Compounds for treatment of huntington's disease

Abstract

The present disclosure provides a compound of Formula (I ') # imgabs0 # or a pharmaceutically acceptable salt thereof and the use of the compounds in, for example, treating a condition, disease or condition having a therapeutic benefit for reducing mutant Huntingtin ("mHTT") in a subject, particularly in the treatment of Huntington's disease ("HD"). The disclosure also features compositions containing the above compounds as well as methods of using and making the compounds.

Description

[0001] Related Applications

[0002] This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 393,496, filed on July 29, 2022, under 35 U.S.C. §119(e), the entire contents of which are incorporated herein by reference. Background Art

[0003] Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder that affects three to seven people in every 100,000 worldwide. HD is caused by an expansion of the cytosine-adenine-guanine (CAG) repeat sequence in the huntingtin (HTT) gene, resulting in the production of a ubiquitously expressed pathogenic mutant HTT (mHTT) protein. The mutant huntingtin protein contains an abnormally long polyglutamine (polyQ) sequence corresponding to the CAG gene expansion; this protein exhibits toxic properties, causing neuronal dysfunction and death. Huntington's disease is characterized by reduced motor, cognitive, psychiatric, and functional abilities.

[0004] Several studies have made progress in identifying therapeutics to reduce HTT protein using a variety of tools, including ribonucleic acid (RNA) interference using short interfering RNA, short hairpin RNA or microRNA and antisense oligonucleotides ("ASO"), causing translation inhibition or messenger RNA (mRNA) degradation. However, these therapies require surgical delivery of viral vectors to reduce chronic HTT transcripts through RNAi, or require repeated infusion of ASOs into the cerebrospinal fluid ("CSF") via lumbar puncture in the clinic.

[0005] Recently, a platform of small molecule compounds that regulate RNA expression (i.e., splicing correction) is being developed. NVS-SM1 (LMI070), now known as branaplam, is a pyridazine derivative. Branaplam has been reported to reduce mHTT protein levels in cells from HD patients, HD mouse models, and blood samples from type I SMA patients who were orally treated for spinal muscular atrophy (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.

[0006] However, there are currently no approved disease-modifying treatments for HD, and thus there remains an unmet need for drugs that can be used to treat or improve HD. Thus, there is a need to find disease-modifying therapies (i.e., treatment options that can slow the progression of the disease) for HD. Summary of the invention

[0007] Described herein are compounds or pharmaceutically acceptable salts thereof that are useful for treating HD in a subject.

[0008] In one aspect, the present disclosure provides a compound of formula (I') or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Where X 1 , X 2 , Y 1 , Y 2 , Z and R 1 As defined herein.

[0011] 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.

[0012] The present disclosure also provides a method of reducing mHTT in a subject, the method comprising administering to the subject a compound of formula (I') or a pharmaceutically acceptable salt thereof.

[0013] The present disclosure also provides a method of treating a disease or condition in a subject that is regulated at least in part by mHTT, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I') or a pharmaceutically acceptable salt thereof.

[0014] The present disclosure further provides a method of treating Huntington's disease ("HD") in a subject in need thereof, the method 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.

[0015] In certain embodiments of the disclosed methods, HD can be treated by reducing mHTT levels in a subject.

[0016] The present disclosure also provides the use of a compound of formula (I'), a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same in any of the methods described herein. In one embodiment, a compound of formula (I') or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in any of the methods described herein is provided. In another embodiment, a compound of formula (I') or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for any of the methods described herein is provided. DETAILED DESCRIPTION

[0017] 1. Compounds

[0018] In a first aspect, the present disclosure provides a compound of formula (I'):

[0019]

[0020] or a pharmaceutically acceptable salt thereof, wherein:

[0021] is a single bond or a double bond, provided that the ring containing X1 and X2 is a 5-membered heteroaryl ring;

[0022] Represents R 1 One of the two positions connected by a dotted line on the 6-membered ring is substituted, and the other position connected by the dotted line is not substituted;

[0023] Z is –C(=O)NR 2 R 3 or –NR 2 C(=O)R 3 ;

[0024] X 1 is S or CH;

[0025] X 2 is N, O or CH;

[0026] Y 1 and Y 2 One of them is N and the other is CH;

[0027] R 1 is a 4- to 12-membered heterocyclic group, a 4- to 12-membered carbocyclic group, -NR 11 R 12 , -C 1-6 Alkylene-NR 13 R 14 OR 15 ,in

[0028] R 1The 4- to 12-membered carbocyclic group or 4- to 12-membered heterocyclic group represented by A Replace;

[0029] Each R A Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated 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 4- to 6-membered saturated heterocyclic group; wherein each R a and R b independently H or C 1-6 Alkyl; wherein R A The 4- to 6-membered saturated heterocyclic group represented by 1-6 Alkyl substitution;

[0030] R 11 Is H or C 1-6 alkyl;

[0031] R 12 It is C 1-6 alkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein R 12 The C 1-6 Alkyl, 6 to 10 membered aryl, 4 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl are optionally substituted with one or more R B Replace;

[0032] R B Is halogenated, C 1-6 Alkyl, -NR a R b , 4 to 6 membered heterocyclic group or -C 1-6 Alkylene-4 to 6 membered heterocyclic group; wherein R B The 4 to 6 membered heterocyclic group represented by 1-6 Alkyl substitution;

[0033] R 13 Is H or C 1-6 alkyl;

[0034] R 14 and R 15 Independently selected from H, C 1-6 Alkyl or –C 1-6Alkylene-4-6 membered saturated heterocyclic group;

[0035] R 2 Is H or C 1-3 alkyl;

[0036] R 3 is a 6- to 10-membered aryl or 6- to 10-membered heteroaryl group, wherein R 3 The 6- to 10-membered aryl and 6- to 10-membered heteroaryl represented by C Replace;

[0037] R C It is halogenated, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, or two R C Together with the atoms therebetween, they form a 5- to 7-membered heterocyclic group; wherein R C The 5- to 7-membered heterocyclic group represented by C1 Substitution; wherein R C1 It is C 1-3 alkyl or oxo; and

[0038] wherein the heterocyclyl contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and the heteroaryl contains 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur;

[0039] Provided that the compound of formula (I') is not represented by:

[0040]

[0041] In a first embodiment, the present disclosure provides a compound of formula (I):

[0042]

[0043] or a pharmaceutically acceptable salt thereof, wherein:

[0044] is a single bond or a double bond, provided that the ring containing X1 and X2 is a 5-membered heteroaryl ring;

[0045] Represents R 1 is substituted at one of the two positions connected by the dashed line on the pyridinyl moiety, and the other position connected by the dashed line is unsubstituted;

[0046] X 1 is S or CH;

[0047] X 2 is N, O or CH;

[0048] R 1 is a 4- to 12-membered heterocyclic group, -NR 11 R 12 or -C 1-6 Alkylene-NR 13 R 14 ,in

[0049] R 1 The 4 to 12 membered heterocyclic group represented by A Replace;

[0050] Each R A Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated 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 4- to 6-membered saturated heterocyclic group; wherein each R a and R b independently H or C 1-6 Alkyl; wherein R A The 4- to 6-membered saturated heterocyclic group represented by 1-6 Alkyl substitution;

[0051] R 11 Is H or C 1-6 alkyl;

[0052] R 12 It is C 1-6 alkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein R 12 The C 1-6 Alkyl, 6 to 10 membered aryl, 4 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl are optionally substituted with one or more R B Replace;

[0053] R B It is C 1-6 Alkyl, -NR a R b , 4 to 6 membered heterocyclic group or -C 1-6 Alkylene-4 to 6 membered heterocyclic group; wherein R B The 4 to 6 membered heterocyclic group represented by 1-6 Alkyl substitution;

[0054] R 13 Is H or C 1-6 alkyl;

[0055] R 14 It is H, C 1-6 Alkyl or -C 1-6 Alkylene-4-6 membered saturated heterocyclic group;

[0056] R 2 Is H or C 1-3 alkyl;

[0057] R 3 is a 6- to 10-membered aryl or 6- to 10-membered heteroaryl group, wherein R 3 The 6- to 10-membered aryl and 6- to 10-membered heteroaryl represented by C Replace;

[0058] R C It is halogenated, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, or two R C Together with the atoms therebetween, they form a 5- to 7-membered heterocyclic group; wherein R C The 5- to 7-membered heterocyclic group represented by C1 Substitution; wherein R C1 It is C 1-3 alkyl or oxo; and

[0059] wherein the heterocyclyl contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and the heteroaryl contains 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur;

[0060] Provided that the compound of formula (I) is not represented by:

[0061]

[0062] In a second embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II):

[0063]

[0064] or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or first embodiment.

[0065] In a third embodiment, the present disclosure provides a compound according to the first aspect or the first or second embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (III):

[0066]

[0067] or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or first embodiment.

[0068] In a fourth embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IV):

[0069]

[0070] or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or first embodiment.

[0071] In a fifth embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (V):

[0072]

[0073] or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or first embodiment.

[0074] In an alternative fifth embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VI):

[0075]

[0076] or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or first embodiment.

[0077] In an alternative fifth embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VII):

[0078]

[0079] or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or first embodiment.

[0080] In another alternative fifth embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (VIII):

[0081]

[0082] or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or first embodiment.

[0083] 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 through fifth embodiments, or any alternative embodiments described therein.

[0084] 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- to 12-membered saturated heterocyclyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiments described therein.

[0085] 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:

[0086] 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, the heterocyclyl is optionally replaced by -NR 7 R 8 ,–C 1-3 Alkylene-NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and optionally further substituted with 1 to 4 R 9 and when the heterocyclyl contains two ring N atoms, the heterocyclyl is optionally substituted by 1 to 3 R 9 replace;

[0087] R 7 and R 8 Each independently is H or C 1-6 Alkyl; or R 7 and R 8 Together with the N to which they are attached, they form an optionally 1 to 2 C 1-6 an alkyl-substituted 4- to 6-membered heterocyclic ring, wherein the 4- to 6-membered heterocyclic ring optionally comprises a second heteroatom selected from N and O;

[0088] R 9 is independently selected at each occurrence from halo, -C(=O)R 10 , C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein R 9 The C 3-6 Cycloalkyl is optionally substituted with one or more independently selected from halo and C 1-6 The alkyl group is substituted with a substituent; wherein R 10 It is H, C 1-3 Alkyl or C 3-6 The definitions for the remaining variables are provided in the first aspect or any one of the first through seventh embodiments, or any alternative embodiments described therein.

[0089] 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:

[0090] 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, the heterocyclyl is optionally replaced by -NR 7 R 8 ,–C 1-3 Alkylene-NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and optionally further substituted with 1 to 2 R 9 and when the heterocyclyl contains two ring N atoms, the heterocyclyl is optionally substituted by 1 to 3 R 9 replace;

[0091] R 7 and R 8 Each independently is H or C 1-6 Alkyl; or R 7 and R 8 Together with the N to which they are attached, they form an optionally 1 to 2 C 1-6 an alkyl-substituted 4- to 6-membered heterocyclic ring, wherein the 4- to 6-membered heterocyclic ring optionally comprises a second heteroatom selected from N and O;

[0092] R 9 is independently selected at each occurrence from 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; wherein R 9 The C 3-6Cycloalkyl is optionally substituted with one or more independently selected from halo and C 1-6 The alkyl group is substituted with a substituent; wherein R 10 It is H, C 1-3 Alkyl or C 3-6 The definitions for the remaining variables are provided in the first aspect or any one of the first through seventh embodiments, or any alternative embodiments described therein.

[0093] 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 heterocyclic group containing one ring N atom and supported by 1 to 4 R 9 The definitions of the remaining variables are provided in the eighth embodiment or any alternative embodiment described therein.

[0094] In an alternative ninth embodiment, the present disclosure provides a compound according to the eighth embodiment or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of pyrrolidinyl, piperidinyl, azabicyclo[3.2.1]octyl and azaspiro[3.4]octyl. The definitions of the remaining variables are provided as in the eighth embodiment or any alternative embodiment described therein.

[0095] 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 Selected from:

[0096]

[0097] Definitions for the remaining variables are provided in the eighth embodiment or any alternative embodiment described therein.

[0098] In a tenth embodiment, the present invention provides a compound according to the eighth embodiment or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclic radical containing one ring nitrogen atom and is replaced by –NR 7 R 8 ,–C 1-3 Alkylene-NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and optionally further substituted with 1 to 2 R 9 The definitions of the remaining variables are provided in the eighth embodiment or any alternative embodiment described therein.

[0099] 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 heterocyclic group selected from azetidinyl, piperidinyl, pyrrolidinyl, octahydro-1H-isoindolyl and 3-azabicyclo[3.1.0]hexyl, each of which is replaced by -NR 7 R 8 ,–C 1-3 Alkylene-NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and optionally further substituted with 1 to 2 R 9 The definitions of the remaining variables are provided in the eighth embodiment or any alternative embodiment described therein.

[0100] In an eleventh embodiment, the present disclosure provides a compound according to the tenth embodiment or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from

[0101] 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 and optionally further substituted with 1 to 2 R 9 The definitions of the remaining variables are provided in the tenth embodiment or any alternative embodiment described therein.

[0102] 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 Selected from

[0103]

[0104] 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 and optionally further substituted with 1 to 2 R 9The definitions of the remaining variables are provided in the tenth embodiment or any alternative embodiment described therein.

[0105] 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 Each independently is H or C 1-3 Alkyl; or, R 7 and R 8 together are C2-C4 alkylene, said alkylene being optionally substituted by 1 or 2 C 1-3 Alkyl substituted. The definitions for the remaining variables are provided in the first aspect or any one of the first through eleventh embodiments or any alternative embodiments described therein.

[0106] In the thirteenth embodiment, the present disclosure provides a compound according to the first 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 Together they are -CH2CH2CH2CH2-, -CH2CH2CH2-, or -CH2C(CH3)2CH2-. The definitions of the remaining variables are provided in the first aspect or any of the first through twelfth embodiments or any alternative embodiments described therein.

[0107] 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 Selected from the group consisting of:

[0108]

[0109] Each of which is optionally further substituted by 1 to 2 R 9 The definitions of the remaining variables are provided in any of the ninth through eleventh embodiments, or any alternative embodiments described therein.

[0110] 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 Selected from the group consisting of:

[0111] Each of which is optionally further substituted by 1 to 2 R9 The definitions of the remaining variables are provided in any of the ninth through eleventh embodiments, or any alternative embodiments described therein.

[0112] 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 heterocyclic group containing two ring N atoms and optionally substituted by 1 to 3 R 9 The definitions of the remaining variables are provided in the eighth embodiment or any alternative embodiment described therein.

[0113] In a sixteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or a pharmaceutically acceptable salt thereof, R 1 The 4- to 12-membered saturated heterocyclic radicals represented are piperazinyl, 4,7-diazaspiro[2.5]octyl, 3,9-diazaspiro[5.5]undecyl, 1-oxa-4,9-diazaspiro[5.5]undecyl, diazabicyclo[2.2.2]octyl, octahydro-2H-pyrido[4,3-b][1,4]oxazinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, 2,5-diazabicyclo[2.2.1]heptyl, octahydropyrrolo[1,2-a]pyrazinyl, decahydro-1,6-naphthyridinyl, 1,6-diazaspiro[3.4]octyl, 1,5-diazaspiro[3.4]octyl, 2λ 2 ,5-diazaspiro[3.4]octyl, 2λ 2 ,6-diazaspiro[3.4]octyl, 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]heptyl, 1,4-diazacycloheptyl, 2,6-diazaspiro[3.5]nonane, 2,6-diazabicyclo[3.2.0]heptyl or 1,7-diazaspiro[4.4]nonyl, each of which is optionally substituted by 1 to 2 R 9 The definitions of the remaining variables are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0114] In an alternative sixteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or a pharmaceutically acceptable salt thereof, R 1The 4- to 12-membered saturated heterocyclic group represented is piperazinyl, diazabicyclo[2.2.2]octyl, octahydro-2H-pyrido[4,3-b][1,4]oxazinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, 2,5-diazabicyclo[2.2.1]heptyl, 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-diazacycloheptyl or 2,6-diazaspiro[3.5]nonane, each of which is optionally substituted by 1 to 2 R 9 The definitions of the remaining variables are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0115] In the 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 heterocyclic group represented is:

[0116]

[0117] Each of which is optionally replaced by 1 or 3 R 9 The definitions of the remaining variables are provided in the sixteenth embodiment or any alternative embodiment described therein.

[0118] 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 heterocyclic group represented is:

[0119]

[0120] Each of which is optionally replaced by 1 or 3 R 9 The definitions of the remaining variables are provided in the sixteenth embodiment or any alternative embodiment described therein.

[0121] In the eighteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered partially saturated heterocyclyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiments described therein.

[0122] In the nineteenth embodiment, the present disclosure provides a compound according to the eighteenth embodiment or a pharmaceutically acceptable salt thereof, wherein R1 The partially saturated heterocyclyl represented 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.

[0123] 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 The partially saturated heterocyclyl represented 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.

[0124] In the twentieth embodiment, the present disclosure provides a compound according to the eighteenth embodiment or a pharmaceutically acceptable salt thereof, wherein R 1 The partially saturated heterocyclic radical represented is selected from the group consisting of:

[0125] Each of which is optionally replaced by 1, 2, 3 or 4 R 9 The definitions of the remaining variables are provided in the eighteenth or nineteenth embodiments, or any alternative embodiments described therein.

[0126] In an alternative twentieth embodiment, the present disclosure provides a compound according to the eighteenth embodiment or the nineteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein the partially saturated heterocyclyl is selected from the group consisting of:

[0127] Each of which is optionally replaced by 1 or 2 R 9 The definitions of the remaining variables are provided in the eighteenth or nineteenth embodiments, or any alternative embodiments described therein.

[0128] In the twenty-first embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to sixteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is –NR 7 R 8 substituted 4 to 12-membered and / or partially unsaturated carbocyclic group, and further optionally substituted by 1 or 2 R 9The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments, or any alternative embodiments described therein.

[0129] In an alternative twenty-first embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to sixteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclohexyl or cyclohexenyl, each of which is replaced by –NR 7 R 8 and further optionally substituted with 1 or 2 R 9 The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments, or any alternative embodiments described therein.

[0130] In yet another alternative twenty-first embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to sixteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from Each of which is –NR 7 R 8 and further optionally substituted with 1 or 2 R 9 The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments, or any alternative embodiments described therein.

[0131] In the 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 Each independently is H or C 1-3 The definitions for the remaining variables are provided in the twenty-first embodiment or any alternative embodiment described therein.

[0132] 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 Each is independently H or -CH3. The definitions of the remaining variables are provided in the twenty-first embodiment or any alternative embodiment described therein.

[0133] In the 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 is independently selected at each occurrence from halo, -C(=O)R 10 , C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6Cycloalkyl; wherein R 9 The C 3-6 The cycloalkyl group is optionally substituted by one to three independently selected from F, Cl and C 1-4 The alkyl group is substituted with a substituent; and R 10 It is H, C 1-2 Alkyl, C 3-4 The 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.

