analytical techniques described herein or known to those skilled in the art.

[0406] As used herein, the term "protected" means that when the compound reacts, the functional group in the compound of formula (I) or its form is in a modified form to prevent undesirable side reactions at the protected site. Suitable protecting groups will be known to those of ordinary skill in the art and reference standard textbooks (e.g., TW Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.). Such functional groups include hydroxyl, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxyl or phenol include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acids include alkyl, aryl or arylalkyl esters. In some cases, the protecting group may also be a polymer resin, such as Wang resin or 2-chlorotrityl-chloro resin. Protecting groups may be added or removed according to standard techniques, which are well known to those skilled in the art, as described herein. It will also be understood by those skilled in the art that, although such protected derivatives of the compounds described herein may not themselves be pharmacologically active, they may be administered to a subject and then metabolized in vivo to form pharmacologically active compounds described herein. Therefore, such derivatives may be referred to as "prodrugs". All prodrugs of the compounds described herein are included within the scope of the uses described herein.

[0407] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents (eg, water, ethanol, etc.), and the description herein is intended to include both solvated and unsolvated forms.

[0408] As used herein, the term "solvate" refers to a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" includes both solution phase and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

[0409] As used herein, the term "hydrate" refers to a solvate wherein the solvent molecule is water.

[0410] The compound of formula (I) can form salts, which are also included in the scope of this specification. Unless otherwise indicated, the compound of formula (I) mentioned herein or its form should be understood to include the form of its salt. The term "salt" used herein refers to an acidic salt formed with an inorganic and / or organic acid, and a basic salt formed with an inorganic and / or organic base. In addition, when the compound of formula (I) or its form comprises a basic part (such as but not limited to an amine part) and an acidic part (such as but not limited to a carboxylic acid), a zwitterion ("inner salt") can be formed, and is included in the term "salt" used herein.

[0411] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals, and that possess biological activity, although other salts are also useful. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) or a form thereof with an amount of an acid or base (e.g., an equal amount of an acid or base) in a medium (e.g., a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization.

[0412] Pharmaceutically acceptable salts include salts of one or more acidic or basic groups present in the compounds described herein. Specific aspects of acid addition salts include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucuronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthenate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, sucrose salt, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as toluenesulfonate), trifluoroacetate, etc. Certain specific aspects of acid addition salts include chloride or dichloride.

[0413] In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic drug compounds are described, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC. Their website). These disclosures are incorporated herein by reference.

[0414] Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, and zinc salts.

[0415] All such acid salts and base salts are included within the scope of the pharmaceutically acceptable salts described herein. In addition, for the purposes of this specification, all such acid salts and base salts are considered equivalent to the free forms of the corresponding compounds.

[0416] The compounds of Formula (I) and forms thereof may also exist as tautomers. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or forms thereof described herein.

[0417] The compounds of formula (I) or forms thereof may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. The present specification is intended to include all stereoisomeric forms of the compounds of formula (I) and mixtures thereof, including racemic mixtures.

[0418] The compounds described herein may include one or more chiral centers and may therefore exist as racemic mixtures (R / S) or substantially pure enantiomers and diastereomers. These compounds may also exist as substantially pure (R) or (S) enantiomers (when there is one chiral center). In a specific aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially containing only (S) isomers. In another specific aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially containing only (R) isomers. As will be appreciated by those skilled in the art, when there is more than one chiral center, the compounds described herein may also exist as (R,R), (R,S), (S,R) or (S,S) isomers as defined by the IUPAC nomenclature recommendations.

[0419] As used herein, the term "chiral" refers to a carbon atom that is bonded to four different substituents. The stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. In describing optically active compounds, the prefixes D and L, or R and S are used to indicate the absolute configuration of the molecule about its one or more chiral centers. The substituents on the chiral center under consideration are ordered according to the order rules of Cahn, Ingold and Prelog (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511).

[0420] As used herein, the term "substantially pure" refers to a compound consisting essentially of a single isomer, with the content of the single isomer being greater than or equal to 90%, greater than or equal to 92%, greater than or equal to 95%, greater than or equal to 98%, greater than or equal to 99%, or equal to 100%.

[0421] In one aspect of the disclosure, the compound of formula (I) or a form thereof is in substantially pure (S) enantiomeric form, which is present in an amount greater than or equal to 90%, greater than or equal to 92%, greater than or equal to 95%, greater than or equal to 98%, greater than or equal to 99%, or equal to 100%.

[0422] In one aspect of the disclosure, the compound of formula (I) or a form thereof is in substantially pure (R) enantiomeric form, which is present in an amount greater than or equal to 90%, greater than or equal to 92%, greater than or equal to 95%, greater than or equal to 98%, greater than or equal to 99%, or equal to 100%.

[0423] As used herein, a "racemate" is any mixture of isomeric forms that is not "enantiomerically pure," including, for example, but not limited to, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20.

[0424] In addition, this specification includes all geometric isomers and positional isomers. For example, if the compound of formula (I) or its form contains double bonds or fused rings, cis and trans forms and their mixtures are included in the scope of the specification. Diastereomeric mixtures can be separated into their respective diastereomers according to their physicochemical differences by methods well known to those skilled in the art (e.g., by chromatography and / or fractional crystallization). Enantiomers can be separated by using chiral HPLC columns or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated in the following manner: by reacting with a suitable optically active compound (e.g., chiral auxiliary, such as chiral alcohol or Mosher's acid chloride), enantiomeric mixtures are converted into diastereomeric mixtures, diastereomers are separated, and each diastereomer is converted (e.g., hydrolyzed) to the corresponding pure enantiomer. In addition, some compounds of formula (I) can be atropisomers (e.g., substituted biaryl) and are considered to be part of this specification.

[0425] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the present invention (including salts, solvates, esters and prodrugs of the compounds and salts, solvates and esters of the prodrugs), for example, stereoisomers that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (even if there is no asymmetric carbon, it may exist), rotational isomers, atropisomers and diastereomeric forms, and positional isomers, are within the scope of the present specification. Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described above.

[0426] The use of the terms "salt", "solvate" and the like is intended to apply equally to the enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers or racemates of the compounds of the invention.

[0427] Used the software provided by PerkinElmer Informatics Ltd. The structure naming feature of software version 20.1.1 obtains chemical names and generally conforms to the IUPAC (International Union for Pure and Applied Chemistry) recommendations for organic chemical nomenclature and CAS indexing rules. Chemical names may have only parentheses, or may have parentheses and square brackets. Stereochemical descriptors may also be placed in different positions of the name itself, depending on naming conventions. Those of ordinary skill in the art will recognize these format changes and understand that they provide the same chemical structure.

[0428] Compound Uses

[0429] Provided herein are methods for treating a disease in a subject in need thereof. As used herein, the term "subject" or "patient" refers to any animal, including mammals. For example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some aspects, the subject is a human.

[0430] As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or agent that causes the biological or pharmaceutical response sought by the researcher, veterinarian, physician or other clinician in a tissue, system, animal, individual or human. In some aspects, the dose of the compound or its pharmaceutically acceptable salt administered to a subject or individual is from about 1 mg to about 2 g, from about 1 mg to about 1000 mg, from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, or from about 50 mg to about 500 mg.

[0431] As used herein, the terms "treating" or "treatment" refer to one or more of the following: (1) preventing a disease; e.g., preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but who is not yet experiencing or displaying the pathology or symptomology of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomology); and (3) ameliorating a disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomology), such as reducing the severity of the disease or reducing or alleviating one or more symptoms of the disease.

[0432] The present application provides a method of treating SCA3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (ie, a compound of formula (I)).

[0433] Also provided herein is a method for treating a subject having a disease caused by an abnormal repeat expansion in the ATXN3 gene, which results in a mutant ATXN3 protein with a polyQ expansion, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula (I)).

[0434] Also provided herein are methods of reducing ATXN3 mutant protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein (ie, a compound of Formula (I)).

[0435] In some aspects of the methods provided herein, the compound is selected from a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0436] Also provided herein are methods of inducing exon skipping of mutant ATXN3 pre-mRNA in a subject, comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

[0437] Also provided herein are methods of inducing exon skipping of mutant ATXN3 pre-mRNA in a cell, comprising contacting the cell (eg, in vitro or in vivo) with a compound of Formula (I) or a form thereof.

[0438] Also provided herein are methods of inducing exon skipping of mutant ATXN3 pre-mRNA in a gene, comprising contacting the gene (eg, in a cell or subject expressing the gene) with a compound of Formula (I) or a form thereof.

[0439] Also provided herein are methods of inducing exon 4 skipping of mutant ATXN3 pre-mRNA in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.

[0440] Also provided herein are methods of inducing exon 4 skipping of mutant ATXN3 pre-mRNA in a cell, the method comprising contacting the cell (eg, in vitro or in vivo) with a compound of Formula (I) or a form thereof.

[0441] Also provided herein are methods of inducing exon 4 skipping of mutant ATXN3 pre-mRNA in a gene, comprising contacting the gene (eg, in a cell or subject expressing the gene) with a compound of Formula (I) or a form thereof.

[0442] Also provided herein are methods of producing ATXN3ΔE4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

[0443] Also provided are methods of producing ATXN3ΔE4 in a cell, the method comprising contacting the cell (eg, in vitro or in vivo) with a compound of formula (I) or a form thereof.

[0444] Also provided herein are methods of producing ATXN3ΔE4 in a gene comprising contacting the gene (eg, in a cell or subject expressing the gene) with a compound of Formula (I) or a form thereof.

[0445] Also provided herein are methods of reducing mutant ATXN3 mRNA in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof. For example, these methods comprise reducing the concentration of mutant ATXN3 mRNA in a serum sample of the subject.

[0446] In some aspects, mutant ATXN3 mRNA can be measured in serum (e.g., in a blood sample obtained from a subject before administration of a compound of Formula (I) or a form thereof, and in a blood sample obtained from a subject after administration of a compound provided herein). In some aspects, a blood sample obtained from a subject after administration is obtained 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, and / or 30 days after administration of a compound provided herein. For example, see FB Axelrod et al., Pediatr Res (2011) 70(5):480-483; and RS Shetty et al., Human Molecular Genetics (2011) 20(21):4093-4101, the entire contents of both of which are incorporated herein by reference.

[0447] Also provided herein is a method for reducing mutant ATXN3 mRNA in a cell, the method comprising contacting the cell (e.g., in vitro or in vivo) with a therapeutically effective amount of a compound of formula (I) or a salt form thereof. Relative to cells in a subject to which the compound provided herein is not administered, the content of mutant ATXN3 mRNA in the treated cell is reduced. The method for reducing the content of mutant ATXN3 mRNA in a cell can be performed by contacting the cell with a compound of formula (I) or a form thereof in vitro, thereby reducing the content of mutant ATXN3 mRNA in the cell in vitro. The uses of this in vitro method for reducing the content of mutant ATXN3 mRNA include, but are not limited to, uses in screening assays (e.g., wherein a compound of formula (I) or a form thereof is used as a positive control or standard, compared to one or more compounds with unknown activity or efficacy in reducing the content of mutant ATXN3 mRNA).

[0448] In some aspects, the level of mutant ATXN3 mRNA is reduced in cells selected from the group consisting of lung cells, muscle cells, liver cells, heart cells, brain cells, kidney cells, spleen cells and nerve cells (e.g., sciatic nerve cells or trigeminal nerve cells) or any combination thereof. In some aspects thereof, the level of mutant ATXN3 mRNA in plasma is reduced.

[0449] The method of reducing mutant ATXN3 mRNA in a cell can be performed by, for example, contacting a cell (e.g., a lung cell, a muscle cell, a liver cell, a heart cell, a brain cell, a kidney cell, a spleen cell, or a nerve cell) with a compound of formula (I) or a form thereof in vivo, thereby reducing the amount of mutant ATXN3 mRNA in a subject in vivo. The contact is achieved by causing an effective amount of a compound of formula (I) or a form thereof to be present in the subject to achieve a reduction in the amount of mutant ATXN3 mRNA. This can be achieved, for example, by administering an effective amount of a compound of formula (I) or a form thereof to the subject. The uses of this in vivo method of reducing the amount of mutant ATXN3 mRNA include, but are not limited to, methods for treating diseases or conditions in which a reduction in the amount of mutant ATXN3 mRNA is beneficial.

[0450] In some aspects thereof, for example, in a subject with SCA3, the level of mutant ATXN3 mRNA is reduced in a cell selected from the group consisting of lung cells, muscle cells, liver cells, heart cells, brain cells, kidney cells, spleen cells, and neural cells (e.g., sciatic nerve cells or trigeminal nerve cells), or any combination thereof. The method is preferably implemented by administering an effective amount of a compound of formula (I) or a form thereof to a subject with SCA3.

[0451] Also provided herein is a method for reducing the expression of ATXN3 mutant proteins in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, these methods include reducing the expression of ATXN3 mutant proteins in a serum sample of the subject. Also provided herein is a method for reducing the average percentage of ATXN3 mutant protein expression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

[0452] Also provided herein is a method for reducing the expression of ATXN3 mutant proteins in cells (e.g., in vitro or in vivo), the method comprising contacting the cells with a therapeutically effective amount of a compound of formula (I) or a form thereof. In certain aspects, the method is an in vitro method. In some aspects, the method is an in vivo method. In some aspects, in cells selected from the group consisting of lung cells, muscle cells, liver cells, heart cells, brain cells, kidney cells, spleen cells and nerve cells (e.g., sciatic nerve cells or trigeminal nerve cells) or any combination thereof, the amount of ATXN3 mutant protein expression is reduced. In some aspects thereof, the amount of ATXN3 mutant protein expression in plasma is reduced.

[0453] Also provided herein are methods for reducing the level of ATXN3 mutant proteins in subjects in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. For example, these methods include reducing the level of ATXN3 mutant proteins in a serum sample of a subject. Also provided herein are methods for reducing the average percentage of ATXN3 mutant protein levels in subjects in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof.

[0454] Also provided herein are methods of reducing the level of an ATXN3 mutant protein in a cell (eg, in vitro or in vivo), the method comprising contacting the cell with a therapeutically effective amount of a compound of Formula (I) or a form thereof.

[0455] In some aspects, the method is an in vitro method. In some aspects, the method is an in vivo method. In some aspects, in cells selected from the group consisting of lung cells, muscle cells, liver cells, heart cells, brain cells, kidney cells, spleen cells and nerve cells (e.g., sciatic nerve cells or trigeminal nerve cells) or any combination thereof, the content of ATXN3 mutant protein levels is reduced. In some aspects thereof, the content of ATXN3 mutant protein levels in plasma is reduced.

[0456] In some aspects, one or more compounds of Formula (I) or forms thereof may be administered to a subject in need thereof in combination with at least one additional pharmaceutical agent.

[0457] Other examples of suitable additional agents for use in combination with the compounds of the present application to treat the diseases provided herein include, but are not limited to, antioxidants, anti-inflammatory agents, steroids, immunosuppressants, or other agents (e.g., therapeutic antibodies). In some aspects, a compound of formula (I) or a form thereof can be administered to a subject in need thereof in combination with at least one additional agent for treating SCA3.

[0458] When used as a therapeutic agent, the compounds provided herein can be administered in the form of a pharmaceutical composition; therefore, the methods described herein may include administering a pharmaceutical composition. These compositions can be prepared as described herein or elsewhere, and can be administered by a variety of routes, depending on whether local or systemic treatment is needed and the area to be treated. Administration can be pulmonary (e.g., by inhalation or blowing of powder or aerosol, including by a 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 rapid administration, or may be, for example, administered by a continuous infusion pump. Conventional drug carriers, aqueous, powdered or oily matrices, thickeners, etc. may be necessary or desirable. In some aspects, the compounds provided herein are suitable for oral administration 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., using a patch or microneedle administration). Pharmaceutical compositions for topical administration may include transdermal patches (e.g., normal or electrically stimulated), ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powdered or oily bases, thickeners, etc. may be necessary or desirable.

[0459] Also provided is a pharmaceutical composition comprising a compound of formula (I) or a form thereof as an active ingredient and one or more pharmaceutically acceptable carriers (excipients). When preparing the compositions provided herein, the active ingredient is usually mixed with an excipient, diluted with an excipient or encapsulated in a carrier, such as a capsule, a pouch, paper or other container. When an excipient is used as a diluent, it can be a solid, semisolid or liquid material, as an excipient, carrier or medium for the active ingredient. Therefore, the composition can be in the form of a tablet, a pill, a powder, a lozenge, a pouch, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol (as a solid or in a liquid medium), an ointment, a soft gelatin capsule and a hard gelatin capsule, a suppository, a sterile injection solution and a sterile packaged powder.

[0460] Some examples of suitable excipients include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may also include, but is not limited to, lubricants (e.g., talc, magnesium stearate, and mineral oil); wetting agents; emulsifiers and suspending agents; preservatives (e.g., methyl hydroxybenzoate and propyl hydroxybenzoate); sweeteners; flavoring agents, or combinations thereof.

[0461] Active compound can be effective in a wide dosage range, and is usually administered in a pharmaceutically effective amount. It should be understood that the amount of the compound to be administered and the administration regimen are usually determined by a doctor according to relevant circumstances (including the disease to be treated, the selected administration route, the actual compound administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.).

[0462] In another aspect, the observed concentration-biological effect relationship for a compound of Formula (I) or a form thereof indicates that the target plasma concentration range is about 0.001 μg·hr / mL to about 50 μg·hr / mL, about 0.01 μg·hr / mL to about 20 μg·hr / mL, about 0.05 μg·hr / mL to about 10 μg·hr / mL, or about 0.1 μg·hr / mL to about 5 μg·hr / mL. To achieve such plasma concentrations, the compounds described herein can be administered at different doses (e.g., but not limited to, 1.0 ng to 10,000 mg).

[0463] In one aspect, a dose to achieve an effective target plasma concentration can be administered based on subject or patient specific factors, wherein the administered dose based on weight can be from about 0.001 mg / kg / day to about 3500 mg / kg / day, or from about 0.001 mg / kg / day to about 3000 mg / kg / day, or from about 0.001 mg / kg / day to about 2500 mg / kg / day, or from about 0.001 mg / kg / day to about 2000 mg / kg / day, or from about 0.001 mg / kg / day to about 1500 mg / kg / day, or from about 0.001 mg / kg / day to about 1000 mg / kg / day, or from about 0.001 mg / kg / day to about 500 mg / kg / day. , or about 0.001 mg / kg / day to about 250 mg / kg / day, or about 0.001 mg / kg / day to about 200 mg / kg / day, or about 0.001 mg / kg / day to about 150 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day, or about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 50 mg / kg / day, or about 0.001 mg / kg / day to about 25 mg / kg / day, or about 0.001 mg / kg / day to about 10 mg / kg / day, or about 0.001 mg / kg / day to about 5 mg / kg / day, or about 0.001 mg / kg / day to about g / 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 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 aboutThe dosage form may be from about 0.01 mg / kg / day to about 1 mg / kg / day, or from about 0.01 mg / kg / day to about 0.5 mg / kg / day, or from about 0.01 mg / kg / day to about 0.1 mg / kg / day, or from about 0.1 mg / kg / day to about 3500 mg / kg / day, or from about 0.1 mg / kg / day to about 3000 mg / kg / day, or from about 0.1 mg / kg / day to about 2500 mg / kg / day, or from about 0.1 mg / kg / day to about 2000 mg / kg / day, or from about 0.1 mg / kg / day to about 1500 mg / kg / day, or from about 0.1 mg / kg / day to about 1000 mg / kg / day, or from about 0.1 mg / kg / day to about 500 mg / kg / day, or from about 0.1 mg / kg / day to about g / 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.

[0464] The effective amount for a given subject can be determined by routine experiments within the skill and judgment of a clinician or technician in this field, depending on factors related to the subject. Dosage and administration can be adjusted to provide sufficient levels of one or more active agents or to maintain the desired effect. Factors that can be considered include genetic screening, severity of the disease state, the state of disease progression, the overall health of the subject, race, age, weight, sex, diet, time of day and frequency of administration, one or more drug combinations, reaction sensitivity, experience with other therapies, and tolerance / response to therapy.

[0465] The dosage to achieve an effective target plasma concentration can be orally administered once (approximately once every 24 hours; i.e., "qd"), twice (approximately once within 12 hours; i.e., "bid" or "q.12h"), three times (approximately once every 8 hours; i.e., "tid" or "q.8h"), or four times (approximately once every 6 hours; i.e., "qds", "qid" or "q.6h") daily.

[0466] In certain aspects, for patients or subjects with a body weight in the range of about 40 kg to about 200 kg, the dosage administered to achieve an effective target plasma concentration may also be administered in a single dose, divided dose, or continuous dose (for patients or subjects above or below this range, particularly children below 40 kg, the dosage may be adjusted). The median body weight of a typical adult subject is expected to be in the range of about 70 kg. Long-acting pharmaceutical compositions may be administered once every 2, 3, or 4 days, once a week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0467] The compounds and compositions described herein can be administered to a subject by 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 administration routes.

[0468] In another aspect, the dosage administered can be adjusted based on the dosage forms described herein, which are formulated for administration at about 0.02 mg / day, 0.025 mg / day, 0.03 mg / day, 0.05 mg / day, 0.06 mg / day, 0.075 mg / day, 0.08 mg / day, 0.09 mg / day, 0.10 mg / day, 0.20 mg / day, 0.25 mg / day, 0.30 mg / day, 0.50 mg / day, 0.60 mg / day, 0.75 mg / day, 0.80 mg / day, 0.90 mg / day, 1.0 mg / day, 1.10 mg / day. 400 mg / day, 500 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day or 4000 mg / day are delivered.

[0469] For any compound, the effective amount can be initially estimated in cell culture assays or relevant animal models (e.g., mouse, guinea pig, chimpanzee, marmoset or tamarin animal models). The 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 the effective dose and route for administration to humans. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50(the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and can be expressed as the ratio, LD 50 / ED 50 In certain aspects, the effective amount is such that a large therapeutic index is achieved. In more specific aspects, the dose is in the range of EDs including little or no toxicity. 50 The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and route of administration.

[0470] Another aspect included within the scope of this specification is the use of in vivo metabolites of the compounds described herein. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, this specification includes the use of compounds produced by a method comprising contacting a compound described herein with a mammalian tissue or mammal for a period of time sufficient to produce a metabolic product thereof.

[0471] Such products are usually identified by preparing a radiolabeled 14 C or 3 H) of formula (I), administering the radiolabeled compound to a mammal (e.g., rat, mouse, guinea pig, dog, monkey, or human) at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism (usually 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 easily isolated because they are "radiolabeled" due to isotope enrichment (others are isolated by using antibodies that can bind to epitopes that survive in the metabolites). The metabolite structure is determined in a conventional manner (e.g., by MS or NMR analysis). In general, the analysis of metabolites can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products, as long as they are not found in vivo, can be used for diagnostic determinations of therapeutic doses of the compounds described herein, even if they themselves do not have biological activity.

[0472] Compounds and preparations

[0473] The embodiments of representative compounds included in the present invention and within the scope of the present invention are provided herein. The following embodiments and preparations are provided to enable those skilled in the art to more clearly understand and implement the present invention. They should not be considered to limit the scope of the present invention, but are merely illustrative and representative.

[0474] General Synthesis Examples

[0475] As disclosed herein, the method for preparing the compound of formula (I) described herein or its form generally uses standard, well-known synthetic methods. Many raw materials are commercially available, or can be prepared in the specific synthetic examples below using techniques known to those skilled in the art. Where chemically feasible, functional transformations of modified substituents can also be performed, and are considered to be included in the general scheme and the knowledge of those of ordinary skill in the art. The compound of formula (I) or its form can be prepared as described in the following scheme. Depending on the properties of the groups described in the following scheme, the final compound or its precursor can be further processed using standard, well-known synthetic methods.

[0476] Option A:

[0477] Compounds of formula (I) can be prepared as described in Scheme A below.

[0478]

[0479] having A and A' atoms and optionally substituted R 1 , R 2 and R 3 Substituted compound A1 can be reacted with cyclic nitroolefin A2 in the presence of a strong base (such as LDA, etc.) in a suitable solvent (such as THF, etc.) at a suitable temperature (such as -78°C) to give A3. Deprotection can be achieved by treatment with an acid (such as HCl in dioxane or HCl in TFA, etc.) followed by reduction with Zn or Fe metal in the presence of an acid (such as acetic acid, etc.) to give A4. Chiral SFC can be used to separate individual diastereomers A5, A6, A7 and A8.

[0480] Option B:

[0481] Compounds of formula (I) can be prepared as described in Scheme B below.

[0482]

[0483] having A and A' atoms and optionally substituted R 1 , R 2 and R 3 Substituted compound B1 can react with nitromethane in the presence of a base (such as NaOH, etc.), and then dehydrated with MsCl in the presence of a suitable base (such as TEA, etc.) to obtain nitroolefin B2. In a suitable solvent (such as toluene, etc.), at a suitable temperature (such as 100° C.), B2 and an optionally substituted olefin undergo a Diels-Alder reaction to obtain B3. In the presence of an acid (such as AcOH, etc.), B3 is reduced with Zn or Fe metal, and then deprotected by the protecting group (if necessary) to obtain B4. Chiral SFC separation gives B5 and B6.

