Compound for treating spinocerebellar ataxia type 3

Abstract

One aspect of the present disclosure relates to compounds useful for improving pre-mRNA splicing in cells. In particular, another aspect of the present disclosure relates to substituted heteroaryl compounds, forms, and pharmaceutical compositions thereof, and methods of use for treating or alleviating spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD).

Description

Technical Field

[0001] Cross - reference to Related Applications 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 TREATING SPINOCEREBELLAR ATAXIA TYPE 3, the content of which is hereby incorporated by reference in its entirety for all purposes. One aspect of the present disclosure relates to compounds useful for improving pre - mRNA splicing in cells. In particular, another aspect of the present disclosure relates to substituted heteroaryl compounds, forms thereof, and pharmaceutical compositions thereof, and methods of use for treating or alleviating spinocerebellar ataxia type 3 (SCA3), also known as Machado - Joseph disease (MJD).

Background Art

[0002] Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a rare autosomal dominant hereditary disorder characterized by progressive motor ataxia. SCA3 is the most common dominant ataxia worldwide. Although the exact patient population is unknown, the average prevalence is 1-5 / 100,000, and it is estimated to be more frequent 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. Based on the age of onset, there are three subtypes of SCA3: subtype 1 (early onset, 10-30 years old), subtype 2 (average onset, 30-50 years old), and subtype 3 (late onset, 50-70 years old). SCA3 patients usually survive 10-20 years after the onset of symptoms. Symptoms include slowly progressive clumsiness in the arms and legs, a staggering and unsteady gait that can be mistaken for drunkenness, difficulty speaking and swallowing, oculomotor disorders sometimes accompanied by diplopia or exophthalmos, and lower limb spasticity; some individuals develop torsions of the body and limbs, repetitive movements, and persistent muscle contractions that cause abnormal postures; others may develop single contractions of the face or tongue, neuropathy, or problems with urination and the autonomic nervous system.

[0003] SCA3 is caused by an unstable expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat in the ATXN3 gene, which transcribes into mutant ATXN3 (mATXN3) mRNA. This expansion in mATXN3 mRNA leads to the production of a mutant ataxin-3 protein (ATXN3) containing a polymorphic polyglutamine (polyQ) tract. Both mATXN3 mRNA and the mutant ATXN3 protein disrupt several cellular processes, leading to neurodegeneration in the cerebellum, brainstem, and other connected brain regions. The number of CAG repeats in ATXN3 mRNA ranges from 10-45 in the healthy population, while in SCA3 patients, it can vary from 61-87. A number of CAG repeats between 45-60 is associated with incomplete penetrance of the disease. As demonstrated in other polyQ disorders, the number of repeats correlates inversely with the age of onset in SCA3 patients.

[0004] In some preclinical models of SCA3, reduction of ATXN3 protein levels improves the pathology of SCA3 and thus confirms the importance of ATXN3 reduction as a therapeutic target to alleviate downstream pathogenic effects. This description relates to the use of a compound of formula (I) or a form or composition thereof for treating SCA3. These sets of compounds induce exon 4 skipping in ATXN3 pre-mRNA during the splicing process. Exon 4 skipping of ATXN3 mRNA changes the open reading frame (ORF) and creates a premature termination codon (PTC) in the ATXN3 exon 4 skipped mRNA (ΔE4mRNA). Such exon skipping splicing events have been shown to be able to help reduce gene expression by signaling to produce an mRNA with a premature termination codon and thus being degraded rather than being translated into a protein. Similarly, the ATXN3 ΔE4 mRNA produced in the presence of these compounds undergoes mRNA degradation, resulting in a decrease in the level of ATXN3 mRNA and a decrease in ATXN3 protein.

[0005] To date, there is no disease-modifying treatment available for SCA3, and there is a need for improved methods and compositions for treating SCA3 and related symptoms. The compounds described herein represent potential ATXN3 pre-mRNA splicing compounds that can be used as disease-modifying treatments for SCA3. All other documents referred to herein are incorporated by reference into this application as if fully set forth herein. SUMMARY OF THE INVENTION

[0006] One aspect of this description includes a compound of formula (I) or a form thereof.

Chemical formula

[0007] One aspect of the present disclosure includes a method for the use of a compound of formula (I) or a form or composition thereof for treating or alleviating SCA3 in a subject in need thereof, comprising administering to the subject an effective amount of the compound of formula (I) or a form or composition thereof. One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof for treating or alleviating SCA3 in a subject in need thereof, comprising administering to the subject an effective amount of the compound of formula (I) or a form thereof. One aspect of the present disclosure includes the use of a compound of formula (I) or a form thereof in the manufacture of a medicament for treating or alleviating SCA3 in a subject in need thereof, comprising administering to the subject an effective amount of the medicament. **DETAILED DESCRIPTION OF THE INVENTION**

[0008] One aspect of the present disclosure relates to a compound of formula (I) or a form thereof, wherein the form of the compound is a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form thereof. **CHEMICAL FORMULA** (wherein: A is selected from the group consisting of CR A and N; A' is selected from the group consisting of S and NR A’ ; L is selected from the group consisting of CH2 and CD2; R A is selected from the group consisting of hydrogen, halo, C 1-6 alkyl, and C 3-8 cycloalkyl; R A’ is selected from the group consisting of hydrogen, C 1-4 alkyl, and halo-C 1-4 alkyl; R B is selected from the group consisting of hydrogen and C 1-6 alkyl; R 1 is selected from the group consisting of phenyl, heteroaryl, C 3-8 cycloalkyl, CO2C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; Heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbocyclic structural group containing 1 to 3 heteroatoms selected from N, O, and S; C 3-8 Cycloalkyl is a saturated or partially unsaturated monocyclic or bicyclic ring system; Phenyl, heteroaryl, and C 3-8 Cycloalkyl is substituted with zero, 1, 2, 3, or 4 independently selected R 1a substituents; R 1a is selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, deutero-C 1-6 alkyl, and C 1-6 alkoxy; R 2 is selected from the group consisting of hydrogen, cyano, halo, C 2-6 alkynyl, C 1-6 alkoxy-C 2-6 alkynyl, and hydroxy-C 2-6 alkynyl; R 3 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, SH, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-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 2-6 alkoxy-C 2-6 alkynyl, hydroxy-C 2-6Alkynyl, (CH3)3Si-C 2-6 Alkynyl, heteroaryl-C 2-6 Alkynyl, C 3-8 Selected from the group consisting of cycloalkyl, phenyl, and heteroaryl, Heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbon atom ring structural group containing 1 to 3 heteroatoms selected from N, O, and S, C 3-8 Examples of each of cycloalkyl, phenyl, and heteroaryl are independently substituted with zero, 1, 2, 3, or 4 independently selected R 3a substituents; R 3a is selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, deutero-C 1-6 alkyl, and C 1-6 alkoxy; Ring Q is

[0009]

Chemical formula

[0010]

Chemical formula

[0011] One aspect includes a compound of formula (I) or a form thereof, which is a compound of formula (Ia).

Chemical formula

[0012] Another aspect is L is CH2 or CD2; R A is hydrogen; R B is hydrogen or CH3; R 2 is Cl or CN, and includes a compound of formula (Ia) or a form thereof.

[0013] One aspect includes a compound of formula (I) or a form thereof, which is a compound of formula (Ib).

Chemical formula

[0014] One aspect includes a compound of formula (I) or a form thereof, which is a compound of formula (Ic).

Chemical formula

[0015] One aspect includes a compound of formula (I) which is a compound of formula (Id) or a form thereof.

Chemical formula

[0016] Another aspect is L is CH2; R A’ is CHF2; R B is hydrogen; R 2 is Cl, and includes a compound of formula (Id) or a form thereof. One aspect includes a compound of formula (I) wherein A is selected from the group consisting of CR A and N. Another aspect includes a compound of formula (I) wherein A is CR A Another aspect includes a compound of formula (I) wherein A is N. One aspect includes a compound of formula (I) wherein A' is selected from the group consisting of S and NR A’ Another aspect includes a compound of formula (I) wherein A' is S. Another aspect includes a compound of formula (I) wherein A' is NR A’ One aspect includes a compound of formula (I) wherein L is selected from the group consisting of CH2 and CD2. One aspect includes a compound of formula (I) wherein R A is selected from the group consisting of hydrogen, halo, C 1-6 alkyl, and C 3-8 cycloalkyl. Another aspect includes a compound of formula (I) wherein R A is hydrogen. One aspect includes a compound of formula (I) wherein R A’ is selected from the group consisting of hydrogen, C 1-4 alkyl, and halo-C 1-4 alkyl. Another aspect includes a compound of formula (I) wherein R A’ is selected from the group consisting of CH3 and CHF2.​​​ One aspect involves an R B selected from the group consisting of hydrogen and C 1-6 alkyl, and includes a compound of formula (I). Another aspect involves an R B selected from the group consisting of hydrogen and CH3, and includes a compound of formula (I).

[0017] One aspect involves an R 1 selected from the group consisting of phenyl, heteroaryl, C 3-8 cycloalkyl, CO2C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbocyclic structural group containing 1 to 3 heteroatoms selected from N, O, and S; C 3-8 cycloalkyl is a saturated or partially unsaturated monocyclic or bicyclic ring system; phenyl, heteroaryl, and C 3-8 cycloalkyl are substituted with zero, 1, 2, 3, or 4 independently selected R 1a substituents, and includes a compound of formula (I). Another aspect involves an R 1 which is phenyl substituted with zero, 1, 2, 3, or 4 independently selected R 1a substituents, and includes a compound of formula (I). Another aspect involves an R 1 which is unsubstituted phenyl, and includes a compound of formula (I). Another aspect involves an R 1 which is phenyl substituted with 1 R 1a substituent, and includes a compound of formula (I).

[0018] Another aspect involves an R 1 which is heteroaryl substituted with zero, 1, 2, 3, or 4 independently selected R 1a substituents, The compound of formula (I) wherein the heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbocyclic structural group containing 1 to 3 heteroatoms selected from N, O and S is included. Another embodiment is that R 1 is unsubstituted heteroaryl, The compound of formula (I) wherein the heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbocyclic structural group containing 1 to 3 heteroatoms selected from N, O and S is included.

[0019] Another embodiment is that R 1 is heteroaryl selected from furanyl, thiophenyl, 1H-pyrazolyl, 1H-imidazolyl, isoxazolyl, 1,3-thiazolyl, 1,3-oxazolyl, tetrazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, and quinolinyl, and the heteroaryl is substituted with zero, 1, 2, 3 or 4 independently selected R 1a substituents, and the compound of formula (I) is included. Another embodiment is that R 1 is heteroaryl selected from furanyl and thiophenyl, and the heteroaryl is substituted with zero, 1, 2, 3 or 4 independently selected R 1a substituents, and the compound of formula (I) is included. Another embodiment is that R 1 is unsubstituted heteroaryl selected from furanyl, thiophenyl, 1,3-thiazolyl, 1,3-oxazolyl, and pyridinyl, and the compound of formula (I) is included.

[0020] Another embodiment is that R 1is heteroaryl selected from furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-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, 1,3-oxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, tetrazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, benzofuran-2-yl, benzofuran-5-yl, and quinolin-4-yl, and the heteroaryl is substituted with zero, 1, 2, 3, or 4 independently selected R 1a including a compound of formula (I) wherein the heteroaryl is substituted with substituents.

[0021] Another embodiment is where R 1 is heteroaryl selected from furan-2-yl, thiophene-2-yl, thiophene-3-yl, 1,3-thiazol-2-yl, 1,3-oxazol-2-yl, and pyridin-4-yl, and the heteroaryl is substituted with zero, 1, 2, 3, or 4 independently selected R 1a including a compound of formula (I) wherein the heteroaryl is substituted with substituents. Another embodiment is where R 1 is unsubstituted heteroaryl selected from furan-2-yl, thiophene-2-yl, thiophene-3-yl, 1,3-thiazol-2-yl, 1,3-oxazol-2-yl, and pyridin-4-yl, including a compound of formula (I). One embodiment is where R 1 is CO2C1-6 It includes a compound of formula (I) which is alkyl. Another embodiment is that R 1 It includes a compound of formula (I) wherein R is CO2CH3. One embodiment is that R 1 is C 3-8 cycloalkyl, and the C 3-8 cycloalkyl is a saturated or partially unsaturated monocyclic or bicyclic ring system substituted with zero, 1, 2, 3 or 4 independently selected R 1a substituents. It includes a compound of formula (I).

[0022] Another embodiment is that R 1 is

Chemical formula

[0023] Another embodiment is that R 1 is

Chemical formula

[0024] Another embodiment is that R 1 is

Chemical formula

[0025] Another embodiment is that R 1 is phenyl, CO2CH3,

Chemical formula

[0026] One aspect includes a compound of formula (I) wherein R 3 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, SH, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-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-C2-6 alkynyl, hydroxy-C 2-6 alkynyl, (CH3)3Si-C 2-6 alkynyl, heteroaryl-C 2-6 alkynyl, C 3-8 selected from the group consisting of cycloalkyl, phenyl, and heteroaryl, wherein heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbocyclic structural group containing 1 to 3 heteroatoms selected from N, O, and S, C 3-8 each example of cycloalkyl, phenyl, and heteroaryl is independently substituted with zero, 1, 2, 3, or 4 independently selected R 3a substituents, and includes a compound of formula (I).

[0027] Another embodiment is that R 3 is hydrogen, cyano, halo, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl, halo-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy-C 2-6 alkynyl, hydroxy-C 2-6 alkynyl, (CH3)3Si-C 2-6 alkynyl, heteroaryl-C 2-6 alkynyl, C 3-8 selected from the group consisting of cycloalkyl and phenyl, wherein heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbocyclic structural group containing 1 to 3 heteroatoms selected from N, O, and S, C 3-8 cycloalkyl, phenyl, and heteroaryl are independently substituted with zero, 1, 2, 3, or 4 independently selected R 3a substituents, and includes a compound of formula (I). Another embodiment is that R 3 is hydrogen, and includes a compound of formula (I). Another embodiment is that R 3It includes a compound of formula (I) wherein it is cyano. Another embodiment includes a compound of formula (I) wherein R 3 is halo. Another embodiment includes a compound of formula (I) wherein R 3 is halo selected from fluoro, chloro, bromo, and iodo. Another embodiment includes a compound of formula (I) wherein R 3 is chloro. Another embodiment includes a compound of formula (I) wherein R 3 is bromo. Another embodiment includes a compound of formula (I) wherein R 3 is iodo. Another embodiment includes a compound of formula (I) wherein R 3 is C 1-6 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl. Another embodiment includes a compound of formula (I) wherein R 3 is methyl. Another embodiment includes a compound of formula (I) wherein R 3 is ethyl. Another embodiment includes a compound of formula (I) wherein R 3 is halo-C 1-6 alkyl selected from the group consisting of CH2F, CHF2, CF3, and CH2CH2F. Another embodiment includes a compound of formula (I) wherein R 3 is hydroxy-C 1-6 alkyl selected from CH2OH. Another embodiment includes a compound of formula (I) wherein R 3 is halo-C 1-6 alkoxy selected from CH2OCHF2. Another embodiment includes a compound of formula (I) wherein R 3 is C 2-6 alkenyl selected from CH=CH2 and CH=C=CH2.

[0028] Another embodiment includes a compound of formula (I) wherein R 3 is

Chemical Formula

[0029] Another embodiment is that R 3 is

Chemical formula

[0030] Another embodiment is that R 3 is

Chemical formula

[0031] Another embodiment is that R 3 is

Chemical formula

[0032] Another embodiment is that R 3 is zero, 1, 2, 3 or 4 independently selected R 3a substituted C selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl 3-8 The compound of formula (I) wherein is cycloalkyl. Another embodiment is that R 3 is zero, 1, 2, 3 or 4 independently selected R 3aIt includes a compound of formula (I) which is a cyclopropyl substituted with a substituent. Another embodiment includes a compound of formula (I) wherein R 3 is unsubstituted cyclopropyl. Another embodiment includes a compound of formula (I) wherein R 3 is phenyl substituted with zero, 1, 2, 3 or 4 independently selected R 3a substituents. Another embodiment includes a compound of formula (I) wherein R 3 is unsubstituted phenyl. One embodiment includes a compound of formula (I) wherein R 3a is selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, deutero-C 1-6 alkyl, and C 1-6 alkoxy. Another embodiment includes a compound of formula (I) wherein R 3a is selected from the group consisting of Cl and OCH3.

[0033] Another embodiment includes a compound of formula (I) wherein R 3 is selected from the group consisting of hydrogen, cyano, Cl, Br, I, CH3, CH2CH3, CHF2, CF3, CH2CH2F, CH2OH, CH2OCHF2, CH=CH2, CH=C=CH2, cyclopropyl, phenyl,

Chemical formula

[0034] One embodiment is that ring Q is

Chemical formula

[0035] Another embodiment includes a compound of formula (I) wherein X is CH2. Another embodiment includes a compound of formula (I) wherein X is CH-R X . Another embodiment includes a compound of formula (I) wherein X is C(R X )2. Another embodiment includes a compound of formula (I) wherein X is CH. Another embodiment includes a compound of formula (I) wherein X is CD. Another embodiment includes a compound of formula (I) wherein X is CR X . Another embodiment includes a compound of formula (I) wherein X is C(O). Another embodiment includes a compound of formula (I) wherein X is NH. Another embodiment includes a compound of formula (I) wherein X is O. One embodiment includes a compound of formula (I) wherein Y is 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.

[0036] Another embodiment includes a compound of formula (I) wherein Y is CH2. Another aspect involves a compound of formula (I), wherein Y is CD2. Another aspect involves a compound of formula (I), wherein Y is CH-R Y as defined herein. Another aspect involves a compound of formula (I), wherein Y is C(R Y )2. Another aspect involves a compound of formula (I), wherein Y is CH. Another aspect involves a compound of formula (I), wherein Y is CD. Another aspect involves a compound of formula (I), wherein Y is CR Y as defined herein. Another aspect involves a compound of formula (I), wherein Y is C=CH2. Another aspect involves a compound of formula (I), wherein Y is O. Another aspect is where Y is N-C 1-4 alkyl, and C 1-4 alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, and involves a compound of formula (I). Another aspect involves a compound of formula (I) where Y is N-CH3. One aspect is where Z is selected from the group consisting of CH2, CD2, CH-R Z , CD-R Z , C(R Z )2, CH, CD, CR Z , NH, N-C 1-4 alkyl, N-phenyl, O, S, S(O), and SO2, and involves a compound of formula (I).

[0037] Another aspect involves a compound of formula (I) where Z is CH2. Another aspect involves a compound of formula (I), wherein Y is CD2. Another aspect involves a compound of formula (I), wherein Y is CH-R Z as defined herein. Another aspect involves a compound of formula (I), wherein Y is C(R Z )2. Another aspect includes a compound of formula (I), wherein Y is NH. Another aspect includes a compound of formula (I) wherein Z is N-phenyl. Another aspect includes a compound of formula (I) wherein Z is O.

