Compounds for treating Huntington's disease

Abstract

The present disclosure provides a compound of formula (I') [Formula 1] JPEG2025526462000224.jpg27165, or a pharmaceutically acceptable salt thereof, and uses thereof, such as in the treatment of conditions, diseases, or disorders in which lowering mutant huntingtin protein ("mHTT") in a subject provides a therapeutic benefit, particularly in the treatment of Huntington's disease ("HD"). The disclosure also features compositions containing same, as well as methods of using and making same.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 393,496, filed July 29, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder with a global prevalence of 3-7 per 100,000 people. HD is caused by an expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin (HTT) gene, resulting in the production of a ubiquitously expressed, pathogenic mutant HTT (mHTT) protein. Mutant huntingtin contains an abnormally long polyglutamine (polyQ) sequence corresponding to the CAG gene expansion, and this protein exhibits toxicity, leading to neuronal dysfunction and death. The disease is characterized by a decline in motor, cognitive, psychiatric, and functional abilities.

[0003] Some studies have progressed in identifying HTT protein-lowering therapies using multiple tools, including ribonucleic acid (RNA) interference using small interfering RNA, short hairpin RNA, or microRNA, and antisense oligonucleotides ("ASOs") that result in translational inhibition or messenger RNA (mRNA) degradation. However, these treatments require either surgical delivery of viral vectors for chronic HTT transcript reduction by RNAi or repeated infusions of ASOs into the cerebrospinal fluid ("CSF") via lumbar puncture in the clinic.

[0004] More recently, small molecule platforms are being developed that regulate RNA expression, i.e., splicing correction. NVS-SM1 (LMI070), now called branapram, is a pyridazine derivative. Branapram has been reported to reduce mHTT protein levels in HD patient cells, HD mouse models, and blood samples from spinal muscular atrophy (SMA) type 1 patients treated orally with SMA (NCT02268552). See Keller, C. et al., An Orally Available, Brain Penetrant, Small Molecule Lowers Huntingtin Levels by Enhancing Pseudoexon Inclusion, Nature Communications, (2022) 13:1150.

[0005] However, there are currently no approved disease-modifying treatments for HD, and there remains a high unmet need for drugs that can be used to treat or ameliorate HD. Therefore, there is a need to identify disease-modifying therapies for HD (i.e., treatment options that can slow disease progression). Summary of the Invention

[0006] Described herein are compounds or pharmaceutically acceptable salts thereof that can be useful in treating HD in a subject.

[0007] In one aspect, the present disclosure provides a compound of formula (I') or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X 1 , X 2 , Y 1 , Y 2 , Z, and R 1 is as described herein).

[0008] Also provided is a pharmaceutical composition comprising a compound of formula (I') or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0009] The present disclosure further provides a method of lowering mHTT in a subject, comprising administering to the subject a compound of formula (I') or a pharmaceutically acceptable salt thereof.

[0010] The present disclosure also provides a method for treating a disease or condition in a subject that is at least partially regulated by mHTT, comprising administering to the subject a therapeutically effective amount of a compound of formula (I') or a pharmaceutically acceptable salt thereof.

[0011] The present disclosure further provides a method of treating Huntington's disease ("HD") in a subject in need thereof, comprising administering to the subject an effective amount of: (1) a compound of formula (I') or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I') or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] In certain embodiments of the methods of the present disclosure, HD can be treated by lowering mHTT levels in a subject.

[0013] The present disclosure also provides the use of a compound of formula (I'), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same in any of the methods described herein. In one embodiment, a compound of formula (I'), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same is provided for use in any of the methods described herein. In another embodiment, a use of a compound of formula (I'), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same for the manufacture of a medicament for any of the methods described herein is provided. DETAILED DESCRIPTION OF THE INVENTION

[0014] 1.Compound In a first aspect, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof, [ka] is a single or double bond, with the proviso that the ring containing X1 and X2 is a 5-membered heteroaryl ring; [ka] is R 1 indicates that one of the two positions on the six-membered ring connected by the dashed line is substituted, and the other position connected by the dashed line is unsubstituted, Z is -C(=O)NR 2 R 3 or -NR 2 C(=O)R 3 and X 1 is S or CH, X 2 is N, O or CH, Y 1 and Y 2 one of which is N and the other is CH; R 1 -NR is a 4- to 12-membered heterocyclyl, a 4- to 12-membered carbocyclyl, 11 R 12 , -C 1-6 Alkylene-NR 13 R 14 , or -OR 15 where: R 1 The 4- to 12-membered carbocyclyl or the 4- to 12-membered heterocyclyl represented by A where: Each R A independently, C 1-6 Alkyl, C 3-6 Cycloalkyl, HaloC 1-6 Alkyl, -NRa R b , -C 1-3 Alkylene-NR a R b , -C 3-6 Cycloalkylene-NR a R b , -C(=O)R a or a 4- to 6-membered saturated heterocyclyl, where each R a and R b are independently H or C 1-6 alkyl, where R A The 4-6 membered saturated heterocyclyl represented by the formula 1-6 optionally substituted with alkyl; R 11 is H or C 1-6 is alkyl, R 12 is C 1-6 alkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, where R 12 The C in question is represented by 1-6 The alkyl, the 6- to 10-membered aryl, the 4- to 12-membered heterocyclyl, or the 5- to 10-membered heteroaryl may be one or more R B where: R B Ha, Halo, C 1-6 Alkyl, -NR a R b , 4- to 6-membered heterocyclyl, or -C 1-6 alkylene-4 to 6 membered heterocyclyl, where R B The 4- to 6-membered heterocyclyl represented by the formula 1-6 optionally substituted with alkyl; R 13 is H or C 1-6 is alkyl, R 14 and R 15 is H, C 1-6 Alkyl, or -C 1-6 alkylene-4-6 membered saturated heterocyclyl; R 2 is H or C 1-3 is alkyl, R 3 is a 6- to 10-membered aryl or a 6- to 10-membered heteroaryl, where R 3 The 6- to 10-membered aryl and the 6- to 10-membered heteroaryl represented by the formula C where: R C Halo, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 Alkoxy or two R C and the intervening atoms together form a 5- to 7-membered heterocyclyl, where R C The 5- to 7-membered heterocyclyl represented by R C1 where R C1 is C 1-3 alkyl or oxo, wherein the heterocyclyl contains 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl contains 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; However, the compound of formula (I') [ka] (not represented by

[0015] In a first embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, [ka] is a single or double bond, with the proviso that the ring containing X1 and X2 is a 5-membered heteroaryl ring; [ka] is R 1 indicates that one of the two positions on the pyridyl moiety connected by the dashed line is substituted and the other position connected by the dashed line is unsubstituted; X 1 is S or CH, X 2 is N, O or CH, R 1 is 4-12 membered heterocyclyl, -NR 11 R 12 , or -C 1-6 Alkylene-NR 13 R 14 where: R 1 The 4- to 12-membered heterocyclyl represented by the formula A where: Each R A independently, C 1-6 Alkyl, C 3-6 Cycloalkyl, HaloC 1-6 Alkyl, -NR a R b , -C 1-3 Alkylene-NR a R b , -C 3-6 Cycloalkylene-NR a R b , -C(=O)R a or a 4- to 6-membered saturated heterocyclyl, where each R a and R b are independently H or C 1-6 alkyl, where R A The 4-6 membered saturated heterocyclyl represented by the formula 1-6 optionally substituted with alkyl; R 11 is H or C 1-6 is alkyl, R 12 is C 1-6alkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, where R 12 The C in question is represented by 1-6 The alkyl, the 6- to 10-membered aryl, the 4- to 12-membered heterocyclyl, or the 5- to 10-membered heteroaryl may be one or more R B where: R B is C 1-6 Alkyl, -NR a R b , 4- to 6-membered heterocyclyl, or -C 1-6 alkylene-4 to 6 membered heterocyclyl, where R B The 4- to 6-membered heterocyclyl represented by the formula 1-6 optionally substituted with alkyl; R 13 is H or C 1-6 is alkyl, R 14 is H, C 1-6 Alkyl, or -C 1-6 alkylene-4 to 6 membered saturated heterocyclyl; R 2 is H or C 1-3 is alkyl, R 3 is a 6- to 10-membered aryl or a 6- to 10-membered heteroaryl, where R 3 The 6- to 10-membered aryl and the 6- to 10-membered heteroaryl represented by the formula C where: R C Halo, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 Alkoxy or two R C and the intervening atoms together form a 5- to 7-membered heterocyclyl, where R C The 5- to 7-membered heterocyclyl represented by R C1 where RC1 is C 1-3 alkyl or oxo, wherein the heterocyclyl contains 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl contains 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur; However, the compound of formula (I) [ka] (not represented by

[0016] In a second embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (II): [ka] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the first aspect or first embodiment.

[0017] In a third embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (III): [ka] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the first aspect or first embodiment.

[0018] In a fourth embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IV): [ka] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the first aspect or first embodiment.

[0019] In a fifth embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (V): [ka] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the first aspect or first embodiment.

[0020] In an alternative fifth embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (VI): [ka] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the first aspect or first embodiment.

[0021] In an alternative fifth embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (VII): [ka] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the first aspect or first embodiment.

[0022] In another alternative fifth embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (VIII): [ka] or a pharmaceutically acceptable salt thereof. Definitions of the variables are provided in the first aspect or first embodiment.

[0023] In a sixth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 2 is H. The definitions of the remaining variables are provided in the first aspect or any one of the first to fifth embodiments or any alternative embodiments described therein.

[0024] In a seventh embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4-12 membered saturated heterocyclyl. The definitions of the remaining variables are provided in the first aspect or any one of the first to sixth embodiments or any alternative embodiments described therein.

[0025] In an eighth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to seventh embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 4-12 membered saturated heterocyclyl containing one or two ring N atoms, provided that when the heterocyclyl contains one ring N atom, -NR 7 R 8 , -C 1-3 Alkylene-NR 7 R 8 or -C 3-6 Cycloalkylene-NR 7 R 8 and one to four R 9 and when the heterocyclyl contains two ring N atoms, one to three R 9 optionally replaced by R 7 and R 8 are each independently H or C 1-6 alkyl or R 7 and R 8 together with the N to which they are attached, form one or two C 1-6forming a 4-6 membered heterocycle optionally substituted with alkyl, wherein the 4-6 membered heterocycle optionally contains a second heteroatom selected from N and O; R 9 For each occurrence, halo, -C(=O)R 10 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, and C 3-6 cycloalkyl, where R 9 The C in question is represented by 3-6 Cycloalkyl includes halo and C 1-6 optionally substituted by one or more substituents independently selected from alkyl, where R 10 is H, C 1-3 Alkyl, or C 3-6 and cycloalkyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through seventh embodiments or any alternative embodiments described therein.

[0026] In an alternative eighth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to seventh embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 4-12 membered saturated heterocyclyl containing one or two ring N atoms, provided that when the heterocyclyl contains one ring N atom, -NR 7 R 8 , -C 1-3 Alkylene-NR 7 R 8 or -C 3-6 Cycloalkylene-NR 7 R 8 and optionally substituted with one to two R 9 and when the heterocyclyl contains two ring N atoms, one to three R 9 optionally replaced by R 7 and R 8 are each independently H or C1-6 alkyl or R 7 and R 8 together with the N to which they are attached, form one or two C 1-6 forming a 4-6 membered heterocycle optionally substituted with alkyl, wherein the 4-6 membered heterocycle optionally contains a second heteroatom selected from N and O; R 9 For each occurrence, halo, -C(=O)R 10 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, and C 3-6 cycloalkyl, where R 9 The C in question is represented by 3-6 Cycloalkyl includes halo and C 1-6 optionally substituted by one or more substituents independently selected from alkyl, where R 10 is H, C 1-3 Alkyl, or C 3-6 and cycloalkyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through seventh embodiments or any alternative embodiments described therein.

[0027] In a ninth embodiment, the present disclosure provides a compound according to the eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclyl containing one ring N atom and one to four R 9 The remaining variable definitions are provided in the eighth embodiment or any alternative embodiment described therein.

[0028] In an alternative ninth embodiment, the present disclosure provides a compound according to the eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1is selected from pyrrolidinyl, piperidinyl, azabicyclo[3.2.1]octanyl, and azaspiro[3.4]octanyl. The definitions of the remaining variables are provided in the eighth embodiment or any alternative embodiment described therein.

[0029] In another alternative ninth embodiment, the present disclosure provides a compound according to the eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] The remaining variable definitions are provided in the eighth embodiment or any alternative embodiment described therein.

[0030] In a tenth embodiment, the present disclosure provides a compound according to the eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclyl containing one ring N atom, -NR 7 R 8 -C 1-3 Alkylene-NR 7 R 8 or -C 3-6 Cycloalkylene-NR 7 R 8 and one to two R 9 The remaining variable definitions are provided in the eighth embodiment or any alternative embodiment described therein.

[0031] In an alternative tenth embodiment, the present disclosure provides a compound according to the eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclyl selected from azetidinyl, piperidinyl, pyrrolidinyl, octahydro-1H-isoindolyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is represented by —NR 7 R 8 , -C 1-3 Alkylene-NR 7 R 8 or -C3-6 Cycloalkylene-NR 7 R 8 and one to two R 9 The remaining variable definitions are provided in the eighth embodiment or any alternative embodiment described therein.

[0032] In an eleventh embodiment, the present disclosure provides a compound according to the tenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] each of which is selected from -NR 7 R 8 , -C 1-3 Alkylene-NR 7 R 8 or -C 3-6 Cycloalkylene-NR 7 R 8 and one to two R 9 The remaining variable definitions are provided in the tenth embodiment or any alternative embodiment described therein.

[0033] In an alternative eleventh embodiment, the present disclosure provides a compound according to the tenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] is selected from Each of them is -NR 7 R 8 , -C 1-3 Alkylene-NR 7 R 8 or -C 3-6 Cycloalkylene-NR 7 R 8 and one to two R 9 The remaining variable definitions are provided in the tenth embodiment or any alternative embodiment described therein.

[0034] In a twelfth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are each independently H or C 1-3 alkyl or R 7 and R 8 are taken together to form a C2-C4 alkylene, with one or two C 1-3 and optionally substituted with alkyl. The definitions of the remaining variables are as provided in the first aspect or any one of the first through eleventh embodiments or any alternative embodiments described therein.

[0035] In a thirteenth embodiment, the present disclosure provides a compound according to the second aspect or any one of the first to twelfth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are each independently H, -CH3, or -CH2CH3, or R 7 and R 8 taken together is -CHCHCHCHCH-, -CHCHCHCH- or -CHC(CH)CH-. Definitions of the remaining variables are provided in the first aspect or any one of the first to twentieth embodiments or any alternative embodiments described therein.

[0036] In a fourteenth embodiment, the present disclosure provides a compound according to any one of the ninth to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] each of which is selected from the group consisting of 1 to 2 R 9 The remaining variable definitions are provided in any one of the ninth through eleventh embodiments or any alternative embodiments described therein.

[0037] In an alternative fourteenth embodiment, the present disclosure provides a compound according to any one of the ninth to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] each of which is selected from the group consisting of 1 to 2 R 9 The remaining variable definitions are provided in any one of the ninth through eleventh embodiments or any alternative embodiments described therein.

[0038] In a fifteenth embodiment, the present disclosure provides a compound according to the eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclyl containing two ring N atoms and one to three R 9 The remaining variable definitions are provided in the eighth embodiment or any alternative embodiment described therein.

[0039] In a sixteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or a pharmaceutically acceptable salt thereof, wherein R 1 The 4- to 12-membered saturated heterocyclyl represented by the formula is piperazinyl, 4,7-diazaspiro[2.5]octanyl, 3,9-diazaspiro[5.5]undecanyl, 1-oxa-4,9-diazaspiro[5.5]undecanyl, diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[4,3-b][1,4]oxazinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[1,2-a]pyrazinyl, decahydro-1,6-naphthyridinyl, 1,6-diazaspiro[3.4]octanyl, 1,5-diazaspiro[3.4]octanyl, 2λ 2 ,5-diazaspiro[3.4]octanyl, 2λ 2,6-diazaspiro[3.4]octanyl, hexahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[3,4-b]pyrrolyl, 3,6-diazabicyclo[3.2.0]heptanyl, 1,4-diazepanyl, 2,6-diazaspiro[3.5]nonane, 2,6-diazabicyclo[3.2.0]heptanyl, or 1,7-diazaspiro[4.4]nonanyl, each of which is selected from the group consisting of one to two R 9 The remaining variable definitions are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0040] In an alternative sixteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or a pharmaceutically acceptable salt thereof, wherein R 1 is piperazinyl, diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[4,3-b][1,4]oxazinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[1,2-a]pyrazinyl, decahydro-1,6-naphthyridinyl, hexahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[3,4-b]pyrrolyl, 1,4-diazepanyl, or 2,6-diazaspiro[3.5]nonane, each of which is selected from one to two R 9 The remaining variable definitions are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0041] In a seventeenth embodiment, the present disclosure provides a compound according to the sixteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 The 4- to 12-membered saturated heterocyclyl represented by [ka] , each of which contains one or three R 9 The remaining variable definitions are provided in the sixteenth embodiment or any alternative embodiment described therein.

[0042] In an alternative seventeenth embodiment, the present disclosure provides a compound according to the sixteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 The 4- to 12-membered saturated heterocyclyl represented by [ka] , each of which contains one or three R 9 The remaining variable definitions are provided in the sixteenth embodiment or any alternative embodiment described therein.

[0043] In an eighteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4-12 membered partially saturated heterocyclyl. The definitions of the remaining variables are provided in the first aspect or any one of the first to sixth embodiments or any alternative embodiments described therein.

[0044] In a nineteenth embodiment, the present disclosure provides a compound according to the eighteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 is 2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine, 1,2,3,6-tetrahydropyridinyl, 6-azabicyclo[3.1.1]hept-2-enyl, or 8-azabicyclo[3.2.1]oct-2-enyl. The definitions of the remaining variables are provided in the eighteenth embodiment or any alternative embodiment described therein.

[0045] In an alternative nineteenth embodiment, the present disclosure provides a compound according to the eighteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 is 2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine, 1,2,3,6-tetrahydropyridinyl, or 8-azabicyclo[3.2.1]oct-2-enyl. The definitions of the remaining variables are provided in the eighteenth embodiment or any alternative embodiment described therein.

[0046] In a twentieth embodiment, the present disclosure provides a compound according to the eighteenth or nineteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 A partially saturated heterocyclyl represented by [ka] each of which is selected from the group consisting of 1, 2, 3 or 4 R 9 The remaining variable definitions are provided in the eighteenth embodiment or the nineteenth embodiment or any alternative embodiment described therein.

[0047] In an alternative twentieth embodiment, the present disclosure provides a compound according to the eighteenth or nineteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein the partially saturated heterocyclyl is: [ka] each of which is selected from the group consisting of one or two R 9 The remaining variable definitions are provided in the eighteenth embodiment or the nineteenth embodiment or any alternative embodiment described therein.

[0048] In a twenty-first embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is -NR7 R 8 and 4- to 12-membered saturated or partially saturated carbocyclyl substituted with one or two R 9 and optionally further substituted by. The definitions of the remaining variables are provided in the first aspect or any one of the first to sixth embodiments or any alternative embodiments described therein.

[0049] In an alternative twenty-first embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclohexyl or cyclohexenyl, each of which is -NR 7 R 8 and one or two R 9 and optionally further substituted by. The definitions of the remaining variables are provided in the first aspect or any one of the first to sixth embodiments or any alternative embodiments described therein.

[0050] In yet another alternative twenty-first embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] each of which is selected from -NR 7 R 8 and one or two R 9 and optionally further substituted by. The definitions of the remaining variables are provided in the first aspect or any one of the first to sixth embodiments or any alternative embodiments described therein.

[0051] In a twenty-second embodiment, the present disclosure provides a compound according to the twenty-first embodiment, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are each independently H or C `1-3The remaining variable definitions are provided in the 21st embodiment or any alternative embodiment described therein.

[0052] In an alternative twenty-second embodiment, the present disclosure provides a compound according to the twenty-first embodiment, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are each independently H or —CH 3 . The definitions of the remaining variables are provided in the twenty-first embodiment or any alternative embodiment described therein.

[0053] In a twenty-third embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 For each occurrence, halo, -C(=O)R 10 , C 1-4 Alkyl, C 1-4 Haloalkyl, and C 3-6 cycloalkyl, where R 9 The C in question is represented by 3-6 Cycloalkyl includes F, Cl, and C 1-4 optionally substituted with 1 to 3 substituents independently selected from alkyl; 10 is H, C 1-2 Alkyl, C 3-4 and cycloalkyl. The definitions of the remaining variables are provided in the first aspect or any one of the first to twenty-second embodiments or any alternative embodiments described therein.

[0054] In a twenty-fourth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 is, at each occurrence, independently selected from F, —CH, —CHCH, —C(═O)CH, —CHCF, —CH(CH), —CD, and cyclopropyl. Definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-second embodiments or any alternative embodiments described therein.

[0055] In an alternative twenty-fourth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 is, at each occurrence, independently selected from -CH, -C(=O)CH, -CHCF, -CH(CH), and cyclopropyl. Definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-second embodiments or any alternative embodiments described therein.

[0056] In a twenty-fifth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -NR 11 R 12 and R 11 is H or C 1-6 is alkyl, R 12 is C 1-6 Alkyl-NR a R b , phenyl, 4-12 membered heterocyclyl containing at least one ring N atom, where R 12 The phenyl represented by the formula: a R b , Het, or -C 1-3 substituted with alkylene-Het, where Het is a 4-6 membered heterocyclyl containing at least one ring N atom and one or two C 1-3 optionally substituted with alkyl, where R 12 The 4-12 membered heterocyclyl represented by the formula: 12a where each R 12a independently, C 1-3 alkyl or halo. The definitions of the remaining variables are provided in the first aspect or any one of the first to sixth embodiments or any alternative embodiments described therein.