[0484] Option C:

[0485] Compounds of formula (I) can be prepared as described in Scheme C below.

[0486]

[0487] having A and A' atoms and optionally substituted R 1 , R 2 and R 3 Substituted compound C1 can react with α-amino ketone C2 in the presence of a strong base (such as LDA, etc.) in a suitable solvent (such as THF, etc.) at a suitable temperature (such as -78°C) to give C3. C3 is treated with a deoxyfluorination agent (such as DAST, etc.) in a suitable solvent (such as DCM, etc.) to give C4. Deprotection can be accomplished by treatment with an acid (such as HCl in dioxane or HCl in TFA, etc.) to give C5.

[0488] Plan D:

[0489] Compounds of formula (I) can be prepared as described in Scheme D below.

[0490]

[0491] Azaindole D1 can react with a suitable electrophile (such as NBS, etc.) to obtain optionally substituted D2. In the presence of a suitable base (such as Cs2CO3, etc.), optionally substituted azaindole D2 can be treated with a suitable electrophile (such as MeI, etc.) to obtain D3. D3 reacts with a suitable oxidant (such as mCPBA, etc.), and then treated with a deoxychlorination agent (such as POCl3, etc.) at a suitable temperature (such as 110°C) to obtain chloropyridine D4. In the presence of a base (such as TEA, etc.), using a suitable solvent (such as DMSO, etc.), at a suitable temperature, compound D4 is treated with an optionally substituted aryl / heteroaryl methylamine, and then protected with Boc2O in the presence of a base (such as TEA, etc.) to obtain intermediate D5. In the presence of a strong base (such as LDA, etc.), in a suitable solvent (such as THF, etc.), at a suitable temperature (such as -78°C), an optionally substituted R 1 , R A and R 3 Substituted compounds D5 can be reacted with cyclic nitroolefins and then treated with a suitable base (e.g., DBU, etc.) to give D6. Deprotection can be accomplished by treatment with an acid (e.g., HCl in dioxane or HCl in TFA, etc.) followed by reduction with Zn or Fe metal in the presence of an acid (e.g., acetic acid, etc.) to give D7. Chiral SFC can be used to separate the individual enantiomers D8 and D9.

[0492] Plan E:

[0493] Compounds of formula (I) can be prepared as described in Scheme E below.

[0494]

[0495] In the presence of a suitable acid (such as AcOH, etc.), the R having A and A' atoms and optionally substituted 1 , R 2 and R 3 Substituted E1 is then reacted with Boc2O to give E2. Compound E2 can be converted to E3 by reacting with an appropriately functionalized organometallic substance in the presence of a catalyst (e.g., Pd(dppf)Cl2, etc.) and a base (e.g., TEA, etc.). Compound E3 can be deprotected with a suitable acid (TFA or HCl, etc.) to give E4. Chiral SFC can then be used to separate individual diastereomers E5, E6, E7, and E8.

[0496] Specific Synthesis Example

[0497] In order to describe in more detail and to facilitate understanding, the following non-limiting examples are provided to more fully illustrate the scope of the compounds described herein, and should not be construed as specifically limiting their scope. These variants of the compounds described herein may now be known or developed later, which can be determined within the capabilities of those skilled in the art, and these variants are considered to fall within the scope of the compounds described herein and claimed below. These examples illustrate the preparation of certain compounds. It will be appreciated by those skilled in the art that the techniques described in these examples represent techniques that work well in synthetic practice as described by those of ordinary skill in the art, and therefore constitute a preferred mode for their implementation. However, it should be understood that, according to the present disclosure, it should be understood by those skilled in the art that, without departing from the spirit and scope of this description, many changes may be made to the disclosed specific methods, and similar or similar results are still obtained.

[0498] Except in the following examples of specific compounds, unless otherwise indicated, all numbers used in the specification and claims to represent the number of ingredients, reaction conditions, experimental data, etc. should be understood to be modified by the term "about". Therefore, all of these numbers represent approximate values, which can vary according to the results of the desired properties or variable experimental conditions that are attempted to be obtained by the reaction. Therefore, within the expected range of experimental reproducibility, in the context of the obtained data, the term "about" refers to the range of the data provided, which can vary according to the standard deviation of the mean value. Similarly, for the experimental results provided, the obtained data can be rounded up or down to present the data consistently without losing significant figures. At least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be interpreted according to the number of significant figures and the rounding techniques used by those skilled in the art.

[0499] Although the numerical ranges and parameters setting forth the broad scope of the specification are approximations, the numerical values ​​set forth in the examples set forth below are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0500] Compound Examples

[0501] As mentioned above, in this specification, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

[0502]

[0503]

[0504]

[0505] Intermediate 1

[0506] tert-Butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0507]

[0508] Step 1: tert-Butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0509] To a solution of tert-butyl (3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (0.50 g, 1.087 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) was added lithium diisopropylamide (0.82 mL, 1.64 mmol, 1.5 equiv) at -78 °C. The solution was stirred for 30 minutes, then dimethylformamide (0.24 mg, 3.2 mmol, 3 equiv) was added. The reaction was stirred at -78 °C for 1 hour, then warmed to room temperature and stirred for another 1 hour. The reaction was then quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organics were washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate in hexanes (0 to 50% gradient) to give tert-butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (340 mg, 65% yield). MS m / z 485.9, 486.6 [M+H] + ; 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.26 (s, 1H), 7.19-7.14 (m, 2H), 6.81 (dd, J=5.1, 3.4 Hz, 1H), 6.74 (dd, J=3.4, 1.1 Hz, 1H), 4.99 (s, 2H), 1.41 (s, 9H).

[0510] Intermediate 2

[0511] tert-Butyl (5-chloro-3-ethylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0512]

[0513] Step 1: tert-Butyl (5-chloro-3-ethylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0514] To an 8 mL vial capped with a septum was added tert-butyl (3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (200 mg, 0.43 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (12 mg, 0.022 mmol, 0.05 equiv). The vial was evacuated and backfilled with argon three times, then anhydrous ether (1 mL) was added. The reaction was placed in an ice bath and stirred under argon for 15 minutes, at which time a solution of ethylmagnesium bromide (1 M) in THF (0.7 mL, 0.7 mmol, 1.5 equiv) was added dropwise via syringe. Shortly thereafter, the ice bath was removed and the reaction was stirred at room temperature under argon for 2 hours. The reaction mixture was then transferred to a separatory funnel and ethyl acetate (20 mL) and saturated aqueous ammonium chloride (20 mL) were added. The layers were separated, the aqueous layer was extracted twice with ethyl acetate (20 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (40 g SiO2, 0% to 10% ethyl acetate in hexanes) to give 85 mg (48% yield) of tert-butyl (5-chloro-3-ethylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate as a white solid cleanly after lyophilization. MS m / z 408.95 [M+H] + , 1 H NMR(DMSO-d6)δppm 7.83(s,1H),7.44(s,1H),7.39-7.42(m,1H),6.82-6.89(m,2H),5.11(s,2H),2.81(q,J=7.46Hz,2H),1.39(s,9H),1.26(t,J=7.50Hz,3H).

[0515] Intermediate 3

[0516] tert-Butyl (5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0517]

[0518] Step 1: tert-Butyl (5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0519] Tert-butyl (3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (200 mg, 0.43 mmol) was added to a 50 mL round bottom flask and iodine (166 mg, 0.65 mmol, 1.5 equiv) was added to a 25 mL conical flask. Both flasks were subjected to 3 cycles of briefly being placed under high vacuum and then backfilled with argon. Anhydrous THF (2.2 mL, degassed with argon directly before use) was added to each flask and the resulting solutions were stirred under a stream of argon. Both flasks were placed in an ice bath. After about 15 minutes, isopropylmagnesium chloride (2M solution in THF, Acros SureSeal, 0.33 mL, 1.5 equiv) was slowly added to the flask containing the aryl bromide. The reaction quickly turned dark red-brown and was stirred at 0°C for 30 minutes, at which time a cold THF solution of iodine was added by cannula transfer. The reactants were stirred at 0 ° C for 1 hour, at which time saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (20 mL) were added. The mixture was stirred briefly, exposed to air, and then transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate (20 mL). The combined organic layers were washed twice with saturated aqueous sodium thiosulfate solution (40 mL), once with brine (40 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (40 g SiO2, 0% to 10% ethyl acetate in hexane). The purified residue was lyophilized to obtain 155 mg (70% yield) of white solid (5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophene-2-ylmethyl) tert-butyl carbamate. MS m / z 506.7[M+H] + , 1 H NMR(DMSO-d6)δppm 8.44(s,1H),7.60(s,1H),7.37-7.42(m,1H),6.83-6.89(m,2H),5.13(s,2H),1.39(s,9H).

[0520] Intermediate 4

[0521] tert-Butyl (2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate

[0522]

[0523] Step 1: 2,4,7-Trichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine

[0524] To a mixture of 2,4,7-trichloro-5H-pyrrolo[3,2-d]pyrimidine (10.0 g, 45 mmol, 1.0 equiv) in dimethylformamide (100 mL) was added sodium chlorodifluoroacetate (8.2 g, 54 mmol, 1.2 equiv) and potassium carbonate (12.4 g, 90 mmol, 2.0 equiv) at room temperature. After stirring at 100 °C for 20 min, the reaction mixture was cooled to room temperature and poured into water (300 mL). The aqueous phase was extracted with EtOAc (3×200 mL), and the combined organics were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (PE / EA 20:1 to 10:1 gradient) to give 2,4,7-trichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine (9.3 g, 75%) as a white solid. MS m / z 271.8[M+H] + .

[0525] Step 2: 2,7-Dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

[0526] To a solution of 2,4,7-trichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine (1.0 g, 3.7 mmol, 1.0 equiv) in tetrahydrofuran (15 mL) was added N,N-diisopropylethylamine (2.6 mL, 15 mmol, 4 equiv) and 2-furanylmethylamine (0.4 g, 4 mmol, 1.1 equiv). After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (PE / EA 50:1) to give 2,7-dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (1.1 g, 89%) as a yellow solid. MS m / z 332.9[M+H] + .

[0527] Step 3: tert-Butyl (2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate

[0528] To a solution of 2,7-dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (1.1 g, 3.3 mmol, 1 eq) in tetrahydrofuran (20 mL) was added (Boc)2O (1.5 g, 6.9 mmol, 2.1 eq), TEA (0.7 g, 7 mmol, 2.1 eq) and DMAP (50 mg, 0.4 mmol, 0.1 eq). After stirring at room temperature for 1 h, the reaction mixture was concentrated and the crude residue was purified by silica gel chromatography (EA / PE 1:10) to give tert-butyl (2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (1.0 g, 70%) as a yellow solid. MS m / z 434.3 [M+H] + ; 1 HNMR (400 MHz, CHLOROFORM-d) δ: 7.82 (s, 1H), 7.26 (d, J = 6.6 Hz, 2H), 6.26-6.16 (m, 2H), 5.3-5.16 (m, 2H), 1.38 (s, 9H).

[0529] Intermediates 5 and 6

[0530]

[0531] 4-Nitro-3,6-dihydro-2H-pyran; 5-Nitro-3,6-dihydro-2H-pyran

[0532] Tetrabutylammonium nitrate (49.8 g, 164 mmol, 1.1 eq) was added to a solution of 3,6-dihydro-2H-pyran (12.5 g, 149 mmol, 1.0 eq) in dichloromethane (250 mL) at room temperature. The solution was then cooled to 0 °C and trifluoroacetic anhydride (34.3 g, 163 mmol, 1.1 eq) was added dropwise over 20 minutes. After stirring at room temperature for 2 hours, the reaction mixture was cooled to 0 °C again, triethylamine (15.0 g, 149 mmol, 1.0 eq) was added and stirred for another hour. The reaction mixture was diluted with DCM (100 mL), washed with ice water (2×150 mL), and then washed with brine (2×150 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EA / PE, 0-10% gradient) to give 4-nitro-3,6-dihydro-2H-pyran (500 mg, 3%) as a yellow oil and 5-nitro-3,6-dihydro-2H-pyran (1.8 g, 10%) as a yellow oil.

[0533] 4-Nitro-3,6-dihydro-2H-pyran: 1H NMR (400 MHz, CHLOROFORM-d) δ: 7.31-7.27 (m, 1H), 4.40 (q, J = 2.9 Hz, 2H), 3.88 (t, J = 5.5 Hz, 2H), 2.71 (ddd, J = 5.4, 4.2, 2.6 Hz, 2H).

[0534] 5-Nitro-3,6-dihydro-2H-pyran: 1 H NMR (400 MHz, CHLOROFORM-d) δ: 7.40 (t, J = 4.2 Hz, 1H), 4.54 (dd, J = 4.3, 2.6 Hz, 2H), 3.78 (t, J = 5.4 Hz, 2H), 2.54-2.42 (m, 2H).

[0535] Intermediate 7

[0536] 3,3-Difluoro-1-nitrocyclohex-1-ene

[0537]

[0538] 3,3-Difluoro-1-nitrocyclohex-1-ene

[0539] To a solution of 3-nitrocyclohex-2-ene-1-one (1 g, 7 mmol) in DCM (7 mL) cooled to 0 ° C, diethylaminosulfur trifluoride (3.43 g, 21 mmol, 3 equiv.) was added. The mixture was stirred at room temperature for 16 hours and then slowly poured into a cooling bath of saturated NaHCO3 aqueous solution. The aqueous phase was extracted with EtOAc (2×100 mL), and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA / PE 1:20) to give 3,3-difluoro-1-nitrocyclohex-1-ene (600 mg, 52%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ: 7.04 (t, J = 5.4 Hz, 1H), 2.74-2.65 (m, 2H), 2.18-2.08 (m, 2H), 2.03-1.96 (m, 2H).

[0540] Intermediate 8

[0541] tert-Butyl (3-bromo-5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0542]

[0543] Step 1: 3-Bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine

[0544] To a solution of 3-bromo-7-chloro-1H-pyrrolo[3,2-b]pyridine (9.5 g, 41 mmol) in DMF (95 mL) was added Cs2CO3 (26.7 g, 82 mmol, 2 eq.) and iodomethane (8.74 g, 62 mmol, 1.5 eq.). After stirring at room temperature for 2 h, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×2). The combined organics were washed with brine (200 mL×2), dried over Na2SO4, filtered, and concentrated in vacuo to give 3-bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine (7 g, 69%) as a yellow solid. MS m / z 246.8[M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ: 8.42 (d, J = 5.1 Hz, 1H), 7.34 (s, 1H), 7.20 (d, J = 5.1 Hz, 1H), 4.15 (s, 3H).

[0545] Step 2: 3-Bromo-5,7-dichloro-1-methyl-1H-pyrrolo[3,2-b]pyridine

[0546] The title compound was prepared from 3-bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine according to the procedure described in step 3 of intermediate 9. MS m / z 281.0 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ: 7.30 (s, 1H), 7.18 (s, 1H), 4.11 (s, 3H).

[0547] Step 3: 3-Bromo-5-chloro-1-methyl-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine

[0548] The title compound was prepared from 3-bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine according to the procedure described in step 4 of intermediate 9. MS m / z 358.0 [M+H] + .

[0549] Step 4: tert-Butyl (3-bromo-5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0550] The title compound was prepared from 3-bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine according to the procedure described in step 5 of intermediate 9. MS m / z 458.1 [M+H] + . 1H NMR (400 MHz, CHLOROFORM-d) δ: 7.24 (d, J = 5.0 Hz, 1H), 7.20 (s, 1H), 6.91 (dd, J = 4.9, 3.3 Hz, 2H), 6.81 (s, 1H), 4.98 (d, J = 7.9 Hz, 2H), 3.50 (s, 3H), 1.50 (s, 9H).

[0551] Intermediate 9

[0552] 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-1-(difluoromethyl)-N-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine

[0553]

[0554] Step 1: tert-Butyl (3-bromo-5-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0555] To a solution of 7-chloro-1H-pyrrolo[3,2-b]pyridine (500 mg, 2 mmol) in N,N-dimethylformamide (5 mL) was added 1-bromopyrrolidine-2,5-dione (700 mg, 4 mmol, 2 equiv). After stirring at room temperature for 4 hours, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was triturated from DCM (20 mL) to give 3-bromo-7-chloro-1H-pyrrolo[3,2-b]pyridine (480 mg, 96%) as a yellow solid. MS m / z 233.1[M+H] + .

[0556] Step 2: 3-Bromo-7-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridine

[0557] To a mixture of 3-bromo-7-chloro-1H-pyrrolo[3,2-b]pyridine (1 g, 4.3 mmol) in acetonitrile (15 mL) was added ethyl 2-bromo-2,2-difluoroacetate (3.5 g, 17 mmol, 4 equiv) and potassium tert-butoxide (1.95 g, 17 mmol, 4 equiv). After stirring at room temperature for 1 hour, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (70 mL×2). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo.

[0558] The crude residue was purified by silica gel column chromatography (EA / PE, 0-5% gradient) to give 3-bromo-7-chloro-1-(difluoromethyl)pyrrolo[3,2-b]pyridine (600 mg, 49%) as a yellow solid. MS m / z 282.9 [M+H] + .

[0559] Step 3: 3-Bromo-5,7-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridine

[0560] To a solution of 3-bromo-7-chloro-1-(difluoromethyl)pyrrolo[3,2-b]pyridine (1.6 g, 5.7 mmol) in DCM (20 mL) at 25 °C was added 3-chloroperoxybenzoic acid (3.5 g, 17 mmol, 3 equiv). After stirring at room temperature for 16 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a crude 3-bromo-5,7-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridine as a white solid. Phosphoryl trichloride (20 mL) was added to the crude material and the reaction mixture was heated at 90 °C for 1 h. The mixture was then cooled to room temperature and carefully poured into ice water (200 mL). The solution was extracted with EtOAc (2×200 mL). The combined organics were washed with saturated aqueous NaHCO3 (3×150 mL), brine (150 mL), dried over Na2SO4, filtered and concentrated to give 3-bromo-5,7-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridine (660 mg, 37%) as a yellow solid. MS m / z 316.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ: 8.52 (s, 1H), 8.23 ​​(t, J = 59.8Hz, 1H), 7.80 (s, 1H).

[0561] Step 4: 3-Bromo-5-chloro-1-(difluoromethyl)-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine

[0562] To a solution of 3-bromo-5,7-dichloro-1-(difluoromethyl)pyrrolo[3,2-b]pyridine (840 mg, 2.7 mmol) in DMSO (10 mL) at room temperature, 2-thienylmethylamine (330 mg, 3 mmol, 1.1 eq) and cesium fluoride (808 mg, 5 mmol, 1.8 eq) were added. After stirring at 110 °C for 16 h, the reaction mixture was cooled to room temperature and poured into water (100 mL). The aqueous solution was extracted with EtOAc (2 x 100 mL), and the combined organics were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 1:1) to give 3-bromo-5-chloro-1-(difluoromethyl)-N-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine (590 mg, 51%) as a yellow solid. MS m / z 393.9 [M+H] + .

[0563] Step 5: tert-Butyl (3-bromo-5-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0564] To a solution of 3-bromo-5-chloro-1-(difluoromethyl)-N-(2-thienylmethyl)pyrrolo[3,2-b]pyridin-7-amine (1.5 g, 3.8 mmol) in THF (20 mL) at room temperature, di-tert-butyl dicarbonate (1.74 g, 8 mmol, 2 eq.), triethylamine (0.8 g, 8 mmol, 2 eq.) and DMAP (0.05 g, 0.4 mmol, 1 eq.) were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (EA / PE 0-10% gradient) to give tert-butyl (3-bromo-5-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thien-2-ylmethyl)carbamate (2 g, 100%) as a yellow solid. MS m / z 494.0 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ: 7.71 (s, 1H), 7.27 (dd, J = 5.2, 1.0 Hz, 1H), 7.18, (d, J = 60.5 Hz, 1H), 6.97-6.90 (m, 2H), 4.97 (d, J = 7.7 Hz, 2H), 1.41, (s, 9H).

[0565] Intermediate 10

[0566] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0567]

[0568] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate was prepared according to the procedures outlined in Intermediate 9, Steps 1-5, by substituting appropriate starting materials, reagents and reaction conditions. MS m / z 448.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:8.44(s,1H),7.80-7.40(m,2H),7.07(s,1H),6.96(dt, J=8.4,2.8Hz,2H),5.17(d,J=15.5Hz,1H),4.86(d,J=15.5Hz,1H),1.36(s,9H).

[0569] Intermediate 11

[0570] tert-Butyl (5-chloro-1-(difluoromethyl)-3-iodo-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0571]

[0572] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate was prepared according to the procedures outlined in Intermediate 9, Steps 1-5, by substituting appropriate starting materials, reagents and reaction conditions. MS m / z 540.1 [M+H] + .

[0573] Intermediate 12

[0574] tert-Butyl (5-chloro-1-(difluoromethyl)-3-iodo-1H-pyrrolo[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[0575]

[0576] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate was prepared according to the procedure outlined in Intermediate 9, Steps 1-5, by substituting appropriate starting materials, reagents and reaction conditions. MS m / z 432.0 [M+H] + .

[0577] Intermediate 13

[0578] tert-Butyl (3-bromo-5-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[0579]

[0580] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate was prepared according to the procedure outlined in Intermediate 9, Steps 1-5, by substituting appropriate starting materials, reagents and reaction conditions. MS m / z 478.3 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ: 7.71 (s, 1H), 7.30-7.12 (m, 1H), 7.04 (s, 1H), 6.25 (s, 1H), 6.17 (d, J = 3.0 Hz, 1H), 5.04 (d, J = 15.9 Hz, 1H), 4.67 (d, J = 15.5 Hz, 1H), 1.37 (s, 9H).

[0581] Intermediate 14

[0582] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0583]

[0584] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate was prepared according to the procedure outlined in Intermediate 9, Steps 1-5, by substituting appropriate starting materials, reagents and reaction conditions. MS m / z 442.2 [M+H] + .

[0585] Intermediate 15

[0586] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0587]

[0588] tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate was prepared according to the procedures outlined in Intermediate 9, Steps 1-5, by substituting appropriate starting materials, reagents and reaction conditions. MS m / z 534.3 [M+H] + .

[0589] Intermediate 16

[0590] tert-Butyl (5-chloro-3-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0591]

[0592] A mixture of tert-butyl (5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (200 mg, 0.4 mmol, 1.0 equiv), methyl 2,2-difluoro-2-fluorosulfonylacetate (0.15 mL, 1.2 mmol, 3 equiv), CuI (75 mg, 0.4 mmol, 1.0 equiv) in DMF (1 mL) was heated at 100°C for 5 hours. The mixture was concentrated in vacuo, the crude residue was diluted with EtOAc, and the solid was removed by filtration. The filtrate was washed with water (50 mL×2), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 0-50% gradient) to give tert-butyl (5-chloro-3-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (177 mg, 56%) as an off-white solid. MS m / z 448.9 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ: ppm 8.19 (s, 1H) 7.26 (d, J = 5.00 Hz, 1H) 7.19 (s, 1H) 6.90 (t, J = 4.25 Hz, 1H) 6.83 (d, J = 3.00 Hz, 1H) 5.08 (s, 2H) 1.49 (s, 9H).

[0593] Intermediate 17

[0594] tert-Butyl (5-chloro-3-(difluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0595]

[0596] Step 1: tert-Butyl (5-chloro-3-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0597] To a solution of tert-butyl (3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophene-2-ylmethyl)carbamate (1.0 g, 2.2 mmol) (prepared according to the procedure described in WO2020 / 17430) in THF (18 mL) cooled to 0 ° C, 2M isopropylmagnesium chloride (1.5 mL, 3 mmol, 1.4 equiv) was added. After stirring at room temperature for 1 hour, DMF (1.7 mL, 20 mmol, 10 equiv) was added and the mixture was stirred for another 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl solution (50 mL) and diluted with water (100 mL). The aqueous phase was extracted with EtOAc (2×100 mL), and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 0-50% gradient) to give tert-butyl (5-chloro-3-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (889 mg, 70%) as a yellow oil. MS m / z 430.7 [M+Na] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ: ppm 10.47 (s, 1H) 8.62 (s, 1H) 7.22-7.29 (m, 2H) 6.80-6.95 (m, 2H) 5.10 (s, 2H) 1.49 (s, 9H).

[0598] Step 2: tert-Butyl (5-chloro-3-(difluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0599] To a solution of tert-butyl (5-chloro-3-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (120 mg, 0.3 mmol) in DCM (0.5 mL) cooled to 0 ° C, DAST (0.08 mL, 0.6 mmol, 2 equiv.) was added. After stirring at 0 ° C for 1 hour, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then cooled to 0 ° C and quenched with aqueous NaHCO3 solution (2 M, 5 mL). After neutralization, the mixture was extracted with EtOAc (3×10 mL). The combined organics were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 0-40% gradient) to give tert-butyl (5-chloro-3-(difluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (100 mg, 79%) as a yellow oil. MS m / z 431.0 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ: ppm 8.12 (s, 1H) 6.98-7.28 (m, 3H) 6.80-6.93 (m, 2H) 5.08 (s, 2H) 1.49 (s, 9H).