[0134] In the 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 independently selected at each occurrence from F, -CH3, -CH2CH3, -C(=O)CH3, -CH2CF3, -CH(CH3)2, -CD3, and cyclopropyl. The definitions of the remaining variables are provided in any one of the first aspect or the first to twenty-second embodiments or any alternative embodiments described therein.

[0135] In an alternative twenty-fourth embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to twenty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 is independently selected at each occurrence from -CH3, -C(=O)CH3, -CH2CF3, -CH(CH3)2, and cyclopropyl. 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.

[0136] 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:

[0137] R 1 Yes - NR 11 R 12 ;

[0138] R 11 Is H or C 1-6 alkyl;

[0139] R 12 It is C 1-6 Alkyl-NR a R b , phenyl, a 4- to 12-membered heterocyclic group containing at least one ring N atom; wherein R 12 The phenyl group represented by a R b , Het or -C 1-3is substituted with alkylene-Het, and Het is a 4- to 6-membered heterocyclyl containing at least one ring N atom and optionally substituted with one or two C 1-3 alkyl substituted; and wherein R 12 The 4 to 12 membered heterocyclic group represented by 12a Replace; wherein 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 through sixth embodiments or any alternative embodiments described therein.

[0140] 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:

[0141] R 1 Yes - NR 11 R 12 ;

[0142] R 11 Is H or C 1-6 alkyl;

[0143] R 12 It is C 1-6 Alkyl-NR a R b , phenyl, a 4- to 12-membered heterocyclic group containing at least one ring N atom; wherein R 12 The phenyl group represented by a R b , Het or -C 1-3 is substituted with alkylene-Het, and Het is a 4- to 6-membered heterocyclyl containing at least one ring N atom and optionally substituted with one or two C 1-3 alkyl substituted; and wherein R 12 The 4- to 12-membered heterocyclic group represented by 1-3 Alkyl substituted. The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiments described therein.

[0144] 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:

[0145] R 1 Yes - NR 11 R 12 ;

[0146] R 11 is H or -CH3;

[0147] R 12 is selected from the group consisting of piperidinyl, hexahydro-1H-pyrrolizinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolizinyl, isoindolyl, phenylazetidinyl, 1,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, benzylpyrrolidinyl and quinuclidine, each of which is optionally substituted by one, two, three, four or five R 12a Substitution; wherein R 12a It 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 through sixth embodiments or any alternative embodiments described therein.

[0148] In some embodiments, for the 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 as in the twenty-fifth embodiment or the twenty-sixth embodiment or any alternative embodiment described therein.

[0149] 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:

[0150] R 1 Yes - NR 11 R 12 ;

[0151] R 11 is H or -CH3;

[0152] R 12 is selected from the group consisting of hexahydro-1H-pyrrolizinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolizinyl, isoindolyl, phenylazetidinyl, 1,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, benzylpyrrolidinyl and quinuclidine, each of which is optionally substituted by one or two independently C 1-2 Alkyl substituted. The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiments described therein.

[0153] 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:

[0154] R 1 Yes - NR 11 R 12 ;

[0155] R 11 is H or -CH3;

[0156] R 12 Selected from the group consisting of:

[0157]

[0158] Each of which is optionally substituted with one, two, three, four or five substituents independently selected from F, -CH3 and -CH2CH3. The definitions of the remaining variables are provided in any one of the first aspect or the first to sixth embodiments or any alternative embodiments described therein.

[0159] 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:

[0160] R 1 Yes - NR 11 R 12 ;

[0161] R 11 is H or -CH3;

[0162] R 12 Selected from the group consisting of:

[0163] Each of which is optionally substituted with one or two substituents independently selected from -CH3 and -CH2CH3. The definitions of the remaining variables are provided in the first aspect or any of the first through sixth embodiments or any alternative embodiments described therein.

[0164] 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:

[0165] R 1 Yes-OR 15 ;

[0166] R 15 It 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; wherein R 15 The phenyl group or the 4- to 12-membered carbocyclic group represented by -NR a R b , Het or -C1-3 is substituted with alkylene-Het, and Het is a 4- to 6-membered heterocyclyl containing at least one ring N atom and optionally substituted with one or two C 1-3 alkyl substituted; and wherein R 15 The 4- to 12-membered heterocyclic group represented by 1-3 Alkyl substituted. The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments or any alternative embodiments described therein.

[0167] In some embodiments, for the compound according to the twenty-eighth embodiment or a pharmaceutically acceptable salt thereof, R 15 is selected from piperidinyl, pyrrolidinyl, 8-azaspiro[4.5]decyl and 7-azaspiro[3.5]nonyl, each of which is optionally substituted by one or two C 1-3 Alkyl substituted, or R 15 It was NR a R b substituted cyclopentyl; and R a and R b Each independently is H or C 1-3 Definitions of the remaining variables are provided in the twenty-eighth embodiment.

[0168] In the 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:

[0169] R 1 Yes-OR 15 ;

[0170] R 15 Selected from the group consisting of:

[0171] wherein each is optionally substituted with one or two substituents independently selected from -CH3 and -CH2CH3; or R 15 Depend on The definitions of the remaining variables are provided in any one of the first aspect or first to sixth embodiments, or any alternative embodiments described therein.

[0172] In the 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 optional with one to three R C substituted 9-membered bicyclic heteroaryl or optionally with one to three R C1Substituted 5-membered heterocyclyl-fused phenyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through twenty-ninth embodiments or any alternative embodiments described therein.

[0173] In the thirty-first embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of indazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrazinyl, benzothiazolyl, triazolopyrazinyl, benzoxazolyl, pyrazolopyrimidinyl and benzothiadiazolyl, each of which is optionally substituted by one to three R C Substitution, or R 3 is 1,3-dihydro-2H-benzo[d]imidazol-2-one or benzo[d]thiazol-2(3H)-one, each of which is optionally replaced by one or two R C1 The definitions of the remaining variables are provided in the first aspect or any one of the first through twenty-ninth embodiments, or any alternative embodiments described therein.

[0174] In the thirty-second embodiment, the present disclosure provides a compound according to the thirtieth or thirty-first embodiment, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of:

[0175] Each of which is optionally replaced by one to three R C replace; or

[0176] R 3 yes Each of which is optionally replaced by one or two R C1 The definitions of the remaining variables are provided in the thirtieth or thirty-first embodiment, or any alternative embodiment described therein.

[0177] In an alternative thirty-second embodiment, the present disclosure provides a compound according to the thirtieth or thirty-first embodiment, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of:

[0178] Each of which is optionally replaced by one to three R C replace; or

[0179] R 3 yes Each of which is optionally replaced by one or two R C1The definitions of the remaining variables are provided in the thirtieth or thirty-first embodiment, or any alternative embodiment described therein.

[0180] In the 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 is independently halo, C 1-3 Alkyl, C 1-2 Haloalkyl or C 1-2 Alkoxy; and R C1 C independently at each occurrence 1-3 The definitions for the remaining variables are provided in the first aspect or any one of the first through thirty-second embodiments, or any alternative embodiments described therein.

[0181] In the 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 independently selected at each occurrence from -F, -CH3, -CH(CH3)2, -CF3, and -OCH3; and R C1 is -CH3. The definitions of the remaining variables are provided in the thirty-third embodiment or any alternative embodiment described therein.

[0182] In the thirty-fifth embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (IIA):

[0183]

[0184] or a pharmaceutically acceptable salt thereof, wherein R 1 is piperazinyl, pyrrolidinyl, diazabicyclo[2.2.1]heptyl, 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]heptyl, octahydropyrrolo[3,4-b]pyrrolyl, piperidinyl, 8-azabicyclo[3.2.1]oct-2-enyl or 1,2,3,6-tetrahydropyridinyl is optionally substituted by 1 to 3 R 9 and the pyrrolidinyl group is optionally substituted with -NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and further optionally substituted by 1 or 2 R 9 replace;

[0185] R7 and R 8 Each independently is H or C 1-4 alkyl;

[0186] R 9 In each occurrence, independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl; and

[0187] R 3 is indazolyl, imidazopyridinyl, imidazopyrazinyl or benzoxazolyl, wherein the indazolyl, imidazopyridinyl, imidazopyrazinyl or benzoxazolyl is optionally substituted by one to two R C replace;

[0188] R C In each occurrence, independently selected from C 1-4 Alkyl and halo. The definitions of the remaining variables are provided in the first aspect or first embodiment.

[0189] In the thirty-sixth embodiment, the present disclosure provides a compound according to the thirty-fifth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of:

[0190] Each of which is optionally replaced by 1 or 2 R 9 Replacement; or R 1 Selected from the group consisting of: Each of which is optionally replaced by 1 to 3 R 9 The definitions of the remaining variables are provided in the thirty-fifth embodiment or any alternative embodiment described therein.

[0191] In the thirty-seventh embodiment, the present disclosure provides a compound according to the thirty-fifth embodiment or the thirty-sixth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of:

[0192] Each of which is optionally replaced by one or two R C The definitions of the remaining variables are provided in the thirty-fifth embodiment or the thirty-sixth embodiment, or any alternative embodiment described therein.

[0193] In the 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 9is independently selected at each occurrence from -CH3 and cyclopropyl. The definitions of the remaining variables are provided in any one of the thirty-fifth to thirty-seventh embodiments or any alternative embodiments described therein.

[0194] In the 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 C is independently selected at each occurrence from -CH3 and F. The definitions of the remaining variables are provided in any one of the thirty-fifth to thirty-eighth embodiments or any alternative embodiments described therein.

[0195] In the fortieth embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:

[0196]

[0197]

[0198] or a pharmaceutically acceptable salt thereof, wherein:

[0199] R 1 is piperazinyl, pyrrolidinyl, piperidinyl, diazaspiro[4.4]nonyl, diazabicyclo[3.2.0]heptyl or diazaspiro[3.4]octyl, wherein the piperazinyl, piperidinyl, diazaspiro[4.4]nonyl, diazabicyclo[3.2.0]heptyl or diazaspiro[3.4]octyl is optionally substituted by 1 to 3 R 9 and the pyrrolidinyl group is optionally substituted with -NR 7 R 8 and further optionally substituted with 1 or 2 R 9 replace;

[0200] R 7 and R 8 Each independently is H or C 1-4 Alkyl; or R 7 and R 8 Together with the N atom to which they are attached, they form a 4- to 6-membered saturated monocyclic heterocyclic group;

[0201] R 9 C independently at each occurrence 1-3 Alkyl; and

[0202] R 3 is indazolyl, pyrazolo[1,5-a]pyridinyl, imidazopyridinyl or imidazopyrazinyl, wherein the indazolyl, imidazopyridinyl or imidazopyrazinyl is optionally substituted by one to two R C replace;

[0203] R C In each occurrence, independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and halo.

[0204] In the 41st embodiment, for the compound of the 40th embodiment or a pharmaceutically acceptable salt thereof, R 1 Selected from the group consisting of:

[0205] Each of which is optionally replaced by 1 or 2 R 9 Replace; and R 9 C independently at each occurrence 1-3 Definitions of the remaining variables are provided in the 40th embodiment. In the 42nd embodiment, for a compound of the 40th or 41st embodiment, or a pharmaceutically acceptable salt thereof, R 3 yes Each of which is optionally replaced by one or two R C The definitions of the remaining variables are provided in the fortieth or forty-first embodiment.

[0206] In the 43rd embodiment, for the compound of the 40th, 41st or 42nd embodiment or a pharmaceutically acceptable salt thereof, R 9 is independently selected at each occurrence from -CH3 and -CH2CH3. The definitions of the remaining variables are provided in the fortieth, forty-first or forty-second embodiment.

[0207] In the 44th embodiment, for the compound of the 40th, 41st, 42nd or 43rd embodiment or a pharmaceutically acceptable salt thereof, R C is independently selected at each occurrence from F, -CH3, -OCH3, and -CHF2. The definitions of the remaining variables are provided in the fortieth, forty-first, forty-second, or forty-third embodiment.

[0208] In one embodiment, the present disclosure provides a compound selected from Compounds 1-269 described in the Examples section and Table 1, a pharmaceutically acceptable salt, a racemic mixture or a stereoisomer thereof.

[0209] Table 1

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247] 2. Definition

[0248] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0249] The term "alkyl" used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl" refers to a radical of the formula -C n H (2n+1) A saturated aliphatic straight or branched monovalent hydrocarbon group. Unless otherwise specified, an alkyl group typically has 1-20, 1-10, or 1-6 carbon atoms. In some embodiments, an alkyl group has 1-6 carbon atoms, i.e., C 1-6 As used herein, "C 1-6 "Alkyl" refers to a group 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, the alkyl group has 1-4 carbon atoms, i.e., C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms, i.e., C 1-3 alkyl.

[0250] As used herein, the term "alkoxy" or "alkoxyl" refers to an O-alkyl group, wherein alkyl is as defined above.

[0251] The term "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms as appropriate. In one embodiment, the alkyl group may be substituted by one to three halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, etc.

[0252] As used herein, the term "alkylene" refers to a group of the formula -C n H 2n-a straight or branched divalent hydrocarbon group. Non-limiting examples include ethylene and propylene.

[0253] The term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated hydrocarbon group with 3 to 12 ring carbons. In one embodiment, the cycloalkyl can have 3 to 7 or 3 to 6 ring carbons. Any substitutable ring atom can be substituted (e.g., substituted by one or more substituents). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl can include multiple fused rings 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. Cycloalkyls also include spirocycles (e.g., spirocyclic bicycles where the two rings are joined by 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.

[0254] The term "heterocyclyl" or "heterocyclic" refers to a group of a 3-12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones ("3-12-membered heterocyclyl"). In some embodiments, the heterocyclyl is a 3-7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-7-membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as long as the valence permits. The heterocyclyl can be a monocyclic system ("monocyclic heterocyclyl"), or a polycyclic system (e.g., a bicyclic system ("bicyclic heterocyclyl"), or a tricyclic system ("tricyclic heterocyclyl"); polycyclic systems include fused, bridged, or spirocyclic systems). Exemplary monocyclic heterocyclic groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxetanyl, thiepanyl, tetrahydropyridinyl, etc. The heterocyclic polycyclic system may include heteroatoms in one or more rings in the polycyclic system. Substituents may be present on one or more rings in the polycyclic system. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially saturated heterocyclic group. The partially saturated heterocyclic group may contain one or more (e.g., 2 or 3) double bonds. The partially saturated polycyclic heterocyclic group may have one or more aromatic rings in the polycyclic system and at least one ring in the polycyclic system is a non-aromatic ring (e.g., fully saturated or partially saturated). For example, a partially saturated bicyclic heterocyclic group may have a phenyl ring or heteroaromatic ring fused to a partially saturated heterocyclic ring.

[0255] Spiroheterocyclyl refers to a 5- to 12-membered polycyclic heterocyclic radical whose rings are linked together by a common carbon atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones), and the remaining ring atoms are C, wherein one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated π electron system. Representative examples of spiroheterocyclyl include, but are not limited to, the following groups:

[0256]

[0257] Fused heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl, wherein each ring in the group shares a pair of adjacent carbon atoms with another ring in the group, wherein one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated π electron system, and wherein the ring has one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones), and the remaining ring atoms are C. Representative examples of fused heterocyclyls include, but are not limited to, the following groups:

[0258]

[0259] Bridged heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl group, wherein any two rings in the group share two non-connected atoms, the rings may have one or more double bonds, but do not have a completely conjugated π electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones) as ring atoms, and the remaining ring atoms are C. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:

[0260]

[0261] In general, cycloalkyl or heterocyclic radicals may be unsubstituted or, where valence permits, substituted with one or more substituents, wherein the substituents may be independently selected from a plurality of groups. Exemplary substituents include, but are not limited to, oxo, -CN, halogen, alkyl, and alkoxy, and optionally, the alkyl substituent may be further substituted.

[0262] 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 a pair of adjacent carbon atoms with the other rings in the system) group, and has a completely conjugated π electron system. The term "aryl" can be used interchangeably with the terms "aromatic ring", "carbocyclic aromatic ring", "aryl" and "carbocyclic aromatic group". Representative examples of aryl are phenyl and naphthyl.

[0263] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (eg, bicyclic) aromatic hydrocarbon in which at least one ring carbon atom has been replaced by a heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heteroaryl is based on C 5-10Aryl, wherein one or more ring carbon atoms are replaced by heteroatoms. Heteroaryl can be connected by ring carbon atoms, or when valence permits, by ring nitrogen atoms. In general, heteroaryl can be unsubstituted, or when valence permits, substituted by one or more substituents. Exemplary substituents include, but are not limited to, halogen, OH, alkyl, alkoxy and amino (e.g., NH2, NH alkyl, N (alkyl)2), optionally, alkyl can be further substituted. Heteroaryl can be a monocyclic system ("monocyclic heteroaryl"), or a polycyclic system (e.g., a bicyclic system ("bicyclic heteroaryl"), or a tricyclic system ("tricyclic heteroaryl"); polycyclic systems include fused, bridged or spirocyclic systems).

[0264] Examples of monocyclic 5-6 membered 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., 1 The polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, indolyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. "Substituted heteroaryl" is substituted at any one or more substitutable ring atoms which are ring carbon atoms or ring nitrogen atoms bonded to a hydrogen.

[0265] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as "substituted" or "optionally substituted." When one of these terms is used to modify a moiety, unless otherwise indicated, it means that any portion of the moiety known to those skilled in the art to be available for substitution can be substituted, including one or more substituents. If more than one substituent is present, each substituent can be independently selected. Such substitution methods are well known in the art and / or taught by the present disclosure. An optional substituent can be any substituent suitable for attachment to the moiety.

[0266] When suitable substituents are not specifically listed, exemplary substituents include, but are not limited to: 1-5 Alkyl, C 1-5 Hydroxyalkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, halogen, hydroxy, 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 NR 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. Each R a1 and each R b1 Independently selected from -H and C 1-5 Alkyl, the alkyl group is optionally substituted by hydroxyl or C 1-3 Alkoxy substituted; R c1 Yes - H, C 1-5 Haloalkyl or C 1-5 Alkyl, wherein the C 1-5 The alkyl group is optionally substituted with a hydroxyl group or a C1-C3 alkoxy group.

[0267] As used herein, the notation Refers to the points where parts are connected.

[0268] Pharmaceutically acceptable salts

[0269] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation and allergic response, and is commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0270] Pharmaceutically acceptable salts of the compounds of any of the above formulae include acid addition salts and base salts.

[0271] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having an acidic group (e.g., carboxylic acid) can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g., sodium salts and potassium salts), and alkaline earth metal salts (e.g., magnesium salts and calcium salts).

[0272] The pharmaceutically acceptable salts of the compounds of any of the above formulae can be prepared by one or more of the following three methods:

[0273] (i) by reacting a compound of any of the above formulae with a desired acid or base;

[0274] (ii) by removing an acid-labile or base-labile protecting group from a suitable precursor of a compound of any of the above formulae, or by ring-opening a suitable cyclic precursor (e.g., a lactone or lactam) using the desired acid or base; or

[0275] (iii) converting one salt of a compound of any of the above formulae into another salt by reacting the salt with a suitable acid or base or with the aid of a suitable ion exchange column.

