Heterocyclic compounds for treating Huntington's disease

Abstract

The present disclosure provides a compound of formula (I) [Formula 1] TIFF2025525683000303.tif5182, or a pharmaceutically acceptable salt thereof, and uses thereof, for example, in treating conditions, diseases, or disorders in which lowering mutant huntingtin protein ("mHTT") in a subject provides a therapeutic benefit, particularly in treating Huntington's disease ("HD"). The disclosure also features compositions containing same, as well as methods of using and making same.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 344,494, filed May 20, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

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

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

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

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

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

[0007] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, X 1 , X 2 , X 3 , X 4 , R 5 , R 6 , and R 7 is as described herein).

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

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

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

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

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

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

[0014] 1.Compound In a first aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, [ka] is a single or double bond, with the proviso that the ring containing X1, X2, X3, and X4 is a bicyclic heteroaryl ring containing at least one N atom; X 1 is C or N, X 2 is O, N or CR 2 and X 3 is N or C, X 4 are N, O, and NR 4 or CR 4 where X 1 If C, then X 2 , X 3 and X 4 At least two of 4 provided that: R 2 and R 4 If present, H, halo, and C 1-6 alkyl, R 5 H, halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 1-6 haloalkoxyl, R 6 is A, -N(R 6a )-A, -C(=O)A, -N(R 6a )C(=O)-A, or -C(=O)N(R 6a )-A and R 7 is B, and furthermore, X 1 If N, then R 6 is B and R7 is A, where R 6a is H or C 1-3 is alkyl, A is -C 1-6 Alkylene-NR 9 R 10 , 4-10 membered carbocyclyl, -C 1-6 Alkylene-(4-10 membered carbocyclyl), Het or -C 1-6 alkylene-Het, where R 9 is H or C 1-6 is alkyl, R 10 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, or -C 1-6 Alkylene-Het 1 where Het 1 is a 4- to 6-membered saturated heterocyclyl; Het -NR 9 R 10 or -C 1-6 Alkylene-NR 9 R 10 and one to four R 11 is a 4- to 12-membered saturated heterocyclyl optionally further substituted with The 4- to 10-membered carbocyclyl represented by A is —NR 9 R 10 or -C 1-6 Alkylene-NR 9 R 10 and optionally substituted by one to two R 11 and optionally further substituted with: R 11 For each occurrence, halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl, -C1-6 Alkylene-C 3-6 Cycloalkyl, Het 2 , and -C 1-6 Alkylene-Het 2 are independently selected from, where Het 2 is a 4- to 6-membered saturated heterocyclyl or a 5- to 10-membered heteroaryl, wherein the Het 2 Or the C 3-6 Cycloalkyl is a group consisting of halo, C 1-6 Alkoxy and C 1-6 optionally substituted by one or more substituents independently selected from alkyl, where R 12 H, D, Halo, C 1-3 Alkyl, C 1-6 Alkoxyl, or C 3-6 is cycloalkyl, B is a 6- to 10-membered aryl, a 4- to 10-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, the 4- to 10-membered heterocyclyl, and the 5- to 10-membered heteroaryl represented by B are optionally substituted with one or more R 8 where: R 8 Halo, -CN, -OH, C 1-6 Alkyl, C 3-6 cycloalkyl, 5- or 6-membered heteroaryl, C 1-6 Haloalkyl, or C 1-6 Alkoxy or two R 8 and the intervening atoms together form one or more R 8b and forming a 4- to 7-membered heterocyclyl optionally substituted by R 8 The 5- or 6-membered heteroaryl represented by the formula 8a where R 8a is C 1-3 alkyl, and R 8b is C 1-3 alkyl or oxo, wherein the heterocyclyl contains 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl contains 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0015] In a first embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, [ka] is a single or double bond, with the proviso that the ring containing X1, X2, X3, and X4 is a bicyclic heteroaryl ring containing at least one N atom; X 1 is C or N, X 2 is O, N or CR 2 and X 3 is N or C, X 4 is N, NR 4 or CR 4 where X 1 If C, then X 2 , X 3 and X 4 At least two of 4 provided that: R 2 and R 4 If present, H, halo, and C 1-6 alkyl, R 5 is a halo, R 6 is A, -N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A and R 7 is B, or X 1 If N, then R6 is B and R 7 is A, where R 6a is H or C 1-3 is alkyl, A is -C 1-6 Alkylene-NR 9 R 10 , 4-10 membered saturated carbocyclyl, Het or -C 1-6 alkylene-Het, where R 9 is H or C 1-6 is alkyl, R 10 is H, C 1-6 Alkyl or -C 1-6 Alkylene-Het 1 where Het 1 is a 4- to 6-membered saturated heterocyclyl; Het is a 4- to 10-membered saturated heterocyclyl, provided that when the 4- to 10-membered saturated heterocyclyl represented by Het does not contain a ring N atom, it is -NR 9 R 10 and one to two R 11 and when the 4- to 10-membered saturated heterocyclyl represented by Het contains one or more ring N atoms, one to three R 11 optionally replaced by The 4- to 10-membered saturated carbocyclyl represented by A is —NR 9 R 10 and one to two R 11 and optionally further substituted with: R 11 For each occurrence, halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, and C 3-6 cycloalkyl, where R 11 The C in question is represented by 3-6 Cycloalkyl includes halo and C 1-6optionally substituted by one or more substituents independently selected from alkyl, where R 12 is H, C 1-3 Alkyl, or C 3-6 is cycloalkyl, B is a 6- to 10-membered aryl, a 4- to 10-membered heterocyclyl, or a 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, the 4- to 10-membered heterocyclyl, and the 5- to 10-membered heteroaryl represented by B are optionally substituted with one or more R 8 where: R 8 Halo, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 Alkoxy or two R 8 and the intervening atoms together form one or more R 8b and forming a 5- to 7-membered heterocyclyl optionally substituted by R 8 The 5- or 6-membered heteroaryl represented by the formula 8a where R 8a is C 1-3 alkyl, and R 8b is C 1-3 alkyl or oxo, wherein the heterocyclyl contains 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl contains 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0016] In a second embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX): [ka] is expressed by

[0017] Definitions of the variables are provided in the first aspect or first embodiment.

[0018] In an alternative second embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II), (III), (IV), (V), (VI), (VII), or (VIII): [ka] is expressed by

[0019] Definitions of the variables are provided in the first aspect or first embodiment.

[0020] 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 has the formula (II): [ka] is expressed by

[0021] Definitions of the variables are provided in the first aspect, or the first or second embodiment.

[0022] In a fourth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to third embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 H, halo, C 1-3 Alkyl, C 1-3 Haloalkoxyl or C 1-3 and alkoxyl. The definitions of the remaining variables are provided in the first aspect or any of the first through third embodiments or any alternative embodiments described therein.

[0023] In an alternative fourth embodiment, the present disclosure provides a compound according to the first aspect or any of the first through third embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5is F or Cl. The definitions of the remaining variables are provided in the first aspect or any of the first through third embodiments or any alternative embodiments described therein.

[0024] In a fifth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to third embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 is H, F, Cl, —CH, —OCHF, —OCH, or —OCF. Definitions of the remaining variables are provided in the first aspect or any of the first through third embodiments or any alternative embodiments described therein.

[0025] In an alternative fifth embodiment, the present disclosure provides a compound according to the first aspect or any of the first through third embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 is F. The definitions of the remaining variables are provided in the first aspect or any of the first through third embodiments or any alternative embodiments described therein.

[0026] In a sixth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is A, -N(R 6a )-A, -N(R 6a )C(=O)-A, or -C(=O)N(R 6a )-A and R 7 is B and R 6a is H or -CH3. The definitions of the remaining variables are provided in the first aspect or any of the first to fifth embodiments or any alternative embodiments described therein.

[0027] In an alternative sixth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is A, -NHC(=O)-A, or -C(=O)NH-A, and R 7is B. The definitions of the remaining variables are provided in the first aspect or any of the first to fifth embodiments or any alternative embodiments described therein.

[0028] In a seventh embodiment, the present disclosure provides a compound according to the first aspect or any of the first to fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein X 1 If N, then R 6 is B and R 7 is A. The definitions of the remaining variables are provided in the first aspect or any of the first to fifth embodiments or any alternative embodiments described therein.

[0029] In an eighth embodiment, the present disclosure provides a compound according to the seventh embodiment, or a pharmaceutically acceptable salt thereof, wherein: X 1 is N, X 2 is CR 2 and X 3 is C, X 4 is N, R 6 is B, R 7 is A.

[0030] Definitions of the remaining variables are provided in the seventh embodiment.

[0031] In a ninth embodiment, the present disclosure provides a compound according to the seventh aspect or any of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 7 If B, then R 6 is A. The definitions of the remaining variables are provided in the first aspect or any of the first to sixth embodiments or any alternative embodiments described therein.

[0032] In a tenth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein X 1 If N, then R 6 is -N(R 6a )-A, -N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A and R 7 is B, where R 6a is H or -CH3. The definitions of the remaining variables are provided in the first aspect or any of the first to sixth embodiments or any alternative embodiments described therein.

[0033] In an alternative tenth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein X 1 If N, then R 6 is -NHC(=O)-A or -C(=O)NH-A, and R 7 is B. The definitions of the remaining variables are provided in the first aspect or any of the first to sixth embodiments or any alternative embodiments described therein.

[0034] In an eleventh embodiment, the present disclosure provides a compound according to the tenth embodiment, or a pharmaceutically acceptable salt thereof, wherein: X 1 is N, X 2 is CR 2 and X 3 is C, X 4 is N, R 6 is -N(R 6a )-A, -N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A, R 6a is H or -CH3, R 7 is B.

[0035] The remaining variable definitions are provided in the tenth embodiment or any alternative embodiment described therein.

[0036] In an alternative eleventh embodiment, the present disclosure provides a compound according to the tenth embodiment, or a pharmaceutically acceptable salt thereof, wherein: X 1 is N, X 2 is CR 2 and X 3 is C, X 4 is N, R 6 is -NHC(=O)-A or -C(=O)NH-A, R 7 is B.

[0037] The remaining variable definitions are provided in the tenth embodiment or any alternative embodiment described therein.

[0038] In an alternative twelfth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein: A is -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-NR 9 R 10 or -C 1-6 alkylene-Het, where Represented by A - C 1-6 The Het in alkylene-Het is a 4- to 6-membered monocyclic saturated heterocyclyl containing a ring N atom, R 9 and R 10 are each independently H or C 1-4 It is alkyl.

[0039] The remaining variable definitions are provided in the first aspect or any of the first to eleventh embodiments or any alternative embodiments described therein.

[0040] In a thirteenth embodiment, the present disclosure provides a compound according to the twelfth embodiment, or a pharmaceutically acceptable salt thereof, wherein -C 1-6 The Het in alkylene-Het is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl. Definitions of the remaining variables are provided in the twelfth embodiment.

[0041] In a fourteenth embodiment, the present disclosure provides a compound according to the twelfth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is [ka] is selected from the group consisting of:

[0042] Definitions of the remaining variables are provided in the twelfth embodiment.

[0043] In an alternative fourteenth embodiment, the present disclosure provides a compound according to the twelfth embodiment, or a pharmaceutically acceptable salt thereof, wherein: A is, [ka] is selected from the group consisting of:

[0044] Definitions of the remaining variables are provided in the twelfth embodiment.

[0045] In a fifteenth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered monocyclic carbocyclyl, a 5- to 8-membered bicyclic saturated bridged carbocyclyl, or Het; Het represented by A is a 4- to 7-membered monocyclic saturated heterocyclyl, a 6- to 8-membered bicyclic saturated bridged heterocyclyl, or a 7- to 12-membered bicyclic saturated spiral or fused heterocyclyl, provided that when Het represented by A does not contain a ring N atom, then -NR 9 R 10 or -C 1-6 Alkylene-NR 9 R 10 and one to two R 11 and when Het represented by A contains one or more ring N atoms, one to two R 11 optionally replaced by The 5-8 membered bicyclic saturated bridged carbocyclyl represented by A is -NR 9 R 10 , 4-6 membered monocyclic saturated heterocyclyl, or -C 1-6 Alkylene-NR 9 R 10 and one to two R 11 and optionally further replaced by R 9 and R 10 are each independently H or C 1-4 It is alkyl.

[0046] The remaining variable definitions are provided in the first aspect or any of the first to eleventh embodiments or any alternative embodiments described therein.

[0047] In an alternative fifteenth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein: A is a 5- to 6-membered monocyclic saturated carbocyclyl, a 5- to 8-membered bicyclic saturated bridged carbocyclyl, or Het; Het represented by A is a 4- to 6-membered monocyclic saturated heterocyclyl, a 6- to 8-membered bicyclic saturated bridged heterocyclyl, or a 7- to 10-membered bicyclic saturated spiral heterocyclyl, provided that when Het represented by A does not contain a ring N atom, then -NR 9 R10 and one to two R 11 and when Het represented by A contains one or more ring N atoms, one to two R 11 optionally replaced by The 5-8 membered bicyclic saturated bridged carbocyclyl represented by A is -NR 9 R 10 and one to two R 11 and optionally further replaced by R 9 and R 10 are each independently H or C 1-4 It is alkyl.

[0048] The remaining variable definitions are provided in the first aspect or any of the first to eleventh embodiments or any alternative embodiments described therein.

[0049] In a sixteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[4.5]decanyl, 4-azaspiro[4.5]decanyl, 5-azaspiro[4.5]decanyl, 6-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 8-azaspiro[4.5]decanyl, 9-azaspiro[4.5]decanyl, 10-azaspiro[4.5]decanyl, 11-azaspiro[4.5]decanyl, 12-azaspiro[4.5]decanyl, 13-azaspiro[4.5]decanyl, 14-azaspiro[4.5]decanyl, 15-azaspiro[4.5]decanyl, 16-azaspiro[4.5]decanyl, 17-azaspiro[4.5]decanyl, 18-azaspiro[4.5]decanyl, 19-azaspiro[4.5]decanyl, 20-azaspiro[4.5]decanyl, 21-azaspiro[4.5]hexyl, 22-azaspiro[4.5]hexyl, 23-azaspiro[4.5]hexyl, 24-azaspiro[4. 2-Azaspiro[2.5]octanyl, 8-azaspiro[4.5]decanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 9-diazaspiro[5.5]undecanyl, 2-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 5-azaspiro[2.4]heptanyl, 5-azaspiro[2.3]hexanyl, 4-azaspiro[2.4]heptanyl, 6-azaspiro[3.4]octanyl, 2-azaspiro[4.4]undecanyl nanyl, 2-azaspiro[3.5]nonanyl, 2-azaspiro[3.4]octanyl, 1-oxa-9-azaspiro[5.5]undecanyl, 3-azabicyclo[3.1.0]hexanyl, diazaspiro[4.5]decane, 7-diazaspiro[3.5]nonanyl, diazaspiro[4.5]decanyl, 7-diazaspiro[4.4]nonanyl, 1-azabicyclo[3.2.1]octanyl, diazaspiro[5.5]undecanyl, azepanyl, 7-azaspiro[3.5]nonanyl, 7-aza spiro[3.5]nonanyl, 5-oxa-2-azaspiro[3.4]octanyl, diazabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.2.0]heptanyl, octahydro-cyclopenta[c]pyrrolyl, hexahydro-1H-pyrrolo[3,4-c]pyrrolyl, octahydro-indolizinyl, 8-diazabicyclo[4.2.0]octanyl, octahydro-isoindolyl, or 1,8-diazaspiro[4.5]decane, each of which is selected from the group consisting of one or two R 11 The remaining variable definitions are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0050] In an alternative sixteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or a pharmaceutically acceptable salt thereof, wherein A is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[4.5]decanyl, 4-azaspiro[2.5]octanyl, 8-azaspiro[4.5]decanyl, 8-azabicyclo[3.2.1]octanyl, or 7-azaspiro[3.5]nonanyl, each of which is selected from one or two R 11 The remaining variable definitions are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0051] In a seventeenth embodiment, the present disclosure provides a compound according to the fifteenth or sixteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is [ka] is selected from the group consisting of Each of them has one or two R 11 The remaining variable definitions are provided in the fifteenth or sixteenth embodiment or any alternative embodiment described therein.

[0052] In an alternative seventeenth embodiment, the present disclosure provides a compound according to the fifteenth or sixteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is [ka] is selected from the group consisting of Each of them has one or two R 11 The remaining variable definitions are provided in the fifteenth or sixteenth embodiment or any alternative embodiment described therein.

[0053] In an eighteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or a pharmaceutically acceptable salt thereof, wherein A is cyclobutyl, cyclopentyl, cyclopenetenyl, cyclohexyl, tetrahydro-2H-pyranyl, 3-oxetanyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptanyl, —CH2-cyclobutyl, bicyclo[2.2.2]octanyl, spiro[5.3]nonanyl, or 2-oxobicyclo[2.1.1]hexyl, each of which is —NR 9 R 10 and one to two R 11 The remaining variable definitions are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0054] In an alternative eighteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or a pharmaceutically acceptable salt thereof, wherein A is cyclopentyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.2]octanyl, or 2-oxobicyclo[2.1.1]hexyl, each of which is selected from the group consisting of -NR 9 R 10 and one to two R 11 The remaining variable definitions are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0055] In a nineteenth embodiment, the present disclosure provides a compound according to the fifteenth or eighteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is [ka] is selected from the group consisting of Each of them is -NR 9 R 10 and one to two R 11The remaining variable definitions are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0056] In an alternative nineteenth embodiment, the present disclosure provides a compound according to the fifteenth or eighteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is [ka] is selected from the group consisting of Each of them is -NR 9 R 10 and one to two R 11 The remaining variable definitions are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0057] In a twentieth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to nineteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 For each occurrence, halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, Het 2 , and -C 1-6 Alkylene-Het 2 are independently selected from, where Het 2 is a 4- to 6-membered saturated heterocyclyl or a 5- to 6-membered heteroaryl, where R 11 The C in question is represented by 3-6 Cycloalkyl or the Het 2 Ha, Halo, C 1-4 Alkoxy and C 1-4 optionally substituted with 1 to 4 substituents independently selected from alkyl; 12 H, D, Halo, C 1-4 Alkoxyl, C1-2 Alkyl, C 3-4 and cycloalkyl. The definitions of the remaining variables are provided in the first aspect or any of the first to nineteenth embodiments or any alternative embodiments described therein.

[0058] In an alternative twentieth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to nineteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 For each occurrence, halo, -C(=O)R 12 , C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 cycloalkyl, where R 11 The C in question is represented by 3-6 Cycloalkyl includes F, Cl, and C 1-4 optionally substituted with 1 to 3 substituents independently selected from alkyl; 12 is H, C 1-2 Alkyl, C 3-4 and cycloalkyl. The definitions of the remaining variables are provided in the first aspect or any of the first to nineteenth embodiments or any alternative embodiments described therein.

[0059] In a twenty-first embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twentieth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 represents, at each occurrence, F, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)cyclopropyl, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2C(CH3)3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CHF2, -CH2CH2F, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl and cyclopentyl, [ka] are independently selected from, where R 11 The cyclopropyl, cyclobutyl, or cyclopentyl represented by the formula: 1-3 Alkoxy and C 1-3 and optionally substituted with 1 to 2 substituents independently selected from alkyl. Definitions of the remaining variables are provided in the first aspect or any of the first through twentieth embodiments or any alternative embodiments described therefor. In some embodiments, R 11 F and C 1-3 and cyclopropyl optionally substituted with 1 to 2 substituents independently selected from alkyl.

[0060] In an alternative twenty-first embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twentieth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 is, at each occurrence, independently selected from F, —C(═O)CH3, —C(═O)CH2CH3, —C(═O)cyclopropyl, —CH3, —CH2CH3, —CH(CH3)2, —CH2CH2OCH3, —CH2CH2CH2OCH3, cyclopropyl, and cyclobutyl; 11 The cyclopropyl represented by the formula: 1-3 and optionally substituted with 1 to 2 substituents independently selected from alkyl. Definitions of the remaining variables are provided in the first aspect or any of the first through twentieth embodiments. In some embodiments, R 11 F and C 1-3 Cyclopropyl optionally substituted with 1 to 2 substituents independently selected from alkyl or any alternative embodiment described therein.

[0061] In a twenty-second embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twenty-first embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 is H or C 1-3 alkyl, and R 10 is H, C3-6 Cycloalkyl or C 1-3 and alkyl. The definitions of the remaining variables are provided in the first aspect or any of the first to twenty-first embodiments or any alternative embodiments described therein.

[0062] In an alternative twenty-second embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twenty-first embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are each independently H or C 1-3 and alkyl. The definitions of the remaining variables are provided in the first aspect or any of the first to twenty-first embodiments or any alternative embodiments described therein.

[0063] In a twenty-third embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twenty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 is H or -CH3, and R 10 is H, cyclopropyl, or —CH. Definitions of the remaining variables are provided in the first aspect or any of the first to twenty-second embodiments or any alternative embodiments described therein.

[0064] In an alternative twenty-third embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twenty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are each independently H or -CH3. The definitions of the remaining variables are provided in the first aspect or any of the first to twenty-second embodiments or any alternative embodiments described therein.

[0065] In a twenty-fourth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twenty-third embodiments, or a pharmaceutically acceptable salt thereof, wherein B is phenyl, naphthalenyl, or 8-10 membered bicyclic heteroaryl, and wherein the phenyl, the naphthalenyl, and the 8-10 membered bicyclic heteroaryl represented by B are selected from the group consisting of 1 to 3 R 8 The remaining variable definitions are provided in the first aspect or any of the first to twenty-third embodiments or any alternative embodiments described therein.

[0066] In a twenty-fifth embodiment, the present disclosure provides a compound according to any one of the first aspect or any of the first to twenty-fourth embodiments, or a pharmaceutically acceptable salt thereof, wherein B is selected from one to three R 8 and R is a 9- or 10-membered bicyclic heteroaryl optionally substituted by: The definitions of the remaining variables are provided in the first aspect or any of the first through twenty-fourth embodiments or any alternative embodiments described therein.

[0067] In an alternative twenty-fifth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twenty-fourth embodiments, or a pharmaceutically acceptable salt thereof, wherein B is selected from one to three R 8 and R is a 9-membered bicyclic heteroaryl optionally substituted by R. Definitions of the remaining variables are provided in the first aspect or any of the first through twenty-fourth embodiments or any alternative embodiments described therein.

[0068] In a twenty-sixth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twenty-third embodiments, or a pharmaceutically acceptable salt thereof, wherein B is phenyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, benzotriazolyl, imidazopyrazinyl, benzoxazolyl, triazolopyridinyl, benzisothiazolyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, thienopyridinyl, R is selected from the group consisting of 1 to 3 R 8 or B is 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onyl, each of which is C 1-3 and optionally substituted with alkyl. The definitions of the remaining variables are provided in the first aspect or any of the first to twenty-third embodiments or any alternative embodiments described therein.

[0069] In an alternative twenty-sixth embodiment, the present disclosure provides a compound according to the first aspect or any of the first through twenty-third embodiments, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of phenyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, benzotriazolyl, imidazopyrazinyl, benzoxazolyl, triazolopyridinyl, benzisothiazolyl, pyrazolopyridinyl, thienopyridinyl, benzothiazolyl, pyrrolopyridinyl, pyrrolopyrazinyl, benzofuranyl, benzothiophenyl, thienopyridinyl, triazolopyridazinyl, benzoxadiazolyl, indolyl, indolin-2-onyl, furopyridine, benzimidazolyl, benzothiadiazole, phthalazinyl, and phthalazin-1-onyl, each of which is selected from the group consisting of one to three R 8or B is 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onyl, each of which is C 1-3 and optionally substituted with alkyl. The definitions of the remaining variables are provided in the first aspect or any of the first to twenty-third embodiments or any alternative embodiments described therein.

[0070] In a 27th embodiment, the present disclosure provides a compound according to the 26th embodiment, or a pharmaceutically acceptable salt thereof, wherein B is [ka] each of which is selected from 1 to 3 R 8 or B is [ka] The remaining variable definitions are provided in the 26th embodiment or any alternative embodiment described therein.

[0071] In an alternative 27th embodiment, the present disclosure provides a compound according to the 26th embodiment, or a pharmaceutically acceptable salt thereof, wherein B is [ka] each of which is selected from 1 to 3 R 8 or B is [ka] The remaining variable definitions are provided in the 26th embodiment or any alternative embodiment described therein.

[0072] In a 28th embodiment, the present disclosure provides a compound according to the first aspect or any of the first to 27th embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 For each occurrence, halo, -CN, -OH, C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-2 Haloalkyl, or C 1-2 and alkoxy. The definitions of the remaining variables are provided in the first aspect or any of the first to twenty-seventh embodiments or any alternative embodiments described therein.

[0073] In a 28th embodiment, the present disclosure provides a compound according to the first aspect or any of the first to 27th embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 For each occurrence, halo, -CN, -OH, C 1-3 Alkyl, C 1-2 Haloalkyl, or C 1-2 and alkoxy. The definitions of the remaining variables are provided in the first aspect or any of the first to twenty-seventh embodiments or any alternative embodiments described therein.

[0074] In a 29th embodiment, the present disclosure provides a compound according to the 28th embodiment, or a pharmaceutically acceptable salt thereof, wherein R 8 is independently selected at each occurrence from -F, -Cl, -Br, -CN, -CH, -CHCH, -CH(CH), -CHF, -CF, -OH, -OCH, -OCHCH, and cyclopropyl. Definitions for the remaining variables are provided in the 28th embodiment or any alternative embodiment described therein.

[0075] In an alternative twenty-ninth embodiment, the present disclosure provides a compound according to the twenty-eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 8is independently selected at each occurrence from -F, -Cl, -CN, -CH, -CHCH, -CH(CH), -CHF, -OH, -OCH, and -OCHCH. Definitions for the remaining variables are provided in the 28th embodiment or any alternative embodiment described therein.

[0076] In a thirtieth embodiment, the present disclosure provides a compound according to the first aspect or any of the first to twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8a is -CH3 or -CH2CH3 for each occurrence, and R 8b is, at each occurrence, -CH3 or oxo. The definitions of the remaining variables are provided in the first aspect or any of the first to twenty-ninth embodiments or any alternative embodiments described therein.

[0077] In a thirty-first embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound has the following formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 5 is a halo, R 6 is A, -NH-C(=O)-A, -C(=O)NH-A or -NH-A, R 7 is B, A is a 4- to 6-membered monocyclic saturated heterocyclyl, a 6- to 10-membered bicyclic saturated fused or spiral heterocyclyl, or C 3-6 Cycloalkyl, wherein 4-6 membered monocyclic saturated heterocyclyl and 6-10 membered bicyclic saturated fused or spiral heterocyclyl are each independently one or two R 11 and C 3-6 Cycloalkyl is -NR 9 R 10 is replaced by R 11 and optionally further replaced by R 9 and R 10 are each independently H or C 1-3 is alkyl, Each R 11 independently, C 1-3 Alkyl or C 3-6 is cycloalkyl, B is 1 to 3 R 8 wherein the 9-membered bicyclic heteroaryl has 2 to 4 N ring atoms; Each R 8 independently, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 It is an alkoxy.

[0078] In a thirty-second embodiment, the present disclosure provides a compound according to the thirty-first embodiment, or a pharmaceutically acceptable salt thereof, wherein: R 5 is F, A is cyclobutyl or Het, where Het is azetidinyl, piperidinyl, 3-azabicyclo[3.1.0]hexanyl, 2,8-diazaspiro[4.5]decanyl, or 2,7-azaspiro[3.5]nonanyl, each of which is C 1-3 Alkyl or C 3-6 cycloalkyl, where cyclobutyl represented by A is —NR 9 R 10 is represented by A in R 9 and R 10 are H or -CH3, B has the following formula: [ka] Each of these is represented by one or two R 8 optionally replaced by Each R 8 independently, C 1-3 Alkyl, C 1-3Haloalkyl or C 1-3 and alkoxy. Definitions of the remaining variables are provided in the thirty-first embodiment.

[0079] In a thirty-third embodiment, the present disclosure provides a compound according to the thirty-first or thirty-second embodiment, or a pharmaceutically acceptable salt thereof, wherein A is of the following formula: [ka] Each of these is represented by C 1-3 and optionally substituted alkyl. Definitions of the remaining variables are provided in the thirty-first or thirty-second embodiment.

[0080] In a thirty-fourth embodiment, the present disclosure provides a compound according to any one of the thirty-first, thirty-second and thirty-third embodiments, or a pharmaceutically acceptable salt thereof, wherein A is a group represented by the following formula: [ka] The definitions of the remaining variables are provided in the thirty-first, thirty-second or thirty-third embodiment.

[0081] In a thirty-fifth embodiment, the present disclosure provides a compound according to any one of the thirty-first to thirty-fourth embodiments, or a pharmaceutically acceptable salt thereof, wherein B is a group represented by the following formula: [ka] The definitions of the remaining variables are provided in the thirty-first, thirty-second, thirty-third or thirty-fourth embodiment.

[0082] In a thirty-sixth embodiment, the present disclosure provides a compound according to any one of the thirty-first to thirty-fifth embodiments or a pharmaceutically acceptable salt thereof, wherein each R 8 is —CH 3 , —CHF 2 , CF 3 , or —OCH 3 . Definitions of the remaining variables are provided in the thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment.

[0083] In one embodiment, the present disclosure provides a compound selected from the compounds disclosed in the Examples and Table 1, a pharmaceutically acceptable salt or stereoisomer thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

[0084] 2.Definition The term "halo" or "halogen," as used herein, refers to fluoride, chloride, bromide, or iodide.

[0085] The term “alkyl” used alone or as part of a larger moiety such as “alkoxy” or “haloalkyl” refers to a group of the formula —C n H (2n+1)"Ci_6 alkyl" refers to a straight-chain or branched-chain monovalent saturated aliphatic hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 20, 1 to 10, or 1 to 6 carbon atoms. In some embodiments, an alkyl group has 1 to 6 atoms, i.e., a Ci_6 alkyl. As used herein, a "Ci_6 alkyl" group refers to a radical having 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like. In some embodiments, an alkyl group has 1 to 4 carbon atoms, i.e., a C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms, i.e., C 1-3 It is alkyl.

[0086] The terms "alkoxy" or "alkoxyl," as used herein, refer to an O-alkyl group, where alkyl is as defined above.

[0087] The term "haloalkyl" refers to an alkyl optionally substituted with one or more halogen atoms. In one embodiment, the alkyl can be substituted with one to three halogens. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like.

[0088] As used herein, the term "alkylene" refers to a group of the formula -C n H 2n - means a straight or branched chain divalent hydrocarbon radical of the formula: -. Non-limiting examples include ethylene and propylene.

[0089] The term "carbocyclyl" refers to any stable non-aromatic hydrocarbon ring containing 3 to 12 carbocyclyl members.

[0090] In one embodiment, a carbocyclyl is a 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic hydrocarbon ring or a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, or unsaturated. Any substitutable ring atom may be substituted (e.g., by one or more substituents). Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In one embodiment, a carbocyclyl is intended to include bridged rings, fused rings, and spirocyclic rings. In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiro[3.3]heptanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In a fused-ring carbocyclyl system, two or more rings can be fused together so that two rings share one common bond. Examples of two- or three-fused-ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.