[0600] Intermediate 18

[0601] tert-Butyl (5-chloro-3-(fluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0602]

[0603] Step 1: tert-Butyl (5-chloro-3-(hydroxymethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To a solution of tert-butyl (5-chloro-3-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (300 mg, 0.7 mmol) (prepared according to Step 1 of Intermediate 17) in THF (2.7 mL) cooled to 0°C was added NaBH4 (17 mg, 0.4 mmol, 0.6 equiv). After stirring at room temperature for 1 hour, the reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 0-50% gradient) to give tert-butyl (5-chloro-3-(hydroxymethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (220 mg, 73%) as a yellow oil. MS m / z 411.0 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ: ppm 7.67 (s, 1H) 7.25 (d, J=5.13 Hz, 1H) 7.10 (s, 1H) 6.79-6.92 (m, 2H) 5.08 (s, 2H) 5.00 (s, 2H) 1.48 (s, 9H).

[0604] Step 2: tert-Butyl (5-chloro-3-(fluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To a solution of tert-butyl (5-chloro-3-(hydroxymethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (630 mg, 1.5 mmol) in DCM (3 mL) cooled to 0°C was added DAST (0.4 mL, 3 mmol, 2 equiv). After stirring at room temperature for 1 hour, the reaction was quenched with saturated aqueous NaHCO3 (5 mL) and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 0-50% gradient) to give tert-butyl (5-chloro-3-(fluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (150 mg, 24%) as a yellow oil. MS m / z 413.0 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ: ppm 7.76 (d, J = 1.88 Hz, 1H) 7.15 (d, J = 5.00 Hz, 1H) 7.02 (s, 1H) 6.68-6.86 (m, 2H) 5.54-5.73 (m, 2H) 4.99 (s, 2H) 1.39 (s, 9H).

[0605] Intermediate 19

[0606] tert-Butyl (5-chloro-3-((difluoromethoxy)methyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0607]

[0608] Step 1: tert-Butyl (5-chloro-3-((difluoromethoxy)methyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0609] A mixture of tert-butyl (5-chloro-3-(hydroxymethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (200 mg, 0.5 mmol) (prepared according to the procedure described in Intermediate 18) and CuI (19 mg, 0.01 mmol, 0.2 eq) in acetonitrile (1 mL) was stirred at 50 °C. 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.1 mL, 1 mmol, 2 eq) was added dropwise to the mixture. After stirring at 50 °C for 1 hour, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give tert-butyl (5-chloro-3-((difluoromethoxy)methyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (100 mg, 45%) as a yellow oil. MS m / z 461.0[M+H] + . 1 H NMR (400MHz, chloroform-d) δ: ppm 7.77-7.82 (m, 1H) 7.25 (d, J = 5.00Hz, 1H) 7.11 (s, 1H) 6.90 (t, J = 4.13Hz, 1H) 6.82 (br d,J=2.63Hz,1H)6.23-6.65(m,1H)5.26(s,2H)5.08(s,2H)1.48(s,9H).

[0610] Intermediate 20

[0611] tert-Butyl (E)-(3-bromo-5-chloro-2-(2-nitrovinyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0613]

[0614] Step 1: tert-Butyl (3-bromo-5-chloro-2-(1-hydroxy-2-nitroethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0615] To a stirred solution of tert-butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (3 g, 6.2 mmol) and nitromethane (1.2 mL, 22.4 mmol, 3.5 equiv) in EtOH (50 mL) cooled to 0°C was added 50% aqueous NaOH (7.2 mL). After stirring at 0°C for 1 hour, the reaction mixture was slowly quenched with 2M HCl (20 mL) and then diluted with water (100 mL). The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 0-50% gradient) to give tert-butyl (3-bromo-5-chloro-2-(1-hydroxy-2-nitroethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (3.4 g, 77%) as a yellow oil. MS m / z 549.6 [M+H] + .

[0616] Step 2: tert-Butyl (E)-(3-bromo-5-chloro-2-(2-nitrovinyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0617] To a solution of tert-butyl (3-bromo-5-chloro-2-(1-hydroxy-2-nitroethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (310 mg, 0.2 mmol) in DCM (2 mL) cooled to 0°C was added methanesulfonyl chloride (0.05 mL, 0.22 mmol, 1.1 equiv) and TEA (0.2 mL, 5 mmol, 2.2 equiv). After stirring for 2 h, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 0-50% gradient) to give tert-butyl (E)-(3-bromo-5-chloro-2-(2-nitrovinyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (300 mg, 93%) as a yellow oil. MS m / z 531.9 [M+H] + . 1 H NMR(chloroform-d)δ:8.41(d,J=13.5Hz,1H),7.64(d,J=13.5Hz,1H),7.24-7.28(m,2H) ,6.92(dd,J=5.0,3.5Hz,1H),6.84(d,J=3.4Hz,1H),5.07(s,2H),1.52(s,9H).

[0618] Example 1

[0619] Preparation of Compound 72, Compound 73, Compound 74 and Compound 75

[0620]

[0621] Step 1: tert-Butyl (3-bromo-5-chloro-2-(2-nitrocycloheptyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0622] To a solution of tert-butyl (3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophene-2-ylmethyl)carbamate (1 g, 2.17 mmol) in THF (10 mL) was added a solution of lithium diisopropylamide (2M) in THF / heptane / ethylbenzene (1.63 mL, 3.26 mmol, 1.5 equiv) at -78 ° C. The mixture was stirred at -78 ° C for 30 minutes. 1-Nitrocyclohept-1-ene (397.8 mg, 2.82 mmol) was then added and the mixture was stirred at -78 ° C for 3 hours. TLC showed that the starting material was retained and a new spot was observed. The reaction mixture was diluted by adding NH4Cl (saturated solution) (125 mL). The organic layer was extracted with EtOAc (125 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and then concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate in petroleum ether (0-50% gradient) to give tert-butyl (3-bromo-5-chloro-2-(2-nitrocycloheptyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (260 mg, 0.43 mmol) as a white solid.

[0623] Step 2: 3-Bromo-5-chloro-2-(2-nitrocycloheptyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0624] To a solution of tert-butyl (3-bromo-5-chloro-2-(2-nitrocycloheptyl)thieno[3,2-b]pyridin-7-yl)(thien-2-ylmethyl)carbamate (50 mg, 0.08 mmol) in CH2Cl2 (8 mL) at 0°C was added TFA (4 mL). After stirring at 25°C for 30 min, the mixture was concentrated in vacuo to give a crude white solid 3-bromo-5-chloro-2-(2-nitrocycloheptyl)-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (40 mg, 0.08 mmol, 96% yield), which was used in the next step without further purification. MS m / z 501.8 [M+H] + .

[0625] Step 3: 2-(2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0626] To a solution of 3-bromo-5-chloro-2-(2-nitrocycloheptyl)-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (150 mg, 0.3 mmol) and zinc (98 mg, 1.5 mmol) in ethanol (8 mL) at 0 °C was added TFA (2 mL, 26.5 mmol). After stirring the reaction at 70 °C for 30 min, the mixture was concentrated and the crude oil was purified by preparative HPLC to give trans-2-(2-aminocycloheptyl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridine-7-amine (25 mg, 0.05 mmol, 18% yield) as an off-white solid and cis-2-(2-aminocycloheptyl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridine-7-amine (60 mg, 0.1 mmol, 43% yield) as an off-white solid.

[0627] Step 4: 2-((1S,2R)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, 2-((1R,2S)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, 2-((1S,2S)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-((1R,2R)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0628] By preparative-SFC (Dr.maish Reprosil Chiral-AM, supercritical CO2 / MeOH (+0.1% 7.0 mol / L Cis-2-(2-aminocycloheptyl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridine-7-amine (60 mg, 0.13 mmol) was purified by HPLC-MS / MS to give 2-[(1R,2R)-2-aminocycloheptyl]-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridine-7-amine (compound 72, 11 mg, 0.02 mmol, 18% yield) and 2-[(1S,2S)-2-aminocycloheptyl]-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridine-7-amine (compound 73, 16 mg, 0.03 mmol, 27% yield) as an off-white solid.

[0629] 2-[(1R,2S)-2-Aminocycloheptyl]-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (compound 74, 2.8 mg, 0.006 mmol, 14% yield) and P2-[(1S,2R)-2-Aminocycloheptyl]-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (compound 75, 2.8 mg, 0.006 mmol, 14% yield) as an off-white solid.

[0630] Compound 72: MS m / z 472.0 [M+H] + ; 1 H NMR(DMSO-d6)δppm 7.97(t,J=5.8Hz,1H),7.40(d,J=5.0Hz,1H),7.10(d,J=2.6Hz,1H),7.00-6.98(m,1 H),6.60(s,1H),4.70(d,J=5.8Hz,2H),3.50(d,J=12Hz,1H),3.31-3.27(m,1H),1.95 -1.77(m,11H),1.23(s,1H).

[0631] Compound 73: MS m / z 472.0 [M+H] + ; 1 H NMR(DMSO-d6)δppm 7.99(t,J=5.8Hz,1H),7.40(d,J=5.2Hz,1H),7.10(d,J=2.6Hz,1H),7.00-6.98(m,1H),6.58(s,1H ), 4.71 (d, J = 6.0Hz, 2H), 3.55 (d, J = 12Hz, 1H), 3.37-3.27 (m, 1H), 2.08-1.43 (m, 11H), 1.25 (s, 1H).

[0632] Compound 74: MS m / z 471.9 [M+H] + ; 1 H NMR(DMSO-d6)δppm 7.96(s,1H),7.40(d,J=4.0Hz,1H),7.10(s,1H),7.05-6.92(m,1H),6.5 7(s,1H),4.72(d,J=5.6Hz,2H),3.20-3.13(m,2H),1.99-1.39(m,12H).

[0633] Compound 75: MS m / z 471.9 [M+H] + ;1 H NMR(DMSO-d6)δppm 7.95(t,J=5.8Hz,1H),7.40(d,J=5.0Hz,1H),7.11(d,J=2.6Hz,1H),7.00-6.98(m ,1H),6.60(s,1H),4.72(d,J=5.8Hz,2H),3.25-3.13(m,2H),1.95-1.45(m,12H).

[0634] According to the procedure of Example 1, by replacing appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641] Example 2

[0642] Preparation of Compound 67 and Compound 68

[0643]

[0644] Step 1: tert-Butyl (7-bromo-2-chloro-6-((1S,2R)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate

[0645] To a solution of tert-butyl (7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (500 mg, 1.1 mmol) in THF (10 mL) was added a solution of lithium diisopropylamide (2M) in THF / heptane / ethylbenzene (0.8 mL, 1.7 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 1 hour. 1-Nitrocyclohex-1-ene (185.7 mg, 1.5 mmol) was then added and the mixture was stirred at -78 ° C for 3 hours. TLC showed that most of the starting material disappeared and a new main spot appeared. The reaction mixture was quenched with saturated ammonium chloride (125 mL) and the organic layer was extracted with EtOAc (125 mL×3). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with (EtOAc / PE=0-50%) to give tert-butyl (7-bromo-2-chloro-6-((1S,2R)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (400 mg, 0.7 mmol, 62% yield) as a white solid. MS m / z 573.0 [M+H] + .

[0646] Step 2: tert-Butyl (7-bromo-2-chloro-6-((1S,2S)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate

[0647] To a solution of tert-butyl (7-bromo-2-chloro-6-((1S,2R)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (329 mg, 0.6 mmol) in THF (10 mL) at 0°C was added DBU (88 mg, 0.6 mmol, 1 eq.). The mixture was stirred at 0°C for 3 hours. The mixture was poured into H2O (50 mL). The organic layer was extracted with EtOAc (50 mL×3), washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with (EtOAc / PE=0-50%) to give tert-butyl (7-bromo-2-chloro-6-((1S,2S)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (221 mg, 0.4 mmol, 67% yield) as a white solid. 1HNMR (chloroform-d) δppm 7.29 (dd, J = 1.8, 0.8 Hz, 1H), 6.32 (d, J = 2.7 Hz, 1H), 6.29 (dd, J = 3.2, 1.8 Hz, 1H), 5.19 (s, 2H), 4.89 (d, J = 4.0 Hz, 1H), 3.95 (d, J = 3.2 Hz, 1H), 2.50 (d, J = 10.0 Hz, 1H), 2.19 (d, J = 14.4 Hz, 1H), 2.10-1.80 (m, 3H), 1.80-1.40 (m, 3H), 1.53 (s, 9H).

[0648] Step 3: 7-Bromo-2-chloro-N-(furan-2-ylmethyl)-6-((1S,2S)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-amine

[0649] To a solution of tert-butyl (7-bromo-2-chloro-6-((1S,2S)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (221 mg, 0.4 mmol) in CH2Cl2 (4 mL) was added TFA (4 mL). The mixture was stirred at 25°C for 1 hour and then concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography eluting with (MeOH / DCM=0-10%) to give 7-bromo-2-chloro-N-(furan-2-ylmethyl)-6-((1S,2S)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-amine (100 mg, 0.2 mmol, 55% yield) as a yellow solid. MS m / z 470.9[M+H] + .

[0650] Step 4: 6-((1R,2R)-2-aminocyclohexyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine and 6-((1S,2S)-2-aminocyclohexyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine

[0651] To a solution of 7-bromo-2-chloro-N-(2-furanylmethyl)-6-[(1S,2S)-2-nitrocyclohexyl]thieno[3,2-d]pyrimidin-4-amine (400 mg, 0.8 mmol) in ethanol (6 mL) and acetic acid ((2 mL, 34.9 mmol) was added iron (785 mg, 14.0 mmol). The mixture was stirred at 65°C for 18 hours. 25 mL of H2O was added to dilute the reaction mixture. The organic layer was extracted with EtOAc (25 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with (MeOH / DCM=0-10%) and then by preparative-SFC ( Supercritical CO2 / MeOH (+0.1% 7.0 mol / L ammonia solution in MeOH) / MeOH) was purified to give 6-((1S,2S)-2-aminocyclohexyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine (Compound 67, 26.4 mg, 18%) as an off-white solid, and 6-((1R,2R)-2-aminocyclohexyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine (Compound 68, 26.3 mg, 18%) as an off-white solid.

[0652] Compound 67: MS m / z 484.1 [M+H] + ; 1 H NMR (methanol-d4) δ ppm 7.43 (dd, J=1.8, 0.8 Hz, 1H), 6.40-6.30 (m, 2H), 4.75 (s, 2H), 3.30-3.20 (m, 1H), 3.10-2.85 (m, 1H), 2.10-2.00 (m, 2H), 2.00-1.80 (m, 2H), 1.60-1.00 (m, 4H) (three exchangeable protons were not observed).

[0653] Compound 68: MS m / z 484.1 [M+H] + ; 1 H NMR (methanol-d4) δ ppm δ: 7.44-7.42 (m, 1H), 6.40-6.30 (m, 2H), 4.75 (s, 2H), 3.30-3.20 (m, 1H), 3.10-2.85 (m, 1H), 2.10-2.00 (m, 2H), 2.00-1.80 (m, 2H), 1.60-1.00 (m, 4H) (three exchangeable protons were not observed).

[0654] According to the procedure of Example 2, by replacing appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672] Example 3

[0673] Preparation of Compound 129 and Compound 138

[0674]

[0675] Step 1: tert-Butyl N-[5-chloro-3-iodo-2-[(1S,2R)-2-nitrocyclohexyl]thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate

[0676] To a solution of tert-butyl N-(5-chloro-3-iodo-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (1.1 g, 2.0 mmol) in THF (10 mL) was added a solution of lithium diisopropylamide (2 M) in THF / heptane / ethylbenzene (1.28 mL) at -78 ° C and stirred for 1 hour, followed by the addition of 1-nitrocyclohexene (2,497.5 mg, 4 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 3 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column eluting with (EtOAc / PE ~ 5.1%) to give tert-butyl N-[5-chloro-3-iodo-2-[(1S,2R)-2-nitrocyclohexyl]thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (1.1 g, 88% yield) as a white solid. MS m / z 633.8 [M+H] + .

[0677] Step 2: N-[5-chloro-2-[(1S,2R)-2-nitrocyclohexyl]-3-phenyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamic acid tert-butyl ester

[0678] To a solution of tert-butyl N-[5-chloro-3-iodo-2-[(1S,2R)-2-nitrocyclohexyl]thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (300 mg, 0.5 mmol) in 1,4-dioxane (6 mL) and H2O (1.2 mL) at 25° C., K2CO3 (163.26 mg, 1.2 mmol) and phenylboronic acid (57.7 mg, 0.473 mmol) were added. The mixture was then stirred at 65° C. for 2.5 hours. The reaction mixture was poured into water and extracted with EtOAc, then washed with brine and dried over Na2SO4, filtered and concentrated to dryness to give the crude product, which was purified by flash column eluting with (EtOAc / PE ~ 15%) to give tert-butyl N-[5-chloro-2-[(1S,2R)-2-nitrocyclohexyl]-3-phenyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (200 mg, 72% yield) as a yellow oil. MS m / z 583.9 [M+H] + .

[0679] Step 3: N-[5-chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamic acid tert-butyl ester

[0680] To a solution of tert-butyl N-[5-chloro-2-[(1S,2R)-2-nitrocyclohexyl]-3-phenyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (200 mg, 0.3 mmol) in THF (5 mL) at 0°C was added diazabicycloundecane (52 mg, 0.3 mmol, 1.0 equiv). The mixture was stirred at 0°C for 5 hours. H2O was added to the mixture and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl N-[5-chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (140 mg, 93% yield) as a light yellow solid. 1 H NMR(chloroform-d)δppm 7.51(t,J=7.3Hz,2H),7.46(d,J=7.2Hz,1H),7.39(d,J=7.0Hz,2H),7.24 (s,1H),6.99(s,1H),6.92–6.88(m,1H),6.83(d,J=3.4Hz,1H),5.03(s,2 H),4.69(td,J=11.4,4.1Hz,1H),3.81–3.71(m,1H),2.37(d,J=12.9Hz,1 H), 2.10 (d, J = 10.6Hz, 1H), 1.98–1.77 (m, 4H), 1.61 (s, 2H), 1.47 (s, 9H).

[0681] Step 4: 5-Chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine

[0682] To a solution of tert-butyl N-[5-chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (140 mg, 0.2 mmol) in DCM (4 mL) was added TFA (4 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to give 5-chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (116 mg, 100% yield) as a crude brown oil. MS m / z 484.0[M+H] + .

[0683] Step 5: 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-phenyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-phenyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0684] To a solution of 5-chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-N-(2-thienylmethyl)thieno[3,2-b]pyridine-7-amine (116 mg, 0.2 mmol) in MeOH (8 mL) and AcOH (2 mL) was added iron (269 mg, 4.8 mmol). The mixture was stirred at 70 °C for 16 hours. The mixture was filtered through celite, then concentrated and purified by flash column, eluting with (MeOH / DCM ~ 6.4%) to give 2-[(1S,2S)-2-aminocyclohexyl]-5-chloro-3-cyclopropyl-N-(2-thienylmethyl)thieno[3,2-b]pyridine-7-amine (8,130 mg) as a yellow oil. The residue was purified by SFC ( OJ, supercritical CO2 / MeOH (+0.1% 7.0 mol / L ammonia solution in MeOH) / MeOH) purified the oil to give 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-phenyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridine-7-amine (compound 129, 28 mg, 22% yield) and 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-phenyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridine-7-amine (compound 138, 42.2 mg, 33% yield) as a white solid.

[0685] Compound 129: MS m / z 454.0 [M+H] + ; 1 H NMR (methanol-d4) δ ppm 7.47 (dd, J = 9.0, 5.7 Hz, 2H), 7.43–7.38 (m, 3H), 7.29 (dd, J = 5.1, 1.2 Hz, 1H), 7.09–7.06 (m, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 6.51 (s, 1H), 4.77 (s, 2H), 2.99–2.81 (m, 2H), 2.07–1.93 (m, 2H), 1.79 (s, 2H), 1.64 (d, J = 11.3 Hz, 1H), 1.51–1.42 (m, 1H), 1.29 (m, 2H) (three exchangeable protons were not observed).

[0686] Compound 138: MS m / z 454.0 [M+H]+ ; 1 H NMR (methanol-d4) δ ppm 7.51 (t, J = 7.2 Hz, 2H), 7.46–7.39 (m, 3H), 7.30 (dd, J = 5.1, 1.2 Hz, 2H), 7.11–7.08 (m, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 4.78 (s, 2H), 3.33 (s, 1H), 3.12 (d, J = 3.5 Hz, 1H), 2.21 (s, 1H), 2.07 (s, 1H), 1.87 (d, J = 10.7 Hz, 2H), 1.82–1.74 (m, 1H), 1.48 (d, J = 11.4 Hz, 1H), 1.38–1.31 (m, 2H) (three exchangeable protons were not observed).

[0687] According to the procedure of Example 3, by replacing appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0688]

[0689]

[0690] Example 4

[0691] Preparation of Compound 103, Compound 104, Compound 105 and Compound 106

[0692]

[0693] Step 1: tert-Butyl (3-bromo-5-chloro-2-(2-nitrocyclooctyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0694] To a solution of 24-1 (1.0 g, 2.17 mmol) in THF (12 mL) was added 2M lithium diisopropylamide (1.63 mL) at -78°C and stirred for 1 hour, then (E)-1-nitrocyclooct-1-ene (506.3 mg, 3.26 mmol) was added at -78°C. The mixture was stirred for 3 hours at -78°C. The reaction mixture was then quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column eluting with (EtOAc / PE~5.1%) to give 24-2 (550 mg, 41% yield) as a white solid. 1H NMR(chloroform-d)δppm 7.22(dd,J=5.1,1.1Hz,1H),7.07(s,1H),6.87(dd,J=5.1,3.5Hz,1H),6.79(d,J=2.9Hz,1H),5.06–4.94(m ,3H),4.27(dt,J=11.0,3.8Hz,1H),2.51–2.32(m,3H),2.10-1.90(m,3H),1.81–1.67(m,6H),1.44(s,9H).

[0695] Step 2: 3-Bromo-5-chloro-2-(2-nitrocyclooctyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0696] To a solution of tert-butyl (3-bromo-5-chloro-2-(2-nitrocyclooctyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (550 mg, 0.89 mmol) in DCM (8 mL) was added TFA (8 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to give 3-bromo-5-chloro-2-(2-nitrocyclooctyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (130 mg, 28% yield) as a crude brown oil. MS m / z 516.0[M+H] + .

[0697] Step 3: 2-((1S,2S)-2-aminocyclooctyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, 2-((1R,2S)-2-aminocyclooctyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-((1S,2R)-2-aminocyclooctyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0698] To a solution of 24-3 (130 mg, 0.25 mmol) in MeOH (8 mL) and AcOH (2 mL) was added iron (82.5 mg, 1.26 mmol). The mixture was stirred at 100 ° C for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, then concentrated and purified by flash column, eluted with (MeOH / DCM ~ 6.4%) to give a white solid. The residue was purified by SFC ( The solid was purified by supercritical CO2 / MeOH (+0.1% 7.0M NH3 in MeOH) / MeOH) to give 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridine-7-amine (Compound 103, 2.3 mg, 3% yield), 2-((1S,2S)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridine-7-amine (Compound 104, 8.9 mg, 3% yield). 11% yield), 2-((1R,2S)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridine-7-amine (compound 105, 1.3 mg, 1.67% yield) and white solid 2-((1S,2R)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridine-7-amine (compound 106, 18.1 mg, 23.21% yield).

[0699] Compound 103: MS m / z 406.0 [M+H] + ; 1 H NMR (methanol-d4) δ ppm 7.29 (dd, J = 5.1, 1.1 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 5.0, 3.5 Hz, 1H), 6.51 (s, 1H), 4.75 (s, 2H), 3.41 (d, J = 6.8 Hz, 1H), 3.21–3.08 (m, 1H), 2.14–1.84 (m, 6H), 1.77–1.58 (m, 6H) (three exchangeable protons were not observed).

[0700] Compound 104: MS m / z 406.0 [M+H] + ; 1 H NMR (methanol-d4) δ ppm 7.29 (dd, J = 5.1, 1.2 Hz, 1H), 7.12 (s, 1H), 7.07 (dd, J = 3.5, 1.1 Hz, 1H), 6.97 (dd, J = 5.1, 3.5 Hz, 1H), 6.49 (s, 1H), 4.74 (s, 2H), 3.50 (dt, J = 10.7, 3.7 Hz, 1H), 3.42–3.34 (m, 1H), 2.21–2.09 (m, 1H), 1.99 (d, J = 13.7 Hz, 1H), 1.91–1.66 (m, 10H) (three exchangeable protons were not observed).