[0057] In an alternative twenty-fifth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -NR 11 R 12 and R 11 is H or C 1-6 is alkyl, R 12 is C 1-6 Alkyl-NR a R b , phenyl, 4-12 membered heterocyclyl containing at least one ring N atom, where R 12 The phenyl represented by the formula: a R b , Het, or -C 1-3 substituted with alkylene-Het, where Het is a 4-6 membered heterocyclyl containing at least one ring N atom and one or two C 1-3 optionally substituted with alkyl, where R 12 The 4- to 12-membered heterocyclyl represented by the formula 1-3 and optionally substituted with alkyl. The definitions of the remaining variables are as provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiment described therein.

[0058] In a twenty-sixth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -NR 11 R 12 and R 11 is H or -CH3, R 12is selected from the group consisting of piperidinyl, hexahydro-1H-pyrrolidinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolizinyl, isoindolinyl, phenylazetidinyl, 1,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, benzylpyrrolidinyl, and quinuclidinyl, each of which is selected from the group consisting of 1, 2, 3, 4, or 5 R 12a where R 12a is C 1-3 alkyl or halo. The definitions of the remaining variables are provided in the first aspect or any one of the first to sixth embodiments or any alternative embodiments described therein.

[0059] In some embodiments, for a compound according to the twenty-fifth or twenty-sixth embodiment or a pharmaceutically acceptable salt thereof, R 12a is methyl or fluoro. The definitions of the remaining variables are provided in the twenty-fifth embodiment or the twenty-sixth embodiment or any alternative embodiment described therein.

[0060] In an alternative twenty-sixth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -NR 11 R 12 and R 11 is H or -CH3, R 12 is selected from the group consisting of hexahydro-1H-pyrrolidinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolizinyl, isoindolinyl, phenylazetidinyl, 1,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, benzylpyrrolidinyl, and quinuclidinyl, each of which independently contains one or two C 1-2and optionally substituted with alkyl. The definitions of the remaining variables are as provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiment described therein.

[0061] In a twenty-seventh embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -NR 11 R 12 and R 11 is H or -CH3, R 12 teeth, [ka] each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, -CH3, and -CH2CH3. Definitions for the remaining variables are provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiment described therein.

[0062] In an alternative twenty-seventh embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -NR 11 R 12 and R 11 is H or -CH3, R 12 teeth, [ka] and each of which is optionally substituted with one or two substituents independently selected from -CH3 and -CH2CH3. Definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiment described therein.

[0063] In a twenty-eighth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 -OR 15 and R 15 is C 1-6 Alkyl-NR a R b , phenyl, 4- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl containing at least one ring N atom, where R 15 The phenyl or the 4- to 12-membered carbocyclyl represented by the formula: a R b , Het, or -C 1-3 substituted with alkylene-Het, where Het is a 4-6 membered heterocyclyl containing at least one ring N atom and one or two C 1-3 optionally substituted with alkyl, where R 15 The 4- to 12-membered heterocyclyl represented by the formula 1-3 and optionally substituted with alkyl. The definitions of the remaining variables are as provided in the first aspect or any one of aspects 1 through 6 or any alternative embodiments described therein.

[0064] In some embodiments, for a compound according to the twenty-eighth embodiment or a pharmaceutically acceptable salt thereof, R 15 is selected from piperidinyl, pyrrolidinyl, 8-azaspiro[4.5]decanyl, and 7-azaspiro[3.5]nonanyl, each of which is selected from one or two C 1-3 optionally substituted with alkyl or R 15 is NR a R b cyclopentyl substituted with R a and R b are each independently H or C 1-3 The definitions of the remaining variables are provided in the twenty-eighth embodiment.

[0065] In a twenty-ninth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 1 -OR 15 and R 15 teeth, [ka] each of which is optionally substituted with one or two substituents independently selected from -CH3 and -CH2CH3, or R 15 teeth, [ka] The remaining variable definitions are provided in the first aspect or any one of aspects 1 through 6 or any alternative embodiments described therein.

[0066] In a thirtieth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is 1 to 3 R C or 1 to 3 R C1 and phenyl fused to a 5-membered heterocyclyl optionally substituted with: The definitions of the remaining variables are as provided in the first aspect or any one of the first to twenty-ninth embodiments or any alternative embodiment described therein.

[0067] In a thirty-first embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3is selected from the group consisting of indazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrazinyl, benzothiazolyl, triazolopyrazinyl, benzoxazolyl, pyrazolopyrimidinyl, and benzothiadiazolyl, each of which is selected from the group consisting of one to three R C or R 3 is 1,3-dihydro-2H-benzo[d]imidazol-2-one or benzo[d]thiazol-2(3H)-one, each of which contains one or two R C1 The remaining variable definitions are provided in the first aspect or any one of the first to twenty-ninth embodiments or any alternative embodiment described therein.

[0068] In a thirty-second embodiment, the present disclosure provides a compound according to the thirty-first embodiment or a pharmaceutically acceptable salt thereof, wherein R 3 teeth, [ka] each of which is selected from the group consisting of 1 to 3 R C or R 3 teeth, [ka] , each of which contains one or two R C1 The remaining variable definitions are provided in the 30th or 31st embodiment or any alternative embodiment described therein.

[0069] In an alternative thirty-second embodiment, the present disclosure provides a compound according to the thirty-first embodiment or a pharmaceutically acceptable salt thereof, wherein R 3 teeth, [ka] each of which is selected from the group consisting of 1 to 3 RC or R 3 teeth, [ka] , each of which contains one or two R C1 The remaining variable definitions are provided in the 30th or 31st embodiment or any alternative embodiment described therein.

[0070] In a thirty-third embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to thirty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R C For each occurrence, independently, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, or C 1-2 is alkoxy, and R C1 is independently generated for each occurrence of C 1-3 and alkyl. The definitions of the remaining variables are provided in the first aspect or any one of the first to thirty-second embodiments or any alternative embodiments described therein.

[0071] In a thirty-fourth embodiment, the present disclosure provides a compound according to the thirty-third embodiment, or a pharmaceutically acceptable salt thereof, wherein R C is, at each occurrence, independently selected from -F, -CH3, -CH(CH3)2, -CF3, and -OCH3; R C1 is —CH 3 . The definitions of the remaining variables are provided in the thirty-third embodiment or any alternative embodiment described therein.

[0072] In a thirty-fifth embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula (IIA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is piperazinyl, pyrrolidinyl, diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[3,4-b]pyrrolyl, piperidinyl, 8-azabicyclo[3.2.1]oct-2-enyl, or 1,2,3,6-tetrahydropyridinyl, wherein the piperazinyl, pyrrolidinyl, diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[3,4-b]pyrrolyl, piperidinyl, 8-azabicyclo[3.2.1]oct-2-enyl, or 1,2,3,6-tetrahydropyridinyl is selected from the group consisting of one to three R 9 and the pyrrolidinyl is optionally substituted with -NR 7 R 8 or -C 3-6 Cycloalkylene-NR 7 R 8 and one or two R 9 and optionally further replaced by R 7 and R 8 are each independently H or C 1-4 is alkyl, R 9 For each occurrence, C 1-4 Alkyl and C 3-6 cycloalkyl; R 3 is indazolyl, imidazopyridinyl, imidazopyrazinyl or benzoxazolyl, wherein the indazolyl, the imidazopyridinyl, the imidazopyrazinyl or the benzoxazolyl is selected from the group consisting of one to two R C optionally replaced by R C For each occurrence, C 1-4 and independently selected from alkyl and halo. The definitions of the remaining variables are provided in the first aspect or first embodiment.

[0073] In a thirty-sixth embodiment, the present disclosure provides a compound according to the thirty-fifth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] each of which is selected from the group consisting of one or two R 9 or R 1 teeth, [ka] each of which is selected from the group consisting of 1 to 3 R 9 The remaining variable definitions are provided in the thirty-fifth embodiment or any alternative embodiment described therein.

[0074] In a thirty-seventh embodiment, the present disclosure provides a compound according to the thirty-fifth or thirty-sixth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 3 teeth, [ka] each of which is selected from the group consisting of 1 to 2 R C The remaining variable definitions are provided in the thirty-fifth or thirty-sixth embodiment or any alternative embodiment described therein.

[0075] In a thirty-eighth embodiment, the present disclosure provides a compound according to any one of the thirty-fifth to thirty-seventh embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 is, at each occurrence, independently selected from -CH and cyclopropyl. The definitions of the remaining variables are provided in any one of the 35th to 37th embodiments or any alternative embodiments described therein.

[0076] In a thirty-ninth embodiment, the present disclosure provides a compound according to any one of the thirty-fifth to thirty-eighth embodiments, or a pharmaceutically acceptable salt thereof, wherein R Cis, at each occurrence, independently selected from —CH and F. The definitions of the remaining variables are provided in any one of embodiments 35 through 38 or any alternative embodiment described therein.

[0077] In a fortieth embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula: [ka] or a pharmaceutically acceptable salt thereof, R 1 is piperazinyl, pyrrolidinyl, piperidinyl, diazaspiro[4.4]nonanyl, diazabicyclo[3.2.0]heptanyl, or diazaspiro[3.4]octanyl, wherein the piperazinyl, the piperidinyl, the diazaspiro[4.4]nonanyl, the diazabicyclo[3.2.0]heptanyl, or the diazaspiro[3.4]octanyl is selected from the group consisting of one to three R 9 and the pyrrolidinyl is optionally substituted with -NR 7 R 8 and one or two R 9 and optionally further replaced by R 7 and R 8 are each independently H or C 1-4 alkyl or R 7 and R 8 together with the N atom to which they are attached form a 4- to 6-membered saturated monocyclic heterocyclyl; R 9 is independently generated for each occurrence of C 1-3 is alkyl, R 3 is indazolyl, pyrazolo[1,5-a]pyridinyl, imidazopyridinyl, or imidazopyrazinyl, wherein the indazolyl, the imidazopyridinyl, or the imidazopyrazinyl is selected from one to two R C optionally replaced by R CFor each occurrence, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy, and halo).

[0078] In a forty-first embodiment, for the compound of the fortieth embodiment or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] each of which is selected from the group consisting of one or two R 9 optionally replaced by R 9 is independently generated for each occurrence of C 1-3 The definitions of the remaining variables are provided in the fortieth embodiment. In a forty-second embodiment, for the compounds of the fortieth or fortieth embodiment or pharmaceutically acceptable salts thereof, R 3 teeth, [ka] Each of these has one or two R C The remaining variable definitions are provided in the fortieth or forty-first embodiment.

[0079] In a 43rd embodiment, for the compound of the 40th, 41st or 42nd embodiment or a pharmaceutically acceptable salt thereof, R 9 is, at each occurrence, independently selected from -CH3 and -CH2CH3. Definitions for the remaining variables are provided in the fortieth, forty-first, or forty-second embodiment.

[0080] In a 44th embodiment, for the compound of the 40th, 41st, 42nd, or 43rd embodiment, or a pharmaceutically acceptable salt thereof, R C is, at each occurrence, independently selected from F, —CH 3 , —OCH 3 , and —CHF 2 . Definitions of the remaining variables are provided in the fortieth, forty-first, forty-second, or forty-third embodiment.

[0081] In one embodiment, the present disclosure provides a compound selected from compounds 1-269 listed in the Examples section and Table 1, a pharmaceutically acceptable salt, racemic mixture, or stereoisomer thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

[0082] 2.Definition The term "halo" or "halogen," as used herein, refers to fluoride, chloride, bromide, or iodide.

[0083] The term “alkyl” used alone or as part of a larger moiety such as “alkoxy” or “haloalkyl” refers to a group of the formula —C n H (2n+1)"Ci_6 alkyl" refers to a straight-chain or branched-chain monovalent saturated aliphatic hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 20, 1 to 10, or 1 to 6 carbon atoms. In some embodiments, an alkyl group has 1 to 6 atoms, i.e., a Ci_6 alkyl. As used herein, a "Ci_6 alkyl" group refers to a radical having 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like. In some embodiments, an alkyl group has 1 to 4 carbon atoms, i.e., a C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms, i.e., C 1-3 It is alkyl.

[0084] The terms "alkoxy" or "alkoxyl," as used herein, refer to an O-alkyl group, where alkyl is as defined above.

[0085] The term "haloalkyl" refers to an alkyl optionally substituted with one or more halogen atoms. In one embodiment, the alkyl can be substituted with one to three halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like.

[0086] As used herein, the term "alkylene" refers to a group of the formula -C n H 2n - means a straight or branched chain divalent hydrocarbon radical of the formula: -. Non-limiting examples include ethylene and propylene.

[0087] The term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon group having 3 to 12 ring carbons. In one embodiment, a cycloalkyl can have 3 to 7 or 3 to 6 ring carbons. Any substitutable atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicyclos in which the two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0088] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (a "3- to 12-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "3- to 7-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl"); polycyclic ring systems include fused, bridged, or spiro ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can contain heteroatoms in one or more rings in the polycyclic ring system. Substituents can be present on one or more rings in the polycyclic ring system. In some embodiments, the heterocyclyl group is a saturated heterocyclyl group. In some embodiments, the heterocyclyl group is a partially saturated heterocyclyl group. A partially saturated heterocyclyl group can contain one or more (e.g., two or three) double bonds. A partially saturated polycyclic heterocyclyl group can have one or more rings in the polycyclic ring system that are aromatic, and at least one ring in the polycyclic ring system is non-aromatic (e.g., fully saturated or partially saturated). For example, a partially saturated bicyclic heterocyclyl group can have a phenyl or heteroaryl ring fused to a partially saturated heterocycle.

[0089] Spiroheterocyclyl refers to a 5-12 membered polycyclic heterocyclyl having rings connected through a common carbon atom (called a spiroatom), wherein the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, with the remaining ring atoms being C, and one or more rings may contain one or more double bonds, and none of the rings has a fully conjugated pi-electron system. Representative examples of spiroheterocyclyl include the following groups: [ka] These include, but are not limited to:

[0090] Fused heterocyclyl refers to a 5-12 membered polycyclic heterocyclyl group in which each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, with the remaining ring atoms being C. Representative examples of fused heterocyclyls include the following groups: [ka] These include, but are not limited to:

[0091] Bridged heterocyclyl refers to a 5-12 membered polycyclic heterocyclyl group in which any two rings in the group share two non-linking atoms, the rings may contain one or more double bonds but do not have a fully conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, as ring atoms, with the remaining ring atoms being C. Representative examples of bridged heterocyclyls include the following groups: [ka] These include, but are not limited to:

[0092] In general, a cycloalkyl or heterocyclyl can be unsubstituted or, valence permitting, substituted with one or more substituents, where the substituents can be independently selected from a number of groups. Exemplary substituents include, but are not limited to, oxo, -CN, halogen, alkyl, and alkoxyl, and optionally, alkyl substituents can be further substituted.

[0093] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the group) group having a completely conjugated pi-electron system. The term "aryl" may be used interchangeably with the terms "aryl ring," "carbocyclic aromatic ring," "aryl group," and "carbocyclic aromatic group." Representative examples of aryl are phenyl and naphthyl.

[0094] The term "heteroaryl," as used herein, refers to a monocyclic or polycyclic (e.g., bicyclic) aromatic hydrocarbon in which at least one of the ring carbon atoms is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur. Preferably, heteroaryl refers to a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 40 -C 41 -C 22 -C 34 -C 42 -C 25 -C 3 5-10Heteroaryl groups are based on aryl. Heteroaryl groups can be attached through a ring carbon atom or, where valence allows, through a ring nitrogen atom. In general, heteroaryls can be unsubstituted or substituted with one or more substituents, where valence allows. Exemplary substituents include, but are not limited to, halogen, OH, alkyl, alkoxyl, and amino (e.g., NH, NH alkyl, N(alkyl)), where alkyl can be optionally further substituted. Heteroaryl groups can be either monocyclic ("monocyclic heteroaryl") or polycyclic (e.g., bicyclic ("bicyclic heteroaryl") or tricyclic ("tricyclic heteroaryl") ring systems, where polycyclic ring systems include fused, bridged, or spiro ring systems).

[0095] Examples of 5- to 6-membered monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. A "substituted heteroaryl group" is substituted at any one or more substitutable ring atoms, which are ring carbon or ring nitrogen atoms to which hydrogen is bonded.

[0096] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as being either "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise noted, it indicates that any portion of the moiety known to those of skill in the art to be available for substitution can be substituted, including one or more substituents. When multiple substituents are present, each substituent can be independently selected. Means for such substitution are known in the art and / or taught by this disclosure. An optional substituent can be any substituent suitable for attachment to that moiety.

[0097] If suitable substituents are not specifically recited, exemplary substituents include C1-5 alkyl, C1-5 hydroxyalkyl, C1-5 haloalkyl, C1-5 alkoxy, C1-5 haloalkoxy, halogen, hydroxyl, cyano, amino, -CN, -NO2, -OR c1 , -NR a1 R b1 , -S(O) i R a1 , -NR a1 S(O) i R b1 , -S(O) i NR a1 R b1 , -C(=O)OR a1 , -OC(=O)OR a1 , -C(=S)OR a1 , -O(C=S)R a1 , -C(=O)NR a1 R b1 , -NR a1 C(=O)R b1 , -C(=S)NR a1 R b1 , -C(=O)R a1 , -C(=S)R a1 , N.R. a1 C(=S)R b1 , -O(C=O)NR a1 R b1 , -NR a1(C=S)OR b1 , -O(C=S)NR a1 R b1 , -NR a1 (C=O)NR a1 R b1 , -NR a1 (C=S)NR a1 R b1 , phenyl, or 5-6 membered heteroaryl. a1 and each R b1 is -H, and hydroxyl or independently selected from C alkyl optionally substituted with C alkoxy; c1 is -H, C1-5 haloalkyl, or C1-5 alkyl, where C1-5 alkyl is optionally substituted with hydroxyl or C1-C3 alkoxy.

[0098] [ka] The symbol as used herein refers to the point at which the moieties are attached.

[0099] pharmaceutically acceptable salts The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0100] Pharmaceutically acceptable salts of the compounds of any one of the above formulas include acid addition and base salts.

[0101] Pharmaceutically acceptable salts of the compounds disclosed herein are included in the present teachings. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings that contain an acidic group, such as a carboxylic acid, can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0102] Pharmaceutically acceptable salts of compounds of any one of the above formulas can be prepared in three ways: (i) reacting a compound of any one of the above formulas with a desired acid or base; (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of any one of the above formulae, or ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid or base; or (iii) may be prepared by one or more of converting one salt of a compound of any one of the above formulas to another salt by reaction with an appropriate acid or base or by use of a suitable ion exchange column.

[0103] All three reactions are typically carried out in solution. The resulting salt precipitates and can be collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to nearly non-ionized.

[0104] Compounds of any one of the above formulas and their pharmaceutically acceptable salts may exist in unsolvated and solvated forms.

[0105] Stereoisomers and other variations Compounds of any one of the above formulas may exhibit one or more types of isomerism (e.g., optical isomers, geometric isomers, or tautomers). Such variations are intended to be implicit in any compound of any one of the above formulas defined by reference to its structural features and are therefore within the scope of this disclosure.

[0106] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or a mixture of both. Stereoisomers are compounds that differ only in spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers that have two or more chiral centers and are not identical or mirror images of each other.

[0107] If a compound is designated in its chemical name to represent a single enantiomer (e.g., when the configuration is indicated by "R" or "S" in the chemical name) or its structure (e.g., when the configuration is indicated by a "wedge" bond), unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or designated enantiomers divided by the total weight of the mixture of both enantiomers.

[0108] Where the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses multiple stereoisomers (e.g., as in the case of a diastereomeric pair), it is understood to include one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0109] When two stereoisomers are designated by their chemical names or structures and the chemical names or structures are connected by "and," a mixture of the two stereoisomers is intended.

[0110] When two stereoisomers are depicted by their chemical names or structures and the chemical names or structures are connected by "or", either one or the other of the two stereoisomers is intended, but not both.

[0111] When disclosed compounds having chiral centers are shown with a structure that does not indicate the configuration at that chiral center, the structure is meant to encompass compounds in which the chiral center is in the S configuration, compounds in which the chiral center is in the R configuration, or compounds in which the chiral center is a mixture of R and S configurations. When disclosed compounds having chiral centers are shown with a chemical name that does not indicate the configuration at that chiral center with "S" or "R," the name is meant to encompass compounds in which the chiral center is in the S configuration, compounds in which the chiral center is in the R configuration, or compounds in which the chiral center is a mixture of R and S configurations.

[0112] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound with one chiral center is named or drawn by a structure without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass both possible enantiomeric forms of the compound (e.g., both enantiomerically pure, enantiomerically enriched, or racemic). When a compound with two or more chiral centers is named or drawn by a structure without indicating the stereochemistry of the chiral centers, the name or structure is understood to encompass all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures)).

[0113] The term "geometric isomer" refers to isomers that differ in the orientation of substituent atoms with respect to a carbon-carbon double bond, a carbocyclic ring, or a bridged bicycle. Substituent atoms (other than hydrogen) on either side of a carbon-carbon double bond can be in either the E or Z configuration according to the Cahn-Ingold-Prelog precedence rules. In the "E" configuration, the highest priority substituents are on opposite sides of the carbon-carbon double bond. In the "Z" configuration, the highest priority substituents are on the same side of the carbon-carbon double bond.

