Compounds for treating spinal muscular atrophy and huntington's disease

Abstract

The present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof and its use in, e.g. treating a condition, disease, or disorder, wherein the disease is Huntington's disease ("HD") or spinal muscular atrophy (SMA). This disclosure also features a composition containing the same as well as methods of using and making the same.

Description

[0001] COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY AND HUNTINGTON'S DISEASE

[0002] RELATED APPLICATION

[0003] This application claims the benefit of the filing date, under 35 U.S.C. §119(e), of U.S. Provisional Application No. 63 / 601552, filed on November 21, 2023, the entire contents of which are incorporated here by reference.

[0004] BACKGROUND

[0005] Spinal muscular atrophy (SMA) is a collection of inherited and acquired central nervous system (CNS) diseases that affects approximately 1 out of every 10,000 people. The most common form of SMA is caused by mutations in the Survival Motor Neuron (SMN) gene and manifests over a wide range of severity affecting infants through adults. The disease is characterized by progressive motor neuron loss in the spinal cord and brainstem causing muscle weakness and muscle atrophy.

[0006] The SMN gene has been mapped by linkage analysis to a complex region in chromosome 5q. In humans, this region contains an approximately 500 thousand base pairs (kb) inverted duplication resulting in two nearly identical copies of the SMN gene. SMA is caused by an inactivating mutation or deletion of the telomeric copy of the gene (SMN1) in both chromosomes, resulting in the loss of SMN1 gene function. However, all patients retain the centromeric copy of the gene (SMN2), and the copy number of the SMN2 gene in SMA patients generally correlates inversely with the disease severity, i.e., patients with less severe SMA have more copies of SMN2. Nevertheless, SMN2 is unable to compensate completely for the loss of SMN1 function due to alternative splicing of exon 7 caused by a translationally silent C to T mutation in exon 7. As a result, the majority of transcripts produced from SMN2 lack exon 7 (A7 SMN2), and encode a truncated SMN protein that has an impaired function and is rapidly degraded.

[0007] The discovery of the genetic cause of SMA has led to the development of several treatment options that affect the genes involved in SMA. Onasemnogene abeparvove (marketed as Zolgensma) is a gene replacement therapy that uses self-complementary adeno- associated virus type 9 (scAAV-9) as a vector to deliver the SMN1 transgene. Nusinersen (marketed as Spinraza) is an antisense nucleotide that modifies the alternative splicing of the SMN2 gene. Risdiplam ( marketed as Evyrsdi), a pyridazine derivative, can increase the amount of functional SMN protein produced by the SMN2 gene through modifying its splicing pattern.

[0008] Despite the recent development and approval of disease-modifying therapies, there is still need for new therapies for treating SMA.

[0009] Huntington’s disease (HD) is an autosomal dominant progressive neurodegenerative disorder, which has a prevalence of between three and seven individuals per 100,000 worldwide. HD is caused by cytosine-adenine-guanine (CAG) repeat expansions 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 that corresponds to the CAG genetic expansion; the protein exhibits toxic properties that cause dysfunction and death of neurons. The disease is characterized by motor, cognitive, psychiatric and functional capacity decline.

[0010] Some research progresses are being made in identifying HTT protein-lowering therapies using multiple tools, including ribonucleic acid (RNA) interference using short interfering RNAs, short-hairpin RNAs, or microRNAs and antisense oligonucleotides ("ASO") causing translational repression or messenger RNA (mRNA) degradation. However, these therapies require either surgical delivery of a viral vector for chronic HTT transcript lowering by RNAi, or repeated infusions into the cerebral spinal fluid ("CSF") by lumbar puncture for ASOs in the clinic.

[0011] More recently, a small molecule compound platform, which modulates RNA expression, i.e. splicing correction, is under development. NVS-SM1 (LMI070), now called branaplam, is a pyridazine derivative. It is reported that branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). See Keller, C. etc., An Orally Available, Brain Penetrant, Small Molecule Lowers Huntingtin Levels by Enhancing Pseudoexon Inclusion, Nature Communications, (2022) 13:1150.

[0012] However, there are no approved disease-modifying treatments for HD till now, leaving a high unmet need for medications that can be used for treating or ameliorating HD. Accordingly, there is a need to find disease-modifying therapies for HD (i.e. therapeutic options that can slow disease progression).

[0013] SUMMARY

[0014] Described herein are compounds or pharmaceutically acceptable salts thereof, which can be useful in treating HD or SMA in a subject. In one aspect, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein X1, X2, X3, X4, R4, and R5are as defined herein.

[0015] Also provided are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0016] The present disclosure further provides methods of treating a disease or condition caused by an inactivating mutation or deletion in the SMN1 gene and / or associated with loss or defect of SMN1 gene function in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0017] The present disclosure also provides methods for the treatment or prevention of SMA 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.

[0018] The present disclosure further provides methods of lowering mHTT in a subject, comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0019] The present disclosure also provides methods of treating a disease or condition modulated at least in part by mHTT in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0020] 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 a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0021] In certain embodiments of the methods of the present disclosure, HD can be treated by lowering mHTT level in a subject.

[0022] The present disclosure also provides a use of a compound of Formula (I), a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same in any of the methods described herein. In one embodiment, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for use in any of the methods described herein. In another embodiment, provided is use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for use in any of the methods described herein.

[0023] DETAILED DESCRIPTION

[0024] 1. Compounds

[0025] In a first aspect, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: is a single bond or double bond;

[0026] X1is CR1or N;

[0027] X2is N or CR2;

[0028] X3is NR3or S;

[0029] X4is N or CR2;

[0030] R1, when present, is H, halo, Ci-ealkyl, or 5- to 10-membered heteroaryl;

[0031] R2and R3, when present, are each independently selected from a group consisting of H, halo, and Ci-ealkyl;

[0032] R4is -Ci-3alkylene-(4 -to 12-membered saturated heterocyclyl), -Ci-3alkylene-(4- to 10-membered carbocyclyl), 4- to 10-membered carbocyclyl, or 4 -to 12-membered saturated heterocyclyl; wherein said 4 to 10 membered carbocyclyl and 4 -to 12-membered saturated heterocyclyl represented by R4or in the group -Ci-3alkylene-(4 -to 12-membered saturated heterocyclyl) and -Ci-3alkylene-(4- to 10-membered carbocyclyl) represented by R4is optionally substituted by -NR6R7or -Ci-6alkylene-NR6R7and is further optionally substituted with 1 to 4 R9; wherein

[0033] R6is H or Ci-ealkyl;

[0034] R7is H, or Ci-ealkyl; or

[0035] R6and R7taken together with the nitrogen to which they are attached is 4 -to 12-membered saturated heterocyclyl. R9, for each occurrence, is independently selected from deuterium, halo, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyCi-ealkyl, Cs-ecycloalkyl, -Ci- ealkylene-Cs-ecycloalkyl, 4- to 6-membered saturated heterocyclyl, or -Ci- ealkylene-(4- to 6-membered saturated heterocyclyl;

[0036] R5is H, 6- to 10-membered aryl, 4- to 10 -membered heterocyclyl or 5- to 10- membered heteroaryl, wherein said 6- to 10-membered aryl, 4- to 10 -membered heterocyclyl or 5- to 10-membered heteroaryl represented by R5are each optionally substituted by one or more R10; wherein:

[0037] R10is halo, -CN, -OH, Ci-ealkyl, Cs-ecycloalkyl, 5- or 6-membered heteroaryl, Ci- ehaloalkyl, or Ci-ealkoxy; or two R10together with the intervening atoms together form a 4- to 7-membered heterocyclyl optionally substituted with one or more R10b; wherein said 5- or 6-membered heteroaryl represented by R10is optionally substituted by one or more R10a; wherein R10ais Ci-3alkyl; and R10bis Ci-3alkyl or oxo.

[0038] In a first embodiment, the present disclosure provides a compound according to the first aspect, or a pharmaceutically acceptable salt thereof, wherein: is a single bond or double bond;

[0039] X1is CR1or N;

[0040] X2is N or CR2;

[0041] X3is NR3or S;

[0042] X4is N or CR2;

[0043] R1, when present, is H, halo, Ci-ealkyl, or 5- to 10-membered heteroaryl;

[0044] R2and R3, when present, are each independently selected from a group consisting of H, halo, and Ci-ealkyl;

[0045] R4is 4- to 10-membered carbocyclyl, or 4 -to 12-membered saturated heterocyclyl; wherein: said 4 to 10 membered carbocyclyl represented by R4is optionally substituted by -NR6R7or -Ci-6alkylene-NR6R7and is further optionally substituted with 1 to 2 R9; wherein

[0046] R6is H or Ci-ealkyl;

[0047] R7is H, or Ci-ealkyl;

[0048] R9, for each occurrence, is independently selected from halo, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyCi-ealkyl, Cs-ecycloalkyl, -Ci-ealkylene-Cs- ecycloalkyl, 4- to 6-membered saturated heterocyclyl or -Ci-6alkylene-(4- to 6- membered saturated heterocyclyl; said 4 -to 12-membered saturated heterocyclyl represented by R4is optionally substituted with 1 to 2 R9;

[0049] R5is H, 6- to 10-membered aryl, 4- to 10 -membered heterocyclyl or 5- to 10- membered heteroaryl, wherein said 6- to 10-membered aryl, 4- to 10 -membered heterocyclyl or 5- to 10-membered heteroaryl represented by R5are each optionally substituted by one or more R10; wherein:

[0050] R10is halo, -CN, -OH, Ci-ealkyl, Cs-ecycloalkyl, 5- or 6-membered heteroaryl, Ci- ehaloalkyl, or Ci-ealkoxy; or two R10together with the intervening atoms together form a 4- to 7-membered heterocyclyl optionally substituted with one or more R10b; wherein said 5- or 6-membered heteroaryl represented by R10is optionally substituted by one or more R10a; wherein R10ais Ci-3alkyl; and R10bis Ci-3alkyl or oxo.

[0051] In a second embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IA): or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or the first embodiment.

[0052] In a third embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IB): or a pharmaceutically acceptable salt thereof. The definitions of the variables are provided in the first aspect or the first embodiment.

[0053] In a fourth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first through the third embodiments or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (II), (III), (IV), or

[0054] (V): or a pharmaceutically acceptable salt thereof. The definitions of the remaining variables are provided in the first aspect or any one of the first through the third embodiments.

[0055] In a fifth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first through the fourth embodiments or a pharmaceutically acceptable salt thereof, wherein:

[0056] R4is 4- to 6-membered monocyclic carbocyclyl, 4- to 7-membered monocyclic saturated heterocyclyl, -CH2-(4- to 7-membered monocyclic saturated heterocyclyl), 6- to 8- membered bicyclic saturated bridged heterocyclyl, -CH2-(6- to 12-membered bicyclic saturated spiro or fused heterocyclyl) or 6- to 12-membered bicyclic saturated spiro or fused heterocyclyl, wherein said 4- to 6-membered monocyclic carbocyclyl is optionally substituted by -NR6R7or -Ci-6alkylene-NR6R7and is further optionally substituted with 1 to 2 R9; and said 4- to 7-membered monocyclic saturated heterocyclyl, 6- to 8-membered bicyclic saturated bridged heterocyclyl, or 6- to 12-membered bicyclic saturated spiro or fused heterocyclyl is optionally substituted by -NR6R7or -Ci-6alkylene-NR6R7and is further optionally substituted with 1 or 4 R9. The definitions of the remaining variables are provided in the first aspect or any one of the first through the fourth embodiments.

[0057] In an alternative fifth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first through the fourth embodiments or a pharmaceutically acceptable salt thereof, wherein:

[0058] R4is 4- to 6-membered monocyclic carbocyclyl, 4- to 7-membered monocyclic saturated heterocyclyl, 6- to 8-membered bicyclic saturated bridged heterocyclyl, or 6- to 12- membered bicyclic saturated spiro or fused heterocyclyl, wherein said 4- to 6-membered monocyclic carbocyclyl is optionally substituted by -NR6R7or -Ci-6alkylene-NR6R7and is further optionally substituted with 1 to 2 R9; and said 4- to 7-membered monocyclic saturated heterocyclyl, 6- to 8-membered bicyclic saturated bridged heterocyclyl, or 6- to 12- membered bicyclic saturated spiro or fused heterocyclyl is optionally substituted with 1 or 2 R9. The definitions of the remaining variables are provided in the first aspect or any one of the first through the fourth embodiments. In a sixth embodiment, the present disclosure provides a compound according to the fifth embodiment or a pharmaceutically acceptable salt thereof, wherein R4is azetidinyl, - CH2-pyrrolidinyl, pyrrolidinyl, -CH2-piperidinyl, piperidinyl, l-azaspiro[3.3]heptanyl, 4- azaspiro[2.5]octanyl, 2-azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 2,6- diazaspiro[3.3]heptanyl, piperazinyl, -CH2-4-azaspiro[2.5]octanyl, 2- azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, or 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted -NR6R7and is further optionally substituted with 1-4 R9. The definitions of the remaining variables are provided in the fifth embodiment or any alternative embodiments described therein.

[0059] In an alternative sixth embodiment, the present disclosure provides a compound according to the fifth embodiment or a pharmaceutically acceptable salt thereof, wherein R4is azetidinyl, pyrrolidinyl, piperidinyl, l-azaspiro[3.3]heptanyl, 4-azaspiro[2.5]octanyl, 2- azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, or 8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with one or two R9. The definitions of the remaining variables are provided in the fifth embodiment or any alternative embodiments described therein.

[0060] In a seventh embodiment, the present disclosure provides a compound according to the fifth or the sixth embodiments or a pharmaceutically acceptable salt thereof, wherein R4is selected from a group consisting of and is futher optionally substituted with 1-4 R9. The definitions of the remaining variables are provided in the fifth or the sixth embodiments or any alternative embodiments described therein.

[0061] In an alternative seventh embodiment, the present disclosure provides a compound according to the fifth or the sixth embodiment or a pharmaceutically acceptable salt thereof, wherein R4is selected from a group consisting of optionally substituted with one or two R9. The definitions of the remaining variables are provided in the fifth or the sixth embodiment or any alternative embodiments described therein.

[0062] In an eighth embodiment, the present disclosure provides a compound according to fifth embodiment or a pharmaceutically acceptable salt thereof, wherein: R4is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with -NR6R7or -Ci-3alkylene-NR6R7, and is optionally further substituted with 1 to 2 R9. The definitions of the remaining variables are provided in the fifth embodiment or any alternative embodiments described therein.

[0063] In a ninth embodiment, the present disclosure provides a compound according to the eighth embodiment or a pharmaceutically acceptable salt thereof, wherein R4is selected from a group consisting of , each of which is substituted with -

[0064] NR6R7or -CH2-NR6R7, and is optionally further substituted with 1 to 2 R9. The definitions of the remaining variables are provided in the eighth embodiment.

[0065] In an alternative ninth embodiment, the present disclosure provides a compound according to the eighth embodiment or a pharmaceutically acceptable salt thereof, wherein R4is selected from a group consisting of each of which is substituted with

[0066] -NR6R7or -CH2-NR6R7, and is optionally further substituted with 1 to 2 R9. The definitions of the remaining variables are provided in the eighth embodiment.

[0067] In a tenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the ninth embodiments or a pharmaceutically acceptable salt thereof, wherein R9, for each occurrence, is independently selected from deuterium, halo, Ci-ealkyl, and Cs-ecycloalkyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through the ninth embodiments or any alternative embodiments described therein.

[0068] In an alternative tenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the ninth embodiments or a pharmaceutically acceptable salt thereof, wherein R9, for each occurrence, is independently selected from Ci-ealkyl and Cs-ecycloalkyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through the ninth embodiments or any alternative embodiments described therein.

[0069] In an eleventh embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the ninth embodiments or a pharmaceutically acceptable salt thereof, wherein R9, for each occurrence, is independently selected from deuterium, -F, -CH3, -CH2CH3, cyclopropyl, and cyclobutyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through the ninth embodiments or any alternative embodiments described therein.

[0070] In an alternative eleventh embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the ninth embodiments or a pharmaceutically acceptable salt thereof, wherein R9, for each occurrence, is independently selected from -CH3, -CH2CH3, cyclopropyl, and cyclobutyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through the ninth embodiments or any alternative embodiments described therein.

[0071] In an twelfth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the eleventh embodiments or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H, or Ci-3alkyl; R6and R7taken together with the intervening nitrogen to which they are attached form 4 to 6 membered heterocyclyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through the eleventh embodiments or any alternative embodiments described therein.

[0072] In an alternative twelfth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the eleventh embodiments or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H or Ci- 3alkyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through the eleventh embodiments or any alternative embodiments described therein.

[0073] In a thirteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the eleventh embodiments or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H or -CH3; R6and R7taken together with the intervening nitrogen to which they are attached form azetidinyl. The definitions of the remaining variables are provided in the first aspect or any one of the first through the eleventh embodiments or any alternative embodiments described therein.

[0074] In an alternative thirteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the eleventh embodiments or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H or - CH3. The definitions of the remaining variables are provided in the first aspect or any one of the first through the eleventh embodiments or any alternative embodiments described therein.

[0075] In a fourteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the thirteenth embodiments or a pharmaceutically acceptable salt thereof, wherein R5is 5- to 10-membered heteroaryl optionally substituted by one or more R10; and R10is halo, -CN, -OH, Ci-ealkyl, Cs-ecycloalkyl, Ci-ehaloalkyl, or Ci- ealkoxy. The definitions of the remaining variables are provided in the first aspect or any one of the first through the thirteenth embodiments or any alternative embodiments described therein.

[0076] In a fifteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the fourteenth embodiments or a pharmaceutically acceptable salt thereof, wherein R5is 9-membered bicyclic heteroaryl optionally substituted by one or two R10. The definitions of the remaining variables are provided in the first aspect or any one of the first through the fourteenth embodiments or any alternative embodiments described therein.

[0077] In a sixteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the fifteenth embodiments or a pharmaceutically acceptable salt thereof, wherein R5is selected from a group consisting of imidazopyridinyl, imidazopyridazinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, triazolopyridazinyl, indazolyl, triazolopyridinyl, benzooxazolyl, oxazolo[5,4-b]pyridinyl, and pyrazolopyridinyl, each of which is optionally substituted by one to three R10. The definitions of the remaining variables are provided in the first aspect or any one of the first through the fifteenth embodiments or any alternative embodiments described therein.

[0078] In an alternative sixteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to the fifteenth embodiments or a pharmaceutically acceptable salt thereof, wherein R5is selected from a group consisting of imidazopyridinyl, imidazopyridazinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, triazolopyridazinyl, indazolyl, triazolopyridinyl, benzooxazolyl, and pyrazolopyridinyl, each of which is optionally substituted by one to three R10. The definitions of the remaining variables are provided in the first aspect or any one of the first through the fifteenth embodiments or any alternative embodiments described therein. In a seventeenth embodiment, the present disclosure provides a compound according to the sixteenth embodiment or a pharmaceutically acceptable salt thereof, wherein R5is selected from: each of which is optionally substituted by one to two R10. The definitions of the remaining variables are provided in the sixteenth embodiment or any alternative embodiments described therein.

[0079] In an alternative seventeenth embodiment, the present disclosure provides a compound according to the sixteenth embodiment or a pharmaceutically acceptable salt thereof, wherein R5is selected from: optionally substituted by one to two R10. The definitions of the remaining variables are provided in the sixteenth embodiment or any alternative embodiments described therein.

[0080] In an eighteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first through the seventeenth embodiments, wherein R10for each occurrence is halo, -CN, Ci-salkyl, Ci-2haloalkyl, or Ci-2alkoxy. The definitions of the remaining variables are provided in the first aspect or any one of the first through the seventeenth embodiments or any alternative embodiments described therein.

[0081] In a nineteenth embodiment, the present disclosure provides a compound according to the seventeenth embodiment or a pharmaceutically acceptable salt thereof, wherein R10for each occurrence is independently selected from -F, -CN, -CH3, -CHF2, and -OCH3. The definitions of the remaining variables are provided in the eighteenth embodiment or any alternative embodiments described therein. In a twentieth embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein:

[0082] R1is H or Ci-ealkyl;

[0083] R4is C4-6cycloalkyl, 5- or 6-membered monocyclic saturated heterocycyl, 8- to 10- membered saturated bicyclic bridged heterocyclyl, or 6 -to 10-membered saturated bicyclic fused heterocyclyl; wherein: said C4-6cycloalkyl represented by R4is optionally substituted by - NR6R7and is further optionally substituted with 1 to 2 R9; wherein

[0084] R6is H or Ci-3alkyl;

[0085] R7is H or Ci-3alkyl;

[0086] R9is Ci-3alkyl,; said 5- or 6-membere monocyclic saturated heterocycyl, 8- to 10- membered saturated bicyclic bridged heterocyclyl, or 6 -to 10-membered saturated bicyclic fused heterocyclylrepresented by R4is optionally substituted with 1 to 2 R9;

[0087] R5is 9-membered bicyclic heteroaryl containing 2 to 4 ring N atoms, wherein said 9- membered bicyclic heteroaryl represented by R5is optionally substituted by one or two R10; wherein: each R10is independently halo, Ci-3alkyl, or Ci-2haloalkyl.

[0088] In a twenty-first embodiment, the present disclosure provides a compound according to the twentieth embodiment or a pharmaceutically acceptable salt thereof, wherein:

[0089] R1is H or Ci-2alkyl;

[0090] R4is cyclohexyl, piperidinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octanyl, piperazinyl, or 3-azabicyclo[3.1.0]hexanyl, wherein cyclohexyl represented by R4is substituted with - NR6R7, and pyrrolidinyl, piperazinyl, and piperidinyl, 8-azabicyclo[3.2.1]octanyl, and 3- azabicyclo[3.1.0]hexanyl are each optinally substituted with Ci-3alkyl or -NR6R7; wherein

[0091] R6is H or Ci-2alkyl;

[0092] R7is H or Ci-2alkyl; R5is triazol opyridazinyl, pyrazolopyrazinyl, pyrrolo[l,2-a]pyrazinyl, indazolyl, imidazopyridinyl, or imidazopyridazinyl, each of which is optionally substituted with one to two substituents independently selected from halo, Ci-salkyl, and Ci-2haloalkyl. The definitions of the remaining variables are provided in the twentieth embodiment.

[0093] In an alternative twenty-first embodiment, the present disclosure provides a compound according to the twentieth embodiment or a pharmaceutically acceptable salt thereof, wherein:

[0094] R1is H or Ci-2alkyl;

[0095] R4is cyclohexyl, piperidinyl, 8-azabicyclo[3.2.1]octanyl, or 3- azabicyclo[3.1.0]hexanyl, wherein cyclohexyl is substituted with -NR6R7, and piperidinyl, 8- azabicyclo[3.2.1]octanyl, and 3-azabicyclo[3.1.0]hexanyl are each optinally substituted with Ci-salkyl; wherein

[0096] R6is H or Ci-2alkyl;

[0097] R7is H or Ci-2alkyl;

[0098] R5is triazolopyridazinyl, pyrazolopyrazinyl, indazolyl, imidazopyridinyl, or imidazopyridazinyl, each of which is optionally substituted with one to two substituents independently selected from halo, Ci-3alkyl, and Ci-2haloalkyl. The definitions of the remaining variables are provided in the twentieth embodiment.

[0099] In a twenty-second embodiment, the present disclosure provides a compound according to the twentieth or twenty-first embodiment or a pharmaceutically acceptable salt thereof, wherein R1is H. The definitions of the remaining variables are provided in the twentieth or twenty-first embodiment or any alternative embodiments described therein.

[0100] In a twenty-third embodiment, the present disclosure provides a compound according to any one of the twentieth through the twenty-second embodiments or a pharmaceutically acceptable salt thereof, wherein R4is represented by the following formula: variables are provided in any of the twentieth through the twenty-second embodiments or any alternative embodiments described therein.

[0101] In an alternative twenty-third embodiment, the present disclosure provides a compound according to any one of the twentieth through the twenty-second embodiments or a pharmaceutically acceptable salt thereof, wherein R4is represented by the following formula: . The definitions of the remaining variables are provided in any of the twentieth through the twenty-second embodiments or any alternative embodiments described therein.

[0102] In a twenty-fourth embodiment, the present disclosure provides a compound according to any one of the twentieth through the twenty-third embodiments or a pharmaceutically acceptable salt thereof, wherein R9is -CH3; R6is -CH3; and R7is -CH3. The definitions of the remaining variables are provided in any one of the twentieth through the twenty-third embodiments or any alternative embodiments described therein.

[0103] In a twenty-fifth embodiment, the present disclosure provides a compound according to the twenty-third embodiment or a pharmaceutically acceptable salt thereof, wherein R4is represented by the following formula: embodiment or any alternative embodiments described therein.

[0104] In an alternative twenty-fifth embodiment, the present disclosure provides a compound according to the twenty-third embodiment or a pharmaceutically acceptable salt thereof, wherein R4is represented by the following formula:

[0105] The definitions of the remaining variables are provided in the twenty-third embodiment or any alternative embodiments described therein.

[0106] In a twenty-sixth embodiment, the present disclosure provides a compound according to any one of the twentieth through the twenty-fifth embodiments or a pharmaceutically acceptable salt thereof, wherein wherein R5is represented by the following formula:

[0107] definitions of the remaining variables are provided in any one of the twentieth through the twenty-fifth embodiments or any alternative embodiments described therein.

[0108] In an alternative twenty-sixth embodiment, the present disclosure provides a compound according to any one of the twentieth through the twenty-fifth embodiments or a pharmaceutically acceptable salt thereof, wherein R5is represented by the following formula: provided in any one of the twentieth through the twenty-fifth embodiments or any alternative embodiments described therein.

[0109] In a twenty- seventh embodiment, the present disclosure provides a compound according to any one of the twentieth through the twenty-sixth embodiments or a pharmaceutically acceptable salt thereof, wherein wherein R10is F, -CH3, or -CHF2.. The definitions of the remaining variables are provided in any one of the twentieth through the twenty-sixth embodiments or any alternative embodiments described therein.

[0110] In one embodiment, the present disclosure provides a compound selected from Compounds 1-146 described in the Examples section and Table 1, a pharmaceutically acceptable salt, a racemic mixture or a stereoisomer thereof.

[0111] Table 1

[0112] Cpd ID Structure

[0113] 2. Definitions

[0114] The term "halo" or "halogen," as used herein, refers to fluoride, chloride, bromide, or iodide. The term "alkyl" used alone or as part of a larger moiety, such as “alkoxy” or

[0115] “haloalkyl” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical of formula -CnH(2n+i). Unless otherwise specified, an alkyl group typically has 1-20, 1-10 or 1-6 carbon atoms. In some embodiments, an alkyl group has 1-6 carbon atoms, i.e. Ci-ealkyl. As used herein, a “Ci-ealkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, / / -propyl, iso-propyl, n-butyl, iso-butyl, tert- butyl, n-pentyl, isopentyl, hexyl, and the like. In some embodiments, an alkyl group has 1-4 carbon atoms, e., Ci-4alkyl. In some embodiments, an alkyl group has 1-3 carbon atoms, e., Ci-3alkyl.

[0116] The term "alkoxy" or “alkoxyl,” as used herein, refers to O-alkyl groups wherein alkyl is as defined above.

[0117] The term "haloalkyl" means alkyl, as the case may be, substituted with one or more halogen atoms. In one embodiment, the alkyl can be substituted by one to three halogens. Examples of haloalkyl, include, but are not limited to, trifluoromethyl, tri chloromethyl, pentafluoroethyl and the like.

[0118] The term “alkylene” as used herein, means a straight or branched chain divalent hydrocarbon group of formula -CnIEn-. Non-limiting examples include ethylene, and propylene.

[0119] The term “carbocyclyl” refers to any stable non-aromatic hydrocarbon ring having 3-12 membered carbocyclyl. In one embodiment, carbocyclyl is 3-, 4-, 5-, 6-, 7-, or 8- membered monocyclic or bicyclic or 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 can 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, carbocyclyl is intended to include, bridged, fused, 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 may be fused together, such 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.

[0120] The term "bridged carbocyclyl" refers to a 5 to 12 membered polycyclic carbocyclyl group, wherein any two rings in the group share two disconnected atoms, the rings can have one or more double bonds but have no completely conjugated 7t-electron system.

[0121] Representative examples of bridged carbocyclyl include, but are not limited to the following groups:

[0122] The term “cycloalkyl” refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon groups having 3 to 12 ring carbons. In one embodiment, cycloalkyl may have 3 to 7 or 3 to 6 ring carbons. Any substitutable ring atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl include: bicyclofl.1.0]butane, bicyclo[2.1.0]pentane, bicyclofl.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, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just 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.

[0123] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (“3-12 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-7 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”); polycyclic ring systems include fused, bridged, or spiro ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system. In some embodiments, a heterocyclyl group is a saturated heterocyclyl group. In some embodiments, a heterocyclyl group is a partially saturaturated heterocyclyl group. A partially saturaturated heterocyclyl group can contain one or more (e.g., 2 or 3) double bonds. A partially satuturated polycyclic heterocyclyl group can have one or more ring in the polycyclic ring system that are aromatic and at least one ring in the polyclyclic ring system is non-aromatic (e.g., fully saturated or partically saturated). For example, a partically saturated bicyclic heterocyclyl group can have a phenyl or a heteroaryl ring fused to a partially saturated heterocyclic ring.

[0124] Spiro heterocyclyl refers to 5 to 12 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called as spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Representative examples of spiro heterocyclyl include, but are not limited to the following groups:

[0125] Fused heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated 7t-electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C. Representative examples of fused heterocyclyl include, but are not limited to the following groups:

[0126] Bridged heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein any two rings in the group share two disconnected atoms, the rings can have one or more double bonds but have no completely conjugated 7t-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone as ring atoms, the remaining ring atoms being C. Representative examples of bridged heterocyclyl include, but are not limited to the following groups:

[0127] Generally, the cycloalkyl, or the heterocyclyl may be unsubstituted, or be substituted with one or more substituents as valency allows, wherein 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, optionally, the alkyl substitution may be further substituted.

[0128] The term “aryl” refers to a 6 to 10 membered all-carbon monocyclic ring or a polycyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with other ring in the system) group, and has a completely conjugated 7t-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.

[0129] The term “heteroaryl,” as used herein, refers to a monocyclic or multicyclic (e.g., bicyclic) aromatic hydrocarbon in which at least one of the ring carbon atoms has been replaced with a heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heteroaryl is based on a C5-10 aryl with one or more of its ring carbon atoms replaced by the heteroatom. A heteroaryl group may be attached through a ring carbon atom or, where valency permits, through a ring nitrogen atom. Generally, the heteroaryl may be unsubstituted, or be substituted with one or more substituents as valency allows. Exemplary substituents include, but are not limited to, halogen, OH, alkyl, alkoxyl, and amino (e.g., NH2, NHalkyl, N(alkyl)2), optionally, the alkyl may be further substituted. A heteroaryl group can either be monocyclic (“monocyclic heteroaryl”) or polycyclic (e.g., a bicyclic system (“bicyclic heteroaryl”) or tricyclic system (“tricyclic heteroaryl”); polycyclic ring systems include fused, bridged, or spiro ring systems).

[0130] Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2- furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl ( e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5- oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrol yl (e.g., 1 -pyrrol yl, 2-pyrrolyl, 3 -pyrrol yl), 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., tetrazol yl), 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 atom, which is a ring carbon or ring nitrogen atom bonded to a hydrogen.

[0131] As used herein, many moi eties (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 denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and / or taught by the instant disclosure. The optional substituents can be any substituents that are suitable to attach to the moiety.

[0132] Where suitable substituents are not specifically enumerated, exemplary substituents include, but are not limited to: Ci-salkyl, Ci-shydroxyalkyl, Ci-shaloalkyl, Ci-salkoxy, Ci-5 haloalkoxy, halogen, hydroxyl, cyano, amino, -CN, -NO2, -ORcl, -NRalRbl, -S(O)iRal, -NRalS(O)iRbl, -S(O)iNRalRbl, -C(=O)ORal, -OC(=O)ORal, -C(=S)ORal, -O(C=S)Ral, -C(=O)NRalRbl, -NRalC(=O)Rbl, -C(=S)NRalRbl, -C(=O)Ral, -C(=S)Ral, NRalC(=S)Rbl, -O(C=O)NRalRbl, -NRal(C=S)ORbl, -O(C=S)NRalRbl, -NRal(C=O)NRalRbl, -NRal(C=S)NRalRbl, phenyl, or 5-6 membered heteroaryl. Each Raland each Rblare independently selected from -H and Ci-salkyl, optionally substituted with hydroxyl or Ci-3alkoxy; Rclis -H, Ci-shaloalkyl or Ci-salkyl, wherein the Ci-salkyl is optionally substituted with hydroxyl or Ci-Csalkoxy.

[0133] The symbol “ ,” as used herein, refers to the point where the moiety attaches.

[0134] Pharmaceutically Acceptable Salts

[0135] 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, and allergic response, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0136] Pharmaceutically acceptable salts of the compounds of any one of the formulae described above include acid addition and base salts.

[0137] Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0138] Pharmaceutically acceptable salts of compounds of any one of the formulae described above may be prepared by one or more of three methods:

[0139] (i) by reacting the compound of any one of the formulae described above with the desired acid or base;

[0140] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of any one of the formulae described above or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

[0141] (iii) by converting one salt of the compound of any one of the formulae described above to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0142] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

[0143] The compounds of any one of the formulae described above, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. Stereoisomers and Other Variations

[0144] The compounds of any one of the formulae described above may exhibit one or more kinds of isomerism (e.g. optical, geometric or tautomeric isomerism). Such variation is implicit to the compounds of any one of the formulae described above defined as they are by reference to their structural features and therefore within the scope of the present disclosure.

[0145] Compounds having one or more chiral centers can exist in various stereoisomeric forms, z.e., each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0146] When a compound is designated by its chemical name (e.g., where the configuration is indicated in the chemical name by “7?” or “S”) or its structure (e.g., the configuration is indicated by “wedge” bonds) that indicates a single enantiomer, unless indicated otherwise, 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 in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0147] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0148] When two stereoisomers are depicted by their chemical names or structures, and the chemical names or structures are connected by an “and”, a mixture of the two stereoisomers is intended.

[0149] When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two stereoisomers is intended, but not both.

[0150] When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “7?”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

[0151] Racemic mixture means 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diasteriomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.

[0152] The term “geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclic ring, or to a bridged bicyclic system. Substituent atoms (other than hydrogen) on each side of a carboncarbon double bond may be in an E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the “E” configuration, the substituents having the highest priorities are on opposite sides in relationship to the carbon-carbon double bond. In the “Z” configuration, the substituents having the highest priorities are oriented on the same side in relationship to the carbon-carbon double bond.

[0153] Substituents around a carbon-carbon double bond can also be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.” The term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0154] Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (“tautomerism”) can occur. This can take the form of proton tautomerism in compounds of any one of the formulae described above containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0155] In certain instances tautomeric forms of the disclosed compounds exist, such as the tautomeric structures shown below:

[0156] When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.

[0157] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[0158] Conventional techniques for the prep aration / i solation of individual enantiomers / diastereomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of any one of the formulae described above contains an acidic or basic moiety, a base or acid such as 1 -phenyl ethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of any one of the formulae described above (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may 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 can be obtained from Chiral Technologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.

[0159] It must be emphasized that the compounds of any one of the formulae described above have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the present disclosure.

[0160] 3. Administration and Dosing

[0161] Typically, a compound of the present disclosure is administered in an amount effective to treat a condition as described herein. The compounds of the present disclosure can be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the present disclosure.

[0162] The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.

[0163] The compounds of the present disclosure may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0164] In another embodiment, the compounds of the present disclosure may also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

[0165] In another embodiment, the compounds of the present disclosure may also be administered topically to the skin or mucosa, that is, 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 may be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may also be administered directly to the eye or ear.

[0166] The dosage regimen for the compounds of the present disclosure and / or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the present disclosure is typically from about 0.001 to about 100 mg / kg (z.e., mg compound of the present disclosure per kg body weight) for the treatment of the indicated conditions discussed herein.

[0167] For oral administration, the compositions may be provided in the form of tablets containing 0.1- 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient. Intravenously, doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0168] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammal such as primates, rodents (mice, rats, hamsters, rabbits etc). In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.

[0169] 4. Pharmaceutical Compositions

[0170] In another embodiment, the present disclosure comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the present disclosure presented, a pharmaceutically acceptable salt, or a stereoisomer thereof with a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances can also be present.

[0171] As used herein, “pharmaceutically acceptable carrier or excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol 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.

[0172] The compositions of present disclosure may be in a variety of forms. These include, 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.

[0173] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. 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.

[0174] Oral administration of a solid dose form may be, for example, presented in discrete 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, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of any one of the formulae described above are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

[0175] In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and / or perfuming agents.

[0176] In another embodiment, the present disclosure comprises a parenteral dose form.

[0177] “Parenteral administration” includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and / or suspending agents.

[0178] In another embodiment, the present disclosure comprises a topical dose form.

[0179] “Topical administration” includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of present disclosure are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, Finnin and Morgan, J. Pharm. Set, 88:955-958, 1999.

[0180] Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of present disclosure is dissolved or suspended in a suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (z.e., absorbable gel sponges, collagen) and non-biodegradable (z.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0181] For intranasal administration or administration by inhalation, the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0182] In another embodiment, the present disclosure comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0183] Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.

[0184] The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman el al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rdEd.), American Pharmaceutical Association, Washington, 1999.

[0185] 5. Method of Treatment

[0186] The terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0187] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of signs or symptoms of the 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 in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0188] The term “treating spinal muscular atrophy (SMA)” or “treatment of spinal muscular atrophy (SMA)” includes one or more of the following effects: (i) reduction or amelioration of the severity of SMA; (ii) delay of the onset of SMA; (iii) inhibition of the progression of SMA; (iv) reduction of hospitalization of a subject; (v) reduction of hospitalization length for a subject; (vi) increase of the survival of a subject; (vii) improvement of the quality of life of a subject; (viii) reduction of the number of symptoms associated with SMA; (ix) reduction of or amelioration of the severity of one or more symptoms associated with SMA; (x) reduction of the duration of a symptom associated with SMA; (xi) prevention of the recurrence of a symptom associated with SMA; (xii) inhibition of the development or onset of a symptom of SMA; and / or (xiii) inhibition of the progression of a symptom associated with SMA.

[0189] More particular, the term “treating SMA” denotes one or more of the following beneficial effects: (i) a reduction in the loss of muscle strength; (ii) an increase in muscle strength; (iii) a reduction in muscle atrophy; (iv) a reduction in the loss of motor function; (v) an increase in motor neurons; (vii) a reduction in the loss of motor neurons; (viii) protection of SMN deficient motor neurons from degeneration; (ix) an increase in motor function; (x) an increase in pulmonary function; and / or (xi) a reduction in the loss of pulmonary function.

[0190] In further detail, the term “treating SMA” refers to the functional ability or retention of the functional ability for a human infant or a human toddler to sit up unaided or for a human infant, a human toddler, a human child or a human adult to stand up unaided, to walk unaided, to run unaided, to breathe unaided, to turn during sleep unaided, or to swallow unaided.