[0701] Compound 105: MS m / z 406.0 [M+H] + ;1 H NMR (methanol-d4) δ ppm 7.29 (dd, J = 5.1, 1.0 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J = 2.6 Hz, 1H), 6.97 (dd, J = 5.0, 3.5 Hz, 1H), 6.53 (s, 1H), 4.75 (s, 2H), 3.63–3.55 (m, 1H), 3.26 (d, J = 7.9 Hz, 1H), 2.15–1.93 (m, 6H), 1.70 (d, J = 67.1 Hz, 6H) (three exchangeable protons were not observed).

[0702] Compound 106: MS m / z 406.0 [M+H] + ; 1 H NMR (methanol-d4) δ ppm 7.29 (d, J = 4.6 Hz, 1H), 7.16 (s, 1H), 7.07 (s, 1H), 7.00–6.90 (m, 1H), 6.51 (s, 1H), 4.75 (s, 2H), 3.57 (s, 2H), 2.10 (s, 2H), 1.89 (s, 3H), 1.72 (d, J = 38.6 Hz, 7H) (three exchangeable protons were not observed).

[0703] According to the procedure of Example 4, by replacing appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0704]

[0705]

[0706] Example 5

[0707] Preparation of compound 31

[0708]

[0709] Step 1: tert-Butyl (2-((2S)-2-((tert-butoxycarbonyl)amino)-1-hydroxycyclohexyl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0710] To a solution of tert-butyl N-(3,5-dichlorothieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (200 mg, 0.4815 mmol) in THF (2 mL) cooled to -78 °C, a solution of lithium diisopropylamide (2.0 M) in THF / heptane / ethylbenzene (0.31 mL, 0.62 mmol, 1.3 equiv) was added. After 15 minutes, a solution of (S)-N-Boc-2-aminocyclohexanone (140 mg, 0.630172 mmol, 1.3 equiv) in THF (1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched with NH4Cl (saturated aqueous solution). The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes (0-50% gradient) to give tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-hydroxy-cyclohexyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (75 mg, 25% yield) as a clear oil. MS m / z 628.3, 630.1 [M+H] + , 1 H NMR(chloroform-d)δ:7.29(s,1H),7.24(dd,J=5.1,0.9Hz,1H),7.03(s,1H),6.90(dd,J=5.0,3.5Hz,1H),6.80(d,J=3.1Hz,1H),5.05(s,2H),4.21(br s,1H),1.80-1.95(m,4H),1.63-1.73(m,2H),1.51-1.63(m,2H),1.48(s,9H),1.30(s,9H).

[0711] Step 2: (2S)-2-amino-1-(3,5-dichloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-ol

[0712] General Boc-deprotection procedure: A solution of tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-hydroxy-cyclohexyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (75 mg, 0.1193 mmol) and HCl (4M) in dioxane (1 mL) was stirred at room temperature for 6 h, the reaction mixture was diluted with ether and filtered. The filter cake was purified on preparative HPLC eluting with 10-100% acetonitrile in water containing 0.1% formic acid to give (2S)-2-amino-1-[3,5-dichloro-7-(2-thienylmethylamino)thieno[3,2-b]pyridin-2-yl]cyclohexanol (28 mg, 50%). MS m / z 427.9, 429.8 [M+H] + , 1 H NMR (Methanol-d4) δ: 7.18-7.22 (m, 1H), 6.98 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 4.9, 3.7 Hz, 1H), 6.47 (s, 1H), 4.66 (s, 2H), 3.81 (dd, J = 11.5, 4.3 Hz, 1H), 2.39-2.57 (m, 1H), 1.75-1.90 (m, 3H), 1.56-1.75 (m, 3H), 1.40-1.56 (m, 1H). HCl salt, (five exchangeable protons were not observed).

[0713] Example 6

[0714] Preparation of compound 32

[0715]

[0716] Step 1: tert-Butyl (2-((1R,2S)-2-((tert-butoxycarbonyl)amino)-1-fluorocyclohexyl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0717] To a solution of tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-hydroxy-cyclohexyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (120 mg, 0.2 mmol) in CH2Cl2 (2 mL) cooled to -78°C was added diethylaminosulfur trifluoride (0.1 mL, 0.8 mmol, 3 equiv). After stirring at -78°C for 1 hour, the reaction was warmed to room temperature and kept for 30 minutes before being quenched with NaHCO3 (saturated aqueous solution). The reaction mixture was diluted with DCM and the organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes (0-40% gradient) to give tert-butyl N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-fluoro-cyclohexyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (58 mg, 48%) as a clear oil. MS m / z 630.1 632.2 [M+H] + , 1 H NMR (chloroform-d) δ: 7.17 (d, J = 5.0Hz, 1H), 6.99 (s, 1H), 6.79-6.84 (m, 1H), 6.73 (d, J = 3.1Hz, 1H), 5.41 (br s,1H),4.96(s,2H),4.11-4.21(m,1H),2.37-2.48(m,1H),2.26-2.37(m,1H),2. 00-2.15(m,2H),1.61-1.72(m,2H),1.48-1.61(m,2H),1.40(s,9H),1.37(s,9H).

[0718] Step 2: Using the general Boc deprotection procedure described in step 2 of Example 5, N-[2-[(2S)-2-(tert-butoxycarbonylamino)-1-fluoro-cyclohexyl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamic acid tert-butyl ester (58 mg, 0.1 mmol) was deprotected to give 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (34 mg, 85%). MS m / z 429.9, 431.8 [M+H] + , 1H NMR (Methanol-d4) δ: 7.20 (d, J = 5.1 Hz, 1H), 6.96-7.00 (m, 1H), 6.85-6.90 (m, 1H), 6.51 (s, 1H), 4.66 (s, 2H), 3.58-3.75 (m, 1H), 2.23-2.45 (m, 1H), 2.05 (br d, J = 10.6 Hz, 1H), 1.87 (br d, J = 11.4 Hz, 1H), 1.71-1.83 (m, 1H), 1.43-1.69 (m, 4H). HCl salt, (four exchangeable protons were not observed).

[0719] According to the procedure of Example 6, by replacing appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0720]

[0721] Example 7

[0722] Preparation of compounds 150 and 151

[0723]

[0724] Step 1: tert-Butyl (3-bromo-5-chloro-2-(3-nitrotetrahydrofuran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0725] To a solution of tert-butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (488 mg, 1.0 mmol, 1.0 equiv) prepared according to the previous procedure in THF (10 mL) was added 1-iodo-3-nitropropane (323 mg, 1.5 mmol, 1.5 equiv). The mixture was cooled to -78 °C, at which time lithium diisopropylamide (1 M in hexanes, 1.3 mL, 1.3 mmol, 1.3 equiv) was added dropwise. The mixture was warmed to room temperature overnight. The mixture was then 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 silica gel column chromatography using ethyl acetate in hexanes (5-35% gradient) to give a diastereomeric mixture of (3-bromo-5-chloro-2-(3-nitrotetrahydrofuran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamic acid tert-butyl ester (368 mg, 64% yield). MS m / z 576.0 [M+H] + .

[0726] Step 2: tert-Butyl (2-(3-aminotetrahydrofuran-2-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0727] The diastereomeric mixture (3-bromo-5-chloro-2-(3-nitrotetrahydrofuran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophene-2-ylmethyl)carbamic acid tert-butyl ester (273 mg, 0.5 mmol, 1.0 equiv) was mixed with iron powder (280 mg, 5 mmol, 10.0 equiv) and acetic acid (5 mL). The mixture was heated at 70 ° C for 2 hours. After the reaction was cooled, the mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with methanol (0.1% NH3) in DCM (0-20% gradient) to give a diastereomeric mixture (2-(3-aminotetrahydrofuran-2-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophene-2-ylmethyl)carbamic acid tert-butyl ester (218 mg, 80% yield). MS m / z 546.0[M+H] + .

[0728] Step 3: 2-(trans-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-(cis-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0729] To a solution of tert-butyl (2-(3-aminotetrahydrofuran-2-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (55 mg, 0.1 mmol, 1.0 equiv) in DCM (2 mL) at room temperature was added trifluoroacetic acid (2 mL). After stirring for 1 hour, the mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography using acetonitrile (0.1% formic acid) in water (0.1% formic acid) (0-40% gradient) to give two separate diastereomers, 2-(trans-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-(cis-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine.

[0730] Compound 150: MS m / z 446.0 [M+H] + ; 1H NMR (Methanol-d4) δ: 8.36 (s, 1H), 7.32 (d, J = 5.1 Hz, 1H), 7.12–7.08 (m, 1H), 7.03–6.97 (m, 1H), 6.63 (s, 1H), 5.41 (s, 1H), 4.78 (s, 2H), 4.38 (td, J = 8.8, 4.2 Hz, 1H), 4.23 (tt, J = 8.3 Hz, 1H), 4.05–3.98 (m, 1H), 2.55–2.42 (m, 1H), 2.20–2.10 (m, 1H). Formate, (four exchangeable protons were not observed).

[0731] Compound 151: MS m / z 446.0 [M+H] + ; 1 H NMR (Methanol-d4) δ: 8.35 (s, 1H), 7.30 (dd, J = 5.1, 1.2 Hz, 1H), 7.12–7.06 (m, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 6.63 (s, 1H), 5.36 (d, J = 4.1 Hz, 1H), 4.77 (s, 2H), 4.41–4.26 (m, 2H), 4.04 (td, J = 9.4, 5.3 Hz, 1H), 2.67 (dt, J = 9.4, 7.0 Hz, 1H), 2.22–2.12 (m, 1H). Formate, (four exchangeable protons were not observed).

[0732] Example 8

[0733] Preparation of compounds 46 and 47

[0734]

[0735] Step 1: tert-Butyl (R,E)-(3-bromo-2-(((tert-butylsulfinyl)imino)methyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0736] Tert-butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (488 mg, 1.0 mmol, 1.0 equiv) prepared according to the previous procedure was dissolved in THF (5 mL). Ti(OEt)4 (456 mg, 2.0 mmol, 2.0 equiv) and (R)-2-methylpropane-2-sulfenamide (182 mg, 1.5 mmol, 1.5 equiv) were added and the vial was heated to 50 °C. The conversion was monitored by LCMS and the mixture was cooled to room temperature after completion. At room temperature, the mixture was poured into an equal volume of brine while stirring rapidly. The resulting suspension was filtered through a plug of diatomaceous earth and the filter cake was washed with EtOAc. The filtrate was transferred to a separatory funnel and the organic layer was washed with brine. The brine layer was extracted once with a small amount of EtOAc and the combined organic portions were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate in hexanes (5-100% gradient) to give tert-butyl (R,E)-(3-bromo-2-(((tert-butylsulfinyl)imino)methyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (561 mg, 95% yield). MS m / z 592.0 [M+H] + .

[0737] Step 2: 2-(3-bromo-7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-1-(tert-butylsulfinyl)piperidine-3-carboxylic acid methyl ester

[0738] To a mixture of tert-butyl (R,E)-(3-bromo-2-(((tert-butylsulfinyl)imino)methyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophene-2-ylmethyl)carbamate (473 mg, 0.8 mmol, 1.0 equiv) in THF (8 mL) was added methyl 5-bromovalerate (234 mg, 1.2 mmol, 1.5 equiv). The reaction mixture was cooled to 0 ° C. Lithium diisopropylamide (1M in hexanes, 1.0 mL, 1.3 equiv) was added dropwise to the reaction. LCMS indicated that the reaction was complete after 1 hour. The reaction was quenched with saturated NH4Cl, then diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate in hexanes (5-50% gradient) to give a diastereomeric mixture of 2-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-1-(tert-butylsulfinyl)piperidine-3-carboxylic acid methyl ester (197 mg, 35% yield). MS m / z 706.1 [M+H] + .

[0739] Step 3: 2-(3-Bromo-7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-1-(tert-butylsulfinyl)piperidine-3-carboxylic acid

[0740] To a solution of methyl 2-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-1-(tert-butylsulfinyl)piperidine-3-carboxylate (353 mg, 0.5 mmol, 1.0 equiv) in MeOH (5 mL) was added lithium hydroxide (24 mg, 1.0 mmol, 2.0 equiv). The reaction mixture was stirred at 50 °C for 4 hours. The reaction was quenched with saturated NH4Cl, then diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate in hexanes (5-100% gradient) to give a diastereomeric mixture of 2-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-1-(tert-butylsulfinyl)piperidine-3-carboxylic acid (296 mg, 84% yield). MS m / z 706.1 [M+H] + .

[0741] Step 4: tert-Butyl (3-bromo-2-(3-((tert-butoxycarbonyl)amino)-1-(tert-butylsulfinyl)piperidin-2-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0742] To a solution of 2-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-1-(tert-butylsulfinyl)piperidine-3-carboxylic acid (141 mg, 0.2 mmol, 1.0 equiv) in tert-butanol (2 mL) was added triethylamine (40 mg, 0.4 mmol, 2.0 equiv) and diphenylphosphoryl azide (83 mg, 0.3 mmol, 1.5 equiv). The reaction was stirred at 90 °C for 3 hours. The reaction was quenched with saturated NH4Cl, then diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate in hexanes (5-50% gradient) to give a mixture of diastereoisomers (tert-butyl (3-bromo-2-(3-((tert-butoxycarbonyl)amino)-1-(tert-butylsulfinyl)piperidin-2-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (70 mg, 46% yield). MS m / z 763.1 [M+H] + .

[0743] Step 5: 2-(trans-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-(cis-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0744] To a solution of tert-butyl (3-bromo-2-(3-((tert-butoxycarbonyl)amino)-1-(tert-butylsulfinyl)piperidin-2-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (152 mg, 0.2 mmol, 1.0 equiv) from step 4 in DCM (2 mL) at room temperature was added 2M HCl in dioxane (1 mL, 2 mmol, 10 equiv). After stirring for 1 h, the mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography with acetonitrile (0.1% formic acid) in water (0.1% formic acid) (0-40% gradient) to give two independent diastereomers, 2-(trans-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-(cis-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine.

[0745] Compound 46: MS m / z 459.0 [M+H] + ; 1H NMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 7.30 (d, J = 5.2 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 6.98 (dd, J = 5.2, 3.5 Hz, 1H), 6.57 (s, 1H), 4.75 (s, 2H), 4.50 (d, J = 2.3 Hz, 1H), 3.53–3.47 (m, 1H), 3.17 (d, J = 12.1 Hz, 1H), 2.86 (td, J = 11.9, 3.0 Hz, 1H), 2.05–1.75 (m, 3H), 1.62–1.52 (m, 1H). Formate, (five exchangeable protons were not observed).

[0746] Compound 47: MS m / z 459.0 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 7.30 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.98 (dd, J = 5.2, 3.5 Hz, 1H), 6.60 (s, 1H), 4.76 (s, 2H), 4.53 (d, J = 2.3 Hz, 1H), 3.63–3.55 (m, 1H), 3.18 (d, J = 11.8 Hz, 1H), 2.88 (dd, J = 13.2, 10.2 Hz, 1H), 2.07–1.90 (m, 2H), 1.89–1.75 (m, 1H), 1.65–1.55 (m, 1H). Formate, (five exchangeable protons were not observed).

[0747] According to the procedure of Example 8, by replacing appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0748]

[0749] Example 9

[0750] Preparation of compounds 147 and 148

[0751]

[0752] Step 1: tert-Butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate

[0753] Tert-butyl (3-bromo-5-chloro-2-iodothieno[3,2-b]pyridin-7-yl)(thiophene-2-ylmethyl)carbamate (584 mg, 1 mmol, 1.0 equiv) (prepared according to the previously described examples) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-1H-aza-1-carboxylate (420 mg, 1.3 mmol, 1.3 equiv) were mixed in 10 mL of dioxane. Catalyst Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 equiv) and 2M K2CO3 aqueous solution (1.25 mL, 2.5 equiv) were added to the reaction. The reaction mixture was vigorously purged with argon for 5 minutes. The reaction was stirred at 80 ° C for 6 hours. The mixture was cooled to room temperature, 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 silica gel column chromatography using ethyl acetate in hexane (5-60% gradient) to give tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (537 mg, 82% yield). MS m / z 656.1[M+H] + .

[0754] Step 2: tert-Butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-hydroxyazepane-1-carboxylate

[0755] A THF solution (6 mL) of tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (524 mg, 0.8 mmol, 1.0 equiv) was cooled to 0°C. A 1M solution of borane THF complex (2.4 mL, 2.4 mmol, 3.0 equiv) was added dropwise to the reaction. The reactants were warmed to room temperature overnight. LCMS showed that the starting material was completely consumed. The reaction was cooled to 0°C, and 2 mL of ethanol, 2M aqueous sodium hydroxide solution (1 mL), and 30% aqueous H2O2 solution (1 mL) were added thereto in sequence. The reaction was warmed to room temperature and stirred for another 2 hours. The reaction mixture was then poured into a separatory funnel and diluted with CH2Cl2. The aqueous layer was washed with CH2Cl2, and the organic layers were combined and dried over Na2SO4. After filtration and removal of the solvent in vacuo, the crude mixture was purified by silica gel chromatography to give tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-hydroxyazepane-1-carboxylate (188 mg, 35% yield). MS m / z 674.1 [M+H] + .

[0756] Step 3: tert-Butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-oxazepane-1-carboxylate

[0757] To a solution of tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-hydroxyazepane-1-carboxylate (337 mg, 0.5 mmol, 1.0 equiv) in DCM (5 mL) was added Dess-Martin periodinane (318 mg, 0.75 mmol, 1.5 equiv). The reaction was stirred at room temperature for 1 hour and quenched with saturated NaHCO3 and saturated Na2S2O3. The reaction mixture was then poured into a separatory funnel and diluted with CH2Cl2. The aqueous layer was washed with CH2Cl2, and the organic layers were combined and dried over Na2SO4. After filtration and removal of the solvent in vacuo, the crude mixture was purified by silica gel chromatography to give tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-oxazepane-1-carboxylate (285 mg, 85% yield). MS m / z 672.1 [M+H] + .

[0758] Step 4: tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-((tert-butylsulfinyl)amino)azepane-1-carboxylate

[0759] Tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-oxazepane-1-carboxylate (168 mg, 0.25 mmol, 1.0 equiv) and (R)-2-methylpropane-2-sulfenamide (61 mg, 0.5 mmol, 2.0 equiv) were mixed in Ti(OEt)4 (3 mL) and heated to 50 °C overnight. After the reaction mixture was cooled to room temperature, THF was added followed by 1 M borane THF complex solution (0.4 mL, 0.4 mmol, 1.6 equiv). The reaction was complete within 10 min. The mixture was added to a stirred K2CO3 aqueous solution. After filtration and removal of the solvent, the crude mixture was purified by silica gel chromatography to give a diastereomeric mixture of tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-((tert-butylsulfinyl)amino)azepane-1-carboxylate (146 mg, 75% yield). MS m / z 777.1 [M+H] + .

[0760] Step 5: 2-(trans-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-(cis-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0761] To a solution of tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-((tert-butylsulfinyl)amino)azepane-1-carboxylate (78 mg, 0.1 mmol, 1.0 equiv) in DCM (2 mL) was added 2M HCl in dioxane (1 mL, 2 mmol, 20 equiv) at room temperature. After stirring for 1 hour, the mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography with acetonitrile (0.1% formic acid) in water (0.1% formic acid) (0 to 40% gradient) to give two independent diastereomers, 2-(trans-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-(cis-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine. MS m / z 473.0 [M+H] + .

[0762] Compound 147: MS m / z 473.0 [M+H] + ; 1 H NMR(DMSO-d6)δ:9.25(brs,1H),8.10(t,J=6.0Hz,2H),7.41(d,J=5.1Hz,1H),7.11( d,J=3.5Hz,1H),6.99(dd,J=5.1,3.5Hz,1H),6.69(s,1H),4.83–4.67(m,2H),4.20–4 .05(m,1H),4.05–3.96(m,1H),3.80–3.65(m,2H),3.30–3.18(m,1H),3.07(t,J=12.0 Hz,1H),2.37–2.27(m,2H),2.24–2.12(m,1H),2.10–2.00(m,1H),1.98–1.85(m,1H).

[0763] Compound 148: MS m / z 473.0 [M+H] + ; 1H NMR(DMSO-d6)δ:9.43(brs,1H,TFApeak),9.21(brs,1H),8.21(brs,2H),8.07(t ,J=6.0Hz,1H),7.41(d,J=5.0Hz,1H),7.11(d,J=3.5Hz,1H),7.00(dd,J=5.0,3. 5Hz,1H),6.70(s,1H),4.85–4.69(m,2H),3.95–3.85(m,1H),3.73–3.63(m,2H), 3.35–3.25(m,2H),3.19(t,J=11.0Hz,1H),2.10–2.02(m,2H),2.02–1.88(m,2H).

[0764] Example 10

[0765] Preparation of Compound 149

[0766]

[0767] Step 1: 2-(trans-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0768] According to the procedure of Example 9, tert-butyl (3-bromo-5-chloro-2-(5,5-dimethyl-2-oxocyclohexyl)thieno[3,2-b]pyridin-7-yl)(thien-2-ylmethyl)carbamate (117 mg, 0.2 mmol) was prepared by substituting the appropriate starting materials. Following the reductive amination / deprotection procedure of Example 11, 2-(trans-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (15 mg, 15% yield) was obtained. MS m / z 486.0 [M+H] + . 1 H NMR (methanol-d4) δ: 8.54 (s, 1H, formic acid), 7.30 (d, J = 5.1 Hz, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 6.60 (s, 1H), 4.76 (s, 2H), 3.60 (td, J = 11.7, 3.8 Hz, 1H), 3.18 (d, J = 11.7 Hz, 1H), 1.99 (dt, J = 13.2, 3.4 Hz, 1H), 1.82–1.69 (m, 2H), 1.66–1.46 (m, 3H), 1.14 (s, 3H), 1.03 (s, 3H). Formate, (four exchangeable protons were not observed).

[0769] According to Example 10, the following compounds were prepared by replacing appropriate raw materials, reagents, reaction conditions, and performing chiral SFC separation as required.

[0770]

[0771]

[0772] Embodiment 11

[0773] Preparation of Compound 139

[0774]

[0775] Step 1: tert-Butyl trans-(3-bromo-5-chloro-2-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0776] A solution of tert-butyl N-(3-bromo-5-chloro-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (1.38 g, 3.0 mmol) and 3,7-dioxabicyclo[4.1.0]heptane (901 mg, 9.0 mmol) in THF (20 mL, 246 mmol, 100 mass%) was cooled at -78°C under argon, followed by dropwise addition of a solution of LDA in THF / hexane. The mixture was stirred at -78°C for 1 hour, the cooling bath was removed and stirred at room temperature for another 1 hour, quenched with NH4Cl (aqueous solution) and stirred for 0.5 hours, extracted with ethyl acetate and dried. The resulting product was purified on a silica gel column, eluted with ethyl acetate in hexane (0-50%) to give tert-butyl (3-bromo-5-chloro-2-(3-hydroxytetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (824 mg, 49% yield). MS m / z 559.9 [M+H] + , 1 H NMR(chloroform-d)δ:7.25(dd,J=5.0,1.0Hz,1H),7.09(s,1H),6.89(dd,J=5.0,3.5Hz,1H),6.80(d,J=3.3Hz,1H),4.97-5.08(m,2H),4.09-4.20(m ,2H),3.99-4.07(m,1H),3.84-3.95(m,1H),3.44-3.60(m,1H),3.25- 3.37(m,1H),2.00-2.04(m,1H),1.81-1.96(m,1H),1.41-1.58(m,9H).

[0777] Step 2: tert-Butyl N-[3-bromo-5-chloro-2-(3-oxotetrahydropyran-4-yl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate

[0778] To a solution of tert-butyl (3-bromo-5-chloro-2-(3-hydroxytetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (824 mg, 1.47 mmol) at 0°C was added Dess-Martin periodinane (965 mg, 2.20 mmol). The cooling bath was removed after the addition and the reaction mixture was stirred at room temperature for 1.5 hours. LC-MS showed complete conversion was achieved. The resulting product was diluted with dichloromethane, washed with sodium thiosulfate, Na2CO3 (aq.), dried and filtered to remove the desiccant. The filtrate was evaporated to dryness and the residue was chromatographed (ethyl acetate in hexane, 0-60%) to give tert-butyl N-[3-bromo-5-chloro-2-(3-oxotetrahydropyran-4-yl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (799 mg, 97% yield). MS m / z 558.7 [M+H] + .