[0114] Substituents around a carbon-carbon double bond may also be referred to as "cis" or "trans," with "cis" referring to substituents on the same side of the double bond and "trans" referring to substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring may also be referred to as "cis" or "trans." The term "cis" refers to substituents on the same side in relation to the plane of the ring and the term "trans" refers to substituents on opposite sides in relation to the plane of the ring. A mixture of compounds having substituents arranged on both the same and opposite sides in relation to the plane of the ring is referred to as "cis / trans."

[0115] Tautomeric isomerism ("tautomerism") can occur where structural isomers are interconvertible via a low energy barrier. This can take the form of proton tautomerism in compounds of any one of the above formulae containing an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. That is, a compound can exhibit more than one form of isomerism.

[0116] In certain cases, tautomeric forms of the disclosed compounds exist, for example, the tautomeric structures shown below: [ka] When a geometric isomer is designated by name or structure, it is understood that the named or depicted isomer is present in greater amount than another isomer, and that the geometric isomer purity of the named or depicted geometric isomer is greater than 50% by weight, e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomer purity is determined by dividing the weight of the named or depicted geometric isomer in a mixture by the total weight of all geometric isomers in the mixture.

[0117] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0118] Conventional techniques for preparing / isolating individual enantiomers / diastereomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, if a compound of any one of the above formulas contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. Chiral compounds of any one of the above formulas (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of 0-50% by volume, typically 2%-20% isopropanol, and a hydrocarbon, typically heptane or hexane, containing 0-5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate yields the enriched mixture. Chiral chromatography using subcritical and supercritical fluids can also be employed. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein). Columns are available from Chiral Technologies, Inc., West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.

[0119] Although compounds of any one of the above formulas are depicted herein in a single tautomeric form, it is emphasized that all possible tautomeric forms are included within the scope of the present disclosure.

[0120] 3. Administration and Dosage Typically, the compound of the present disclosure is administered in an amount effective to treat the conditions described herein.The compound of the present disclosure can be administered as the compound itself or alternatively as a pharmaceutically acceptable salt.For the purpose of administration and dosage, the compound itself or its pharmaceutically acceptable salt will simply be referred to as the compound of the present disclosure.

[0121] The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, in a dose effective for the intended treatment. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.

[0122] The compounds of the present disclosure can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or by buccal or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0123] In another embodiment, the compounds of the present disclosure can also be administered directly into the bloodstream, into muscle, or into an internal organ.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous.Suitable devices for parenteral administration include needle-based (including microneedle-based) injectors, needle-free injectors, and infusion techniques.

[0124] In another embodiment, the compounds of the present disclosure can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the present disclosure can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure can also be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure can also be administered directly to the eye or ear.

[0125] The dosage regimen for the compounds of the present disclosure and / or compositions containing the compounds is based on various factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, dosage regimens can vary widely. In one embodiment, the total daily dose of the compounds of the present disclosure is typically about 0.001 to about 100 mg / kg (i.e., mg of the compound of the present disclosure per kg of body weight) for the treatment of the indicated conditions discussed herein.

[0126] For oral administration, the composition may be provided in the form of tablets containing 0.1 to 500 milligrams of the active ingredient to allow for symptomatic adjustment of the patient's dosage. Medicaments typically contain about 0.01 mg to about 500 mg of the active ingredient. Intravenously, the dose may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0127] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals, for example, primates, rodents (mouse, rat, hamster, rabbit, etc.). In one embodiment, a human is a suitable subject. Human subjects may be of either gender and at any stage of development.

[0128] 4. Pharmaceutical Compositions In another embodiment, the present disclosure includes pharmaceutical compositions. Such pharmaceutical compositions include a compound of the present disclosure, a pharmaceutically acceptable salt, or a stereoisomer thereof, together with a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances may also be present.

[0129] As used herein, "pharmaceutically acceptable carriers or excipients" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof; isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol or sorbitol, may be included in the composition. Pharmaceutically acceptable substances, such as wetting agents, or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.

[0130] The compositions of the present disclosure may be in a variety of forms, including, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0131] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0132] Oral administration of solid dosage forms can be provided in separate units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure.In another embodiment, oral administration can be in powder or granular form.In another embodiment, oral dosage forms are sublingual, such as lozenges.In such solid dosage forms, the compound of any one of the above formulas is usually combined with one or more adjuvants.Such capsules or tablets can contain controlled-release formulations.In the case of capsules, tablets, and pills, dosage forms can also contain buffering agents or be prepared with enteric coatings.

[0133] In another embodiment, oral administration can be in liquid dosage form.Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, which contain inert diluents commonly used in the art (e.g., water).Such compositions can also contain auxiliary agents such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or flavoring agents.

[0134] In another embodiment, the present disclosure comprises a parenteral dosage form.

[0135] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersing agents, wetting agents, and / or suspending agents.

[0136] In another embodiment, the present disclosure comprises a topical dosage form.

[0137] "Topical administration" includes, for example, transdermal administration via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Topical administration compositions also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present disclosure are administered via a transdermal device, administration is achieved using a patch, either of the reservoir and porous membrane type or various solid matrices. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may also be incorporated. See, e.g., Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0138] Suitable formulations for topical administration to the eye include, for example, eye drops, in which the compound of the present disclosure is dissolved or suspended in a suitable carrier. A typical formulation suitable for intraocular or intraaural administration may be in the form of droplets of a micronized suspension or solution in pH-adjusted, isotonic, sterile saline. Other formulations suitable for intraocular and intraaural administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicular systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose-based polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum may be incorporated along with preservatives such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0139] For intranasal administration or inhalation administration, the compound of the present disclosure can be conveniently delivered in the form of solution or suspension from a pump spray container that is pushed or pumped by the patient, or in the form of aerosol spray from a pressurized container or nebulizer with the use of suitable propellant.The formulation suitable for intranasal administration is typically administered in the form of dry powder from a dry powder inhaler (either alone, as a mixture (for example, dry blend with lactose), or as mixed component particles (for example, mixed with phospholipids such as phosphatidylcholine)), or as aerosol spray from a pressurized container, pump, spray, atomizer (preferably, electrohydrodynamic atomizer to generate fine mist), or nebulizer with or without the use of suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.For intranasal administration, powder can contain bioadhesive agent, for example, chitosan or cyclodextrin.

[0140] In another embodiment, the present disclosure includes a rectal dosage form. Suitable rectal dosage forms may be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, although various alternatives may be used as appropriate.

[0141] Other carrier materials and dosage forms known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, including effective formulation and administration procedures.

[0142] The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. Drug formulations are described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3 rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0143] 5.Treatment method The terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0144] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have appeared or been observed (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in light of a history of symptoms and / or exposure to a pathogen). Treatment may be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0145] The term "prevention" (or "prevent" or "preventing"), as used herein, refers to eliminating, avoiding, forestalling, arresting, reducing, arresting, or impeding the symptoms of a disease, disorder, and / or condition. Prevention includes administration to a subject who does not exhibit symptoms of the disease, disorder, and / or condition at the time of administration.

[0146] The terms "condition," "disease," and "disorder" are used interchangeably.

[0147] The terms "administer," "administering," or "administration" refer to methods of introducing a compound disclosed herein, or a composition thereof, into or onto a patient. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be employed with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0148] Generally, the effective amount of the compounds taught herein will vary depending on various factors, such as the given drug or compound, pharmaceutical formulation, route of administration, type of disease or disorder, characteristics of the subject or host being treated, etc., but can be routinely determined by one of ordinary skill in the art. The effective amount of the compounds of the present teachings can be readily determined by one of ordinary skill in the art by conventional methods known in the art.

[0149] The term "therapeutically effective amount" means an amount that, when administered to a subject, produces a beneficial or desired result, including a clinical result that, for example, inhibits, suppresses, or alleviates the symptoms of the condition being treated in the subject compared to a control. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular anti-cancer agent, its mode of administration, co-treatment with other therapies, etc.

[0150] The present disclosure is directed to compounds of formula (I) (including all embodiments thereof) that are useful for the treatment and / or prevention of diseases and / or conditions associated with or modulated by HTT, and in particular, where lowering mHTT in a subject is of therapeutic benefit, including, but not limited to, the treatment and / or prevention of HD.

[0151] In one embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0152] In one embodiment, the present disclosure relates to a compound of (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body.

[0153] The present disclosure further provides a method of treating HD in a subject in need thereof, comprising administering to the subject an effective amount of: (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0154] In one embodiment, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0155] In one embodiment, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

[0156] 6. Medical Kit One aspect of the present invention relates to a kit for conveniently and effectively carrying out the method or use according to the present invention. Generally, pharmaceutical packs or kits include one or more containers containing one or more of the components of the pharmaceutical compositions of the present invention. Such kits are particularly suitable for the delivery of solid oral forms such as tablets or capsules. Such kits may also preferably include a card containing several unit doses, arranging the doses in order of their intended use. If desired, a memory aid may be provided, indicating, for example, in the form of numbers, letters, or other markings, or a calendar insert, the days on which the doses in the treatment regimen are to be administered. Such container(s) may optionally be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, indicating that the agency has approved the manufacture, use, or sale for human administration.

[0157] The following representative examples contain important additional information, exemplification, and guidance that can enable the present invention to be adapted to practice in its various embodiments and equivalents thereof. These examples are intended to help illustrate the invention and are not intended, and should not be construed, as limiting its scope. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art upon consideration of the specification, including the examples that follow and by reference to the scientific and patent literature cited herein.

[0158] The contents of the cited references are incorporated herein by reference to help illustrate the state of the art.

[0159] Additionally, for purposes of the present invention, chemical elements are defined as those elements listed in the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "Organic Chemistry," Morrison & Boyd (3rd Ed.), the entire contents of both of which are incorporated herein by reference.

[0160] 7. Preparation Any one compound of the above formula can be prepared by the general and specific methods described below using the general common knowledge of a person skilled in the art of synthetic organic chemistry. Such general common knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII (published by Wiley-Interscience). The starting materials used herein are commercially available or can be prepared by conventional methods known in the art.

[0161] It should be noted that in the preparation of compounds of any one of the above formulas, some of the preparative methods described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls in precursors of any one of the above formulas). The need for such protection varies depending on the nature of the remote functional group and the conditions of the preparation method. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill of the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0162] For example, certain compounds contain primary amine or carboxylic acid functional groups that, if left unprotected, can interfere with the reaction of other portions of the molecule. Therefore, such functional groups can be protected by appropriate protecting groups that can be removed in a subsequent step. Protecting groups suitable for protecting amines and carboxylic acids include those commonly used in peptide synthesis (e.g., Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which are generally not chemically reactive under the described reaction conditions and can typically be removed without chemically altering other functionalities in the compounds of any one of the above formulas.

[0163] The schemes set forth below are intended to provide a general description of the methodology employed in the preparation of compounds of the present disclosure. Some of the compounds of the present disclosure may contain single or multiple chiral centers, having the stereochemical designation (R) or (S). It will be apparent to those skilled in the art that all synthetic transformations can be carried out in a similar manner, whether the material is enantiomerically enriched or racemic. Furthermore, resolution to the desired optically active material can be carried out at any desired point in the sequence using well-known methods, such as those described herein and in the chemical literature.

[0164] [Table 2-1] [Table 2-2]

[0165] Section 1. General and analytical methods a. General method Unless otherwise noted, the compounds in the examples were analyzed or purified according to one of the purification methods mentioned below. When preparative TLC / HPLC or silica gel chromatography is used, one skilled in the art can select any solvent combination to purify the desired compound. Silica gel column chromatography was performed using 20-40 mm (particle size), 250-400 mesh, or 400-632 mesh silica gel, using either a Teledyne ISCO Combiflash RF or Grace Reveleris X2 with an ELSD purification system, or by using pressurized nitrogen (approximately 10-15 psi) to pass the solvent through the column ("flash chromatography"). When an SCX column was used, the eluent conditions were MeOH followed by methanolic ammonia. Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum.

[0166] b.Analysis method Analytical LCMS instrument specifications: Waters Acquity iClass UPLC equipped with a QDa mass spectrometer and a PDA (photodiode array detector)

[0167] RxnQC / FrxQC / Purity QC Analytical LC / MS Method Conditions: Ammonium hydroxide (basic pH) conditions Method 1 MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 um; part number 186002350 Modifier: ammonium hydroxide 0.2% (v / v) concentration Method: 95% H2O / 5% MeCN (initial condition) held for 0.1 min, linear gradient to 5% H2O / 95% MeCN in 3.25 min, held at 5% H2O / 95% MeCN for 3.5 min. Flow rate: 0.8 mL / min.

[0168] Method 2 MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters ACQUITY UPLC BEH C18 2.1 x 30 mm, 1.7 um; part number 186002349 Modifier: ammonium hydroxide 0.2% (v / v) concentration Method: 95% H2O / 5% MeCN (initial condition), linear gradient to 5% H2O / 95% MeCN 1.0 min, 5% H2O / 95% MeCN hold until 1.3 min. Flow rate: 0.7 mL / min.

[0169] Trifluoroacetic acid (acidic pH) conditions Method 3 MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 um; part number 186002350 Modifier: Trifluoroacetic acid 0.1% (v / v) concentration Method: 95% H2O / 5% MeCN (initial condition) held for 0.1 min, linear gradient to 5% H2O / 95% MeCN in 3.25 min, held at 5% H2O / 95% MeCN for 3.5 min. Flow rate: 0.8 mL / min.

[0170] Method 4 MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 um; part number 186002349 Modifier: Trifluoroacetic acid 0.1% (v / v) concentration Method: 95% H2O / 5% MeCN (initial condition), linear gradient to 5% H2O / 95% MeCN in 1.0 min, hold at 5% H2O / 95% MeCN until 1.3 min. Flow rate: 0.7 mL / min.

[0171] Analytical LCMS instrument specifications: Agilent 1200 Series LC / MSD system with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass spectrometer; Agilent Technologies 1260 Infinity LC / MSD system with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6120B mass spectrometer; Agilent Technologies 1260 Infinity II LC / MSD system with DAD\ELSD G7102A, 1290 Infinity II and Agilent LC\MSD G6120B mass spectrometer; Agilent 1260 Series LC / MSD system with DAD\ELSD and Agilent LC\MSD (G6120B) mass spectrometer; UHPLC Agilent with DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer 1290 Series LC / MSD system, Shimadzu LCMS-2020.

[0172] RxnQC / FrxQC / Purity QC Analytical LC / MS Method Conditions: Formic acid (acidic pH) conditions Method 5 Injection volume: 0.5 μl, column temperature: 60°C, UV scan: 207–223 nM, 246–262 nM, 272–288 nM, Agilent Poroshell 120 SB-C18 4.6 × 30 mm 2.7 μm and UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6 × 5 mm 2.7 μm, mobile phase A: 0.1% FA / water, mobile phase B: 0.1% FA / acetonitrile. [Table 3]

[0173] Method 6 Injection volume: 0.5 μl; Column temperature: 60°C; UV scan: 207–223 nM, 246–262 nM, 272–288 nM Agilent Poroshell 120 SB-C18 4.6 x 30 mm 2.7 μm and UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6 x 5 mm 2.7 μm. Mobile phase A: 0.1% FA / water, Mobile phase B: 0.1% FA / acetonitrile. [Table 4]

[0174] Method 7 MS mode: MS ESI+ scan range 100-1000 daltons PDA: Scan range of 190~370nm Column: Xtimate C18 2.1*30mm, 3um Modifier: Phase A: water (4 L) + TFA (1.5 mL), Phase B: acetonitrile (4 L) + TFA (0.75 mL) Method: Elution gradient of 10% to 80% (solvent B) at 1.35 or 3.35 min and 80% held for 0.9 min, with a flow rate of 0.8 ml / min.

[0175] [Table 5]

[0176] explanation: Mobile phase: 5% ACN (0.018% TFA) / water (0.037% TFA) gradient to 95% ACN in 3.0 min at a flow rate of 1.0 mL / min; then hold at 95% ACN for 0.60 min at a flow rate of 1.0 mL / min to 1.5 mL / min; then return to 5% ACN / water for 0.40 min at a flow rate of 1.5 mL / min. The column temperature was 50°C. The column is Shim-pack Velox SP-C18 2.7μm 3.0*30mm.

[0177] [Table 6]

[0178] explanation: Mobile phase: 5% ACN (0.01875% TFA) / water (0.0375% TFA) gradient to 95% ACN / water in 0.60 min at a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; then return to 5% ACN / water for 0.02 min at a flow rate of 2.0 mL / min. The column temperature was 50°C. The column is a Kinetex® EVO C18 2.1×30 mm 5 um.

[0179] Method 10 explanation: Mobile phase: 5% ACN (0.01875% TFA) / water (0.0375% TFA) gradient to 95% ACN in 3.20 min, flow rate set at 1.5 mL / min; then hold at 95% ACN for 0.30 min, flow rate set at 1.5 mL / min; return to 5% ACN / water for 0.30 min. Flow rate set at 2.0 mL / min. Column temperature: 50°C. Column: Kinetex® EVO C18 4.6 x 50 mm 5 um.

[0180] Preparative HPLC-MS conditions: HPLC-MS instrument specifications Waters Autopurification equipped with a QDa mass spectrometer and PDA (photodiode array detector).

[0181] Ammonium hydroxide (basic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters XSELECT CSH C18 PREP 19 x 100 mm, 5 um; part number 186005421 Modifier: 0.2% ammonium hydroxide (v / v) concentration Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters XSELECT CSH C18 PREP 30 x 100 mm, 5 um; part number 186005425 Modifier: 0.2% ammonium hydroxide (v / v) concentration Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters XSELECT CSH C18 PREP 30 x 50 mm, 5 um; part number 186005423 Modifier: 0.2% ammonium hydroxide (v / v) concentration Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Column: Boston Prime C18 150 x 30 mm x 5 um; Conditions: Water (NH3H2O + NH4HCO3)-ACN; Gradient (% organic matter): 0-100% optimized for each example; Flow rate (mL / min): 25. Column: YMC Actus Trial C18 20*100 5 mkm column; gradient mixture H2O-MeOH-ammonia 0.1% as mobile phase optimized for each example

[0182] Trifluoroacetic acid (acidic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters Sunfire OBD C18 PREP 19 x 100 mm, 5 um; part number 186002567 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters Sunfire OBD C18 PREP 30 x 100 mm, 5 um; part number 186002572 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters Sunfire OBD C18 PREP 30 x 50 mm, 5 μm; Part Number 186002570 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min.

[0183] Formic acid (FA, acidic pH) conditions Column: Welch Xtimate C18 150 x 30 mm x 5 um or Phenomenex luna C18 150 x 25 mm x 10 um; Conditions: Water (FA)-ACN; Gradient (% organic matter): optimized for each example; Flow rate (mL / min) 25.

[0184] Hydrochloric acid (HCl, acidic pH) conditions Column: Boston Green ODS 150 x 30 mm x 5 um; Conditions: Water (HCl)-ACN; Gradient (% organic matter): 0-100% optimized for each example; Flow rate (mL / min): 25.

[0185] Analytical SFC instrument specifications Waters Acquity UPC equipped with a QDa mass spectrometer and a PDA (photodiode array detector) 2 SFC Analytical screening conditions MS mode: MS:ESI+ scan range 100-650 daltons PDA: Scan range of 200~400nm Column: see below Solvent: Airgas Bone Dry CO2 Co-solvent: methanol, ethanol, or isopropanol containing either 0.1% diethylamine, 0.1% dimethylethanolamine, or neutral Method: Isocratic conditions; typically 60% CO2:40% co-solvent or 70% CO2:30% co-solvent, flow rate: 3.0 mL / min.

[0186] Preparative SFC instrument specifications Waters Prep100 SFC equipped with a QDa mass spectrometer, PDA (photodiode array detector) and a 2767 collection bed. Fractionation conditions Method: X% cosolvent (with Y% modifier) / CO2, isocratic conditions. Flow rate: 100mL / min Automatic back pressure regulator: 120 bar Manual backpressure regulator: 40 psi for MeOH or EtOH, 60 psi for iPrOH Column oven temperature: 40°C MS mode: MS:ESI+ scan range 150-650 daltons PDA: Scan range of 200~400nm.

[0187] SFC column (analysis): AD-H: Daicel Chiralpak AD-H, 4.6mm x 250mm, 5um, part number 19325 AS-H: Daicel Chiralpak AS-H, 4.6mm x 250mm, 5um, part number 20325 OD-H: Daicel Chiralpak OD-H, 4.6mm x 250mm, 5um, part number 14325 OX-H: Daicel Chiralpak OX-H, 4.6mm x 250mm, 5um, part number 63325 IA: Daicel Chiralpak IA, 4.6mm x 250mm, 5um, part number 80325 IB: Daicel Chiralpak IB, 4.6mm x 250mm, 5um, part number 81325 IC: Daicel Chiralpak IC, 4.6mm x 250mm, 5um, part number 83325 IG: Daicel Chiralpak IG, 4.6mm x 250mm, 5um, part number 87325 Cell-2: Phenomenex Lux Cellulose-2, 4.6mm x 150mm, 3um, part number 00F-4456-E0 Cell-4: Phenomenex Lux Cellulose-4, 4.6mm x 150mm, 3um, part number 00F-4490-E0

[0188] SFC column (preparative): AD-H: Daicel Chiralpak AD-H, 30mm x 250mm, 5µm, part number 19475 AS-H: Daicel Chiralpak AS-H, 30mm x 250mm, 5µm, part number 20475 OD-H: Daicel Chiralpak OD-H, 30mm x 250mm, 5um, part number 14475 OX-H: Daicel Chiralpak OX-H, 30mm x 250mm, 5um, part number 63475 IA: Daicel Chiralpak IA, 30mm x 250mm, 5um, part number 80475 IB: Daicel Chiralpak IB, 30mm x 250mm, 5um, part number 81475 IC: Daicel Chiralpak IC, 30mm x 250mm, 5um, part number 83475 IG: Daicel Chiralpak IG, 30mm x 250mm, 5um, part number 87475 Cell-2: Phenomenex Lux Cellulose-2, 30mm x 250mm, 5um, part number 00G-4457-U0-AX Cell-4: Phenomenex Lux Cellulose-4, 30mm x 250mm, 5um, part number 00G-4491-U0-AX

[0189] 1 H-NMR 1 H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. 1H NMR spectra were recorded on a Bruker Avance III HD 500MHz, Bruker Avance III 500MHz, Bruker Avance DRX 500, Bruker Avance III 400MHz, Varian-400 VNMRS, Varian Unityplus 400, or Varian-400 MR. Characteristic chemical shifts (d) are abbreviated for tetramethylsilane (H) using conventional abbreviations for the major peak designations, e.g., s: singlet; d: doublet; t: triplet; q: quartet; dd: double doublet; dt: double triplet; m: multiplet; br: broad. 1 The NMR spectra are given in parts per million downfield from the NMR spectrum (for H-NMR). The following abbreviations are used for common solvents: CDCl3: deuterated chloroform; DMSO-d6: hexadeuterodimethylsulfoxide; and MeOH-d4: deuterated methanol. If necessary, tautomers may be recorded in the NMR data, and some exchangeable protons may not be visible.