[0191] The term “treating Huntington’s disease (HD)”or “treatment of Huntington’s disease (HD)” includes one or more of the following effects: (i) reduction or amelioration of the severity of HD; (ii) delay of the onset of HD; (iii) inhibition of the progression of HD; (iv) reduction of hospitalization of a subject; (v) reduction of hospitalization length for a subject; (vi) increase of the survival of a subject; (vii) improvement of the quality of life of a subject; (viii) reduction of the number of symptoms associated with HD; (ix) reduction of or amelioration of the severity of one or more symptoms associated with HD; (x) reduction of the duration of a symptom associated with HD; (xi) prevention of the recurrence of a symptom associated with HD; (xii) inhibition of the development or onset of a symptom of HD; and / or (xiii) inhibition of the progression of a symptom associated with HD.

[0192] Symptoms of HD can include, but are not limited to uncontrollable dance-like movements (chorea), tremor, unusal eye movements, abnormal body postures, slurred speech, problems with swallowing, eating, speaking, and especially walking, as well as problems with behavior, emotion, thinking, and personality. The term “prevention” (or “prevent” or “preventing”), as used herein, refers to precluding, averting, obviating, forestalling, reducing the incidence of, stopping, or hindering the symptoms of a disease, disorder and / or condition. Prevention includes administration to a subject who does not exhibit symptoms of a disease, disorder, and / or condition at the time of administration.

[0193] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0194] The term “administer,” “administering,” or “administration” refers to methods introducing a compound disclosed herein, or a composition thereof, in or on a patient. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergam on; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0195] Generally, an effective amount of a compound taught herein varies depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. An effective amount of a compound of the present teachings may be readily determined by one of ordinary skill by routine methods known in the art.

[0196] The term “therapeutically effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as 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 anticancer agent, its mode of administration, combination treatment with other therapies, and the like.

[0197] The present disclosure is directed to compounds of formula (I) (including all its embodiments), which are useful in the treatment and / or prevention of a disease and / or condition associated with or modulated by HTT, especially wherein lowering mHTT in a subject is of therapeutic benefit, including but not limited to the treatment and / or prevention of HD.

[0198] In one embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. 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.

[0199] The present disclosure further provides a method of treating spinal muscular atrophy (SMA) 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.

[0200] In one embodiment, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of SMA in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0201] In one embodiment, the present disclosure provides a use for a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of SMA in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

[0202] In some embodiments, the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can enhance inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 gene, thereby increasing expression of SMN protein in a human subject in need thereof.

[0203] In one embodiment the present disclosure provides a method for treatment or prevention of diseases caused by an inactivating mutation or deletion in the SMN1 gene and / or associated with loss or defect of SMN1 gene function, particularly for the treatment or prevention of SMA, 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.

[0204] In one embodiment, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases caused by an inactivating mutation or deletion in the SMN1 gene and / or associated with loss or defect of SMN1 gene function, particularly for the treatment or prevention of SMA, in a subject in need thereof, comprising, administering to the subject an effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0205] In one embodiment, the present disclosure provides a use for a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of diseases caused by an inactivating mutation or deletion in the SMN1 gene and / or associated with loss or defect of SMN1 gene function, particularly for the treatment or prevention of SMA in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

[0206] 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.

[0207] In one embodiment, the present disclosure provides a use for 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 the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0208] In one embodiment, the present disclosure provides a use for 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 to the subject an effective amount of the medicament.

[0209] 6. Treatment Kits

[0210] One aspect of the present invention relates to a kit for conveniently and effectively carrying out the methods or uses in accordance with the present invention. In general, the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0211] The following representative examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and the equivalents thereof. These examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit 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 review of this document, including the examples which follow and the references to the scientific and patent literature cited herein.

[0212] The contents of the cited references are incorporated herein by reference to help illustrate the state of the art.

[0213] In addition, for purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “Organic Chemistry,” Morrison & Boyd (3d Ed), the entire contents of both of which are incorporated herein by reference.

[0214] 7. Preparation

[0215] The compounds of any one of the formulae described above, may be prepared by the general and specific methods described below, using the common general knowledge of one skilled in the art of synthetic organic chemistry. Such common general 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 may be prepared by routine methods known in the art.

[0216] In the preparation of the compounds of any one of the formulae described above, it is noted that some of the preparation methods described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in any one of the formulae described above precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protect! on / deprotecti on methods is also within the skill in 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.

[0217] For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxy carbonyl (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 reaction conditions described and can typically be removed without chemically altering other functionality in the any one of the formulae described above compounds.

[0218] The Schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present disclosure. Some of the compounds of the present disclosure may contain single or multiple chiral centers with the stereochemical designation (R) or (5). It will be apparent to one skilled in the art that all of the synthetic transformations can be conducted in a similar manner whether the materials are enantio-enriched or racemic. Moreover, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and in the chemistry literature.

[0219] EXAMPLES

[0220]

[0221] Section 1. General Methods and Analytical Methods a. General Methods

[0222] The compounds of the Examples were analyzed or purified according to one of the Purification Methods referred to below unless otherwise described. Where preparative TLC / HPLC or silica gel chromatography have been used, one skilled in the art may choose any combination of solvents 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 a Grace Reveleris X2 with ELSD purification systems or using pressurized nitrogen (-10-15 psi) to drive solvent through the column (“flash chromatography”). Wherein an SCX column has been used, the eluant conditions are MeOH followed by methanolic ammonia. Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum. b. Analytical Methods

[0223] Analytical LCMS instrumentation specifications:

[0224] Waters Acquity iClass UPLC with QDa mass spectrometer and PDA (photodiode array detector)

[0225] RxnQC / FrxQC / PurityQC Analysis LC / MS method conditions:

[0226] Ammonium hydroxide (basic pH) conditions

[0227] METHOD 1

[0228] MS mode: MS:ESI+ scan range 165-650 daltons

[0229] PDA: 200-400nm scan range

[0230] Column: Waters ACQUITY UPLC BEH C18 2.1x50mm, 1.7um; Part No. 186002350 Modifier: Ammonium hydroxide 0.2% (v / v) cone.

[0231] Method: 95% H2O / 5% MeCN (initial conditions) hold O.lmin, linear gradient to 5%H2O / 95% MeCN at 3.25min, hold 5% H20 / 95% MeCN to 3.5min. Flow rate, 0.8mL / min. METHOD 2

[0232] MS mode: MS:ESI+ scan range 165-650 daltons

[0233] PDA: 200-400nm scan range

[0234] Column: Waters ACQUITY UPLC BEH C18 2.1x30mm, 1.7um; Part No. 186002349

[0235] Modifier: Ammonium hydroxide 0.2% (v / v) cone.

[0236] Method: 95% H2O / 5% MeCN (initial conditions), linear gradient to 5% H2O / 95% MeCN at l.Omin, hold 5% H2O / 95% MeCN to 1.3min. Flow rate, 0.7mL / min.

[0237] Trifluoroacetic acid (acidic pH) conditions

[0238] METHOD 3

[0239] MS mode: MS:ESI+scan range 165-650 daltons

[0240] PDA: 200-400nm scan range

[0241] Column: Waters ACQUITY UPLC BEH C18 2.1x50mm, 1.7um; Part No. 186002350

[0242] Modifier: Trifluoroacetic acid 0.1% (v / v) cone.

[0243] Method: 95% H2O / 5% MeCN (initial conditions) hold 0. Imin, linear gradient to 5% H2O / 95% MeCN at 3.25min, hold 5% H2O / 95% MeCN to 3.5min. Flow rate, 0.8mL / min.

[0244] METHOD 4

[0245] MS mode: MS:ESI+ scan range 165-650 daltons

[0246] PDA: 200-400nm scan range

[0247] Column: Waters ACQUITY UPLC BEH C18 2.1x50mm, 1.7um; Part No. 186002349

[0248] Modifier: Trifluoroacetic acid 0.1% (v / v) cone.

[0249] Method: 95% H2O / 5% MeCN (initial conditions), linear gradient to 5% H2O / 95% MeCN at l.Omin, hold 5% H2O / 95% MeCN to 1.3min. Flow rate, 0.7mL / min.

[0250] Analytical LCMS instrumentation specifications:

[0251] 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 1290 Series LC / MSD system with DAD\ELSD and Agilent LC\MSD (G6125B) mass-spectrometer, Shimadzu LCMS-2020.

[0252] RxnQC / FrxQC / PurityQC Analysis LC / MS method conditions:

[0253] Formic acid (acidic pH) conditions

[0254] METHOD 5

[0255] Inject volume: 0.5 pl, Column Temperature: 60 °C, UV scan: 207-223 nM, 246-262 nM, 272- 288 nM, Agilent Poroshell 120 SB-C18 4.6x30mm 2.7 pm with UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6x 5mm 2.7 pm, Mobile phase A: 0.1% FA in Water, Mobile phase B: 0.1% FA in Acetonitrile.

[0256] Details of Elution

[0257] METHOD 6

[0258] Inject volume: 0.5 pl ; Column Temperature : 60 °C; UV scan: 207-223 nM, 246-262 nM, 272-288 nM

[0259] Agilent Poroshell 120 SB-C18 4.6x30mm 2.7 pm with UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6x 5mm 2.7 pm, Mobile phase A: 0.1% FA in Water, Mobile phase B: 0.1% FA in Acetonitrile

[0260] Details of Elution

[0261] METHOD 7

[0262] MS mode: MS ESI+ scan range 100-1000 daltons PDA: 190-370 nm scan range

[0263] Column: Xtimate C18 2.1*30mm, 3um

[0264] Modifier: A Phase: water(4L)+TFA(1.5mL), B Phase: acetonitrile(4L)+TFA(0.75mL)

[0265] Method: using the elution gradient 10%-80% (solvent B) over 1.35 or 3.35 minutes and holding at 80% for 0.9 minutes at a flow rate of 0.8 ml / min.

[0266] METHOD 8

[0267] Description:

[0268] Mobile phase: Ramp from 5% ACN (0.018%TFA) in water (0.037%TFA) to 95% ACN in 3.0min, Flow rate is set at l.OmL / min; then hold at 95% ACN for 0.60 minutes Flow rate is set from 1.OmL / min to 1.5mL / min; return back to 5% ACN in water and hold for 0.40 min.

[0269] Flow rate is set at 1.5mL / min.

[0270] Column temperature at 50 °C.

[0271] The column is of Shim-pack Velox SP-C18 2.7pm 3.0*30mm. METHOD 9

[0272] Description:

[0273] Mobile phase: Ramp from 5% ACN (0.01875%TFA) in water (0.0375%TFA) to 95% ACN in water in 0.60 min, Flow rate is set at 2.0mL / min; then hold at 95% ACN for 0.18 minutes Flow rate is set at 2.0mL / min; return back to 5% ACN in water and hold for 0.02 min. Flow rate is set at 2.0mL / min.

[0274] Column temperature at 50°C.

[0275] The column is of Kinetex® EVO C18 2.1x30mm 5um.

[0276] METHOD 10

[0277] Description:

[0278] Mobile phase: Ramp from 5% ACN (0.01875%TFA) in water (0.0375%TFA) to 95% ACN in 3.20 min, Flow rate is set at 1.5mL / min; then hold at 95% ACN for 0.30 minutes Flow rate is set at 1.5mL / min; return back to 5% ACN in water and hold for 0.30 min. Flow rate is set at 2. OmL / min. Column temperature at 50°C. The column is of Kinetex® EVO C18 4.6x50mm 5um.

[0279] METHOD 11 (3 min)

[0280] Ramp from 0%-60% (solvent B) over 2 minutes holding at 60% for 0.48 minutes at flow rate of ImL / minutes. Wavelength: 220 and 254 nm.

[0281] METHOD 12:

[0282] Ramp from 0%-60% (solvent B) over 3 minutes holding at 60% for 0.5 minutes at flow rate of 0.8mL / minutes. Wavelength: UV 220 and 254 nm.

[0283] METHOD 13 (7 mins): Ramp from 0%-60% (solvent B) over 6 minutes holding at 60% for 0.5 minutes at flow rate of 0.8mL / minutes. Wavelength: UV 220 and 254 nm.

[0284] METHOD 14 (10-80 6 min):

[0285] MS mode: MS ESI+ scan range 100-1000 daltons

[0286] PDA: 190-370 nm scan range

[0287] Column: Xtimate C18 2.1*30mm, 3um

[0288] Modifier: A Phase: water(4L)+TFA(1.5mL), B Phase: acetonitrile(4L)+TFA(0.75mL)

[0289] Method: using the elution gradient 10%-80% (solvent B) over 5.35 minutes and holding at 80% for 0.9 minutes at a flow rate of 0.8 ml / min. Wavelength: UV 220 and 254 nm.

[0290] METHOD 15:

[0291] Modifier: A Phase: water(4L)+TFA(1.5mL), B Phase: acetonitrile(4L)+TFA(0.75mL)

[0292] Ramp from 0%-60% (solvent B) over 4 minutes holding at 60% for 0.5 minutes at flow rate of 0.8mL / minutes. Wavelength: UV 220 and 254 nm.

[0293] METHOD 16:

[0294] Modifier: A Phase: water(4L)+TFA(1.5mL), B Phase: acetonitrile(4L)+TFA(0.75mL)

[0295] Ramp from 0%-60% (solvent B) over 8 minutes holding at 60% for 0.5 minutes at flow rate of 0.8mL / minutes. Wavelength: UV 220 and 254 nm.

[0296] METHOD 17:

[0297] Modifier: A Phase: water(4L)+TFA(1.5mL), B Phase: acetonitrile(4L)+TFA(0.75mL)

[0298] Ramp from 10%-80% (solvent B) over 2 minutes holding at 60% for 0.5 minutes at flow rate of 0.8mL / minutes. Wavelength: UV 220 and 254 nm.

[0299] METHOD 18:

[0300] Modifier: A Phase: water(4L)+TFA(1.5mL), B Phase: acetonitrile(4L)+TFA(0.75mL)

[0301] Ramp from 10%-80% (solvent B) over 2 minutes holding at 60% for 0.5 minutes at flow rate of 0.8mL / minutes. Wavelength: UV 220 and 254 nm.

[0302] METHOD 19:

[0303] Modifier: A Phase: water(4L)+TFA(1.5mL), B Phase: acetonitrile(4L)+TFA(0.75mL) Ramp from 30%-100% (solvent B) over 6 minutes holding at 60% for 0.5 minutes at flow rate of 0.8mL / minutes. Wavelength: UV 220 and 254 nm.

[0304] METHOD 20:

[0305] Modifier: A Phase: water(4L)+TFA(1.5mL), B Phase: acetonitrile(4L)+TFA(0.75mL)

[0306] Ramp from 30%-90% (solvent B) over 3 minutes holding at 60% for 0.5 minutes at flow rate of 0.8mL / minutes. Wavelength: UV 220 and 254 nm.

[0307] Preparative HPLC-MS conditions:

[0308] HPLC-MS instrumentation specifications

[0309] Waters Autopurification with QDa mass spectrometer and PDA (photodiode array detector).

[0310] Ammonium hydroxide (basic pH) conditions

[0311] Flow rate: 30mL / min

[0312] MS mode: MS:ESI+ scan range 165-650 daltons

[0313] PDA: 200-400nm scan range

[0314] Column: Waters XSELECT CSH C18 PREP 19x100mm, 5um; Part No. 186005421

[0315] Modifier: 0.2% Ammonium hydroxide (v / v) cone.

[0316] Method: A%H2O / B%MeCN (initial conditions) hold 0.5min, linear gradient to A% H2O / B% MeCN at 8min, ramp to 5% H2O / 95% MeCN at 8.5min, HOLD 5% H2O / 95% MeCN to lOmin.

[0317] Flow rate: 50mL / min

[0318] MS mode: MS:ESI+ scan range 165-650 daltons

[0319] PDA: 200-400nm scan range

[0320] Column: Waters XSELECT CSH C18 PREP 30x100mm, 5um; Part No. 186005425

[0321] Modifier: 0.2% Ammonium hydroxide (v / v) cone.

[0322] Method: A% H2O / B% MeCN (initial conditions) hold 0.5min, linear gradient to A%H20 / B%MeCN at 8min, ramp to 5% H2O / 95% MeCN at 8.5min, HOLD 5% H2O / 95% MeCN to lOmin.

[0323] Flow rate, 60mL / min

[0324] MS mode: MS:ESI+ scan range 165-650 daltons

[0325] PDA: 200-400nm scan range

[0326] Column: Waters XSELECT CSH C18 PREP 30x50mm, 5um; Part No. 186005423 Modifier: 0.2% Ammonium hydroxide (v / v) cone.

[0327] Method: A% H2O / B% MeCN (initial conditions) hold 0.5min, linear gradient to A% H2O / B%

[0328] MeCN at 8min, ramp to 5% H2O / 95% MeCN at 8.5min, HOLD 5% H2O / 95% MeCN to lOmin.

[0329] Column: Boston Prime C18 150 x 30 mm x 5 um; Condition: water (NH3H2O+NH4HCO3)- ACN; Gradient (% organic): 0-100% optimized for each example; Flow Rate (mL / min) 25.

[0330] Column: YMC Actus Trial Cl 8 20*100 5 mkm column; gradient mixture H2O-MeOH-

[0331] Ammonia 0.1% as a mobile phase optimized for each example

[0332] Trifluoroacetic acid (acidic pH) conditions

[0333] Flow rate, 30mL / min

[0334] MS mode: MS:ESI+ scan range 165-650 daltons

[0335] PDA: 200-400nm scan range

[0336] Column: Waters Sunfire OBD C18 PREP 19x100mm, 5um; Part No. 186002567

[0337] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0338] Method: A% H2O / B% MeCN (initial conditions) hold 0.5min, linear gradient to A% H2O / B% MeCN at 8min, ramp to 5% H2O / 95% MeCN at 8.5min, HOLD 5% H2O / 95% MeCN to lOmin.

[0339] Flow rate, 50mL / min

[0340] MS mode: MS:ESI+ scan range 165-650 daltons

[0341] PDA: 200-400nm scan range

[0342] Column: Waters Sunfire OBD C18 PREP 30x100mm, 5um; Part No. 186002572

[0343] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0344] Method: A% H2O / B% MeCN (initial conditions) hold 0.5min, linear gradient to A% H2O / B% MeCN at 8min, ramp to 5% H2O / 95% MeCN at 8.5min, HOLD 5% H2O / 95% MeCN to lOmin.

[0345] Flow rate, 60mL / min

[0346] MS mode: MS:ESI+ scan range 165-650 daltons

[0347] PDA: 200-400nm scan range

[0348] Column: Waters Sunfire OBD C18 PREP 30x50mm, 5um; Part No. 186002570

[0349] Modifier: 0.1% Trifluoroacetic acid (v / v) cone.

[0350] Method: A% H2O / B% MeCN (initial conditions) hold 0.5min, linear gradient to A% H2O / B% MeCN at 8min, ramp to 5% H2O / 95% MeCN at 8.5min, HOLD 5% H2O / 95% MeCN to lOmin. Formic acid (FA, acidic pH) conditions

[0351] Column: Welch Xtimate C18 150 x 30 mm x 5 um or Phenomenex luna C18 150 x 25 mm x 10 um; Condition: water(FA)-ACN; Gradient (% organic): optimized for each example; Flow Rate (mL / min) 25.

[0352] Hydrochloric acid (HC1, acidic pH) conditions

[0353] Column: Boston Green ODS 150 x 30 mm x 5 um; Condition: water(HCl)-ACN; Gradient (% organic): 0-100% optimized for each example; Flow Rate (mL / min) 25.

[0354] Analytical SFC instrumentation specifications

[0355] Waters Acquity UPC2SFC with QDa mass spectrometer and PDA (photodiode array detector).

[0356] Analytical Screening Conditions

[0357] MS mode: MS:ESI+ scan range 100-650 daltons

[0358] PDA: 200-400nm scan range

[0359] Columns: See below

[0360] Solvent: Airgas Bone Dry CO2

[0361] Cosolvents: Methanol, Ethanol, or Isopropanol with either 0.1% Diethylamine, 0.1% Dimethylethanolamine, or neutral

[0362] Method: Isocratic conditions; typically 60% CO2: 40% cosolvent or 70% CO2: 30% cosolvent, Flow rate, 3.0mL / min.

[0363] Preparative SFC instrumentation specifications

[0364] Waters PreplOO SFC with QDa mass spectrometer, PDA (photodiode array detector,) and 2767 Collection bed.

[0365] Preparative Conditions

[0366] Method: X% Cosolvent w / Y% modifier in CO2, isocratic conditions.

[0367] Flow rate: lOOmL / min

[0368] Automated back pressure regulator: 120 bar

[0369] Manual back pressure regulator: 40psi for MeOH or EtOH, 60psi for iPrOH

[0370] Column oven temperate: 40° C

[0371] MS mode: MS:ESI+ scan range 150-650 daltons

[0372] PDA: 200-400nm scan range. SFC Columns, Analytical:

[0373] AD-H: Daicel Chiralpak AD-H, 4.6mm x 250mm, 5um, Part No 19325

[0374] AS-H: Daicel Chiralpak AS-H, 4.6mm x 250mm, 5um, Part No 20325 OD-H: Daicel Chiralpak OD-H, 4.6mm x 250mm, 5um, Part No 14325 OX-H: Daicel Chiralpak OX-H, 4.6mm x 250mm, 5um, Part No 63325 IA: Daicel Chiralpak IA, 4.6mm x 250mm, 5um, Part No 80325 IB: Daicel Chiralpak IB, 4.6mm x 250mm, 5um, Part No 81325 IC: Daicel Chiralpak IC, 4.6mm x 250mm, 5um, Part No 83325 IG: Daicel Chiralpak IG, 4.6mm x 250mm, 5um, Part No 87325

[0375] Cell-2: Phenomenex Lux Cellulose-2, 4.6mm x 150mm, 3 um, Part No. 00F-4456-E0 Cell-4: Phenomenex Lux Cellulose-4, 4.6mm x 150mm, 3 um, Part No. 00F-4490-E0

[0376] SFC Columns, Preparative:

[0377] AD-H: Daicel Chiralpak AD-H, 30mm x 250mm, 5um, Part No 19475

[0378] AS-H: Daicel Chiralpak AS-H, 30mm x 250mm, 5um, Part No 20475 OD-H: Daicel Chiralpak OD-H, 30mm x 250mm, 5um, Part No 14475 OX-H: Daicel Chiralpak OX-H, 30mm x 250mm, 5um, Part No 63475 IA: Daicel Chiralpak IA, 30mm x 250mm, 5um, Part No 80475 IB: Daicel Chiralpak IB, 30mm x 250mm, 5um, Part No 81475 IC: Daicel Chiralpak IC, 30mm x 250mm, 5um, Part No 83475 IG: Daicel Chiralpak IG, 30mm x 250mm, 5um, Part No 87475

[0379] Cell-2: Phenomenex Lux Cellulose-2, 30mm x 250mm, 5 um, Part No. 00G-4457-U0-AX Cell -4: Phenomenex Lux Cellulose-4, 30mm x 250mm, 5 um, Part No. 00G-4491-U0-AX

[0380] 'II NMR

[0381] 1H nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. The1H NMR spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance DRX 500, Bruker Avance III 400 MHz, Varian-400 VNMRS, Varian Unityplus 400, or Varian-400 MR. Characteristic chemical shifts (d) are given in parts-per-million downfield from tetramethyl silane (for 'H NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: chloroform-t / , deuterochloroform; dimethyl sulfoxide- e, hexadeuterodimethyl sulfoxide; and methanol -c , deuteromethanol. Where appropriate, tautomers may be recorded within the NMR data; and some exchangeable protons may not be visible.

[0382] Section 2. Preparation of Intermediates

[0383] Intermediate 1

[0384] Step a: 5-bromo-6-chloropyrazin-2-amine (44.0 g, 211.1 mmol, 1.0 eq.) and tert-butyl 4- ethynylpiperidine-1 -carboxylate (48.6 g, 232.2 mmol 1.1 eq.) were dissolved in toluene (1.0 L, 0.21 M) then treated with Cui (4.0 g, 21.1 mmol, 0.1 eq.), Pd(PPhs)4 (24.4 g, 21.1 mmol, 0.1 eq.), and TEA (106.8 g, 1.1 mol, 147.1 mL, 5.2 eq.). The solution was then stirred at 100 °C for 3 hours. The mixture was filtered and concentrated to give the residue, which was added MTBE / EtOAc (10 / 1, 400.0 mL) and stirred at 25 °C for 1 hour. The mixture was filtered to give tert-butyl 4-((5-amino-3-chloropyrazin-2-yl)ethynyl)piperidine-l-carboxylate (45.5 g, 89.2% yield) as a white solid. MS: m / z 359.1 [M+Na]+; RT 0.49 min (Method 9).JH NMR (400MHz, dimethyl sulfoxide-t / 6): 8 (ppm) 7.77 (s, 1H), 7.22 (s, 2H), 3.54-3.65 (m, 2H), 3.16- 3.24 (m, 2H), 2.85-2.95 (m, 1H), 1.78-1.86 (m, 2H), 1.46-1.57 (m, 2H), 1.40 (s, 9H).

[0385] Step b: A solution of tert-butyl 4-((5-amino-3-chloropyrazin-2-yl)ethynyl)piperidine-l- carboxylate (45.5 g, 135.1 mmol, 1 eq.) in DMF (500 mL, 0.27 M) was treated with NaHS (27.5 g, 343.8 mmol, 2.5 eq., 70% purity) at 20 °C. The solution was then heated at 90 °C under N2 for 2 hours. The reaction mixture was concentrated to give the crude residue, which was suspended in EtOAc (300.0 mL) and stirred at 50 °C for 1 hour. The suspension was filtered and the mother liquor was concentrated to give tert-butyl 4-(3-aminothieno[2,3-Z>]pyrazin-6- yl)piperidine-l -carboxylate (27.2 g, crude) as a red solid, which was used without further purification MS: m / z 357.0 [M+Na]+; 0.46 min (Method 9). 'H NMR (400MHz, dimethyl sulfoxide-t / e): 6 (ppm) 7.92 (s, 1H), 7.04 (s, 1H), 6.60 (s, 1H), 3.93-4.12 (m, 2H), 2.95-3.06 (m, 1H), 2.77-2.92 (m, 2H), 1.91-2.01 (m, 2H), 1.46-1.54 (m, 2H), 1.41 (s, 9H). Step c: A solution of tert-butyl 4-(3-aminothieno[2,3-Z>]pyrazin-6-yl)piperidine-l-carboxylate (23.0 g, 68.8 mmol, 1.0 eq.) in DCM (250.0 mL, 0.28 M) at 0 °C was treated with isopentyl nitrite (36.6 g, 275.1 mmol, 4.0 eq.) then TMSC1 (22.4 g, 206.3 mmol, 22.4 mL, 3.0 eq.) then stirred at 20 °C for 1.5 hours. The mixture was quenched with water (300.0 mL) and extracted with DCM (200.0 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatograph on silica gel (EtOAc in PE from 0 % to 17 %) to afford tert-butyl 4-(3- chlorothieno[2,3-Z>]pyrazin-6-yl)piperidine-l -carboxylate (8.2 g, 33.5% yield) as a light yellow solid. MS: RT m / z 298.0 [M-Boc+H]+; RT 4.20 (Method 14). 'H NMR (400MHz, dimethyl sulfoxide-t / e): 8 (ppm) 8.79 (s, 1H), 7.49 (s, 1H), 3.96-4.17 (m, 2H), 3.16-3.27 (m, 1H), 2.73- 3.05 (m, 2H), 2.93-2.13 (m, 2H), 1.53-1.63 (m, 2H), 1.41 (s, 9H).

[0386] Intermediate 2

[0387] Step a: 3-bromo-5-chloro-2-iodopyridine (9.0 g, 28.2 mmol, 1.0 eq.) and tert-butyl 4- ethynylpiperidine-1 -carboxylate (6.5 g, 31.1 mmol 1.1 eq.) were dissolved in toluene (90 mL, 0.21 M) then treated with Cui (538.4 mg, 2.8 mmol, 0.1 eq.), Pd(PPhs)4 (3.3 g, 2.8 mmol, 0.1 eq.), and TEA (14.3 g, 141.3 mmol, 19.7 mL, 5.2 eq.). The solution was then stirred at 100 °C for 3 hours. The mixture was filtered and concentrated to give the residue, which was added MTBE / EtOAc (10 / 1, 100.0 mL) and stirred at 25 °C for 1 hour. The mixture was filtered to give tert-butyl 4-((3-bromo-5-chloropyridin-2-yl)ethynyl)piperidine-l-carboxylate (9.1 g, 95.5% yield) as a brown oil. MS: m / z 344.7 [M+H-56]+; RT 0.53 min (Method 9). 'H NMR (400MHz, chloroform-t / ): 5 (ppm) 8.43 (d, J= 2.0 Hz, 1H), 7.91 (d, J= 2.4 Hz, 1H), 3.69-3.72 (m, 2H), 3.35-3.38 (m, 2H), 2.94-2.95 (m, 1H), 1.87-1.88 (m, 2H), 1.75-1.78 (m, 2H), 1.46 (s, 9H).

[0388] Step b: A solution of tert-butyl 4-((3-bromo-5-chloropyridin-2-yl)ethynyl)piperidine-l- carboxylate (9.0 g, 26.7 mmol, 1 eq.) in DMF (120 mL, 0.27 M) was treated with NaHS (5.4 g, 66.8 mmol, 2.5 eq., 70% purity) at 20 °C. The solution was then heated at 90 °C under N2 for 1 hour. The reaction mixture was concentrated to give the crude residue, which was suspended in EtOAc and filtered. The mother liquor was concentrated to give the crude product, which was purified on silica gel column chromatography (from PE / EtOAc = 1 / 0 to 85 / 15, TLC: PE / EtOAc = 3 / 1, Rf = 0.3) to give tert-butyl 4-(6-chlorothieno[3,2-Z>]pyridin-2- yl)piperidine-l -carboxylate (8.5 g, 68.1% yield) as a white solid. MS: m / z 353.1 [M+H]+; RT 4.63 min (Method 14). ' H NMR (400MHz, methanol-^): 5 (ppm) 8.53 (d, J = 2.0 Hz, 1H), 8.37 (d, J= 2.4 Hz, 1H), 7.27 (s, 2H), 4.20 (d, J= 13.2 Hz, 2H), 3.17-3.31 (m, 1H), 2.95 (br s, 2H), 2.09 (d, J= 12.4 Hz, 2H), 1.63-1.72 (m, 2H), 1.48 (s, 9H).

[0389] Intermediate 3

[0390] Step a: 6-chloro-3-iodopyridazin-4-amine (7.4 g, 45.1 mmol, 1.0 eq.) and tert-butyl 4- ethynylpiperidine-1 -carboxylate (9.4 g, 45.12 mmol, 1.1 eq.) were dissolved in acetonitrile (100 mL, 0.45 M) then treated with Cui (257.8 mg, 1.35 mmol, 0.03 eq.), and TEA (22.8 g, 225.62 mmol, 31.45 mL, 5.0 eq.). The solution was degassed and purged with N2 for 3 time, then Pd(PPhs)4 (3.3 g, 2.8 mmol, 0.1 eq.) was added and the mixture was stirred at 60 °C for 6 hours under N2 atmosphere. The mixture was filtered and concentrated to give the crude residue, which was suspended in EtOAc (150.0 mL) and stirred at 25 °C for 30 minutes. The mixture was filtered to obtain the crude residue, which was dissolved in H2O (100.0 mL) and stirred at 25 °C for another 30 min. The suspension was filtered again the crude product was concentrated under reduced pressure to give tert-butyl 4-((4-amino-6-chloropyridazin-3- yl)ethynyl)piperidine-l -carboxylate (1.3 g, 63.30% yield) as a white solid. MS: m / z 281.0 [M+H]+; RT 0.4 min (Method 9). *HNMR (400MHz, dimethyl sulfoxide-tL): 5 (ppm) 7.35 (s, 1H), 6.78 (br s, 2H), 3.63-3.78 (m, 2H), 3.00-3.10 (m, 2H), 2.90-2.99 (m, 1H), 1.85-1.89 (m, 2H), 1.59-1.63 (m, 2H), 1.40 (s, 9H).

[0391] Step b: A solution of tert-butyl 4-((4-amino-6-chloropyridazin-3-yl)ethynyl)piperidine-l- carboxylate (24.0 g, 71.26 mmol) in dibromomethane (200.0 mL) was treated with isopentyl nitrite (35.9 g, 306.40 mmol, 41.16 mL) at 0 °C. Then TMSBr (32.7 g, 213.77 mmol, 28.2 mL) was added dropwise to the mixture at 0 °C under N2, and the mixture was stirred at 25 °C for 16 hours. The mixture was diluted with H2O (300.0 mL), extracted with DCM (100.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 4 / 1) to give tert-butyl 4- ((4-bromo-6-chloropyridazin-3-yl)ethynyl)piperidine-l -carboxylate (7.2 g, crude) as a brown oil. MS: m / z 423.9 [M+H]+; RT 0.49 min (Method 9).

[0392] Step c: A solution of tert-butyl 4-((4-bromo-6-chloropyridazin-3-yl)ethynyl)piperidine-l- carboxylate (14.2 g, 35.44 mmol, 1 eq.) in DMF (100 mL, 0.35 M) was treated with NaHS (2.8 g, 35.44 mmol, 1.0 eq., 70% purity. The solution was heated at 90 °C under N2 for 2 hours. The reaction mixture was concentrated to give the crude residue, which was suspended in EtOAc and filtered. The mother liquor was concentrated to give the crude product, which was purified on silica gel column chromatography (from PE / EtOAc = 1 / 0 to 2 / 1) to give tert-butyl 4-(6-chlorothieno[3,2-Z>]pyridin-2-yl)piperidine-l-carboxylate (3.2 g, 25.52% yield) as a yellow solid. MS: m / z 353.9 [M+H]+; RT 0.46 min (Method 9). ' H NMR: (400MHz, dimethyl sulfoxide-t / e) 8 (ppm) 8.61 (s, 1H), 7.69 (s, 1 H), 4.04-4.10 (m, 2H), 3.16-3.27 (m, 1H), 2.80- 2.90 (m, 2H), 2.03-2.06 (m, 2H), 1.53-1.64 (m, 2H), 1.41 (s, 9H).

[0393] Intermediate 4

[0394] Step a: 5-bromo-6-chloropyrazin-2-amine (58.0 g, 278.25 mmol, 1.0 eq.), trimethylsilylacetylene (35.5 g, 361.7 mmol, 51.1 mL, 1.1 eq.), Cui (2.6 g, 13.9 mmol, 0.1 eq.), and TEA (106.8 g, 1.1 mol, 147.1 mL, 5.2 eq.), were dissolved in THF (1.0 L, 0.21 M) and the solution was degassed and purged with N2 3 times. The mixture was treated with Pd(PPhs)4 (9.8 g, 13.9 mmol, 0.1 eq.) then stirred at 80 °C for 16 hours under N2. The mixture was filtered and concentrated to give the residue, which was suspended in EtOAc (100.0 mL) and stirred at 25 °C for 30 minutes. The mixture was filtered and the filter cake was washed with PE (3 x lOOmL) to give 6-chloro-5-((trimethylsilyl)ethynyl)pyrazin-2- amine (53.2 g, 84.7% yield) as a brown solid. MS: m / z 225.9 [M+H]+; RT 0.49 min (Method 9). 'H NMR (400MHz, dimethyl sulfoxide-t / 6): 8 (ppm) 7.78 (s, 1H), 7.38 (br s, 2H), 0.22 (s, 9H).

[0395] Step b: A solution of 6-chloro-5-((trimethylsilyl)ethynyl)pyrazin-2-amine (53.0 g, 234.8 mmol, 1 eq.) in DMF (500 mL, 0.27 M) was treated with NaHS (33.5 g, 586.9 mmol, 2.5 eq., 70% purity) at 20 °C. The solution was then heated at 90 °C under N2 for 2 hours. The reaction mixture was concentrated to give the crude residue, which was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 1 / 1) to give thieno[2,3-Z>]pyrazin-3-amine (23.5 g, 66.2% yield) as a light-yellow solid. MS: m / z 151.9 [M+H]+; RT 0.24 min (Method 9). 'H NMR (400MHz, dimethyl sulfoxide-t / 6): 6 (ppm) 7.98 (s, 1H), 7.49 (d, J = 6.0 Hz, 1H), 7.26 (d, J= 6.0 Hz, 1H), 6.71 (s, 2H).

[0396] Step c: A solution of thieno[2,3-Z>]pyrazin-3-amine (30.0 g, 198.4 mmol) in DMF (150.0 mL) and Acetic acid (150 mL) was treated with NIS (66.9 g, 297.6 mmol) and stirred at 25 °C for 2 hours. The mixture was concentrated to give the crude residue, which was purified by column chromatography (SiCh, PE / EtOAc = 100 / 1 to 1 / 1) to afford 6-iodothieno[2,3-Z>]pyrazin-3- amine (21.0 g, 60.00% yield) as an orange solid. MS: m / z 277.8 [M+H]+; RT 0.36 min (Method 9). 'H NMR (400MHz, dimethyl sulfoxide- e): 6 (ppm) 7.88 (s, 1H), 7.62 (s, 1H), 6.81 (br s, 2H).

[0397] Step d: A solution of 6-iodothieno[2,3-Z>]pyrazin-3-amine (22.0 g, 79.4 mmol, 1.0 eq.) in DCM (200.0 mL, 0.40 M) at 0 °C under N2 was treated first with isopentyl nitrite (42.3 g, 317.6 mmol, 4.0 eq.), then TMSC1 (25.9 g, 238.2 mmol, 30.2 mL, 3.0 eq.) was added dropwise. The solution was stirred at 20 °C for 16 hours under N2 atmosphere. The mixture was quenched with water (200.0 mL) and extracted with DCM (100.0 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by preparative HPLC (Column: Phenomenex luna C18 (250 x 70mm, 10 pm) Condition: water (HC1) - ACN; B%: 40% - 75%, 25 min) followed by lyophilization to give 3-chloro-6-iodothieno[2,3-Z>]pyrazine (9.89 g, 42.6% yield) as a yellow solid. MS: m / z 296.8 [M+H]+; RT 0.53 min (Method 9). ' H NMR (400MHz, dimethyl sulfoxide- e): 6 (ppm) 8.76 (s, 1H), 8.09 (s, 1H).

[0398] Intermediate 5 A and B

[0399] Step a: A solution of tert-butyl (LS',5>)-6-formyl-3-azabicyclo[3. l ,0]hexane-3-carboxylate (9.00 g, 42.6 mmol, 1.0 eq.) in MeOH (150 mL, 0.28 M) was treated with 1-diazo-l- dimethoxyphosphoryl-propan-2-one (8.19 g, 42.6 mmol, 1.0 eq.) and K^CCL (10.17 g, 85.2 mmol, 2.0 eq.) then the mixture was stirred at 20 °C for 12 hours. The mixture was filtered and concentrated to obtain the crude residue, which was purified by flash column chromatography on silica gel (PE:EtOAc from 0% to 15 %) to afford tert-butyl (1 R,5S)-6- ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (6 g, 28.95 mmol, 67.95% yield) as a yellow solid. TLC (PE / EtOAc =3 / 1, Rf= 0.61, 0.7). 'H NMR (400MHz, chloroform^): 8 (ppm) 3.70-3.52 (m, 2H), 3.43-3.28 (m, 2H), 1.88 (d, J= 2.1 Hz, 1H), 1.85-1.80 (m, 2H), 1.43 (s, 9H), 1.13-1.08 (m, 1H).

