4-aminopyrrolo[2,l-f][l,2,4]triazines and preparation and uses thereof

Abstract

4-Aminopyrrolo[2,l-f][l,2,4]triazine compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of 4-aminopyrrolo[2,l-f][l,2,4]triazine compounds or analogs thereof, in the treatment of disorders characterized by overexpression of DYRK1A (e.g., cancer, Down syndrome, Alzheimer's disease, diabetes, and osteoarthritis).

Description

SMi.089PCT (BTP-002WO) 4-AMINOPYRROLO[2,1-F][1,2,4]TRIAZINES AND PREPARATION AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 5 63 / 642,225, filed May 3, 2024, which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] This disclosure relates to inhibitors of dual-specificity tyrosine phosphorylation-regulated 1A kinase, and compositions comprising the same. More 10 particularly, it concerns the use of a 4-aminopyrrolo[2,1-f][1,2,4]triazine compound or salts or analogs thereof, in the treatment of disorders characterized by the abnormal expression and / or activity of DYRK1A (e.g., cancer, Down syndrome, Alzheimer's disease, diabetes, and osteoarthritis). BACKGROUND 15

[0003] Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2- 4) comprise a family of protein kinases within the CMGC group of the eukaryotic kinome. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine / methionine / folate regulation, body temperature 20 regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and / or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease, and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease, and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 25 deficiency disorder. DYRKs are also involved in diabetes, abnormal folate / methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium) (International Journal of 30 Molecular Sciences (2021), 22(11), 6047). DYRK1A has also been identified as a critical stabilizer of EGFR (Cell Death & Disease (2019), 10, 282) which is a crucial factor contributing to the keratinization, cell hyperproliferation, abnormal differentiation and inflammatory infiltration during the progress of psoriasis. 1SMi.089PCT (BTP-002WO) SUMMARY

[0004] The present disclosure provides methods and reagents, involving contacting a cell with an agent, such as a 4-aminopyrrolo[2,1-f][1,2,4]triazine compound, in a sufficient amount to antagonize DYRK1A activity, e.g., reduced the proliferation of head and 5 neck squamous cell carcinoma, luminal / HER2 breast cancer (Cell (2016), 164(1-2), 293–309) or pancreatic adenocarcinoma, as well as impaired the self-renewal capacity of glioblastoma and compromised ovarian cancer spheroid cell viability (Molecular Cancer Research (2017), 15(4), 371–381).

[0005] The present disclosure also provides methods and reagents, involving 10 contacting a cell with an agent, such as a 4-aminopyrrolo[2,1-f][1,2,4]triazine compound, in a sufficient amount to antagonize DYRK1A activity, e.g., i) to normalize prenatal and early postnatal brain development; ii) to improve cognitive function in youth and adulthood; and / or iii) to attenuate Alzheimer’s-type neurodegeneration.

[0006] Some embodiments disclosed herein include DYRK1A inhibitors 15 containing a 4-aminopyrrolo[2,1-f][1,2,4]triazine core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.

[0007] One embodiment disclosed herein includes a compound having the structure of Formula I:20 I or a pharmaceutically acceptable salt thereof, wherein, A1, A2, A3, A4, and A5are independently selected from the group consisting of carbon and nitrogen with the proviso that at least two of A1, A2, A3, A4, and A5are nitrogen; 25 if A1and A3are both nitrogen then R2bis absent; if A1and A4are both nitrogen then R3is absent; if A1and A5are both nitrogen then R2ais absent; if A1, A3, and A4are all nitrogen then R2band R3are absent; if A1, A4, and A5are all nitrogen then R2aand R3are absent; if A1, A3, and A5are all nitrogen then R2aand R2bare absent; if A1, A3, A4, and A5are all nitrogen then R2a, R2b, and R3are all absent; if A2and A3are both nitrogen then R2bis absent; if A2and 30 A4are both nitrogen then R3is absent; if A2and A5are both nitrogen then R2ais absent; if A2,SMi.089PCT (BTP-002WO) A3, and A4are all nitrogen then R2band R3are absent; if A2, A4, and A5are all nitrogen then R2aand R3are absent; if A2, A3, and A5are all nitrogen then R2aand R2bare absent; if A2, A3, A4, and A5are all nitrogen then R2a, R2b, and R3are all absent; R1is selected from the group consisting of H and halide; 5 R2ais selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), and unsubstituted –(C1-9haloalkyl); R2bis selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), unsubstituted –(C1-9haloalkyl), and – C(=O)N(R6)2; 10 R3is selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), and unsubstituted –(C1-9haloalkyl); R4is selected from the group consisting of H, unsubstituted –(C1-6 alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), unsubstituted –(C1-6haloalkyl), and –carbocyclyl optionally substituted with 1-10 R7; 15 R5is selected from the group consisting of –heterocyclyl optionally substituted with 1- 10 R8and –carbocyclyl optionally substituted with 1-12 R9; each R6is independently selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9 alkenyl), and unsubstituted –(C2-9 alkynyl); each R7is halide; 20 each R8is independently selected from the group consisting of halide, unsubstituted – (C1-9 alkyl), unsubstituted –(C2-9 alkenyl), unsubstituted –(C2-9 alkynyl), unsubstituted –(C1-9 haloalkyl), –heterocyclyl optionally substituted with 1-10 R10, –(C1-5alkylene)OR11, –SO2R12, and –C(=O)R13, wherein the –(C1-5alkylene) is optionally substituted with 1-5 halide and / or 1- 3 unsubstituted –(C1-3alkyl); 25 each R9is independently selected from the group consisting of halide, unsubstituted – (C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), unsubstituted –(C1-9haloalkyl), –OR14, and –NR15C(=O)R16; each R10is halide; R11is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted 30 –(C2-6 alkenyl), unsubstituted –(C2-6 alkynyl), and unsubstituted –(C1-6 haloalkyl); R12is selected from the group consisting of unsubstituted –(C1-6alkyl), unsubstituted – (C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); R13is selected from the group consisting of unsubstituted –(C1-6alkyl), unsubstituted – (C2-6alkenyl), unsubstituted –(C2-6alkynyl), unsubstituted –(C1-6haloalkyl), and –(C1-535 alkylene)OR17, wherein the –(C1-5alkylene) is optionally substituted with 1-5 halide and / or 1- 3 unsubstituted –(C1-3alkyl);SMi.089PCT (BTP-002WO) R14is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl), and –(C1-5alkylene)OR18, wherein the –(C1-5alkylene) is optionally substituted with 1-5 halide and / or 1- 3 unsubstituted –(C1-3alkyl); 5 R15is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); R16is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); R17is selected from the group consisting of H, unsubstituted –(C1-6 alkyl), unsubstituted 10 –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); R18is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6 alkenyl), unsubstituted –(C2-6 alkynyl), and unsubstituted –(C1-6 haloalkyl); and wherein each H atom is optionally, independently replaced by2H (D) (deuterium).

[0008] Some embodiments include stereoisomers and pharmaceutically 15 acceptable salts of a compound of Formula (I). Some embodiments include pharmaceutically acceptable salts of a compound of Formula (I).

[0009] Some embodiments include pro-drugs of a compound of Formula (I).

[0010] Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, 20 diluent, or excipient.

[0011] Other embodiments disclosed herein include methods of inhibiting DYRK1A by administering to a patient affected by a disorder or disease in which DYRK1A overexpression is implicated, such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, CDKL5 Deficiency Disorder, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 25 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick’s Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor and Stroke.

[0012] Inhibitors of DYRK1A can also be used to treat tauopathies. Tauopathies 30 are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The spectrum of tau pathologies expands beyond the traditionally discussed disease forms like Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. Emerging entities and pathologies include globular glial tauopathies, primary age-related tauopathy, which includes neurofibrillary tangle dementia, chronic 35 traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and aging-related tau astrogliopathy. Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson syndrome, parkinsonism, pure akinesia with gaitSMi.089PCT (BTP-002WO) freezing and, rarely, motor neuron symptoms or cerebellar ataxia (Handbook of Clinical Neurology (2018), 145, 355-368 and Aging Cell (2019), 18(5), e13000).

[0013] Inhibitors of DYRK1A can also be used to treat disorders associated with abnormal folate / methionine metabolism. 5

[0014] Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetes, psoriasis, knee osteoarthritis, tendinopathy, human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), hepatitis C virus (HCV), and herpes simplex virus 1 (HSV-1).

[0015] Some embodiments of the present disclosure include methods to prepare 10 compounds of Formula (I).

[0016] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed. DETAILED DESCRIPTION 15

[0017] Provided herein are compositions and methods for inhibiting DYRK1A.

[0018] Some embodiments provided herein relate to a method for treating a disease including, but not limited to, neurological diseases or disorders, cancers, cognitive deficits, knee osteoarthritis, tendinopathy, viral infections, unicellular parasite infections, and motor deficits. 20

[0019] In some embodiments, non-limiting examples of a neurological disease or disorder which can be treated with the compounds and compositions provided herein include, but are not limited to, Alzheimer’s disease, amyotrophic lateral sclerosis, Down Syndrome, frontotemporal dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease tauopathies, and additional diseases with pronounced neurodegeneration 25 such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.

[0020] In some embodiments, non-limiting examples of cancers which can be treated with the compounds and compositions provided herein include solid cancers (e.g., 30 glioblastoma, ovarian, breast, and pancreatic cancers) and leukemias (e.g., acute lymphoblastic leukemia, acute megakaryoblastic leukemia, and chronic myeloid leukemia).

[0021] In some embodiments, pharmaceutical compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by DYRK1A overexpression. The composition includes a pharmaceutically acceptable carrier and a 35 compound as described herein.SMi.089PCT (BTP-002WO) Definitions

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications 5 are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0023] As used herein, “alkyl” means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can 10 either be unsubstituted or substituted with one or more substituents. In some embodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0024] As used herein, “alkenyl” means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double 15 bond, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In various embodiments, alkenyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0025] As used herein, “alkynyl” means a straight or branched chain chemical 20 group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, and the like. In various embodiments, alkynyl groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms). 25

[0026] As used herein, “alkylene” means a bivalent branched or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n- propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene. Alkylene groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, alkylene groups include 1 30 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0027] As used herein, “alkenylene” means a bivalent branched or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1- 35 butenylene, 2-butenylene, and the like. In various embodiments, alkenylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkenylene groups willSMi.089PCT (BTP-002WO) comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0028] As used herein, “alkynylene” means a bivalent branched or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon 5 triple bond, such as ethynylene, 1-propynylene, 1-butynylene, 2-butynylene, and the like. In various embodiments, alkynylene groups can either be unsubstituted or substituted with one or more substituents. Typically, alkynylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0029] As used herein, “alkoxy” means an alkyl-O— group in which the alkyl10 group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear or branched positional isomers thereof.

[0030] As used herein, “haloalkoxy” means a haloalkyl-O— group in which the haloalkyl group is as described herein. Exemplary haloalkoxy groups include fluoromethoxy, 15 difluoromethoxy, trifluoromethoxy, and also the linear or branched positional isomers thereof.

[0031] As used herein, “carbocyclyl” means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that none of the rings in the ring system are 20 aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

[0032] As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, 25 or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic. Aryl groups can either be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3- dihydro-1H-indenyl, and others. In some embodiments, the aryl is phenyl.

[0033] As used herein, the term “heteroaryl” means a mono-, bi-, tri- or polycyclic 30 group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, 35 oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl,SMi.089PCT (BTP-002WO) isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4- b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3- 5 dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0034] As used herein, “halo”, “halide” or “halogen” is a chloro, bromo, fluoro, or iodo atom radical. In some embodiments, a halo is a chloro, bromo or fluoro. For example, 10 a halide can be fluoro.

[0035] As used herein, “haloalkyl” means a hydrocarbon substituent, which is a linear or branched alkyl, alkenyl or alkynyl substituted with one or more chloro, bromo, fluoro, and / or iodo atom(s). In some embodiments, a haloalkyl is a fluoroalkyl, wherein one or more of the hydrogen atoms have been substituted by fluoro. In some embodiments, haloalkyls are 1 15 to 3 carbons in length (e.g., 1 to 2 carbons in length or 1 carbon in length). The term “haloalkylene” means a diradical variant of haloalkyl, and such diradicals may act as spacers between radicals, other atoms, or between a ring and another functional group.

[0036] As used herein, “heterocyclyl” means a nonaromatic cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include 20 multiple fused rings such as bicyclic and spirocyclic heterocyclyls. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 3-11 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N and S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, and S. Examples of heterocyclyl include 3- 25 azabicyclo[3.2.1]octane, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonane, azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,4-dioxaspirodecanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, octahydrocyclopenta[c]pyrrolyl, oxazinyl, 1- oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, thiazinyl, thiinyl, thiazolidinyl, 30 isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others. In some embodiments, the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

[0037] As used herein, “monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Heterocyclyls may 35 be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 3-7 members. In six membered monocyclic heterocycles, the heteroatom(s) are selected from one to three of O, N and S, and wherein when the heterocycle is fiveSMi.089PCT (BTP-002WO) membered, it can have one or two heteroatoms selected from O, N, and S. Examples of monocyclic heterocyclyls include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2- dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, 5 oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.

[0038] As used herein, “bicyclic heterocyclyl” means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone. Bicyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, 10 bicyclic heterocycles have 4-11 members with the heteroatom(s) being selected from one to five of O, N and S. Examples of bicyclic heterocyclyls include 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- 15 azabicyclo[4.2.0]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, and the like.

[0039] As used herein, “spirocyclic heterocyclyl” means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone and with the rings connected through just one atom. Spirocyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, spirocyclic heterocycles have 5-11 20 members with the heteroatom(s) being selected from one to five of O, N and S. Examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, and the like.

[0040] The term “substituted” refers to moieties having substituents replacing a 25 hydrogen on one or more non-hydrogen atoms of the molecule. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Substituents can30 include, for example, –(C1-9 alkyl) optionally substituted with one or more of hydroxyl, -NH2, - NH(C1-3alkyl), and –N(C1-3alkyl)2; -(C1-9haloalkyl); a halide; a hydroxyl; a carbonyl [such as -C(O)OR, and -C(O)R]; a thiocarbonyl [such as -C(S)OR, -C(O)SR, and -C(S)R]; –(C1-9alkoxy) optionally substituted with one or more of halide, hydroxyl, -NH2, -NH(C1-3alkyl), and –N(C1-3alkyl)2; -OPO(OH)2; a phosphonate [such as -PO(OH)2and -PO(OR’)2]; -35 OPO(OR’)R”; -NRR’; -C(O)NRR’; -C(NR)NR’R”; -C(NR’)R”; a cyano; a nitro; an azido; - SH; -S-R; -OSO2(OR); a sulfonate [such as -SO2(OH) and -SO2(OR)]; -SO2NR’R”; and -SO2R; in which each occurrence of R, R’ and R” are independently selected from H; –(C1-9alkyl); C6-SMi.089PCT (BTP-002WO) 10aryl optionally substituted with 1-3 R’’’; 5-10 membered heteroaryl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R’’’; C3-7carbocyclyl optionally substituted with 1-3 R’’’; and 3-8 membered heterocyclyl having from 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with 5 1-3 R’’’; wherein each R’’’ is independently selected from –(C1-6alkyl), –(C1-6haloalkyl), a halide (e.g., F), a hydroxyl, -C(O)OR, -C(O)R, –(C1-6alkoxyl), -NRR’, -C(O)NRR’, and a cyano, in which each occurrence of R and R’ is independently selected from H and –(C1-6alkyl). In some embodiments, the substituent is selected from –(C1-6alkyl), -(C1-6haloalkyl), a halide (e.g., F), a hydroxyl, -C(O)OR, -C(O)R, –(C1-6 alkoxyl), -NRR’, -C(O)NRR’, and a cyano, in 10 which each occurrence of R and R’ is independently selected from H and –(C1-6alkyl).

[0041] As used herein, when two groups are indicated to be “linked” or “bonded” to form a “ring”, it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. The skilled artisan will recognize that such 15 rings can and are readily formed by routine chemical reactions. In some embodiments, such rings have from 3-7 members, for example, 5 or 6 members.

[0042] The skilled artisan will recognize that some chemical structures described herein may be represented on paper by one or more other resonance forms; or may exist in one or more other tautomeric forms, even when kinetically, the artisan recognizes that such 20 tautomeric forms represent only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this disclosure, though such resonance forms or tautomers are not explicitly represented herein.

[0043] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures 25 of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure 30 without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0044] The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic 35 mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include, but are not limited to, isotopes of hydrogen, such as2H (deuterium) and3H (tritium), isotopes of carbon, such as11C,13C and14C, isotopes ofSMi.089PCT (BTP-002WO) chlorine, such as36Cl, isotopes of fluorine, such as18F, isotopes of iodine, such as123I and125I, isotopes of nitrogen, such as13N and15N, isotopes of oxygen, such as15O,17O and18O, isotopes of phosphorus, such as32P, and isotopes of sulfur, such as35S.

[0045] The term “administration” or “administering” refers to a method of 5 providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method of administration is, e.g., orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye 10 chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, 15 intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic device. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease. 20

[0046] A “diagnostic” as used herein is a compound, method, system, or device that assists in the identification or characterization of a health or disease state. The diagnostic can be used in standard assays as is known in the art.

[0047] The term “mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, 25 goats, and non-human primates, but also includes many other species.

[0048] The terms “pharmaceutically acceptable carrier”, “pharmaceutically acceptable diluent” and “pharmaceutically acceptable excipient” include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable. The use of such media 30 and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck 35 Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Brunton et al. (Eds.) (2017);SMi.089PCT (BTP-002WO) Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 13th Ed., The McGraw- Hill Companies.

[0049] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not 5 biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Many such salts are known in the art, for example, as described in WO 87 / 05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, 10 hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically 15 acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, 20 substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0050] “Patient” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate, or a bird, e.g., a 25 chicken, as well as any other vertebrate or invertebrate. In some embodiments, the patient is a human.

[0051] A “therapeutically effective amount” of a compound as provided herein is one which is sufficient to achieve the desired physiological effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. 30 “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula I in combination with one or more other agents that are effective to treat the diseases and / or conditions described herein. The combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the compounds when administered in 35 combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may beSMi.089PCT (BTP-002WO) employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient’s height, weight, sex, age, and medical history.

[0052] A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease. 5

[0053] “Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing, or 10 preventing the further development of a disorder, and / or reducing the severity of symptoms that will or are expected to develop.

[0054] “Drug-eluting” and / or controlled release as used herein refers to any and all mechanisms, e.g., diffusion, migration, permeation, and / or desorption by which the drug(s) incorporated in the drug-eluting material pass therefrom over time into the surrounding body 15 tissue.

[0055] “Drug-eluting material” and / or controlled release material as used herein refers to any natural, synthetic, or semi-synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time. 20

[0056] “Elutable drug” as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body. Compounds 25

[0057] The compounds and compositions described herein can be used to inhibit DYRK1A for treating a disorder or disease in which DYRK1A overexpression is implicated, such as in neurological diseases or disorders, cancers, cognitive deficits, knee osteoarthritis, tendinopathy, viral infections, unicellular parasite infections, and motor deficits.

[0058] Some embodiments of the present disclosure include compounds of 30 Formula I:SMi.089PCT (BTP-002WO)I or salts, pharmaceutically acceptable salts, or prodrugs thereof.

[0059] In some embodiments of Formula I, A1, A2, A3, A4, and A5are 5 independently selected from the group consisting of carbon and nitrogen.

[0060] In some embodiments of Formula I, there is the proviso that at least two of A1, A2, A3, A4, and A5are nitrogen.

[0061] In some embodiments of Formula I, if A1and A3are both nitrogen then R2bis absent; in some embodiments of Formula I, if A1and A4are both nitrogen then R3is 10 absent; in some embodiments of Formula I, if A1and A5are both nitrogen then R2ais absent; in some embodiments of Formula I, if A1, A3, and A4are all nitrogen then R2band R3are absent; in some embodiments of Formula I, if A1, A4, and A5are all nitrogen then R2aand R3are absent; in some embodiments of Formula I, if A1, A3, and A5are all nitrogen then R2aand R2bare absent; in some embodiments of Formula I, if A1, A3, A4, and A5are all nitrogen then R2a, R2b, 15 and R3are all absent; in some embodiments of Formula I, if A2and A3are both nitrogen then R2bis absent; in some embodiments of Formula I, if A2and A4are both nitrogen then R3is absent; in some embodiments of Formula I, if A2and A5are both nitrogen then R2ais absent; in some embodiments of Formula I, if A2, A3, and A4are all nitrogen then R2band R3are absent; in some embodiments of Formula I, if A2, A4, and A5are all nitrogen then R2aand R3are absent; 20 in some embodiments of Formula I, if A2, A3, and A5are all nitrogen then R2aand R2bare absent; and in some embodiments of Formula I, if A2, A3, A4, and A5are all nitrogen then R2a, R2b, and R3are all absent.

[0062] In some embodiments of Formula I, A1and A3are nitrogen, and A2, A4, and A5are carbon; in some embodiments of Formula I, A1and A4are nitrogen, and A2, A3, and 25 A5are carbon; in some embodiments of Formula I, A1and A5are nitrogen, and A2, A3, and A4are carbon; in some embodiments of Formula I, A1, A3, and A4are nitrogen, and A2and A5are carbon; in some embodiments of Formula I, A1, A4, and A5are nitrogen, and A2and A3are carbon; in some embodiments of Formula I, A1, A3, and A5are nitrogen, and A2and A4are carbon; and in some embodiments of Formula I, A1, A3, A4, and A5are nitrogen, and A2is 30 carbon.SMi.089PCT (BTP-002WO)

[0063] In some embodiments of Formula I, A2and A3are nitrogen, and A1, A4, and A5are carbon; in some embodiments of Formula I, A2and A4are nitrogen, and A1, A3, and A5are carbon; in some embodiments of Formula I, A2and A5are nitrogen, and A1, A3, and A4are carbon; in some embodiments of Formula I, A2, A3, and A4are nitrogen, and A1and A5are 5 carbon; in some embodiments of Formula I, A2, A4, and A5are nitrogen, and A1and A3are carbon; in some embodiments of Formula I, A2, A3, and A5are nitrogen, and A1and A4are carbon; and in some embodiments of Formula I, A2, A3, A4, and A5are nitrogen, and A1is carbon.

[0064] In some embodiments of Formula I, A3and A4are nitrogen, and A1, A2, 10 and A5are carbon; in some embodiments of Formula I, A3and A5are nitrogen, and A1, A2, and A4are carbon; in some embodiments of Formula I, A4and A5are nitrogen, and A1, A2, and A3are carbon; and in some embodiments of Formula I, A3, A4, and A5are nitrogen, and A1and A2are carbon.

[0065] In some embodiments of Formula15SMi.089PCT (BTP-002WO)5 selected from the group consisting of H, unsubstituted –(C1-5 alkyl), and unsubstituted –(C1-5 haloalkyl); R2bis selected from the group consisting of H, unsubstituted –(C1-5alkyl), unsubstituted –(C1-5haloalkyl), and –C(=O)NHR6.

[0067] In some embodiments of Formulaselected from the 10SMi.089PCT (BTP-002WO)selected from the group consisting of H and Me; and R2bis selected from the group consisting of unsubstituted –(C1-5alkyl), unsubstituted –(C1-5fluoroalkyl), and –C(=O)NHMe.is H; R3is selected from the group consisting of H and Me; and R2bis selected from the group consisting of unsubstituted –(C1-5alkyl), unsubstituted –(C1-5fluoroalkyl), and –C(=O)NHMe.SMi.089PCT (BTP-002WO)

[0070] In some embodiments of Formula I, R1is selected from the group consisting of H and halide (e.g., F, Cl, Br, I).

[0071] In some embodiments of Formula I, R1is selected from the group consisting of H and F; in some embodiments of Formula I, R1is selected from the group 5 consisting of H, F, and Cl; in some embodiments of Formula I, R1is H; in some embodiments of Formula I, R1is F; in some embodiments of Formula I, R1is Cl; in some embodiments of Formula I, R1is Br; in some embodiments of Formula I, R1is I.

[0072] In some embodiments of Formula I, R2ais selected from the group consisting of H, unsubstituted –(C1-9 alkyl), unsubstituted –(C2-9 alkenyl), unsubstituted –(C2-9 10 alkynyl), and unsubstituted –(C1-9haloalkyl).

[0073] In some embodiments of Formula I, R2ais selected from the group consisting of H, unsubstituted –(C1-5 alkyl), and unsubstituted –(C1-5 haloalkyl).

[0074] In some embodiments of Formula I, R2ais selected from the group consisting of H, unsubstituted –(C1-5alkyl), and unsubstituted –(C1-5fluoroalkyl). 15

[0075] In some embodiments of Formula I, R2ais H.

[0076] In some embodiments of Formula I, R2bis selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), unsubstituted –(C1-9 haloalkyl), and –C(=O)N(R6)2.

[0077] In some embodiments of Formula I, R2bis selected from the group 20 consisting of H, unsubstituted –(C1-5alkyl), unsubstituted –(C1-5haloalkyl), and –C(=O)NHR6.

[0078] In some embodiments of Formula I, R2bis selected from the group consisting of H, unsubstituted –(C1-3alkyl), unsubstituted –(C1-3fluoroalkyl), and – C(=O)NH(C1-3alkyl).

[0079] In some embodiments of Formula I, R2bis selected from the group 25 consisting of unsubstituted –(C1-3alkyl), unsubstituted –(C1-3fluoroalkyl), and –C(=O)NHMe.

[0080] In some embodiments of Formula I, R3is selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), and unsubstituted –(C1-9haloalkyl).

[0081] In some embodiments of Formula I, R3is selected from the group 30 consisting of H, unsubstituted –(C1-5 alkyl), and unsubstituted –(C1-5 haloalkyl).

[0082] In some embodiments of Formula I, R3is selected from the group consisting of H, unsubstituted –(C1-3alkyl), and unsubstituted –(C1-3fluoroalkyl).

[0083] In some embodiments of Formula I, R3is selected from the group consisting of H and Me. 35

[0084] In some embodiments of Formula I, R4is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6SMi.089PCT (BTP-002WO) alkynyl), unsubstituted –(C1-6haloalkyl), and –carbocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R7.