[0038] One aspect is each R w , R X , R Y , R Z is independently selected from the group consisting of halo, hydroxy, 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 can combine to form a carbocyclic or heterocyclic ring, and includes a compound of formula (I). Another aspect is each R w , R X , R Y , R Z is independently halo selected from fluoro, chloro, bromo, and iodo, and includes a compound of formula (I). Another aspect is each R w , R X , R Y , R Z is independently fluoro, and includes a compound of formula (I). Another aspect is each R w , R X , R Y , R Z is independently hydroxy, and includes a compound of formula (I). Another aspect is each R w , R X , R Y , R Z is independently C1-6 It includes a compound of formula (I) which is alkyl. Another embodiment is that each R w , R X , R Y , R Z is independently methyl, and includes a compound of formula (I). Another embodiment is that each R w , R X , R Y , R Z is independently C 1-6 alkoxy, and includes a compound of formula (I). Another embodiment is that each R w , R X , R Y , R Z is independently methoxy, and includes a compound of formula (I). Another embodiment is that each R w , R X , R Y , R Z is independently CO2H, and includes a compound of formula (I). Another embodiment is that each R w , R X , R Y , R Z is independently CO2C 1-6 alkyl, and includes a compound of formula (I). Another embodiment is that each R w , R X , R Y , R Z is independently CO2CH2CH3, and includes a compound of formula (I). Another embodiment is that each R w , R X , R Y , R Z is independently C(O)NH2, and includes a compound of formula (I). Another embodiment is that each R w , R X , R Y , R Z is independently C(O)N(C 1-6 alkyl)2, and includes a compound of formula (I). Another embodiment is that each R w , R X , RY and R Z is independently C(O)N(CH3)2, and the compound of formula (I) is included. Another aspect is that each R w and R X and R Y and R Z is independently C(O)-heterocyclyl, and the compound of formula (I) is included.

[0039] Another aspect is that each R w and R X and R Y and R Z is independently

Chemical formula

[0040] Another aspect is that each R w and R X and R Y and R Z is independently

Chemical formula

[0041] One aspect is

Chemical formula

[0042] Another aspect is

Chemical formula

[0043] Another aspect is

Chemical formula

[0044] One aspect is that ring Q is

Chemical formula

[0045] One aspect is that ring Q is

Chemical formula

[0046] One aspect is that ring Q is

Chemical formula

[0047] One aspect is that ring Q is

Chemical formula

[0048] One aspect is that ring Q is

Chemical formula

[0049] One aspect contains a compound of formula (I) or a form thereof selected from the group consisting of the following, wherein " # " indicates that the compound is a racemic mixture of enantiomers, and wherein " & " indicates that the compound can exist as an enantiomer:

Chemical formula

[0050] One aspect includes a compound of formula (I) selected from the following or a form thereof, [Table 1] JPEG2025521545000067.jpg232170 JPEG2025521545000068.jpg253170 JPEG2025521545000069.jpg245170 JPEG2025521545000070.jpg247170 JPEG2025521545000071.jpg250166 JPEG2025521545000072.jpg254170 JPEG2025521545000073.jpg253170 JPEG2025521545000074.jpg254170 JPEG2025521545000075.jpg253170 JPEG2025521545000076.jpg242170 JPEG2025521545000077.jpg252170 JPEG2025521545000078.jpg252170 JPEG2025521545000079.jpg245170 JPEG2025521545000080.jpg232170 JPEG2025521545000081.jpg249170 JPEG2025521545000082.jpg236170 JPEG2025521545000083.jpg236170 JPEG2025521545000084.jpg236170 JPEG2025521545000085.jpg251170 JPEG2025521545000086.jpg241170 JPEG2025521545000087.jpg249166 JPEG2025521545000088.jpg226170 JPEG2025521545000089.jpg234170 JPEG2025521545000090.jpg244170 JPEG2025521545000091.jpg244170 JPEG2025521545000092.jpg231170 JPEG2025521545000093.jpg253170 JPEG2025521545000094.jpg246170 JPEG2025521545000095.jpg244170 JPEG2025521545000096.jpg250170 JPEG2025521545000097.jpg245170 JPEG2025521545000098.jpg237170 JPEG2025521545000099.jpg253170 JPEG2025521545000100.jpg253170 JPEG2025521545000101.jpg253170 JPEG2025521545000102.jpg237170 Here, the form of the compound is its pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotope-enriched form.

[0051] One aspect includes a compound of formula (I) or a form thereof selected from the following,

Table 2

[0052] This application further provides a method of treating spinocerebellar ataxia type 3 (SCA3), the method comprising administering to a subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. One aspect of the method or use involves a compound of formula (I) or a form thereof, in which exon 4 skipping in ATXN3 pre-mRNA is induced during the splicing process. One aspect of the method or use involves a compound of formula (I) or a form thereof, in which the level of ATXN3 mRNA is decreased. One aspect of the method or use involves a compound of formula (I) or a form thereof, in which the ATXN3 protein is reduced. One aspect of the present description relates to a pharmaceutical composition for administration to a subject for the treatment of spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), comprising a compound of formula (I) or a form thereof and at least one pharmaceutically acceptable excipient. One aspect of the present description relates to the manufacture of a medicament for the treatment of spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), in a subject, comprising a compound of formula (I) or a form thereof and at least one pharmaceutically acceptable excipient.

[0053] Unless otherwise defined, all technical and chemical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references described herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0054] Chemical Definitions The chemical terms used above and throughout the description herein will be understood by those of ordinary skill in the art to have the meanings shown below, unless specifically defined otherwise. As used herein, "C" 1-6The term "alkyl" generally refers to a saturated hydrocarbon group having from 1 to 8 carbon atoms in a straight-chain or branched-chain configuration, including, but not limited to, methyl, ethyl, n-propyl (also referred to as propyl or propanil), isopropyl, n-butyl (also referred to as butyl or butanil), isobutyl, sec-butyl, tert-butyl, n-pentyl (also referred to as pentyl or pentanil), n-hexyl (also referred to as hexyl or hexanil), etc. In certain embodiments, C 1-6 alkyl includes, but is not limited to, C 1-6 alkyl, C 1-4 alkyl, etc. C 1-6 The alkyl group is optionally substituted with substituent species as described herein, when possible by available valences.

[0055] As used herein, the term "C 2-6 alkenyl" generally refers to a partially unsaturated hydrocarbon group having from 2 to 8 carbon atoms and one or more carbon-carbon double bonds therein in a straight-chain or branched-chain configuration, including, but not limited to, ethenyl (also referred to as vinyl), allyl, propenyl, etc. In certain embodiments, C 2-6 alkenyl includes, but is not limited to, C 2-6 alkenyl, C 2~4 alkenyl, etc. C 2-6 The alkenyl group is optionally substituted with substituent species as described herein, when possible by available valences.

[0056] As used herein, the term "C 2-6 alkynyl" generally refers to a partially unsaturated hydrocarbon group having from 2 to 8 carbon atoms and one or more carbon-carbon triple bonds therein in a straight-chain or branched-chain configuration, including, but not limited to, ethynyl (also referred to as acetylenyl), propynyl, butynyl, etc. In certain embodiments, C 2-6 alkynyl includes, but is not limited to, C 2-6 alkynyl, C2-4 including alkynyl, etc. C 2-6 The alkynyl group is optionally substituted with substituent species as described herein, if possible by available valences.

[0057] As used herein, "C 1-6 The term "alkoxy" generally includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, etc., and refers to a saturated hydrocarbon group having from 1 to 8 carbon atoms in a straight-chain or branched-chain configuration of the formula: -O-C 1-6 alkyl. In certain embodiments, C 1-6 Alkoxy includes, but is not limited to, C 1-6 alkoxy, C 1-4 alkoxy, etc. C 1-6 The alkoxy group is optionally substituted with substituent species as described herein, if possible by available valences.

[0058] As used herein, "C 1-6 alkoxy-C 2-6 The term "alkynyl" refers to a group of the formula: -C 2-6 alkynyl-O-C 1-6 alkyl, and C 2-6 alkynyl is partially or completely substituted with one or more C 1-6 alkoxy groups, if possible by available valences. As used herein, the term "oxo" refers to a group of the formula: =O. As used herein, the term "carboxyl" refers to a group of the formula: -COOH, -C(O)OH or -CO2H. As used herein, "C 1-6 The term "alkoxy-carbonyl" or "CO2C 1-6 alkyl" refers to a group of the formula: -COO-C 1-6 alkyl, -C(O)O-C 1-6Alkyl or -CO2-C 1-6 Refers to a group of alkyl. As used herein, the term "carbamoyl" refers to a group of the formula: -C(O)NH2.

[0059] As used herein, "C 3-8 cycloalkyl", the term generally refers to saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon groups including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, etc. In certain embodiments, C 3-8 cycloalkyl includes, but is not limited to, C 3-8 cycloalkyl, C 5-8 cycloalkyl, etc. C 3-10 The cycloalkyl group is optionally substituted with substituent species as described herein, where possible by available valences. As used herein, the term "aryl" generally refers to monocyclic, bicyclic or polycyclic aromatic carbon atom ring structural groups including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. The aryl group is optionally substituted with substituent species as described herein, where possible by available valences.

[0060] As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbocyclic structural group in which one or more carbon ring members are replaced by one or more heteroatoms such as O, S or N atoms, when possible due to structural stability, including but not limited to furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, etc. When possible due to available valences, the heteroaryl group is optionally substituted on a carbon or nitrogen ring member with substituent species as described herein.

[0061] In certain embodiments, the nomenclature for heteroaryl groups may vary. For example, by way of non-limiting example, furanyl may sometimes be referred to as furyl, thiophenyl may sometimes be referred to as thienyl, pyridinyl may sometimes be referred to as pyridyl, benzothiophenyl may sometimes be referred to as benzothienyl, and 1,3-benzoxazolyl may sometimes be referred to as 1,3-benzoxazolyl.

[0062] In certain other embodiments, the term for a heteroaryl group may include other positional isomers. For example, by way of non-limiting example, the term pyrrolyl may include 2H-pyrrolyl, 3H-pyrrolyl, etc.; the term pyrazolyl may include 1H-pyrazolyl, etc.; the term imidazolyl may include 1H-imidazolyl, etc.; the term triazolyl may include 1H-1,2,3-triazolyl, etc.; the term oxadiazolyl may include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc.; the term tetrazolyl may include 1H-tetrazolyl, 2H-tetrazolyl, etc.; the term indolyl may include 1H-indolyl, etc.; the term indazolyl may include 1H-indazolyl, 2H-indazolyl, etc.; the term benzimidazolyl may include 1H-benzimidazolyl; the term purinyl may include 9H-purinyl, etc.

[0063] As used herein, the term "heterocyclyl" generally refers to, but is not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, tetrahydropyranyl, thiopyranyl, 1,3-dioxanyl, 1,3-oxazinanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, etc., and refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure group in which one or more carbon atom ring members are replaced by heteroatoms such as O, S or N atoms when possible due to structural stability. The heterocyclyl group is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein when possible due to available valences. As used herein, "C 1-4 alkyl-amino" refers to a group of the formula: -NH-C 1-4 alkyl. As used herein, "halo-C 1-4 alkyl-amino" refers to a group of the formula: -NH-C 1-4 alkyl, where C 1-4 alkyl is partially or fully substituted with one or more halogen atoms when possible due to available valences. As used herein, "(C 1-4 alkyl)2-amino" refers to a group of the formula: -N(C 1-4 alkyl)2. As used herein, "C 1-6The term "alkyl-thio" refers to a group of the formula: -S-C 1-6 alkyl. As used herein, the term "C 1-6 alkyl-sulfoxyl" refers to a group of the formula: -S(O)-C 1-6 alkyl. As used herein, the term "C 1-6 alkyl-sulfonyl" refers to a group of the formula: -SO2-C 1-6 alkyl. As used herein, the term "halo" or "halogen" generally refers to a halogen atom group, including fluoro, chloro, bromo, and iodo. As used herein, the term "halo-C 1-6 alkyl" refers to a group of the formula: -C 1-6 alkyl-halo, where C 1-6 alkyl is partially or completely substituted with one or more halogen atoms, if possible by available valences. As used herein, the term "halo-C 1-6 alkoxy" refers to a group of the formula: -O-C 1-6 alkyl-halo, where C 1-6 alkyl is partially or completely substituted with one or more halogen atoms, if possible by available valences. As used herein, the term "deutero-C 1-6 alkyl" refers to a group of the formula: -C 1-6 alkyl, where C 1-6 alkyl is partially or completely substituted with one or more deuterium atoms, if possible by available valences. As used herein, the term "hydroxy" refers to a group of the formula: -OH. As used herein, the term "hydroxy-C 1-6 alkyl" refers to a group of the formula: -C 1-6 alkyl-OH, where C 1-6 alkyl is partially or completely substituted with one or more hydroxy groups, if possible by available valences. As used herein, "hydroxy-C 2-6 alkynyl" refers to a group of the formula: -C 2-6 alkynyl-OH, where C 2-6 alkynyl is partially or fully substituted with one or more hydroxy groups, where possible depending on the available valency. As used herein, "thio-C 1-6 alkyl" refers to a group of the formula: -C 1-6 alkyl-SH, where C 1-6 alkyl is partially or fully substituted with one or more -SH groups, where possible depending on the available valency.

[0064] As used herein, "C 1-6 alkoxy-C 2-6 alkynyl" refers to a group of the formula -C 2-6 alkynyl-C 1-6 alkoxy, where C 2-6 alkynyl is partially or fully substituted with one or more hydroxy groups, where possible depending on the available valency. As used herein, "(CH3)3Si-C 2-6 alkynyl" refers to a group of the formula -C 2-6 alkynyl-Si(CH3)3. As used herein, "heteroaryl-C 2-6 alkynyl" refers to a group of the formula C 2-6 alkynyl-heteroaryl.

[0065] As used herein, the term "substituent" means a positional variable element on an atom of a core molecule that is substituted at the designated atomic position, replacing one or more hydrogens on the designated atom, provided that the normal valence of the designated atom is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variable elements are only acceptable if such combinations result in a stable compound. One of ordinary skill in the art should note that any carbon and heteroatom having a valence that appears not to be satisfied as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the described or shown valence. In certain instances, one or more substituents having a double bond as an attachment point (e.g., "oxo" or "=O") may be described, shown, or listed within a group of substituents herein, and the structure may only show a single bond as the attachment point to the core structure of formula (I). One of ordinary skill in the art will understand that while only a single bond is shown, a double bond is intended for those substituents.

[0066] As used herein, the term "such as" means, with reference to the chemical term definitions provided herein, that variations in chemical structures that may be expected by one of ordinary skill in the art include, without limitation, isomers (including chain, branched, or positional isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic, or polycyclic ring structures), and all other variations that result in a stable compound when possible by available valences.

[0067] For the purposes of this description, when one or more substituent variable elements of a compound of formula (I) or a form thereof include a functional group incorporated into the compound of formula (I), each functional group that appears at any position within the disclosed compound is independently selected and may be independently and / or optionally substituted where appropriate.

[0068] As used herein, the terms "independently selected" or "each selected" refer to the functional variable elements in a list of substituents that may occur more than once on the structure of formula (I), and the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Further, the use of any formula or structural general substituent variable element for the compounds described herein is understood to include replacement of the general substituent with a species substituent included within a particular genus, e.g., aryl can be replaced with phenyl or naphthalenyl, etc., and the resulting compounds should be included within the scope of the compounds described herein.

[0069] As used herein, the terms "each instance of" or "in each instance, where present" when used prior to a phrase such as "...C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocyclyl and heterocyclyl-C 1-4 alkyl" are intended to refer to cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each is present either alone or as a substituent. 3-10 As used herein, the term "optionally substituted" means an optional substitution with a specified substituent variable element, group, radical or moiety. As used herein, the term "D" refers to a deuterium atom.

[0070] ​As used herein, the term "isotope enrichment" means a compound of Formula I or a form thereof that is identical in all respects except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of Formula I or forms thereof described herein include, respectively, H 2 、H 3 、C 13 、C 14 、N 15 、O 18 、O 17 、P 31 、P 32 、S 35 、F 18 、Cl 35及び Cl 36 and the like, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, each of which is also within the scope of this description.

[0071] Compound form As used herein, the term "form" means a compound of Formula (I) having a form selected from the group consisting of its free acid, free base, salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomeric form. In certain embodiments described herein, the form of the compound of Formula (I) is its free acid, free base or salt. In certain embodiments described herein, the form of the compound of Formula (I) is its salt. In certain embodiments described herein, the form of the compound of Formula (I) is its stereoisomer, racemate, enantiomer or diastereomer. In certain embodiments described herein, the form of the compound of Formula (I) is its tautomer. In certain embodiments described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form. In certain embodiments described herein, the compound of formula (I) or a form thereof is isolated for use. As used herein, the term "isolated" means the physical state of a compound of formula (I) or a form thereof after being isolated and / or purified from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof, in sufficient purity to be characterized by standard analytical techniques described herein or well known to those of skill in the art, according to an isolation or purification process or a process described herein or well known to those of skill in the art (e.g., chromatography, recrystallization, etc.).

[0072] As used herein, the term "protected" means that a functional group in a compound of formula (I) or a form thereof is in a modified form that prevents undesired side reactions at the protecting site when the compound is subjected to a reaction. Suitable protecting groups are recognized by one of ordinary skill in the art and by reference to standard textbooks such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, etc. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. In certain examples, the protecting group may be a polymeric resin such as Wang resin or 2-chlorotrityl-chloride resin. The protecting groups can be added or removed according to standard techniques well known to those skilled in the art and as described herein. Such protected derivatives of the compounds described herein may not have pharmacological activity as such, but it will also be recognized by those skilled in the art that they can be administered to a subject and then metabolized in vivo to form the compounds described herein that are pharmacologically active. Such derivatives can, therefore, be described as "prodrugs". All prodrugs of the compounds described herein are included within the scope of the uses described herein. One or more of the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and the descriptions herein are intended to embrace both solvated and unsolvated forms.

[0073] As used herein, the term "solvate" means a physical association of a compound described herein with one or more solvent molecules. This physical association involves various degrees of ionic and covalent bonds, including hydrogen bonds. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both the solution phase and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. As used herein, the term "hydrate" means a solvate wherein the solvent molecule is water.

[0074] The compounds of formula (I) can form salts, which are intended to be included within the scope of this description. References to the compounds of formula (I) herein or to their forms are understood to include references to their salt forms, unless otherwise indicated. The term "salt" as used herein refers to acidic salts formed with inorganic acids and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound of formula (I) or its form contains both a basic moiety such as, without limitation, an amine moiety, and an acidic moiety such as, without limitation, a carboxylic acid, an amphoteric ion ("inner salt") may be formed and is included within the term "salt" as used herein. The term "pharmaceutically acceptable salt" as used herein means a salt of a compound described herein that is safe and effective for use in mammals (i.e., non-toxic and physiologically acceptable) and possesses biological activity, although other salts may also be useful. The salts of the compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) or its form with a certain amount of an acid or base, such as an equivalent amount, in a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0075] Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in the compounds described herein. Specific embodiments of acid addition salts include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucarate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate (embonate), pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, and the like. Certain specific embodiments of acid addition salts include chloride or dichloride.

[0076] Additionally, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are considered 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, D.C. on their website). These disclosures are incorporated herein by reference. Suitable basic salts include, but are not limited to, aluminum salts, ammonium salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. All such acidic and basic salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. Additionally, all such acid and base salts are considered to be equivalent to the free form of the corresponding compound for the purposes of this description. The compounds of formula (I) and their forms can further exist in tautomeric forms. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of formula (I) or their forms as described herein. The compounds of formula (I) or their forms can contain an asymmetry or chiral center and, therefore, can exist in different stereoisomeric forms. This description is intended to include all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof including racemic mixtures.

[0077] The compounds described herein can contain one or more chiral centers and, therefore, can exist as a racemic mixture (R / S) or as substantially pure enantiomers and diastereomers. The compounds can also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In a particular embodiment, the compounds described herein are the (S) isomers and can exist as an enantiomerically pure composition consisting essentially of only the (S) isomers. In another particular embodiment, the compounds described herein are the (R) isomers and can exist as an enantiomerically pure composition consisting essentially of only the (R) isomers. As will be recognized by those skilled in the art, when more than one chiral center is present, the compounds described herein can also exist as (R,R), (R,S), (S,R), or (S,S) isomers as defined by the IUPAC nomenclature recommendations.