[0779] Step 3: trans-2(-3-aminotetrahydropyran-4-yl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; 2,2,2-trifluoroacetic acid

[0780] A mixture of tert-butyl N-[3-bromo-5-chloro-2-(3-oxotetrahydropyran-4-yl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (400 mg, 0.72 mmol) and ammonium acetate (553 mg, 7.17 mmol) in methanol (1.5 mL) was stirred at room temperature for 30 minutes, and then NaBH3CN (47 mg, 0.72 mmol) was added. The mixture was stirred at room temperature overnight, diluted with ethyl acetate and water and separated. The aqueous layer was extracted with ethyl acetate. The combined organics were washed with water and brine, dried and concentrated. The residue was separated by chromatography (ethyl acetate in hexanes, 0-100%) to give tert-butyl N-[2-[(3R,4S)-3-aminotetrahydropyran-4-yl]-3-bromo-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate. This was dissolved in dichloromethane (2 mL), treated with trifluoroacetic acid (2 mL) at room temperature for 1.5 hours and evaporated. The residue was purified on a preparative C18 column (Sunfire C18) eluted with 0.1% TFA in acetonitrile (0-100%) to give trans-2-(3-aminotetrahydropyran-4-yl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; 2,2,2-trifluoroacetic acid (75 mg, 18% yield). MS m / z 460.0[M+H] + , 1 H NMR (Methanol-d4) δ 7.27-7.34 (m, 1H), 7.05-7.12 (m, 1H), 6.95-7.02 (m, 1H), 6.60-6.68 (m, 1H), 4.76-4.81 (m, 2H), 4.18-4.26 (m, 1H), 4.06-4.15 (m, 1H), 3.68-3.79 (m, 1H), 3.55-3.67 (m, 2H), 3.47-3.55 (m, 1H), 2.04-2.16 (m, 2H). Trifluoroacetate, (four exchangeable protons were not observed).

[0781] According to the procedure of Example 11, by substituting appropriate starting materials, reagents and reaction conditions, and then performing chiral SFC resolution as required, the following compounds were prepared.

[0782]

[0783]

[0784]

[0785] Example 12

[0786] Preparation of Compound 146

[0787]

[0788] Step 1: trans-4-(3-bromo-7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)tetrahydro-2H-pyran-3-yl methanesulfonate

[0789] To a solution of tert-butyl N-[3-bromo-5-chloro-2-(3-hydroxytetrahydropyran-4-yl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (162 mg, 0.29 mmol), N,N-diisopropylamine (101 μL, 0.58 mmol) prepared in Example 11 in dichloromethane (5 mL) was added methanesulfonyl chloride (27 μL, 0.35 mmol) at -50°C and stirred for 0.5 h, then warmed to room temperature and stirred for an additional 0.5 h. LC / MS showed complete conversion was achieved. The reaction was quenched with NaHCO3 (aq.) and the organics were separated and dried, evaporated to dryness and used directly. MS m / z 639.1 [M+H] + .

[0790] Step 2: cis-N-[2-(3-azidotetrahydropyran-4-yl)-3-bromo-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamic acid tert-butyl ester

[0791] The material prepared in step 1 was treated with sodium azide (188 mg, 2.90 mmol) in DMSO (1.0 mL) at 80°C overnight, cooled, diluted with ethyl acetate, washed with water and brine, dried over anhydrous MgSO4, and filtered. Removal of solvent and chromatography (ethyl acetate in hexanes, 0-70%) of the residue afforded tert-butyl N-[2-(3-azidotetrahydropyran-4-yl)-3-bromo-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (24 mg, 14% yield). MS m / z 585.5 [M+H] + .

[0792] Step 3: tert-Butyl cis-(2-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0793] To a solution of cis-N-[2-(3-azidotetrahydropyran-4-yl)-3-bromo-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamic acid tert-butyl ester (24 mg, 0.041 mmol) in tetrahydrofuran (1 mL, 12.3 mmol, 100 mass %) and water (0.25 mL, 14 mmol) was added triphenylphosphine (12 mg, 0.045 mmol). The mixture was stirred at 50 °C for 6 hours and evaporated. The crude residue was used without further purification. MS m / z 559.6 [M+H] + .

[0794] Step 4: 2-(3-aminotetrahydropyran-4-yl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; formic acid

[0795] The above material was treated with dichloromethane (0.5 mL) and trifluoroacetic acid (1 mL) at room temperature for 3 hours and evaporated to dryness. The residue was purified on a Sunfire column using acetonitrile / H2O (0-100%) modified with 0.1% formic acid to give 2-(3-aminotetrahydropyran-4-yl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; formic acid as a white powder (14 mg, 62% yield, 2 steps). MS m / z 459.7 [M+H] + , 1 H NMR (Methanol-d4) δ 8.19-8.43 (m, 1H), 7.30 (d, J = 5.0 Hz, 1H), 7.05-7.13 (m, 1H), 6.94-7.03 (m, 1H), 6.61 (s, 1H), 4.77 (s, 2H), 4.13-4.23 (m, 1H), 3.97-4.13 (m, 2H), 3.85-3.97 (m, 2H), 3.64-3.79 (m, 1H), 2.41-2.58 (m, 1H), 1.92-2.08 (m, 1H). Formate, (four exchangeable protons were not observed).

[0796] Example 13

[0797] Preparation of Compound 127

[0798]

[0799] Step 1: tert-Butyl (2-((1R / S,5S / R,6S / R)-5-((tert-butyldimethylsilyl)oxy)-6-nitrocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0800] To a solution of tert-butyl (E)-(3,5-dichloro-2-(2-nitrovinyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (1.04 g, 2.15 mmol, 1.0 equiv) in toluene (4.3 mL) was added butylated hydroxytoluene (BHT, 118 mg, 0.53 mmol, 0.25 equiv) followed by (E)-(butyl-1,3-diethylenetriamine-1-yloxy)(tert-butyl)dimethylsilane (792 mg, 4.3 mmol, 2.0 equiv). The mixture was carefully purged with nitrogen and sealed, protected from light, at 120 °C before stirring for 24 h. The crude reaction mixture was crudely purified by short silica gel column with ethyl acetate and hexanes (5-30% gradient) to give tert-butyl (2-((1R / S,5S / R,6S / R)-5-((tert-butyldimethylsilyl)oxy)-6-nitrocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate: tert-Butyl (2-((1S / R,2S / R,6R / S)-2-((tert-butyldimethylsilyl)oxy)-6-nitrocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate: a 2:2:1 mixture of tert-butyl (2-((1S / R,2S / R,6R / S)-2-((tert-butyldimethylsilyl)oxy)-6-nitrocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate. The desired positional isomer and diastereomer (tert-butyl 2-((1R / S,5S / R,6S / R)-5-((tert-butyldimethylsilyl)oxy)-6-nitrocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (370 mg) was isolated after C18 chromatography with 0.1% formic acid modified aqueous acetonitrile (30 to 100% gradient). MS m / z 692.1 [M+Na] +1 H NMR(400MHz, chloroform-d)δ:7.21(dd,J=5.2,1.3Hz,1H),7.08(s,1H),6.86(dd,J=5.1,3.5Hz,1H),6.77(d,J=3.5Hz,1H),5.83–5.73(m,1H),5.65 (d,J=10.3Hz,1H),5.08–4.82(m,4H),4.20(td,J=11.3,6.0Hz,1H),2.64–2.42(m,2H),1.43(s,9H),0.85(s,9H),0.08(s,3H),0.00(s,3H).

[0801] Step 2: (1S / R, 5R / S, 6S / R)-6-amino-5-(3,5-dichloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol

[0802] To a solution of tert-butyl (3-chloro-2-((1R / S,5S / R,6S / R)-5-((tert-butyldimethylsilyl)oxy)-6-nitrocyclohex-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (94 mg, 0.14 mmol, 1.0 equiv) in methanol (1.4 mL) were added iron powder (78 mg, 1.4 mmol, 10 equiv) and ammonium chloride (374 mg, 7.0 mmol, 50 equiv) and the resulting suspension was stirred at 70 °C for 16 h. The suspension was neutralized with aqueous sodium bicarbonate and filtered through celite which was washed with ethyl acetate. The resulting bilayer was extracted with ethyl acetate and the combined extracts were washed with saturated sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a residue (87 mg) which was used without further purification. The residue was dissolved in THF (1.1 mL) cooled to 0°C, and tetrabutylammonium fluoride (1.0 M, 0.14 mL) solution was added dropwise. The mixture was stirred at 0°C for another 20 minutes, then quenched with sodium bicarbonate aqueous solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a residue (48 mg) which was used without further purification. The residue was dissolved in a 4M hydrochloric acid solution in dioxane (1 mL), and the solution was heated to 40°C for 40 minutes. At this time the reaction mixture was concentrated in vacuo and purified by C18 chromatography with 0.1% formic acid in acetonitrile in water (30% to 100% gradient) to afford (1S / R,5R / S,6S / R)-6-amino-5-(3,5-dichloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol (30 mg, 50% yield). MS m / z 425.9 [M+H] +1 HNMR (methanol-d4) δ: 7.21 (d, J = 5.1 Hz, 1H), 6.98 (s, 1H), 6.88 (t, J = 4.2 Hz, 1H), 6.51 (s, 1H), 5.71 (d, J = 11.0 Hz, 1H), 5.62 (d, J = 10.5 Hz, 1H), 4.66 (s, 2H), 4.07 (d, J = 8.2 Hz, 1H), 3.54 (q, J = 9.5 Hz, 1H), 3.12 (t, J = 10.1 Hz, 1H), 2.40 (s, 2H) (four exchangeable protons were not observed).

[0803] According to the procedure of Example 13, by substituting appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819] Embodiment 14

[0820] Preparation of compound 24

[0821]

[0822] Step 1: (2S,3S)-methyl 2-(7-((tert-butoxycarbonyl)(2-fluorobenzyl)amino)-3,5-dichlorothieno[3,2-b]pyridin-2-yl)tetrahydro-2H-pyran-3-carboxylate

[0823] To a solution of tert-butyl N-(3,5-dichloro-2-formyl-thieno[3,2-b]pyridin-7-yl)-N-[(2-fluorophenyl)methyl]carbamate (500mg, 1.1mmol) and methyl 5-bromopentanoate (0.2mL, 1mmol) in THF (5mL) cooled to 0°C was added a solution of lithium diisopropylamide (2.0M) in THF / heptane / ethylbenzene (1.2mL, 2.4mmol, 2.3 equivalents). The ice bath was removed and the reaction was stirred at room temperature for 16 hours. The reaction was quenched with NH4Cl (saturated aqueous solution). The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes (0-40% gradient) to give (2S,3S)-2-[7-[tert-butoxycarbonyl-[(2-fluorophenyl)methyl]amino]-3,5-dichloro-thieno[3,2-b]pyridin-2-yl]tetrahydropyran-3-carboxylic acid methyl ester (167 mg, 27% yield) as a light yellow oil. MS m / z 568.8, 570.7 [M+H] + ; 1 HNMR (chloroform-d) δ: 7.21-7.36 (m, 2H), 6.94-7.16 (m, 3H), 5.16 (d, J = 10.1 Hz, 1H), 4.93-5.08 (m, 2H), 4.15-4.22 (m, 1H), 3.63-3.77 (m, 1H), 3.54 (s, 3H), 2.77 (ddd, J = 12.0, 10.1, 3.8 Hz, 1H), 2.15-2.29 (m, 1H), 1.96-2.07 (m, 1H), 1.79 (br s, 2H), 1.43 (s, 9H).

[0824] Step 2: (2S,3S)-2-(7-((tert-Butyloxycarbonyl)(2-fluorobenzyl)amino)-3,5-dichlorothieno[3,2-b]pyridin-2-yl)tetrahydro-2H-pyran-3-carboxylic acid

[0825] A mixture of (2S,3S)-2-[7-[tert-butoxycarbonyl-[(2-fluorophenyl)methyl]amino]-3,5-dichloro-thieno[3,2-b]pyridin-2-yl]tetrahydropyran-3-carboxylic acid methyl ester (167 mg, 0.3 mmol), aqueous lithium hydroxide solution (2.2 mL, 2.2 mmol, 1 mol / L) and methanol (5 mL) was stirred at 50 °C for 2 hours, cooled to room temperature and concentrated. Diluted with DCM and neutralized with 1 M citric acid. The organic phase was separated and concentrated to give crude tert-butyl N-[3,5-dichloro-2-[(2S)-tetrahydropyran-2-yl]thieno[3,2-b]pyridin-7-yl]-N-[(2-fluorophenyl)methyl]carbamate; carbon dioxide (126 mg, 77% yield), which was used in the next step without further purification. MS m / z 554.8,556.8[M+H] + .

[0826] Step 3: tert-Butyl (2-((2S,3S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl)(2-fluorobenzyl)carbamate

[0827] A mixture of tert-butyl N-[3,5-dichloro-2-[(2S)-tetrahydropyran-2-yl]thieno[3,2-b]pyridin-7-yl]-N-[(2-fluorophenyl)methyl]carbamate; carbon dioxide (126 mg, 0.2 mmol), triethylamine (0.06 mL, 0.4 mmol, 2.0 equiv), diphenylphosphoryl azide (0.1 mL, 0.5 mmol, 2.0 equiv) and tert-butyl alcohol (2 mL) was heated at 50° C. for 1 hour. The reaction mixture was then cooled to room temperature and concentrated. The crude residue was purified on silica gel eluting with ethyl acetate in hexanes (0-40%) to give tert-butyl N-[2-[(2S,3S)-3-(tert-butoxycarbonylamino)tetrahydropyran-2-yl]-3,5-dichloro-thieno[3,2-b]pyridin-7-yl]-N-[(2-fluorophenyl)methyl]carbamate (85 mg, 60% yield). MS m / z 625.8, 627.6 [M+H] + ; 1H NMR(chloroform-d)δ:7.22-7.27(m,2H),6.96-7.12(m,3H),5.02(s,2H),4.75(d,J=9.6Hz,1H),4.49-4.61(m,1H),4.16-4.19(m,1H) ),3.66-3.79(m,1H),3.50-3.64(m,1H),2.22-2.33(m,1H),1.78-1.99(m,2H),1.61-1.69(m,1H),1.44(s,9H),1.18(s,9H).

[0828] Step 4: 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine

[0829] A mixture of tert-butyl N-[3,5-dichloro-2-[rac-(2S,3S)-3-(tert-butoxycarbonylamino)tetrahydropyran-2-yl]thieno[3,2-b]pyridin-7-yl]-N-[(2-fluorophenyl)methyl]carbamate (85 mg, 0.1 mmol) and HCl (4M in dioxane) (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated and the solid was triturated with Et2O and filtered to give 3,5-dichloro-N-[(2-fluorophenyl)methyl]-2-[rac-(2S,3S)-3-aminotetrahydropyran-2-yl]thieno[3,2-b]pyridin-7-amine hydrochloride (72 mg, 69% yield). MS m / z 425.9 [M+H] + ; 1 H NMR (methanol-d4) δ: 7.33-7.50 (m, 2H), 7.11-7.23 (m, 2H), 6.78 (s, 1H), 5.01 (d, J = 9.8 Hz, 1H), 4.74 (s, 2H), 4.09-4.23 (m, 1H), 3.67-3.77 (m, 1H), 3.41 (td, J = 10.4, 4.1 Hz, 1H), 2.28-2.41 (m, 1H), 1.82-1.97 (m, 3H) (four exchangeable protons were not observed).

[0830] According to the procedure of Example 14, by substituting appropriate starting materials, reagents and reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0831]

[0832] Embodiment 15

[0833] Preparation of Compound 290

[0834]

[0835] Step 1: tert-Butyl (3-bromo-2-((1S / R,6S / R)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0836] To a solution of tert-butyl (2-((1S / R, 6S / R)-6-aminocyclohex-3-ene-1-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (201 mg, 0.36 mmol) (prepared according to Example 13 using intermediate 20) in THF (1.8 mL) were added potassium carbonate (100 mg, 0.73 mmol, 2.0 equiv) and diisopropylethylamine (0.127 mL, 0.73 mmol, 2.0 equiv). The mixture was stirred until the starting material was consumed as determined by UPLCMS. The reaction mixture was separated between NH4Cl (saturated aqueous solution) (15 mL) and ethyl acetate (15 mL). The aqueous layer was extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine, dried over MgSO4, filtered, and then concentrated on celite. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes to afford tert-butyl (3-bromo-2-((1S / R,6S / R)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (200 mg, 0.31 mmol, 84% yield) as a white solid. MS m / z 677.9 [M+Na] + .

[0837] Step 2: tert-Butyl (3-bromo-2-((1S / R,3S / R,4S / R,6R / S)-4-((tert-butoxycarbonyl)amino)bicyclo[4.1.0]heptane-3-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0838] At 0°C, diethylzinc solution (1M in CH2Cl, 0.46 mL, 0.46 mmol) was added to CH2Cl2 (0.76 mL), followed by the dropwise addition of diiodomethane (0.055 mL, 0.69 mmol). After stirring at 0°C for 1 hour, a solution of tert-butyl (3-bromo-2-((1S / R,6S / R)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (50 mg, 0.076 mmol) in CH2Cl2 (0.2 mL) was added, and the reaction was allowed to warm to 25°C overnight with stirring. The resulting mixture was diluted in CH2Cl2, washed with NH4Cl (saturated aqueous solution) and brine, dried over MgSO4, filtered, and then concentrated onto celite. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes to afford single diastereomers and tert-butyl (3-bromo-2-((1S / R,3S / R,4S / R,6R / S)-4-((tert-butoxycarbonyl)amino)bicyclo[4.1.0]heptane-3-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (31 mg, 0.0.46 mmol, 61% yield) as a white solid. MS m / z 691.9 [M+Na] + .

[0839] Step 3: 2-((1S / R,3S / R,4S / R,6R / S)-4-aminobicyclo[4.1.0]hept-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0840] A solution of tert-butyl (3-bromo-2-((1S / R,3S / R,4S / R,6R / S)-4-((tert-butoxycarbonyl)amino)bicyclo[4.1.0]heptan-3-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (31 mg, 0.046 mmol) in 4M HCl in dioxane (1 mL) was stirred at 30 °C for 30 min. The mixture was basified with 1M NaOH and partitioned between ethyl acetate and water. The free base reaction mixture was concentrated and the crude oil was purified by reverse phase C18 chromatography in TFA modified water and acetonitrile to afford 2-((1S / R,3S / R,4S / R,6R / S)-4-aminobicyclo[4.1.0]heptane-3-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (15 mg, 69% yield) as an off-white solid. MS m / z [M+H] + 470.0; 1H NMR (methanol-d4) δ: 7.33 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 3.4 Hz, 1H), 7.00 (dd, J = 5.1, 3.6 Hz, 1H), 6.66 (s, 1H), 4.79 (s, 2H), 3.50 (td, J = 11.4, 6.1 Hz, 1H), 3.39–3.34 (m, 1H), 2.73–2.62 (m, 1H), 2.42–2.35 (m, 2H), 1.70 (t, J = 12.3 Hz, 1H), 1.33–1.13 (m, 2H), 0.88 (td, J = 8.9, 5.0 Hz, 1H), 0.36 (q, J = 5.3 Hz, 1H). Trifluoroacetate, (four exchangeable protons were not observed).

[0841] Example 16

[0842] Preparation of compound 342

[0843]

[0844] Step 1: tert-Butyl (2-((1S / R,5S / R,6R / S)-6-amino-5-((tert-butyldimethylsilyl)oxy)cyclohex-3-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0845] To tert-butyl (2-((1S / R,5S / R,6R / S)-5-((tert-butyldimethylsilyl)oxy)-6-nitrocyclohex-3-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (3 g, 4.6 mmol, prepared according to Example 13), iron powder (2.06 g, 36.8 mmol, 8.0 equiv) and ammonium chloride (12.3 g, 230 mmol, 50 equiv) was added MeOH (46 mL) and the slurry was stirred at 55° C. until the starting material was consumed as determined by UPLCMS. The reaction mixture was filtered through celite, concentrated in vacuo, and partitioned between 1 M NaOH (200 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give crude orange semisolid tert-butyl (2-((1S / R,5S / R,6R / S)-6-amino-5-((tert-butyldimethylsilyl)oxy)cyclohex-3-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (2.6 g) which was used without further purification. MS m / z 620.6 [M+H] +.

[0846] Step 2: tert-Butyl (2-((1S / R,2R / S,3S / R)-2-amino-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0847] Crude tert-butyl (2-((1S / R,5S / R,6R / S)-6-amino-5-((tert-butyldimethylsilyl)oxy)cyclohex-3-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (750 mg, 1.2 mmol) was added as a solution in MeOH (2 mL) to a slurry of 20% w / w palladium on carbon (300 mg) in MeOH (5 mL) under an inert atmosphere. The resulting mixture was sparged in vacuo with nitrogen and hydrogen before pressurizing to 7 atm under a hydrogen atmosphere and stirred for 5 days. The reaction mixture was filtered through celite and concentrated in vacuo to give crude colorless semisolid tert-butyl (2-((1S / R,2R / S,3S / R)-2-amino-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (746 mg) which was used without further purification. MS m / z 622.5 [M+H] + .

[0848] Step 3: tert-Butyl 2-((1S / R,5S / R,6R / S)-6-amino-5-hydroxycyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0849] To a solution of crude tert-butyl (2-((1S / R,2R / S,3S / R)-2-amino-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (480 mg, 0.77 mmol) in THF (7.7 mL) was added a solution of TBAF (1 M in THF, 2.3 mL, 3 equiv) dropwise over 15 min at 0° C. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo on celite, then purified by silica gel chromatography in a DCM / MeOH gradient to give tert-butyl 2-((1S / R,2R / S,3S / R)-2-amino-3-hydroxycyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (320 mg) as a colorless semisolid. MS m / z 622.5 [M+H] + ; 1 H NMR (chloroform-d) δ: 7.15 (d, J = 5.1 Hz, 1H), 6.91 (s, 1H), 6.79 (t, J = 4.4 Hz, 1H), 6.70 (d, J = 3.4 Hz, 1H), 5.01–4.85 (m, 2H), 3.36 (s, 1H), 3.02–2.91 (m, 1H), 2.58 (s, 1H), 2.34 (s, 3H), 2.00 (d, J = 11.4 Hz, 1H), 1.89–1.71 (m, 2H), 1.70–1.62 (m, 2H), 1.38 (s, 10H). (Three exchangeable protons were not observed).

[0850] Step 4: tert-Butyl (2-((1S / R,2R / S,3S / R)-2-((tert-butoxycarbonyl)amino)-3-hydroxycyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0851] To tert-butyl (2-((1S / R,2R / S,3S / R)-2-amino-3-hydroxycyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (160 mg, 0.31 mmol), DMAP (19 mg, 0.16 mmol, 0.5 eq) and potassium carbonate (131 mg, 0.95 mmol, 3 eq) in THF (3.1 mL) at 0°C was added Boc anhydride solution (1 M in DCM, 0.47 mL, 1.5 eq). The reaction was allowed to warm to room temperature with stirring until the substrate was consumed as seen by UPLCMS, at which point the reaction was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous phase was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo on celite, then purified by silica gel chromatography in an EtOAc / hexanes gradient to afford tert-butyl (2-((1S / R,2R / S,3S / R)-2-((tert-butoxycarbonyl)amino)-3-hydroxycyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (100 mg, 52% yield) as a colorless semisolid. MS m / z 608.1 [M+H] + ; 1 H NMR (chloroform-d) δ: 7.24 (d, J = 5.0Hz, 1H), 6.98 (s, 1H), 6.89 (t, J = 4.2Hz, 1H), 6.80 (s, 1H), 5.05 (s, 2H), 4.43 (s, 1H), 3.74 (s, 1H) ),3.43(t,J=9.2Hz,1H),3.30(s,1H),2.45(s,3H),2.01(d,J=13.2Hz,1H),1.91(s,1H),1.66–1.45(m,13H),1.27(s,9H).

[0852] Step 5: tert-Butyl (2-((1S / R,2R / S,3R / S)-2-((tert-butoxycarbonyl)amino)-3-fluorocyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0853] To tert-butyl (2-((1S / R,2R / S,3S / R)-2-amino-3-hydroxycyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (24.5 mg, 0.04 mmol) in DCM (0.4 mL) in a PTFE vial at 0°C was added diethylaminosulfur trifluoride (DAST, 1 M in DCM, 0.052 mL, 0.052 mmol, 1.3 equiv) and the reaction was stirred at 0°C for 7 h, at which time the reaction was quenched with aqueous sodium bicarbonate and extracted with DCM (2×10 mL). The combined organic layers were washed with aqueous sodium bicarbonate and brine, then dried over MgSO4 and concentrated in vacuo to afford tert-butyl (2-((1S / R,2R / S,3R / S)-2-((tert-butoxycarbonyl)amino)-3-fluorocyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (MS m / z 610.0 [M+H] + ) was used without further purification.

[0854] Step 6: 2-((1S / R,2R / S,3R / S)-2-amino-3-fluorocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0855] To crude tert-butyl (2-((1S / R,2R / S,3R / S)-2-((tert-butoxycarbonyl)amino)-3-fluorocyclohexyl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate was added TFA (0.5 mL) and the solution was heated to 40°C and stirred for 15 minutes. The reaction was purified by C18 reverse phase chromatography in a TFA modified water / MeCN gradient to give 2-((1S / R,2R / S,3R / S)-2-amino-3-fluorocyclohexyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (5 mg). MS m / z[M+H] + 409.9; 1H NMR (methanol-d4) δ: 7.20 (dd, J = 5.1, 1.2 Hz, 1H), 6.98 (dd, J = 3.5, 1.3 Hz, 1H), 6.88 (dd, J = 5.1, 3.5 Hz, 1H), 6.49 (s, 1H), 5.10–4.88 (m, 1H), 4.67 (s, 2H), 3.65–3.44 (m, 2H), 2.30 (s, 3H), 2.19 (s, 1H), 2.00 (d, J = 11.4 Hz, 1H), 1.86–1.61 (m, 4H). Trifluoroacetate, (three exchangeable protons were not observed).