[0085] In some embodiments of Formula I, R4is selected from the group consisting of H, unsubstituted –(C1-3alkyl), unsubstituted –(C1-3haloalkyl), and –carbocyclyl 5 optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) fluorines.

[0086] In some embodiments of Formula I, R4is selected from the group consisting of H, unsubstituted –(C1-3alkyl), unsubstituted –(C1-3fluoroalkyl), and unsubstituted –(3-6 membered carbocyclyl).

[0087] In some embodiments of Formula I, R4is selected from the group 10 consisting of H and unsubstituted –(C1-3alkyl).

[0088] In some embodiments of Formula I, R4is unsubstituted –(C1-3alkyl).

[0089] In some embodiments of Formula I, R4is Me.

[0090] In some embodiments of Formula I, R4is H.

[0091] In some embodiments of Formula I, R5is selected from the group 15 consisting of –heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R5, and –carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1- 7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R6.

[0092] In some embodiments of Formula I, R5is selected from the group consisting of –heterocyclyl optionally substituted with 1-4 (e.g., 2-4, 1-3, 2-3, 3-4, 1-2, 1) R8, 20 and –carbocyclyl optionally substituted with 1-4 (e.g., 2-4, 1-3, 2-3, 3-4, 1-2, 1) R9.

[0093] In some embodiments of Formula I, R5is –carbocyclyl optionally substituted with 1-3 R9, wherein the carbocyclyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0094] In some embodiments of Formula I, R5is –carbocyclyl optionally 25 substituted with 1-3 R9, wherein the carbocyclyl is selected from the group consisting of cyclobutyl and cyclohexyl.

[0095] In some embodiments of Formula I, R5is selected from the group 30SMi.089PCT (BTP-002WO)

[0096] In some embodiments of Formula I, R5is selected from the group consisting of:, wherein each R9is independently selected from the group consisting of F, Me, – , and –OCH2CH2OH.7] In some embodiments of Formula I, R5is –heterocyclyl optionally substituted with 1-3 R8, wherein the heterocyclyl is selected from the group consisting of 3- azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.1]octane, 7-azaspiro[3.5]nonane, 2- azaspiro[3.5]nonane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 3-oxabicyclo[3.1.0]hexane, 1-oxaspiro[3.5]nonane, and oxaspiro[3.3]heptanyl.

[0098] In some embodiments of Formula I, R5is selected from the groupindependently selected from the group consisting of F, Me, Et, iPr, iBu, –CH2F, –CHF2, –CF3,SMi.089PCT (BTP-002WO) –CH2OH, –CH2OMe, –OH, –OMe, –OEt, –OCD3, –OCF3, –CH2CH2F, –CH2CHF2, –CH2CF3, CH2OH, –C(=O)Me, –C(=O)Et, –C(=O)iPr, –ith the proviso that F, –OH, –OMe, –OEt, –OCD3, and –OCF3are not attached to N. 5

[0099] In some embodiments of Formula I, R5is selected from the groupwherein each R8is independently selected from the group consisting of F, Me, –CH2CH2F, –the proviso that F is 10 not attached to N.

[0100] In some embodiments of Formula I, R5is selected from the groupeach R8is selected from the group consisting of Me, –C(=O)Me, –C(=O)CH2OH, –SO2Me, and . 15

[0101] In some embodiments of Formula I, each R6is independently selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9alkenyl), and unsubstituted –(C2-9 alkynyl).

[0102] In some embodiments of Formula I, each R6is independently selected from the group consisting of H and unsubstituted –(C1-5alkyl). 20

[0103] In some embodiments of Formula I, each R6is independently selected from the group consisting of H and Me.

[0104] In some embodiments of Formula I, each R7is halide (e.g., F, Cl, Br, I).

[0105] In some embodiments of Formula I, each R7is F.

[0106] In some embodiments of Formula I, each R8is independently selected from25 the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted –(C1-9alkyl), unsubstituted –(C2-9 alkenyl), unsubstituted –(C2-9 alkynyl), unsubstituted –(C1-9 haloalkyl), –heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R10, –(C1-5alkylene)OR11, –SO2R12, and –C(=O)R13, wherein the –(C1-5alkylene) is optionally substituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) halide (e.g., F, Cl, Br, I) and / or 1-3 (e.g., 1-2, 1) unsubstituted 30 –(C1-3alkyl).SMi.089PCT (BTP-002WO)

[0107] In some embodiments of Formula I, each R8is independently selected from the group consisting of halide, unsubstituted –(C1-5alkyl), unsubstituted –(C1-5haloalkyl), –(3- 6 membered heterocyclyl) optionally substituted with 1-3 R10, –(C1-3alkylene)OR11, –SO2R12, and –C(=O)R13, wherein the –(C1-3alkylene) is unsubstituted. 5

[0108] In some embodiments of Formula I, each R8is independently selected from the group consisting of F, unsubstituted –(C1-5alkyl), unsubstituted –(C1-5fluoroalkyl), unsubstituted –(3-4 membered heterocyclyl), –CH2CH2OR11, –SO2Me, and –C(=O)Me.

[0109] In some embodiments of Formula I, each R9is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted –(C1-9 alkyl), unsubstituted –(C2-109alkenyl), unsubstituted –(C2-9alkynyl), unsubstituted –(C1-9haloalkyl), –OR14, and – NR15C(=O)R16.

[0110] In some embodiments of Formula I, each R9is independently selected from the group consisting of halide, unsubstituted –(C1-5alkyl), unsubstituted –(C1-5haloalkyl), – OR14, and –NHC(=O)R16. 15

[0111] In some embodiments of Formula I, each R9is independently selected from the group consisting of F, unsubstituted –(C1-3alkyl), unsubstituted –(C1-3fluoroalkyl), –OH, – O(C1-3alkylene)OR18, and –NHC(=O)Me.

[0112] In some embodiments of Formula I, each R10is halide (e.g., F, Cl, Br, I).

[0113] In some embodiments of Formula I, each R10is F. 20

[0114] In some embodiments of Formula I, R11is selected from the group consisting of H, unsubstituted –(C1-6 alkyl), unsubstituted –(C2-6 alkenyl), unsubstituted –(C2-6 alkynyl), and unsubstituted –(C1-6haloalkyl).

[0115] In some embodiments of Formula I, R11is selected from the group consisting of H, Me, Et, and CF3. 25

[0116] In some embodiments of Formula I, R12is selected from the group consisting of unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl).

[0117] In some embodiments of Formula I, R12is selected from the group consisting of Me and Et. 30

[0118] In some embodiments of Formula I, R13is selected from the group consisting of unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), unsubstituted –(C1-6haloalkyl), and –(C1-5alkylene)OR17, wherein the –(C1-5alkylene) is optionally substituted with 1-5 halide and / or 1-3 unsubstituted –(C1-3alkyl).

[0119] In some embodiments of Formula I, R13is selected from the group 35 consisting of unsubstituted –(C1-3alkyl) and –CH2OH.

[0120] In some embodiments of Formula I, R14is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6SMi.089PCT (BTP-002WO) alkynyl), and unsubstituted –(C1-6haloalkyl), and –(C1-5alkylene)OR18, wherein the –(C1-5alkylene) is optionally substituted with 1-5 halide and / or 1-3 unsubstituted –(C1-3alkyl).

[0121] In some embodiments of Formula I, R14is selected from the group consisting of H, Me, Et, and –CH2CH2OH. 5

[0122] In some embodiments of Formula I, R15is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl).

[0123] In some embodiments of Formula I, R15is selected from the group consisting of H and Me. 10

[0124] In some embodiments of Formula I, R16is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6 haloalkyl).

[0125] In some embodiments of Formula I, R16is Me.

[0126] In some embodiments of Formula I, R17is selected from the group 15 consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl).

[0127] In some embodiments of Formula I, R17is selected from the group consisting of H and Me.

[0128] In some embodiments of Formula I, R18is selected from the group 20 consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6 haloalkyl).

[0129] In some embodiments of Formula I, R18is selected from the group consisting of H and Me.

[0130] In some embodiments of Formula I, each H atom is optionally, 25 independently replaced by2H (D) (deuterium).

[0131] Illustrative compounds of Formula I are shown in Table 1.SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)29SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)33SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)40SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO) 4 4 4 4Administration and Pharmaceutical Compositions

[0132] Some embodiments include pharmaceutical compositions comprising: (a) 5 a therapeutically effective amount of a compound provided herein, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.

[0133] The compounds provided herein may also be useful in combination (administered together or sequentially) with other known agents. 10

[0134] Non-limiting examples of diseases which can be treated with a combination of a compound of Formula (I) and another active agent are colorectal cancer, ovarian cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, acute lymphoblastic leukemia (ALL), pancreatic cancer, brain tumors, acute megakaryoblastic leukemia (AMKL), and osteoarthritis. For example, a compound of Formula (I) can be 15 combined with one or more chemotherapeutic compounds.

[0135] In some embodiments, hepatocellular carcinoma can be treated with a combination of a compound of Formula (I) and one or more of the following drugs / therapies:SMi.089PCT (BTP-002WO) sorafenib (Nexavar®); regorafenib (Stivarga®, Regonix®), nivolumab (Opdivo®); lenvatinib (Lenvima®); Pembrolizumab (Keytruda®); cabozantinib (Cometriq®, Cabometyx®); 5- fluorouracil (5-FU®); ramucirumab (Cyramza®); combination of gemcitabine and oxaliplatin (GEMOX). Other therapies that can be performed in combination with a compound of Formula 5 (I) are i) transcatheter arterial chemoembolization (TACE) in combination with doxorubicin (DOXIL®), cisplatin, or mitomycin C (Mitosol®, Mutamycin®, Jelmyto®); ii) low-dose brachytherapy.

[0136] In some embodiments, head and neck squamous cell carcinoma can be treated with a combination of a compound of Formula (I) and one or more of the following 10 drugs / therapies: TransOral Robotic Surgery (TORS); TORS with radiation therapy; larotrectinib (Vitrakvi®); EGFR inhibitors, e.g., erlotinib (Tarceva®), osimertinib (Tagrisso®), neratinib (Nerlynx®), gefitinib (Iressa®), cetuximab (Erbitux®), panitumumab (Vectibix®), dacomitinib (Vizimpro®), lapatinib (Tykerb®), necitumumab (Portrazza), and vandetanib (Caprelsa®). 15

[0137] In some embodiments, acute lymphoblastic leukemia (ALL) can be treated with a combination of a compound of Formula (I) and one or more of the following drugs / therapies: remission induction therapy; consolidation therapy; nelarabine (Arranon®); Asparaginase Erwinia Chrysanthemi (Erwinaze®); Asparaginase Erwinia Chrysanthemi (Recombinant)-rywn (Rylaze®); calaspargase Pegol-mknl (Asparlas®); inotuzumab ozogamicin 20 (Besponsa®); blinatumomab (Blincyto®); daunorubicin hydrochloride (Cerubidine®); clofarabine (Clolar®); cyclophosphamide; methotrexate sodium (Trexall®); cytarabine (Cytosar-U®); dasatinib (Sprycel®); dexamethasone; imatinib mesylate (Gleevec®); ponatinib hydrochloride (Iclusig®); mercaptopurine (Purinethol®, Purixan®); tisagenlecleucel (Kymriah®); vincristine sulfate liposome (Marqibo®); pegaspargase (Oncaspar®); prednisone; 25 daunorubicin hydrochloride (Rubidomycin®); and vincristine sulfate.

[0138] In some embodiments, pancreatic cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs / therapies: ablation and embolization treatment; gemcitabine (Gemzar®); 5-fluorouracil (5-FU®); oxaliplatin (Eloxatin®); albumin-bound paclitaxel (Abraxane®); capecitabine (Xeloda®); cisplatin; 30 irinotecan (Camptosar®); liposomal Irinotecan (Onivyde®); paclitaxel (Taxol®), and docetaxel (Taxotere®).

[0139] In some embodiments, brain tumors can be treated with a combination of a compound of Formula (I) and one or more of the following drugs / therapies: carmustine can be administered by way of a gliadel wafer; for glioblastoma and high-grade glioma, radiation 35 therapy with daily low-dose temozolomide (Temodar®) followed by monthly doses of temozolomide after radiation therapy for 6 months to 1 year; lomustine (Gleostine®), procarbazine (Matulane®), and vincristine (Vincasar®), have been used along with radiationSMi.089PCT (BTP-002WO) therapy; anti-angiogenesis therapy with bevacizumab (Avastin®, Mvasi®); and targeted therapy using larotrectinib (Vitrakvi®).

[0140] In some embodiments, acute megakaryoblastic leukemia (AMKL) can be treated with a combination of a compound of Formula (I) and one or more of the following 5 drugs / therapies: cytarabine (Cytosar-U®), etoposide (Vepesid®), and anthracycline drugs. Anthracyclines include daunorubicin (Cerubidine®), idarubicin (Idamycin®), and mitoxantrone (Novantrone®).

[0141] In some embodiments, acute myeloid leukemia (AML) can be treated with a combination of a compound of Formula (I) and one or more of the following drugs / therapies: 10 venetoclax and hypomethylating agents (e.g., decitabine, azacitidine), induction chemotherapy (cytarabine and an anthracycline (e.g., daunorubicin or idarubicin), all-trans-retinoic acid (ATRA) and either arsenic trioxide (ATO) monotherapy or an anthracycline), consolidation therapy (cytarabine).

[0142] In some embodiments, myelodysplastic syndrome (MDS) can be treated 15 with a combination of a compound of Formula (I) and one or more of the following drugs / therapies: 5-azacytidine, decitabine, lenalidomide, and decitabine / cedazuridine (Inqovi®).

[0143] In some embodiments, colorectal cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: 5-Fluorouracil (5-FU), 20 which can be administered with the vitamin-like drug leucovorin (also called folinic acid); capecitabine (XELODA®), irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx 25 (Capecitabine and oxaliplatin). For rectal cancer, chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).

[0144] In some embodiments, ovarian cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (DOXIL®), Gemcitabine (GEMZAR®), Cyclophosphamide (CYTOXAN®), 30 Vinorelbine (NAVELBINE®), Ifosfamide (IFEX®), Etoposide (VP-16), Altretamine (HEXALEN®), Capecitabine (XELODA®), Irinotecan (CPT-11, CAMPTOSAR®), Melphalan, Pemetrexed (ALIMTA®) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE®). Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine, 35 ifosfamide, and cisplatin) and VIP (etoposide [VP-16], ifosfamide, and cisplatin). Ovarian cancer can also be treated with a combination of a compound of Formula (I) and immune checkpoint blockade (ICB) therapy.SMi.089PCT (BTP-002WO)

[0145] In some embodiments, a compound of Formula (I) can be used to treat cancer in combination with any of the following methods: (a) Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) Ablation or embolization procedures such as radiofrequency ablation (RFA), 5 ethanol (alcohol) ablation, microwave thermotherapy and cryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy using anti-metabolites such as azathioprine and mercaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and 10 Vindesine) and taxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposide and docetaxel; (g) Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i) Chemotherapy using 15 tyrosine-kinase inhibitors such as Imatinib mesylate (GLEEVEC®, also known as STI–571), Gefitinib (Iressa, also known as ZD1839), Erlotinib (marketed as TARCEVA®), Bortezomib (VELCADE®) , tamoxifen , tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax, navitoclax (ABT-263), oblimersen (G3139), venetoclax (ABT-199), Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib, Rucaparib, Niraparib, Talazoparib), PI3K inhibitors (e.g. perifosine in a 20 phase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MABTHERA®or RITUXAN®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as ERBITUX®), and 25 Bevacizumab (marketed as AVASTIN®); (k) Chemotherapy using KRAS G12C inhibitors such as sotorasib (Lumakras®and Lumykras®), adagrasib (MRTX849), and ARS-3248 (Wellspring Biosciences); (l) Chemotherapy using checkpoint inhibitor therapy such as Ipilimumab (Yervoy®), Nivolumab (Opdivo®), Pembrolizumab (Keytruda®), Atezolizumab (Tecentriq®), Avelumab (Bavencio), Durvalumab (Imfinzi), Cemiplimab (Libtayo®), and Spartalizumab 30 (PDR001); (m) Chemotherapy using antibody-drug conjugates (ADC) such as Gemtuzumab ozogamicin, Brentuximab vedotin, Trastuzumab emtansine, Inotuzumab ozogamicin, Polatuzumab vedotin, Enfortumab vedotin, Trastuzumab deruxtecan, Sacituzumab govitecan, Belantamab mafodotin, Moxetumomab pasudotox, and Loncastuximab tesirine; (n) Chemotherapy using proteasome inhibitors such as carfilzomib, lactacystin, disulfiram,35 salinosporamide A (marizomib), oprozomib, delanzomib, epoxomicin, MG132, -hydroxy - methylbutyric acid (HMB), bortezomib, ixazomib (alone or in in combination with lenalidomide and dexamethasone); and (o) radiation therapy.SMi.089PCT (BTP-002WO)

[0146] In some embodiments, a compound of Formula I, can be used to treat diabetes mellitus in combination with any of the following methods: (a) injections of insulin; (b) biguanides such as metformin (Glucophage), phenformin (DBI), and buformin; (c) thiazolidinediones (TZDs) such as rosiglitazone (Avandia), pioglitazone (Actos), and 5 yroglitazone (Rezulin); (d) lyn kinase activators such as glimepiride (Amaryl®) and tolimidone (MLR-1023); (e) secretagogues such as sulfonylureas (non-limiting examples are acetohexamide, carbutamide, chlorpropamide, glycyclamide (tolcyclamide), metahexamide, tolazamide, tolbutamide, glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glyclopyramide, and glimepiride) and meglitinides (nonlimiting10 examples are repaglinide (Prandin), nateglinide (Starlix), and mitiglinide (Glufast)); (f) alpha- glucosidase inhibitors such as acarbose (Glucobay, Precose, Prandase), miglitol (Glyset), and voglibose; (g) injectable incretin mimetics such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP), nonlimiting examples of injectable glucagon-like peptide (GLP) analogs and agonists are exenatide (Exendin-4, 15 marketed as Byetta), liraglutide (Victoza, Saxenda), taspoglutide, lixisenatide (Lyxumia), Semaglutide (Ozempic, Rybelsus), dulaglutide (Trulicity), albiglutide (Tanzeum), nonlimiting examples of dipeptidyl peptidase-4 (DPP-4) inhibitors are sitagliptin (Januvia), vildagliptin (Galvus), saxagliptin (Onglyza), linagliptin (Tradjenta), gemigliptin (Zemiglo), anagliptin (Suiny), teneligliptin (Tenelia), alogliptin (Nesina, Vipidia, Kazano, Vipidomet (with 20 metformin), Oseni, Incresync (with pioglitazone)), trelagliptin (Zafatek, Wedica), omarigliptin (MK-3102), evogliptin (Suganon, Evodine), gosogliptin (Saterex), and dutogliptin; (h) injectable amylin analogues such as pramlintide (Symlin); (i) glycosurics (SGLT2 inhibitors) such as canagliflozin (Invokana, Sulisent, Prominad), dapagliflozin (Forxiga, Farxiga, Edistride), empagliflozin (Jardiance, Sciampa-M), ertugliflozin (Steglatro), ipragliflozin 25 (Suglat), luseogliflozin (Lusefi), remogliflozin etabonate (pro-drug of remogliflozin), sergliflozin etabonate (GW869682X), sotagliflozin (Zynquista), and tofogliflozin (CSG452).

[0147] In some embodiments, a compound of Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (d) injections of a Wnt signaling pathway inhibitor (e.g. lorecivivint); (a) Nonsteroidal anti-inflammatory drugs 30 (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine; (f) in combination with braces and / or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices); (g) realigning bones (osteotomy); 35 (h) joint replacement (arthroplasty); and (i) in combination with a chronic pain class.

[0148] In some embodiments, a compound of Formula (I) can be used to treat Alzheimer’s disease in combination with aducanumab (Aduhelm™); acetylcholinesteraseSMi.089PCT (BTP-002WO) inhibitors, e.g., tacrine, rivastigmine (Exelon®), galantamine (Razadyne®and GalantaMind™), and donepezil (Aricept®); and memantine (Axura®, Ebixa®, Namenda®).

[0149] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration, including, but 5 not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro- otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, 10 intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. In some embodiments, the administration method 15 includes oral or parenteral administration.

[0150] Compounds provided herein intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, 20 liquids, suspensions, suppositories, aerosols, implants, controlled release, or the like. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The 25 compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants, and the like, for prolonged and / or timed, pulsed administration at a predetermined rate.

[0151] The compounds can be administered either alone or in combination with a 30 conventional pharmaceutical carrier, excipient, or the like. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- -tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, 35 buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-SMi.089PCT (BTP-002WO) chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as -, β, and -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, 5including 2- and 3-hydroxypropyl- -cyclodextrins, or other solubilized derivatives can also beused to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. The contemplated compositions may contain 0.001%-100% of a compound provided herein, in one embodiment 0.1-95%, in another 10 embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK.2012).

[0152] In one embodiment, the compositions will take the form of a unit dosage 15 form such as a pill or tablet and thus the composition may contain, along with a compound provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable 20 oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated. 25

[0153] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. a compound provided herein and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol, or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension. If desired, the pharmaceutical composition can also contain minor amounts of 30 nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).

[0154] Injectables can be prepared in conventional forms, either as liquid35 solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solidforms suitable for reconstitution in liquid prior to injection. The percentage of a compound provided herein contained in such parenteral compositions is highly dependent on the specificSMi.089PCT (BTP-002WO) nature thereof, as well as the activity of the compound and the needs of the patient. However, percentages of active ingredient of 0.01% to 10% in solution are employable and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages. 5

[0155] It is to be noted that concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration 10 ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0156] In one embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other 15 suitable device or technique.

[0157] In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size may be desired to 20 maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth. For delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 μm are useful (e.g., about 1 to about 10 microns). Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid 25 droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.

[0158] In some embodiments, compounds of Formula (I) disclosed herein 30 intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, as non-aqueous solutions, or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates, or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump 35 systems (like the soft mist inhalers, the Aerodose®or the AERx®systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substanceSMi.089PCT (BTP-002WO) effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.

[0159] In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., 5 U.S. Pat. Nos.6,440,102 and 6,648,873) can be used.

[0160] Alternatively, formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No.6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

[0161] If desired, formulations of the disclosure can be incorporated into a gel 10 formulation (e.g., U.S. Pat. Nos.4,474,752 and 6,911,211).

[0162] In some embodiments, compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to 15 a needle through temporal bone into the cochlea.

[0163] Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments the acidic or basic solid compound of Formula (I) can be delivered from the reservoir of an external or internal 20 implanted pumping system.

[0164] Formulations of the disclosure also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No.6,377,849 and Ser. No.11 / 337,815).

[0165] Intratympanic injection of therapeutic agents is the technique of injecting 25 a therapeutic agent behind the tympanic membrane into the middle and / or inner ear. In one embodiment, the formulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional 30 embodiments, the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.

[0166] In some embodiments, the compounds of Formula (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, 35 jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.SMi.089PCT (BTP-002WO)

[0167] Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing a compound provided herein with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode / dissolve in the rectum and release the compound. 5 Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted. 10

[0168] Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the compound provided herein, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the compound is comprised in a single, physically shaped solid form or article. In other words, the solid composition is 15 coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.

[0169] Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In one embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized 20 tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the compound.

[0170] On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the 25 like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick 30 dispersion and absorption of the compound.

[0171] Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with a compound provided herein so that the compound is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular 35 weight excipient may be useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the compound and, for example, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol,SMi.089PCT (BTP-002WO) a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.

[0172] Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one 5 or more delivery systems, e.g., for delivering or administering a compound as provided herein, and directions for use of the kit (e.g., instructions for treating a patient). In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer. In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the 10 contents are to be administered to a patient with one or more of glioblastoma, ovarian, breast, pancreatic cancers, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, chronic myeloid leukemia, Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, CDKL5 Deficiency Disorder, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, Autism, Dementia, Epilepsy, Huntington’s 15 Disease, and Multiple Sclerosis. Methods of Treatment

[0173] The compounds and compositions provided herein can be used as inhibitors of DYRK1A, and thus can be used to treat a variety of disorders and diseases in 20 which over expression of DYRK1A is implicated, such as cancer and neurological conditions / disorders / diseases. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, CDKL5 Deficiency Disorder, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, 25 Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, Stroke, tauopathies (e.g., Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, 30 globular glial tauopathies, primary age-related tauopathy, which includes neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and aging-related tau astrogliopathy. Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson syndrome, parkinsonism, pure akinesia with gait freezing and, rarely, motor neuron symptoms or cerebellar ataxia, diabetes, 35 psoriasis, knee osteoarthritis, tendinopathy, human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), hepatitis C virus (HCV), and herpes simplex virus 1 (HSV- 1).SMi.089PCT (BTP-002WO)

[0174] The gene encoding DYRK1A is located on chromosome 21, within the Down syndrome critical region (DSCR), the triploidy of which is responsible for most Down syndrome-associated deficiencies (FEBS Journal (2011), 278, 246–256). There is considerable genetical and pharmacological evidence showing that the mere 1.5-fold overexpression of 5 DYRK1A is responsible for most cognitive deficits observed in Down syndrome patients (Pharmacology & Therapeutics (2019), 194, 199-221 and Brain Science (2018), 8(10), 187). Genetical normalization of DYRK1A levels or pharmacological inhibition of its catalytic activity restores cognitive functions. The development of pharmacological inhibitors of DYRK1A is a major avenue for the treatment of cognitive deficits associated with Down 10 syndrome.

[0175] DYRK1A and DYRK1B are utilized during human cytomegalovirus (HCMV) placental replication. Inhibition of DYRKs prevent replication of various viruses, including hepatitis C virus (HCV), human cytomegalovirus (HCMV), human immunodeficiency virus type 1 (HIV-1), and herpes simplex virus 1 (HSV-1) (Journal of 15 Virology (2020), 94(6) and PLoS ONE (2015), 10, e0144229).