[0276] All three reactions are usually carried out in solution. The resulting salt may precipitate and be collected by filtration, or it may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from fully ionized to almost non-ionized.

[0277] The compounds of any of the above formulae and their pharmaceutically acceptable salts may exist in unsolvated and solvated forms.

[0278] Stereoisomers and other variants

[0279] Compounds of any of the above formulae may exhibit one or more isomerisms (e.g., optical isomerism, geometric isomerism, or tautomerism). Such variations are unambiguous for compounds of any of the above formulae, as they are defined by reference to their structural features and are therefore within the scope of the present disclosure.

[0280] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have either the R configuration or the S configuration, or can be a mixture of the two. Stereoisomers are compounds that differ only in their 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 are not identical and are not mirror images of each other, and they have two or more chiral centers.

[0281] When a compound is named in its chemical name (e.g., when "R" or "S" is used in the chemical name to indicate configuration) or in its structure (e.g., when a "wedge-shaped" bond is used to indicate configuration) to indicate a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure"). The optical purity is the weight of the named or depicted enantiomer in the mixture divided by the total weight of the mixture of two enantiomers.

[0282] When the stereochemistry of a disclosed compound is named or depicted by a structure and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is understood to include one encompassed stereoisomer or any mixture of encompassed stereoisomers. It is also understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomeric purity 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.

[0283] When two stereoisomers are depicted in their chemical names or structures and connected with "and" between the chemical names or structures, a mixture of the two stereoisomers is intended.

[0284] When two stereoisomers are depicted in their chemical names or structures, and the names or structures are linked with "and", it is intended to refer to one or the other of the two stereoisomers, but not both.

[0285] When a disclosed compound having a chiral center is depicted by a structure, but the configuration of the chiral center is not shown, the structure is intended to include compounds in the S configuration at the chiral center, compounds in the R configuration at the chiral center, or compounds in a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is depicted by its chemical name, but without indicating whether the chiral center is in the "S" or "R" configuration, the name is intended to encompass compounds in the S configuration at the chiral center, compounds in the R configuration at the chiral center, or compounds in a mixture of R and S configurations at the chiral center.

[0286] A racemic mixture refers to 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound having one chiral center is named or depicted, but the stereochemistry of the chiral center is not shown, it is understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or racemic forms). When a compound having two or more chiral centers is named or described, but the stereochemistry of the chiral center is not shown, it is understood that the name or structure encompasses 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).

[0287] The term "geometric isomer" refers to isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, a carbocyclic ring, or a bridged bicyclic ring system. Substituent atoms (except 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 priority rules. In the "E" configuration, the substituents with the highest priority are on opposite sides of the carbon-carbon double bond. In the "Z" configuration, the substituents with the highest priority orientation are on the same side of the carbon-carbon double bond.

[0288] Substituents around a carbon-carbon double bond may also be referred to as "cis" or "trans," where "cis" means that the substituents are on the same side of the double bond, and "trans" means that the substituents are on opposite sides of the double bond. Arrangements of substituents around a carbon ring may also be designated as "cis" or "trans." The term "cis" means that the substituents are on the same side of the plane of the ring, while the term "trans" means that the substituents are on opposite sides of the plane of the ring. A mixture of compounds in which substituents are placed on both the same side and opposite sides of the plane of the ring is designated "cis / trans."

[0289] Tautomerism ("tautomerism") occurs when structural isomers can be interconverted across a low energy barrier. This can result in proton tautomeric forms for compounds of any of the above formulae containing, for example, an imino, keto or oxime group, or so-called valence tautomeric forms for compounds containing aromatic moieties. Thus, a single compound may exhibit multiple types of isomers.

[0290] In some cases, there are tautomeric forms of the disclosed compounds, such as the tautomeric structures shown below:

[0291]

[0292] When geometric isomers are depicted by name or structure, it is understood that the named or depicted isomer is present to a greater extent than the other isomer, that is, the geometric purity of the named or depicted geometric isomer is greater than 50%, for example, at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight. Geometric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0293] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0294] 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 pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound (e.g., an alcohol), or, in the case of a compound of any of the above formulas containing an acidic or basic moiety, with a base or acid (e.g., 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization, and one or both diastereomers may be converted to the corresponding pure enantiomer by methods well known to those skilled in the art. A chiral compound of any of the above formulae (and its chiral precursor) can be obtained in an enantiomerically enriched form on an asymmetric resin using chromatography (typically HPLC), wherein the mobile phase consists of a hydrocarbon (typically heptane or hexane) containing 0 to 50% by volume of isopropanol (typically 2% to 20%) and 0 to 5% by volume of an alkylamine (typically 0.1% diethylamine). The eluent is concentrated to obtain an enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be used. Chiral chromatography that can be used in some embodiments of the present disclosure is 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), pages 223-249 and references cited therein). Chromatographic columns can be obtained from Chiral Technologies, Inc. of West Chester, Pa., USA (located in Tokyo, Japan). Chemical Industries, Ltd. subsidiary).

[0295] It must be emphasized that compounds of any of the above formulae are drawn herein in a single tautomeric form and that all possible tautomeric forms are included within the scope of the present disclosure.

[0296] 3. Administration and Dosage

[0297] Typically, the compounds of the present disclosure are administered in an amount effective to treat the disorders described herein. The compounds of the present disclosure can be administered in the form of the compounds themselves, or in the form of pharmaceutically acceptable salts. For the purposes of administration and dosage, the compounds themselves or their pharmaceutically acceptable salts will be referred to as compounds of the present disclosure.

[0298] The compounds of the present disclosure may be administered by any suitable route in the form of a pharmaceutical composition suitable for such route and in a dose effective for the intended treatment. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally or topically.

[0299] The compounds of the present disclosure can be administered orally. Oral administration can involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be employed, in which case the compound enters the bloodstream directly from the mouth.

[0300] In another embodiment, the compounds of the present disclosure can also be directly administered to the bloodstream, muscle or internal organs. Suitable modes for parenteral administration include, for example, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes and infusion techniques.

[0301] In another embodiment, the compounds of the present disclosure may also be topically applied to or to the skin or mucous membrane, i.e., transdermally or transdermally. In another embodiment, the compounds of the present disclosure may also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may also be directly applied to the eyes or ears.

[0302] The dosage regimen of the disclosed compounds and / or compositions containing the compounds is based on a variety of 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 used. Therefore, the dosage regimen may vary greatly. In one embodiment, the total daily dose of the disclosed compounds for treating the indications discussed herein is typically about 0.001 to about 100 mg / kg (i.e., mg of the disclosed compound / kg body weight).

[0303] For oral administration, the composition can be provided in the form of tablets containing 0.1-500 mg of active ingredient, and this dosage can be adjusted according to the patient's symptoms. One medicament usually contains about 0.01 mg to about 500 mg of active ingredient. When administered intravenously, the dosage range can be about 0.01 to about 10 mg / kg / min during infusion at a constant rate.

[0304] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals, such as primates, rodents (mice, rats, hamsters, rabbits, etc.). In one embodiment, humans are suitable subjects. Human subjects can be of any gender and are at any stage of development.

[0305] 4. Pharmaceutical Composition

[0306] In another embodiment, the present disclosure includes a pharmaceutical composition. The pharmaceutical composition comprises a provided compound of the present disclosure, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances may also be present.

[0307] As used herein, "pharmaceutically acceptable carriers or excipients" include 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, and isotonic agents, such as sugars, sodium chloride, or polyols, such as mannitol or sorbitol, may be included in the composition. Pharmaceutically acceptable substances, such as wetting agents or small amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, will extend the shelf life or effectiveness of the antibody or antibody portion.

[0308] Compositions of the present disclosure can be in various forms. These include, for example, liquid, semisolid 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.

[0309] 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 administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular administration). In another embodiment, the antibody is administered by intravenous infusion or injection. In another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0310] Oral administration of solid dosage forms can be presented, for example, in discrete units, such as hard or soft capsules, pills, cachets, buccal tablets or tablets, each unit containing a predetermined amount of at least one compound of the present disclosure. In another embodiment, oral administration can be in the form of a powder or granules. In another embodiment, the oral dosage form is a sublingual dosage form, such as a buccal tablet. In such solid dosage forms, the compound of any of the above formulas is typically combined with one or more adjuvants. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets and pills, the dosage form may also contain a buffer, or may be prepared to have an enteric coating.

[0311] In another embodiment, oral administration can be a 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 may also include adjuvants, such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners) and / or aromatics.

[0312] In another embodiment, the present disclosure encompasses parenteral dosage forms.

[0313] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (such as sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersants, wetting agents and / or suspending agents.

[0314] In another embodiment, the present disclosure comprises a topical dosage form.

[0315] "Topical application" includes, for example, transdermal administration, such as by transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhaled administration. Compositions for topical application also include, for example, topical gels, sprays, ointments and creams. Topical preparations may include compounds that enhance the absorption or penetration of active ingredients through the skin or other affected areas. When the compounds of the present disclosure are applied by transdermal devices, the application will be achieved using reservoir-type and porous membrane-type or solid matrix-type patches. Typical preparations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, talcum powders, dressings, foams, membranes, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol and propylene glycol. Permeation enhancers may be incorporated, see, eg, Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0316] Preparations suitable for topical application to eyes include, for example, eye drops, in which the compounds of the present disclosure are dissolved or suspended in a suitable carrier. Typical preparations suitable for eye or ear administration can be in the form of drops of micronized suspensions or solutions in isotonic sterile saline with adjusted pH. Other preparations suitable for eye and ear administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silica gel) implants, wafers, lenses and particles or vesicle systems, such as vesicles or liposomes. Polymers can be incorporated with preservatives (e.g., benzalkonium chloride), such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum). Such preparations can also be delivered by iontophoresis.

[0317] For intranasal administration or administration by inhalation, the disclosed compounds are preferably delivered in the form of solutions or suspensions, squeezed or pumped by the patient through a pump spray container, or delivered from a pressurized container or atomizer using a suitable propellant in an aerosol spray form. Preparations suitable for intranasal administration are usually administered in dry powder form (alone, in a mixture form, such as a dry blend with lactose, or in a mixed component granular form, such as mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, or in an aerosol spray form from a pressurized container, pump, sprayer, atomizer (preferably using an electrohydrodynamic sprayer to produce a fine mist) or atomizer, with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, powders may include bioadhesives, such as chitosan or cyclodextrin.

[0318] In another embodiment, the present disclosure includes a rectal dosage form. Such a rectal dosage form can be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, but various substitutes can also be used as desired.

[0319] Other carrier materials and modes of administration known in the pharmaceutical art may also be used.The pharmaceutical compositions of the present disclosure may be prepared by any well-known pharmaceutical techniques, such as effective formulation and administration procedures.

[0320] The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. Pharmaceutical formulations are discussed in, for example, 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 (3rd ed.), American Pharmaceutical Association, Washington, 1999.

[0321] 5. Treatment Methods

[0322] The terms "subject," "individual," or "patient" are used interchangeably and mean any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0323] The terms "treatment", "treat" and "treating" refer to reversing, alleviating or inhibiting the progression of a disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of a disease have developed or been observed (i.e., therapeutic treatment). In other embodiments, treatment can be administered in the absence of signs or symptoms of the disease. For example, treatment can be administered to a susceptible individual (i.e., prophylactic treatment) prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen). Treatment can also be continued after symptoms subside, e.g., to delay or prevent recurrence.

[0324] As used herein, the term "prevention" (or "prevent" or "preventing") refers to excluding, avoiding, eliminating, preventing in advance, reducing the occurrence of a disease, disorder and / or condition, stopping or hindering its symptoms. Prevention includes the administration of a drug to a subject who does not show symptoms of the disease, disorder and / or condition at the time of administration.

[0325] The terms "disease," "disease," and "condition" are used interchangeably.

[0326] The terms "administer," "administering," or "administration" refer to methods of introducing a compound disclosed herein or a composition thereof into or on the body of a patient. These methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal administration, and the like. Administration techniques that can be used with the agents and methods described herein are found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0327] In general, the effective amount of the compound taught herein depends on various factors, such as a given drug or compound, pharmaceutical formulation, route of administration, type of disease or condition, identity of the subject or host to be treated, etc., but can still be routinely determined by those skilled in the art. One of ordinary skill in the art can easily determine the effective amount of the compound taught by the present invention by conventional methods known in the art.

[0328] The term "therapeutically effective amount" refers to an amount that produces beneficial or desired results (including clinical results) when administered to a subject, such as an amount that inhibits, suppresses or alleviates the symptoms of the subject's treated disorder compared to a control. The exact amount required will vary from subject to subject, depending on the subject's species, age and general condition, the severity of the disease, the specific anticancer agent, its mode of administration, combined treatment with other therapies, etc.

[0329] The present disclosure relates to compounds of formula (I) (including all embodiments thereof), which are useful for treating and / or preventing diseases and / or conditions associated with or regulated by HTT, particularly where reducing mHTT in a subject has therapeutic benefit, including but not limited to treating and / or preventing HD.

[0330] In one embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0331] In one embodiment, the disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body.

[0332] The present disclosure also provides a method for treating HD in a subject in need thereof, the method 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.

[0333] In one embodiment, the present disclosure provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating HD in a subject in need thereof, the treatment comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0334] In one embodiment, the disclosure provides the 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, the treatment comprising administering to the subject an effective amount of the medicament.

[0335] 6. Treatment kit

[0336] One aspect of the present invention relates to a kit for conveniently and effectively implementing the method or use according to the present invention. In general, a medicine pack or kit comprises one or more containers filled with one or more ingredients of the pharmaceutical composition of the present invention. Such kits are particularly suitable for delivering solid oral dosage forms such as tablets or capsules. Such kits preferably include a plurality of unit doses and may also include a card with the doses arranged in the order of their intended use. If necessary, a memory aid may be provided, for example in the form of numbers, letters or other markings, or with a calendar insert specifying the dates on which the doses may be administered in the treatment plan. The container may optionally be accompanied by a certain form of instructions issued by a government agency that regulates the manufacture, use or sale of the drug product, the instructions reflecting the approval of the agency that manufactures, uses or sells the drug for human administration.

[0337] The following representative examples contain important additional information, illustrations and guidance, which are applicable to various embodiments and equivalents thereof of the present invention. These examples are intended to help illustrate the present invention, but are not intended to, nor should they be interpreted as limiting the scope of the present invention. In fact, it will be apparent to those skilled in the art by reviewing this document (including the following examples and the scientific and patent literature cited herein) that various modifications of the present invention and many other embodiments thereof except those shown and described herein will be apparent.

[0338] The contents of the cited references are incorporated herein by reference to help illustrate the state of the art.

[0339] In addition, for the purpose of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 75th edition, inside cover). In addition, general principles of organic chemistry as well as specific functional moieties and reactivity are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999 and "Organic Chemistry," Morrison & Boyd (3rd edition), the entire contents of both books are incorporated herein by reference.

[0340] 7. Preparation

[0341] The compounds of any of the above formulas can be prepared using the common knowledge of those skilled in the art of synthetic organic chemistry by the general and specific methods described below. Such common knowledge can be found in standard reference books, such as Comprehensive Organic Chemistry, edited by 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 material used herein is commercially available or can be prepared by conventional methods known in the art.

[0342] When preparing the compound of any of the above formulas, it should be noted that some preparation methods described herein may need to protect the distal functional group (e.g., the precursor of the primary amine, secondary amine, and carboxyl group in any of the above formulas). The demand for such protection will vary depending on the properties of the distal functional group and the conditions of the preparation method. Those skilled in the art can easily determine whether such protection is required. The use of such protection / deprotection methods is also within the skill range of the art. For a general description of protecting groups and their use, refer to Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0343] For example, some compounds contain primary amine or carboxylic acid functional groups, which, if not protected, may interfere with reactions at other sites of the molecule. Therefore, these functional groups may be protected with appropriate protecting groups, which can be removed in subsequent steps. Suitable protecting groups for protecting amines and carboxylic acids include those commonly used in peptide synthesis (e.g., N-tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines, and lower carbon alkyl or benzyl esters for carboxylic acids), which generally do not react chemically under the described reaction conditions, and can usually be removed without changing the other functional groups in the compounds of any of the above formulae.

[0344] The following scheme is intended to provide a general description of the methods for preparing the disclosed compounds. Certain compounds of the present disclosure may contain single or multiple chiral centers, with stereochemistry designated as (R) or (S). It will be apparent to those skilled in the art that all synthetic transformations can be performed in a similar manner, whether the material is enantiomerically enriched or racemic. In addition, well-known methods described herein and in the chemical literature can also be used to split into the desired optically active material at any desired point in the sequence.

[0345] Example

[0346]

[0347]

[0348] Section 1. General methods and analytical approaches

[0349] a. General Methods

[0350] Unless otherwise described, otherwise according to the analysis of one of the purification process mentioned below or the compound of purification embodiment.When using preparative TLC / HPLC or silica gel chromatography, those skilled in the art can select any solvent combination to purify the desired compound.Use 20-40mM (particle diameter), 250-400 mesh or 400-632 mesh silica gel, use Teledyne ISCOCombiflash RF or the Grace Reveleris X2 with ELSD purification system, or use pressurized nitrogen (about 10-15psi) to drive solvent to perform silica gel column chromatography by post (" flash chromatography ").Wherein use SCX post, eluent condition is MeOH, followed by methanol ammonia.When pointed out, solution and reaction mixture are concentrated by rotary evaporation under vacuum.

[0351] b. Analytical methods

[0352] Analytical LCMS Instrument Specifications:

[0353] Waters Acquity iClass UPLC with QDa mass spectrometer and PDA (photodiode array detector)

[0354] RxnQC / FrxQC / PurityQC analysis LC / MS method conditions:

[0355] Ammonium Hydroxide (Alkaline pH) Conditions

[0356] Method 1

[0357] MS mode: MS: ESI + scan range 165-650 Daltons

[0358] PDA: 200-400nm scanning range

[0359] Column: Waters ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 um; Part No. 186002350

[0360] Modifier: 0.2% (v / v) ammonium hydroxide

[0361] Method: 95% H2O / 5% MeCN (initial condition) held for 0.1 min, linear gradient to 5% H2O / 95% MeCN at 3.25 min, held at 5% H2O / 95% MeCN until 3.5 min. Flow rate, 0.8 mL / min.

[0362] Method 2

[0363] MS mode: MS: ESI + scan range 165-650 Daltons

[0364] PDA: 200-400nm scanning range

[0365] Column: Waters ACQUITY UPLC BEH C18 2.1×30 mm, 1.7 um; Part No. 186002349

[0366] Modifier: 0.2% (v / v) ammonium hydroxide

[0367] Method: 95% H2O / 5% MeCN (initial conditions), linear gradient to 5% H2O / 95% MeCN, 1.0 min, hold 5% H2O / 95% MeCN to 1.3 min. Flow rate, 0.7 mL / min.