[0091] The term "bridged carbocyclyl" refers to a 5- to 12-membered polycyclic carbocyclyl group in which any two rings in the group share two non-linking atoms, and the rings may have one or more double bonds but do not have a completely conjugated pi-electron system. Representative examples of bridged carbocyclyls include the following groups: [ka] The term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon group having 3 to 12 ring carbons. In one embodiment, a cycloalkyl can have 3 to 7 or 3 to 6 ring carbons. Any substitutable atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl can include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicyclos in which the two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0092] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (a "3- to 12-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "3- to 7-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl"); polycyclic ring systems include fused, bridged, or spirocyclic ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can contain heteroatoms in one or more rings in the polycyclic ring system. Substituents can be present on one or more rings in the polycyclic ring system.

[0093] Spiroheterocyclyl refers to a 5-12 membered polycyclic heterocyclyl having rings connected through a common carbon atom (called a spiroatom), wherein the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, with the remaining ring atoms being C, and one or more rings may contain one or more double bonds, and none of the rings has a fully conjugated pi-electron system. Representative examples of spiroheterocyclyl include the following groups: [ka] These include, but are not limited to:

[0094] Fused heterocyclyl refers to a 5-12 membered polycyclic heterocyclyl group in which each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, with the remaining ring atoms being C. Representative examples of fused heterocyclyls include the following groups: [ka] These include, but are not limited to:

[0095] Bridged heterocyclyl refers to a 5-12 membered polycyclic heterocyclyl group in which any two rings in the group share two non-linking atoms, the rings may contain one or more double bonds but do not have a fully conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, as ring atoms, with the remaining ring atoms being C. Representative examples of bridged heterocyclyls include the following groups: [ka] These include, but are not limited to:

[0096] In general, a carbocyclyl, cycloalkyl, or heterocyclyl can be unsubstituted or, valence permitting, substituted with one or more substituents, where the substituents can be independently selected from a number of groups. Exemplary substituents include, but are not limited to, oxo, -CN, halogen, alkyl, and alkoxyl, and optionally, alkyl substituents can be further substituted.

[0097] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the group) group having a completely conjugated pi-electron system. The term "aryl" may be used interchangeably with the terms "aryl ring," "carbocyclic aromatic ring," "aryl group," and "carbocyclic aromatic group." Representative examples of aryl are phenyl and naphthyl.

[0098] The term "heteroaryl," as used herein, refers to a monocyclic or polycyclic (e.g., bicyclic) aromatic hydrocarbon in which at least one of the ring carbon atoms is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur. Preferably, heteroaryl refers to a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 26 -C 27 -C 28 -C 29 -C 30 -C 31 -C 32 -C 33 -C 40 -C 41 -C 22 -C 34 -C 42 -C 25 -C 35 -C 43 -C 26 -C 36 -C 44 -C 27 -C 37 -C 45 -C 28 -C 29 -C 38 -C 45 -C 29 -C 39 -C 46 -C 29 -C 38 -C 47 -C 29 -C 39 -C 48 -C 49 -C 50 -C 51 -C 52 -C 53 -C 54 -C 55 -C 56 -C 57 -C 58 -C 59 -C 60 -C 61 -C 62 -C 63 -C 64 -C 65 -C 66 -C 67 -C 68 -C 70 -C 71 -C 72 -C 73 -C 74 -C 75 -C 76 -C 77 -C 78 -C 79 -C 80 5-10 Heteroaryl groups are based on aryl. Heteroaryl groups can be attached through a ring carbon atom or, where valence allows, through a ring nitrogen atom. In general, heteroaryls can be unsubstituted or substituted with one or more substituents, where valence allows. Exemplary substituents include, but are not limited to, halogen, OH, alkyl, alkoxyl, and amino (e.g., NH, NH alkyl, N(alkyl)), and optionally, alkyl can be further substituted.

[0099] Examples of 5- to 6-membered monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrimidinyl, pyridinyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. A "substituted heteroaryl group" is substituted at any one or more substitutable ring atoms, which are ring carbon or ring nitrogen atoms to which hydrogen is bonded.

[0100] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as being either "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise noted, it indicates that any portion of the moiety known to those of skill in the art to be available for substitution can be substituted, including one or more substituents. When multiple substituents are present, each substituent can be independently selected. Means for such substitution are known in the art and / or taught by this disclosure. An optional substituent can be any substituent suitable for attachment to that moiety.

[0101] If suitable substituents are not specifically recited, exemplary substituents include C1-5 alkyl, C1-5 hydroxyalkyl, C1-5 haloalkyl, C1-5 alkoxy, C1-5 haloalkoxy, halogen, hydroxyl, cyano, amino, -CN, -NO2, -OR c1 , -NR a1 R b1 , -S(O) i R a1 , -NR a1 S(O) i R b1 , -S(O) i NR a1 R b1 , -C(=O)OR a1 , -OC(=O)OR a1 , -C(=S)OR a1 , -O(C=S)R a1 , -C(=O)NR a1 R b1 , -NR a1 C(=O)R b1 , -C(=S)NR a1 R b1 , -C(=O)R a1 , -C(=S)R a1 , N.R. a1 C(=S)R b1 , -O(C=O)NR a1 R b1 , -NR a1 (C=S)ORb1 , -O(C=S)NR a1 R b1 , -NR a1 (C=O)NR a1 R b1 , -NR a1 (C=S)NR a1 R b1 , phenyl, or 5-6 membered heteroaryl. a1 and each R b1 is independently selected from -H and C alkyl optionally substituted with hydroxyl or C alkoxy; R c1 is -H, C1-5 haloalkyl, or C1-5 alkyl, where C1-5 alkyl is optionally substituted with hydroxyl or C1-C3 alkoxy.

[0102] [ka] The symbol as used herein refers to the point at which the moieties are attached.

[0103] pharmaceutically acceptable salts The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0104] Pharmaceutically acceptable salts of the compounds of any one of the above formulas include acid addition and base salts.

[0105] Pharmaceutically acceptable salts of the compounds disclosed herein are included in the present teachings. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings that contain an acidic group, such as a carboxylic acid, can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0106] Pharmaceutically acceptable salts of compounds of any one of the above formulas can be prepared in three ways: (i) reacting a compound of any one of the above formulas with a desired acid or base; (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of any one of the above formulae, or ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid or base; or (iii) may be prepared by one or more of converting one salt of a compound of any one of the above formulas to another salt by reaction with an appropriate acid or base or by use of a suitable ion exchange column.

[0107] All three reactions are typically carried out in solution. The resulting salt precipitates and can be collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to nearly non-ionized.

[0108] Compounds of any one of the above formulas and their pharmaceutically acceptable salts may exist in unsolvated and solvated forms.

[0109] Stereoisomers and other variations Compounds of any one of the above formulas may exhibit one or more types of isomerism (e.g., optical isomers, geometric isomers, or tautomers). Such variations are intended to be implicit in any compound of any one of the above formulas defined by reference to its structural features and are therefore within the scope of this disclosure.

[0110] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or a mixture of both. Stereoisomers are compounds that differ only in spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers that have two or more chiral centers and are not identical or mirror images of each other.

[0111] If a compound is designated in its chemical name to represent a single enantiomer (e.g., when the configuration is indicated by "R" or "S" in the chemical name) or its structure (e.g., when the configuration is indicated by a "wedge" bond), unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or designated enantiomers divided by the total weight of the mixture of both enantiomers.

[0112] Where the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses multiple stereoisomers (e.g., as in the case of a diastereomeric pair), it is understood to include one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0113] When two stereoisomers are designated by their chemical names or structures and the chemical names or structures are connected by "and," a mixture of the two stereoisomers is intended.

[0114] When two stereoisomers are depicted by their chemical names or structures and the chemical names or structures are connected by "or", either one or the other of the two stereoisomers is intended, but not both.

[0115] When disclosed compounds having chiral centers are shown with a structure that does not indicate the configuration at that chiral center, the structure is meant to encompass compounds in which the chiral center is in the S configuration, compounds in which the chiral center is in the R configuration, or compounds in which the chiral center is a mixture of R and S configurations. When disclosed compounds having chiral centers are shown with a chemical name that does not indicate the configuration at that chiral center with "S" or "R," the name is meant to encompass compounds in which the chiral center is in the S configuration, compounds in which the chiral center is in the R configuration, or compounds in which the chiral center is a mixture of R and S configurations.

[0116] A racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound with one chiral center is named or drawn by a structure without indicating the stereochemistry of the chiral center, the name or structure is understood to encompass both possible enantiomeric forms of the compound (e.g., both enantiomerically pure, enantiomerically enriched, or racemic). When a compound with two or more chiral centers is named or drawn by a structure without indicating the stereochemistry of the chiral centers, the name or structure is understood to encompass all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures)).

[0117] The term "geometric isomer" refers to isomers that differ in the orientation of substituent atoms with respect to a carbon-carbon double bond, a carbocyclic ring, or a bridged bicycle. Substituent atoms (other than hydrogen) on either side of a carbon-carbon double bond can be in either the E or Z configuration according to the Cahn-Ingold-Prelog precedence rules. In the "E" configuration, the highest priority substituents are on opposite sides of the carbon-carbon double bond. In the "Z" configuration, the highest priority substituents are on the same side of the carbon-carbon double bond.

[0118] Substituents around a carbon-carbon double bond may also be referred to as "cis" or "trans," with "cis" referring to substituents on the same side of the double bond and "trans" referring to substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring may also be referred to as "cis" or "trans." The term "cis" refers to substituents on the same side in relation to the plane of the ring and the term "trans" refers to substituents on opposite sides in relation to the plane of the ring. A mixture of compounds having substituents arranged on both the same and opposite sides in relation to the plane of the ring is referred to as "cis / trans."

[0119] Tautomeric isomerism ("tautomerism") can occur where structural isomers are interconvertible via a low energy barrier. This can take the form of proton tautomerism in compounds of any one of the above formulae containing an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. That is, a compound can exhibit more than one form of isomerism.

[0120] In certain cases, tautomeric forms of the disclosed compounds exist, for example, the tautomeric structures shown below: [ka]

[0121] When a geometric isomer is designated by name or structure, it is understood that the named or depicted isomer is present in greater amount than another isomer, and that the geometric isomer purity of the named or depicted geometric isomer is greater than 50% by weight, e.g., at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomer purity is determined by dividing the weight of the named or depicted geometric isomer in a mixture by the total weight of all geometric isomers in the mixture.

[0122] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0123] Conventional techniques for preparing / isolating individual enantiomers / diastereomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, if a compound of any one of the above formulas contains an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art. Chiral compounds of any one of the above formulas (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of 0-50% by volume, typically 2%-20% isopropanol, and a hydrocarbon, typically heptane or hexane, containing 0-5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate yields the enriched mixture. Chiral chromatography using subcritical and supercritical fluids can also be employed. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein). Columns are available from Chiral Technologies, Inc., West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.

[0124] Although compounds of any one of the above formulas are depicted herein in a single tautomeric form, it is emphasized that all possible tautomeric forms are included within the scope of the present disclosure.

[0125] 3. Administration and Dosage Typically, the compound of the present disclosure is administered in an amount effective to treat the conditions described herein.The compound of the present disclosure can be administered as the compound itself or alternatively as a pharmaceutically acceptable salt.For the purpose of administration and dosage, the compound itself or its pharmaceutically acceptable salt will simply be referred to as the compound of the present disclosure.

[0126] The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, in a dose effective for the intended treatment. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.

[0127] The compounds of the present disclosure can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or by buccal or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0128] In another embodiment, the compounds of the present disclosure can also be administered directly into the bloodstream, into muscle, or into an internal organ.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous.Suitable devices for parenteral administration include needle-based (including microneedle-based) injectors, needle-free injectors, and infusion techniques.

[0129] In another embodiment, the compounds of the present disclosure can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the present disclosure can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure can also be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure can also be administered directly to the eye or ear.

[0130] The dosage regimen for the compounds of the present disclosure and / or compositions containing the compounds is based on various factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, dosage regimens can vary widely. In one embodiment, the total daily dose of the compounds of the present disclosure is typically about 0.001 to about 100 mg / kg (i.e., mg of the compound of the present disclosure per kg of body weight) for the treatment of the indicated conditions discussed herein.

[0131] For oral administration, the composition may be provided in the form of tablets containing 0.1 to 500 milligrams of the active ingredient to allow for symptomatic adjustment of the patient's dosage. Medicaments typically contain about 0.01 mg to about 500 mg of the active ingredient. Intravenously, the dose may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0132] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals, for example, primates, rodents (mouse, rat, hamster, rabbit, etc.). In one embodiment, a human is a suitable subject. Human subjects may be of either gender and at any stage of development.

[0133] 4. Pharmaceutical Compositions In another embodiment, the present disclosure includes pharmaceutical compositions. Such pharmaceutical compositions include a compound of the present disclosure, a pharmaceutically acceptable salt, or a stereoisomer thereof, together with a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances may also be present.

[0134] As used herein, "pharmaceutically acceptable carriers or excipients" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof; isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol or sorbitol, may be included in the composition. Pharmaceutically acceptable substances, such as wetting agents, or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.

[0135] The compositions of the present disclosure may be in a variety of forms, including, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0136] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0137] Oral administration of solid dosage forms can be provided in separate units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure.In another embodiment, oral administration can be in powder or granular form.In another embodiment, oral dosage forms are sublingual, such as lozenges.In such solid dosage forms, the compound of any one of the above formulas is usually combined with one or more adjuvants.Such capsules or tablets can contain controlled-release formulations.In the case of capsules, tablets, and pills, dosage forms can also contain buffering agents or be prepared with enteric coatings.

[0138] In another embodiment, oral administration can be in liquid dosage form.Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, which contain inert diluents commonly used in the art (e.g., water).Such compositions can also contain auxiliary agents such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or flavoring agents.

[0139] In another embodiment, the present disclosure comprises a parenteral dosage form.

[0140] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersing agents, wetting agents, and / or suspending agents.

[0141] In another embodiment, the present disclosure comprises a topical dosage form.

[0142] "Topical administration" includes, for example, transdermal administration via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Topical administration compositions also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present disclosure are administered via a transdermal device, administration is achieved using a patch, either of the reservoir and porous membrane type or various solid matrices. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may also be incorporated. See, e.g., Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0143] Formulations suitable for topical administration to the eye include, for example, eye drops, in which the compound of the present disclosure is dissolved or suspended in a suitable carrier. A typical formulation suitable for intraocular or intraaural administration may be in the form of droplets of a micronized suspension or solution in pH-adjusted, isotonic, sterile saline. Other formulations suitable for intraocular and intraaural administration include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicular systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum may be incorporated along with preservatives such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0144] For intranasal administration or inhalation administration, the compound of the present disclosure can be conveniently delivered in the form of solution or suspension from a pump spray container that is pushed or pumped by the patient, or in the form of aerosol spray from a pressurized container or nebulizer with the use of suitable propellant.The formulation suitable for intranasal administration is typically administered in the form of dry powder from a dry powder inhaler (either alone, as a mixture (for example, dry blend with lactose), or as mixed component particles (for example, mixed with phospholipids such as phosphatidylcholine)), or as aerosol spray from a pressurized container, pump, spray, atomizer (preferably, electrohydrodynamic atomizer to generate fine mist), or nebulizer with or without the use of suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.For intranasal administration, powder can contain bioadhesive agent, for example, chitosan or cyclodextrin.

[0145] In another embodiment, the present disclosure includes a rectal dosage form. Suitable rectal dosage forms may be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, although various alternatives may be used as appropriate.

[0146] Other carrier materials and dosage forms known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, including effective formulation and administration procedures.

[0147] The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. Drug formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0148] 5.Treatment method The terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0149] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have appeared or been observed (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in light of a history of symptoms and / or exposure to a pathogen). Treatment may be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0150] The term "prevention" (or "prevent" or "preventing"), as used herein, refers to eliminating, avoiding, forestalling, arresting, reducing, arresting, or impeding the symptoms of a disease, disorder, and / or condition. Prevention includes administration to a subject who does not exhibit symptoms of the disease, disorder, and / or condition at the time of administration.

[0151] The terms "condition," "disease," and "disorder" are used interchangeably.

[0152] The terms "administer," "administering," or "administration" refer to methods of introducing a compound disclosed herein, or a composition thereof, into or onto a patient. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be employed with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0153] Generally, the effective amount of the compounds taught herein will vary depending on various factors, such as the given drug or compound, pharmaceutical formulation, route of administration, type of disease or disorder, characteristics of the subject or host being treated, etc., but can be routinely determined by one of ordinary skill in the art. The effective amount of the compounds of the present teachings can be readily determined by one of ordinary skill in the art by conventional methods known in the art.

[0154] The term "therapeutically effective amount" means an amount that, when administered to a subject, produces a beneficial or desired result, including a clinical result that, for example, inhibits, suppresses, or alleviates the symptoms of the condition being treated in the subject compared to a control. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular anti-cancer agent, its mode of administration, co-treatment with other therapies, etc.

[0155] The present disclosure is directed to compounds of formula (I) (including all embodiments thereof) that are useful for the treatment and / or prevention of diseases and / or conditions associated with or modulated by HTT, and in particular, where lowering mHTT in a subject is of therapeutic benefit, including, but not limited to, the treatment and / or prevention of HD.

[0156] In one embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0157] In one embodiment, the present disclosure relates to a compound of (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body.

[0158] The present disclosure further provides a method of treating HD in a subject in need thereof, comprising administering to the subject an effective amount of: (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0159] In one embodiment, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating HD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0160] In one embodiment, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HD in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

[0161] 6. Medical Kit One aspect of the present invention relates to a kit for conveniently and effectively carrying out the method or use according to the present invention. Generally, pharmaceutical packs or kits include one or more containers containing one or more of the components of the pharmaceutical compositions of the present invention. Such kits are particularly suitable for the delivery of solid oral forms such as tablets or capsules. Such kits may also preferably include a card containing several unit doses, arranging the doses in order of their intended use. If desired, a memory aid may be provided, indicating, for example, in the form of numbers, letters, or other markings, or a calendar insert, the days on which the doses in the treatment regimen are to be administered. Such container(s) may optionally be accompanied by a notice in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, indicating that the agency has approved the manufacture, use, or sale for human administration.

[0162] The following representative examples contain important additional information, exemplification, and guidance that can enable the present invention to be adapted to practice in its various embodiments and equivalents thereof. These examples are intended to help illustrate the invention and are not intended, and should not be construed, as limiting its scope. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art upon consideration of the specification, including the examples that follow and by reference to the scientific and patent literature cited herein.

[0163] The contents of the cited references are incorporated herein by reference to help illustrate the state of the art.

[0164] Additionally, for purposes of the present invention, chemical elements are defined as those elements listed in the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "Organic Chemistry," Morrison & Boyd (3rd Ed.), the entire contents of both of which are incorporated herein by reference.

[0165] 7. Preparation Any one compound of the above formula can be prepared by the general and specific methods described below using the general common knowledge of a person skilled in the art of synthetic organic chemistry. Such general common knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII (published by Wiley-Interscience). The starting materials used herein are commercially available or can be prepared by conventional methods known in the art.

[0166] It should be noted that in the preparation of compounds of any one of the above formulas, some of the preparative methods described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls in precursors of any one of the above formulas). The need for such protection varies depending on the nature of the remote functional group and the conditions of the preparation method. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill of the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0167] For example, certain compounds contain primary amine or carboxylic acid functional groups that, if left unprotected, can interfere with the reaction of other portions of the molecule. Therefore, such functional groups can be protected by appropriate protecting groups that can be removed in a subsequent step. Protecting groups suitable for protecting amines and carboxylic acids include those commonly used in peptide synthesis (e.g., Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids), which are generally not chemically reactive under the described reaction conditions and can typically be removed without chemically altering other functionalities in the compounds of any one of the above formulas.

[0168] The schemes set forth below are intended to provide a general description of the methodology employed in the preparation of compounds of the present disclosure. Some of the compounds of the present disclosure may contain single or multiple chiral centers, having the stereochemical designation (R) or (S). It will be apparent to those skilled in the art that all synthetic transformations can be carried out in a similar manner, whether the material is enantiomerically enriched or racemic. Furthermore, resolution to the desired optically active material can be carried out at any desired point in the sequence using well-known methods, such as those described herein and in the chemical literature. [Example]

[0169] [Table 2-1] [Table 2-2]

[0170] Section 1. General and analytical methods a. General method Unless otherwise noted, the compounds in the examples were analyzed or purified according to one of the purification methods mentioned below. When preparative TLC / HPLC or silica gel chromatography is used, one skilled in the art can select any solvent combination to purify the desired compound. Silica gel column chromatography was performed using 20-40 mm (particle size), 250-400 mesh, or 400-632 mesh silica gel, using either a Teledyne ISCO Combiflash RF or Grace Reveleris X2 with an ELSD purification system, or by using pressurized nitrogen (approximately 10-15 psi) to pass the solvent through the column ("flash chromatography"). When an SCX column was used, the eluent conditions were MeOH followed by methanolic ammonia. Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum.

[0171] b.Analysis method Analytical LCMS instrument specifications: Waters Acquity iClass UPLC equipped with a QDa mass spectrometer and a PDA (photodiode array detector)

[0172] RxnQC / FrxQC / Purity QC Analytical LC / MS Method Conditions: Ammonium hydroxide (basic pH) conditions Method 1 MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 um; part number 186002350 Modifier: ammonium hydroxide 0.2% (v / v) concentration Method: 95% H2O / 5% MeCN (initial condition) held for 0.1 min, linear gradient to 5% H2O / 95% MeCN in 3.25 min, held at 5% H2O / 95% MeCN for 3.5 min. Flow rate: 0.8 mL / min.

[0173] Method 2 MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters ACQUITY UPLC BEH C18 2.1 x 30 mm, 1.7 um; part number 186002349 Modifier: ammonium hydroxide 0.2% (v / v) concentration Method: 95% H2O / 5% MeCN (initial condition), linear gradient to 5% H2O / 95% MeCN in 1.0 min, hold at 5% H2O / 95% MeCN until 1.3 min. Flow rate: 0.7 mL / min.

[0174] Trifluoroacetic acid (acidic pH) conditions Method 3 MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 um; part number 186002350 Modifier: Trifluoroacetic acid 0.1% (v / v) concentration Method: 95% H2O / 5% MeCN (initial condition) held for 0.1 min, linear gradient to 5% H2O / 95% MeCN 3.25 min, 5% H2O / 95% MeCN held until 3.5 min. Flow rate: 0.8 mL / min.

[0175] Method 4 MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 um; part number 186002349 Modifier: Trifluoroacetic acid 0.1% (v / v) concentration Method: 95% H2O / 5% MeCN (initial condition), linear gradient to 5% H2O / 95% MeCN in 1.0 min, hold at 5% H2O / 95% MeCN until 1.3 min. Flow rate: 0.7 mL / min.

[0176] Analytical LCMS instrument specifications: Agilent 1200 Series LC / MSD system with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass spectrometer; Agilent Technologies 1260 Infinity LC / MSD system with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6120B mass spectrometer; Agilent Technologies 1260 Infinity II LC / MSD system with DAD\ELSD G7102A, 1290 Infinity II and Agilent LC\MSD G6120B mass spectrometer; Agilent 1260 Series LC / MSD system with DAD\ELSD and Agilent LC\MSD (G6120B) mass spectrometer; UHPLC Agilent with DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer 1290 Series LC / MSD system.

[0177] RxnQC / FrxQC / Purity QC Analytical LC / MS Method Conditions: Formic acid (acidic pH) conditions Method 5 Injection volume: 0.5 μl, column temperature: 60°C, UV scan: 207–223 nM, 246–262 nM, 272–288 nM, Agilent Poroshell 120 SB-C18 4.6×30 mm 2.7 μm and UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6×5 mm 2.7 μm, mobile phase A: 0.1% FA / water, mobile phase B: 0.1% FA / acetonitrile [Table 3]

[0178] Method 6 Injection volume: 0.5 μl; Column temperature: 60°C; UV scan: 207–223 nM, 246–262 nM, 272–288 nM Agilent Poroshell 120 SB-C18 4.6 x 30 mm 2.7 μm and UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6 x 5 mm 2.7 μm. Mobile phase A: 0.1% FA / water, Mobile phase B: 0.1% FA / acetonitrile. [Table 4]

[0179] Method 7 MS mode: MS ESI+ scan range 100-1000 daltons PDA: Scan range of 190~370nm Column: Xtimate C18 2.1*30mm, 3um Modifier: Phase A: water (4 L) + TFA (1.5 mL), Phase B: acetonitrile (4 L) + TFA (0.75 mL) Method: An elution gradient of 10% to 80% (solvent B) was used over 1.35 min and a 0.9 min hold at 80%, with a flow rate of 0.8 ml / min.

[0180] Method 8 [Table 5]

[0181] explanation: Mobile phase: 5% ACN (0.018% TFA) / water (0.037% TFA) gradient to 95% ACN in 3.0 min at a flow rate of 1.0 mL / min; then hold at 95% ACN for 0.60 min at a flow rate of 1.0 mL / min to 1.5 mL / min; then return to 5% ACN / water for 0.40 min at a flow rate of 1.5 mL / min. The column temperature was 50°C. The column is Shim-pack Velox SP-C18 2.7μm 3.0*30mm.

[0182] Method 9 [Table 6]

[0183] explanation: Mobile phase: 5% ACN (0.01875% TFA) / water (0.0375% TFA) gradient to 95% ACN / water in 0.60 min at a flow rate of 2.0 mL / min; then hold at 95% ACN for 0.18 min at a flow rate of 2.0 mL / min; then return to 5% ACN / water for 0.02 min at a flow rate of 2.0 mL / min. The column temperature was 50°C. The column is a Kinetex® EVO C18 2.1×30 mm 5 um.

[0184] Method 10 explanation: Mobile phase: 5% ACN (0.01875% TFA) / water (0.0375% TFA) gradient to 95% ACN in 3.20 min, flow rate set at 1.5 mL / min; then hold at 95% ACN for 0.30 min, flow rate set at 1.5 mL / min; return to 5% ACN / water for 0.30 min. Flow rate set at 2.0 mL / min. Column temperature: 50°C. Column: Kinetex® EVO C18 4.6 x 50 mm 5 um.

[0185] Preparative HPLC-MS conditions: HPLC-MS instrument specifications Waters Autopurification equipped with a QDa mass spectrometer and a PDA (photodiode array detector) Ammonium hydroxide (basic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters XSELECT CSH C18 PREP 19 x 100 mm, 5 um; part number 186005421 Modifier: 0.2% ammonium hydroxide (v / v) concentration Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters XSELECT CSH C18 PREP 30 x 100 mm, 5 um; part number 186005425 Modifier: 0.2% ammonium hydroxide (v / v) concentration Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters XSELECT CSH C18 PREP 30 x 50 mm, 5 um; part number 186005423 Modifier: 0.2% ammonium hydroxide (v / v) concentration Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Column: Boston Prime C18 150 x 30 mm x 5 um; Conditions: Water (NH3H2O + NH4HCO3)-ACN; Gradient (% organic matter): 0-100% optimized for each example; Flow rate (mL / min): 25. Column: YMC Actus Trial C18 20*100 5 mkm column; gradient mixture H2O-MeOH-ammonia 0.1% as mobile phase optimized for each example.

[0186] Trifluoroacetic acid (acidic pH) conditions Flow rate: 30mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters Sunfire OBD C18 PREP 19 x 100 mm, 5 um; part number 186002567 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Flow rate: 50mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters Sunfire OBD C18 PREP 30 x 100 mm, 5 um; part number 186002572 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min. Flow rate: 60mL / min MS mode: MS:ESI+ scan range 165-650 daltons PDA: Scan range of 200~400nm Column: Waters Sunfire OBD C18 PREP 30 x 50 mm, 5 μm; Part Number 186002570 Modifier: 0.1% trifluoroacetic acid (v / v) Method: A%H20 / B%MeCN (initial conditions) held for 0.5 min, linear gradient to A%H20 / B%MeCN in 8 min, gradient to 5%H20 / 95%MeCN in 8.5 min, hold at 5%H20 / 95%MeCN until 10 min.

[0187] Formic acid (FA, acidic pH) conditions Column: Welch Xtimate C18 150 x 30 mm x 5 um; Conditions: Water (FA)-ACN; Gradient (% organic matter): optimized for each example; Flow rate (mL / min) 25.

[0188] Hydrochloric acid (HCl, acidic pH) conditions Column: Boston Green ODS 150 x 30 mm x 5 um; Conditions: Water (HCl)-ACN; Gradient (% organic matter): 0-100% optimized for each example; Flow rate (mL / min): 25.

[0189] Analytical SFC instrument specifications Waters Acquity UPC equipped with a QDa mass spectrometer and a PDA (photodiode array detector) 2 SFC Analytical screening conditions MS mode: MS:ESI+ scan range 100-650 daltons PDA: Scan range of 200~400nm Column: see below Solvent: Airgas Bone Dry Co2 Co-solvent: methanol, ethanol, or isopropanol containing either 0.1% diethylamine, 0.1% dimethylethanolamine, or neutral Method: Isocratic conditions; typically 60% CO2:40% co-solvent or 70% CO2:30% co-solvent, flow rate: 3.0 mL / min.

[0190] Preparative SFC instrument specifications Waters Prep100 SFC equipped with a QDa mass spectrometer, PDA (photodiode array detector) and 2767 collection bed Separation conditions Method: X% cosolvent (with Y% modifier) / CO2, isocratic conditions. Flow rate: 100mL / min Automatic back pressure regulator: 120 bar Manual backpressure regulator: 40 psi for MeOH or EtOH, 60 psi for iPrOH Column oven temperature: 40°C MS mode: MS:ESI+ scan range 150-650 daltons PDA: Scan range of 200~400nm

[0191] SFC column (analysis): AD-H: Daicel Chiralpak AD-H, 4.6mm x 250mm, 5um, part number 19325 AS-H: Daicel Chiralpak AS-H, 4.6mm x 250mm, 5um, part number 20325 OD-H: Daicel Chiralpak OD-H, 4.6mm x 250mm, 5um, part number 14325 OX-H: Daicel Chiralpak OX-H, 4.6mm x 250mm, 5um, part number 63325 IA: Daicel Chiralpak IA, 4.6mm x 250mm, 5um, part number 80325 IB: Daicel Chiralpak IB, 4.6mm x 250mm, 5um, part number 81325 IC: Daicel Chiralpak IC, 4.6mm x 250mm, 5um, part number 83325 IG: Daicel Chiralpak IG, 4.6mm x 250mm, 5um, part number 87325 Cell-2: Phenomenex Lux Cellulose-2, 4.6mm x 150mm, 3um, part number 00F-4456-E0 Cell-4: Phenomenex Lux Cellulose-4, 4.6mm x 150mm, 3um, part number 00F-4490-E0

[0192] SFC column (preparative): AD-H: Daicel Chiralpak AD-H, 30mm x 250mm, 5µm, part number 19475 AS-H: Daicel Chiralpak AS-H, 30mm x 250mm, 5µm, part number 20475 OD-H: Daicel Chiralpak OD-H, 30mm x 250mm, 5um, part number 14475 OX-H: Daicel Chiralpak OX-H, 30mm x 250mm, 5um, part number 63475 IA: Daicel Chiralpak IA, 30mm x 250mm, 5um, part number 80475 IB: Daicel Chiralpak IB, 30mm x 250mm, 5um, part number 81475 IC: Daicel Chiralpak IC, 30mm x 250mm, 5um, part number 83475 IG: Daicel Chiralpak IG, 30mm x 250mm, 5um, part number 87475 Cell-2: Phenomenex Lux Cellulose-2, 30mm x 250mm, 5um, part number 00G-4457-U0-AX Cell-4: Phenomenex Lux Cellulose-4, 30mm x 250mm, 5um, part number 00G-4491-U0-AX

[0193] 1 H-NMR 1 H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. 1H NMR spectra were recorded on a Bruker Avance III HD 500MHz, Bruker Avance III 500MHz, Bruker Avance DRX 500, Bruker Avance III 400MHz, Varian-400 VNMRS, Varian Unityplus 400, or Varian-400 MR. Characteristic chemical shifts (d) are abbreviated for tetramethylsilane (H) using conventional abbreviations for the major peak designations, e.g., s: singlet; d: doublet; t: triplet; q: quartet; dd: double doublet; dt: double triplet; m: multiplet; br: broad. 1 The NMR spectra are given in parts per million downfield from the NMR spectrum (for H-NMR). The following abbreviations are used for common solvents: CDCl3: deuterated chloroform; DMSO-d6: hexadeuterodimethylsulfoxide; and MeOH-d4: deuterated methanol. If necessary, tautomers may be recorded in the NMR data, and some exchangeable protons may not be visible.