[0176] There is a growing body of evidence showing that DYRK1A / 1B inhibitors induce the proliferation of insulin-producing pancreatic -cells, making DYRK1A / 1B kinases attractive therapeutic targets for -cell regeneration for both type 1 and type 2 diabetes mellitus and gestational diabetes (Nature Communications (2015), 6(8372); Diabetes (2016), 65(6), 20 1660–1671; JCI Insight (2020), 5(1), e132594; Science Translational Medicine (2020), 12(530); International Journal of Molecular Sciences (2021), 22(16), 9083; and Journal of Medicinal Chemistry (2021), 64(6), 2901–2922). Other forms of diabetes that may be treated with DYRK inhibitors are maturity onset diabetes of the young (MODY, monogenic diabetes), cases of diabetes that are caused by the body's tissue receptors not responding to insulin, double 25 diabetes (when a type 1 diabetic becomes insulin resistant), diabetes associated with excessive secretion of insulin-antagonistic hormones, malnutrition-related diabetes mellitus (ICD-10 code E12), and diabetes caused by any genetic mutations (autosomal or mitochondrial) that leads to defects in beta cell function.

[0177] There is abundant literature linking DYRK1A with solid cancers and 30 leukemias (Pharmacology & Therapeutics (2015), 151, 87–98; Cancers (2020), 12(8), 2106; and Cellular and Molecular Life Sciences (2021), 78, 603–619). The most prominent examples are pancreatic cancer (Gut (2019), 68(8), 1465–1476 and Gene (2020), 758, 144960), brain tumors, glioblastoma (Journal of Clinical Investigation (2013), 123(6), 2475-2487), acute megakaryoblastic leukemia (AMKL) (Journal of Clinical Investigation (2012), 122(3), 948– 35 962), and acute lymphoblastic leukemia (ALL) (Journal of Clinical Investigation (2021), 131(1), e135937). Other cancers linked to DYRK1A are ovarian (Frontiers in Oncology (2021), 11, 637193), head and neck squamous cell carcinoma (Scientific Reports (2016), 6, 36132),SMi.089PCT (BTP-002WO) hepatocellular carcinoma (Cell Death & Disease (2021), 12, 125), DYRK1A regulates DNA damage response (Scientific Reports (2019), 9, 6014 and Scientific Reports (2019), 9, 6539). In some situations, DYRK1A appears to function as a tumor-suppressor protein (Molecular & Cellular Oncology (2015), 2(1), e970048 and Nature (2016), 529, 172–177). 5

[0178] Other cancers can also be treated with the compounds and compositions described herein.

[0179] More particularly, cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following:

[0180] 1) Breast cancers, including, for example ER+breast cancer, ER- breast 10 cancer, her2- breast cancer, her2+breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive 15 lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; chemoresistant breast cancers (TNBC), and miscellaneous malignant neoplasms. Further examples of breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER-), progesterone receptor negative, and her2 negative (her2-). In some embodiments, breast cancer 20 may have a high risk Oncotype score.

[0181] 2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.

[0182] 3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., 25 squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; chemoresistant small cell lung cancer (SCLC), and mesothelioma.

[0183] 4) Gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; 30 cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; colon cancers with APC gene mutations; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular 35 adenoma, villous adenoma, hamartoma, and leiomyoma.

[0184] 5) Genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia;SMi.089PCT (BTP-002WO) cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma. 5

[0185] 6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

[0186] 7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's 10 sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.

[0187] 8) Nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the 15 meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma. 20

[0188] 9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial cancers (e.g., carcinoma, endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinomas, mixed or undifferentiated carcinoma (including mixed Müllerian tumor), endometrial stromal sarcoma, squamous cell carcinoma of the endometrium, urothelial carcinoma, endometrial cancer with CTNNB1 mutations); cancers of 25 the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., BRCA-mutant ovarian cancer, surface epithelial-stromal tumors (epithelial ovarian cancer (Type 1 (endometroid, mucinous, clear cell, low grade serous) or Type 2 (poorly differentiated, carcinosarcoma, and high grade serous))), ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid tumors, small cell ovarian 30 cancer (small cell ovarian cancer of hypercalcemic type, small cell ovarian cancer of pulmonary type) unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal 35 rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma, primary fallopian tube cancer; Primary peritoneal cancer (also known as serous surface papillary carcinoma, primarySMi.089PCT (BTP-002WO) peritoneal carcinoma, extra-ovarian serous carcinoma, primary serous papillary carcinoma, and psammomacarcinoma).

[0189] 10) Hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndromes 5 (refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemias with excess blasts I and II, refractory cytopenia of childhood), and myeloproliferative neoplasms, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic 10 syndrome, myelodysplastic–myeloproliferative diseases, Hodgkin's lymphoma, non-Hodgkin’s lymphoma (malignant lymphoma) and Waldenström's macroglobulinemia.

[0190] 11) Skin cancers and skin disorders, including, for example, malignant melanoma and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma. 15

[0191] 12) Adrenal gland cancers, including, for example, neuroblastoma.

[0192] 13) Soft-tissue sarcomas (STS) such as fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, Kaposi's sarcoma, lymphangiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors (also called neurofibrosarcomas, malignant schwannomas, and 20 neurogenic sarcomas), neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, extraskeletal mesenchymal, embryonal, alveolar soft part sarcoma, and infantile hemangio-pericytoma.

[0193] More particularly, tumors of the central nervous system that may be treated by the compounds, compositions and methods described herein include: 25

[0194] 1) Astrocytic tumors, e.g., diffuse astrocytoma (fibrillary, protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), pilocytic astrocytoma (pilomyxoid astrocytoma), pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosis cerebri. 30

[0195] 2) Oligodendroglial tumors, e.g., oligodendroglioma and anaplastic oligodendroglioma.

[0196] 3) Oligoastrocytic tumors, e.g., oligoastrocytoma and anaplastic oligoastrocytoma.

[0197] 4) Ependymal tumors, e.g., subependymoma, myxopapillary 35 ependymoma, ependymoma, (cellular, papillary, clear cell, tanycytic), and anaplastic (malignant) ependymoma.SMi.089PCT (BTP-002WO)

[0198] 5) Choroid plexus tumors, e.g., choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma.

[0199] 6) Neuronal and mixed neuronal-glial tumors, e.g., gangliocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplastic gangliocytoma of 5 the cerebellum (Lhermitte-Duclos), desmoplastic infantile astrocytoma / ganglioglioma, central neurocytoma, anaplastic ganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma, Papillary glioneuronal tumor, Rosette-forming glioneuronal tumor of the fourth ventricle, and paraganglioma of the filum terminale.

[0200] 7) Pineal tumors, e.g., pineocytoma, pineoblastoma, papillary tumors 10 of the pineal region, and pineal parenchymal tumor of intermediate differentiation.

[0201] 8) Embryonal tumors, e.g., medulloblastoma (medulloblastoma with extensive nodularity, anaplastic medulloblastoma, desmoplastic, large cell, melanotic, medullomyoblastoma), medulloepithelioma, supratentorial primitive neuroectodermal tumors, and primitive neuroectodermal tumors (PNETs) such as neuroblastoma, ganglioneuroblastoma, 15 ependymoblastoma, and atypical teratoid / rhabdoid tumor.

[0202] 9) Neuroblastic tumors, e.g., olfactory (esthesioneuroblastoma), olfactory neuroepithelioma, and neuroblastomas of the adrenal gland and sympathetic nervous system.

[0203] 10) Glial tumors, e.g., astroblastoma, chordoid glioma of the third 20 ventricle, and angiocentric glioma.

[0204] 11) Tumors of cranial and paraspinal nerves, e.g., schwannoma, neurofibroma Perineurioma, and malignant peripheral nerve sheath tumor.

[0205] 12) Tumors of the meninges such as tumors of meningothelial cells, e.g., meningioma (atypical meningioma and anaplastic meningioma); mesenchymal tumors, e.g., 25 lipoma, angiolipoma, hibernoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid hemangioendothelioma, haemangiopericytoma, anaplastic haemangiopericytoma, angiosarcoma, Kaposi Sarcoma, and Ewing Sarcoma; primary melanocytic lesions, e.g., diffuse 30 melanocytosis, melanocytoma, malignant melanoma, meningeal melanomatosis; and hemangioblastomas.

[0206] 13) Tumors of the hematopoietic system, e.g., malignant Lymphomas, plasmocytoma, and granulocytic sarcoma.

[0207] 14) Germ cell tumors, e.g., germinoma, embryonal carcinoma, yolk sac 35 tumor, choriocarcinoma, teratoma, and mixed germ cell tumors.

[0208] 15) Tumors of the sellar region, e.g., craniopharyngioma, granular cell tumor, pituicytoma, and spindle cell oncocytoma of the adenohypophysis.SMi.089PCT (BTP-002WO)

[0209] Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term “tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders.

[0210] A method of treating cancer using a compound or composition as described 5 herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be administered before, during, or after another anticancer agent or treatment.

[0211] There is mounting evidence for a role of DYRK1A in the onset of 10 Alzheimer’s Disease (Future Medicinal Chemistry (2016), 8(6), 681–696 and European Journal of Medicinal Chemistry (2018), 158, 559-592). DYRK1A phosphorylates key substrates involved in Alzheimer’s Disease and dementia: Tau, septin 4, amyloid precursor protein (APP), presenilin 1, neprilysin, Munc18-1, -synuclein, RCAN1, and -tubulin. By modulating alternative splicing of Tau exon 10, DYRK1A favors the production of the 3R-Tau 15 splice isoform (characteristic for DS / AD / tauopathy) over the 4R-Tau isoform (Journal of Biological Chemistry (2015), 290, 15219–15237).

[0212] Genome-wide association studies (GWAS) have revealed that DYRK1A is a risk factor for Parkinson’s Disease (The Lancet Neurology (2019), 18(12), 1091–1102). DYRK1A phosphorylates key factors for Parkinson’s Disease such as parkin, septin 4, and - 20 synuclein. Upregulation of micro-RNAs specific for Parkinson’s Disease targets DYRK1A expression. There is further evidence that DYRK1A expression is increased in Parkinson’s Disease and in Pick’s disease (Neurobiology of Disease (2005), 20(2), 392–400).

[0213] The compounds and compositions provided herein can be used as inhibitors and / or modulators of the enzyme DYRK1A, and thus can be used to treat a variety 25 of disorders and diseases associated with tau protein, including, but not limited to, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), down syndrome, frontotemporal dementia (FTD) including FTD with Parkinsonism-17 (FTDP-17), behavioural variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (also called corticobasal 30 ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), globular glial tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also called Steinert disease), myotonic dystrophy type 2 (DM2) (also called proximal myotonic myopathy), Guam complex, argyrophilic grain disease, dementia pugilistica, post-encephalitic parkinsonism, Lewy body dementia, Parkinson’s disease, Pick's disease, and additional diseases with 35 pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor, and stroke.SMi.089PCT (BTP-002WO)

[0214] Non-limiting examples of neurological disorders (e.g., neurological conditions and neurological diseases) which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, 5 autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic 10 inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin–Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, 15 Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial spastic paralysis, 20 febrile seizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barré syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, 25 Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne 30 syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease35 (Spinocerebellar ataxia type 3), macrencephaly, macropsia, megalencephaly, Melkersson- Rosenthal syndrome, Meniere’s disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrialSMi.089PCT (BTP-002WO) myopathy, Mobius syndrome, monomelic amyotrophy, motor neuron disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic 5 Encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic 10 hypotension, palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, 15 primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement 20 disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing 25 panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform 30 encephalopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease, and Zellweger syndrome.

[0215] The compounds and compositions may also be useful in the inhibition of 35 the development of invasive cancer, tumor angiogenesis and metastasis.SMi.089PCT (BTP-002WO)

[0216] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0217] In some embodiments, the disorder or disease is cancer. 5

[0218] In some embodiments, the disorder or disease is metastatic melanoma.

[0219] In some embodiments, the disorder or disease is diabetes.

[0220] In some embodiments, the disorder or disease is a neurological disorder.

[0221] In some embodiments, the disorder or disease is Alzheimer's disease.

[0222] In some embodiments, the patient is a human. 10

[0223] In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma, and ovarian cancer. 15

[0224] In some embodiments, the cancer is chosen from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, synovial sarcoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer – melanoma, small intestine cancer, stomach (gastric) cancers, testicular cancer, thymus 20 cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder 25 cancer, bile duct cancer, anal cancer and adrenal cortical cancer.

[0225] In some embodiments, the cancer is hepatocellular carcinoma; in some embodiments, the cancer is colon cancer; in some embodiments, the cancer is colorectal cancer; in some embodiments, the cancer is breast cancer; in some embodiments, the cancer is pancreatic cancer; in some embodiments, the cancer is chronic myeloid leukemia (CML); in 30 some embodiments, the cancer is chronic myelomonocytic leukemia; in some embodiments, the cancer is chronic lymphocytic leukemia (CLL); in some embodiments, the cancer is acute myeloid leukemia; in some embodiments, the cancer is acute lymphocytic leukemia; in some embodiments, the cancer is Hodgkin lymphoma; in some embodiments, the cancer is lymphoma; in some embodiments, the cancer is sarcoma; in some embodiments, the cancer is 35 ovarian cancer; in some embodiments, the cancer is lung cancer - non-small cell; in some embodiments, the cancer is lung cancer - small cell; in some embodiments, the cancer is multiple myeloma; in some embodiments, the cancer is nasopharyngeal cancer; in someSMi.089PCT (BTP-002WO) embodiments, the cancer is neuroblastoma; in some embodiments, the cancer is osteosarcoma; in some embodiments, the cancer is penile cancer; in some embodiments, the cancer is pituitary tumors; in some embodiments, the cancer is prostate cancer; in some embodiments, the cancer is retinoblastoma; in some embodiments, the cancer is rhabdomyosarcoma; in some 5 embodiments, the cancer is salivary gland cancer; in some embodiments, the cancer is skin cancer - basal and squamous cell; in some embodiments, the cancer is skin cancer – melanoma; in some embodiments, the cancer is small intestine cancer; in some embodiments, the cancer is stomach (gastric) cancers; in some embodiments, the cancer is testicular cancer; in some embodiments, the cancer is thymus cancer; in some embodiments, the cancer is thyroid cancer; 10 in some embodiments, the cancer is uterine sarcoma; in some embodiments, the cancer is vaginal cancer; in some embodiments, the cancer is vulvar cancer; in some embodiments, the cancer is Wilms tumor; in some embodiments, the cancer is laryngeal or hypopharyngeal cancer; in some embodiments, the cancer is kidney cancer; in some embodiments, the cancer is Kaposi sarcoma; in some embodiments, the cancer is gestational trophoblastic disease; in some 15 embodiments, the cancer is gastrointestinal stromal tumor; in some embodiments, the cancer is gastrointestinal carcinoid tumor; in some embodiments, the cancer is gallbladder cancer; in some embodiments, the cancer is eye cancer (melanoma and lymphoma); in some embodiments, the cancer is Ewing tumor; in some embodiments, the cancer is esophagus cancer; in some embodiments, the cancer is endometrial cancer; in some embodiments, the 20 cancer is colorectal cancer; in some embodiments, the cancer is cervical cancer; in some embodiments, the cancer is brain or spinal cord tumor; in some embodiments, the cancer is bone metastasis; in some embodiments, the cancer is bone cancer; in some embodiments, the cancer is bladder cancer; in some embodiments, the cancer is bile duct cancer; in some embodiments, the cancer is anal cancer; and in some embodiments, the cancer is adrenal cortical 25 cancer.

[0226] In some embodiments, the disorder or disease is a neurological condition, disorder, or disease, wherein the neurological disease is selected from: Alzheimer's disease, frontotemporal dementias, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), 30 inclusion body myositis, autism, degenerative myopathies.

[0227] In some embodiments, the disorder or disease is selected from the group consisting of: Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced 35 neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, and Stroke.SMi.089PCT (BTP-002WO)

[0228] In some embodiments, a compound of Formula (I) inhibits DYRK1A.

[0229] In some embodiments, the method treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically 5 acceptable salt thereof.

[0230] In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.

[0231] In some embodiments, the method inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound 10 (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof. 15

[0233] In some embodiments, the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the method treats a disease or disorder associated 20 with aberrant cellular proliferation in a patient, the method comprises administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more other agents. Evaluation of Biological Activity 25

[0235] The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art. For example, the activity of a compound may be tested using one or more of the test methods outlined below.

[0236] For example, in vitro assays for DYRK1A biological activity may be used, e.g., regulation of microtubule-associated protein tau (MAPT / Tau) phosphorylation in neuronal 30 cell lines such as the human SH-SY5Y neuroblastoma cell line. Assays for DYRK1A-regulated level of phosphorylation can include monitoring levels of basal pSer396 Tau, which can be measured, for example, by serial dilutions of a candidate inhibitor composition using a ten micromolar top concentration and detected by ELISA or Western Blotting. An exemplary assay for DYRK-1A-regulated phosphorylation uses the SH-SY5Y cells cultured in a 96 well plate 35 format for a period of time sufficient to stabilize microtubules and Tau phosphorylation, usually at least 2 days, then treated with a 1 / 3 serial dilution of compounds overnight and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with anSMi.089PCT (BTP-002WO) antibody specific for pSer396 Tau. The chemiluminescence signal for HRP-linked antibodies used in western blotting is detected using a Carestream Image Station and blot densitometry for pSer396 and beta-actin are analyzed using ImageJ (NIH).

[0237] In a further example, the activity of a candidate compound can be 5 measured by phosphoTau (Thr212) AlphaLISA by adding the lysate mentioned above onto total Tau-coated plates and detected with a specific pThr212Tau antibody. Colorimetric detection of AlphaLISA signal is performed by EnVision Multilabel Plate Reader (Perkin Elmer).

[0238] To further illustrate this disclosure, the following examples are included. 10 The examples should not, of course, be construed as specifically limiting the disclosure. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the disclosure as described and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the disclosure without exhaustive 15 examples. EXAMPLES Compound preparation

[0239] The starting materials used in preparing the compounds of the disclosure are known, made by known methods, or are commercially available. It will be apparent to the 20 skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.

[0240] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and 25 practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7thEd., John Wiley & 30 Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5thEd., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2ndEd., John Wiley & Sons (1999) (incorporated herein by reference in its entirety)and the like.

[0241] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any 35 undesirable side reactions and / or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesiredSMi.089PCT (BTP-002WO) reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in P. Wuts Greene's Protective Groups in Organic Synthesis, 5th Ed., John Wiley & Sons (2014), incorporated herein by reference in its entirety. 5

[0242] Trademarks used herein are examples only and reflect illustrative materials used at the time of the disclosure. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of 10 the disclosure.

[0243] (1H) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for1H or Avance TM DRX500, 500 MHz for1H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz for1H). Peak positions are expressed in parts per million (ppm) downfield from 15 tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets of doublets; d / ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; m, multiplet.

[0244] The following abbreviations have the indicated meanings: 20 Boc = tert-butyloxycarbonyl BrettPhos = dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl) phosphine BrettPhos Pd G3 = [(2-di-cyclohexylphosphino-3,6-dimethoxy-2 ,4 ,6 - triisopropyl-1,1 -biphenyl)-2-(2 -amino-1,1 -biphenyl)]palladium(II) methanesulfonate methanesulfonate25tBuXPhos-Pd-G3 = methanesulfonato(2-di-tbutylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) brine = saturated aqueous sodium chloride CBzCl = benzyl chloroformate CDCl3= deuterated chloroform 30 Cs2CO3 = cesium carbonate DCE = 1,2-dichloroethane DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DME = 1,2-dimethoxyethane, or glyme, or monoglyme 35 DMF = N,N-dimethylformamide DMSO-d6= deuterated dimethylsulfoxide ESIMS = electron spray mass spectrometrySMi.089PCT (BTP-002WO) EtOAc = ethyl acetate HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate HCl = hydrochloric acid 5 HOAc = acetic acid ISCO = Teledyne ISCO, Inc brand CombiFlash®Rf 200 KHMDS = potassium bis(trimethylsilyl)amide KOAc = potassium acetate LCMS = liquid chromatography–mass spectrometry 10 LiHMDS = lithium bis(trimethylsilyl)amide MCPBA = meta-chloroperoxybenzoic acid MeCN = acetonitrile MeOH = methanol MeTHF = 2-methyltetrahydrofuran 15 MgSO4= magnesium sulfate MTBE = methyl tert-butyl ether MW = microwave irradiation NaOtBu = Sodium tert-butoxide NaHCO3= sodium bicarbonate 20 NaBH(OAc)3= Sodium triacetoxyborohydride Na2SO4 = sodium sulfate NMR = nuclear magnetic resonance ON = overnight Pd / C = palladium on carbon 25 Pd(dppf)Cl2= 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride Pd(OAc)2= palladium(II) acetate PE = petroleum ether Phosphazene base P2-Et = 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2 5,4 5-catenadi(phosphazene) or tetramethyl(tris(dimethylamino)phosphoranylidene) 30 phosphorictriamid-Et-imin QPhos = pentaphenyl(di-tert-butylphosphino)ferrocene RP = reverse phase r.t. = room temperature SFC = supercritical fluid chromatography 35 TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuranSMi.089PCT (BTP-002WO) TLC = thin layer chromatography TMSOK = potassium trimethylsilanolate XPhos = dicyclohexyl[2 ,4 ,6 -tris(propan-2-yl)[1,1 -biphenyl]-2-yl]phosphane5

[0245] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds of the disclosure will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is thoroughly equipped to prepare these compounds by those 10 methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only and should not be construed as or confused with same numberings in other sections of the application. Unless otherwise indicated, all variables are as defined above. 15 General procedures

[0246] Compounds of Formula I of the present disclosure can be prepared as depicted in Scheme 1.Scheme 1 20

[0247] Scheme 1 describes a method for preparation of 4-alkylaminopyrrolo[2,1- f][1,2,4]triazine derivatives (VII) by first displacing the 4-chloride (I) with a variety of amines (II) to produce 2-chloro-5-bromo-4-aminopyrrolo[2,1-f][1,2,4]triazine III. Formation of a variety of boronic acid pinacol esters by reacting various bromides (IV) with25 bis(pinacolato)diboron followed by Suzuki coupling with bromide (III) produces 2-chloro-4-SMi.089PCT (BTP-002WO) aminopyrrolo[2,1-f][1,2,4]triazine (V). The chloro is then displaced with a variety of amines (VI) to produce the final 4-aminopyrrolo[2,1-f][1,2,4]triazine (VII).

[0248] Compounds of Formula I of the present disclosure can also be prepared as 5 depicted in Scheme 2.Scheme 2

[0249] Scheme 2 describes a method for preparation of 4-aminopyrrolo[2,1- 10 f][1,2,4]triazine derivatives (VII) by first displacing the 4-chloride (VIII) with a variety of amines (II) to produce 2,5-dichloro-4-aminopyrrolo[2,1-f][1,2,4]triazine IX. The 2-chloro is then displaced with a variety of amines (VI) to produce 5-chloro-4-aminopyrrolo[2,1- f][1,2,4]triazine (X). Formation of a variety of boronic acid pinacol esters by reacting various bromides (IV) with bis(pinacolato)diboron followed by Suzuki coupling with chloride (X) 15 produces the final 4-aminopyrrolo[2,1-f][1,2,4]triazine (VII).SMi.089PCT (BTP-002WO) Illustrative Compound Examples

[0250] Preparation of intermediate 5-bromo-2-chloro-N-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine (XV) is depicted below in Scheme 3.5 Scheme 3 Step 1

[0251] To a solution of methyl 3-bromo-1H-pyrrole-2-carboxylate (XI) (100 g, 490.15 mmol, 1 eq.) in MeCN (2 L) was added Cs2CO3 (255.52 g, 784.23 mmol, 1.6 eq.) in one 10 portion at 20 °C (not exothermic). The reaction was stirred at room temperature for 5 h. A solution of O-(2,4-dinitrophenyl)hydroxylamine (146.40 g, 735.22 mmol, 1.5 eq.) in MeCN (2 L) was then added dropwise at 0~5°C under N2. After addition, the reaction was warmed to room temperature for 16 h. The reaction mixture was filtered, and the filtrate was diluted with MTBE (2 L) and washed with brine (2 L x 3). The above reaction was performed six times. 15

[0252] The combined organics of six batches were combined, dried over MgSO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography on silica gel (0 50% DCM / PE, then 20% EtOAc / PE) togive methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (XII) (380 g, 1.62 mol, 55.1% yield, 93.3% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) ppm 3.84 (3 H, s), 6.24 (1 20 H, d, J=2.8 Hz), 6.38 (2 H, br s), 7.12 (1 H, d, J=2.8 Hz).

[0253] To a solution of methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (XII) (190 g, 867.44 mmol, 1 eq.) in THF (1900 mL) was added dropwise 2,2,2-trichloroacetyl 25 isocyanate (179.76 g, 954.18 mmol, 113.06 mL, 1.1 eq.) at 0~5°C, then warmed to room temperature for 1 h. The reaction was then added dropwise to NH3 / MeOH (7 M, 1.24 L, 10 eq)SMi.089PCT (BTP-002WO) at room temperature, stirred at room temperature for 1 h to give a yellow suspension. The above reaction was performed twice.

[0254] The two reactions were combined and concentrated under vacuum. The residue was triturated with MTBE (4 L) at room temperature for 30 min, filtered. The filter 5 cake was washed with MTBE ( 500 mL x 3), dried under vacuum to give methyl 3-bromo-1- ureido-1H-pyrrole-2-carboxylate (XIII) (402 g, 1.53 mol, 88.2% yield, 99.78% purity) as an off-white solid.1H NMR (400 MHz, DMSO-d6) ppm 3.75 (3 H, s), 6.27 (2 H, br s), 6.28 (1 H, d, J=2.8 Hz), 7.10 (1 H, d, J=2.8 Hz), 9.27 (1 H, br s); ESIMS found for C7H8BrN3O3m / z 262.1 (79BrM+H). 10 Step 4

[0255] To a solution of methyl 3-bromo-1-ureido-1H-pyrrole-2-carboxylate (XIII) (67 g, 255.67 mmol, 1 eq.) in THF (4 L) was added TMSOK (65.60 g, 511.33 mmol, 2 eq.) in portions at 0~5°C under N2. After stirring for 5 min, the reaction became a thick slurry. 15 The reaction mixture was stirred vigorously at room temperature for 16 h. LCMS showed ~25.8% of starting material remained. An additional portion of TMSOK (16.40 g, 127.83 mmol, 0.5 eq.) was added at room temperature and stirred for 3 h. LCMS showed the reaction was complete. The reaction was concentrated. The residue was diluted with H2O (1.6 L), cooled with ice-bath, added dropwise HCl (4 M, 160 mL) to pH 2~3, and filtered. The filter cake was 20 washed with H2O (600 mL x 3). The above reaction was performed six times.