[0078] As used herein, the term "chiral" refers to a carbon atom bonded to four non-identical substituents. The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. When describing an optically active compound, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511). As used herein, the term "substantially pure" refers to a compound consisting essentially of a single isomer in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100% of a single isomer. In one aspect of the description, the compound of formula (I) or a form thereof is in a substantially pure (S) enantiomeric form present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100%. In one aspect of the description, the compound of formula (I) or a form thereof is in a substantially pure (R) enantiomeric form present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100%. As used herein, "racemate" includes, without limitation, any mixture of enantiomeric forms that is not "optically pure", including mixtures in ratios such as about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20.

[0079] In addition, this description encompasses all geometric and positional isomers. For example, if a compound of formula (I) or a form thereof incorporates a double bond or a fused ring, both cis and trans forms as well as mixtures are encompassed within the scope of the description. Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by the use of chiral HPLC columns or other chromatography methods known to those skilled in the art. Enantiomers can also be separated by converting an enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Also, some of the compounds of formula (I) can be atropisomers (e.g., substituted biaryls) and are considered part of this description.

[0080] All stereoisomers of the present compounds (e.g., geometric isomers, optical isomers, etc.) (including those of salts, solvates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of prodrugs), which can exist, for example, by asymmetric carbons on various substituents, are contemplated within the scope of this description in enantiomeric forms (which can exist even in the absence of asymmetric carbons), rotational isomeric forms, atropisomers, and diastereomeric forms, as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl, etc.). The individual stereoisomers of the compounds described herein can, for example, be substantially free of other isomers or can exist as racemic mixtures as described above. The use of terms such as "salt", "solvate", etc. is intended to apply equally to enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, or racemates of the present compounds. The chemical name was obtained using the structure naming function of ChemDraw® software version 20.1.1 provided by PerkinElmer Informatics, Inc., and generally conforms to the IUPAC (International Union of Pure and Applied Chemistry) recommendations and CAS index rules in organic chemical nomenclature. The chemical name may have only parentheses or may have parentheses and brackets. Stereochemical descriptors can also be placed at different positions within the name itself, depending on the naming convention. Those skilled in the art will recognize these format variations and understand that they provide the same chemical structure.

[0081] Compound Use Provided herein is a method of treating a disease in a subject in need thereof. As used herein, the terms "subject" or "patient" refer to any animal, including mammals. For example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

[0082] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human. In some embodiments, the dosage of the compound, or a pharmaceutically acceptable salt thereof, administered to a subject or individual is from about 1 mg to about 2 g, from about 1 mg to about 1000 mg, from about 1 mg to about 500 mg, from about 1 mg to about 100 mg, from about 1 mg to 50 mg, or from about 50 mg to about 500 mg.

[0083] As used herein, the terms "treating" or "treatment" refer to: (1) preventing a disease; e.g., preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but has not yet experienced or manifested the pathological state or overall symptoms of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or manifesting the pathological state or overall symptoms of the disease, condition or disorder (i.e., stopping further development of the pathological state and / or overall symptoms); and (3) alleviating a disease; e.g., alleviating a disease, condition or disorder in an individual who is experiencing or manifesting the pathological state or overall symptoms of the disease, condition or disorder (i.e., reversing the pathological state and / or overall symptoms), e.g., reducing the severity of the disease, or reducing or alleviating one or more symptoms of the disease. This 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 (i.e., a compound of formula (I)).

[0084] Also provided herein is a method of treating a subject having a disease caused by abnormal repeat expansion in the ATXN3 gene that results in a mutant ATXN3 protein having a polyQ expansion, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula (I)). Also provided herein is a method of reducing mutant ATXN3 protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of formula (I)). In some embodiments of the methods provided herein, the compound is selected from the group consisting of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method of inducing exon skipping in 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. Also provided herein is a method of inducing exon skipping in mutant ATXN3 pre-mRNA in a cell, comprising contacting a compound of formula (I) or a form thereof with the cell (e.g., ex vivo or in vivo).

[0085] Also provided herein is a method of inducing exon skipping in mutant ATXN3 pre-mRNA in a gene, comprising contacting a compound of formula (I) or a form thereof with the gene (e.g., in a cell or subject expressing the gene). Also provided is a method of inducing exon 4 skipping in 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. Also provided is a method of inducing exon 4 skipping in mutant ATXN3 pre-mRNA in a cell, the method comprising contacting a compound of formula (I) or a form thereof with the cell (e.g., ex vivo or in vivo).

[0086] Also provided herein is a method of inducing exon 4 skipping in mutant ATXN3 pre-mRNA in a gene, comprising contacting a compound of formula (I) or a form thereof with the gene (e.g., in a cell or subject expressing the gene). Also provided is a method of generating ATXN3 ΔE4 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. Also provided is a method of generating ATXN3 ΔE4 in a cell, the method comprising contacting a compound of formula (I) or a form thereof with the cell (e.g., ex vivo or in vivo). Also provided herein is a method for generating ATXN3 ΔE4 in a gene, comprising contacting a compound of formula (I) or a form thereof with the gene (e.g., in a cell or subject expressing the gene). Also provided herein is a method for reducing mutant ATXN3 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. For example, such methods comprise reducing the mutant ATXN3 mRNA concentration in a serum sample from the subject.

[0087] In some embodiments, the mutant ATXN3 mRNA can be measured in serum, e.g., in a blood sample obtained from the subject prior to administration of a compound of formula (I) or a form thereof and in a blood sample obtained from the subject following administration of the compound as provided herein. In some embodiments, the blood sample obtained from the subject following administration is obtained 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, 28, and / or 30 days after administration of the compound as provided herein. See, e.g., F.B. Axelrod et al., Pediatr Res (2011) 70(5): 480-483; and R.S. Shetty et al., Human Molecular Genetics (2011) 20(21): 4093-4101, which are incorporated by reference in their entireties.

[0088] Further provided herein is a method for reducing mutant ATXN3 mRNA in a cell, the method comprising contacting a cell (e.g., ex vivo or in vivo) with a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The amount of mutant ATXN3 mRNA in the treated cell is reduced relative to the cell in a subject in the absence of the compound provided herein. The method for reducing the amount of mutant ATXN3 mRNA in a cell is effected by contacting the cell in vitro with a compound of formula (I) or a pharmaceutically acceptable salt thereof, whereby the amount of mutant ATXN3 mRNA in the cell can be reduced in vitro. The use of such in vitro methods for reducing the amount of mutant ATXN3 mRNA includes, but is not limited to, use in screening assays (e.g., where a compound of formula (I) or a pharmaceutically acceptable salt thereof is used as a positive control or standard in comparison to one or more compounds of unknown activity or efficacy in reducing the amount of mutant ATXN3 mRNA). In some embodiments, the amount 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 nerve cells (e.g., sciatic nerve cells or trigeminal nerve cells), or any combination thereof. In some of those embodiments, the amount of mutant ATXN3 mRNA is reduced in plasma.

[0089] Methods for reducing mutant ATXN3 mRNA in cells can be carried out, for example, by contacting a compound of formula (I) or a form thereof with cells (e.g., lung cells, muscle cells, liver cells, heart cells, brain cells, kidney cells, spleen cells, or nerve cells) in vivo, thereby reducing the amount of mutant ATXN3 mRNA in a subject in vivo. The contacting is achieved by causing the compound of formula (I) or a form thereof to be present in the subject in an amount effective to achieve a decrease in the amount of mutant ATXN3 mRNA. This can be achieved, for example, by administering an effective amount of the compound of formula (I) or a form thereof to the subject. The use of such in vivo methods for reducing the amount of mutant ATXN3 mRNA includes, but is not limited to, use in methods for treating diseases or conditions in which a decrease in the amount of mutant ATXN3 mRNA is beneficial. In some of its embodiments, the amount of mutant ATXN3 mRNA is decreased in cells selected from the group consisting of, for example, 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 a subject suffering from SCA3. The method is preferably carried out by administering an effective amount of the compound of formula (I) or a form thereof to a subject suffering from SCA3.

[0090] Also provided herein is a method for reducing 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 pharmaceutically acceptable salt thereof. For example, such methods include reducing ATXN3 mutant protein expression in a serum sample from the subject. Further 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.

[0091] Also provided herein is a method for reducing the expression of mutant ATXN3 protein in cells (e.g., ex vivo 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 some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method. In some embodiments, the amount of mutant ATXN3 protein expression 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 of its embodiments, the amount of mutant ATXN3 protein expression is reduced in plasma.

[0092] Also provided herein is a method for reducing the level of mutant ATXN3 protein 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. For example, such methods include reducing the level of mutant ATXN3 protein in a serum sample from the subject. Further provided herein is a method for reducing the average percentage level of mutant ATXN3 protein 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. Also provided herein is a method for reducing the level of mutant ATXN3 protein in cells (e.g., ex vivo or in vivo), the method comprising contacting the cells with a therapeutically effective amount of a compound of formula (I) or a form thereof.

[0093] In some embodiments, the method is an in vitro method. In some embodiments, the method is an in vivo method. In some embodiments, the amount of the ATXN3 mutant protein level is decreased 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 of those embodiments, the amount of the ATXN3 mutant protein level is decreased in plasma. In some embodiments, one or more of the compounds of formula (I) or a form thereof can be administered to a subject in need thereof in combination with at least one additional pharmaceutical agent.

[0094] Additional examples of suitable additional pharmaceutical agents for use in combination with the compounds of the present application for the treatment of the diseases provided herein include, but are not limited to, antioxidants, anti-inflammatory agents, steroids, immunosuppressive agents, or other agents such as therapeutic antibodies. In some embodiments, the compound of formula (I) or a form thereof can be administered to a subject in need thereof in combination with at least one additional pharmaceutical agent for the treatment of SCA3.

[0095] When used as a therapeutic agent, the compounds provided herein can be administered in the form of a pharmaceutical composition; thus, the methods described herein can include administering a pharmaceutical composition. These compositions can be prepared as described herein or elsewhere and can be administered by various routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be by the lungs (e.g., by inhalation or insufflation of powder or aerosol, including with a nebulizer; intratracheally or intranasally), orally, or parenterally. Parenteral administration can include, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial (e.g., intrathecal, intraocular, or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickening agents, etc. may be necessary or desirable. In some embodiments, the compounds provided herein are suitable for oral and parenteral administration. In some embodiments, the compounds provided herein are suitable for oral administration. In some embodiments, the compounds provided herein are suitable for parenteral administration. In some embodiments, the compounds provided herein are suitable for intravenous administration. In some embodiments, the compounds provided herein are suitable for transdermal administration (e.g., administration using a patch or microneedles). Pharmaceutical compositions for local administration can include transdermal patches (e.g., normal or electrically stimulated), ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickening agents, etc. may be necessary or desirable.

[0096] Also provided is a pharmaceutical composition containing, as an active ingredient, a compound of formula (I) or a form thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). When preparing the compositions provided herein, the active ingredient is typically admixed with an excipient, diluted by an excipient, or enclosed within such a carrier in the form of, for example, capsules, sachets, papers, or other containers. When the excipient acts as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0097] Some examples of suitable excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may additionally include, without limitation, lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxy-benzoates; sweetening agents; flavoring agents, or combinations thereof.

[0098] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. The amount of the compound administered and the dosing schedule are usually determined by a physician according to relevant circumstances including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.

[0099] In another aspect, the concentration-biological effect relationship observed for the compound of formula (I) or a form thereof indicates a target plasma concentration in the range of approximately 0.001 μg·hr / mL to approximately 50 μg·hr / mL, approximately 0.01 μg·hr / mL to approximately 20 μg·hr / mL, approximately 0.05 μg·hr / mL to approximately 10 μg·hr / mL, or approximately 0.1 μg·hr / mL to approximately 5 μg·hr / mL. To achieve such plasma concentrations, the compounds described herein can be administered at varying doses, for example, without limitation, from 1.0 ng to 10,000 mg.

[0100] In one aspect, the dose administered to achieve an effective target plasma concentration can be administered based on subject- or patient-specific factors, and the dose administered on a body weight basis is 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 from about 0.001 mg / kg / day to about 250 mg / kg / day, or from about 0.001 mg / kg / day to about 200 mg / kg / day, or from about 0.001 mg / kg / day to about 150 mg / kg / day, or from about 0.001 mg / kg / day to about 100 mg / kg / day, or from about 0.001 mg / kg / day to about 75 mg / kg / day, or from about 0.001 mg / kg / day to about 50 mg / kg / day, or from about 0.001 mg / kg / day to about 25 mg / kg / day, or from about 0.001 mg / kg / day to about 10 mg / kg / day, or from about 0.001 mg / kg / day to about 5 mg / kg / day, or from about 0.001 mg / kg / day to about 1 mg / kg / day, or from about 0.001 mg / kg / day to about 0.5 mg / kg / day, or from about 0.001 mg / kg / day to about 0.1 mg / kg / day, or from about 0.01 mg / kg / day to about 3500 mg / kg / day, or from about 0.01 mg / kg / day to about 3000 mg / kg / day, or from about 0.01 mg / kg / day to about 2500 mg / kg / day, or from about 0.01 mg / kg / day to about 2000 mg / kg / day, or from about 0.01 mg / kg / day to about 1500 mg / kg / day, or from about 0.01 mg / kg / day to about 1000 mg / kg / day, or from about 0.01 mg / kg / day to about 500 mg / kg / day, or from about 0.01 mg / kg / day to about 250 mg / kg / day, or from about 0.01 mg / kg / day to about 200 mg / kg / day, or from about 0.01 mg / kg / day to about 150 mg / kg / day, or from about 0.01 mg / kg / day to about 100 mg / kg / day, or from about 0.01 mg / kg / day to about 75 mg / kg / day, or from about 0.01 mg / kg / day to about 50 mg / kg / day, or from about 0.01 mg / kg / day to about 25 mg / kg / day, or from about 0.It may be in the range of 0.01 mg / kg / day to about 10 mg / kg / day, or about 0.01 mg / kg / day to about 5 mg / kg / day, or about 0.01 mg / kg / day to about 1 mg / kg / day, or about 0.01 mg / kg / day to about 0.5 mg / kg / day, or about 0.01 mg / kg / day to about 0.1 mg / kg / day, or about 0.1 mg / kg / day to about 3500 mg / kg / day, or about 0.1 mg / kg / day to about 3000 mg / kg / day, or about 0.1 mg / kg / day to about 2500 mg / kg / day, or about 0.1 mg / kg / day to about 2000 mg / kg / day, or about 0.1 mg / kg / day to about 1500 mg / kg / day, or about 0.1 mg / kg / day to about 1000 mg / kg / day, or about 0.1 mg / kg / day to about 500 mg / kg / day, or about 0.1 mg / kg / day to about 250 mg / kg / day, or about 0.1 mg / kg / day to about 200 mg / kg / day, or about 0.1 mg / kg / day to about 150 mg / kg / day, or about 0.1 mg / kg / day to about 100 mg / kg / day, or about 0.1 mg / kg / day to about 75 mg / kg / day, or about 0.1 mg / kg / day to about 50 mg / kg / day, or about 0.1 mg / kg / day to about 25 mg / kg / day, or about 0.1 mg / kg / day to about 10 mg / kg / day, or about 0.1 mg / kg / day to about 5 mg / kg / day, or about 0.1 mg / kg / day to about 1 mg / kg / day, or about 0.1 mg / kg / day to about 0.5 mg / kg / day.

[0101] The effective amount for a given subject can be determined by routine experimental methods within the skill and judgment of a clinician or practitioner skilled in the art, in light of factors relevant to the subject. The dosage and administration can be adjusted to provide a sufficient level of the active agent or to maintain the desired effect. Factors that may be considered include genetic screening, severity of the medical condition, state of disease progression, general health of the subject, ethnicity, age, weight, gender, diet, time and frequency of administration, drug combination, response sensitivity, experience with other therapies, and tolerance / response to the treatment.

[0102] The dose administered to achieve an effective target plasma concentration can be administered orally once daily (once in an approximately 24-hour period; i.e., "q.d."), twice (once in an approximately 12-hour period; i.e., "b.i.d." or "q.12h"), three times (once in an approximately 8-hour period; i.e., "t.i.d." or "q.8h"), or four times (once in an approximately 6-hour period; i.e., "q.d.s.", "q.i.d." or "q.6h").

[0103] In certain embodiments, the dose administered to achieve an effective target plasma concentration can also be administered as a single, divided, or continuous dose for patients or subjects having a body weight in the range between about 40 to about 200 kg (this dose can be adjusted for patients or subjects above or below this range, particularly for pediatric patients less than 40 kg). A typical adult subject is expected to have a median body weight in the range of about 70 kg. The long-acting pharmaceutical composition can be administered once every two days, three days or four days, once a week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation. The compounds and compositions described herein can be administered to a subject via any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, and pulmonary routes of administration.

[0104] In another embodiment, the dose administered can be adjusted based on the dosage forms described herein formulated for delivery at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000 or 4000 mg / day.

[0105] For any compound, an effective amount can initially be estimated either in a cell culture assay or in a relevant animal model, such as a mouse, guinea pig, chimpanzee, marmoset or tamarin animal model. The relevant animal model can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful dosages and routes for administration in humans. Therapeutic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED 50 (the therapeutically effective dose in 50% of the population) and LD 50 (the lethal dose in 50% of the population). The dose ratio between the therapeutic and toxic effects is the therapeutic index and can be expressed as the ratio, LD 50 / ED 50 . In certain embodiments, the effective amount is such that a large therapeutic index is achieved. In a further particular embodiment, the dosage is within the range of circulating concentrations that include an ED 50 with little or no toxicity. The dosage can vary within this range depending on the dosage form employed, the susceptibility of the patient, and the route of administration. Another embodiment included within the scope of this description is the use of in vivo metabolites of the compounds described herein. Such products can result, for example, mainly from enzymatic processes such as oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound. Accordingly, the description includes the use of compounds produced by a process that includes contacting a compound described herein with mammalian tissue or a mammal for a time period sufficient to obtain its metabolites.

[0106] Such products are typically radiolabeled (e.g., 14 C or 3H) The compound is prepared, administered to a mammal, such as a rat, mouse, guinea pig, dog, monkey or human, at a detectable dose of the radiolabeled compound (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identified by identifying metabolite conversion products from urine, bile, blood or other biological samples. The conversion products are easily isolated because they are "radiolabeled" by being isotopically enriched (otherwise isolated by the use of antibodies that can bind to epitopes surviving in the metabolites). The metabolite structure is determined in a conventional manner, e.g., by MS or NMR analysis. Generally, the analysis of metabolites can be carried out in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products are useful in diagnostic assays for the therapeutic dosing of the compounds described herein even if they do not have their own biological activity, unless they are otherwise found in vivo.

[0107] Compounds and Preparations Examples of representative compounds encompassed by and within the scope of the present invention are provided herein. These examples and preparations that follow are provided to enable those skilled in the art to more clearly understand and practice the present invention. They are to be considered merely as illustrative and representative of the present invention, but not as limiting the scope thereof.

[0108] General Synthetic Examples As disclosed herein, the methods for preparing the compounds of formula (I) described herein or forms thereof commonly use standard and well-known synthetic methodologies. Many of the starting materials are commercially available or can be prepared in the specific synthetic examples that follow using techniques known to those skilled in the art. Functional conversions for modifying substituents can also be carried out when chemically feasible and are considered to be within the scope of general schemes and the knowledge of those skilled in the art. The compounds of formula (I) or forms thereof can be prepared as described in the following schemes. Depending on the nature of the groups illustrated in the following schemes, the final compounds or their precursors can be further elaborated using standard and well-known synthetic methods.

[0109] Scheme A: The compounds of formula (I) can be prepared as described in Scheme A below.

Chemical formula

[0110] A and A ’ atoms and optionally substituted R 1 、R 2 、and R 3 Compound A1 having substituents can react with cyclic nitroolefin A2 in the presence of a strong base (e.g., LDA, etc.) in a suitable solvent (e.g., THF, etc.) at an appropriate temperature, e.g., -78 °C, to obtain A3. Deprotection can be achieved by treatment with an acid (e.g., HCl in dioxane or TFA, etc.), followed by reduction using Zn or Fe metal in the presence of an acid (e.g., acetic acid, etc.), to deliver A4. Chiral SFC can be used to separate the individual diastereomers A5, A6, A7, and A8.