[0194] Section 2. Preparation of intermediates Intermediate 1 [ka] A solution of 5-bromo-3-fluoro-pyridin-2-amine (623.79 mg, 3.27 mmol) and tert-butyl 4-(2-bromo-acetyl)piperidine-1-carboxylate (1 g, 3.27 mmol) in water (30 mL) was stirred at 60° C. for 12 h. The mixture was concentrated to give a residue, which was purified by flash silica gel chromatography (EtOAc / petroleum ether, 0-25%) to give tert-butyl 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (900 mg, 2.26 mmol, 69% yield) as a pale yellow solid. MS: m / z 297.9 [M+H] + ; 1H NMR (400 MHz, chloroform-d) δ ppm: 8.03 (s, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 6.97 (dd, J=9.5, 1.2 Hz, 1 H), 4.12 - 4.27 (m, 2 H), 2.79 - 2.97 (m, 3 H), 2.06 (br d, J=13.0 Hz, 2 H), 1.64 (br dd, J=12.3, 2.8 Hz, 2 H), 1.43 - 1.46 (m, 9 H).

[0195] Intermediate 2 [ka] To a solution of tert-butyl 4-(6-bromo-8-fluoroimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (4 g, 10.04 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.10 g, 20.09 mmol) in dioxane (150 mL), cyclopentyl(diphenyl)phosphane dichloromethane dichloropalladium; iron (820.19 mg, 1.00 mmol) and KOAc (2.96 g, 30.13 mmol) were added and stirred at 100° C. under a N atmosphere for 48 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give tert-butyl 4-[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (3.12 g, 7.01 mmol, 69% yield) as a yellow solid. MS: m / z 446.3 [M+H] +

[0196] Intermediate 3 [ka] To a solution of 5-bromo-3-fluoro-pyridin-2-amine (480 mg, 2.51 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (480 mg, 2.51 mmol) in dioxane (5 mL) and water (1 mL) was added K2CO3 (694 mg, 5.03 mmol) and Pd(dppf)Cl2 (367 mg, 0.50 mmol). The mixture was stirred under nitrogen at 90 °C for 16 hours. The mixture was extracted with EtOAc (15 mL × 3) and dried over Na2SO4. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40% to 100% EtOAc:PE) to give 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-fluoro-pyridin-2-amine (446 mg, 1.73 mmol, 68% yield) as a yellow solid. MS: m / z 258.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ: 8.48 (s, 1H), 7.97 - 7.92 (m, 2H), 7.59 (s, 1H), 6.72 (s, 2H), 2.56 (s, 3H), 2.38 (s, 3H).

[0197] Intermediate 4 [ka] To a solution of 7-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (3.18 g, 11.52 mmol) in dioxane (60 mL) and water (20 mL) was added 5-bromo-3-fluoropyridin-2-amine (2 g, 10.47 mmol), potassium phosphate tripotassium (4.45 g, 20.94 mmol), and cyclopentyl(diphenyl)phosphane dichloropalladium; iron (766.18 mg, 1.05 mmol). The mixture was stirred at 100° C. under a N atmosphere for 12 hours. The mixture was concentrated, and then water (50 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The crude material was purified by flash silica gel chromatography (CH2Cl2:MeOH = 100 / 1 to 20 / 1) to give 3-fluoro-5-(7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-amine (1.77 g, 6.78 mmol, 64.72% yield, 99% purity) as a yellow solid. MS: m / z 261.0 [M+H] + , 1 H NMR (400 Hz, DMSO-d6) δ: 8.46 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.73-7.80 (m, 2H), 7.35-7.39 (m, 1H), 6.33 (s, 2H), 4.20 (s, 3H).

[0198] Intermediate 5 [ka] To a solution of 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid (50 mg, 26 μmol) in thionyl chloride (3 mL) was added one drop of DMF at 25°C and stirred at 78°C for 1 h. The mixture was then concentrated in vacuo, and the residue was dissolved in THF (5 mL) and acetonitrile (5 mL) and cooled to 0°C. Diazomethyl(trimethyl)silane (2 M, 327 μL) was then added to the solution. The mixture was stirred at 0°C for 0.5 h, and then HBr (64 mg, 785 μmol) was added at the same temperature and stirred for an additional 1 h. The mixture was then concentrated in vacuo to give 2-bromo-1-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)ethan-1-one (60 mg, crude) as a colorless oil, which was used directly in the next step. MS: m / z 269.9 [M+2H] +

[0199] Intermediate 6 [ka] Step a: To a solution of 6-bromo-4-fluoro-2H-benzo[d][1,2,3]triazole (14.08 g, 65 mmol) in DMF (12 mL), NaH (1.88 g, 78 mmol, 60% in oil) was added, and the mixture was stirred at 25 °C for 0.5 h. Then, Mel (10.2 g, 71.7 mmol) was added, and the reaction mixture was stirred at the same temperature for 12 h. The resulting mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (Hex: EtOAc = 3:1) to give 6-bromo-4-fluoro-2-methyl-2H-benzo[d][1,2,3]triazole as a yellow solid (3 g, 20% yield).

[0200] Step b: To a solution of 6-bromo-4-fluoro-2-methyl-2H-benzo[d][1,2,3]triazole (3 g, 13 mmol) in dioxane (50 mL) was added bis(pinacolato)diboron (6.6 g, 26 mmol) and potassium acetate (2.55 g, 26 mmol). The reaction mixture was degassed and backfilled with argon, and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride in dichloromethane (0.265 g, 0.32 mmol) was added. The reaction mixture was stirred at 100 °C for 10 h. The resulting mixture was partitioned between EtOAc and water, and the organic layer was concentrated under reduced pressure and purified on a silica column using eluent (Hex: EtOAc = 7:3) to give 1.6 g of 4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d][1,2,3]triazole. 1 H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 7.29 (d, J = 11.1Hz, 1H), 4.56 (s, 3H), 1.33 (s, 12H). M+=277

[0201] Intermediate 7 [ka] Step a: 5-Bromo-3-fluoropyridin-2-amine (28 g, 146.6 mmol) was dissolved in toluene (300 mL) and 1,1-dimethoxy-N,N-dimethylethanamine (35 mL, 234.5 mmol) was added. The reaction mixture was stirred at reflux overnight. The solvent was then evaporated to give 35 g of N'-(5-bromo-3-fluoropyridin-2-yl)-N,N-dimethylacetimidamide, which was used in the next step without further purification.

[0202] Step b: Crude N'-(5-bromo-3-fluoropyridin-2-yl)-N,N-dimethylacetimidamide (35 g, 134.5 mmol) was dissolved in MeOH (300 mL) and hydroxylamine hydrochloride (1.4 g, 161.5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solid was then filtered off to give N-(5-bromo-3-fluoropyridin-2-yl)-N'-hydroxyacetimidamide (15 g, 41% yield).

[0203] Step c: N-(5-bromo-3-fluoropyridin-2-yl)-N'-hydroxyacetimidamide (15 g, 60.5 mmol) was dissolved in THF (200 mL). The solution was cooled, and 2,2,2-trifluoroacetic anhydride (17.1 mL, 120.9 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The solvent was then evaporated under vacuum. The residue was dissolved in a DCM / water mixture and neutralized with NaHCO to pH = 8-9. The organic layer was washed with brine, dried under NaSO, and evaporated under reduced pressure to give 6-bromo-8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (7 g, 50% yield).

[0204] Step d: 6-Bromo-8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (17) (7 g, 30.4 mmol), bis(pinacolato)diborane (8.1 g, 32 mmol), and potassium acetate (6 g, 60.8 mmol) were mixed in dioxane (50 mL). The resulting mixture was evacuated and backfilled with argon (3 cycles), and then Pd(dppf)Cl·DCM (0.53 g, 1.52 mmol) was added under an argon atmosphere. The reaction mixture was stirred at 90 °C under an argon atmosphere for 18 h, then cooled, filtered through SiO, and concentrated under reduced pressure. The solid was dissolved in MTBE, stirred for 30 minutes, and filtered off to give 8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (5.5 g, 65% yield). 1H NMR (400MHz, DMSO-d6) δ 8.74 (s, 1H), 7.48 (d, J = 10.3Hz, 1H), 2.54 (s, 3H), 1.33 (s, 12H). M+=277

[0205] Intermediate 8 [ka] Step a: To a mixture of 5-bromo-3-fluoropyridin-2-amine (5 g, 26.2 mmol) and pyridine (2.1 g, 26.2 mmol, 2.1 mL), 4-methylbenzene-1-sulfonyl chloride (5 g, 26.2 mmol) was added at 0° C., and the reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The mixture was concentrated, and then water (300 mL) was added. The mixture was extracted with EtOAc (200 mL×2) and concentrated to give N-(5-bromo-3-fluoropyridin-2-yl)-4-methylbenzenesulfonamide (6.9 g, 19 mmol) as an off-white solid. MS: m / z 347.0 [M+2H] +

[0206] Step b: To a solution of N-(5-bromo-3-fluoro-2-pyridyl)-4-methyl-benzenesulfonamide (20 g, 57.94 mmol) and 2-iodoacetamide (10.72 g, 57.94 mmol) in DMF (100 mL) was added DIPEA (14.98 g, 115.88 mmol, 20.2 mL). The reaction mixture was stirred at 80 °C for 16 h. The mixture was concentrated, and the crude material was purified by silica column chromatography (DCM / MeOH = 10 / 1 to 6 / 1) to give 2-[(2E)-5-bromo-3-fluoro-2-(p-tolylsulfonylimino)-1-pyridyl]acetamide (6.5 g, 28% yield) as a white solid.

[0207] Step c: To a solution of 2-[(2E)-5-bromo-3-fluoro-2-(p-tolylsulfonylimino)-1-pyridyl]acetamide (6 g, 14.92 mmol) in DCM (80 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (18.80 g, 89.50 mmol, 12.4 mL) at 0 °C, and the reaction mixture was stirred under N atmosphere at 25 °C for 12 h. The mixture was concentrated, and the crude material was purified by silica column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) to give N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (3 g, 61% yield) as an off-white solid.

[0208] Step d: To a solution of N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (3.2 g, 9.81 mmol) in THF (30 mL) and water (6 mL) at 20 °C, NaOH (1.18 g, 29.44 mmol) was added. The reaction mixture was stirred at 60 °C under a N atmosphere for 12 hours. The mixture was concentrated. The residue was diluted with water (30 mL) and extracted with DCM (60 mL × 3). The organic layer was washed with brine (100 mL), dried over Na SO , filtered, and concentrated to give 6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-amine (2.0 g, 88% yield) as a pale yellow solid. MS: m / z 229.8 [M+H] +

[0209] Intermediate 9 [ka] Step a: To a stirred solution of methyl 2-amino-3-methylbenzoate (48 g, 290.6 mmol) in acetonitrile (500 mL) was added N-bromosuccinimide (52 g, 290.6 mmol) in several portions at room temperature. The resulting mixture was stirred at room temperature overnight. The acetonitrile was evaporated under reduced pressure. The residue was diluted with water (500 mL), and the product was extracted with DCM (3 × 200 mL). The combined organic layers were washed with water (3 × 150 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give 67 g (95% yield) of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate.

[0210] Step b: To a stirred solution of methyl 2-amino-5-bromo-3-methylbenzoate (65 g, 266.3 mmol) in AcOH (3000 mL) was added sodium nitrite (21 g, 306.2 mmol) as an aqueous solution. The resulting mixture was stirred overnight. The formed precipitate was filtered off. The mother liquor was concentrated under reduced pressure. The residue was diluted with water (400 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with water (3 × 150 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give 34 g (50% yield) of methyl 5-bromo-2H-indazole-7-carboxylate.

[0211] Step c: To a stirred solution of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate (25 g, 98 mmol) in DCM (300 mL) was added triethyloxonium tetrafluoroborate (18.1 g, 122.5 mmol) in several portions at 0 °C. The reaction mixture was stirred at room temperature for 3 days. The resulting mixture was washed with water (3 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated under vacuum to give 19 g (73% yield) of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate.

[0212] Step d: To a stirred solution of methyl 5-bromo-2H-indazole-7-carboxylate (10 g, 37.2 mmol) in THF was added KOH (2.7 g, 48.3 mmol) as an aqueous solution. The reaction mixture was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and acidified with NaHSO4 to a weakly acidic pH. The precipitate was filtered and dried to give 9 g of the corresponding acid, which was dissolved in THF, and 1,1'-carbonyldiimidazole (8.6 g, 55.7 mmol) was added in several portions. The resulting mixture was stirred for 4 hours. Gaseous ammonia was then bubbled through the reaction mixture for 15 minutes. The resulting mixture was concentrated under vacuum. The solid residue was washed several times with water and dried to give 8.4 g of 5-bromo-2-methyl-2H-indazole-7-carboxamide.

[0213] Step e: To a stirred mixture of 5-bromo-2-methyl-2H-indazole-7-carboxamide (8.4 g, 33 mmol) and pyridine (13 g, 165.3 mmol) in DCM (100 mL) was added TFAA (10.4 g, 49.5 mmol) dropwise. The resulting mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (100 mL) and washed with water (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated in vacuo to give 7.7 g (98% yield) of 5-bromo-2-methyl-2H-indazole-7-carbonitrile.

[0214] Step f: 5-Bromo-2-methyl-2H-indazole-7-carbonitrile (8) (7.8 g, 33 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (9.2 g, 36.3 mmol), and potassium acetate (6.5 g, 66 mmol) were mixed in dioxane (80 mL). The resulting mixture was evacuated and backfilled with argon (3 cycles), and then Pd(dppf)Cl·DCM (0.78 g, 3.3 mmol) was added under an argon atmosphere. The reaction mixture was stirred at 90 °C under an argon atmosphere for 15 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2 × 20 mL) and discarded. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MTBE and filtered through a short pad of SiO. The MTBE was evaporated under reduced pressure. The residue was crystallized from MTBE / hexane to give 3.2 g of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-7-carbonitrile. 1 H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H), 8.48 (s, 1H), 7.91 (s, 1H), 4.26 (s, 3H), 1.32 (s, 12H). M+1=283

[0215] Intermediate 10 [ka] Step a: To a stirred solution of 4-bromo-2,6-difluorobenzaldehyde (50.0 g, 226.25 mmol, 226.25 mL) in THF (700 mL) was added hydrazine (48.33 g, 1.51 mol, 48.33 mL) at 0° C. The resulting mixture was warmed to 25° C. and stirred at the same temperature for 16 h. The solvent was removed under reduced pressure. The residual solid was dissolved in DMSO (600 mL), and then triethylamine (45.79 g, 452.49 mmol, 63.07 mL) was added, and the reaction mixture was stirred at 80° C. for 18 h. The resulting mixture was poured into water (1000 mL) and extracted with EtOAc (700 mL). The organic phase was separated, dried over Na2SO4, and evaporated to dryness to give 6-bromo-4-fluoro-1H-indazole.

[0216] Step b: To a mixture of 6-bromo-4-fluoro-1H-indazole (40.0 g, 186.03 mmol) in THF (700 mL) at 20° C. was added potassium tert-butoxide (31.31 g, 279.04 mmol). The mixture was stirred at 20° C. for 30 minutes, and then iodomethane (39.61 g, 279.04 mmol, 17.37 mL, 1.5 equiv.) was added over 30 minutes. The mixture was stirred at 60° C. overnight. An aliquot was taken, resulting in 1 H NMR data indicated complete conversion. The reaction mixture was then poured into water (1000 mL) and extracted with EtOAc (1000 mL). The organic phase was dried over NaSO and evaporated to dryness to give 56 g of a yellow solid. The product was purified by FC (ISCO®: Interchim; 330 g SiO, Hex / EtOAc, 0-95% EtOAc, flow rate = 120 mL / min, R f =5 CV) to give 6-bromo-4-fluoro-1-methyl-1H-indazole (20.0 g, 44% yield) as a yellow solid.

[0217] Step c: Potassium acetate (4.28 g, 43.66 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.1 g, 24.01 mmol) were added to a solution of 6-bromo-4-fluoro-1-methyl-1H-indazole (5.0 g, 21.83 mmol) in anhydrous dioxane (700 mL). The solution was degassed with argon gas for 30 minutes. d(dppf)Cl2·CHCl2 (1.78 g, 2.18 mmol) was then added, and the resulting solution was stirred under reflux for 12 hours. An aliquot was taken, yielding 1 H NMR data indicated complete conversion. The reaction mixture was then evaporated to dryness, poured into water (350 mL), extracted with EtOAc (450 mL), and the organic phase was dried over Na2SO4 and evaporated to dryness. The product was purified by FC (ISCO®: Interchim; 120 g SiO2, Hex / EtOAc, 0-95% EtOAc, flow rate = 120 mL / min) to give 4-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.02 g, 10% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 8.54 (s, 1H), 7.78 (s, 1H), 6.86 (d, J = 10.9Hz, 1H), 4.20 (s, 3H), 1.30 (s, 12H). M+= 277

[0218] Intermediate 11 [ka] Step a: To the previously prepared suspension of LiAlH (0.68 g, 17.8 mmol) in THF (50 mL) under an argon atmosphere, a solution of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate (4 g, 14.9 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1.5 h, and then water (5 mL) was added dropwise as a 20% solution in THF. The reaction mixture was filtered, and the mother liquor was concentrated under reduced pressure to give 2.6 g of 5-bromo-2-methyl-2H-indazol-7-yl)methanol.

[0219] Step b: To a stirred solution of 5-bromo-2-methyl-2H-indazol-7-yl)methanol (2.6 g, 10.8 mmol) in THF (50 mL) was added MnO (4.7 g, 53.9 mmol). The resulting mixture was stirred at 70 °C for 2 days. The reaction mixture was filtered, and the mother liquor was concentrated in vacuo to give 2.2 g of 5-bromo-2-methyl-2H-indazole-7-carbaldehyde.

[0220] Step c: To a stirred solution of 5-bromo-2-methyl-2H-indazole-7-carbaldehyde (2.2 g, 9.2 mmol) in DCM (40 mL) was added diethylaminosulfur trifluoride (DAST, 5 g, 27.6 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with Na2CO3 solution. The organic layer was washed with water (2 × 30 mL), dried over Na2SO4, filtered, and evaporated under vacuum to give 2.5 g of 5-bromo-7-(difluoromethyl)-2-methyl-2H-indazole.

[0221] Step d: 5-Bromo-7-(difluoromethyl)-2-methyl-2H-indazole (2.5 g, 9.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.67 g, 10.5 mmol), and potassium acetate (1.88 g, 19.2 mmol) were mixed in dioxane (40 mL). The resulting mixture was evacuated and backfilled with argon (3 cycles), and then Pd(dppf)Cl·DCM (0.25 g, 9.6 mmol) was added under an argon atmosphere. The reaction mixture was stirred at 90 °C under an argon atmosphere for 15 h, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2 × 20 mL) and discarded. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MTBE and filtered through a short pad of SiO. The MTBE was evaporated under reduced pressure. The residue was crystallized from MTBE / hexane to give 1.17 g of 7-(difluoromethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole. 1 H NMR (400MHz, chloroform-d) δ 8.34 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.32 - 6.98 (m, 2H), 4.29 (s, 3H), 1.38 (s, 12H). M+=227

[0222] Intermediate 12 [ka] Step a: To a solution of 5-bromo-3-fluoropyridin-2-amine (5 g, 26 mmol) in DCM (50 mL) cooled in an ice bath was added a solution of (O-(mesitylsulfonyl)hydroxylamine) (6.2 g, 29 mmol) in DCM (100 mL) dropwise. The reaction mixture was stirred at room temperature overnight. The precipitated solid was collected and dried to give 6.2 g of crude desired compound (58% yield), which was carried forward as is.

[0223] Step b: To a solution of the salt obtained from the previous step (6.2 g, 15 mmol) and KOH (1.28 g, 23 mmol) in methanol (100 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (3.2 g, 15 mmol), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was evaporated under reduced pressure, and the residue was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give 3.8 g of tert-butyl 4-(6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)piperidine-1-carboxylate (62% yield), which was used crude. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 1.5 Hz, 1H), 7.95 (dd, J = 9.9, 1.6 Hz, 1H), 3.96 (d, J = 13.1 Hz, 2H), 3.11 (tt, J = 11.6, 4.0 Hz, 1H), 2.96 (bs, 2H), 2.01 (dd, J = 13.7, 3.7 Hz, 2H), 1.73 - 1.58 (m, 2H), 1.41 (s, 9H). LCMS:1.47 min, 298.2 [M-tBu] +

[0224] Intermediate 13 [ka] Step a: To a solution of 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (50 mg, 229.78 μmol, 1.0 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (70.02 mg, 275.73 μmol, 1.2 equiv.) in dioxane (3 mL, 0.077 M), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (16.81 mg, 22.98 μmol, 0.1 equiv.) and KOAc (45.10 mg, 459.55 μmol, 2.0 equiv.) were added. The mixture was stirred at 90° C. under nitrogen for 2 hours. The material was then filtered, the filtrate concentrated and the concentrate used directly in the next step without further purification. MS: m / z 365.1 [M+3MeO-2F] + ;RT: 1.78 minutes (method 10)

[0225] Intermediate 14 [ka] To a solution of 5-bromo-3-fluoro-pyridin-2-amine (964 mg, 3.49 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (1 g, 5.24 mmol) in dioxane (12 mL) and water (4 mL) was added CsCO (3.41 g, 10.47 mmol) and Pd(dppf)Cl (255 mg, 0.35 mmol). The mixture was stirred under nitrogen at 90 °C for 16 h. The mixture was extracted with EtOAc (15 mL × 3) and dried over NaSO. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 100% EtOAc:PE) to give 3-fluoro-5-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyridin-2-amine (312 mg, 1.2 mmol, 34% yield) as a white fluffy solid. MS: m / z 261.1 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.68 (s, 1H), 8.16 (s, 1H), 7.85 - 7.67 (m, 2H), 7.48 (d, J = 13.0 Hz, 1H), 6.44 (s, 2H), 2.36 (s, 3H).

[0226] Section 3. Synthetic Processes for Preparing the Compounds of the Disclosure Example 1 - Compound 64 [ka] Step a: tert-Butyl 3-(2-bromoacetyl)azetidine-1-carboxylate (455 mg, 1.64 mmol, 1.25 equiv.) and 5-bromo-3-fluoro-pyridin-2-amine (250 mg, 1.31 mmol, 1.0 equiv.) were dissolved in water (6.5 mL, 0.2 M) and heated to 80 °C for 16 h. The solution was then concentrated and dry-loaded onto a normal-phase silica column and purified with 0-100% EtOAc:heptane over 7 min, followed by 0-25% MeOH:DCM over 5 min. The product eluted with 1% MeOH. tert-Butyl 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)azetidine-1-carboxylate (227.5 mg, 24% yield) was isolated. MS: m / z 313.9 [M+H] + .

[0227] Step b: tert-Butyl 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)azetidine-1-carboxylate (56.9 mg, 78.38 μmol, 1.0 equiv.) and 7-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (29.40 mg, 94.06 mmol, 1.2 equiv.) were dissolved in water (1 mL, 0.078 M) and dioxane (1 mL, 0.078 M), followed by the addition of cesium carbonate (51.08 mg, 156.7 μmol, 2 equiv.) and Pd(dppf)2Cl DCM adduct (6.40 mg, 7.84 μmol, 0.1 equiv.). The solution was degassed with nitrogen and heated to 100 °C for 16 h. The solution was then concentrated, and the crude tert-butyl 3-(8-fluoro-6-(7-fluoro-2-methyl-2H-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl)azetidine-1-carboxylate was then carried forward to deprotection. MS: m / z 440.2 [M+H] +

[0228] Step c: tert-Butyl 3-(8-fluoro-6-(7-fluoro-2-methyl-2H-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl)azetidine-1-carboxylate (34.44 mg, 78.38 μmol, 1.0 equiv) was dissolved in DCM (1 mL, 0.078 M) followed by the addition of 4 M HCl in dioxane (196 μL, 10 equiv). The solution was then stirred at 40° C. for 16 hours, after which it was concentrated and subjected to HPLC purification (Column: Sunfire C18 100×19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give 5-(2-(azetidin-3-yl)-8-fluoroimidazo[1,2-a]pyridin-6-yl)-7-fluoro-2-methyl-2H-indazole (2.5 mg, 7.05%). MS: m / z 340.2 [M+H]; RT: 0.99 min (Method 4); NMR: 1H NMR (600 MHz, DMSO-d6 ) δ ppm 4.21 - 4.34 (m, 9 H) 7.45 - 7.51 (m, 1 H) 7.70 - 7.75 (m, 1 H) 7.91 - 7.95 (m, 1 H) 7.98 - 8.02 (m, 1 H) 8.54 - 8.58 (m, 1 H) 8.88 - 8.91 (m, 1 H).

[0229] Using the procedure described for Example 1 above, additional compounds described herein were prepared by substituting the appropriate bromoketone starting material in step a, the appropriate boronic ester or acid equivalent in step b, the appropriate reagents and reaction conditions to provide compounds such as those selected from the following: [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0230] Example 2 - Compound 66 [ka] Step a: To a solution of tert-butyl 4-(2-bromoacetyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (70 mg, 230 μmol) in t-BuOH (5 mL), 3-fluoro-5-(7-fluoro-2-methyl-indazol-5-yl)pyridin-2-amine (50 mg, 192 μmol) and NaHCO (32 mg, 384 μmol) were added, and the mixture was stirred at 70° C. for 16 hours. The mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (PE / EA=1 / 1) to give tert-butyl 4-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (50 mg, 56% yield) as a yellow solid. MS: m / z 466.6 [M+H] +

[0231] Step b: tert-Butyl 4-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (50 mg, 107 μmol) was dissolved in 4M HCl in EtOAc (20 mL), and the mixture was stirred at 25 ° C. for 1 hour. The mixture was concentrated in vacuo and purified by preparative HPLC (Boston Prime C18 150 * 30 mm * 5 um; water NH 3 H 2 O + NH 4 HCO 3) -ACN) to give 2-(2-azabicyclo[2.1.1]hexane-4-yl)-8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine (4.1 mg, 10% yield). MS: m / z 366.2 [M + H] +

[0232] Step c: To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine (30 mg, 82.1 μmol) in 1,2-dichloroethane (0.4 mL) and EtOH (2 mL), paraformaldehyde (98.5 mg, 82.1 μmol, 112 μL) and TEA (164 μmol, 23 μL) were added, and the mixture was stirred for 10 min at 25° C. Then, sodium triacetoxyborohydride (35 mg, 164 μmol) was added, and the mixture was stirred at 25° C. for 0.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (Boston Prime C18 150*30mm*5um; water NH3H2O+NH4HCO3)-ACN) to give 7-fluoro-5-[8-fluoro-2-(2-methyl-2-azabicyclo[2.1.1]hexan-4-yl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-indazole (6.2 mg, 20% yield) as a white solid. MS: m / z 380.3 [M+H] + ; 1 H NMR (500 MHz, methanol-d4) δ ppm = 8.59 (d, J = 1.37 Hz, 1H), 8.38 (d, J = 2.59 Hz, 1H), 7.89 (d, J = 2.90 Hz, 1H), 7.82 (d, J = 1.22 Hz, 1H), 7.52 (dd, J = 12.05, 1.37 Hz, 1H), 7.37 (dd, J = 12.66, 1.37 Hz, 1H), 4.26 (s, 3H), 3.66 (s, 1H), 3.27-3.14 (m, 2H), 2.69 (s, 3H), 2.28 (s, 2H), 2.08-1.99 (m, 2H).

[0233] Using the procedure described for Example 2 above, additional compounds described herein were prepared by substituting the appropriate bromoketone and aminopyridine starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 8]

[0234] Example 3 - Compound 79 [ka] Step a: To a solution of tert-butyl N-[1-(2-bromoacetyl)-2-oxabicyclo[2.1.1]hexan-4-yl]carbamate (92.3 mg, 288.2 μmol) in t-BuOH (5 mL) was added 3-fluoro-5-(7-fluoro-2-methyl-indazol-5-yl)pyridin-2-amine (50 mg, 192.1 μmol) and NaHCO (48.4 mg, 576.39 μmol), and the mixture was stirred at 70 °C for 16 h. The crude material was purified by flash silica gel chromatography (Combi-Flash (PE / EA = 3 / 1 to 1 / 5). MS: m / z 482.1 [M+H] +

[0235] Step b: To a solution of tert-butyl N-[1-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-oxabicyclo[2.1.1]hexan-4-yl]carbamate (100 mg, 207.6 μmol) in THF (5 mL), NaH (16.6 mg, 415.3 μmol, 60% purity) was added at 0° C. and stirred for 0.5 hours. Then, iodomethane (415.3 μmol, 26 μL) was added, and the mixture was stirred at 20° C. for 2 hours. The mixture was concentrated, and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give tert-butyl-N-[1-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-oxabicyclo[2.1.1]hexan-4-yl]-N-methyl-carbamate (30 mg), which was used crude in the next reaction. MS: m / z 496.1 [M+H] +.

[0236] Step c: A solution of tert-butyl N-[1-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-oxabicyclo[2.1.1]hexan-4-yl]-N-methyl-carbamate (30 mg, 60.54 μmol) in TFA (1 mL) and DCM (3 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and purified by preparative HPLC (Boston Prime C18 150 * 30 mm * 5 um; water NH3H2O + NH4HCO3) -ACN) to give 1-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-N-methyl-2-oxabicyclo[2.1.1]hexan-4-amine (2.7 mg, 11%). MS: m / z 396.3 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ ppm = 8.62 (d, J = 1.31 Hz, 1H), 8.37 (d, J = 2.62 Hz, 1H), 7.97 (d, J = 2.98 Hz, 1H), 7.82 (d, J = 1.07 Hz, 1H), 7.52 (dd, J = 12.10, 1.25 Hz, 1H), 7.37 (dd, J = 12.64, 1.19 Hz, 1H), 4.26 (s, 3H), 3.80 (s, 2H), 2.52 (s, 3H), 2.41-2.33 (m, 2H), 2.06-1.95 (m, 2H).