[0256] The filter cakes of six reactions were combined, triturated with H2O (6 L) at room temperature, for 2 h and then filtered. The filter cake was dried in a vacuum drying oven at 60°C for 24 h to give 5-bromopyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (XIV) (320 g, 1.28 mol, 83.4% yield, 91.95% purity) as a white solid.1H NMR (400 MHz, DMSO- 25 d6) ppm 6.49 (1 H, d, J=2.8 Hz), 7.17 (1 H, d, J=2.8 Hz), 11.30 (1 H, br s); ESIMS found for C6H4BrN3O2m / z 232.0 (81BrM+H). Step 5

[0257] To a solution of POCl3(1500 mL) was added 5-bromopyrrolo[2,1- 30 f][1,2,4]triazine-2,4(1H,3H)-dione (XIV) (180 g, 782.55 mmol, 1 eq.) in portions at room temperature. N,N-Diethylaniline (291.95 g, 1.96 mol, 312.92 mL, 2.5 eq.) was then added dropwise at room temperature (a little exothermic). After addition, the reaction was heated to 105°C for 48 h. LCMS showed the starting material was consumed but the intermediate remained, ~4.3% of desired product was formed. The reaction was cooled to 90°C, added an 35 additional POCl3(500 mL) in one portion, then heated to reflux gently for 24 h. LCMS showed most of intermediate remained, ~11.9% of desired product was formed. The reaction was heated to reflux gently for another 4 days. LCMS showed ~7.4% of intermediate remained, ~55.5%SMi.089PCT (BTP-002WO) of desired product was formed. The reaction was cooled to 40°C and distilled under reduced pressure to remove most of POCl3. The residue was diluted with MeTHF (5 L), poured into ice- H2O (2 L), the added brine (1 L), and separated. The aqueous layer was extracted with MeTHF (1.5 L x 2). The combined organic were washed with brine (1.5 L x 2), dried over MgSO4, 5 filtered, and concentrated under vacuum to give the crude product. The crude product was purified by column chromatography on silica gel (4 kg, 100 ~ 200 mesh, 0 20% DCM / PE)and triturated with n-heptane (500 mL) at room temperature for 3 h, then filtered to afford 5- bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (I) (150 g, 556.14 mmol, 71.1% yield, 98.96% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) ppm 7.02 (1 H, d, J=2.4 Hz), 7.79 (1 10 H, d, J=2.4 Hz); ESIMS found for C6H2BrCl2N3m / z 266.1 (79BrM+H).

[0258] To a stirred solution of 5-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (I) (10 g, 37.47 mmol) in THF (250 mL) was added methylammonium chloride (6.33 g, 93.75 15 mmol) and DIPEA (22.9 mL, 131.47 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water, extracted in EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated on rotavapor, and the crude mixture was purified on ISCO (0 10% MeOH / CHCl3) to obtain 5-bromo-2-chloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XV) (8.9 g, 34.033 mmol, 90.8% yield) as a white 20 solid. ESIMS found for C7H6BrClN4m / z 261.0 (M+H).

[0259] The following intermediates were prepared in accordance with the procedure described in the above Scheme 3.XVI 25

[0260] 5-Bromo-2-chloro-N-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XVI): Beige solid (503.6 mg, 1.831 mmol, 97.6% yield). ESIMS found C8H8BrClN4m / z 275.0 (M+H).XVIISMi.089PCT (BTP-002WO)

[0261] 5-Bromo-2-chloro-N-isopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XVII): White solid (453.0 g, 1.564 mmol, 83.5% yield). ESIMS found C9H10BrClN4m / z 289.0 (M+H).5 XVIII

[0262] 5-Bromo-2-chloro-N-(methyl-d3)pyrrolo[2,1-f][1,2,4]triazin-4-amine (XVIII): Orange solid (647 mg, 2.446 mmol, 21.8% yield). ESIMS found C7H3D3BrClN4m / z 264.0 (M+H). 10

[0263] Preparation of intermediate 5-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin- 4-amine (XIX) is depicted below in Scheme 4. 15

[0264] To a stirred solution of ammonium hydroxide (4.7 mL, 37.47 mmol) in THF (10 mL) was added 5-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (I) (1 g, 3.75 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was extracted in DCM, washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated on20 rotavapor and dried under high vacuo to obtain 5-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin- 4-amine (XIX) (900 mg, 3.637 mmol, 97.1% yield) as an off-white solid. ESIMS found for C6H4BrClN4m / z 246.95 (M+H).

[0265] The following intermediate was prepared in accordance with the procedure described in the above Scheme 4. 25

[0266] 2,5-Dichloropyrrolo[2,1-f][1,2,4]triazin-4-amine (XX): Pale-orange solid (308 mg,1.517 mmol, 16.9% yield). ESIMS found C6H4Cl2N4m / z 203.0 (M+H).SMi.089PCT (BTP-002WO)

[0267] Preparation of intermediate 2,5-dichloro-N-methylpyrrolo[2,1- f][1,2,4]triazin-4-amine (XXI) is depicted below in Scheme 5.5 Scheme 5 Step 1

[0268] To a stirred solution of 2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine (commercially available from PharmaBlock Sciences Inc.) (VIII) (2 g, 8.99 mmol) in THF (50 10 mL) were added methylammonium chloride (1.51 g, 22.36 mmol) and DIPEA (5.48 mL, 31.46 mmol) at -78oC and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution, extracted with DCM, washed with brine, and dried over anhydrous Na2SO4.The solvent was evaporated on rotavapor and dried under high vacuo to obtain 2,5-dichloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XXI) (1.92 g, 15 8.846 mmol, 98.4% yield) as a yellow solid. ESIMS found for C7H6Cl2N4m / z 217.0 (M+H).

[0269] Preparation of intermediates 5-bromo-2-chloro-6-fluoro-4- methoxypyrrolo [2,1-f][1,2,4]triazine (XXXI) and 5-bromo-2-chloro-6-fluoro-N- methylpyrrolo[2,1-f][1,2,4] triazin-4-amine (XXXII) are depicted below in Scheme 6.SMi.089PCT (BTP-002WO)Scheme 6 Step 1 5

[0270] To a solution of methyl 4-fluoro-1H-pyrrole-2-carboxylate (XXII) (commercially available from PharmaBlock (USA), Inc.) (1 g, 6.99 mmol) in CHCl3(9 mL) at 0oC was added N-bromosuccinimide (2.64 g, 14.68 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with 10% sodium thiosulfate (50 mL) and extracted with CHC3(3x30 mL). The organic layers were combined and washed with10 aqueous saturated NaCl (50 mL) and evaporated under reduced pressure to produce methyl 3,5- dibromo-4-fluoro-1H-pyrrole-2-carboxylate (XXIII) (2.1 g, 6.979 mmol, 99.9% yield) as a beige solid. The product was used as is without further purification. ESIMS found for C6H4Br2FNO2m / z 299.9 (M+H). 15 Step 2

[0271] To a solution of methyl 3,5-dibromo-4-fluoro-1H-pyrrole-2-carboxylate (XXIII) (2.1 g, 6.98 mmol) in dry THF (25 mL) at 0°C under N2was added slowly NaH (430SMi.089PCT (BTP-002WO) mg, 10.63 mmol) in small portions. The suspension was stirred at 0°C for 30 min. To the suspension was added (2-(chloromethoxy)ethyl)trimethylsilane (1.9 mL, 10.74 mmol) at 0°C under N2. The reaction mixture was stirred at 0°C for 2 h before quenching with ice-water (20 mL) and extracted with EtOAc (3x30 mL). The EtOAc layer was evaporated under reduced 5 pressure and purified by silica gel column chromatography (100% hexanes) to produce methyl 3,5-dibromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (XXIV) (2.76 g, 6.401 mmol, 91.7% yield) as an amber liquid.1H NMR (499 MHz, DMSO-d6) ppm -0.07 (9 H, s), 0.81 (2 H, t, J=7.80 Hz), 3.50 (2 H, t, J=7.80 Hz), 3.82 (3 H, s), 5.69 (2 H, s). 10 Step 3

[0272] To solution of methyl 3,5-dibromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrrole-2-carboxylate (XXIV) (2.76 g, 6.4 mmol) in dry THF (60 mL) at -78°C under N2was added nBuLi (2.4 mL, 6. mmol). The reaction mixture was stirred at -78°C for 1 h. The mixture was carefully quenched with ice water (20 mL), warmed to room temperature, 15 and extracted with EtOAc (3x20 mL). The organics were dried over anhydrous Na2SO4, filtered, and evaporated onto Celite® and purified by silica gel column chromatography (0 6%EtOAc / hexanes) to produce methyl 3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrole-2-carboxylate (XXV) (760 mg, 2.157 mmol, 33.7% yield) as a clear oil.1H NMR (500 MHz, DMSO-d6) ppm -0.06 (9 H, s), 0.80 (2 H, t, J=7.96 Hz), 3.41 - 3.50 (2 H, m), 3.80 20 (3 H, s), 5.56 (2 H, s), 7.52 (1 H, d, J=3.29 Hz). Step 4

[0273] To a stirred solution of methyl 3-bromo-4-fluoro-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-pyrrole-2-carboxylate (XXV) (881 mg, 2.5 mmol) in DCM (23 mL) was 25 added TFA (23 mL) and the mixture was stirred at room temperature for 10 min. The solvents were concentrated, the residue taken in a mixture of MeOH (12 mL) / water (6 mL). To this mixture was added K2CO3(1.75 g, 12.66 mmol) and stirred at room temperature for 4 h. Water (10 mL) was added, and the solution was neutralized with 1 H HCl and washed with CHCl3(3x10 mL). The organic layer was stripped onto Celite®and purified by silica gel column30 chromatography (0 5% 7 N NH3 in MeOH / CHCl3) to produce methyl 3-bromo-4-fluoro-1H-pyrrole-2-carboxylate (XXVI) (450 mg, 2.027 mmol, 81.0% yield) as an off white solid.1H NMR (499 MHz, DMSO-d6) ppm 3.80 (3 H, s), 7.15 (1 H, d, J=3.56 Hz), 12.29 (1 H, br s); ESIMS found for C6H5BrFNO2m / z 222.0 (M+H). 35 Step 5

[0274] To a solution of methyl 3-bromo-4-fluoro-1H-pyrrole-2-carboxylate (XXVI) (500 mg, 2.25 mmol) in dry DMF (7 mL) at 0oC was slowly added NaH (120 mg, 2.93SMi.089PCT (BTP-002WO) mmol). After 30 min, O-(2,4-dinitrophenyl)hydroxylamine (490 mg, 2.48 mmol)) was added in one portion and the reaction was stirred in the ice bath for 1 h and at room temperature for 1 h. LC / MS showed the reaction was incomplete so an additional portion of O-(2,4- dinitrophenyl)hydroxylamine (490 mg, 2.48 mmol) was added and stirred at room temperature 5 for another 15 min. The reaction was diluted with water (100 mL) and extracted with EtOAc (3x75 mL). The combined extracts were stripped onto Celite®and purified by silica gel column chromatography (100% CHCl3) to produce methyl 1-amino-3-bromo-4-fluoro-1H-pyrrole-2- carboxylate (XXVII) (501 mg, 2.114 mmol, 93.9% yield) as an off-white solid.1H NMR (499 MHz, DMSO-d6) ppm 3.80 (3 H, s), 6.36 (2 H, s), 7.25 (1 H, d, J=3.29 Hz); ESIMS found 10 for C6H6BrFN2O2m / z 237.0 (M+H). Step 6

[0275] To a solution of methyl 1-amino-3-bromo-4-fluoro-1H-pyrrole-2- carboxylate (XXVII) (500 mg, 2.11 mmol) in DCM (10 mL) was added pyridine (210 μL, 2.6 15 mmol) and methyl carbonochloridate (180 μL, 2.33 mmol) dropwise. The reaction was stirred at room temperature for 20 min. DCM (100 mL) was added and washed with 1 N HCl (2x50 mL), stripped onto Celite® and purified by silica gel column chromatography (0 100%EtOAc / hexanes) to produce methyl 3-bromo-4-fluoro-1-((methoxycarbonyl) amino)-1H- pyrrole-2-carboxylate (XXVIII) (560 mg, 1.898 mmol, 89.8% yield) as a clear oil.1H NMR 20 (499 MHz, DMSO-d6) ppm 3.69 (3 H, br s), 3.76 (3 H, s), 7.48 (1 H, br d, J=1.92 Hz), 10.76 (1 H, br s); ESIMS found for C8H8BrFN2O4 m / z 295.0 (M+H). Step 7

[0276] To NH4OH (35 mL, 263.7 mmol) in a sealed tube was added methyl 3- 25 bromo-4-fluoro-1-((methoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (XXVIII) (560 mg, 1.9 mmol). The reaction was sealed and heated to 110°C for 16 h. The solvent was removed under vacuum and the residue was dissolved in MeCN. The solvent was stripped (3x to remove water) and placed under high vacuum for 1 h, to produce 5-bromo-6-fluoropyrrolo[2,1- f][1,2,4]triazine-2,4(1H,3H)-dione (XXIX) (440 mg, 1.774 mmol, 93.5% yield) as a light 30 brown solid. The product was used as is without further purification.1H NMR (499 MHz, DMSO-d6) ppm 7.04 (1 H, d, J=3.29 Hz), 7.13 (1 H, br s), 9.58 (1 H, br s); ESIMS found for C6H3BrFN3O2m / z 247.9 (M+H). Step 8 35

[0277] To a solution of neat POCl3(3 mL, 32.19 mmol) was added 5-bromo-6- fluoropyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (XXIX) (440 mg, 1.77 mmol) in portions at room temperature. N,N-Diethylaniline (0.7 mL, 4.4 mmol) was then added dropwise at roomSMi.089PCT (BTP-002WO) temperature. The reaction was heated at 105°C for 16 h. The solvent was removed under vacuum before adding water (20 mL) and extracting with EtOAc. The organic layer was stripped onto Celite® and purified by silica gel column chromatography (0 100%EtOAc / hexanes) to produce 5-bromo-2,4-dichloro-6-fluoropyrrolo[2,1-f][1,2,4]triazine (XXX) 5 (175 mg, 0.614 mmol, 34.6% yield) as an off-white solid.1H NMR (499 MHz, DMSO-d6) ppm 7.92 (1 H, d, J=3.29 Hz); ESIMS found for C6HBrCl2FN3m / z 283.9 (M+H). Step 9

[0278] To a solution of 5-bromo-2,4-dichloro-6-fluoropyrrolo[2,1- 10 f][1,2,4]triazine (XXX) (175 mg, 0.61 mmol) in MeOH (664 μL) and DCM (2 mL) was added K2CO3(254.1 mg, 1.84 mmol). The flask was capped and the reaction and stirred at room temperature for 16 h. Water (50 mL) was added and extracted with DCM (3x50 mL). The organic layers were separated and washed with water (2x50 mL) and brine (50 mL). The solvent was removed under vacuum to produce 5-bromo-2-chloro-6-fluoro-4-methoxypyrrolo[2,1- 15 f][1,2,4]triazine (XXXI) (163 mg, 0.581 mmol, 94.6% yield) as a beige solid.1H NMR (500 MHz, DMSO-d6) ppm 4.12 (3 H, s), 8.34 (1 H, d, J=3.29 Hz); ESIMS found for C7H4BrClFN3O m / z 279.95 (M+H). Step 10 20

[0279] To a solution of 5-bromo-2,4-dichloro-6-fluoropyrrolo[2,1-f][1,2,4]triazine (XXX) (4.0 g, 14.04 mmol) in THF (100 mL) were added methylammonium chloride (1.04 g, 15.4 mmol) and DIPEA (8.4 mL, 48.23 mmol) at 0°C. The reaction was stirred vigorously for 5 h at room temperature. The solvent was evaporated on rotavapor, and the reaction mixture was extracted with DCM and washed with aqueous NH4Cl solution and then reduced in vacuo.25 The crude mixture was purified on ISCO (0 40% EtOAc in hexanes). Appropriate fractionswere collected and concentrated under reduced pressure and dried under high vacuo to obtain 5-bromo-2-chloro-6-fluoro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XXXII) (3.55 g, 12.701 mmol, 90.5% yield) as a fluffy yellow solid. ESIMS found for C7H5BrClFN4m / z 278.95 (M+H). 30

[0280] The following intermediates were prepared in accordance with the procedure described in the above Scheme 6.XXXIIISMi.089PCT (BTP-002WO)

[0281] 5-Bromo-2-chloro-4-ethoxy-6-fluoropyrrolo[2,1-f][1,2,4]triazine (XXXIII): Pale-yellow solid (264 mg, 0.896 mmol, 85.1% yield). ESIMS found C8H6BrClFN3O m / z 293.95 (M+H).5 XXXIV

[0282] 5-Bromo-2-chloro-N-(2,4-dimethoxybenzyl)-6-fluoropyrrolo[2,1- f][1,2,4] triazin-4-amine (XXXIV): Beige solid (670 mg, 1.612 mmol, 91.8% yield). ESIMS found C15H13BrClFN4O2m / z 415.0 (M+H).

[0283] Preparation of intermediate 5-chloro-3-(2-fluoroethyl)-3H-imidazo[4,5- 10 b]pyridine (XXXVI) is depicted below in Scheme 7.Scheme 7 Step 1 15

[0284] A mixture of 5-chloro-3H-imidazo[4,5-b]pyridine (XXXV) (1 g, 6.51 mmol), K2CO3 (1.8 g, 13.02 mmol) and 1-fluoro-2-iodoethane (1.7 g, 9.77 mmol) in DMSO (6 mL) was stirred at room temperature for 48 h. The reaction mixture was poured into a solution of EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, 20 and concentrated. The crude product was purified via column chromatography (80 g of silica gel) (50 100% EtOAc / hexanes) to obtain 5-chloro-3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridine (XXXVI) (470 mg, 2.355 mmol, 36.2% yield) as a beige solid which was used for next step without further purification. ESIMS found C8H7ClFN3m / z 200.05 (M+H).

[0285] The following intermediates were prepared in accordance with the 25 procedure described in the above Scheme 7.SMi.089PCT (BTP-002WO)XXXVII

[0286] 5-Chloro-3-(2-fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XXXVII): Beige solid (220 mg, 1.030 mmol, 57.5% yield). ESIMS found C9H9ClFN3 m / z 5 214.05 (M+H).XXXVIII

[0287] 5-Chloro-3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XXXVIII): Beige solid (830 mg, 3.583 mmol, 60.1% yield). ESIMS found C9H8ClF2N3m / z 10 232.0 (M+H).XXXIX

[0288] 5-Chloro-2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine (XXXIX): Beige solid (372 mg, 1.490 mmol, 50.0% yield). ESIMS found C9H7ClF3N3m / z 15 250.0 (M+H).XLSMi.089PCT (BTP-002WO)

[0289] 5-Chloro-3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridine (XL): White solid (253 mg, 1.163 mmol, 20.5% yield). ESIMS found C8H6ClF2N3m / z 218.0 (M+H).XLI 5

[0290] 5-Chloro-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine (XLI): Light yellow solid (335 mg, 1.422 mmol, 21.8% yield). ESIMS found C8H5ClF3N3m / z 236.0 (M+H).

[0291] Preparation of intermediate 5-chloro-3-(2,2-difluoroethyl)-3H- [1,2,3]triazolo[4,5-b]pyridine (XLVI) is depicted below in Scheme 8. 10

[0292] To a solution of 2,6-dichloro-3-nitropyridine (XLII) (14.0 g, 73.30 mmol)15 in DCM (500.0 mL) cooled to 0 was added 2,2-difluoroethan-1-amine (XLIII) (8.91 g,109.95 mmol) at 0 . DIPEA (18.91 g, 146.60 mmol) was then added, and the reaction waswarmed to room temperature for 16 h. The reaction mixture was extracted with DCM (500 mL x 2). The combined organics were washed with brine (500 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude was purified by silica20 gel column chromatography (PE / EtOAc = 10:1 5:1) to give 6-chloro-N-(2,2-difluoroethyl)-3-nitropyridin-2-amine (XLIV) (12.0 g, 50.507 mmol, 68.9%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 4.01 – 3.93 (m, 2H), 6.43 – 6.03 (m, 1H), 6.95 – 6.79 (m, 1H), 8.54 – 8.40 (m, 1H), 8.81 (t, J = 5.4 Hz, 1H). 25 Step 2

[0293] 6-Chloro-N-(2,2-difluoroethyl)-3-nitropyridin-2-amine (XLIV) (12.0 g, 50.51 mmol) was added to a mixture of NH4Cl (7.37 g, 139.00 mmol) in EtOH / H2O (300 / 100 mL, 3:1 ratio). The resulting mixture was sealed and heated at 80 . Fe (12.97 g, 231.66 mmol)was then added at 80 , sealed and heated at 80 for 1 h. The reaction mixture was cooled toSMi.089PCT (BTP-002WO) room temperature, filtered, and diluted with EtOAc (300 mL x 2). The solution was washed with water (300 mL x 2), and the aqueous portion was extracted with EtOAc (300 mL x 2). The combined organic extracts were washed with brine (300 mL x 2), dried over anhydrous Na2SO4, filtrated, and concentrated in vacuo to afford the crude product. The crude product was purified 5by silica gel column chromatography (PE / EtOAc = 10:1 3:1) to afford the 6-chloro-N2-(2,2-difluoroethyl)pyridine-2,3-diamine (XLV) (10.0 g, 48.167 mmol, 95.4% yield) as a purple solid.1H NMR (400 MHz, DMSO-d6) 6.76 (d, J = 7.8 Hz, 1H), 3.76 – 3.66 (m, 2H), 4.93 (s, 2H), 6.11 (tt, J = 56.6, 4.2 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H); ESIMS found for C7H8ClF2N3m / z 208.1 (M+H). 10 Step 3

[0294] To a solution of 6-chloro-N2-(2,2-difluoroethyl)pyridine-2,3-diamine (XLV) (10.0 g, 48.17 mmol) in HCl (360 mL) at 0 was added NaNO2 (4.00 g, 57.97 mmol)in H2O (55 mL). The mixture was stirred at room temperature at 16 h under N2. The reaction 15 mixture was adjusted to pH=9 with 4 M NaOH and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10:1 1:1) to yield 5-chloro-3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (XLVI) (6.2 g, 28.364 mmol, 58.9% yield) as a yellow solid.1H 20 NMR (400 MHz, DMSO-d6) 5.25 (td, J=16.0, 3.0 Hz, 2H), 6.85 – 6.41 (m, 1H), 7.65 (d, J=8.6 Hz, 1H), 8.72 (d, J=8.6 Hz, 1H); ESIMS found for C7H5ClF2N4 m / z 219.0 (M+H).

[0295] The following intermediates were prepared in accordance with the procedure described in the above Scheme 8.25 XLVII

[0296] 5-Chloro-3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (XLVII): Yellow solid (2.7 g, 13.460 mmol, 39.3% yield).1H NMR (400 MHz, DMSO-d6) 5.02 – 4.90 (m, 2H), 5.10 – 5.03 (m, 2H), 7.62 (d, J = 8.6 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H); ESIMS found for C7H6ClFN4m / z 201.1 (M+H). 30XLVIIISMi.089PCT (BTP-002WO)

[0297] 5-Chloro-3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (XLVIII): Yellow solid (3.1 g, 13.103 mmol, 42.2%).1H NMR (400 MHz, DMSO-d6) 5.83 (q, J = 9.2 Hz, 2H), 7.70 (d, J = 8.6 Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H); ESIMS found for C7H4ClF3N4m / z 237.0 (M+H). 5

[0298] Preparation of intermediate 3-(2,2-difluoroethyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine (XLIX) is depicted below in Scheme 9. 10

[0299] 5-Chloro-3-(2,2-difluoroethyl)triazolo[4,5-b]pyridine (XLVI) (5.43 g, 24.84 mmol), bis(pinacolato)diboron (8.16 g, 32.13 mmol), Pd(dppf)Cl2 (1.02 g, 1.25 mmol) 15 and KOAc (7.35 g, 74.89 mmol) were suspended in dry 1,4-dioxane (100 mL). The reaction was sonicated and degassed with Ar for 5 minutes. The reaction was stirred at 90°C for 2.5 h. Celite®was added and the reaction mixture was reduced in vacuo and then purified by RP column chromatography (C18Aq with loading column to trap Pd) (0 28% MeCN / H2O (0.1%formic acid)). Appropriate fractions were pooled and reduced in vacuo to 100 mL and the20 resulting precipitate was filtered to give [3-(2,2-difluoroethyl)triazolo[4,5-b]pyridin-5- yl]boronic acid (XLIX) (4.207 g, 18.455 mmol, 74.3% yield) as a fluffy white solid. ESIMS found for C7H7BF2N4O2m / z 229.05 (M+H).