[0111] Scheme B: The compounds of formula (I) can be prepared as described in Scheme B below. [Chemical]

[0112] A and A ’ atoms and optionally substituted R 1 , R 2 , and R 3 Compound B1 having a substituent is reacted with nitromethane in the presence of a base (e.g., NaOH, etc.), and then dehydrated using MsCl in the presence of a suitable base (e.g., TEA, etc.) to obtain nitroolefin B2. In a suitable solvent (e.g., toluene, etc.), at a suitable temperature (e.g., 100 °C), a Diels-Alder reaction with an optionally substituted olefin gives B3. Reduction using Zn or Fe metal in the presence of an acid (e.g., AcOH, etc.), and then, if necessary, deprotection of the protecting group provides B4. Chiral SFC separation provides B5 and B6.

[0113] Scheme C: The compound of formula (I) can be prepared as described in Scheme C below. [Chemical]

[0114] A and A ’ atoms and optionally substituted R 1 , R 2 , and R 3 Compound C1 having a substituent can be reacted with α-aminoketone C2 in the presence of a strong base (e.g., LDA, etc.) in a suitable solvent (e.g., THF, etc.) at a suitable temperature, e.g., -78 °C, to obtain C3. Treatment with a deoxofluorination reagent (e.g., DAST, etc.) in a suitable solvent (e.g., DCM, etc.) gives C4. Deprotection can be achieved by treatment with an acid (e.g., HCl or TFA in dioxane, etc.) to deliver C5.

[0115] Scheme D: The compound of formula (I) can be prepared as described in Scheme D below. [Chemical formula]

[0116] Azaindole D1 can deliver optionally substituted D2 by reacting with a suitable electrophile (e.g., NBS, etc.). Optionally substituted azaindole D2 can be treated with a suitable electrophile (e.g., MeI, etc.) in the presence of a suitable base (e.g., Cs2CO3, etc.) to obtain D3. Reaction with a suitable oxidant (e.g., mCPBA, etc.), followed by treatment with a dechlorination reagent (e.g., POCl3, etc.) at a suitable temperature (e.g., 110 °C) provides chloropyridine D4. Compound D4 is treated with an optionally substituted aryl / heteroarylmethylamine in the presence of a base (e.g., TEA, etc.) using a suitable solvent (e.g., DMSO, etc.) at a suitable temperature, and then protected with Boc2O in the presence of a base (e.g., TEA, etc.) to obtain intermediate D5. Optionally substituted R 1 , R A , and R 3 Compound D5 having substituents can be reacted with a cyclic nitroolefin in a suitable solvent (e.g., THF, etc.) in the presence of a strong base (e.g., LDA, etc.) at a suitable temperature, e.g., -78 °C, and then treated with a suitable base (e.g., DBU, etc.) to obtain D6. Deprotection can be achieved by treatment with an acid (e.g., HCl in dioxane or TFA, etc.) followed by reduction using Zn or Fe metal in the presence of an acid (e.g., acetic acid, etc.) to deliver D7. Chiral SFC can be used to separate the individual enantiomers D8 and D9.

[0117] Scheme E: The compound of formula (I) can be prepared as described in Scheme E below. [Chem.]

[0118] Using Zn or Fe metal in the presence of a suitable acid (e.g., AcOH, etc.), A and A ’ atoms and optionally substituted R 1 , R 2 , and R 3 substituents, followed by reaction with Boc2O to afford E2. Compound E2 can be converted to E3 via reaction with a suitably functionalized organometallic species 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 afford E4. Chiral SFC can then be used to separate the individual diastereomers E5, E6, E7, and E8.

[0119] Specific Synthesis Examples To describe in more detail and assist in 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 that scope. Such variations of the compounds described herein that are now known or may later be developed, to the extent that those skilled in the art would recognize, are considered to fall within the scope of the compounds as described herein and claimed hereinafter. These examples illustrate the preparation of certain compounds. Those skilled in the art will understand that the techniques described in these examples function well in the practice of synthesis as described by those skilled in the art and thus represent techniques that constitute a preferred mode for that practice. However, those skilled in the art should recognize that, in light of the present disclosure, many changes can be made in the disclosed specific methods and still obtain similar or like results without departing from the spirit and scope of the description.

[0120] Except as otherwise indicated in the following examples of the compounds embodied, all amounts of ingredients, reaction conditions, experimental data, and all other numbers representing various things used in this specification and the claims should be understood to be modified by the term "about." Accordingly, all such numbers represent approximations that can vary depending on the desired properties sought to be obtained by the reaction or as a result of variable experimental conditions. Thus, within the expected range of experimental reproducibility, the term "about" in the context of the resulting data refers to a range of data, provided that it can vary according to the standard deviation from the mean. Similarly, for the experimental results provided, the resulting data may be consistently rounded up or down for this data without loss of significant figures. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and rounding method used by those of ordinary skill in the art.

[0121] While the numerical ranges and parameters setting forth the broad scope of this description are approximations, the numerical values set forth in the examples described 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 test measurements.

[0122] Compound Example As used above and throughout this description, the following abbreviations are understood to have the following meanings unless otherwise indicated: [Table 3] JPEG2025521545000124.jpg172155

[0123] Intermediate 1 tert-Butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate [Chemistry]

[0124] Step 1: tert-Butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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, and 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 stirring was continued for 1 hour. The reaction was then quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic matter was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography using ethyl acetate in hexane (0% - 50% gradient) gave 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).

[0125] Intermediate 2 tert-Butyl (5-chloro-3-ethylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate [Chem.]

[0126] Step 1: tert-Butyl (5-chloro-3-ethylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To a septum-capped 8 mL vial were added t-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 filled and re-filled with argon three times, and then anhydrous diethyl ether (1 mL) was added. The reaction mixture was placed in an ice bath and stirred under argon for 15 minutes, at which point ethylmagnesium bromide (1 M in THF, 0.7 mL, 0.7 mmol, 1.5 equiv) was added dropwise via syringe. Immediately thereafter the ice bath was removed and the reaction mixture 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 solution (20 mL) were added. The layers were separated, the aqueous layer was extracted twice with ethyl acetate (20 mL), the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude reaction mixture by silica gel chromatography (40 g of SiO2, 0% - 10% ethyl acetate in hexane) gave 85 mg (48% yield) of t-butyl (5-chloro-3-ethylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate as a white solid, clean after lyophilization. MS m / z 408.95 [M+H] + , 1 H NMR (DMSO-d6) δ ppm 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=7.46 Hz, 2H), 1.39 (s, 9H), 1.26 (t, J=7.50 Hz, 3H).

[0127] Intermediate 3 tert-Butyl (5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chem.

[0128] Step 1: tert-Butyl (5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate t-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 Erlenmeyer flask. Both flasks were subjected to three cycles of being placed under high vacuum for a short time and then backfilled with argon. Anhydrous THF (2.2 mL, degassed with argon immediately prior to 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 (2 M solution in THF, Acros SureSeal, 0.33 mL, 1.5 equiv) was slowly added to the flask containing the aryl bromide. The reaction mixture rapidly turned dark reddish-brown and was stirred at 0 °C for 30 minutes, at which point a cold solution of iodine in THF was added via cannula transfer. The reaction mixture was stirred at 0 °C for 1 hour, at which point saturated aqueous ammonium chloride (20 mL) and ethyl acetate (20 mL) were added. The mixture was stirred briefly, opened to air, and then transferred to a separatory funnel. The layers were separated, and the aqueous layer was then extracted twice with ethyl acetate (20 mL). The combined organic layers were washed twice with saturated aqueous sodium thiosulfate (40 mL) and 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 of SiO2, 0% - 10% ethyl acetate gradient in hexane). Freeze-drying of the purified residue gave 155 mg (70% yield) of t-butyl (5-chloro-3-iodothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate as a white solid. MS m / z 506.7 [M+H] + , 1 H NMR (DMSO-d6) δ ppm 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).

[0129] Intermediate 4 tert-Butyl (2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate

Chem.

[0130] Step 1: 2,4,7-Trichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine 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 minutes, the reaction mixture was cooled to room temperature and poured into water (300 mL). The aqueous phase was extracted with EtOAc (3 × 200 mL), 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 (gradient of PE / EA 20:1 to 10:1) to afford 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] + 。

[0131] Step 2: 2,7-Dichloro-5-(difluoromethyl)-N-(furan-2-ylmethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine To a solution of 2,4,7-trichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine (1.0 g, 3.7 mmol, 1.0 eq) in tetrahydrofuran (15 mL) were added N,N-diisopropylethylamine (2.6 mL, 15 mmol, 4 eq) and 2-furylmethanamine (0.4 g, 4 mmol, 1.1 eq). 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. Purification of the crude residue by silica gel chromatography (PE / EA 50:1) afforded 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] + .

[0132] Step 3: tert-Butyl (2,7-dichloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate 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) were 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 afford 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] + ; 1HNMR (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).

[0133] Intermediates 5 and 6

Chemical Structure

[0134] Intermediate 7 3,3 - Difluoro - 1 - nitrocyclohex - 1 - ene [Chemical formula] 3,3 - Difluoro - 1 - nitrocyclohex - 1 - ene To a solution of 3 - nitrosocyclohex - 2 - en - 1 - one (1 g, 7 mmol) in DCM (7 mL) cooled to 0 °C was added diethylaminosulfur trifluoride (3.43 g, 21 mmol, 3 equiv). The mixture was stirred at room temperature for 16 h and slowly poured into a cooling bath of saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAc (2 × 100 mL), the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude material by silica gel column chromatography (EA / PE 1:20) afforded 3,3 - difluoro - 1 - nitrocyclohex - 1 - ene (600 mg, 52%) as a yellow oil. 1 1H 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).

[0135] Intermediate 8 tert - Butyl (3 - bromo - 5 - chloro - 1 - methyl - 1H - pyrrolo[3,2 - b]pyridin - 7 - yl)(thiophen - 2 - ylmethyl)carbamate [Chemical formula]

[0136] Step 1: 3-Bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine 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 equiv) and iodomethane (8.74 g, 62 mmol, 1.5 equiv). After stirring for 2 h at room temperature, 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, 1 H), 7.34 (s, 1H), 7.20 (d, J = 5.1 Hz, 1H), 4.15 (s, 3H). Step 2: 3-Bromo-5,7-dichloro-1-methyl-1H-pyrrolo[3,2-b]pyridine The title compound was prepared from 3-bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine according to the procedure described in Intermediate 9, Step 3. 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).

[0137] Step 3: 3-Bromo-5-chloro-1-methyl-N-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine The title compound was prepared from 3-bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine according to the procedure described in Intermediate 9, Step 4. MS m / z 358.0 [M+H] + 。

[0138] Step 4: tert-Butyl (3-bromo-5-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate The title compound was prepared from 3-bromo-7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine according to the procedure described in Intermediate 9, Step 5. MS m / z 458.1 [M+H] + . 1 H 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).

[0139] Intermediate 9 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

Chemical Structure

[0140] Step 1: tert-Butyl (3-bromo-5-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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 for 4 h at room temperature, 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 afford the crude product. Trituration of the crude from DCM (20 mL) gave 3-bromo-7-chloro-1H-pyrrolo[3,2-b]pyridine (480 mg, 96%) as a yellow solid. MS m / z 233.1 [M+H] + 。

[0141] Step 2: 3-Bromo-7-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridine To a mixture of 3-bromo-7-chloro-1H-pyrrolo[3,2-b]pyridine (1 g, 4.3 mmol) in acetonitrile (15 mL) were added ethyl 2-bromo-2,2-difluoro-acetate (3.5 g, 17 mmol, 4 equiv) and potassium tert-butoxide (1.95 g, 17 mmol, 4 equiv). After stirring for 1 h at room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (70 mL×2). The combined organic was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel column chromatography (EA / PE, 0 - 5% gradient) gave 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] + 。

[0142] Step 3: 3-Bromo-5,7-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridine A solution of 3-bromo-7-chloro-1-(difluoromethyl)pyrrolo[3,2-b]pyridine (1.6 g, 5.7 mmol) in DCM (20 mL) was added with 3-chloroperoxybenzoic acid (3.5 g, 17 mmol, 3 equiv) at 25 °C. After stirring at room temperature for 16 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give crude 3-bromo-5,7-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridine as a white solid. To this crude material was added phosphoryl trichloride (20 mL) 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 (400 MHz, DMSO-d6) δ: 8.52 (s, 1H), 8.23 (t, J = 59.8 Hz, 1H), 7.80 (s, 1H).

[0143] Step 4: 3-Bromo-5-chloro-1-(difluoromethyl)-N-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine 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) were added 2-thienylmethanamine (330 mg, 3 mmol, 1.1 equiv) and cesium fluoride (808 mg, 5 mmol, 1.8 equiv) at room temperature. 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 × 100 mL), the combined organics were washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel column chromatography (EA / Hex 1:1) afforded 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] + .

[0144] Step 5: tert-Butyl (3-bromo-5-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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) were added di-tert-butyl dicarbonate (1.74 g, 8 mmol, 2 equiv), triethylamine (0.8 g, 8 mmol, 2 equiv) and DMAP (0.05 g, 0.4 mmol, 0.1 equiv) at room temperature. After stirring at room temperature for 1 h, the reaction mixture was concentrated and the crude residue was purified by silica gel column chromatography (EA / PE 0 - 10% gradient) to afford tert-butyl (3-bromo-5-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (2 g, 100%) as a yellow solid. MS m / z 494.0 [M+H] + . 11H 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).

[0145] Intermediate 10 tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chemical Structure

[0146] Intermediate 11 tert-Butyl (5-chloro-1-(difluoromethyl)-3-iodo-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chemical Structure

[0147] Intermediate 12 tert-butyl (5-chloro-1-(difluoromethyl)-3-iodo-1H-pyrrolo[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate [Chemical Structure] By substituting appropriate starting materials, reagents, and reaction conditions, 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. MS m / z 432.0 [M+H] + .

[0148] Intermediate 13 tert-butyl (3-bromo-5-chloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(furan-2-ylmethyl)carbamate [Chemical Structure] By substituting appropriate starting materials, reagents, and reaction conditions, 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. MS m / z 478.3 [M+H] + . 11H 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).

[0149] Intermediate 14 tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chemical Structure

[0150] Intermediate 15 tert-Butyl (3,5-dichloro-1-(difluoromethyl)-1H-pyrrolo[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chemical Structure

[0151] Intermediate 16 tert-Butyl (5-chloro-3-(trifluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chem.

[0152] Intermediate 17 tert-Butyl (5-chloro-3-(difluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chem.

[0153] Step 1: tert-Butyl (5-chloro-3-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To a solution of tert-butyl (3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-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 eq) was added. After stirring for 1 h at room temperature, DMF (1.7 mL, 20 mmol, 10 eq) was added and the mixture was stirred for an additional 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and diluted with water (100 mL). The aqueous phase was extracted with EtOAc (2 × 100 mL), the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel column chromatography (EA / Hex 0 - 50% gradient) gave 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, 1 H) 8.62 (s, 1 H) 7.22 - 7.29 (m, 2 H) 6.80 - 6.95 (m, 2 H) 5.10 (s, 2 H) 1.49 (s, 9 H).

[0154] Step 2: tert-Butyl (5-chloro-3-(difluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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 was added dropwise with DAST (0.08 mL, 0.6 mmol, 2 eq). After stirring at 0 °C for 1 h, 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 (2 M, 5 mL). After neutralization, the mixture was extracted with EtOAc (3×10 mL). The combined organic layers 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] + . 1 H NMR (400 MHz, chloroform-d) δ: ppm 8.12 (s, 1 H) 6.98 - 7.28 (m, 3 H) 6.80 - 6.93 (m, 2 H) 5.08 (s, 2 H) 1.49 (s, 9 H).

[0155] Intermediate 18 tert-Butyl (5-chloro-3-(fluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chem.

[0156] Step 1: tert-Butyl (5-chloro-3-(hydroxymethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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 eq). 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. Purification of the crude residue by silica gel column chromatography (EA / Hex 0 - 50% gradient) gave 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, 1 H) 7.25 (d, J = 5.13 Hz, 1 H) 7.10 (s, 1 H) 6.79 - 6.92 (m, 2 H) 5.08 (s, 2 H) 5.00 (s, 2 H) 1.48 (s, 9 H).

[0157] Step 2: tert-butyl (5-chloro-3-(fluoromethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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 eq). 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), the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel column chromatography (EA / Hex 0 - 50% gradient) gave 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, 1 H) 7.15 (d, J = 5.00 Hz, 1 H) 7.02 (s, 1 H) 6.68 - 6.86 (m, 2 H) 5.54 - 5.73 (m, 2 H) 4.99 (s, 2 H) 1.39 (s, 9 H).

[0158] Intermediate 19 tert-butyl (5-chloro-3-((difluoromethoxy)methyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chemical Structure

[0159] Step 1: tert-butyl (5-chloro-3-((difluoromethoxy)methyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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. To this mixture, 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.1 mL, 1 mmol, 2 eq) was added dropwise. After stirring at 50 °C for 1 h, 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 (400 MHz, chloroform-d) δ: ppm 7.77 - 7.82 (m, 1 H) 7.25 (d, J=5.00 Hz, 1 H) 7.11 (s, 1 H) 6.90 (t, J=4.13 Hz, 1 H) 6.82 (br d, J=2.63 Hz, 1 H) 6.23 - 6.65 (m, 1 H) 5.26 (s, 2 H) 5.08 (s, 2 H) 1.48 (s, 9 H).

[0160] Intermediate 20 tert-butyl (E)-(3-bromo-5-chloro-2-(2-nitrovinyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate

Chemical Structure

[0161] Step 1: tert-butyl (3-bromo-5-chloro-2-(1-hydroxy-2-nitroethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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 solution (7.2 mL). After stirring at 0 °C for 1 h, the reaction mixture was slowly quenched with 2 M HCl (20 mL) and then diluted with water (100 mL). The aqueous phase was extracted with EtOAc (2 × 100 mL), the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel column chromatography (EA / Hex 0 - 50% gradient) gave 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] + .

[0162] Step 2: tert-butyl (E)-(3-bromo-5-chloro-2-(2-nitrovinyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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 with 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 × 50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel column chromatography (EA / Hex 0~50% gradient) gave 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 1H NMR (chloroform-d) δ: 8.41 (d, J = 13.5 Hz, 1H), 7.64 (d, J = 13.5 Hz, 1H), 7.24 - 7.28 (m, 2H), 6.92 (dd, J = 5.0, 3.5 Hz, 1H), 6.84 (d, J = 3.4 Hz, 1H), 5.07 (s, 2H), 1.52 (s, 9H).

[0163] (Example 1) Preparation of Compound 72, Compound 73, Compound 74, and Compound 75

Chemical Structure

[0164] Step 1: tert-butyl (3-bromo-5-chloro-2-(2-nitrocycloheptyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate A solution of tert-butyl (3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (1 g, 2.17 mmol) in THF (10 mL) was added with lithium diisopropylamide (2 M) 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. Then, 1-nitrocyclohepta-1-ene (397.8 mg, 2.82 mmol) was added and the mixture was stirred at -78 °C for 3 hours. TLC indicated that the starting material remained and new spots were observed. The reaction mixture was diluted by adding NH4Cl (saturated aqueous 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 eluting with ethyl acetate in petroleum ether (0 - 50% gradient) to afford 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.