[0368] Trifluoroacetic acid (acidic pH) conditions

[0369] Method 3

[0370] MS mode: MS: ESI + scan range 165-650 Daltons

[0371] PDA: 200-400nm scanning range

[0372] Column: Waters ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 um; Part No. 186002350

[0373] Modifier: 0.1% (v / v) trifluoroacetic acid

[0374] Method: 95% H2O / 5% MeCN (initial condition) held for 0.1 min, linear gradient to 5% H2O / 95% MeCN at 3.25 min, held at 5% H2O / 95% MeCN until 3.5 min. Flow rate, 0.8 mL / min.

[0375] Method 4

[0376] MS mode: MS: ESI + scan range 165-650 Daltons

[0377] PDA: 200-400nm scanning range

[0378] Column: Waters ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 um; Part No. 186002349

[0379] Modifier: 0.1% (v / v) trifluoroacetic acid

[0380] Method: 95% H2O / 5% MeCN (initial conditions), linear gradient to 5% H2O / 95% MeCN at 1.0 min, hold 5% H2O / 95% MeCN to 1.3 min. Flow rate, 0.7 mL / min.

[0381] Analytical LCMS Instrument Specifications:

[0382] Agilent 1200 Series LC / MSD System with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B Mass Spectrometers; Agilent Technologies 1260 Infinity LC / MSD System with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6120B Mass Spectrometers; Agilent Technologies 1260 Infinity II LC / MSD System with DAD\ELSD G7102A 1290 Infinity II and Agilent LC\MSD G6120B Mass Spectrometers; Agilent 1260 Series LC / MSD System with DAD\ELSD and Agilent LC\MSD (G6120B) Mass Spectrometers; UHPLC Agilent 1290 Series LC / MSD System with DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer, Shimadzu LCMS-2020.

[0383] RxnQC / FrxQC / PurityQC analysis LC / MS method conditions:

[0384] Formic acid (acidic pH) conditions

[0385] Method 5

[0386] Injection volume: 0.5 μl, column temperature: 60 °C, UV scan: 207–223 nM, 246–262 nM, 272–288 nM, Agilent Poroshell 120SB-C18 4.6×30 mm 2.7 μm, equipped with UHPLC Guard Infinity Lab Poroshell120SB-C18 4.6×5 mm 2.7 μm, mobile phase A: water containing 0.1% FA, mobile phase B: acetonitrile containing 0.1% FA.

[0387] Elution Details

[0388] Time (minutes) Flow rate (mL / min) ％A ％B 0.00 3.00 99 1 0.01 3.00 99 1 1.5 3.00 0 100 1.73 3.00 0 100 1.74 3.00 99 1

[0389] Method 6

[0390] Injection volume: 0.5 μl; column temperature: 60°C; UV scan: 207–223 nM, 246–262 nM, 272–288 nM

[0391] Agilent Poroshell 120SB-C18 4.6×30mm 2.7μm, equipped with UHPLC Guard InfinityLab Poroshell 120SB-C18 4.6×5mm 2.7μm, mobile phase A: water with 0.1% FA, mobile phase B: acetonitrile with 0.1% FA

[0392] Elution Details

[0393] Time (minutes) Flow rate (mL / min) ％A ％B 0.00 1.5 99 1 0.01 1.5 99 1 5.00 1.5 0 100 5.99 1.5 0 100 6.00 1.5 99 1

[0394] Method 7

[0395] MS mode: MS:ESI+ scanning range 100-1000 Daltons

[0396] PDA: 190-370nm scanning range

[0397] Column: Xtimate C18 2.1*30mm, 3um

[0398] Modifier: Phase A: water (4 L) + TFA (1.5 mL), Phase B: acetonitrile (4 L) + TFA (0.75 mL)

[0399] Method: An elution gradient of 10%-80% (Solvent B) was used, the elution time was 1.35 or 3.35 minutes, and held at 80% for 0.9 minutes, and the flow rate was 0.8 ml / min.

[0400] Method 8

[0401]

[0402]

[0403] describe:

[0404] Mobile phase: 5% ACN (0.018% TFA) in water (0.037% TFA) to 95% ACN in 3.0 minutes, flow rate set to 1.0 mL / min; then hold at 95% ACN for 0.60 minutes, flow rate set from 1.0 mL / min to 1.5 mL / min; return to 5% ACN in water and hold for 0.40 minutes. Flow rate set to 1.5 mL / min.

[0405] The column temperature was at 50°C.

[0406] The column was Shim-pack Velox SP-C18 2.7 μm 3.0*30 mm.

[0407] Method 9

[0408]

[0409]

[0410] describe:

[0411] Mobile phase: 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in 0.60 min, flow rate set to 2.0 mL / min; then hold at 95% ACN for 0.18 min, flow rate from 2.0 mL / min; return to 5% ACN in water and hold for 0.02 min. Flow rate set to 2.0 mL / min.

[0412] The column temperature was at 50°C.

[0413] Column is EVO C18 2.1×30mm 5um.

[0414] Method 10

[0415] describe:

[0416] Mobile phase: 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in 3.20 minutes, flow rate set to 1.5 mL / min; then 95% ACN for 0.30 minutes, flow rate from 1.5 mL / min; return to 5% ACN in water and hold for 0.30 minutes. Flow rate set to 2.0 mL / min. Column temperature at 50°C. Column is EVO C18 4.6×50mm 5um.

[0417] Preparative HPLC-MS conditions:

[0418] HPLC-MS Instrument Specifications

[0419] Waters Autopurification equipped with QDa mass spectrometer and PDA (photodiode array detector).

[0420] Ammonium Hydroxide (Alkaline pH) Conditions

[0421] Flow rate: 30mL / min

[0422] MS mode: MS: ESI + scan range 165-650 Daltons

[0423] PDA: 200-400nm scanning range

[0424] Column: Waters XSELECT CSH C18 PREP 19×100mm, 5um; Part No. 186005421

[0425] Modifier: 0.2% (v / v) ammonium hydroxide

[0426] Method: A% H2O / B% MeCN (initial conditions) held for 0.5 min, linear gradient to A% H2O / B% MeCN at 8 min, increased to 5% H2O / 95% MeCN at 8.5 min, held at 5% H2O / 95% MeCN until 10 min.

[0427] Flow rate: 50mL / min

[0428] MS mode: MS: ESI + scan range 165-650 Daltons

[0429] PDA: 200-400nm scanning range

[0430] Column: Waters XSELECT CSH C18 PREP 30×100mm, 5um; Part No. 186005425

[0431] Modifier: 0.2% (v / v) ammonium hydroxide

[0432] Method: A% H2O / B% MeCN (initial conditions) held for 0.5 min, linear gradient to A% H2O / B% MeCN at 8 min, increased to 5% H2O / 95% MeCN at 8.5 min, held at 5% H2O / 95% MeCN until 10 min.

[0433] Flow rate, 60 mL / min

[0434] MS mode: MS: ESI + scan range 165-650 Daltons

[0435] PDA: 200-400nm scanning range

[0436] Column: Waters XSELECT CSH C18 PREP 30×50mm, 5um; Part No. 186005423

[0437] Modifier: 0.2% (v / v) ammonium hydroxide

[0438] Method: A% H2O / B% MeCN (initial conditions) held for 0.5 min, linear gradient to A% H2O / B% MeCN at 8 min, increased to 5% H2O / 95% MeCN at 8.5 min, held at 5% H2O / 95% MeCN until 10 min.

[0439] Column: Boston Prime C18 150×30 mm×5 um; Conditions: water (NH 3 H 2 O+NH 4 HCO 3 )-ACN; Gradient (organic %): 0-100%, optimized for each example; Flow rate (mL / min): 25.

[0440] Column: YMC Actus Trial C18 20*100 5mkm column; H2O-MeOH-ammonia 0.1% gradient mixture was used as the mobile phase, which was optimized for each example.

[0441] Trifluoroacetic acid (acidic pH) conditions

[0442] Flow rate, 30 mL / min

[0443] MS mode: MS: ESI + scan range 165-650 Daltons

[0444] PDA: 200-400nm scanning range

[0445] Column: Waters Sunfire OBD C18 PREP 19×100mm, 5um; Part No. 186002567

[0446] Modifier: 0.1% (v / v) trifluoroacetic acid

[0447] Method: A% H2O / B% MeCN (initial conditions) held for 0.5 min, linear gradient to A% H2O / B% MeCN at 8 min, increased to 5% H2O / 95% MeCN at 8.5 min, held at 5% H2O / 95% MeCN until 10 min.

[0448] Flow rate, 50 mL / min

[0449] MS mode: MS: ESI + scan range 165-650 Daltons

[0450] PDA: 200-400nm scanning range

[0451] Column: Waters Sunfire OBD C18 PREP 30×100mm, 5um; Part No. 186002572

[0452] Modifier: 0.1% (v / v) trifluoroacetic acid

[0453] Method: A% H2O / B% MeCN (initial conditions) held for 0.5 min, linear gradient to A% H2O / B% MeCN at 8 min, increased to 5% H2O / 95% MeCN at 8.5 min, held at 5% H2O / 95% MeCN until 10 min.

[0454] Flow rate, 60 mL / min

[0455] MS mode: MS: ESI + scan range 165-650 Daltons

[0456] PDA: 200-400nm scanning range

[0457] Column: Waters Sunfire OBD C18 PREP 30×50mm, 5um; Part No. 186002570

[0458] Modifier: 0.1% (v / v) trifluoroacetic acid

[0459] Method: A% H2O / B% MeCN (initial conditions) held for 0.5 min, linear gradient to A% H2O / B% MeCN at 8 min, increased to 5% H2O / 95% MeCN at 8.5 min, held at 5% H2O / 95% MeCN until 10 min.

[0460] Formic acid (FA, acidic pH) conditions

[0461] Column: Welch Xtimate C18 150×30 mm×5 um or Phenomenex luna C18 150×25 mm x10 um; Conditions: water (FA)-ACN; Gradient (organic %): optimized for each example; Flow rate (mL / min): 25.

[0462] Hydrochloric acid (HCl, acidic pH) conditions

[0463] Column: Boston Green ODS 150×30 mm×5 um; Conditions: water (HCl)-ACN; Gradient (organic %): 0-100%, optimized for each example; Flow rate (mL / min): 25.

[0464] Analytical SFC Instrument Specifications

[0465] Waters Acquity UPC with QDa mass spectrometer and PDA (photodiode array detector) 2 SFC.

[0466] Analysis filter conditions

[0467] MS mode: MS: ESI + scan range 100-650 Daltons

[0468] PDA: 200-400nm scanning range

[0469] Column: See below

[0470] Solvent: Airgas Bone Dry CO2

[0471] Co-solvent: methanol, ethanol or isopropanol containing 0.1% diethylamine, 0.1% dimethylethanolamine, or neutral

[0472] Method: Isocratic conditions; typically 60% CO2:40% co-solvent or 70% CO2:30% co-solvent, flow rate is 3.0 mL / min.

[0473] Preparative SFC Instrument Specifications

[0474] Waters Prep 100 SFC equipped with QDa mass spectrometer, PDA (photodiode array detector) and 2767 collection bed.

[0475] Preparation conditions

[0476] Method: X% cosolvent in CO2 with Y% modifier, isocratic conditions.

[0477] Flow rate: 100mL / min

[0478] Automatic back pressure regulator: 120 bar

[0479] Manual back pressure regulator: MeOH or EtOH, 40psi; iPrOH, 60psi

[0480] Column box temperature: 40°C

[0481] MS mode: MS:ESI+ scanning range 150-650 Daltons

[0482] PDA: 200-400nm scanning range.

[0483] SFC columns, analytical:

[0484] AD-H: Daicel Chiralpak AD-H, 4.6mm×250mm, 5um, part number 19325

[0485] AS-H: Daicel Chiralpak AS-H, 4.6mm×250mm, 5um, part number 20325

[0486] OD-H: Daicel Chiralpak OD-H, 4.6mm×250mm, 5um, part number 14325

[0487] OX-H: Daicel Chiralpak OX-H, 4.6mm×250mm, 5um, part number 63325

[0488] IA: Daicel Chiralpak IA, 4.6mm×250mm, 5um, part number 80325

[0489] IB: Daicel Chiralpak IB, 4.6mm×250mm, 5um, part number 81325

[0490] IC: Daicel Chiralpak IC, 4.6mm×250mm, 5um, part number 83325

[0491] IG: Daicel Chiralpak IG, 4.6mm×250mm, 5um, part number 87325

[0492] Cell-2: Phenomenex Lux Cellulose-2, 4.6mm×150mm, 3um, part number 00F-4456-E0

[0493] Cell-4: Phenomenex Lux Cellulose-4, 4.6mm×150mm, 3um, part number 00F-4490-E0

[0494] SFC columns, preparative:

[0495] AD-H: Daicel Chiralpak AD-H, 30mm×250mm, 5um, part number 19475

[0496] AS-H: Daicel Chiralpak AS-H, 30mm×250mm, 5um, part number 20475

[0497] OD-H: Daicel Chiralpak OD-H, 30mm×250mm, 5um, part number 14475

[0498] OX-H: Daicel Chiralpak OX-H, 30mm×250mm, 5um, part number 63475

[0499] IA: Daicel Chiralpak IA, 30mm×250mm, 5um, part number 80475IB: Daicel Chiralpak IB, 30mm×250mm, 5um, part number 81475IC: Daicel Chiralpak IC, 30mm×250mm, 5um, part number 83475IG: Daicel Chiralpak IG, 30mm×250mm, 5um, part number 87475

[0500] Cell-2: Phenomenex Lux Cellulose-2, 30mm×250mm, 5um, part number 00G-4457-U0-AX

[0501] Cell-4: Phenomenex Lux Cellulose-4, 30mm×250mm, 5um, part number 00G-4491-U0-AX

[0502] 1 H-NMR

[0503] 1 H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. 1 H NMR spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance DRX 500, Bruker Avance III 400 MHz, Varian-400 VNMRS, Varian Unityplus 400, or Varian-400 MR. Characteristic chemical shifts (d) are relative to tetramethylsilane (for 1 H-NMR) are reported in parts per million downfield, using conventional abbreviations for the major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; br, broad. The following abbreviations are used for common solvents: CDCl3, deuterated chloroform; DMSO-d6, hexadeuterated dimethyl sulfoxide; MeOH-d4, deuterated methanol. Where appropriate, tautomers may be recorded in the NMR data; and some exchangeable protons may not be visible.

[0504] Section 2. Preparation of intermediates

[0505] Intermediate 1

[0506]

[0507] Step a: 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (500 mg, 2.34 mmol, 1.0 eq.) was dissolved in ethanol (11.70 mL, 0.2 M), followed by the addition of HCl in dioxane (4 M, 1.76 mL, 3 eq.). The solution was then stirred at 80 °C for 16 hours and then concentrated to afford ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (503.4 mg, 80% yield) as an off-white powder, which was used crude. MS: m / z 242.0 [M+H] + .

[0508] Step b: N,N-dimethylpyrrolidin-3-amine (190.98 mg, 1.67 mmol, 1.1 eq.), 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid ethyl ester (408.31 mg, 1.52 mmol, 1.0 eq.) and DIPEA (1.38 g, 10.64 mmol, 1.85 mL, 7 eq.) were dissolved in dioxane (7.60 mL, 0.2 M), heated to 80° C. for 72 hours, then dried and loaded onto a normal phase silica gel column and purified by 0-25% MeOH:DCM to give 6-[3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid ethyl ester (468.0 mg, 93% yield). MS: m / z 320.0 [M+H] + .

[0509] Step c: Ethyl 6-[3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (482.47 mg, 1.47 mmol, 1.0 eq.) 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 eq.). The solution was then heated at 80°C for 16 hours and then concentrated to give 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] + .

[0510] Intermediate 2

[0511]

[0512] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (500 mg, 2.34 mmol, 1.0 eq.) 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 eq.), HATU (978.87 mg, 2.57 mmol, 1.0 eq.) and DIPEA (665.43 mg, 5.15 mmol, 896 μL). The solution was then stirred at room temperature for 1 hour, then concentrated and injected directly onto a normal phase silica gel column and purified by 0-25% MeOH:DCM for 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 used as is. MS: m / z 343.0 [M+H] + .

[0513] Intermediate 3

[0514]

[0515] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 117.02 μmol, 1.0 eq.), 2,7-dimethylindazol-5-amine (22.64 mg, 140.42 μmol, 1.2 eq.), HATU (48.94 mg, 128.72 μmol, 1.1 eq.) and DIPEA (33.27 mg, 257.44 μmol, 44 μL, 2.2 eq.) were dissolved in dichloromethane (585.09 μL, 0.2 M), followed by stirring at room temperature for 2 hours. The solution was then purified by silica gel 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, yield 100%) as a brown solid. MS: m / z 357.0 [M+H] + .

[0516] Intermediate 4

[0517]

[0518] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 117.02 μmol, 1.0 eq.), 2-methylimidazo[1,2-a]pyrazin-6-amine (20.81 mg, 140.42 μmol, 1.2 eq.), HATU (48.94 mg, 128.72 μmol, 1.1 eq.) and triethylamine (26.05 mg, 257.4 μmol, 36 μL, 2.2 eq.) was dissolved in dichloromethane (585.09 μL, 0.2 M) and then stirred at room temperature for 2 hours, then directly injected onto a normal phase silica gel column and purified by 0-25% MeOH: DCM for 3.5 minutes to obtain 6-chloro-N-(2-methylimidazo[1,2-a]pyrazine-6-yl)thieno[2,3-b]pyridine-2-carboxamide (25.8 mg, yield 61%) as a brown solid, which was used as is. MS: m / z 344.0 [M+H] + .

[0519] Intermediate 5

[0520]

[0521] 6-Chlorothieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 117.02 μmol, 1.0 eq.), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (22.78 mg, 140.42 μmol, 1.2 eq.), HATU (48.94 mg, 128.72 μmol, 1.1 eq.) and triethylamine (26.05 mg, 257.44 μmol, 35.88 μL, 2.2 eq.) were dissolved in dichloromethane (585.09 μL, 0.2 M) and then stirred at room temperature for 2 hours, then the crude product was injected onto a normal phase silica gel column and purified by 0-25% MeOH:DCM for 3.5 minutes. The product was eluted at 20%. The identified eluted fractions were collected 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 used as is. MS: m / z 358.1 [M+H] + .

[0522] Intermediate 6

[0523]

[0524] At 20°C, 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]-dimethylammonium 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). 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, which 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, yield 64%) as a brown solid. MS: m / z 361.2 [M+H] + .

[0525] Intermediate 7

[0526]

[0527] Step a: Ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (265 mg, 1.02 mmol, 1.0 eq.) 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 eq.) and (3S)-N,N-dimethylpyrrolidin-3-amine (465.89 mg, 4.08 mmol, 518.23 mL, 4 eq.). The solution was then heated to 80°C for 16 hours, then concentrated and loaded in dry form onto a normal phase silica gel column and purified by 0-25% MeOH:DCM over 12 minutes. The product eluted at 11% MeOH. The identified eluted fractions were collected and concentrated to obtain ethyl 6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (258.2 mg, 808.34 μmol, yield 79%) as a white powder. MS: m / z 320.0 [M+H] + .