[0237] Using the procedure described for Example 3 above, additional compounds described herein were prepared by substituting the appropriate bromoketone and aminopyridine starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 9]

[0238] Example 4 - Compounds 161 and / or 185 [ka] Step a: To a solution of (1S,5R)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (600 mg, 2.64 mmol) in DCM (4 mL) was added (COCl) (402.14 mg, 3.17 mmol, 268.10 μL) and 2 drops of DMF at 0° C. The reaction was stirred at the same temperature for 0.5 h and then concentrated under vacuum. The residue was redissolved in THF (4 mL), DCM (4 mL), and diazomethyl(trimethyl)silane (2 M, 1.32 mL), and the mixture was stirred at 0° C. for 1 h, after which HBr (1.60 g, 7.92 mmol, 40% purity) was added at 0° C. The reaction was then stirred at 0° C. for 1 h. The solution was concentrated in vacuo to give tert-butyl (1S,5R)-6-(2-bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (600 mg, crude) as a yellow oil that was used directly in the next step.

[0239] Step b: To a solution of tert-butyl (1S,5R)-6-(2-bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 986.26 μmol) and 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-fluoro-pyridin-2-amine (100 mg, 388.70 μmol) in t-BuOH (4 mL) was added NaHCO (165.71 mg, 1.97 mmol, 76.72 μL). The reaction was stirred at 80 °C for 16 h. The mixture was filtered and concentrated, and the residue was purified by preparative HPLC. tert-Butyl (1S,5R)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (60 mg, 125.55 μmol, 12.7% yield, 96.8% purity) was obtained as a yellow oil. MS: m / z 463.3 [M+H] + .

[0240] Step c: To a solution of tert-butyl (1S,5R)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 43.24 μmol) in EtOAc was added HCl (0.5 mL). The mixture was stirred at 25° C. for 1 hour. The mixture was filtered and concentrated. The residue was purified by preparative HPLC. 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-8-fluoro-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (10 mg, 24.83 μmol, 57.4% yield) was obtained as a white solid. MS: m / z 363.2 [M+H] + ;RT:1.948 minutes (method 8); 1 H NMR:(400MHz, methanol-d4) δ ppm = 8.99 (s, 1H), 8.47 (s, 0.5H), 7.93 (s, 1H), 7.90 (s, 1H), 7.80-7.70 (m, 1H), 7.58 (s, 1H), 3.60-3.50 (m, 4H), 2.67 (s, 3H), 2.49 (s, 3H), 2.40-2.30 (m, 2H), 2.15-2.10 (m, 1H).

[0241] Step d: To a solution of 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-8-fluoro-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (30 mg, 82.78 μmol) in EtOH (3 mL) was added paraformaldehyde (99.30 mg, 82.78 μmol, 112.84 μL), TEA (25.13 mg, 248.34 μmol, 34.61 μL), and DCE (16.38 mg, 165.56 μmol, 13.11 μL). The mixture was stirred at 25 °C for 20 min. Sodium triacetoxyborohydride (35.09 mg, 165.56 μmol) was then added, and the mixture was stirred at 25 ° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (Column: Boston Green ODS 150 * 30 mm * 5 μm; Conditions: water (FA)-ACN, start B3, end B33; Gradient time (min): 12; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give 6-[8-fluoro-2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (4.7 mg, 12.5 μmol, 15.1% yield) as a yellow solid. MS: m / z 377.3 [M+H] + ;RT:0.628 minutes (method 10); 1 H NMR:(400MHz, methanol-d4) δ ppm = 8.95 (d, J = 0.8, 1H), 8.51 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.80-7.70 (m, 1H), 7.56 (s, 1H), 3.55-3.50 (m, 3H), 3.20-3.10 (m, 2H), 2.71 (s, 3H), 2.66 (s, 3H), 2.48 (s, 3H), 2.40-2.30 (m, 1H), 2.20-2.10 (m, 2H).

[0242] Using the procedure described for Example 4 above, additional compounds described herein were prepared by substituting the appropriate carboxylic acid starting material in step a and the aminopyridine intermediate in step b, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6]

[0243] Example 5 - Compound 1 [ka] Step a: To a solution of tert-butyl 4-[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (550 mg, 1.24 mmol), 6-chloro-2,8-dimethyl-imidazo[1,2-b]pyridazine (224.31 mg, 1.24 mmol), and K2CO3 (512 mg, 3.71 mmol) in dioxane (1 mL) and water (0.5 mL), Pd(dppf)Cl2 (90.3 mg, 123.5 μmol) was added under N2 at 25 °C. The mixture was stirred at 90 °C for 2 hours. The mixture was filtered and concentrated to give the crude product. The crude material was purified by flash silica gel chromatography (PE to EtOAc, 0-100%) to afford tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (270 mg, 47% yield) as a white solid. MS: m / z 465.2 [M+H] +

[0244] Step b: To a solution of tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (60 mg, 0.129 mmol) in DCM (5 mL) was added TFA (6.53 mmol, 0.5 mL) at 20° C. The mixture was stirred at 20° C. for 20 min. The mixture was concentrated to give a residue, which was purified by preparative HPLC (Column: Waters Xbridge BEH C18100*25mm*5um; Condition: Water (0.225% FA)-ACN; Start B: 0; End B: 20; Gradient time (min): 12; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give 6-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-8-fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridine (43 mg, 91% yield) as an off-white solid. MS: m / z 365.1 [M+H] + ; 1H NMR:(400 MHz, methanol-d4) δ ppm = 9.28 (s, 1 H), 8.19 - 8.35 (m, 2 H), 7.98 - 8.11 (m, 2 H), 3.55 (br d, J=12.8 Hz, 2 H), 3.15 - 3.30 (m, 3 H), 2.71 - 2.87 (m, 3 H), 2.65 (s, 3 H), 2.29 - 2.41 (m, 2 H), 1.97 - 2.13 (m, 2 H).

[0245] Using the procedure described for Example 5 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester equivalent starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8]

[0246] Example 6 - Compounds 153 and / or 166 [ka] Step a: tert-Butyl 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (885.3 mg, 1.93 mmol, 1.0 equiv.) was dissolved in dioxane (11.11 mL, 0.174 M), followed by the addition of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (736.64 mg, 2.90 mmol, 1.5 equiv.) and potassium acetate (379.59 mg, 3.87 mmol, 2 equiv.). The solution was then sparged with nitrogen, followed by the addition of Pd(dppf)Cl2CHCl2 (78.96 mg, 96.69 μmol, 0.05 equiv.). The solution was then stirred at 60°C for 4 hours, then heated to 100°C and stirred for 16 hours. The solution was then concentrated in vacuo, and the crude material was loaded onto normal phase and purified with 0-25% MeOH:DCM. The product was eluted with 15% MeOH over 12 minutes. The identified fractions were combined and concentrated to give [2-(1-tert-butoxycarbonyl-4-piperidyl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]boronic acid (796.8 mg, 1.82 mmol, 94% yield). MS: m / z 308.0 [M+H] + ;RT:0.54 minutes (method 4).

[0247] Step b: 6-chloro-8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazine (37.52 mg, 0.126 mmol, 1.1 equiv.) was dissolved in dioxane (1.5 mL, 0.08 M) and water (0.25 mL, 0.46 M), followed by the addition of [2-(1-tert-butoxycarbonyl-4-piperidyl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]boronic acid (50 mg, 0.114 mmol, 1.0 equiv.) and potassium carbonate (111.6 mg, 0.343 mmol, 3 equiv.). The solution was then sparged with nitrogen, followed by the addition of Pd(dppf)Cl2CHCl2 (11.1 mg, 17.14 μmol, 0.15 equiv.). The solution was then stirred at 120° C. for 16 hours before being concentrated and carried forward crude. tert-Butyl 4-(6-(8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-8-fluoroimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate was obtained in quantitative yield (57.19 mg, 0.114 mmol, 72.3% yield). MS: m / z 501.2 [M+H] + RT: 0.66 minutes (method 4).

[0248] Step c: tert-Butyl 4-(6-(8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-8-fluoroimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (57.19 mg, 0.114 mmol, 1.0 equiv.) was dissolved in DCM (3 mL, 0.04 M), followed by the addition of 4 M HCl in dioxane (285 μL, 1.14 mmol, 10.0 equiv.). The solution was then stirred at 50° C. for 2 hours, after which an additional aliquot of 4 M HCl in dioxane (285 μL, 0.114 mmol, 1.0 equiv.) was added. The solution was stirred at 50°C for an additional 16 hours, then concentrated and purified by preparative HPLC (column: Sunfire C18 100 x 19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA) to give 8-(difluoromethyl)-6-(8-fluoro-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)-2-methylimidazo[1,2-b]pyridazine (5.4 mg, 9% yield). MS: m / z 401.3 [M+H] + ;RT:0.93 min (Method 3) 1H NMR (600 MHz, DMSO-d6 ) δ ppm 1.86 - 1.95 (m, 2 H) 2.15 - 2.23 (m, 2 H) 2.41 - 2.49 (m, 3 H) 3.03 - 3.16 (m, 3 H) 3.37 - 3.42 (m, 2 H) 7.50 - 7.58 (m, 1 H) 7.80 - 7.86 (m, 1 H) 7.95 - 8.02 (m, 2 H) 8.26 - 8.30 (m, 1 H) 8.30 - 8.39 (m, 1 H) 8.57 - 8.66 (m, 1 H) 9.28 - 9.38 (m, 1 H).

[0249] Step d: 8-(Difluoromethyl)-6-[8-fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (17.32 mg, 38.93 μmol, 1.0 equiv.) was dissolved in acetonitrile (203.31 μL, 0.2 M) and TEA (7.88 mg, 77.86 μmol, 2.0 equiv.) was added. The solution was stirred for 1 minute, followed by the addition of paraformaldehyde (46.70 mg, 38.93 μmol, 1.0 equiv.) and acetic acid (11.69 mg, 194.66 μmol, 5.0 equiv.). The solution immediately began to smoke and was stirred at room temperature for 10 minutes before the addition of sodium cyanoborohydride (4.89 mg, 77.86 μmol, 2.0 equiv.). The solution was then stirred for 30 minutes, concentrated, then recovered with DMSO, filtered, and the crude material was then injected onto a reverse phase column and purified by HPLC (column: Sunfire C18 100 x 19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA). The identified fractions were collected, combined, and concentrated to obtain a clear film. The material was then recovered with a minimal amount of ACN and water, and then lyophilized to obtain 8-(difluoromethyl)-6-[8-fluoro-2-(1-methyl-4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (10 mg, 47.15% yield) as a fluffy yellow powder, which was recorded as is. MS: m / z 415.2 [M+H] + RT: 0.46 min (Method 4). 1H NMR (400 MHz, methanol-d4) δ ppm 2.00 - 2.13 (m, 2H), 2.33 - 2.42 (m, 2H), 2.55 - 2.58 (m, 3H), 2.93 - 2.98 (m, 3H), 3.15 - 3.26 (m, 3H), 3.63 - 3.70 (m, 2H), 7.19 - 7.48 (m, 1H), 7.92 - 8.00 (m, 2H), 8.07 - 8.11 (m, 1H), 8.18 - 8.22 (m, 1H), 9.18 - 9.21 (m, 1H).

[0250] Using the procedure described for Example 6 above, additional compounds described herein were prepared by substituting the appropriate heteroaryl halide starting material, suitable reagents, and reaction conditions in step b to provide compounds such as those selected from the following: [Table 12-1] [Table 12-2]

[0251] Example 7 - Compound 4 [ka] 6-[8-Fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (29.85 mg, 67.13 μmol, 1.0 equivalent) was dissolved in DCM (370 μL, 0.2 M), and then acetic acid (4 μL, 67.13 μmol, 1 equivalent) was added, followed by paraformaldehyde (80.5 mg, 67.13 μmol, 1.0 equivalent). The solution was then stirred for 5 minutes, after which sodium cyanoborohydride (4.2 mg, 67.1 μmol, 1.0 equivalent) was added. The solution was then stirred at room temperature for 4 hours, concentrated, then recovered in DMSO, filtered, and subjected to HPLC purification (column: Sunfire C18 100 x 19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA). 6-[8-fluoro-2-(1-methyl-4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (8.8 mg, 27% yield) was obtained as a yellow solid. MS: m / z 365.3 [M+H] +RT: 0.70 min (method 4).1H NMR (600 MHz, DMSO-d6 ) δ ppm 1.88 - 1.97 (m, 2 H) 2.23 - 2.29 (m, 2 H) 2.49 (q, J=1.65 Hz, 3 H) 2.82 - 2.88 (m, 3 H) 2.99 - 3.06 (m, 1 H) 3.08 - 3.18 (m, 2 H) 3.52 - 3.60 (m, 2 H) 7.73 - 7.76 (m, 1 H) 7.77 - 7.81 (m, 1 H) 7.98 - 8.01 (m, 1 H) 8.10 - 8.13 (m, 1 H) 8.14 - 8.18 (m, 1 H) 9.19 - 9.23 (m, 1 H)

[0252] Using the procedure described for Example 7 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 13-1] [Table 13-2]

[0253] Example 8 - Compound 69 [ka] To a solution of 6-[8-fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (20 mg, 54.88 μmol) in EtOH (1 mL) and DCE (0.2 mL) was added cyclobutanone (5.7 mg, 82.3 μmol, 6 μL) and TEA (109.7 μmol, 15 μL), and the mixture was stirred for 10 min at 25° C. Sodium triacetoxyborohydride (23 mg, 109.7 μmol) was then added, and the mixture was stirred at 25° C. for 0.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (Boston Prime C18 150*30mm*5um; water NH3H2O+NH4HCO3)-ACN) to give 6-[2-(1-cyclobutyl-4-piperidyl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (14.5 mg, 63% yield) as a white solid. MS: m / z 419.3 [M+H] + ;1H NMR (500 MHz, methanol-d4) δ ppm = 8.99 (s, 1H), 7.92 (s, 1H), 7.83 (d, J = 2.59 Hz, 1H), 7.78 (d, J = 11.90 Hz, 1H), 7.57 (s, 1H), 3.02 (d, J = 11.60 Hz, 2H), 2.88-2.76 (m, 2H), 2.67 (s, 3H), 2.48 (s, 3H), 2.21-2.08 (m, 4H), 2.04-1.90 (m, 4H), 1.82-1.72 (m, 4H).

[0254] Using the procedure described for Example 8 above, additional compounds described herein were prepared by substituting the appropriate amine and carbonyl starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 14-1] [Table 14-2]

[0255] Example 9 - Compound 46 [ka] A solution of 6-[8-fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (30 mg, 82.32 μmol), 1-bromo-2-methoxyethane (11.4 mg, 82.32 μmol, 8 μL) and CsCO (53.6 mg, 164 μmol) in DMF (2 mL) was stirred at 80° C. for 2 h. The mixture was filtered and concentrated to give the crude product. The crude material was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, mobile phase of water (NH3H2O+NH4HCO3)-ACN, 32%-62%, gradient time (min): 10, flow rate (ml / min): 25) to give 6-[8-fluoro-2-[1-(2-methoxyethyl)-4-piperidyl]imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (14.7 mg, 42% yield) as a white solid. MS: m / z 423.2 [M+H] + ;1H NMR:(400 MHz, methanol-d4) δ ppm = 9.01-8.95 (m, 1H), 7.92 (s, 1H), 7.85-7.72 (m, 2H), 7.56 (s, 1H), 3.62-3.54 (m, 2H), 3.362 (s, 3H), 3.17-3.06 (m, 2H), 2.83-2.75 (m, 1H), 2.69-2.62 (m, 5H), 2.48 (s, 3H), 2.32-2.23 (m, 2H), 2.20-2.09 (m, 2H), 1.91-1.74 (m, 2H).

[0256] Using the procedure described for Example 9 above, additional compounds described herein were prepared by substituting the appropriate alkyl halide starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 15-1] [Table 15-2]

[0257] Example 10 - Compound 74 [ka] A solution of 6-[8-fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (60 mg, 164.6 μmol), acetyl acetate (164.65 μmol, 16 μL) and pyridine (164.65 μmol, 13 μL) in DCM (2 mL) was stirred at 25° C. for 16 h. The mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, mobile phase of water (NH3H2O+NH4HCO3)-ACN, 30% to 70%, gradient time (min): 10, flow rate (ml / min): 25) to give 1-[4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]ethanone (25 mg, 37% yield) as a white solid. MS: m / z 407.2 [M+H] + ; 1H NMR:(400 MHz, methanol-d4) δ ppm = 9.00-8.99 (d, J = 1.4 Hz, 1H), 7.92 (s, 1H), 7.87-7.76 (m, 2H), 7.58-7.57 (d, J = 10.8 Hz, 1H), 4.67-4.60 (m, 1H), 4.09-4.01 (m, 1H), 3.37-3.32 (m, 1H), 3.13-3.04 (m, 1H), 2.89-2.79 (m, 1H), 2.67-2.66 (d, J = 0.8 Hz, 3H), 2.48 (s, 3H), 2.22-2.1 (m, 5H), 1.83-1.63 (m, 2H).

[0258] Example 11 - Compound 120 [ka] 6-[8-Fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (20 mg, 52.14 μmol, 1.0 equiv.) was dissolved in DCM (260 μL, 0.2 M), followed by the addition of TEA (15.8 mg, 156.4 μmol, 3.0 equiv.). Then, propanoic acid propanoate (7.5 mg, 57.3 μmol, 1.1 equiv.) was slowly added, and the solution was stirred at room temperature for 16 hours, concentrated, recovered in DMSO, filtered, and then subjected to HPLC purification (column: Sunfire C18 100 × 19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA). 1-[4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-1-piperidyl]propan-1-one (7.2 mg, 26% yield) was obtained as a white powder. MS: m / z 421.3 [M+H] + ;RT:0.96 minutes (method 3) 1H NMR (600 MHz, DMSO-d6 ) δ ppm 0.99 - 1.04 (m, 3 H) 1.47 - 1.55 (m, 1 H) 1.60 - 1.68 (m, 1 H) 1.99 - 2.07 (m, 2 H) 2.33 - 2.39 (m, 2 H) 2.44 - 2.47 (m, 3 H) 2.62 - 2.66 (m, 3 H) 2.70 - 2.77 (m, 1 H) 3.01 - 3.07 (m, 1 H) 3.14 - 3.19 (m, 1 H) 3.92 - 3.97 (m, 1 H) 4.44 - 4.50 (m, 1 H) 7.75 - 7.79 (m, 1 H) 7.80 - 7.85 (m, 1 H) 7.95 - 7.98 (m, 1 H) 8.16 - 8.19 (m, 1 H) 9.20 - 9.22 (m, 1 H).

[0259] Using the procedure described for Example 11 above, additional compounds described herein were prepared by substituting the appropriate acyl chloride starting material, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 16]

[0260] Example 12 - Compound 113 [ka] To a solution of 6-[8-fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (50 mg, 137 μmol) in MeOH (1 mL) was added (1-ethoxycyclopropoxy)-trimethyl-silane (36 mg, 206 μmol, 41 μL), TEA (137 μmol, 19 μL), and sodium cyanoborohydride (14 mg, 220 μmol), and the mixture was stirred for 20 minutes at 25° C. Then, acetic acid (412 μmol, 24 μL) was added, and the mixture was stirred at 60° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by preparative HPLC (Column: Boston Green ODS 150 x 30 mm x 5 μm; Conditions: water (HCl)-ACN; Gradient (% organic material): 0-100% optimized for each example; Flow rate (mL / min): 25) to give 6-[2-(1-cyclopropyl-4-piperidyl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (13 mg, 23%) as a white solid. MS: m / z 405.1 [M+H]+; RT: 1.31 min.

[0261] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 17]

[0262] Example 13 - Compound 129 [ka] Step a: A mixture of ethyl 6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylate (1 g, 3.48 mmol), 7-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (1.20 g, 3.83 mmol, hydrochloride salt), Pd(dppf)Cl DCM (284.46 mg, 348.3 μmol), dicesium carbonate (3.40 g, 10.45 mmol) in dioxane (9.3 mL) and water (2.3 mL) was stirred at 90 °C under N for 4 h. After cooling to room temperature, the mixture was filtered through Celite and MgSO (eluent: DCM / EtOAc), concentrated, and purified by silica gel chromatography (24 g, 0-100% 3:1 EtOAc:EtOH / heptane, 10 min) to give ethyl 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylate (250 mg, 20% yield). MS: m / z 357.1 [M+H] +

[0263] Step b: A mixture of ethyl 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylate (250 mg, 701.6 μmol) and lithium hydroxide hydrate (58.88 mg, 1.40 mmol) in methanol (467 μL), THF (3.4 mL), and water (841 μL) was stirred at room temperature for 4 hours, neutralized with 4N HCl in dioxane at room temperature under stirring, concentrated under reduced pressure, and dried under high vacuum to give 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylic acid, which was used crude in the next reaction (estimated yield 100%). MS: m / z 329.0 [M+H] +

[0264] Step c: T3P (274.1 μmol, 163 μL, 50% purity in ethyl acetate) followed by NEt3 (365.55 μmol, 51 μL) were added to a solution of 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylic acid (30 mg, 91 μmol) and N,1-dimethylpiperidin-4-amine (23.4 mg, 182.7 μmol) in THF (1.1 mL) at 0° C. The ice bath was then removed, and the mixture was stirred at room temperature overnight. The mixture was quenched with water, extracted with EtOAc, dried over MgSO, filtered, concentrated, and subjected to HPLC purification (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)-N-methyl-N-(1-methyl-4-piperidyl)imidazo[1,2-a]pyridine-2-carboxamide (3.8 mg, 7% yield). MS: m / z 349.2 [M+H] + ;RT:0.50 minutes (method 4)

[0265] Using the procedure described for Example 17 above, additional compounds described herein were prepared by substituting the appropriate boronic ester starting material, suitable reagents, and reaction conditions in step b to provide compounds such as those selected from the following: [Table 18]

[0266] Example 14 - Compounds 355 & 362 [ka] Step a: To a solution of tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (1.36 g, 3.83 mmol) in DMF (10 mL) was added K2CO3 (1.59 g, 11.49 mmol) and 5-bromo-7-fluoro-2H-indazole (823 mg, 3.83 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The crude was purified by flash silica gel chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give the product. The compound tert-butyl 4-(5-bromo-7-fluoro-indazol-2-yl)piperidine-1-carboxylate (492 mg, 1.24 mmol, 32.26% yield) was obtained as a yellow oil. MS: m / z 342.0 [M+H] + ;RT:0.52 minutes (method 3)

[0267] Step b: To a mixture of tert-butyl 4-(5-bromo-7-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate (5 g, 12.6 mmol) in dioxane (120 mL), bis(pinacolato)diboron (3.83 g, 15.1 mmol), KOAc (2.46 g, 25.1 mmol), and Pd(dppf)Cl (459.3 mg, 627.7 mmol) were added at 25 °C. The mixture was stirred at 120 °C under a nitrogen atmosphere for 16 hours. The mixture was concentrated, and then water (150 mL) was added. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na SO , filtered, and concentrated. The crude material was then purified by flash chromatography (PE / EtOAc = 5 / 1 to 2 / 1) to give tert-butyl 4-(7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)piperidine-1-carboxylate (4.85 g, 10.9 mmol, 87% yield) as a white solid. MS: m / z 446.3 [M+H] +;RT:0.748 minutes (method 3)

[0268] Step c: To a solution of tert-butyl 4-[7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]piperidine-1-carboxylate (50 mg, 112 μmol) in dioxane / HO (5 mL), 5-chloro-2,7-dimethyl-pyrazolo[1,5-a]pyrimidine (20 mg, 112.28 μmol), KCO (46 mg, 336.8 μmol), and PdCl(dppf) (8 mg, 11.23 μmol) were added. The reaction mixture was stirred at 90 °C for 2 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE / EtOAc = 5 / 1 to 1 / 3) to give the product tert-butyl 4-[5-(2,7-dimethylpyrazolo[1,5-a]pyrimidin-5-yl)-7-fluoro-indazol-2-yl]piperidine-1-carboxylate (30 mg, 59.22 μmol) as a yellow solid. MS: m / z 465.3 [M+H] + ;RT:0.468 minutes (method 3)

[0269] Step d: tert-Butyl 4-[5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-indazol-2-yl]piperidine-1-carboxylate (78 mg, 168 μmol) was dissolved in MeOH (4 mL), treated with 4N HCl in dioxane (292 μL), and stirred at room temperature for 24 hours. The reaction was concentrated and used crude in the next step. MS: m / z 365.1 [M+H] + ;RT:0.45 minutes (method 4)

[0270] Step e: 6-(7-Fluoro-2-(piperidin-4-yl)-2H-indazol-5-yl)-2,8-dimethylimidazo[1,2-b]pyridazine (40 mg, 109.8 μmol) was dissolved in THF (1 mL) with paraformaldehyde (131 mg, 109 μmol, 149 μL), acetic acid (66 mg, 1.1 mmol, 63 μL), and sodium cyanoborohydride (21 mg, 329 μmol) and stirred at 70° C. overnight. The resulting material was diluted with water, extracted with EtOAc, dried over sodium sulfate, and purified by FCC using a gradient of 0-100% EtOAc-heptane to give the title compound (41.5 mg, 36 μmol). MS: m / z 379.1 [M+H] + ;RT:1.63 minutes (method 3)

[0271] Using the procedure described for Example 17 above, additional compounds described herein were prepared by substituting the appropriate boronic ester starting material, suitable reagents, and reaction conditions in step b to provide compounds such as those selected from the following: [Table 19]

[0272] Example 15 - Compound 135 [ka] Step a: 6-Bromo-4-fluoro-2H-indazole (1 g, 4.65 mmol) was dissolved in DMF (10 mL). Potassium carbonate (6.4 g, 46.5 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (1.45 g, 4.65 mmol) were added and the mixture was heated to 100 °C overnight. The resulting mixture was diluted with water and EtOAc, extracted with EtOAc, and the crude product was purified by silica column chromatography using a gradient of 0 to 100% EtOAc-heptane to give tert-butyl 4-(6-bromo-4-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate (60 mg, 3% yield). MS: m / z 341.8 [M-tBu+H] +

[0273] Step b: A mixture of tert-butyl 4-(6-bromo-4-fluoro-indazol-2-yl)piperidine-1-carboxylate (30 mg, 75 μmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (21 mg, 75 μmol), PdCl(dippf) (45 mg, 7.5 μmol) and CsCO (49 mg, 151 μmol) in dioxane (3 mL) and water (847 μL) was degassed with N and then heated in a microwave at 100 °C for 1 h. The resultant was diluted with water and EtOAc, the phases separated and concentrated to give tert-butyl 4-(6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate, which was used crude (assumed 100% yield). MS: m / z 465.1 [M+H] +

[0274] Step c: tert-Butyl 4-(6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate (30 mg, 75 μmol) was dissolved in DCM (1 mL), treated with TFA (0.5 mL), and stirred at room temperature for 2 h. The reaction was concentrated and purified by reverse-phase HPLC using a Waters XSelect CSH Prep C18 5 μm OBD 30 × 100 mm column and a 5-65% gradient of ACN-water using TFA modifier (2.8 mg, 10% yield). MS: m / z 365.1 [M+H] + ;RT 1.01 min (method 3)

[0275] Example 16 - Compounds 139 and / or 376 [ka] Step a: 6-Bromo-4-fluoro-2H-benzotriazole (500 mg, 2.31 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (11.57 mL, 0.2 M) followed by the addition of tert-butyl 4-hydroxypiperidine-1-carboxylate (465.86 mg, 2.31 mmol, 1.0 equiv.) and triphenylphosphine (607.11 mg, 2.31 mmol, 1.0 equiv.). DIAD (468 mg, 456 μL, 2.31 mmol, 1.0 equiv.) was then slowly added. The solution was stirred at room temperature for 16 h, then concentrated and directly loaded onto a normal-phase silica column and purified using 0-100% EtOAc:heptane over 7 min. The product eluted with 70% EtOAc. The identified fractions were combined and concentrated to give tert-butyl 4-(6-bromo-4-fluoro-benzotriazol-2-yl)piperidine-1-carboxylate (488.5 mg, 1.14 mmol, 49% yield), which was carried forward directly. MS: m / z 344.9 [M+H] + ;RT 1.05 minutes (method 4).

[0276] Step b: tert-Butyl 4-(6-bromo-4-fluoro-benzotriazol-2-yl)piperidine-1-carboxylate (100 mg, 232.93 μmol, 1.0 equiv) was dissolved in water (376 μL, 0.186 M) and dioxane (877 μL, 0.186 M), followed by the addition of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (76.35 mg, 279.52 μmol, 1.2 equiv) and cesium carbonate (303.6 mg, 931.7 μmol, 4.0 equiv). The solution was then degassed with nitrogen, after which Pd(dppf)2Cl2DCM adduct (15 mg, 18.4 μmol, 0.1 equiv.) was added, and the solution was heated to 90 °C for 6 h, then concentrated, dry loaded onto normal phase, and purified with 0-25% MeOH:DCM over 12 min. The product was eluted with 10% MeOH. Identified fractions were collected, combined, concentrated, and carried forward directly (111.3 mg, 231.9 μmol, 99% yield). MS: m / z 466.2 [M+H] + ;RT 0.74 min (method 4).