[0856] According to the procedure of Example 16, by substituting appropriate starting materials, reagents and reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0857]

[0858] Embodiment 17

[0859] Preparation of compound 371

[0860]

[0861] Step 1: tert-Butyl (3-bromo-2-((1S / R,5R / S,6R / S)-6-((tert-butoxycarbonyl)amino)-5-methoxycyclohex-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0862] To tert-butyl (3-bromo-2-((1S / R,5R / S,6R / S)-6-((tert-butoxycarbonyl)amino)-5-hydroxycyclohexyl-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (46.8 mg, 0.070 mmol, prepared according to Example 13) and silver(I) oxide (80.8 mg, 0.35 mmol, 5.0 equiv) in acetonitrile (0.35 mL) was added methyl iodide (0.043 mL, 0.70 mmol, 10 equiv) and the resulting mixture was stirred for an additional 3 days. The crude slurry was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, and concentrated onto celite. Purification by silica gel chromatography in a gradient EtOAc / hexanes gave tert-butyl (3-bromo-2-((1S / R,5R / S,6R / S)-6-((tert-butoxycarbonyl)amino)-5-methoxycyclohex-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (23 mg, 48% yield) as a colorless semisolid. MS m / z [M+H] + 685.8; 1 H NMR(chloroform-d)δ:7.25(dd,J=5.1,1.3Hz,1H),7.03(s,1H),6.90(dd,J=5.1,3.5Hz,1H),6.82–6.74(m,1H),5.93–5.80(m,2H),5.13–4.90 (m,2H),4.58(s,1H),4.16(dd,J=10.6,6.5Hz,1H),3.94(q,J=7.4Hz,2H),3.44(s,3H),2.62–2.44(m,2H),1.48(s,9H),1.21(s,9H).

[0863] Step 2: 2-((1S / R,5R / S,6R / S)-6-amino-5-methoxycyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0864] To tert-butyl (3-bromo-2-((1S / R,5R / S,6R / S)-6-((tert-butoxycarbonyl)amino)-5-methoxycyclohex-3-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (23 mg, 0.057 mmol) was added 4M HCl in dioxane (0.5 mL) and the solution was heated to 40 °C with stirring for 30 min, then 2 mL of ether was added. The resulting precipitate was filtered and washed with ether to give (2R / S,3S / R)-2-amino-3-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-one (31 mg, 90% yield). MS m / z [M+H] + 471.7; 1 H NMR(DMSO-d6)δ:8.30–8.20(m,2H),8.16(t,J=6.0Hz,1H),7.42(dd,J=5.1,1.3Hz,1H),7.17–7.06(m,1H),7.00(dd,J=5.1,3.5Hz,1H),6.69(s,1H), 4.82–4.62(m,3H),4.54(s,1H),3.72(t,J=11.7Hz,1H),3.57(s,1H),2.88 (td,J=14.0,6.0Hz,1H),2.28–2.06(m,3H),1.76(t,J=13.6Hz,1H).HCl salt.

[0865] Embodiment 18

[0866] Preparation of Compound 192

[0867]

[0868] Step 1: tert-Butyl (3-bromo-2-((1S / R,2R / S)-2-((tert-butoxycarbonyl)amino)-3-oxocyclohexyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0869] To tert-butyl (3-bromo-2-((1S / R,2R / S,3R / S)-2-((tert-butoxycarbonyl)amino)-3-hydroxycyclohexyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (49 mg, 0.073 mmol, prepared according to Example 13), sodium bicarbonate (61.2 mg, 0.73 mmol, 10.0 equiv) and Dess-Martin periodinane (DMP, 46.3 mg, 0.11 mmol, 1.5 equiv) in DCM (0.35 mL) was added water (0.0013 mL, 0.073 mmol, 1.0 equiv) and the resulting mixture was stirred for an additional 2 h. The reaction was quenched with 1:1 saturated aqueous sodium thiosulfate:saturated aqueous sodium bicarbonate (2 mL) while stirring for 30 min. The crude slurry was separated between water and DCM, extracted with DCM, the combined organic layers were washed with brine, dried over MgSO4, and concentrated on diatomaceous earth. Purified by silica gel chromatography in gradient EtOAc / hexanes, a colorless semisolid (3-bromo-2-((1S / R, 2R / S)-2-((tert-butoxycarbonyl)amino)-3-oxocyclohexyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophene-2-ylmethyl)carbamic acid tert-butyl ester (38 mg, 78% yield) was obtained. 1 H NMR(chloroform-d)δ:7.46–6.53(m,4H),5.38–4.86(m,2H),4.77–4.37(m,1H),3.61(td,J=12.1,3.6 Hz,1H),2.95–2.47(m,2H),2.47–2.09(m,3H),2.02–1.71(m,1H),1.48(s,9H),1.21(s,9H).

[0870] Step 2: (2R / S,3S / R)-2-amino-3-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-one

[0871] To tert-butyl (3-bromo-2-((1S / R,2R / S)-2-((tert-butoxycarbonyl)amino)-3-oxocyclohexyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (38 mg, 0.035) was added TFA (0.5 mL) and the solution was heated to 40 °C with stirring for 15 min. The reaction was purified by C18 reverse phase chromatography in a TFA modified water / MeCN gradient to give 2-((1S / R,5R / S,6R / S)-6-amino-5-methoxycyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (30 mg, 89% yield). MS m / z [M+H] + 486.0; 1 H NMR(DMSO-d6)δ:8.13(s,3H),7.41(dd,J=5.1,1.3Hz,1H),7.12(d,J=3.4Hz,1H),7.00(dd,J=5.1,3.4Hz,1H),6.68(d,J=2.1 Hz,1H),5.95(d,J=11.7Hz,2H),4.75(d,J=5.0Hz,2H),4.19(s,1H),3.73(s,1H),3.57(s,1H),3.40(s,3H)2.60–2.52(m,2H).

[0872] Embodiment 19

[0873] Preparation of compound 307

[0874]

[0875] Step 1: tert-butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-(pyridin-3-ylethynyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0876] To an oven-dried 10 mL vial, Pd(PPH3)2Cl2 (4 mg, 0.006 mmol), CuI (2 mg, 0.012 mmol) and racemic-2-((1S,6S)-6-aminocyclohex-3-ene-1-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine (70 mg, 0.099 mmol) were added. The vial was placed under an argon stream for 10 minutes. 3-Ethynylpyridine (103 mg, 0.996 mmol), Et3N (0.67 mL) and THF (0.67 mL) were then added and the solution was stirred overnight under an argon atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL) and then washed with water (2×5 mL) followed by a brine solution (5 mL). Dry over anhydrous Na2SO4, filter and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate in hexanes (5-70% gradient) to give tert-butyl rac-(2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-(pyridin-3-ylethynyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (48.4 mg, 72% yield) as a white solid. MS m / z 677.3 [M+H] + .

[0877] Step 2: rac-2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(pyridin-3-ylethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0878] To a solution of tert-butyl rac-(2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-(pyridin-3-ylethynyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (48 mg, 0.071 mmol, 1.0 equiv) in DCM (1.5 mL) was added trifluoroacetic acid (1.5 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography using acetonitrile (0.1% trifluoroacetic acid) in water (0.1% trifluoroacetic acid) (0-70% gradient) to give rac-2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(pyridin-3-ylethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine. MS m / z 477.3 [M+H] + ; 1H NMR(400MHz, methanol-d4)δ:8.92(s,1H),8.62(d,J=5.0Hz,1H),8.36–8.22(m,1H),7.64–7.61 (m,1H),7.32(d,J=5.0Hz,1H),7.11(d,J=3.0Hz,1H),7.00–6.98(m,1H),6.67(s,1H),5.9 4 (d, J = 10.2 Hz, 1H), 5.82 (d, J = 10.1 Hz, 1H), 4.79 (s, 2H), 4.00–3.94 (m, 1H), 3.91–3.74 (m, 1H), 2.83–2.72 (m, 2H), 2.71–2.63 (m, 1H), 2.45–2.28 (m, 1H). Trifluoroacetate (four exchangeable protons were not observed).

[0879] According to the procedure of Example 19, by substituting appropriate starting materials, reagents and reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0880]

[0881]

[0882]

[0883]

[0884] Example 20 Preparation of Compound 445

[0885]

[0886] Step 1: tert-Butyl (E)-(5-chloro-3-methyl-2-(3-oxoprop-1-en-1-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0887] To a solution of tert-butyl (5-chloro-2-formyl-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (6.9 g, 16.3 mmol) in toluene (100 mL) was added (triphenylphosphaneylidene)acetaldehyde (5.46 g, 18 mmol, 1.1 equiv). After stirring at 110 °C for 12 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM / PE 0-60% gradient) to give tert-butyl (E)-(5-chloro-3-methyl-2-(3-oxoprop-1-en-1-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (5.6 g, 76%) as a yellow solid. MS m / z 449.0 [M+H] + .

[0888] Step 2: (4S,5S)-4-(7-((tert-Butyloxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-nitrocyclohex-1-ene-1-carboxylic acid ethyl ester

[0889] To a solution of tert-butyl (E)-(5-chloro-3-methyl-2-(3-oxoprop-1-en-1-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (5.6 g, 12.5 mmol) was added ethyl 2-(diethoxyphosphoryl)-4-nitrobutyrate (4.45 g, 15 mmol, 1.2 equiv) (prepared according to the procedure described in J. Med. Chem. 2005, 48, 3516-3521), (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (812 mg, 2.5 mmol, 0.2 equiv), DABCO (1.4 g, 12.5 mmol, 1.0 equiv) and LiClO4 (1.33 g, 12.5 mmol, 1.0 equiv). After stirring at room temperature for 48 hours, the reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / PE 0-15% gradient) to give (4S,5S)-ethyl 4-(7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-nitrocyclohex-1-ene-1-carboxylate (1.1 g, 15%) as a yellow solid. MS m / z 592.0 [M+H] + .

[0890] Step 3: (4S,5S)-5-amino-4-(7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid ethyl ester

[0891] To a solution of (4S,5S)-4-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-nitrocyclohex-1-ene-1-carboxylic acid ethyl ester (500 mg, 844 mmol) in MeOH (18 mL) and H2O (2 mL) were added iron powder (472 mg, 8.4 mol, 10 eq) and NH4Cl (903 mg, 17 mmol, 2.0 eq). After stirring the reaction mixture at 70°C for 12 h, the reaction mixture was cooled to room temperature, filtered through a celite pad, and washed with MeOH (50 mL×2). The filtrate was concentrated to give crude yellow solid (4S,5S)-ethyl 5-amino-4-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylate (450 mg, 95%), which was used without further purification. MS m / z 562.0 [M+H] + .

[0892] Step 4: (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid ethyl ester

[0893] To a solution of ethyl (4S,5S)-5-amino-4-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylate (450 mg, 800 mmol) in DCM (5 mL) was added TFA (2 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo and purified by reverse phase silica gel chromatography (MeCN / H2O 5-95% gradient) and then by preparative SFC (Dr.Maish Reprosil Chiral-AM, supercritical CO2 / MeOH (+0.1% 7.0 mol / L NH3 in MeOH) / MeOH) to give (4S,5S)-5-amino-4-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid ethyl ester (35 mg, 10%) as a white solid. MS m / z 462.0 [M+H] + ;]+ ; 1 H NMR (Methanol-d4) δ: 7.34-7.25 (m, 1H), 7.09–7.01 (m, 2H), 6.99–6.94 (m, 1H), 6.58-6.49 (m, 1H), 4.72 (s, 2H), 4.26-4.12 (m, 2H), 3.40-3.34 (m, 2H), 2.91–2.82 (m, 1H), 2.80-2.65 (m, 1H), 2.59-2.49 (m, 1H), 2.45-2.25 (m, 4H), 1.33-1.25 (m, 3H). (Three exchangeable protons were not observed).

[0894] According to the procedure of Example 20, by substituting appropriate starting materials, reagents and reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0895]

[0896] Embodiment 21

[0897] Preparation of Compound 446

[0898]

[0899] Step 1: (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid

[0900] (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid ethyl ester was hydrolyzed according to the procedure described in step 2 of Example 22 to give (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid (30 mg, 60%) as a white solid. MS m / z 433.9 [M+H] + ; 1 H NMR(methanol-d4)δ:7.35-7.25(m,1H),7.18-7.05(m,2H),7.05-6.95(m,1H),6.54(s,1H),4.75(s,2H),4.60(s,2H) ,3.82-3.65(m,2H),3.05-2.97(m,1H),2.90-2.87(m,1H),2.75-2.68(m,1H),2.62-2.54(m,1H),2.40(s,3H).

[0901] Embodiment 22

[0902] Preparation of Compound 274

[0903]

[0904] Step 1: (4S,5S)-4-(7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-((tert-butoxycarbonyl)amino)cyclohex-1-ene-1-carboxylic acid ethyl ester

[0905] To a solution of (4S,5S)-5-amino-4-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid ethyl ester (280 mg, 0.5 mmol) (prepared according to Example 20) in THF (5 mL) was added Boc2O (217 mg, 1.0 mmol, 2 equiv) and TEA (151 mg, 1.5 mmol, 3 equiv). After stirring at room temperature for 12 hours, the reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel column chromatography (EA / PE 0-15% gradient) to give (4S,5S)-4-(7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-((tert-butoxycarbonyl)amino)cyclohex-1-ene-1-carboxylic acid ethyl ester (320 mg, 98%) as a white solid. MS m / z 661.9 [M+H] + .

[0906] Step 2: (4S,5S)-4-(7-((tert-Butyloxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-((tert-Butyloxycarbonyl)amino)cyclohex-1-ene-1-carboxylic acid

[0907] To a solution of ethyl (4S,5S)-4-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-((tert-butoxycarbonyl)amino)cyclohex-1-ene-1-carboxylate (290 mg, 0.44 mmol) in a mixture of THF (4 mL), MeOH (1 mL) and H2O (1 mL) was added lithium hydroxide monohydrate (92 mg, 2.2 mmol, 5 eq). After stirring at room temperature for 3 h, the reaction mixture was diluted with H2O (20 mL), acidified to pH 5 with 1 M HCl, and extracted with EtOAc (20 mL×2). The combined organics were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo to give a crude white solid (4S,5S)-4-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-((tert-butoxycarbonyl)amino)cyclohex-1-ene-1-carboxylic acid (260 mg, 94%). MS m / z 634.0 [M+H] + .

[0908] Step 3: tert-Butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)-4-carbamoylcyclohex-3-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0909] To a solution of (4S,5S)-4-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-methylthieno[3,2-b]pyridin-2-yl)-5-((tert-butoxycarbonyl)amino)cyclohex-1-ene-1-carboxylic acid (100 mg, 0.16 mmol) in DMF (2 mL) were added HATU (73 mg, 0.19 mmol, 1.2 eq), NH4Cl (42 mg, 0.8 mmol, 5 eq) and DIEA (102 mg, 0.8 mmol, 1.2 eq). After stirring at room temperature for 12 h, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL×2). The combined organics were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude yellow oil (tert-butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)-4-carbamoylcyclohex-3-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (99 mg, 99%), which was used without further purification. MS m / z 633.1 [M+H] + .

[0910] Step 4: (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxamide

[0911] According to the procedure described in step 2 of Example 5, tert-butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)-4-carbamoylcyclohex-3-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-yl)(thien-2-ylmethyl)carbamate was deprotected to give (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxamide (54 mg, 79%) as a white solid. MS m / z 433.1 [M+H] + ; 1 H NMR(methanol-d4)δ:7.29(t,J=4.9Hz,1H),7.07(t,J=5.8Hz,1H),6.97(dd,J=8.4,4.6Hz,1H),6.80(d,J=29.9Hz,1H ), 6.61 (d, J = 5.4Hz, 1H), 4.76 (d, J = 11.6Hz, 2H), 3.91–3.60 (m, 2H), 3.06–2.45 (m, 4H), 2.42 (d, J = 7.7Hz, 3H).

[0912] According to the procedure of Example 22, by replacing appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0913]

[0914] Embodiment 23

[0915] Preparation of Compound 246

[0916]

[0917] Step 1: 3-Methyl-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-5-carbonitrile

[0918] A mixture of tert-butyl (5-chloro-3-methyl-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (prepared according to the procedure described in Example 13) (1.0 g, 0.4 mmol), zinc cyanide (900 mg, 1.5 mmol, 4 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (110 mg, 0.2 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium (88 mg, 0.1 mmol, 0.2 equiv) and DMF (10 mL) was heated in a microwave reactor at 160 ° C for 1 hour. The reaction mixture was allowed to cool to room temperature and diluted with water (50 mL). The aqueous solution was extracted with EtOAc (50 mL×2). The combined organics were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / Hex 0-50% gradient) to give 3-methyl-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-5-carbonitrile (280 mg, 35%) as a white solid. MS m / z 411.1 [M+H] + .

[0919] Step 2: tert-Butyl (2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-chloro-5-cyanothieno[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate

[0920] According to the procedure described in step 4 of Example 2, 3-methyl-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-5-carbonitrile was reduced and then separated by SFC (using the conditions described in Example 1) to give 3-methyl-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-5-carbonitrile (70 mg, 30%) as a white solid. MS m / z 381.2 [M+H]+; 1 H NMR (400 MHz, methanol-d4) δ: 7.32–7.26 (m, 1H), 7.13–7.05 (m, 1H), 7.01–6.94 (m, 1H), 6.91 (s, 1H), 5.82–5.70 (m, 2H), 4.80 (s, 2H), 3.41–3.32 (m, 1H), 3.22–3.11 (m, 1H), 2.55–2.31 (m, 6H), 2.20–2.00 (m, 1H).

[0921] According to the procedure of Example 23, by substituting appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required, the following compounds were prepared.

[0922]

[0923] Embodiment 24

[0924] Preparation of Compound 199

[0925]

[0926] Step 1: 3,5-Dichlorothieno[3,2-b]pyridin-7-ol

[0927] To a solution of 3,5,7-trichlorothieno[3,2-b]pyridine (30 g, 126 mmol) in a mixture of DMSO (300 mL) and H2O (60 mL) was added NaOH (12.6 g, 314 mmol, 2.5 equiv). After stirring at 110 °C for 12 h, the reaction mixture was cooled to room temperature, diluted with H2O (300 mL), and acidified to pH 5 with concentrated HCl. The mixture was filtered to give 3,5-dichlorothieno[3,2-b]pyridine-7-ol (27 g, 98%) as a yellow solid, which was used without further purification. MS m / z 219.8 [M+H] + .

[0928] Step 2: 3,5-Dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine

[0929] To a solution of 3,5-dichlorothieno[3,2-b]pyridine-7-ol (27 g, 123 mmol) and TEA (85.3 mL, 613 mmol, 5 equiv) in DMF (200 mL) at 0°C was added MOMBr (30 mL, 368 mmol, 3 equiv). After stirring at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (500 mL) and washed with water (500 mL×5) and brine (500 mL×2). The organic solution was dried over Na2SO4, filtered, and concentrated in vacuo. The crude solid was purified by silica gel column chromatography (EA / PE 0-20% gradient) to give 3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine (20 g, 62%) as a yellow solid. MS m / z 263.8[M+H] + .

[0930] Step 3: 3,5-Dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine-2-carbaldehyde

[0931] According to the procedure described in step 1 of intermediate 1, 3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine (20 g, 76 mmol) was used to obtain crude yellow solid 3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine-2-carbaldehyde (22.1 g, 99%). MS m / z 291.8 [M+H] + .

[0932] Step 4: (E)-3,5-dichloro-7-(methoxymethoxy)-2-(2-nitrovinyl)thieno[3,2-b]pyridine

[0933] According to the procedure described in steps 2 and 3 of Intermediate 1, 3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine-2-carbaldehyde (22 g, 75 mmol) was used to give (E)-3,5-dichloro-7-(methoxymethoxy)-2-(2-nitrovinyl)thieno[3,2-b]pyridine (21 g, 83%) as a yellow solid. MS m / z 335.2 [M+H] + .

[0934] Step 5: 3,5-dichloro-7-(methoxymethoxy)-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)thieno[3,2-b]pyridine

[0935] According to the procedure described in step 1 of Example 13, 3,5-dichloro-7-(methoxymethoxy)-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)thieno[3,2-b]pyridine (7 g, 21 mmol) was used to give a crude yellow oil (E)-3,5-dichloro-7-(methoxymethoxy)-2-(2-nitrovinyl)thieno[3,2-b]pyridine (23 g, 99%). MS m / z 388.8 [M+H] + .

[0936] Step 6: (1S,6S)-6-(3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-amine

[0937] According to the procedure described in step 2 of Example 13, 3,5-dichloro-7-(methoxymethoxy)-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)thieno[3,2-b]pyridine (23 g, 59 mmol) was used to give a crude yellow solid (1S,6S)-6-(3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-amine (20 g, 94%). MS m / z 359.0 [M+H] +.

[0938] Step 7: 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-ol

[0939] To a solution of crude (1S,6S)-6-(3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-amine (20 g, 56 mmol) in EtOAc (200 mL) was added 4M HCl (solution in dioxane, 20 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to give a crude yellow solid 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-ol (17 g, 97%), which was used without further purification. MS m / z 315.0 [M+H] + .

[0940] Step 8: tert-Butyl ((1S,6S)-6-(7-((tert-butoxycarbonyl)oxy)-3,5-dichlorothieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate

[0941] To a solution of crude 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-ol (17 g, 28 mmol) in THF (30 mL) was added TEA (20 mL, 141 mmol, 5 eq) and Boc2O (12.3 g, 57 mmol, 2 eq). After stirring at room temperature for 12 h, the reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel column chromatography (EA / PE 0-15% gradient) to give tert-butyl ((1S,6S)-6-(7-((tert-butoxycarbonyl)oxy)-3,5-dichlorothieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate (9.5 g, 48%) as a yellow oil. MS m / z 414.8 [M-Boc+H] + .

[0942] Step 9: tert-Butyl ((1S,6S)-6-(3,5-dichloro-7-hydroxythieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate

[0943] To a solution of tert-butyl ((1S,6S)-6-(7-((tert-butoxycarbonyl)oxy)-3,5-dichlorothieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate (9.5 g, 18 mmol) in methanol (20 mL) was added NaOEt (2.5 g, 37 mmol, 2 equiv). After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo to give a crude yellow solid tert-butyl ((1S,6S)-6-(3,5-dichloro-7-hydroxythieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate (4.5 g, 59%) which was used without further purification. MS m / z 414.8 [M+H] + .

[0944] Step 10: 2-((1S,6S)-6-((tert-Butoxycarbonyl)amino)cyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate

[0945] To a solution of crude 2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate (3.0 g, 7.2 mmol) in pyridine (30 mL) cooled to 0°C was added TF2O (1.8 mL, 10.8 mmol, 1.5 equiv). After stirring at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×5) and brine (200 mL×2). The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / PE 0-10% gradient) to give 2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate (2.5 g, 63%) as a white solid. MS m / z 546.8 [M+H] + .

[0946] Step 11: tert-Butyl ((1S,6S)-6-(3,5-dichloro-7-((oxazol-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate

[0947] A mixture of 2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate (500 mg, 0.9 mmol), oxazol-2-ylmethylamine hydrochloride (148 mg, 1.1 mmol, 1.2 equiv), K3PO4 (156 mg, 4 mmol, 4 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22 mg, 0.02 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium (17 mg, 0.01 mmol, 0.1 equiv) and dioxane (10 mL) was stirred at 110° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by silica gel column chromatography to give tert-butyl ((1S,6S)-6-(3,5-dichloro-7-((oxazol-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate (200 mg, 44%) as a yellow oil. MS m / z 494.9 [M+H] + .

[0948] Step 12: 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(oxazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0949] According to the procedure described in step 2 of Example 5, tert-butyl ((1S,6S)-6-(3,5-dichloro-7-((oxazol-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate (200 mg, 0.4 mmol) was deprotected to give 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(oxazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (33 mg, 21%) as a white solid. MS m / z 395.1 [M+H] + ; 1 H NMR (methanol-d4) δ: 7.95-6.85 (m, 1H), 7.24-7.10 (m, 1H), 6.70-6.59 (m, 1H), 5.85-5.70 (m, 2H), 4.65 (s, 2H), 3.59–3.50 (m, 1H), 3.28-3.14 (m, 1H), 2.60–2.38 (m, 3H), 2.30-2.05 (m, 1H).