[0528] 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 eq.) 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 eq.). The solution was then heated at 60 °C for 96 hours and then concentrated to a white powder to obtain 6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (241.1 mg) as a pale yellow powder, which was used as is. MS: m / z 292.0 [M+H] + .

[0529] Intermediate 8

[0530]

[0531] Step a: Ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (150 mg, 552.35 μmol, 1.0 eq.) 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 eq.) and (3R)-N,N-dimethylpyrrolidin-3-amine (828.5 μmol, 105 μL, 1.5 eq.). The solution was then heated to 80°C for 16 hours, then concentrated and loaded onto normal phase silica gel in dry form and purified by 0-25% MeOH:DCM over 12 minutes. The product was eluted at 11% MeOH. The identified eluted fractions were collected and concentrated to obtain ethyl 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylate (162.9 mg, yield 89%) as a white powder. MS: m / z 320.0 [M+H] + .

[0532] 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 eq.) 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 eq.). The solution was then heated at 50 °C for 16 hours and then concentrated to a white powder to obtain 6-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (157.9 mg) as a pale yellow powder, which was used as is. MS: m / z 292.0 [M+H] + .

[0533] Intermediate 9

[0534]

[0535] Step a: Sodium tert-butoxide (16.99 g, 176.76 mmol) and BINAP (18.34 g, 29.46 mmol) were added to a solution of 6-bromo-2,8-dimethyl-imidazo[1,2-a]pyrazine (22.2 g, 98.20 mmol) in toluene (250 mL), followed by diphenylmethylene (35.59 g, 196.40 mmol, 32.96 mL) under N2. The mixture was stirred at 90 ° C for 16 hours. Then, the mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was evaporated in vacuo and the crude product was purified by flash column chromatography (silica gel; EtOAc in petroleum ether, 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]pyrazine-6-amine (25.2 g) as a yellow oil. MS: m / z 327.1[M+H] + .

[0536] Step b: To a mixture of N-(2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)-1,1-diphenyl-formimine (25.2 g, 77.21 mmol) in THF (150 mL) was added HCl (2M, 120 mL) at 20°C. The mixture was stirred at 20°C for 1 hour. 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 2N 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]pyrazine-6-amine (8.2 g, 50.56 mmol, 65% yield) as a brown solid. MS: m / z 163.1[M+H] + .

[0537] Intermediate 10

[0538]

[0539] 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-diphenylphosphino-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphine (505.24 mg, 873.18 μmol) in dioxane (30 mL) was added cesium carbonate (4.27 g, 13.10 mmol) and Pd2(dba)3 (399.79 mg, 436.59 μmol) at 20°C under N2. The reaction was stirred at 100°C for 14 hours. The mixture was filtered and the filtrate was concentrated 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] + .

[0540] Step b: At 20 ° C, HCl (143.91 mg, 3.95 mmol, 0.5 mL) was added to a solution of N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-1,1-diphenyl-formimide (1.3 g, 3.95 mmol) in HCl (4M, 8 mL). The reaction was stirred at 20 ° C for 14 hours. The solution was evaporated in vacuo, and the residue was adjusted to pH = 7 with saturated NaHCO3 aqueous solution (100 mL) and extracted with DCM (50 mL×3). The combined organic layers were dried over Na2SO4 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] + .

[0541] Intermediate 11

[0542]

[0543] 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-diphenylphosphino-1-naphthyl)-2-naphthyl]-diphenyl-phosphine (165.98 mg, 266.57 μmol) were added toluene (6 mL) and diphenylformimide (483.11 mg, 2.67 mmol, 447.32 μL) under N2. The reaction mixture was stirred at 130°C for 12 hours. The mixture was concentrated and the residue was purified by column chromatography (0% to 70% EtOAc in heptane) to give N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-1,1-diphenyl-methanimine (455.1 mg) as a light yellow solid. MS: m / z 326.1 [M+H] + .

[0544] Step b: To a mixture of N-(diphenylmethylene)-2,8-dimethylimidazo[1,2-a]pyridine-6-amine (95.4 mg, 293.17 μmol) in THF (2 mL) was added hydrochloric acid (4M in dioxane, 219.88 μL) at 20 ° C. The mixture was stirred at 20 ° C for 1 hour. 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]pyridine-6-amine (52.4 mg, 265.10 μmol, 90% yield, hydrochloride) as a light yellow solid. MS: m / z 162.1 [M+H] + .

[0545] Intermediate 12

[0546]

[0547] Step a: At 20 ° C, to a mixture of 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (800 mg, 3.32 mmol) in toluene (30 mL) was added diphenylmethamine (902.09 mg, 4.98 mmol, 835.27 μL), sodium tert-butoxide (574.03 mg, 5.97 mmol), Pd2(dba)3 (303.87 mg, 331.83 μmol) and [1-(2-diphenylphosphino-1-naphthyl)-2-naphthyl]-diphenyl-phosphine (413.25 mg, 663.67 μmol). Under N2 atmosphere, the mixture was stirred at 130 ° C for 16 hours. The mixture was filtered and the filtrate was concentrated. Then, water (50 mL) was 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] + .

[0548] Step b: At 20 ° C, HCl (2M, 2.71 mL) was added to a mixture of N-(diphenylmethylene)-8-methoxy-2-methylimidazo[1,2-a]pyridine-6-amine (1 g, 2.93 mmol) in THF (10 mL). The mixture was stirred for 2 hours at 20 ° C under an N2 atmosphere. The mixture was concentrated under reduced pressure. The aqueous phase was adjusted to pH 3-4 with HCl (2N) and extracted with DCM (50 mL). Then, saturated NaOH (1N) was added to the aqueous phase to adjust the pH to 14 and extracted with DCM (100 mL). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 8-methoxy-2-methylimidazo[1,2-a]pyridine-6-amine (200 mg, 1.13 mmol, 39% yield) as a yellow-brown solid. MS: m / z 178.2[M+H] + .

[0549] Intermediate 13

[0550]

[0551] Step a: Under N2 atmosphere, toluene (1 mL) and diphenylmethanamine (94.95 mg, 523.91 μmol, 87.92 μL) were added 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). The reaction mixture was stirred at 110 ° C for 12 hours. The reaction mixture was concentrated and the residue was purified by column flash chromatography (0% to 60% EtOAc in heptane) to obtain N-(7-fluoro-2-methyl-indazole-5-yl)-1,1-diphenyl-methanamine (107.3 mg, 325.77 μmol, 74% yield) as a light yellow solid. MS: m / z 330.1[M+H] + .

[0552] Step b: At 20 ° C, to a mixture of N-(7-fluoro-2-methyl-indazole-5-yl)-1,1-diphenyl-formimine (107.3 mg, 325.77 μmol) in THF (2 mL) was added hydrochloric acid (4M in dioxane, 244.33 μL). 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-indazole-5-amine (36.1 mg, 218.57 μmol, 67% yield) as a light yellow solid. MS: m / z 166.0[M+H] + .

[0553] Intermediate 14

[0554]

[0555] 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-trioxatriphosphine 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 in 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] + .

[0556] Intermediate 15

[0557]

[0558] 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 hours, then concentrated and then purified by flash column chromatography (0-15% MeOH:DCM, 12 minutes). The identified eluted fractions were collected and concentrated to obtain 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, yield 91.64%, purity 98%) as a light brown white plastic solid. MS: m / z 358.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δppm 2.38-2.41(m,3H)2.73-2.75(m,3H)7.58-7.65(m,1H)7.96-8.01(m,1H)8 .43-8.49(m,1H)8.56-8.61(m,1H)9.12-9.17(m,1H)11.31-11.36(m,1H).

[0559] Intermediate 16

[0560]

[0561] 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 at 50°C under N2 atmosphere for 16 hours. The reaction mixture was filtered and concentrated to give (E)-1-(5-bromo-2,3-difluoro-4-methoxy-phenyl)-N-methoxy-formylidene (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-formanimine (2.6 g, 9.28 mmol) in THF (30 mL) was added NH2NH2 at 25°C under N2 atmosphere. .H2O (9.89 g, 197.56 mmol, 8.2 mL). The mixture was stirred at 80 ° C and N2 for 90 hours. 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 layer was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 9 / 2) to give 5-bromo-7-fluoro-6-methoxy-1H-indazole (2 g, 8.16 mmol, yield 87.92%) as a light yellow solid. MS: m / z 246.9[M+H] + .

[0562] 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 hours. The mixture was filtered and concentrated to give 5-bromo-7-fluoro-6-methoxy-2-methyl-indazole (5.9 g, 22.77 mmol, yield 85.85%). MS: m / z 259.0 [M+H] + .

[0563] Step c: A mixture of 5-bromo-7-fluoro-6-methoxy-2-methyl-indazole (5.9 g, 22.77 mmol), diphenylmethamine (6.19 g, 34.16 mmol, 5.73 mL), sodium 2-methylpropan-2-ol (6.57 g, 68.32 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (1.81 g, 2.28 mmol) in dioxane (100 mL) was degassed and purged with N2 three times. The mixture was stirred at 90° C. under N2 atmosphere for 3 hours. 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-formanimine (5.7 g, 15.86 mmol, yield 69.64%). MS: m / z 360.1 [M+H] + .

[0564] Step d: A mixture of N-(7-fluoro-6-methoxy-2-methyl-indazol-5-yl)-1,1-diphenyl-formanimine (5.7 g, 15.86 mmol) and HCl / EtOAc (2M, 200.00 mmol, 100 mL) in EtOAc (1000 mL) was stirred at 25 °C for 1 hour. 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). MS: m / z 268.1 [M+H] + . 1 H NMR (400MHz, MeOD) δppm: 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).

[0565] Intermediate 17

[0566]

[0567] Step a: To a solution of 5-bromo-4-methoxy-pyridin-2-amine (57 g, 280.74 mmol) in DCM (300 mL) and H2O (300 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazobicyclo[2.2.2]octane ditetrafluoroborate (198.91 g, 561.48 mmol) and the mixture was stirred at 25 °C for 3 h.

[0568] The aqueous phase was adjusted to pH 8 with NaHCO3 and extracted with DCM (200 mL×3). The organic layers were combined and 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] + .

[0569] Step b: 1-Chloropropan-2-one (18.78 g, 202.97 mmol, 16.16 mL) was added to a solution of 5-bromo-3-fluoro-4-methoxy-pyridin-2-amine (4.5 g, 20.36 mmol) in EtOH (50 mL). The mixture was stirred at 100 ° C for 8 hours. The mixture was concentrated in vacuo and redissolved in H2O (100 mL) and adjusted to pH 8 with NaHCO3. Then, the mixture was re-extracted with ethyl acetate (3×60 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4 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] + .

[0570] 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), Cs2CO3 (15.59 g, 47.86 mmol) in dioxane (100 mL) was degassed and purged with N2 three times, and then BrettPhos Pd G3 (6.51 g, 7.18 mmol) was added. The mixture was stirred at 100 ° C for 2 hours under N2. The residue was diluted with H2O (200 mL) and extracted with ethyl acetate (100 ml×4). The organic phases were combined and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 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, yield 75.74%) as a yellow solid. MS: m / z 237.9 [M+H] + .

[0571] Step d: HCl (12M, 129.62mmol, 10.80mL) was added to a solution of N-(8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-yl)acetamide (4.1g, 17.28mmol) in MeOH (60mL). The mixture was stirred at 60°C for 3 hours. The reactant was concentrated, diluted with H2O (100ml) and adjusted to pH 7 with NaHCO3. The mixture was extracted with ethyl acetate (100ml×3). The organic layers 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 0 / 1) to give 8-fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-amine (1.8g, 9.22mmol, 53.36% yield) as a gray solid. MS: m / z 195.9[M+H] + .

[0572] Intermediate 18

[0573]

[0574] 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-trioxatriphosphine-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 flash column chromatography (0% to 10% MeOH in 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] + .

[0575] Intermediate 19

[0576]

[0577] At 25 ° C, HATU (373.75 mg, 982.96 μmol) and DIPEA (127.04 mg, 982.96 μmol, 171.21 μL) were added 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-indazole-5-amine (127.91 mg, 655.31 μmol) in DMF (3 mL) in one portion. 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 under vacuum 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] + .

[0578] Intermediate 20

[0579]

[0580] 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, yield 39.26%, purity 61.95%) as a yellow solid. MS: m / z 373.1 [M+H] + .

[0581] Intermediate 21

[0582]

[0583] Step a: 5-bromo-2,7-dimethyl-pyrazolo[3,4-c]pyridine (400 mg, 1.77 mmol), sodium 2-methylpropan-2-ol (340.08 mg, 3.54 mmol) and Pd-binap-G3 (175.52 mg, 176.93 μmol) were added to a microwave vial, evacuated and refilled with N2 three times. Then, diphenylformimine (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 hours. Then, the reaction mixture was 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-diphenyl-methanimine (454.9 mg, 1.39 mmol, yield 78.77%). MS: m / z 327.1 [M+H] + .

[0584] Step b: At 20 ° C, to a mixture of N-(2,7-dimethylpyrazolo[3,4-c]pyridin-5-yl)-1,1-diphenyl-formimine (454.9 mg, 1.39 mmol) in THF (4 mL) was added hydrochloric acid (4M, 1.05 mL). The reaction was stirred at 20 ° C for 1 hour. The mixture was concentrated, and then dioxane and toluene were added. The mixture was filtered and the precipitate was collected to obtain 2,7-dimethylpyrazolo[3,4-c]pyridin-5-amine (245.6 mg, 1.24 mmol, yield 88.71%, hydrochloride) as a light yellow solid. MS: m / z 163.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δppm 2.90 (s, 3H), 4.28 (s, 3H), 6.94 (s, 1H), 8.42 (s, 1H).

[0585] Intermediate 22

[0586]

[0587] 8-Fluoro-7-methoxy-2-methyl-imidazo[1,2-a]pyridine-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) were added to a solution of 6-chlorothieno[2,3-b]pyridine-2-carboxylic acid (200 mg, 936.15 μmol) in DMF (10 mL). The reaction mixture was stirred at 25 ° C for 2 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, 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, yield 94.90%, purity 99.2%) as a yellow solid. MS: m / z 391.0 [M+H] + .

[0588] Intermediate 23

[0589]

[0590] 7-Fluoro-2-methyl-indazol-5-amine (83.34 mg, 504.59 μmol, hydrochloride) 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-trioxatriphosphine 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 in 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] + .

[0591] Intermediate 24

[0592]

[0593] 2,7-Dimethylpyrazolo[3,4-c]pyridin-5-amine (111.58 mg, 561.69 μmol, hydrochloride) 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-trioxatriphosphine 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 in 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]+

[0594] Section 3. Synthetic Methods for Preparing the Disclosed Compounds

[0595] Example 1 - Compound 2

[0596]

[0597] 6-Chloro-N-(2,7-dimethylindazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide (25.78 mg, 69.36 μmol, 1.0 eq.) was dissolved in dioxane (346.80 μL), and potassium tert-butoxide (31.13 mg, 277.44 μmol) was added. Then, (2R, 6S)-2,6-dimethylpiperazine (11.9 mg, 104.04 μmol, 1.5 eq.) was added to the solution, followed by heating at 120°C for 6 hours, followed by concentration, and then redissolved in DMSO, filtered and purified by preparative HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA) to obtain N-(2,7-dimethylindazol-5-yl)-6-[(3S, 5R)-3,5-dimethylpiperazin-1-yl]thieno[2,3-b]pyridine-2-carboxamide (9.7 mg, yield 25%) as an orange oil. MS: m / z 435.3 [M+H] + ; RT: 1.17min (Method 3). 1H NMR(600MHz,DMSO-d6)δppm 1.19(br dd,J=11.25,6.68Hz,2H)1.29-1.34(m,6H)2.52-2.55(m,3H)2.83-2.89(m,2H)4.11-4.19(m,3H)4.58-4.65(m,2H)7.24-7 .27(m,1H)7.96-8.00(m,1H)8.13-8.19(m,2H)8.25-8.29(m,1H)8.52-8.59(m,1H)9.11-9.17(m,1H)10.22-10.25(m,1H).

[0598] Using the procedure described in Example 1 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0599]

[0600] Example 2 - Compound 1

[0601]

[0602] N,N-dimethylpyrrolidin-3-amine (42.64 mg, 373.39 μmol, 2.0 eq.), 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 eq.) and DIPEA (560.09 μmol, 97 μL, 3.0 eq.) were dissolved in dioxane (933 μL, 0.2 M) and heated to 80° C. for 16 hours, then concentrated, then redissolved in a small amount of DMSO, filtered, and subjected to reverse phase HPLC purification (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; 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, yield 30%) as a brown oil. MS: m / z 421.1 [M+H] +; RT 0.87min (Method 3). 1H NMR(600MHz,DMSO-d6)δppm 2.20-2.27(m,1H)2.44-2.49(m,3H)2.83-2.97(m,6H)3.47-3.53(m,2H)3.63-3.69(m,1H)3.75-3.81(m,1H)3.97-4.06 (m,2H)6.75-6.84(m,1H)7.89-8.02(m,1H)8.14-8.24(m,2H)9.50-9.57(m,1H)9.94-10.11(m,1H)10.77-10.86(m,1H).

[0603] Using the procedure described in Example 2 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0604]

[0605]

[0606]

[0607]

[0608] Example 3 - Compound 3

[0609]

[0610] 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 eq.) 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 eq.), potassium tert-butoxide (25.56 mg, 227.8 μmol) and DIPEA (85.4 μmol, 15 μL). The solution was heated at 120°C for 72 hours, then concentrated, then redissolved in DMSO, filtered, and purified by reverse phase HPLC purification (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; 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, yield 34%) as an orange oil. MS: m / z 422.2 [M+H] +; RT 0.88 min (Method 3). 1 H NMR(400MHz,DMSO-d6)δppm 2.36-2.42(m,3H)2.42-2.46(m,3H)2.52-2.57(m,2H)2.71-2.78(m,3H)2.83-2.88(m,2H)3.13-3.20(m,3H)3.53-3.58(m,2H)4.53-4.60 (m,2H)7.14-7.18(m,1H)7.95-8.00(m,1H)8.12-8.16(m,1H)8.38-8.41(m,1H)9.10-9.13(m,1H)9.82-9.90(m,1H)10.99-11.04(m,1H).