[0300] The following intermediates were prepared in accordance with the procedure described in the above Scheme 9. 25SMi.089PCT (BTP-002WO)

[0301] 3-(3-Fluoropropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H- [1,2,3]triazolo[4,5-b]pyridine (L): Yellow solid (1.79 g, 7.991 mmol).1H NMR (400 MHz, CD3OD) ppm 2.34 (2 H, br s), 4.31 - 4.56 (2 H, m), 4.85 (4 H, br s), 7.86 (1 H, d, J=8.50 Hz), 8.37 (1 H, br s); ESIMS found for C14H20BFN4O2m / z 307.1 (M+H). 5

[0302] Preparation of intermediate cis-3-amino-1-ethylcyclobutan-1-ol (LIX) is depicted below in Scheme 10. 10

[0303] To a cloudy solution of ethyltriphenylphosphonium bromide (30.08 g, 81.08 mmol) in THF (240 mL) at -78 under N2 was added a 1 M solution of KHMDS in THF(80 mL, 81.08 mmol) at -78 . The mixture was stirred for 30 minutes before adding tert-butyl15 (3-oxocyclobutyl)carbamate (LI) (10 g, 54.05 mmol ) in THF (50 mL) dropwise at -78°C. The reaction mixture was stirred at room temperature for 2 h. The reaction solution was quenched with brine (200 mL) and extracted with EtOAc (2 x 200 mL). The organic layer was washed with H2O (150 mL) and brine (150 mL), then separated, dried over anhydrous Na2S04, and concentrated in vacuo. The crude was purified by silica gel column chromatography (silica, 20 100-200 mesh, 10% EtOAc / PE) to obtain tert-butyl (3-ethylidenecyclobutyl)carbamate (LII) (1.5 g, 7.603 mmol, 14.1% yield) as an off-white solid.1H NMR (400 MHz, CDCl3) ppm 1.37 (s, 9H), 1.43 (dd, J = 7.0, 3.4 Hz, 3H), 2.49 – 2.29 (m, 2H), 2.93 (s, 2H), 4.05 (s, 1H), 4.69 (s, 1H), 5.15 (s, 1H);.SMi.089PCT (BTP-002WO) Step 2

[0304] To a solution of tert-butyl (3-ethylidenecyclobutyl)carbamate (LII) (1.0 g, 5.08 mmol) in DCM (40 mL) at 0 was added MCPBA (1.75 g, 10.15 mmol). The mixturewas stirred at room temperature for 3 h. The mixture was quenched with brine (50 mL) and 5 extracted with DCM (2 x 80 mL). The organic layer was separated, then washed with saturated aqueous NaHCO3solution (50 mL) and brine (50 mL). The organic layer was separated, dried over anhydrous Na2S04, and concentrated in vacuo to give tert-butyl (2-methyl-1- oxaspiro[2.3]hexan-5-yl)carbamate (LIII) (1.0 g, 4.689 mmol, 92.3% yield) as a white solid which was used in the next step without further purification. ESIMS found for C11H19NO3 m / z 10 158.1 (M-tBu+H).

[0305] To a solution of tert-butyl (2-methyl-1-oxaspiro[2.3]hexan-5-yl)carbamate (LIII) (1.0 g, 4.69 mmol) in THF (10 mL) at 0 was added LiAlH4 (6 mL, 6.17 mmol). The15 mixture was stirred at room temperature for 1h. The mixture was added sodium sulfate decahydrate and then filtered through a Celite®pad, and the filtrate was concentrated to give the crude product. The crude product was chromatographed on silica gel (silica, 100-200 mesh, 30% EtOAc / PE) to give the tert-butyl (3-ethyl-3-hydroxycyclobutyl)carbamate (LIV) (200 mg, 0.929 mmol, 19.8% yield) as a white oil.1H NMR (400 MHz, DMSO-d6) ppm 0.79 (dt, J = 20 19.6, 7.4 Hz, 3H), 1.36 (s, 9H), 1.43 (dd, J = 14.4, 7.2 Hz, 2H), 1.81 (dd, J = 14.2, 5.6 Hz, 2H), 2.26 – 2.02 (m, 2H), 4.05 – 3.37 (m, 1H), 4.60 (d, J = 45.8 Hz, 1H), 6.90 (t, J = 73.8 Hz, 1H).

[0306] tert-Butyl (3-ethyl-3-hydroxycyclobutyl)carbamate (LIV) (500 mg, 2.33 25 mmol) was dissolved in a solution of 4 M HCl in dioxane (5 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and dried under vacuum to produce desired 3-amino-1-ethylcyclobutan-1-ol (LV) (500 mg, assuming quantitative) as a yellow oil which was used in the next step without further purification. 30

[0307] To a solution of crude 3-amino-1-ethylcyclobutan-1-ol (LV) (500 mg, 2.33 mmol) in mixture of EtOAc (20 mL) and aqueous NaHCO3 (10 mL) at 0 was added benzylchloroformate (515.7 mg, 3.02 mmol). The mixture was stirred at room temperature for 16 h. The mixture was quenched with brine (50 mL) and extracted with EtOAc (2 x 100 mL). The 35 organic layer was separated, dried over anhydrous Na2S04, and concentrated in vacuo. The crude product was chromatographed on silica gel (silica, 100-200 mesh, 30% EtOAc / PE) to yield the racemic benzyl (3-ethyl-3-hydroxycyclobutyl)carbamate (LVI) (450 mg, 1.805 mmol,SMi.089PCT (BTP-002WO) 77.5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 0.80 (dt, J = 19.6, 7.4 Hz, 3H), 1.44 (dt, J = 13.8, 7.0 Hz, 2H), 1.90 – 1.77 (m, 2H), 2.30 – 2.06 (m, 2H), 4.20 – 3.39 (m, 1H), 4.66 (d, J = 47.4 Hz, 1H), 4.99 (s, 2H), 7.54 – 7.09 (m, 6H); ESIMS found for C14H19NO3m / z 250.1 (M+H). 5

[0308] Racemic benzyl (3-ethyl-3-hydroxycyclobutyl)carbamate (LVI) (2.5 g, 10.0 mmol) was purified by SFC (Table 2) to afford the benzyl (cis-3-ethyl-3- hydroxycyclobutyl)carbamate (LVIII) (1.8 g, 7.220 mmol) as a white solid1H NMR (400 MHz, DMSO-d6) ppm 0.82 (t, J = 7.2 Hz, 3H), 1.43 (q, J = 7.2 Hz, 2H), 1.85 (td, J = 8.8, 2.4 Hz, 2H), 2.33 – 2.14 (m, 2H), 3.59 – 3.40 (m, 1H), 4.72 (s, 1H), 4.99 (s, 2H), 7.60 – 7.09 (m,10 6H), ESIMS found for C14H19NO3m / z 250.1 (M+H), and benzyl (trans-3-ethyl-3- hydroxycyclobutyl)carbamate (LVII) (0.3 g, 1.203 mmol) as a white solid. Table 2. Chiral pre-SFC Method15 Step 6

[0309] To a solution of benzyl (cis-3-ethyl-3-hydroxycyclobutyl)carbamate (LVIII) (1.8 g, 7.22 mmol) in MeOH (50 mL) was added Pd / C (360 mg). The mixture was stirred at room temperature under H2(1 atm) for 16 h. The mixture was filtered through Celite®, and the filtrate was concentrated to give cis-3-amino-1-ethylcyclobutan-1-ol (LIX) (540 mg, 20 4.688 mol, 64.9% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) ppm 0.80 (t, J = 7.4 Hz, 3H), 1.37 (q, J = 7.4 Hz, 2H), 1.64 – 1.54 (m, 2H), 2.27 – 2.17 (m, 2H), 2.85 – 2.73 (m, 1H), 3.17 (s, 1H).

[0310] The following intermediate was prepared in accordance with the procedure described in the above Scheme 10.SMi.089PCT (BTP-002WO)LX

[0311] trans-3-Amino-1-ethylcyclobutan-1-ol (LX):1H NMR (400 MHz, DMSO-d6) ppm 0.77 (t, J = 7.4 Hz, 3H), 1.46 (q, J = 7.4 Hz, 2H), 1.58 – 1.50 (m, 2H), 2.12 5 – 2.03 (m, 2H), 3.17 (s, 1H), 3.52 – 3.38 (m, 1H).

[0312] Preparation of intermediate (3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4- amine (LXIV) is depicted below in Scheme 11. 10

[0313] 2-Methyl-2-propanyl[(3R,4S)-3-fluoro-4-piperidinyl]carbamate (LXI) (commercially available from PharmaBlock (USA), Inc.) (1 g, 4.58 mmol) and 3 Å MS (5 15 beads) were suspended in dry DCE (10 mL) before adding oxetan-3-one (LXII) (805 μL, 13.74 mmol). The reaction was stirred at 80°C for 1 h. NaBH(OAc)3(1.5 g, 7.08 mmol) was added whilst hot and the reaction was stirred for a further 30 min. The reaction mixture was poured into a mixture of saturated aqueous NaHCO3solution and DCM, and the organic layer was separated. The aqueous layer was extracted with DCM (×3) and the combined organic layers20 were reduced in vacuo to give the product tert-butyl N-[(3R,4S)-3-fluoro-1-(oxetan-3- yl)piperidin-4-yl]carbamate (LXIII) (1.259 g, 4.589 mmol, 100.2% yield), assuming quantitative yield, as a viscous orange oil and was used without purification. ESIMS found for C13H23FN2O3m / z 275.15 (M+H). 25 Step 2

[0314] To a solution of tert-butyl N-[(3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin- 4-yl]carbamate (LXIII) (1.26 g, 4.59 mmol) in DCM (16 mL) was added TFA (4 mL) The reaction was stirred at room temperature for 1 h. The reaction mixture was blown dry, and the product was directly purified by RP chromatography (H2O with 0.1% formic acid). Appropriate 30 fractions were pooled and lyophilized to give a pale orange viscous oil. TFA was still detected, therefore, the product was dissolved in 7.0 M NH3 in MeOH and dry loaded onto Celite®andSMi.089PCT (BTP-002WO) then purified by column chromatography (0 5% 7.0 M NH3 in MeOH / CHCl3) to produce(3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-amine (LXIV) (413 mg, 2.371 mmol, 51.7% yield) as a pale-yellow oil. ESIMS found for C8H15FN2O m / z 175.1 (M+H). 5

[0315] Preparation of 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin- 5-yl)-6-fluoro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1- f][1,2,4]triazine-2,4-diamine (260) is depicted below in Scheme 12.10 Scheme 12 Step 1

[0316] 5-Bromo-2-chloro-4-ethoxy-6-fluoropyrrolo[2,1-f][1,2,4]triazine (XXXII) (250 mg, 0.85 mmol), [3-(2,2-difluoroethyl)triazolo[4,5-b]pyridin-5-yl]boronic acid 15 (XLIX) (201 mg, 0.88 mmol), Pd(OAc)2(11 mg, 0.05 mmol), QPhos (59 mg, 0.08 mmol) and Na2CO3(270 mg, 2.55 mmol) were suspended in 1,4-dioxane (3 mL) and water (1.5 mL). The reaction mixture was purged with argon for 5 min, and the reaction was heated to 85°C for 1 h. The reaction mixture was loaded onto Celite®and purified by column chromatography (0 20% EtOAc / hexanes) to yield 5-(2-chloro-4-ethoxy-6-fluoropyrrolo[2,1-f][1,2,4]triazin-20 5-yl)-3-(2,2-difluoroethyl)triazolo[4,5-b] pyridine (LXV) (133 mg, 0.334 mmol, 39.4% yield) as a pale-red solid. ESIMS found for C15H11ClF3N7O m / z 398.1 (M+H).

[0317] 5-(2-Chloro-4-ethoxy-6-fluoropyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-(2,2-25 difluoroethyl)triazolo[4,5-b]pyridine (LXV) (133 mg, 0.33 mmol), (3R,4S)-3-fluoro-1-SMi.089PCT (BTP-002WO) (oxetan-3-yl)piperidin-4-amine (LXIV) (68 mg, 0.39 mmol), and tBuXphos-Pd-G3 (25 mg, 0.03 mmol) were suspended in dry THF (3 mL) and the solution was degassed with Ar for 3 min. Phosphazene base P2-Et (134 μL, 0.4 mmol) was then added slowly down the sides of the vessel and the reaction was stirred at room temperature for 10 min. The crude reaction mixture 5was purified by column chromatography (0 30% EtOAc / hexanes) to give 5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-ethoxy-6-fluoro-N-((3R,4S)-3-fluoro- 1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (LXVI) (58 mg, 0.108 mmol, 32.4% yield) as a beige solid. ESIMS found for C23H25F4N9O2m / z 536.2 (M+H). 10 Step 3

[0318] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-ethoxy- 6-fluoro-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2- amine (LXVI) (58 mg, 0.11 mmol) was suspended in 7 M ammonia in MeOH (3 mL, 21 mmol). The reaction was stirred in a sealed tube for 16 h at 80°C. The reaction mixture was15 loaded onto Celite® and purified by column chromatography (0 4% 7.0 M NH3 inMeOH / CHCl3). The product was further purified using RP column chromatography (0 50%MeCN / H2O (0.1% formic acid)) to produce 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-6-fluoro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1- f][1,2,4]triazine-2,4-diamine (260) (10 mg, 0.0120 mmol, 18.2% yield) as a yellow fluffy solid. 201H NMR (499 MHz, DMSO-d6) ppm 1.70 (1 H, br dd, J=8.62, 3.97 Hz), 1.87 (1 H, qd, J=12.09, 3.42 Hz), 1.94 - 2.02 (1 H, m), 2.11 (1 H, dd, J=37.05, 12.59 Hz), 2.74 (1 H, br d, J=12.05 Hz), 2.90 - 3.03 (1 H, m), 3.48 (1 H, quin, J=6.43 Hz), 3.71 - 3.89 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.53 (2 H, td, J=6.50, 2.60 Hz), 4.86 (1 H, d, J=49.35 Hz), 5.19 (2 H, td, J=16.08, 2.33 Hz), 6.19 (1 H, d, J=8.21 Hz), 7.68 (1 H, d, J=2.19 Hz), 7.74 25 (1 H, br s), 7.94 (1 H, d, J=9.03 Hz), 8.67 (1 H, d, J=9.03 Hz), 9.70 (1 H, br s); ESIMS found for C21H22F4N10O m / z 507.2 (M+1). Example 2.

[0319] Preparation of N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-30 (2-fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine (236) is depicted below in Scheme 13.SMi.089PCT (BTP-002WO)5

[0320] To an oven-dried microwave vial containing tert-Butyl N-(2,5- dichloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-N-methylcarbamate (LXVII) (400 mg, 1.26 mmol), tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (LXVIII) (358 mg, 1.64 mmol), BrettPhos Pd G3 (92 mg, 0.1 mmol), BrettPhos (54 mg, 0.1 mmol) was added dry 1,4-dioxane (7 mL). A 1 M solution of LiHMDS in THF (3.16 mL, 3.16 mmol) was added, and the 10 suspension was purged and sonicated with Ar for 5 min. The reaction was then heated to 105°C for 30 min. The reaction mixture was added to Celite®and purified by column chromatography (0 20% EtOAc / hexanes) to yield tert-butyl (3R,4S)-4-((4-((tert-butoxycarbonyl)(methyl)amino)-5-chloropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3- fluoropiperidine-1-carboxylate (LXIX) (374 mg, 0.750 mmol, 59.4% yield) as a foamy beige 15 solid. ESIMS found for C17H24ClFN6O2m / z 399.2 (M-Boc+H). Step 2

[0321] To a solution of tert-butyl (3R,4S)-4-((4-((tert-butoxycarbonyl)(methyl) amino)-5-chloropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidine-1-carboxylate 20 (LXIX) (374 mg, 0.75 mmol) in DCM (8 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 2 h. The mixture was evaporated, and the crude product was purified by column chromatography (0 5% 7.0 M NH3 in MeOH / CHCl3) to give 5-chloro-N2-((3R,4S)-3-fluoropiperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXX) (226 mg, 0.757 mmol, 100.9% yield) as a fluffy white solid. ESIMS found for C12H16ClFN625 m / z 299.05 (M+1).SMi.089PCT (BTP-002WO) Step 3

[0322] 5-chloro-N2-((3R,4S)-3-fluoropiperidin-4-yl)-N4-methylpyrrolo[2,1- f][1,2,4]triazine-2,4-diamine (LXX) (80 mg, 0.27 mmol) was suspended in dry DCE (2 mL) 5 before adding oxetan-3-one (LXII) (50 μL, 0.85 mmol). NaH(OAc)3(85 mg, 0.4 mmol) was added and the reaction was heated to 60°C for 30 min. LCMS showed SM remaining, therefore, an additional portion of oxetan-3-one (LXII) (50 μL, 0.85 mmol) and NaH(OAc)3(85 mg, 0.4 mmol) were added and the reaction was heated 60°C for another 5 min. LCMS showed the reaction to be complete. The reaction mixture was loaded onto Celite®and purified by column10 chromatography (0 2% MeOH / CHCl3) to give 5-chloro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXI) (71 mg, 0.200 mmol, 74.7% yield) as a pale-yellow solid. ESIMS found for C15H20ClFN6O m / z 355.2 (M+1). Step 4 15

[0323] To a solution of 5-chloro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin- 4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXI) (13 mg, 0.04 mmol) in 1,4- dioxane (300 μL) was added a 2 M aqueous solution of K2PO4(55 μL, 0.11 mmol). The reaction was purged and sonicated with Ar for 5 min. The reaction was then heated to 110°C and then removed from the heat before adding [3-(2-fluoroethyl)triazolo[4,5-b]pyridin-5-yl]boronic acid 20 (LXXII) (15 mg, 0.07 mmol), Pd(OAc)2(1 mg, 0. mmol), and XPhos (3 mg, 0.01 mmol). The reaction was sealed and stirred at 110°C for 20 min. The mixture was loaded onto Celite®and purified by column chromatography (0 4% MeOH / CHCl3). The product was further purifiedby HPLC (0 30% MeCN / H2O (0.1% formic acid)) to produce N2-((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4- 25 methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (236) (14 mg, 0.029 mmol, 78.9% yield) as a fluffy yellow solid.1H NMR (499 MHz, DMSO-d6) ppm 1.67 - 1.75 (1 H, m), 1.88 (1 H, qd, J=12.05, 3.83 Hz), 1.96 - 2.04 (1 H, m), 2.14 (1 H, dd, J=37.00, 12.87 Hz), 2.75 (1 H, br d, J=10.95 Hz), 2.92 - 3.03 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.49 (1 H, quin, J=6.37 Hz), 3.74 - 3.91 (1 H, m), 4.40 (1 H, t, J=6.16 Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.57, 3.29 30 Hz), 4.91 (1 H, d, J=50.15 Hz), 4.97 - 5.05 (2 H, m), 5.08 (2 H, s), 6.15 (1 H, d, J=7.94 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 8.08 (1 H, d, J=9.03 Hz), 8.53 (1 H, d, J=9.04 Hz), 11.00 (1 H, q, J=4.47 Hz); ESIMS found for C22H26F2N10O m / z 243.2 (M / 2+1). 35

[0324] Preparation of 1-((3R,4S)-3-Fluoro-4-((5-(3-(2-fluoroethyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)piperidin-1-yl)ethan-1-one (235) is depicted below in Scheme 14.SMi.089PCT (BTP-002WO)Scheme 14 Step 1 5

[0325] To a solution of HATU (107 mg, 0.28 mmol) in DCM (2 mL) was added HOAc (19 μL, 0.33 mmol) and DIPEA (98 μL, 0.56 mmol) were added and the reaction was stirred for 5 min. 5-Chloro-N2-((3R,4S)-3-fluoropiperidin-4-yl)-N4-methylpyrrolo[2,1- f][1,2,4]triazine-2,4-diamine (LXX) (70 mg, 0.23 mmol) was then added and the reaction was stirred at room temperature for 10 min. The reaction mixture was purified by column10 chromatography (0 2% MeOH / CHCl3) to produce 1-((3R,4S)-4-((5-chloro-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one (LXXIII) (85 mg, 0.249 mmol, 106.5% yield) as a fluffy white solid. ESIMS found for C14H18ClFN6O m / z 341.1 (M+H). 15

[0326] To a solution of 1-((3R,4S)-4-((5-chloro-4-(methylamino)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one (LXXIII) (13 mg, 0.04 mmol) in 1,4-dioxane (300 μL) was added a 2 M aqueous solution of K2PO4(57 μL, 0.11 mmol) and the reaction was purged and sonicated with Ar for 5 min. The reaction was the heated to 110°C20 and then removed from the heat before adding [3-(2-fluoroethyl)triazolo[4,5-b]pyridin-5- yl]boronic acid (LXXII) (16 mg, 0.08 mmol), Pd(OAc)2 (1 mg, 0.0045 mmol), and XPhos (3 mg, 0.01 mmol). The reaction was sealed and stirred at 110°C for 20 min. The reaction mixture was loaded onto Celite® and the product was purified by column chromatography (0 3%MeOH / CHCl3). The product was further purified by HPLC (0 60% MeCN / H2O (0.1% formic25 acid)) to give 1-((3R,4S)-3-Fluoro-4-((5-(3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one (235) (9 mg, 0.019 mmol, 50.1% yield) as a fluffy yellow solid after lyophilization.1H NMR (499 MHz, DMSO-d6) ppm 1.59 - 1.89 (2 H, m), 1.96 - 2.07 (3 H, m), 2.59 - 2.78 (1 H, m), 2.79 - 2.95 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.83 - 4.00 (1 H, m), 4.01 - 4.19 (1 H, m), 4.40 - 4.75 30 (1 H, m), 4.89 - 5.02 (1 H, m), 4.97 - 5.06 (2 H, m), 5.08 (2 H, s), 6.27 (1 H, d, J=7.94 Hz), 7.33 (1 H, d, J=3.29 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.09 (1 H, d, J=9.31 Hz), 8.54 (1 H, d, J=9.03 Hz), 11.01 (1 H, q, J=4.95 Hz); ESIMS found for C21H24F2N10O m / z 471.2 (M+1).SMi.089PCT (BTP-002WO) Example 4.

[0327] Preparation of 5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)- N2-((3R,4S)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4- 5Scheme 15 Step 1

[0328] To a stirring solution of 2-bromoethyl methyl ether (LXXIV) (30 μL, 0.3210 mmol) in DMF (1 mL) was added K2CO3(51 mg, 0.37 mmol) and 5-chloro-N2-((3R,4S)-3- fluoropiperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXX) (95 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h before pouring mixture into a mixture of EtOAc and water. The aqueous layer was extracted with EtOAc (2x), the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated.15 The crude product was purified via column chromatography (8 g of silica gel ) (0 8% 7 NNH3in MeOH / CHCl3) to yield 5-chloro-N2-((3R,4S)-3-fluoro-1-(2-methoxyethyl)piperidin-4- yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXV) (91 mg, 0.266 mmol, 79.6% yield) as an amber viscous solid. ESIMS found for C14H20ClFN6O m / z 343.1 (M+1). 20

[0329] To a solution of 5-chloro-N2-((3R,4S)-3-fluoro-1-(2- methoxyethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXV) (15 mg, 0.04 mmol) in 1,4-dioxane (0.5 mL) was added a 2 M aqueous solution of K2PO4(66 μL, 0.13 mmol) and the mixture was heated to 110°C and then removed from the heat before adding [3-(2,2- 25 difluoroethyl)imidazo[4,5-b]pyridin-5-yl]boronic acid (LXXVI) (28.3 mg, 0.12 mmol), Pd(OAc)2(2.4 mg, 0.01 mmol), and XPhos (4.8 mg, 0.01 mmol). The reaction was sealed and heated at 110°C for 30 min. The reaction mixture was loaded onto Celite®and the product was purified via reverse phase chromatography using a 15.5 g ISCO column (0 100% MeCN / H2O(0.1% formic acid)) to produce 5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N2- 30 ((3R,4S)-3-fluoro-1-(2-methoxyethyl) piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (121) (22 mg, 0.045 mmol, 51.4% yield) as a white solid after lyophilization.1H NMR (499 MHz, DMSO-d6) ppm 1.59 - 1.71 (1 H, m), 1.83 (1 H, qd, J=12.18, 3.70 Hz), 2.15 (1 H, br t,SMi.089PCT (BTP-002WO) J=11.09 Hz), 2.29 (1 H, dd, J=38.10, 12.59 Hz), 2.51 (2 H, t, J=5.75 Hz), 2.82 - 2.94 (1 H, m), 3.08 - 3.18 (1 H, m), 3.24 (3 H, s), 3.43 (2 H, t, J=5.75 Hz), 3.68 - 3.85 (1 H, m), 4.74 (2 H, td, J=16.63, 2.05 Hz), 4.84 (1 H, d, J=50.20 Hz), 5.79 (1 H, d, J=8.21 Hz), 6.48 (1 H, tt, J=54.30, 2.46 Hz), 7.14 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.59 (1 H, br s), 7.88 (1 H, d, 5 J=8.76 Hz), 8.15 (1 H, d, J=8.49 Hz), 8.40 (1 H, s), 10.57 (1 H, br s); ESIMS found for C22H26F3N9O m / z 490.2 (M+1).