[0190] Section 2. Preparation of intermediates Intermediate 1 [ka] Step a: 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (500 mg, 2.34 mmol, 1.0 equiv) was dissolved in ethanol (11.70 mL, 0.2 M), followed by the addition of HCl in dioxane (4 M, 1.76 mL, 3 equiv). The solution was then stirred at 80 °C for 16 h before being concentrated to give ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (503.4 mg, 80% yield) as an off-white powder, which was carried forward crude. MS: m / z 242.0 [M+H] + .

[0191] Step b: N,N-Dimethylpyrrolidin-3-amine (190.98 mg, 1.67 mmol, 1.1 equiv), ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (408.31 mg, 1.52 mmol (1.0 equiv), and DIPEA (1.38 g, 10.64 mmol, 1.85 mL, 7 equiv) were dissolved in dioxane (7.60 mL, 0.2 M) and heated to 80 °C for 72 h. The solution was then dry-loaded onto a normal-phase silica column and purified with 0-25% MeOH:DCM to give ethyl 6-[3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (468.0 mg, 93% yield). MS: m / z 320.0 [M+H] + .

[0192] Step c: Ethyl 6-[3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (482.47 mg, 1.47 mmol, 1.0 equiv) was dissolved in dioxane (515 μL, 1.42 M) and water (515 μL, 1.42 M), followed by the addition of lithium hydroxide (35.09 mg, 1.47 mmol, 1.0 equiv). The solution was then heated at 80° C. for 16 hours and then concentrated to afford 6-[3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (535.7 mg, 99% yield) as an off-white powder. MS: RT m / z 292.0 [M+H] + .

[0193] Intermediate 2 [ka] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (500 mg, 2.34 mmol, 1.0 equiv) was dissolved in dichloromethane (11.70 mL, 0.2 M), followed by the addition of 2-methylimidazo[1,2-a]pyridin-6-amine (344.45 mg, 2.34 mmol, 1.0 equiv), HATU (978.87 mg, 2.57 mmol, 1.0 equiv), and DIPEA (665.43 mg, 5.15 mmol, 896 μL). The solution was then stirred at room temperature for 1 hour, concentrated, and loaded directly onto a normal-phase silica column and purified with 0-25% MeOH:DCM over 3.5 minutes to give 6-chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (420.9 mg, 44% yield) as a brown solid, which was carried forward directly. MS: m / z 343.0 [M+H] + .

[0194] Intermediate 3 [ka] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 117.02 μmol, 1.0 equiv.), 2,7-dimethylindazol-5-amine (22.64 mg, 140.42 μmol, 1.2 equiv.), HATU (48.94 mg, 128.72 μmol, 1.1 equiv.), and DIPEA (33.27 mg, 257.44 μmol, 44 μL, 2.2 equiv.) were dissolved in dichloromethane (585.09 μL, 0.2 M) and stirred at room temperature for 2 hours. The solution was then purified by silica column chromatography (0–25% MeOH:DCM, 3.5 min) to give 6-chloro-N-(2,7-dimethylindazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide (49.5 mg, 100% yield) as a brown solid. MS: m / z 357.0 [M+H] + .

[0195] Intermediate 4 [ka] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 117.02 μmol, 1.0 equiv.), 2-methylimidazo[1,2-a]pyrazin-6-amine (20.81 mg, 140.42 μmol, 1.2 equiv.), HATU (48.94 mg, 128.72 μmol, 1.1 equiv.), and triethylamine (26.05 mg, 257.4 μmol, 36 μL, 2.2 equiv.) were added to dichlorothieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 117.02 μmol, 1.0 equiv.). Dissolution in methane (585.09 μL, 0.2 M) and stirring at room temperature for 2 h was followed by direct injection onto a normal phase silica column and purification with 0-25% MeOH:DCM over 3.5 min to give 6-chloro-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (25.8 mg, 61% yield) as a brown solid, which was carried forward as is. MS: m / z 344.0 [M+H] + .

[0196] Intermediate 5 [ka] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 117.02 μmol, 1.0 equiv.), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (22.78 mg, 140.42 μmol, 1.2 equiv.), HATU (48.94 mg, 128.72 μmol, 1.1 equiv.), and triethylamine (26.05 mg, 257.44 μmol, 35.88 μL, 2.2 equiv.) were dissolved in dichloromethane (585.09 μL, 0.2 M) and stirred at room temperature for 2 h. The crude material was then loaded onto a normal-phase silica column and purified with 0-25% MeOH:DCM over 3.5 min. The product eluted at 20%. The identified fractions were combined and concentrated to give 6-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (42.9 mg, 91% yield) as a brown solid, which was carried forward directly. MS: m / z 358.1 [M+H] + .

[0197] Intermediate 6 [ka] To a solution of 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (150 mg, 702.1 μmol) in DMF (20 mL) was added N-ethyl-N-isopropyl-propan-2-amine (2.11 mmol, 367 μL), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium; hexafluorophosphate (320.36 mg, 842.54 μmol), and 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (115.97 mg, 702.11 μmol) at 20° C. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (PE / EtOAc = 3 / 1 to 0 / 1, TLC: PE / EtOAc = 0 / 1) to give 6-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (180 mg, 64% yield) as a brown solid. MS: m / z 361.2 [M+H] + .

[0198] Intermediate 7 [ka] Step a: Ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (265 mg, 1.02 mmol, 1.0 equiv) was dissolved in dioxane (5 mL, 0.2 M), followed by the addition of TEA (309.54 mg, 3.06 mmol, 426.36 μL, 3.0 equiv) and (3S)-N,N-dimethylpyrrolidin-3-amine (465.89 mg, 4.08 mmol, 518.23 mL, 4 equiv). The solution was then heated to 80 °C for 16 h, concentrated, and dry-loaded onto a normal-phase silica column and purified with 0-25% MeOH:DCM over 12 min. The product eluted with 11% MeOH. The identified fractions were collected and concentrated to give ethyl 6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (258.2 mg, 808.34 μmol, 79% yield) as a white powder. MS: m / z 320.0 [M+H] + .

[0199] Step b: Ethyl 6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (258.2 mg, 842.10 μmol, 1.0 equiv.) was dissolved in THF (1 mL, 0.4 M) and water (1 mL, 0.4 M), followed by the addition of lithium hydroxide (23.23 mg, 970.01 μmol, 1.2 equiv.). The solution was then heated at 60° C. for 96 hours and then concentrated to a white powder, affording 6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (241.1 mg) as an off-yellow-white powder, which was carried forward as is. MS: m / z 292.0 [M+H] + .

[0200] Intermediate 8 [ka] Step a: Ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (150 mg, 552.35 μmol, 1.0 equiv.) was dissolved in dioxane (1.84 mL, 0.3 M), followed by the addition of TEA (167.68 mg, 1.66 mmol, 230.96 μL, 3.0 equiv.) and (3R)-N,N-dimethylpyrrolidin-3-amine (828.5 μmol, 105 μL, 1.5 equiv.). The solution was then heated to 80 °C for 16 h, concentrated, dry-loaded onto normal-phase silica, and purified with 0-25% MeOH:DCM over 12 min. The product eluted with 11% MeOH. The identified fractions were collected and concentrated to give ethyl 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (162.9 mg, 89% yield) as a white powder. MS: m / z 320.0 [M+H] + .

[0201] Step b: Ethyl 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (162.9 mg, 494.69 μmol, 1.0 equiv.) was dissolved in dioxane (1.24 mL, 0.2 M) and water (1.24 mL, 0.2 M), followed by the addition of lithium hydroxide (13.03 mg, 544.15 μmol, 1.1 equiv.). The solution was then heated at 50° C. for 16 hours and concentrated to a white powder, affording 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (157.9 mg) as an off-white powder, which was carried forward as is. MS: m / z 292.0 [M+H] + .

[0202] Intermediate 9 [ka] Step a: To a solution of 6-bromo-2,8-dimethyl-imidazo[1,2-a]pyrazine (22.2 g, 98.20 mmol) in toluene (250 mL) was added sodium tert-butoxide (16.99 g, 176.76 mmol) and BINAP (18.34 g, 29.46 mmol), followed by diphenylmethanimine (35.59 g, 196.40 mmol, 32.96 mL) under N2. The mixture was stirred at 90 °C for 16 h. The mixture was then diluted with EtOAc (50 mL) and filtered. The filtrate was evaporated in vacuo, and the crude product was purified by flash column chromatography (silica; EtOAc / petroleum 0% to 100%). The desired product was collected and the solvent was evaporated in vacuo to give N-(diphenylmethylene)-2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (25.2 g) as a yellow oil. MS: m / z 327.1 [M+H] + .

[0203] Step b: To a mixture of N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-1,1-diphenyl-methanimine (25.2 g, 77.21 mmol) in THF (150 mL) was added HCl (2 M, 120 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h. The solution was concentrated and then dissolved in water (150 mL). The mixture was extracted with DCM (200 mL × 3). The aqueous phase was neutralized with 2 N NaOH (to pH = 13) and extracted with DCM (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (8.2 g, 50.56 mmol, 65% yield) as a brown solid. MS: m / z 163.1 [M+H] + .

[0204] Intermediate 10 [ka] Step a: To a solution of 6-bromo-8-fluoro-2-methyl-imidazo[1,2-a]pyridine (1 g, 4.37 mmol), diphenylmethanimine (1.19 g, 6.55 mmol, 1.10 mL), and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (505.24 mg, 873.18 μmol) in dioxane (30 mL) was added cesium carbonate (4.27 g, 13.10 mmol) and Pd(dba) (399.79 mg, 436.59 μmol) under N at 20 °C. The reaction was stirred at 100 °C for 14 h. The mixture was filtered, and the filtrate was evaporated under vacuum. The residue was purified by column chromatography (PE: EtOAc 5:1 to 1:1) to give N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-1,1-diphenyl-methanimine (1.3 g, 3.95 mmol, 90% yield) as an off-white solid. MS: m / z 330.2 [M+H] + .

[0205] Step b: To a solution of N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-1,1-diphenyl-methanimine (1.3 g, 3.95 mmol) in HCl (4 M, 8 mL) was added HCl (143.91 mg, 3.95 mmol, 0.5 mL) at 20 °C. The reaction was stirred at 20 °C for 14 h. The solution was evaporated in vacuo, and the residue was adjusted to pH = 7 with saturated aqueous NaHCO (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over NaSO and filtered. The filtrate was evaporated in vacuo. The residue was purified by column chromatography (PE: EtOAc 3:1 to 0:1) to give 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (470 mg, 2.85 mmol, 72% yield) as a brown solid. MS: m / z 166.1 [M+H] + .

[0206] Intermediate 11 [ka] Step a: To a mixture of Pd2(dba)3 (122.05 mg, 133.28 μmol), 6-bromo-2,8-dimethyl-imidazo[1,2-a]pyridine (300 mg, 1.33 mmol), sodium tert-butoxide (256.18 mg, 2.67 mmol), and [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (165.98 mg, 266.57 μmol) under N2, toluene (6 mL) and diphenylmethanimine (483.11 mg, 2.67 mmol, 447.32 μL) were added. The reaction mixture was stirred at 130 °C for 12 h. The mixture was concentrated, and the residue was purified by column chromatography (0% to 70% EtOAc / heptane) to give N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1-diphenyl-methanimine (455.1 mg) as a pale yellow solid. MS: m / z 326.1 [M+H] + .

[0207] Step b: To a mixture of N-(diphenylmethylene)-2,8-dimethylimidazo[1,2-a]pyridin-6-amine (95.4 mg, 293.17 μmol) in THF (2 mL) was added hydrochloric acid (4 M in dioxane, 219.88 μL) at 20° C. The mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo, and then DCM (1 mL) was added. The mixture was filtered. The precipitate was collected to give 2,8-dimethylimidazo[1,2-a]pyridin-6-amine (52.4 mg, 265.10 μmol, 90% yield, hydrochloride salt) as a pale yellow solid. MS: m / z 162.1 [M+H] + .

[0208] Intermediate 12 [ka] Step a: To a mixture of 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (800 mg, 3.32 mmol) in toluene (30 mL), diphenylmethanimine (902.09 mg, 4.98 mmol, 835.27 μL), sodium tert-butoxide (574.03 mg, 5.97 mmol), Pd(dba) (303.87 mg, 331.83 μmol), and [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenylphosphane (413.25 mg, 663.67 μmol) was added at 20 °C. The mixture was stirred at 130 °C under a N atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated. Water (50 mL) was then added, and the mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography (petroleum ether / EtOAc = 5 / 1 to 0 / 1) to give N-(diphenylmethylene)-8-methoxy-2-methylimidazo[1,2-a]pyridin-6-amine (1 g, 2.93 mmol, 88% yield) as a brown oil. MS: m / z 342.3 [M+H] + .

[0209] Step b: To a mixture of N-(diphenylmethylene)-8-methoxy-2-methylimidazo[1,2-a]pyridin-6-amine (1 g, 2.93 mmol) in THF (10 mL) was added HCl (2 M, 2.71 mL) at 20 °C. The mixture was stirred under a N atmosphere at 20 °C for 2 h. The mixture was concentrated under reduced pressure. The aqueous phase was adjusted to pH 3-4 with HCl (2 N) and extracted with DCM (50 mL). The aqueous phase was then adjusted to pH 14 with saturated NaOH (1 N) and extracted with DCM (100 mL). The organic layer was washed with brine (80 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 8-methoxy-2-methylimidazo[1,2-a]pyridin-6-amine (200 mg, 1.13 mmol, 39% yield) as a tan solid. MS: m / z 178.2 [M+H] + .

[0210] Intermediate 13 [ka] Step a: To a mixture of 5-bromo-7-fluoro-2-methyl-indazole (100 mg, 436.59 μmol), rac-BINAP-Pd-G3 (43.31 mg, 43.66 μmol), and sodium tert-butoxide (83.92 mg, 873.18 μmol) under a N atmosphere, toluene (1 mL) and diphenylmethanimine (94.95 mg, 523.91 μmol, 87.92 μL) were added. The reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated, and the residue was purified by column flash chromatography (0% to 60% EtOAc / heptane) to afford N-(7-fluoro-2-methyl-indazol-5-yl)-1,1-diphenylmethanimine (107.3 mg, 325.77 μmol, 74% yield) as a pale yellow solid. MS: m / z 330.1 [M+H] + .

[0211] Step b: To a mixture of N-(7-fluoro-2-methyl-indazol-5-yl)-1,1-diphenyl-methanimine (107.3 mg, 325.77 μmol) in THF (2 mL) was added hydrochloric acid (4 M in dioxane, 244.33 μL) at 20° C. The mixture was stirred at 20° C. for 1 hour. The mixture was concentrated, and then water was added. The mixture was extracted with DCM (5 mL×3). The aqueous phase was neutralized to pH=11 with 2N NaOH, and the residue was extracted with DCM (5 mL×3). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give 7-fluoro-2-methyl-indazol-5-amine (36.1 mg, 218.57 μmol, 67% yield) as a pale yellow solid. MS: m / z 166.0 [M+H] + .

[0212] Intermediate 14 [ka] 8-Methoxy-2-methyl-imidazo[1,2-a]pyridin-6-amine (91.24 mg, 514.88 μmol) and 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (100 mg, 468.07 μmol) were dissolved in dioxane (2 mL), followed by the addition of 2,4,6-tripropyl-1,3,5,2,4,6 trioxatriphosphinane 2,4,6-trioxide (446.80 mg, 702.11 μmol, 417.96 μL, 50% purity). The reaction mixture was stirred at 60° C. for 16 hours and then concentrated in vacuo. The residue was purified by column flash chromatography (0% to 10% MeOH / DCM) to give 6-chloro-N-(8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (145.3 mg, 389.72 μmol, 83.26% yield). MS: m / z 373.1 [M+H] + .

[0213] Intermediate 15 [ka] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (422.11 mg, 1.98 mmol) was dissolved in dioxane (10.87 mL), followed by the addition of 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (352.5 mg, 2.17 mmol), T3P (3.77 g, 5.93 mmol, 2.66 mL, 50% purity), and TEA (599.79 mg, 5.93 mmol, 826.15 μL). The solution was heated to 60 °C for 16 h, then concentrated and purified by column flash chromatography (0–15% MeOH:DCM, 12 min). Identified fractions were pooled and concentrated to give 6-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (661.1 mg, 1.81 mmol, 91.64% yield, 98% purity) as a tan-white plastic solid. MS: m / z 358.1 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 - 2.41 (m, 3 H) 2.73 - 2.75 (m, 3 H) 7.58 - 7.65 (m, 1 H) 7.96 - 8.01 (m, 1 H) 8.43 - 8.49 (m, 1 H) 8.56 - 8.61 (m, 1 H) 9.12 - 9.17 (m, 1 H) 11.31 - 11.36 (m, 1 H).

[0214] Intermediate 16 [ka] Step a: A mixture of 5-bromo-2,3-difluoro-4-methoxy-benzaldehyde (20.4 g, 81.27 mmol), O-methylhydroxylamine hydrochloride (8.82 g, 105.65 mmol), and K2CO3 (24.71 g, 178.79 mmol) in DME (200 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 50 °C for 16 h. The reaction mixture was filtered and concentrated to give (E)-1-(5-bromo-2,3-difluoro-4-methoxy-phenyl)-N-methoxy-methanimine (22.1 g, 78.91 mmol, 97.10% yield). To a solution of (E)-1-(5-bromo-2,3-difluoro-4-methoxy-phenyl)-N-methoxy-methanimine (2.6 g, 9.28 mmol) in THF (30 mL) was added NH . HO (9.89 g, 197.56 mmol, 8.2 mL) was added at 25 °C under N atmosphere. The mixture was stirred at 80 °C under N for 90 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The pH of the aqueous phase was adjusted to neutral. The combined organic layers were washed with brine (150 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 9 / 2) to give 5-bromo-7-fluoro-6-methoxy-1H-indazole (2 g, 8.16 mmol, 87.92% yield) as a yellowish solid. MS: m / z 246.9 [M+H] + .

[0215] Step b: To a solution of 5-bromo-7-fluoro-6-methoxy-1H-indazole (6.5 g, 26.53 mmol) in EtOAc (100 mL) was added trimethyloxonium tetrafluoroborate (5.88 g, 39.79 mmol). The reaction was stirred at 25 °C for 3 h. The mixture was filtered and concentrated to give 5-bromo-7-fluoro-6-methoxy-2-methyl-indazole (5.9 g, 22.77 mmol, 85.85% yield). MS: m / z 259.0 [M+H] + .

[0216] Step c: A mixture of 5-bromo-7-fluoro-6-methoxy-2-methyl-indazole (5.9 g, 22.77 mmol), diphenylmethanimine (6.19 g, 34.16 mmol, 5.73 mL), sodium 2-methylpropan-2-olate (6.57 g, 68.32 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.81 g, 2.28 mmol) in dioxane (100 mL) was degassed and purged with N three times. The mixture was stirred at 90 °C under N atmosphere for 3 h. The mixture was concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 9 / 2) to give N-(7-fluoro-6-methoxy-2-methyl-indazol-5-yl)-1,1-diphenyl-methanimine (5.7 g, 15.86 mmol, 69.64% yield). MS: m / z 360.1 [M+H] + .

[0217] Step d: A mixture of N-(7-fluoro-6-methoxy-2-methyl-indazol-5-yl)-1,1-diphenyl-methanimine (5.7 g, 15.86 mmol) and HCl / EtOAc (2 M, 200.00 mmol, 100 mL) in EtOAc (1000 mL) was stirred at 25 °C for 1 h. The mixture was filtered and the precipitate was washed with EtOAc to give 7-fluoro-6-methoxy-2-methyl-indazol-5-amine (3.91 g, 14.58 mmol, 91.95% yield, hydrochloride salt). MS: m / z 268.1 [M+H] + . 1 H NMR (400MHz, MeOD) δ ppm: 9.34 - 9.31 (m, 1H), 7.92 (s, 1H), 7.50 - 7.44 (m, 2H), 7.34 - 7.27 (m, 3H), 2.88 - 2.86 (m, 3H), 2.53 (s, 3H).

[0218] Intermediate 17 [ka] Step a: To a solution of 5-bromo-4-methoxy-pyridin-2-amine (57 g, 280.74 mmol) in DCM (300 mL) and HO (300 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (198.91 g, 561.48 mmol) and the mixture was stirred at 25 °C for 3 h.

[0219] The aqueous phase was adjusted to pH 8 with NaHCO3 and extracted with DCM (200 mL x 3). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 4 / 1) to give 5-bromo-3-fluoro-4-methoxy-pyridin-2-amine (5.6 g, 25.34 mmol, 9.02% yield) as an orange-red solid. MS: m / z 222.8 [M+H] + .