[0611] Using the procedure described in Example 3 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0612]

[0613]

[0614]

[0615] Example 4 - Compound 6

[0616]

[0617] N,N-Dimethylpyrrolidin-3-amine (26.68 mg, 142.59 μmol, dihydrochloride, 2.0 eq.) 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 eq.) were dissolved in dioxane (356 μL, 0.2 M), followed by the addition of DIPEA (178.2 μmol, 31 μL, 2.5 eq.). The solution was heated at 120°C for 72 hours, then concentrated, redissolved in DMSO, filtered, and purified by reverse phase HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; 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, yield 26%) as an orange oil. MS: m / z 422.2 [M+H] +; RT 0.82min (method 3); 1 H NMR(400MHz,DMSO-d6)δppm 2.38-2.44(m,3H)2.84-2.96(m,6H)3.66(br d,J=4.50Hz,2H)3.73-3.82(m,3H)3.98-4.07(m,2H)6.74-6.79(m,1H)8.01-8.05(m,1H)8.07-8.12( m,1H)8.34-8.38(m,1H)8.86-8.89(m,1H)9.25-9.28(m,1H)10.01-10.11(m,1H)11.01-11.07(m,1H).

[0618] Example 5 - Compound 66

[0619]

[0620] 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, yield 28%) as a yellow solid. MS: m / z 451.0 [M+H] + ; RT 1.53 min (Method 7).

[0621] Using the procedure described in Example 5 above, other compounds described herein are prepared by substituting the appropriate amine and amide starting materials, suitable reagents and reaction conditions in step a to obtain, for example, compounds selected from the following:

[0622]

[0623]

[0624]

[0625]

[0626] Example 6 - Compounds 67 and 68

[0627]

[0628] 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 umol, 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, which 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 0.71min (Method 7)

[0629] 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 2M 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) as a white solid. MS: m / z 439.0 [M+H] +; RT 1.53min (Method 7), which was separated by preparative SFC (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: 40% to 40% of 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 (3.4mg, 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, yield 47%), all as white solids. MS: m / z 439.1 [M+H] + ; RT 1.50 min (Method 7).

[0630] Using the procedure described in Example 5 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0631]

[0632]

[0633] Example 7 - Compound 10

[0634]

[0635] 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (14.81 mg, 89.66 μmol, 1.1 eq.) 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 eq.) and T3P (155.61 mg, 244.54 μmol, 145.57 μL, 50% purity in ethyl acetate, 3.0 eq.). Then, the solution was stirred at room temperature for 16 hours, after which it was concentrated, redissolved in a small amount of DMSO, filtered, and purified by reverse phase HPLC purification (column: XSelect CSH Prep C18 5um OBD 19×100mm; mobile phase A: MeCN; mobile phase B: H2O, modifier: 0.1% NH4OH) to obtain 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, yield 74%) as a brown oil. MS: m / z 439.1[M+H] + ; RT 1.07 min (Method 3). 1 H NMR(600MHz,DMSO-d6)δppm 2.20-2.27(m,1H)2.36-2.42(m,3H)2.86-2.91(m,6H)3.48(br s,2H)3.66(br d,J=4.58Hz,1H)3.75-3.78(m,1H)3.99-4.05(m,2H)6.76-6.80(m,1H)7.47-7.55( m,1H)8.01-8.15(m,2H)9.07-9.12(m,1H)9.96-10.04(m,1H)10.53-10.59(m,1H).

[0636] Using the procedure described in Example 7 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0637]

[0638]

[0639] Example 8 - Compound 54

[0640]

[0641] 6-[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 83.81 μmol, 1.0 eq.) 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 eq.) and T3P (148 μL, 251.42 μmol, 50% purity in ethyl acetate, 3.0 eq.). Then, the solution was stirred at 50° C. for 4 hours, after which it was concentrated, redissolved in a small amount of DMSO, filtered, and purified by HPLC purification (column: XSelect CSH Prep C185um OBD 19×100mm; mobile phase A: MeCN; mobile phase B: H2O, modifier: 0.1% NH4OH) to obtain 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, yield 28%) as a brown oil. MS: m / z 439.2[M+H] + ; RT 0.89 min (Method 3).

[0642] Using the procedure described in Example 8 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0643]

[0644] Example 9 - Compound 55

[0645]

[0646] 6-[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]thieno[2,3-b]pyridine-2-carboxylic acid (25 mg, 85.80 μmol, 1.0 eq.) 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 eq.) and T3P (163.80 mg, 257.4 μmol, 3.0 eq., 50% pure in ethyl acetate). Then, the solution was stirred at 50° C. for 4 hours, after which it was concentrated, redissolved in a small amount of DMSO, filtered, and purified by HPLC purification (column: XSelect CSH Prep C185um OBD 19×100mm; mobile phase A: MeCN; mobile phase B: H2O, modifier: 0.1% NH4OH) to obtain 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, yield 19%). MS: m / z 439.2[M+H] + ; RT 0.90 min (Method 3). 1 H NMR(600MHz,DMSO-d6)δppm 1.81-1.90(m,1H)2.17-2.21(m,1H)2.23-2.30(m,6H)2.33-2.38(m,3H)2.82-2.91(m,1H)3.19-3.26(m,1H)3.40-3.47(m,1H)3.65-3.73 (m,1H)3.75-3.82(m,1H)6.67-6.72(m,1H)7.27-7.34(m,1H)7.88-7.93(m,1H)8.03-8.10(m,2H)8.98-9.02(m,1H)10.35-10.40(m,1H).

[0647] Using the procedure described in Example 9 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0648]

[0649]

[0650] Example 10 - Compound 8

[0651]

[0652] Step a: To a vial containing 8-fluoro-2-methyl-imidazo[1,2-a]pyridine-6-amine (50.16 mg, 303.68 μmol) and 5-chlorofurano[3,2-b]pyridine-2-carboxylic acid (50 mg, 253.07 μmol) was added 2,4,6-tripropyl-1,3,5,2,4,6 trioxatriphosphine 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). 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 light yellow solid. MS: m / z 345.0 [M+H] + ; RT 0.52min (Method 4)

[0653] 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-diphenylphosphino-1-naphthyl)-2-naphthyl]-diphenylphosphine (8.04 mg, 12.91 μmol), sodium tert-butoxide (18.61 mg, 193.63 μmol) was evacuated and refilled with N2 three times. Then, tetrahydrofuran (1 mL) and (3S)-N,N-dimethylpyrrolidin-3-amine (44.22 mg, 387.26 μmol) were added under N2 atmosphere. The reaction mixture was stirred at 90 °C for 12 hours. 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: H2O; 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, yield 71%). MS: m / z 423.1 [M+H] + ; RT 0.73 min (Method 3).

[0654] Using the procedure described in Example 10 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0655]

[0656] Example 11 - Compound 9

[0657]

[0658] Step a: N, N-dimethylpyrrolidin-3-amine (57.83 mg, 309.05 μmol, dihydrochloride, 3.0 eq.), 5-chlorothiazolo[5,4-b]pyridine-2-carboxylic acid ethyl ester (25 mg, 103.02 μmol, 1.0 eq.) and DIPEA (13.31 mg, 103.02 μmol. 1.0 eq.) were dissolved in dioxane (515.08 μL, 0.2 M), heated to 80 ° C. for 16 hours, then the crude product was injected into the normal phase and purified by 0-25% MeOH:DCM over 3.5 minutes. The product was eluted at 22% methanol. 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 wet beige solid, which was used as is (assumed 100% yield). MS: m / z 321.1 [M+H] + ; RT 0.49min (Method 4)

[0659] Step b: Ethyl 5-[3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylate (121.31 mg, 318.03 μmol, 1.0 eq.) 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 eq.). The solution was then heated to 80 °C and stirred for 16 hours, then concentrated and carried forward as crude 5-[3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylic acid (50.8 mg, 52% yield) as an off-white solid. MS: m / z 293.0 [M+H] + ; RT 0.35min (Method 4)

[0660] Step c: 5-[3-(Dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylic acid (50.80 mg, 165.07 μmol, 1.0 eq.) was dissolved in acetonitrile (695.04 μL, 0.24 M), followed by the addition of 2-methylimidazo[1,2-a]pyridine-6-amine (24.29 mg, 165.07 μmol, 1.0 eq.), HATU (69.04 mg, 181.58 μmol, 1.1 eq.) and DIPEA (46.93 mg, 363.16 μmol, 2.2 eq.). The solution was then stirred at room temperature for 3 hours, after which it was concentrated and redissolved in a small amount of DMSO, filtered, and purified by reverse phase HPLC purification (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA) to obtain 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, yield 13%) as a brown solid. MS: m / z 422.2 [M+H] + ; RT 0.87min (Method 3)

[0661] Example 12 - Compound 84

[0662]

[0663] 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)Cl2 (8.32 mg, 11.36 μmol), K2CO3 (31.41 mg, 227.28 μmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (35.14 mg, 113.64 μmol). The mixture was stirred at 90°C under N2 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 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-carboxylic acid tert-butyl ester (30 mg, yield 50%). MS: m / z 508.0 [M+H] + ; RT 0.43min (Method 7)

[0664] Step b: To a stirred solution of 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-carboxylic acid tert-butyl ester (10 mg, 19.70 μmol) in DCM (1 mL) was added 4M 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 / z407.8[M+H] + ; RT 0.25min (Method 7); 1H NMR (400MHz, methanol-d4) δ=9.44(s,1H),8.35(d,J=8.4Hz,1H),8.24(s,1H),8.12(s,1H),8.01(d,J=12.8Hz,1H),7.89(d,J=8.4Hz,1H),7.08-7.06(m,1H),4.35(d,J=1.6Hz,2H),3.45-3.42(m,2H),2.72-3.71(m,2H),2.58(s,3H).

[0665] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting the appropriate boronate starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0666]

[0667]

[0668] Example 13 - Compounds 81 and 82

[0669]

[0670] 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 umol) in MeOH (10 mL) was added Pd / C (6.71 mg, 63.04 umol) under N2. The mixture was stirred at 25°C under 50 psi of H2 for 12 h. 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, yield 27%) as a white solid. MS: m / z 510.2 [M+H] + ; RT 0.42min (Method 7), by preparative SFC (column: Chiralpak AD-3 50×4.6mm ID, 3um, mobile phase: A phase is CO2, and B phase is IPA (0.05% DEA); isocratic elution: 40% in A B, flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar) was further purified to obtain (3R)-3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylic acid tert-butyl ester and (3S)-3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylic acid tert-butyl ester.

[0671] Step b: In a separate vial, (3R)-3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylic acid tert-butyl ester (10.00 mg, 19.62 umol) and (3S)-3-[2-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyridin-6-yl]piperidine-1-carboxylic acid tert-butyl ester (10.00 mg, 19.62 umol) were dissolved in DCM (1 mL) and treated 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-piperidinyl]thieno[2,3-b]pyridine-2-carboxamide (1.6 mg, yield 19%). MS: m / z 410.0 [M+H] +; RT 0.26min (Method 7); 1 H NMR (400MHz, methanol-d4) δ = 9.41 (s, 1H), 8.37 (d, J = 8.4Hz, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.94(d,J=12.0Hz,1H),7.52(d,J=8.4Hz,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-piperidinyl]thieno[2,3-b]pyridine-2-carboxamide (3.8 mg, yield 45%), all yellow solids. MS: m / z 410.0 [M+H] + ; RT 0.25min (Method 7); 1H NMR (400MHz, 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=8.4Hz, 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).

[0672] Using the procedure described in Example 5 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0673]

[0674]

[0675] Example 14 - Compound 86

[0676]

[0677] Step a: 6-bromofurano[3,2-b]pyridine-2-carboxylic acid (200 mg, 826.36 μmol) was dissolved in ethanol (10 mL), followed by the addition of HCl in dioxane (4 M, 619.77 μL). The solution was then stirred at 80 °C for 16 hours and then concentrated to afford ethyl 6-chlorothieno[2,3-b]pyridine-2-carboxylate (ethyl 6-bromofurano[3,2-b]pyridine-2-carboxylate (244 mg)) as an off-white powder, which was used crude. MS: m / z 271.9 [M+H]+.

[0678] A microwave vial containing 6-bromofurano[3,2-b]pyridine-2-carboxylic acid ethyl ester (55.80 mg, 183.86 μmol), cesium carbonate (179.72 mg, 551.59 μmol), (5-diphenylphosphino-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphine (21.28 mg, 36.77 μmol) and tris(dibenzylideneacetone)dipalladium (16.84 mg, 18.39 μmol) was evacuated and refilled three times with N2. Then, dioxane (1 mL) and N,N-dimethylpyrrolidin-3-amine (41.99 mg, 367.73 μmol) were added under N2 atmosphere. The reaction mixture was stirred at 90 °C for 12 hours. The mixture was concentrated in vacuo and purified by flash silica gel chromatography (MeOH / CH2Cl2 / =0 to 10 / 1) to obtain ethyl 6-[3-(dimethylamino)pyrrolidin-1-yl]furo[3,2-b]pyridine-2-carboxylate (28.4 mg, yield 51%). MS: m / z 304.1 [M+H]+.

[0679] 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), and then lithium hydroxide (2.99 mg, 125.06 μmol, 1.5 eq.) was added. 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]+.

[0680] 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-(ethyliminomethylamino)-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 overnight at room temperature and at 40°C, then concentrated, redissolved in DMSO, filtered, and purified by HPLC purification (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; 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, yield 7.39%). MS: m / z 423.1 [M+H]+; RT 0.79 min (Method 3). 1 H NMR(600MHz, DMSO-d6)δppm1.87(m,1H)2.17-2.22(m,1H)2.24(s,7H)2.35(s,3H)2.84-2.89(m,1H)3.18(t,J=8.77Hz,1H)3.52(t,J=8.39Hz,1H)3.5 9(m,1H)7.09(d,J=1.53Hz,1H)7.37(d,J=12.59Hz,1H)7.76(s,1H)7.93(d ,J=2.67Hz,1H)8.17(d,J=2.29Hz,1H)9.08(d,J=0.76Hz,1H)10.50(s,1H).

[0681] Example 15 - Compound 89

[0682]

[0683] Step a: (3R)-N,N-dimethylpyrrolidin-3-amine (35.29 mg, 0.309 mmol, 0.75 eq.), ethyl 5-chlorothiazolo[5,4-b]pyridine-2-carboxylate (100 mg, 0.412 mmol, 1.0 eq.) and DIPEA (106.51 mg, 0.824 mmol, 2.0 eq.) were dissolved in dioxane (1 mL, 0.4 M) and then heated to 80° C. for 16 hours. The solution was then concentrated by biotage V10, then redissolved in a small amount of methanol and purified by 0-20% MeOH:DCM over 7 minutes. The product was eluted at about 10% MeOH. Obtained ethyl 5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thiazolo[5,4-b]pyridine-2-carboxylate (47.3 mg, 0.148 mmol, yield 35.9%). MS: m / z 321.0.[M+H] + ; RT 0.50 min (Method 4).

[0684] Step b: 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (17.73 mg, 107.32 umol, 1.2 eq.) and 5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]thiazo[5,4-b]pyridine-2-carboxylic acid methyl ester (27.4 mg, 89.43 umol, 1.0 eq.) were dissolved in toluene (447.15 uL, 0.2 M), followed by the addition of LiHMDS (1 M, 178.86 umol, 178.86 uL, 2.0 eq.). The solution was then stirred at room temperature for 16 hours, after which it was concentrated and then redissolved in a small amount of DMSO, water and methanol, then filtered and directly injected into the reverse phase under acidic conditions. The identified eluted fractions were collected, combined, and concentrated to obtain 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, yield 39.2%) was obtained. MS: m / z 440.2.[M+H] + ; RT 0.42 min (Method 3). 1H NMR (400MHz, methanol-d4) δppm 2.32-2.43(m,1H)2.55-2.59(m,3H)2.62-2.67(m,1H)2.99-3.05(m,6H)3.60-3.69(m,1H)3.79-3.86(m,1H) 3.87-3.94(m,1H)4.06-4.19(m,2H)6.87-6.93(m,1H)8.09-8.14(m,2H)8.21-8.27(m,1H)9.44-9.48(m,1H).

[0685] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in steps a and b to obtain, for example, a compound selected from the following:

[0686]

[0687]

[0688]

[0689]

[0690]

[0691] Example 16 - Compounds 140 and 139

[0692]

[0693] Step a: At 20°C, 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 eq.), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine- To a mixture of tert-butyl 1-formate (90 mg, 266.86 umol, 1.0 eq.) and K2CO3 (110.64 mg, 800.57 umol, 3.0 eq.) in dioxane (2 mL, 133 mM) and water (0.4 mL, 133 mM) were added di-tert-butyl (cyclopentyl) phosphine; dichloropalladium; iron (17.39 mg, 26.69 umol, 0.1 eq.) The mixture was stirred at 90°C for 1 hour. The reaction mixture was concentrated to give a crude product, which was purified by preparative TLC (DCM: MeOH = 10 / 1) to give 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-carboxylic acid tert-butyl ester (70 mg, 130.45 umol, yield 48.88%) as a yellow solid. MS: m / z 537.3.[M+H] + ; RT 0.95 min (Method 7).

[0694] 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 eq.) in DCM (2 mL, 56 mM) was added HCl / dioxane (2 mL, 70 eq.) at 20° C. The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated to give a crude product, which was purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 um; conditions: water (FA)-ACN, start B3, end B18, gradient time (min) 12, 100% B holding time (min) 2, flow rate (mL / min) 25, injection number 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 umol, yield 52.25%) as a white solid. MS: m / z 437.1.[M+H]+ ; RT 1.65 min (Method 8).

[0695] 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 eq.) in MeOH (20 mL, 2.86 mM) was added Pd / C (60.95 mg, 57.27 umol, 10% purity, 1.0 eq.) at 20° C. The mixture was stirred at 20° C. under H2 (15 psi) for 16 h. The reaction mixture was filtered and concentrated to give a crude product, which was purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 um; conditions: water (HCl)-ACN, start B10, end B 40, gradient time (min) 10, 100% B hold time (min) 2, flow rate (mL / min) 25, injection number 1.) to give 5-[(2S,6R)-2,6-dimethyl-4-piperidinyl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)thiazolo[5,4-b]pyridine-2-carboxamide (2.2 mg, 5.02 umol, yield 8.76%) as a yellow solid. MS: m / z 439.1.[M+H] + ; RT 1.63min (Method 8)

[0696] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate boronic acid / boronic ester and amide starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0697]

[0698]

[0699] Example 17 - Compound 268

[0700]

[0701] 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 ground 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 0.423min (Method 9)

[0702] Step b: 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 to a solution of (1R,5R)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylic acid tert-butyl ester (17 mg, 83 μmol) in dioxane (2 mL). 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 (cold) to give a crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; conditions: water (FA)-ACN, start B 2, end B 32; gradient time (min): 14; 100% B holding time (min): 2; flow rate (ml / min): 25) to give (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-carboxylic acid tert-butyl ester (30 mg, 57 μmol, yield 69%) as a yellow solid. MS: m / z 524.2 [M+H] + ; RT 1.135min (Method 10)

[0703] Step c: To a solution of (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-carboxylic acid tert-butyl ester (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 hours. The mixture was quenched with water (30.0 mL) and extracted with ethyl acetate (20.0 mL×3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered and concentrated in vacuo (cold) to give 3-[(1S,5R)-3,6-diazabicyclo[3.2.0]hept-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 1.300min (Method 8)

[0704] Step d: To a solution of 3-[(1S,5R)-3,6-diazabicyclo[3.2.0]hept-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 hours. Then, NaCNBH3 (8 mg, 118 μmol) was added to the mixture. The mixture was stirred at 25 ° C 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 Na2SO4, filtered and concentrated in vacuo (cold) to give a crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; conditions: water (FA)-ACN, starting B 2, ending B 32; gradient time (min): 14; 100% B holding 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]hept-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 1.17min (Method 10)

[0705] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in steps a and b to obtain, for example, a compound selected from the following:

[0706]

[0707]

[0708] Example 18 - Compounds 147 and 148

[0709]

[0710] 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) was added K2CO3 (138 mg, 995 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (103 mg, 332 μmol) and PdCl2(dppf) (24 mg, 33 μmol). The mixture was stirred at 90° C. for 2 hours under N2. 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 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-carboxylic acid tert-butyl ester (100 mg, 197 μmol) was obtained as a yellow solid. MS: m / z 509.4 [M+H] + ; RT 0.392min (Method 9)

[0711] Step b: Under argon, tert-butyl 4-[6-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyrazine-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (20 mg, 39 μmol) was added to MeOH (10 mL). Pd / C (20 mg, 188 μmol) was added to the mixture under argon. Then, the mixture was stirred for 16 hours at 25 ° C and 35 Psi H2. 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 in vacuo (low temperature) to give a crude product. The crude product was purified by silica gel column chromatography (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 min (Method 10).