[0400] Step b: A solution of tert-butyl (lA,55)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.00 g, 24.12 mmol, 1.0 eq.) and 5-bromo-6-chloropyrazin-2-amine (5.03 g, 24.12 mmol, 1.0 eq.) in toluene (150 mL, 0.16 M) was treated with Pd(PPhs)4 (2.79 g, 2.41 mmol, 0.1 eq.), Cui (229.71 mg, 1.21 mmol, 0.05 eq.), and TEA (12.21 g, 120.62 mmol, 16.81 mL, 5.0 eq.) in turn at 20 °C. The mixture was stirred at 100 °C for 3 hours under N2. The mixture was filtered and concentrated under reduced pressure to obtain the crude residue, which was purified by column chromatography on silica gel (EtOAc / PE = 0 / 1 to 1 / 1, TLC: EtOAc / PE = 1 / 1 Rf = 0.15, 0.25) to afford tert-butyl (15,5A)-6-[2-(5-amino-3-chloro-pyrazin-2-yl)ethynyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (5.3 g, 15.83 mmol, 65.62% yield) as a light yellow solid. MS: m / z 335.0 [M+H]+; RT 0.47 min (Method 9). ' H NMR (400MHz, chloroform-tZ): 6 (ppm) 7.83-7.78 (m, 1H), 4.79 (br s, 2H), 3.76-3.54 (m, 3H), 3.45-3.34 (m, 2H), 2.03-1.89 (m, 2H), 1.48-1.42 (m, 9H).

[0401] Step c: A solution of tert-butyl (15,5A)-6-[2-(5-amino-3-chloro-pyrazin-2-yl)ethynyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (5.3 g, 15.83 mmol, 1.0 eq.) in DMF (100 mL, 0.16 M) was treated with NaHS (2.26 g, 39.58 mmol, 2.5 eq.) at 20 °C. The reaction mixture was stirred at 90 °C for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude residue, which was purified by column chromatography on silica gel (EtOAc / PE = 0 / 1 to 1 / 1, TLC: EtOAc / PE = 1 / 1, Rf = 0.2, 0.1) to afford tert-butyl (lA,55)-6-(3-aminothieno[2,3- Z>]pyrazin-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (4.5 g, 13.54 mmol, 85.51% yield) as light yellow oil. MS: m / z 333.0 [M+H]+; RT 0.46 min (Method 9).JH NMR (400MHz, chloroform-tZ): 8 (ppm) 7.99-7.96 (m, 1H), 6.95-6.91 (m, 1H), 4.60-4.51 (m, 2H), 3.86-3.70 (m, 2H), 3.52-3.43 (m, 2H), 2.01-1.92 (m, 3H), 1.47 (s, 9H).

[0402] Step d: A solution of tert-butyl (lA,55)-6-(3-aminothieno[2,3-Z>]pyrazin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (4.5 g, 13.54 mmol, 1.0 eq.) in DCM (150 mL, 0.1 M) at 0 °C was treated with isopentyl nitrite (6.82 g, 58.21 mmol, 7.82 mL, 4.3 eq.) then TMSC1 (4.41 g, 40.61 mmol, 5.15 mL, 3.0 eq.) was added dropwise. The mixture was warmed to room temperature and stirred at 20 °C for 1.5 hours. The reaction was quenched with water (100.00 mL) and extracted with DCM (100.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue, which was purified by column chromatography on silica gel (EtOAc / PE = 0 / 1 to 1 / 6, TLC: EtOAc / PE = 1 / 3, Rf = 0.7) to afford tert-butyl (lA,55)-6-(3-chlorothieno[2,3-Z>]pyrazin- 6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 5 A, 2.7 g, 7.67 mmol, 56.69% yield) as a light yellow solid and tert-butyl (lA,55)-6-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-3- azabicyclo[3.1.0]hexane-3 -carboxylate (Intermediate 5B, 270 mg, 767.37 pmol, 5.67% yield) as a brown solid.

[0403] Product A:

[0404] MS: m / z 351.9 [M+H]+; RT 0.58 min (Method 9). 'HNMR (400MHz,chloroform-tZ): 5 (ppm) 8.56-8.50 (m, 1H), 7.13-7.05 (m, 1H), 3.89-3.73 (m, 2H), 3.55-3.46 (m, 2H), 2.11-2.08 (m, 1H), 2.07-2.02 (m, 2H), 1.47 (s, 9H).

[0405] Product B:

[0406] MS: m / z 351.9 [M+H]+RT 0.53 min (Method 9). 'H-NMR (400MHz,chloroform-tZ): 5 (ppm) 8.63 (s, 1H), 7.34 (d, J= 1.2 Hz, 1H), 3.84 (dd, J= 11.9, 6.1 Hz, 2H), 3.50-3.40 (m, 2H), 2.45-2.37 (m, 1H), 2.21-2.14 (m, 2H), 1.01 (s, 9H). Intermediate 6

[0407] Step a: A solution of 4-chloropyrimidin-2-amine (50 g, 385.96 mmol, 1.0 eq.) in DMF (500 mL, 0.78 M) was treated with NIS (130.25 g, 578.94 mmol, 1.5 eq.) under N2 atmosphere. The mixture was stirred at 45 °C for 16 h. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow solid. The yellow solid was suspended in PE / EtOAc (1 / 1, 400 mL) and stirred at 25 °C for 1 h. The suspension was filtered and solid was collected, washed with PE / EtOAc (1 / 1, 200 mL x 2) and dried under vacuum to obtain 4-chloro-5-iodopyrimidin-2-amine (72.5 g, 283.82 mmol, 73.54% yield) as a white solid. MS: m / z 255.8 [M+H]+; RT 0.25 min (Method 9). 'H NMR (400MHz, dimethyl sulfoxide- e): 5 (ppm) 8.46 (s, 1H), 7.27 (s, 2H).

[0408] Step b: A solution of tert-butyl 4-ethynylpiperidine-l -carboxylate (55.30 g, 264.25 mmol, 1.0 eq.) and 4-chloro-5-iodopyrimidin-2-amine (67.5 g, 264.25 mmol, 1.0 eq.) in toluene (1400 mL, 0.18 M) was treated with Cui (5.03 g, 26.42 mmol, 0.1 eq.), Pd(PPhs)4 (30.54 g, 26.42 mmol, 0.1 eq.), and TEA (133.70 g, 1.32 mol, 184.15 mL, 5.0 eq.) in turn at 20 °C under N2 atmosphere. The mixture was stirred at 100 °C for 3 hours. The mixture was filtered and concentrated under reduced pressure to obtain the crude residue, which was suspended in MTBE (500 mL) and stirred at 25 °C for 1 h. The mixture was filtered to obtain tert-butyl 4- ((2-amino-4-chloropyrimidin-5-yl)ethynyl)piperidine-l-carboxylate (57.8 g, 171.61 mmol, 64.94% yield) as a brown solid. MS: m / z 359.0 [M+Na]+; RT 0.50 min (Method 9).JH NMR (400MHz, dimethyl sulfoxide-t / 6): 8 (ppm) 8.32 (s, 1H), 3.71-3.62 (m, 2H), 3.32-3.16 (m, 2H), 2.95-2.81 (m, 1H), 1.85-1.81 (m, 2H), 1.53-1.49 (m, 2H), 1.40 (s, 9H).

[0409] Step c: A solution of tert-butyl 4-[2-(2-amino-4-chloro-pyrimidin-5-yl)ethynyl]piperidine-l- carboxylate (57 g, 169.23 mmol, 1.0 eq.) in DMF (500 mL, 0.34 M) was treated with NaHS (34.49 g, 423.08 mmol, 2.5 eq., 70% purity) at 20 °C. The mixture was stirred at 90 °C under N2 for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography (EtOAc in PE from 50% to 95%) to afford tert-butyl 4-(2-aminothieno[2,3-J]pyrimidin-6-yl)piperidine-l-carboxylate (27.5 g, 82.23 mmol, 48.59% yield) as a yellow solid. MS: m / z 335.1 [M+H]+; RT 0.40 min (Method 9). 'H NMR (400MHz, dimethyl sulfoxide- e): 5 (ppm) 8.60 (s, 1H), 6.94 (s, 1H), 6.68 (s, 1H), 4.04-4.01 (m, 2H), 3.32-2.95 (m, 1H), 2.89-2.82 (m, 2H), 1.97-1.93 (m, 2H), 1.52- 1.41 (m, 2H), 1.40 (s, 9H).

[0410] Step d: A solution of tert-butyl 4-(2-aminothieno[2,3-J]pyrimidin-6-yl)piperidine-l- carboxylate (27 g, 80.73 mmol, 1.0 eq.) in DCM (300 mL, 0.27 M) at 0 °C was treated with isopentyl nitrite (40.67 g, 347.15 mmol, 46.64 mL, 4.3 eq.), then TMSC1 (26.31 g, 242.20 mmol, 30.74 mL, 3.0 eq.) was added dropwise to the solution over 10 min. The reaction mixture was warmed to room temperature and stirred at 25 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel with petroleum ether and ethyl acetate (from 0% to 40% of EtOAc in PE) to afford tert-butyl 4-(2-chlorothieno[2,3-J]pyrimidin-6-yl)piperidine-l-carboxylate (12.1 g, 34.19 mmol, 42.35% yield) as a yellow solid. MS: m / z 354.0 [M+H]+; RT 2.27 min (Method 19). 'H NMR (400MHz, dimethyl sulfoxide-t / 6): 8 (ppm) 9.11 (s, 1H), 7.37 (s, 1H), 4.07-4.04 (m, 2H), 3.34-3.31 (m, 1H), 2.98-2.85 (m, 2H), 2.03-1.99 (m, 2H), 1.60-1.59 (m, 2H), 1.41 (s, 9H).

[0411] Intermediate 7

[0412] Step a: A solution of 5-bromo-6-chloropyrazin-2-amine (1 g, 4.80 mmol) in toluene (25 mL) under N2atmosphere was treated with Cui (91.37 mg, 479.75 pmol), Pd(PPh3)4(554.38 mg, 479.75 pmol), TEA (2.43 g, 23.99 mmol, 3.34 mL) and tert-butyl 3-ethynylpiperidine-l- carboxylate (1.00 g, 4.80 mmol). The reaction mixture was stirred at 60°C under N2for 16 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography (SiO2, PE / EtOAc = 7 / 3) to afford tert-butyl 3-((5-amino-3-chloropyrazin-2- yl)ethynyl)piperidine-l -carboxylate (1.11 g, 54.41% yield, 79.2% purity) as a white solid. MS: m / z 281.0 [M-tbu+H]+; RT 0.44 min (Method 9).

[0413] Step b: A solution of tert-butyl 3-((5-amino-3-chloropyrazin-2-yl)ethynyl)piperidine-l- carboxylate (1 g, 2.97 mmol) in DMF (15 mL) was treated with NaHS (416.12 mg, 7.42 mmol) and then the mixture was stirred at 90 °C for 24 hours. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (60 mL x 3). The combined ogranic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 5 / 4) to afford tert-butyl 3-(3-aminothieno[2,3-Z>]pyrazin-6-yl)piperidine-l-carboxylate (951 mg, 93.86% yield, 98% purity) as a yellow solid. MS: m / z 335.1 [M+H]+; RT0.42 min (Method 9). 'H NMR (400 MHz, chloroform^ / ): 8 (ppm) 8.00 (s, 1H), 7.06 (s, 1H), 4.64 (d, J= 2.4 Hz, 1H), 4.19-4.44 (m, 1H), 4.05-4.08 (m, 1H), 2.96-3.02 (m, 1H), 2.79-2.87 (m, 1H), 2.20 (d, J= 13.2 Hz, 1H), 1.75-1.78 (m, 1H), 1.56-1.71 (m, 2H), 1.47 (s, 9H).

[0414] Step c: A solution of tert-butyl 3-(3-aminothieno[2,3-Z>]pyrazin-6-yl)piperidine-l-carboxylate (851 mg, 2.54 mmol) and CuCl (377.87 mg, 3.82 mmol) in CH3CN (10 mL) at 0 °C under N2atmosphere was treated with tert-butyl nitrite (655.99 mg, 6.36 mmol, 756.63 pL). The mixture was warmed to 60 °C and stirred for 15 hours under N2. The reaction mixture was concentrated under reduced pressure then diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 5 / 1) to afford tert-butyl 3-(3-chlorothieno[2,3- Z>]pyrazin-6-yl)piperidine-l-carboxylate (240 mg, 26.12% yield, 98% purity) as a yellow solid. MS: m / z 298.0 [M-tbu+H]+; RT 0.55 min (Method 9). 'HNMR (400 MHz, dimethyl sulfoxide-t / ,): 6 (ppm) 8.80 (s, 1H), 7.54 (s, 1H), 3.94-4.15 (m, 1H), 3.73-3.84 (m, 1H), 3.18 (br s, 1H), 2.95-3.04 (m, 1H), 2.13 (d, J= 11.2 Hz, 1H), 1.66-1.81 (m, 2H), 1.44-1.62 (m, 2H), 1.41 (s, 9H).

[0415] Intermediate 8

[0416] Step a: A solution of tert-butyl 7-ethynyl-4-azaspiro[2.5]octane-4-carboxylate (1.39 g, 6.67 mmol 1.0 eq.), Cui (254 mg, 1.33 mmol, 0.2 eq.), Pd(PPh3)4 (468 mg, 0.67 mmol, 0.1 eq.), and TEA (2.03 g, 20.02 mmol, 2.79 mL, 3.0 eq.) in DMF (36 mL, 37 mM) under N2 atmosphere was stirred at 25 C for 1 hour. The reaction mixture was treated with 5-bromo-6-chloropyrazin- 2-amine (1.57g, 6.67 mmol, 1.0 eq.) and then stirred at 90 °C for 16 hours under N2 atmosphere. The mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EtOAc = 1 / 0 to 3 / 7) to afford tertbutyl 7-((5-amino-3-chloropyrazin-2-yl)ethynyl)-4-azaspiro[2.5]octane-4-carboxylate (1.02 g, 42.1% yield) as a yellow solid. MS: m / z 363.1 [M+H]+; RT 2.04 min (Method 7).JH NMR (400 MHz, chloroform-tZ): 8 (ppm) 7.83 (s, 1H), 3.90-3.94 (m, 1H), 2.99-3.12 (m, 2H), 1.92- 1.97 (m, 2H), 1.67-1.74 (m, 2H), 1.47 (s, 9H), 1.14-1.17 (m, 1H), 0.93-0.96 (m, 1H), 0.65-0.70 (m, 1H), 0.49-0.55 (m, 1H).

[0417] Step b: A solution of tert-butyl 7-((5-amino-3-chloropyrazin-2-yl)ethynyl)-4- azaspiro[2.5]octane-4-carboxylate (1.02 g, 2.81 mmol, 1 eq.) in DMF (32 mL, 88 mM) was treated with NaHS (2.29 g, 28.11 mmol, 10.0 eq.) at 20 °C. The solution was then heated at 90 °C under N2 for 2 hours. The reaction mixture was concentrated to obtain the crude residue, which was purified by flash column chromatography (PE / EtOAc = 1 / 0 to 3 / 2) to afford tertbutyl 7-(3-aminothieno[2,3-Z>]pyrazin-6-yl)-4-azaspiro[2.5]octane-4-carboxylate (27.2 g, crude) as a red solid, which was used without further purification MS: m / z 361.1 [M+H]+; RT 1.94 min (Method 7).1H NMR (400MHz, chloroform-tZ): 5 (ppm) 8.00 (s, 1H), 7.00 (d, J= 1.0 Hz, 1H), 4.12-4.18 (m, 1H), 3.23-3.30 (m, 1H), 2.98-3.05 (m, 1H), 2.17-2.23 (m, 1H), 2.02- 2.03 (m, 1H), 1.68-1.73 (m, 2H), 1.48 (s, 9H), 1.32-1.35 (m, 1H), 0.91-0.98 (m, 1H), 0.59-0.63 (m, 1H), 0.52-0.57 (m, 1H).

[0418] Step c: A solution of tert-butyl 7-(3-aminothieno[2,3-Z>]pyrazin-6-yl)-4-azaspiro[2.5]octane-4- carboxylate (537 mg, 1.49 mmol, 1.0 eq.) in DCM (8.0 mL, 0.19 M) at 0 °C under N2 atmosphere was treated with isopentyl nitrite (698 mg, 5.96 mmol, 800.52 pL, 4.0 eq.) then TMSC1 (485 mg, 4.47 mmol, 567.21 pL, 3.0 eq.) then stirred at 20 °C for 16 hours under N2 atmosphere. The mixture was quenched with water (10.0 mL) and extracted with DCM (10.0 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatograph on silica gel (PE / EtOAc = 1 / 0 to 9 / 1) to afford tert-butyl 7-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-4- azaspiro[2.5]octane-4-carboxylate (370 mg, 65.38% yield) as a yellow solid.. MS: m / z 323.9 [M-tBu+H]+; RT 6.13 min (Method 18).JH NMR (400MHz, chloroform-t / ): 5 (ppm) 8.56 (s, 1H), 7.19 (s, 1H), 4.17-4.20 (m, 1H), 3.33-3.41 (m, 1H), 3.00-3.07 (m, 1H), 2.21-2.27 (m, 1H), 2.06-2.10 (m, 1H), 1.49 (s, 9H), 1.33-1.38 (m, 2H), 0.95-0.99 (m, 2H), 0.61-0.67 (m, 1H), 0.54- 0.59 (m, 1H).

[0419] Intermediate 9

[0420] Step a: A solution of 5-bromo-6-chloropyrazin-2-amine (1.14g, 3.00 mmol, 1.0 eq.), tertbutyl 7-ethynyl-4-azaspiro[2.5]octane-4-carboxylate (470 mg, 2.00 mmol 0.67 eq.), Cui (38.04 mg, 0.30 mmol, 0.1 eq.), and Pd(PPhs)4 (70.09 mg, 0.3 mmol, 0.1 eq.) in Toluene (30 mL, 100 mM) under N2 atmosphere was treated with DIEA (1.03 g, 7.99 mmol, 1.39 mL, 2.7 eq.) at 0 °C. The reaction mixture was treated with and then stirred at 60 °C for 16 hours under N2 atmosphere. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL><4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1) to afford tert-butyl 7-((3-bromo-5-chloropyridin-2- yl)ethynyl)-4-azaspiro[2.5]octane-4-carboxylate (670 mg, 66.97% yield, 85% purity) as a yellow solid MS: m / z 370.9 [M+H]+; RT 0.56 min (Method 9). Step b: a solution of tert-butyl 7-((3-bromo-5-chloropyridin-2-yl)ethynyl)-4- azaspiro[2.5]octane-4-carboxylate (660 mg, 1.32 mmol) in DMF (15 mL) was treated with NaHS (150.40 mg, 2.64 mmol) at 25 °C. The reaction mixture was then stirred at 90 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 5 / 1) to afford tert-butyl 7-(6-chlorothieno[3,2-Z>]pyridin-2-yl)-4-azaspiro[2.5]octane-4-carboxylate (450 mg, 84.72% yield, 94% purity) as a yellow solid. MS: m / z 379.0 [M+H]+; RT 0.58 min (Method 9). 'H NMR (400MHz, chloroform-tZ): 8 (ppm) 8.55 (d, J= 2.0 Hz, 1H), 8.04 (d, J= 1.6 Hz, 1H), 7.20 (s, 1H), 3.27-3.41 (m, 1H), 2.03-2.26 (m, 2H), 1.60-1.81 (m, 2H), 1.48 (s, 9H), 1.31-1.36 (m, 2H), 0.81-0.99 (m, 2H), 0.53-0.64 (m, 2H).

[0421] Intermediate 10

[0422] Step a: A solution of 4-chloro-5-iodopyrimidin-2-amine (814.13 mg, 3.19 mmol) and tert-butyl 7-ethynyl-4-azaspiro[2.5]octane-4-carboxylate (500 mg, 2.12 mmol) in toluene (10 mL) was treated with PdChfPPhs)? (149.14 mg, 212.48 pmol), Cui (40.47 mg, 212.48 pmol) and DIEA (860.02 mg, 8.50 mmol, 1.19 mL) at 25 °C under N2 atmosphere. The mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (petroleum ether / EtOAc =5 / 1) to tert-butyl 7-((2-amino-4-chloropyrimidin-5-yl)ethynyl)-4-azaspiro[2.5]octane-4- carboxylate (560 mg, 794.66 pmol, 37.40% yield) as a yellow solid. MS: 307.1 [M+H-t-Bu]+; RT 0.45 min (Method 9). *H NMR (400MHz, methanol-^): 6 (ppm) 8.20 (s, 1H), 3.84-3.91 (m, 1H), 3.17 (t, J = 11.2 Hz, 1H), 3.00-3.06 (m, 1H), 1.84-1.95 (m, 2H), 1.52-1.66 (m, 2H), 1.47 (s, 9H), 1.09-1.13 (m, 1H), 0.91-0.97 (m, 1H), 0.64-0.70 (m, 1H), 0.57-0.63 (m, 1H).

[0423] Step b: A solution of tert-butyl 7-((2-amino-4-chloropyrimidin-5-yl)ethynyl)-4- azaspiro[2.5]octane-4-carboxylate (560 mg, 1.54 mmol) in DMF (20 mL) was treated with NaHS (352.31 mg, 6.17 mmol) then the mixture was stirred at 90 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over ISfeSCU, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / EtOAc =5 / 1) to afford tert-butyl 7-(2-aminothieno[2,3- J]pyrimidin-6-yl)-4-azaspiro[2.5]octane-4-carboxylate (380 mg, 1.05 mmol, 68.31% yield) as a white solid. MS: m / z 361.1 [M+H]+; RT 0.41 min (Method 9). ' H NMR (400MHz, methanol- d4) 5 (ppm) 8.56 (s, 1H), 6.92 (s, 1H), 2.86-3.11 (m, 2H), 2.04-2.15 (m, 2H), 1.60-1.64 (m, 1H), 1.48 (s, 9H), 1.24-1.39 (m, 3H), 0.93-0.95 (m, 1H), 0.62 (t, J= 8.0 Hz, 2H).

[0424] Step c: A solution of tert-butyl 7-(2-aminothieno[2,3-J]pyrimidin-6-yl)-4-azaspiro[2.5]octane- 4-carboxylate (270 mg, 749.02 pmol) and TMSC1 (244.12 mg, 2.25 mmol, 285.19 pL) in DCM (15 mL) was treated with tert-Butyl nitrite (332.13 mg, 3.22 mmol, 383.07 pL) at 0 °C, purged with N2 3 times, then the mixture was stirred at 25°C for 1 hour under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / EtOAc =5 / 1) to afford tert-butyl 7-(2- chlorothieno[2,3-J]pyrimidin-6-yl)-4-azaspiro[2.5]octane-4-carboxylate (140 mg, 368.51 pmol, 49.20% yield) as a yellow solid. MS: m / z 379.9 [M+H]+; RT 0.52 min (Method 9). 'H NMR (400MHz, dimethyl sulfoxide-t / 6): 8 (ppm) 8.96 (s, 1H), 7.25 (d, J= 0.4 Hz, 1H), 3.43- 3.50 (m, 1H), 3.11 (t, J = 12.0 Hz, 1H), 2.08-2.17 (m, 2H), 1.62-1.73 (m, 1H), 1.48 (s, 9H), 1.41-1.45 (m, 1H), 1.21-1.32 (m, 2H), 0.93-0.99 (m, 1H), 0.62-0.67 (m, 2H).

[0425] Intermediate 11

[0426] Step a: A solution of tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (3 g, 13.56 mmol) and 5-bromo-6-chloropyrazin-2-amine (2.83 g, 13.56 mmol) in Toluene (60 mL) was treated with Pd(PPh3)4(783.27 mg, 677.83 pmol), Cul (27.57 mg, 144.74 pmol) and TEA (1.22 g, 12.06 mmol, 1.68 mL) then the mixture was stirred at 100 °C for 3 hours. The reaction mixture was filtered over Celite and concentrated under reduced pressure to obtain the crude product. The crude was purified by flash column chromatography (EtOAc in PE from 0% to 50%) to afford tert-butyl 6-((5-amino-3-chloropyrazin-2-yl)ethynyl)-2-azaspiro[3.3]heptane- 2-carboxylate (3.1 g, 8.89 mmol, 65.55% yield) as a light-yellow solid. TLC: PE:EtOAc = 1 : 1, Rf= 0.25. ' H NMR (400MHz, chloroform^): 8 (ppm) 7.85 (s, 1H), 4.83 (s, 2H), 3.96 (d, J = 2.4 Hz, 4H), 3.18-3.23 (m, 1H), 2.54-2.69 (m, 2H), 2.38-2.51 (m, 2H), 1.45 (s, 9H).

[0427] Step b: A solution of tert-butyl 6-((5-amino-3-chloropyrazin-2-yl)ethynyl)-2- azaspiro[3.3]heptane-2-carboxylate (3 g, 8.60 mmol) in DMF (50 mL) was treated with NaHS (1.38 g, 17.20 mmol, 70% purity) at 20 °C. The mixture was stirred at 90 °C under N2for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude residue, which was purified by combi flash (EtOAc in PE from 0 % to 60%) to afford tert-butyl 6-(3-aminothieno[2,3-Z>]pyrazin-6-yl)-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g, 7.22 mmol, 83.91% yield) as a light-yellow solid. TLC: PE:EtOAc = 1 : 1, Rf = 0.15. 'H NMR (400MHz, dimethyl sulfoxide-t / 6): 6 (ppm) 7.92 (s, 1H), 7.02 (d, J= 0.8 Hz, 1H), 6.60 (s, 2H), 3.96 (br s, 2H), 3.79 (br s, 2H), 3.53-3.62 (m, 1H), 2.58-2.64 (m, 2H), 2.30-2.36 (m, 2H), 1.37 (s, 9H).

[0428] Step c: A solution of tert-butyl 6-(3-aminothieno[2,3-Z>]pyrazin-6-yl)-2-azaspiro[3.3]heptane- 2-carboxylate (2.5 g, 7.22 mmol) in DCM (50 mL) was treated with TMSC1 (2.43 g, 22.37 mmol, 2.84 mL) at 0 °C. Then isopentyl nitrite (3.63 g, 31.03 mmol, 4.17 mL) was added to mixture at 0 °C dropwise via syringe. The mixture was stirred at 20 °C under N2for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (EtOAc in PE from 0% to 30%) to afford tert-butyl 6-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-2-azaspiro[3.3]heptane-2- carboxylate (1.5 g, 4.10 mmol, 56.81% yield) as a light-yellow solid. TLC: PE:EtOAc = 3: 1, Rf= 0.4. 'H NMR (400MHz, dimethyl sulfoxide-t / 6): 6 (ppm) 8.79 (s, 1H), 7.47 (s, 1H), 3.98 (s, 2H), 3.74-3.84 (m, 3H), 2.66-2.72 (m, 2H), 2.41-2.45 (m, 2H), 1.38 (s, 9H).

[0429] Intermediate 12

[0430] Step a: A solution of 5-bromo-6-chloropyrazin-2-amine (1 g, 4.80 mmol), tert-butyl 3- ethynylazeti dine- 1 -carboxylate (956 mg, 5.28 mmol) in Toluene (30.0 mL), Pd(PPh3)4(554 mg, 479.75 pmol), Cui (91 mg, 479.75 pmol) and TEA (1.46 g, 2.01 mL) was added. The mixture was stirred at 100 °C for 20 hours under N2. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (PE ZEtOAc = 1 / 0 to 3 / 2) to afford tert-butyl 3-((5-amino-3-chloropyrazin-2-yl)ethynyl)azetidine-l -carboxylate (300 mg, 20.25% yield) as a yellow solid. MS: m / z 331.1 [M+H+Na]+; RT 1.77 min (Method 7).JH NMR (500 MHz, dimethyl sulfoxide-tZ): 8 (ppm) 7.78 (s, 1H), 4.15-4.20 (m, 2H), 3.72-3.82 (m, 2H), 3.67-3.71(m, 1H), 1.38 (s, 9H).

[0431] Step b: A solution of tert-butyl 3-((5-amino-3-chloropyrazin-2-yl)ethynyl)azetidine-l- carboxylate (300 mg, 971.62 pmol) in DMF (10.0 mL) was treated with NaHS (545 mg, 9.72 mmol) then the mixture was stirred at 100 °C for 16 hours under N2atmosphere. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (PE ZEtOAc = 1 / 0 to 7 / 3) to afford tert-butyl 3-(3-aminothieno[2,3-Z>]pyrazin- 6-yl)azetidine-l -carboxylate (200 mg, 67.18% yield) as a yellow solid. MS: m / z 307.1 [M+H]+; RT 1.63 (Method 7). 'H NMR (500 MHz, dimethyl sulfoxide-tZ): 5 (ppm) 7.94 (s, 1H), 7.21 (s, 1H), 4.25-4.30 (m, 2H), 4.00-4.03 (m, 1H), 3.87-3.92 (m, 2H), 1.40 (s, 9H).

[0432] Step c: A solution of tert-butyl 3-(3-aminothieno[2,3-Z>]pyrazin-6-yl)azetidine-l-carboxylate (200 mg, 652.78 pmol) in CH3CN (8.0 mL) was added tert-butyl nitrite (169 mg, 194 pL), diiodomethane (175 mg, 52 pL) and Cui (62 mg, 326.39 pmol). The mixture was stirred at 65 °C for 16 hours under N2atmosphere. The mixture was concentrated under reduced pressure and purified by flash column chromatography (PE / EtOAc = 1 / 0 to 7 / 3) to afford tert-butyl 3- (3-iodothieno[2,3-Z>]pyrazin-6-yl)azetidine-l-carboxylate (120 mg, 44.06% yield) as a yellow solid. MS: m / z 418.0 [M+H]+; RT 2.12 (Method 7). 'H NMR (500 MHz, dimethyl sulfoxide- d6. 5 (ppm) 8.95 (s, 1H), 7.61 (s, 1H), 4.31-4.34 (m, 2H), 4.20-4.26 (m, 1H), 3.98-4.01 (m, 2H), 1.40 (s, 9H). Intermediate 13

[0433] A solution of rac-tert-butyl (2A,55 -5-formyl-2-methylpiperidine-l-carboxylate (3.5 g, 14.63 mmol) in MeOH (40 mL) was treated with compound 6 (2.81 g, 14.63 mmol) and K2CO3 (4.04 g, 29.26 mmol) then the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography (PE / EtOAc = 3 / 1, Rf = 0.7) to afford rac-tert-butyl (2 / ?,5 / ?)-5-ethynyl- 2-methylpiperidine-l -carboxylate (1.9 g, 53.51% yield, 92% purity) as white solid. TLC: PE / EtOAc = 3 / 1, Rf= 0.7 'H NMR (400 MHz, chloroform-tZ): 6 (ppm) 4.53-4.03 (m, 3H), 2.73-2.85 (m, 1H), 2.37-2.30 (m, 1H), 1.89 (d, J= 10.4 Hz, 1H), 1.65-1.69 (m, 1H), 1.51-1.53 (m, 1H), 1.46 (s, 10H), 1.14 (d, J= 6.8 Hz, 3H).

[0434] Intermediate 14

[0435] Step a: A solution of tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (2.5 g, 11.10 mmol) in THF (50 mL) was treated with LiHMDS (1 M, 22.19 mmol, 22.19 mL) at -78°C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 1 hr and then a solution of 1,1,1 -trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (4.76 g, 13.32 mmol) in THF (10 mL) was added dropwise. The reaction mixture was warmed to 20°C and stirred overnight. The reaction was diluted with sat. aqueous NH4CI (20 mL) and concentrated under reduced pressure. The resulting residue was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude was purified by silica gel chromatography (PE / EA=0 to 4 / 1, TLC: PE / EtOAc 4: 1 Rf=0.6) to afford tert-butyl 2-(trifluoromethylsulfonyloxy)-6-azaspiro[3.4]oct- 2-ene-6-carboxylate (1.68 g, 4.70 mmol, 42.37% yield) as colorless oil. TLC: PE / EtOAc 4: 1 Rf= 0.6. 'HNMR (500 MHz, chloroform-f / ): 8 (ppm) 5.47 (s, 1H), 3.30 - 3.58 (m, 4H), 2.72 -

[0436] 2.93 (m, 2H), 1.85 - 2.04 (m, 2H), 1.46 (s, 9H). Step b: A mixture of tert-butyl 2-(trifluoromethylsulfonyloxy)-6-azaspiro[3.4]oct-2-ene-6- carboxylate (50 mg, 139.92 pmol) , 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (71.06 mg, 279.84 pmol), K2CO3 (38.68 mg, 279.84 pmol) and Pd(dppf)C12 (10.24 mg, 13.99 pmol) in Dioxane (1 mL) was stirred at 80 °C for 1 hr under N2 atmosphere. The reaction mixture was cooled to rt and filtered through a Celite545 plug. The filtrate was concentrated under reduced pressure, and the residue was dried in vacuo to afford tert-butyl 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6-azaspiro[3.4]oct-2-ene- 6-carboxylate (35 mg, 104.40 pmol, 74.61% yield) as a crude material, which was used for the next step without purification. TLC: PE / EtOAc = 4 / 1 Rf= 0.5.

[0437] Intermediate 15

[0438] Step a: A solution of 5-bromo-6-chloropyrazin-2-amine (3.5 g, 16.79 mmol) and rac-tert-butyl (A)-3-ethynylpyrrolidine-l -carboxylate (3.61 g, 18.47 mmol) in toluene (15 mL) was treated with Cui (319.79 mg, 1.68 mmol), TEA (5.10 g, 50.37 mmol, 7.02 mL) and Pd(PPh3)4(1.94 g, 1.68 mmol) under N2and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted in water, and extracted with EtOAc (100 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (from 0% to 80% of EtOAc in PE) to afford rac-tert-butyl (A)-3-((5-amino-3- chloropyrazin-2-yl)ethynyl)pyrrolidine-l -carboxylate (3.8 g, 11.77 mmol, 70.11% yield) as a yellow solid. MS: m / z 222.9 [M+H-Boc]+; RT 0.93 min (Method 4). 'H NMR (400 MHz, dimethyl sulfoxide- e): 5 (ppm) 7.77 (s, 1H), 7.25 (s, 2H), 3.53-3.57 (m, 1H), 3.35-3.43 (m, 1H), 3.22-3.30 (m, 3H), 2.14-2.19 (m, 1H), 1.91-1.95 (m, 1H), 1.40 (s, 9H).

[0439] Step b: A solution of rac-tert-butyl (A)-3-((5-amino-3-chloropyrazin-2-yl)ethynyl)pyrrolidine- 1-carboxylate (1.50 g, 4.65 mmol) in DMF (15 mL) was treated with NaHS (1.04 g, 18.59 mmol) at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with H20 (80 mL), and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography on silica gel with petroleum ether and ethyl acetate (from 0% to 100% of EtOAc in PE) to afford rac-tert-butyl (A)-3-(3-aminothieno[2,3-Z>]pyrazin-6-yl)pyrrolidine-l- carboxylate (1 g, 3.12 mmol, 67.16% yield) as a yellow solid. MS: m / z 321.0 [M+H]+; RT 0.89 min (Method 4).JH NMR (400 MHz, dimethyl sulfoxide- e): 5 (ppm) 7.93 (s, 1H), 7.10 (s, 1H), 6.64 (br s, 2H), 3.68-3.73 (m, 2H), 3.44-3.47 (m, 1H), 3.26-3.31 (m, 2H), 2.27-2.33 (m, 1H), 1.99-2.04 (m, 1H), 1.41 (s, 9H).

[0440] Step c: A solution of rac-tert-butyl (A)-3-(3-aminothieno[2,3-Z>]pyrazin-6-yl)pyrrolidine-l- carboxylate (970.00 mg, 3.03 mmol) in THF (10 mL) was treated with tert-butyl nitrite (1.52 g, 13.02 mmol, 1.75 mL) at 0 °C under N2atmosphere. Then TMSC1 (986.70 mg, 9.08 mmol, 1.15 mL) was added drop-wise to the solution at 0 °C over 10 min and the mixture was stirred at 25 °C for 16 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (Column: Boston Prime C18 150*30mm*5um; Condition: water (NH3H2O+NH4HCO3)-ACN; Begin B: 38%; End B: 68%; Flow Rate (mL / min): 25) to afford rac-tert-butyl (A)-3-(3-chlorothieno[2,3- Z>]pyrazin-6-yl)pyrrolidine-l -carboxylate (310 mg, 912.20 mol, 30.13% yield, 100% purity) as a white solid. MS: m / z 340.1 [M+H]+; RT 1.59 min (Method 20) 'H NMR (400 MHz, dimethyl sulfoxide- e): 5 (ppm) 8.80 (s, 1H), 7.54 (s, 1H), 3.76-3.85 (m, 2H), 3.47-3.50 (m, 1H), 3.37-3.41 (m, 1H), 3.29-3.31 (m, 1H), 2.38 (br s, 1H), 2.09-2.12 (m, 1H), 1.42 (s, 9H).

[0441] Inter mediate 16

[0442] Step a: A solution of 4-bromo-6-chloropyridazin-3-amine (80 g, 383.80 mmol) in MeOH (800 mL) was treated with NaOMe (82.94 g, 1.54 mol) at 0 °C. The mixture was then stirred at 35 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water (500 mL) and extracted with DCM (500 mL x 3). The combined organic phase was washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 6- chloro-4-methoxypyridazin-3-amine (60 g, 97.97% yield) as a yellow solid which was used in next step without further purification. TLC: PE / EtOAc = 1 / 1, Rf = 0.2.JH NMR (400 MHz, dimethyl sulfoxide- e): 5 (ppm) 7.01 (s, 1H), 6.43 (s, 2H), 3.89 (s, 3H).

[0443] Step b: A solution of 6-chloro-4-methoxypyridazin-3-amine (60 g, 376.00 mmol) and 1,1- di m eth ox y-A.A-di methyl -ethanamine (250.40 g, 1.88 mol, 274.86 mL) in EtOH (600 mL) was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the resulting crude residue was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic phase was washed with brine (1000 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product. The crude material was purified by chromatography (petroleum ether / EtOAc = 5 / 1 to 0 / 1, TLC: PE / EtOAc = 0 / 1, Rf = 0.1) to afford A'-(6-chloro-4- methoxypyridazin-3-yl)- / V-dimethylacetimidamide (85 g, 98.86% yield) as a yellow solid. ‘HNMR (400 MHz, chloroform-f / ): 8 (ppm) 6.71 (s, 1H), 3.86 (s, 3H), 3.11 (s, 6H), 2.07 (s, 3H).