[0950] Embodiment 25

[0951] Preparation of compound 393

[0952]

[0953] Step 1: rac-2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-3-carbonitrile

[0954] A dried 8 mL reaction vial was charged with Pd(PPH3)4 (11.6 mg, 0.01 mmol, 0.1 equiv), zinc cyanide (7 mg, 0.06 mmol, 0.6 equiv) and tert-butyl rac-(2-((3R,4S)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (70.6 mg, 0.1 mmol) prepared according to the procedure in Example 11. DMF (1 mL) was added to the mixture and the solution was degassed with argon. The sealed vial was heated at 100°C overnight. After cooling, 0.2 mL NH4Cl (saturated aqueous solution) and 0.2 mL NaHCO3 (saturated aqueous solution) were added. The mixture was filtered and washed with DCM (0.5 mL×3). The combined filtrates were concentrated and purified by preparative HPLC eluting with 10-100% acetonitrile in water containing 0.1% TFA to give rac-2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-3-carbonitrile (16.2 mg, 40% yield). MS m / z 405.1 [M+H] + ; 1 H NMR (methanol-d4) δ: 7.32 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 3.5 Hz, 1H), 6.99 (dd, J = 5.1, 3.5 Hz, 1H), 6.70 (s, 1H), 4.79 (s, 2H), 4.08 (dd, J = 12.7, 3.6 Hz, 1H), 4.03–3.96 (m, 1H), 3.93–3.84 (m, 1H), 3.84–3.78 (m, 1H), 3.75 (dt, J = 10.0, 5.2 Hz, 1H), 3.64 (ddd, J = 12.2, 9.1, 4.0 Hz, 1H), 2.00–1.85 (m, 2H). (Three exchangeable protons were not observed).

[0955] Embodiment 26

[0956] Preparation of compound 324

[0957]

[0958] Step 1: tert-butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-(propan-1,2-diethylenetriamine-1-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0959] To an oven dried 8 mL reaction vial was charged PPH3 (39.3 mg, 0.15 mmol, 1.5 equiv), N-isopropylidene-N'-2-nitrobenzenesulfonyl hydrazine (IPNBSH) (33.9 mg, 0.15 mmol, 1.5 equiv) and tert-butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-(3-hydroxyprop-1-yn-1-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (63.0 mg, 0.1 mmol) prepared according to the procedure of Example 19. Anhydrous THF (1.0 mL) was added to the reaction vial. The solution was cooled to 0 °C and DIAD (30.3 mg, 0.15 mmol, 1.5 equiv) was added dropwise. After 5 min, the solution was warmed to room temperature and stirred for 2 h. A 1:1 mixture of trifluoroethanol / H2O was added and the mixture was stirred overnight. The crude mixture was concentrated in vacuo and then purified by silica flash column chromatography on silica gel eluting with 0-100% ethyl acetate in hexanes to give tert-butyl racemate (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-(propan-1,2-diethylenetriamine-1-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (27.6 mg, 45% yield). MS m / z 614.2 [M+H] + .

[0960] Step 2: rac-2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(propane-1,2-diethylenetriamine-1-yl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0961] The Boc group was removed following the general procedure described in step 2 of Example 19 to give rac-2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(propan-1,2-diethylenetriamine-1-yl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (13.6 mg, 73% yield). MS m / z 414.1 [M+H] +; 1 H NMR (methanol-d4) δ: 7.30 (dd, J=5.1, 1.2Hz, 1H), 7.08 (dd, J=3.5, 1.2Hz, 1H), 6.98 (dd, J=5 .1,3.5Hz,1H),6.75(t,J=7.1Hz,1H),6.58(s,1H),5.94–5.87(m,1H),5.80–5.74(m, 1H), 5.28–5.08 (m, 2H), 4.76 (s, 2H), 4.06 (td, J=9.3, 5.7 Hz, 1H), 3.73 (td, J=9.3, 5.4 Hz, 1H), 2.72–2.58 (m, 2H), 2.59–2.43 (m, 1H), 2.34–2.23 (m, 1H). (Three exchangeable protons were not observed).

[0962] Embodiment 27

[0963] Preparation of compound 303

[0964]

[0965] Step 1: tert-butyl (rac-(1S,6S)-6-(7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-iodothieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)(methyl)carbamate

[0966] To a solution of tert-butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (70 mg, 0.1 mmol) (prepared according to the procedure of Example 13) in THF (1.0 mL) was added dropwise a solution of sodium bis(trimethylsilyl)amide (1.0 mol / L) in THF (0.12 mL, 0.12 mmol, 1.2 equiv) followed by methyl trifluoromethanesulfonate (24.5 mg, 0.15 mmol, 1.5 equiv) at -78 °C. The reaction was stirred at -50 °C for 1 hour and then quenched with saturated aqueous NH4Cl. 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 0-100% ethyl acetate in hexanes to give tert-butyl (rac-(1S,6S)-6-(7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chloro-3-iodothieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)(methyl)carbamate (53.7 mg, 75% yield). MS m / z 716.1 [M+H] + .

[0967] Step 2: tert-Butyl (rac-(1S,6S)-6-(7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-(4-hydroxybut-1-yn-1-yl)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)(methyl)carbamate

[0968] Addition of the alkynyl group following the general procedure described in step 1 of Example 19 afforded tert-butyl (rac-(1S,6S)-6-(7-((tert-butoxycarbonyl)(thien-2-ylmethyl)amino)-5-chloro-3-(4-hydroxybut-1-yn-1-yl)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)(methyl)carbamate (42.3 mg, 86% yield). MS m / z 658.2 [M+H] + .

[0969] Step 3: 4-(5-chloro-2-(rac-(1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol

[0970] The Boc group was removed following the general procedure described in step 2 of Example 19 to give 4-(5-chloro-2-(rac-(1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol (17.7 mg, 60% yield). MS m / z 458.1 [M+H] + ; 1 H NMR (methanol-d4) δ: 7.30 (dd, J = 5.1, 1.3 Hz, 1H), 7.09 (dd, J = 3.6, 1.3 Hz, 1H), 6.98 (dd, J = 5.1, 3.6 Hz, 1H), 6.62 (s, 1H), 5.93 (d, J = 10.3 Hz, 1H), 5.81 (d, J = 10.3 Hz, 1H), 4.76 (s, 2H), 3.95–3.84 (m, 2H), 3.81 (t, J = 6.1 Hz, 2H), 2.77 (t, J = 6.1 Hz, 2H), 2.74 (s, 3H), 2.70–2.60 (m, 3H), 2.42–2.30 (m, 1H). (Three exchangeable protons were not observed.

[0971] According to Example 27, the following compounds were prepared by replacing appropriate starting materials, reagents, reaction conditions, and performing chiral SFC separation as required.

[0972]

[0973] Embodiment 28

[0974] Preparation of Compound 259

[0975]

[0976] Step 1: tert-Butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0977] At -78 ° C, to N- (3-bromo-5-chloro-thieno [3,2-b] pyridin-7-yl) -N- (2-thienylmethyl) carbamic acid tert-butyl ester (5g, 11mmol) (prepared according to the procedure described in WO2020 / 17430) in THF (50mL) solution, 2M lithium diisopropylamide (6mL, 1.2 equivalents) was added and stirred for 1 hour, followed by DMF (2.4g) at -78 ° C. After stirring for another 3 hours at -78 ° C, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (2×100mL). The combined organics were dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (DCM / PE 1:3) to give tert-butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (5.1 g, 96%) as a pale yellow solid. MS m / z 488.8 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ: 10.32 (s, 1H), 7.23 (d, J = 7.1 Hz, 2H), 6.87 (dd, J = 4.9, 3.6 Hz, 1H), 6.81 (d, J = 3.3 Hz, 1H), 5.06 (s, 2H), 1.47 (s, 9H).

[0978] Step 2: tert-Butyl (3-bromo-5-chloro-2-(1-hydroxy-2-nitroethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0979] To a solution of NaOH (1M aqueous solution, 36 mL) in MeOH (120 mL) cooled to -10°C was added tert-butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (14.4 g, 30 mmol), followed by dropwise addition of a solution of nitromethane (2.16 g, 30 mmol, 1.0 equiv) in MeOH (50 mL). After stirring at 0°C for 1 hour, the reaction mixture was poured into water (300 mL) and extracted with EtOAc (3×400 mL). The combined organic phases were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (EA / PE 0-15% gradient) to give tert-butyl (3-bromo-5-chloro-2-(1-hydroxy-2-nitroethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (13.3 g, 82%) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ: 7.23 (dd, J=5.1, 1.1Hz, 1H), 6.88 (dd, J=5.1, 3.5Hz, 1H), 6.80 (d, J=2.6Hz, 1H), 5.95 (dd, J=6.4, 3.3 Hz,1H),5.09-4.96(m,2H),4.78(dd,J=13.5,2.6Hz,1H),4.60(dd,J=13.5,9.6Hz,1H),4.17(t,J=8.2Hz,1H),1.48(s,9H).

[0980] Step 3: tert-Butyl (3-bromo-5-chloro-2-(2-nitroacetyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0981] To a solution of tert-butyl N-[3-bromo-5-chloro-2-(1-hydroxy-2-nitro-ethyl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (13.3 g, 24 mmol) in DCM (130 mL) cooled to 0°C, Na2CO3 (3.98 g, 48 mmol, 2 eq) and Dess-Martin periodinane (15.1 g, 35.6 mmol, 1.5 eq) were added. After stirring at 0°C for 3 hours, hexane (400 mL) was added and the solution was stirred at room temperature for 10 minutes. The solution was then filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / PE, 0-20% gradient) to give tert-butyl N-[3-bromo-5-chloro-2-(2-nitroacetyl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (11 g, 83%) as a yellow solid. MS m / z 548.0 [M+H]+ .

[0982] Step 4: tert-Butyl (3-bromo-5-chloro-2-(3-methylene-5-nitro-3,4-dihydro-2H-pyran-6-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0983] To a solution of tert-butyl N-[3-bromo-5-chloro-2-(2-nitroacetyl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (11 g, 20.12 mmol) in DMF (110 mL) was added 3-iodo-2-(iodomethyl)prop-1-ene (11.55 g, 37.51 mmol, 1.9 equiv) and DIPEA (6.49 g, 50.2 mmol, 2.5 equiv). After stirring at 60 °C for 2 h, the reaction mixture was cooled to room temperature and diluted with water (100 mL). The aqueous phase was extracted with EtOAc (3×100 mL) and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / PE 0-20% gradient) to give tert-butyl N-[3-bromo-5-chloro-2-(5-methylene-3-nitro-4H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (5.5 g, 46%) as a colorless oil. MS m / z 599.7 [M+H] + .

[0984] Step 5: tert-Butyl (3-bromo-5-chloro-2-(5-methylene-3-nitrotetrahydro-2H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0985] To a solution of tert-butyl N-[3-bromo-5-chloro-2-(5-methylene-3-nitro-4H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate (5.5 g, 9.2 mmol) in chloroform (165 mL) and 2-propanol (33 mL) at 25°C, silica gel (14.6 g) and NaBH4 (1.3 g, 34 mmol, 3.7 equiv) were added. After stirring at room temperature for 2 h, the reaction mixture was quenched with aqueous NH4Cl (1 M, 100 mL), diluted with water, and extracted with EtOAc (3×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / PE 0-20% gradient) to give a mixture of diastereomers (tert-butyl 3-bromo-5-chloro-2-(5-methylene-3-nitrotetrahydro-2H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (2.7 g, 2.0 mmol, 67%). MS m / z 602.0 [M+H] + .

[0986] Step 6: tert-Butyl (3-bromo-5-chloro-2-((2S,3S)-5-methylene-3-nitrotetrahydro-2H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

[0987] To a solution of tert-butyl (3-bromo-5-chloro-2-(5-methylene-3-nitrotetrahydro-2H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (680 mg, 1.1 mmol) in THF (20 mL) at 0°C and N2 was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (86 mg, 0.56 mmol, 0.5 equiv). The mixture was stirred at 0°C for 2 hours, then quenched with water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / PE 0-20% gradient) to give tert-butyl (3-bromo-5-chloro-2-((2S,3S)-5-methylene-3-nitrotetrahydro-2H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (260 mg, 38%) as a white solid. MS m / z 602.0 [M+H] + .

[0988] Step 7: rac-2-((2S,3S)-3-amino-5-methylenetetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0989] To a solution of tert-butyl (3-bromo-5-chloro-2-((2S,3S)-5-methylene-3-nitrotetrahydro-2H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (1 g, 2 mmol) in EtOH (15 mL) and AcOH (5 mL) at 25° C., iron (1.55 g, 28 mmol, 2.9 equiv) was added. After stirring at 65° C. for 12 hours, the reaction mixture was cooled to room temperature, filtered, and rinsed with DCM (50 mL×2). The filtrate was concentrated and the crude residue was purified by silica gel column chromatography (MeOH / DCM 0-10% gradient) to give rac-2-((2S,3S)-3-amino-5-methylenetetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (870 mg, 92%) as a yellow solid. MS m / z 471.8 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ: 7.29 (dd, J = 5.1, 1.2 Hz, 1H), 7.08 (dd, J = 3.5, 1.0 Hz, 1H), 6.97 (dd, J = 5.1, 3.5 Hz, 1H), 6.63 (s, 1H), 5.14 (t, J = 12.2 Hz, 3H), 4.76 (s, 2H), 4.41 (d, J = 12.6 Hz, 1H), 4.26 (d, J = 12.7 Hz, 1H), 3.46 (ddd, J = 11.7, 9.7, 4.7 Hz, 1H), 2.95 (dd, J = 13.5, 4.0 Hz, 1H), 2.66 (d, J = 12.3 Hz, 1H) (three exchangeable protons were not observed).

[0990] Embodiment 29

[0991] Preparation of Compound 284

[0992]

[0993] Step 1: rac-2-((2S,3S,5S)-3-amino-5-methyltetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine

[0994] To a 1.0 mL solution of rac-2-((2S,3S)-3-amino-5-methylenetetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (23.6 mg, 0.05 mmol) (prepared according to the procedure of Example 28) in MeOH, Pd / C (10 wt.% loading, 10.6 mg, 0.01 mmol, 0.2 equiv) was added. Hydrogen was sparged into the reaction mixture using a hydrogen balloon for 5 minutes. The reaction was then allowed to stir at room temperature under a hydrogen balloon for 2 hours. The catalyst was filtered off and washed with MeOH. The mixture was concentrated and purified by flash column chromatography on silica gel eluting with 0-40% methanol in DCM to give rac-2-((2S,3S,5S)-3-amino-5-methyltetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (20.8 mg, 88% yield). MS m / z 472.0 [M+H] + ; 1 H NMR (methanol-d4) δ: 7.30 (dd, J = 5.1, 1.3 Hz, 1H), 7.12–7.06 (m, 1H), 6.98 (dd, J = 5.1, 3.6 Hz, 1H), 6.64 (s, 1H), 4.98 (d, J = 9.4 Hz, 1H), 4.77 (s, 2H), 3.88–3.83 (m, 2H), 3.73–3.59 (m, 1H), 2.24–2.14 (m, 1H), 2.14–2.00 (m, 2H), 1.28 (d, J = 7.1 Hz, 3H). (Three exchangeable protons were not observed).

[0995] Biological Examples

[0996] The following in vitro biological examples demonstrate the effectiveness of the compounds of the present description for treating SCA3.

[0997] In order to describe and help understand this specification in more detail, the following non-limiting biological examples are provided to more fully illustrate the scope of this specification, but should not be interpreted as specifically limiting its scope. Such variations of this specification that are now known or later developed that can be determined by those skilled in the art are considered to fall within the scope of this specification and are claimed below.

[0998] Example 1

[0999] Analysis of endogenous total ATXN3 (tATXN3) protein

[1000] Meso-Scale Discovery (MSD) 96-well or 384-well plates were coated with 0.5 μg / mL Ataxin3 mouse monoclonal antibody (Invitrogen, MA3-082) in PBS overnight at 4°C (30 μL per well). The plates were washed three times with 5% BSA (Meso Scale Diagnostics, R93BA-1; 5% BSA in PBS) and then washed three times with washing buffer at room temperature for 2 h.

[1001] The test compound was serially diluted 3.16 times in 100% DMSO to obtain a 7-point concentration curve. An aliquot of 0.5 μL of the diluted compound was transferred to a 96-well flat bottom plate by a liquid handler. An aliquot of 0.5 μL of DMSO was also transferred to different wells and used as a control. Replicates were set for each compound concentration and DMSO control.

[1002] The cells were thawed and incubated in cell culture medium (DMEM, 10% FBS and 1% antibiotic mixture) for 72 hours. The cells were trypsinized, counted, and resuspended in cell culture medium to a concentration of 100,000 cells / mL. 100 μL aliquots of the cell suspension were plated in a 96-well microtiter plate containing the compound at a density of 10,000 cells per well and incubated in a cell culture incubator (37°C, 5% CO2, 100% relative humidity). After 48 hours, the culture medium was removed and 50-100 μL of 1X halt protease inhibitor cocktail (Thermo Scientific, Halt TM Protease Inhibitor Cocktail, 78430) in lysis buffer (Meso Scale Diagnostics, R60TX-2) to provide "cell lysate". The plate was placed on a shaker at 4°C for 30 minutes and then stored at -80°C.

[1003] Cell lysate samples (25 μL) were transferred to the antibody-coated MSD plates and incubated overnight at 4°C. After the lysate was removed, the plates were washed three times with wash buffer and 25 μL of Ataxin 3 recombinant rabbit monoclonal antibody (Invitrogen, #702788) secondary antibody (at 0.05% -20 blocking buffer diluted to 0.25μg / mL) was added to each well and incubated with shaking at room temperature for 1-2h. After incubation with the secondary antibody, the wells were rinsed with washing buffer, and then 25μL of anti-rabbit antibody goat (Anti Rabbit Antibody Goat) SULFO-TAG labeled (Meso Scale Diagnostics, R32AB-1) detection antibody (at 0.05% -20 blocking buffer diluted to 0.25 μg / mL) and incubated with shaking at room temperature for 1 hour. After washing three times with wash buffer, 150 μL of surfactant-containing reading buffer T (tris-based buffer containing tripropylamine, Meso Scale Diagnostics, R92TC-1) was added to each empty well and the plate was imaged on an SI 6000 Imager (MSD) according to the manufacturer's instructions for 96-well or 384-well plates. The average IC of representative compounds tested is shown in Table 1 50 Value (μM).

[1004] Average IC 50 >1 μM is indicated by one star (*), between >0.3 μM and ≤1 μM is indicated by two stars (**), between >0.03 μM and ≤0.3 μM is indicated by three stars (***), and ≤0.03 μM is indicated by four stars (****).

[1005] Table 1

[1006]

[1007]

[1008]

[1009]

[1010]

[1011] Example 2

[1012] RT-qPCR detection of exon 4 skipping of ATXN3 pre-mRNA in quantified cells

[1013] The test compound was serially diluted 3.16 times in 100% DMSO to obtain a 7-point concentration curve. An aliquot of 0.5 μL of the diluted compound was transferred to a 96-well flat bottom plate by a liquid handler. An aliquot of 0.5 μL of DMSO was also transferred to different wells and used as a control. Replicates were set for each compound concentration and DMSO control.

[1014] The cells were thawed and incubated in cell culture medium (DMEM, 10% FBS and 1% antibiotic mixture) for 72 hours. The cells were trypsinized, counted, and resuspended in cell culture medium to a concentration of 100,000 cells / mL. An aliquot of 100 μL of the cell suspension was plated in a 96-well microtiter plate containing the compound at a density of 10,000 cells per well and cultured in a cell culture incubator (37° C., 5% CO 2 , 100% relative humidity).

[1015] After 24 hours, the culture medium was aspirated from the cells and 50 μL of RCL2 lysis buffer (10 mM Tris-HCL pH 7.4, 150 mM NaCl, 0.33% CA-630) was added to each well and incubated at room temperature for 1 minute. Nuclease-free chilled water (50 μL per well) was added and the plate was immediately transferred to ice. After 1 minute on ice, the plate was frozen at -80°C overnight.

[1016] Preparation of RT-qPCR reaction mixture:

[1017]

[1018] Using a liquid handler, 2 μL / well aliquots of the cell lysate were transferred to an Armadillo 384-well PCR plate containing 8 μL / well of the RT-qPCR reaction mixture prepared as detailed above. TM The plate was sealed with optical adhesive film, then rotated for 1 minute and placed in a CFX384 thermal cycler (BioRad).

[1019] RT-qPCR was performed at the following temperatures for the indicated times:

[1020] Step 1: 48°C (30 minutes)

[1021] Step 2: 95°C (10 minutes)

[1022] Step 3: 95°C (15 seconds)

[1023] Step 4: 60°C (1 minute);

[1024] Then, repeat steps 3 and 4 for a total of 40 cycles.

[1025] The percentage of exon 4 skipping for each dose of compound treatment was calculated using Equations 1 and 2.

[1026] Equation 1

[1027]

[1028] Equation 2

[1029]

[1030] The data were fitted to a dose-response curve and used Statistics and curve fitting software packages for IC 50 Table 2 shows the IC values ​​of representative compounds tested. 50 Value (μM).

[1031] Average IC 50 >1 μM is indicated by one star (*), between >0.3 μM and ≤1 μM is indicated by two stars (**), between >0.03 μM and ≤0.3 μM is indicated by three stars (***), and ≤0.03 μM is indicated by four stars (****).

[1032] Table 2

[1033]

[1034]

[1035]

[1036]

[1037] All documents cited herein are incorporated by reference into this application for any and all purposes, regardless of whether or not a document cited herein is specifically and individually indicated as incorporated by reference, to the same extent as if each individual reference was fully set forth herein.

[1038] Having now fully described the claimed subject matter, those of ordinary skill in the art will appreciate that the same may be implemented within a broad range of equivalents without affecting the scope of the subject matter or the specific aspects described herein. It is intended that the appended claims be interpreted to include all such equivalents.

Claims

1. A compound of formula (I) or a form thereof: in A is selected from CR A and N; A' is selected from S and NR A’ The group composed of; L is selected from the group consisting of CH2 and CD2; R A Selected from hydrogen, halogen, C 1-6 Alkyl and C 3-8 A group consisting of cycloalkyl groups; R A’ Selected from hydrogen, C 1-4 Alkyl and halo-C 1-4 A group consisting of alkyl groups; R B Selected from hydrogen and C 1-6 A group consisting of alkyl groups; R1 is selected from phenyl, heteroaryl, C 3-8 Cycloalkyl, CO2C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 A group consisting of alkynyl groups; Wherein heteroaryl is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S; Among them C 3-8 Cycloalkyl is a saturated or partially unsaturated monocyclic or bicyclic ring system; Among them, phenyl, heteroaryl and C 3-8 The cycloalkyl group is replaced by 0, 1, 2, 3 or 4 independently selected R 1a Substituent substitution, R 1a Selected from cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, deuterated-C 1-6 Alkyl and C 1-6 A group consisting of alkoxy groups; R 2 Selected from hydrogen, cyano, halogen, C 2-6 Alkynyl, C 1-6 Alkoxy-C 2-6 Alkynyl and Hydroxyl-C 2-6 A group consisting of alkynyl groups; R 3 Selected from hydrogen, cyano, halogen, hydroxyl, SH, C 1-6 Alkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, C 1-6 Alkoxy, halo-C 1-6 Alkoxy, thio-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy-C 2-6 Alkynyl, Hydroxyl-C 2-6 Alkynyl, (CH3)3Si-C 2-6 Alkynyl, Heteroaryl-C 2-6 Alkynyl, C 3-8 The group consisting of cycloalkyl, phenyl and heteroaryl, wherein heteroaryl is a 5-11 membered monocyclic or bicyclic aromatic carbon atom ring structure group containing 1-3 heteroatoms selected from N, O and S, and Among them C 3-8 Cycloalkyl, phenyl and heteroaryl are each independently substituted with 0, 1, 2, 3 or 4 independently selected R 3a Substituent substitution; R 3a Selected from cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, deuterated-C 1-6 Alkyl and C 1-6 A group consisting of alkoxy groups; Ring Q is R 4 Selected from hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy and halo-C 1-6 A group consisting of alkoxy groups; R 5 Selected from amino, C 1-4 Alkyl-amino and (C 1-4 alkyl)2-amino group; W is selected from CH2, CD2, CH-R W , CD-R W , C(R W )2 and C(O); X is selected from CH2, CD2, CH-R X , CD-R X , C(R X )2. CH, CD, CR X , C=CH2, C=CD2, C=C(R X )2. C(O), NH, NC 1-4 the group consisting of alkyl, N-phenyl, O, S, S(O) and SO2; Y is selected from CH2, CD2, CH-R Y , CD-R Y , C(R Y )2. CH, CD, CR Y , C=CH2, C=CD2, C=C(R Y )2. the group consisting of N-phenyl, O, S, S(O), and SO2; Z is selected from CH2, CD2, CH-R Z , CD-R Z , C(R Z )2. CH, CD, CR Z , NH, NC 1-4 the group consisting of alkyl, N-phenyl, O, S, S(O) and SO2; Each R W , R X , R Y , R Z Independently selected from halogen, hydroxyl, C 1-6 Alkyl, halo-C 1-6 Alkyl, C 1-6 Alkoxy, halo-C 1-6 Alkoxy, amino, C 1-4 Alkyl-amino, (C 1-4 Alkyl)2-amino, CO2H, CO2C 1-6 Alkyl, C(O)NH2, C(O)N(C 1-6 alkyl)2, C(O)-heterocyclyl and C(O)NH-phenyl, and each R W , R X , R Y , R Z may combine to form a carbocyclic or heterocyclic ring; n is selected from the group consisting of 0, 1, 2, and 3; and When the valence permits, independently represent a single bond or a double bond; The compound is in the form of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form thereof.