[0165] Step 2: 3-Bromo-5-chloro-2-(2-nitrocycloheptyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine To a solution of tert-butyl (3-bromo-5-chloro-2-(2-nitrocycloheptyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (50 mg, 0.08 mmol) in CH2Cl2 (8 ml) was added TFA (4 mL) at 0 °C. After stirring at 25 °C for 30 minutes, the mixture was concentrated in vacuo to give crude 3-bromo-5-chloro-2-(2-nitrocycloheptyl)-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (40 mg, 0.08 mmol, 96% yield) as a white solid, which was used in the next step without further purification. MS m / z 501.8 [M+H] +

[0166] Step 3: 2-(2-Aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine 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) was added TFA (2 mL, 26.5 mmol) at 0 °C. The reaction mixture was stirred at 70 °C for 30 minutes, then concentrated, and the crude oil was purified by PreP-HPLC to give trans-2-(2-aminocycloheptyl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-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]pyridin-7-amine (60 mg, 0.1 mmol, 43% yield) as an off-white solid. MS m / z 471.8 [M+H] +

[0167] Step 4: 2-((1S,2R)-2-Aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, 2-((1R,2S)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, 2-((1S,2S)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, and 2-((1R,2R)-2-aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine Cis-2-(2-Aminocycloheptyl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (60 mg, 0.13 mmol) was purified by Prep-SFC (Dr. maish Reprosil Chiral-AM, supercritical CO2 / MeOH (MeOH + 0.1% 7.0 mol / l NH3) / MeOH) to obtain 2-[(1R,2R)-2-aminocycloheptyl]-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-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]pyridin-7-amine (Compound 73, 16 mg, 0.03 mmol, 27% yield) as off-white solids. 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 off-white solids. Compound 72: MS m / z 472.0 [M+H] + ; 1 H NMR (DMSO-d6) δ ppm 7.97 (t, J = 5.8 Hz, 1H), 7.40 (d, J = 5.0 Hz, 1H), 7.10 (d, J = 2.6 Hz, 1H), 7.00 - 6.98 (m, 1H), 6.60 (s, 1H), 4.70 (d, J = 5.8 Hz, 2H), 3.50 (d, J = 12 Hz, 1H), 3.31 - 3.27(m, 1H), 1.95 - 1.77 (m, 11H), 1.23 (s, 1H). Compound 73: MS m / z 472.0 [M+H] + ; 11H NMR (DMSO-d6) δ ppm 7.99 (t, J = 5.8 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.10 (d, J = 2.6 Hz, 1H), 7.00 - 6.98 (m, 1H), 6.58 (s, 1H), 4.71 (d, J = 6.0 Hz, 2H), 3.55 (d, J = 12 Hz, 1H), 3.37 - 3.27(m, 1H), 2.08 - 1.43 (m, 11H), 1.25 (s, 1H). Compound 74: MS m / z 471.9 [M+H] + ; 1 1H NMR (DMSO-d6) δ ppm 7.96 (s, 1H), 7.40 (d, J = 4.0 Hz, 1H), 7.10 (s, 1H), 7.05 - 6.92 (m, 1H), 6.57 (s, 1H), 4.72 (d, J = 5.6 Hz, 2H), 3.20 - 3.13 (m, 2H), 1.99 - 1.39 (m, 12H). Compound 75: MS m / z 471.9 [M+H] + ; 1 1H NMR (DMSO-d6) δ ppm 7.95 (t, J = 5.8 Hz, 1H), 7.40 (d, J = 5.0 Hz, 1H), 7.11 (d, J = 2.6 Hz, 1H), 7.00 - 6.98 (m, 1H), 6.60 (s, 1H), 4.72 (d, J = 5.8 Hz, 2H), 3.25 - 3.13 (m, 2H), 1.95 - 1.45 (m, 12H).

[0168] Following the procedure of Example 1, substituting the appropriate starting materials, reagents, and reaction conditions, and subsequently, if necessary, by chiral SFC resolution, the following compounds were prepared.

Table 4

[0169] (Example 2) Preparation of Compound 67 and Compound 68 [Chemical Structure Diagram]

[0170] Step 1: tert-Butyl (7-bromo-2-chloro-6-((1S,2R)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate To a solution of tert-butyl (7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate (500 mg, 1.1 mmol) in THF (10 mL) was added lithium diisopropylamide (2 M) in THF / heptane / ethylbenzene (0.8 mL, 1.7 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 hour. Then, 1-nitrocyclohex-1-ene (185.7 mg, 1.5 mmol) was added and the mixture was stirred at -78 °C for 3 hours. TLC showed that most of the starting material had disappeared and a new major spot was shown. 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 column chromatography on silica gel eluted 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] + .

[0171] Step 2: tert-Butyl (7-bromo-2-chloro-6-((1S,2S)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-yl)(furan-2-ylmethyl)carbamate 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) was added DBU (88 mg, 0.6 mmol, 1 equiv) at 0 °C. The mixture was stirred at 0 °C for 3 h. 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 column chromatography on silica gel eluting with (EtOAc / PE = 0 - 50%) to afford 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. 1 1H NMR (chloroform-d) δ ppm 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).

[0172] Step 3: 7-Bromo-2-chloro-N-(furan-2-ylmethyl)-6-((1S,2S)-2-nitrocyclohexyl)thieno[3,2-d]pyrimidin-4-amine 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 to 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 column chromatography on silica gel 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] + .

[0173] 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 To a solution of 7-bromo-2-chloro-N-(furan-2-ylmethyl)-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 h. The reaction mixture was diluted by adding 25 mL of H2O. 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. Purification by column chromatography on silica gel eluting with (MeOH / DCM = 0 - 10%) followed by purification by Prep-SFC (DAICEL CHIRALPAK® OJ, supercritical CO2 / MeOH (MeOH + 0.1% 7.0 mol / l ammonia) / MeOH) of the crude residue afforded 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. 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) (3 exchangeable protons not visible). Compound 68: MS m / z 484.1 [M+H] + ; 11H 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 are not visible).

[0174] Following the procedure of Example 2, appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compounds were prepared by chiral SFC resolution if necessary. [Table 5] JPEG2025521545000153.jpg248147 JPEG2025521545000154.jpg250159 JPEG2025521545000155.jpg255159 JPEG2025521545000156.jpg249151 JPEG2025521545000157.jpg250155 JPEG2025521545000158.jpg245161 JPEG2025521545000159.jpg247162 JPEG2025521545000160.jpg251162 JPEG2025521545000161.jpg248153 JPEG2025521545000162.jpg245162 JPEG2025521545000163.jpg245161 JPEG2025521545000164.jpg249151 JPEG2025521545000165.jpg253160 JPEG2025521545000166.jpg251152 JPEG2025521545000167.jpg220161

[0175] (Example 3) Preparation of Compound 129 and Compound 138 [Chemical formula]

[0176] 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 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 lithium diisopropylamide (2 M) in THF / heptane / ethylbenzene (1.28 mL) at -78 °C, and the mixture was stirred for 1 hour. Then, 1-nitrocyclohexene (2, 497.5 mg, 4 mmol) was added 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 chromatography eluting with (EtOAc / PE ca. 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] + .

[0177] Step 2: tert-Butyl N-[5-chloro-2-[(1S,2R)-2-nitrocyclohexyl]-3-phenyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate 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) was added with K2CO3 (163.26 mg, 1.2 mmol) and phenylboronic acid (57.7 mg, 0.473 mmol) at 25 °C. Then, the mixture was stirred at 65 °C for 2.5 h. The reaction mixture was poured into water, extracted with EtOAc, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness in vacuo to afford the crude product, which was purified by flash column eluting with (EtOAc / PE ca. 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] + 。

[0178] Step 3: tert-butyl N-[5-chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate 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) was added diazabicycloundecane (52 mg, 0.3 mmol, 1.0 equiv) at 0 °C. The mixture was stirred at 0 °C for 5 h. The mixture was added to H2O 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 pale yellow solid.1 1H NMR (in chloroform-d) δ ppm 7.51 (t, J = 7.3 Hz, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 7.0 Hz, 2H), 7.24 (s, 1H), 6.99 (s, 1H), 6.92 - 6.88 (m, 1H), 6.83 (d, J = 3.4 Hz, 1H), 5.03 (s, 2H), 4.69 (td, J = 11.4, 4.1 Hz, 1H), 3.81 - 3.71 (m, 1H), 2.37 (d, J = 12.9 Hz, 1H), 2.10 (d, J = 10.6 Hz, 1H), 1.98 - 1.77 (m, 4H), 1.61 (s, 2H), 1.47 (s, 9H).

[0179] Step 4: 5-Chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine 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 crude 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 brown oil. MS m / z 484.0 [M+H] + .

[0180] Step 5: 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-phenyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine and 2-((1R,2R)-2-aminocyclohexyl)-5-chloro-3-phenyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine To a solution of 5-chloro-2-[(1S,2S)-2-nitrocyclohexyl]-3-phenyl-N-(2-thienylmethyl)thieno[3,2-b]pyridin-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 h. The mixture was filtered through celite and then concentrated and purified by flash column eluting with (MeOH / DCM ca. 6.4%) to give 2-[(1S,2S)-2-aminocyclohexyl]-5-chloro-3-cyclopropyl-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine (8, 130 mg) as a yellow oil. Purification of the oil by SFC (DAICEL CHIRALPAK® OJ, supercritical CO2 / MeOH (MeOH + 0.1% 7.0 mol / l ammonia) / MeOH) gave 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-phenyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-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]pyridin-7-amine (Compound 138, 42.2 mg, 33% yield) as white solids. 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) (3 exchangeable protons not visible). 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 are not visible).

[0181] Following the procedure of Example 3, appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compounds were prepared by chiral SFC resolution if necessary.

Table 6

[0182] (Example 4) Preparation of Compound 103, Compound 104, Compound 105, and Compound 106

Chemical formula

[0183] Step 1. tert-Butyl (3-bromo-5-chloro-2-(2-nitrosocyclooctyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To a solution of 24-1 (1.0 g, 2.17 mmol) in THF (12 mL) was added 2 M lithium diisopropylamide (1.63 mL) at -78 °C, and the mixture was stirred for 1 h. Then, (E)-1-nitrocyclooct-1-ene (506.3 mg, 3.26 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 3 h. 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. Purification of the crude residue by flash column chromatography eluting with (EtOAc / PE ca. 5:1) afforded 24-2 (550 mg, 41% yield) as a white solid. 1 H NMR (chloroform-d) δ ppm 7.22 (dd, J = 5.1, 1.1 Hz, 1H), 7.07 (s, 1H), 6.87 (dd, J = 5.1, 3.5 Hz, 1H), 6.79 (d, J = 2.9 Hz, 1H), 5.06 - 4.94 (m, 3H), 4.27 (dt, J = 11.0, 3.8 Hz, 1H), 2.51 - 2.32 (m, 3H), 2.10 - 1.90 (m, 3H), 1.81 - 1.67 (m, 6H), 1.44 (s, 9H).

[0184] Step 2. 3-Bromo-5-chloro-2-(2-nitrocyclooctyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine 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 h. The mixture was concentrated in vacuo to afford crude 3-bromo-5-chloro-2-(2-nitrocyclooctyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (130 mg, 28% yield) as a brown oil. MS m / z 516.0 [M+H] + 。

[0185] Step 3.2 - ((1S,2S)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, 2-((1R,2S)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine, and 2-((1S,2R)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine 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 h. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, then concentrated and purified by flash column eluting with (MeOH / DCM ca. 6.4%) to afford a white solid. The solid was purified by SFC (DAICEL CHIRALPAK® IC, supercritical CO2 / MeOH (MeOH + 0.1% 7.0 M NH3 / MeOH)) to give 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (Compound 103, 2.3 mg, 3% yield), 2-((1S,2S)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (Compound 104, 8.9 mg, 11% yield), 2-((1R,2S)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (Compound 105, 1.3 mg, 1.67% yield) and 2-((1S,2R)-2-aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (Compound 106, 18.1 mg, 23.21% yield) as white solids. Compound 103: MS m / z 406.0 [M+H] + ; 11H 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) (3 exchangeable protons not visible). Compound 104: MS m / z 406.0 [M+H] + ; 1 1H 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) (3 exchangeable protons not visible). Compound 105: MS m / z 406.0 [M+H] + ; 1 1H 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) (3 exchangeable protons not visible). Compound 106: MS m / z 406.0 [M+H]+ ; 1 1H 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) (3 exchangeable protons not visible).

[0186] Following the procedure of Example 4, appropriate starting materials, reagents, and reaction conditions were substituted, and then the following compound was prepared by chiral SFC resolution if necessary. [Table 7] JPEG2025521545000173.jpg99160

[0187] (Example 5) Preparation of Compound 31 [Chemical formula]

[0188] 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 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 was added with lithium diisopropylamide (2.0 M) in THF / heptane / ethylbenzene (0.31 mL, 0.62 mmol, 1.3 equiv). 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 eluting with ethyl acetate in hexane (0 - 50% gradient) to afford 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, 0.9 Hz, 1H), 7.03 (s, 1H), 6.90 (dd, J=5.0, 3.5 Hz, 1H), 6.80 (d, J=3.1 Hz, 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).

[0189] Step 2: (2S)-2-Amino-1-(3,5-dichloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol 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 (4 M) in dioxane (1 mL) was stirred at room temperature for 6 hours. The reaction mixture was diluted with diethyl ether and filtered. The filter cake was purified by preparative HPLC eluting with 10 - 100% ACN in water with 0.1% formic acid to afford (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, (5 exchangeable protons not visible).

[0190] (Example 6) Preparation of Compound 32

Chemical Structure

[0191] 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 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 treated with diethylaminosulfur trifluoride (0.1 mL, 0.8 mmol, 3 equiv). After stirring at -78 °C for 1 h, the reaction was warmed to room temperature for 30 min and then quenched with NaHCO3 (saturated aqueous solution). The reaction mixture was diluted with DCM, the organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by flash column chromatography eluting with ethyl acetate in hexanes (0-40% gradient) afforded 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 = 5.0 Hz, 1H), 6.99 (s, 1H), 6.79 - 6.84 (m, 1H), 6.73 (d, J = 3.1 Hz, 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).

[0192] Step 2: Deprotection of 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, 0.1 mmol) using the general Boc deprotection procedure described in Step 2 of Example 5 gave 2-((1R,2S)-2-amino-1-fluorocyclohexyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (34 mg, 85%). MS m / z 429.9, 431.8 [M+H] + , 1 H 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, (4 exchangeable protons not visible).

[0193] Following the procedure of Example 6, appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compounds were prepared, if necessary, by chiral SFC resolution.

Table 8

[0194] (Example 7) Preparation of Compounds 150 and 151

Chemical Structure

[0195] Step 1: tert-Butyl (3-bromo-5-chloro-2-(3-nitrotetrahydrofuran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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 and at this point, 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. Purification of the residue by silica gel column chromatography using ethyl acetate in hexanes (5 - 35% gradient) afforded tert-butyl (3-bromo-5-chloro-2-(3-nitrotetrahydrofuran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate as a mixture of diastereomers (368 mg, 64% yield). MS m / z 576.0 [M+H] + 。

[0196] Step 2: tert-Butyl (2-(3-aminotetrahydrofuran-2-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate tert-Butyl (3-bromo-5-chloro-2-(3-nitrotetrahydrofuran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (273 mg, 0.5 mmol, 1.0 equiv) as a mixture of diastereomers 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 h. After the reaction mixture was cooled, the mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using methanol (0.1% NH3) in DCM (0–20% gradient) to afford tert-butyl (2-(3-aminotetrahydrofuran-2-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate as a mixture of diastereomers (218 mg, 80% yield). MS m / z 546.0 [M+H] + .

[0197] Step 3: 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 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 eq) in DCM (2 mL) was added trifluoroacetic acid (2 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% formic acid) in water (0.1% formic acid) (0 - 40% gradient) to afford 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 as two separate diastereomers. Compound 150: MS m / z 446.0 [M+H] + ; 1 H 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, (4 exchangeable protons not visible). Compound 151: MS m / z 446.0 [M+H] + ; 11H 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, (4 exchangeable protons not visible).

[0198] (Example 8) Preparation of Compounds 46 and 47 [Chemical Structure]

[0199] 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 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-methylpropan-2-sulfinamide (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 after completion the mixture was cooled to room temperature. Once at room temperature, the mixture was poured into an equal volume of brine with rapid stirring. The resulting suspension was filtered through a plug of celite and the filter cake was washed with EtOAc. The filtrate was transferred to a separatory funnel where the organic layer was washed with brine. The brine layer was extracted once with a small volume of EtOAc and the combined organic portions were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by silica gel column chromatography using ethyl acetate in hexanes (5 - 100% gradient) gave 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] + .

[0200] Step 2: 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 A mixture of tert-butyl (R,E)-(3-bromo-2-(((tert-butylsulfinyl)imino)methyl)-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (473 mg, 0.8 mmol, 1.0 equiv) in THF (8 mL) was added to methyl 5-bromovalerate (234 mg, 1.2 mmol, 1.5 equiv). The reaction mixture was cooled to 0 °C. Lithium diisopropylamide (1 M in hexanes, 1.0 mL, 1.3 equiv) was added dropwise to the reaction. LCMS indicated that the reaction was complete after 1 h. 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. Purification of the residue by silica gel column chromatography using ethyl acetate in hexanes (5–50% gradient) gave 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 (197 mg, 35% yield) as a mixture of diastereomers. MS m / z 706.1 [M+H] + .

[0201] Step 3: 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 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 treated with lithium hydroxide (24 mg, 1.0 mmol, 2.0 equiv). The reaction mixture was stirred at 50 °C for 4 h. 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 afford 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) as a mixture of diastereomers. MS m / z 706.1 [M+H] + .

[0202] 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 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 with triethylamine (40 mg, 0.4 mmol, 2.0 equiv) and diphenylphosphoryl azide (83 mg, 0.3 mmol, 1.5 equiv). The reaction mixture was stirred at 90 °C for 3 h. 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 hexane (5 - 50% gradient) to give 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) as a mixture of diastereomers. MS m / z 763.1 [M+H] + .

[0203] Step 5: 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 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) in DCM (2 mL) was added 2M HCl in dioxane (1 mL, 2 mmol, 10 equiv) at room temperature. After stirring for 1 h, 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 afford 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 as two separate diastereomers. Compound 46: 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), 7.08 (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, (5 exchangeable protons not visible). Compound 47: MS m / z 459.0 [M+H] + ; 11H 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, (5 exchangeable protons not visible)

[0204] Following the procedure of Example 8, appropriate starting materials, reagents, and reaction conditions were substituted, and then the following compounds were prepared by chiral SFC resolution if necessary. [Table 9]

[0205] (Example 9) Preparation of Compounds 147 and 148 [Chemical formula]

[0206] 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 tert-Butyl (3-bromo-5-chloro-2-iodothieno[3,2-b]pyridin-7-yl)(thiophen-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-azepine-1-carboxylate (420 mg, 1.3 mmol, 1.3 equiv) were mixed in 10 mL of dioxane. The catalyst Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 equiv) and 2 M aqueous K2CO3 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. Purification of the residue by silica gel column chromatography using ethyl acetate in hexane (5 - 60% gradient) gave 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] + .

[0207] 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 A solution 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) in THF (6 mL) was cooled to 0 °C. A 1 M solution of borane-THF complex (2.4 mL, 2.4 mmol, 3.0 equiv) was added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature and stirred overnight. LCMS indicated complete consumption of the starting material. The reaction mixture was cooled to 0 °C, and 2 mL of ethanol, 1 mL of 2 M aqueous sodium hydroxide solution, and 1 mL of 30% aqueous H2O2 solution were sequentially added thereto. The reaction mixture was warmed to maximum room temperature and stirred for an additional 2 h. 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] + .

[0208] Step 3: tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-oxoazepane-1-carboxylate 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 afford tert-butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-oxoazepane-1-carboxylate (285 mg, 85% yield). MS m / z 672.1 [M+H] + .