[0220] Step b: To a solution of 5-bromo-3-fluoro-4-methoxy-pyridin-2-amine (4.5 g, 20.36 mmol) in EtOH (50 mL) was added 1-chloropropan-2-one (18.78 g, 202.97 mmol, 16.16 mL). The mixture was stirred at 100 °C for 8 h. The mixture was concentrated in vacuo, redissolved in HO (100 mL), and then adjusted to pH 8 with NaHCO. The mixture was then re-extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with brine (30 mL), dried over NaSO, and concentrated to give 6-bromo-8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridine (4 g, crude) as a brown oil. MS: m / z 258.9 [M+H] + .

[0221] Step c: A mixture of 6-bromo-8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridine (6.2 g, 23.93 mmol), acetamide (14.14 g, 239.31 mmol), and CsCO (15.59 g, 47.86 mmol) in dioxane (100 mL) was degassed and purged with N three times, and then BrettPhos Pd G (6.51 g, 7.18 mmol) was added. The mixture was stirred under N at 100 °C for 2 h. The mixture was diluted with HO (200 ml) and extracted with ethyl acetate (100 ml × 4). The organic phases were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 3 / 2) to give N-(8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)acetamide (4.3 g, 18.13 mmol, 75.74% yield) as a yellow solid. MS: m / z 237.9 [M+H] + .

[0222] Step d: To a solution of N-(8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)acetamide (4.1 g, 17.28 mmol) in MeOH (60 mL) was added HCl (12 M, 129.62 mmol, 10.80 mL). The mixture was stirred at 60 °C for 3 h. The reaction was concentrated, diluted with HO (100 mL), and adjusted to pH 7 with NaHCO. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give 8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-amine (1.8 g, 9.22 mmol, 53.36% yield) as a gray solid. MS: m / z 195.9 [M+H] + .

[0223] Intermediate 18 [ka] 6-Methoxy-2-methyl-indazol-5-amine (99.53 mg, 561.69 μmol) and 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (100 mg, 468.07 μmol) were dissolved in dioxane (2 mL), followed by the addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (446.80 mg, 702.11 μmol, 417.96 μL, 50% purity). The reaction mixture was stirred at 40° C. for 16 hours and then concentrated in vacuo. The residue was purified by column flash chromatography (0% to 10% MeOH / DCM) to give 6-chloro-N-(6-methoxy-2-methyl-indazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide (138.6 mg, 371.75 μmol, 79.42% yield). MS: m / z 373.1 [M+H] + .

[0224] Intermediate 19 [ka] To a mixture of 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (140 mg, 655.31 μmol) and 7-fluoro-6-methoxy-2-methyl-indazol-5-amine (127.91 mg, 655.31 μmol) in DMF (3 mL) was added HATU (373.75 mg, 982.96 μmol) and DIPEA (127.04 mg, 982.96 μmol, 171.21 μL) in one portion at 25° C. The mixture was stirred at 25° C. for 90 minutes and then concentrated under reduced pressure. The suspension was filtered, and the solid was collected and washed with EtOAc (50 mL×5). The residue was evacuated to give 6-chloro-N-(7-fluoro-6-methoxy-2-methyl-indazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide (148.5 mg, 379.97 μmol, 57.98% yield) as a yellow solid. MS: m / z 391.0 [M+H] + .

[0225] Intermediate 20 [ka] To a solution of 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (72.34 mg, 338.60 μmol) and 6-methoxy-2-methyl-pyrazolo[1,5-a]pyridin-5-amine (60 mg, 338.60 μmol) in pyridine (3 mL) was added T4P (3 mL). The reaction was stirred at 20° C. for 2 hours, then quenched, filtered, and concentrated under reduced pressure to give 6-chloro-N-(6-methoxy-2-methyl-pyrazolo[1,5-a]pyridin-5-yl)thieno[2,3-b]pyridine-2-carboxamide (80 mg, 132.93 μmol, 39.26% yield, 61.95% purity) as a yellow solid. MS: m / z 373.1 [M+H] + .

[0226] Intermediate 21 [ka] Step a: 5-Bromo-2,7-dimethyl-pyrazolo[3,4-c]pyridine (400 mg, 1.77 mmol), sodium; 2-methylpropan-2-olate (340.08 mg, 3.54 mmol), and Pd-binap-G3 (175.52 mg, 176.93 μmol) were added to a microwave vial, which was evacuated and refilled with N2 three times. Then, diphenylmethanimine (384.79 mg, 2.12 mmol, 356.29 μL) and toluene (10 mL) were added under N2. The reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was then concentrated, and the residue was purified by column chromatography (0% to 100% EA / heptane) to give N-(2,7-dimethylpyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenylmethanimine (454.9 mg, 1.39 mmol, 78.77% yield). MS: m / z 327.1 [M+H] + .

[0227] Step b: To a mixture of N-(2,7-dimethylpyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenyl-methanimine (454.9 mg, 1.39 mmol) in THF (4 mL) was added hydrochloric acid (4 M, 1.05 mL) at 20 °C. The reaction was stirred at 20 °C for 1 h. The mixture was concentrated, and then dioxane and toluene were added. The mixture was filtered, and the precipitate was collected to give 2,7-dimethylpyrazolo[3,4-c]pyridin-5-amine (245.6 mg, 1.24 mmol, 88.71% yield, hydrochloride salt) as a pale yellow solid. MS: m / z 163.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.90 (s, 3 H), 4.28 (s, 3 H), 6.94 (s, 1 H), 8.42 (s, 1 H).

[0228] Intermediate 22 [ka] To a solution of 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (200 mg, 936.15 μmol) in DMF (10 mL) was added 8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-amine (182.73 mg, 936.15 μmol), DIPEA (362.97 mg, 2.81 mmol, 489.18 μL), and HATU (427.14 mg, 1.12 mmol). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE / EtOAc = 10 / 1 to 0 / 1) to give 6-chloro-N-(8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (350 mg, 888.39 μmol, 94.90% yield, 99.2% purity) as a yellow solid. MS: m / z 391.0 [M+H] + .

[0229] Intermediate 23 [ka] 7-Fluoro-2-methyl-indazol-5-amine (83.34 mg, 504.59 μmol, hydrochloride salt) and 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (100 mg, 458.71 μmol) were dissolved in dioxane (2 mL), followed by the addition of 2,4,6-tripropyl-1,3,5,2,4,6 trioxatriphosphinane 2,4,6-trioxide (437.86 mg, 688.07 μmol, 409.60 μL, 50% purity). The reaction mixture was stirred at 40° C. for 16 hours and then concentrated in vacuo. The residue was purified by column flash chromatography (0% to 10% MeOH / DCM) to give 6-chloro-N-(7-fluoro-2-methyl-indazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide (105.6 mg, 292.69 μmol, 63.81% yield) as a white solid. MS: m / z 361.1 [M+H]+ .

[0230] Intermediate 24 [ka] 2,7-Dimethylpyrazolo[3,4-c]pyridin-5-amine (111.58 mg, 561.69 μmol, hydrochloride salt) and 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (100 mg, 468.08 μmol) were dissolved in dioxane (2 mL), followed by the addition of 2,4,6-tripropyl-1,3,5,2,4,6 trioxatriphosphinane 2,4,6-trioxide (446.80 mg, 702.11 μmol, 417.96 μL, 50% purity). The reaction mixture was stirred at 40° C. for 16 hours and then concentrated in vacuo. The residue was purified by column flash chromatography (0% to 10% MeOH / DCM) to give 6-chloro-N-(2,7-dimethylpyrazolo[3,4-c]pyridin-5-yl)thieno[2,3-b]pyridine-2-carboxamide (138.7 mg, 387.63 μmol, 82.81% yield) as a white solid. MS: m / z 358.1 [M+H]

[0231] Section 3. Synthetic Processes for Preparing Compounds of the Present Disclosure Example 1 - Compound 2 [ka] 6-Chloro-N-(2,7-dimethylindazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide (25.78 mg, 69.36 μmol, 1.0 equiv) was dissolved in dioxane (346.80 μL) and potassium tert-butoxide (31.13 mg, 277.44 μmol) was added. (2R,6S)-2,6-Dimethylpiperazine (11.9 mg, 104.04 μmol, 1.5 equiv.) was then added to the solution, which was then heated at 120° C. for 6 hours before being concentrated, then recovered in DMSO, filtered, and purified by preparative HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA) to give N-(2,7-dimethylindazol-5-yl)-6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]thieno[2,3-b]pyridine-2-carboxamide (9.7 mg, 25% yield) as an orange oil. MS: m / z 435.3 [M+H] + ;RT: 1.17 minutes (method 3). 1 H NMR (600 MHz, DMSO-d6) δ ppm 1.19 (br dd, J=11.25, 6.68 Hz, 2 H) 1.29 - 1.34 (m, 6 H) 2.52 - 2.55 (m, 3 H) 2.83 - 2.89 (m, 2 H) 4.11 - 4.19 (m, 3 H) 4.58 - 4.65 (m, 2 H) 7.24 - 7.27 (m, 1 H) 7.96 - 8.00 (m, 1 H) 8.13 - 8.19 (m, 2 H) 8.25 - 8.29 (m, 1 H) 8.52 - 8.59 (m, 1 H) 9.11 - 9.17 (m, 1 H) 10.22 - 10.25 (m, 1 H).

[0232] Using the procedures described for Example 1 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 7]

[0233] Example 2 - Compound 1 [ka] N,N-Dimethylpyrrolidin-3-amine (42.64 mg, 373.39 μmol, 2.0 equiv.), 6-chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (100 mg, 186.70 μmol, 1.0 equiv.), and DIPEA (560.09 μmol, 97 μL, 3.0 equiv.) were dissolved in dioxane (933 μL, 0.2 M) and heated to 80° C. for 16 h, then concentrated, then taken up in a minimum amount of DMSO, filtered, and purified by reverse-phase HPLC (column: Sunfire C18 100 × 19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give 6-[3-(dimethylamino)pyrrolidin-1-yl]-N-(2-methylimidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (29.5 mg, 30% yield) as a brown oil. MS: m / z 421.1 [M+H] + ;RT 0.87 min (Method 3).1H NMR (600 MHz, DMSO-d6 ) δ ppm 2.20 - 2.27 (m, 1 H) 2.44 - 2.49 (m, 3 H) 2.83 - 2.97 (m, 6 H) 3.47 - 3.53 (m, 2 H) 3.63 - 3.69 (m, 1 H) 3.75 - 3.81 (m, 1 H) 3.97 - 4.06 (m, 2 H) 6.75 - 6.84 (m, 1 H) 7.89 - 8.02 (m, 1 H) 8.14 - 8.24 (m, 2 H) 9.50 - 9.57 (m, 1 H) 9.94 - 10.11 (m, 1 H) 10.77 - 10.86 (m, 1 H).

[0234] Using the procedure described for Example 2 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0235] Example 3 - Compound 3 [ka] 6-Chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (22.90 mg, 56.95 μmol, 1.0 equiv.) was dissolved in dioxane (1.17 mL, 0.05 M), followed by the addition of 1-methylpiperazine (14.26 mg, 142.3 μmol, 2.5 equiv.), potassium tert-butoxide (25.56 mg, 227.8 μmol), and DIPEA (85.4 μmol, 15 μL). The solution was placed at 120° C. for 72 hours, then concentrated, then taken up in DMSO, filtered, and purified by reverse-phase HPLC (Column: Sunfire C18 100×19 mm, 5 mm; Mobile Phase A: MeCN; Mobile Phase B: HO; Modifier: 0.1% TFA) to give N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-6-(4-methylpiperazin-1-yl)thieno[2,3-b]pyridine-2-carboxamide (10.4 mg, 34% yield) as an orange oil. MS: m / z 422.2 [M+H] + ;RT 0.88 min (method 3). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 - 2.42 (m, 3 H) 2.42 - 2.46 (m, 3 H) 2.52 - 2.57 (m, 2 H) 2.71 - 2.78 (m, 3 H) 2.83 - 2.88 (m, 2 H) 3.13 - 3.20 (m, 3 H) 3.53 - 3.58 (m, 2 H) 4.53 - 4.60 (m, 2 H) 7.14 - 7.18 (m, 1 H) 7.95 - 8.00 (m, 1 H) 8.12 - 8.16 (m, 1 H) 8.38 - 8.41 (m, 1 H) 9.10 - 9.13 (m, 1 H) 9.82 - 9.90 (m, 1 H) 10.99 - 11.04 (m, 1 H).

[0236] Using the procedure described for Example 3 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 9-1] [Table 9-2]

[0237] Example 4 - Compound 6 [ka] N,N-Dimethylpyrrolidin-3-amine (26.68 mg, 142.59 μmol, dihydrochloride salt, 2.0 equiv.) and 6-chloro-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (25.8 mg, 71.29 μmol, 1.0 equiv.) were dissolved in dioxane (356 μL, 0.2 M), followed by the addition of DIPEA (178.2 μmol, 31 μL, 2.5 equiv.). The solution was then warmed to 120°C for 72 hours, concentrated, taken up in DMSO, filtered, and purified by reverse-phase HPLC (Column: Sunfire C18 100 x 19 mm, 5 mm; Mobile Phase A: MeCN; Mobile Phase B: HO; Modifier: 0.1% TFA) to give 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (10.2 mg, 26% yield) as an orange oil. MS: m / z 422.2 [M+H] + ;RT 0.82 minutes (method 3); 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.38 - 2.44 (m, 3 H) 2.84 - 2.96 (m, 6 H) 3.66 (br d, J=4.50 Hz, 2 H) 3.73 - 3.82 (m, 3 H) 3.98 - 4.07 (m, 2 H) 6.74 - 6.79 (m, 1 H) 8.01 - 8.05 (m, 1 H) 8.07 - 8.12 (m, 1 H) 8.34 - 8.38 (m, 1 H) 8.86 - 8.89 (m, 1 H) 9.25 - 9.28 (m, 1 H) 10.01 - 10.11 (m, 1 H) 11.01 - 11.07 (m, 1 H).

[0238] Example 5 - Compound 66 [ka] To a solution of 6-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (15 mg, 41.58 μmol) and (3aS,6aS)-1-methyl-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[2,3-c]pyrrole (10.49 mg, 83.15 μmol) in dioxane (2 mL) was added TEA (124.73 μmol, 17 μL). The reaction mixture was stirred at 90° C. for 12 hours. It was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (HCl conditions) to give 6-[(3aS,6aS)-1-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-5-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (5.3 mg, 28% yield) as a yellow solid. MS: m / z 451.0 [M+H] + ;RT 1.53 minutes (Method 7).

[0239] Using the procedures described for Example 5 above, additional compounds described herein were prepared by substituting the appropriate amine and amide starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 10-1] [Table 10-2] [Table 10-3]

[0240] Example 6 - Compounds 67 and 68 [ka] Step a: To a stirred solution of 6-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (15 mg, 41.58 μmol) in dioxane (1 mL) was added TEA (207.88 μmol, 29 μL) and tert-butyl N-ethyl-N-[(3S)-pyrrolidin-3-yl]carbamate (8.91 mg, 41.58 μmol). The reaction mixture was stirred at 90° C. for 12 hours. The mixture was filtered and concentrated to give a residue that was purified by preparative HPLC (neutral conditions) to give tert-butyl N-ethyl-N-[(3S)-1-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]pyrrolidin-3-yl]carbamate (15 mg, 54% yield) as a yellow solid. MS: m / z 539.2 [M+H] + ;RT 0.71 min (method 7)

[0241] Step b: To a solution of tert-butyl N-ethyl-N-[(3S)-1-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]pyrrolidin-3-yl]carbamate (15 mg, 27.85 μmol) in DCM (1 mL) was added 2 M HCl in EtOAc (1 mL). The reaction mixture was stirred at 20 ° C. for 2 h. The mixture was filtered and concentrated to give a residue which was purified by preparative HPLC (neutral conditions) to give 6-[(3S)-3-(ethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (8 mg, 63% yield) MS: m / z 439.0 [M+H] +RT 1.53 min (Method 7) was obtained as a white solid, which was separated by preparative SFC (Column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); Mobile phase: 40%-40% 0.1% NH3H2O MEOH; Flow rate (ml / min): 150; Column temperature: 35°C) to give 6-[(3S)-3-(ethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (3.4 mg, 42% yield) MS: m / z 439.1 [M+H] + RT 1.67 min (Method 7) and 6-[(3R)-3-(ethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (3.9 mg, 47% yield) were obtained as white solids. MS: m / z 439.1 [M+H] + ;RT 1.50 minutes (method 7).

[0242] Using the procedure described for Example 5 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 11-1] [Table 11-2]

[0243] Example 7 - Compound 10 [ka] 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (14.81 mg, 89.66 μmol, 1.1 equiv.) was dissolved in pyridine (407 μL, 0.2 M), followed by the addition of 6-[3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 81.51 μmol, 1.0 equiv.) and T3P (155.61 mg, 244.54 μmol, 145.57 μL, 50% purity in ethyl acetate, 3.0 equiv.). The solution was then stirred at room temperature for 16 hours, then concentrated, taken up in a minimal amount of DMSO, filtered, and purified by reverse-phase HPLC (column: XSelect CSH Prep C18 5 um OBD 19 x 100 mm; mobile phase A: MeCN; mobile phase B: HO, modifier: 0.1% NH4OH) to give 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (26.3 mg, 74% yield) as a brown oil. MS: m / z 439.1 [M+H] + ;RT 1.07 minutes (method 3). 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.20 - 2.27 (m, 1 H) 2.36 - 2.42 (m, 3 H) 2.86 - 2.91 (m, 6 H) 3.48 (br s, 2 H) 3.66 (br d, J=4.58 Hz, 1 H) 3.75 - 3.78 (m, 1 H) 3.99 - 4.05 (m, 2 H) 6.76 - 6.80 (m, 1 H) 7.47 - 7.55 (m, 1 H) 8.01 - 8.15 (m, 2 H) 9.07 - 9.12 (m, 1 H) 9.96 - 10.04 (m, 1 H) 10.53 - 10.59 (m, 1 H).

[0244] Using the procedure described for Example 7 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 12]

[0245] Example 8 - Compound 54 [ka] 6-[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 83.81 μmol, 1.0 equiv.) was dissolved in pyridine (1 mL, 0.083 M), followed by the addition of 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (13.84 mg, 83.81 μmol, 1.0 equiv.) and T3P (148 μL, 251.42 μmol, 50% purity in ethyl acetate, 3.0 equiv.). The solution was then stirred at 50° C. for 4 hours, then concentrated, taken up in a minimal amount of DMSO, filtered, and purified by HPLC (column: XSelect CSH Prep C18 5 um OBD 19×100 mm; mobile phase A: MeCN; mobile phase B: HO, modifier: 0.1% NH4OH) to give 6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (11.1 mg, 28% yield) as a yellow solid. MS: m / z 439.2 [M+H] + ;RT 0.89 minutes (method 3).

[0246] Using the procedure described for Example 8 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 13]

[0247] Example 9 - Compound 55 [ka] 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 85.80 μmol, 1.0 equiv.) was dissolved in pyridine (1 mL, 0.09 M) followed by the addition of 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (14.17 mg, 85.80 μmol, 1.0 equiv.) and T3P (163.80 mg, 257.4 μmol, 3.0 equiv., 50% pure in ethyl acetate). The solution was stirred at 50°C for 4 hours, then concentrated, taken up in DMSO, filtered, and purified by HPLC (Column: XSelect CSH Prep C18 5um OBD 19x100mm; Mobile Phase A: MeCN; Mobile Phase B: HO, Modifier: 0.1% NH4OH) to give 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (7.3 mg, 19% yield). MS: m / z 439.2 [M+H] + ;RT 0.90 minutes (method 3). 1 H NMR (600 MHz, DMSO-d6) δ ppm 1.81 - 1.90 (m, 1 H) 2.17 - 2.21 (m, 1 H) 2.23 - 2.30 (m, 6 H) 2.33 - 2.38 (m, 3 H) 2.82 - 2.91 (m, 1 H) 3.19 - 3.26 (m, 1 H) 3.40 - 3.47 (m, 1 H) 3.65 - 3.73 (m, 1 H) 3.75 - 3.82 (m, 1 H) 6.67 - 6.72 (m, 1 H) 7.27 - 7.34 (m, 1 H) 7.88 - 7.93 (m, 1 H) 8.03 - 8.10 (m, 2 H) 8.98 - 9.02 (m, 1 H) 10.35 - 10.40 (m, 1 H).

[0248] Using the procedure described for Example 9 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 14-1] [Table 14-2]

[0249] Example 10 - Compound 8 [ka] Step a: To a vial containing 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (50.16 mg, 303.68 μmol) and 5-chlorofuro[3,2-b]pyridine-2-carboxylic acid (50 mg, 253.07 μmol), 2,4,6-tripropyl-1,3,5,2,4,6 trioxatriphosphinane 2,4,6-trioxide (483.13 mg, 759.20 μmol, 451.94 μL, 50% purity), N-ethyl-N-isopropyl-propan-2-amine (98.12 mg, 759.20 μmol, 132.24 μL), and dioxane (2 mL) were added. The reaction mixture was stirred at 60° C. overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography (0% to 20% MeOH / DCM) to give 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (58.6 mg, 67% yield) as a pale yellow solid. MS: m / z 345.0 [M+H] + ;RT 0.52 min (method 4)

[0250] Step b: A microwave vial containing 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (25 mg, 64.54 μmol), diacetoxypalladium (1.45 mg, 6.45 μmol), [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]diphenylphosphane (8.04 mg, 12.91 μmol), and sodium tert-butoxide (18.61 mg, 193.63 μmol) was evacuated and refilled with N three times. Tetrahydrofuran (1 mL) and (3S)-N,N-dimethylpyrrolidin-3-amine (44.22 mg, 387.26 μmol) were then added under a N atmosphere. The reaction mixture was stirred at 90 °C for 12 h. The mixture was concentrated in vacuo and purified by HPLC (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give 5-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (19.5 mg, 71% yield). MS: m / z 423.1 [M+H] + ;RT 0.73 minutes (method 3).