[0330] Preparation of 1-((3R,4S)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-10 [1,2,3] triazolo[4,5-b]pyridin-5-yl)-6-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3- fluoropiperidin-1-yl)ethan-1-one (258) is depicted below in Scheme 16.Scheme 16 15 Step 1

[0331] 5-Bromo-2-chloro-N-(2,4-dimethoxybenzyl)-6-fluoropyrrolo[2,1- f][1,2,4] triazin-4-amine (XXXIV) (507 mg, 1.22 mmol) and DMAP (75 mg, 0.61 mmol) were dissolved in DCE (5 mL) and di-tert-butyl decarbonate (420 μL, 1.83 mmol) and TEA (520 μL, 3.73 mmol) were added and the reaction was stirred at 45°C for 16 h. LCMS showed the 20 reaction to be complete. The reaction mixture was loaded onto Celite®and was purified by column chromatography (0 5% EtOAc / hexanes) to yield tert-butyl (5-bromo-2-chloro-6-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)(2,4-dimethoxybenzyl)carbamate (LXXVII) (385 mg, 0.747 mmol, 61.2% yield) as a pale-yellow foamy solid. ESIMS found for C20H21BrClFN4O4m / z 415. (M-Boc+1). 25SMi.089PCT (BTP-002WO)

[0332] tert-Butyl (5-bromo-2-chloro-6-fluoropyrrolo[2,1-f][1,2,4]triazin-4- yl)(2,4-dimethoxybenzyl)carbamate (LXXVII) (100 mg, 0.19 mmol) andtBuXPhos-Pd-G3 (17 mg, 0.02 mmol) were suspended in dry 1,4-dioxane (2 mL) and the reaction mixture was bubbled with Ar for 2 min. tert-Butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate 5 (LXVIII) (53 mg, 0.24 mmol) and sodium tert-butoxide (70 mg, 0.73 mmol) were added, the reaction vial was sealed and stirred at 90°C for 30 min. LCMS showed the reaction to be complete. The reaction mixture poured into a saturated aqueous NH4Cl solution and DCM, and the organic layer was separated. The aqueous layer was extracted with DCM (×2) and the combined organic layers were dried (MgSO4) and reduced in vacuo to give the crude product 10 as an orange semi-solid. The product was purified by column chromatography (wet load in DCM, 0 45% EtOAc / hexanes) to give tert-butyl (3R,4S)-4-((5-bromo-4-((tert-butoxycarbonyl)(2,4-dimethoxybenzyl)amino)-6-fluoropyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)-3-fluoropiperidine-1-carboxylate (LXXVIII) (68 mg, 0.098 mmol, 50.3% yield) as a pale-yellow semi-solid. ESIMS found for C30H39BrF2N6O6did not ionize. 15 Step 3

[0333] tert-Butyl (3R,4S)-4-((5-bromo-4-((tert-butoxycarbonyl)(2,4- dimethoxybenzyl)amino)-6-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidine- 1-carboxylate (LXXVIII) (68 mg, 0.1 mmol) was dissolved in DCM (4 mL) before adding 20 TFA (1 mL). The reaction was stirred at room temperature for 1 h. LCMS showed the reaction to be complete. The reaction mixture was blown dry and the resulting green semi-solid was purified by column chromatography (0 3% hold 7.0 M NH3 in MeOH / CHCl3) to produce 5-bromo-6-fluoro-N2-((3R,4S)-3-fluoropiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXIX) (30 mg, 0.086 mmol, 88.6% yield) as a pale-yellow semi-solid. ESIMS found for 25 C11H13BrF2N6m / z 347.0 (M+1). Step 4

[0334] HATU (39 mg, 0.1 mmol) was dissolved in DCM (300 μL) and acetic acid (13 μL, 0.23 mmol) and DIPEA (37 μL, 0.21 mmol) were added. The reaction was stirred at30 room temperature for 5 min. 5-Bromo-6-fluoro-N2-((3R,4S)-3-fluoropiperidin-4- yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXIX) (30 mg, 0.09 mmol) was dissolved in DCM (300 μL) and this was added to the reaction which was stirred at room temperature for 10 min. LCMS confirmed the reaction to be complete. The reaction mixture was added to Celite® and the product was purified by column chromatography (0 3% hold MeOH / CHCl3)35 to give 1-((3R,4S)-4-((4-amino-5-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3- fluoropiperidin-1-yl)ethan-1-one (LXXX) (15 mg, 0.039 mmol, 44.6% yield) as a pale-yellow semi-solid. ESIMS found for C13H15BrF2N6O m / z 389.05 (M+1).SMi.089PCT (BTP-002WO) Step 5

[0335] 1-((3R,4S)-4-((4-amino-5-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazin-2- yl) amino)-3-fluoropiperidin-1-yl)ethan-1-one (LXXX) (5 mg, 0.01 mmol) and XPhos Pd G3 5 (0.5 mg, 0.0006 mmol) were suspended in dry 1,4-dioxane (200 μL) before adding a 2 M aqueous solution of K2PO4(19 μL, 0.04 mmol). The reaction was sonicated and bubbled with Ar for 2 min and then heated to 90°C. (3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin- 5-yl)boronic acid (XLIX) (6 mg, 0.03 mmol) was added and the reaction was sealed and stirred at 90oC for 15 min. LCMS showed starting material remaining, therefore, the reaction was 10 removed from the heat and an additional portion of XPhos Pd G3 (0.5 mg, 0.0006 mmol) and a 2 M aqueous solution of K2PO4(19 μL, 0.04 mmol) were added and the reaction was sonicated and bubbled with Ar for 2 min before reheating to 90°C. An additional portion of (3-(2,2- difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)boronic acid (XLIX) (6 mg, 0.03 mmol) was added and the reaction vial was resealed and stirred at 90oC for 10 min. LCMS showed the 15 reaction to be complete. The reaction mixture was added to Celite®and the product was purified by column chromatography (0 3% hold MeOH / CHCl3). The product was further purifiedusing HPLC (0 60% hold MeCN / H2O in 0.1% formic acid) to yield 1-((3R,4S)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoropyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one (258) (6 mg, 0.012 mmol, 20 94.8% yield) as a fluffy yellow solid.1H NMR (499 MHz, DMSO-d6) ppm 1.59 - 1.69 (1 H, m), 1.71 - 1.87 (1 H, m), 1.99 (3 H, s), 2.59 - 2.73 (1 H, m), 3.09 - 3.24 (1 H, m), 3.82 - 3.96 (1 H, m), 3.98 - 4.17 (1 H, m), 4.41 - 4.72 (1 H, m), 4.93 (1 H, d, J=49.90 Hz), 5.19 (2 H, td, J=16.22, 2.33 Hz), 6.31 (1 H, d, J=8.21 Hz), 6.60 (2 H, tt, J=54.00, 2.60 Hz), 7.68 (1 H, d, J=1.92 Hz), 7.75 (1 H, br s), 7.94 (1 H, d, J=8.76 Hz), 8.67 (1 H, d, J=9.03 Hz), 9.71 (1 H, br 25 s); ESIMS found for C20H20F4N10O m / z 493.15 (M+1).

[0336] The following compounds were prepared in accordance with the procedures described in the above Schemes 1-16.30 38

[0337] 1-((3R,4S)-4-((4-Amino-6-fluoro-5-(imidazo[1,2-b]pyridazin-6- yl)pyrrolo [2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one 38.SMi.089PCT (BTP-002WO)

[0338] Pale-yellow fluffy solid (10 mg, 0.023 mmol, 91.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.60 - 1.70 (1 H, m), 1.71 - 1.86 (1 H, m), 1.99 (3 H, s), 2.61 - 2.89 (1 H, m), 3.13 - 3.24 (1 H, m), 3.82 - 3.96 (1 H, m), 3.97 - 4.17 (1 H, m), 4.40 - 4.73 (1 H, m), 4.92 (1 H, d, J=49.05 Hz), 6.27 (1 H, d, J=8.21 Hz), 6.662 (1 H, s), 7.57 (1 H, d, J=8.76 Hz), 5 7.68 (1 H, d, J=2.19 Hz), 7.80 (1 H, d, J=1.10 Hz), 7.99 (1 H, br s), 8.21 (1 H, d, J=9.86 Hz), 8.31 (1 H, s); ESIMS found for C19H19F2N9O m / z 428.15 (M+1).39

[0339] 6-Fluoro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo 10 [1,2-b]pyridazin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 39.

[0340] Fluffy pale-yellow solid (4 mg, 0.009 mmol, 91.3% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.64 - 1.74 (1 H, m), 1.86 (1 H, qd, J=11.96, 3.56 Hz), 1.94 - 2.03 (1 H, m), 2.11 (1 H, dd, J=36.75, 12.59 Hz), 2.73 (1 H, br d, J=11.77 Hz), 2.97 (1 H, br t, J=10.95 Hz), 3.48 (1 H, quin, J=6.50 Hz), 3.71 - 3.87 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, 15 J=6.16 Hz), 4.53 (2 H, td, J=6.50, 2.60 Hz), 4.86 (1 H, d, J=49.90 Hz), 6.16 (1 H, d, J=8.21 Hz), 6.71 (1 H, br s), 7.57 (1 H, d, J=8.76 Hz), 7.68 (1 H, d, J=2.19 Hz), 7.80 (1 H, d, J=1.37 Hz), 7.99 (1 H, br s), 8.21 (1 H, d, J=9.86 Hz), 8.30 (1 H, s); ESIMS found for C20H21F2N9O m / z 442.15 (M+1).20 40

[0341] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-6-fluoro-5-(imidazo[1,2-b] pyridazin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 40.

[0342] Pale-yellow fluffy solid (3 mg, 0.007 mmol, 32.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.69 - 1.87 (2 H, m), 2.06 - 2.18 (1 H, m), 2.24 (3 H, s), 2.32 (1 H, dd, 25 J=26.60, 12.32 Hz), 2.77 (1 H, br d, J=11.50 Hz), 2.99 - 3.10 (1 H, m), 4.12 - 4.29 (1 H, m), 6.35 (1 H, br d, J=9.58 Hz), 6.79 (1 H, br s), 7.57 (1 H, d, J=9.58 Hz), 7.70 (1 H, d, J=2.19 Hz), 7.80 (1 H, s), 8.00 (1 H, br s), 8.21 (1 H, d, J=9.58 Hz), 8.30 (1 H, s); ESIMS found for C18H18F3N9 m / z 418.2 (M+1).SMi.089PCT (BTP-002WO)

[0343] (R)-1-(4-((4-Amino-6-fluoro-5-(imidazo[1,2-b]pyridazin-6- yl)pyrrolo[2,1-f] [1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one 41. 5

[0344] Pale-yellow fluffy solid (4 mg, 0.009 mmol, 66.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.55 - 1.80 (1 H, m), 1.81 - 1.96 (1 H, m), 2.06 (3 H, s), 2.97 (1 H, br t, J=10.95 Hz), 3.59 - 3.88 (1 H, m), 4.07 - 4.25 (1 H, m), 4.40 - 4.56 (2 H, m), 6.55 (1 H, br d, J=9.31 Hz), 6.70 (1 H, s), 7.57 (1 H, d, J=9.03 Hz), 7.69 (1 H, d, J=2.19 Hz), 7.81 (1 H, d, J=1.10 Hz), 8.01 (1 H, br s), 8.21 (1 H, d, J=9.58 Hz), 8.31 (1 H, s); ESIMS found for 10 C19H18F3N9O m / z 446.15 (M+1).43

[0345] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-6-fluoro-5-(imidazo [1,2-b]pyridazin-6-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 43. 15

[0346] Pale-yellow fluffy solid (5 mg, 0.011 mmol, 76.4% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 - 1.82 (1 H, m), 1.82 - 1.90 (1 H, m), 2.11 (1 H, br t, J=10.54 Hz), 2.34 (1 H, dd, J=26.60, 11.50 Hz), 2.74 (1 H, br d, J=11.50 Hz), 2.95 - 3.06 (1 H, m), 3.59 (1 H, quin, J=6.37 Hz), 4.19 - 4.34 (1 H, m), 4.43 (2 H, dt, J=14.10, 6.09 Hz), 4.54 (2 H, td, J=6.57, 3.56 Hz), 6.42 (1 H, br d, J=9.58 Hz), 6.71 (1 H, br s), 7.57 (1 H, d, J=9.03 Hz), 7.69 20 (1 H, d, J=2.19 Hz), 7.80 (1 H, d, J=1.10 Hz), 8.00 (1 H, br s), 8.21 (1 H, d, J=9.58 Hz), 8.30 (1 H, s); ESIMS found for C20H20F3N9O m / z 460.2 (M+1).

[0347] (R)-1-(3,3-Difluoro-4-((5-(imidazo[1,2-b]pyridazin-6-yl)-4- 25 (methylamino) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one 46.SMi.089PCT (BTP-002WO)

[0348] Yellow solid (11 mg, 0.025 mmol, 82.9% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.56 - 1.81 (1 H, m), 1.83 - 1.98 (1 H, m), 2.07 (3 H, s), 2.94 - 3.06 (1 H, m), 3.15 (3 H, d, J=4.65 Hz), 3.58 - 3.92 (1 H, m), 4.07 - 4.29 (1 H, m), 4.41 - 4.61 (2 H, m), 6.53 (1 H, d, J=3.83 Hz), 7.25 (1 H, d, J=3.01 Hz), 7.46 (1 H, d, J=3.01 Hz), 7.76 (1 H, d, J=1.10 5 Hz), 7.82 (1 H, d, J=9.86 Hz), 8.14 (1 H, d, J=9.86 Hz), 8.43 (1 H, s), 9.99 (1 H, q, J=4.38 Hz); ESIMS found for C20H21F2N9O m / z 442.15 (M+1).

[0349] (R)-N2-(3,3-Difluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(imidazo[1,2- 10 b]pyridazin-6-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 48.

[0350] Yellow solid (7 mg, 0.015 mmol, 58.6% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.79 - 1.92 (1 H, m), 1.94 - 2.04 (1 H, m), 2.98 (3 H, s), 3.11 - 3.19 (1 H, m), 3.16 (3 H, d, J=4.65 Hz), 3.44 (1 H, dd, J=25.80, 12.05 Hz), 3.53 - 3.64 (1 H, m), 3.72 - 3.83 (1 H, m), 4.40 - 4.57 (1 H, m), 6.60 (1 H, d, J=9.58 Hz), 7.25 (1 H, d, J=3.01 Hz), 7.45 (1 H, d, 15 J=3.01 Hz), 7.76 (1 H, s), 7.82 (1 H, d, J=9.86 Hz), 8.14 (1 H, d, J=9.86 Hz), 8.43 (1 H, s), 10.00 (1 H, q, J=4.47 Hz); ESIMS found for C19H21F2N9O2S m / z 478.2 (M+1).

[0351] 1-((3R,4S)-3-Fluoro-4-((6-fluoro-5-(imidazo[1,2-b]pyridazin-6-yl)-4- 20 (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one 53.

[0352] Pale yellow solid (28 mg, 0.063 mmol, 79.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.61 - 1.71 (1 H, m), 1.72 - 1.88 (1 H, m), 1.99 (3 H, s), 2.59 - 2.92 (1 H, m), 3.07 (3 H, d, J=4.93 Hz), 3.12 - 3.23 (1 H, m), 3.83 - 3.99 (1 H, m), 4.01 - 4.16 (1 H, m), 4.39 - 4.73 (1 H, m), 4.94 (1 H, d, J=49.35 Hz), 6.40 (1 H, d, J=7.94 Hz), 7.59 (1 H, d, J=9.31 Hz), 25 7.65 (1 H, d, J=2.19 Hz), 7.81 (1 H, d, J=1.09 Hz), 8.21 (1 H, d, J=9.86 Hz), 8.47 (1 H, s), 9.13 (1 H, q, J=4.65 Hz); ESIMS found for C20H21F2N9O m / z 442.1 (M+1).SMi.089PCT (BTP-002WO)54

[0353] 6-Fluoro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo [1,2-b]pyridazin-6-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 54. 5

[0354] Orange solid (23 mg, 0.051 mmol, 80.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.64 - 1.75 (1 H, m), 1.88 (1 H, qd, J=12.14, 3.56 Hz), 1.95 - 2.04 (1 H, m), 2.12 (1 H, dd, J=37.60, 12.59 Hz), 2.69 - 2.80 (1 H, m), 2.90 - 3.02 (1 H, m), 3.07 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.30 Hz), 3.70 - 3.89 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.53 (2 H, td, J=6.50, 3.15 Hz), 4.89 (1 H, d, J=49.65 Hz), 6.28 (1 H, d, J=7.94 10 Hz), 7.59 (1 H, d, J=9.58 Hz), 7.64 (1 H, d, J=2.19 Hz), 7.81 (1 H, d, J=1.10 Hz), 8.21 (1 H, d, J=9.58 Hz), 8.46 (1 H, s), 9.12 (1 H, q, J=4.65 Hz); ESIMS found for C21H23F2N9O m / z 456.2 (M+1).55 15

[0355] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-6-fluoro-5-(imidazo[1,2-b] pyridazin-6-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 55.

[0356] Pale yellow solid (14 mg, 0.033 mmol, 90.3% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.71 - 1.90 (2 H, m), 2.14 (1 H, td, J=11.23, 2.74 Hz), 2.25 (3 H, s), 2.34 (1 H, ddd, J=26.85, 11.77, 1.65 Hz), 2.32 (1 H, br d, J=11.77 Hz), 2.77 (1 H, br d, J=11.77 Hz), 20 3.00 - 3.06 (1 H, m), 3.08 (3 H, d, J=4.93 Hz), 4.12 - 4.31 (1 H, m), 6.44 (1 H, br d, J=9.31 Hz), 7.59 (1 H, d, J=9.58 Hz), 7.66 (1 H, d, J=2.19 Hz), 7.81 (1 H, s), 8.21 (1 H, d, J=9.86 Hz), 8.46 (1 H, s), 9.14 (1 H, q, J=4.65 Hz); ESIMS found for C19H20F3N9 m / z 432.2 (M+1).56 25

[0357] (R)-1-(3,3-Difluoro-4-((6-fluoro-5-(imidazo[1,2-b]pyridazin-6-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one 56.SMi.089PCT (BTP-002WO)

[0358] Off-white solid (15 mg,0.033 mmol, 90.9% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.54 - 1.78 (1 H, m), 1.81 - 1.99 (1 H, m), 2.06 (3 H, s), 2.98 (1 H, br t, J=11.23 Hz), 3.09 (3 H, d, J=4.65 Hz), 3.66 - 3.91 (1 H, m), 4.08 - 4.26 (1 H, m), 4.42 - 4.59 (2 H, m), 6.64 (1 H, br d, J=9.58 Hz), 7.60 (1 H, d, J=9.58 Hz), 7.65 (1 H, d, J=2.19 Hz), 7.82 5 (1 H, d, J=1.10 Hz), 8.22 (1 H, d, J=9.58 Hz), 8.47 (1 H, s), 9.16 (1 H, q, J=4.75 Hz); ESIMS found for C20H20F3N9O m / z 460.15 (58

[0359] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-6-fluoro-5- 10 (imidazo[1,2-b]pyridazin-6-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 58.

[0360] Yellow solid (15 mg, 0.032 mmol, 88.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.71 - 1.83 (1 H, m), 1.84 - 1.92 (1 H, m), 2.07 - 2.19 (1 H, m), 2.37 (1 H, ddd, J=26.05, 11.50, 1.65 Hz), 2.75 (1 H, br d, J=11.50 Hz), 2.94 - 3.04 (1 H, m), 3.08 (3 H, d, J=4.65 Hz), 3.59 (1 H, quin, J=6.30 Hz), 4.16 - 4.35 (1 H, m), 4.43 (2 H, dt, J=14.78, 6.16 Hz), 15 4.54 (2 H, td, J=6.57, 3.56 Hz), 6.52 (1 H, d, J=9.58 Hz), 7.59 (1 H, d, J=9.58 Hz), 7.66 (1 H, d, J=2.19 Hz), 7.81 (1 H, d, J=1.09 Hz), 8.21 (1 H, d, J=9.58 Hz), 8.46 (1 H, s), 9.14 (1 H, q, J=4.65 Hz); ESIMS found for C21H22F3N9O m / z 474.2 (M+1).20

[0361] (1r,4r)-4-((4-Amino-5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 112.

[0362] Fluffy pale yellow solid (6 mg, 0.014 mmol, 41.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.13 (3 H, s), 1.34 - 1.48 (4 H, m), 1.53 - 1.63 (2 H, m), 1.77 - 1.89 (2 H, m), 3.61 (1 H, br d, J=3.83 Hz), 4.22 (1 H, s), 4.58 (2 H, dt, J=27.70, 4.65 Hz), 4.82 (2 H, 25 dt, J=47.15, 4.65 Hz), 5.78 (1 H, d, J=8.21 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.47 (1 H, br s), 7.86 (1 H, d, J=8.76 Hz), 8.12 (1 H, d, J=8.76 Hz), 8.41 (1 H, s), 10.68 (1 H, br s); ESIMS found for C21H25FN8O m / z 425.2 (M+1).SMi.089PCT (BTP-002WO)

[0363] N2-((3R,4S)-3-Fluoro-1-methylpiperidin-4-yl)-5-(3-(2-fluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 113. 5

[0364] White solid (6 mg, 0.014 mmol, 28.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.60 - 1.71 (1 H, m), 1.86 (1 H, qd, J=12.27, 3.97 Hz), 1.97 - 2.06 (1 H, m), 2.07 - 2.21 (1 H, m), 2.18 (3 H, s), 2.78 (1 H, br d, J=11.23 Hz), 2.98 - 3.09 (1 H, m), 3.64 - 3.84 (1 H, m), 4.58 (2 H, dt, J=27.70, 4.65 Hz), 4.82 (2 H, dt, J=46.90, 4.65 Hz), 4.85 (1 H, d, J=50.20 Hz), 5.80 (1 H, d, J=8.21 Hz), 7.15 (1 H, d, J=2.74 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.61 10 (1 H, br s), 7.87 (1 H, d, J=8.76 Hz), 8.13 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 10.76 (1 H, br s); ESIMS found for C20H23F2N9m / z 428.25 (M+1).

[0365] N2-((3R,4S)-3-Fluoro-1-(2-methoxyethyl)piperidin-4-yl)-5-(3-(2- 15 fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 114.

[0366] White solid (10 mg, 0.021 mmol, 24.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.59 - 1.71 (1 H, m), 1.83 (1 H, qd, J=12.27, 3.70 Hz), 2.15 (1 H, br t, J=10.81 Hz), 2.29 (1 H, dd, J=38.15, 12.59 Hz), 2.51 - 2.53 (2 H, m), 2.89 (1 H, br d, J=11.22 Hz), 3.14 (1 H, br t, J=10.54 Hz), 3.24 (3 H, s), 3.43 (2 H, t, J=5.75 Hz), 3.68 - 3.85 (1 H, m), 4.58 (2 H, 20 dt, J=27.70, 4.65 Hz), 4.82 (2 H, dt, J=46.90, 4.65 Hz), 4.84 (1 H, d, J=49.90 Hz), 5.80 (1 H, d, J=8.21 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=3.01 Hz), 7.60 (1 H, br s), 7.87 (1 H, d, J=8.76 Hz), 8.13 (1 H, d, J=8.49 Hz), 8.42 (1 H, s), 10.76 (1 H, br s); ESIMS found for C22H27F2N9O m / z 472.2 (M+1). 25SMi.089PCT (BTP-002WO)

[0367] 1-((3R,4S)-4-((4-Amino-5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin- 5-yl) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one 115.

[0368] White solid (8 mg, 0.018 mmol, 19.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.57 - 1.85 (2 H, m), 1.96 - 2.06 (3 H, m), 2.60 - 2.97 (2 H, m), 3.81 - 3.97 5 (1 H, m), 3.99 - 4.18 (1 H, m), 4.37 - 4.51 (1 H, m), 4.59 (2 H, dt, J=27.70, 4.65 Hz), 4.83 (2 H, dt, J=47.15, 4.65 Hz), 4.95 (1 H, d, J=48.80 Hz), 6.00 (1 H, d, J=4.93 Hz), 7.16 (1 H, d, J=2.74 Hz), 7.40 (1 H, d, J=3.01 Hz), 7.61 (1 H, br s), 7.88 (1 H, d, J=8.76 Hz), 8.13 (1 H, d, J=8.49 Hz), 8.42 (1 H, s), 10.78 (1 H, br s); ESIMS found for C21H23F2N9O m / z 456.1 (M+1).10 116

[0369] N2-((3S,4R)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2- fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 116.

[0370] White solid (17.4 mg, 0.037 mmol, 42.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.65 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.14, 3.56 Hz), 1.93 - 2.02 (1 H, m), 15 2.12 (1 H, dd, J=37.30, 12.59 Hz), 2.69 - 2.79 (1 H, m), 2.91 - 3.03 (1 H, m), 3.48 (1 H, quin, J=6.43 Hz), 3.72 - 3.90 (1 H, m), 4.39 (1 H, t, J=6.30 Hz), 4.45 (1 H, t, J=6.02 Hz), 4.53 (2 H, td, J=6.57, 2.74 Hz), 4.58 (2 H, dt, J=28.00, 4.65 Hz), 4.82 (2 H, dt, J=47.20, 4.65 Hz), 4.88 (1 H, d, J=49.35 Hz), 5.88 (1 H, d, J=8.21 Hz), 7.15 (1 H, d, J=3.29 Hz), 7.39 (1 H, d, J=3.29 Hz), 7.60 (1 H, br s), 7.87 (1 H, d, J=8.76 Hz), 8.13 (1 H, d, J=8.21 Hz), 10.76 (1 H, br s); ESIMS 20 found for C22H25F2N9O m / z 470.15 (M+1).117

[0371] N2-((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2- fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 117. 25

[0372] Off-white solid (19.8 mg, 0.042 mmol, 47.9% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 (1 H, br d, J=9.86 Hz), 1.85 (1 H, qd, J=11.86, 2.74 Hz), 1.93 - 2.01 (1 H, m), 2.11 (1 H, dd, J=37.30, 12.59 Hz), 2.73 (1 H, br d, J=10.40 Hz), 2.96 (1 H, br t, J=10.40 Hz), 3.47 (1 H, quin, J=6.05 Hz), 3.71 - 3.88 (1 H, m), 4.39 (1 H, br t, J=6.02 Hz), 4.45 (1 H, br t, J=6.02 Hz), 4.48 - 4.55 (2 H, m), 4.55 - 4.65 (2 H, m), 4.83 (2 H, dt, J=47.20, 4.28 Hz),SMi.089PCT (BTP-002WO) 4.88 (1 H, d, J=49.35 Hz), 5.88 (1 H, br d, J=8.21 Hz), 7.14 (1 H, d, J=2.74 Hz), 7.39 (1 H, d, J=2.19 Hz), 7.61 (1 H, br s), 7.87 (1 H, br d, J=8.21 Hz), 8.14 (1 H, br d, J=7.67 Hz), 10.77 (1 H, br s); ESIMS found for C22H25F2N9O m / z 470.2 (M+1).5 118

[0373] (R)-1-(4-((4-Amino-5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one118.

[0374] Fluffy pale-yellow solid (26 mg, 0.055 mmol, 47.3% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.52 - 1.78 (1 H, m), 1.80 - 1.97 (1 H, m), 2.02 - 2.08 (3 H, m), 2.91 - 10 3.02 (1 H, m), 3.63 - 3.89 (1 H, m), 4.08 - 4.28 (1 H, m), 4.40 - 4.54 (2 H, m), 4.59 (2 H, dt, J=27.70, 4.65 Hz), 4.83 (2 H, dt, J=47.15, 4.65 Hz), 6.29 (1 H, br d, J=6.02 Hz), 7.17 (1 H, d, J=3.01 Hz), 7.41 (1 H, d, J=1.37 Hz), 7.64 (1 H, br s), 7.88 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 10.82 (1 H, br s); ESIMS found for C21H22F3N9O m / z 474.2 (M+1).15 119

[0375] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)- 3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 119.