[0209] 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 tert-Butyl 4-(3-bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)-5-oxoazepane-1-carboxylate (168 mg, 0.25 mmol, 1.0 equiv) and (R)-2-methylpropan-2-sulfinamide (61 mg, 0.5 mmol, 2.0 equiv) were mixed in Ti(OEt)4 (3 mL) and heated at 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 in 10 minutes. The mixture was added to a stirred solution of aqueous K2CO3. After filtration and removal of the solvent, 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-((tert-butylsulfinyl)amino)azepane-1-carboxylate (146 mg, 75% yield) as a mixture of diastereomers. MS m / z 777.1 [M+H] + .

[0210] Step 5: 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 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 with 2 M HCl (1 mL, 2 mmol, 20 equiv) in dioxane at room temperature. After stirring for 1 h, 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 afford 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 as two separate diastereomers. MS m / z 473.0 [M+H] + . Compound 147: MS m / z 473.0 [M+H] + ; 1 H NMR (DMSO-d6) δ: 9.25 (brs, 1H), 8.10 (t, J = 6.0 Hz, 2H), 7.41 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 3.5 Hz, 1H), 6.99 (dd, J = 5.1, 3.5 Hz, 1H), 6.69 (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). Compound 148: MS m / z 473.0 [M+H] + ; 11H NMR (DMSO-d6) δ: 9.43 (brs, 1H, TFA peak), 9.21 (brs, 1H), 8.21 (brs, 2H), 8.07 (t, J = 6.0 Hz, 1H), 7.41 (d, J = 5.0 Hz, 1H), 7.11 (d, J = 3.5 Hz, 1H), 7.00 (dd, J = 5.0, 3.5 Hz, 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 = 11.0 Hz, 1H), 2.10 - 2.02 (m, 2H), 2.02 - 1.88 (m, 2H).

[0211] (Example 10) Preparation of Compound 149 [Chemical formula]

[0212] Step 1: 2-(trans-2-Amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine According to the procedure of Example 9, by substituting the appropriate starting materials, tert-butyl (3-bromo-5-chloro-2-(5,5-dimethyl-2-oxocyclohexyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (117 mg, 0.2 mmol) was prepared. The reductive amination / deprotection procedure was according to Example 11, and thus 2-(trans-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (15 mg, 15% yield) was obtained. MS m / z 486.0 [M+H] + . 11H 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, (4 exchangeable protons not visible).

[0213] According to Example 10, appropriate starting materials, reagents, and reaction conditions were substituted, and then the following compound was prepared by chiral SFC resolution if necessary. [Table 10]

[0214] (Example 11) Preparation of Compound 139 [Chemical formula]

[0215] Step 1: trans-tert-butyl (3-bromo-5-chloro-2-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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% by mass) was cooled to -78 °C under argon, and then LDA (3.9 mL, 3.9 mmol, 1.0 mol / L) in THF / hexane was added dropwise. The mixture was stirred at -78 °C for 1 hour, the cooling bath was removed, and it was further stirred at room temperature for 1 hour, quenched with NH4Cl (aqueous solution), stirred for 0.5 hour, extracted with ethyl acetate, and dried. Purification on a silica column eluted with ethyl acetate in hexane (0 - 50%) gave tert-butyl (3-bromo-5-chloro-2-(3-hydroxy-tetrahydro-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 1H NMR (chloroform-d) δ: 7.25 (dd, J = 5.0, 1.0 Hz, 1H), 7.09 (s, 1H), 6.89 (dd, J = 5.0, 3.5 Hz, 1H), 6.80 (d, J = 3.3 Hz, 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).

[0216] 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 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) was added with Dess-Martin periodinane (965 mg, 2.20 mmol) at 0 °C. After the addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. LC-MS indicated that complete conversion was achieved. This was diluted with dichloromethane, washed with sodium thiosulfate, Na2CO3 (aqueous solution), dried, and filtered to remove the desiccant. The filtrate was evaporated to dryness and the residue was subjected to chromatography (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] + .

[0217] 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 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 organic layers were washed with water and brine, dried, and concentrated. The residue was subjected to chromatography (ethyl acetate in hexane, 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) and treated with trifluoroacetic acid (2 mL) at room temperature for 1.5 hours and evaporated. The residue was purified on a prep C18 column (Sunfire C18) eluting with 0.1% TFA-modified acetonitrile in water (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-trifluoroacetate (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, (4 exchangeable protons not visible).

[0218] According to the procedure of Example 11, appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compound was prepared by chiral SFC resolution if necessary. [Table 11] JPEG2025521545000185.jpg187159

[0219] (Example 12) Preparation of Compound 146 [Chemical formula]

[0220] Step 1: trans-4-(3-Bromo-7-((tert-butoxycarbonyl)(thiophen-2-ylmethyl)amino)-5-chlorothieno[3,2-b]pyridin-2-yl)tetrahydro-2H-pyran-3-ylmethanesulfonate 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) and N,N-diisopropylamine (101 μL, 0.58 mmol) in dichloromethane (5 mL) at -50 °C, methanesulfonyl chloride (27 μL, 0.35 mmol) was added, and the mixture was stirred for 0.5 h, then warmed to room temperature and stirred for an additional 0.5 h. LC / MS indicated that a clean conversion was achieved. The reaction was quenched with NaHCO3 (aqueous solution), the organic layer was separated, dried, evaporated to dryness, and used directly. MS m / z 639.1 [M+H] + .

[0221] Step 2: cis-tert-butyl N-[2-(3-azidotetrahydropyran-4-yl)-3-bromo-5-chloro-thieno[3,2-b]pyridin-7-yl]-N-(2-thienylmethyl)carbamate 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. The solvent was removed, and the residue was subjected to chromatography (ethyl acetate in hexane, 0 - 70%) to give 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] + .

[0222] Step 3: cis-tert-butyl (2-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To a solution of cis-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, 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] + .

[0223] Step 4: 2-(3-aminotetrahydropyran-4-yl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; formic acid 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 0.1% formic acid-modified acetonitrile / H2O (0 - 100%) to give 2-(3-aminotetrahydropyran-4-yl)-3-bromo-5-chloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine; formate (14 mg, 62% yield, two steps) as a white powder. 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, (4 exchangeable protons not visible).

[0224] (Example 13) Preparation of Compound 127

Chemical Structure

[0225] 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 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 treated with butylated hydroxytoluene (BHT, 118 mg, 0.53 mmol, 0.25 equiv), followed by (E)-(buta-1,3-dien-1-yloxy)(tert-butyl)dimethylsilane (792 mg, 4.3 mmol, 2.0 equiv). The mixture was carefully sparged with nitrogen, sealed prior to stirring, and protected from light at 120 °C for 24 h. The crude reaction mixture was crudely purified via a short silica gel column using ethyl acetate and hexane (5–30% gradient) to afford a 2:2:1 mixture of 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-((1R / S,5R / S,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 (937 mg, 65% yield). From this, the desired regio- 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 using 0.1% formic acid-modified acetonitrile in water (30–100% gradient). MS m / z 692.1 [M+Na] + 11H NMR (400 MHz, chloroform-d) δ: 7.21 (dd, J = 5.2, 1.3 Hz, 1H), 7.08 (s, 1H), 6.86 (dd, J = 5.1, 3.5 Hz, 1H), 6.77 (d, J = 3.5 Hz, 1H), 5.83 - 5.73 (m, 1H), 5.65 (d, J = 10.3 Hz, 1H), 5.08 - 4.82 (m, 4H), 4.20 (td, J = 11.3, 6.0 Hz, 1H), 2.64 - 2.42 (m, 2H), 1.43 (s, 9H), 0.85 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H)

[0226] Step 2: (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 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 eq) in methanol (1.4 mL) was added to iron powder (78 mg, 1.4 mmol, 10 eq) and ammonium chloride (374 mg, 7.0 mmol, 50 eq), and the resulting suspension was stirred at 70 °C for 16 h. The suspension was neutralized with aqueous sodium bicarbonate, filtered through celite, and the celite 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 afford a residue (87 mg) which was used without further purification. The residue was dissolved in THF (1.1 mL) cooled to 0 °C, and a solution of tetrabutylammonium fluoride (1.0 M, 0.14 mL) was added dropwise. The mixture was stirred at 0 °C for an additional 20 min, then quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford a residue (48 mg) which was used without further purification. The residue was dissolved in 4 M hydrochloric acid in dioxane (1 mL), and the solution was heated at 40 °C for 40 min. At this point, the reaction mixture was concentrated in vacuo and purified by C18 chromatography using 0.1% formic acid-modified acetonitrile in water (30 - 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] + 11H NMR (in 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) (4 exchangeable protons not visible).

[0227] Following the procedure of Example 13, appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compound was prepared by chiral SFC resolution if necessary. [Table 12] JPEG2025521545000189.jpg250155 JPEG2025521545000190.jpg251157 JPEG2025521545000191.jpg248151 JPEG2025521545000192.jpg248153 JPEG2025521545000193.jpg251157 JPEG2025521545000194.jpg250150 JPEG2025521545000195.jpg255159 JPEG2025521545000196.jpg250158 JPEG2025521545000197.jpg248152 JPEG2025521545000198.jpg253161 JPEG2025521545000199.jpg247161 JPEG2025521545000200.jpg250156 JPEG2025521545000201.jpg129163

[0228] (Example 14) Preparation of Compound 24 [Chemical formula]

[0229] Step 1: Methyl (2S,3S)-2-(7-((tert-butoxycarbonyl)(2-fluorobenzyl)amino)-3,5-dichlorothieno[3,2-b]pyridin-2-yl)tetrahydro-2H-pyran-3-carboxylate To a solution of tert-butyl N-(3,5-dichloro-2-formyl-thieno[3,2-b]pyridin-7-yl)-N-[(2-fluorophenyl)methyl]carbamate (500 mg, 1.1 mmol), prepared according to the procedure for Intermediate 1, and methyl 5-bromovalerate (0.2 mL, 1 mmol) in THF (5 mL) cooled to 0 °C, lithium diisopropylamide (2.0 M) in THF / heptane / ethylbenzene (1.2 mL, 2.4 mmol, 2.3 equivalents) was added dropwise. 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 over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (0 - 40% gradient) to give methyl (2S,3S)-2-[7-[tert-butoxycarbonyl-[(2-fluorophenyl)methyl]amino]-3,5-dichloro-thieno[3,2-b]pyridin-2-yl]tetrahydropyran-3-carboxylate (167 mg, 27% yield) as a pale yellow oil. MS m / z 568.8, 570.7 [M+H] + ; 11H NMR (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).

[0230] Step 2: (2S,3S)-2-(7-((tert-Butoxycarbonyl)(2-fluorobenzyl)amino)-3,5-dichlorothieno[3,2-b]pyridin-2-yl)tetrahydro-2H-pyran-3-carboxylic acid A mixture of methyl (2S,3S)-2-[7-[tert-butoxycarbonyl-[(2-fluorophenyl)methyl]amino]-3,5-dichloro-thieno[3,2-b]pyridin-2-yl]tetrahydropyran-3-carboxylate (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) was obtained and used in the next step without further purification. MS m / z 554.8, 556.8 [M+H] + 。

[0231] 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 tert-Butyl N-[3,5-dichloro-2-[(2S)-tetrahydropyran-2-yl]thieno[3,2-b]pyridin-7-yl]-N-[(2-fluorophenyl)methyl]carbamate; A mixture of carbon dioxide (126 mg, 0.2 mmol), triethylamine (0.06 mL, 0.4 mmol, 2.0 eq), diphenylphosphoryl azide (0.1 mL, 0.5 mmol, 2.0 eq), 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 by silica gel eluting with ethyl acetate in hexane (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] + ; 1 H NMR (chloroform-d) δ: 7.22 - 7.27 (m, 2H), 6.96 - 7.12 (m, 3H), 5.02 (s, 2H), 4.75 (d, J = 9.6 Hz, 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).

[0232] Step 4: 2-((2S,3S)-3-Aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(2-fluorobenzyl)thieno[3,2-b]pyridin-7-amine 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 (4 M in dioxane) (2 mL) was stirred at room temperature for 2 hours. 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) (4 exchangeable protons not visible).

[0233] Following the procedure of Example 14, appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compounds were prepared, if necessary, by chiral SFC resolution.

Table 13

[0234] (Example 15) Preparation of Compound 290

Chemical Structure

[0235] 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 To a solution of tert-butyl (2-((1S / R,6S / R)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (201 mg, 0.36 mmol, prepared using Intermediate 20 according to Example 13) in THF (1.8 mL) was 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 over celite. Flash column chromatography on silica gel eluting with ethyl acetate in hexanes was used to purify the crude residue 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] +

[0236] Step 2: 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 A solution of diethylzinc (1 M in CH2Cl, 0.46 mL, 0.46 mmol) was added to CH2Cl2 (0.76 mL) at 0 °C, and then diiodomethane (0.055 mL, 0.69 mmol) was added dropwise. 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 stir overnight at 25 °C. The resulting mixture was diluted in CH2Cl2, washed with NH4Cl (saturated aqueous solution) and brine, dried over MgSO4, filtered, and then concentrated over celite. Purification of the crude residue by flash column chromatography eluting with ethyl acetate in hexanes gave 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, 0.0.46 mmol, 61% yield) as a single diastereomer and a white solid. MS m / z 691.9 [M+Na] +

[0237] Step 3: 2-((1S / R,3S / R,4S / R,6R / S)-4-aminobicyclo[4.1.0]heptan-3-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine 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 minutes. The mixture was basified with 1M NaOH, separated between ethyl acetate and water, and the free base reaction mixture was concentrated and purified by reverse phase C18 chromatography in TFA-modified water and acetonitrile to give 2-((1S / R,3S / R,4S / R,6R / S)-4-aminobicyclo[4.1.0]heptan-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; 1 H 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, (4 exchangeable protons not visible).

[0238] (Example 16) Preparation of Compound 342

Chemical Structure

[0239] 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 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 equivalents), and ammonium chloride (12.3 g, 230 mmol, 50 equivalents) were combined, and MeOH (46 mL) was added. 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 then concentrated to give 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 as a crude, orange semi-solid (2.6 g), which was used without further purification. MS m / z 620.6 [M+H] + .

[0240] 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 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 vacuum sparged with nitrogen and hydrogen and then pressurized to 7 atm under a hydrogen atmosphere and left for 5 days with vigorous stirring. The reaction mixture was filtered through celite and concentrated in vacuo to give 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 as a colorless semi-solid (746 mg), which was used without further purification. MS m / z 622.5 [M+H] + .

[0241] 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 To a 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) at 0 °C was added dropwise a solution of TBAF (1 M in THF, 2.3 mL, 3 eq) over 15 min. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo through a pad of celite, and purified by silica gel chromatography in a DCM / MeOH gradient to afford 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 as a colorless semi-solid (320 mg). 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 are not visible).

[0242] 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 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 equiv), and potassium carbonate (131 mg, 0.95 mmol, 3 equiv) in THF (3.1 mL) were treated at 0 °C with a solution of Boc anhydride (1 M in DCM, 0.47 mL, 1.5 equiv). The reaction was allowed to warm to room temperature with stirring until the substrate was found to be consumed by UPLCMS, at which point the reaction was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo through a pad of Celite, and purified by silica gel chromatography in an EtOAc / hexane 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 as a colorless semi-solid (100 mg, 52% yield). MS m / z 608.1 [M+H] + ; 1 H NMR (chloroform-d) δ: 7.24 (d, J = 5.0 Hz, 1H), 6.98 (s, 1H), 6.89 (t, J = 4.2 Hz, 1H), 6.80 (s, 1H), 5.05 (s, 2H), 4.43 (s, 1H), 3.74 (s, 1H), 3.43 (t, J = 9.2 Hz, 1H), 3.30 (s, 1H), 2.45 (s, 3H), 2.01 (d, J = 13.2 Hz, 1H), 1.91 (s, 1H), 1.66 - 1.45 (m, 13H), 1.27 (s, 9H).

[0243] 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 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) at 0 °C in a PTFE vial was added diethylaminosulfur trifluoride (DAST, 1 M in DCM, 0.052 mL, 0.052 mmol, 1.3 equiv). The reaction was held at 0 °C with stirring for 7 h, at which point 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, dried over MgSO4, and concentrated in vacuo to give a crude mixture containing 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] + ) which was used without further purification.

[0244] Step 6: 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 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, TFA (0.5 mL) was added and the solution was heated to 40 °C with stirring for 15 minutes. The reaction product was purified by C18 reverse-phase chromatography in a TFA-modified water / MeCN gradient to afford 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; 1 H 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, (3 exchangeable protons not visible).

[0245] Following the procedure of Example 16, appropriate starting materials, reagents, and reaction conditions were substituted and subsequently, if necessary, by chiral SFC resolution, the following compounds were prepared. [Table 14]

[0246] (Example 17) Preparation of Compound 371 [Chemical formula]

[0247] 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 To tert-butyl (3-bromo-2-((1S / R,5R / S,6R / S)-6-((tert-butoxycarbonyl)amino)-5-hydroxycyclohex-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 eq) in acetonitrile (0.35 mL) was added methyl iodide (0.043 mL, 0.70 mmol, 10 eq), and the resulting mixture was stirred for 3 days. The crude slurry was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over MgSO4, and concentrated over celite. Purification by silica gel chromatography in 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 semi-solid. MS m / z [M+H] + 685.8; 11H NMR (chloroform-d) δ: 7.25 (dd, J = 5.1, 1.3 Hz, 1H), 7.03 (s, 1H), 6.90 (dd, J = 5.1, 3.5 Hz, 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, 6.5 Hz, 1H), 3.94 (q, J = 7.4 Hz, 2H), 3.44 (s, 3H), 2.62 - 2.44 (m, 2H), 1.48 (s, 9H), 1.21 (s, 9H).

[0248] Step 2: 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 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 4 M HCl (0.5 mL) in dioxane, and the solution was heated to 40 °C with stirring for 30 minutes, and then 2 mL of diethyl 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)cyclohexan-1-one (31 mg, 90% yield) MS m / z [M+H] + 471.7; 11H NMR (DMSO-d6) δ: 8.30 - 8.20 (m, 2H), 8.16 (t, J = 6.0 Hz, 1H), 7.42 (dd, J = 5.1, 1.3 Hz, 1H), 7.17 - 7.06 (m, 1H), 7.00 (dd, J = 5.1, 3.5 Hz, 1H), 6.69 (s, 1H), 4.82 - 4.62 (m, 3H), 4.54 (s, 1H), 3.72 (t, J = 11.7 Hz, 1H), 3.57 (s, 1H), 2.88 (td, J = 14.0, 6.0 Hz, 1H), 2.28 - 2.06 (m, 3H), 1.76 (t, J = 13.6 Hz, 1H). HCl salt.

[0249] (Example 18) Preparation of Compound 192 [Chemical Structure Diagram]

[0250] 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 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) were treated with water (0.0013 mL, 0.073 mmol, 1.0 equiv), and the resulting mixture was stirred for 2 h. The reaction was quenched by stirring with a 1:1 aqueous saturated sodium thiosulfate:saturated aqueous sodium bicarbonate solution (2 mL) 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 over celite. Purification by silica gel chromatography in gradient EtOAc / hexanes gave 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, 78% yield) as a colorless semi-solid. 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).

[0251] Step 2: (2R / S,3S / R)-2-Amino-3-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-one 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), TFA (0.5 mL) was added and the solution was heated to 40 °C with stirring for 15 minutes. The reaction product 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, 1.3 Hz, 1H), 7.12 (d, J = 3.4 Hz, 1H), 7.00 (dd, J = 5.1, 3.4 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 5.95 (d, J = 11.7 Hz, 2H), 4.75 (d, J = 5.0 Hz, 2H), 4.19 (s, 1H), 3.73 (s, 1H), 3.57 (s, 1H), 3.40 (s, 3H) 2.60 - 2.52 (m, 2H).