[0277] Step c: tert-Butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-benzotriazol-2-yl]piperidine-1-carboxylate (111.3 mg, 231.9 μmol, 1.0 equiv) was dissolved in DCM (1.16 mL, 0.2 M), followed by the addition of 4 M HCl in dioxane (579.7 μL, 2.32 mmol, 10 equiv) and the solution was heated to 40° C. for 1 h. A precipitate formed and was further precipitated by the addition of a few mL of diethyl ether. The product was filtered off, washed with diethyl ether, and dried to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(piperidin-4-yl)-2H-benzo[d][1,2,3]triazole (87.1 mg, 216.7 μmol, 93% yield) as a white powder. MS: m / z 366.2 [M+H] + ;RT:0.44 minutes (method 4). 1H NMR (400 MHz, methanol-d4 ) δ ppm 2.54 - 2.66 (m, 4 H) 2.66 - 2.67 (m, 3 H) 2.79 - 2.83 (m, 3 H) 3.34 - 3.42 (m, 2 H) 3.60 - 3.67 (m, 2 H) 5.32 - 5.40 (m, 1 H) 7.98 - 8.04 (m, 1 H) 8.34 - 8.40 (m, 2 H) 8.59 - 8.62 (m, 1 H)

[0278] Step d: 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(4-piperidyl)benzotriazole (10 mg, 27.37 μmol, 1.0 equiv) was dissolved in acetonitrile (136.83 μL, 0.2 M), followed by the addition of acetaldehyde (3.62 mg, 82.10 μmol, 3.0 equiv) and acetic acid (8.22 mg, 136.83 μmol, 5.0 equiv). The solution was then stirred for 5 minutes, after which sodium cyanoborohydride (3.44 mg, 54.73 μmol, 2.0 equiv) was added. The solution was then stirred for 15 minutes, concentrated, and then recovered with DMSO, water, and methanol, followed by HPLC purification (Column: Sunfire C18 100 x 19 mm, 5 mm; Mobile Phase A: MeCN; Mobile Phase B: HO; Modifier: 0.1% TFA). The identified fractions were collected, combined, and concentrated to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(1-ethyl-4-piperidyl)-4-fluoro-benzotriazole (3.9 mg, 28.08% yield, 100% purity) as a white powder, which was registered as such. MS: m / z 394.1 [M+H] + ;RT:2.33 minutes (method 1). 1H NMR (600 MHz, DMSO-d6 ) δ ppm 1.25 - 1.30 (m, 3 H) 2.41 - 2.43 (m, 3 H) 2.43 - 2.49 (m, 2 H) 2.62 - 2.65 (m, 3 H) 3.08 - 3.18 (m, 2 H) 3.19 - 3.29 (m, 4 H) 3.70 - 3.76 (m, 2 H) 5.26 - 5.35 (m, 1 H) 7.82 - 7.93 (m, 1 H) 7.96 - 8.04 (m, 1 H) 8.06 - 8.13 (m, 1 H) 8.56 - 8.60 (m, 1 H) 9.43 - 9.55 (m, 1 H)

[0279] Using the procedure described for Example 17 above, additional compounds described herein were prepared by substituting the appropriate boronic ester starting material, suitable reagents, and reaction conditions in step b to provide compounds such as those selected from the following: [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4]

[0280] Example 17 - Compound 140 [ka] Step a: To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10 g, 43.62 mmol) in DMF (75 mL) and pyridine (75 mL) was added CDI (7.78 g, 47.9 mmol). The mixture was stirred at 60° C. for 4 hours. 5-Bromo-3-fluorobenzene-1,2-diamine (8.94 g, 43.62 mmol) was added, and the whole mixture was stirred at 130° C. for 12 hours. The mixture was concentrated under reduced pressure. Then, AcOH (350 mL) was added, and the whole mixture was stirred at 100° C. for 1 hour. The mixture was concentrated, and then saturated aqueous NaHCO3 (200 mL) was added. The mixture was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: YMC-Triart Prep C18 150*40mm*7um; condition: water (NH3H2O+NH4HCO3)-CAN, start B36, end B76, gradient time (min) 9; flow rate (ml / min): 60), followed by lyophilization to give tert-butyl 4-(5-bromo-7-fluoro-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (3.12g, 17% yield) as a yellow solid. MS: m / z 400.1 [M+H] + .

[0281] Step b: A mixture of tert-butyl 4-(5-bromo-7-fluoro-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (39 mg, 0.10 mmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (41 mg, 0.15 mmol), XPhos Pd G3 (8.5 mg, 0.01 mmol), and K3PO4 (64 mg, 0.3 mmol) in dioxane (0.8 mL) and water (0.2 mL) was stirred for 2 hours at 60 °C. The reaction solution was washed with brine and extracted with EtOAc (2 mL, twice). The combined organics were dried over MgSO4 and concentrated in vacuo to give tert-butyl 4-(5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate, which was carried on to the next step without further purification (assumed 100% yield). MS: m / z 465.2 [M+H] + .

[0282] Step c: To a mixture of tert-butyl 4-(5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (46.4 mg, 0.1 mmol) in hexafluoroisopropanol (1 mL) was added TFA (23 μL). After stirring at room temperature for 16 h, the reaction mixture was diluted with 10 mL of DCM, transferred to a separatory funnel, and 25 mL of saturated aqueous NaHCO was added. The layers were separated, and the aqueous layer was extracted twice more with DCM. The combined organics were dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Waters XSelect CSH Prep C18 5um OBD 30x100mm and 5-65% gradient ACN-water, 0.1% TFA modifier) to give 6-(7-fluoro-2-(piperidin-4-yl)-1H-benzo[d]imidazol-5-yl)-2,8-dimethylimidazo[1,2-b]pyridazine (4 mg, 11%). MS: m / z 365.2 [M+H] + .1 H NMR (400 MHz, methanol-d4) δ ppm 1.83 - 1.98 (m, 2 H), 2.10 (br d, J=12.01 Hz, 2 H), 2.48 (s, 3 H), 2.66 (s, 3 H), 2.80 (br t, J=11.76 Hz, 2 H), 3.06 - 3.25 (m, 3 H), 7.58 (s, 1 H), 7.67 (d, J=12.01 Hz, 1 H), 7.89 (s, 1 H), 7.96 (s, 1 H)

[0283] Using the procedure described for Example 17 above, additional compounds described herein were prepared by substituting the appropriate boronic ester or acid equivalent, suitable reagents and reaction conditions in step b to provide compounds such as those selected from the following: [Table 21-1] [Table 21-2] [Table 21-3]

[0284] Example 18 - Compounds 131 and 133 [ka] Step a: To a solution of 5-bromo-3-fluoro-pyridin-2-amine (0.5 g, 2.6 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (809 mg, 2.62 mmol) in dioxane (10 mL) and HO (2 mL) was added KCO (723 mg, 5.2 mmol) and Pd(dppf)Cl (192 mg, 262 μmol) at 20° C. The mixture was stirred at 90° C. under N for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by silica column chromatography (PE / EtOAc = 1 / 1 to 0 / 1) to give tert-butyl 4-(6-amino-5-fluoro-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.75 g, 2.51 mmol, 95% yield) as a yellow solid. MS: m / z 294.2 [M+H]

[0285] Step b: To a solution of tert-butyl 4-(6-amino-5-fluoro-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.1 g, 341 μmol) in MeOH (10 mL) was added Pd / C (36 mg, 34 μmol, 10% purity) under N at 20° C. The mixture was stirred under 15 psi of H at 25° C. for 2 h. The residue was purified by preparative HPLC (neutral conditions) to give tert-butyl 4-(6-amino-5-fluoro-3-pyridyl)piperidine-1-carboxylate (0.05 g, 48% yield) as a yellow solid. MS: m / z 296.0 [M+H] +

[0286] Step c: To a solution of 2-bromo-1-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)ethanone (150 mg, 559 μmol), tert-butyl 4-(6-amino-5-fluoro-3-pyridyl)piperidine-1-carboxylate (100 mg, 338 μmol), and NaHCO (57 mg, 677 μmol) in t-BuOH (5 mL) at 25° C. The mixture was stirred at 80° C. for 16 hours. The mixture was concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography (0-100% PE-EtOAc) to afford tert-butyl 4-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]piperidine-1-carboxylate (100 mg, 63% yield) as a yellow solid. MS: m / z 465.7 [M+H] +

[0287] Step d: To a solution of tert-butyl 4-[2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]piperidine-1-carboxylate (100 mg, 215 μmol) in 4 M HCl in dioxane (20 mL) at 25° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (C18-1 150*30mm*5um, mobile phase of water (NH4HCO3)-ACN, 23% to 53%, gradient time (min): 15, flow rate (ml / min): 25) to give 6-(8-fluoro-6-(piperidin-4-yl)imidazo[1,2-a]pyridin-2-yl)-2,8-dimethylimidazo[1,2-b]pyridazine (30 mg, 37% yield) as a white solid. MS: m / z 365.1 [M+H] + ;RT 0.64 min (method 7)

[0288] Step e: A solution of 6-[8-fluoro-6-(4-piperidyl)imidazo[1,2-a]pyridin-2-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (10 mg, 27.44 μmol), paraformaldehyde (66 mg, 54 μmol, 75 μL), and triethylamine (8 μL, 55 μmol) in 1,2-dichloroethane (5 μL, 55 μmol) and EtOH (5 mL) was stirred for 0.5 h at 25° C. Then, sodium triacetoxyborohydride (12 mg, 55 μmol) was added and stirred for 1 h. The mixture was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, mobile phase of water (NH3H2O+NH4HCO3)-ACN, 31% to 61%, gradient time (min): 10, flow rate (ml / min): 25) to give 6-[8-fluoro-6-(1-methyl-4-piperidyl)imidazo[1,2-a]pyridin-2-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (6 mg, 57% yield) as a white solid. MS: m / z 379.1 [M+H] + ;RT 1.73 minutes (method 7)

[0289] Using the procedure described for Example 19 above, additional compounds described herein were prepared by substituting the appropriate boronic ester starting material in step a, the aldehyde in step e, and the appropriate reagents and reaction conditions to provide compounds such as those selected from the following: [Table 22]

[0290] Example 19 - Compound 127 [ka] Step a: To a mixture of 5-bromo-3-fluoropyridin-2-amine (5 g, 26.2 mmol) and pyridine (2.1 g, 26.2 mmol, 2 mL) was added 4-methylbenzene-1-sulfonyl chloride (5 g, 26.2 mmol) at 0 °C, and the reaction mixture was stirred at 100 °C under a N atmosphere for 12 h. The mixture was concentrated, then diluted with water (300 mL), extracted with EtOAc, and concentrated to give N-(5-bromo-3-fluoropyridin-2-yl)-4-methylbenzenesulfonamide (6.9 g, 20 mmol, 76% yield) as an off-white solid. MS: m / z 345 [M+H] + ;RT 0.78 min (Method 7).

[0291] Step b: To a solution of tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (98 mg, 319 μmol) and N-(5-bromo-3-fluoro-2-pyridyl)-4-methyl-benzenesulfonamide (100 mg, 290 μmol) in DMF (2 mL) was added NaHCO (50 mg, 594 μmol). The mixture was stirred at 100° C. for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (Column: Boston Green ODS 150*30mm*5um; Conditions: Water (FA)-ACN, Start B65, End B95; Gradient time (min): 12; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give tert-butyl 4-[2-[(2E)-5-bromo-3-fluoro-2-(p-tolylsulfonylimino)-1-pyridyl]acetyl]piperazine-1-carboxylate (50 mg, 30% yield) as a yellow solid. MS: m / z 571 [M+H] + ;RT 0.692 minutes (Method 7).

[0292] Step c: To a solution of tert-butyl 4-[2-[(2E)-5-bromo-3-fluoro-2-(p-tolylsulfonylimino)-1-pyridyl]acetyl]piperazine-1-carboxylate (35 mg, 61 μmol) in DCM (2 mL) was added TFAA (3 g, 14 mmol, 2 mL) and the mixture was stirred at 40 °C for 16 h. The mixture was concentrated under vacuum to give a residue, which was purified by preparative HPLC (Boston Green ODS 150*30mm*5um; Conditions: water (FA)-ACN, start B49, end B59; Gradient time (min): 12; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give 1-[4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperazin-1-yl]-2,2,2-trifluoro-ethanone (20 mg, 83% yield) as a white solid.

[0293] Step d: To a solution of 1-[4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperazin-1-yl]-2,2,2-trifluoroethanone (20 mg, 50 μmol) in dioxane (3 mL) and water (0.5 mL), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (14 mg, 51 μmol), K2CO3 (21 mg, 152 μmol), and Pd(dppf)Cl2 (4 mg, 5 μmol) were added under N2. The mixture was stirred at 80 °C for 2 hours. The mixture was concentrated, and then water (50 mL) was added. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue, which was purified by preparative HPLC (Column: Boston Prime C18 150*30 mm*5 um; Conditions: Water (NH3H2O+NH4HCO3)-ACN, Start B44, End B74; Gradient time (min): 10; 100% B Retention time (min): 2; Flow rate (ml / min): 25) to give 6-(8-Fluoro-2-piperazin-1-yl-imidazo[1,2-a]pyridin-6-yl)-2,8-dimethyl-imidazo[1,2-b]pyridazine (8 mg, 44% yield). MS: m / z 366.0 [M+H] + ;RT 1.2 minutes (Method 7).

[0294] Example 20 - Compound 150 [ka] Step a: A mixture of tert-butyl 4-(6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)piperidine-1-carboxylate (60 mg, 150.3 μmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (53.4 mg, 195.36 μmol), Pd(dppf)Cl DCM (12.27 mg, 15.03 μmol), dicesium carbonate (146.8 mg, 450.8 μmol) in dioxane (1.2 mL) and water (300 μL) was stirred at 90 °C under N for 4 h. The mixture was filtered through Celite / MgSO4 (eluent: DCM / EtOAc), concentrated, and used crude in the next reaction (estimated yield 100%). MS: m / z 466.3 [M+H] +

[0295] Step b: A mixture of tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]piperidine-1-carboxylate (70 mg, 150.37 μmol) and HCl (4 M in dioxane, 300 μL) in DCM (3.0 mL) was stirred at room temperature for 3 h. The mixture was concentrated and then purified by preparative HPLC (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(4-piperidyl)-[1,2,4]triazolo[1,5-a]pyridine (16.4 mg, 23% yield). MS: m / z 366.2 [M+H] + ;RT: 0.38 minutes (method 4)

[0296] Using the procedure described for Example 20 above, additional compounds described herein were prepared by substituting the appropriate boronic ester, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 23]

[0297] Example 21 - Compounds 294 and / or 264 [ka] Step a: To a solution of 6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-amine (200 mg, 869 μmol) in dioxane (20 mL) and water (1 mL) was added 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (237 mg, 869 μmol), Pd(dppf)Cl (64 mg, 87 μmol), and KCO (360 mg, 2.61 mmol) under N. The mixture was stirred at 90 °C for 2 hours. The mixture was concentrated, and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by Combi-Flash (DCM / MeOH=10 / 1) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-amine (200 mg, 674.99 μmol, 77.64% yield) as a brown solid. MS: m / z 297.2 [M+H] + ;RT: 0.1237 minutes (method 10)

[0298] Step b: To a solution of 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-amine (400 mg, 1.35 mmol) in pyridine (10 mL), 1-tert-butoxycarbonylazetidine-3-carboxylic acid (326 mg, 1.62 mmol) and EDCI (388 mg, 2 mmol) were added, and the mixture was stirred at 90 °C for 1 hour. The mixture was then concentrated, and water (80 mL) was added. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by Combi-Flash (DCM / MeOH=20 / 1) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (250 mg, 521 umol, 39% yield) as a yellow solid. MS: m / z 480.3 [M+H] + ;RT: 0.798 minutes (method 4)

[0299] Step c: To a solution of tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (50 mg, 104 μmol) in DCM (2 mL) was added TFA (2 mL) and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo and purified by preparative HPLC (FA) to give N-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]azetidine-3-carboxamide (22 mg, 57 μmol, 55% yield) as a white solid. MS: m / z 380.0 [M+H] + ;RT: 0.777 minutes (method 7)

[0300] Step d: A solution of N-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]azetidine-3-carboxamide (30 mg, 79 umol) and cyclobutanone (17 mg, 237 umol, 18 uL) in DCE / EtOH (4 mL) was stirred at 20° C. for 20 minutes. Sodium triacetoxyborohydride (50 mg, 237 umol) was added to the reaction mixture and stirred at 20° C. for 12 hours. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 1-cyclobutyl-N-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]azetidine-3-carboxamide (4.6 mg, 10 μmol, 13% yield, 97% purity) as a yellow solid. MS: m / z 434.1 [M+H] + ;RT: 1.23 min (method 8); 1H NMR: (400MHz, methanol-d4) δ ppm = 9.05 (s, 1H), 8.34 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.81 (d, J = 12.4 Hz, 1H), 7.60 (s, 1H), 3.73-3.68 (m, 2H), 3.56-3.48 (m, 3H), 2.68 (s, 3H), 2.64-2.58 (m, 1H), 2.49 (s, 3H), 1.01 (d, J = 6.4 Hz, 6H).

[0301] Using the procedure described for Example 21 above, additional compounds described herein were prepared by substituting the appropriate boronic ester, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4]

[0302] Example 22 - Compound 126 [ka] Step a: tert-Butyl 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (100 mg, 251 μmol) was dissolved in DCM (2.5 mL), NCS (34 mg, 251 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting product was purified by silica gel flash chromatography using a 0-100% EtOAc / heptane gradient to give tert-butyl 4-(6-bromo-3-chloro-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (67 mg, 61% yield). MS: m / z 432 [M+H]+.

[0303] Step b: tert-Butyl 4-(6-bromo-3-chloro-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (39.5 mg, 91.24 μmol) was dissolved in dioxane (1.5 mL) and water (0.8 mL) along with 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (26.0 mg, 100.4 μmol), cesium carbonate (59.5 mg, 182.4 μmol), and di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; and iron (5.9 mg, 9.12 μmol). The mixture was degassed with N and microwaved to 90 °C for 2 h. The resulting mixture was cooled to room temperature and purified by silica gel flash chromatography using a gradient of 0-100% EtOAc / heptane. MS: m / z 485 [M+H] + .

[0304] Step c: tert-Butyl 4-[3-chloro-8-fluoro-6-(2-methylimidazo[1,2-b]pyridazin-6-yl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (5.6 mg, 12 μmol) was dissolved in DCM (1 mL), and HCl (4 M in dioxane, 57 μL) was added and stirred at room temperature for 1 h. The resulting mixture was concentrated to dryness to give 6-[3-chloro-8-fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (4 mg, 90% yield). 1 H NMR (500 MHz, methanol-d4) δ ppm 2.00 - 2.18 (m, 4 H) 2.57 (s, 3 H) 3.06 - 3.16 (m, 3 H) 3.25 - 3.32 (m, 1 H) 3.43 - 3.52 (m, 4 H) 7.92 (br d, J=11.60 Hz, 1 H) 8.32 (s, 1 H) 8.36 - 8.47 (m, 2 H) 8.87 - 8.93 (m, 1 H) MS:m / z385[M+H] + .

[0305] Example 23 - Compounds 154 & 456 [ka] Step a: A mixture of 2-amino-5-bromo-3-fluoro-phenol (360 mg, 1.75 mmol) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (400.6 mg, 1.75 mmol) in PPA (3 mL) was stirred at 160° C. for 0.5 h. It was used directly in the next step without further purification. [M+2+H] = 301.0

[0306] Step b: A solution of 6-bromo-4-fluoro-2-(4-piperidyl)-1,3-benzoxazole (400 mg, 1.34 mmol), TEA (1.34 mmol, 186 μL), tert-butoxycarbonyl tert-butyl carbonate (291.8 mg, 1.34 mmol, 307.2 μL) in THF (15 mL) and water (40 mL) was stirred at 0° C. for 0.5 h. The mixture was concentrated, and then water (50 mL) was added. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 3 / 1, TLC: PE / EtOAc = 3 / 1) to give tert-butyl 4-(6-bromo-4-fluoro-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (366 mg, 68% yield) as a yellow solid. [M-tBu+2+H] = 344.8

[0307] Step c: To a solution of tert-butyl 4-(6-bromo-4-fluoro-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (50 mg, 125.2 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (34.2 mg, 125.2 μmol) in dioxane (3 mL) and water (1 mL) was added Pd(dppf)Cl (9.16 mg, 12.52 μmol) and KCO (34.6 mg, 250.4 μmol). The mixture was degassed with N three times and stirred at 80 °C for 2 h. The reaction mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (NH.H.sub.2O modifier) to give tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (30 mg, 51% yield) as a white solid. [M+H] = 466.3

[0308] Step d: To a solution of tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (20 mg, 42.9 μmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1 mL) was added TFA (14.70 mg, 128.8 μmol, 9.87 μL). The mixture was stirred at 20° C. for 1 h. The reaction mixture was diluted with CH3CN (2 mL) and purified by preparative HPLC (Column: Boston Green ODS 150*30 mm*5 um; Conditions: water (FA)-ACN, start B42, end B72; Gradient time (min): 12; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(4-piperidyl)-1,3-benzoxazole (11.2 mg, 71% yield) as a white solid. [M+H] = 366.1; 1 H NMR (400 MHz, methanol-d4) δ: 8.16 (s, 1H), 7.96 (s, 1H), 7.88 (m, 1H), 7.66 (s, 1H), 3.80-3.75 (m, 1H), 3.20-3.10 (m, 2H), 2.80-2.70 (m, 2H), 2.69 (s, 3H), 2.51 (s, 3H), 2.25-2.15 (m, 2H), 2.20-2.10 (m, 2H).

[0309] Using the procedure described for Example 23 above, additional compounds described herein were prepared by substituting the appropriate boronic ester, suitable reagents, and reaction conditions in step c to provide compounds such as those selected from the following: [Table 25]

[0310] Example 25 - Compound 439 [ka] Step a: To a solution of 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(4-piperidyl)-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 82 μmol), 1-bromo-2-methoxy-ethane (11 mg, 82 μmol, 8 μL) and CsCO (54 mg, 164 μmol) in DMF (3 mL) at 25° C., the mixture was stirred at 90° C. for 1 h. The mixture was concentrated in vacuo to give the crude product. The crude material was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, mobile phase of water (NH3H2O + NH4HCO3)-ACN, 29% to 59%, gradient time (min): 10, flow rate (ml / min): 25) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-[1-(2-methoxyethyl)-4-piperidyl]-[1,2,4]triazolo[1,5-a]pyridine (9.3 mg, 21.96 umol, 26.75% yield, 100% purity) as a white solid. MS: m / z 424.2 [M+H] + ;RT:1.612 minutes (method 10)

[0311] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 26]

[0312] Example 26 - Compounds 443 & 453 [ka] Step a: To a solution of 5-bromo-3-fluoro-pyridin-2-amine (2 g, 10 mmol) in MeCN (15 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (2.1 g, 10 mmol) at 25 °C. The mixture was stirred at 40 °C for 16 h. The mixture was filtered and the solvent removed to give 5-bromo-3-fluoro-pyridin-1-ium-1,2-diamine (3 g, crude) as a yellow solid. 5-Bromo-3-fluoro-pyridin-1-ium-1,2-diamine (3 g, crude) was then dissolved in DMSO (6 mL) and stored. MS: m / z 206.0 [M+H] + ;RT:0.463 minutes (method 10)

[0313] Step b: To a solution of 5-bromo-3-fluoro-pyridine-1,2-diamine (98 mg, 473 umol, 1.5 mL) and tert-butyl (1S,5R)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 473 umol) in MeOH (4 mL), KOH (2 M, 355 uL) was added and the mixture was stirred at 25° C. for 1 h, then the reaction mixture was partitioned between EtOAc (30 mL) and water (5 mL). After the reaction was quenched, the reaction mixture was poured into a separatory funnel and separated. The mixture was then dissolved in MeOH, filtered, and purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: 40%-80% water (FA)-ACN) to give tert-butyl (1S,5R)-6-(6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (97 mg, 243 umol, 51% yield) as a white solid. MS: m / z 397.1 [M+H] + ;RT:1.147 minutes (method 7)

[0314] Step c: To a solution of tert-butyl (1S,5R)-6-(6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (40 mg, 100 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (33 mg, 120 μmol) in dioxane (3 mL) and water (1 mL), Pd(dppf)Cl (1.5 mg, 2 μmol) and KCO (28 mg, 201 μmol) were added. The mixture was stirred at 90 °C under nitrogen for 16 h. The mixture was extracted with EtOAc (15 mL × 3) and dried over NaSO. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% to 100% EtOAc:PE) to give tert-butyl (1S,5R)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 64 μmol, 64% yield) as a yellow solid. MS: m / z 464.2 [M+H] + ;RT:1.999 minutes (method 10)

[0315] Step d: To a solution of tert-butyl (1R,5S)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (15 mg, 32 umol) in hexafluoroisopropanol (4 mL), TFA (18 mg, 161 umol, 12 uL) was added and the mixture was stirred at 25 °C for 1 h. The solution was evaporated under reduced pressure in a water bath, and then the mixture was dissolved in MeOH, filtered, and purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; mobile phase: 0%-15% water (FA)-ACN) to give 2-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine (10 mg, 28 umol, 86% yield) as a white solid. MS: m / z 364.1 [M+H] + ;RT:1.213 minutes (method 10)

[0316] Step e: To a solution of 2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine (16 mg, 43 μmol) and paraformaldehyde (51 mg, 43 μmol, 58 μL) in MeOH (2 mL) was added acetic acid (13 mg, 215 μmol, 12 μL) and the mixture was stirred for 20 min at 25° C. Sodium cyanoborohydride (8 mg, 129 μmol) was then added and the mixture was stirred at 25° C. for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by preparative HPLC to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]-[1,2,4]triazolo[1,5-a]pyridine (9 mg, 25 μmol, 57% yield) as a yellow solid. MS: m / z 378.2 [M+H] +;RT:1.233 minutes (method 10)

[0317] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 27]

[0318] Example 27 - Compound 539 [ka] Step a: To a solution of tert-butyl (1S,5R)-6-(2-bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.64 mmol) in t-BuOH (10 mL) was added NaHCO (276 mg, 3.29 mmol, 127 μL) and 5-bromo-3-methoxy-pyridin-2-amine (333 mg, 1.64 mmol). The mixture was stirred at 80 °C for 12 h. The mixture was filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE / EtOAc = 10 / 1 to 0 / 1, TLC: PE / EtOAc = 1 / 1, Rf = 0.45) to give the product. The compound tert-butyl (1S,5R)-6-(6-bromo-8-methoxy-imidazo[1,2-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (323 mg, 791 μmol, 48% yield) was obtained as a yellow solid. MS: m / z 408.0 [M+H] + ;RT:0.375 minutes (method 9)

[0319] Step b: To a stirred solution of tert-butyl (1S,5R)-6-(6-bromo-8-methoxy-imidazo[1,2-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (70 mg, 171 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (47 mg, 171 μmol) in dioxane (5 mL), K2CO3 (71 mg, 514 μmol) and Pd(dppf)Cl2 (13 mg, 17 μmol) were added. The reaction mixture was stirred at 90 °C for 1 hour. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC purification (neutral conditions). The compound tert-butyl (1S,5R)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-methoxy-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (30 mg, 62 μmol, 36% yield) was obtained as a white solid. MS: m / z 475.3 [M+H] + ;RT:0.283 minutes (method 9)

[0320] Step c: To a solution of tert-butyl (1S,5R)-6-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (12 mg, 23 μmol) in HCl / EtOAc (2 mL). The mixture was stirred at 25 °C for 8 h. The mixture was filtered and concentrated to give a residue. The crude compound was used in the next step without further purification. The compound 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-6-yl]-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (8 mg, 19.5 μmol, 82% yield) was obtained as a white solid. MS: m / z 411.1 [M+H] + ;RT:0.241 minutes (method 9)

[0321] Step d: To a stirred solution of 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (20 mg, 53 μmol) and paraformaldehyde (64 mg, 53 μmol, 73 μL) in DCE / EtOH (6 mL), TEA (16 mg, 160 μmol, 23 μL) was added and stirred at 20° C. for 15 minutes. After the addition, sodium triacetoxyborohydride (23 mg, 107 μmol) was added and the mixture was stirred at 20° C. for 2 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC purification (neutral conditions). The compound 6-[8-methoxy-2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (8 mg, 20 μmol, 37% yield) was obtained as a yellow solid. MS: m / z 389.1 [M+H] + ;RT:0.183 minutes (method 9)

[0322] Using the procedure described for Example 1 above, additional compounds described herein were prepared by substituting the appropriate bromoketone starting material in step a, the appropriate boronic ester or acid equivalent in step b, the appropriate reagents and reaction conditions to provide compounds such as those selected from the following: [Table 28]

[0323] Example 28 - Compound 537 [ka] Step a: tert-Butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (400.33 mg, 1.31 mmol, 1.25 equiv) and 5-bromo-3-(difluoromethoxy)pyridin-2-amine (250 mg, 1.05 mmol, 1.0 equiv) were dissolved in water (5.23 mL) and heated to 80 °C for 16 h. The mixture was then concentrated and dry-loaded onto normal-phase silica and purified with 0-25% MeOH:DCM over 12 min. The des-boc material eluted with 20% MeOH, and the boc material eluted with 4% MeOH. Identified fractions were pooled, concentrated, quantitatively analyzed, and carried forward. MS: m / z 392.1 [M+H-tBu] + ;RT 0.67 min (method 4).

[0324] Step b: tert-Butyl 4-[6-bromo-8-(difluoromethoxy)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (98.7 mg, 221 μmol, 1.0 equiv.) was dissolved in dioxane (1 mL, 0.2 M) and water (1 mL, 0.2 mL), followed by the addition of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (66.4 mg, 239 μmol, 1.1 equiv.) and cesium carbonate (216.2 mg, 663 μmol, 3 equiv.). The solution was then thoroughly degassed with nitrogen, followed by the addition of Pd(dppf)Cl DCM (18 mg, 22.1 μmol, 0.1 equiv.). The solution was then heated at 80° C. for 2 hours and carried on crude with an estimated yield of 100%.

[0325] Step c: tert-Butyl 4-[8-(difluoromethoxy)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (113.4 mg, 221.2 μmol, 1.0 equiv.) was dissolved in DCM (3 mL, 0.07 M), followed by the addition of 4 M HCl in dioxane (80.63 mg, 2.21 mmol, 10.0 equiv.). The solution was then stirred at 50° C. for 2 hours, concentrated, then recovered in DMSO, filtered, and purified by HPLC (Sunfire C18 100×19 mm, 5 mm column; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA). The identified fractions were collected, combined, and concentrated to give 6-[8-(difluoromethoxy)-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine as a yellow oil (18.3 mg, 15.7% yield). MS: m / z 413.3 [M+H] + ;RT 1.88 min (method 1).1H NMR (600 MHz, DMSO-d6 ) δ ppm 1.87 - 1.97 (m, 2 H) 2.15 - 2.19 (m, 2 H) 2.19 - 2.49 (m, 3 H) 2.52 - 2.73 (m, 3 H) 3.05 - 3.20 (m, 4 H) 3.43 - 3.57 (m, 1 H) 7.66 - 7.68 (m, 1 H) 7.69 - 7.71 (m, 1 H) 7.72 - 7.75 (m, 1 H) 7.95 - 7.98 (m, 1 H) 8.12 - 8.16 (m, 1 H) 8.27 - 8.36 (m, 1 H) 8.54 - 8.65 (m, 1 H) 9.19 - 9.23 (m, 1 H)

[0326] Using the procedure described for Example 1 above, additional compounds described herein were prepared by substituting the appropriate bromoketone starting material in step a, the appropriate boronic ester or acid equivalent in step b, the appropriate reagents and reaction conditions to provide compounds such as those selected from the following: [Table 29]

[0327] Example 29 - Compound 549 [ka] Step a: To a solution of 5-bromo-3-(trifluoromethoxy)pyridin-2-amine (250 mg, 0.97 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (265.7 mg, 0.97 mmol) in dioxane (4.6 mL) and water (1.6 mL) was added CsCO (950.8 mg, 2.92 mmol) and Pd(dppf)Cl (79.4 mg, 97.2 μmol). The mixture was stirred at 90 °C under nitrogen for 16 h. The mixture was extracted with EtOAc (15 mL × 3) and dried over NaSO. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 20% MeOH:DCM) to give 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(trifluoromethoxy)pyridin-2-amine (247.2 mg, 0.76 mmol, 79% yield) as a yellow solid. MS: m / z 324.1 [M+H] + .

[0328] Step b: To a solution of tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (56.8 mg, 185.6 μmol) in t-BuOH (2 mL) was added 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(trifluoromethoxy)pyridin-2-amine (60 mg, 185.6 μmol) and NaHCO (46.8 mg, 556.8 μmol), and the mixture was stirred at 80° C. for 16 h. The mixture was concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (0% to 10% MeOH:DCM) to give tert-butyl 4-(6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-(trifluoromethoxy)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (69.2 mg, 70% yield) as a yellow solid. MS: m / z 531.3 [M+H] + .