[0444] Step c: A solution of A'-(6-chloro-4-methoxypyridazin-3-yl)- / V-dimethylacetimidamide (85 g, 350.22 mmol) in MeOH (800 mL) was treated with NH2OH HCI (35.05 g, 504.32 mmol) and stirred at 20 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford A-(6-chloro-4-methoxypyridazin-3-yl)-A'- hydroxyacetimidamide (75 g, 98.86% yield) as a yellow solid which was used in next step without further purification. MS: m / z 216.8 [M+H]+; RT 0.30 min (Method 4). *HNMR (400 MHz, chloroform-t / ): 5 (ppm) 9.43 (s, 1H), 8.39 (s, 1H), 6.78 (s, 1H), 4.00 (s, 3H), 2.52-2.55 (m, 3H).

[0445] Step d: A solution of A-(6-chloro-4-methoxypyridazin-3-yl)-A'-hydroxyacetimidamide (70 g, 323.14 mmol) in Toluene (700 mL) was treated with TFAA (495.45 g, 2.36 mol, 327.89 mL) then the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with sat. aq NaHCCL solution (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic phase was washed with brine (1000 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude material was purified by chromatography (petroleum ether / EtOAc = 5 / 1 to 1 / 1, TLC: PE / EtOAc = 0 / 1, Rf = 0.5) to afford 6-chloro-8-methoxy-2-methyl-[l,2,4]triazolo[l,5-Z>]pyridazine (26.5 g, 40.93% yield, 99.12% purity) as a yellow solid. MS: m / z 198.8 [M+H]+; RT 0.59 min (Method 4). 'HNMR (400 MHz, chloroform-tZ): 8 (ppm) 6.68 (s, 1H), 4.14 (s, 3H), 2.62 (s, 3H).

[0446] Step a: Aa solution of 6-chloro-4-methylpyridazin-3-amine (15 g, 104.48 mmol) and 1,1- di m eth ox y-AA-di methyl -ethanamine (69.57 g, 522.38 mmol, 76.37 mL) in EtOH (200 mL) was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude material was purified by chromatography (petroleum ether / EtOAc = 5 / 1 to 0 / 1, TLC: PE / EtOAc = 0 / 1, Rf = 0.1) to afford A'-(6-chloro-4- methylpyridazin-3-yl)-AA-dimethylacetimidamide (22 g, 99.01% yield) as a yellow solid. TLC: PE / EtOAc = 0 / 1, Rf= 0.1. ‘HNMR (400 MHz, chloroform^ / ): 6 (ppm) 7.13 (s, 1H), 3.09 (s, 6H), 2.13 (s, 3H), 2.05 (s, 3H).

[0447] Step b: A solution of A'-(6-chloro-4-methylpyridazin-3-yl)-A,A-dimethylacetimidamide (22 g, 103.44 mmol) in MeOH (200 mL) was treated with NH2OH HCI (10.35 g, 148.96 mmol) and stirred at 20 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford A-(6-chloro-4-methylpyridazin-3-yl)-A'-hydroxyacetimidamide (20 g, 96.37% yield) as a yellow solid which was used in next step without further purification. MS: m / z 200.8 [M+H]+; RT 0.44 (Method 4). 'H NMR (400 MHz, chloroform-tZ): 8 (ppm) 9.42 (s, 1H), 7.24 (s, 1H), 6.38 (s, 1H), 2.47 (s, 3H), 2.30 (s, 3H).

[0448] Step c: A solution of A-(6-chloro-4-methylpyridazin-3-yl)-A'-hydroxyacetimidamide (19 g, 94.70 mmol) in Toluene (200 mL) was treated with TFAA (145.20 g, 691.34 mmol, 96.10 mL) and the mixture was stirred at 90 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with sat. aq NaHCCh solution (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic phase was washed with brine (500 mL), dried with anhydrous ISfeSCh, filtered and concentrated under reduced pressure to obtain the crude product. The crude material was purified by chromatography (PE / EtOAc = 5 / 1 to 1 / 1, TLC: PEZEtOAc = 0 / 1, Rf = 0.5) to afford 6-chloro- 2,8-dimethyl-[l,2,4]triazolo[l,5-Z>]pyridazine (7.8 g, 45.01% yield, 99.79% purity) as a yellow solid. MS: m / z 182.8 [M+H]+; RT 0.61 min (Method 4). *HNMR (400 MHz, chloroform-; / ): 6 (ppm) 7.18 (s, 1H), 2.68 (s, 3H), 2.64 (s, 3H).

[0449] Step d: A solution of 6-chloro-2,8-dimethyl-[l,2,4]triazolo[l,5-Z>]pyridazine (36.52 mg, 200 pmol), Bis(pinacolato)diboron (50.79 mg, 200.00 pmol), Pd(dppf)C12-CH2C12 (16.33 mg, 20.00 pmol), and KOAc (58.89 mg, 600.00 pmol) in Dioxane (2 mL) was heated at 90 °C for 2 hours. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the (2,8-dimethyl-[l,2,4]triazolo[l,5-Z>]pyridazin-6-yl)boronic acid, which was used directly without further purification. Quantitative yield assumed. MS: m / z 193.1 [M+H]+; RT 0.40 min (Method 4).

[0450] Intermediate 18

[0451] Step a: A solution of 6-chloropyridazin-3 -amine (10 g, 77.19 mmol) in MeCN (500 mL) was treated with 1,10-phenanthroline (1.39 g, 7.72 mmol), 1,2-di chlorobenzene (14.75 g, 100.35 mmol, 11.30 mL), CuBr (1.11 g, 7.72 mmol, 235.10 pL), Znl2(4.93 g, 15.44 mmol), I2(19.59 g, 77.19 mmol), KI (14.10 g, 84.91 mmol), and K2CO3 (32.00 g, 231.58 mmol) at 25°C. The mixture was then stirred at 130°C for 16 h under N2 atmosphere. The mixture was filtered over Celite then the filtrate was diluted with saturated ISfeSCL solution (300 ml) and

[0452] 66 stirred at 25°C for 30 min. The mixture was concentrated under reduced pressure and the residue was diluted in water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over ISfeSCU, filtered, and concentrated under reduced pressure obtain the crude product. The crude product was purified by column chromatography (PE / EtOAc = 5 / 1 to 1 / 1, TLC: PEZEtOAc = 1 / 1, Rf = 0.6) to afford 6-chloro-2-methyl-[l,2,4]triazolo[l,5-Z>]pyridazine (4.1 g, 24.32 mmol, 31.51% yield) as a yellow solid. MS: m / z 169.1 [M+H]+.

[0453] Step b: A solution of 6-chloro-2-methyl-[l,2,4]triazolo[l,5-Z>]pyridazine (3 g, 17.90 mmol) in MeCN (30 mL) and H2O (10.5 mL) was treated with sodium difluoromethanesulfmate (4.98 g, 35.80 mmol), TFA (3.06 g, 26.85 mmol, 2.06 mL), and AgNCL (3.33 g, 19.60 mmol) at 25 °C. The reaction was stirred at 80 °C for 20 minutes under N2 atmosphere. The reaction mixture was then added dropwise to a solution of (NH4)2S20S (4.53 g, 19.87 mmol) in H2O (12 mL) then stirred under N2 atmosphere at 80 °C for an additional 20 minutes. The mixture was concentrated under vacuum to obtain the crude product, which was purified by column chromatography (SiCL, PE:EtOAc = 1 / 0 to 5 / 1) to yield 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[l,2-Z>]pyridazine (1 g, 4.60 mmol, 25.67% yield) as a yellow solid. MS: m / z 219.0 [M+H]+; RT 0.49 min (Method 9). 'H NMR (400 MHz, chloroform-tZ): 5 (ppm) 7.60 (s, 1H), 7.27 (s, 1H), 7.14 (t, J= 48.4 Hz, 1H), 2.70 (s, 3H).

[0454] Step c: A solution of 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[l,2-Z>]pyridazine (43.72 mg, 200 pmol), Bis(pinacolato)diboron (50.79 mg, 200.00 pmol), Pd(dppf)C12-CH2C12 (16.33 mg, 20.00 pmol), and KOAc (58.89 mg, 600.00 pmol) in Dioxane (2 mL) was heated at 90 °C for 2 hours. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the (8-(difluoromethyl)-2-methyl- [l,2,4]triazolo[l,5-Z>]pyridazin-6-yl)boronic acid, which was used directly without further purification. Quantitative yield assumed. MS: m / z 229.1 [M+H]+; RT 0.41 min (Method 4).

[0455] Intermediate 19

[0456]

[0457] Step a: A mixture of 3,4,5-tribromo-U / -pyrazole (50.0 g, 164.1 mmol) and K2CO3 (68.0 g, 492.2 mmol) in acetone (500 mL) was added l-chloropropan-2-one (35.2 g, 380.4 mmol) at 0 °C. The resulting mixture was stirred at 50 °C for 2 hours under N2 atmosphere. The reaction mixture was quenched with the addition of H2O (200 mL) then the mixture was concentrated under reduced pressure to obtain the crude residue, which was triturated with H2O (500 mL) at 25 °C for 30 min. The suspension was filtered to afford l-(3,4,5-tribromo-l / / -pyrazol-l- yl)propan-2-one (56.7 g, 98.8% yield) as a yellow solid. 'H NMR (400 MHz, chloroform-t / ): 5 (ppm) 4.97 (s, 2H), 2.19 (s, 3H).

[0458] Step b: A mixture of l-(3,4,5-tribromo-U / -pyrazol-l-yl)propan-2-one (56.7 g, 157.1 mmol), tributyl(l-ethoxyvinyl)stannane (69.6 g, 192.8 mmol), and Pd(PPh3)2C12 (5.5 g, 7.9 mmol) in dioxane (500 mL) was stirred at 100 °C for 16 hours under N2 atmosphere. The reaction was cooled to 25 °C and treated with HC1 (1.0 M, 235.7 mL). The resulting mixture was stirred at 60 °C for 1 hour. The reaction mixture was quenched with the addition of saturated aqueous KF (600 mL) at 25 °C and stirred for 1 hour. The solution was filtered, and the organic layer was separated, and the aqueous layer was extracted with EtOAc (500 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiCL, PE / EtOAc = 15 / 1 to 10 / 1, TLC: PEZEtOAc = 3 / 1, Rf = 0.6) to afford l-(5-acetyl-3,4-dibromo-17 / -pyrazol-l-yl)propan-2- one (30.2 g, 57.5% yield) as a white solid.1H NMR (400 MHz, chloroform-tZ): 5 (ppm) 5.29 (s, 2H), 2.70 (s, 3H), 2.24 (s, 3H).

[0459] Step c: A mixture of l-(5-acetyl-3,4-dibromo-U / -pyrazol-l-yl)propan-2-one (30.2 g, 93.2 mmol) and NH4OAC (35.9 g, 466.1 mmol) in AcOH (300 mL) was stirred at 120 °C for 30 min under N2 atmosphere. The mixture was cooled to 25 °C and diluted with H2O (1 L) then filtered. The crude solid was triturated with H2O (200 mL) at 25 °C for 30 min then the suspension was filtered to afford 2,3-dibromo-4,6-dimethylpyrazolo[l,5-a]pyrazine (24.4 g, 85.8% yield) as a brown solid. 'H NMR (400 MHz, chloroform-t / ): 5 (ppm) 7.97 (s, 1H), 2.94 (s, 3H), 2.46 (s, 3H).

[0460] Step d: A solution of 2,3-dibromo-4,6-dimethylpyrazolo[l,5-a]pyrazine (24.4 g, 3.2 mmol) in THF (250 mL) was treated wtih iPrMgCl (2.0 M, 86.0 mL) dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred at 0 °C for 1 hour under N2 atmosphere. The reaction mixture was quenched with the addition of MeOH (150 mL) at 0 °C under N2 atmosphere. The mixture was partitioned between EtOAc (300mL x 3) and H2O (300 mL). The combined organic layers were dried over Na2SO4 and concentrated to obtain the crude product, which was purified by column chromatography (SiCh, PE / EtOAc = 10 / 1 to 6 / 1, TLC: PE / EtOAc = 3 / 1, Rf = 0.3) to afford 2-bromo-4,6-dimethylpyrazolo[l,5-a]pyrazine (11.6 g, 63.3% yield, 95.52% purity) as a white solid. MS: m / z 226.1, 228.1 [M+H]+; RT 2.26 min (Method 14).XH NMR (400 MHz, chloroform-tZ): 8 (ppm) 8.45 (s, 1H), 7.16 (s, 1H), 2.63 (s, 3H), 2.39 (s, 3H).

[0461] Step e: A solution of 2-bromo-4,6-dimethyl-pyrazolo[l,5-a]pyrazine (500 mg, 2.21 mmol), Bis(pinacolato)diboron (561.63 mg, 2.21 mmol), Pd(dppf)C12-CH2C12 (180.61 mg, 221.17 pmol), and KOAc (651.18 mg, 6.64 mmol) in Dioxane (6 mL) was heated at 90 °C for 16 hours. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the crude (4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)boronic acid as a brown solid. The material was used directly in the next step without purification. MS: m / z 192.0 [M+H]+; RT 0.91 min (Method 4).

[0462] Intermediate 20

[0463] A solution of 5-chloro-2,7-dimethyl-pyrazolo[4,3-Z>]pyridine (36.32 mg, 200 pmol), Bis(pinacolato)diboron (50.79 mg, 200.00 pmol), Pd(dppf)C12-CH2C12 (16.33 mg, 20.00 pmol), KOAc (58.89 mg, 600.00 pmol), in Dioxane (2 mL) was heated at 90 °C for 2 hours. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the crude (2,7-dimethyl-2J / -pyrazolo[4,3-Z>]pyridin-5-yl)boronic acid, which was used directly without further purification. MS: m / z 192.1 [M+H]+; RT 0.36 min (Method 4). Intermediate 21

[0464] A solution of 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[l,2-b]pyridazine (59.70 mg, 200 pmol, HBr salt), Bis(pinacolato)diboron (50.79 mg, 200.00 pmol), Pd^ppfJCh CEECh (16.33 mg, 20.00 pmol), and KOAc (58.89 mg, 600.00 pmol) in Dioxane (2 mL) was heated at 90 °C for 2 hours. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the crude (8-(difluoromethyl)-2-methylimidazo[l,2- Z>]pyridazin-6-yl)boronic acid, which was used directly. MS: m / z 228.1 [M+H]+; RT 0.39 min (Method 4).

[0465] Intermediate 22

[0466] To a solution of compound 3,5-dichloro-2-iodopyrazine (1.24 g, 4.5 mmol), ((trimethylsilyl)ethynyl)cyclohexan-l-one (500 mg, 4.1 mmol), Cui (79.56 mg, 0.41 mmol), PdC12(PPh3)2 (143.5 mg, 0.2 mmol) in Toluene (20 mL) was added DIPEA (1.66 g, 16.37 mmol, 2.29mL), the mixture was stirred at 60 °C for 16 h under N2. LCMS showed -69% of desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography (SiO2, Ethyl acetate / Petroleum ether from 0 % to 14%) to give 4-((3,5-dichloropyrazin-2- yl)ethynyl)cyclohexan-l-one (600 mg, 54.47% yield) as a yellow solid. MS: m / z 269.0 [M+H]+ To a solution of 4-((3,5-dichloropyrazin-2-yl)ethynyl)cyclohexan-l-one (480 mg, 1.78 mmol) in NMP (5 mL) was added NaHS (218.12 mg, 2.68 mmol, 70% purity). The reaction solution was stirred at 100 °C for 30 min. LCMS showed the reaction was completed. The reaction solution were concentrated to give a residue, which was purified on silica gel column chromatography (from Petroleum ether / EtOAc = 1 / 0 to 3 / 1, TLC: Petroleum ether / EtOAc = 3 / 1, Rf = 0.32) to give 4-(3-chlorothieno[2,3-b]pyrazin-6-yl)cyclohexan-l-one ) (130 mg, 487.35 pmol, 27.32% yield) as an off-white solid. MS: m / z 266.9 [M+H]+

[0467] ’H NMR: (400 MHz, CDC13) 8 ppm: 8.58 (s, 1H), 7.27 (s, 1H), 3.38-3.54 (m, 1H), 2.53-2.64 (m, 4H), 2.43-2.52 (m, 2H), 1.98-2.16 (m, 2H).

[0468] Intermediate: 23

[0469] To a solution of 2,4-dichloro-5-iodopyrimidine and Pd PPhs^Ch (657.8 mg, 937.2 pmol) in THF (150 mL) was added Cui (460.5 mg, 2.4 mmol), DIPEA (9.3 g, 72.3 mmol, 12.6 mL) at 20 °C, the mixture was stirred at 25 °C for 10 min under N2. Then solution of tert-butyl (lR,5S,6r)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.0 g, 24.1 mmol) in THF (50.0 mL) was added, the mixture was stirred at 25 °C for 16 hours under N2. LCMS showed the starting material disappeared and 32% of desired mass was observed. The mixture was diluted with H2O (200.0 mL), and extracted with EtOAc (200.0 mL x 3), dried over ISfeSCh, filtered and concentrated under reduced pressure to give a residue, which was purified by combi flash (Petroleum ether / EtOAc = 6 / 1 to 3 / 1, TLC: Petroleum ether / EtOAc =3 / 1, Rf = 0.38) to give tert-butyl (lR,5S,6r)-6-((2,4-dichloropyrimidin-5-yl)ethynyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (6.8 g, 79.6% yield) as a yellow solid. LCMS: (MS (ESI) 297.9 [M-t-Bu+H]+).

[0470] To a solution of tert-butyl (lR,5S,6r)-6-((2,4-dichloropyrimidin-5-yl)ethynyl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (6.3 g, 17.8 mmol) in DMF (120.0 mL) was added NaHS (1.5 g, 17.8 mmol, 70.0% purity) at 20 °C, the mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure, which was purified by combi flash (Petroleum ether / EtOAc = 20 / 1 to 3 / 1, TLC: PEZEtOAc = 3 / 1, Rf = 0.26) to give tert-butyl (lR,5S,6s)-6-(2-chlorothieno[2,3- d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexane-3 -carboxylate (4.5 g, 71.9% yield) as a white solid.

[0471] LCMS: (MS (ESI) 352.0 [M + H]+). HPLC: (Purity: 98.19%).

[0472] 1H NMR: (400MHz, CDC13) 5 ppm :8.85 (s, 1H), 7.05 (s, 1H), 3.79-3.87 (m, 1H), 3.68-3.76 (m, 1H), 3.41-3.50 (m, 2H), 2.20-2.27 (m, 1H), 2.00-2.13 (m, 2H), 1.04 (s, 9H).

[0473] Intermediate: 24

[0474] To a solution of tert-butyl ((lr,4r)-4-formylcyclohexyl)carbamate (5 g, 22.00 mmol) in MeOH (60 mL) was added K2CO3 (6.08 g, 43.99 mmol) and dimethyl (l-diazo-2- oxopropyl)phosphonate (5.07 g, 26.40 mmol) at 0 °C. And then the reaction mixture was stirred at 20 °C for 4 hours. The reaction was complete detected by TLC (Petroleum ether / EtOAc = 3 / 1 Rf = 0.5). The reaction mixture was concentrated in vacuo. The residue diluted with H2O (150 mL) and extracted with Petroleum ether (70 mL x 2). Combined organic phases and washed with brine (150 mL), dried over ISfeSCU, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc in Petroleum ether from 0% to 30%) to get tert-butyl ((lr,4r)-4-ethynylcyclohexyl)carbamate (4.1 g, 18.36 mmol, 83.46% yield) as yellow solid.

[0475] 'HNMR: (400 MHz, CDCI3) 8 ppm: 4.36-4.45 (m, 1H), 3.41-3.48 (m, 1H), 2.22-2.35 (m, 1H), 1.96-2.07 (m, 4H), 1.47-1.50 (m, 2H), 1.46 (s, 9H), 1.08-1.12 (m, 2H). To a solution of tert-butyl ((lr,4r)-4-ethynylcyclohexyl)carbamate (4 g, 17.91 mmol) and 4- chloro-5-iodopyrimidin-2-amine (5.03 g, 19.70 mmol) in THF (50 mL) was added TEA (5.44 g, 53.74 mmol, 7.49 mL), Cui (341.14 mg, 1.79 mmol), Pd(PPh3)4 (2.07 g, 1.79 mmol) under N2. The mixture was stirred at 90 °C for 2 h. LCMS showed desired mass was detected.

[0476] The reaction mixture was concentrated in vacuo. The residue diluted with diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 3). Combined organic phases and washed with brine (300 mL), dried over ISfeSCL, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc in Petroleum ether from 30% to 100%, TLC: Petroleum ether / EtOAc = 2 / 1 Rf = 0.3) to give tert-butyl ((lr,4r)-4-((2-amino-4- chloropyrimidin-5-yl)ethynyl)cyclohexyl)carbamate (5.3 g, 15.11 mmol, 84.34% yield) as yellow solid. LCMS: ([M-tBu+H] = 294.8).

[0477] To a solution of tert-butyl ((lr,4r)-4-((2-amino-4-chloropyrimidin-5- yl)ethynyl)cyclohexyl)carbamate (5.25 g, 14.96 mmol) in DMF (50 mL) was added NaHS (2.44 g, 29.93 mmol, 70% purity). The mixture was stirred at 100 °C for 2 h under nitrogen. LCMS showed desired mass was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (50 mL x 3). Combined organic phases and washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc in Petroleum ether from 30% to 100%, TLC: EtOAc, Rf = 0.35) to get tert-butyl ((lr,4r)-4-(2-aminothieno[2,3-d]pyrimidin-6- yl)cyclohexyl)carbamate (4.1 g, 11.77 mmol, 78.63% yield) as yellow solid. LCMS: ([M+H] = 349.1). 'HNMR: (400 MHz, DMSO-tL) 8 ppm: 8.59 (s, 1H), 6.91 (s, 1H), 6.80 (d, J= 8.0 Hz, 1H), 6.67 (s, 2H), 3.25 (br s, 1H), 2.64-2.77 (m, 1H), 1.95-2.05 (m, 2H), 1.80-1.92 (m, 2H), 1.42-1.55 (m, 2H), 1.39 (s, 9H), 1.21-1.35 (m, 2H).

[0478] To a solution of tert-butyl ((lr,4r)-4-(2-aminothieno[2,3-d]pyrimidin-6- yl)cyclohexyl)carbamate (4.1 g, 11.77 mmol) in DCM (50 mL) was added isopentyl nitrite (4.14 g, 35.30 mmol, 4.74 mL) and TMSC1 (3.83 g, 35.30 mmol, 4.48 mL) at 0 °C. Then the mixture was stirred at 20 °C for 4 h under nitrogen. LCMS showed desired mass was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (50 mL x 3). Combined organic phases and washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc in Petroleum ether from 0% to 40%, TLC: Petroleum ether / EtOAc = 1 / 1, Rf = 0.56) to get tert-butyl ((lr,4r)-4-(2-chlorothieno[2,3-d]pyrimidin-6-yl)cyclohexyl)carbamate (1.2 g, 3.26 mmol, 27.72% yield) as yellow solid. LCMS: ([M+H] = 367.9).

[0479] Section 3. Synthetic Processes to Prepare Compounds of the Disclosure

[0480] Example 1- Compound 79

[0481] Step a: A solution of tert-butyl 4-(3-chlorothieno[2,3-b]pyrazin-6-yl)piperidine-l -carboxylate (Intermediate 1, 75.0 mg, 0.21 mmol, 1.0 eq.) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (74.31 mg, 0.21 mmol, 1.0 eq.) in DMF (2.0 mL) was treated with aq. K2CO3 (0.1 mL, 2.00 M, 2.00 eq.) and XPhos-Pd-G3 (16.92 mg, 0.02 mmol, 0.10 eq.) under an atmosphere of nitrogen. The reaction mixture was stirred at 80 °C for 16 hours. The mixture was diluted with 3.00 mL of H2O and extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude residue tert-butyl 4-(3-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)piperidine-l-carboxylate. MS: m / z 465.3 [M+H]+RT 1.00 (Method 4).

[0482] Step b: The crude compound from step a (140 mg, 302.66 pmol) was dissolved in DCM (3 mL), treated with HCl / dioxane (2 M, 1 mL), then stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5um; Condition: water (FA)-ACN; Begin B: 0%; End B: 20%; Flow Rate (ml / min): 25) to afford 3-(2,8-dimethylimidazo[l,2- b]pyridazin-6-yl)-6-(piperidin-4-yl)thieno[2,3-b]pyrazine (34.53 mg, 9.51 pmol, 45.27% yield, FA salt) as a white solid. MS: m / z 365.1 [M+H]+; RT 0.65 min (Method 4).JH NMR (500 MHz, dimethyl sulfoxide- e): 5 (ppm) 8.32 (s, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.52 (s, 1H), 3.21-3.28 (m, 2H), 2.84 (br t, J= 11.5 Hz, 3H), 2.65 (s, 3H), 2.43 (s, 3H), 2.12 (br d, J= 11.5 Hz, 2H), 1.77-1.80 (m, 2H).

[0483] Using the procedure described for Example 1 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0484] Example 2 - Compound 78

[0485] Step a: A solution of tert-butyl (U?,55)-6-(3-chlorothieno[2,3-b]pyrazin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 2, 35.20 mg, 0.10 mmol, 1.0 eq.) and 2,8- dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-b]pyridazine (27.30 mg, 0.097 mmol, 1.0 eq.) in EtOH (2.0 mL) was treated with aq. ISfeCCL (0.1 mL, 2.00 M, 2.00 eq.) and XPhos-Pd-G3 (8.46 mg, 0.01 mmol, 0.10 eq.) under an atmosphere of nitrogen. The reaction mixture was stirred at 70 °C for 16 hours. The mixture was diluted with 3.00 mL of H2O and extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude residue tert-butyl (lA,55,6r)-6-(3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6- yl)-3-azabicyclo[3.1.0]hexane-3 -carboxylate. MS: m / z 463.0 [M+H]+; RT 2.14 min (Method 7).

[0486] Step b: The crude compound from step a (140 mg, 302.66 pmol) was dissolved in DCM (3 mL), treated with HCl / dioxane (2 M, 1 mL), then stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5um, Condition: water (FA)-ACN; Begin B: 3; End B: 33; Gradient Time (min): 12; 100% B Hold Time (min): 2; Flow Rate (ml / min): 25)) to afford 6-((lA,55,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-3-(2,8- dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazine (6.2 mg, 6.38 pmol, 6.38% yield) as a yellow solid. MS: m / z 364.2 [M+H]+; RT 1.66 (0-603 min). 'H NMR (400 MHz, dimethyl sulfoxide-t / e): 8 (ppm) 9.24 (d, J= 2.0 Hz, 1H), 9.00 (d, J = 1.6 Hz , 1H), 8.32-8.40 (m, 1H), 8.07 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 3.28-3.30-3.35 (m, 3H), 2.90-2.97 (m, 2H), 2.61 (s, 3H), 2.41 (s, 3H), 2.16 (d, J= 12.4 Hz, 2H), 1.82-1.87 (m, 2H).

[0487] Using the procedure described for Example 2 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0488] Example 3- Compound 94

[0489] Step a: A solution of tert-butyl 4-(3 -chi orothieno[3,2-c]pyridazin-6-yl)piperi dine- 1- carboxylate (Intermediate 3, 80 mg, 0.23 mmol, 1.0 eq.) and 2,8-dimethyl-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-b]pyridazine (60 mg, 0.22 mmol, 0.97 eq.) in DMF (4.0 mL) was treated with aq. K2CO3 (0.4 mL, 1.00 M, 2.00 eq.) and XPhos-Pd-G3 (16.92 mg, 0.02 mmol, 0.10 eq.) under an atmosphere of nitrogen. The reaction mixture was stirred at 70 °C for 16 hours. The mixture was diluted with 6.00 mL of H2O and extracted with EtOAc (3 x 6 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude residue tert-butyl 4-(3-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[3,2-c]pyridazin-6-yl)piperidine-l-carboxylate. MS: m / z 465.2 [M+H]+RT 0.88 min (Method 4).

[0490] Step b: The crude compound from step a (50 mg, 107.62 pmol) was dissolved in DCM (3 mL), treated with HCl / dioxane (2 M, 1 mL), then stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep- HPLC (: 26; Gradient Time (min): 11; 100%B Hold Time (min): 1; Flow Rate (mL / min): 25) to afford 3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(piperidin-4-yl)thieno[3,2- c]pyridazine (18 mg, 49.39 pmol,45.89% yield) as a white solid. MS: m / z 365.1 [M+H]+; RT 1.21 min (Method 7). 'H NMR (400 MHz, methanol-^): 8 (ppm) 9.34 (s, 1H), 8.90 (d, J= 0.8 Hz, 1H), 8.41 (s, 1H), 7.82 (s, 1H), 3.57-3.62 (m, 3H), 3.25-3.22 (m, 2H), 2.86 (s, 3H), 2.69 (s, 3H), 2.43-2.47 (m, 2H), 2.09-2.13 (m, 2H).

[0491] Using the procedure described for Example 3 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Example 4- Compound 14

[0492] Step a: A solution of tert-butyl 4-(2-chlorothieno[2,3-t ]pyrimidin-6-yl)piperidine-l- carboxylate (Intermediate 6, 35.30 mg, 0.10 mmol, 1.0 eq.) and 7-fhioro-2-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2J / -indazole (27.30 mg, 0.097 mmol, 1.0 eq.) in DMF (2.0 mL) was treated with aq. K2CO3 (0.2 mL, 1.00 M, 2.00 eq.) and XPhos-Pd-G3 (8.46 mg, 0.01 mmol, 0.10 eq.) under an atmosphere of nitrogen. The reaction mixture was stirred at 70 °C for 16 hours. The mixture was diluted with 3.00 mL of H2O and extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to afford the crude residue tert-butyl tert-butyl 4-(2-(7- fluoro-2-methyl-27 / -indazol-5-yl)thieno[2,3-t / ]pyrimidin-6-yl)piperidine- l -carboxylate. MS: m / z 463.0 [M+H]+RT 0.50 min (Method 9).

[0493] Step b: The crude compound from step a (20 mg, 42.78 pmol) was dissolved in DCM (3 mL), treated with HCl / dioxane (2 M, 1 mL), then stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep- HPLC (Column: Boston Green ODS 150*30mm*5um; Condition: water (HCl)-ACN; Begin B: 0%; End B: 25%; Flow Rate (ml / min): 25) to afford 2-(7-fluoro-2-methyl-2J7-indazol-5-yl)- 6-(piperidin-4-yl)thieno[2,3-t ]pyrimidine (8.35 mg, 22.28 pmol, 52.08% yield) as a yellow solid. MS: m / z 368.0 [M+H]+; RT 2.24 min (Method 12). 'H NMR (400 MHz, methanol-^): 5 (ppm) 9.15 (s, 1H), 8.73 (s 1H), 8.50-8.58 (m, 1H), 8.47 (s, 1H), 8.06-8.16 (m, 1H), 7.32 (s, 1H), 4.27 (s, 3H), 3.46-3.56 (m, 3H), 3.15-3.24 (m, 2H), 2.30-2.43 (m, 2H), 1.98-2.04 (m, 2H).

[0494] Using the procedure described for Example 4 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0495] Example 5 - Compound 96

[0496] Step a: A solution of tert-butyl (lA,55)-6-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 5A, 35.10 mg, 0.10 mmol, 1.0 eq.) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (27.30 mg, 0.097 mmol, 1.0 eq.) in DMF (2.0 mL) was treated with aq. K2CO3 (0.2 mL, 1.00 M, 2.00 eq.) and XPhos-Pd-G3 (8.46 mg, 0.01 mmol, 0.10 eq.) under an atmosphere of nitrogen. The reaction mixture was stirred at 70 °C for 16 hours. The mixture was diluted with 3.00 mL of H2O and extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude residue tert-butyl (lA,55,6r)-6-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6- yl)-3-azabicyclo[3.1.0]hexane-3 -carboxylate. MS: m / z 463.0 [M+H]+RT 0.88 min (Method 4).

[0497] Step b: The crude compound from step a (140 mg, 302.66 pmol) was dissolved in DCM (3 mL), treated with HCl / dioxane (2 M, 1 mL), then stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5um; Condition: water (HCl)-ACN; Begin B: 0%; End B: 25%; Flow Rate (ml / min): 25) to afford 6-((lA,55,6r)-3- azabicyclo[3.1.0]hexan-6-yl)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3- Z>]pyrazine (32 mg, 0.09 mmol, 88.62% yield) as a yellow solid. MS: m / z 363.2 [M+H]+; RT 0.72 min (Method 17). 'HNMR (400 MHz, methanol-^): 8 (ppm) 9.60 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 7.41 (s, 1H), 3.61-3.78 (m, 4H), 2.83 (s, 3H), 2.69 (s, 3H), 2.62-2.64 (m, 1H), 2.53 (br s, 2H).

[0498] Using the procedure described for Example 5 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0499] Ill

[0500] Example 6 - Compound 1

[0501] Step a: A solution of tert-butyl (lA,55,65)-6-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 5B, 200 mg, 568.42 pmol) in Dioxane (2 mL) and water (0.5 mL) was treated with 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (186.31 mg, 682.11 pmol), Pd(dppf)Cl2(41.59 mg, 56.84 pmol) and K2CO3(235.68 mg, 1.71 mmol) then stirred at 90 °C for 2 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by / 'c -TLC (PEZEtOAc = 1 / 2, Rf= 0.3) to afford tert-butyl (lA,55,65)-6-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 302.66 pmol, 53.25% yield) as a yellow solid. MS: m / z 463.0 [M+H]+; RT 0.66 min (Method 9).

[0502] Step b: A solution of tert-butyl (lA,55,65)-6-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6- yl)thieno[2,3-Z>]pyrazin-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 302.66 pmol) in DCM (3 mL) was treated with HCl / dioxane (2 M, 1 mL) then stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 6-((lA,55,65)-3- azabicyclo[3.1.0]hexan-6-yl)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3- Z>]pyrazine (107 mg, 268.23 pmol, 88.62% yield, 100% purity, Hydrochloride) as a yellow solid. MS: m / z 363.2 [M+H]+; RT 1.43 min (Method 11). 'H NMR (400 MHz, dimethyl sulfoxide-t / e): 8 (ppm) 9.71 (s, 1H), 8.67 (s, 1H), 8.41 (s, 1H), 7.69 (s, 1H), 3.71-3.74 (m, 2H), 3.66-3.70 (m, 2H), 2.84 (s, 3H), 2.75-2.78 (m, 1H), 2.68 (s, 3H), 2.58-2.63 (m, 2H). Using the procedure described for Example 6 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0503] Example 7 - Compound 46

[0504] Step a: A solution of tert-butyl 7-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-4-azaspiro[2.5]octane- 4-carboxylate (Intermediate 8, 200 mg, 526.45 pmol, 1.0 eq.), 2-methyl-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (103 mg, 579.09 pmol, 1.1 eq.), Pd(dppf)C12-CH2C12 (34 mg, 52.64pmol, 0.1 eq.), and K2CO3 (218 mg, 1.58 mmol, 3.0 eq.) in Dioxane (5.0 mL) and H2O (1.0 mL) was stirred at 85 °C for 16 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by flash column (PE ZEtOAc = 1 / 0 to 7 / 3) to afford tert-butyl 7-(3-(2- methylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)-4-azaspiro[2.5]octane-4- carboxylate (100 mg, 39.86% yield) as a yellow solid. MS: m / z 477.2 [M+H]+; RT 5.02 min (Method 18). 'H NMR (400 MHz, chloroform-tZ): 8 (ppm) 9.59 (s, 1H), 8.15 (d, J = 9.5 Hz, 1H), 7.97 (d, J = 9.5 Hz, 1H), 7.86 (s, 1H), 7.11-7.16 (m, 1H), 4.19-4.23 (m, 1H), 3.39-3.48 (m, 1H), 3.03-3.10 (m, 1H), 2.56 (s, 3H), 2.11-2.15 (m, 2H), 1.50 (s, 9H), 1.36-1.43 (m, 2H), 0.84-1.02 (m, 2H), 0.56-0.69 (m, 2H).

[0505] Step b: A solution of tert-butyl 7-(3-(2-methylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3- Z>]pyrazin-6-yl)-4-azaspiro[2.5]octane-4-carboxylate (100 mg, 209.82 pmol) in DCM (3.0 mL) was treated with TFA (478 mg, 4.20 mmol, 209.82 pL) and stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by Prep-HPLC (Column: Gemini NX 150x30mm, 5pm; Condition: water (NH4HCO3)- ACN; Begin B: 25%; End B: 55%; Gradient Time (min): 11; 100% B Hold Time (min): 2.5; Flow Rate (mL / min): 25) to afford 3-(2-methylimidazo[l,2-Z>]pyridazin-6-yl)-6-(4- azaspiro[2.5]octan-7-yl)thieno[2,3-Z>]pyrazine (38.5 mg, 48.74% yield, 100% purity) as a gray solid. MS: m / z 377.1 [M+H]+; RT 3.38 min (Method 18). 'H NMR (400 MHz, dimethyl sulfoxide-t / e) : 8 (ppm) 9.50 (s, 1H), 8.21 (s, 1H), 8.14-8.17 (m, 1H), 8.05-8.09 (m, 1H), 7.49 (s, 1H), 2.98-3.02 (m, 1H), 2.72-2.77 (m, 1H), 2.66-2.70 (m, 1H), 2.44 (s, 3H), 2.03-2.10 (m, 2H), 1.57-1.68 (m, 1H,), 1.41-1.46 (m, 1H), 0.54-0.60 (m, 1H), 0.41-0.52 (m, 3H). Using the procedure described for Example 7 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Example 8 - Compound 62 Step a: A solution of tert-butyl 7-(6-chlorothieno[3,2-Z>]pyridin-2-yl)-4-azaspiro[2.5]octane-4- carboxylate (Intermediate 9, 50.94 mg, 134.44 pmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (45 mg, 112.03 pmol), K2CO3(38.71 mg, 280.08 pmol), and XPhos-Pd-G3 (9.48 mg, 11.20 pmol) in Dioxane (2 mL) was stirred at 100 °C for 3 h under N2atmosphere. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc from 0% to 50%) to afford tert-butyl 7-(6-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[3,2-Z>]pyridin-2-yl)-4-azaspiro[2.5]octane-4- carboxylate (50 mg, 75.66% yield, 83% purity) as a yellow solid. MS: m / z 490.2 [M+H]+; RT 0.43 min (Method 9).