[0251] Using the procedure described for Example 10 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 15]

[0252] Example 11 - Compound 9 [ka] Step a: N,N-Dimethylpyrrolidin-3-amine (57.83 mg, 309.05 μmol, dihydrochloride, 3.0 equiv.), ethyl 5-chlorothiazolo[5,4-b]pyridine-2-carboxylate (25 mg, 103.02 μmol, 1.0 equiv.), and DIPEA (13.31 mg, 103.02 μmol, 1.0 equiv.) were dissolved in dioxane (515.08 μL, 0.2 M) and heated to 80 °C for 16 h. The crude material was then loaded onto a normal phase column and purified with 0–25% MeOH:DCM over 3.5 min. The product eluted with 22% MeOH. The identified fractions were collected, combined, and concentrated to give ethyl 5-[3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylate as a damp beige solid, which was carried forward as is (estimated 100% yield). MS: m / z 321.1 [M+H] + ;RT 0.49 minutes (method 4)

[0253] Step b: Ethyl 5-[3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylate (121.31 mg, 318.03 μmol, 1.0 equiv.) was dissolved in dioxane (795.08 μL, 0.2 M) and water (795.08 μL, 0.2 M), followed by the addition of lithium hydroxide (7.62 mg, 318.03 μmol, 1.0 equiv.). The solution was then heated to 80° C. and stirred for 16 hours. After concentration, crude 5-[3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylic acid (50.8 mg, 52% yield) was carried forward as a yellow-white solid. MS: m / z 293.0 [M+H] + ;RT 0.35 minutes (method 4)

[0254] Step c: 5-[3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylic acid (50.80 mg, 165.07 μmol, 1.0 equiv) was dissolved in acetonitrile (695.04 μL, 0.24 M), followed by the addition of 2-methylimidazo[1,2-a]pyridin-6-amine (24.29 mg, 165.07 μmol, 1.0 equiv), HATU (69.04 mg, 181.58 μmol, 1.1 equiv), and DIPEA (46.93 mg, 363.16 μmol, 2.2 equiv). The solution was then stirred at room temperature for 3 hours, concentrated, taken up in a minimal amount of DMSO, filtered, and purified by reverse-phase HPLC (Column: Sunfire C18 100 x 19 mm, 5 mm; Mobile Phase A: MeCN; Mobile Phase B: HO; Modifier: 0.1% TFA) to give 5-[3-(dimethylamino)pyrrolidin-1-yl]-N-(2-methylimidazo[1,2-a]pyridin-6-yl)thiazolo[5,4-b]pyridine-2-carboxamide (11.7 mg, 13% yield) as a brown solid. MS: m / z 422.2 [M+H] + ;RT 0.87 min (method 3)

[0255] Example 12 - Compound 84 [ka] Step a: To a solution of 6-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (41 mg, 113.64 μmol) in dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl (8.32 mg, 11.36 μmol), KCO (31.41 mg, 227.28 μmol), and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (35.14 mg, 113.64 μmol). The reaction mixture was stirred at 90 °C under N for 12 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give tert-butyl 5-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (30 mg, 50% yield). MS: m / z 508.0 [M+H] + ;RT 0.43 minutes (method 7)

[0256] Step b: To a stirred solution of tert-butyl 5-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (10 mg, 19.70 μmol) in DCM (1 mL) was added 4 M HCl in EtOAc (2 mL). The reaction mixture was stirred at 20 ° C. for 2 hours. The mixture was filtered and concentrated to give a residue, which was purified by preparative HPLC (neutral conditions) to give N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-5-yl)thieno[2,3-b]pyridine-2-carboxamide (2.3 mg, 27% yield) as a yellow solid. MS: m / z 407.8 [M+H] +;RT 0.25 min (method 7);1H NMR (400 MHz, methanol-d4) δ = 9.44 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.01 (d, J = 12.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.08-7.06 (m, 1H), 4.35 (d, J = 1.6 Hz, 2H), 3.45-3.42 (m, 2H), 2.72-3.71 (m, 2H), 2.58 (s, 3H).

[0257] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate boronic ester starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 16]

[0258] Example 13 - Compounds 81 and 82 [ka] Step a: To a solution of tert-butyl 5-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]-3,4-dihydro-2H-pyridine-1-carboxylate (32 mg, 63.04 μmol) in MeOH (10 mL) was added Pd / C (6.71 mg, 63.04 μmol) under N. The mixture was stirred at 25° C. under 50 psi of H for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylate (9 mg, 27% yield) MS: m / z 510.2 [M+H] +RT 0.42 min (Method 7) was obtained as a white solid which was purified by preparative SFC (Column: Chiralpak AD-3 50 x 4.6 mm ID, 3 um, Mobile phase: CO2 in phase A and IPA (0.05% DEA) in phase B; Isocratic elution: 40% B / A Further purification by HPLC (flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar) gave tert-butyl (3R)-3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylate and tert-butyl (3S)-3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylate.

[0259] Step b: In separate vials, tert-butyl (3R)-3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylate (10.00 mg, 19.62 umol) and tert-butyl (3S)-3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylate (10.00 mg, 19.62 umol) were dissolved in DCM (1 mL) and then triturated with 2M HCl in EtOAc. After stirring at room temperature for 2 hours, the mixture was filtered and concentrated to give a residue which was purified by preparative HPLC (neutral conditions) to give N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-6-[(3R)-3-piperidyl]thieno[2,3-b]pyridine-2-carboxamide (1.6 mg, 19% yield) MS: m / z 410.0 [M+H] + ;RT 0.26 min (method 7); 1H NMR (400 MHz, methanol-d4) δ = 9.41 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.94 (d, J = 12.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 3.62 - 3.48 (m, 4H), 3.21 - 3.14 (m, 1H), 2.57 (s, 3H), 2.26 - 2.22 (m, 1H), 2.03 - 1.99 (m, 1H), 1.98 - 1.92 (m, 2H) and N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-6-[(3S)-3-piperidyl]thieno[2,3-b]pyridine-2-carboxamide (3.8 mg, 45% yield) were obtained as yellow solids. MS: m / z 410.0 [M+H] + ;RT 0.25 min (method 7);1H NMR (400 MHz, methanol-d4) δ = 9.38 (s, 1H), 8.37 (d, J = 8.0Hz, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.90 (d, J = 11.6Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 3.61- 3.19, (m, 4H), 3.19-3.13(m, 1H), 2.56(s, 3H), 2.26-2.20 (m, 1H), 2.00-1.92(m, 3H).

[0260] Using the procedure described for Example 5 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 17]

[0261] Example 14 - Compound 86 [ka] Step a: 6-Bromofuro[3,2-b]pyridine-2-carboxylic acid (200 mg, 826.36 μmol) was dissolved in ethanol (10 mL), followed by the addition of HCl / dioxane (4 M, 619.77 μL). The solution was then stirred at 80 °C for 16 h and then concentrated to give ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (ethyl 6-bromofuro[3,2-b]pyridine-2-carboxylate (244 mg) as an off-white powder, which was carried forward crude. MS: m / z 271.9 [M+H]+.

[0262] A microwave vial containing ethyl 6-bromofuro[3,2-b]pyridine-2-carboxylate (55.80 mg, 183.86 μmol), cesium carbonate (179.72 mg, 551.59 μmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (21.28 mg, 36.77 μmol), and tris(dibenzylideneacetone)dipalladium (16.84 mg, 18.39 μmol) was evacuated and refilled with N three times. Dioxane (1 mL) and N,N-dimethylpyrrolidin-3-amine (41.99 mg, 367.73 μmol) were then added under a N atmosphere. The reaction mixture was stirred at 90 °C for 12 h. The mixture was concentrated in vacuo and purified by flash silica gel chromatography (MeOH / CH2Cl2 / =0-10 / 1) to give ethyl 6-[3-(dimethylamino)pyrrolidin-1-yl]furo[3,2-b]pyridine-2-carboxylate (28.4 mg, 51% yield). MS: m / z 304.1 [M+H]+.

[0263] Step b: Ethyl 6-[3-(dimethylamino)pyrrolidin-1-yl]furo[3,2-b]pyridine-2-carboxylate (28.42 mg, 83.37 μmol) was dissolved in dioxane (0.5 mL) and water (0.5 mL), followed by the addition of lithium hydroxide (2.99 mg, 125.06 μmol, 1.5 equiv.). The solution was then heated at 50° C. for 2 hours and then concentrated to give 6-[3-(dimethylamino)pyrrolidin-1-yl]furo[3,2-b]pyridine-2-carboxylic acid (22.9 mg) as an off-white powder. MS: RT m / z 276.0 [M+H]+.

[0264] Step c: 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (27.52 mg, 166.60 μmol), 6-[3-(dimethylamino)pyrrolidin-1-yl]furo[3,2-b]pyridine-2-carboxylic acid (22.93 mg, 83.3 μmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (31.94 mg, 166.60 μmol), and 1-hydroxybenzotriazole hydrate (25.51 mg, 166.60 μmol) were added to a vial. Then, DMF (1 mL) and N-ethyl-N-isopropyl-propan-2-amine (43.06 mg, 333.20 μmol, 58.04 μL) were added. The reaction mixture was stirred at room temperature overnight at 40 °C, then concentrated, taken up in DMSO, filtered, and purified by HPLC (Column: Sunfire C18 100 x 19 mm, 5 mm; Mobile Phase A: MeCN; Mobile Phase B: HO; Modifier: 0.1% TFA) to give 6-[3-(dimethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (2.6 mg, 6.15 μmol, 7.39% yield). MS: m / z 423.1 [M+H]; RT 0.79 min (Method 3). 1H NMR (600 MHz, DMSO-d6) δ ppm 1.87 (m, 1 H) 2.17 - 2.22 (m, 1 H) 2.24 (s, 7 H) 2.35 (s, 3 H) 2.84 - 2.89 (m, 1 H) 3.18 (t, J = 8.77 Hz, 1 H) 3.52 (t, J=8.39 Hz, 1 H) 3.59 (m, 1 H) 7.09 (d, J = 1.53 Hz, 1 H) 7.37 (d, J = 12.59 Hz, 1 H) 7.76 (s, 1 H) 7.93 (d, J = 2.67 Hz, 1 H) 8.17 (d, J = 2.29 Hz, 1 H) 9.08 (d, J = 0.76 Hz, 1 H) 10.50 (s, 1 H).

[0265] Example 15 - Compound 89 [ka] Step a: (3R)-N,N-dimethylpyrrolidin-3-amine (35.29 mg, 0.309 mmol, 0.75 equiv), ethyl 5-chlorothiazolo[5,4-b]pyridine-2-carboxylate (100 mg, 0.412 mmol, 1.0 equiv), and DIPEA (106.51 mg, 0.824 mmol, 2.0 equiv) were dissolved in dioxane (1 mL, 0.4 M) and heated to 80 °C for 16 h. The solution was then concentrated on a Biotage V10, taken up in a minimal amount of methanol, and purified with 0-20% MeOH:DCM over 7 min. The product eluted near 10% MeOH. Ethyl 5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylate (47.3 mg, 0.148 mmol, 35.9% yield) was obtained. MS: m / z 321.0. [M+H] + ;RT 0.50 min (method 4).

[0266] Step b: 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (17.73 mg, 107.32 μmol, 1.2 equiv.) and methyl-5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylate (27.4 mg, 89.43 μmol, 1.0 equiv.) were dissolved in toluene (447.15 μL, 0.2 M), followed by the addition of LiHMDS (1 M, 178.86 μmol, 178.86 μL, 2.0 equiv.). The solution was then stirred at room temperature for 16 hours, concentrated, and then recovered with a minimal amount of DMSO, water, and methanol, filtered, and injected directly into reverse phase under acidic conditions. The identified fractions were collected, combined, and concentrated to give an orange-yellow solid, which was registered as is. 5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thiazolo[5,4-b]pyridine-2-carboxamide (19.8 mg, 0.035 mmol, 39.2% yield) was obtained. MS: m / z 440.2. [M+H] + ;RT 0.42 minutes (method 3). 1 H NMR (400 MHz, methanol-d4 ) δ ppm 2.32 - 2.43 (m, 1 H) 2.55 - 2.59 (m, 3 H) 2.62 - 2.67 (m, 1 H) 2.99 - 3.05 (m, 6 H) 3.60 - 3.69 (m, 1 H) 3.79 - 3.86 (m, 1 H) 3.87 - 3.94 (m, 1 H) 4.06 - 4.19 (m, 2 H) 6.87 - 6.93 (m, 1 H) 8.09 - 8.14 (m, 2 H) 8.21 - 8.27 (m, 1 H) 9.44 - 9.48 (m, 1 H).

[0267] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in steps a and b to provide compounds such as those selected from the following: [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4]

[0268] Example 16 - Compounds 140 and 139 [ka] Step a: 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thiazolo[5,4-b]pyridine-2-carboxamide (115.85 mg, 320.23 umol, 1.2 equiv.), tert-butyl 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3, To a mixture of 2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (90 mg, 266.86 μmol, 1.0 equiv.) and KCO (110.64 mg, 800.57 μmol, 3.0 equiv.), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; and iron (17.39 mg, 26.69 μmol, 0.1 equiv.) were added at 20° C. The mixture was stirred at 90° C. for 1 hour. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC (DCM:MeOH=10 / 1) to give tert-butyl 4-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thiazolo[5,4-b]pyridin-5-yl]-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylate (70 mg, 130.45 μmol, 48.88% yield) as a yellow solid. MS: m / z 537.3. [M+H] + ;RT 0.95 minutes (Method 7).

[0269] Step b: To a mixture of tert-butyl-4-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thiazolo[5,4-b]pyridin-5-yl]-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylate (60 mg, 111.81 umol, 1.0 equiv) in DCM (2 mL, 56 mM) was added HCl / dioxane (2 mL, 70 equiv) at 20° C. The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated to give the crude material, which was purified by preparative HPLC (Column: Boston Green ODS 150 x 30 mm x 5 μm; Conditions: Water (FA)-ACN, Start B3, End B18, Gradient Time (min) 12, 100% B Retention Time (min) 2, Flow Rate (mL / min) 25, Injection 12) to give 5-[(2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thiazolo[5,4-b]pyridine-2-carboxamide (25.5 mg, 58.42 μmol, 52.25% yield) as a white solid. MS: m / z 437.1. [M+H] + ;RT 1.65 minutes (Method 8).

[0270] Step c: To a mixture of 5-[(2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thiazolo[5,4-b]pyridine-2-carboxamide (25 mg, 57.27 umol, 1.0 equiv) in MeOH (20 mL, 2.86 mM) was added Pd / C (60.95 mg, 57.27 umol, 10% purity, 1.0 equiv) at 20° C. The mixture was stirred at 20° C. under H (15 psi) for 16 h. The reaction mixture was filtered and concentrated to give the crude product, which was purified by preparative HPLC (Column: Boston Green ODS 150 x 30 mm x 5 μm; Conditions: water (HCl)-ACN, Start B10, End B40, Gradient Time (min) 10, 100% B Retention Time (min) 2, Flow Rate (mL / min) 25, Inject 1) to give 5-[(2S,6R)-2,6-dimethyl-4-piperidyl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thiazolo[5,4-b]pyridine-2-carboxamide (2.2 mg, 5.02 μmol, 8.76% yield) as a yellow solid. MS: m / z 439.1. [M+H] + ;RT 1.63 minutes (method 8)

[0271] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate boronic acid / ester and amide starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 19]

[0272] Example 17 - Compound 268 [ka] Step a: To a solution of 3-chlorothieno[2,3-b]pyrazine-6-carboxylic acid (50 mg, 233 μmol) in pyridine (5 mL) was added EDCl (45 mg, 233 μmol) and 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (39 mg, 233 μmol). The mixture was stirred at 80° C. for 2 hours. The mixture was concentrated. The crude product was triturated with ethyl acetate (3 mL) and water (10 mL) at 25° C. for 1 hour. The crude compound was used in the next step without further purification. The compound 3-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyrazine-6-carboxamide (50 mg, 138 μmol) was obtained as a black solid. MS: m / z 362.0 [M+H] + ;RT 0.423 minutes (Method 9)

[0273] Step b: To a solution of tert-butyl (1R,5R)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (17 mg, 83 μmol) in dioxane (2 mL), TEA (25 mg, 249 μmol, 35 μL) and 3-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyrazine-6-carboxamide (30 mg, 83 μmol) were added. The mixture was stirred at 90° C. for 2 hours. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo (low temperature) to give the crude product. The crude material was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; conditions: water (FA)-ACN, start B2, end B32; gradient time (min): 14; 100% B retention time (min): 2; flow rate (ml / min): 25) to give tert-butyl (1R,5R)-6-[6-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyrazin-3-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (30 mg, 57 μmol, 69% yield) as a yellow solid. MS: m / z 524.2 [M+H] + ;RT 1.135 minutes (method 10)

[0274] Step c: To a solution of tert-butyl (1R,5R)-6-[6-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyrazin-3-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (30 mg, 57 μmol) in DCM (2 mL) was added TFA (7 mg, 57 μmol, 5 μL). The mixture was stirred at 25 °C for 0.5 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over NaSO, filtered, and concentrated in vacuo (cold) to give 3-[(1S,5R)-3,6-diazabicyclo[3.2.0]heptan-6-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyrazine-6-carboxamide (20 mg, crude) as a yellow solid. MS: m / z 424.1 [M+H] + ;RT 1.300 minutes (method 8)

[0275] Step d: To a solution of 3-[(1S,5R)-3,6-diazabicyclo[3.2.0]heptan-6-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyrazine-6-carboxamide (20 mg, 47 μmol) in MeOH (20 mL) was added TEA (14 mg, 142 μmol, 20 μL) and paraformaldehyde (57 mg, 47 μmol, 64 μL). The mixture was stirred at 25 °C for 0.5 h. Then, NaCNBH (8 mg, 118 μmol) was added to the mixture. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (30.0 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum (low temperature) to give a crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 um; condition: water (FA)-ACN, start B2, end B32; gradient time (min): 14; 100% B retention time (min): 2; flow rate (ml / min): 25) to give N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-3-[(1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl]thieno[2,3-b]pyrazine-6-carboxamide (5 mg, 12 μmol) as a yellow solid. MS: m / z 438.2 [M+H] + ;RT 1.17 minutes (method 10)

[0276] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in steps a and b to provide compounds such as those selected from the following: [Table 20]

[0277] Example 18 - Compounds 147 and 148 [ka] Step a: To a solution of 3-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyrazine-6-carboxamide (120 mg, 332 μmol) in dioxane (2.5 mL) and water (0.5 mL), KCO (138 mg, 995 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (103 mg, 332 μmol), and PdCl(dppf) (24 mg, 33 μmol) were added. The mixture was stirred at 90 °C under N for 2 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 20:1 to 10:1). The compound tert-butyl 4-[6-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyrazin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 197 μmol) was obtained as a yellow solid. MS: m / z 509.4 [M+H] + ;RT 0.392 minutes (method 9)

[0278] Step b: tert-Butyl 4-[6-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyrazin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (20 mg, 39 μmol) was added to MeOH (10 mL) under argon. Pd / C (20 mg, 188 μmol) was added to the mixture under argon. The mixture was then stirred under H at 25 °C and 35 Psi for 16 hours. The mixture was quenched with water (30.0 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo (low temperature) to give the crude product. The crude product was purified by chromatography on silica gel (DCM / MeOH=10 / 0 to 10 / 1) to give tert-butyl 4-[6-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyrazin-3-yl]piperidine-1-carboxylate (15 mg, 29 μmol) as a yellow solid. MS: m / z 511.3 [M+H] + ;RT 0.953 minutes (Method 10).

[0279] Step c: tert-Butyl 4-[6-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyrazin-3-yl]piperidine-1-carboxylate (15 mg, 29 μmol) was added to HCl / EA (2 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and concentrated in vacuo (low temperature) to give the crude product. The crude was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; conditions: water (FA)-ACN, start B2, end B32; gradient time (min): 14; 100% B retention time (min): 2; flow rate (ml / min): 25) to give N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-3-(4-piperidyl)thieno[2,3-b]pyrazine-6-carboxamide (5.4 mg, 13 μmol) as a yellow solid. MS: m / z 411.1 [M+H] + ;RT 1.570 minutes (method 10).