[0376] White solid (5 mg, 0.010 mmol, 12.3% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.66 - 1.82 (1 H, m), 1.86 (1 H, br dd, J=8.49, 4.11 Hz), 2.11 (1 H, br t, 20 J=10.68 Hz), 2.35 (1 H, dd, J=26.30, 11.77 Hz), 2.74 (1 H, br d, J=11.23 Hz), 2.94 - 3.07 (1 H, m), 3.59 (1 H, quin, J=6.37 Hz), 4.17 - 4.36 (1 H, m), 4.43 (2 H, dt, J=13.83, 6.23 Hz), 4.54 (2 H, dt, J=6.60, 3.60 Hz), 4.59 (2 H, dt, J=27.60, 4.65 Hz), 4.83 (2 H, dt, J=47.15, 4.65 Hz), 6.16 (1 H, br d, J=9.31 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.64 (1 H, br s), 7.88 (1 H, d, J=8.76 Hz), 8.13 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 10.81 (1 H, br s); ESIMS found for 25 C22H24F3N9O m / z 488.2 (M+1).SMi.089PCT (BTP-002WO)

[0377] 5-(3-(2,2-Difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N2-((3R,4S)-3- fluoro-1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 120. 5

[0378] White solid (7 mg, 0.016 mmol, 31.3% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.61 - 1.71 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.70 Hz), 2.02 (1 H, br t, J=11.09 Hz), 2.08 - 2.20 (1 H, m), 2.18 (2 H, s), 2.78 (1 H, br d, J=10.95 Hz), 2.98 - 3.09 (1 H, m), 3.62 - 3.83 (1 H, m), 4.74 (2 H, td, J=16.50, 2.05 Hz), 4.85 (1 H, d, J=49.95 Hz), 5.80 (1 H, d, J=7.94 Hz), 6.48 (1 H, tt, J=54.30, 2.70 Hz), 7.14 (1 H, d, J=2.74 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.59 10 (1 H, br s), 7.88 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.49 Hz), 8.40 (1 H, s), 10.57 (1 H, br s); ESIMS found for C20H22F3N9m / z 446.2 (M+1).

[0379] 5-(3-(2,2-Difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N2-((3R,4S)-3- 15 fluoro-1-(2-methoxyethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 121.

[0380] White solid (22 mg, 0.045 mmol, 51.4% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.59 - 1.71 (1 H, m), 1.83 (1 H, qd, J=12.18, 3.70 Hz), 2.15 (1 H, br t, J=11.09 Hz), 2.29 (1 H, dd, J=38.10, 12.59 Hz), 2.51 (2 H, t, J=5.75 Hz), 2.82 - 2.94 (1 H, m), 3.08 - 3.18 (1 H, m), 3.24 (3 H, s), 3.43 (2 H, t, J=5.75 Hz), 3.68 - 3.85 (1 H, m), 4.74 (2 H, td, 20 J=16.63, 2.05 Hz), 4.84 (1 H, d, J=50.20 Hz), 5.79 (1 H, d, J=8.21 Hz), 6.48 (1 H, tt, J=54.30, 2.46 Hz), 7.14 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.59 (1 H, br s), 7.88 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.49 Hz), 8.40 (1 H, s), 10.57 (1 H, br s); ESIMS found for C22H26F3N9O m / z 490.2 (M+1).SMi.089PCT (BTP-002WO)

[0381] 5-(3-(2,2-Difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N2-((3S,4R)-3- fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 122. 5

[0382] Off-white solid (15 mg, 0.031 mmol, 35.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.64 - 1.76 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.70 Hz), 1.94 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.60, 12.59 Hz), 2.74 (1 H, br d, J=11.23 Hz), 2.97 (1 H, br t, J=10.13 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.70 - 3.90 (1 H, m), 4.39 (1 H, t, J=6.02 Hz), 4.45 (1 H, t, J=6.02 Hz), 4.54 (2 H, td, J=6.43, 2.74 Hz), 4.75 (2 H, td, J=16.70, 2.19 Hz), 4.88 (1 H, d, J=49.95 10 Hz), 5.88 (1 H, d, J=8.21 Hz), 6.48 (1 H, tt, J=54.30, 2.47 Hz), 7.14 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.58 (1 H, br s), 7.88 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.49 Hz), 8.41 (1 H, s), 10.58 (1 H, br s); ESIMS found for C22H24F3N9O m / z 488.2 (M+1).15

[0383] (1r,4r)-4-((4-Amino-5-(3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5- b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 123.

[0384] Off-white solid (1 mg, 0.002 mmol, 9.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.14 (3 H, s), 1.34 - 1.47 (4 H, m), 1.53 - 1.62 (2 H, m), 1.78 - 1.88 (2 H, m), 3.58 - 3.69 (1 H, m), 4.22 (1 H, br s), 5.20 (2 H, q, J=9.22 Hz), 5.77 (1 H, d, J=8.21 Hz), 7.13 20 (1 H, d, J=2.74 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.53 (1 H, br s), 7.91 (1 H, d, J=8.76 Hz), 8.17 (1 H, d, J=8.49 Hz), 8.47 (1 H, s), 10.36 (1 H, br s); ESIMS found for C21H23F3N8O m / z 461.2 (M+1).SMi.089PCT (BTP-002WO)

[0385] (R)-N2-(4,4-Difluoro-1-methylpyrrolidin-3-yl)-5-(3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 124.

[0386] Off-white solid (20 mg, 0.043 mmol, 66.6% yield).1H NMR (499 MHz, DMSO-d6) ppm 2.27 (3 H, s), 2.38 (1 H, t, J=9.03 Hz), 2.51 - 2.62 (1 H, m), 3.17 - 3.24 (2 H, 5 m), 4.53 - 4.67 (1 H, m), 5.21 (2 H, q, J=9.22 Hz), 6.31 (1 H, d, J=9.31 Hz), 7.18 (1 H, d, J=3.01 Hz), 7.42 (1 H, d, J=2.74 Hz), 7.73 (1 H, br s), 7.94 (1 H, d, J=8.76 Hz), 8.19 (1 H, d, J=8.49 Hz), 8.48 (1 H, s), 10.49 (1 H, br s); ESIMS found for C19H18F5N9m / z 468.1 (M+1).10

[0387] N2-((3R,4S)-3-Fluoro-1-methylpiperidin-4-yl)-5-(3-(2,2,2-trifluoroethyl)- 3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 125.

[0388] White solid (6 mg, 0.013 mmol, 25.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.61 - 1.72 (1 H, m), 1.86 (1 H, qd, J=12.14, 3.56 Hz), 2.04 (1 H, br t, J=10.81 Hz), 2.16 (1 H, dd, J=37.55, 13.14 Hz), 2.19 (1 H, s), 2.79 (1 H, br d, J=10.95 Hz), 3.00 - 3.09 15 (1 H, m), 3.67 - 3.80 (1 H, m), 4.86 (1 H, d, J=49.65 Hz), 5.20 (2 H, q, J=9.13 Hz), 5.81 (1 H, d, J=8.21 Hz), 7.16 (1 H, d, J=2.74 Hz), 7.41 (1 H, d, J=2.74 Hz), 7.68 (1 H, br s), 7.93 (1 H, d, J=8.76 Hz), 8.18 (1 H, d, J=8.49 Hz), 8.48 (1 H, s), 10.44 (1 H, br s); ESIMS found for C20H21F4N9m / z 464.15 (M+1). 20

[0389] N2-((3R,4S)-3-Fluoro-1-(2-methoxyethyl)piperidin-4-yl)-5-(3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 126.

[0390] Beige solid (23 mg, 0.045 mmol, 51.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.61 - 1.71 (1 H, m), 1.84 (1 H, qd, J=12.23, 3.83 Hz), 2.16 (1 H, br t, J=11.09 25 Hz), 2.30 (1 H, dd, J=38.10, 12.59 Hz), 2.52 (2 H, t, J=5.89 Hz), 2.90 (1 H, br d, J=11.50 Hz), 3.10 - 3.18 (1 H, m), 3.24 (3 H, s), 3.43 (2 H, br t, J=5.89 Hz), 3.69 - 3.84 (1 H, m), 4.84 (1 H, d, J=49.90 Hz), 5.20 (2 H, q, J=9.03 Hz), 5.80 (1 H, d, J=8.21 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.41 (1 H, d, J=2.74 Hz), 7.67 (1 H, br s), 7.92 (1 H, d, J=8.76 Hz), 8.18 (1 H, d, J=8.76 Hz), 8.47 (1 H, s), 10.44 (1 H, br s); ESIMS found for C22H25F4N9O m / z 508.2 (M+1).SMi.089PCT (BTP-002WO)127

[0391] 1-((3R,4S)-4-((4-Amino-5-(3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b] pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one 127. 5

[0392] White solid (7 mg, 0.014 mmol, 15.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.58 - 1.70 (1 H, m), 1.71 - 1.88 (1 H, m), 1.97 - 2.05 (3 H, m), 2.58 - 2.95 (2 H, m), 3.83 - 3.99 (1 H, m), 4.02 - 4.19 (1 H, m), 4.38 - 4.74 (1 H, m), 4.95 (1 H, d, J=48.85 Hz), 5.21 (2 H, q, J=9.22 Hz), 6.00 (1 H, d, J=4.93 Hz), 7.17 (1 H, d, J=2.74 Hz), 7.41 (1 H, d, J=3.01 Hz), 7.68 (1 H, br s), 7.93 (1 H, d, J=8.76 Hz), 8.18 (1 H, d, J=8.76 Hz), 8.48 (1 H, s), 10 10.46 (1 H, br s); ESIMS found for C21H21F4N9O m / z 492.2 (M+1).128

[0393] N2-((3S,4R)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 128. 15

[0394] White solid (11 mg, 0.022 mmol, 24.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 (1 H, br dd, J=13.00, 3.70 Hz), 1.85 (1 H, qd, J=12.14, 3.56 Hz), 1.94 - 2.03 (1 H, m), 2.12 (1 H, dd, J=37.85, 12.59 Hz), 2.74 (1 H, br d, J=10.95 Hz), 2.92 - 3.04 (1 H, m), 3.48 (1 H, dt, J=12.66, 6.40 Hz), 3.71 - 3.89 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.43, 2.74 Hz), 4.88 (1 H, d, J=49.65 Hz), 5.21 (2 H, q, J=9.22 20 Hz), 5.88 (1 H, d, J=8.21 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.41 (1 H, d, J=2.74 Hz), 7.67 (1 H, br s), 7.92 (1 H, d, J=8.76 Hz), 8.18 (1 H, br d, J=8.49 Hz), 8.49 (1 H, br s), 10.45 (1 H, br s); ESIMS found for C22H23F4N9O m / z 506.2 (M+1).SMi.089PCT (BTP-002WO)

[0395] N2-((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 129.

[0396] White solid (12 mg, 0.024 mmol, 27.0% yield).1.64 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.05, 3.01 Hz), 1.93 - 2.03 (1 H, m), 2.12 (1 H, dd, J=37.60, 12.59 Hz), 2.69 - 5 2.80 (1 H, m), 2.91 - 3.03 (1 H, m), 3.48 (1 H, quin, J=6.30 Hz), 3.72 - 3.89 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.53 (2 H, td, J=6.57, 2.74 Hz), 4.88 (1 H, d, J=49.65 Hz), 5.15 - 5.26 (2 H, m), 5.88 (1 H, d, J=8.21 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.41 (1 H, d, J=2.74 Hz), 7.67 (1 H, br s), 7.92 (1 H, d, J=8.76 Hz), 8.18 (1 H, d, J=8.76 Hz), 8.48 (1 H, s), 10.45 (1 H, br s); ESIMS found for C22H23F4N9O m / z 506.2 (M+1). 10

[0397] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 131.

[0398] White solid (6 mg, 0.012 mmol, 13.7% yield).1H NMR (499 MHz, 15 DMSO-d6) ppm 1.68 - 1.81 (1 H, m), 1.86 (1 H, br dd, J=8.49, 4.11 Hz), 2.11 (1 H, br t, J=10.81 Hz), 2.34 (1 H, dd, J=26.30, 11.77 Hz), 2.74 (1 H, br d, J=11.23 Hz), 2.95 - 3.06 (1 H, m), 3.59 (1 H, quin, J=6.30 Hz), 4.20 - 4.37 (1 H, m), 4.43 (2 H, dt, J=13.83, 6.25 Hz), 4.54 (2 H, td, J=6.57, 3.56 Hz), 5.21 (2 H, q, J=9.22 Hz), 6.16 (1 H, br d, J=9.58 Hz), 7.17 (1 H, d, J=3.01 Hz), 7.41 (1 H, d, J=3.01 Hz), 7.71 (1 H, br s), 7.93 (1 H, d, J=8.49 Hz), 8.18 (1 H, d, 20 J=8.76 Hz), 8.48 (1 H, s), 10.49 (1 H, br s); ESIMS found for C22H22F5N9O m / z 524.15 (M+1).

[0399] (1r,3r)-1-Methyl-3-((4-(methylamino)-5-(3-(2,2,2-trifluoroethyl)-3H- imidazo [4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutan-1-ol 132. 25

[0400] Beige solid (22 mg, 0.049 mmol, 55.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.27 (3 H, s), 1.91 - 2.00 (2 H, m), 2.24 - 2.33 (2 H, m), 3.10 (3 H, d, J=4.93 Hz), 4.26 (1 H, sxt, J=7.56 Hz), 4.74 (1 H, s), 5.35 (2 H, q, J=9.31 Hz), 6.38 (1 H, d, J=7.12 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.95 (1 H, d, J=8.76 Hz), 8.18 (1 H, d,SMi.089PCT (BTP-002WO) J=8.76 Hz), 8.48 (1 H, s), 10.87 (1 H, q, J=4.38 Hz); ESIMS found for C20H21F3N8O m / z 447.2 (M+1).5

[0401] 1-((3R,4S)-4-((5-(3-Ddifluoromethyl)-2-methyl-3H-imidazo[4,5- b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1- yl)ethan-1-one 134.

[0402] Fluffy off-white solid (5 mg, 0.010 mmol, 43.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.56 - 1.71 (1 H, m), 1.73 - 1.88 (1 H, m), 1.99 (3 H, s), 2.71 (3 H, s), 10 3.08 (3 H, d, J=4.65 Hz), 3.14 - 3.24 (1 H, m), 3.81 - 4.00 (1 H, m), 4.02 - 4.18 (1 H, m), 4.36 - 4.75 (2 H, m), 4.97 (1 H, d, J=49.35 Hz), 6.11 (1 H, br d, J=8.21 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.95 (1 H, d, J=8.76 Hz), 8.09 (1 H, t, J=57.05 Hz), 8.05 - 8.13 (1 H, m), 10.78 (1 H, q, J=4.56 Hz); ESIMS found for C22H24F3N9O m / z 488.2 (M+1).15 135

[0403] 5-(3-(Difluoromethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N2- ((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 135.

[0404] Fluffy off-white solid (2 mg, 0.004 mmol, 20.2% yield).1H NMR (499 20 MHz, DMSO-d6) ppm 1.67 - 1.75 (1 H, m), 1.87 (1 H, qd, J=12.18, 3.97 Hz), 1.96 - 2.04 (1 H, m), 2.13 (1 H, dd, J=37.77, 12.53 Hz), 2.71 (3 H, s), 2.74 (1 H, br d, J=12.59 Hz), 2.94 - 3.02 (1 H, m), 3.07 (3 H, d, J=4.38 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.71 - 3.92 (1 H, m), 4.40 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.57, 3.01 Hz), 4.90 (1 H, d, J=49.60 Hz), 5.98 (1 H, d, J=8.21 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.94 25 (1 H, d, J=8.76 Hz), 8.08 (1 H, t, J=57.05 Hz), 8.08 (1 H, d, J=8.76 Hz), 10.77 (1 H, q, J=4.56 Hz); ESIMS found for C23H26F3N9O m / z 502.2 (M+1).SMi.089PCT (BTP-002WO)

[0405] (R)-1-(4-((4-Amino-5-(3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5- b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one 5 139.

[0406] White solid (5 mg, 0.010 mmol, 14.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.52 - 1.80 (1 H, m), 1.82 - 1.98 (1 H, m), 2.03 - 2.08 (3 H, m), 2.92 - 3.07 (1 H, m), 3.58 - 3.92 (1 H, m), 4.06 - 4.28 (1 H, m), 4.35 - 4.61 (2 H, m), 5.21 (2 H, q, J=9.22 Hz), 6.29 (1 H, br d, J=2.46 Hz), 7.18 (1 H, d, J=3.01 Hz), 7.41 (1 H, dd, J=2.87, 1.51 Hz), 10 7.71 (1 H, br s), 7.94 (1 H, d, J=8.76 Hz), 8.19 (1 H, d, J=8.76 Hz), 8.48 (1 H, s), 10.51 (1 H, br s); ESIMS found for C21H20F5N9O m / z 510.2 (M+1).

[0407] N2-((3S,4R)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-15 fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 141.

[0408] White solid (9 mg, 0.019 mmol, 28.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 (1 H, br dd, J=9.03, 4.11 Hz), 1.85 (1 H, qd, J=12.14, 3.83 Hz), 1.93 - 2.02 (1 H, m), 2.11 (1 H, dd, J=37.60, 12.59 Hz), 2.59 (3 H, s), 2.68 - 2.79 (1 H, m), 2.97 (1 H, 20 br t, J=10.95 Hz), 3.48 (1 H, dt, J=12.59, 6.30 Hz), 3.69 - 3.88 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.50 - 4.56 (2 H, m), 4.55 (2 H, dt, J=27.70, 4.65 Hz), 4.78 (2 H, dt, J=47.15, 4.65 Hz), 4.87 (1 H, d, J=49.90 Hz), 5.84 (1 H, d, J=8.21 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=3.01 Hz), 7.59 (1 H, br s), 7.80 (1 H, d, J=8.49 Hz), 7.98 (1 H, br d, J=8.49 Hz), 10.80 (1 H, br s); ESIMS found for C23H27F2N9O m / z 484.2 (M+1).SMi.089PCT (BTP-002WO)

[0409] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(2-fluoroethyl)-2- methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 142. 5

[0410] White solid (4 mg, 0.009 mmol, 23.0% yield). 1H NMR (499 MHz,DMSO-d6) ppm 1.69 - 1.88 (2 H, m), 2.05 - 2.16 (1 H, m), 2.25 (3 H, s), 2.27 - 2.37 (1 H, m), 2.59 (3 H, s), 2.71 - 2.81 (1 H, m), 3.04 (1 H, td, J=9.65, 7.53 Hz), 4.14 - 4.31 (1 H, m), 4.55 (2 H, dt, J=27.70, 4.65 Hz), 4.78 (2 H, dt, J=47.20, 4.65 Hz), 6.03 (1 H, d, J=9.31 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.64 (1 H, br s), 7.81 (1 H, d, J=8.49 Hz), 7.98 (1 10 H, d, J=8.49 Hz), 10.84 (1 H, br s); ESIMS found for C21H24F3N9m / z 460.25 (M+1).

[0411] (1r,4r)-4-((4-Amino-6-fluoro-5-(3-(2-fluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 15 143.

[0412] Fluffy white solid (2.3 mg, 0.005 mmol, 9.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.13 (3 H, s), 1.34 - 1.47 (4 H, m), 1.51 - 1.63 (2 H, m), 1.74 - 1.88 (2 H, m), 2.61 (3 H, s), 3.61 (1 H, br dd, J=8.21, 4.38 Hz), 4.21 (1 H, s), 4.56 (2 H, dt, J=27.45, 4.65 Hz), 4.78 (2 H, dt, J=47.15, 4.73 Hz), 5.86 (1 H, d, J=8.21 Hz), 7.52 (1 H, br s), 7.59 (1 H, d, J=2.46 20 Hz), 7.69 (1 H, d, J=8.21 Hz), 8.06 (1 H, d, J=8.49 Hz), 10.02 (1 H, br s); ESIMS found for C22H26F2N8O m / z 457.2 (M+1).SMi.089PCT (BTP-002WO)

[0413] 1-((3R,4S)-4-((4-Amino-6-fluoro-5-(3-(2-fluoroethyl)-2-methyl-3H- imidazo [4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1- yl)ethan-1-one 144.

[0414] White solid (7 mg, 0.014 mmol, 93.1% yield).1H NMR (499 MHz, 5 DMSO-d6) ppm 1.58 - 1.70 (1 H, m), 1.71 - 1.86 (1 H, m), 1.99 (3 H, s), 2.61 (3 H, s), 2.64 - 2.93 (1 H, m), 3.11 - 3.23 (1 H, m), 3.83 - 3.98 (1 H, m), 3.98 - 4.16 (1 H, m), 4.37 - 4.49 (1 H, m), 4.56 (2 H, dt, J=27.40, 4.56 Hz), 4.78 (2 H, dt, J=47.20, 4.73 Hz), 4.93 (1 H, d, J=49.35 Hz), 6.09 - 6.13 (1 H, m), 7.59 (1 H, d, J=2.46 Hz), 7.65 (1 H, br s), 7.70 (1 H, d, J=8.21 Hz), 8.07 (1 H, d, J=8.21 Hz), 10.11 (1 H, br s); ESIMS found for C22H24F3N9O m / z 488.2 (M+1). 10145

[0415] 6-Fluoro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2- fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 145. 15

[0416] Off-white solid ((3 mg, 0.006 mmol, 60.3% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.65 - 1.74 (1 H, m), 1.85 (1 H, qd, J=12.14, 3.56 Hz), 1.94 - 2.02 (1 H, m), 2.10 (1 H, dd, J=37.05, 12.59 Hz), 2.61 (3 H, s), 2.69 - 2.78 (1 H, m), 2.92 - 3.01 (1 H, m), 3.48 (1 H, quin, J=6.43 Hz), 3.70 - 3.87 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.53 (2 H, td, J=6.50, 2.87 Hz), 4.56 (2 H, dt, J=27.40, 4.65 Hz), 4.78 (2 H, dt, J=46.90, 4.79 20 Hz), 4.86 (1 H, d, J=49.10 Hz), 5.99 (1 H, d, J=8.21 Hz), 7.59 (1 H, d, J=2.46 Hz), 7.64 (1 H, br s), 7.70 (1 H, d, J=8.21 Hz), 8.07 (1 H, d, J=8.49 Hz), 10.10 (1 H, br s); ESIMS found for C23H26F3N9O m / z 502.2 (M+1).25

[0417] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-6-fluoro-5-(3-(2- fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 146.SMi.089PCT (BTP-002WO)

[0418] Fluffy white solid (3.8 mg, 0.008 mmol, 30.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.71 - 1.86 (2 H, m), 2.06 - 2.17 (1 H, m), 2.25 (3 H, s), 2.31 (1 H, ddd, J=27.15, 13.15, 1.65 Hz), 2.61 (3 H, s), 2.77 (1 H, br d, J=11.23 Hz), 2.98 - 3.10 (1 H, m), 4.11 - 4.28 (1 H, m), 4.56 (2 H, dt, J=27.15, 4.65 Hz), 4.78 (2 H, dt, J=47.20, 4.73 Hz), 6.19 (1 H, 5 br d, J=9.31 Hz), 7.60 (1 H, d, J=2.46 Hz), 7.69 (1 H, br s), 7.70 (1 H, d, J=8.49 Hz), 8.07 (1 H, d, J=8.49 Hz), 10.15 (1 H, br s); ESIMS found for C21H23F4N9m / z 478.2 (M+1).

[0419] (R)-1-(4-((4-Amino-6-fluoro-5-(3-(2-fluoroethyl)-2-methyl-3H-10 imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1- yl)ethan-1-one 147.

[0420] White solid (13 mg, 0.026 mmol, 64.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.53 - 1.79 (1 H, m), 1.80 - 1.96 (1 H, m), 2.06 (3 H, s), 2.61 (3 H, s), 2.96 (1 H, br t, J=10.95 Hz), 3.60 - 3.89 (1 H, m), 4.11 - 4.28 (1 H, m), 4.40 - 4.51 (2 H, m), 4.57 (2 15 H, dt, J=27.40, 4.65 Hz), 4.78 (2 H, dt, J=47.20, 4.65 Hz), 6.40 (1 H, br d, J=9.31 Hz), 7.59 (1 H, d, J=2.46 Hz), 7.69 (1 H, br s), 7.71 (1 H, d, J=8.21 Hz), 8.07 (1 H, d, J=8.21 Hz), 10.16 (1 H, br s); ESIMS found for C22H23F4N9O m / z 506.2 (M+1).20

[0421] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-6-fluoro-5-(3-(2- fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 149.

[0422] White solid (11 mg, 0.021 mmol, 52.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 - 1.81 (1 H, m), 1.82 - 1.90 (1 H, m), 2.04 - 2.16 (1 H, m), 2.33 (1 H, 25 dd, J=26.35, 12.05 Hz), 2.61 (3 H, s), 2.74 (1 H, br d, J=10.95 Hz), 2.92 - 3.05 (1 H, m), 3.59 (1 H, quin, J=6.16 Hz), 4.19 - 4.34 (1 H, m), 4.38 - 4.48 (2 H, m), 4.54 (2 H, td, J=6.50, 2.87 Hz), 4.56 (2 H, dt, J=27.40, 4.65 Hz), 4.78 (2 H, dt, J=47.15, 4.65 Hz), 6.27 (1 H, br d, J=9.86SMi.089PCT (BTP-002WO) Hz), 7.60 (1 H, d, J=2.19 Hz), 7.68 (1 H, br s), 7.70 (1 H, d, J=8.21 Hz), 8.07 (1 H, d, J=8.21 Hz), 10.15 (1 H, br s); ESIMS found for C23H25F4N9O m / z 520.2 (M+1).5

[0423] N2-((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2- fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 157.

[0424] Fluffy white solid (8 mg, 0.016 mmol, 19.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.67 - 1.75 (1 H, m), 1.81 - 1.92 (1 H, m), 1.96 - 2.04 (1 H, m), 2.13 (1 H, 10 dd, J=37.60, 12.59 Hz), 2.61 (3 H, s), 2.74 (1 H, br d, J=10.40 Hz), 2.92 - 3.02 (1 H, m), 3.11 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.73 - 3.90 (1 H, m), 4.40 (1 H, t, J=6.02 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.30, 3.01 Hz), 4.60 (2 H, dt, J=26.60, 4.65 Hz), 4.89 (1 H, d, J=49.50 Hz), 4.89 (2 H, dt, J=47.20, 4.65 Hz), 5.92 (1 H, br d, J=7.94 Hz), 7.09 (1 H, d, J=2.74 Hz), 7.35 (1 H, d, J=2.74 Hz), 7.81 (1 H, d, J=8.49 Hz), 7.98 (1 H, d, J=8.49 Hz), 15 11.11 (1 H, q, J=4.15 Hz); ESIMS found for C24H29F2N9O m / z 498.2 (M+1).