[0329] Step c: 4-(6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-(trifluoromethoxy)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (69.2 mg, 130.4 μmol) was dissolved in 4 M HCl in dioxane (0.26 mL) and DCM (2 mL). The mixture was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo and purified by preparative HPLC (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give 2,8-dimethyl-6-(2-(piperidin-4-yl)-8-(trifluoromethoxy)imidazo[1,2-a]pyridin-6-yl)imidazo[1,2-b]pyridazine trifluoroacetate (1.3 mg, 1.8% yield) as a white solid. MS: m / z 431.3 [M+H] + .

[0330] Example 30 - Compounds 551 & 552 [ka] Step a: 5-Bromopyridin-2-amine (500 mg, 2.89 mmol) was dissolved in ACN (3.47 mL) and toluene (2.31 mL). Sodium bicarbonate (242 mg, 2.89 mmol) was added, followed by tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (884 mg, 2.89 mmol). The mixture was stirred at 90 °C overnight. The product was concentrated and purified by flash elution with a gradient of 0-100% EtOAc / heptane. MS: m / z 415.2 [M+H] + ;RT:0.86 minutes (method 4)

[0331] Step b: tert-Butyl 4-(6-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (200 mg, 525.93 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (158 mg, 578 μmol) were mixed with PdCl(dippf) (31 mg, 52 μmol) and cesium carbonate (514 mg, 1.6 mmol) in dioxane (1.58 mL) and water (1 mL). The mixture was purged with N and then heated in a microwave at 90 °C for 1 h. The solution was diluted with water, extracted with EtOAc, and dried over sodium sulfate. The resulting mixture was taken up in 2 mL of DCM and treated with 2 mL of HCl 4N in dioxane. The solution was then stirred at room temperature for an additional 3 hours. The solution was concentrated and purified by acidic preparative HPLC. MS: m / z 347.1 [M+H] + ;RT 0.54 min (method 3).

[0332] Step c: 2,8-Dimethyl-6-[2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]imidazo[1,2-b]pyridazine (10 mg, 28.9 μmol) was dissolved in ACN (1 mL), paraformaldehyde (35 mg, 28.9 μmol, 40 μL), acetic acid (17 mg, 289 μmol, 17 μL), and sodium cyanoborohydride (6 mg, 87 μmol) and heated to 70° C. overnight. The product was concentrated and purified by acidic preparative HPLC. MS: m / z 361.1 [M+H] + ;RT 1.032 minutes (Method 10).

[0333] Using the procedure described for Example 1 above, additional compounds described herein were prepared by substituting the appropriate bromoketone starting material in step a, the appropriate boronic ester or acid equivalent in step b, the appropriate reagents and reaction conditions to provide compounds such as those selected from the following: [Table 30]

[0334] Example 31 - Compound 557 [ka] Step a: tert-Butyl 4-(6-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (270 mg, 710 μmol) was dissolved in chloroform (4 mL) at 0°C. DMAP (87 mg, 710 μmol) was then added, followed by 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane; ditetrafluoroborate (503 mg, 1.42 mmol). The reaction was stirred at 0°C for 2 hours, then heated to 55°C for 6 hours, quenched with saturated aqueous sodium carbonate, and extracted with EtOAc. The crude material was purified by RPHPLC using an acidic gradient of 0-70% ACN-water. MS: m / z 397.0 [M+H] + ;RT:0.70 minutes (method 4).

[0335] Step b: tert-Butyl 4-(6-bromo-3-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (45 mg, 113 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (34 mg, 124 μmol) were dissolved in dioxane (1.6 mL) and water (1.1 mL) along with PdCl(dippf) (7 mg, 11.3 μmol) and cesium carbonate (110 mg, 339 μmol). This mixture was degassed with N and microwaved at 90 °C for 1 h. The resulting mixture was extracted with water / EtOAc and dried over sodium sulfate. The organic material was concentrated, dissolved in DCM (2 mL), and treated with HCl 4N in dioxane (2 mL). The solution was stirred at room temperature for 3 hours, then concentrated and purified by acidic preparative HPLC. MS: m / z 365.1 [M+H] + ;RT:0.68 minutes (method 3).

[0336] Example 32 - Compounds 350 & 363 [ka] Step a: To a solution of tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (1.36 g, 3.83 mmol) in DMF (10 mL) was added K2CO3 (1.59 g, 11.49 mmol) and 5-bromo-7-fluoro-2H-indazole (823 mg, 3.83 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with HO (40 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE / EtOAc = 10 / 1 to 5 / 1, TLC: PE / EtOAc = 5 / 1, Rf = 0.30) to give the product. The compound tert-butyl 4-(5-bromo-7-fluoro-indazol-2-yl)piperidine-1-carboxylate (492 mg, 1.24 mmol, 32% yield) was obtained as a yellow oil. MS: m / z 342.0 [M-56] + ;RT:0.518 minutes (Method 9).

[0337] Step b: To a solution of tert-butyl 4-(5-bromo-7-fluoro-indazol-2-yl)piperidine-1-carboxylate (60 mg, 150 μmol) in dioxane (2 mL), KOAc (29 mg, 301 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (46 mg, 181 μmol), and PdCl (dppf) (22 mg, 30 μmol) were added. The mixture was stirred at 90° C. under N for 2 hours. The crude compound was used in the next step without further purification. MS: m / z 446.3 [M+H] + ;RT:0.813 minutes (method 7).

[0338] Step c: To a solution of tert-butyl 4-[7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]piperidine-1-carboxylate (100 mg, 224 μmol) in dioxane (2 mL) and HO (1 mL), CsCO (219.5 mg, 673 μmol), 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (32 mg, 134 μmol), and PdCl(dppf) (10 mg, 13 μmol) were added. The mixture was stirred at 90 °C under N for 2 h. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20:1 to 1:1). The desired product was obtained as a white solid. MS: m / z 501.0 [M+H] + ;RT:0.80 minutes (method 4).

[0339] Step d: To a solution of tert-butyl 4-(5-(8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate (70 mg, 139.86 μmol) in DCM (2 ml) was added 4N HCl in dioxane (34 uL). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated to give a residue. The crude compound was used in the next step without further purification. MS: m / z 400.9 [M+H] + ;RT:0.0.55 minutes (method 4).

[0340] Step e: 8-(Difluoromethyl)-6-[7-fluoro-2-(4-piperidyl)indazol-5-yl]-2-methyl-imidazo[1,2-b]pyridazine (43 mg, 109 μmol) was dissolved in THF (1 mL) with paraformaldehyde (132 mg, 109 μmol, 149 μL), acetic acid (66 mg, 1.10 mmol, 63 μL), and sodium cyanoborohydride (21 mg, 329 μmol). The mixture was warmed to 70 °C and stirred overnight. The resulting material was diluted with water, extracted with EtOAc, and concentrated. The crude material was purified by FCC using a gradient of 0-100% EtOAc in heptane to give compound. MS: m / z 415.2 [M+H] + ;RT:1.83 minutes (method 4).

[0341] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 31]

[0342] Example 33 - Compound 196 [ka] Step a: To a solution of 6-bromo-2-cyclopent-3-en-1-yl-8-fluoro-imidazo[1,2-a]pyridine (30 mg, 106 μmol) in dioxane (5 mL), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (35 mg, 128 μmol), Pd(dppf)Cl (8 mg, 11 μmol), and KCO (30 mg, 213 μmol) were added under N. The mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated, and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by preparative HPLC (FA) to give 6-(2-cyclopent-3-en-1-yl-8-fluoro-imidazo[1,2-a]pyridin-6-yl)-2,8-dimethyl-imidazo[1,2-b]pyridazine (6.6 mg, 19.00 μmol, 17.80% yield) as a yellow solid. MS: m / z 348.1 [M+H] + ;RT: 1.88 minutes (method 10)

[0343] Example 34 - Compound 226 [ka] Step a: To a solution of 6-bromo-2-cyclopent-3-en-1-yl-8-fluoro-imidazo[1,2-a]pyridine (200 mg, 711 μmol) in acetone (15 mL) and water (15 mL) was added NMO (166 mg, 1.42 mmol) dipotassium; (dioxo)osmium dioxide; dihydrate (52 mg, 142 μmol) at 25° C. The reaction was stirred at 25° C. for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product, 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)cyclopentane-1,2-diol (200 mg, 634 μmol, 89% yield) as a gray solid. MS: m / z 316.9 [M+2H] + ;RT:1.022 minutes (method 10)

[0344] Step b: To a solution of 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)cyclopentane-1,2-diol (200 mg, 634.64 μmol) in dioxane (10 mL) and water (10 mL) was added sodium periodate (271 mg, 1.27 mmol) at 25° C. The reaction was stirred at 25° C. for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 2 / 1) to give 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)pentanedial (180 mg, 574.86 μmol, 90% yield) as a yellow solid. MS: m / z 314.9 [M+2H] + ;RT:1.035 minutes (method 10)

[0345] Step c: To a mixture of 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)pentanedial (80 mg, 255.49 μmol) and 1-methylcyclopropanamine (22 mg, 306.59 μmol) in EtOH (5 mL) and DCE (5 mL) was added acetic acid (46 mg, 766 μmol, 44 μL) in one portion at 25° C. After 30 minutes, sodium triacetoxyborohydride (162 mg, 766 μmol) was added. The mixture was concentrated, and then water (60 mL) was added. The mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30mm*5um; conditions: water (NH4HCO3)-ACN; start B40; end B70; gradient time (min) 11; 100% B retention time (min) 2; flow rate (ml / min) 25) to give 6-bromo-8-fluoro-2-[1-(1-methylcyclopropyl)-4-piperidyl]imidazo[1,2-a]pyridine (20 mg, 56.78 μmol, 22% yield) as a yellow solid. MS: m / z 352.1 [M+H] + ;RT:0.687 minutes (method 10)

[0346] Step d: To a mixture of 6-bromo-8-fluoro-2-[1-(1-methylcyclopropyl)-4-piperidyl]imidazo[1,2-a]pyridine (20 mg, 56.78 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (17 mg, 62.46 μmol) in dioxane (5 mL), Pd(dppf)Cl (5 mg, 5.68 μmol) and KCO (24 mg, 170.34 μmol) were added in one portion under N at 25 °C. The mixture was stirred at 90 °C for 16 h. The mixture was concentrated, and then water was added. The mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude material was purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30mm*5um; conditions: water (NH4HCO3)-ACN; start B40; end B70; gradient time (min) 11; 100% B retention time (min) 2; flow rate (ml / min) 25) to give 6-[8-fluoro-2-[1-(1-methylcyclopropyl)-4-piperidyl]imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (3.7 mg, 8.84 μmol, 15% yield) as a yellow solid. MS: m / z 419.3 [M+H] + ;RT:1.935 minutes (method 10)

[0347] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 32]

[0348] Example 35 - Compound 207 [ka] Step a: 6-[8-Fluoro-2-(4-piperidyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (30 mg, 82 μmol) and (1-ethoxycyclopropoxy)-trimethyl-silane (43 mg, 246 μmol, 49.65 μL) were dissolved in THF (2 mL) and treated with deuterio-2,2,2-trideuterioacetate (52 mg, 823 μmol, 50 μL) and sodium cyanoborodeuteride (16 mg, 246.97 μmol). The mixture was stirred at 65° C. overnight. The reaction was purified by preparative HPLC (TFA). MS: m / z 406.3 [M+H] + ;RT:0.86 minutes (method 3)

[0349] Example 36 - Compound 555 [ka] Step a: To a solution of 5-bromo-3-methylpyridin-2-amine (250 mg, 1.34 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (365.1 mg, 1.34 mmol) in dioxane (4.6 mL) and water (1.6 mL), CsCO (1.31 g, 4.01 mmol) and Pd(dppf)Cl (109.2 mg, 133.7 μmol) were added. The mixture was stirred under nitrogen at 90 °C for 16 h. The mixture was extracted with EtOAc (15 mL × 3) and dried over NaSO. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 20% MeOH:DCM) to give 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-methylpyridin-2-amine (263.7 mg, 1.04 mmol, 78% yield) as a yellow solid. MS: m / z 254.1 [M+H] + .

[0350] Step b: To a solution of tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (48.4 mg, 157.9 μmol) in t-BuOH (2 mL), 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-methylpyridin-2-amine (40 mg, 157.9 μmol) and NaHCO (39.8 mg, 473.7 μmol) were added, and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in 4 M HCl in dioxane (0.39 mL) and DCM (2 mL). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give 2,8-dimethyl-6-(8-methyl-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)imidazo[1,2-b]pyridazine trifluoroacetate (29.7 mg, 39.6% yield) as a white solid. MS: m / z 361.3 [M+H] + . RT: 0.72 minutes (method 3)

[0351] Example 37 - Compound 556 [ka] Step a: To a solution of 5-bromo-3-chloropyridin-2-amine (250 mg, 1.21 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (329.1 mg, 1.21 mmol) in dioxane (4.6 mL) and water (1.6 mL) was added CsCO (1.18 g, 3.62 mmol) and Pd(dppf)Cl (98.4 mg, 120.5 μmol). The mixture was stirred under nitrogen at 90 °C for 16 h. The mixture was extracted with EtOAc (15 mL × 3) and dried over NaSO. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 20% MeOH:DCM) to give 3-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyridin-2-amine (283.6 mg, 1.04 mmol, 86% yield) as a yellow solid. MS: m / z 274.1 [M+H] + .

[0352] Step b: To a solution of tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (44.8 mg, 146.1 μmol) in t-BuOH (2 mL), 3-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyridin-2-amine (40 mg, 146.1 μmol) and NaHCO (36.8 mg, 438.4 μmol) were added, and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in 4 M HCl in dioxane (0.37 mL) and DCM (2 mL). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give 6-(8-chloro-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)-2,8-dimethylimidazo[1,2-b]pyridazine trifluoroacetate (2.2 mg, 3.0% yield) as a white solid. MS: m / z 381.2 [M+H] + . RT: 0.81 minutes (method 3)

[0353] Example 38 - Compound 535 [ka] Step a: A mixture of 2-amino-4-bromo-6-chlorophenol (500 mg, 2.25 mmol) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (515.3 mg, 2.3 mmol) in PPA (5 mL) was stirred at 160 °C for 14 hours. The mixture was poured into cold water, neutralized with sodium bicarbonate, and the pH was adjusted to approximately 8 by slowly adding TEA (22.7 mg, 224.8 µmol, 31.33 µL). The mixture was then added with tert-butoxycarbonyl tert-butyl carbonate (490.5 mg, 2.3 mmol, 516.3 µL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 1 / 1) to give tert-butyl 4-(5-bromo-7-chloro-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (400 mg, 962.2 μmol, 42.81% yield) as a brown solid. MS: m / z 415.1 [M+H] +.

[0354] Step b: To a solution of tert-butyl 4-(5-bromo-7-chloro-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (90 mg, 216.5 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (60 mg, 219.7 μmol) in dioxane (4.5 mL) and water (0.5 mL), Pd(dppf)Cl (31.7 mg, 43.3 μmol) and KCO (59.8 mg, 433.0 μmol) were added, and the mixture was degassed three times with N and stirred at 80 °C for 2 h. The mixture was then dissolved in MeOH, filtered, and purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: 60% to 90% water (NH4HCO3)-CAN) to give tert-butyl 4-[7-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (30 mg, 62.2 μmol, 28.8% yield) as a white solid. MS: m / z 482.3 [M+H] +.

[0355] Step c: To a solution of tert-butyl 4-[7-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (30 mg, 62.2 μmol) in hexafluoroisopropanol (5 mL), TFA (35.5 mg, 311.2 μmol, 23.8 μL) was added and the mixture was stirred at 25 °C for 1 h. The mixture was then dissolved in MeCN, filtered, and purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: 25% to 55% water (NH4HCO3)-CAN) to give 7-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(4-piperidyl)-1,3-benzoxazole (8.5 mg, 22.3 μmol, 35.8% yield) as a white solid. MS: m / z 382.1 [M+H] + .RT:1.57 minutes (method 10)

[0356] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 33]

[0357] Example 39 - Compound 533 [ka] Step a: rel-(2R,4R)-1-ethyl-N,2-dimethyl-piperidin-4-amine (41.2 mg, 263.5 μmol) and NEt (48.5 mg, 479.1 μmol, 66.8 μL) were added to a mixture of 5-bromo-2-chloro-7-fluoro-1,3-benzoxazole (60 mg, 239.6 μmol) in DCM (1.5 mL) at 0 °C, and the reaction was stirred at room temperature for 2 h, quenched with water, extracted with DCM (2 × 10 mL), dried over MgSO, filtered, and concentrated to give rel-5-bromo-N-((2S,4S)-1-ethyl-2-methylpiperidin-4-yl)-7-fluoro-N-methylbenzo[d]oxazol-2-amine, which was used crude in the next step.

[0358] Step b: A mixture of rel-5-bromo-N-((2S,4S)-1-ethyl-2-methylpiperidin-4-yl)-7-fluoro-N-methylbenzo[d]oxazol-2-amine (237.7 μmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (64.9 mg, 237.7 μmol), Pd(dppf)Cl DCM (19.4 mg, 23.8 μmol), dicesium carbonate (232.3 mg, 713.0 μmol) in dioxane (1.9 mL) and water (475.3 μL) was stirred at 90 °C under N for 4 h. The residue was filtered through Celite / MgSO (eluent: DCM / EtOAc) and concentrated. The mixture was purified by column chromatography (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile phase A: MeCN; Mobile phase B: HO; Modifier: 0.1% TFA) to give rel-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-N-((2S,4S)-1-ethyl-2-methylpiperidin-4-yl)-7-fluoro-N-methylbenzo[d]oxazol-2-amine (24.9 mg, 45.2 μmol, 19% yield, trifluoroacetic acid). MS: m / z 437.3 [M+H] + .RT:1.15 minutes (method 3)

[0359] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 34]

[0360] Example 40 - Compound 468 [ka] Step a: To a solution of 6-bromo-2-chloro-4-fluoro-1,3-benzoxazole (200 mg, 798.6 μmol) and 8-methyl-2,8-diazaspiro[4.5]decane (123.2 mg, 798.6 μmol) in dioxane (8 mL) was added TEA (242.4 mg, 2.40 mmol, 333.9 μL). The mixture was stirred at 100 °C for 2 h. The reaction was filtered and concentrated. The residue was purified by flash silica gel chromatography (MeOH / EtOAc = 0 / 100 to 20 / 80) to give 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzo[d]oxazole (250 mg, 678.9 μmol, 85% yield) as a yellow solid. MS: m / z 369.8 [M+H] + .

[0361] Step b: A mixture of 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzo[d]oxazole (55.2 mg, 150 μmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (40.9 mg, 150 μmol), Pd(dppf)Cl CHCl (12.2 mg, 15.0 μmol), and dicesium carbonate (450 mg, 146 μmol) in dioxane (1.9 mL) and water (475.3 μL) was stirred at 90 °C under N for 4 h. The residue was filtered through Celite / MgSO (eluent: DCM / EtOAc) and concentrated. The mixture was purified by column chromatography (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile Phase A: MeCN; Mobile Phase B: HO; Modifier: 0.1% TFA) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzo[d]oxazole, trifluoroacetic acid (18.0 mg, 32.8 μmol, 27.6% yield, trifluoroacetic acid). MS: m / z 437.3 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ ppm 1.72 - 1.78 (m, 1 H) 1.83 - 1.94 (m, 4 H) 2.08 (t, J=7.25 Hz, 1 H) 2.43 - 2.47 (m, 3 H) 2.60 - 2.64 (m, 3 H) 2.78 - 2.85 (m, 3 H) 3.06 - 3.14 (m, 2 H) 3.40 (br d, J=11.83 Hz, 2 H) 3.50 (s, 1 H) 3.68 (s, 1 H) 3.72 (br t, J=7.06 Hz, 1 H) 3.76 (br t, J=7.06Hz, 1H) 7.77 - 7.83 (m, 1 H) 7.88 (br d, J=1.14 Hz, 1 H) 7.96 - 8.04 (m, 1 H) 8.15 (s, 1 H) 9.47 (br s, 1 H).

[0362] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 35-1] [Table 35-2] [Table 35-3]

[0363] Example 41 - Compound 507 [ka] Step a: To a solution of 6-bromo-2-chloro-4-fluoro-1,3-benzoxazole (200 mg, 798.6 μmol) and 8-methyl-2,8-diazaspiro[4.5]decane (123.2 mg, 798.6 μmol) in dioxane (8 mL) was added TEA (242.4 mg, 2.40 mmol, 333.9 μL). The mixture was stirred at 100 °C for 2 h. The reaction was filtered and concentrated. The residue was purified by flash silica gel chromatography (MeOH / EtOAc = 0 / 100 to 20 / 80) to give 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzo[d]oxazole (250 mg, 678.9 μmol, 85% yield) as a yellow solid. MS: m / z 369.8 [M+H] + .

[0364] Step b: To a solution of 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)-1,3-benzoxazole (200 mg, 543.1 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (179.3 mg, 706.1 μmol) in dioxane (20 mL), KOAc (159.9 mg, 1.6 mmol) and Pd(dppf)Cl (39.7 mg, 54.3 μmol) were added. The mixture was stirred at 90 °C under nitrogen for 2 hours. The crude compound was used in the next step without further purification.

[0365] Step c: To a solution of 4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (60 mg, 144.5 μmol) and 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (31.44 mg, 144.5 μmol) in HO (0.8 mL) and dioxane (4 mL), Pd(dppf)Cl (10.6 mg, 14.5 μmol) and KCO (59.9 mg, 433.4 μmol) were added. The mixture was stirred at 90 °C under nitrogen for 2 h. The mixture was extracted with EtOAc (25 mL × 3) and dried over NaSO. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: 25% to 55% water (NH4HCO3)-CAN) to give 6-(8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzo[d]oxazole (10.6 mg, 22.5 μmol, 15.6% yield) as a white solid. MS: m / z 471.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ ppm = 1.80-1.90 (s, 4H), 2.05 (t, J = 6.7 Hz, 2H), 2.50 (s, 3H), 2.65 (s, 3H), 2.86-3.05 (m, 4H), 3.60 (s, 2H), 3.79 (t, J = 6.9 Hz, 2H), 7.12-7.39 (m, 1H), 7.75 (d, J = 11.3 Hz, 1H), 7.88 (d, J = 10.6 Hz, 2H), 8.03 (s, 1H), 8.54 (s, 1H).

[0366] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 36]

[0367] Example 42 - Compound 545 [ka] Step a: tert-Butyl 4-(5-bromo-7-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (75 mg, 182 mmol) was mixed with 8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (55 mg, 182 mmol) and CsCO (119 mg, 365 mmol). The solid was dissolved in dioxane (2.4 mL) and water (0.6 mL), degassed with N, and SPhos Pd G (13.1 mg, 18 mmol) was added. The reaction was heated in a microwave at 90 °C for 1 h. The resulting material was purified by flash chromatography using a 0-100% EtOAc-heptane gradient to give the title compound. MS: m / z 480.2 [M+H] + ] + ;RT:0.67 minutes (method 4)

[0368] Step b: To a solution of tert-butyl 4-(5-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (161 mg, 337 mmole) in DCM was added TFA (25 uL). The reaction was heated to 45° C. for 2 hours. The reaction was quenched with sodium bicarbonate and the product was extracted with chloroform:IPA (3:1). The organic layer was concentrated in vacuo to give the title compound. MS: m / z 380.1 [M+H] + ;RT:0.83 minutes (method 3)

[0369] Using the procedure described for Example 17 above, additional compounds described herein were prepared by substituting the appropriate boronic ester starting material, suitable reagents, and reaction conditions in step b to provide compounds such as those selected from the following: [Table 37]

[0370] Example 43 - Compound 548 [ka] Step a: 6-Bromo-4-methoxy-2H-benzotriazole (114.02 mg, 0.5 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (3.5 mL, 0.14 M) followed by the addition of tert-butyl 4-hydroxypiperidine-1-carboxylate (100 mg, 500 µmol, 1.0 equiv.), DIAD (101.11 mg, 500 µmol, 1.0 equiv.), and triphenylphosphine (131315 mg, 500 µmol, 1.0 equiv.). The solution was then stirred at room temperature for 16 h, concentrated, and then dry-loaded onto normal-phase silica for purification. The reaction was purified with 0–100% EtOAc:heptane over 7.0 min. The product eluted at approximately 70% EtOAc. The identified fractions were combined and concentrated to give tert-butyl 4-(6-bromo-4-methoxy-benzotriazol-2-yl)piperidine-1-carboxylate (92.3 mg, 23.79% yield). MS: m / z 357.0 [M+H-tBu] + ;RT:1.03 minutes (method 4)

[0371] Step b: tert-Butyl 4-(6-bromo-4-methoxy-benzotriazol-2-yl)piperidine-1-carboxylate (46.15 mg, 112.21 μmol, 1.0 equiv.), 8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (30.98 mg, 112.21 μmol, 1.0 equiv.), cesium carbonate (73.12 mg, 224.31 μmol, 2.0 equiv.), and Pd(dppf)Cl CHCl (9.16 mg, 11.22 μmol, 0.1 equiv.) were dissolved in water (1 mL, 0.56 M) and dioxane (1 mL, 0.56 M) and heated to 100° C. for 16 h. The solution was then carried forward crude. A solution of tert-butyl 4-[6-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-4-methoxy-benzotriazol-2-yl]piperidine-1-carboxylate (estimated yield 100%) was obtained. MS: m / z 481.3 [M+H] + ;RT:0.72 minutes (method 4)

[0372] Step c: tert-Butyl 4-[6-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-4-methoxy-benzotriazol-2-yl]piperidine-1-carboxylate (53.82 mg, 112 μmol, 1.0 equiv.) was dissolved in DCM (1 mL, 0.11 M), followed by the addition of 4 M HCl in dioxane (440.84 mg, 1.12 mmol, 10.0 equiv.). The solution was then stirred at 60 °C for 16 hours, concentrated, recovered with a minimum amount of DMSO, filtered, and purified by HPLC (column: XSelect CSH Prep C18 5 μm OBD 19 × 100 mm; mobile phase A: MeCN; mobile phase B: HO, modifier: 0.1% NH OH). 6-(8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-4-methoxy-2-(4-piperidyl)benzotriazole (5.2 mg, 12% yield) was obtained as a brown solid. MS: m / z 481.1 [M+H] + ;RT:0.83 minutes (method 3)

[0373] Example 44 - Compound 550 [ka] Step a: To a solution of 2-amino-5-bromo-phenol (500 mg, 2.66 mmol) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (609.7 mg, 2.66 mmol) in DCM (10 mL) was added HATU (1.01 g, 2.66 mmol) and TEA (403.6 mg, 3.99 mmol, 556 μL). The mixture was stirred under nitrogen at 25 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (20 mL × 3), washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (20–30% EtOAc / petroleum ether) to give the desired product, tert-butyl 4-[(4-bromo-2-hydroxy-phenyl)carbamoyl]piperidine-1-carboxylate (500 mg, 1.25 mmol, 47.1% yield) as a yellow oil.

[0374] Step b: To a solution of tert-butyl 4-[(4-bromo-2-hydroxy-phenyl)carbamoyl]piperidine-1-carboxylate (2 g, 5.01 mmol) in THF (30 mL) was added triphenylphosphane (1.45 g, 5.51 mmol) and isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (1.11 g, 5.51 mmol, 1.1 mL). The mixture was stirred under nitrogen at 25° C. for 8 hours. The mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (50 mL×3), washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (20-30% EtOAc / petroleum ether) to give the desired product, tert-butyl 4-(6-bromo-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (1.6 g, 4.20 mmol, 83.8% yield) as a purple oil.

[0375] Step c: To a solution of tert-butyl 4-(6-bromo-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (70 mg, 183.60 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (50.2 mg, 183.60 μmol) in dioxane (2 mL) was added Pd(dppf)Cl (26.9 mg, 36.72 μmol) and KCO (50.8 mg, 367.20 μmol). The mixture was stirred at 90 °C under nitrogen for 16 h. The mixture was purified by preparative HPLC (Column: Boston Green ODS 150 x 30 mm x 5 um; Conditions: water (0.05% HCl)-ACN; Start B: 35; End B: 55; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (35 mg, 78.21 μmol, 42.6% yield) as a yellow solid. MS: m / z 448.2 [M+H] + .

[0376] Step d: A solution of tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (30 mg, 67.03 μmol) in HCl / dioxane (2 mL) was stirred under nitrogen at 25° C. for 16 hours. The mixture was purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 um; Conditions: water (10 mM NH4HCO3)-ACN; Start B: 12; End B: 32; Gradient time (min): 10; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(4-piperidyl)-1,3-benzoxazole (6 mg, 17.27 μmol, 25.8% yield) as a white solid. MS: m / z 348.2 [M+H] + .RT:1.3 minutes (method 10).

[0377] Example 45 - Compound 293 [ka] Step a: To a solution of 6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-amine (30 mg, 130.41 μmol) and 1-tert-butoxycarbonylazetidine-3-carboxylic acid (28.87 mg, 143.46 μmol) in pyridine (2 mL) was added EDCl (37.50 mg, 195.62 μmol). The reaction was stirred at 90° C. for 2 hours. The mixture was then filtered and concentrated. The residue was triturated with MeOH (5 mL) and HO (15 mL) at 20° C. for 15 minutes. The mixture was filtered to give tert-butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)carbamoyl]azetidine-1-carboxylate (30 mg, 68.21 μmol, 52.30% yield) as a brown solid. MS: m / z 413.1 [M+H] + .

[0378] Step b: To a solution of tert-butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)carbamoyl]azetidine-1-carboxylate (76 mg, 183.91 μmol) in dioxane (5 mL), KOAc (54.15 mg, 551.74 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (46.70 mg, 183.91 μmol), and Pd(dppf)Cl (20.19 mg, 27.59 μmol) were added. The mixture was stirred at 90 °C under N for 16 h. 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 (low temperature) to give a crude product, which was purified by silica gel chromatography (PE / EA = 1 / 1 = 1 / 0 to 10 / 1) to give tert-butyl 3-[[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (60 mg, 130.35 μmol, 70.9% yield) as a yellow solid.

[0379] Step c: To a solution of tert-butyl 3-[[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (100 mg, 217.25 μmol) in dioxane (5 mL) and water (0.5 mL), 6-chloro-2,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine (47.61 mg, 260.70 μmol), Pd(dppf)Cl (15.90 mg, 21.72 μmol), and KCO (90.07 mg, 651.74 μmol) were added under N. The reaction was stirred at 90 °C for 2 hours. The mixture was then concentrated, followed by the addition of water (80 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by Combi-Flash (DCM / MeOH = 10 / 1) to give tert-butyl 3-[[6-(2,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (60 mg, 124.87 μmol, 57.5% yield) as a brown solid. MS: m / z 481.3 [M+H] + .