[0712] Step c: tert-Butyl 4-[6-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]thieno[2,3-b]pyrazine-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 Na2SO4, filtered and concentrated in vacuo (low temperature) to give a crude product. The crude product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; conditions: water (FA)-ACN, start B 2, end B 32; gradient time (min): 14; 100% B holding time (min): 2; flow rate (ml / min): 25) to give N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-3-(4-piperidinyl)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 min (Method 10).

[0713] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate boronic acid / boronic ester and amide starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0714]

[0715]

[0716] Example 19 - Compound 152

[0717]

[0718] Step a: (3S)-N,N-dimethylpyrrolidin-3-amine (49.94 mg, 437.3 mmol, 1.0 eq.), methyl 2-chlorothieno[2,3-d]pyrimidine-6-carboxylate (100 mg, 437.3 mmol, 1.0 eq.) and DIPEA (113 mg, 875 mmol, 2.0 eq.) were dissolved in dioxane (1 mL, 0.44 M) and then heated to 80° C. for 16 hours. The solution was then concentrated by biotage V10 before being redissolved in a small amount of methanol and purified by 0-20% MeOH:DCM over 7 minutes. The product eluted at 10% MeOH. The identified eluted fractions were collected, combined, and concentrated to obtain methyl 2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-d]pyrimidine-6-carboxylate (111.3 mg, 363 mmol, yield 83%). MS: m / z 307.0.[M+H] + ; RT 0.45min (Method 4)

[0719] Step b: 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (16.17 mg, 97.92 umol, 1.2 eq.) and 2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (25.00 mg, 81.60 umol, 1.0 eq.) were dissolved in toluene (407.99 uL, 0.2 M), followed by the addition of LiHMDS (1 M, 163.19 umol, 2.0 eq.). The solution was then stirred at room temperature for 16 hours, after which it was concentrated, then redissolved in DMSO, methanol, and water, filtered, and directly injected into the reverse phase under acidic conditions. The identified eluted fractions were collected and concentrated, and then registered as is. 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 (400MHz, methanol-d4) δppm 2.30-2.40(m,1H)2.54-2.57(m,3H)2.58-2.65(m,1H)2.99-3.02(m,6H)3.66-3.74(m,1H)3.82-3.88(m,1H)3.96-4.04(m,1H) 4.05-4.13(m,1H)4.18-4.25(m,1H)7.94-7.99(m,1H)8.06-8.08(m,1H)8.08-8.10(m,1H)8.91-8.94(m,1H)9.37-9.40(m,1H). MS:m / z 440.2.[M+H] + ; RT 0.43 min (Method 4).

[0720] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in steps a and b to obtain, for example, a compound selected from the following:

[0721]

[0722] Example 20 - Compound 153

[0723]

[0724] 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 chloride (2M, 824.05 μL) and N,N-diethylethylamine (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 to 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 an off-white solid. MS: m / z 361.1 [M+H] + .

[0725] 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-ol (19.98 mg, 207.88 μmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphine (6.28 mg, 6.93 μmol) were added to a microwave vial. The mixture was evacuated and refilled with N2 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: H 2 O; 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, yield 12.18%) as a yellow solid. MS: m / z 361.1 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δppm2.09-2.20(m,1H),2.35(s,3H),2.39(br s,1H),2.55(s,1H),2.59-2.85(m,6H),3.45-3.57(m,2H),3.76(br t,J=8.39Hz,1H),3.94(br s,1H),6.75(d,J=8.77Hz,1H),7.31(d,J=12.59Hz,1H),7.91(d,J=1.91Hz,1H),8.10-8.14(m,2H),9.00(s,1H),10.42(s,1H).

[0726] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate acid starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0727]

[0728] Example 21 - Compound 156

[0729]

[0730] Step a: Dissolve rac-(2S,6R)-4-hydroxy-2,6-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (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) in DMF (1 mL), and then add sodium hydride (9.98 mg, 415.75 μmol). Then, heat the solution to 40 ° C for 16 hours. Concentrate the reaction in vacuo. The crude product is used directly in the next step.

[0731] 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 (4M, 1.11 mmol, 277.17 μL). The mixture was stirred for 2 hours and then concentrated. The residue was purified by HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA) to give 6-[[(2SR,6RS)-2,6-dimethyl-4-piperidinyl]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, yield 15.27%) as a yellow solid. MS: m / z 454.2 [M+H] + ; RT 1.10 min (Method 3).

[0732] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate alcohol and amide starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0733]

[0734] Example 22 - Compound 163

[0735]

[0736] Step a: To a mixture of 5-chlorofurano[3,2-b]pyridine-2-carboxylic acid (20 mg, 101.23 μmol) and 8-fluoro-2-methyl-imidazo[1,2-a]pyridine-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) at 25 °C. The mixture was stirred at 90 °C for 80 minutes. Then, the mixture was 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, yield 60.18%) as a brown solid. MS: m / z 345.1 [M+H] + .

[0737] 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) was added K2CO3 (24.05 mg, 174.05 μmol), Pd(dppf)Cl2 (42.45 mg, 58.02 μmol) and stirred at 90° C. for 6 hours. The mixture was filtered and concentrated to give a 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, yield 66.32%) as a brown solid. MS: m / z 406.2 [M+H] + .

[0738] 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, purity 10%). 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 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column Boston Prime C18 150×30 mm×5 um; condition water (NH3H2O+NH4HCO3)-ACN; start B44; end B 74; gradient time (min) 10; 100% B holding 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-piperidinyl)furo[3,2-b]pyridine-2-carboxamide (4.42 mg, 10.85 μmol, yield 17.59%, purity 100%) as a white solid. MS: m / z 408.2 [M+H] + ; RT 2.572 min (Method 8). 1 H NMR (400MHz, methanol-d4) δppm=9.10(d,J=1.6Hz,1H),8.07(d,J=9.2Hz,1H),7.79-7.74(m,2H),7.50(d,J=8.8Hz,1H),7. 39-7.36(m,1H),3.14(d,J=10.8Hz,2H),2.99-2.90(m,1H),2.46-2.42(m,6H),2.40-2.31(m,2H),2.04-2.02(m,4H).

[0739] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate amine starting material in step a and the boronic acid / boronic ester starting material in step b, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0740]

[0741] Example 23 - Compound 168

[0742]

[0743] Step a: To a solution of 5-chlorofurano[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]pyridine-6-amine (89.69 mg, 506.14 μmol). The mixture was stirred at 25 ° C for 16 hours. Then, the mixture was 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 Na2SO4, filtered and concentrated in vacuo (cryogenically) 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] + .

[0744] 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 (1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylic acid tert-butyl ester (50.02 mg, 252.27 μmol). The mixture was stirred at 80° C. for 2 hours under N2. The mixture was filtered and concentrated. The residue was purified by column chromatography (DCM: MeOH = 10: 1) to give (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-carboxylic acid tert-butyl ester (79 mg, 152.34 μmol, yield 90.58%) as a yellow oil. MS: m / z 519.3 [M+H] + .

[0745] Step c: To a solution of (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-carboxylic acid tert-butyl ester (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 hour. 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] + .

[0746] Step d: To a solution of 5-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-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) was added TEA (36.27 mg, 358.47 μmol, 49.96 μL) and paraformaldehyde (143.33 mg, 119.49 μmol, 162.88 μL). The mixture was stirred at 25 °C for 10 minutes. Then, sodium triacetoxyborate (75.97 mg, 358.47 μmol) was added. The mixture was stirred at 25 °C for 2 hours. The mixture was filtered and concentrated. The residue was purified by HPLC purification (column Boston Prime C18 150×30 mm×5 um; condition water (NH3H2O+NH4HCO3)-ACN; start B 44; end B 74; gradient time (min) 10; 100% B holding time (min) 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]hept-6-yl]furo[3,2-b]pyridine-2-carboxamide (6.27 mg, 14.50 μmol, yield 12.13%) as a yellow solid. MS: m / z 433.1 [M+H] + ; RT 0.663 min (Method 10). 1H NMR (400MHz, methanol-d4) δppm=8.77(d,J=1.2Hz,1H),7.81(d,J=9.2Hz,1H),7.56(s,1H) ,7.48(s,1H),6.91(s,1H),6.51(d,J=9.2Hz,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=11.2Hz,1H),3.26–3.20(m,1H),3.1 5(d,J=10.4Hz,1H),2.46(s,3H),2.38(s,3H),2.28–2.23(m,1H),2.20–2.15(m,1H).

[0747] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate amine starting material, suitable reagents and reaction conditions in steps a and b to obtain, for example, a compound selected from the following:

[0748]

[0749]

[0750]

[0751] Example 24 - Compound 176

[0752]

[0753] 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) and HATU (534 mg, 1.40 mmol) and 8-fluoro-2-methyl-imidazo[1,2-a]pyridine-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]pyridine-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 0.648min (Method 9)

[0754] 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 PdCl2(dppf) (8 mg, 14 mmol). The mixture was degassed with N2 and stirred at 90 °C for 2 hours. The resultant was cooled at room temperature, diluted with water, extracted with EtOAc and concentrated. The crude product was purified by passing through an acidic SCX column, acidified with methanolic HCl and released with 2N methanolic ammonia to give the title compound (21 mg, 0.045 mmol). MS: m / z 464.1 [M+H]+; RT 0.49 min (Method 4)

[0755] 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), 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 hours, then the mixture was cooled to room temperature and filtered on celite, washed with DCM (3×5 mL) and concentrated. The resultant was purified by RPHPLC 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.

[0756] Using the procedure described in Example 15 above, other compounds described herein are prepared by substituting the appropriate amine starting material in step a and the boronic acid / boronic ester starting material in step b, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0757]

[0758]

[0759]

[0760] Example 25 - Compound 210

[0761]

[0762] 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 eq.) in DMF (80 mL, 0.087 M) were added 3,3-dimethoxypyrrolidine (1.82 g, 13.86 mmol, 2.0 eq.), sodium 2-methylpropan-2-ol (2.00 g, 20.79 mmol, 3.0 eq.) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine (1.08 g, 1.39 mmol, 0.2 eq.). The mixture was then stirred at 130° C. for 12 h under N2 atmosphere. The residue was poured into water (100 mL), and the aqueous phase was extracted with EtOAc (100 mL×3). The combined organic phase was washed with water (100 mL×3), brine (200 mL×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 2.067min (Method 10)

[0763] 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 eq.) in ACN (13 mL, 13 mL, 0.2 M) was added HCl (1 M, 2.6 mL, 1.0 eq.). Then, the mixture was stirred at 25 ° C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. DMSO (20 mL) was added to the solid and stirred at 100 ° C for 1 hour. The mixture was cooled to 25°C and filtered, the filter cake was washed with EtOAc (20 mL×3), and the filter cake was concentrated under reduced pressure to obtain 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, yield 58.84%, purity 93.67%) as a yellow solid. MS: m / z 410.1 [M+H] + ; RT 2.367min (Method 10)

[0764] 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 umol, 1.0 eq.) and cyclopropylmethylamine (20.84 mg, 293.09 umol, 6.0 eq.) in MeOH (4 mL, 0.012 M) was added acetic acid (14.67 mg, 244.24 umol, 5.0 eq.) in one portion at 25°C and N2. After half an hour, sodium cyanoborodeuteride (9.21 mg, 146.54 umol, 3.0 eq.) was added. The mixture was stirred at 25°C for 2 hours. The mixture was further purified by preparative HPLC (column Welch Xtimate C18150*25mm*5um, condition water (FA)-ACN, start B 2, end B22, gradient time (min) 12, 100% B holding 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, 21.53umol, yield 44%). MS: m / z 465.3[M+H] + ; RT 0.68min (Method 7), which was further purified by preparative SFC (column: Chiralpak IC 50*4.6mm 3um, mobile phase A: hexane (0.1% DEA), and phase B: IPA / MeCN=2:1, isocratic A / B=40 / 60, flow rate: 1mL / 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.

[0765] Section 3. Bioassays and Data

[0766] HTT mutant and total HTRF iPSC assay protocol

[0767] The in vitro cellular assay measured mutant and total Huntingtin (HTT) protein in human induced pluripotent stem cells (iPSCs) derived from HTT patients with poly-Q49 mutations. Measurements in this assay were performed by homogeneous time-resolved fluorescence (HTRF). The mutant HTT antibody was labeled with the d-2 receptor and recognizes a region within the poly Q region. The terbium (Tb) donor antibody recognizes sequences at the N-terminus of the protein. The total HTT antibody was labeled with the d2 receptor and recognizes sequences outside the poly Q region. For each experiment, frozen iPSC aliquots were thawed from liquid nitrogen storage and cultured in flasks coated with Matrigel (Corning #354227) using complete culture medium (mTeSR TM 1 Plus Basal Medium (STEMCELL Technologies Cat. No. 05825) supplemented with mTeSR TM1 Plus (STEMCELL Technologies catalog number 05852) and penicillin / streptomycin (Gibco catalog number 10378016)) and grown in the presence of 10uM Rock inhibitor (Sigma #Y0503). The flasks containing the cells were incubated overnight at 37°C and 5% CO2 (Thermo), and the next day, the medium was replaced with fresh complete medium without Rock inhibitor and incubated at 37°C and 5% CO2 for 48 hours for cell expansion. Cells were collected from the flasks using Accutase (Gibco #A1110501) and counted on a Cellometer (Nexcelom Vision). A total of 10,000 cells / well were added to a 384-well tissue culture plate (Perkin Elmer #NC1758152) pre-coated with Matrigel in a 30ul volume of complete medium containing 10uM rock inhibitor. The cell plate was centrifuged and the cells were allowed to attach overnight in a high humidity incubator (Thermo Cytomat 10) at 37°C and 5% CO2. The next day, the cells were treated with compounds. The compounds were pre-diluted in complete medium without rock inhibitors using an intermediate plate. The compounds were diluted and distributed into empty 384-well PP plates (Griener#784201) using ECHO (Labcyte#Echo555). A total of 60ul complete medium was added to each well using multidrop Combi (Thermo#5840300). Starting from 10uM, the compounds were tested in 10-point, 3-fold titrations. The culture medium in the cell plate was removed by flicking off the culture medium, and the plate was placed on a tissue and blotted dry. A 50uL volume was transferred from the compound plate to the cell assay plate using Integra (Viaflow384). The cell plate was incubated for 48 hours at 37°C, 5% CO2 and high humidity. Cell lysates were prepared by first removing the culture medium from the plate and then adding 40ul MPER lysis buffer (Thermo #78501) per well containing protease and phosphate inhibitors (Pierce #A32961). The plate was placed on an orbital shaker for 30 minutes at RT and 5ul of cell lysate was transferred to two 384-well black plates (Sigma Aldrich #CLS3821) using an Apricot Dispenser (SPT Labtech). Each plate contained 5ul of mutants per well or 5ul of total HTT HTRF assay mixture per well.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 per well in HTRF assay buffer (CisBio #62SDBRDF), and the MW1 (poly-Q specific)-d2 "acceptor" (Sigma #MABN2427) antibody at a final concentration of 40 ng per well in HTRF assay buffer. The total HTT HTRF assay mix contained 2B7Ab-Tb "donor" N-terminally labeled antibody at a final concentration of 0.4 ng per well in HTRF assay buffer and MAB2166-d2 (anti-huntingtin [1HU-4C8] mAb-d2 "acceptor" antibody) at a final concentration of 40 ng per well in HTRF assay buffer. All antibodies were labeled at Perkin Elmer. The assay plate was sealed and placed on an orbital shaker for one minute, then centrifuged for one minute and then incubated at room temperature for four hours. The plate was read on a PHERAstar instrument (BMG LAB TECH) and the HTRF ratio was calculated from the (337 nm / 665 nm) and (337 nm / 620 nm) outputs. IC. 50 Values ​​are derived from intact concentration-response curves, which are plotted as percent activity versus compound concentration and fit to a variable 4-parameter logistic model.

[0768] IC 50 The results are summarized in Table 2, where "A" represents IC 50 Values ​​less than 100 nM, "B" represents IC 50 The values ​​are between 100 nM and 1 μM, and “C” stands for IC 50 Values ​​ranged between 1 μM and 9 μM.