[0506] Step b: The crude compound from step a (55 mg, 112.33 pmol) was dissolved in DCM (3 mL), treated with TFA (46.70 mg, 3.92 mmol, 0.3 mL), then stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep-HPLC (Instrument: CAS-CD-SEMI-PREP-I; Method; Column: Phenomenex luna C18 150*25mm* lOum; Condition: water (FA)-ACN; Begin B: 1; End B: 25; Gradient Time(min): 8; 100%B Hold Time(min): 2; Flow Rate (ml / min): 30) to afford 6-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)-2-(4-azaspiro[2.5]octan-7-yl)thieno[3,2-Z>]pyridine (22.82 mg, 48.32% yield, 98.12% purity, formic acid salt) as a white solid. MS: m / z 390.1 [M+H]+; RT 0.26 min (Method 9).1H NMR (400 MHz, methanol-^): 5 (ppm) 9.22 (d, J= 2.0 Hz, 1H), 8.92-8.95 (m, 1H), 8.53 (s, 1H), 7.95 (s, 1H), 7.67 (s, 1H), 7.36 (s, 1H), 3.41-3.49 (m, 1H), 3.26-3.30 (m, 1H), 3.01-3.08 (m, 1H), 2.69 (s, 3H), 2.50 (s, 3H), 2.21-2.26 (m, 2H), 1.81- 1.88 (m, 1H), 1.57-1.65 (m, 1H), 0.70-0.85 (m, 4H).

[0507] Using the procedure described for Example 8 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0508] Example 9 - Compound 58

[0509] Step a: A solution of tert-butyl 7-(2-chlorothieno[2,3-J]pyrimidin-6-yl)-4- azaspiro[2.5]octane-4-carboxylate (Intermediate 10, 80 mg, 210.58 pmol, 1 eq.), 7-fluoro-2- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2J7-indazole (87.22 mg, 315.87 pmol, 1.5 eq.), K2CO3(87.31 mg, 631.74 pmol, 3.0 eq.), and XPhos-Pd-G3 (17.83 mg, 21.06 pmol, 0.1 eq.) in Dioxane (5 mL) and water (1 mL) was stirred at 90 °C for 2 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc from 0% to 50%) to afford tert-butyl 7-(2-(7-fluoro-2-methyl-27 / -indazol-5-yl)thieno[2,3-t / ]pyrimidin-6- yl)-4-azaspiro[2.5]octane-4-carboxylate (50 mg, 75.66% yield, 83% purity) as a yellow oil. MS: m / z 494.2 [M+H]+; RT 0.56 min (Method 9). ‘H NMR (400 MHz, methanol-^): 5 (ppm) 9.10 (s,lH), 8.71 (s, 1H), 8.45 (d, J= 2.4 Hz, 1H), 8.10 (d, J= 13.2 Hz, 1H), 7.23 (s, 1H), 4.26 (s, 3H), 3.47-3.49 (m, 2H), 3.11-3.15 (m, 1H), 2.11-2.24 (m, 2H), 1.66-1.79 (m, 1H), 1.50 (s, 9H), 1.43-1.47 (m, 1H), 1.28-1.32 (m, 1H), 0.96-0.99 (m, 1H), 0.64-0.69 (m, 2H).

[0510] Step b: The crude compound from step a (65 mg, 131.69 mol) was dissolved in DCM (5 mL), treated with TFA (1.49 mg, 13.06 mmol, 1 mL), then stirred at 25 °C for 2 h. The reaction mixture was adjusted to pH 7 with ammonium hydroxide and concentrated under reduced pressure to afford the crude product. The crude was purified by prep-HPLC (Column: Phenomenex luna C18 150><25mmx lOum; condition: water (NH4HCO3)-ACN; Begin B:5; End B:35; Gradient Time (min): 10; 100%B Hold Time (min): 3; Flow Rate (mL / min): 25; Detection wavelength: 220 nm) to afford 2-(7-fluoro-2-methyl-27 / -indazol-5-yl)-6-(4- azaspiro[2.5]octan-7-yl)thieno[2,3-J]pyrimidine (27.4 mg, 46.19% yield, 97.56% purity, formic acid salt) as a yellow solid. MS: m / z 394.0 [M+H]+; RT 0.33 min (Method 9). 'H NMR (400 MHz, m ethanol -tZ4): 8 (ppm) 9.11 (s, 1H), 8.70 (d, J= 1.2 Hz, 1H), 8.43-8.47 (m, 2H), 8.05-8.10 (m, 1H), 7.26 (s, 1H), 4.25 (s, 3H), 3.44-3.52 (m, 2H), 3.20-3.27 (m, 1H), 2.35-2.44 (m, 2H), 1.92-2.00 (m, 1H), 1.71-1.75 (m, 1H), 0.98-1.03 (m, 2H), 0.87-0.91-0.74 (m, 2H).

[0511] Using the procedure described for Example 9 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Example 10 - Compound 53

[0512] Step a: A solution of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)imidazo[l,2-Z>]pyridazine (156.61 mg, 819.95 pmol) and tert-butyl 6-(3-chlorothieno[2,3- Z>]pyrazin-6-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 11, 200 mg, 546.63 pmol) in Dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl2(26.72 mg, 41.00 pmol), K2CO3(151.10 mg, 1.09 mmol) at 20 °C. The mixture was stirred at 100 °C under N2for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (EtOAc in PE from 0% to 100%) to afford tertbutyl 6-(3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)-2- azaspiro[3.3]heptane-2-carboxylate (110 mg, 260.52 pmol, 42.22% yield) as a light-yellow solid. MS: m / z 477.2 [M+H]+; RT 0.44 min (Method 9).

[0513] Step b: A solution of tert-butyl 6-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3- b]pyrazin-6-yl)-2-azaspiro[3.3]heptane-2-carboxylate (110 mg, 230.81 pmol) in DCM (5 mL) was treated with TFA (744.50 mg, 6.53 mmol, 0.5 mL) then stirred at 20 °C under N2for 30 minutes. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (Instrument: CASC-CD-SEMI-PREP-Q; Column: Phenomenex luna C18 150*25mm* lOum; Condition: water (FA)-ACN; Begin B: 0; End B: 28; Gradient Time(min) : 11; 100%B Hold Time(min): 2; Flow Rate (mL / min): 25) to afford 3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(2-azaspiro[3.3]heptan-6-yl)thieno[2,3- Z>]pyrazine (4.63 mg, 12.19 pmol, 5.28% yield, 99.10% purity) as a yellow solid. MS: m / z 377.0 [M+H]+; RT 0.25 min (Method 9). 'H NMR (400 MHz, dimethyl sulfoxide- e): 5 (ppm) 9.49 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.48 (s, 1H), 3.80-3.85 (m, 1H), 3.62 (s, 2H), 3.46 (s, 2H), 2.70 (s, 2H), 2.65 (s, 3H), 2.43 (s, 3H), 2.35-2.40 (m, 2H).

[0514] Using the procedure described for Example 10 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0515] Example 11 - Compound 103

[0516] Step a: A solution of tert-butyl 3-(3-iodothieno[2,3-Z>]pyrazin-6-yl)azetidine-l-carboxylate (Intermediate 12, 93 mg, 222.88 pmol) in Toluene (5.0 mL), MeOH (5.0 mL) and H2O (1.0 mL) was treated with 6-chl oro-2, 8-dimethylimidazo[l,2-Z>]pyridazine (45 mg, 245.17 pmol), B2Pin2(113 mg, 445.76 pmol), cataCXium A (64 mg, 178.30 pmol), Pd(OAc)2(20 mg, 89.15 pmol) and CsF (203 mg, 1.34 mmol). The mixture was stirred at 100 °C for 2 hours under N2atmosphere. The mixture was concentrated under reduced pressure and purified by flash column chromatography (PEZEtOAc = 1 / 0 to 4 / 1) to afford tert-butyl 3-(3-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)azetidine-l-carboxylate (80 mg, 82.23% yield) as a yellow solid. MS: m / z 437.2 [M+H]+; RT 2.08 min (Method 7).JH NMR (400 MHz, dimethyl sulfoxide-t / 6): 8 (ppm) 9.51 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.71 (s, 1H), 4.35-4.38 (m, 2H), 4.28-4.32 (m, 1H), 4.01-4.05 (m, 2H), 2.64 (s, 3H), 2.43 (s, 3H), 1.42 (s, 9H).

[0517] Step b: A solution of tert-butyl 3-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3- Z>]pyrazin-6-yl)azetidine-l -carboxylate (15 mg, 34.36 pmol) in DCM (2.0 mL) was treated with TFA (39 mg, 26.31 pL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by prep- HPLC (Column: Boston Green ODS 150*30mm*5um, Condition: water (FA)-ACN; Begin B: 0; End B: 26; Gradient Time (min): 14; 100% B Hold Time (min): 2; Flow Rate (ml / min): 25) to afford 6-(azetidin-3-yl)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazine (7.0 mg, 60.55% yield) as a yellow solid. MS: 337.1 [M+H]+; RT 1.55 min (Method 11). 'H NMR (400 MHz, dimethyl sulfoxide- e): 5 (ppm) 9.50 (s, 1H), 8.33 (br s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 4.38-4.43 (m, 1H), 4.11-4.16 (m, 2H), 3.92-3.96 (m, 2H), 2.64 (s, 3H), 2.43 (s, 3H).

[0518] Step c: A solution of 6-(azetidin-3-yl)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6- yl)thieno[2,3-Z>]pyrazine (50 mg, 148.63 pmol) in MeOH (2.0 mL) was treated with TEA (0.5 mL). The mixture was stirred at 25 °C for 1 hours, then paraformaldehyde (267 mg, 222.94 pmol), acetic acid (714 mg, 680 pL) and NaBH3CN (14 mg, 222.94 pmol) were added. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was filtered then purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5um, Condition: water (FA)-ACN; Begin B: 0; End B: 30; Gradient Time (min): 12; 100% B Hold Time (min): 2; Flow Rate (ml / min): 25) to afford 3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(l-methylazetidin-3- yl)thieno[2,3-Z>]pyrazine (9.0 mg, 17.28% yield) as a grey solid. MS: m / z 351.1 [M+H]+; RT 1.16 (Method 20).XH NMR (400 MHz, methanol-^): 5 (ppm) 9.53 (s, 1H), 8.46 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 4.40-4.51 (m, 3H), 4.16-4.21 (m, 2H), 2.89 (s, 3H), 2.67 (s, 3H), 2.49 (s, 3H).

[0519] Using the procedure described for Example 11 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0520] Example 12 - Compound 65

[0521] Step a: A solution of 3-chloro-6-iodo-thieno[2,3-Z>]pyrazine (Intermediate 4, 250 mg, 843.13 pmol, 1.0 eq.) tert-butyl (lA,55)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-8- azabicyclo[3.2.1]oct-2-ene-8-carboxylate (282.65 mg, 843.13 pmol, 1.0 eq.) K3PO4 (536.90 mg, 2.53 mmol, 3.0 eq.) and SPhos-Pd-G3 (65.87 mg, 84.31 pmol, 0.1 eq.) in 4: l(v / v) dioxane (6 mL):water (1.5 mL) was heated at 90 °C for 16 hours. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the crude product as a brown solid, which was used directly without purification. MS: m / z 378.1 [M+H]+; RT = 1.09 min (Method 4). ' H NMR (400 MHz, methanol-^): 8 (ppm) 8.45 (s, 1H), 7.16 (s, 1H), 6.58 - 6.67 (m, 1H), 4.41 - 4.56 (m, 2H), 2.24 (br d, J= 16.6 Hz, 2H), 1.90 - 1.97 (m, 2H), 1.79 - 1.88 (m, 2H), 1.48 (s, 9H).

[0522] Step b: The crude product from step b (160 mg, 423.41 pmol, 1.0 eq.) was dissolved in 4: 1 (v / v) dioxane (6 mL):water (1.5 mL), treated with 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (116 mg, 423.41 pmol, 1.0 eq.) XPhos-Pd-G3 (35.84 mg, 42.34 pmol, 0.1 eq.) and CS2CO3 (413.86 mg, 1.27 mmol, 3.0 eq.) then heated at 90 °C for 16 hours. The crude product was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was transferred to a silica gel column and purified by flash column chromatography (0-100% ethyl acetate in heptanes) to obtain tert-butyl (15,5A)-3-(3-(2,8-dimethylimidazo[l,2- Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate as a yellow solid (113 mg, 231.13 pmol, 54.62% yield). MS: m / z 489.2 [M+H]+; RT = 0.81 min (Method 4).

[0523] Step c: The product from step b (100 mgs, 204.66 pmol) was dissolved in 2-methyl THF (2 mL), treated with Pd / C (109 mg, 1.02 mmol, 5.0 eq.) and formic acid (1.22 g, 26.51 mmol, 1.0 mL, 129 eq.). The reaction vessel was sealed and heated at 90 °C for 16 hours. The rection mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (Waters SunFire Prep C18 5um OBD 30x100mm, TFA_prep_05_35_12min) to obtain 6-((lA,55)-8- azabicyclo[3.2.1]octan-3-yl)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3- Z>]pyrazine (16.2 mg, 41.52 pmol, 15.72% yield) as a yellow solid. MS: m / z 391.2 [M+H]+; RT 0.99 min (Method 3). 'HNMR: (500 MHz, dimethyl sulfoxide- e): 5 (ppm) 9.53 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.55 (s, 1H), 4.13 (s, 2H), 3.72 (m, 2H), 2.67 (s, 3H), 2.55 (m, 1H), 2.45 (s, 3H), 2.14 (m, 3H), 2.10 (m, 2H), 2.05, (m, 2H).

[0524] Using the procedure described for Example 12 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step b, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0525] Example 13 - Compound 39

[0526] Step a: To a 20-mL scintillation vial containing 6-bromo-2-chlorothieno[2,3-d]pyrimidine (124.8 mg, 500.0 pmol, 1.0 eq.) and tert-butyl (3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)cyclohex-3-en-l-yl)- X-azanecarboxylate (193.9 mg, 600.0 pmol, 1.2 eq.) was added dioxane (4.00 mL) and water (1.00 mL). Potassium carbonate (318.4 mg, 1.50 mmol, 3.0 eq.) was then added to the solution and the vial was thoroughly purged with N2. After addition of SPhos-Pd-G3, the reaction mixture was stirred for approximately 16 h at 85 °C. The reaction mixture was then filtered through Celite with the aid of EtOAc and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0 to 50% EtOAc in heptane) to provide tert-butyl (3-(2-chlorothieno[2,3-d]pyrimidin-6-yl)cyclohex-3-en-l-yl)- A- azanecarboxylate as a yellow solid (90.5 mg, 50% yield). MS: m / z 366.1 [M+H]+; RT 0.97 min (Method 4).

[0527] Step b: To a solution of tert-butyl (3-(2-chlorothieno[2,3-d]pyrimidin-6-yl)cyclohex-3-en-l- yl)- / .-azanecarboxylate (90.50 mg, 247.4 pmol, 1.0 eq.) and 7-fluoro-2-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazole (77.32 mg, 247.4 pmol, 1.0 eq.) was added dioxane (2.00 mL) and water (500.0 pL), followed by addition of potassium carbonate (102.6 mg, 742.05 pmol, 3.0 eq.). The vial was placed under N2 atmosphere and XPhos-Pd-G3 (20.94 mg, 24.74 pmol, 0.10 eq.) was added to the vial. The reaction mixture was heated at 85 °C for approximately 16 h, after which time it was filtered through Celite and concentrated under reduced pressure to obtain crude tert-butyl (3-(2-(7-fluoro-2-methyl-2H-indazol-5- yl)thieno[2,3-d]pyrimidin-6-yl)cyclohex-3-en-l-yl)- -azanecarboxylate, which was used without further purification assuming quantitative yield.

[0528] Step c: To a solution of crude tert-butyl (3-(2-(7-fluoro-2-methyl-2H-indazol-5- yl)thieno[2,3-d]pyrimidin-6-yl)cyclohex-3-en-l-yl)- A-azanecarboxylate (118.6 mg, 311.0 pmol, 1.0 eq.) in 2-MeTHF (3.11 mL) was added 10 wt.% Pd / C (82.73 mg, 77.74 pmol, 0.25 eq.). Formic acid (1.76 mL, 46.64 mmol, 150.0 eq.) was then added to the solution, and the reaction mixture was heated at 70 °C for approximately 16 h. After this time, the reaction mixture was filtered through Celite and directly concentrated to provide the crude residue, which was further purified by preparative HPLC (Waters SunFire Prep C18 5um OBD 30x100mm column; 5 to 55% MeCN in water; TFA mod.) to provide 3-(2-(7-fluoro-2- methyl-2 / / -indazol-5-yl)thieno[2,3-J]pyrimidin-6-yl)cyclohexan-l-amine as an orange solid as the corresponding TFA salt (4.7 mg, 3.1% yield). MS: m / z 380.2 [M+H]+; RT 1.43 min (Method 3) ' H NMR (600 MHz, dimethyl sulfoxide- e): 5 (ppm) 9.26 (s, 1 H), 8.75 (d, J= 1.14 Hz, 1 H), 8.66 (d, 2.67 Hz, 1 H), 8.03 - 8.00 (m, 1 H), 7.41 (s, 1 H), 6.48-6.41 (br s,

[0529] 1 H), 4.24 (s, 3 H), 3.54 - 3.48 (m, 1 H), 2.90 (br dd, J= 16.02, 4.58 Hz, 1 H), 2.48 - 2.36 (m, 3 H), 2.06-1.94 (m, 1 H), 1.71-1.61 (m, 1 H).

[0530] Using the procedure described for Example 13 above, additional compounds described herein were prepared by substituting the appropriate amine starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0531] Example 14- Compound 22

[0532] Step a: A solution of tert-butyl 3 -(3 -chi orothieno[2, 3 -Z>]pyrazin-6-yl)piperi dine- 1 -carboxylate (Intermediate 7, 220 mg, 621.70 pmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (118.74 mg, 621.70 pmol) in dioxane (5 mL) and H2O (0.5 mL) under N2atmosphere was treated with SPhos (25.52 mg, 62.17 pmol), Pd2(dba)3(56.93 mg, 62.17 pmol) and K3PO4(263.93 mg, 1.24 mmol). The mixture was stirred at 100

[0533] °C under N2for 16 hours. The reaction mixture was concentrated under reduced pressure and then diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 3 / 2) to afford tert-butyl 3-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6- yl)piperidine-l -carboxylate (110 mg, 33.90% yield, 89% purity) as a white solid. MS: m / z 465.1 [M+H]+; RT 0.42 (Method 9). ‘H NMR (400 MHz, chloroforms / ): 8 (ppm) 9.58 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.34 (s, 1H), 4.03-4.18 (m, 2H), 3.13-3.18 (m, 1H), 2.83-3.00 (m, 2H), 2.77 (s, 3H), 2.57 (s, 3H), 2.21-2.36 (m, 2H), 1.80-1.86 (m, 2H), 1.50 (s, 9H). Step b: The product from step a (110 mg, 236.77 pmol) was dissolved in DCM (5 mL) then treated with TFA (744.50 mg, 6.53 mmol, 0.5 mL). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue and then purified by prep-HPLC (Instrument: CASCD-SEMI-PREP-G Method Column Welch Xtimate C18 150*25mm*5um; Condition: water (HCl)-ACN; Begin B: 0 End B: 20; Gradient Time (min) 10; 100% B; Hold Time (min): 5; Flow Rate (ml / min) : 25) to afford 3-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(piperidin-3-yl)thieno[2,3-Z>]pyrazine (10.4 mg, 24.87% yield, HC1 salt) as a yellow solid. MS: m / z 365.1 [M+H]+; RT 1.88 min (Method 15). 'H NMR (400 MHz, methanol-^): 8 (ppm) 9.59 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.51 (s, 1H), 3.69-3.72 (m, 1H), 3.44-3.55 (m, 2H), 3.23-3.28 (m, 1H), 3.04-3.12 (m, 1H), 2.71 (s, 3H), 2.51 (s, 3H), 2.34-2.40 (m, 1H), 2.09-2.16 (m, 1H), 1.91-2.04 (m, 2H).

[0534] Example 15-Compound 76 and 91

[0535] Step a: A solution of tert-butyl 3 -(3 -chi orothieno[2, 3 -Z>]pyrazin-6-yl)piperi dine- 1 -carboxylate (Intermediate 7, 800 mg, 2.26 mmol) and 4(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)boronic acid (Intermediate 19, 431.79 mg, 2.26 mmol) in dioxane (20 mL) and H2O (4 mL) under N2atmosphere was treated with Pd(dppf)Cl2CH2CI2 (147.34 mg, 226.07 pmol) and K2CO3(781.12 mg, 5.65 mmol). The mixture was stirred at 100 °C under N2for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (EtOAc in PE from 0% to 85%, PE / EtOAc = 1 / 4, Rf = 0.2) to afford rac-tert-butyl (A)-3-(3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3- Z>]pyrazin-6-yl)piperidine-l-carboxylate (300 mg, 28.56% yield) as a light yellow solid. MS: m / z 465.2 [M+H]+; RT 0.50 min (Method 9).1H NMR (400 MHz, chloroforms / ): 6 (ppm) 9.31 (s, 1H), 8.09 (s, 1H), 7.38 (s, 1H), 7.24 (s, 1H), 3.93-4.44 (m, 2H), 3.03- 3.17 (m, 1H), 2.80- 2.85 (m, 2H), 2.77 (s, 3H), 2.49 (s, 3H), 2.22 (d, J = 11.6 Hz, 1H), 1.57-1.82 (m, 3H), 1.43 (s, 9H).

[0536] Step b: The product from step a (200 mg, 430.49 pmol) was dissolved in DCM (5 mL) then treated with TFA (744.50 mg, 6.53 mmol, 0.5 mL). The mixture was stirred at 25 °C for 20 minutes. The reaction mixture was concentrated under reduced pressure to afford the crude residue rac-(A)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6-(piperidin-3-yl)thieno[2,3- Z>]pyrazine (190 mg, 92.43% yield, TFA salt) as a light yellow solid. MS: m / z 365.2 [M+H]+; RT 0.29 min (Method 9). Step c: Compound 8 (50 mg, 104.72 pmol, TFA) was separated by CHIRAL-HPLC (Instrument: PREP-NPLC-F; Column: DAICEL CHIRALPAK IE (50*250mm, 10pm); Condition: Heptane-(IPA: ACN=4: 1) (0.1%NH3.H2O); Begin B: 70; End B: 90; Gradient Time(min): 15; 100%B Hold Time(min): 10; Flow Rate (mL / min):90) to give (S)-3-(4,6- dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6-(piperidin-3-yl)thieno[2,3-Z>]pyrazine (91, 10.33 mg, 27.19 pmol, 51.93% yield, 95.94% purity) and (A)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2- yl)-6-(piperidin-3-yl)thieno[2,3-Z>]pyrazine (76, 6.33 mg, 17.25 pmol, 32.95% yield, 99.34% purity) and both as a white solid.

[0537] Compound 76 :

[0538] MS: m / z 365.3 [M+H]+; RT 1.96 min (Method 15)

[0539] ‘H NMR (400 MHz, chloroform-^ 5 ppm 9.38 (s, 1H), 8.14 (s, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 3.63-3.78 (m, 1H), 3.30-3.59 (m, 2H), 2.93-3.05 (m, 1H), 2.78-2.81 (m, 4H), 2.53 (s, 3H), 2.32- 2.41 (m, 1H), 1.95-2.08 (m, 2H), 1.76-1.83 (m, 1H). 95.94% ee.

[0540] Compound 91 :

[0541] MS: m / z 365.1 [M+H]+; RT 1.95 min (Method 15)

[0542] 'H NMR (400 MHz, methanol-^): 8 (ppm) 9.37 (s, 1H), 8.14 (s, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 3.63-3.78 (m, 1H), 3.30-3.59 (m, 2H), 2.93-3.05 (m, 1H), 2.78-2.81 (m, 4H), 2.53 (s, 3H), 2.32-2.41 (m, 1H), 1.95-2.08 (m, 2H), 1.76-1.83 (m, 1H). 99.18%.

[0543] Example 16 - Compound 100

[0544] A solution of 3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(piperidin-3-yl)thieno[2,3- Z>]pyrazine (22, 90 mg, 217.30 pmol) in acetaldehyde (11.49 mg, 260.76 pmol, 14.63 pL) in MeOH (3 mL) was treated with NaBH3CN (40.97 mg, 651.91 pmol) at 20 °C. The mixture was then stirred at 60 °C for 0.5 h. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by pre-HPLC (Instrument: CAS-CD-SEMI-PREP-L; Method; Column: Waters xbridge 150*25mm 10pm; Condition: water (NHJICO3)-CAN; Begin B: 40; End B: 70; Gradient Time (min): 11; 100%B Hold Time (min): 2; Flow Rate(mL / min): 30) to afford rac-(A)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(l- ethylpiperidin-3-yl)thieno[2,3-Z>]pyrazine (40 mg, 44.08% yield, 94.16% purity) as a yellow solid (MS: m / z 393.1 [M+H]+;RT 0.72 min (Method 9)). The product was then separated by Chiral-HPLC (Instrument: CAS-CD-Prep-SFC-A; Method; Column: DAICEL CHIRALPAK AS (250mm*30mm,10um); Condition: CCh-MeOH (0.1%NH3H2O); Begin B: 15; End B: 15; Gradient Time (min): 3.7; 100%B Hold Time (min): 0; Flow Rate (ml / min): 120) to afford re / - (A)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(l-ethylpiperidin-3-yl)thieno[2,3- Z>]pyrazine (7.28 mg, 19.14% yield, 98.88% purity) as a yellow solid. MS: m / z 393.1 [M+H]+;

[0545] RT 1.49 (Method 11). ‘H NMR (400 MHz, methanol-^): 5 (ppm) 9.54 (s, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.42 (s, 1H), 3.35-3.42 (m, 1H), 3.01-3.23 (m, 2H), 2.70 (s, 3H), 2.61-2.64 (m, 2H), 2.51 (s, 3H), 2.35-2.44 (m, 1H), 2.19-2.28 (m, 2H), 1.88-2.01 (m, 1H), 1.64-1.87 (m, 2H),

[0546] 1.20 (t, J= 7.2 Hz, 3H). 98.88% ee.

[0547] Using the procedure described for Example 16 above, additional compounds described herein were prepared by substituting the appropriate aldehyde or ketone starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0548] Example 17- Compound 90

[0549] A solution of 3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(piperidin-4-yl)thieno[2,3- Z>]pyrazine (79, 60 mg, 149.65 mol, HC1 salt) in MeOH (2 mL) was treated with (1- ethoxycyclopropoxy)trimethylsilane (65.22 mg, 374.13 mol, 75.22 pL) and TEA was added dropwise to adjust pH to 7-8. The reaction mixture was then stirred at 25°C for 10 min. The solution was treated with acetic acid was to adjust the pH to 5-7 and the mixture was stirred at 25 °C another for 10 min. The reaction mixture was then treated with NaBH3CN (45.14 mg, 718.33 pmol) and stirred at 90 °C for 2 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5um; Condition: water (HCl)-ACN; Begin B: 7%; End B: 27%; Flow Rate (mL / min): 25) to afford 6-(l-cyclopropylpiperidin-4-yl)-3-(2,8-dimethylimidazo[l,2- Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazine (28 mg, 69.22 mol, 46.25% yield, 100% purity) as an orange solid. MS: 405.2 [M+H]+; RT 0.55 min (Method 9). 'HNMR (500 MHz, methanol-^): 5 (ppm) 9.67 (s, 1H), 8.69 (s, 1H), 8.41 (s, 1H), 7.53 (s, 1H), 3.82-3.86 (m, 2H), 3.51-3.57 (m, 1H), 3.43-3.47 (m, 2H), 2.90-2.93 (m, 1H), 2.83 (s, 3H), 2.68 (s, 3H), 2.46-2.50 (m, 2H), 2.13- 2.18 (m, 2H), 1.10-1.12 (m, 2H), 1.02-1.04 (m, 2H).

[0550] Example 18- Compound 48

[0551] A solution of 3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(piperidin-4-yl)thieno[2,3- Z>]pyrazine (79, 47 mg, 128.96 pmol) in MeOH (2.0 mL) was treated with TEA (0.5 mL) and the mixture was stirred at 25 °C for 1 hour. The mixture was treated with paraformaldehyde (232.03 mg, 193.43 pmol), acetic acid (619 mg, 590 pL) and NaBH3CN (12.16 mg, 193.43 pmol) then stirred at 25 °C for 3 hours. The mixture was filtered then purified by prep-HPLC (Column: Boston Prime C18 150*30mm*5um, Condition: water (NH3H2O+NH4HCO3)- ACN; Begin B: 57; End B: 87; Gradient Time (min): 10; 100% B Hold Time (min): 2; Flow Rate (ml / min): 25) to afford 3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(l- methylpiperidin-4-yl)thieno[2,3-Z>]pyrazine (7.0 mg, 14.34% yield) as a grey solid. MS: m / z 379.2 [M+H]+; RT 1.51 min (Method 20). 'HNMR (400 MHz, methanol-^): 8 (ppm) 9.47 (s, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.34 (s, 1H), 3.09 (d, J= 9.5 Hz, 3H), 2.67 (s, 3H), 2.49 (s, 3H), 2.41 (s, 3H), 2.34 (t, J= 11.4 Hz, 2H), 2.19 (d, J= 13.4 Hz, 2H), 1.87-1.98 (m, 2H).

[0552] Using the procedure described for Example 18 above, additional compounds described herein were prepared by substituting the appropriate amine starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0553] Example 19- Compound 86 Step a: A solution of 5-bromo-6-chloropyrazin-2-amine (918.49 mg, 4.41 mmol) and tertbutyl N-[(lr,4r)-4-ethynylcyclohexyl]carbamate (820 mg, 3.67 mmol) in Toluene (10 mL) was treated with Pd(PPh3)4(128.87 mg, 183.60 pmol), Cui (41.96 mg, 220.32 pmol) and TEA (1.86 g, 18.36 mmol, 2.56 mL) in turn at 20 °C, then the mixture was stirred at 100 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (EtOAc in PE from 0% to 50%) to afford tert-butyl ((lr,4r)-4-(5-amino-3-chloropyrazin-2- yl)cyclohexyl)carbamate (900 mg, 69.86% yield) as a light yellow solid. MS: m / z 335.1 [M+H]+; RT 0.45 min (Method 9). 'HNMR (400 MHz, chloroform-r / ): 8 (ppm) 7.83 (s, 1H), 4.65-4.92 (m, 1H), 3.28-3.63 (m, 1H), 2.03-2.13 (m, 3H), 1.59-1.81 (m, 3H), 1.44 (s, 9H), 1.02-1.23 (m, 2H).

[0554] Step b: A solution of tert-butyl ((lr,4r)-4-(5-amino-3-chloropyrazin-2- yl)cyclohexyl)carbamate (500.00 mg, 1.43 mmol) in DMF (5 mL) was treated with NaHS (1.22 g, 21.38 mmol) at 20 °C, then the mixture was stirred at 90 °C for 3 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc from 0% to 100%) to afford tert-butyl (( l / ',4 / -4-(3-chlorothieno[2,3- / i]pyrazin-6- yl)cyclohexyl)carbamate (310 mg, 56.81% yield, 91% purity) as a yellow solid. MS: m / z 349.1 [M+H]+; RT 0.42 min (Method 9). ‘HNMR (400 MHz,chloroform-tZ): 6 (ppm) 7.98 (s, 1H), 6.99 (s, 1H), 4.56 (s, 2H), 4.35-4.49 (m, 1H), 3.42-3.57 (m, 1H), 2.78 (t, J= 12.0 Hz, 1H), 2.16 (d, J= 12.0 Hz, 4H), 1.62 (d, J= 10.8 Hz, 2H), 1.46 (s, 9H), 1.23-1.30 (m, 2H). Step c: A solution of tert-butyl ((lr,4r)-4-(3-chlorothieno[2,3-Z>]pyrazin-6- yl)cyclohexyl)carbamate (300 mg, 783.44 pmol) in DCM (5 mL) was treated with isopentyl nitrite (394.64 mg, 3.37 mmol, 452.57 pL) and TMSC1 (255.34 mg, 2.35 mmol, 298.30 pL) at 0 °C, then the mixture was stirred at 20 °C for 0.5 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl ((lr,4r)-4-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)cyclohexyl)carbamate (290 mg, 98.62% yield) as a yellow solid. MS: 312.0 [M+H]+; RT 0.47 min (Method 9). ‘HNMR (400 MHz, chloroform-t / ): 5 (ppm) 8.54 (s, 1H), 7.18 (s, 1H), 4.33-4.56 (m, 1H), 3.44-3.68 (m, 1H), 2.82-3.97 (m, 1H), 2.19 (d, J= 11.2 Hz, 4H), 1.67 (d, J= 10.4 Hz, 2H), 1.46 (s, 9H), 1.25- 1.32 (m, 2H). Step d: A solution of tert-butyl ((lr,4r)-4-(3-chlorothieno[2,3-Z>]pyrazin-6- yl)cyclohexyl)carbamate (280 mg, 586.04 pmol) and 4,6-dimethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyrazine (111.93 mg, 586.04 pmol) in Dioxane (3 mL) and H2O (0.2 mL) was treated with K2CO3(202.49 mg, 1.47 mmol) and Pd(dppf)Cl2CH2C12 (38.19 mg, 58.60 pmol) at 20 °C. The mixture was then stirred at 100 °C for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc from 0% to 100%) to afford tert-butyl ((lr,4r)-4-(3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2- yl)thieno[2,3-Z>]pyrazin-6-yl)cyclohexyl)carbamate (175 mg, 53.03% yield, 85% purity) as a yellow solid. MS: m / z 479.4 [M+H]+; RT 0.49 min (Method 9).

[0555] Step e: A solution of tert-butyl ((lr,4r)-4-(3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2- yl)thieno[2,3-Z>]pyrazin-6-yl)cycloheyl)carbamate (175 mg, 310.80 pmol) in DCM (5 mL) was treated with TFA (177.19 mg, 1.55 mmol, 119.00 pL) then stirred at 20 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to afford (lr,4r)-4-(3- (4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3-Z>]pyrazin-6-yl)cyclohexan-l-amine (120 mg, 317.05 pmol, 102.01% yield) as a yellow solid. MS: m / z 379.1 [M+H]+RT 0.28 min (Method 9).

[0556] Step f: A solution of (lr,4r)-4-(3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3- Z>]pyrazin-6-yl)cyclohexan-l -amine (110 mg, 290.63 pmol) in MeOH (1 mL) was treated with NaBEfCN (54.79 mg, 871.88 pmol) and paraformaldehyde (174.31 mg, 145.31 pmol, 198.08 pL) at 20 °C, then the mixture was stirred at 60 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product which was purified by pre-HPLC (Instrument: CASCD-SEMI-PREP-R; Method; Column: Welch Xtimate C18 150*25mm*5um; Condition: water (HCl)-CAN; Begin B: 10; End B: 40; Gradient Time(min): 10; 100%B Hold Time(min): 5; Flow Rate (mL / min): 25) to afford (lr,4r)-4-(3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3-Z>]pyrazin-6-yl)-N,N- dimethyl cyclohexan-1 -amine (10.38 mg, 83.52% yield, 95.07% purity) as a yellow solid. MS: m / z 407.2 [M+H]+; RT 0.35 min (Method 9). 'H NMR (400 MHz, methanol-^): 8 (ppm) 9.45 (s, 1H), 9.00 (s, 1H), 8.31 (s, 1H), 7.40 (s, 1H), 3.40 (br s, 1H), 3.15-3.24 (m, 1H), 3.14 (s, 3H), 2.91 (s, 6H), 2.69 (s, 3H), 2.40 (d, J= 6.0 Hz, 2H), 2.29 (br s, 2H), 1.81 (t, J= 10.0 Hz, 4H). Using the procedure described for Example 19 above, additional compounds described herein were prepared by substituting the appropriate ethynyl starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0557] Example 20- Compound 93 Step a: A solution of rac-tert-butyl (2 / ?)-5-ethynyl-2-methylpiperidine- l -carboxylate (Intermediate 13, 1.9 g, 7.83 mmol) in Toluene (30 mL) was treated with 5-bromo-6- chloropyrazin-2-amine (1.63 g, 7.83 mmol), Cui (89.45 mg, 469.66 pmol), Pd(PPhs)4 (904.54 mg, 782.77 pmol) and TEA (3.96 g, 39.14 mmol, 5.46 mL) at 25 °C, then the mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography (PE / EtO Ac = 1 / 1, Rf = 0.5) to afford rac-tert-butyl (2>,5 ’)-5-(5-amino-3-chloropyrazin-2-yl)-2- methylpiperidine-1 -carboxylate (2.4 g, 83.90% yield, 96% purity) as yellow solid. TLC (PE / EtO Ac = 1 / 1 Rf= 0.50). 'HNMR (400 MHz, chloroform^): 8 (ppm) 7.84 (s, 1H), 4.52- 4.05 (m, 3H), 2.92 (t, J = 11.6 Hz, 1H), 2.67-2.55 (m, 1H), 2.03-1.96 (m, 1H), 1.80-1.85 (m, 1H), 1.72-1.68 (m, 1H), 1.47 (s, 10H), 1.16 (d, J= 6.8 Hz, 3H).

[0558] Step b: A solution of rac-tert-butyl (2A,5A)-5-(5-amino-3-chloropyrazin-2-yl)-2- methylpiperidine-1 -carboxylate (2.4 g, 6.57 mmol) in DMF (40 mL) was treated with NaHS (936.96 mg, 16.42 mmol) at 25 °C, then the mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography (PE / EtOAc = 1 / 1, Rf = 0.4) to afford rac-tert- butyl (2A,5A)-5-(3-aminothieno[2,3-Z>]pyrazin-6-yl)-2-methylpiperidine-l -carboxylate (1.85 g, 80.04% yield, 99% purity) as yellow solid. TLC (PE / EtOAc = 1 / 1 Rf= 0.40). 'HNMR (400 MHz, chloroform-tZ): 5 (ppm) 7.95 (s, 1H), 7.05 (s, 1H), 4.49-4.42 (m, 1H), 4.17-4.20 (m, 1H), 3.00-2.90 (m, 2H), 2.02-1.97 (m, 1H), 1.88-1.83 (m, 1H), 1.75-1.69 (m, 1H), 1.48 (s, 10H), 1.22 (d, J= 6.8 Hz, 3H).

[0559] Step c: A solution of rac-tert-butyl (2A,5A)-5-(3-aminothieno[2,3-Z>]pyrazin-6-yl)-2- methylpiperidine-1 -carboxylate (1.85 g, 5.26 mmol) in DCM (30 mL) was treated with isopentyl nitrite (1.97 g, 16.82 mmol, 2.26 mL) and TMSC1 (2.46 g, 22.60 mmol, 2.87 mL) at 0 °C, then the mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography (PE / EtOAc = 3 / 1, Rf = 0.6) to afford rac-tert-butyl (2R.5 R)-5 -(?•>- chlorothieno[2,3-Z>]pyrazin-6-yl)-2-methylpiperidine-l-carboxylate (1.47 g, 68.42% yield, 90% purity) as yellow solid. TLC (PE / EtOAc = 1 / 1 Rf= 0.60). 'H NMR (400 MHz, m ethanol -tTj): 8 (ppm) 8.64 (s, 1H), 7.39 (s, 1H), 4.52-4.44 (m, 1H), 4.25 (d, J= 10.8 Hz, 1H), 3.15-3.03 (m, 2H), 2.08-2.03 (m, 1H), 1.92-1.85 (m, 1H), 1.77-1.72 (m, 1H), 1.48 (s, 10H), 1.26-1.23 (m, 3H).