[0252] (Example 19) Preparation of Compound 307 [Chemical formula]

[0253] Step 1: rac-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. Into a 10 mL oven-dried vial, Pd(PPh3)2Cl2 (4 mg, 0.006 mmol), CuI (2 mg, 0.012 mmol), and rac-2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine (70 mg, 0.099 mmol) were added. The vial was placed under argon flow 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 left stirring 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 brine solution (5 mL). It was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate in hexane (5 - 70% gradient) to obtain rac-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 as a white solid (48.4 mg, 72% yield). MS m / z 677.3 [M+H] + .

[0254] Step 2: rac-2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-3-(pyridin-3-ylethynyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine. A solution of rac-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 (48 mg, 0.071 mmol, 1.0 eq) 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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine. MS m / z 477.3 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ: 8.92 (s, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.36 - 8.22 (m, 1H), 7.64 - 7.61 (m, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 7.00 - 6.98 (m, 1H), 6.67 (s, 1H), 5.94 (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 (4 exchangeable protons not visible).

[0255] Following the procedure of Example 19, appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compounds were prepared by chiral SFC resolution if necessary.

Table 15

[0256] (Example 20) Preparation of Compound 445 [Chemical formula]

[0257] 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 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 (triphenylphosphanylidene)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] + .

[0258] Step 2: Ethyl (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-carboxylate 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 with ethyl 2-(diethoxyphosphoryl)-4-nitrobutanoate (4.45 g, 15 mmol, 1.2 equiv) (prepared according to the procedure 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 h, the reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (EA / PE 0 - 15% gradient) to give ethyl (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-carboxylate (1.1 g, 15%) as a yellow solid. MS m / z 592.0 [M+H] + .

[0259] Step 3: 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 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-nitrocyclohex-1-ene-1-carboxylate (500 mg, 844 mmol) in MeOH (18 mL) and H2O (2 mL) was added with Fe powder (472 mg, 8.4 mol, 10 eq) and NH4Cl (903 mg, 17 mmol, 2.0 eq). After the reaction mixture was stirred at 70 °C for 12 h, the reaction mixture was cooled to room temperature, filtered through a pad of celite, and washed with MeOH (50 mL×2). The filtrate was concentrated to give crude 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, 95%) as a yellow solid, which was used without further purification. MS m / z 562.0 [M+H] + .

[0260] Step 4: Ethyl (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-carboxylate 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 with TFA (2 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo and purified by reverse-phase silica gel chromatography (MeCN / H2O 5 - 95% gradient), followed by prep-SFC (Dr. Maish Reprosil Chiral-AM, supercritical CO2 / MeOH ( + 0.1% 7.0 mol / l NH3 in MeOH) / MeOH) to give 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 (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 are not visible).

[0261] Following the procedure of Example 20, appropriate starting materials, reagents, and reaction conditions were substituted, and then the following compounds were prepared by chiral SFC resolution if necessary.

Table 16

[0262] (Example 21) Preparation of Compound 446

Chem.

[0263] Step 1: (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 (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-carboxylate (50 mg, 0.1 mmol) (prepared in Step 4 of Example 20) 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).

[0264] (Example 22) Preparation of Compound 274

Chem.

[0265] Step 1: 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 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 (280 mg, 0.5 mmol) (prepared according to Example 20) in THF (5 mL) were 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 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 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 (320 mg, 98%) as a white solid. MS m / z 661.9 [M+H] + 。

[0266] Step 2: (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 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×2), dried over Na2SO4, filtered, and concentrated in vacuo to afford crude (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%) as a white solid. MS m / z 634.0 [M+H] + .

[0267] 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 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) was added with HATU (73 mg, 0.19 mmol, 1.2 equiv), NH4Cl (42 mg, 0.8 mmol, 5 equiv), and DIEA (102 mg, 0.8 mmol, 1.2 equiv). 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 × 2), dried over Na2SO4, filtered, and concentrated in vacuo to give crude 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%) as a yellow oil, which was used without further purification. MS m / z 633.1 [M+H] + 。

[0268] Step 4: (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-carboxamide (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-carboxamide (54 mg, 79%) was obtained as a white solid by deprotecting 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 (100 mg, 0.16 mmol) according to the procedure described in Example 5, Step 2. MS m / z 433.1 [M+H]+ ; 1 1H NMR (methanol-d4) δ: 7.29 (t, J = 4.9 Hz, 1H), 7.07 (t, J = 5.8 Hz, 1H), 6.97 (dd, J = 8.4, 4.6 Hz, 1H), 6.80 (d, J = 29.9 Hz, 1H), 6.61 (d, J = 5.4 Hz, 1H), 4.76 (d, J = 11.6 Hz, 2H), 3.91 - 3.60 (m, 2H), 3.06 - 2.45 (m, 4H), 2.42 (d, J = 7.7 Hz, 3H).

[0269] Following the procedure of Example 22, appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compound was prepared by chiral SFC resolution if necessary. [Table 17]

[0270] (Example 23) Preparation of Compound 246 [Chemical formula]

[0271] 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 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 (110 mg, 0.2 mmol, 0.2 equiv), tris(dibenzylideneacetone)palladium (88 mg, 0.1 mmol, 0.2 equiv), and a mixture of DMF (10 mL) were heated in a microwave reactor at 160 °C for 1 h. The reaction mixture was cooled 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] + .

[0272] 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 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 (250 mg, 0.6 mmol) was reduced, followed by SFC separation (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).

[0273] Following the procedure of Example 23, substituting the appropriate starting materials, reagents, and reaction conditions, and subsequently, if necessary, by chiral SFC resolution, the following compounds were prepared.

Table 18

[0274] (Example 24) Preparation of Compound 199

Chem.

[0275] Step 1: 3,5-Dichlorothieno[3,2-b]pyridin-7-ol 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 with NaOH (12.6 g, 314 mmol, 2.5 eq). 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 obtain 3,5-dichlorothieno[3,2-b]pyridin-7-ol (27 g, 98%) as a yellow solid, which was used without further purification. MS m / z 219.8 [M+H] + .

[0276] Step 2: 3,5-Dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine To a cooled solution of 3,5-dichlorothieno[3,2-b]pyridin-7-ol (27 g, 123 mmol) and TEA (85.3 mL, 613 mmol, 5 eq) in DMF (200 mL) was added MOMBr (30 mL, 368 mmol, 3 eq) dropwise at 0 °C. After stirring at room temperature for 2 h, 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 obtain 3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine (20 g, 62%) as a yellow solid. MS m / z 263.8 [M+H] + .

[0277] Step 3: 3,5-Dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine-2-carbaldehyde Following the procedure described in Step 1 of Intermediate 1, by using 3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine (20 g, 76 mmol), crude 3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine-2-carbaldehyde (22.1 g, 99%) was obtained as a yellow solid. MS m / z 291.8 [M+H] + . Step 4: (E)-3,5-Dichloro-7-(methoxymethoxy)-2-(2-nitrovinyl)thieno[3,2-b]pyridine Following the procedure described in Steps 2 and 3 of Intermediate 1, by using 3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine-2-carbaldehyde (22 g, 75 mmol), (E)-3,5-dichloro-7-(methoxymethoxy)-2-(2-nitrovinyl)thieno[3,2-b]pyridine (21 g, 83%) was obtained as a yellow solid. MS m / z 335.2 [M+H] + .

[0278] Step 5: 3,5-Dichloro-7-(methoxymethoxy)-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)thieno[3,2-b]pyridine Following the procedure described in Step 1 of Example 13, by using 3,5-dichloro-7-(methoxymethoxy)-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)thieno[3,2-b]pyridine (7 g, 21 mmol), crude (E)-3,5-dichloro-7-(methoxymethoxy)-2-(2-nitrovinyl)thieno[3,2-b]pyridine (23 g, 99%) was obtained as a yellow oil. MS m / z 388.8 [M+H] + . Step 6: (1S,6S)-6-(3,5-Dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridine-2-yl)cyclohex-3-en-1-amine According to the procedure described in step 2 of Example 13, using 3,5-dichloro-7-(methoxymethoxy)-2-((1S,6S)-6-nitrocyclohex-3-en-1-yl)thieno[3,2-b]pyridine (23 g, 59 mmol), crude (1S,6S)-6-(3,5-dichloro-7-(methoxymethoxy)thieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-amine (20 g, 94%) was obtained as a yellow solid. MS m / z 359.0 [M+H] + .

[0279] Step 7: 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-ol 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 crude 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-ol (17 g, 97%) as a yellow solid, which was used without further purification. MS m / z 315.0 [M+H] + .

[0280] 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 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] + .

[0281] Step 9: tert-butyl ((1S,6S)-6-(3,5-dichloro-7-hydroxythieno[3,2-b]pyridin-2-yl)cyclohex-3-en-1-yl)carbamate 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 MeOH (20 mL) was added NaOEt (2.5 g, 37 mmol, 2 eq). After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo to give crude 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%) as a yellow solid, which was used without further purification. MS m / z 414.8 [M + H] + .

[0282] Step 10: 2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-3,5-dichlorothieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate 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 dropwise with Tf2O (1.8 mL, 10.8 mmol, 1.5 equiv). After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL × 5) and brine (200 mL × 2). The organic matter was 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] + 。

[0283] 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 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-ylmethanamine 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) were stirred 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 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] + 。

[0284] 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 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 according to the procedure described in Example 5, Step 2 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] + ; 11H 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).

[0285] (Example 25) Preparation of Compound 393 [Chemical formula]

[0286] 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 Into an oven-dried 8 mL reaction vial, Pd(PPh3)4 (11.6 mg, 0.01 mmol, 0.1 equiv), zinc cyanide (7 mg, 0.06 mmol, 0.6 equiv), and rac-tert-butyl (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 were charged. DMF (1.0 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 of NH4Cl (saturated aqueous solution) and 0.2 mL of NaHCO3 (saturated aqueous solution) were added. The mixture was filtered and washed with DCM (0.5 mL × 3). The combined filtrate was concentrated and purified by preparative HPLC eluting with 10 - 100% ACN in water with 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 are not visible).

[0287] (Example 26) Preparation of Compound 324 [Chemical formula]

[0288] Step 1: rac-tert-butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-(prop-1,2-dien-1-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To an oven-dried 8 mL reaction vial were added PPh3 (39.3 mg, 0.15 mmol, 1.5 equiv), N-isopropylidene-N'-2-nitrobenzenesulfonylhydrazine (IPNBSH) (33.9 mg, 0.15 mmol, 1.5 equiv), and rac-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 then DIAD (30.3 mg, 0.15 mmol, 1.5 equiv) was added dropwise. After 5 minutes, the solution was then warmed to room temperature and stirred for 2 hours. A 1:1 trifluoroethanol / H2O mixture was added, and the mixture was stirred overnight. The crude mixture was concentrated in vacuo and then purified by silica gel flash column chromatography eluting with 0 - 100% EtOAc in hexane to give rac-tert-butyl (2-((1S,6S)-6-((tert-butoxycarbonyl)amino)cyclohex-3-en-1-yl)-5-chloro-3-(prop-1,2-dien-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] + .

[0289] Step 2: rac-2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(prop-1,2-dien-1-yl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine Removal of the Boc group according to the general procedure described in Step 2 of Example 19 gave rac-2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-(prop-1,2-dien-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, 1.2 Hz, 1H), 7.08 (dd, J = 3.5, 1.2 Hz, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 6.75 (t, J = 7.1 Hz, 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 are not visible).

[0290] (Example 27) Preparation of Compound 303

Chemical Structure

[0291] Step 1: 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 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 in Example 13) in THF (1.0 mL) was added sodium bis(trimethylsilyl)amide (1.0 mol / L) in THF (0.12 mL, 0.12 mmol, 1.2 equiv) dropwise at -78 °C, followed by the addition of methyl trifluoromethanesulfonate (24.5 mg, 0.15 mmol, 1.5 equiv). The reaction was stirred at < -50 °C for 1 h 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% EtOAc in hexanes to afford 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] + 。

[0292] Step 2: tert-butyl (rac-(1S,6S)-6-(7-((tert-butoxycarbonyl)(thiophen-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 Installation of the alkyne group according to the general procedure described in Step 1 from Example 19 provided tert-butyl (rac-(1S,6S)-6-(7-((tert-butoxycarbonyl)(thiophen-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] + 。

[0293] 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 Removal of the Boc group according to the general procedure described in Step 2 from Example 19 provided 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 are not visible).

[0294] According to Example 27, the appropriate starting materials, reagents, and reaction conditions were substituted, and subsequently, the following compounds were prepared by chiral SFC resolution if necessary.

Table 19

[0295] (Example 28) Preparation of Compound 259

Chemical Structure

[0296] Step 1: tert-Butyl (3-bromo-5-chloro-2-formylthieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To a solution of tert-butyl N-(3-bromo-5-chloro-thieno[3,2-b]pyridin-7-yl)-N-(2-thienylmethyl)carbamate (5 g, 11 mmol) (prepared according to the procedure described in WO2020 / 17430) in THF (50 mL) was added 2M lithium diisopropylamide (6 mL, 1.2 equiv) at -78 °C, and the mixture was stirred for 1 hour, followed by the addition of DMF (2.4 g) at -78 °C. After stirring at -78 °C for an additional 3 hours, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2 × 100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. Purification of the crude residue by silica gel column chromatography (DCM / PE 1:3) gave 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] + . 11H 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).

[0297] Step 2: tert-Butyl (3-bromo-5-chloro-2-(1-hydroxy-2-nitroethyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate To a solution of NaOH (1 M 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), and then nitromethane (2.16 g, 30 mmol, 1.0 equiv) in MeOH (50 mL) was added dropwise. 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. Purification of the crude residue by silica gel column chromatography (EA / PE 0 - 15% gradient) gave 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. 11H NMR (400 MHz, chloroform-d) δ: 7.23 (dd, J = 5.1, 1.1 Hz, 1H), 6.88 (dd, J = 5.1, 3.5 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 5.95 (dd, J = 6.4, 3.3 Hz, 1H), 5.09 - 4.96 (m, 2H), 4.78 (dd, J = 13.5, 2.6 Hz, 1H), 4.60 (dd, J = 13.5, 9.6 Hz, 1H), 4.17 (t, J = 8.2 Hz, 1H), 1.48 (s, 9H).

[0298] Step 3: tert-Butyl (3-bromo-5-chloro-2-(2-nitroacetyl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate 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 equiv) and Dess-Martin periodinane (15.1 g, 35.6 mmol, 1.5 equiv) were added. After stirring at 0 °C for 3 h, hexane (400 mL) was added and the solution was stirred at room temperature for 10 min. 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] + 。

[0299] 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 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), the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel column chromatography (EA / PE 0–20% gradient) gave 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] + .

[0300] 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 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) was added silica gel (14.6 g) and NaBH4 (1.3 g, 34 mmol, 3.7 equiv) at 25 °C. After stirring for 2 h at room temperature, the reaction mixture was quenched with NH4Cl aqueous solution (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 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%) as a mixture of diastereomers. MS m / z 602.0 [M+H] + .

[0301] 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 A solution of tert-butyl (3-bromo-5-chloro-2-(5-methylene-3-nitro- tetrahydro-2H-pyran-2-yl)thieno[3,2-b]pyridin-7-yl)(thiophen-2-ylmethyl)carbamate (680 mg, 1.1 mmol) in THF (20 mL) was added dropwise with 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (86 mg, 0.56 mmol, 0.5 equiv) at 0 °C under N2. The mixture was stirred at 0 °C for 2 h. The reaction was 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-nitro- tetrahydro-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] + .

[0302] Step 7: 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 A solution of tert-butyl (3-bromo-5-chloro-2-((2S,3S)-5-methylenetetrahydro-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) was added iron (1.55 g, 28 mmol, 2.9 equiv) at 25 °C. After stirring at 65 °C for 12 h, the reaction mixture was cooled to room temperature, filtered, and washed 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) (3 exchangeable protons not visible).

[0303] (Example 29) Preparation of Compound 284

Chemical Structure

[0304] Step 1: 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 To a 1.0 mL solution of MeOH 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) provided according to the procedure in Example 28 was added Pd / C (10 mass% loading, 10.6 mg, 0.01 mmol, 0.2 equivalent). The reaction mixture was sparged with hydrogen gas for 5 minutes using a hydrogen balloon. The reaction was then stirred 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% MeOH in DCM to provide 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 are not visible). Biological Examples The following in vitro biological examples demonstrate the utility of the compounds described herein for treating SCA3.

[0305] To describe in more detail and to assist understanding, the following non-limiting biological examples are provided to more fully illustrate the scope of the compounds described herein and should not be construed as specifically limiting that scope. Such variations of the compounds described herein that are now known or may later be developed, to the extent recognized by those of ordinary skill in the art, are considered to fall within the scope of this description and as claimed hereinafter.

[0306] (Example 1) Endogenous total ATXN3 (tATXN3) protein assay A Meso Scale Discovery (MSD) 96-well or 384-well plate was coated overnight at 4 °C with an ataxin 3 mouse monoclonal antibody (Invitrogen, MA3-082) at a concentration of 0.5 μg / mL in PBS (30 μL per well). The plate was then washed three times with 300 μL of wash buffer (0.05% TWEEN®-20, polysorbate monolaurate, in PBS), blocked for 2 hours at room temperature with rotation and shaking (Meso Scale Diagnostics, R93BA-1; 5% BSA in PBS), and then washed three times with wash buffer.

[0307] A 7-point concentration curve was generated by serially diluting the test compound 3.16-fold in 100% DMSO. An aliquot of 0.5 μL of the diluted compound was transferred to a 96-well flat-bottom plate using a liquid handler. An aliquot of 0.5 μL of DMSO was also transferred to a separate well and used as a control. Duplicate samples were set up for each compound concentration and the DMSO control.

[0308] The cells were thawed and incubated in cell culture medium (DMEM, 10% FBS, and 1% antibiotic cocktail) for 72 hours. The cells were trypsinized, counted, and resuspended in cell culture medium at a concentration of 100,000 cells / mL. A 100 μL aliquot of the cell suspension was plated at 10,000 cells per well in a 96-well microtiter plate containing the compound and incubated in a cell culture incubator (37 °C, 5% CO2, 100% relative humidity). After 48 hours, the medium was removed, and "cell lysates" were obtained by adding 50 - 100 μL of lysis buffer (Meso Scale Diagnostics, R60TX-2) containing 1X Halt protease inhibitor cocktail (Thermo Scientific, Halt™ Protease Inhibitor Cocktail, 78430) to the cells. The plate was placed on a shaker at 4 °C for 30 minutes and then stored at -80 °C.

[0309] The cell lysate sample (25 μL) was transferred to an antibody-coated MSD plate and incubated overnight at 4 °C. After removal of the lysate, the plate was washed three times with wash buffer, and 25 μL of Ataxin3 recombinant rabbit monoclonal antibody (Invitrogen, #702788) secondary antibody (diluted to 0.25 μg / mL in 0.05% TWEEN®-20 in blocking buffer) was added to each well and incubated at room temperature for 1 - 2 hours with shaking. Following incubation with the secondary antibody, the wells were rinsed with wash buffer, and then 25 μL of anti-rabbit antibody goat SULFO-TAG labeled (Meso Scale Diagnostics, R32AB-1) detection antibody (diluted to 0.25 μg / mL in 0.05% TWEEN®-20 in blocking buffer) was added to each well and incubated at room temperature for 1 hour with shaking. After rinsing three times with wash buffer, 150 μL of Read Buffer T with surfactant (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 provided for 96 or 384 well plates. The average IC 50 values (μΜ) are shown in Table 1.

[0310] 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 ( **** ).

[0311]

Table 20

[0312] (Example 2) RT-qPCR assay for quantifying exon 4 skipping in ATXN3 pre-mRNA in cells A 7-point concentration curve was generated by serially diluting the test compound 3.16-fold in 100% DMSO. An aliquot of 0.5 μL of the diluted compound was transferred to a 96-well flat-bottom plate using a liquid handler. An aliquot of 0.5 μL of DMSO was also transferred to a separate well and used as a control. Duplicate samples were set up for each compound concentration and the DMSO control.