[0380] Step d: To a solution of tert-butyl 3-[[6-(2,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (10 mg, 20.81 μmol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to give N-[6-(2,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]azetidine-3-carboxamide (10 mg, crude) as a yellow solid. MS: m / z 381.1 [M+H] + .RT:1.453 minutes (method 10)

[0381] Using the procedure described for Example 21 above, additional compounds described herein were prepared by substituting the appropriate boronic ester, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 38-1] [Table 38-2]

[0382] Example 46 - Compound 324 Step a: To a solution of 6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (300 mg, 1.30 mmol) in dioxane (10 mL) and water (1 mL) was added 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (354.69 mg, 1.30 mmol), Pd(dppf)Cl (95.02 mg, 129.86 μmol) and KCO (538.42 mg, 3.90 mmol) under N. [ka]

[0383] The reaction was stirred at 90° C. for 2 hours. The mixture was concentrated, and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was washed with water (30 mL) and evacuated to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (300 mg, 1.01 mmol, 77.71% yield) as a brown solid.

[0384] Step b: To a mixture of 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (50 mg, 168.19 μmol) and 1-tert-butoxycarbonylazetidine-3-carboxylic acid (33.84 mg, 168.19 μmol) in pyridine (3 mL), T3P (3 mL) was added and stirred at 25 °C for 2 hours. The reaction mixture was quenched with water (50 mL). The aqueous layer was separated and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product. The crude material was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 2 / 1) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (28.9 mg, 60.15 μmol, 35.76% yield) as a yellow solid. MS: m / z 481.2 [M+H] + .

[0385] Step c: tert-Butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (20 mg, 41.62 μmol) was added in one portion to HCl / EA (5 mL) at 25 °C. The mixture was stirred for 16 h. The reaction mixture was concentrated to give the crude product, N-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]azetidine-3-carboxamide (15 mg, 39.43 μmol, 94.74% yield), as a yellow solid. The crude product was used directly in the next step.

[0386] Step d: A mixture of N-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]azetidine-3-carboxamide (10 mg, 26.29 μmol) and acetone (4.58 mg, 78.87 μmol, 5.79 μL) in EtOH (5 mL). After 30 min, sodium triacetoxyborohydride (16.72 mg, 78.87 μmol) was added in one portion at 25 °C. The reaction was stirred at 25 °C for 3 h. The mixture was concentrated and purified by preparative HPLC (Column: Welch Xtimate C18 150 x 25 mm x 5 μm; Conditions: Water (FA)-ACN; Start B 0; End B 30; Gradient Time (min) 11; 100% B Retention Time (min) 2; Flow Rate (ml / min) 25) to give N-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-1-isopropyl-azetidine-3-carboxamide (2.3 mg, 5.44 μmol, 20.71% yield) as a white solid. MS: m / z 423.2 [M+H] + ;RT:1.583 (Method 10).

[0387] Using the procedure described for Example 21 above, additional compounds described herein were prepared by substituting the appropriate boronic ester, suitable reagents, and reaction conditions in step a to provide compounds such as those selected from the following: [Table 39]

[0388] Example 47 - Compounds 361 and 367 [ka] Step a: tert-Butyl 6-(5-bromo-7-fluoro-indazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 252.36 μmol, 1.0 equiv) was dissolved in dioxane (1.51 mL, 0.14 M) along with 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (75.82 mg, 277.60 μmol, 1.1 equiv), PdCl(dppf) (15.03 mg, 25.24 μmol, 0.1 equiv), and CsCO (246.67 mg, 757.09 μmol, 3.0 equiv). Water (0.25 mL, 0.14 M) was added and degassed with N2. The vial was sealed and microwaved at 90 °C for 1 h. The organic material was then loaded onto silica and purified by FCC using a gradient of 0-100% EtOAc-heptane to give tert-butyl 6-[5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-indazol-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate. MS: m / z 463.5 [M+H] + ;RT 0.74 min (method 4).

[0389] Step b: tert-Butyl-6-[5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-indazol-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (85.00 mg, 183.78 μmol, 1.0 equiv) was dissolved in DCM (2 mL, 0.09 M). Hydrochloric acid (67.01 mg, 1.84 mmol, 10.0 equiv) was added and stirred at room temperature for 1 h. The reaction was concentrated, and a portion was carried forward crude. The other portion was purified by HPLC (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile Phase A: MeCN; Mobile Phase B: HO; Modifier: 0.1% TFA). MS: m / z 363.3 [M+H] + ;RT 1.72 minutes (method 1).

[0390] Step c: 6-[2-[(1R,5S)-3-Azabicyclo[3.1.0]hexan-6-yl]-7-fluoro-indazol-5-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (35 mg, 96 μmol) was dissolved in DCM (965 μL). Sodium cyanoborohydride (18 mg, 289.73 μmol) and cyclopropanecarbaldehyde (7 mg, 96.58 μmol, 7 μL) were mixed at room temperature overnight. The resulting mixture was diluted with water and extracted with EtOAc. It was then purified by preparative HPLC to give 6-[2-[(1R,5S)-3-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-7-fluoro-indazol-5-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (11.6 mg, 27.85 μmol, 28.84% yield). MS: m / z 417.3 [M+H] + ;RT 1.11 min (Method 4).

[0391] Example 48 - Compounds 374 and / or 375 [ka] Step a: tert-Butyl 4-(6-bromo-4-fluoro-benzotriazol-2-yl)piperidine-1-carboxylate (362.06 mg, 734.53 μmol) was dissolved in dioxane (3.67 mL), followed by the addition of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (279.79 mg, 1.10 mmol) and potassium acetate (144.17 mg, 1.47 mmol). The solution was then sparged with nitrogen, followed by the addition of Pd(dppf)Cl CHCl (29.99 mg, 36.73 μmol). The solution was then stirred at 100 °C for 1 h, concentrated in vacuo, and the crude material was loaded onto normal phase and purified with 0-25% MeOH:DCM. The product elutes with 15% MeOH over 12 minutes. The identified fractions were combined and concentrated to give tert-butyl 4-[4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazol-2-yl]piperidine-1-carboxylate (430.1 mg, 85.28% yield). MS: m / z 391.2 [M+H-tBu] + ;RT 1.15 minutes (method 4).

[0392] Step b: tert-Butyl 4-[4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazol-2-yl]piperidine-1-carboxylate (390.26 mg, 874.39 μmol), 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (313.22 mg, 1.05 mmol, hydrobromide), and cesium carbonate (1.14 g, 3.50 mmol) were dissolved in dioxane (3.28 mL) and water (1.09 mL). The solution was then sparged with nitrogen, followed by the addition of Pd(dppf)Cl CHCl (71.41 mg, 87.44 μmol). The solution was then stirred at 110 °C for 16 h, then concentrated and dry-loaded onto normal phase silica and purified with 0-25% MeOH:DCM over 12 min. The product eluted with 13% MeOH. The identified fractions were collected, combined, and concentrated to give tert-butyl 4-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-benzotriazol-2-yl]piperidine-1-carboxylate (214.9 mg, 48.03% yield). MS: m / z 501.2 [M+H] + ;RT 0.69 minutes (method 4).

[0393] Step c: tert-Butyl 4-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-benzotriazol-2-yl]piperidine-1-carboxylate (214.9 mg, 419.94 μmol) was dissolved in DCM (908.87 μL), followed by addition of HCl (4 M, 4.20 mmol, 1.05 mL). The solution immediately became fuming and cloudy, then stirred at 40° C. for 16 hours, at which point a precipitate formed. The solution was then diluted with diethyl ether, causing the formation of a further amount of precipitate, which was filtered off. The precipitate was washed several times with diethyl ether and then redissolved in DMSO, water, and methanol. It was then filtered and purified by reverse-phase basic HPLC (column: XSelect CSH Prep C18 5 μm OBD 19 × 100 mm; mobile phase A: MeCN; mobile phase B: HO, modifier: 0.1% NH4OH). The identified fractions were collected, concentrated, and directly submitted for registration. 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-(4-piperidyl)benzotriazole (99.1 mg, 57.62% yield) was obtained as a white powder. 1H NMR (400 MHz, methanol-d4) δ ppm 2.22 - 2.39 (m, 4 H) 2.51 - 2.56 (m, 3 H) 2.82 - 2.92 (m, 2 H) 3.21 - 3.29 (m, 2 H) 5.00 - 5.10 (m, 1 H) 7.15 - 7.42 (m, 1 H) 7.89 - 7.94 (m, 1 H) 8.03 - 8.05 (m, 1 H) 8.10 - 8.12 (m, 1 H) 8.43 - 8.45 (m, 1 H). MS:m / z 402.2 [M+H ]+ ;RT 0.52 min (method 4).

[0394] Step d: 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-(4-piperidyl)benzotriazole (50 mg, 117.09 μmol) was dissolved in acetonitrile (537.93 μL) and then triethyl ether (TEA) (23.70 mg, 234.19 μmol) was added. The solution was stirred for 1 minute, followed by the addition of paraformaldehyde (140.46 mg, 117.09 μmol) and acetic acid (35.16 mg, 585.47 μmol). The solution immediately began to smoke and was stirred at room temperature for 10 minutes before the addition of sodium cyanoborohydride (14.72 mg, 234.19 μmol). The solution was then stirred for 30 minutes, concentrated, and then recovered with DMSO and filtered. The crude was then injected into reverse phase and purified by HPLC purification (column: Sunfire C18 100 × 19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: HO; modifier: 0.1% TFA) to give 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-(1-methyl-4-piperidyl)benzotriazole (21.7 mg, yield 30.45%). 1H NMR (400 MHz, methanol-d4 ) δ ppm 2.56 - 2.57 (m, 3 H) 2.59 - 2.65 (m, 2 H) 2.70 - 2.77 (m, 2 H) 2.99 - 3.01 (m, 3 H) 3.37 - 3.43 (m, 2 H) 3.58 - 3.64 (m, 1 H) 3.76 - 3.83 (m, 2 H) 7.31 - 7.34 (m, 1 H) 7.98 - 8.02 (m, 1 H) 8.14 - 8.17 (m, 1 H) 8.19 - 8.21 (m, 1 H) 8.50 - 8.53 (m, 1 H).MS:m / z 416.2 [M+H ]+ ;RT 0.55 min (method 4).

[0395] Using the procedure described for Example 17 above, additional compounds described herein were prepared by substituting the appropriate boronic ester starting material, suitable reagents, and reaction conditions in step b to provide compounds such as those selected from the following: [Table 40-1] [Table 40-2]

[0396] Example 48: Compound 380 [ka] Step a: To a stirred solution of tert-butyl 4-(6-bromo-4-fluoro-benzotriazol-2-yl)piperidine-1-carboxylate (0.1 g, 250.47 umol, 1.0 equiv) in DCM (5 mL, 0.05 M) was added HCl / EtOAc (35 mg, 1 mmol, 4 equiv). The reaction mixture was stirred at room temperature for 1 hour. The mixture was filtered and concentrated to give a residue. The crude compound was used in the next step without further purification. 6-Bromo-4-fluoro-2-(4-piperidyl)benzotriazole (0.05 g, 59.86% yield) was obtained as a white solid. MS: m / z 299.9 [M+H] + ;RT 0.29 min (Method 9).

[0397] Step b: To a stirred solution of 6-bromo-4-fluoro-2-(4-piperidyl)benzotriazole (0.065 g, 217.29 μmol, 1.0 equiv) in 1,2-dichloroethane (1 mL, 0.2 M) and EtOH (5 mL, 0.04 M) was added paraformaldehyde (260.65 mg, 217.29 μmol, 1.0 equiv) and TEA (43.97 mg, 434.58 μmol, 2.0 equiv). The mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (92.10 mg, 434.58 μmol, 2.0 equiv) was then added. After stirring at room temperature for 30 minutes, the mixture was filtered and concentrated to give a residue. 6-Bromo-4-fluoro-2-(1-methyl-4-piperidyl)benzotriazole (35 mg, 110.98 μmol, 51.07% yield, 99.3% purity) was obtained as a white solid. MS: m / z 314.8 [M+H] +;RT 0.32 minutes (Method 9).

[0398] Step c: To a stirred solution of 6-bromo-4-fluoro-2-(1-methyl-4-piperidyl)benzotriazole (20 mg, 63.86 μmol, 1.0 equiv.) in dioxane (2.5 mL, 0.02 M) and water (0.5 mL, 0.02 M), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (46.73 mg, 63.86 μmol, 0.1 equiv.), KCO (8.83 mg, 63.86 μmol, 1.0 equiv.), and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (17.44 mg, 63.86 μmol, 1.0 equiv.) were added. The reaction mixture was stirred at 95° C. under N for 12 h. The mixture was filtered and concentrated to give a residue. The residue was purified by HPLC (column: XSelect CSH Prep C18 5um OBD 19x100mm; mobile phase A: MeCN; mobile phase B: HO, modifier: 0.1% NH4OH) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(1-methyl-4-piperidyl)benzotriazole (2.8mg, 7.34umol, 11.50% yield, 99.5% purity) as a white solid. MS: m / z 380.0 [M+H] + ;RT 0.26 min (Method 9).

[0399] Example 49 - Compound 339 [ka] Step a: To a stirred solution of 6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (650 mg, 2.51 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (388.95 mg, 2.26 mmol) in DMF (10 mL) was added HATU (1.14 g, 3.01 mmol) and DIPEA (972.95 mg, 7.53 mmol, 1.31 mL). The reaction was stirred at 20 °C for 1 h. The residue was triturated with EtOAc (20 mL) at 20 °C for 30 min. tert-Butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl)amino]azetidine-1-carboxylate (400 mg, 803.41 μmol, 32.02% yield) was obtained as a yellow solid.

[0400] Step b: To a stirred solution of tert-butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl)amino]azetidine-1-carboxylate (150 mg, 362.98 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (99.14 mg, 362.98 μmol) in dioxane (10 mL) and HO (2 mL), KCO (150.50 mg, 1.09 mmol) and Pd(dppf)Cl (26.56 mg, 36.30 μmol) were added. The reaction mixture was stirred at 90 °C for 2 h. The mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography (DCM / MeOH = 10 / 1 to 5 / 1, TLC: DCM / MeOH = 10 / 1, Rf = 0.66) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl]amino]azetidine-1-carboxylate (40 mg, 62.56 μmol, 17.24% yield, 75% purity) as a yellow solid. MS: m / z 480.2 [M+H] + ;RT:0.357 minutes (Method 9).

[0401] Step c: To a solution of tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl]amino]azetidine-1-carboxylate (50 mg, 104.27 μmol) in EtOAc (2 mL) was added HCl / EtOAc (2 mL). The reaction was stirred at 20 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxamide (40 mg, crude) as a yellow solid. MS: m / z 380.1 [M+H] + ;RT:0.243 minutes (method 9).

[0402] Step d: To a solution of N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxamide (20 mg, 52.72 μmol) in DCE / EtOH (5 mL) was added cyclopropanecarbaldehyde (5.54 mg, 79.07 μmol, 5.91 μL) and TEA (16.00 mg, 158.15 μmol, 22.04 μL). The reaction was stirred at 25° C. for 15 minutes, after which sodium triacetoxyborohydride (4.97 mg, 79.07 μmol) was added. The reaction was stirred at 25° C. for 12 hours. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (FA conditions) to give N-[1-(cyclopropylmethyl)azetidin-3-yl]-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxamide (4.49 mg, 10.03 μmol, 19.04% yield) as a white solid. MS: m / z 434.1 [M+H] + ;RT:1.432 minutes (method 10).

[0403] Using the procedure described for Example 49 above, additional compounds described herein were prepared by substituting the appropriate amine in step a and / or boronic ester starting material in step b, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 41]

[0404] Example 49 - Compound 338 [ka] Step a: To a solution of N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxamide (20 mg, 52.72 μmol), KCO (14.57 mg, 105.43 μmol) in DMF (5 mL) was added 1-iodo-2-methoxyethane (9.80 mg, 52.72 μmol). The reaction was stirred at 60° C. for 12 h. The mixture was filtered and concentrated under reduced pressure to give a residue that was purified by preparative HPLC to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-N-[1-(2-methoxyethyl)azetidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamide (3.38 mg, 7.04 μmol, 13.3% yield) as a yellow solid. MS: m / z 438.2 [M+H] + ;RT: 1.43 minutes (method 8).

[0405] Example 50 - Compound 208 [ka] Step a: To a solution of tert-butyl N-[3-(2-bromoacetyl)-1-bicyclo[1.1.1]pentanyl]carbamate (220 mg, 723.26 μmol, 1.0 equiv) and 5-bromo-3-fluoro-pyridin-2-amine (165.77 mg, 867.91 μmol, 1.2 equiv) in 2-methylpropan-2-ol (5 mL, 0.14 M) was added NaHCO (121.52 mg, 1.45 mmol, 2.0 equiv). The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE / EtOAc = 6 / 1 to 3 / 1, TLC: PE / EtOAc = 3 / 1, Rf = 0.3) to give tert-butyl N-[3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-bicyclo[1.1.1]pentanyl]carbamate (40 mg, 98.70 μmol, 27.29% yield, 97.78% purity) as a white solid. MS: m / z 398.0 [M+H] + ;RT:0.406 minutes (Method 9).

[0406] Step b: To a solution of tert-butyl N-[3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-bicyclo[1.1.1]pentanyl]carbamate (100 mg, 252.36 umol, 1.0 equiv) in THF (3 mL) was added NaH (18.17 mg, 757.09 umol, 3.0 equiv) and MeI (70.75 mg, 504.73 umol, 2.0 equiv) at 0° C. The reaction was stirred at 20° C. for 3 h. The reaction mixture was diluted with HO (20 mL), extracted with EtOAc (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give tert-butyl N-[3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-carbamate (100 mg, 209.04 μmol, 82.83% yield) as a yellow solid. MS: m / z 410.0 [M+H] + ;RT:0.543 minutes (Method 9).

[0407] Step c: To a solution of tert-butyl N-[3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-carbamate (100 mg, 243.74 μmol, 1.0 equiv) in EtOAc (3 mL, 0.04 M) was added HCl / EtOAC (3 mL, 0.04 M). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-N-methyl-bicyclo[1.1.1]pentan-1-amine (60 mg, 193.45 μmol, 79.37% yield) as a yellow solid. MS: m / z 312.0 [M+H] + ;RT:0.251 minutes (Method 9).

[0408] Step d: To a solution of 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-N-methyl-bicyclo[1.1.1]pentan-1-amine (40 mg, 128.96 μmol, 1.0 equiv.) in MeOH (2 mL, 0.064 M), (1-ethoxycyclopropoxy)-trimethyl-silane (33.72 mg, 193.45 μmol, 1.5 equiv.), TEA (13.05 mg, 128.96 μmol, 1.0 equiv.), and sodium; cyanoboranide (12.97 mg, 206.34 μmol, 1.6 equiv.) were added and stirred at 20° C. for 20 minutes. Then, acetic acid (23.23 mg, 386.89 μmol, 3.0 equiv.) was added, and the mixture was stirred at 60° C. for 16 hours. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA conditions) to give 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-N-cyclopropyl-N-methyl-bicyclo[1.1.1]pentan-1-amine (35 mg, 99.51 μmol, 77.16% yield) as a yellow oil. MS: m / z 349.9 [M+H] + ;RT:0.241 minutes (Method 9).

[0409] Step e: To a solution of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (27.30 mg, 99.93 umol, 1.0 equiv) and 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-N-cyclopropyl-N-methyl-bicyclo[1.1.1]pentan-1-amine (35 mg, 99.93 umol, 1.0 equiv) in dioxane / HO (5 mL, 0.02 M) was added cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (7.31 mg, 9.99 umol, 0.1 equiv) and KCO (41.43 mg, 299.80 umol, 3.0 equiv) under N. The reaction mixture was stirred at 90 °C for 2 hours. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions) to give N-cyclopropyl-3-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-N-methyl-bicyclo[1.1.1]pentan-1-amine (13.1 mg, 30.80 µmol, 30.82% yield) as a yellow solid. MS: m / z 417.2 [M+H] + ;RT: 1.02 minutes (method 8).

[0410] Example 51 - Compound 335 [ka] Step a: To a solution of 5-bromo-3-fluoropyridin-2-amine (25 g, 130.89 mmol, 1.0 equiv) in EtOH (300 mL, 0.44 M) was added ethyl 3-bromo-2-oxopropanoate (25.52 g, 130.89 mmol, 1.0 equiv). The mixture was stirred at 78 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was washed with saturated NaHCO (400 mL * 1) and extracted with (3 × 500 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude material was purified by silica gel column chromatography (pure DCM to DCM / MeOH=10 / 1, TLC: PE / EA=5 / 1, Rf=0.2) to give ethyl 6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylate (15 g, 52.25 mmol, 39.92% yield) as a white solid. MS: m / z 288.9 [M+H] + ;RT:0.37 minutes (Method 9).

[0411] Step b: To a solution of ethyl 6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylate (800 mg, 2.79 mmol, 1.0 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (849.16 mg, 3.34 mmol, 1.2 equiv.) in dioxane (10 mL, 0.28 M), KOAc (546.96 mg, 5.57 mmol, 2.0 equiv.) and Pd(dppf)Cl (203.90 mg, 278.66 mmol, 0.1 equiv.) were added under N. The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give (2-ethoxycarbonyl-8-fluoro-imidazo[1,2-a]pyridin-6-yl)boronic acid (600 mg, crude, 85% yield) as a black solid. MS: m / z 253.0 [M+H] + ;RT:0.26 minutes (Method 9).

[0412] Step c: To a solution of (2-ethoxycarbonyl-8-fluoro-imidazo[1,2-a]pyridin-6-yl)boronic acid (600 mg, 2.38 mmol, 1.0 equiv.) and 6-chloro-2,8-dimethyl-imidazo[1,2-b]pyridazine (432.42 mg, 2.38 mmol, 1.0 equiv.) in dioxane (5 mL, 0.4 M) and HO (1 mL, 0.4 M), KCO (987.19 mg, 7.14 mmol, 3.0 equiv.) and Pd(dppf)Cl (174.21 mg, 238.09 mmol, 0.1 equiv.) were added under N. The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (PE / EtOAc 10 / 1 to 5 / 1, TLC: PE / EtOAc 3 / 1, Rf = 0.25) to give ethyl 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylate (600 mg, 1.25 mmol, 52.59% yield) as a yellow solid. MS: m / z 354.0 [M+H] + ;RT:0.29 minutes (Method 9).

[0413] Step d: To a solution of ethyl 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylate (300 mg, 849.02 μmol, 1.0 equiv) in MeOH (2 mL, 0.34 M) was added NaOH (101.88 mg, 2.55 mmol, 0.3 equiv) in HO (0.5 mL, 0.34). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by adding 1 N HCl at 0 °C to pH = 5 and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (270 mg, crude, 98% yield) as a yellow solid. MS: m / z 326.0 [M+H] + ;RT:0.33 minutes (Method 9).

[0414] Step e: To a solution of 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (40 mg, 122.96 umol, 1.0 equiv) in pyridine (5 mL, 0.025 M) was added tert-butyl-2-(aminomethyl)piperidine-1-carboxylate (52.70 mg, 245.93 umol, 2.0 equiv) and EDCl (28.29 mg, 147.56 umol, 1.2 equiv). The reaction mixture was stirred at 80° C. for 12 hours. The mixture was filtered and concentrated to give a residue. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (DCM / MeOH=10 / 1, TLC: DCM / MeOH=10 / 1, Rf=0.30). tert-Butyl (2R)-2-[[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl]amino]methyl]piperidine-1-carboxylate (25 mg, 42.66 μmol, 34.69% yield) was obtained as a yellow solid. MS: m / z 522.4 [M+H] + ;RT:0.48 minutes (Method 9).

[0415] Step f: A solution of tert-butyl (2R)-2-[[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl]amino]methyl]piperidine-1-carboxylate (25 mg, 47.93 μmol, 1.0 equiv) in HCl / EtOAc (3 mL, 0.016 M) was stirred at 25° C. for 1 h. The mixture was filtered and concentrated to give a residue. The crude compound was used in the next step without further purification. 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-N-[[(2R)-2-piperidyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide (15 mg, 34.52 μmol, 72.02% yield) was obtained as a yellow solid. MS: m / z 422.2 [M+H] + ;RT:0.28 minutes (Method 9).

[0416] Step g: To a solution of 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-N-[[(2R)-2-piperidyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide (15 mg, 35.59 μmol, 1.0 equiv) in DCE / EtOH (3 mL, 0.012 M) was added paraformaldehyde (64.04 mg, 53.38 μmol, 1.5 equiv) and acetic acid (6.41 mg, 106.77 μmol, 3.0 equiv). The reaction mixture was stirred at 25° C. for 10 minutes, and then sodium triacetoxyboranide (11.31 mg, 53.38 μmol, 1.5 equiv) was added, and the reaction mixture was stirred at 25° C. for 12 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC (NH4HCO3 condition). 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-N-[[(2R)-1-methyl-2-piperidyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide (3.5 mg, 7.70 μmol, 21.64% yield) was obtained as a yellow solid. MS: m / z 436.2 [M+H] + ;RT:2.51 minutes (method 8). [Table 42]

[0417] Example 52 - Compound 540 [ka] Step a: To a solution of tert-butyl-6-(6-bromo-8-methoxy-imidazo[1,2-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (190 mg, 465.36 umol, 1.0 equiv) in dioxane (5 mL, 0.093 M) was added KOAc (137.01 mg, 1.40 mmol, 3.0 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (129.99 mg, 511.89 umol, 1.1 equiv) and cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (68.10 mg, 93.07 umol, 0.2 equiv). The mixture was stirred at 90° C. under N for 12 h. The crude compound was used in the next step without further purification. MS: m / z 455.9 [M+H] + ;RT:0.56 minutes (Method 9).

[0418] Step b: tert-Butyl-6-[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 219.61 μmol, 1.0 μg) in dioxane (5 mL, 0.037 M) and HO (1 mL 0.037 M). To a solution of 1,000 sachets ... The compound tert-butyl-6-[6-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-8-methoxy-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (19 mg, 40.04 μmol, 18.23% yield). MS: m / z 511.3 [M+H] + ;RT:0.38 minutes (Method 9).

[0419] Step c: To a solution of tert-butyl-6-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (12 mg, 23.50 μmol, 1.0 equiv) in HCl / EtOAc (2 mL, 0.012 M). The mixture was stirred at 25° C. for 8 hours. The mixture was filtered and concentrated to give a residue. The crude compound was used in the next step without further purification. Compound 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-6-yl]-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (8 mg, 19.49 μmol, 82.93% yield). MS: m / z 411.1 [M+H] + ;RT:0.24 minutes (Method 9).

[0420] Step d: To a solution of 6-[2-[3-azabicyclo[3.1.0]hexan-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-6-yl]-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (8 mg, 19.49 μmol, 1.0 equiv) in DCE / EtOH (4 mL, 0.004 M) was added paraformaldehyde (23.38 mg, 19.49 μmol, 1.0 equiv). The mixture was stirred at 25° C. for 10 minutes. Then, sodium triacetoxyboranide (12.39 mg, 58.48 μmol, 3.0 equiv) was added. The mixture was stirred at 25° C. for 2 hours. LCMS showed that the mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC (basic conditions). The compound 8-(difluoromethyl)-6-[8-methoxy-2-[3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (6.71 mg, 15.81 μmol, 81.10% yield) was obtained as a white solid. MS: m / z 425.2 [M+H] + ;RT:0.75 minutes (method 10).

[0421] Using the procedure described for Example 52 above, additional compounds described herein were prepared by substituting the appropriate boronic ester starting material, suitable reagents, and reaction conditions in step b to provide compounds such as those selected from the following: [Table 43]

[0422] Example 53 - Compound 290 [ka] Step a: A mixture of tert-butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)carbamoyl]azetidine-1-carboxylate (60 mg, 145.19 μmol, 1.0 equiv.) and TFA (1.49 g, 13.06 mmol, 90 equiv.) in DCM (3 mL 0.05 M) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)azetidine-3-carboxamide (30 mg, 95.81 μmol, 65.99% yield) as a yellow solid. MS: m / z 313.0 [M+H] + ;RT: 1.72 minutes (method 10).

[0423] Step b: To a solution of N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)azetidine-3-carboxamide (30 mg, 95.81 μmol, 1.0 equiv) in EtOH (3 mL, 0.032 M), acetone (5.56 mg, 95.81 μmol, 1.0 equiv), DCE (18.96 mg, 191.62 μmol, 2.0 equiv), and acetic acid (17.26 mg, 287.42 μmol, 3.0 equiv) were added, and the mixture was stirred at 25° C. for 20 minutes. Sodium triacetoxyboranide (32.49 mg, 153.29 μmol, 1.6 equiv) was added, and the mixture was stirred at 25° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC to give N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-isopropyl-azetidine-3-carboxamide (30 mg, 84.46 μmol, 88.15% yield) as a yellow solid. MS: m / z 357.0 [M+H] + ;RT:0.94 minutes (method 10)

[0424] Step c: To a solution of N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-isopropyl-azetidine-3-carboxamide (10 mg, 28.15 μmol) and [8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]boronic acid (12.78 mg, 56.31 μmol, 1.0 equiv.) in dioxane (3 mL, 0.007 M) and water (1 mL, 0.007 M), Pd(dppf)Cl (2.06 mg, 2.82 μmol, 0.1 equiv.) and KCO (7.78 mg, 56.31 μmol, 2.0 equiv.) were added. The mixture was stirred under nitrogen at 90 °C for 2 hours. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um; condition: water (FA)-ACN, start B8, end B38; gradient time (min): 14; 100% B retention time (min): 2; flow rate (ml / min): 25) to give N-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-1-isopropyl-azetidine-3-carboxamide (3.3 mg, 7.21 μmol, 25.62% yield) as a yellow solid. MS: m / z 458.2 [M+H] + ;RT:1.12 minutes (method 10)

[0425] Using the procedure described for Example 53 above, additional compounds described herein were prepared by substituting the appropriate amine in step c and / or boronic ester starting material in step b, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 44]

[0426] Example 54 - Compound 411 [ka] Step a: To a solution of 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-(4-piperidyl)benzotriazole (20 mg, 49.83 μmol, 1.0 equiv.) in MeCN (2 mL, 0.025 M) was added KCO (13.77 mg, 99.65 μmol, 2.0 equiv.) and 1-bromo-2-methoxyethane (6.93 mg, 49.83 μmol, 1.0 equiv.). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (neutral conditions) to give 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-[1-(2-methoxyethyl)-4-piperidyl]benzotriazole (14.9 mg, 31.61 μmol, 63.44% yield) as a yellow solid. MS: m / z 460.1 [M+H] + ;RT: 1.35 minutes (method 8) [Table 45]

[0427] Example 55 - Compound 457 [ka] Step a: To a solution of 6-bromo-2-chloro-4-fluoro-1,3-benzoxazole (200 mg, 798.56 μmol) and 8-methyl-2,8-diazaspiro[4.5]decane (123.18 mg, 798.56 μmol) in dioxane (8 mL) was added TEA (242.42 mg, 2.40 mmol, 333.91 μL). The mixture was stirred at 100 °C for 2 h. The reaction was filtered and concentrated. The residue was purified by flash silica gel chromatography (MeOH / EtOAc = 0 / 100 to 20 / 80) to give the product as a yellow solid (250 mg, 678.9 μmol, 85% yield). MS: m / z 369.8 [M+H] + .

[0428] Step b: To a solution of 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)-1,3-benzoxazole (200 mg, 543.12 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (179.29 mg, 706.06 μmol) in dioxane (20 mL), KOAc (159.91 mg, 1.63 mmol) and Pd(dppf)Cl (39.74 mg, 54.31 μmol) were added. The mixture was stirred at 90 °C under nitrogen for 2 hours. The crude compound was used in the next step without further purification.