[0280] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate boronic acid / ester and amide starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 21]

[0281] Example 19 - Compound 152 [ka] Step a: (3S)-N,N-Dimethylpyrrolidin-3-amine (49.94 mg, 437.3 mmol, 1.0 equiv.), methyl 2-chlorothieno[2,3-d]pyrimidine-6-carboxylate (100 mg, 437.3 mmol, 1.0 equiv.), and DIPEA (113 mg, 875 mmol, 2.0 equiv.) were dissolved in dioxane (1 mL, 0.44 M) and heated to 80 °C for 16 h. The solution was then concentrated on a Biotage V10, taken up in a minimal amount of methanol, and purified with 0-20% MeOH:DCM over 7 min. The product eluted with 10% MeOH. The identified fractions were collected, combined, and concentrated to give methyl 2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-d]pyrimidine-6-carboxylate (111.3 mg, 363 mmol, 83% yield). MS: m / z 307.0. [M+H] + ;RT 0.45 minutes (method 4)

[0282] Step b: 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (16.17 mg, 97.92 μmol, 1.2 equiv.) and methyl 2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-d]pyrimidine-6-carboxylate (25.00 mg, 81.60 μmol, 1.0 equiv.) were dissolved in toluene (407.99 μL, 0.2 M), followed by the addition of LiHMDS (1 M, 163.19 μmol, 2.0 equiv.). The solution was then stirred at room temperature for 16 hours, concentrated, and then recovered with DMSO, methanol, and water, filtered, and directly injected onto a reverse-phase column under acidic conditions. The identified fractions were collected, concentrated, and subsequently registered. 2-[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-d]pyrimidine-6-carboxamide (22.8 mg, 41.19 umol, 50.48% yield, trifluoroacetic acid) was obtained as an orange-yellow solid. 1H NMR (400 MHz, methanol-d4 ) δ ppm 2.30 - 2.40 (m, 1 H) 2.54 - 2.57 (m, 3 H) 2.58 - 2.65 (m, 1 H) 2.99 - 3.02 (m, 6 H) 3.66 - 3.74 (m, 1 H) 3.82 - 3.88 (m, 1 H) 3.96 - 4.04 (m, 1 H) 4.05 - 4.13 (m, 1 H) 4.18 - 4.25 (m, 1 H) 7.94 - 7.99 (m, 1 H) 8.06 - 8.08 (m, 1 H) 8.08 - 8.10 (m, 1 H) 8.91 - 8.94 (m, 1 H) 9.37 - 9.40 (m, 1 H).MS:m / z 440.2.[M+H] + ;RT 0.43 min (method 4).

[0283] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in steps a and b to provide compounds such as those selected from the following: [Table 22]

[0284] Example 20 - Compound 153 [ka] Step a: To a solution of 8-fluoro-2-methyl-imidazo[1,2-a]pyridine-6-carboxylic acid (80 mg, 412.03 μmol) and 6-chlorothieno[2,3-b]pyridin-2-amine (91.29 mg, 494.43 μmol) in DCM (2 mL) was added oxalyl dichloride (2 M, 824.05 μL) and N,N-diethylethanamine (166.77 mg, 1.65 mmol, 229.71 μL). The reaction mixture was stirred at 60° C. overnight and then concentrated. The residue was purified by column chromatography (0-10% MeOH / DCM) to give N-(6-chlorothieno[2,3-b]pyridin-2-yl)-8-fluoro-2-methyl-imidazo[1,2-a]pyridine-6-carboxamide (66.0 mg, 182.93 μmol, 44.40% yield) as a pale solid. MS: m / z 361.1 [M+H] + .

[0285] Step b: N-(6-chlorothieno[2,3-b]pyridin-2-yl)-8-fluoro-2-methyl-imidazo[1,2-a]pyridine-6-carboxamide (25 mg, 69.29 μmol), sodium; 2-methylpropan-2-olate (19.98 mg, 207.88 μmol), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (6.28 mg, 6.93 μmol) were added to a microwave vial. The mixture was evacuated and refilled with N three times. Then, 2-Me-THF (1 mL) and (3S)-N,N-dimethylpyrrolidin-3-amine (23.74 mg, 207.88 μmol, 26.67 μL) were added. The reaction mixture was stirred at 90° C. for 12 hours and then concentrated in vacuo. The residue was purified by HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA) to give N-[6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridin-2-yl]-8-fluoro-2-methyl-imidazo[1,2-a]pyridine-6-carboxamide (3.7 mg, 8.44 μmol, 12.18% yield) as a yellow solid. MS: m / z 361.1 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.09 - 2.20 (m, 1 H), 2.35 (s, 3 H), 2.39 (br s, 1 H), 2.55 (s, 1 H), 2.59 - 2.85 (m, 6 H), 3.45 - 3.57 (m, 2 H), 3.76 (br t, J=8.39 Hz, 1 H), 3.94 (br s, 1 H), 6.75 (d, J=8.77 Hz, 1 H), 7.31 (d, J=12.59 Hz, 1 H), 7.91 (d, J=1.91 Hz, 1 H), 8.10 - 8.14 (m, 2 H), 9.00 (s, 1 H), 10.42 (s, 1 H).

[0286] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate acidic starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 23]

[0287] Example 21 - Compound 156 [ka] Step a: tert-Butyl rac-(2S,6R)-4-hydroxy-2,6-dimethyl-piperidine-1-carboxylate (23.83 mg, 103.94 μmol) and 6-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (25 mg, 69.29 μmol) were dissolved in DMF (1 mL), and then sodium hydride (9.98 mg, 415.75 μmol) was added. The solution was then heated to 40° C. for 16 hours. The reaction was concentrated in vacuo. The residue was used directly in the next step.

[0288] Step b: To a solution of tert-butyl (2S,6R)-4-((2-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)thieno[2,3-b]pyridin-6-yl)oxy)-2,6-dimethylpiperidine-1-carboxylate in DCM (1 mL) was added HCl (4 M, 1.11 mmol, 277.17 μL). The mixture was stirred for 2 h and then concentrated. The residue was purified by HPLC (column: Sunfire C18 100 × 19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA) to give 6-[[(2SR,6RS)-2,6-dimethyl-4-piperidyl]oxy]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (4.8 mg, 10.58 μmol, 15.27% yield) as a yellow solid. MS: m / z 454.2 [M+H] + ;RT 1.10 minutes (method 3).

[0289] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate alcohol and amide starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 24]

[0290] Example 22 - Compound 163 [ka] Step a: To a mixture of 5-chlorofuro[3,2-b]pyridine-2-carboxylic acid (20 mg, 101.23 μmol) and 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (16.72 mg, 101.23 μmol) in DMF (2 mL) was added HATU (57.73 mg, 151.84 μmol) and DIPEA (19.62 mg, 151.84 μmol, 26.45 μL) in one portion at 25° C. The mixture was stirred at 90° C. for 80 minutes. The mixture was then cooled to 25° C. and concentrated under reduced pressure. The residue was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to give 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (21 mg, 60.92 μmol, 60.18% yield) as a brown solid. MS: m / z 345.1 [M+H] + .

[0291] Step b: To a mixture of 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (20 mg, 58.02 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (12.94 mg, 58.02 μmol) in dioxane (3 mL), KCO (24.05 mg, 174.05 μmol), Pd(dppf)Cl (42.45 mg, 58.02 μmol) were added and stirred at 90° C. for 6 hours. The reaction mixture was filtered and concentrated to give the crude product. The mixture was further purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to give N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)furo[3,2-b]pyridine-2-carboxamide (15.6 mg, 38.48 μmol, 66.32% yield) as a brown solid. MS: m / z 406.2 [M+H] + .

[0292] Step c: To a solution of N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)furo[3,2-b]pyridine-2-carboxamide (25 mg, 61.66 μmol) in MeOH (5 mL) and THF (5 mL) was added Pd / C (19.69 mg, 18.50 μmol, 10% purity). The suspension was degassed under vacuum and purged with H2 several times. The mixture was heated to 35 °C (45 psi) and stirred for 5 h. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Boston Prime C18 150 x 30 mm x 5 μm column; conditions: water (NH3H2O + NH4HCO3)-ACN; start: B44; end: B74; gradient time (min): 10; 100% B retention time (min): 2; flow rate (ml / min): 25) to give N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-5-(1-methyl-4-piperidyl)furo[3,2-b]pyridine-2-carboxamide (4.42 mg, 10.85 μmol, 17.59% yield, 100% purity) as a white solid. MS: m / z 408.2 [M+H] + ;RT 2.572 minutes (Method 8). 1 H NMR (400 MHz, methanol-d4) δ ppm = 9.10 (d, J = 1.6 Hz, 1 H), 8.07 (d, J = 9.2 Hz, 1 H), 7.79 - 7.74 (m, 2 H), 7.50 (d, J = 8.8 Hz, 1 H), 7.39-7.36 (m, 1 H), 3.14 (d, J = 10.8 Hz, 2 H), 2.99 - 2.90 (m, 1 H), 2.46 - 2.42 (m, 6 H), 2.40 - 2.31 (m, 2 H), 2.04-2.02 (m, 4 H).

[0293] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate amine starting material in step a and boronic acid / ester starting material in step b, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 25]

[0294] Example 23 - Compound 168 [ka] Step a: To a solution of 5-chlorofuro[3,2-b]pyridine-2-carboxylic acid (100 mg, 506.14 μmol) and HATU (384.90 mg, 1.01 mmol) in DMF (2 mL) was added N-ethyl-N-isopropyl-propan-2-amine (196.24 mg, 1.52 mmol, 264.48 μL) and 8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-amine (89.69 mg, 506.14 μmol). The mixture was stirred at 25 °C for 16 h. The mixture was then quenched with water (30.0 mL) and extracted with EA (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over NaSO, filtered, and concentrated in vacuo (cold) to give 5-chloro-N-(8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (70 mg, 196.21 μmol, 38.77% yield) as a yellow solid. MS: m / z 356.8 [M+H] + .

[0295] Step b: To a solution of 5-chloro-N-(8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (60 mg, 168.18 μmol) in THF (15 mL) was added sodium tert-butoxide (48.49 mg, 504.54 μmol), 5-chloro-N-(8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (60 mg, 168.18 μmol), and tert-butyl (1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (50.02 mg, 252.27 μmol). The mixture was stirred at 80 °C under N for 2 hours. The mixture was filtered and concentrated. The residue was purified by column chromatography (DCM:MeOH=10:1) to give tert-butyl (1S,5S)-6-[2-[(8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]furo[3,2-b]pyridin-5-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (79 mg, 152.34 μmol, 90.58% yield) as a yellow oil. MS: m / z 519.3 [M+H] + .

[0296] Step c: To a solution of tert-butyl (1S,5S)-6-[2-[(8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]furo[3,2-b]pyridin-5-yl]-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (79 mg, 152.34 μmol) in HFIP (3 mL) was added TFA (34.74 mg, 304.69 μmol, 23.33 μL). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated. The crude compound was used in the next step without further purification. MS: m / z 419.3 [M+H] + .

[0297] Step d: To a solution of 5-[(1R,5S)-3,6-diazabicyclo[3.2.0]heptan-6-yl]-N-(8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)furo[3,2-b]pyridine-2-carboxamide (50 mg, 119.49 μmol) in DCE / EtOH (4 mL), TEA (36.27 mg, 358.47 μmol, 49.96 μL) and paraformaldehyde (143.33 mg, 119.49 μmol, 162.88 μL) were added. The mixture was stirred at 25° C. for 10 minutes. Sodium triacetoxyboranide (75.97 mg, 358.47 μmol) was then added. The mixture was stirred at 25° C. for 2 hours. The mixture was filtered and concentrated. The residue was purified by HPLC (Boston Prime C18 150 x 30 mm x 5 μm column; conditions: water (NH3H2O + NH4HCO3)-ACN; start: B44; end: B74; gradient time (min): 10; retention time (min): 100% B: 2; flow rate (ml / min): 25) to give N-(8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)-5-[(1R,5S)-3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl]furo[3,2-b]pyridine-2-carboxamide (6.27 mg, 14.50 μmol, 12.13% yield) as a yellow solid. MS: m / z 433.1 [M+H] + ;RT 0.663 minutes (Method 10). 1H NMR (400MHz, methanol-d4) δ ppm = 8.77 (d, J = 1.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 6.91 (s, 1H), 6.51 (d, J = 9.2 Hz, 1H), 4.88 - 4.85 (m, 1H), 4.15 - 4.10 (m, 1H), 4.02 (s, 3H), 3.86 - 3.83 (m, 1H), 3.42 (d, J = 11.2 Hz, 1H), 3.26 - 3.20 (m, 1H), 3.15 (d, J = 10.4 Hz, 1H), 2.46 (s, 3H), 2.38 (s, 3H), 2.28 - 2.23 (m, 1H), 2.20 - 2.15 (m, 1H).

[0298] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in steps a and b to provide compounds such as those selected from the following: [Table 26-1] [Table 26-2] [Table 26-3]

[0299] Example 24 - Compound 176 [ka] Step a: To a stirred solution of 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (250 mg, 1.2 mmol) in DMF (10 mL) was added DIPEA (454 mg, 3.51 mmol, 611 μL), HATU (534 mg, 1.40 mmol), and 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (193.3 mg, 1.17 mmol). The reaction mixture was stirred at 20° C. for 14 hours. The reaction mixture was washed with EtOAc (20 mL×3), filtered, and concentrated under reduced pressure to give a residue. 6-Chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (270 mg, 739.07 μmol, 63.16% yield) was obtained as a brown solid. MS: m / z 360.8 [M+H] + ;RT 0.648 minutes (Method 9)

[0300] Step b: 6-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (50 mg, 138 mmol) was dissolved in dioxane (1 mL) and water (0.3 mL). 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (37 mg, 138 mmol) was added, followed by cesium carbonate (90 mg, 277 mmol) and PdCl(dppf) (8 mg, 14 mmol). The mixture was degassed with N and stirred at 90 °C for 2 h. The mixture was cooled to room temperature, diluted with water, extracted with EtOAc, and concentrated. The crude was purified by acidic SCX column, acidified with HCl in methanol and released with 2N ammonia in methanol to give the title compound (21 mg, 0.045 mmol). MS: m / z 464.1 [M+H]; RT 0.49 min (Method 4).

[0301] Step c: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[2,3-b]pyridine-2-carboxamide (21 mg, 45 mmol) was dissolved in MeOH (1 mL) and ammonium formate (28 mg, 0.45 mmol) was added, followed by Pd / C (10%) (5 mg, 4.5 μmol). The mixture was stirred at 60 °C for 2 h. The mixture was then cooled to room temperature, filtered through Celite, washed with DCM (3 × 5 mL), and concentrated. The resulting material was purified by RP-HPLC using a basic modifier and a 20–75% ACN / water gradient to give the title compound (3.9 mg, 8 μmol) as an orange solid.

[0302] Using the procedure described for Example 15 above, additional compounds described herein were prepared by substituting the appropriate amine starting material in step a and boronic acid / ester starting material in step b, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 27-1] [Table 27-2]

[0303] Example 25 - Compound 210 [ka] Step a: To a solution of 6-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (2.5 g, 6.93 mmol, 1.0 equiv.) in DMF (80 mL, 0.087 M) was added 3,3-dimethoxypyrrolidine (1.82 g, 13.86 mmol, 2.0 equiv.), sodium; 2-methylpropan-2-olate (2.00 g, 20.79 mmol, 3.0 equiv.), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (1.08 g, 1.39 mmol, 0.2 equiv.). The mixture was then stirred at 130 °C under a N atmosphere for 12 hours. The residue was poured into water (100 mL), and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic phase was washed with water (100 mL x 3), brine (200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was purified by chromatography (DCM / MeOH = 100 / 1 to 50 / 1, TLC: DCM / MeOH = 10 / 1) to give 6-(3,3-dimethoxypyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (1.5 g, 3.29 mmol, 47.52% yield) as a yellow solid. MS: m / z 456.1 [M+H] + ;RT 2.067 minutes (method 10)

[0304] Step b: To a solution of 6-(3,3-dimethoxypyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (1.3 g, 2.85 mmol, 1.0 equiv.) in ACN (13 mL, 13 mL, 0.2 M) was added HCl (1 M, 2.6 mL, 1.0 equiv.). The mixture was then stirred at 25° C. for 2 hours. The mixture was filtered, and the filter cake was dried under reduced pressure. DMSO (20 mL) was added to the solid, and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to 25° C., filtered, the filter cake was washed with EtOAc (20 mL×3), and the filter cake was concentrated under reduced pressure to give N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-oxopyrrolidin-1-yl)thieno[2,3-b]pyridine-2-carboxamide (734 mg, 1.68 mmol, 58.84% yield, 93.67% purity) as a yellow solid. MS: m / z 410.1 [M+H] + ;RT 2.367 minutes (method 10)

[0305] Step c: To a mixture of N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-6-(3-oxopyrrolidin-1-yl)thieno[2,3-b]pyridine-2-carboxamide (20 mg, 48.85 μmol, 1.0 equiv.) and cyclopropylmethanamine (20.84 mg, 293.09 μmol, 6.0 equiv.) in MeOH (4 mL, 0.012 M), acetic acid (14.67 mg, 244.24 μmol, 5.0 equiv.) was added in one portion at 25° C. under N2. After 30 min, sodium cyanoborane (9.21 mg, 146.54 μmol, 3.0 equiv.) was added. The mixture was stirred at 25° C. for 2 h. The mixture was further purified by preparative HPLC (Column Welch Xtimate C18 150*25mm*5um, Conditions: Water (FA)-ACN, Start B2, End B22, Gradient Time (min): 12, Retention Time (min): 2, Flow Rate (ml / min): 25) to give 6-(3-((cyclopropylmethyl)amino)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide (10 mg, 21.53 umol, 44% yield). MS: m / z 465.3 [M+H] + RT 0.68 min (Method 7) This was further purified by preparative SFC (column: Chiralpak IC 50*4.6 mm 3 um, mobile phase A: hexane (0.1% DEA) and phase B: IPA / MeCN = 2:1, isocratic A / B = 40 / 60, flow rate: 1 mL / min; elution: column temperature: 35 °C; to give rel-(R)-6-(3-((cyclopropylmethyl)amino)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)thieno[2,3-b]pyridine-2-carboxamide.

[0306] Section 3. Biological Assays and Data HTT mutant and whole HTRF iPSC assay protocol This in vitro cell assay measures mutant and total HTT protein in induced pluripotent stem cells (iPSCs) derived from HTT (Huntington's) patients with a polyQ49 mutation. Assay measurements were performed by homogeneous time-resolved fluorescence (HTRF). The mutant HTT antibody was labeled with a d2 acceptor and recognizes a portion within the polyQ region. The terbium (Tb) donor antibody recognizes a sequence at the N-terminus of the protein. The total HTT antibody was labeled with a d2 acceptor and recognizes a sequence beyond the polyQ region. For each experiment, frozen aliquots of iPSCs were thawed from liquid nitrogen storage and grown in Matrigel (Corning #354227)-coated flasks using complete medium (mTeSR™1 Plus (STEMCELL Technologies Cat. No. 05852) and supplemented with penicillin / streptomycin (Gibco Cat. No. 10378016) (mTeSR™1 Plus Basal Medium (STEMCELL Technologies Cat. No. 05825)) in the presence of 10 μM Rock Inhibitor (Sigma #Y0503). Flasks containing cells were incubated overnight at 37°C, 5% CO2 (Thermo). The next day, the medium was replaced with fresh complete medium without Rock Inhibitor and incubated for 48 hours at 37°C, 5% CO2 for cell expansion. Cells were harvested from the flasks using Accutase (Gibco #A1110501) and placed on a Cellometer (Nexcelom). Cells were counted using a 3D Imaging System (Vision). A total of 10,000 cells / well were added to a Matrigel-precoated 384-well tissue culture plate (Perkin Elmer #NC1758152) containing 30 μl of complete medium containing 10 μM of ROCK inhibitor. The cell plate was centrifuged, and the cells were allowed to adhere overnight at 37°C and 5% CO2 in a humidified incubator (Thermo Cytomat10). The following day, cells were treated with compound. Intermediate plates were used to pre-dilute compounds in complete medium without ROCK inhibitor.Compounds were diluted and dispensed into empty 384-well PP plates (Griener #784201) using an ECHO (Labcyte #Echo555). A total of 60 μl of complete medium was added per well using a Multidrop Combi (Thermo #5840300). Compounds were tested in a 10-point, 3-fold titration starting at 10 μM. Media was removed from the cell plates by flicking, and the plates were blotted onto tissue paper. A 50 μL volume was transferred from the compound plate to the cell assay plate using an Integra (Viaflow384). The cell plates were incubated at 37°C, 5% CO2, and high humidity for 48 hours. Cell lysates were prepared by first removing the media from the plates and then adding 40 μl per well of MPER lysis buffer (Thermo #78501) containing protease and phosphatase inhibitors (Pierce #A32961). The plate was placed on an orbital shaker for 30 minutes at room temperature, and 5 μl of cell lysate was transferred to two 384-well black plates (Sigma Aldrich #CLS3821) using an apricot dispenser (SPT Labtech). Each plate contained either 5 μl / well of mutant HTT HTRF assay mix or 5 μl / well of the entire HTT HTRF assay mix. The mutant HTT HTRF assay mix contained the 2B7Ab-Tb "donor" antibody (Thermo #CHDI-9000830) N-terminally labeled antibody at a final concentration of 0.4 ng / well and the MW1 (polyQ-specific)-d2 "acceptor" antibody (Sigma #MABN2427) at a final concentration of 40 ng / well in HTRF detection buffer (CisBio #62SDBRDF). The total HTT HTRF assay mix contained the 2B7Ab-Tb "donor" N-terminally labeled antibody at a final concentration of 0.4 ng / well and the MAB2166-d2 (anti-huntingtin [1HU-4C8] mAb-d2 "acceptor" antibody at a final concentration of 40 ng / well in HTRF detection buffer. All antibodies were labeled at Perkin Elmer. The assay plate was sealed and placed on an orbital shaker for 1 min, then centrifuged for 1 min before being incubated at room temperature for 4 h.The plates were read on a PHERAstar instrument (BMG LAB TECH) and the HTRF ratio was calculated from the (337nm / 665nm) and (337nm / 620nm) outputs. IC from the full concentration response curve. 50 Values were generated and curves were plotted as percent activity versus compound concentration fitted to a variable four-parameter logistic model.