[0313] The cells were thawed and incubated for 72 hours in cell culture medium (DMEM, 10% FBS, and 1% antibiotic cocktail). The cells were trypsinized, counted, and resuspended in cell culture medium at a concentration of 100,000 cells / mL. A 100 μL aliquot of the cell suspension was plated at 10,000 cells per well in a compound-containing 96-well microtiter plate and incubated in a cell culture incubator (37 °C, 5% CO2, 100% relative humidity).

[0314] After 24 hours, the 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% IGEPAL® CA-630) was added to each well and incubated at room temperature for 1 minute. Cold nuclease-free water (50 μL per well) was added and the plate was immediately transferred onto ice. After 1 minute on ice, the plate was frozen at -80 °C overnight.

[0315] Preparation of the RT-qPCR reaction mixture: [Table 21]

[0316] Using a liquid handler, an aliquot of 2 μL / well of cell lysate was transferred to an Armadillo 384-Well PCR plate containing 8 μL / well of RT-qPCR reaction mixture prepared as detailed above. The plate was then sealed with MicroAmp™ Optical Adhesive Film, followed by a 1-minute spin-down and placed in a CFX384 thermocycler (BioRad).

[0317] RT-qPCR was performed at the following temperatures for the indicated times: Step 1: 48 °C (30 minutes) Step 2: 95 °C (10 minutes) Step 3: 95 °C (15 seconds) Step 4: 60 °C (1 minute); Steps 3 and 4 were then repeated for a total of 40 cycles.

[0318] Using Equations 1 and 2, the percent exon 4 skipping was calculated for each dose of compound treatment. Equation 1

Number

Number

[0319] Average IC 50 > 1 μM is indicated by one star ( * ), between > 0.3 μM to ≦ 1 μM is indicated by two stars ( ** ), between > 0.03 μM to ≦ 0.3 μM is indicated by three stars ( *** ), and ≦ 0.03 μM is indicated by four stars (**** ) is shown by

[0320]

Table 22

[0321] Regardless of whether the documents cited in this specification are specifically and individually shown as being incorporated by reference, all documents mentioned in this specification are hereby incorporated by reference into this application for any and all purposes to the same extent as if each individual reference were set forth in full herein.

[0322] Since the subject matter of the claims has been fully described heretofore, it will be understood by those skilled in the art that modifications can be made within the broad scope of equivalents without affecting the scope of the subject matter described herein or the particular embodiments. The appended claims are intended to be construed to include all such equivalents.

Claims

1. A compound of formula (I) or a form thereof, wherein the form of the compound is a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form, the compound or a form thereof. 【Chemical Formula 1】 (I) (wherein, A is selected from the group consisting of CR A and N; A' is selected from the group consisting of S and NR A’ and; L is selected from the group consisting of CH 2 and CD 2 ; R A is selected from the group consisting of hydrogen, halo, C 1-6 alkyl, and C 3-8 cycloalkyl; R A’ is selected from the group consisting of hydrogen, C 1-4 alkyl, and halo-C 1-4 alkyl; R B is selected from the group consisting of hydrogen and C 1-6 alkyl; R 1 is selected from the group consisting of phenyl, heteroaryl, C 3-8 cycloalkyl, CO 2 C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; Heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbon atom ring structural group containing 1 to 3 heteroatoms selected from N, O and S; C 3-8 Cycloalkyl is a saturated or partially unsaturated monocyclic or bicyclic ring system; Phenyl, heteroaryl, and C 3-8 Cycloalkyl is substituted with zero, 1, 2, 3, or 4 independently selected R 1a substituents, R 1a is selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, deuterio-C 1-6 alkyl, and C 1-6 alkoxy; R 2 is selected from the group consisting of hydrogen, cyano, halo, C 2-6 alkynyl, C 1-6 alkoxy-C 2-6 alkynyl, and hydroxy-C 2-6 alkynyl; R 3 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, SH, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-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, hydroxy-C 2-6 alkynyl, (CH 3 ) 3 Si-C 2-6 alkynyl, heteroaryl-C 2-6 alkynyl, C 3-8 cycloalkyl, phenyl, and heteroaryl, Heteroaryl is a 5- to 11-membered monocyclic or bicyclic aromatic carbon atom ring structural group containing 1 to 3 heteroatoms selected from N, O and S, C 3-8 Examples of cycloalkyl, phenyl, and heteroaryl are each independently substituted with zero, 1, 2, 3, or 4 independently selected R 3a substituents; R 3a is selected from the group consisting of cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl, deuterio-C 1-6 alkyl, and C 1-6 alkoxy; Ring Q is 【Chemical 2】 wherein; R 4 is selected from the group consisting of hydrogen, cyano, halo, hydroxy, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, and halo-C 1-6 alkoxy; R 5 is selected from the group consisting of amino, C 1-4 alkyl-amino, and (C 1-4 alkyl) 2 -amino; W is CH 2 , CD 2 , CH-R w , CD-R w , C(R w ), 2 and is selected from the group consisting of C(O); X is CH 2 CD 2 CH-R X CD-R X C(R X ) 2 CH, CD, CR X C=CH 2 C=CD 2 C=C(R X ) 2 C(O), NH, N-C 1-4 alkyl, N-phenyl, O, S, S(O), and SO 2 is selected from the group consisting of; Y is CH 2 CD 2 CH-R Y CD-R Y C(R Y ) 2 CH, CD, CR Y C=CH 2 C=CD 2 C=C(R Y ) 2 selected from the group consisting of N-phenyl, O, S, S(O), and SO 2 ; Z is CH 2 , CD 2 , CH-R Z , CD-R Z , C(R Z ), 2 , CH, CD, CR Z , NH, N-C 1-4 alkyl, N-phenyl, O, S, S(O), and SO 2 selected from the group consisting of; Each R w 、R X 、R Y 、R Z is independently selected from the group consisting of halo, hydroxy, 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, CO 2 H, CO 2 C 1-6 alkyl, C(O)NH 2 、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 can combine to form a carbocyclic or heterocyclic ring; n is selected from the group consisting of 0, 1, 2, and 3; 【Chemical Formula 3】 independently represents a single bond or a double bond as permitted by valence)

2. The compound according to claim 1, which is a compound of formula (Ia) or a form thereof. 【Chemical 4】 (wherein, L is CH 2 or CD 2 and; R A is hydrogen; R B is hydrogen or CH 3 ; R 2 is Cl or CN)

3. The compound according to claim 1, which is a compound of formula (Ib) or a form thereof. 【Chemical Formula 5】 (wherein, L is CH 2 and; R B is hydrogen; R 2 is Cl)

4. The compound according to claim 1, which is a compound of formula (Ic) or a form thereof. 【Chemical Formula 6】 (wherein, L is CH 2 and; R A is hydrogen; R A’ is CH 3 or CHF 2 and; R B is hydrogen; R 2 is Cl)

5. The compound according to claim 1, which is a compound of formula (Id) or a form thereof. 【Chemical 7】 (wherein, L is CH 2 and; R A’ is CHF 2 and is: R B is hydrogen; R 2 is Cl)

6. R 1 is phenyl, CO 2 CH 3 , 【Chemical 8】 The compound according to any one of claims 1 to 5, which is

7. R 3 is hydrogen, cyano, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 OH, CH 2 OCHF 2 , CH=CH 2 , CH=C=CH 2 , cyclopropyl, phenyl, 【Chemical Formula 9】 The compound according to any one of claims 1 to 6, which is

8. Q is 【Chemical 10】 or any stereoisomeric form thereof, the compound according to any one of claims 1 to 7.

9. R 4 is hydrogen, F, or hydroxy; R 5 is amino, NH(CH 3 ), or N(CH 3 ), and the compound according to any one of claims 1 to 8. 2 ​

10. R W 、R X 、R Y 、R Z are F, hydroxy, CH 3 、OCH 3 、CO 2 H、CO 2 CH 2 CH 3 、C(O)NH 2 、C(O)N(CH 3 ) 2 、 【Chemical 11】 The compound according to any one of claims 1 to 9, which is independently selected from each of

11. A compound selected from the following: 2-((1S,2S)-2-aminocyclopentyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclopentyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclopentyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclopentyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclopentyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclopentyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclopentyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclopentyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocyclopentyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclopentyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclopentyl)-5-chloro-3-ethyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclopentyl)-5-chloro-3-ethyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocyclohexyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocyclohexyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-Aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-Aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-Aminotetrahydro-2H-pyran-2-yl)-3,5-dichloro-N-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocyclohexyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Amino-4,4-difluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-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)cyclohexan-1-ol; 2-((1R,2S)-2-Amino-1-fluorocyclohexyl)-3,5-dichloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-3,5-dichloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-ethyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-ethyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-3-ethyl-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-Aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-Aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-Aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3S)-3-Aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-Aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-Aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-Aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocyclohexyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocyclohexyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-Aminotetrahydro-2H-pyran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-3-iodo-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocycloheptyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocycloheptyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocycloheptyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocycloheptyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocycloheptyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocycloheptyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocycloheptyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocycloheptyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocycloheptyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocycloheptyl)-5-chloro-3-methyl-N-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-5-chloro-3-ethyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-3-ethyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-3-ethyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocycloheptyl)-5-chloro-3-ethyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocycloheptyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocycloheptyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocycloheptyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclooctyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-aminocyclooctyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-aminocyclooctyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclooctyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-aminocyclooctyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclooctyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclooctyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocyclooctyl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclooctyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclooctyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocyclooctyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocyclooctyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2S)-2-Aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclooctyl)-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R)-2-Aminocyclooctyl)-5-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclopentyl)-5-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclooctyl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-Amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-Amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3S)-3-Amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-Amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-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-((thiophen-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-((thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-cyclopropyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclopentyl)-5-chloro-3-phenyl-N-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-3-cyclopropyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3R,4S)-3-Aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocycloheptyl)-5-chloro-3-phenyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocycloheptyl)-5-chloro-3-phenyl-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6SR)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4S)-3-aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((4R,5R)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((4S,5S)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((4R,5S)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((4S,5R)-5-aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3S)-3-aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3R)-3-Aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-Aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S,3S)-3-Aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Amino-4,4-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Amino-4,4-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (1R,5S,6R)-6-Amino-5-(3-bromo-5-chloro-7-((thiophen-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-((thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclooctyl)-5-chloro-3-ethyl-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocycloheptyl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclooctyl)-5-chloro-3-ethyl-N-(thiophen-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)thieno[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)penta-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)penta-4-yn-1-ol; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R,6S)-2-Amino-6-fluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-2-chloro-7-iodo-N-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-aminocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thiophen-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-(thiophen-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)cyclohexan-1-one; (2S,3R)-2-amino-3-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-4-Aminotetrahydro-2H-pyran-3-yl)-3-bromo-5-chloro-N-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-Aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thiophen-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)penta-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)penta-4-yn-1,2-diol; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thiophen-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-(thiophen-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)cyclohexan-1-one; 2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (1R,2R,3S)-2-Amino-3-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; (1S,2S,3R)-2-Amino-3-(3-bromo-5-chloro-7-((thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6R)-6-Aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-((difluoromethoxy)methyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-3-((difluoromethoxy)methyl)-N-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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)penta-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2R,3R)-3-Aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-N-(thiophen-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine; 6-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-2-chloro-7-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 2-((1R,6S)-6-Amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6R)-6-Amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thiophen-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-((thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thiophen-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; Ethyl (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-carboxylate; 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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((2S)-2-Aminocyclohexyl)-5-chloro-3-(difluoromethyl)-N-(thiophen-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-(thiophen-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-(thiophen-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)penta-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)penta-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]heptan-3-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,3S,4S,6R)-4-Aminobicyclo[4.1.0]heptan-3-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,6S)-6-Amino-2,2-difluorocyclohexyl)-3,5-dichloro-N-(thiophen-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)penta-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)penta-4-yn-1-ol; 2-((1R,5S,6R)-6-Amino-5-methylcyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(thiophen-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-(thiophen-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-(thiophen-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)penta-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)penta-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-((thiophen-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-((thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thiophen-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)hepta-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-(prop-1,2-dien-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-(prop-1,2-dien-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-(thiophen-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-((thiophen-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-((thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Amino-5,5-difluorocyclohexyl)-5-chloro-3-methyl-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2S,6R)-2-Amino-6-fluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-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)penta-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,2R,3R)-2-Amino-3-fluorocyclohexyl)-5-chloro-3-methyl-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(thiophen-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(thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)penta-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-(thiophen-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-((thiophen-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-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; (1S,2R,3S)-3-Amino-2-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-N-(thiophen-2-ylmethyl)-3-(trifluoromethyl)thieno[3,2-b]pyridin-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-Amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-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-(cyclopenta-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thiophen-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)glycinate methyl ester; (2-((1R,6R)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; (2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-5-chloro-3-methyl-N-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; (1S,2R,3S)-2-Amino-3-(5-chloro-3-methyl-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol; 3-Bromo-5-chloro-2-((1R,2R)-2-(methylamino)cyclohexyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 3-Bromo-5-chloro-2-((1S,2S)-2-(methylamino)cyclohexyl)-N-(thiophen-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-((thiophen-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-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 6-((1R,6R)-6-Aminocyclohex-3-en-1-yl)-7-bromo-2-chloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 5-Chloro-3-iodo-2-((1S,6S)-6-(methylamino)cyclohex-3-en-1-yl)-N-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine; 6-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-2,7-dichloro-N-(thiophen-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]pyridine-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridine-7-amine; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-3-(fluoromethyl)-N-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine; 2-((1S,2S)-2-Aminocyclohexyl)-3,5-dichloro-1-(difluoromethyl)-N-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thiophen-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; Ethyl (4R,5S)-5-amino-4-(5-chloro-3-methyl-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-1-ene-1-carboxylate; (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; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-3-((3-chloropyridin-4-yl)ethynyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-N-(thiophen-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(thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)penta-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)penta-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)penta-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)penta-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)penta-4-yn-1-ol; 2-((1R,6R)-6-Aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-((E)-penta-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)-penta-2-en-1-yl)thieno[3,2-b]pyridin-7-amine; or a form thereof, wherein the form of the compound is a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form of the compound or a form thereof.

12. A compound selected from the following: 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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((1S,2R)-2-Amino-4,4-difluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; (1R,2S)-2-Amino-1-(3,5-dichloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-ol hydrochloride; 2-((1R,2S)-2-Amino-1-fluorocyclohexyl)-3,5-dichloro-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2S,3R)-3-Aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3R)-3-Aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2S,3S)-3-Aminopiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-methyl-N-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3R)-3-Amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2S,3S)-3-Amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3S)-3-Amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((2S,3R)-3-Amino-1-phenylpiperidin-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-Aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((3S,4S)-3-Aminotetrahydro-2H-pyran-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((4R,5R)-5-Aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((4S,5S)-5-Aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((4R,5S)-5-Aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((4S,5R)-5-Aminoazepan-4-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,2R)-2-Amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-Amino-5,5-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3S)-3-Aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2S,3R)-3-Aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2R,3R)-3-Aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((2S,3S)-3-Aminotetrahydrofuran-2-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1R,2R)-2-Amino-4,4-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-Amino-4,4-dimethylcyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; (1R,5S,6R)-6-Amino-5-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol formate; (1S,5R,6S)-6-Amino-5-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol formate; 5-(2-((1R,6R)-6-Aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)penta-4-yn-1-ol formate; 5-(2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)penta-4-yn-1-ol formate; 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-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; 2-((1R,6R)-6-Aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-(prop-1-yn-1-yl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; -(2R,3S)-2-Amino-3-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-1-one hydrochloride; (2S,3R)-2-Amino-3-(3-bromo-5-chloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohexan-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-4-Aminotetrahydro-2H-pyran-3-yl)-3-bromo-5-chloro-N-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,6R)-6-Aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-3-iodo-N-(thiophen-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)penta-4-ene-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-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)penta-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; (1R,2R,3S)-2-Amino-3-(3-bromo-5-chloro-7-((thiophen-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-((thiophen-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-(thiophen-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-(thiophen-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-(thiophen-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)penta-4-yn-1-ol trifluoroacetate; 2-((2R,3R)-3-Aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((2S,3S)-3-Aminotetrahydro-2H-pyran-2-yl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine hydrochloride; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-N-(thiophen-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1R,6S)-6-Amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6R)-6-Amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-Aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3R,4S)-3-Aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-5-chloro-3-iodo-N-(thiophen-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-(thiophen-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-(thiophen-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)penta-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)penta-4-yn-1-ol trifluoroacetate; 2-((1R,3R,4R,6S)-4-Aminobicyclo[4.1.0]heptan-3-yl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,3S,4S,6R)-4-Aminobicyclo[4.1.0]heptan-3-yl)-3-bromo-5-chloro-N-(thiophen-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)penta-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)penta-4-yn-1-ol trifluoroacetate; 2-((1R,2R)-2-Aminocyclohexyl)-N-benzyl-5-chloro-3-iodothieno[3,2-b]pyridin-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]pyridin-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-(thiophen-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)penta-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)penta-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-3,5-dichloro-N-(thiophen-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-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-3-yl)hepta-6-yn-1-ol formate; 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-(prop-1,2-dien-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-(prop-1,2-dien-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-((thiophen-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-((thiophen-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-(cyclopenta-1-en-1-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-3-bromo-5-chloro-N-(cyclopenta-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,2R,3R)-2-Amino-3-fluorocyclohexyl)-5-chloro-3-methyl-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 6-((3R,4S)-3-Aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 6-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-7-bromo-2-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine formate; 2-((3R,4S)-3-Aminotetrahydro-2H-pyran-4-yl)-5-chloro-N-(thiophen-2-ylmethyl)-3-vinylthieno[3,2-b]pyridin-7-amine formate; 2-((3S,4R)-3-Aminotetrahydro-2H-pyran-4-yl)-5-chloro-N-(thiophen-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-((thiophen-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-((thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-Amino-2,2-difluorocyclohexyl)-3-bromo-5-chloro-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; Methyl (2-((1S,6S)-6-aminocyclohex-3-en-1-yl)-3-bromo-5-chlorothieno[3,2-b]pyridin-7-yl)glycinate formate; 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-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-d]pyrimidin-4-amine trifluoroacetate; (1R,2S,3R)-2-amino-3-(5-chloro-3-methyl-7-((thiophen-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-((thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 3-bromo-5-chloro-2-((1S,2S)-2-(methylamino)cyclohexyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; (1R,5S,6R)-5-Amino-6-(3,5-dichloro-7-((thiophen-2-ylmethyl)amino)thieno[3,2-b]pyridin-2-yl)cyclohex-2-en-1-ol formate; 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-(thiophen-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-(thiophen-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-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,2S)-2-Aminocyclohexyl)-5-chloro-3-(fluoromethyl)-N-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine formate; 2-((1R,2R)-2-Aminocyclohexyl)-5-chloro-3-(fluoromethyl)-N-(thiophen-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-(thiophen-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-7-amine formate; 2-((1S,2S)-2-Aminocyclohexyl)-3,5-dichloro-1-(difluoromethyl)-N-(thiophen-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-(thiophen-2-ylmethyl)thieno[3,2-b]pyridin-7-amine trifluoroacetate; 2-((1S,6S)-6-Aminocyclohex-3-en-1-yl)-5-chloro-N-(thiophen-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)penta-4-yn-1-ol formate; 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)penta-4-yn-1-ol formate; or a form thereof, wherein the form of the compound is a hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, tautomer or isotopically enriched form of the compound or a form thereof.

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

14. The method of claim 13, wherein an effective amount of the compound or a form thereof induces exon skipping in ATXN3 pre-mRNA in a subject. **Claim 15** The method of claim 13, wherein an effective amount of the compound or a form thereof induces exon skipping in a subject. **Claim 16** A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 12, mixed with a pharmaceutically acceptable excipient.

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