[0769] Table 2: mHTT protein reduction

[0770]

[0771]

[0772]

[0773]

Claims

1. A compound represented by formula (I'): or a pharmaceutically acceptable salt thereof, wherein: is a single bond or a double bond, provided that the ring containing X1 and X2 is a 5-membered heteroaryl ring; Represents R 1 One of the two positions connected by a dotted line on the 6-membered ring is substituted, and the other position connected by the dotted line is not substituted; Z is –C(=O)NR 2 R 3 or –NR 2 C(=O)R 3 ; X 1 is S or CH; X 2 is N, O or CH; Y 1 and Y 2 One of them is N and the other is CH; R 1 is a 4- to 12-membered heterocyclic group, a 4- to 12-membered carbocyclic group, -NR 11 R 12 , -C 1-6 Alkylene-NR 13 R 14 OR 15 ,in R 1 The 4- to 12-membered carbocyclic group or 4- to 12-membered heterocyclic group represented by A Replace; Each R A Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated 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 4- to 6-membered saturated heterocyclic group; wherein each R a and R b independently H or C 1-6 Alkyl; wherein R A The 4- to 6-membered saturated heterocyclic group represented by 1-6 Alkyl substitution; R 11 Is H or C 1-6 alkyl; R 12 It is C 1-6 alkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein R 12 The C 1-6 Alkyl, 6 to 10 membered aryl, 4 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl are optionally substituted with one or more R B Replace; R B Is halogenated, C 1-6 Alkyl, -NR a R b , 4 to 6 membered heterocyclic group or -C 1-6 Alkylene-4 to 6 membered heterocyclic group; wherein R B The 4 to 6 membered heterocyclic group represented by 1-6 Alkyl substitution; R 13 Is H or C 1-6 alkyl; R 14 and R 15 Independently selected from H, C 1-6 Alkyl or –C 1-6 Alkylene-4-6 membered saturated heterocyclic group; R 2 Is H or C 1-3 alkyl; R 3 is a 6- to 10-membered aryl or 6- to 10-membered heteroaryl group, wherein R 3 The 6- to 10-membered aryl and 6- to 10-membered heteroaryl represented by C Replace; R C It is halogenated, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, or two R C Together with the atoms therebetween, they form a 5- to 7-membered heterocyclic group; wherein R C The 5- to 7-membered heterocyclic group represented by C1 Substitution; wherein R C1 It is C 1-3 alkyl or oxo; and wherein the heterocyclyl contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and the heteroaryl contains 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur; Provided that the compound of formula (I') is not represented by:

2. The compound according to claim 1, wherein the compound is represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: is a single bond or a double bond, provided that the ring containing X1 and X2 is a 5-membered heteroaryl ring; Represents R 1 is substituted at one of the two positions connected by the dashed line on the pyridinyl moiety, 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 a 4- to 12-membered heterocyclic group, -NR 11 R 12 or -C 1-6 Alkylene-NR 13 R 14 ,in R 1 The 4 to 12 membered heterocyclic group represented by A Replace; Each R A Independently C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated 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 4- to 6-membered saturated heterocyclic group; wherein each R a and R b independently H or C 1-6 Alkyl; wherein R A The 4- to 6-membered saturated heterocyclic group represented by 1-6 Alkyl substitution; R 11 Is H or C 1-6 alkyl; R 12 It is C 1-6 alkyl, 6- to 10-membered aryl, 4- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein R 12 The C 1-6 Alkyl, 6 to 10 membered aryl, 4 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl are optionally substituted with one or more R B Replace; R B It is C 1-6 Alkyl, -NR a R b , 4 to 6 membered heterocyclic group or -C 1-6 Alkylene-4 to 6 membered heterocyclic group; wherein R B The 4 to 6 membered heterocyclic group represented by 1-6 Alkyl substitution; R 13 Is H or C 1-6 alkyl; R 14 It is H, C 1-6 Alkyl or -C 1-6 Alkylene-4-6 membered saturated heterocyclic group; R 2 Is H or C 1-3 alkyl; R 3 is a 6- to 10-membered aryl or 6- to 10-membered heteroaryl group, wherein R 3 The 6- to 10-membered aryl and 6- to 10-membered heteroaryl represented by C Replace; R C It is halogenated, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, or two R C Together with the atoms therebetween, they form a 5- to 7-membered heterocyclic group; wherein R C The 5- to 7-membered heterocyclic group represented by C1 Substitution; wherein R C1 It is C 1-3 alkyl or oxo; and wherein the heterocyclyl contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and the heteroaryl contains 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur; Provided that the compound of formula (I) is not represented by:

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (II):

4. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (III):

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (IV):

6. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (V):

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (VI):

8. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (VII):

9. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (VIII):

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 2 It's H.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 It is a 4- to 12-membered saturated heterocyclic group.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, in: 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, the heterocyclyl is optionally replaced by -NR 7 R 8 ,–C 1-3 Alkylene-NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and optionally further substituted with 1 to 4 R 9 and when the heterocyclyl contains two ring N atoms, the heterocyclyl is optionally substituted by 1 to 3 R 9 replace; R 7 and R 8 Each independently is H or C 1-6 Alkyl; or R 7 and R 8 Together with the N to which they are attached, they form an optionally 1 to 2 C 1-6 an alkyl-substituted 4- to 6-membered heterocyclic ring, wherein the 4- to 6-membered heterocyclic ring optionally comprises a second heteroatom selected from N and O; R 9 is independently selected at each occurrence from 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; wherein R 9 The C 3-6 Cycloalkyl is optionally substituted with one or more independently selected from halo and C 1-6 The alkyl group is substituted with a substituent; wherein R 10 It is H, C 1-3 Alkyl or C 3-6 Cycloalkyl.

13. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, in: 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, the heterocyclyl is optionally replaced by -NR 7 R 8 ,–C 1-3 Alkylene-NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and optionally further substituted with 1 to 2 R 9 and when the heterocyclyl contains two ring N atoms, the heterocyclyl is optionally substituted by 1 to 3 R 9 replace; R 7 and R 8 Each independently is H or C 1-6 Alkyl; or R 7 and R 8 Together with the N to which they are attached, they form an optionally 1 to 2 C 1-6 an alkyl-substituted 4- to 6-membered heterocyclic ring, wherein the 4- to 6-membered heterocyclic ring optionally comprises a second heteroatom selected from N and O; R 9 is independently selected at each occurrence from 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; wherein R 9 The C 3-6 Cycloalkyl is optionally substituted with one or more independently selected from halo and C 1-6 The alkyl group is substituted with a substituent; wherein R 10 It is H, C 1-3 Alkyl or C 3-6 Cycloalkyl.

14. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclic group containing one ring N atom and supported by 1 to 4 R 9 replace.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from pyrrolidinyl, piperidinyl, azabicyclo[3.2.1]octyl and azaspiro[3.4]octyl.

16. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from:

17. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclic radical containing one ring nitrogen atom and is substituted by –NR 7 R 8 、 –C 1-3 Alkylene-NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and optionally further substituted with 1 to 2 R 9 replace.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclic group selected from azetidinyl, piperidinyl, pyrrolidinyl, octahydro-1H-isoindolyl and 3-azabicyclo[3.1.0]hexyl, each of which is replaced by -NR 7 R 8 ,–C 1-3 Alkylene-NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and optionally further substituted with 1 to 2 R 9 replace.

19. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 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 and optionally further substituted with 1 to 2 R 9 replace.

20. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 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 and optionally further substituted with 1 to 2 R 9 replace.

21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R 7 and R 8 Each independently is H or C 1-3 Alkyl; or R 7 and R 8 together are C2-C4 alkylene, said alkylene being optionally substituted by 1 or 2 C 1-3 Alkyl substitution.

22. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein R 7 and R 8 are each independently H, –CH3 or –CH2CH3; or R 7 and R 8 Together they are –CH2CH2CH2CH2–, –CH2CH2CH2–, or –CH2C(CH3)2CH2-.

23. A compound according to any one of claims 17 to 20 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: Each of which is optionally further substituted by 1 to 2 R 9 replace.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 17 to 19, wherein R 1 Selected from the group consisting of: Each of which is optionally further substituted by 1 to 2 R 9 replace.

25. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 12-membered saturated heterocyclic group containing two ring N atoms and optionally substituted by 1 to 3 R 9 replace.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 1 The 4- to 12-membered saturated heterocyclic group represented is piperazinyl, 4,7-diazaspiro[2.5]octyl, 3,9-diazaspiro[5.5]undecyl, 1-oxa-4,9-diazaspiro[5.5]undecyl, diazabicyclo[2.2.2]octyl, octahydro-2H-pyrido[4,3-b][1,4]oxazinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, 2,5-diazabicyclo[2.2.1]heptyl, octahydropyrrolo[1,2-a]pyrazinyl, decahydro-1,6-naphthyridinyl, 1,6-diazaspiro[3.4]octyl, 1,5-diazaspiro[3.4]octyl, 2λ 2 ,5-diazaspiro[3.4]octyl, 2λ 2 ,6-diazaspiro[3.4]octyl, 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]heptyl, 1,4-diazacycloheptyl, 2,6-diazaspiro[3.5]nonane, 2,6-diazabicyclo[3.2.0]heptyl or 1,7-diazaspiro[4.4]nonyl, each of which is optionally substituted by 1 to 2 R 9 replace.

27. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 1 The 4- to 12-membered saturated heterocyclic group represented is piperazinyl, diazabicyclo[2.2.2]octyl, octahydro-2H-pyrido[4,3-b][1,4]oxazinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, 2,5-diazabicyclo[2.2.1]heptyl, 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-diazacycloheptyl or 2,6-diazaspiro[3.5]nonane, each of which is optionally substituted by 1 to 2 R 9 replace.

28. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R 1 The 4- to 12-membered saturated heterocyclic group represented is: Each of which is optionally replaced by 1 or 3 R 9 replace.

29. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 1 The 4- to 12-membered saturated heterocyclic group represented is: Each of which is optionally replaced by 1 or 3 R 9 replace.

30. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 1 It is a 4- to 12-membered partially saturated heterocyclic group.

31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein the partially saturated heterocyclic group 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.

32. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein the partially saturated heterocyclic group 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.

33. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 or 31, wherein the partially saturated heterocyclic group is selected from the group consisting of: Each of which is optionally replaced by 1, 2, 3 or 4 R 9 replace.

34. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 or 31, wherein the partially saturated heterocyclic group is selected from the group consisting of: Each of which is optionally replaced by 1 or 2 R 9 replace.

35. A compound as described in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 1 is –NR 7 R 8 substituted 4 to 12 membered saturated or partially saturated carbocyclic group, and further optionally substituted by 1 or 2 R 9 replace.

36. A compound as described in any one of claims 35 or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclohexyl or cyclohexenyl, each of which is replaced by –NR 7 R 8 and further optionally substituted by 1 or 2 R 9 replace.

37. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 35 or 36, wherein R 1 Selected from Each of which is –NR 7 R 8 and further optionally substituted by 1 or 2 R 9 replace.

38. A compound as described in any one of claims 35 to 37, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Each independently is H or C 1-3 alkyl.

39. A compound as described in any one of claims 35 to 37, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Each is independently H or -CH3.

40. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 39, wherein R 9 is independently selected at each occurrence from halo, -C(=O)R 10 , C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl; wherein R 9 The C 3-6 The cycloalkyl group is optionally substituted by one to three independently selected from F, Cl and C 1-4 The alkyl group is substituted with a substituent; and R 10 It is H, C 1-2 Alkyl, C 3-4 Cycloalkyl.

41. A compound as described in any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 9 is independently selected at each occurrence from F, -CH3, -CH2CH3, -C(=O)CH3, -CH2CF3, -CH(CH3)2, -CD3 and cyclopropyl.

42. A compound as described in any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 9 is independently selected at each occurrence from -CH3, -C(=O)CH3, -CH2CF3, -CH(CH3)2 and cyclopropyl.

43. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 1 Yes - NR 11 R 12 ; R 11 Is H or C 1-6 alkyl; R 12 It is C 1-6 Alkyl-NR a R b , phenyl, a 4- to 12-membered heterocyclic group containing at least one ring N atom; wherein R 12 The phenyl group represented by a R b , Het or -C 1-3 is substituted with alkylene-Het, and Het is a 4- to 6-membered heterocyclyl containing at least one ring N atom and optionally substituted with one or two C 1-3 alkyl substituted; and wherein R 12 The 4 to 12 membered heterocyclic group represented by 12a Replace; wherein each R 12a Independently C 1-3 Alkyl or halogenated.

44. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 1 Yes - NR 11 R 12 ; R 11 Is H or C 1-6 alkyl; R 12 It is C 1-6 Alkyl-NR a R b , phenyl, a 4- to 12-membered heterocyclic group containing at least one ring N atom; wherein R 12 The phenyl group represented by a R b , Het or -C 1-3 is substituted with alkylene-Het, and Het is a 4- to 6-membered heterocyclyl containing at least one ring N atom and optionally substituted with one or two C 1-3 alkyl substituted; and wherein R 12 The 4- to 12-membered heterocyclic group represented by 1-3 Alkyl substitution.

45. The compound of any one of claims 1-10 and 43, or a pharmaceutically acceptable salt thereof, wherein: R 1 Yes - NR 11 R 12 ; R 11 is H or -CH3; R 12 is selected from the group consisting of piperidinyl, hexahydro-1H-pyrrolizinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolizinyl, isoindolyl, phenylazetidinyl, 1,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, benzylpyrrolidinyl and quinuclidine, each of which is optionally substituted by one, two, three, four or five R 12a Substitution; wherein R 12a It is C 1-3 Alkyl or halogenated.

46. ​​A compound as described in any one of claims 43-45 or a pharmaceutically acceptable salt thereof, wherein R 12a It is methyl or fluorine.

47. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-10 and 43, wherein: R 1 Yes - NR 11 R 12 ; R 11 is H or -CH3; R 12 is selected from the group consisting of hexahydro-1H-pyrrolizinyl, octahydrocyclopenta[c]pyrrolyl, octahydroindolizinyl, isoindolyl, phenylazetidinyl, 1,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, benzylpyrrolidinyl and quinuclidine, each of which is optionally substituted by one or two independently C 1-2 Alkyl substitution.

48. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-10 and 43, wherein: R 1 Yes - NR 11 R 12 ; R 11 is H or -CH3; R 12 Selected from the group consisting of: Each of which is optionally substituted with one, two, three, four or five substituents independently selected from F, -CH3 and -CH2CH3.

49. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-10 and 43, wherein: R 1 Yes - NR 11 R 12 ; R 11 is H or -CH3; R 12 Selected from the group consisting of: Each of which is optionally substituted with one or two substituents independently selected from -CH3 and -CH2CH3.

50. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: R 1 is - OR 15 ; R 15 It 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; wherein R 15 The phenyl group or the 4- to 12-membered carbocyclic group represented by -NR a R b , Het or -C 1-3 is substituted with alkylene-Het, and Het is a 4- to 6-membered heterocyclyl containing at least one ring N atom and optionally substituted with one or two C 1-3 alkyl substituted; and wherein R 15 The 4- to 12-membered heterocyclic group represented by 1-3 Alkyl substitution.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 15 is selected from piperidinyl, pyrrolidinyl, 8-azaspiro[4.5]decyl and 7-azaspiro[3.5]nonyl, each of which is optionally substituted by one or two C 1-3 Alkyl substituted, or R 15 It was NR a R b substituted cyclopentyl; and R a and R b Each independently is H or C 1-3 alkyl.

52. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein: R 1 is - OR 15 ; R 15 Selected from the group consisting of: wherein each is optionally substituted with one or two substituents independently selected from -CH3 and -CH2CH3; or R 15 Depend on express.

53. A compound as described in any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R 3 is optional with one to three R C substituted 9-membered bicyclic heteroaryl, or optionally with one to three R C1 Substituted 5-membered heterocyclic fused phenyl.

54. A compound as described in any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of indazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrazinyl, benzothiazolyl, triazolopyrazinyl, benzoxazolyl, pyrazolopyrimidinyl and benzothiadiazolyl, each of which is optionally substituted by one to three R C Substitution, or R 3 is 1,3-dihydro-2H-benzo[d]imidazol-2-one or benzo[d]thiazol-2(3H)-one, each of which is optionally replaced by one or two R C1 replace.

55. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of: Each of which is optionally replaced by one to three R C replace; or R 3 yes Each of which is optionally replaced by one or two R C1 replace.

56. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of: Each of which is optionally replaced by one to three R C replace; or R 3 yes Each of which is optionally replaced by one or two R C1 replace.

57. A compound as described in any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein R C is independently halo, C 1-3 Alkyl, C 1-2 Haloalkyl or C 1-2 Alkoxy; and R C1 C independently at each occurrence 1-3 alkyl.

58. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein R C is independently selected at each occurrence from -F, -CH3, -CH(CH3)2, -CF3, and -OCH3; and R C1 It is –CH3.

59. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (IIA): or a pharmaceutically acceptable salt thereof, wherein: R 1 is piperazinyl, pyrrolidinyl, diazabicyclo[2.2.1]heptyl, 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]heptyl, octahydropyrrolo[3,4-b]pyrrolyl, piperidinyl, 8-azabicyclo[3.2.1]oct-2-enyl or 1,2,3,6-tetrahydropyridinyl is optionally substituted by 1 to 3 R 9 and the pyrrolidinyl group is optionally substituted with -NR 7 R 8 or –C 3-6 Cycloalkylene-NR 7 R 8 and further optionally substituted by 1 or 2 R 9 replace; R 7 and R 8 Each independently is H or C 1-4 alkyl; R 9 In each occurrence, independently selected from C 1-4 Alkyl and C 3-6 cycloalkyl; and R 3 is indazolyl, imidazopyridinyl, imidazopyrazinyl or benzoxazolyl, wherein the indazolyl, imidazopyridinyl, imidazopyrazinyl or benzoxazolyl is optionally substituted by one to two R C replace; R C In each occurrence, independently selected from C 1-4 Alkyl and halo.

60. The compound of claim 59 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: Each of which is optionally replaced by 1 or 2 R 9 replace; or R 1 Selected from Each of which is optionally replaced by 1 to 3 R 9 replace.

61. The compound of claim 59 or 60, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of: Each of which is optionally replaced by one or two R C replace.

62. A compound as described in any one of claims 59-61 or a pharmaceutically acceptable salt thereof, wherein R 9 is independently selected at each occurrence from -CH3 and cyclopropyl.

63. A compound as described in any one of claims 59-62 or a pharmaceutically acceptable salt thereof, wherein R C is independently selected at each occurrence from -CH3 and F.

64. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein: R 1 is piperazinyl, pyrrolidinyl, piperidinyl, diazaspiro[4.4]nonyl, diazabicyclo[3.2.0]heptyl or diazaspiro[3.4]octyl, wherein the piperazinyl, piperidinyl, diazaspiro[4.4]nonyl, diazabicyclo[3.2.0]heptyl or diazaspiro[3.4]octyl is optionally substituted by 1 to 3 R 9 and the pyrrolidinyl group is optionally substituted with -NR 7 R 8 and further optionally substituted with 1 or 2 R 9 replace; R 7 and R 8 Each independently is H or C 1-4 Alkyl; or R 7 and R 8 Together with the N atom to which they are attached, they form a 4- to 6-membered saturated monocyclic heterocyclic group; R 9 C independently at each occurrence 1-3 Alkyl; and R 3 is indazolyl, pyrazolo[1.5.a]pyridinyl, imidazopyridinyl or imidazopyrazinyl, wherein the indazolyl, imidazopyridinyl or imidazopyrazinyl is optionally substituted by one to two R C replace; R C In each occurrence, independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and halo.

65. The compound of claim 64 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: Each of which is optionally replaced by 1 or 2 R 9 Replace; and R 9 C independently at each occurrence 1-3 alkyl.

66. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein R 3 yes Each of which is optionally replaced by one or two R C replace.

67. A compound as described in claim 64, 65 or 66, or a pharmaceutically acceptable salt thereof, wherein R 9 is independently selected at each occurrence from -CH3 and -CH2CH3.

68. A compound as described in any one of claims 64-67 or a pharmaceutically acceptable salt thereof, wherein R C is independently selected at each occurrence from F, -CH3, -OCH3 and -CHF2.

69. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1 or a pharmaceutically acceptable salt thereof.

70. A pharmaceutical composition comprising the compound of any one of claims 1-69 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

71. A method of treating Huntington's disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-69 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 70.

Images