[0560] Step d: A solution of rac-tert-butyl (2A,5A)-5-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-2- methylpiperidine-1 -carboxylate (100 mg, 244.64 pmol) and 2,8-dimethyl-6-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (163.53 mg, 856.23 pmol) in Dioxane (2 mL) and H2O (0.4 mL) was treated with K2CO3 (101.43 mg, 733.91 pmol) and Pd(dppf)C12-CH2C12 (15.94 mg, 24.46 pmol) at 25 °C, then the mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography (PE / EtOAc = 1 / 1, Rf = 0.45) to afford rac-tert-butyl (2A,5A)-5-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6- yl)thieno[2,3-Z>]pyrazin-6-yl)-2-methylpiperidine-l -carboxylate (110 mg, 76.10% yield, 81% purity) as yellow solid. MS: m / z 479.2 [M+H]+; RT 0.46 min (Method 9). Step e: A solution of rac-tert-butyl (2A,5A)-5-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6- yl)thieno[2,3-Z>]pyrazin-6-yl)-2-methylpiperidine-l -carboxylate (110 mg, 186.16 pmol) in DCM (5 mL) was treated with TFA (1.33 g, 11.64 mmol, 891.00 pL) at 25 °C, the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude residue, which was purified by pre-HPLC (Instrument: CAS-CD- SEMI-PREP-L; Method; Column: Phenomenex Cl 8 150*25mm*10um; Condition: water (NH4HCO3)-ACN; Begin B: 38; End B: 68; Gradient Time(min): 11; 100%B Hold Time(min): 2; Flow Rate (mL / min): 30) to afford rac-3-(2,8-dimethylimidazo[l,2- Z>]pyridazin-6-yl)-6-((3A,6A)-6-methylpiperidin-3-yl)thieno[2,3-Z>]pyrazine (27.65 mg, 38.93% yield, 99.215% purity) as yellow solid. MS: m / z 379.1 [M+H]+; RT 0.26 min (Method 9). 'HNMR (400 MHz, chloroform-tZ): 8 (ppm) 9.50 (s, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.45 (s, 1H), 3.33-3.39 (m, 2H), 3.16-3.22 (m, 1H), 2.92-3.01 (m, 1H), 2.69 (s, 3H), 2.50 (s, 3H), 2.04-2.24 (m, 2H), 1.67-1.79 (m, 1H), 1.47-1.61 (m, 1H), 1.17 (d, J= 6.8 Hz, 3H).

[0561] Using the procedure described for Example 20 above, additional compounds described herein were prepared by substituting the appropriate ethynyl starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0562] Example 21 -Compound 101

[0563] Step a: A solution of rac-tert-butyl (A)-3-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)pyrrolidine-l- carboxylate (Intermediate 15, 100.00 mg, 294.26 mol) in H2O (0.2 mL) and dioxane (1 mL) was treated with (4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)boronic acid (Intermediate 19, 56.20 mg, 294.26 pmol), Pd2(dba)3(26.95 mg, 29.43 pmol), SPhos (24.16 mg, 58.85 pmol) and K3PO4 (187.38 mg, 882.77 pmol) then the mixture was stirred at 95 °C for 16 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure, diluted in water, and extracted with EtOAc (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography on silica gel with petroleum ether and ethyl acetate (from 0% to 100% of EtOAc in PE) to afford rac-tert-butyl (A)-3-(3-(4,6-dimethylpyrazolo[l,5- a]pyrazin-2-yl)thieno[2,3-Z>]pyrazin-6-yl)pyrrolidine-l-carboxylate (60 mg, 133.17 mol, 45.26% yield) as a yellow solid. MS: m / z = 451.2 [M+H]+; RT 0.99 min (Method 4) 'H NMR (400 MHz, dimethyl sulfoxide- e): 5 (ppm) 9.37 (s, 1H), 8.57 (s, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 3.78-3.84 (m, 2H), 3.48-3.52 (m, 1H), 3.37-3.45 (m, 2H), 2.74 (s, 3H), 2.44 (s, 3H), 1.98- 2.18 (m, 2H), 1.43 (s, 9H).

[0564] Step b: The product from step a was dissolved in DCM (2 mL), treated with HCl / dioxane (4 M, 0.2 mL), then stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5um; Condition: water (HCl)-ACN; Begin B: 10%; End B: 30%; Flow Rate (ml / min): 25) to afford rac-(A)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6-(pyrrolidin-3-yl)thieno[2,3-Z>]pyrazine (101, 10 mg, 25.74 mol, 19.33% yield, 99.58% purity, HC1 salt) as a yellow solid. MS: m / z 351.1 [M+H]+; RT 2.73 min (Method 16)XH NMR (400 MHz, dimethyl sulfoxide-t / 6): 8 (ppm) 9.52 (s, 1H), 9.02 (s, 1H), 8.34 (s, 1H), 7.58 (s, 1H), 4.05-4.10 (m, 1H), 3.87-3.93 (m, 1H), 3.60-3.64 (m, 1H), 3.46-3.53 (m, 2H), 3.13 (s, 3H), 2.69 (s, 3H), 2.38-2.69 (m, 1H), 2.35-2.37 (m, 1H).

[0565] Example 22-Compound 104

[0566] Step a: A solution of rac-tert-butyl (A)-3-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)pyrrolidine-l- carboxylate (100 mg, 260.22 pmol) and 6-chl oro-2, 8-dimethylimidazo[l,2-Z>]pyridazine (51.99 mg, 286.24 pmol) in water (1.6 mL) and MeOH (3 mL) was treated with Pd(OAc)2(23.37 mg, 104.09 pmol), CsF (237.17 mg, 1.56 mmol, 57.64 pL), B2Pin2(132.16 mg, 520.44 pmol) and cataCXium A (74.64 mg, 208.18 pmol). The mixture was stirred at 100 °C for 2 h. The mixture was concentrated and purified by prep-TLC (EtOAc / EtOH = 20 / 1) to afford rac -tert-butyl (A)-3-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6- yl)pyrrolidine-l -carboxylate (20 mg, 44.39 pmol, 17.06% yield) as a yellow solid. MS: m / z = 451.1 [M+H]+; RT 0 / 88 min (Method 4).

[0567] Step b: The product from step a (80 mg, 177.56 pmol) was dissolved in DCM (3 mL), treated with HCl / dioxane (64.74 mg, 1.78 mmol, 443.90 pL), and stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to afford rac-(A)-3-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(pyrrolidin-3-yl)thieno[2,3-Z>]pyrazine (50 mg, crude, HC1 salt) as a yellow solid. MS: m / z 351.1 [M+H]+; RT 0.49 min (Method 4).

[0568] Step c: A solution of rac-(A)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(pyrrolidin-3- yl)thieno[2,3-Z>]pyrazine (50 mg, 129.23 pmol, HC1 salt) in MeOH (5 mL) was treated with paraformaldehyde (19.40 mg, 646.16 pmol, 22.05 pL) and NaBH3CN (32.48 mg, 516.93 pmol). The resulting mixture was stirred at 60 °C for 0.5 h under N2atmosphere. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (Column: Phenomenex Gemini-NX 150*30mm*5um; Condition: water (NH4HCO3)-ACN; Begin B: 40; End B: 70; Gradient Time (min): 11; 100%B Hold Time (min): 2; Flow Rate (mL / min): 25) to afford rac-(A)-3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-6-(l-methylpyrrolidin-3-yl)thieno[2,3- Z>]pyrazine (20 mg, 54.87 pmol, 42.46% yield, 100% purity) as yellow solid. MS: m / z 365.1 [M+H]+; RT 1.96 min (Method 7). 'HNMR (400 MHz, methanol-^): 8 (ppm) 9.48 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.38 (s, 1H), 3.89-3.94 (m, 1H), 3.30-3.32 (m, 1H), 2.78-2.84 (m, 3H), 2.68 (s, 3H), 2.50-2.53 (m, 1H), 2.50 (s, 3H), 2.46 (s, 3H), 2.12-2.15 (m, 1H).

[0569] Example 23 -Compound 83 and 84 Step a: A solution of rac-(A)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6-(pyrrolidin-3- yl)thieno[2,3-Z>]pyrazine (101, 80 mg, 206.77 pmol, HC1 salt) in MeOH (3 mL) was treated with TEA to pH = 7-8 then stirred at 25°C for 10 min. Acetic acid was added to adjust the pH to 6-7 and the solution was stirred at 25°C another for 10 min. Paraformaldehyde (24.80 mg, 20.68 pmol, 28.19 pL) was added at 25°C and the reaction mixture was stirred at 80 °C for 20 min. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (Column: Phenomenex Gemini NX 150x30mm, 5pm; Condition: water (NHJTCOaj-ACN; Begin B: 38%; End B: 68%; Flow Rate ml / min): 25) to give rac-(A)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6-(l-methylpyrrolidin-3- yl)thieno[2,3-Z>]pyrazine (45 mg, 123.47 pmol, 59.71% yield) as a yellow solid. MS: m / z 365.0 [M+H]+; RT 0.71 min (Method 4). 'H NMR (400 MHz, methanol-^): 8 (ppm) 9.36 (s, 1H), 8.37 (s, 1H), 7.61 (s, 1H), 7.39 (s, 1H), 3.92-3.97 (m, 1H), 3.26 (br s, 1H), 2.90-2.97 (m, 3H), 2.79 (s, 3H), 2.56 (s, 3H), 2.51 (s, 3H), 2.17-2.21 (m, 1H), 1.28-1.34 (m, 1H).

[0570] Step b: rac-(A)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6-(l-methylpyrrolidin-3- yl)thieno[2,3-Z>]pyrazine (45 mg, 123.47 pmol) was purified by SFC (Column: DAICEL CHIRALPAK IC (250mm*30mm, lOum); Condition: CCh-EtOH; Begin B: 60%; End B: 60%; Flow Rate (mL / min): 80) to afford (5)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6- (l-methylpyrrolidin-3-yl)thieno[2,3-Z>]pyrazine (83, 17 mg, 46.64 pmol, 37.78% yield, 100% purity) as a white solid and (A)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6-(l- methylpyrrolidin-3-yl)thieno[2,3-Z>]pyrazine (84, 15 mg, 41.16 pmol, 33.33% yield, 100% purity) as a white solid.

[0571] Compound 83 :

[0572] MS: m / z 365.2 [M+H]+; RT 1.89 min (Method 7). 'H NMR (500 MHz, methanol-^): 6 (ppm) 9.32 (s, 1H), 8.34 (s, 1H), 7.57 (d, J= 1.0, 1H), 7.35 (s, 1H), 3.87-3.91 (m, 1H), 3.14- 3.17 (m, 1H), 2.78-2.83 (m, 3H), 2.78 (s, 3H), 2.51-2.54 (m, 1H), 2.50 (s, 3H), 2.47 (s, 3H), 2.11-2.16 (m, 1H). 96.76% ee.

[0573] Compound 84:

[0574] MS: m / z 365.2 [M+H]+; RT 1.87 min (Method 7). 'H NMR (400 MHz, methanol-^): 6 (ppm) 9.33 (s, 1H), 8.35 (s, 1H), 7.58 (s, 1H), 7.36 (s, 1H), 3.89-3.94 (m, 1H), 3.13-3.18 (m, 1H), 2.79-2.83 (m, 3H), 2.78 (s, 3H), 2.50-2.57 (m, 1H), 2.50 (s, 3H), 2.47 (s, 3H), 2.13-2.16 (m, 1H). 94.19% ee Example 24 - Compound 107

[0575] Step a: A solution of tert-butyl 4-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)piperidine-l- carboxylate (Intermediate 1, 20 mg, 100.70 pmol) and 6-chloro-8-methoxy-2-methyl- [l,2,4]triazolo[l,5-Z>]pyridazine (35.63 mg, 100.70 pmol) in Toluene (1 mL), MeOH (1 mL) and H2O (0.2 mL) was treated with cataCXium A (21.66 mg, 60.42 pmol), Pd(OAc)2(9.04 mg, 40.28 pmol), CsF (91.78 mg, 604.20 pmol, 22.30 pL) and B2Pin2 (102.29 mg, 402.80 pmol) and the mixture was stirred at 90 °C for 12 hours under N2atmosphere. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 4). The organic layers were dried over ISfeSCU, filtered, and concentrated under reduced pressure to obtain the crude residue which was purified by prep-TLC (SiO2, PE / EtOAc = 0 / 1, Rf= 0.4) to afford tert-butyl 4-(3-(8-methoxy-2-methyl-[l,2,4]triazolo[l,5-Z>]pyridazin-6-yl)thieno[2,3- Z>]pyrazin-6-yl)piperidine-l-carboxylate (18 mg, 34.15% yield, 92% purity) as a yellow solid. MS: / z 482.2 [M+H]+; RT 0.50 (Method 9). *H NMR (400 MHz, dimethyl sulfoxide- d(, . 5 (ppm) 9.55 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 3.30 (s, 3H), 3.25-3.27 (m, 2H), 2.59- 2.60 (m, 2H), 2.11 (d, J= 2.8 Hz, 1H), 1.90 (d, J= 4.4 Hz, 2H), 1.69 (d, J= 1.6 Hz, 2H), 1.43 (s, 9H), 1.38 (s, 2H).

[0576] Step b: A solution of tert-butyl 4-(3-(8-methoxy-2-methyl-[l,2,4]triazolo[l,5-Z>]pyridazin-6- yl)thieno[2,3-Z>]pyrazin-6-yl)piperidine-l -carboxylate (18 mg, 34.39 pmol) in DCM (1 mL) was treated with TFA (7.84 mg, 68.78 pmol, 5.27 pL) and the mixture was stirred at 20 °C for 0.5 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain 3-(8-methoxy-2-methyl-[l,2,4]triazolo[l,5-Z>]pyridazin-6-yl)-6- (piperidin-4-yl)thieno[2,3-Z>]pyrazine (15 mg, 94.91% yield, 83% purity) as a yellow solid. MS: m / z 382.0 [M+H]+; RT 0.31 min (Method 9).

[0577] Steb c: The product from step b was dissolved in MeOH (1 mL) and the solution was treated with TEA to pH 5-6. The mixture was treated sequentially with NaBH3CN (6.15 mg, 97.91 pmol) and paraformaldehyde (19.58 mg, 16.32 pmol, 22.24 pL), then stirred at 60 °C for 1 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (Instrument: CASCD-SEMI-PREP-R; Method; Column: Phenomenex Luna C18 150*30mm*5um; Condition: water (HCl)-CAN; Begin B: 5; End B : 35; Gradient Time(min): 10; 100%B Hold Time (min): 5; FlowRate (mL / min): 25) to afford 3-(8-methoxy-2-methyl- [l,2,4]triazolo[l,5-Z>]pyridazin-6-yl)-6-(l-methylpiperidin-4-yl)thieno[2,3-Z>]pyrazine (2.45 mg, 18.60% yield, 97.97% purity) as a yellow solid. MS: m / z 396.3 [M+H]+; RT 0.31 min (Method 9). 'HNMR (400 MHz, methanol-^): 5 (ppm) 9.64 (s, 1H), 8.01 (s, 1H), 7.50 (s, 1H), 4.30 (s, 3H), 3.70 (d, J= 12.8 Hz, 2H), 3.43-3.51 (m, 1H), 3.20-3.28 (m, 2H), 2.97 (s,

[0578] 3H), 2.63 (s, 3H), 2.43-2.53 (m, 2H), 2.03-2.18 (m, 2H).

[0579] Using the procedure described for Example 24 above, additional compounds described herein were prepared by substituting the appropriate aryl halide intermediate starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0580] Example 25 - Compound 36 Step a: A solution of tert-butyl (15,5A)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2 g, 9.65 mmol), 4-chloro-5-iodo-pyrimidin-2-amine (2.96 g, 11.58 mmol), Cui (110.26 mg, 578.96 pmol), and Pd(PPh3)4(1.12 g, 964.93 pmol) in Toluene (70 mL) was added TEA (4.88 g, 48.25 mmol, 6.72 mL) at 25°C, the mixture was stirred at 100°C for 4h under N2 atmosphere. The reaction mixture was diluted with water (8 mL) and extracted with EtOAc (5 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography (SiCL, PE / EtOAc from 0 % to 30%) to give tert-butyl (15,5A)-6-[2-(2-amino-4-chloro-pyrimidin-5-yl)ethynyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (1.1 g, 2.96 mmol, 30.64% yield, 90% purity) as yellow solid. MS: m / z 335.0 [M+H]+; RT 0.45 min (Method 9). 'H NMR (400 MHz, m ethanol -tZ4): 8 (ppm) 8.29 (s, 1H), 7.43 (s, 2H), 3.51 (d, J= 10.8 Hz, 4H), 1.33-1.43 (m, 12H).

[0581] Step b: A mixture of tert-butyl (15,5A)-6-[2-(2-amino-4-chloro-pyrimidin-5-yl)ethynyl]-3- azabicyclo[3.1.0]hexane-3-carboxylate (1.1 g, 2.66 mmol)and NaHS (607.53 mg, 10.65 mmol) in DMF (40 mL), and then the mixture was stirred at 90 °C for 3h. The reaction mixture was diluted with water (120 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc from 0 % to 50%) to give tert-butyl (lA,55)-6-(2-aminothieno[2,3-t ]pyrimidin-6- yl)-3-azabicyclo[3.1.0]hexane-3 -carboxylate (380 mg, 1.03 mmol, 38.66% yield, 90% purity) as a white solid. MS: 333.1 [M+H]+; RT 0.41 min (Method 9). 'H NMR (400 MHz, m ethanol -t / 4): 5 (ppm) 8.54 (s, 1H), 6.73 (s, 1H), 5.00 (s, 2H), 3.68-3.84 (m, 2H), 3.48 (d, J= 8.2 Hz, 2H), 1.93 (s, 3H), 1.47 (s, 9H).

[0582] Step c: A solution of tert-butyl (lA,55)-6-(2-aminothieno[2,3- ]pyrimidin-6-yl)-3- azabicyclo[3.1.0]hexane-3 -carboxylate (300 mg, 812.23 pmol) in DCM (8 mL) was treated with isopentyl nitrite (409.14 mg, 3.49 mmol, 469.20 pL) at 0 °C under N2 atmosphere, then chloro(trimethyl)silane (264.73 mg, 2.44 mmol, 309.26 pL) was added at 0°C under N2 , the mixture was stirred at 20 °C for 16 hours under N2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL x 4). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography (SiO2, PE / EtOAc from 0 % to 50%) to afford tert-butyl (lA,55)-6-(2-chlorothieno[2,3- ]pyrimidin-6-yl)-3-azabicyclo[3. L0]hexane-3-carboxylate (140 mg, 314.34 pmol, 38.70% yield, 79% purity) as a yellow solid. MS: m / z 352.0 [M+H]+;

[0583] RT 0.48 min (Method 9).

[0584] Step d: A solution of tert-butyl (lA,55)-6-(2-chlorothieno[2,3-t ]pyrimidin-6-yl)-3- azabicyclo[3.1.0]hexane-3 -carboxylate (120 mg, 341.05 pmol) and 7-fluoro-2-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indazole (103.59 mg, 375.16 pmol) in Dioxane (3 mL) and H2O (0.3 mL) was treated with Pd(dppf)C12 (24.96 mg, 34.11 pmol) and K2CO3 (117.84 mg, 852.64 pmol) at 25°C, the mixture was stirred at 100°C for 5 h under N2 atmosphere. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiCh, PE / EtOAc from 0 % to 75%) to give tert-butyl (lA,55)-6-[2-(7- fhioro-2-methyl-indazol-5-yl)thieno[2,3-J]pyrimidin-6-yl]-3-azabicyclo[3.L0]hexane-3- carboxylate (120 mg, 206.21 pmol, 60.46% yield, 80% purity) as a yellow solid. MS: m / z 466.1 [M+H]+; RT 0.58 min (Method 9).

[0585] Step e: A solution of tert-butyl (lA,55)-6-[2-(7-fluoro-2-methyl-indazol-5-yl)thieno[2,3- t ]pyrimidin-6-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (110.00 mg, 189.03 pmol) in DCM (5 mL) was treated with TFA (744.50 mg, 6.53 mmol, 0.5 mL) and the mixture was stirred at 25°C for 0.5h. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (Instrument: CAS-CD-SEMI-PREP-I; Method; Column: Phenomenex luna Cl 8 150*25mm* lOum; Condition: water(FA)-ACN; Begin B: 5; End B: 35; Gradient Time(min): 8; 100%B Hold Time(min): 2; FlowRate(ml / min): 30) to afford 6-[(lA,55)-3-azabicyclo[3.1.0]hexan-6- yl]-2-(7-fluoro-2-methyl-indazol-5-yl)thieno[2,3-J]pyrimidine (80 mg, 175.14 pmol, 92.65% yield, 80% purity) as a yellow solid. MS: m / z 366.0 [M+H]+; RT 0.32 min (Method 9). ' H NMR (400 MHz, methanol-^): 5 (ppm) 9.06 (s, 1H), 8.68 (s, 1H), 8.44 (d, J= 2.4 Hz, 1H), 8.06 (d, J= 13.4 Hz, 1H), 7.18 (s, 1H), 4.26 (s, 3H), 3.54-3.67 (m, 4H), 2.31-2.42 (m, 3H).

[0586] Example 26-Compound 70

[0587]

[0588] Step a: A solution of tert-butyl 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6- azaspiro[3.4]oct-2-ene-6-carboxylate (Intermediate 14, 1.5 g, 2.68 mmol) and 3-chloro-6- iodo-thieno[2,3-Z>]pyrazine (Intermediate 4, 796.03 mg, 2.68 mmol) in dioxane (10 mL) and H2O (2 mL) was treated with K3PO4 (1.14 g, 5.37 mmol) and cataCXium A-Pd-G3 (179.50 mg, 268.46 pmol) under N2 atmosphere. The mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure then the resulting residue was diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude was purified by silica gel chromatography (EA in PE from 20% to 50%,TLC: PEZEtOAc 3 : 1 Rf = 0.4) to afford tertbutyl 2-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-6-azaspiro[3.4]oct-2-ene-6-carboxylate (310 mg, 820.35 pmol, 30.56% yield) as yellow solid. MS: m / z 378.1 [M+H]+; RT 0.55 min (Method 9).

[0589] Step b: A solution of compound tert-butyl 2-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)-6- azaspiro[3.4]oct-2-ene-6-carboxylate (145 mg, 383.71 pmol) and (4,6-dimethylpyrazolo[l,5- a]pyrazin-2-yl)boronic acid (Intermediate 19, 87.94 mg, 460.45 pmol) in dioxane (2 mL) and H2O (0.4 mL) was treated with K2CO3 (106.06 mg, 767.42 pmol) and Pd^ppfJCh CEECh (25.01 mg, 38.37 pmol) under N2 atmosphere. The mixture was stirred at 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure then the resulting residue was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude was purified by silica gel chromatography (EA in PE from 30% to 70%,TLC: EA Rf = 0.38) to afford tert-butyl 2-[3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3-Z>]pyrazin-6-yl]-6- azaspiro[3.4]oct-2-ene-6-carboxylate (110 mg, 225.13 pmol, 58.67% yield) as yellow solid. MS: m / z 489.2 [M+H]+; RT 0.54 min (Method 9).

[0590] Step c: A solution of tert-butyl 2-[3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3- Z>]pyrazin-6-yl]-6-azaspiro[3.4]oct-2-ene-6-carboxylate (100 mg, 204.66 pmol) in MeOH (5 mL) was treated with Pd / C (21.78 mg, 20.47 pmol, 10% purity) under H2 atmosphere. The suspension was degassed and purged with H2 5 times then the mixture was stirred under H2 (50 Psi) at 50 °C for 4 h. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-[3-(4,6-dimethylpyrazolo[l,5- a]pyrazin-2-yl)thieno[2,3-Z>]pyrazin-6-yl]-6-azaspiro[3.4]octane-6-carboxylate (60 mg, crude) as a brown oil. The crude material was used in next step without further purification. MS: 491.1 [M+H]+; RT 0.52 min (Method 9).

[0591] Step d: A solution of tert-butyl 2-[3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3- Z>]pyrazin-6-yl]-6-azaspiro[3.4]octane-6-carboxylate (60 mg, 122.29 pmol) in DCM (2 mL) was treated with TFA (557.78 mg, 4.89 mmol, 374.60 pL) and the mixture was stirred at 25 °C for 2 hours. The solution was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (Column: Phenomenex luna Cl 8 150*25mm* lOum; Condition: water( FA)-ACN; Begin B: 9; End B: 39; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL / min): 25; Detection wavelength: 220 nm) to afford 6-(6- azaspiro[3.4]octan-2-yl)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3-b]pyrazine (1.42 mg, 3.18 pmol, 2.60% yield, 97.85% purity, Formic acid salt) as a yellow solid. MS: m / z 391.1 [M+H]+; RT 0.30 min (Method 9). 'HNMR (400 MHz, methanol-t / 4): 5 (ppm) 9.39 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 7.64 (s, 1H), 7.34 - 7.41 (m, 1H), 3.98 - 4.06 (m, 1H), 3.48 (s, 1H), 3.39 - 3.41 (m, 2H), 3.29 (s, 1H), 2.82 (s, 3H), 2.62 - 2.71 (m, 2H), 2.48 - 2.57 (m, 5H), 2.32 (br t, J= 7.2 Hz, 1H), 2.15 (s, 1H)

[0592] Step e: A solution of 6-(6-azaspiro[3.4]octan-2-yl)-3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2- yl)thieno[2,3-Z>]pyrazine (15 mg, 38.41 pmol) in MeOH (1 mL) was treated with TEA to pH 5~6. The solution was then treated with decaethylene glycol monododecyl ether (23.04 mg, 19.21 pmol, 26.18 pL) and the mixture was stirred at 60 °C for 1 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by prep-HPLC (Column: Phenomenex luna C18 150*25mm* lOum; Condition: water (FA)- ACN; Begin B: 8; End B: 38; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL / min): 25; Detection wavelength: 220 nm) to afford 3-(4,6-dimethylpyrazolo[l,5- a]pyrazin-2-yl)-6-(6-methyl-6-azaspiro[3.4]octan-2-yl)thieno[2,3-Z>]pyrazine (2.34 mg, 5.10 pmol, 13.29% yield, 98.28% purity, Formic acid salt) as a yellow solid. MS: m / z 405.1 [M+H]+; RT 1.77 min (Method 11). 'HNMR (400 MHz, methanol-^): 8 (ppm) 9.35 (s, 1H), 8.55 (br s, 1H), 8.37 (s, 1H), 7.60 (s, 1H), 7.32 (s, 1H), 4.02 - 3.90 (m, 1H), 3.24 (br d, J= 13.6 Hz, 2H), 3.19 (s, 1H), 3.12 (br d, J= 7.6 Hz, 1H), 2.86 - 2.72 (m, 6H), 2.69 - 2.61 (m, 2H), 2.58 - 2.45 (m, 5H), 2.37 (br t, J= 1A Hz, 1H), 2.18 (br d, J= 6.9 Hz, 1H).

[0593] Example 27- Compound 24 and 25

[0594] Step a: A solution of methyl 3-ethynylcyclobutane-l-carboxylate (2.56 g, 18.53 mmol) and 5- bromo-6-chloropyrazin-2-amine (4.63 g, 22.23 mmol) in THF (30 mL) was treated with Cui (176.44 mg, 926.44 pmol), TEA (5.62 g, 55.59 mmol, 7.75 mL) and PdCl2(PPh3)2 (650.26 mg, 926.44 pmol) under N2 atmosphere. The mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with H2O (30 mL) and extracted with Petroleum ether (20 mL x 2). The organic phases were combined and washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude was purified by silica gel chromatography (PEZEtOAc = 10 / 3 to 10 / 7, TLC: PE / EtOAc = 3 / 1 Rf = 0.3) to afford methyl 3-((5-amino-3-chloropyrazin-2-yl)ethynyl)cyclobutane-l-carboxylate (1.8 g, 6.77 mmol, 36.56% yield) as yellow solid. MS: m / z 266.1 [M+H]+; RT 0.62 (Method 9). 'H NMR (400 MHz, chloroform-t / ): 5 (ppm) 7.83-7.85 (m, 1H), 3.65-3.75 (m, 3H), 3.02-3.49 (m, 2H), 2.46- 2.72 (m, 4H).

[0595] Step b: A solution of methyl 3-((5-amino-3-chloropyrazin-2-yl)ethynyl)cyclobutane-l- carboxylate (500.00 mg, 1.88 mmol) in THF (5 mL) at 0 °C was treated with LAH (107.14 mg, 2.82 mmol) under N2 atmosphere. The mixture was then stirred for 1 hour at 0 °C. The reaction mixture was quenched by ISfeSC ’lO^O (909.49 mg, 2.82 mmol, 622.94 pL) and the reaction mixture was filtered. The filter cake was washed with additional THF (5 mL x 3) and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude was purified by silica gel chromatography (PE / EtOAc = 10 / 3 to 0 / 1, TLC: PEZEtOAc = 1 / 1 Rf = 0.3) to afford (3-((5-amino-3-chloropyrazin-2-yl)ethynyl)cyclobutyl)methanol (136 mg, 572.19 pmol, 30.41% yield) as yellow solid. MS: m / z 238.1 [M+H]+; 0.59 min (Method 9). 'H NMR (400 MHz, chloroform^): 8 (ppm) 7.70-7.77 (m, 1H), 3.56 (dd, J= 6.0, 18.4 Hz, 2H), 3.13-3.29 (m, 1H), 2.40-2.49 (m, 2H), 2.17-2.34 (m, 2H), 1.91-2.02 (m, 1H).

[0596] Step c: A solution of (3-((5-amino-3-chloropyrazin-2-yl)ethynyl)cyclobutyl)methanol (116 mg, 488.04 pmol) in DMF (2 mL) was treated with NaHS (27.36 mg, 488.04 pmol). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (15 mL), dried over ISfeSCL, filtered and concentrated under vacuum to obtain the crude product. The crude was purified by silica gel chromatography (EtOAc in PE from 30% to 100%, TLC: EtOAc, Rf = 0.34) to afford (3-(3-aminothieno[2,3-Z>]pyrazin-6- yl)cyclobutyl)methanol (93 mg, 395.23 pmol, 80.98% yield) as yellow solid. MS: m / z 236.0 [M+H]+; RT 0.73 min (Method 4).XH NMR (400 MHz, chloroform-tZ): 6 (ppm) 8.00 (d, J= 1.6 Hz, 1H), 6.99-7.01 (m, 1H), 3.75-3.80 (m, 1H), 3.59 - 3.69 (m, 2H), 2.52-2.58 (m, 1H), 2.29- 2.44 (m, 2H), 1.95-2.10 (m, 2H).

[0597] Step d: A solution of (3-(3-aminothieno[2,3-Z>]pyrazin-6-yl)cyclobutyl)methanol (93 mg, 395.23 pmol) in DCM (l mL) was treated with isopentyl nitrite (138.90 mg, 1.19 mmol, 159.29 pL) and TMSC1 (128.82 mg, 1.19 mmol, 150.49 pL) at 0 °C. The mixture was then stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude was purified by silica gel chromatography (EtOAc in PE from 0% to 40%, TLC: PE / EtOAc = 2 / 1, Rf = 0.54) to afford (3-(3-chlorothieno[2,3-Z>]pyrazin-6- yl)cyclobutyl)methanol (60 mg, 235.54 pmol, 59.60% yield) as yellow solid. MS: m / z 254.8 [M+H]+; RT 0.86 min (Method 4). Step e: A solution of (3-(3-chlorothieno[2,3-Z>]pyrazin-6-yl)cyclobutyl)methanol (55 mg, 215.91 pmol) and compound 11 (49.49 mg, 259.09 pmol) in dioxane (1 mL) and H2O (0.2 mL) was treated with K3PO4 (137.49 mg, 647.73 pmol), SPhos (17.73 mg, 43.18 pmol) and Pd2(dba)s (19.77 mg, 21.59 pmol) under N2 atmosphere. The mixture was stirred at 100 °C for 12 h. The solution was concentrated under vacuum and purified by column chromatography (EtOAc in PE from 50% to 100%, TLC: EtOAc Rf= 0.3) to afford (3-(3-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)cyclobutyl)methanol (50 mg, 136.82 pmol, 63.37% yield) as a yellow solid. MS: m / z 366.0 [M+H]+; RT 0.77 min (Method 8).

[0598] Step f: A solution of (3-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6- yl)cyclobutyl)methanol (143 mg, 391.30 pmol) and TsCl (149.20 mg, 782.59 pmol) in DCM (3 mL) was treated with DMAP (4.78 mg, 39.13 pmol) and TEA (118.39 mg, 1.17 mmol, 163.07 pL) under N2 atmosphere. The mixture was then stirred for 12 hours at 20 °C. The mixture was concentrated under vacuum and the crude residue was purified by silica gel chromatography (EtOAc in PE from 50% to 100%, TLC: EtOAc, Rf = 0.6) to afford (3-(3-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)cyclobutyl)methyl 4- methylbenzenesulfonate (160 mg, 307.91 pmol, 78.69% yield) as yellow solid. MS: 520.2 [M+H]+; RT 0.95 min (Method 8).

[0599] Step g: A solution of (3-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin- 6-yl)cyclobutyl)methyl 4-methylbenzenesulfonate (90 mg, 173.20 pmol) in DMF (1 mL) and H2O (1 mL) was treated with K2CO3 (71.81 mg, 519.59 pmol) and A A-di methyl amine (46.85 mg, 1.04 mmol, 68.90 pL). The mixture was stirred at 90 °C for 6 hours. The solution was concentrated under vacuum and purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5um; Condition: water (HCl)-ACN; Begin B: 13; End B: 33; Gradient Time (min): 11; 100%B Hold Time (min): 2; Flow Rate (mL / min): 25; Detection wavelength: 220 nm) to afford l-(3-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6- yl)cyclobutyl)-A,A-dimethylmethanamine (25 mg, 63.69 pmol, 36.77% yield) as a white solid. MS: 393.2 [M+H]+; RT 0.70 min (Method 8).

[0600] Step h: l-(3-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6- yl)cyclobutyl)-A,A-dimethylmethanamine was separated by SFC (Column: DAICEL CHIRALPAK AD (250mm*30mm,10um); Condition: CO2-iPrOH(0.1% NH3.H2O) Begin B: 60%, End B: 60% ; Flow Rate (mL / min): 80) to afford l-((lr,3r)-3-(3-(2,8- dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)cyclobutyl)-A,A- dimethylmethanamine (24, 5.17 mg, 13.17 pmol, 23.50% yield, 100% purity) and 1 -((15,35)- 3-(3-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazin-6-yl)cyclobutyl)-A,A- dimethylmethanamine (25, 6.82 mg, 17.37 pmol, 31.00% yield, 100% purity) both as a white solid.

[0601] Compound 24:

[0602] MS: m / z 393.1 [M+H]+; RT 1.80 min (Method 15). *H NMR (400 MHz, methanol-^): 8 (ppm) 5 9.41 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.30 (s, 1H), 3.87-3.98 (m, 1H), 2.69-2.79 (m, 1H), 2.65 (s, 3H), 2.59 (d, J = 7.2 Hz, 2H), 2.45-2.53 (m, 5H), 2.35-2.42 (m, 2H), 2.28 (s, 6H). 99.27% ee.

[0603] Compound 25:

[0604] MS: m / z 393.1 [M+H]+; RT 1.82 (Method 15). 'HNMR (400 MHz, methanol-^): 6 (ppm) 9.52 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 7.37 (s, 1H), 3.89-4.00 (m, 1H), 2.93 (s, 6H), 2.80- 2.87 (m, 2H), 2.72 (s, 6H), 2.53 (s, 3H), 2.17-2.28 (m, 2H). 97.45% ee.

[0605] Example 28 - Compound 72

[0606] Step a: A solution of 3-bromo-5-chloropyrazin-2-amine (1 g, 4.80 mmol) and tert-butyl 4- ethynylpiperidine-1 -carboxylate (1.51 g, 7.2 mmol) in THF (20 mL) was treated with Cui (274.10 mg, 1.44 mmol), TEA (970.91 g, 9.59 mmol, 1.34 mL) and Pd(PPh3)4(L i l g, 959.49 pmol) at 25 °C under N2 atmosphere. The mixture was stirred at 60 °C for 12 hours under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude was purified by flash silica gel chromatography (petroleum ether / EtOAc =5 / 1) to afford tert-butyl 4-((2-amino-5-chloropyridin-3-yl)ethynyl)piperidine-l-carboxylate (1.5 g, 3.16 mmol, 65.82% yield) as a yellow solid. MS: m / z 281.0 [M+H-t-Bu]+; RT 0.48 min (Method 9). 'HNMR (400 MHz, chloroform-tZ): 6 (ppm) 7.94 (s, 1H), 5.02 (br s, 2H), 3.80 (br d, J= 13.6 Hz, 2H), 3.15-3.23 (m, 2H), 2.86-2.91 (m, 1H), 1.90-1.93 (m, 2H), 1.67-1.76 (m, 2H), 1.47 (s, 9H).

[0607] Step b: A solution of tert-butyl 4-((2-amino-5-chloropyridin-3-yl)ethynyl)piperidine-l- carboxylate (600 mg, 1.78 mmol) in NMP (20 mL) was treated with t-BuOK (599.68 mg, 5.34 mmol) and the mixture was stirred at 75 °C for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude was purified by flash silica gel chromatography (from petroleum ether / EtOAc = 100 / 1 to 3 / 1) to afford tert-butyl 4-(2- chloro-57 / -pyrrolo[2,3- / i]pyrazin-6-yl)piperidine- l -carboxylate (450 mg, 1.04 mmol, 58.50% yield) as a yellow solid. MS: m / z 337.2 [M+H]+; RT 0.50 min (Method 9). 'H NMR (400 MHz, chloroform-tZ): 8 (ppm) 8.07 (s, 1H), 6.31 (s, 1H), 4.20-4.23 (m, 2H), 2.93-3.01 (m, 3H), 1.56-1.86 (m, 4H), 1.45 (s, 9H).

[0608] Step c: A solution of tert-butyl 4-(2-chl oro-5 J / -pyrrolo[2, 3 -Z>]pyrazin-6-yl )piperi dine- 1- carboxylate (100 mg, 296.90 pmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)imidazo[l,2-Z>]pyridazine (198.47 mg, 1.04 mmol) in Dioxane (5 mL) and water (1 mL) was treated with Pd(dppf)C12 (19.35 mg, 29.69 pmol) and K2CO3 (123.10 mg, 890.69 pmol) then the mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude was purified by flash silica gel chromatography (from petroleum ether / EtOAc = 100 / 1 to 1 / 3) to afford tertbutyl 4-(2-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-5J / -pyrrolo[2,3-Z>]pyrazin-6- yl)piperidine-l-carboxylate (100 mg, 165.11 pmol, 37.63% yield,) as a yellow solid. MS: m / z 448.2 [M+H]+; RT 0.37 min (Method 9).