[0429] Step c: To a solution of 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (30.67 mg, 140.95 μmol) and 2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (56 mg, 140.95 μmol) in dioxane (3 mL) and water (1 mL) was added KCO (38.96 mg, 281.89 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (20.63 mg, 28.19 μmol).

[0430] The mixture was stirred under nitrogen at 90°C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (Column: Boston Green ODS 150*30mm*5um; Conditions: Water (FA)-ACN, Start B16, End B46; Gradient time (min): 18; 100% B retention time (min): 2; Flow rate (ml / min): 25) to give 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-2-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)-1,3-benzoxazole (7.6 mg, 16.80 μmol, 11.92% yield, 100% purity) as a yellow solid. MS: m / z 453.3 [M+H] +;RT:1.403 minutes (method 10)

[0431] Example 56 - Compound 531 [ka] Step a: To a solution of 6-bromo-4-fluoro-1,3-benzoxazole-2-carboxylic acid (100 mg, 384.59 μmol) in pyridine (1 mL), tert-butyl 3-aminoazetidine-1-carboxylate (79.48 mg, 461.51 μmol) and EDCI (147.45 mg, 769.18 μmol) were added. The reaction was stirred at 90° C. for 1 hour. The mixture was then concentrated, and water (80 mL) was added. The residue was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by Combi-Flash (DCM / MeOH=10 / 1) to give tert-butyl 3-[(6-bromo-4-fluoro-1,3-benzoxazole-2-carbonyl)amino]azetidine-1-carboxylate (100 mg, 241.41 μmol, 62.77% yield) as a yellow solid. MS: m / z 417.0 [M+H] + .

[0432] Step b: To a solution of tert-butyl 3-[(6-bromo-4-fluoro-1,3-benzoxazole-2-carbonyl)amino]azetidine-1-carboxylate (30 mg, 72.42 μmol) in dioxane (5 mL) and water (0.5 mL), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (19.78 mg, 72.42 μmol), Pd(dppf)Cl (5.30 mg, 7.24 μmol), and KCO (30.03 mg, 217.27 μmol) were added under N under N. The reaction was stirred at 90 °C for 2 h. The mixture was concentrated, and then water (80 mL) was added. The residue was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (FA) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-1,3-benzoxazole-2-carbonyl]amino]azetidine-1-carboxylate (20 mg, 41.62 μmol, 57.47% yield) as a brown solid. MS: m / z 481.2 [M+H] + .

[0433] Step c: To a solution of tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-1,3-benzoxazole-2-carbonyl]amino]azetidine-1-carboxylate (10 mg, 20.81 μmol) in TFA (1 mL) was added DCM (2 mL). The mixture was stirred at 20 °C for 1 h and then concentrated in vacuo to give N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-1,3-benzoxazole-2-carboxamide (10 mg, crude) as a yellow solid. MS: m / z 381.1 [M+H] + .

[0434] Step d: To a solution of N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-1,3-benzoxazole-2-carboxamide (10 mg, 26.29 μmol) in EtOH (2 mL) and DCE (0.5 mL) was added TEA (5.32 mg, 52.58 μmol, 7.33 μL) and acetone (1.53 mg, 26.29 μmol, 1.93 μL). The reaction was stirred at 20° C. for 10 minutes. Sodium triacetoxyborohydride (11.14 mg, 52.58 μmol) was then added, and the reaction was stirred at 20° C. for an additional 0.5 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by preparative HPLC (FA) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-N-(1-isopropylazetidin-3-yl)-1,3-benzoxazole-2-carboxamide (1 mg, 2.37 μmol, 9.00% yield) as a white solid. MS: m / z 423.2 [M+H] + ;RT:0.92 minutes (method 10).

[0435] Example 57 - Compound 245 [ka] Step a: 5-Bromo-3-fluoro-pyridin-2-amine (1 g, 5.24 mmol) and ethyl 2-bromoacetate (2.62 g, 15.71 mmol, 1.74 mL) were added to a 20 mL microwave vial. The reaction was stirred at 90 °C for 3 hours. The resulting pinkish solid was filtered and added to another 20 mL microwave vial, followed by phosphoryl trichloride (16.06 g, 104.71 mmol, 9.76 mL). The mixture was stirred at 90 °C overnight. The residue was transferred to a 500 mL round-bottom flask. Methanol was slowly added to quench the POCl3 until gas evolution ceased, and the resulting suspension was concentrated, redissolved in heptane, and filtered to give 6-bromo-2-chloro-8-fluoro-imidazo[1,2-a]pyridine (1.33 g, 5.34 mmol, 100% yield) as a yellow solid. MS: m / z 250.9 [M+H]+ .

[0436] Step b: A 20 mL microwave vial was charged with Pd(dppf)Cl (130.94 mg, 160.34 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (481.75 mg, 1.76 mmol), evacuated, and refilled with N three times. A solution of 6-bromo-2-chloro-8-fluoro-imidazo[1,2-a]pyridine (400 mg, 1.60 mmol) in dioxane (4 mL) (purged with N) and a solution of dicesium carbonate (1.57 g, 4.81 mmol) in water (purged) were added to the vial under N. The mixture was stirred at 90 °C for 16 h. The residue was concentrated to V10 and purified by column chromatography (EA / hexane, 0–100%, 20 min) to give 6-(2-chloro-8-fluoro-imidazo[1,2-a]pyridin-6-yl)-2,8-dimethyl-imidazo[1,2-b]pyridazine (253 mg, 801.31 μmol, 49.98% yield) as a pale solid. MS: m / z 316.0 [M+H] + .

[0437] Step c: 6-(2-chloro-8-fluoro-imidazo[1,2-a]pyridin-6-yl)-2,8-dimethyl-imidazo[1,2-b]pyridazine (25 mg, 79.18 μmol), 8-methyl-2,8-diazaspiro[4.5]decane (30.20 mg, 158.36 μmol, hydrochloride), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (7.25 mg, 7.92 μmol) and sodium; 2-methylpropane-2-olate (45.66 mg, 475.09 μmol) were added to a microwave vial, evacuated and refilled with N three times, and then dioxane (1 mL) was added. The reaction mixture was stirred at 90 °C for 12 hours. The residue was concentrated in vacuo and purified by HPLC (Column: Sunfire C18 100 × 19 mm, 5 mm; Mobile Phase A: MeCN; Mobile Phase B: HO; Modifier: 0.1% TFA) to give 2-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-8-methyl-2,8-diazaspiro[4.5]decane (1.5 mg, 2.74 μmol, 3.46% yield, trifluoroacetic acid) as an orange solid. MS: m / z 434.3 [M+H] + ;RT:0.35 minutes (method 4).

[0438] Example 58 - Compound 349 [ka] Step a: To a mixture of ethyl 6-chloro-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (90 mg, 369.42 μmol, 1.0 equiv.), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (100.90 mg, 369.42 μmol, 1.0 equiv.) in dioxane (10 mL, 0.037 M), Pd(dppf)Cl (27.03 mg, 36.94 μmol, 0.1 equiv.), KCO (153.17 mg, 1.11 mmol, 3.0 equiv.) were added and stirred at 90° C. under N for 2 h. The reaction mixture was then quenched with water (50 mL). The aqueous layer was separated and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product. The mixture was further purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give ethyl 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (103 mg, 290.68 μmol, 78.69% yield) as a brown solid. MS: m / z 355.2 [M+H] + ;RT: 1.58 minutes (method 10).

[0439] Step b: A mixture of ethyl 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (100 mg, 282.22 μmol, 1.0 equiv) in MeOH (8 mL, 0.018 M) and HO (8 mL, 0.018 M) containing NaOH (56.44 mg, 1.41 mmol, 5.0 equiv) was stirred at 25 °C for 2 h. The reaction mixture was quenched with dilute hydrochloric acid (1 mol / L, 5 mL) and water (50 mL). The aqueous layer was separated and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give crude 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (90 mg, 275.83 μmol, 97.74% yield) as a white solid. MS: m / z 327.0 [M+H] + ;RT: 1.05 minutes (method 10).

[0440] Step c: To a mixture of 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (90 mg, 275.83 μmol, 1.0 equiv.) and tert-butyl 3-aminoazetidine-1-carboxylate (47.51 mg, 275.83 μmol, 1.0 equiv.) in pyridine (5 mL, 0.055 M), EDCl (158.63 mg, 827.50 μmol, 3.0 equiv.) was added in one portion at 25°C under N2. The mixture was stirred at 90°C for 2 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (40 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Boston Green ODS 150*30 mm*5 um; condition: water (FA)-ACN; start B20; end B50; gradient time (min) 12; 100% B retention time (min) 2; flow rate (ml / min) 25) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carbonyl]amino]azetidine-1-carboxylate (43 mg, 89.49 μmol, 32.44% yield) as a yellow solid. MS: m / z 481.2 [M+H] + ;RT: 1.09 minutes (method 10).

[0441] Step d: To tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carbonyl]amino]azetidine-1-carboxylate (40 mg, 83.25 μmol, 1.0 equiv) in DCM (3 mL, 0.028 M) was added TFA (47.46 mg, 416.24 μmol, 5.0 equiv) in one portion at 25° C. The mixture was stirred for 16 h. The reaction mixture was concentrated to give crude N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (30 mg, 78.87 μmol, 94.74% yield) as a yellow solid. The crude material was used directly in the next step. MS: m / z 381.2 [M+H] + ;RT:0.89 minutes (method 10).

[0442] Step e: To a mixture of N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (30 mg, 78.87 μmol, 1.0 equiv.) and acetone (22.90 mg, 394.34 μmol, 5.0 equiv.) in EtOH (10 mL, 0.008 M), TEA (39.90 mg, 394.34 μmol, 54.96 μL, 5.0 equiv.) was added. The solution was then stirred for 5 minutes, after which acetic acid (23.68 mg, 394.34 μmol, 5.0 equiv.) was added. After 30 minutes, sodium triacetoxyboranide (50.15 mg, 236.61 μmol, 3.0 equiv) was added in one portion at 25° C. The mixture was stirred at 25° C. for 3 hours. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; conditions: water (FA)-ACN; start B 0; end B 30; gradient time (min) 11; 100% B retention time (min) 2; flow rate (ml / min) 25) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-N-(1-isopropylazetidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (17.2 mg, 40.71 μmol, 51.62% yield) as a white solid. MS: m / z 423.2 [M+H] + ;RT: 1.64 minutes (method 10).

[0443] Section 3. Biological Assays and Data HTT mutant and whole HTRF iPSC assay protocol This in vitro cell assay measures mutant and total HTT protein in induced pluripotent stem cells (iPSCs) derived from HTT (Huntington's) patients with a polyQ49 mutation. Assay measurements were performed by homogeneous time-resolved fluorescence (HTRF). The mutant HTT antibody was labeled with a d2 acceptor and recognizes a portion within the polyQ region. The terbium (Tb) donor antibody recognizes a sequence at the N-terminus of the protein. The total HTT antibody was labeled with a d2 acceptor and recognizes a sequence beyond the polyQ region. For each experiment, frozen aliquots of iPSCs were thawed from liquid nitrogen storage and grown in Matrigel (Corning #354227)-coated flasks using complete medium (mTeSR™1 Plus (STEMCELL Technologies Cat. No. 05852) and supplemented with penicillin / streptomycin (Gibco Cat. No. 10378016) (mTeSR™1 Plus Basal Medium (STEMCELL Technologies Cat. No. 05825)) in the presence of 10 μM Rock Inhibitor (Sigma #Y0503). Flasks containing cells were incubated overnight at 37°C, 5% CO2 (Thermo). The next day, the medium was replaced with fresh complete medium without Rock Inhibitor and incubated for 48 hours at 37°C, 5% CO2 for cell expansion. Cells were harvested from the flasks using Accutase (Gibco #A1110501) and placed on a Cellometer (Nexcelom). Cells were counted using a 3D Imaging System (Vision). A total of 10,000 cells / well were added to a Matrigel-precoated 384-well tissue culture plate (Perkin Elmer #NC1758152) containing 30 μl of complete medium containing 10 μM of ROCK inhibitor. The cell plate was centrifuged, and the cells were allowed to adhere overnight at 37°C and 5% CO2 in a humidified incubator (Thermo Cytomat10). The following day, cells were treated with compound. Intermediate plates were used to pre-dilute compounds in complete medium without ROCK inhibitor.Compounds were diluted and dispensed into empty 384-well PP plates (Griener #784201) using an ECHO (Labcyte #Echo555). A total of 60 μl of complete medium was added per well using a Multidrop Combi (Thermo #5840300). Compounds were tested in a 10-point, 3-fold titration starting at 10 μM. Media was removed from the cell plates by flicking, and the plates were blotted onto tissue paper. A 50 μL volume was transferred from the compound plate to the cell assay plate using an Integra (Viaflow384). The cell plates were incubated at 37°C, 5% CO2, and high humidity for 48 hours. Cell lysates were prepared by first removing the media from the plates and then adding 40 μl per well of MPER lysis buffer (Thermo #78501) containing protease and phosphatase inhibitors (Pierce #A32961). The plate was placed on an orbital shaker for 30 minutes at room temperature, and 5 μl of cell lysate was transferred to two 384-well black plates (Sigma Aldrich #CLS3821) using an apricot dispenser (SPT Labtech). Each plate contained either 5 μl / well of mutant HTT HTRF assay mix or 5 μl / well of the entire HTT HTRF assay mix. The mutant HTT HTRF assay mix contained the 2B7Ab-Tb "donor" antibody (Thermo #CHDI-9000830) N-terminally labeled antibody at a final concentration of 0.4 ng / well and the MW1 (polyQ-specific)-d2 "acceptor" antibody (Sigma #MABN2427) at a final concentration of 40 ng / well in HTRF detection buffer (CisBio #62SDBRDF). The total HTT HTRF assay mix contained the 2B7Ab-Tb "donor" N-terminally labeled antibody at a final concentration of 0.4 ng / well and the MAB2166-d2 (anti-huntingtin [1HU-4C8] mAb-d2 "acceptor" antibody at a final concentration of 40 ng / well in HTRF detection buffer. All antibodies were labeled at Perkin Elmer. The assay plate was sealed and placed on an orbital shaker for 1 min, then centrifuged for 1 min before being incubated at room temperature for 4 h.The plates were read on a PHERAstar instrument (BMG LAB TECH) and the HTRF ratio was calculated from the (337nm / 665nm) and (337nm / 620nm) outputs. IC from the full concentration response curve. 50 Values were generated and curves were plotted as percent activity versus compound concentration fitted to a variable four-parameter logistic model.

[0444] I C 50 A summary of the results is shown in Table 2. "A" indicates an IC<100 nM 50 "B" represents the IC value between 100 nM and 1 µM 50 "C" represents the IC value, ranging from 1 µM to 9 µM 50 Represents a value. [Table 46-1] [Table 46-2] [Table 46-3] [Table 46-4] [Table 46-5] [Table 46-6]

Claims

1. Formulas (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX): 【Chemistry 1】 Compounds of or pharmaceutically acceptable salts thereof (wherein the formula, R ５ It is a halo, R ６ is A, -N(R ６ａ )C(=O)-A, or -C(=O)N(R ６ａ ) - A, R ７ B is, and furthermore Regarding equations (II) and (VII), R ６ B is R ７ A is, and here, R ６ａ is H or C １－３ alkyl, A is -C １－６ Alkylene-NR ９ R １０ , 4-10 member saturated carbocyclyl, Het or -C １－６ Alkylene-Het, and here, R ９ is H or C １－６ It is alkyl, R １０ H, C １－６ Alkyl or -C １－６ Alkylene-Het １ And here, Het １ It is a saturated heterocycline with 4 to 6 members. Het is a 4- to 10-membered saturated heterocycline, provided that the 4- to 10-membered saturated heterocycline represented by Het does not contain a ring N atom, then -NR ９ R １０ Substituted by, 1-2 R １１ If the 4-10 member saturated heterocycline represented by Het is further optionally substituted, then 1-3 R １１ Replaced by optional selection, The 4-10 member saturated carbocyclyl represented by A is -NR ９ R １０ Substituted by, 1-2 R １１ Then, by optional selection, it is further replaced, and here, R １１ Each time it appears, Halo, -C(=O)R １２ , C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy C １－６ Alkyl and C ３－６ Selected independently from cycloalkyl, where R １１ The C represented by ３－６ Cycloalkyls are halo and C １－６ Optionally substituted with one or more substituents independently selected from the alkyl group, where R １２ H, C １－３ Alkyl, or C ３－６ It is a cycloalkyl, B is a 6-10 member aryl, a 4-10 member heterocyclyl, or a 5-10 member heteroaryl, where the 6-10 member aryl, the 4-10 member heterocyclyl, and the 5-10 member heteroaryl represented by B are one or more R ８ It is optionally replaced by, here, R ８ is halo, -CN, -OH, C １－６ Alkyl, C １－６ Haloalkyl, or C １－６ It is either an alkoxy or two Rs ８ Together with the intervening atom, one or more R ８ｂ A 5-7 member heterocycline is formed by arbitrary selection substitution, where R ８ The five-membered or six-membered heteroaryl represented by the above is one or more R ８ａ It is optionally replaced by R, where R ８ａ C １－３ It is alkyl, R ８ｂ C １－３ Alkyl or oxo, Here, the heterocyclyl comprises 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl comprises 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

2. The compound is of formula (II), (III), (IV), (V), (VI), (VII), or (VIII): 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [the specified formula].

3. The aforementioned compound is of formula (II): 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [the specified formula].

4. R ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein F is present.

5. R ６ However, A, -NHC(=O)-A, or -C(=O)NH-A, R ７ However, B is, X １ If R is N, ６ B is R ７ A is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. R ７ If R is B, ６ A is, or For equation (II) or (VII), R ６ is -NHC(=O)-A or -C(=O)NH-A, and R ７ B is The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. A is -C １－６ Alkylene-NR ９ R １０ or -C １－６ Alkylene-Het, and here, -C represented by A １－６ The Het in alkylene-Het is a 4-6 member monocyclic saturated heterocycline containing a ring N atom. R ９ and R １０ However, each is independent of H or C １－４ It is alkyl, By arbitrary choice, -C is represented by A. １－６ The Het in alkylene-Het is azetidinil, pyrrolidinil, piperidinil, morpholinil, or piperazinil. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. A, (i) 【Chemistry 4】 or (ii) 【Transformation 5】 Selected from the group consisting of, The compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. (i) A is a 5-6 member monocyclic carbocyclyl, a 5-8 member bicyclic saturated crosslinked carbocyclyl, or Het. The Het represented by A is a 4-7 member monocyclic saturated heterocycline, a 6-8 member bicyclic saturated bridged heterocycline, or a 7-12 member bicyclic saturated spiral or condensed heterocycline, provided that the Het represented by A does not contain a ring N atom, -NR ９ R １０ or -C １－６ Alkylene-NR ９ R １０ Substituted by, 1-2 R １１ If further substitutions are made by choice, and the Het represented by A contains one or more ring N atoms, then 1 to 2 R １１ Replaced by optional selection, The 5-8 member bicyclic saturated crosslinked carbocyclyl represented by A is -NR ９ R １０ , 4-6 member monocyclic saturated heterocyclyl, or -C １－６ Alkylene-NR ９ R １０ Substituted by, 1-2 R １１ Then, it is further replaced by optional selection, R ９ and R １０ However, each is independent of H or C １－４ Alkyl, or (ii) A is a 5-6 member monocyclic saturated carbocyclyl, a 5-8 member bicyclic saturated crosslinked carbocyclyl, or Het. Het represented by A is a 4- to 6-member monocyclic saturated heterocyclyl, a 6- to 8-member bicyclic saturated bridged heterocyclyl, or a 7- to 10-member bicyclic saturated spiral heterocyclyl, provided that when Het represented by A does not contain a ring N atom, it is substituted by -NR ９ R １０ and optionally further substituted by one or two R １１ ; when Het represented by A contains one or more ring N atoms, it is optionally substituted by one or two R １１ . The 5-8 member bicyclic saturated crosslinked carbocyclyl represented by A is -NR ９ R １０ Substituted by, 1-2 R １１ Then, it is further replaced by optional selection, R ９ and R １０ are each independently H or C １－４ alkyl, or (iii) A is azetidinil, pyrrolidinil, piperidinil, morpholinil, piperazinil, 2-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptanil, 2-azabicyclo[3.1.1]heptanil, 2-azabicyclo[2.2.1]heptanil, 1-azaspiro[3.3]heptanil, 2-azaspiro[4.5]decanil, 4-azaspiro[2.5]octanil, 8-azaspiro[4.5]decanil, 8-azabi Cyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 9-diazaspiro[5.5]undecanyl, 2-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 5-azabispiro[2.4]heptanyl, 5-azabispiro[2.3]hexanyl, 4-azabispiro[2.4]heptanyl, 6-azabispiro[3.4]octanyl, 2-azabispiro[4.4]nonanyl, 2-azabispiro[3.5]no Nanyl, 2-azaspiro[3.4]octanyl, 1-oxa-9-azaspiro[5.5]undecanyl, 3-azabicyclo[3.1.0]hexanyl, diazaspiro[4.5]decane, 7-diazaspiro[3.5]nonanyl, diazaspiro[4.5]decanyl, 7-diazaspiro[4.4]nonanyl, 1-azabicyclo[3.2.1]octanyl, diazaspiro[5.5]undecanyl, azepanyl, 7-azaspiro[3.5]nonanyl, 5-ox sa-2-azaspiro[3.4]octanyl, diazabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.2.0]heptanyl, octahydro-cyclopenta[c]pyrrolyl, hexahydro-1H-pyrrollo[3,4-c]pyrrolyl, octahydro-indolidinyl, 8-diazabicyclo[4.2.0]octanyl, octahydro-isoindolyl, or 1,8-diazaspiro[4.5]decane, each containing one or two R １１ A is optionally substituted, preferably A is azetidinil, pyrrolidinil, piperidinil, morpholinil, piperazinil, 2-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptanil, 2-azabicyclo[3.1.1]heptanil, 2-azabicyclo[2.2.1]heptanil, 1-azaspiro[3.3]heptanil, 2-azaspiro[4.5]decanil, 4-azaspiro[2.5]octanil, 8-azaspiro[4.5]decanil, 8-azabicyclo[3.2.1]octanil, or 7-azaspiro[3.5]nonanil, each of which has one or two R １１ Replaced by optional selection, or (iv) A, 【Transformation 6】 A group consisting of is selected, and each of them has one or two R １１ It is optionally replaced, preferably A is 【Transformation 7】 A group consisting of is selected, and each of them has one or two R １１ Replaced by optional selection, or (v) A is cyclobutyl, cyclopentyl, cyclopenetenyl, cyclohexyl, tetrahydro-2H-pyranyl, 3-oxetanyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptanyl, -CH ２ -Cyclobutyl, bicyclo[2.2.2]octanyl, spiro[5.3]nonanyl, or 2-oxobicyclo[2.1.1]hexyl, each of which is -NR ９ R １０ Substituted by, 1-2 R １１ The following are optionally substituted, preferably A is cyclopentyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.2]octanyl, or 2-oxobicyclo[2.1.1]hexyl, each of which is -NR ９ R １０ Substituted by, 1-2 R １１ It is further replaced by optional selection, or (vi) A is 【Transformation 8】 A group consisting of the following is selected, and each of them is -NR ９ R １０ Substituted by, 1-2 R １１ It is further replaced by optional selection, preferably A is 【Chemistry 9】 A group consisting of the following is selected, and each of them is -NR ９ R １０ Substituted by, 1-2 R １１ And it is further replaced by optional selection. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. (i) R １１ However, each time it appears, Halo, -C(=O)R １２ , C １－４ Alkyl, C １－４ Alkoxy C １－４ Alkyl, C ３－６ Selected independently from cycloalkyl, where R １１ The C represented by ３－６ Cycloalkyls are composed of F, Cl, and C １－４ Optionally substituted with one to three substituents independently selected from the alkyl group, R １２ H, C １－２ Alkyl, C ３－４ It is cycloalkyl, or (ii) R １１ However, each time it appears, F, -C (=O)CH ３ -C(=O)CH ２ CH ３ -C(=O)cyclopropyl, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ３ ien-CH ２ C (CH ３ ) ３ ien-CH ２ CH ２ OCH ３ ien-CH ２ CH ２ CH ２ OCH ３ ien-CH ２ CH ２ CH ２ OCH ３ ien-CH ２ CHF ２ ien-CH ２ CH ２ F, -CH ２ - Independently selected from cyclopropyl, cyclopropyl, cyclobutyl and cyclopentyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. (i) R ９ and R １０ However, each is independent of H or C １－３ It is alkyl. (ii) R ９ However, H or -CH ３ And R １０ However, H, cyclopropyl or -CH ３ is, or (iii) R ９ and R １０ However, each is independent of H or -CH ３ That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. (i) B is phenyl, naphthalenyl, or an 8-10 membered bicyclic heteroaryl, where B represents phenyl, naphthalenyl, and an 8-10 membered bicyclic heteroaryl with 1-3 R ８ Replaced by choice, (ii) B has 1 to 3 R ８ A 9-membered or 10-membered bicyclic heteroaryl that is optionally substituted by, (iii) B has 1 to 3 R ８ It is a nine-membered bicyclic heteroaryl that is optionally substituted by, or (iv) B is selected from the group consisting of phenyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, benzotriazolyl, imidazopyradinyl, benzoxazolyl, triazolopyridinyl, benzoisothiazolyl, pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyridinyl, thienopyridinyl, thienopyridinyl, benzothiazolyl, pyrrolopyridinyl, pyrrolopyridinyl, benzofuranil, benzothiophenyl, isoquinolinyl, pyrrolotriadinyl, thienopyridinyl, triazolopyridazinyl, benzoxadiazolyl, indolyl, indoline-2-onyl, flopyridine, benzimidazolyl, benzothiadiazole, phthalazinyl, and phthalazine-1-onyl, each of which has 1 to 3 R ８ Replaced by choice, or B is 2H-pyrido[3,2-b][1,4]oxazine-3(4H)-onyl, and each of them is C １－３ Optionally substituted with alkyl groups, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. B, 【Chemistry 10】 Selected from, each of which has 1 to 3 R ８ Replaced by choice, or B, 【Chemistry 11】 The compound according to claim 12 or a pharmaceutically acceptable salt thereof.

14. (i) R ８ However, each time it appears, it is halo, -CN, -OH, C １－３ Alkyl, C １－２ Haloalkyl, or C １－２ It is an alkoxy, or (ii) R ８ However, each time it appears, -F, -Cl, -CN, -CH ３ ien-CH ２ CH ３ , -CH(CH ３ ) ２ ,-CHF ２ -OH, -OCH ３ , and -OCH ２ CH ３ Selected independently of The compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Request Item 15】 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 【Chemistry 12-5】 【Chemistry 12-6】 【Chemistry 12-7】 【Chemistry 12-8】 【Chemistry 12-9】 【Chemistry 12-10】 【Chemistry 12-11】 【Chemistry 12-12】 [Chemistry 12-13] 【Chemistry 12-14】 【Chemistry 12-15】 【Chemistry 12-16】 【Chemistry 12-17】 【Chemistry 12-18】 【Chemistry 12-19】 【Chemistry 12-20】 【Chemistry 12-21】 【Chemistry 12-22】 [Chemistry 12-23] [Chemistry 12-24] [Chemistry 12-25] [Chemistry 12-26] [Chemistry 12-27] [Chemistry 12-28] [Chemistry 12-29] 【Chemistry 12-30】 【Chemistry 12-31】 【Chemistry 12-32】 【Chemistry 12-33】 [Chemistry 12-34] 【Chemistry 12-35】 【Chemistry 12-36】 【Chemistry 12-37】 【Chemistry 12-38】 【Chemistry 12-39】 【Chemistry 12-40】 【Chemistry 12-41】 【Chemistry 12-42】 [Chemistry 12-43] [Chemistry 12-44] 【Chemistry 12-45】 [Chemistry 12-46] [Chemistry 12-47] 【Chemistry 12-48】 [Chemistry 12-49] 【Chemistry 12-50】 【Chemistry 12-51】 【Chemistry 12-52】 [Chemistry 12-53] [Chemistry 12-54] 【Chemistry 12-55】 [Chemistry 12-56] 【Chemistry 12-57】 [Chemistry 12-58] [Chemistry 12-59] 【Chemistry 12-60】 【Chemistry 12-61】 【Chemistry 12-62】 [Chemistry 12-63] [Chemistry 12-64] 【Chemistry 12-65】 【Chemistry 12-66】 【Chemistry 12-67】 【Chemistry 12-68】 [Chemistry 12-69] 【Chemistry 12-70】 【Chemistry 12-71】 【Chemistry 12-72】 【Chemistry 12-73】 [Chemistry 12-74] 【Chemistry 12-75】 【Chemistry 12-76】 【Chemistry 12-77】 【Chemistry 12-78】 【Chemistry 12-79】 【Chemistry 12-80】 A compound selected from either or a pharmaceutically acceptable salt thereof.

16. The aforementioned compound is given by the following formula: 【Chemistry 13】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, represented by the formula (wherein R ５ It is a halo, R ６ is A, -NH-C(=O)-A, or -C(=O)NH-A, R ７ B is, A is a monocyclic saturated heterocyclyl with 4 to 6 members, a bicyclic saturated condensed or spiral heterocyclyl with 6 to 10 members, or C ３－６ It is a cycloalkyl group, where 4-6 membered monocyclic saturated heterocyclils and 6-10 membered bicyclic saturated condensed or spiral heterocyclils have one or two R groups. １１ Each is replaced by an arbitrary selection, C ３－６ Cycloalkyl is -NR ９ R １０ Replaced with R １１ Then, it is further replaced by an optional selection, R ９ and R １０ These are, independently, H or C １－３ It is alkyl, Each R １１ Independently, C １－３ Alkyl or C ３－６ It is a cycloalkyl, B is 1 to 3 R ８ A 9-membered bicyclic heteroaryl is optionally substituted, where the 9-membered bicyclic heteroaryl has 2 to 4 N-ring atoms. Each R ８ Independently, C １－３ Alkyl, C １－３ Haloalkyl or C １－３ (It is an alkoxy.)

17. R ５ F is, A is cyclobutyl or Het, where Het is azetidinil, piperidinil, 3-azabicyclo[3.1.0]hexanil, 2,8-diazaspiro[4.5]decanil, or 2,7-azaspiro[3.5]nonanil, each of which is C １－３ Alkyl or C ３－６ Optionally substituted with a cycloalkyl group, where cyclobutyl represented by A is -NR ９ R １０ It is represented by A, R ９ and R １０ However, each is H or -CH ３ And, B is given by the following equation: 【Chemistry 14】 Represented by, each of which is one or two R ８ Replaced by optional selection, Each R ８ However, independently, C １－３ Alkyl, C １－３ Haloalkyl or C １－３ It is an alkoxy. The compound according to claim 16 or a pharmaceutically acceptable salt thereof.

18. A is given by the following equation: 【Chemistry 15】 Represented by, B is given by the following equation: 【Chemistry 16】 Represented by, each R ８ However, -CH ３ ,-CHF ２ CF ３ , or OCH ３ That is, The compound according to claim 17, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19 for treating Huntington's disease (HD) in a subject.

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