[0307] I C 50 A summary of the results is shown in Table 2. "A" indicates an IC<100 nM 50 "B" represents the IC value between 100 nM and 1 µM 50 "C" represents the IC value, ranging from 1 µM to 9 µM 50 Represents a value. [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4]

Claims

1. Formulas (II), (III), (IV), (V), (VI), (VII), or (VIII): 【Chemistry 1】 Compounds of or pharmaceutically acceptable salts thereof (wherein the formula, R １ These include 4-12 member heterocyclyl, 4-12 member carbocyclyl, and -NR １１ R １２ , -C １－６ Alkylene-NR １３ R １４ , or -OR １５ And here, R １ The 4- to 12-membered carbocyclic ring or the 4- to 12-membered heterocyclic ring represented by R Ａ is optionally substituted with one or more R Each R Ａ Independently, C １－６ Alkyl, C ３－６ Cycloalkyl, Halo C １－６ Alkyl, -NR ａ R ｂ , -C １－３ Alkylene-NR ａ R ｂ , -C ３－６ Cycloalkylene-NR ａ R ｂ , -C(=O)R ａ , or a saturated heterocycline with 4 to 6 members, where each R ａ and R ｂ H or C １－６ It is alkyl, and here, R Ａ The 4-6 member saturated heterocycline represented by the above is one or more C １－６ Optionally substituted with alkyl groups, R １１ is H or C １－６ It is alkyl, R １２ C １－６ Alkyl, 6-10 membered aryl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl, where R １２ The C represented by １－６ Alkyl, the 6-10 membered aryl, the 4-12 membered heterocyclyl, or the 5-10 membered heteroaryl may have one or more R Ｂ It is optionally replaced by, here, R Ｂ Hello, C １－６ Alkyl, -NR ａ R ｂ , 4-6 member heterocyclyl, or -C １－６ It is an alkylene-4 to 6-membered heterocycline, where R Ｂ The 4-6 member heterocyclyl represented by the above is one or more C １－６ Optionally substituted with alkyl groups, R １３ is H or C １－６ It is alkyl, R １４ and R １５ H, C １－６ Alkyl, or -C １－６ Independently selected from alkylene-4 to 6-membered saturated heterocyclines, R ２ H is, R ３ This is 1 to 3 R's Ｃ A 9-membered bicyclic heteroaryl or 1 to 3 R members optionally substituted by Ｃ１ A phenyl compound condensed with a five-membered heterocycline that has been optionally substituted, where, R Ｃ is halo, -CN, -OH, C １－６ Alkyl, C １－６ Haloalkyl, or C １－６ It is either an alkoxy or two Rs Ｃ The intervening atoms come together to form a 5-7 member heterocycline, where R Ｃ The 5-7 member heterocycline represented by R Ｃ１ It is optionally replaced by R, where R Ｃ１ C １－３ Alkyl or oxo, Here, the heterocyclyl comprises 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl comprises 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. However, the aforementioned compound is 【Chemistry 2】 (Not represented by)

2. (i) R １ However, it is a saturated heterocycline with 4 to 12 members. (ii) R １ However, it is a 4- to 12-membered saturated heterocycline containing one or two ring N atoms, provided that if the heterocycline contains one ring N atom, -NR ７ R ８ , -C １－３ Alkylene-NR ７ R ８ or -C ３－６ Cycloalkylene-NR ７ R ８ Replaced by arbitrary selection, 1 to 4 R ９ The R atoms are further optionally substituted, and if the heterocyclyl contains two ring N atoms, then 1 to 3 R atoms are substituted. ９ Replaced by optional selection, R ７ and R ８ However, each is independent of H or C １－６ It is alkyl, or R ７ and R ８ However, together with the N to which they are bonded, they form 1-2 C １－６ A 4-6 membered heteroring is formed by optional substitution with an alkyl group, wherein the 4-6 membered heteroring contains a second heteroatom optionally selected from N and O, and R ９ is, for each occurrence, halo, -C(=O)R １０ , C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxyC １－６ alkyl, and C ３－６ cycloalkyl, independently selected, where the C ９ cycloalkyl represented by R ３－６ is optionally substituted by one or more substituents independently selected from halo and C １－６ alkyl, where R １０ is H, C １－３ alkyl, or C ３－６ cycloalkyl, or (iii) R １ is a 4- to 12-membered saturated heterocyclyl containing one or two ring N atoms, provided that when the heterocyclyl contains one ring N atom, -NR ７ R ８ , -C １－３ alkylene-NR ７ R ８ or -C ３－６ cycloalkylene-NR ７ R ８ is optionally substituted with, and further optionally substituted with 1 to 2 R ９ s, and when the heterocyclyl contains two ring N atoms, it is optionally substituted with 1 to 3 R ９ s, R ７ and R ８ However, each is independent of H or C １－６ It is alkyl, or R ７ and R ８ However, together with the N to which they are bonded, they form 1-2 C １－６ A 4-6 membered heteroring is formed by optional substitution with an alkyl group, wherein the 4-6 membered heteroring contains a second heteroatom optionally selected from N and O, and R ９ However, each time it appears, Halo, -C(=O)R １０ , C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy C １－６ Alkyl and C ３－６ Selected independently from cycloalkyl, where R ９ The C represented by ３－６ Cycloalkyls are halo and C １－６ Optionally substituted with one or more substituents independently selected from the alkyl group, where R １０ H, C １－３ Alkyl, or C ３－６ It is a cycloalkyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. (i) R １ However, it is a 4-12 member saturated heterocycline containing one ring N atom, and 1-4 R atoms. ９ Replaced with, optionally, (a) R １ However, selected from pyrrolidinil, piperidinil, azabicyclo[3.2.1]octanil, and azaspiro[3.4]octanil, (b) R １ but, 【Transformation 3】 Selected from, (ii) R １ However, it is a 4-12 member saturated heterocycline containing one ring N atom, and -NR ７ R ８ , -C １－３ Alkylene-NR ７ R ８ or -C ３－６ Cycloalkylene-NR ７ R ８ Substituted by, 1-2 R ９ Then it is replaced by an optional selection, and by an optional selection, (a) R １ However, these are 4- to 12-membered saturated heterocyclines selected from azetidinil, piperidinil, pyrrolidinil, octahydro-1H-isoindolyl, and 3-azabicyclo[3.1.0]hexanil, each of which is -NR ７ R ８ , -C １－３ Alkylene-NR ７ R ８ or -C ３－６ Cycloalkylene-NR ７ R ８ Substituted by, 1-2 R ９ And it is further replaced by optional selection. (b) R １ but, 【Chemistry 4】 Selected from, each of them is -NR ７ R ８ , -C １－３ Alkylene-NR ７ R ８ or -C ３－６ Cycloalkylene-NR ７ R ８ Substituted by, 1-2 R ９ And it is further replaced by optional selection, or (c) R １ but, 【Transformation 5】 Selected from, each of them is -NR ７ R ８ , -C １－３ Alkylene-NR ７ R ８ or -C ３－６ Cycloalkylene-NR ７ R ８ Substituted by, 1-2 R ９ And it is further replaced by optional selection. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

4. (i) R ７ and R ８ However, each is independent of H or C １－３ It is alkyl, or R ７ and R ８ But together, C ２ -C ４ It is an alkylene, and contains one or two C １－３ Optionally substituted with alkyl, or (ii) R ７ and R ８ However, independently of each other, H and -CH ３ or -CH ２ CH ３ is or, R ７ and R ８ But together, -CH ２ CH ２ CH ２ CH ２ -ien-CH ２ CH ２ CH ２ - or -CH ２ C (CH ３ ) ２ CH ２ - is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R １ but, (i) 【Transformation 6】 A group consisting of is selected, and each of them has 1 to 2 R ９ And it is further replaced by optional selection, or (ii) 【Transformation 7】 A group consisting of is selected, and each of them has 1 to 2 R ９ And it is further replaced by optional selection. The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

6. R １ However, it is a 4-12 member saturated heterocycline containing two ring N atoms, and 1-3 R atoms. ９ It is replaced by optional selection, and by optional selection, (i) R １ The 4- to 12-membered saturated heterocyclyl represented by is piperazinyl, 4,7-diazaspiro[2.5]octanyl, 3,9-diazaspiro[5.5]undecanyl, 1-oxa-4,9-diazaspiro[5.5]undecanyl, diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[4,3-b][1,4]oxazinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[1,2-a]pyradinyl, decahydro-1,6-naphthilidinyl, 1,6-diazaspiro[3.4]octanyl, 1,5-diazaspiro[3.4]octanyl, 2λ ２ , 5-diazaspiro[3.4]octanyl, 2λ ２ ,6-diazaspiro[3.4]octanyl, hexahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[3,4-b]pyrrolyl, 3,6-diazabicyclo[3.2.0]heptanyl, 1,4-diazepanyl, 2,6-diazaspiro[3.5]nonane, 2,6-diazabicyclo[3.2.0]heptanyl, or 1,7-diazaspiro[4.4]nonanyl, each of which contains 1 to 2 R ９ Replaced by optional selection, (ii) R １ The 4- to 12-membered saturated heterocyclyl represented by is piperazinyl, diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[4,3-b][1,4]oxazinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[1,2-a]pyradinyl, decahydro-1,6-naphthilidinyl, hexahydropyrrolo[3,4-c]pyrrol, octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[3,4-b]pyrrol, 1,4-diazepanil, or 2,6-diazaspiro[3.5]nonane, each of which has 1 to 2 R ９ Replaced by optional selection, (iii) R １ The 4-12 member saturated heterocycline represented by the above is 【Transformation 8】 And each of them has one or three R ９ Replaced by optional selection, or (iv)R １ The 4-12 member saturated heterocycline represented by the above is 【Chemistry 9】 And each of them has one or three R ９ Replaced by optional selection, The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

7. R １ However, it is a 4-12 member partially saturated heterocycline, and is selected at will. (a) The partially saturated heterocyclyl is 2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine, 1,2,3,6-tetrahydropyridinyl, 6-azabicyclo[3.1.1]hepta-2-enyl, or 8-azabicyclo[3.2.1]octa-2-enyl (b) The partially saturated heterocyclil is 2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine, 1,2,3,6-tetrahydropyridinyl, or 8-azabicyclo[3.2.1]octa-2-enyl. (c) The partially saturated heterocycline is 【Chemistry 10】 A group is selected from which each consists of 1, 2, 3, or 4 R ９ Replaced by optional selection, or (d) The partially saturated heterocycline is 【Chemistry 11】 A group consisting of is selected, and each of them has one or two R ９ Replaced by optional selection, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. (i) R １ However, -NR ７ R ８ A 4- to 12-membered saturated or partially saturated carbocyclyl substituted with one or two R ９ And it is further replaced by optional selection. (ii) R １ However, these are cyclohexyl or cyclohexenyl, each of which is -NR ７ R ８ Replaced by one or two R ９ And it is further replaced by optional selection, or (iii) R １ but, 【Chemistry 12】 Selected from, each of them is -NR ７ R ８ Replaced by one or two R ９ Then it is replaced by an optional selection, and by an optional selection, R ７ and R ８ However, each is independent of the others. (i) H or C １－３ Alkyl, or (ii) H or -CH ３ That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. R ９ However, each time it appears, (i) Halo, -C(=O)R １０ , C １－４ Alkyl, C １－４ Haloalkyl and C ３－６ Selected independently from cycloalkyl, where R ９ The C represented by ３－６ Cycloalkyls are composed of F, Cl, and C １－４ Optionally substituted with one to three substituents independently selected from the alkyl group, R １０ However, H, C １－２ Alkyl, C ３－４ It is a cycloalkyl, (ii) F, -CH ３ ien-CH ２ CH ３ -C(=O)CH ３ ien-CH ２ CF ３ , -CH(CH ３ ) ２ , -CD ３ , and cyclopropyl, independently selected, or (iii)-CH ３ -C(=O)CH ３ ien-CH ２ CF ３ , -CH(CH ３ ) ２ , and cyclopropyl, independently selected The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. (i) R １ However, -NR １１ R １２ And, R １１ However, H or C １－６ It is alkyl, R １２ However, C １－６ Alkyl-NR ａ R ｂ , phenyl, a 4-12 member heterocycline containing at least one ring N atom, where R １２ The phenyl represented by -NR ａ R ｂ , Het, or -C １－３ Substituted with alkylene-Het, where Het is a 4- to 6-membered heterocycline containing at least one ring N atom and one or two C atoms. １－３ It is optionally substituted with an alkyl group, where R １２ The 4- to 12-membered heterocycline represented by the above is 1, 2, 3, 4 or 5 R １２ａ It is replaced by an optional choice, where each R １２ａ Independently, C １－３ Alkyl or halo, optionally R １２ａ However, it is methyl or fluoro. (ii) R １ However, -NR １１ R １２ And, R １１ However, H or C １－６ It is alkyl, R １２ However, C １－６ Alkyl-NR ａ R ｂ , phenyl, a 4-12 member heterocycline containing at least one ring N atom, where R １２ The phenyl represented by -NR ａ R ｂ , Het, or -C １－３ Substituted with alkylene-Het, where Het is a 4- to 6-membered heterocycline containing at least one ring N atom and one or two C atoms. １－３ It is optionally substituted with an alkyl group, where R １２ The 4- to 12-membered heterocyclyl represented by the above is one or two C １－３ Optionally substituted by alkyl groups, (iii) R １ However, -NR １１ R １２ And, R １１ However, H or -CH ３ And, R １２ However, the following are selected from the group consisting of piperidinyl, hexahydro-1H-pyrrolidinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolidinyl, isoindolinyl, phenylazetidinyl, 1,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, benzylpyrrolidinyl, and quinuclidinyl, each of which has 1, 2, 3, 4 or 5 R １２ａ It is replaced by an optional choice, where R １２ａ C １－３ Alkyl or halo, optionally selected. R １２ａ However, it is methyl or fluoro. (iv)R １ However, -NR １１ R １２ And, R １１ However, H or -CH ３ And, R １２ The compounds are selected from the group consisting of hexahydro-1H-pyrrolidinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolidinyl, isoindolinyl, phenylazetidinyl, 1,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, benzylpyrrolidinyl, and quinuclidinyl, each of which independently contains one or two C １－２ Optionally substituted with alkyl groups, (v) R １ However, -NR １１ R １２ And, R １１ However, H or -CH ３ And, R １２ but, 【Chemistry 13】 A group consisting of F, -CH is selected, and each of them is F, -CH ３ and -CH ２ CH ３ It is optionally substituted with one, two, three, four, or five substituents independently selected from, or (vi)R １ However, -NR １１ R １２ And, R １１ However, H or -CH ３ And, R １２ but, 【Chemistry 14】 A group consisting of is selected, and each of them is -CH ３ and -CH ２ CH ３ Optionally substituted with one or two substituents independently selected from The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. (i) R １ However, -OR １５ And, R １５ but, (a) C １－６ Alkyl-NR ａ R ｂ , phenyl, 4-12 membered carbocyrill, 4-12 membered heterocyclyl containing at least one ring N atom, where R １５ The phenyl or the 4-12 membered carbocyclyl represented by -NR ａ R ｂ , Het, or -C １－３ Substituted with alkylene-Het, where Het is a 4- to 6-membered heterocycline containing at least one ring N atom and one or two C atoms. １－３ It is optionally substituted with an alkyl group, where R １５ The 4- to 12-membered heterocyclyl represented by the above is one or two C １－３ Optionally substituted by alkyl groups, or (b) Selected from piperidinil, pyrrolidinil, 8-azaspiro[4.5]decanil, and 7-azaspiro[3.5]nonanil, each of which contains one or two C １－３ Optionally substituted with alkyl, or R １５ However, NR ａ R ｂ It is a cyclopentyl substituted with R ａ and R ｂ These are H or C, each independently. １－３ Alkyl, or (ii) R １ However, -OR １５ And, R １５ but, 【Chemistry 15】 A group consisting of is selected, and each of them is -CH ３ and -CH ２ CH ３ It is optionally substituted with one or two substituents independently selected from R １５ but, 【Chemistry 16】 Represented by, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. (i) R ３ However, the group is selected from indazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyradinyl, benzothiazolyl, triazolopyradinyl, benzoxazolyl, pyrazolopyrimidinyl, and benzothiadiazolyl, each of which has 1 to 3 R Ｃ It is either replaced by optional selection or R ３ However, these are 1,3-dihydro-2H-benzo[d]imidazole-2-one or benzo[d]thiazole-2(3H)-one, each of which contains one or two R groups. Ｃ１ Replaced by optional selection, (ii) R ３ but, 【Chemistry 17】 A group consisting of is selected, and each of them has 1 to 3 R Ｃ It is either replaced by an optional choice, or R ３ but, [Chemistry 18] And each of them has one or two R Ｃ１ Replaced by optional selection, or (iii) R ３ but, 【Chemistry 19】 A group consisting of is selected, and each of them has 1 to 3 R Ｃ Then it is further replaced by optional selection, or R ３ but, 【Chemistry 20】 And each of them has one or two R Ｃ１ Replaced by optional selection, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. (i) R Ｃ However, each time they appear, independently, Halo, C １－３ Alkyl, C １－２ Haloalkyl, or C １－２ It is an alkoxy, R Ｃ１ However, each time it appears, independently, C １－３ Alkyl, or (ii) R Ｃ However, each time it appears, -F, -CH ３ , -CH(CH ３ ) ２ , -CF ３ , and -OCH ３ Selected independently from, R Ｃ１ However, -CH ３ That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. The aforementioned compound is given by the following formula (IIA): 【Chemistry 21】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by (R １ These are piperazinyl, pyrrolidinyl, diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[3,4-b]pyrrolyl, piperidinyl, 8-azabicyclo[3.2.1]octa-2-enyl, or 1,2,3,6-tetrahydropyridinyl, where piperazinyl, pyrrolidinyl, diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[3,4-b]pyrrolyl, piperidinyl, 8-azabicyclo[3.2.1]octa-2-enyl, or 1,2,3,6-tetrahydropyridinyl, which have 1 to 3 R ９ The pyrrolidinil is optionally substituted, and the pyrrolidinil is -NR ７ R ８ or -C ３－６ Cycloalkylene-NR ７ R ８ Replaced by choice, one or two R ９ Then, it is further replaced by an optional selection, R ７ and R ８ These are, independently, H or C １－４ It is alkyl, R ９ Each time it appears, C １－４ Alkyl and C ３－６ Selected independently from cycloalkyl, R ３ is indazolyl, imidazopyridinyl, imidazopyradinyl, or benzoxazolyl, where indazolyl, imidazopyridinyl, imidazopyradinyl, or benzoxazolyl contains 1 to 2 R Ｃ Replaced by optional selection, R Ｃ Each time it appears, C １－４ Selected independently from alkyl and halo, and optionally, (i) R １ but, 【Chemistry 22】 A group consisting of is selected, and each of them has one or two R ９ It is either replaced by an optional choice, or R １ but, 【Chemistry 23】 Selected from, each of which has 1 to 3 R ９ Replaced by optional selection, (ii) R ３ but, 【Chemistry 24】 A group consisting of is selected, and each of them has 1 to 2 R Ｃ Replaced by optional selection, (iii) R ９ However, each time it appears, -CH ３ and independently selected from cyclopropyl, and / or (iv)R Ｃ However, each time it appears, -CH ３ (and selected independently from F).

15. The aforementioned compound is given by the following formula: 【Chemistry 25】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by (R １ is piperazinyl, pyrrolidinyl, piperidinyl, diazaspiro[4.4]nonanyl, diazabicyclo[3.2.0]heptanyl, or diazaspiro[3.4]octanyl, where piperazinyl, piperidinyl, diazaspiro[4.4]nonanyl, diazabicyclo[3.2.0]heptanyl, or diazaspiro[3.4]octanyl has 1 to 3 R ９ The pyrrolidinil is optionally substituted, and the pyrrolidinil is -NR ７ R ８ Replaced by choice, one or two R ９ Then, it is further replaced by an optional selection, R ７ and R ８ These are H or C, each independently. １－４ Alkyl or R ７ and R ８ These, together with the N atoms to which they are bonded, form a 4-6 member saturated monocyclic heterocycline. R ９ Each instance, independently, C １－３ It is alkyl, R ３ is indazolyl, pyrazolo[1.5.a]pyridinyl, imidazopyridinyl, or imidazopyradinyl, where indazolyl, imidazopyridinyl, or imidazopyradinyl contains 1 to 2 R Ｃ Replaced by optional selection, R Ｃ Each time it appears, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Selected independently from alkoxys and halos, and optionally, (i) R １ but, 【Chemistry 26】 A group consisting of is selected, and each of them has one or two R ９ Replaced by optional selection, R ９ Each instance, independently, C １－３ It is alkyl. (ii) R ３ but, 【Chemistry 27】 And each of them has 1 to 2 R Ｃ Replaced by optional selection, (iii) R ９ However, each time it appears, -CH ３ and -CH ２ CH ３ Selected independently from, and / or (iv)R Ｃ However, each time it appears, F, -CH ３ , -OCH ３ , and -CHF ２ (Selected independently of the others). 【Request Item 16】 【Chemistry 28-1】 【Chemistry 28-2】 【Chemistry 28-3】 【Chemistry 28-4】 【Chemistry 28-5】 【Chemistry 28-6】 【Chemistry 28-7】 【Chemistry 28-8】 [Chemistry 28-9] 【Chemistry 28-10】 【Chemistry 28-11】 【Chemistry 28-12】 【Chemistry 28-13】 [Chemistry 28-14] 【Chemistry 28-15】 [Chemistry 28-16] 【Chemistry 28-17】 【Chemistry 28-18】 [Chemistry 28-19] 【Chemistry 28-20】 【Chemistry 28-21】 [Chemistry 28-22] [Chemistry 28-23] [Chemistry 28-24] [Chemistry 28-25] [Chemistry 28-26] [Chemistry 28-27] 【Chemistry 28-28】 [Chemistry 28-29] [Chemistry 28-30] [Chemistry 28-31] [Chemistry 28-32] [Chemistry 28-33] [Chemistry 28-34] [Chemistry 28-35] [Chemistry 28-36] [Chemistry 28-37] A compound or a pharmaceutically acceptable salt thereof, selected from the above.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition according to claim 17 for treating Huntington's disease (HD).

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