[0609] Step d: A solution of tert-butyl 4-(2-(2,8-dimethylimidazo[l,2-Z>]pyridazin-6-yl)-5JT- pyrrolo[2,3-Z>]pyrazin-6-yl)piperidine-l -carboxylate (100 mg, 201.10 pmol) in DCM (1 mL) was treated with TFA (0.2 mL) and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was adjusted pH~6 with ammonium hydroxide and concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC ((Welch Ultimate C18 150*25mm*10um; Condition: water (FA)-ACN; Begin B: 0%; End B: 23%; Gradient Time (min): 10; 100% B Hold Time (min): 2; Flow Rate (mL / min): 25) to afford 2,8- dimethyl-6-(6-(piperidin-4-yl)-5J / -pyrrolo[2,3-Z>]pyrazin-2-yl)imidazo[l,2-Z>]pyridazine (10.56 mg, 26.57 pmol, 11.89% yield, 98.992% purity) as a white solid. MS: m / z 348.1 [M+H]+; RT 1.09 min (Method 15). 'H NMR (400 MHz, methanol-^): 6 (ppm) 9.12 (s, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 6.57 (s, 1H), 3.55 (br d, J= 12.4 Hz, 2H), 3.17-3.26(m, 3H), 2.69 (s, 3H), 2.50 (s, 3H), 2.41 (br d, J= 12.8 Hz, 2H), 1.97-2.10 (m, 2H).

[0610] Example 29- Compound 106

[0611] Step a: A solution of 5-bromo-3-fluoropyridin-2-amine (13 g, 68.06 mmol) and tert-butyl 4- (2 -bromoacetyl )piperi dine- 1 -carboxylate (25.01 g, 81.68 mmol) at 20 °C was treated with NaHCCh (11.44 g, 136.13 mmol, 5.29 mL) and the resulting mixture was stirred at 80 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure then purified by column chromatography (PE / EtOAc = 3 / 1 to 0 / 1, TLC: PEZEtOAc = 1 / 1, Rf = 0.3) to afford the crude product. The crude product was suspended in PEZEtOAc(l / 5, 180 mL) then stirred at 20 °C for 3 h. The mixture was filtered, washed with EtOAc (30 mL x 2) and the solid was dried under vacuum to afford tert-butyl 4-(6-bromo-8-fluoroimidazo[l,2- a]pyridin-2-yl)piperidine-l -carboxylate (10.2 g, 37.51% yield, 99.68% purity) as a white solid. MS: m / z 398.1, 400.1 [M+H]+; RT 2.87 min (Method 7). 'HNMR (400 MHz, chloroform-tZ): 8 (ppm) 8.06 (d, J= 1.2 Hz, 1H), 7.37 (d, J= 3.2 Hz, 1H), 6.99 (dd, J= 1.2, 9.6 Hz, 1H), 4.30-4.11 (m, 2H), 2.98-2.83 (m, 3H), 2.08 (d, J= 11.4 Hz, 2H), 1.71-1.60 (m, 2H), 1.47 (s, 9H).

[0612] Step b: A solution of tert-butyl 4-(6-bromo-8-fluoroimidazo[l,2-a]pyridin-2-yl)piperidine-l- carboxylate (39.83 mg, 100.0 pmol), 6-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)thieno[3,2-t ]pyrimidine (27.62 mg, 100.0 pmmol), Pd(dppf)C12-CH2C12 (8.17 mg, 10.00 pmol) and CS2CO3 (97.75 mg, 300.0 pmol) in Dioxane (0.8 mL and water (0.2 mL) was stirred at 90 °C for 16 h. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the crude tert-butyl 4-(8-fluoro-6-(6- methylthieno[3,2-J]pyrimidin-2-yl)imidazo[l,2-a]pyridin-2-yl)piperidine-l -carboxylate, which was used directly without further purification. Quantitative yield assumed.

[0613] Step c: The crude tert-butyl 4-(8-fluoro-6-(6-methylthieno[3,2-J]pyrimidin-2-yl)imidazo[l,2- a]pyridin-2-yl)piperidine-l -carboxylate from step b was dissolved in hexafluoroisopropanol (1 mL) and treated with TFA. The reaction mixture was stirred at room temp for 16 h. The reaction mixture was then diluted with ~10 mL DCM and washed with ~25 mL sat. aq.

[0614] NaHCCh. The layers were separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organics were dried over JSfeSCU, filtered, and concentrated under reduced pressure to obtain the crude product. The crude was purified by prep-HPLC (Waters SunFire Prep C18 5um OBD 30x100mm, TFA_prep_05_40_12min) to afford 2-(8-fluoro-2- (piperidin-4-yl)imidazo[l,2-a]pyridin-6-yl)-6-methylthieno[3,2-J]pyrimidine (2.30 mg, 6.26 pmol, 6.26% yield, 100.0% purity) as a tan solid. MS: m / z 368.1 [M+H]+; RT 1.32 min (Method 3). 'H NMR (500 MHz, dimethyl sulfoxide- e): 5 (ppm) 9.49 (d, J= 1.3 Hz, 1H), 9.47 (d, .7= 0.6 Hz, 1H), 8.13 (d, J= 2.7 Hz, 1H), 7.98 (dd, J= 11.3, 3.6 Hz, 1H), 7.42 (s, 1H), 3.42-3.36 (m, 2H), 3.14-3.05 (m, 3H), 2.75 (s, 3H), 2.22-2.15 (m, 2H), 1.94-1.84 (m, 2H).

[0615] Example 30- Compound 33 Preparation of 2-(7-fluoro-2-methyl-27 / -indazol-5-yl)-6-(2- azaspiro[3.3]heptan-6-yl)thieno[2,3-J]pyrimidine

[0616] Step a: A solution of tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (400 mg, 1.81 mmol) and 4-chloro-5-iodopyrimidin-2-amine (277.04 mg, 1.81 mmol) in Toluene (10 mL) was treated with Pd(PPh3)4(208.87 mg, 180.75 pmol), Cui (20.65 mg, 108.45 pmol) and TEA (914.53 mg, 9.04 mmol, 1.26 mL) then the mixture was stirred at 100 °C for 2 hours under N2 atmosphere. The reaction mixture was filtered over Celite and concentrated under reduced pressure to obtain the crude product. The crude was purified by flash column chromatography (EtOAc in PE from 0% to 30%) to afford tert-butyl 6-((2-amino-4-chloropyrimidin-5- yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 659.35 pmol, 36.48% yield) as a light-yellow solid. MS: m / z 293.0 [M+H-tBu]+; RT 0.45 min (Method 9).

[0617] Step b: A solution of tert-butyl 6-((2-amino-4-chloropyrimidin-5-yl)ethynyl)-2- azaspiro[3.3]heptane-2-carboxylate (230 mg, 659.35 pmol) in DMF (5 mL) was treated with NaHS (150.52 mg, 2.64 mmol) at 25 °C. The mixture was stirred at 90 °C under N2for 2 hours. The reaction mixture was quenched with brine (5 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography (EtOAc in PE from 0 % to 15%) to afford tert-butyl 6-(2-aminothieno[2,3- J]pyrimidin-6-yl)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 577.29 pmol, 87.55% yield) as a white solid. MS: m / z 347.0 [M+H-tBu]+; RT 0.42 min (Method 9). 'H NMR (400MHz, chloroform-t / ): 5 (ppm) 8.56 (s, 1H), 6.76 (s, 1H), 5.00 (br s, 2H), 4.04 (s, 2H), 3.89 (s, 2H), 3.56 (t, J= 8.4 Hz, 1H), 2.63-2.69 (m, 2H), 2.35-2.41 (m, 2H), 1.45 (s, 9H).

[0618] Step c: A solution of tert-butyl 6-(2-aminothieno[2,3-t ]pyrimidin-6-yl)-2- azaspiro[3.3]heptane-2-carboxylate (300 mg, 865.94 pmol) in DCM (5 mL) was treated with TMSC1 (282.23 mg, 2.60 mmol, 329.71 pL) at 0 °C. Then tert-butyl nitrite (405.76 mg, 3.46 mmol, 465.33 pL) was added to mixture at 0 °C dropwise via syringe. The mixture was stirred at 25 °C under N2for 4 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, dried over ISfeSCL, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (EtOAc in PE from 0% to 50%) to afford tert-butyl 6-(2-chlorothieno[2,3-J]pyrimidin-6-yl)-2-azaspiro[3.3]heptane-2-carboxylate (120 mg, 327.98 pmol, 37.88% yield) as a yellow solid. MS: m / z 366.0 [M+H]+; RT 0.49 min (Method 9).

[0619] Step d: A solution of tert-butyl 6-(2-chlorothieno[2,3-t ]pyrimidin-6-yl)-2- azaspiro[3.3]heptane-2-carboxylate (120 mg, 327.98 pmol) and 7-fluoro-2-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2J / -indazole (99.62 mg, 360.78 pmol) in Dioxane (5 mL) and water (1 mL) was treated with Pd(dppf)C12 (21.38 mg, 32.80 pmol) and K2CO3 (135.99 mg, 983.94 pmol) at 25 °C. The mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel chromatography (from Petroleum ether / EtOAc = 100 / 1 to 1 / 2) to afford tert-butyl 6-(2-(7-fluoro-2-methyl-2 / / -indazol-5-yl)thieno[2,3-t / ]pyrimidin-6-yl)-2- azaspiro[3.3]heptane-2-carboxylate (100 mg, 197.82 pmol, 60.32% yield) as a yellow solid. MS: m / z 480.2 [M+H]+; RT 0.54 (Method 9). 'HNMR (400MHz, chloroform^ / ): 8 (ppm) 9.03 (s, 1H), 8.70 (s, 1H), 8.06-8.18 (m, 2H), 6.99 (s, 1H), 4.29 (s, 3H), 4.08 (s, 2H), 3.92 (s, 2H), 3.67-3.72 (m, 1H), 2.72-2.78 (m, 2H), 2.44-2.49 (m, 2H), 1.46 (s, 9H).

[0620] Step e: A solution of tert-butyl 6-(2-(7-fluoro-2-methyl-2J / -indazol-5-yl)thieno[2,3- ]pyrimidin-6-yl)-2-azaspiro[3.3]heptane-2-carboxylate (50 mg, 10426 pmol) in DCM (5 mL) was treated with TFA (1 mL) and stirred at 25 °C for 1 hour. The crude product was purified by prep-HPLC (Column: Boston Green ODS 150*25mm*10um; Condition: water (FA)-ACN; 10%-38%; Flow Rate (mL / min): 25) to afford 2-(7-fluoro-2-methyl-2J / -indazol- 5-yl)-6-(2-azaspiro[3.3]heptan-6-yl)thieno[2,3-J]pyrimidine (11.43 mg, 26.86 pmol, 25.77% yield, 100% purity) as a yellow solid. MS: m / z 380.0 [M+H]+; RT 1.37 (Method 8). ' H NMR (400MHz, chloroform-t / ): 6 (ppm) 9.22 (s, 1H), 8.73 (s, 1H), 8.65 (d, J= 2.8 Hz, 1H), 8.39 (s, 1H), 8.02 (d, J= 13.2 Hz, 1H), 7.31 (s, 1H), 4.23 (s, 3H), 3.92 (s, 2H), 3.75 (br s, 3H), 2.69- 2.75 (m, 2H), 2.37-2.42 (m, 2H).

[0621] Example 31- (Compound 119)

[0622] Step a: To a solution of 4-(3-chlorothieno[2,3-b]pyrazin-6-yl)cyclohexan-l-one (46 mg, 172.45 pmol), 6-chloro-8-(difluoromethyl)-2-methylimidazo[l,2-b]pyridazine (45.03 mg, 206.94 pmol), B2Pin2 (87.58 mg, 344.90 pmol), CsF (104.78 mg, 689.79 pmol), and Cataxium A (12.37 mg, 34.49 pmol) in Toluene (2 mL) and MeOH (2 mL) and H2O (1.2 mL) was added Pd(OAc)2 (7.74 mg, 34.49 pmol) under N2. The reaction was stirred at 90 °C for 1 h. LCMS showed -31.196% of desired mass was observed. The reaction solution were concentrated to give a residue, which was purified on silica gel column chromatography (from Petroleum ether / EtOAc = 1 / 0 to 1 / 1, TLC: Petroleum ether / EtOAc = 1 / 1, Rf = 0.41) to give compound 3 (44 mg, 106.17 pmol, 61.57% yield) as a brown solid. MS: m / z 414.1 [M+H]+

[0623] Step b: To a solution of 4-(3-(8-(difluoromethyl)-2-methylimidazo[l,2-b]pyridazin-6- yl)thieno[2,3-b]pyrazin-6-yl)cyclohexan-l-one (35 mg, 84.45 pmol), azetidine (14.47 mg, 253.36 pmol, 17.08 pL) in MeOH (0.5 mL) was added NaBH3CN (15.92 mg, 253.36 pmol). The reaction was stirred at 60 °C for 1 h. LCMS showed the reaction was completed. The reaction was concentrated to give residue and which was purification by prep-HPLC (Column: CD01 -Phenom enex luna C18 150*25 *10um; Condition: water (FA)-ACN; Begin B: 13; End B: 43; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL / min): 25; Detection wavelength: 220 nm) to give 6-((lr,4r)-4-(azetidin-l-yl)cyclohexyl)-3-(8- (difluoromethyl)-2-methylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazine (4 mg, 8.41 pmol, 9.96% yield, 95.81% purity) as a yellow solid MS: m / z 454.9 [M+H]+ 1H NMR (400 MHz, MeOD) 5 ppm: 9.54-9.65 (m, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 7.18-7.50 (m, 2H), 3.69- 3.89 (m, 4H), 3.37-3.43 (m, 1H), 2.77-3.11 (m, 1H), 2.55 (s, 3H), 2.28-2.35 (m, 3H), 2.05-2.20 (m, 2H), 1.78-2.05 (m, 1H), 1.61-1.77 (m, 2H), 1.22-1.43 (m, 2H).

[0624] Example 32- Compound 128

[0625] To a solution of ethane- 1,2-diol (23.02 g, 370.91 mmol, 20.68 mL) and diethyl 3- oxopentanedioate (25 g, 123.64 mmol, 22.46 mL) in Toluene (400 mL) was added TsOH.H2O (2.35 g, 12.36 mmol), MgSO4 (29.76 g, 247.28 mmol) at 25 °C. The mixture was stirred at 100 °C for 12 hours. TLC (Petroleum ether / EtOAc = 3 / 1, Rf = 0.3) showed that the starting material was consumed and a new spot was detected. The mixture was diluted with water (400mL) and extracted with EtOAc (100 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the residue, which was purified by silica gel chromatography (EtOAc in Petroleum ether from 0% to 30%) to give diethyl 2,2'- (l,3-dioxolane-2,2-diyl)diacetate (11 g, 44.67 mmol, 36.13% yield) as a yellow oil. 1H NMR: (400 MHz, CDC13) 5 ppm 4.15 (q, J = 7.2 Hz, 4H), 4.01 (s, 4H), 2.93 (s, 4H), 1.26 (t, J = 7.2 Hz, 6H).

[0626] To a solution of LiAlD4 (2.97 g, 70.66 mmol) in THF (150 mL) was added diethyl 2,2'-(l,3- dioxolane-2,2-diyl)diacetate (8.7 g, 35.33 mmol) in THF (2 mL) dropwise at 0 °C, the mixture was stirred at 0 °C for 0.5 hour. TLC (Petroleum ether / EtOAc = 3 / 1, Rf = 0.01) showed that the starting material was consumed and a new spot was detected. The mixture was quenched with water (3 mL), 15% NaOH (3 mL), water (9 mL), added slowly under N2 protection. The mixture was dried over ISfeSCL, filtered and concentrated to give 2,2'-(l ,3 - dioxolane-2, 2-diyl)bis(ethan-l,l-d2-l-ol) (3.6 g, 21.66 mmol, 61.31% yield) as a light yellow oil^H NMR: (400 MHz, CDCI3) 8 ppm 4.05 (s, 4H), 2.48 (s, 2H), 1.97 (s, 4H).

[0627] To a solution of 2,2'-(l,3-dioxolane-2,2-diyl)bis(ethan-l,l-d2-l-ol) (2.5 g, 15.04 mmol) and TsCl (8.60 g, 45.12 mmol) in DCM (100 mL) was added TEA (9.13 g, 90.25 mmol, 12.58 mL) at 25 °C. The mixture was stirred at 25 °C for 12 hours. LCMS showed that -44% of desired MS was detected. TLC (Petroleum ether / EtOAc = 3 / 1, Rf = 0.25) showed that new spot was detected. The mixture was concentrated to give the residue, which was purified by combi flash (EtOAc in Petroleum ether from 0% to 40%) to give (1,3 -di oxolane-2, 2- diyl)bis(ethane-2,l-diyl-l,l-d2) bis(4-methylbenzenesulfonate) (5.6 g, 11.80 mmol, 78.45% yield) as a yellow oil.

[0628] ‘HNMR: (400 MHz, CDCI3) 6 ppm 7.78 (d, J= 8.4 Hz, 4H), 7.35 (d, J= 8.4 Hz, 4H), 3.84 (s, 4H), 2.45 (s, 6H), 1.94 (s, 4H).

[0629] To a solution of (l,3-dioxolane-2,2-diyl)bis(ethane-2,l-diyl-l,l-d2) bis(4- methylbenzenesulfonate) (6.4 g, 13.49 mmol) and BnNH2 (1.59 g, 14.83 mmol, 1.62 mL) in MeCN (150 mL) was added K2CO3 (7.46 g, 53.94 mmol), at 25 °C, The mixture was stirred at 90 °C for 12 hours. TLC (DCM / MeOH = 20 / 1, Rf = 0.3) showed that the starting material was consumed and a new spot was detected. LCMS showed that the desired MS was detected. The mixture was diluted with water (200 mL) and extracted with DCM (40 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the residue, which was purified by silica gel chromatography (DCM in MeOH from 0% to 10%) to give 8-benzyl-l,4-dioxa-8-azaspiro[4.5]decane-7,7,9,9-d4 (2.7 g, 11.38 mmol, 84.36% yield) as a colorless oil. LCMS: m / z 454.9 [M+H]+= 237.9) 'H NMR: (400 MHz, CDC13) 8 ppm 7.23-7.35 (m, 5H), 3.95 (s, 4H), 3.53 (s, 2H), 1.73 (s, 4H).

[0630] To a solution of 8-benzyl-l,4-dioxa-8-azaspiro[4.5]decane-7,7,9,9-d4 (2.7 g, 11.38 mmol) in MeOH (40 mL) was added HC1 (2 M, 48.00 mmol, 24 mL) at 25 °C, the mixture was stirred at 90 °C for 12 hours. TLC (DCM / MeOH = 10 / 1, Rf = 0.3) showed that the starting material was consumed and a new spot was detected. LCMS showed that the desired MS was detected. The mixture was quenched with sat. NaHCOs (200 mL, until PH = 8), remove the MeOH by concentration and extracted with DCM (50 mL x 4), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the residue, which was purified by silica gel chromatography (MeOH in DCM from 0% to 8%) to give 1- benzylpiperidin-4-one-2,2,6,6-d4 (1.8 g, 9.31 mmol, 81.86% yield) as a colorless oil. ' H NMR: (400 MHz, CDCI3) 6 ppm 7.27-7.39 (m, 5H), 3.63 (s, 2H), 2.44 (s, 4H)

[0631] To a solution of l-benzylpiperidin-4-one-2,2,6,6-d4 (1.4 g, 7.24 mmol) in THF (20 mL) was added LiHMDS (1 M, 9.42 mmol, 9.42 mL) at -78 °C, after stirred at -78°C for 0.5 hour, the PhNTf2 (5.18 g, 14.49 mmol) in THF (2 mL) was added to the mixture at -78°C and stirred at -78-20 °C for 12 hours. TLC (DCM / MeOH=20 / l, Rf = 0.5) showed that the starting material was consumed and a new spot was detected. LCMS showed that the desired MS was detected.

[0632] The mixture was quenched with water (20 mL) and extracted with EtOAc (10 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the residue, which was purified by silica gel chromatography (MeOH in DCM from 0% to 1%) to give l-benzyl-l,2,3,6-tetrahydropyridin-4-yl-2,2,6,6-d4 trifluoromethanesulfonate (2.2 g, 6.76 mmol, 93.36% yield) as a yellow solid. 'H NMR: (400 MHz, CDCI3) 6 ppm 7.53-7.65 (m, 5H), 5.70-5.77 (m, 1H), 3.50-3.80 (m, 2H), 2.28-2.65 (m, 2H).

[0633] To a solution of l-benzyl-l,2,3,6-tetrahydropyridin-4-yl-2,2,6,6-d4 trifluoromethanesulfonate (2.2 g, 6.76 mmol) and B2Pin2 (3.43 g, 13.52 mmol) in dioxane (60 mL) was added Pd(dppf)C12 (494.79 mg, 676.22 pmol), KO Ac (1.66 g, 16.91 mmol) at 25 °C, the mixture was stirred at 90 °C for 1 hour. TLC (Petroleum ether ZEtOAc = 3 / 1, Rf = 0.3) showed that the starting material was consumed and a new spot was detected. LCMS showed that the desired MS was detected. The mixture of l-benzyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-2,2,6,6-d4 (2 g, crude) in dioxane was obtained as a brown liquid, which was used for next step directly. LCMS: ([M+H] = 304.2)

[0634] To a solution of 3-chloro-6-iodothieno[2,3-b]pyrazine (500 mg, 1.67 mmol) and l-benzyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine-2,2,6,6-d4 (761.83 mg, 2.51 mmol) in dioxane (20 mL) and water (4 mL) was added Pd(dppf)C12 (122.55 mg, 167.49 pmol), K2CO3 (578.69 mg, 4.19 mmol) at 25 °C, the mixture was stirred at 60 °C for IHour under N2. TLC (Petroleum ether / EtOAc = 2 / 1, Rf = 0.3) showed that the starting material was consumed and a new spot was detected. LCMS showed that the desired MS was detected. The mixture was concentrated to give the residue, which was purified by silica gel chromatography (EtOAc in Petroleum ether from 0% to 35%) to give 6-(l-benzyl-l,2,3,6- tetrahydropyridin-4-yl-2,2,6,6-d4)-3-chlorothieno[2,3-b]pyrazine (300 mg, 862.32 pmol, 51.49% yield) as a light yellow solid. LCMS: ([M+H] = 345.9)

[0635] To a solution of intermediate 19 (74.48 mg, 287.44 pmol) and 6-(l-benzyl-l,2,3,6- tetrahydropyridin-4-yl-2,2,6,6-d4)-3-chlorothieno[2,3-b]pyrazine 100 mg, 287.44 pmol) in doxane (10 mL) and H2O mL) was added Pd(dppf)C12 (21.03 mg, 28.74 pmol) and K2CO3 (99.31 mg, 718.60 pmol) at 25 °C. The mixture was stirred at 100 °C for 2 hours under N2. TLC (Petroleum ether / EtOAc = 0 / 1, Rf = 0.25) showed that the starting material was consumed and a new spot was detected. LCMS showed that the desired MS was detected. The mixture was concentrated to give the residue, which was purified by silica gel chromatography (EtOAc in Petroleum ether from 0% to 100%) to give 6-(l-benzyl-l,2,3,6- tetrahydropyridin-4-yl-2,2,6,6-d4)-3-(2-methylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3- b]pyrazine (90 mg, 202.44 pmol, 70.43% yield) as a yellow solid. LCMS: ([M+H] = 443.1)

[0636] To a solution of 6-(l-benzyl-l,2,3,6-tetrahydropyridin-4-yl-2,2,6,6-d4)-3-(2- methylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazine (70 mg, 157.45 pmol) in MeOH (10 mL) was added Pd / C (50.27 mg, 47.23 pmol, 10% purity) at 25 °C. The mixture was stirred at 20 °C for 12 hours under H2 (15 psi). LCMS showed that the desired MS was detected. The mixture was filtered, washed with DCM (10 mL x 6) and concentrated to give 6-(l-benzylpiperidin-4-yl-2,2,6,6-d4)-3-(2-methylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3- b]pyrazine (35 mg, 78.37 pmol, 49.77% yield) as a yellow solid, which was used for next step directly. LCMS: ([M+H] = 445.2)

[0637] To a solution of 6-(l-benzylpiperidin-4-yl-2,2,6,6-d4)-3-(2-methylimidazo[l,2-b]pyridazin-6- yl)thieno[2,3-b]pyrazine (20 mg, 44.78 pmol) and DIPEA (57.88 mg, 447.83 pmol, 78.00 pL) in DCE (5 mL) was added ACE-CI (32.01 mg, 223.91 pmol, 24.16 pL) at 25 °C, the mixture was stirred at 90 °C for 2 hours. LCMS showed that the starting material was consumed and desired MS was detected. The mixture was quenched with MeOH (10 mL) and concentrated to give the residue, which was purified by prep-HPLC (Instrument; SemiPre-HPLC-C (FA); Column: CD04-Welch Utimate C18 150*25*7um; Condition: water (FA)-ACN; Begin B: 0; End B: 26; Gradient Time(min): 10; 100% B Hold Time(min): 2; Flow Rate (mL / min): 30) to get 3-(2-methylimidazo[l,2-b]pyridazin-6-yl)-6-(piperidin-4-yl- 2,2,6,6-d4)thieno[2,3-b]pyrazine (0.76 mg, 1.90 pmol, 4.24% yield, 100% purity, Formic acid) as a yellow solid.

[0638] LCMS: ([M+H] = 355.0) HPLC: (Purity: 100.0%) 'HNMR: (400 MHz, MeOD) 5 ppm 9.41 (s, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 7.63 (s, 1H), 7.42 (s, 1H), 3.40-3.46 (m, 1H), 2.80 (s, 3H), 2.52 (s, 3H), 2.35-2.40 (m, 2H), 1.93-2.10 (m, 2H).

[0639] Example 33- Compound 114

[0640] A mixture of intermediate 4 (100 mg, 337.25 pmol), rac-tert-butyl (R)-(4-(3-chlorothieno[2,3- b]pyrazin-6-yl)cyclohex-3-en-l-yl)carbamate (119.91 mg, 370.98 pmol), Pd(dppf)C12 (24.68 mg, 33.73 pmol) and K2CO3 (139.83 mg, 1.01 mmol) in dioxane (4 mL) and water (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was quenched by addition water (10 mL) at 20 °C, and then diluted with water (30 mL) and extracted with EtOAc 30 mL (10 mL x 3). The combined organic layers were washed with EtOAc 30 mL (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude was purified by column chromatography (from pure Petroleum ether to Petroleum ether / EtOAc = 4 / 1) to give rac-tert-butyl (R)-(4-(3- chlorothieno[2,3-b]pyrazin-6-yl)cyclohex-3-en-l-yl)carbamate (80 mg, 218.65 pmol, 64.83% yield) as a black solid. LCMS: ([M+H] = 366.2)

[0641] 'H NMR: (400 MHz, METHANOL-^) 8 ppm 8.60 (s, 1H), 7.38 (s, 1H), 6.45-6.48 (m, 1H), 3.66-3.82 (m, 1H), 2.71-2.79 (m, 1H), 2.56-2.70 (m, 2H), 2.16-2.25 (m, 1H), 2.06-2.12 (m, 1H), 1.69-1.82 (m, 1H), 1.48 (s, 9H).

[0642] A mixture of (R)-(4-(3-chlorothieno[2,3-b]pyrazin-6-yl)cyclohex-3-en-l-yl)carbamate (65 mg, 177.66 pmol), 6-chloro-8-(difluoromethyl)-2-methylimidazo[l,2-b]pyridazine (38.66 mg, 177.66 pmol), B2Pin2(90.23 mg, 355.31 pmol), Pd(OAc)2(7.98 mg, 35.53 pmol), CsF (161.92 mg, 1.07 mmol, 39.35 pL) and bis(l-adamantyl)-butyl-phosphane (25.48 mg, 71.06 pmol) in Toluene (2 mL), MeOH (2 mL) and water (0.5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2atmosphere. LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give crude product. The crude was purified by column chromatography (from pure Petroleum ether to Petroleum ether / EtOAc = 2 / 1) to give rac-tert-butyl (R)-(4-(3-(8-(difluoromethyl)-2- methylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)cyclohex-3-en-l-yl)carbamate (35 mg, 68.28 pmol, 38.44% yield) as a yellow solid. LCMS: ([M+H] = 513.3)

[0643] To a solution of (R)-(4-(3-(8-(difluoromethyl)-2-methylimidazo[l,2-b]pyridazin-6- yl)thieno[2,3-b]pyrazin-6-yl)cyclohex-3-en-l-yl)carbamate (50 mg, 97.55 pmol) in THF (3 mL) was added Pd / C (10.38 mg, 9.75 pmol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (30 Psi) at 25 °C for 16 hours. LCMS showed the reaction was completed. The mixture was cooled down to room temperature. After filtration, the filtrate was concentrated. No further purification as it is used for the next step directly. rac-tert-butyl(4-(3-(8-(difluoromethyl)-2- methylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)cyclohexyl)carbamate (25 mg, crude) was obtained as a brown solid.

[0644] LCMS: ([M+H] = 515.3) To a solution of rac-tert-butyl(4-(3-(8-(difluoromethyl)-2-methylimidazo[l,2-b]pyridazin-6- yl)thieno[2,3-b]pyrazin-6-yl)cyclohexyl)carbamate (25 mg, 48.58 pmol) in HCl / Dioxane (3 mL). The mixture was stirred at 20 °C for 2 hours. LCMS showed the reaction was completed. The crude was concentrated. The crude was purified by prep-HPLC (Welch Xtimate Cl 8 150*25mm*5um, water (FA)-ACN as a mobile phase, from 15% to 45%, Gradient Time (min):

[0645] 11, Flow Rate (mL / min): 25) to give rac-4-(3-(8-(difhioromethyl)-2-methylimidazo[l,2- b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)cyclohexan-l-amine (7.63 mg, 16.30 pmol, 33.55% yield, 98.38% purity, Formic acid) as a yellow solid. LCMS: ([M+H] = 415.1) HPLC: (purity: 98.38%). 'HNMR: (400 MHz, METHANOL-^) 8 ppm 9.60 (d, J=4.8 Hz, 1H), 8.54 (s, 1H), 8.42 (d, .7=0.8 Hz, 1H), 8.18 (s, 1H), 7.20-7.48 (m, 2H), 3.36-3.43 (m, 1H), 3.15-3.26

[0646] (m, 1H), 2.55 (s, 3H), 2.30-2.36 (m, 1H), 2.11-2.24 (m, 3H), 1.99-2.06 (m, 1H), 1.77-1.88 (m, 2H), 1.57-1.67 (m, 1H).

[0647] Using the procedure described for Example 33 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0648] Example 34- (Compound 116) To a solution of intermediate 23 (60 mg, 170.53 pmol), 7-(difluoromethyl)-2-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazole (87.57 mg, 170.53 pmol), and K2CO3 (70.70 mg, 511.58 pmol) in H2O (1 mL) and Dioxane (8 mL) was added Pd(dtppf)C12 (11.11 mg, 17.05 pmol) at 25 °C. The mixture was stirred at 90 °C for Ih under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by Flash column (50-80% EtOAc in petroleum ether) to afford tert-butyl (lR,5S,6r)-6-(2-(7- (difluoromethyl)-2-methyl-2H-indazol-5-yl)thieno[2,3-d]pyrimidin-6-yl)-3- azabicyclo[3.1.0]hexane-3 -carboxylate (70 mg, 140.69 pmol, 82.50% yield) as a yellow oil. LCMS: ([M+H] = 498.4).

[0649] A mixture of tert-butyl (lR,5S,6r)-6-(2-(7-(difluoromethyl)-2-methyl-2H-indazol-5- yl)thieno[2,3-d]pyrimidin-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (60 mg, 120.59 pmol) in DCM (1 mL) was added HCl / dioxane (2 M, 2 mL) at 20 °C. The mixture was stirred at 20 °C for 2h. TLC (EtOAc, Rf = 0) showed the reaction was complete. The mixture was concentrated and purified by pre-HPLC (Column: Welch Xtimate C18 150*25mm*5um, Condition: water (FA)-ACN, 10%~40%, Flow Rate (mL / min): 25) to give 6-((lR,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-2-(7-(difluoromethyl)-2-methyl-2H-indazol-5- yl)thieno[2,3-d]pyrimidine (37.16 mg, 79.21 pmol, 65.69% yield, 94.53% purity, Formic acid) as a white solid. LCMS: ([M+H] = 398.1). HPLC: (purity: 94.53%). SFC: (purity: 100%). 'HNMR: (500 MHz, MeOD) 5 ppm 9.09 (s, IH), 8.99 (s, IH), 8.65-8.67 (m, IH), 8.49 (s, IH), 8.46 (s, IH), 7.13-7.35 (m, 2H), 4.28 (s, 3H), 3.55-3.60 (m, 2H), 3.46-3.50 (m, 2H), 2.34 (s, 3H).

[0650] Using the procedure described for Example 34 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0651] Example 35- Compound 122

[0652] To a solution of tert-butyl ((lr,4r)-4-(2-(7-fluoro-2-methyl-2H-indazol-5-yl)thieno[2,3- d]pyrimidin-6-yl)cyclohexyl)carbamate (35.00 mg, 72.68 pmol) in THF (5 mL) was added NaH (5.81 mg, 145.35 pmol, 60% purity) at 0 °C. Then Methyl iodide (30.95 mg, 218.03 pmol, 13.57 pL) was added to the mixture and stirred at 60 °C under N2 for 12 hours. LCMS showed that the starting material was remained and desired mass was detected. The mixture was quenched with MeOH (1 ml) and concentrated to give the residue, which was purified by prep-HPLC (Instrument; CASCD-SEMI-PREP-U; Column: Phenomenex luna Cl 8 150*25mm* lOum; Condition: water (FA)-ACN; Begin B: 38; End B: 68; Gradient Time(min): 10; 100%B Hold Time (min): 2; Flow Rate (mL / min): 25) to give tert-butyl ((lr,4r)-4-(2-(7-fluoro-2-methyl-2H-indazol-5-yl)thieno[2,3-d]pyrimidin-6- yl)cyclohexyl)(methyl)carbamate (15 mg, 30.27 pmol, 41.64% yield) as a yellow solid. LCMS: ([M+H] =496.2)

[0653] To a solution of tert-butyl ((lr,4r)-4-(2-(7-fluoro-2-methyl-2H-indazol-5-yl)thieno[2,3- d]pyrimidin-6-yl)cyclohexyl)(methyl)carbamate (15 mg, 30.27 pmol) in DCM (1 mL) was added HC1 (2 M, 1.00 mmol, 0.5 mL) at 28 °C. The mixture was stirred at 28 °C under N2 for 4 hours. LCMS showed that the starting material was consumed and desired MS was detected. The mixture was concentrated to give the residue, which was purified by pre-HPLC (Instrument; CASCD-SEMI-PREP-U; Column: Phenomenex luna Cl 8 150*25mm* lOum; Condition: water (HCl)-ACN; Begin B: 8; End B: 28; Gradient Time(min): 10; 100%B Hold Time(min): 2; Flow Rate (mL / min): 25) to give (lr,4r)-4-(2-(7-fluoro-2-methyl-2H-indazol- 5-yl)thieno[2,3-d]pyrimidin-6-yl)-N-methylcyclohexan-l-amine (9.7 mg, 22.46 pmol, 74.20% yield, 100% purity, Hydrochloride) as a yellow solid. LCMS: ([M+H] = 396.0) 'H NMR: (400 MHz, MeOD) 5 ppm 9.06-9.23 (m, 1H), 8.74 (s, 1H), 8.50 (d, J= 2.4 Hz, 1H), 8.05-8.20 (m, 1H), 7.30 (s, 1H), 4.29 (s, 3H), 3.03-3.23 (m, 2H), 2.77 (s, 3H), 2.26-2.41 (m, 4H), 1.71-1.86 (m, 2H), 1.55-1.69 (m, 2H).

[0654] Example 36- Compound 129

[0655] To a solution of rac-tert-butyl (R)-(4-(3-chlorothieno[2,3-b]pyrazin-6-yl)cyclohex-3-en-l- yl)carbamate (200.00 mg, 546.63 pmol), Hexamethylditin (358.18 mg, 1.09 mmol, 226.70 pL) in dioxane (0.5 mL) and toluene (2 mL) was added Pd(PPhs)4 (63.17 mg, 54.66 pmol) under N2. The reaction was stirred at 130 °C for 3 h under N2. LCMS showed the reaction was completed. The reaction was concentrated to give rac-tert-butyl (R)-(4-(3- (trimethylstannyl)thieno[2,3-b]pyrazin-6-yl)cyclohex-3-en-l-yl)carbamate (250 mg, crude) as a black oil, which was used to next step directly without purification. LCMS: ([M+H]=496.0)

[0656] To a solution of rac-tert-butyl (R)-(4-(3-(trimethylstannyl)thieno[2,3-b]pyrazin-6-yl)cyclohex- 3-en-l-yl)carbamate (100 mg, 202.33 pmol), compound 5 (44.23 mg, 202.33 pmol) in dioxane (2 mL) was added Cui (7.71 mg, 40.47 pmol) and Pd(PPh3)4 (46.76 mg, 40.47 pmol) under N2. The reaction was stirred at 100 °C for 12 h under N2. LCMS showed the reaction was completed. The mixture was concentration to give the residue and which was purified on silica gel column chromatography (from Petroleum ether / EtOAc = 1 / 0 to 1 / 1, TLC: Petroleum ether / EtOAc = 1 / 1, Rf = 0.23) to give rac-tert-butyl (R)-(4-(3-(8-(difluoromethyl)-2-methyl- [ 1 , 2, 4]tri azolof 1 ,5-b]pyridazin-6-yl)thieno[2,3 -b]pyrazin-6-yl)cyclohex-3 -en- 1 -yl)carbamate (60 mg, 107.22 pmol, 52.99% yield, Formic acid) as a yellow solid. LCMS: ([M+H]=514.1) To a solution of rac-tert-butyl (R)-(4-(3-(8-(difluoromethyl)-2-methyl-[l,2,4]triazolo[l,5- b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)cyclohex-3-en-l-yl)carbamate (60 mg, 116.83 pmol) in THF (5 mL) was added Pd / C (248.66 mg, 233.66 pmol, 10% purity) under Ar. The reaction was stirred at 20 °C for 12 h under H2 (15 psi). LCMS showed the reaction was completed. The suspension was filtered through a pad of filter paper and the filter cake was washed with DCM (50 mL><3). The combined filtrates were concentrated to give a residue and which was purified on silica gel column chromatography (from Petroleum ether / EtOAc = 1 / 0 to 1 / 1, TLC: Petroleum ether / EtOAc = 1 / 1, Rf = 0.29) to give tert-butyl ((lr,4r)-4-(3-(8- (difluoromethyl)-2-methyl-[l, 2, 4]tri azolof l,5-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6- yl)cyclohexyl)carbamate (30 mg, 58.19 pmol, 49.80% yield) as a white solid. LCMS: ([M+H]= 516.2)

[0657] To a solution of tert-butyl ((lr,4r)-4-(3-(8-(difluoromethyl)-2-methyl-[l,2,4]triazolo[l,5- b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)cyclohexyl)carbamate (30 mg, 58.19 pmol) in DCM (1 mL) was added HCl / dioxane (2 M, 200.00 pmol, 0.1 mL). The reaction was stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The reaction was concentrated to give (lr,4r)-4-(3-(8-(difhioromethyl)-2-methyl-[l,2,4]triazolo[l,5-b]pyridazin-6- yl)thieno[2,3-b]pyrazin-6-yl)cyclohexan-l -amine (24 mg, crude, HC1) as a yellow oil, which was used to next step without purification. LCMS: ([M+H]= 416.0)

[0658] ((lr,4r)-4-(3-(8-(difhioromethyl)-2-methyl-[l,2,4]triazolo[l,5-b]pyridazin-6-yl)thieno[2,3- b]pyrazin-6-yl)cyclohexyl)carbamate (25 mg, 62.67 pmol, HC1) was separated by Chiral- HPLC (Column: REGIS (R,R)WHELK-Ol(250mm*25mm, 10 urn) Condition: CO2-ACN / i- PrOH(0.1% NH3 H2O); Begin B: 55; End B 55; Gradient Time(min): 10; FlowRate(ml / min): 90 ) to give the crude product. The crude product was purified by prep-HPLC (Column: CD04- Welch Utimate C18 150*25 *7um; Condition: water (FA)-ACN; Begin B: 10 ;End B: 40; Gradient Time(min): 10; 100%B Hold Time(min):2; Flow Rate(mL / min): 25) to give Sch-139- 7 (1.49 mg, 3.16 pmol, 8.15% yield, 97.867% purity, Formic acid) as white solid

[0659] LCMS: BIIB-100993-207-P1A1 ([M+H] = 415.9) HPLC: (purity: 97.867%) SFC: (purity: 100%) ‘H NMR: (400 MHz, MeOD) 5 ppm: 9.65 (s, 1H) 8.78 (s, 1H) 8.55 (s, 1H) 7.19-7.52 (m, 2H) 3.16 (br s, 1H) 3.05-3.12 (m, 1H) 2.69 (s, 3H) 2.27-2.39 (m, 2H) 2.13-2.23 (m, 2 H) 1.72-1.84 (m, 2H) 1.50-1.64 (m, 2H)

[0660] Example 37- Compound 144

[0661] 6-[(ll?,41?)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-(2,8-dimethylimidazo[l,2-6]pyridazin-

[0662] 6-yl)thieno [2,3-b] pyrazine

[0663] Step a: A solution of 3-chloro-6-iodothieno[2,3-Z>]pyrazine (59.3 mg, 0.2 mmol) and (3R)-3- (azetidine-l-yl)pyrrolidine (32.82 mg, 0.2 mmol) in dioxane (2 mL) was treated with CS2CO3 (325.82 mg, 1.0 mmol) and BINAP-Pd-G3 (19.7 mg, 20 pmol) at 20 °C. The reaction mixture was then stirred at 65 °C for 16h. The solution was filtered over Celite and the filtrate was concentrated under vacuum to obtain the crude product. The crude was transferred to a silica gel column and purified by flash chromatography (methanol / EtOAc from 0% to 100%) to afford (6-[(3A)-3-(azetidin-l-yl)pyrrolidin-l-yl]-3-chloro-thieno[2,3- Z>]pyrazine as a beige solid (47 mg, 159.43 pmol, 79.71% yield). LCMS m / z = 295.0 [M+H]+; RT 0.50 min (Method 4).