2. The compound according to claim 1, wherein the compound is a compound of formula (Ia) or a form thereof: in L is CH2 or CD2; R A It is hydrogen; R B is hydrogen or CH3; and R 2 It is Cl or CN.

3. The compound according to claim 1, wherein the compound is a compound of formula (Ib) or a form thereof: in L is CH2; R B is hydrogen; and R 2 It is Cl.

4. The compound according to claim 1, wherein the compound is a compound of formula (Ic) or a form thereof: in L is CH2; R A It is hydrogen; R A’ is CH3 or CHF2; R B is hydrogen; and R 2 It is Cl.

5. The compound according to claim 1, wherein the compound is a compound of formula (Id) or a form thereof: in L is CH2; R A’ It is CHF2; R B is hydrogen; and R 2 It is Cl.

6. A compound according to any one of claims 1 to 5, wherein R 1 It is phenyl, CO2CH3, 7. A compound according to any one of claims 1 to 6, wherein R 3 is hydrogen, cyano, Cl, Br, I, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CH2F, CH2OH, CH2OCHF2, CH=CH2, CH=C=CH2, cyclopropyl, phenyl, 8. A compound according to any one of claims 1 to 7, wherein Q is: or any stereoisomeric form thereof.

9. A compound according to any one of claims 1 to 8, wherein R 4 is hydrogen, F or hydroxy; and R 5 It is amino, NH(CH3) or N(CH3)2.

10. A compound according to any one of claims 1 to 9, wherein R W , R X , R Y , R Z Each independently selected from F, hydroxyl, CH3, OCH3, CO2H, CO2CH2CH3, C(O)NH2, C(O)N(CH3)2, 11. A compound selected from the group consisting of: 2-((1S,2S)-2-aminocyclopentyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclopentyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclopentyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclopentyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-[(2S,3S)-3-aminotetrahydropyran-2-yl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 3-Bromo-5-chloro-2-[(2R,3S)-3-aminotetrahydropyran-2-yl]-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; 3-Bromo-5-chloro-2-[(2S,3R)-3-aminotetrahydropyran-2-yl]-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclohexyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-5-chlorothieno[3,2-b]pyridin-7-amine; 2-(3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-amino-4,4-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-amino-4,4-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (1R,2S)-2-amino-1-(3,5-dichloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-ol; 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(2-fluorobenzyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1R,2R)-2-aminocyclohexyl)-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((1S,2S)-2-aminocyclohexyl)-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3S)-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,2R)-2-aminocyclohexyl)-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((1S,2S)-2-aminocyclohexyl)-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,2R)-2-aminocyclohexyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((1S,2S)-2-aminocyclohexyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-[(1S,2S)-2-aminocyclohexyl]-N-benzyl-7-bromo-2-chloro-thieno[3,2-d]pyrimidin-4-amine; 6-((1R,2R)-2-aminocyclohexyl)-N-benzyl-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine; 6-((1R,2R)-2-aminocyclohexyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,2S)-2-aminocyclohexyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocycloheptyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocycloheptyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocycloheptyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocycloheptyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminobicyclo[3.2.1]octan-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminobicyclo[3.2.1]octan-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocycloheptyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocycloheptyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclooctyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclooctyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclooctyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclooctyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclooctyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclooctyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclooctyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclooctyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclooctyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclooctyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclooctyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclooctyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclooctyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclooctyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclopentyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-amino-1-fluorocyclopentyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclooctyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3S)-3-amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; (1R,5S,6R)-6-amino-5-(3,5-dichloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol; (1S,5R,6S)-6-amino-5-(3,5-dichloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol; 6-((1R,2S)-2-amino-1-fluorocyclopentyl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-phenyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-cyclopropyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-5-chloro-3-phenyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; ((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-5-chloro-3-phenyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-cyclopropyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-cyclopropyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-3-phenyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-5-chloro-3-phenyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1S,6RS)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6SR)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((4R,5R)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((4S,5S)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((4R,5S)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((4S,5R)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3S)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-amino-4,4-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-amino-4,4-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (1R,5S,6R)-6-amino-5-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol; (1S,5R,6S)-6-amino-5-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol; 2-((1R,2R)-2-aminocyclopentyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclooctyl)-5-chloro-3-ethyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclopentyl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine; 2-((1S,2S)-2-aminocyclohexyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 5-(2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 4-(2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol; 4-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S,6R)-2-amino-6-fluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R,6S)-2-amino-6-fluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-7-iodo-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-N-(furan-2-ylmethyl)-3-iodothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; (2R,3S)-2-amino-3-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-one; (2S,3R)-2-amino-3-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-one; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-3-bromo-5-chloro-N-(pyridin-4-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(pyridin-4-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(oxazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-(but-2-yn-1-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(pyridin-4-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-4-aminotetrahydro-2H-pyran-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((6R)-6-amino-2,2-difluorocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((6S)-6-amino-2,2-difluorocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-ethynylthieno[3,2-b]pyridin-7-amine; (R)-5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1,2-diol; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 4-(2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol; 4-(2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(pyridin-4-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-7-bromo-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; (S)-5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1,2-diol; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-3-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-(but-2-yn-1-yl)-2-chloro-7-iodothieno[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (3S,4S)-4-amino-3-(3,5-dichloro-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-one; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-7-methyl-N-(thiazol-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-1-(difluoromethyl)-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-1-(difluoromethyl)-N-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1R,2R)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-(prop-1-yn-1-yl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-(prop-1-yn-1-yl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (1R,2R,3S)-2-amino-3-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-ol; (1S,2S,3R)-2-amino-3-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-2-chloro-7-iodothieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-amino-3,4-dimethylcyclohex-3-en-1-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-7-methyl-N-(pyridin-4-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)hex-5-yn-1-ol; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-((3-fluoropyridin-4-yl)methyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1S,2S)-2-aminocyclohexyl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-((3-fluoropyridin-4-yl)methyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-chloro-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridine-5-carbonitrile; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2,7-dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-methyl-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-5-carbonitrile; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thien-3-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-7-bromo-2-chloro-5-(difluoromethyl)-N-(thien-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-amino-3,4-dimethylcyclohex-3-en-1-yl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-(but-2-yn-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(pyridin-4-ylmethyl)thieno[3,2-b]pyridin-7-amine; 3-(2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)prop-2-yn-1-ol; 3-(2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)prop-2-yn-1-ol; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-N-((3-fluoropyridin-4-yl)methyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-5-(difluoromethyl)-7-iodo-N-(thien-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 3-(6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-4-((furan-2-ylmethyl)amino)thieno[3,2-d]pyrimidin-7-yl)prop-2-yn-1-ol; 3-(6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-4-((furan-2-ylmethyl)amino)thieno[3,2-d]pyrimidin-7-yl)prop-2-yn-1-ol; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-((difluoromethoxy)methyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-((difluoromethoxy)methyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-amino-5-methylenetetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-amino-5-methylenetetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-1-(difluoromethyl)-N-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-2,7-dichlorothieno[3,2-d]pyrimidin-4-amine; 5-(5-chloro-2-((1S,2S)-2-(methylamino)cyclohexyl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-N-(thien-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-7-methyl-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-1-(difluoromethyl)-N-(furan-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2,7-dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-1-(difluoromethyl)-N-(furan-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxamide; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine; (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid ethyl ester; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((2R)-2-aminocyclohexyl)-5-chloro-3-(difluoromethyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S)-2-aminocyclohexyl)-5-chloro-3-(difluoromethyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-1-(difluoromethyl)-N-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-4-((furan-2-ylmethyl)amino)-7-methylthieno[3,2-d]pyrimidine-2-carbonitrile; 2-((1S,2S)-2-aminocyclohexyl)-N-(but-2-yn-1-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 2-((2R,3R,5R)-3-amino-5-methyltetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S,5S)-3-amino-5-methyltetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,2S)-2-aminocyclohexyl)-N-(but-2-yn-1-yl)-2-chloro-7-iodothieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 5-(5-chloro-2-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 5-(5-chloro-2-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-7-((furan-2-ylmethyl)amino)-3-methylthieno[3,2-b]pyridine-5-carbonitrile; 2-((1R,3R,4R,6S)-4-aminobicyclo[4.1.0]hept-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,3S,4S,6R)-4-aminobicyclo[4.1.0]hept-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 5-(2-chloro-6-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidin-7-yl)pent-4-yn-1-ol; 5-(2-chloro-6-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidin-7-yl)pent-4-yn-1-ol; 2-((1R,5S,6R)-6-amino-5-methylcyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,5R,6S)-6-amino-5-methylcyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; (1R,2R,3S)-2-amino-3-(3,5-dichloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-N-((E)-but-2-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-N-((E)-but-2-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-((E)-but-2-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 4-(5-chloro-2-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol; 6-((1S,2S)-2-aminocyclohexyl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2,7-dichloro-5-(difluoromethyl)-N-(thiophen-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-(but-2-yn-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(pyridin-3-ylethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-N-(but-2-yn-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 5-(5-chloro-2-((2R,3R)-3-(methylamino)tetrahydro-2H-pyran-2-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 5-(5-chloro-2-((2S,3S)-3-(methylamino)tetrahydro-2H-pyran-2-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-ethynyl-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)-N,N-dimethylcyclohex-1-ene-1-carboxamide; ((4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-en-1-yl)(morpholino)methanone; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-((trimethylsilyl)ethynyl)thieno[3,2-d]pyrimidin-4-amine; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-((trimethylsilyl)ethynyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1R,2R)-2-aminocyclohexyl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-(prop-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 7-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)hept-6-yn-1-ol; 2-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-3-methyl-N-(phenylmethyl-d2)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(propane-1,2-diethylenetriamine-1-yl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(propane-1,2-diethylenetriamine-1-yl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-1-(difluoromethyl)-3-iodo-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-2-chloro-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-N-(furan-2-ylmethyl)-3-iodothieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; (1R,5R,6S)-5-amino-6-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol; (1S,5S,6R)-5-amino-6-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-7-ethynyl-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-7-ethynyl-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,2S)-2-aminocyclohexyl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-(prop-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(cyclopent-1-en-1-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(cyclopent-1-en-1-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-amino-5,5-difluorocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-amino-5,5-difluorocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,2S)-2-aminocyclohexyl)-2,7-dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((1R,2R)-2-aminocyclohexyl)-2,7-dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1R,2R,6S)-2-amino-6-fluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S,6R)-2-amino-6-fluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((furan-2-ylmethyl)(methyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(thiazol-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-N-(2-fluorobenzyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1R,2S,3S)-2-amino-3-fluorocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R,3R)-2-amino-3-fluorocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-ethynylthieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2,7-dichloro-5-(difluoromethyl)-N-(thiophen-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2,7-dichloro-5-(difluoromethyl)-N-(thiophen-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-2-chloro-5-(difluoromethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-(methyl(thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-N-(thiophen-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-N-(thiophen-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-1-methyl-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-5-chloro-1-(difluoromethyl)-3-iodo-1H-pyrrolo[3,2-b]pyridin-7-amine; (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)-N-phenylcyclohex-1-ene-1-carboxamide; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2,7-dichloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2,7-dichloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; (1R,2S,3R)-3-amino-2-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; (1S,2R,3S)-3-amino-2-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-N-(thien-2-ylmethyl)-3-(trifluoromethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-N-(thien-2-ylmethyl)-3-(trifluoromethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-ethynyl-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (2-((1S,2S)-2-aminocyclohexyl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)methanol; (2-((1R,2R)-2-aminocyclohexyl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)methanol; 2-((1S,2S)-2-aminocyclohexyl)-3-bromo-5-chloro-N-(cyclopent-1-en-1-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2-chloro-7-iodo-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1S,2S)-2-aminocyclohexyl)-N-(but-2-yn-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(pyridin-4-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)glycine methyl ester; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,5S,6S)-6-amino-5-methoxycyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,5R,6R)-6-amino-5-methoxycyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(pyridin-4-ylmethyl)thieno[3,2-b]pyridin-7-amine; (1R,2S,3R)-2-amino-3-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; (1S,2R,3S)-2-amino-3-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; 3-Bromo-5-chloro-2-((1R,2R)-2-(methylamino)cyclohexyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 3-Bromo-5-chloro-2-((1S,2S)-2-(methylamino)cyclohexyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-((3-fluoropyridin-4-yl)methyl)thieno[3,2-b]pyridin-7-amine; (1R,5S,6R)-5-amino-6-(3,5-dichloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-((E)-but-2-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-N-(but-2-yn-1-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-N-(but-2-yn-1-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-1-methyl-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-N-(but-2-yn-1-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine; 5-Chloro-3-iodo-2-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 5-Chloro-3-iodo-2-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-4-aminotetrahydro-2H-pyran-3-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-vinylthieno[3,2-d]pyrimidin-4-amine; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-vinylthieno[3,2-d]pyrimidin-4-amine; 6-((1R,2R)-2-aminocyclohexyl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-N-benzyl-2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-3-carbonitrile; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-3-carbonitrile; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-((2-methoxypyridin-3-yl)ethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(pyridin-4-ylethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-2-chloro-5-(difluoromethyl)-7-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-(fluoromethyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-(fluoromethyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine; 2-((1R,2S,6R)-6-amino-2-methylcyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R,6S)-6-amino-2-methylcyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-4-aminotetrahydro-2H-pyran-3-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-4-aminotetrahydro-2H-pyran-3-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thiazol-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-N-benzyl-2-chloro-7-iodothieno[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-3-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-5-(difluoromethyl)-7-iodo-N-(thien-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-N-benzyl-3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((1S,2S)-2-aminocyclohexyl)-N-benzyl-2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((1R,2R)-2-aminocyclohexyl)-N-benzyl-2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thien-3-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-benzyl-3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-3,5-dichloro-1-(difluoromethyl)-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-3,5-dichloro-1-(difluoromethyl)-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2,7-dichloro-5-(difluoromethyl)-N-(thiophen-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-N-benzyl-2-chloro-5-(difluoromethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-3-bromo-N-((E)-but-2-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-3-bromo-N-((E)-but-2-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-1-(difluoromethyl)-N-(furan-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-1-(difluoromethyl)-3-iodo-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-ethynyl-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclohexyl)-3-bromo-5-chloro-N-(pyridin-4-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(pyridin-4-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-N-benzyl-7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2-chloro-N-((3-fluoropyridin-4-yl)methyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2-chloro-7-methyl-N-(pyridin-4-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1R,6R)-6-amino-3,4-dimethylcyclohex-3-en-1-yl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-((3-fluoropyridin-4-yl)methyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(pyridin-4-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl)-2-chloro-7-methyl-N-(thiazol-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1S,2S)-2-aminocyclohexyl)-N-((Z)-but-2-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-chloro-7-((furan-2-ylmethyl)amino)thieno[3,2-b]pyridine-5-carbonitrile; 2-((1R,6R)-6-amino-3,4-dimethylcyclohex-3-en-1-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (4R,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid ethyl ester; (4S,5S)-5-amino-4-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylic acid; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-((3-chloropyridin-4-yl)ethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine; 2-((1S,2R,5S,6S)-6-amino-2,5-dimethylcyclohex-3-en-1-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 5-(2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-(methyl(thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 5-(2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((furan-2-ylmethyl)(methyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-7-(benzyl(methyl)amino)-5-chlorothieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 5-(5-chloro-2-((1R,6R)-6-(dimethylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 5-(5-chloro-2-((1S,6S)-6-(dimethylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-((E)-pent-2-en-1-yl)thieno[3,2-b]pyridin-7-amine; and 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-((E)-pent-2-en-1-yl)thieno[3,2-b]pyridin-7-amine; or forms thereof, wherein the compound is in the form of a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form thereof.

12. A compound selected from the group consisting of: 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((2R,3R)-3-Aminotetrahydro-2H-pyran-2-yl)-N-benzyl-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2S,3S)-3-Aminotetrahydro-2H-pyran-2-yl)-N-benzyl-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-(3-Aminotetrahydro-2H-pyran-2-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2S,3S)-3-Aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,2S)-2-amino-4,4-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((1S,2R)-2-amino-4,4-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; (1R,2S)-2-amino-1-(3,5-dichloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-ol hydrochloride; 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-N-(2-fluorobenzyl)-3-methylthieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine hydrochloride; 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine hydrochloride; 2-((2R,3S)-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((2S,3R)-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((2R,3R)-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((2S,3S)-3-aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3R)-3-aminobicyclo[3.2.1]octan-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2S,3S)-3-aminobicyclo[3.2.1]octan-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3R)-3-amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((2S,3S)-3-amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((2R,3S)-3-amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2S,3R)-3-amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((3S,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((4R,5R)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((4S,5S)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((4R,5S)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((4S,5R)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,2R)-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3S)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2S,3R)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3R)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((2S,3S)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1R,2R)-2-amino-4,4-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-amino-4,4-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; (1R,5S,6R)-6-amino-5-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol carboxylate; (1S,5R,6S)-6-amino-5-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol carboxylate; 5-(2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol carboxylate; 5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol carboxylate; 4-(2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol trifluoroacetate; 4-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol trifluoroacetate; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; -(2R,3S)-2-amino-3-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-one hydrochloride; (2S,3R)-2-amino-3-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexane-1-one hydrochloride; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 6-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 2-((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-4-aminotetrahydro-2H-pyran-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((6R)-6-Amino-2,2-difluorocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((6S)-6-Amino-2,2-difluorocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; (R)-5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1,2-diol trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-N-(furan-2-ylmethyl)-3-methylthieno[3,2-b]pyridin-7-amine trifluoroacetate; 4-(2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol trifluoroacetate; 4-(2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol trifluoroacetate; (S)-5-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1,2-diol trifluoroacetate; 2-((1R,2R)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-(prop-1-yn-1-yl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-(prop-1-yn-1-yl)thieno[3,2-b]pyridin-7-amine formate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; (1R,2R,3S)-2-amino-3-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol trifluoroacetate; (1S,2S,3R)-2-amino-3-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol trifluoroacetate; 6-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)hex-5-yn-1-ol trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine formate; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-iodothieno[3,2-d]pyrimidin-4-amine formate; 3-(2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)prop-2-yn-1-ol trifluoroacetate; 3-(2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)prop-2-yn-1-ol trifluoroacetate; 3-(6-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-4-((furan-2-ylmethyl)amino)thieno[3,2-d]pyrimidin-7-yl)prop-2-yn-1-ol trifluoroacetate; 3-(6-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-2-chloro-4-((furan-2-ylmethyl)amino)thieno[3,2-d]pyrimidin-7-yl)prop-2-yn-1-ol trifluoroacetate; 2-((2R,3R)-3-amino-5-methylenetetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2S,3S)-3-amino-5-methylenetetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 5-(5-chloro-2-((1S,2S)-2-(methylamino)cyclohexyl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol trifluoroacetate; 2-((2R,3R)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((2S,3S)-3-aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-N-(thien-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3R,5R)-3-amino-5-methyltetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2S,3S,5S)-3-amino-5-methyltetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 5-(5-chloro-2-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol trifluoroacetate; 5-(5-chloro-2-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol trifluoroacetate; 2-((1R,3R,4R,6S)-4-aminobicyclo[4.1.0]hept-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,3S,4S,6R)-4-aminobicyclo[4.1.0]hept-3-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-N-benzyl-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine trifluoroacetate; 5-(2-chloro-6-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidin-7-yl)pent-4-yn-1-ol trifluoroacetate; 5-(2-chloro-6-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-4-((thiophen-2-ylmethyl)amino)thieno[3,2-d]pyrimidin-7-yl)pent-4-yn-1-ol trifluoroacetate; 2-((1R,2R)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridine-7-amine formate; 2-((1S,2S)-2-aminocyclohexyl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine formate; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-N-((E)-but-2-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine formate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-N-((E)-but-2-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine formate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-N-((E)-but-2-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridine-7-amine formate; 4-(5-chloro-2-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)but-3-yn-1-ol trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(pyridin-3-ylethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 5-(5-chloro-2-((2R,3R)-3-(methylamino)tetrahydro-2H-pyran-2-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol trifluoroacetate; 5-(5-chloro-2-((2S,3S)-3-(methylamino)tetrahydro-2H-pyran-2-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-((trimethylsilyl)ethynyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-((trimethylsilyl)ethynyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 7-(2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)hept-6-yn-1-ol carboxylate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-5-chloro-3-methyl-N-(phenylmethyl-d2)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(propyl-1,2-diethylenetriamine-1-yl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(propan-1,2-diethylenetriamine-1-yl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; (1R,5R,6S)-5-amino-6-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol trifluoroacetate; (1S,5S,6R)-5-amino-6-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol trifluoroacetate; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-7-ethynyl-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-7-ethynyl-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(cyclopent-1-en-1-ylmethyl)thieno[3,2-b]pyridine-7-amine formate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(cyclopent-1-en-1-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 6-((1S,2S)-2-aminocyclohexyl)-2,7-dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine formate; 6-((1R,2R)-2-aminocyclohexyl)-2,7-dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine formate; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 2-((1R,2S,3S)-2-amino-3-fluorocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,2R,3R)-2-amino-3-fluorocyclohexyl)-5-chloro-3-methyl-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-N-(thien-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine formate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-N-(thien-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine formate; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2,7-dichloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2,7-dichloro-N-(furan-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; (1R,2S,3R)-3-amino-2-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol trifluoroacetate; (1S,2R,3S)-3-amino-2-(3-bromo-5-chloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol trifluoroacetate; 2-((1R,6R)-6-amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)glycine formic acid methyl ester; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-3-bromo-N-(but-2-yn-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,5S,6S)-6-amino-5-methoxycyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((1S,5R,6R)-6-amino-5-methoxycyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-7-bromo-2-chloro-N-(thien-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; (1R,2S,3R)-2-amino-3-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol trifluoroacetate; (1S,2R,3S)-2-amino-3-(5-chloro-3-methyl-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol trifluoroacetate; 3-Bromo-5-chloro-2-((1R,2R)-2-(methylamino)cyclohexyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 3-Bromo-5-chloro-2-((1S,2S)-2-(methylamino)cyclohexyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; (1R,5S,6R)-5-amino-6-(3,5-dichloro-7-((thien-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol carboxylate; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-N-((E)-but-2-en-1-yl)-5-chloro-3-methylthieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3-bromo-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-N-(but-2-yn-1-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-N-(but-2-yn-1-yl)-5-chloro-3-iodothieno[3,2-b]pyridin-7-amine trifluoroacetate; 5-Chloro-3-iodo-2-((1R,6R)-6-(methylamino)cyclohex-3-en-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 5-Chloro-3-iodo-2-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((3R,4S)-3-Aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-N-benzyl-3,5-dichlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 6-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-vinylthieno[3,2-d]pyrimidin-4-amine formate; 6-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-chloro-N-(furan-2-ylmethyl)-7-vinylthieno[3,2-d]pyrimidin-4-amine formate; 2-((3R,4S)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-3-carbonitrile trifluoroacetate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridine-3-carbonitrile trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-((2-methoxypyridin-3-yl)ethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(pyridin-4-ylethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-(fluoromethyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-(fluoromethyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((3S,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(furan-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,2R)-2-aminocyclohexyl)-3,5-dichloro-1-(difluoromethyl)-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-aminocyclohexyl)-3,5-dichloro-1-(difluoromethyl)-N-(thien-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine formate; 2-((1R,6S)-6-amino-2,2-difluorocyclohexyl)-3-bromo-N-((E)-but-2-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6R)-6-amino-2,2-difluorocyclohexyl)-3-bromo-N-((E)-but-2-en-1-yl)-5-chlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,2S)-2-aminocyclohexyl)-N-((Z)-but-2-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-((3-chloropyridin-4-yl)ethynyl)-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-N-(thien-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 6-((1R,6R)-6-aminocyclohex-3-en-1-yl-2,2,3,4,5,5-d6)-2-chloro-N-(furan-2-ylmethyl)-7-methylthieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 5-(5-chloro-2-((1R,6R)-6-(dimethylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol carboxylate; and 5-(5-chloro-2-((1S,6S)-6-(dimethylamino)cyclohex-3-en-1-yl)-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)pent-4-yn-1-ol carboxylate; or forms thereof, wherein the compound is in the form of a hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form thereof.

13. A method for treating spinocerebellar ataxia type 3, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 12.

14. The method of claim 13, wherein the effective amount of the compound or a form thereof induces exon skipping in ATXN3 pre-mRNA in the subject.

15. The method of claim 13, wherein the effective amount of the compound or a form thereof induces exon skipping in the subject.

16. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 12 in admixture with a pharmaceutically acceptable excipient.

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