[0664] Step b: A mixture of (6-[(3A)-3-(azetidin-l-yl)pyrrolidin-l-yl]-3-chloro-thieno[2,3- Z>]pyrazine (47 mg, 159.43 pmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)imidazo[l,2-Z>]pyridazine (43.55 mg, 159.43 pmol), XPhos-Pd-G3 (13.49 mg, 15.94 pmol), and K2CO3 (66.10 mg, 478.29 pmol) in dioxane (2 mL) and water (0.5 mL) was stirred at 85 °C for 16h. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude was purified by prep-HPLC (Waters SunFire Prep C18 5um OBD 30x100mm, TFA_prep_05_35_ retention time 12min) to afford (A)-6-(3-(azetidin-l-yl)pyrrolidin-l-yl)-3-(2,8-dimethylimidazo[l,2- Z>]pyridazin-6-yl)thieno[2,3-Z>]pyrazine as a yellow oil as the corresponding TFA salt (2.2 mg, 3.4 pmol, 2.18% yield). LCMS m / z = 406.1 [M+H]+; RT 0.92 min (Method 3).

[0665] Using the procedure described for Example 37 above, additional compounds described herein were prepared by substituting the appropriate boronic acid or ester and amine starting material in step a, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

[0666] Example 38- Compound 123

[0667]

[0668] To a solution of 3-chloro-6-iodothieno[2,3-b]pyrazine (200 mg, 674.50 pmol) in THF (10 mL) was added n-BuLi (2.5 M, 1.01 mmol, 404.70 pL) at -78 °C under N2. The mixture was stirred at -78 °C for 5 min under N2. Then tert-butyl (lR,4R)-5-oxo-2- azabicyclo[2.2.1]heptane-2-carboxylate (142.49 mg, 674.50 pmol) in THF (1 mL) was added to the mixture at -78 °C under N2. The mixture was stirred at -78 °C for 2 hours under N2. LCMS showed desired product mass was detected. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) then diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over ISfeSCh, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / EtOAc =1 / 1) to give tertbutyl (lR,4R,5RS)-5-(3-chlorothieno[2,3-b]pyrazin-6-yl)-5-hydroxy-2- azabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 340.42 pmol, 50.47% yield) as a yellow solid. LCMS: ([M+Na] = 404.1) 'HNMR: (400 MHz, CHLOROFORM-d) 5 ppm 8.60 (s, 1H), 7.34 (s, 1H), 4.36 (s, 1H), 3.95 (d, J= 10.0 Hz, 1H), 3.26-3.30 (m, 1H), 2.86 (s, 1H), 2.44-2.49 (m, 1H), 2.09 (d, J= 13.6 Hz, 1H), 1.89 (s, 2H), 1.50 (s, 9H).

[0669] To a solution of tert-butyl (lR,4R,5RS)-5-(3-chlorothieno[2,3-b]pyrazin-6-yl)-5-hydroxy-2- azabicyclo[2.2.1]heptane-2-carboxylate (111.58 mg, 408.51 pmol) and 2,8-dimethyl-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-b]pyridazine (130 mg, 340.42 pmol) in Dioxane (5 mL) and water (1 mL) was added Pd(dtbpf)C12 (22.19 mg, 34.04 pmol) and K2CO3 (141.15 mg, 1.02 mmol) at 25 °C under N2. The mixture was stirred at 90 °C for 1 hour under N2. LCMS showed desired product mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / EtOAc =1 / 2) to give tert-butyl (lR,4R,5RS)-5-(3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)-5- hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (130 mg, 263.91 pmol, 77.52% yield) as a yellow solid. LCMS: ([M+H] = 493.1) *H NMR: (400 MHz, METHANOL-^) 5 ppm 9.55 (s, 1H), 8.09 (d, J= 0.8 Hz, 1H), 8.00 (s, 1H), 7.50 (s, 1H), 4.30 (s, 1H), 3.94-3.98 (m, 1H), 3.23-3.26 (m, 1H), 2.88-2.85 (m, 1H), 2.71 (d, J= 0.8 Hz, 3H), 2.51 (s, 3H), 2.45-2.49 (m, 1H), 2.01-2.07 (m, 2H), 1.94-1.87 (m, 1H), 1.51 (s, 9H).

[0670] To a solution of tert-butyl (lR,4R,5RS)-5-(3-(2,8-dimethylimidazo[l,2-b]pyridazin-6- yl)thieno[2,3-b]pyrazin-6-yl)-5-hydroxy-2-azabicyclo[2.2. l]heptane-2-carboxylate (60 mg, 121.80 pmol) in DCM (5 mL) was added Mesyl anhydride (212.18 mg, 1.22 mmol), DIPEA (472.27 mg, 3.65 mmol, 636.49 pL) and DMAP (14.88 mg, 121.80 pmol) at 25 °C. The mixture was stirred at 40 °C for 12 hours. LCMS showed desired product mass was detected. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over ISfeSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / EtOAc =0 / 1) to give tert-butyl 5-(3-(2,8- dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)-2-azabicyclo[2.2.1]hept-5- ene-2-carboxylate (35 mg, 73.75 pmol, 60.55% yield) as a yellow solid. LCMS: ([M+H] = 475.2)

[0671] To a solution of Pd / C (672.73 pg, 6.32 pmol) in EtOAc (1 mL) was added give tert-butyl 5- (3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)-2- azabicyclo[2.2.1]hept-5-ene-2-carboxylate (30 mg, 63.21 pmol) under Ar at 25 °C. The mixture was stirred at 25°C for 2 hours under H2 (15 psi). LCMS showed desired product mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (lR,4S,5RS)-5-(3-(2,8-dimethylimidazo[l,2-b]pyridazin-6- yl)thieno[2,3-b]pyrazin-6-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (25 mg, 52.46 pmol, 82.98% yield) as a yellow solid.

[0672] LCMS: ([M+H] = 477.2) To a solution of tert-butyl (lR,4S,5RS)-5-(3-(2,8-dimethylimidazo[l,2-b]pyridazin-6- yl)thieno[2,3-b]pyrazin-6-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (20 mg, 41.96 pmol) in DCM (1 mL) was added TFA (297.80 mg, 2.61 mmol, 0.2 mL) at 25 °C. The mixture was stirred at 25°C for 1 hour. LCMS showed desired product mass was detected. The reaction mixture was adjusted pH to 7 with NH3 H2O, concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Phenomenex luna Cl 8 150 x 25mm x lOum; condition: water (FA)-ACN; Begin B:0; End B:30; Gradient Time (min): 10; 100%B Hold Time (min): 10; Flow Rate (mL / min): 25; Detection wavelength: 220 nm) to give 6-((lR,4S,5RS)-2-azabicyclo[2.2.1]heptan-5-yl)-3-(2,8-dimethylimidazo[l,2- b]pyridazin-6-yl)thieno[2,3-b]pyrazine (13.17 mg, 31.06 pmol, 74.01% yield, 99.63% purity, Formic acid) as a yellow solid. LCMS: ([M+H] = 377.1) HPLC: (purity: 99.63%). 'H NMR: (400 MHz, METHANOL-^) 5 ppm 9.56 (s, 1H), 8.55 (s, 1H), 8.05 (d, J= 0.8 Hz, 1H), 7.99 (s, 1H), 7.51 (d, J= 1.2 Hz, 1H), 4.16 (s, 1H), 3.89-3.93 (m, 1H), 3.03-3.12 (m, 3H), 2.70 (s, 3H), 2.48-2.52 (m, 4H), 2.13-2.18 (m, 2H), 2.01 (d, J= 10.4 Hz, 1H).

[0673] Example 39- Compound 145

[0674] To a solution of tert-butyl (lS,4S,5RS)-5-[3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2- yl)thieno[2,3-b]pyrazin-6-yl]-5-hydroxy-2-azabicyclo[2.2. l]heptane-2-carboxylate (130 mg, 263.91 pm ol) in DCM (3 mL) was added DAST (85.08 mg, 527.82 pmol, 69.74 pL) at 0 °C under N2. The mixture was stirred at 0-25°C for 12 hours under N2.

[0675] LC-MS showed material was consumed completely and one main peak was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.

[0676] The residue was purified by flash silica gel chromatography (from PEZEtOAc = 100 / 1 to 1 / 2, TLC: PEZEtOAc = 0 / 1, Rf = 0.5) to give tert-butyl (lS,4S,5RS)-5-[3-(4,6- dimethylpyrazolo[l,5-a]pyrazin-2-yl)thieno[2,3-b]pyrazin-6-yl]-5-fluoro-2- azabicyclo[2.2.1]heptane-2-carboxylate (90 mg, 181.97 pmol, 68.95% yield) as a yellow solid. LCMS ([M+H] = 495.3)

[0677] To a solution of tert-butyl (lS,4S,5RS)-5-[3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2- yl)thieno[2,3-b]pyrazin-6-yl]-5-fluoro-2-azabicyclo[2.2. l]heptane-2-carboxylate (30 mg, 60.66 pmol) in DCM (2 mL) was added HC1 (2 M, 4.00 mmol, 2 mL) at 20 °C . The mixture was stirred at 20°C for 2 hours . LC-MS showed material was consumed completely and one main peak was detected. The reaction mixture was concentrated under reduced pressure to give 3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-6-[(lR,4R,5RS)-5-fluoro-2- azabicyclo[2.2.1]heptan-5-yl]thieno[2,3-b]pyrazine (22.59 mg, 50.05 pmol, 82.51% yield, 95.478% purity, Hydrochloride) as a yellow solid. HPLC: (Purity: 95.478%) LCMS: ([M+H] = 395.0) ‘HNMR: (400 MHz, METHANOL-d4) 5 = 9.55 (br s, 1H), 8.65 (br s, 1H), 7.96 (br s, 1H), 7.83 (br d, J = 1.9 Hz, 1H), 4.41 (br s, 1H), 2.94 - 2.79 (m, 6H), 2.70 - 2.54 (m, 6H), 2.09 (br d, J = 12.0 Hz, 1H).

[0678] Example 40 - (Compound 117)

[0679] To a solution of tert-butyl (E)-3-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methylene)pyrrolidine-l -carboxylate (200 mg, 646.81 pmol), Pd(dppf)C12 DCM (52.82 mg, 64.68 pmol) and K2CO3 (178.79 mg, 1.29 mmol) in Dioxane (3 mL) and H2O (0.5 mL) was added 2-chloro-6-iodothieno[2,3-d]pyrimidine (161.39 mg, 646.81 pmol). The mixture was stirred at 90 °C for Ih under N2. LCMS showed the reaction was completed. The mixture was concentrated and filtered to get crude, which was purified by flash column (petroleum ether / EtOAc =1 / 0 to 1 / 1, TLC: petroleum ether / EtOAc = 1 / 1, Rf=0.28) to give tert-butyl (E)- 3 -((2-chlorothieno[2, 3 -d]pyrimidin-6-yl)m ethyl ene)pyrrolidine-l -carboxylate (135 mg, 383.69 pmol, 59.32% yield) as yellow solid. LCMS: ([M+H] = 352.0)

[0680] To a solution of tert-butyl (E)-3-((2-chlorothieno[2,3-d]pyrimidin-6-yl)methylene)pyrrolidine- 1-carboxylate (120 mg, 341.05 pmol), K2CO3 (94.27 mg, 682.11 pmol) and Pd(dppf)C12 DCM (27.85 mg, 34.11 pmol) in Dioxane (3 mL) and H2O (0.5 mL) was added 7-fluoro-2-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazole (113.00 mg, 409.26 pmol). The mixture was stirred at 80 °C for 2h under N2. LCMS showed -16% desired mass was observed. The mixture was concentrated to give crude, which was purified by flash column (petroleum ether / EtOAc =1 / 0 to 1 / 1, TLC: petroleum ether / EtOAc = 1 / 1, Rf=0.45) to give tert-butyl (E)- 3-((2-(7-fluoro-2-methyl-2H-indazol-5-yl)thieno[2,3-d]pyrimidin-6- yl)methylene)pyrrolidine-l -carboxylate (70 mg, 60.14 pmol, 17.64% yield, 40% purity) as yellow solid. LCMS: ([M+H] = 466.1)

[0681] To a solution of tert-butyl (E)-3-((2-(7-fluoro-2-methyl-2H-indazol-5-yl)thieno[2,3- d]pyrimidin-6-yl)methylene)pyrrolidine-l -carboxylate (70 mg, 150.36 pmol) in THF (2 mL) and MeOH (2 mL) was added Pd / C (32.00 mg, 300.72 pmol) under N2. The mixture reaction was degassed under vacuum and purged with H2 several times. Then the mixture was stirred under H2 (15 Psi) at 25 °C for 16 h. LCMS showed the reaction was completed. The mixture was filtered and concentrated to give tert-butyl 3-((2-(7-fluoro-2-methyl-2H-indazol-5- yl)thieno[2,3-d]pyrimidin-6-yl)methyl)pyrrolidine-l-carboxylate (32 mg, 34.22 pmol, 22.76% yield, 50% purity) as yellow oil. LCMS: ([M+H] = 468.2)

[0682] To a solution of tert-butyl 3-((2-(7-fluoro-2-methyl-2H-indazol-5-yl)thieno[2,3-d]pyrimidin- 6-yl)methyl)pyrrolidine-l -carboxylate (30 mg, 64.16 pmol) in DCM (1 mL) and was added TFA (0.5 mL). The mixture was stirred at 25 °C for 24h. LCMS showed the reaction was completed. The mixture was concentrated and purified by Prep-HPLC (Boston Green ODS 150*30mm*5um; Condition: water (FA)-ACN; Begin B: 12; End B: 42; Gradient Time (min): 10; 100%B Hold Time (min):2; Flow Rate (ml / min): 25) to give rac-(R)-2-(7-fluoro-2-methyl- 2H-indazol-5-yl)-6-(pyrrolidin-3-ylmethyl)thieno[2,3-d]pyrimidine (10 mg, 27.22 pmol, 42.42% yield, 100% purity) as a white solid. LCMS: ([M+H] = 368.1) HPLC: (purity: 96.39%).JH NMR: (400 MHz, MeOD) 5 ppm: 9.14 (s, 1H), 8.73 (s, 1H), 8.54 (s, 0.5H), 8.46 (s, 1H), 8.11 (d, .7=12.8 Hz, 1H), 7.29 (s, 1H), 4.27 (s, 3H), 3.31-3.45 (m, 3H), 3.16-3.19 (m, 2H), 2.95-2.99 (m, 1H), 2.75-2.80 (m, 1H), 2.26-2.28 (m, 1H), 1.74-1.85 (m, 1H).

[0683] Example 41- Compound 132

[0684] To a solution of tert-butyl (E)-3-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methylene)pyrrolidine-l -carboxylate (200 mg, 646.81 pmol), Pd(dppf)C12 DCM (52.82 mg, 64.68 pmol) and K2CO3 (178.79 mg, 1.29 mmol) in Dioxane (3 mL) and H2O (0.5 mL) was added 3-chloro-6-iodothieno[2,3-b]pyrazine (191.79 mg, 646.81 pmol). The mixture was stirred at 90 °C for Ih under N2. LCMS showed the reaction was completed. The mixture was concentrated to get crude, which was purified by flash column (petroleum ether / EtOAc =1 / 0 to 3 / 1, TLC: petroleum ether / EtOAc = 3 / 1, Rf=0.40) to give tert-butyl (E)-3-((3- chlorothieno[2,3-b]pyrazin-6-yl)methylene)pyrrolidine-l-carboxylate (140 mg, 397.90 pmol, 61.52% yield) as yellow solid.

[0685] LCMS: ([M+H] = 352.1)

[0686] To a solution of tert-butyl (E)-3-((3-chlorothieno[2,3-b]pyrazin-6-yl)methylene)pyrrolidine-l- carboxylate (130 mg, 369.48 pmol), Pd(dppf)C12 DCM (30.17 mg, 36.95 pmol) and K2CO3 (102.13 mg, 738.95 pmol) in Dioxane (5 mL) and H2O (0.5 mL) was added 2,8-dimethyl-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-b]pyridazine (100.92 mg, 369.48 pmol). The mixture was stirred at 80 °C for 2h under N2. LCMS showed -63% desired mass was observed. The mixture was concentrated to give crude, which was purified by flash column (petroleum ether / EtOAc =1 / 0 to 3 / 1, TLC: petroleum ether / EtOAc = 3 / 1, Rf=0.39) to give tert-butyl (E)-3-((3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6- yl)methylene)pyrrolidine-l -carboxylate (60 mg, 129.71 pmol, 35.11% yield) as yellow solid. LCMS: ([M+H] = 463.2)

[0687] To a solution of tert-butyl (E)-3-((3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3- b]pyrazin-6-yl)methylene)pyrrolidine-l -carboxylate (60 mg, 128.88 pmol) in DCM (10 mL) and THF (1 mL) was added Pd / C (13.72 mg, 12.89 pmol, 10% purity) under N2. The mixture reaction was degassed under vacuum and purged with H2 several times. Then the mixture was stirred under H2 (15 Psi) at 25 °C for 4 h. LCMS showed the reaction was completed. The mixture was filtered and concentrated to give tert-butyl 3-((3-(2,8-dimethylimidazo[l,2- b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)methyl)pyrrolidine-l-carboxylate (50 mg, 106.94 pmol, 82.97% yield) as yellow oil. LCMS: ([M+H] = 465.2)

[0688] To a solution of tert-butyl 3-((3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3- b]pyrazin-6-yl)methyl)pyrrolidine-l -carboxylate (50 mg, 107.62 pmol) in DCM (1 mL) and was added TFA (0.5 mL). The mixture was stirred at 25 °C for 24h. LCMS showed the reaction was completed. The mixture was purified by Prep-HPLC (Boston Green ODS 150*30mm*5um; Condition: water (FA)-ACN; Begin B: 12; End B: 42; Gradient Time (min): 10; 100%B Hold Time (min):2; Flow Rate (mL / min): 25) to give 3-(2,8-dimethylimidazo[l,2- b]pyridazin-6-yl)-6-(pyrrolidin-3-ylmethyl)thieno[2,3-b]pyrazine (17 mg, 46.61 pmol, 43.31% yield, 99.93% purity) as a white solid. LCMS: ([M+H] = 365.1) HPLC: (purity: 99.91%). 'H NMR: (400 MHz, MeOD) 5 ppm: 9.57 (s, 1H), 8.51 (br s, 0.5H), 8.08 (s, 1H), 8.01 (s, 1H), 7.44 (s, 1H), 3.49-3.53 (m, 2H), 3.25-3.31 (m, 3H), 3.02-3.05 (m, 1H), 2.75-2.86 (m, 1H), 2.71 (s, 3H), 2.52 (s, 3H), 2.29-2.31 (m, 1H), 1.85-1.88 (m, 1H).

[0689] Example 42- (Compound 121)

[0690]

[0691] To a solution of 3-chloro-6-iodothieno[2,3-b]pyrazine (300 mg, 1.01 mmol) in Dioxane (8 mL) and H2O (1.6 mL) was added tert-butyl 4-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methylene)piperidine-l -carboxylate (327.03 mg, 1.01 mmol), Pd(dppf)C12 (74.03 mg, 101.08 pmol) and K2CO3 (419.49 mg, 3.04 mmol). The mixture was stirred at 90 °C for 3 h under N2 atmosphere. LCMS showed that desired mass was detected. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give a residue, which was purified by Flash column (Petroleum ether / EtOAc = 1 / 0 to 4 / 1) to give tert-butyl 4- ((3 -chi orothieno[2, 3 -b]pyrazin-6-yl)methylene)piperi dine- 1 -carboxylate (237 mg, 647.76 pmol, 64.02% yield) as a yellow solid. LCMS: ([M+H-t-Bu] = 309.8) ' H NMR: (400 MHz, CDCl3) 8 ppm: 8.56 (s, 1H), 7.24 (s, 1H), 6.50 (s, 1H), 3.52-3.58 (m, 4H), 2.71 (br t, J=5.6 Hz, 2H), 2.43 (br t, .7=5,7 Hz, 2H), 1.50 (s, 9H).

[0692] To a solution of tert-butyl 4-((3-chlorothieno[2,3-b]pyrazin-6-yl)methylene)piperidine-l- carboxylate (227 mg, 620.43 pmol) in Dioxane (8 mL) and H2O (1.6 mL) was added 2,8- dimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-b]pyridazine (169.46 mg, 620.43 pmol), Pd(dppf)C12 (45.40 mg, 62.04 pmol) and K2CO3 (257.24 mg, 1.86 mmol). The mixture was stirred at 90 °C for 3 h under N2 atmosphere. LCMS showed that desired mass was detected. The mixture was concentrated to give a residue, which was purified by Flash column (Petroleum ether / EtOAc = 1 / 0 to 3 / 2) to give tert-butyl 4-((3-(2,8- dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)methylene)piperidine-l- carboxylate (256 mg, 537.15 pmol, 86.58% yield) as a yellow solid. LCMS: ([M+H] = 477.2) 'H NMR: (400 MHz, CDCh) 6 ppm: 9.59 (s, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 7.33 (s, 1H), 6.57 (s, 1H), 3.57 (q, J=6.0 Hz, 4H), 2.78 (br s, 5H), 2.58 (s, 3H), 2.44-2.48 (m, 2H), 1.51 (s, 9H).

[0693] To a solution of tert-butyl 4-((3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3- b]pyrazin-6-yl)methylene)piperidine-l -carboxylate (246 mg, 516.16 umol) in THF (10 mL) was added Pd / C (54.93 mg, 51.62 pmol, 10% purity) under N2. The mixture was degassed under vacuum and purged with H2 several times. Then the mixture was stirred under H2 (15 Psi) at 50 °C for 12 h. LCMS showed the desired mass was observed. The catalyst Pd / C was removed by filtration and the filter was concentrated to give a residue, which was purified by Flash column (Petroleum ether / EtOAc = 1 / 0 to 3 / 2) to give tert-butyl 4-((3-(2,8- dimethylimidazof 1 ,2-b]pyridazin-6-yl)thieno[2,3 -b]pyrazin-6-yl)methyl)piperidine- 1 - carboxylate (110 mg, 229.83 pmol, 44.53% yield) as a yellow solid. LCMS: ([M+H] = 478.9) ‘HNMR: (400 MHz, CDCh) 8 ppm: 9.58 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H), 4.08- 4.22 (m, 2H), 2.95-2.96 (m, 2H), 2.75 (s, 3H), 2.69-2.73 (m, 2H), 2.56 (s, 3H), 1.87-1.93 (m, 1H), 1.78 (br d, J=12.8 Hz, 2H), 1.47 (s, 9H), 1.24-1.32 (m, 2H).

[0694] To a solution of tert-butyl 4-((3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3- b]pyrazin-6-yl)methyl)piperidine-l -carboxylate (100 mg, 208.94 pmol) in DCM (5 mL) was added HCl / di oxane (2 M, 5.22 mL). The mixture was stirred at 25 °C for 12 h. LCMS showed that the starting material was consumed. The mixture was concentrated and purified by prep- HPLC (Column: Boston Green ODS 150*30mm*5um; Condition: water (FA)-ACN; Begin B: 13; End B: 43; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL / min): 25) to give 3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)-6-(piperidin-4-ylmethyl)thieno[2,3- b]pyrazine (44 mg, 102.73 pmol, 49.17% yield, 99.12% purity, Formic acid) as a creamy-white solid.

[0695] LCMS: ([M+H] = 379.1). HPLC: (Purity: 99.13%) 'H NMR: (500 MHz, DMSO-tL) 6 ppm: 9.49 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H), 3.10-3.13 (m, 2H), 2.99-3.01 (m, 2H), 2.68 (br s, 2H), 2.65 (s, 3H), 2.43 (s, 3H), 1.91-1.96 (m, 1H), 1.74-1.80 (m, 2H), 1.27- 1.37 (m, 2H).

[0696] Example 43- Compound 134

[0697]

[0698] TMP (344.85 mg, 2.44 mmol, 412.01 pL) in THF (10 mL) was added n-BuLi (2.5 M, 2.44 mmol, 976.55 pL) at -78 °C under N2. Then the reaction mixture was stirred at -78 °C for 10 min. Subsequently, bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methane (713.67 mg, 2.66 mmol) in THF (3 mL) was added dropwise, the reaction mixture was stirred at -78 °C for 15 min. Then, tert-butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate (500 mg, 2.22 mmol) in THF (3 mL) was added dropwise, the reaction mixture was stirred at -78 °C for 20 min. LCMS showed desired MS was detected. The reaction mixture was quenched with added water (60 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4 and concentrated to give tert-butyl (Z)-7- ((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene)-4-azaspiro[2.5]octane-4- carboxylate (700 mg, crude) as a colourless oil, which was used in next step without further purification. LCMS: ([M+H] = 293.9)

[0699] To a solution of tert-butyl (Z)-7-((4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene)-4- azaspiro[2.5]octane-4-carboxylate (700 mg, 2.00 mmol) and 3-chloro-6-iodothieno[2,3- b]pyrazine (594.27 mg, 2.00 mmol) in Dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)C12 (146.65 mg, 200.42 pmol) and K2CO3 (553.98 mg, 4.01 mmol) under N2. The mixture was stirred at 90 °C for 2 h. LCMS showed desired MS was detected. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc in petroleum ether from 0% to 20%, TLC: petroleum ether / EtOAc = 3 / 1, Rf = 0.46) to get tert-butyl (Z)-7-((3-chlorothieno[2,3-b]pyrazin-6-yl)methylene)-4-azaspiro[2.5]octane-4- carboxylate (410 mg, 1.05 mmol, 52.20% yield) as yellow oil LCMS: ([M+H] = 392.0)

[0700] To a solution of tert-butyl (Z)-7-((3-chlorothieno[2,3-b]pyrazin-6-yl)methylene)-4- azaspiro[2.5]octane-4-carboxylate (150 mg, 382.74 pmol) and 2,8-dimethyl-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)imidazo[l,2-b]pyridazine (104.54 mg, 382.74 pmol) in Dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)C12 (28.01 mg, 38.27 pmol) and K2CO3 (158.69 mg, 1.15 mmol) under N2. The mixture was stirred at 90 °C for 2 h. LCMS showed desired MS was detected. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc in petroleum ether from 0% to 50%, TLC: petroleum ether / EtOAc = 1 / 1, Rf= 0.20) to get tert-butyl (Z)-7-((3-(2,8-dimethylimidazo[l,2- b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6-yl)methylene)-4-azaspiro[2.5]octane-4-carboxylate (145 mg, 288.48 pmol, 75.37% yield) as yellow solid. LCMS: ([M+H] = 503.3) 'H NMR: (400 MHz, CDC13) 5 ppm: 9.57 (d, .7=2,4 Hz, 1H), 7.97 (br d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.32 (s, 1H), 6.38-6.64 (m, 1H), 3.54-3.66 (m, 2H), 2.72-2.76 (m, 3H), 2.65 (br d, J=11.6 Hz, 2H), 2.56 (s, 3H), 2.44-2.49 (m, 1H), 2.31 (br s, 1H), 1.50 (s, 9H), 0.90-0.96 (m, 2H), 0.65- 0.72 (m, 2H).

[0701] To a solution of (Z)-7-((3-(2,8-dimethylimidazo[l,2-b]pyridazin-6-yl)thieno[2,3-b]pyrazin-6- y...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: is a single bond or double bond;X1is CR1or N;X2is N or CR2;X3is NR3or S;X4is N or CR2;R1, when present, is H, halo, Ci-ealkyl, or 5- to 10-membered heteroaryl;R2and R3, when present, are each independently selected from a group consisting of H, halo, and Ci-ealkyl;R4is -Ci-3alkylene-(4 -to 12-membered saturated heterocyclyl), -Ci-3alkylene-(4- to 10-membered carbocyclyl), 4- to 10-membered carbocyclyl, or 4 -to 12-membered saturated heterocyclyl; wherein said 4 to 10 membered carbocyclyl and 4 -to 12-membered saturated heterocyclyl represented by R4or in the group -Ci-3alkylene-(4 -to 12-membered saturated heterocyclyl) and -Ci-3alkylene-(4- to 10-membered carbocyclyl) represented by R4are optionally substituted by -NR6R7or -Ci-6alkylene-NR6R7and is further optionally substituted with 1 to 4 R9; whereinR6is H or Ci-ealkyl;R7is H, or Ci-ealkyl; orR6and R7taken together with the nitrogen to which they are attached is 4 -to 12-membered saturated heterocyclyl.R9, for each occurrence, is independently selected from deuterium, halo, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxyCi-ealkyl, Cs-ecycloalkyl, -Ci- ealkylene-Cs-ecycloalkyl, 4- to 6-membered saturated heterocyclyl, or -Ci- ealkylene-(4- to 6-membered saturated heterocyclyl;R5is H, 6- to 10-membered aryl, 4- to 10 -membered heterocyclyl or 5- to 10- membered heteroaryl, wherein said 6- to 10-membered aryl, 4- to 10 -membered heterocyclyl and 5- to 10-membered heteroaryl represented by R5are each optionally substituted by one or more R10; wherein:R10is halo, -CN, -OH, Ci-ealkyl, Cs-ecycloalkyl, 5- or 6-membered heteroaryl, Ci-ehaloalkyl, or Ci-ealkoxy; or two R10together with the intervening atoms together form a 4- to 7-membered heterocyclyl optionally substituted with one or more R10b; wherein said 5- or 6-membered heteroaryl represented by R10is optionally substituted by one or more R10a; wherein R10ais Ci-3alkyl; and R10bis Ci-3alkyl or oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IA):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IB):or a pharmaceutically acceptable salt thereof4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (II), (III), (IV), or (V):

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein:R4is 4- to 6-membered monocyclic carbocyclyl, 4- to 7-membered monocyclic saturated heterocyclyl, -CH2-(4- to 7-membered monocyclic saturated heterocyclyl), 6- to 8- membered bicyclic saturated bridged heterocyclyl, -CH2-(6- to 12-membered bicyclic saturated spiro or fused heterocyclyl) or 6- to 12-membered bicyclic saturated spiro or fused heterocyclyl, wherein said 4- to 6-membered monocyclic carbocyclyl is optionally substituted by -NR6R7or -Ci-6alkylene-NR6R7and is further optionally substituted with 1 to 2 R9; and said 4- to 7-membered monocyclic saturated heterocyclyl, 6- to 8-membered bicyclic saturated bridged heterocyclyl, or 6- to 12-membered bicyclic saturated spiro or fused heterocyclyl is optionally substituted by -NR6R7or -Ci-6alkylene-NR6R7and is further optionally substituted with 1 or 4 R9.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R4is azetidinyl, -Cth-pyrrolidinyl, pyrrolidinyl, -CFh-piperidinyl, piperidinyl, 1- azaspiro[3.3]heptanyl, 4-azaspiro[2.5]octanyl, 2-azaspiro[3.4]octanyl, 3- azabicyclo[3.1.0]hexanyl, 2,6-diazaspiro[3.3]heptanyl, piperazinyl, -CH2-4- azaspiro[2.5]octanyl, 2-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, or 8- azabicyclo[3.2.1]octanyl, each of which is optionally substituted -NR6R7and is further optionally substituted with 1-4 R9.

7. The compound of claim 5 or 6 or a pharmaceutically acceptable salt thereof, wherein R4is selected from a group consisting of:each of which is optionally substituted with -NR6R7or -Ci-3alkylene-NR6R7, and is futher optionally substituted with 1-4 R9.

8. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R4is cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with -NR6R7or -Ci- 3alkylene-NR6R7, and is optionally further substituted with 1 to 2 R9.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R4is selected from a group consisting of, each of which is substituted with -NR6R7or -CH2-NR6R7, and is optionally further substituted with 1 to 2 R9.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R9, for each occurrence, is independently selected from deuterium, halo, Ci-ealkyl, and Cs-ecycloalkyl.

11. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R9, for each occurrence, is independently selected from deuterium, -F, -CH3, - CH2CH3, cyclopropyl, and cyclobutyl.

12. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H, or Ci-3alkyl; R6and R7taken together with the intervening nitrogen to which they are attached form 4 to 6 membered heterocyclyl.

13. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently H or -CH3; R6and R7taken together with the intervening nitrogen to which they are attached form azetidinyl.

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein R5is 5- to 10-membered heteroaryl optionally substituted by one or more R10; and R10is halo, -CN, -OH, Ci-ealkyl, Cs-ecycloalkyl, Ci-ehaloalkyl, or Ci-ealkoxy.

15. The compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein R5is 9-membered bicyclic heteroaryl optionally substituted by one or two R10.

16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein R5is selected from a group consisting of imidazopyridinyl, imidazopyridazinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, triazolopyridazinyl, indazolyl, triazolopyridinyl, benzooxazolyl, oxazolo[5,4-b]pyridinyl, and pyrazolopyridinyl, each of which is optionally substituted by one to three R10.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R5is selected from:each of which is optionally substituted by one to two R10.

18. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein R10for each occurrence is halo, -CN, Ci-3alkyl, Ci-2haloalkyl, or Ci-2alkoxy.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R10for each occurrence is independently selected from -F, -CN, -CH3, -CHF2, and -OCH3.

20. The compound of claim 1, wherein the compound is represented by the following formula:or a pharmaceutically acceptable salt thereof, wherein:R1is H or Ci-ealkyl;R4is C4-6cycloalkyl, 5- or 6-membered monocyclic saturated heterocycyl, 8- to 10- membered saturated bicyclic bridged heterocyclyl, or 6 -to 10-membered saturated bicyclic fused heterocyclyl; wherein: said C4-6cycloalkyl represented by R4is optionally substituted by - NR6R7and is further optionally substituted with 1 to 2 R9; said 5- or 6-membered monocyclic saturated heterocycyl, 8- to 10- membered saturated bicyclic bridged heterocyclyl, or 6 -to 10-membered saturated bicyclic fused heterocyclyl represented by R4is optionally substituted by -NR6R7and is further optionally substituted with 1 to 2 R9; whereinR6is H or Ci-3alkyl;R7is H or Ci-3alkyl;R9is Ci-3alkyl;R5is 9-membered bicyclic heteroaryl containing 2 to 4 ring N atoms, wherein said 9- membered bicyclic heteroaryl represented by R5is optionally substituted by one or two R10; wherein: each R10is independently halo, Ci-3alkyl, or Ci-2haloalkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein: R1is H or Ci-2alkyl;R4is cyclohexyl, piperidinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octanyl, piperazinyl, or 3-azabicyclo[3.1.0]hexanyl, wherein cyclohexyl represented by R4is substituted with - NR6R7, and pyrrolidinyl, piperazinyl, and piperidinyl, 8-azabicyclo[3.2.1]octanyl, and 3- azabicyclo[3.1.0]hexanyl are each optinally substituted with Ci-3alkyl or -NR6R7; whereinR6is H or Ci-2alkyl;R7is H or Ci-2alkyl;R5is triazol opyridazinyl, pyrazolopyrazinyl, pyrrolo[l,2-a]pyrazinyl, indazolyl, imidazopyridinyl, or imidazopyridazinyl, each of which is optionally substituted with one to two substituents independently selected from halo, Ci-3alkyl, and Ci-2haloalkyl.

22. The compound of claim 20 or 21, wherein R1is H.

23. The compound of any one of claims 20-22, wherein R4is represented by the following formula:

24. The compound of any one of claims 20-23, wherein R9is -CH3; R6is H or -CH3; andR7is H or -CH3.

25. The compound of claim 23, wherein R4is represented by the following formula:

26. The compound of any one of claims 20-25, wherein wherein R5is represented by the following formula:

27. The compound of any one of claims 20-26, wherein each R10is independently F, - CH3, or -CHF2.

28. A pharmaceutical composition comprising a compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

29. A method of treating Huntington’s disease (HD) or spinal muscular atrophy (SMA) in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof or a pharmaceutically composition of claim 28.

30. The method of claim 29, wherein the method is for treating HD.

31. The method of claim 29, wherein the method is for treating SMA.

Images