[0425] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)- 2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 20 160.

[0426] Off-white solid (9 mg, 0.018 mmol, 32.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.71 - 1.84 (1 H, m), 1.84 - 1.93 (1 H, m), 2.14 (1 H, br t, J=10.54 Hz), 2.38 (1 H, dd, J=26.85, 12.05 Hz), 2.61 (3 H, s), 2.74 (1 H, br d, J=10.95 Hz), 2.95 - 3.05 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.21 - 4.37 (1 H, m), 4.44 (2 H, dt, 25 J=14.44, 6.19 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 4.61 (2 H, dt, J=26.90, 4.93 Hz), 4.90 (2 H, dt, J=46.90, 4.93 Hz), 6.17 (1 H, d, J=9.58 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.82 (1 H, d, J=8.76 Hz), 7.99 (1 H, d, J=8.49 Hz), 11.14 (1 H, q, J=4.95 Hz); ESIMS found for C24H28F3N9O m / z 516.2 (M+1).SMi.089PCT (BTP-002WO)

[0427] (1r,4r)-4-((6-Fluoro-5-(3-(2-fluoroethyl)-2-methyl-3H-imidazo[4,5-b] pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan- 5 1-ol 162.

[0428] Fluffy white solid (4.8 mg, 0.010 mmol, 97.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.14 (3 H, s), 1.36 - 1.47 (4 H, m), 1.54 - 1.61 (2 H, m), 1.79 - 1.88 (2 H, m), 2.63 (3 H, s), 3.06 (3 H, d, J=4.65 Hz), 3.61 (1 H, br d, J=2.74 Hz), 4.21 (1 H, s), 4.61 (2 H, dt, J=26.60, 4.79 Hz), 4.88 (2 H, dt, J=46.90, 4.79 Hz), 5.97 (1 H, d, J=7.94 Hz), 7.57 (1 H, d, 10 J=2.19 Hz), 7.70 (1 H, d, J=8.49 Hz), 8.07 (1 H, d, J=8.49 Hz), 10.31 (1 H, q, J=4.56 Hz); ESIMS found for C23H28F2N8O m / z 471.2 (M+1).163

[0429] 1-((3R,4S)-3-Fluoro-4-((6-fluoro-5-(3-(2-fluoroethyl)-2-methyl-3H-15 imidazo [4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)piperidin-1-yl)ethan-1-one 163.

[0430] White solid (9.4 mg, 0.019 mmol, 86.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.61 - 1.71 (1 H, m), 1.72 - 1.88 (1 H, m), 1.99 (3 H, s), 2.63 (3 H, s), 2.66 - 2.94 (1 H, m), 3.08 (3 H, d, J=4.65 Hz), 3.13 - 3.25 (1 H, m), 3.84 - 3.97 (1 H, m), 3.98 - 4.16 20 (1 H, m), 4.43 (1 H, br dd, J=12.32, 2.46 Hz), 4.61 (2 H, dt, J=26.60, 4.79 Hz), 4.89 (2 H, dt, J=46.65, 4.79 Hz), 4.95 (1 H, d, J=49.35 Hz), 6.22 (1 H, dd, J=7.94, 2.46 Hz), 7.56 (1 H, d, J=2.46 Hz), 7.71 (1 H, d, J=8.21 Hz), 8.08 (1 H, d, J=8.49 Hz), 10.38 - 10.45 (1 H, m); ESIMS found for C23H26F3N9O m / z 502.4 (SMi.089PCT (BTP-002WO) 164

[0431] 6-Fluoro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2- fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 164. 5

[0432] Fluffy white solid (11 mg, 0.021 mmol, 59.4% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.65 - 1.76 (1 H, m), 1.87 (1 H, qd, J=12.18, 3.70 Hz), 1.95 - 2.05 (1 H, m), 2.12 (1 H, dd, J=36.75, 12.56 Hz), 2.63 (3 H, s), 2.74 (1 H, br d, J=11.22 Hz), 2.97 (1 H, br t, J=11.64 Hz), 3.07 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.23 Hz), 3.69 - 3.89 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.53 (2 H, td, J=6.57, 3.01 Hz), 4.61 (2 H, dt, 10 J=26.60, 4.79 Hz), 4.89 (2 H, dt, J=46.90, 4.65 Hz), 4.89 (1 H, d, J=49.50 Hz), 6.10 (1 H, d, J=8.21 Hz), 7.56 (1 H, d, J=2.19 Hz), 7.71 (1 H, d, J=8.21 Hz), 8.08 (1 H, d, J=8.49 Hz), 10.40 (1 H, q, J=4.56 Hz); ESIMS found for C24H28F3N9O m / z 516.2 (M+1).15

[0433] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-6-fluoro-5-(3-(2- fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 165.

[0434] Fluffy white solid (11.7 mg, 0.024 mmol, 56.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.71 - 1.89 (2 H, m), 2.09 - 2.19 (1 H, m), 2.25 (3 H, s), 2.35 (1 H, dd, 20 J=27.15, 12.32 Hz), 2.63 (3 H, s), 2.77 (1 H, br d, J=11.23 Hz), 3.00 - 3.07 (1 H, m), 3.09 (3 H, d, J=4.93 Hz), 4.09 - 4.28 (1 H, m), 4.61 (2 H, dt, J=26.60, 4.79 Hz), 4.89 (2 H, dt, J=46.90, 4.93 Hz), 6.26 (1 H, d, J=9.31 Hz), 7.58 (1 H, d, J=2.19 Hz), 7.71 (1 H, d, J=8.49 Hz), 8.08 (1 H, d, J=8.49 Hz), 10.42 (1 H, q, J=4.38 Hz); ESIMS found for C22H25F4N9m / z 492.2 (M+1).25 166

[0435] (R)-1-(3,3-Difluoro-4-((6-fluoro-5-(3-(2-fluoroethyl)-2-methyl-3H- imidazo [4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)piperidin-1-yl)ethan-1-one 166.SMi.089PCT (BTP-002WO)

[0436] White solid (4.2 mg, 0.008 mmol, 24.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.56 - 1.79 (1 H, m), 1.81 - 1.99 (1 H, m), 2.06 (3 H, s), 2.64 (3 H, s), 2.91 - 3.04 (1 H, m), 3.10 (3 H, d, J=4.93 Hz), 3.60 - 3.91 (1 H, m), 4.07 - 4.29 (1 H, m), 4.39 - 4.56 (2 H, m), 4.61 (2 H, dt, J=26.90, 4.65 Hz), 4.89 (2 H, dt, J=46.60, 4.79 Hz), 6.46 - 6.50 (1 H, 5 m), 7.57 (1 H, s), 7.71 (1 H, d, J=8.21 Hz), 8.08 (1 H, d, J=8.49 Hz), 10.44 (1 H, q, J=4.47 Hz); ESIMS found for C23H25F4N9O m / z 520.2 (M+1).

[0437] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-6-fluoro-5-(3-(2-10 fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 168.

[0438] Fluffy white solid (12.3 mg, 0.023 mmol, 55.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 - 1.82 (1 H, m), 1.83 - 1.92 (1 H, m), 2.08 - 2.19 (1 H, m), 2.37 (1 H, dd, J=26.60, 12.32 Hz), 2.63 (3 H, s), 2.74 (1 H, br d, J=11.77 Hz), 2.93 - 3.05 (1 H, m), 15 3.09 (3 H, d, J=4.65 Hz), 3.59 (1 H, quin, J=6.37 Hz), 4.17 - 4.34 (1 H, m), 4.43 (2 H, dt, J=14.44, 6.19 Hz), 4.54 (2 H, td, J=6.71, 3.56 Hz), 4.61 (2 H, dt, J=26.85, 4.79 Hz), 4.89 (2 H, dt, J=46.90, 4.79 Hz), 6.34 (1 H, d, J=9.58 Hz), 7.57 (1 H, d, J=2.19 Hz), 7.71 (1 H, d, J=8.21 Hz), 8.08 (1 H, d, J=8.49 Hz), 10.42 (1 H, q, J=4.56 Hz); ESIMS found for C24H27F4N9O m / z 534.2 (M+1). 20

[0439] 1-((3R,4S)-4-((5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5- b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1- yl)-2-hydroxyethan-1-one 174. 25

[0440] Fluffy pale-yellow solid (23 mg, 0.044 mmol, 72.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.64 - 1.88 (2 H, m), 2.62 (3 H, s), 2.72 - 3.04 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.76 (1 H, br d, J=13.96 Hz), 3.94 - 4.19 (4 H, m), 4.55 - 4.60 (1 H, m), 4.66 (1 H, br t, J=12.59 Hz), 4.78 (2 H, td, J=15.88, 2.46 Hz), 4.96 (1 H, d, J=49.10 Hz), 6.12 (1 H, d,SMi.089PCT (BTP-002WO) J=3.56 Hz), 6.64 (1 H, tt, J=54.30, 3.01 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.99 (1 H, q, J=4.47 Hz); ESIMS found for C23H26F3N9O2m / z 518.2 (M+1).5 175

[0441] (R)-1-(4-((5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin- 5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-2- hydroxyethan-1-one 175.

[0442] Fluffy pale-yellow solid (34 mg, 0.064 mmol, 82.1% yield).1H NMR (499 10 MHz, DMSO-d6) ppm 1.61 - 1.82 (1 H, m), 1.84 - 1.98 (1 H, m), 2.63 (3 H, s), 3.00 - 3.10 (1 H, m), 3.15 (3 H, d, J=4.65 Hz), 3.60 - 3.83 (1 H, m), 4.03 - 4.27 (3 H, m), 4.39 - 4.62 (2 H, m), 4.78 (2 H, td, J=15.95, 2.79 Hz), 4.79 - 4.84 (1 H, m), 6.36 (1 H, br d, J=9.58 Hz), 6.64 (1 H, tt, J=54.30, 3.01 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.86 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.02 (1 H, q, J=4.56 Hz); ESIMS found for C23H25F4N9O2m / z 15 536.2 (M+1).177

[0443] (R)-1-(4-((5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin- 5-yl)-6-fluoro-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin- 20 1-yl)ethan-1-one 177.

[0444] Fluffy white solid (10 mg, 0.019 mmol, 98.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.56 - 1.80 (1 H, m), 1.81 - 1.96 (1 H, m), 2.06 (3 H, s), 2.64 (3 H, s), 2.92 - 3.03 (1 H, m), 3.11 (3 H, d, J=4.65 Hz), 3.63 - 3.90 (1 H, m), 4.09 - 4.26 (1 H, m), 4.42 - 4.58 (2 H, m), 4.78 (2 H, td, J=15.95, 2.79 Hz), 6.49 (1 H, d, J=9.58 Hz), 6.63 (2 H, tt, J=54.30, 3.15 25 Hz), 7.58 (1 H, d, J=2.19 Hz), 7.74 (1 H, d, J=8.21 Hz), 8.11 (1 H, d, J=8.49 Hz), 10.26 (1 H, q, J=4.56 Hz); ESIMS found for C23H24F5N9O m / z 538.2 (M+1).SMi.089PCT (BTP-002WO)

[0445] 5-(3-Ethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoro-N2-((3R,4S)- 3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 5 214.

[0446] Light yellow solid (21 mg, 0.043 mmol, 60.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.62 (3 H, t, J=7.39 Hz), 1.67 - 1.75 (1 H, m), 1.89 (1 H, qd, J=12.14, 3.83 Hz), 1.95 - 2.04 (1 H, m), 2.13 (1 H, dd, J=37.05, 12.59 Hz), 2.70 - 2.80 (1 H, m), 2.93 - 3.04 (1 H, m), 3.11 (3 H, d, J=4.65 Hz), 3.49 (1 H, quin, J=6.37 Hz), 3.70 - 3.88 (1 H, m), 4.40 (1 10 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.57, 3.01 Hz), 4.75 (2 H, q, J=7.30 Hz), 4.89 (1 H, d, J=49.35 Hz), 6.28 (1 H, d, J=8.21 Hz), 7.63 (1 H, d, J=2.19 Hz), 7.91 (1 H, d, J=9.03 Hz), 8.61 (1 H, d, J=9.04 Hz), 10.54 (1 H, q, J=4.65 Hz); ESIMS found for C22H26F2N10O m / z 485.2 (M+1). 15

[0447] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-ethyl-3H- [1,2,3]triazolo [4,5-b]pyridin-5-yl)-6-fluoro-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 215.

[0448] Light yellow solid (17 mg, 0.037 mmol, 91.6% yield).1H NMR (499 MHz, 20 DMSO-d6) ppm 1.62 (3 H, t, J=7.39 Hz), 1.73 - 1.88 (2 H, m), 2.15 (1 H, td, J=11.23, 2.46 Hz), 2.25 (3 H, s), 2.35 (1 H, ddd, J=27.15, 12.35, 1.90 Hz), 2.73 - 2.85 (1 H, m), 2.98 - 3.09 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 4.12 - 4.30 (1 H, m), 4.76 (2 H, q, J=7.39 Hz), 6.45 (1 H, d, J=9.58 Hz), 7.65 (1 H, d, J=2.19 Hz), 7.92 (1 H, d, J=9.03 Hz), 8.62 (1 H, d, J=8.76 Hz), 10.55 (1 H, q, J=4.65 Hz); ESIMS found for C20H23F3N10m / z 461.2 (M+1). 25SMi.089PCT (BTP-002WO) 216

[0449] (R)-1-(4-((5-(3-Ethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoro-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one 216. 5

[0450] Light yellow solid (19 mg, 0.039 mmol, 96.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.62 (3 H, t, J=7.26 Hz), 1.71 - 1.81 (1 H, m), 1.82 - 1.96 (1 H, m), 2.07 (3 H, s), 2.91 - 3.04 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.62 - 3.91 (1 H, m), 4.09 - 4.30 (1 H, m), 4.41 - 4.58 (2 H, m), 4.76 (2 H, q, J=7.39 Hz), 6.64 (1 H, br d, J=9.58 Hz), 7.62 - 7.65 (1 H, m), 7.92 (1 H, d, J=9.03 Hz), 8.62 (1 H, d, J=9.03 Hz), 10.58 (1 H, q, J=4.38 Hz); ESIMS found 10 for C21H23F3N10O m / z 489.2 (M+1).220

[0451] N2-((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2- fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 15 220.

[0452] Yellow solid (8 mg, 0.017 mmol, 19.3% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 (1 H, br d, J=10.40 Hz), 1.81 - 1.91 (1 H, m), 1.93 - 2.03 (1 H, m), 2.12 (1 H, dd, J=37.05, 12.59 Hz), 2.69 - 2.81 (1 H, m), 2.90 - 3.04 (1 H, m), 3.48 (1 H, quin, J=5.89 Hz), 3.72 - 3.90 (1 H, m), 4.39 (1 H, br t, J=6.02 Hz), 4.45 (1 H, br t, J=5.89 Hz), 4.50 - 4.58 20 (2 H, m), 4.88 (1 H, d, J=49.65 Hz), 4.93 (2 H, dt, J=36.20, 4.65 Hz), 5.01 (2 H, dt, J=16.20, 4.65 Hz), 6.07 (1 H, br d, J=7.94 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.45 (1 H, d, J=3.01 Hz), 7.70 (1 H, br s), 8.08 (1 H, d, J=9.03 Hz), 8.53 (1 H, d, J=9.03 Hz), 10.58 (1 H, br s); ESIMS found for C21H24F2N10O m / z 471.2 (M+1). 25

[0453] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(2-fluoroethyl)-3H- [1,2,3] triazolo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 221.

[0454] Light yellow solid (5 mg, 0.011 mmol, 17.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 - 1.88 (2 H, m), 2.07 - 2.18 (1 H, m), 2.25 (3 H, s), 2.33 (1 H, dd,SMi.089PCT (BTP-002WO) J=27.70, 11.77 Hz), 2.77 (1 H, br d, J=11.77 Hz), 2.98 - 3.11 (1 H, m), 4.12 - 4.31 (1 H, m), 4.93 (2 H, dt, J=36.50, 4.65 Hz), 5.01 (2 H, dt, J=16.75, 4.30 Hz), 6.25 (1 H, d, J=9.58 Hz), 7.35 (1 H, d, J=3.01 Hz), 7.47 (1 H, d, J=3.01 Hz), 7.75 (1 H, br s), 8.08 (1 H, d, J=9.04 Hz), 8.53 (1 H, d, J=8.76 Hz), 10.61 (1 H, br s); ESIMS found for C19H21F3N10m / z 447.2 (M+1). 5

[0455] (R)-1-(4-((4-Amino-5-(3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one 222. 10

[0456] Light yellow solid (8 mg, 0.017 mmol, 24.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.52 - 1.80 (1 H, m), 1.82 - 1.98 (1 H, m), 2.01 - 2.09 (3 H, m), 2.92 - 3.06 (1 H, m), 3.61 - 3.91 (1 H, m), 4.08 - 4.27 (1 H, m), 4.40 - 4.59 (2 H, m), 4.94 (2 H, dt, J=37.30, 4.90 Hz), 4.99 - 5.05 (2 H, m), 6.48 (1 H, br d, J=3.01 Hz), 7.37 (1 H, d, J=3.29 Hz), 7.46 (1 H, dd, J=2.87, 1.51 Hz), 7.75 (1 H, br s), 8.09 (1 H, d, J=9.03 Hz), 8.54 (1 H, d, J=8.76 Hz), 15 10.63 (1 H, br s); ESIMS found for C20H21F3N10O m / z 475.2 (M+1).

[0457] N2-(4,4-Difluorocyclohexyl)-5-(3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5- b] pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 233. 20

[0458] Fluffy yellow solid (8 mg, 0.018 mmol, 43.6% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.55 - 1.70 (2 H, m), 1.80 - 2.01 (4 H, m), 2.02 - 2.17 (2 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.72 - 3.86 (1 H, m), 4.97 - 5.05 (2 H, m), 5.08 (2 H, s), 6.31 (1 H, d, J=7.67 Hz), 7.31 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 8.07 (1 H, d, J=9.03 Hz), 8.53 (1 H, d, J=8.76 Hz), 10.95 (1 H, q, J=4.56 Hz); ESIMS found for C20H22F3N9m / z 446.2 (M+1). 25SMi.089PCT (BTP-002WO) 234

[0459] (1r,4r)-4-((5-(3-(2-Fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 234.

[0460] Yellow solid (16 mg, 0.036 mmol, 42.0% yield).1H NMR (499 MHz, 5 DMSO-d6) ppm 1.14 (3 H, s), 1.36 - 1.50 (4 H, m), 1.54 - 1.65 (2 H, m), 1.79 - 1.91 (2 H, m), 3.12 (3 H, d, J=4.38 Hz), 3.64 (1 H, br s), 4.21 (1 H, s), 5.00 (2 H, dt, J=20.30, 4.40 Hz), 5.08 (2 H, s), 6.02 (1 H, d, J=8.21 Hz), 7.29 (1 H, d, J=3.29 Hz), 7.43 (1 H, d, J=2.74 Hz), 8.07 (1 H, d, J=9.31 Hz), 8.52 (1 H, d, J=9.31 Hz), 10.92 (1 H, q, J=4.93 Hz); ESIMS found for C21H26FN9O m / z 440.2 (M+1). 10

[0461] 1-((3R,4S)-3-Fluoro-4-((5-(3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1- one 235. 15

[0462] Fluffy yellow solid (9 mg, 0.019 mmol, 50.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.59 - 1.89 (2 H, m), 1.96 - 2.07 (3 H, m), 2.59 - 2.78 (1 H, m), 2.79 - 2.95 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.83 - 4.00 (1 H, m), 4.01 - 4.19 (1 H, m), 4.40 - 4.75 (1 H, m), 4.89 - 5.02 (1 H, m), 4.97 - 5.06 (2 H, m), 5.08 (2 H, s), 6.27 (1 H, d, J=7.94 Hz), 7.33 (1 H, d, J=3.29 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.09 (1 H, d, J=9.31 Hz), 8.54 (1 H, d, J=9.03 Hz), 20 11.01 (1 H, q, J=4.95 Hz); ESIMS found for C21H24F2N10O m / z 471.2 (M+1).236

[0463] N2-((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2- fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 25 2,4-diamine 236.

[0464] Fluffy yellow solid (14 mg, 0.029 mmol, 78.9% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.67 - 1.75 (1 H, m), 1.88 (1 H, qd, J=12.05, 3.83 Hz), 1.96 - 2.04 (1 H, m), 2.14 (1 H, dd, J=37.00, 12.87 Hz), 2.75 (1 H, br d, J=10.95 Hz), 2.92 - 3.03 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.49 (1 H, quin, J=6.37 Hz), 3.74 - 3.91 (1 H, m), 4.40 (1 H, t, J=6.16SMi.089PCT (BTP-002WO) Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.57, 3.29 Hz), 4.91 (1 H, d, J=50.15 Hz), 4.97 - 5.05 (2 H, m), 5.08 (2 H, s), 6.15 (1 H, d, J=7.94 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 8.08 (1 H, d, J=9.03 Hz), 8.53 (1 H, d, J=9.04 Hz), 11.00 (1 H, q, J=4.47 Hz); ESIMS found for C22H26F2N10O m / z 243.2 (M / 2+1). 5

[0465] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(2-fluoroethyl)-3H- [1,2,3] triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 237.

[0466] Fluffy yellow solid (14 mg, 0.030 mmol, 55.9% yield).1H NMR (499 10 MHz, DMSO-d6) ppm 1.72 - 1.90 (2 H, m), 2.10 - 2.21 (1 H, m), 2.25 (3 H, s), 2.36 (1 H, dd, J=27.15, 12.39 Hz), 2.77 (1 H, br d, J=11.50 Hz), 2.95 - 3.08 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.15 - 4.32 (1 H, m), 4.96 - 5.05 (2 H, m), 5.08 (2 H, s), 6.31 (1 H, d, J=9.31 Hz), 7.33 (1 H, d, J=3.01 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.09 (1 H, d, J=9.04 Hz), 8.54 (1 H, d, J=8.76 Hz), 11.01 (1 H, q, J=4.56 Hz); ESIMS found for C20H23F3N10m / z 231.1 (M / 2+1). 15

[0467] (R)-1-(3,3-Difluoro-4-((5-(3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1- one 238. 20

[0468] Fluffy yellow solid (7 mg, 0.014 mmol, 51.4% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.54 - 1.81 (1 H, m), 1.83 - 1.99 (1 H, m), 2.01 - 2.09 (3 H, m), 2.89 - 3.06 (1 H, m), 3.16 (3 H, d, J=4.93 Hz), 3.59 - 3.90 (1 H, m), 4.08 - 4.30 (1 H, m), 4.40 - 4.61 (2 H, m), 4.97 - 5.06 (2 H, m), 5.09 (2 H, s), 6.51 (1 H, d, J=4.11 Hz), 7.34 (1 H, d, J=3.29 Hz), 7.44 (1 H, dd, J=2.87, 1.78 Hz), 8.09 (1 H, d, J=9.03 Hz), 8.54 (1 H, d, J=9.04 Hz), 10.99 - 11.09 (1 25 H, m); ESIMS found for C21H23F3N10O m / z 489.25 (M+1).SMi.089PCT (BTP-002WO)239

[0469] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)- 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 5 239.

[0470] Fluffy yellow solid (13 mg, 0.026 mmol, 56.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.72 - 1.83 (1 H, m), 1.84 - 1.92 (1 H, m), 2.08 - 2.21 (1 H, m), 2.32 - 2.44 (1 H, m), 2.70 - 2.79 (1 H, m), 2.93 - 3.06 (1 H, m), 3.15 (3 H, d, J=4.65 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.20 - 4.37 (1 H, m), 4.44 (2 H, dt, J=14.58, 6.26 Hz), 4.55 (2 H, td, J=6.64, 10 3.70 Hz), 4.96 - 5.06 (2 H, m), 5.09 (2 H, s), 6.39 (1 H, d, J=9.58 Hz), 7.33 (1 H, d, J=3.29 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.09 (1 H, d, J=9.31 Hz), 8.54 (1 H, d, J=9.04 Hz), 11.02 (1 H, q, J=4.47 Hz); ESIMS found for C22H25F3N10O m / z 503.3 (M+1).248 15

[0471] (1r,4r)-4-((6-Fluoro-5-(3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1- methylcyclohexan-1-ol 248.

[0472] Fluffy white solid (7.5 mg, 0.016 mmol, 67.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.14 (3 H, s), 1.35 - 1.50 (4 H, m), 1.52 - 1.64 (2 H, m), 1.76 - 1.90 (2 H, m), 20 3.08 (3 H, d, J=4.93 Hz), 3.54 - 3.68 (1 H, m), 4.21 (1 H, s), 5.01 (2 H, dt, J=20.55, 4.65 Hz), 5.08 (2 H, s), 6.14 (1 H, d, J=7.94 Hz), 7.65 (1 H, d, J=2.19 Hz), 7.92 (1 H, d, J=9.03 Hz), 8.64 (1 H, d, J=9.03 Hz), 10.20 (1 H, q, J=4.65 Hz); ESIMS found for C21H25F2N9O m / z 458.2 (M+1). 25SMi.089PCT (BTP-002WO)

[0473] 1-((3R,4S)-3-Fluoro-4-((6-fluoro-5-(3-(2-fluoroethyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)piperidin-1-yl)ethan-1-one 249.

[0474] Fluffy yellow solid (15 mg, 0.031 mmol, 82.5% yield).1H NMR (499 5 MHz, DMSO-d6) ppm 1.61 - 1.72 (1 H, m), 1.73 - 1.90 (1 H, m), 1.99 (3 H, s), 2.61 - 2.89 (1 H, m), 3.10 (3 H, d, J=4.65 Hz), 3.14 - 3.26 (1 H, m), 3.83 - 3.98 (1 H, m), 4.00 - 4.19 (1 H, m), 4.39 - 4.68 (1 H, m), 4.94 (1 H, d, J=49.50 Hz), 5.02 (2 H, dt, J=22.75, 4.65 Hz), 5.09 (2 H, s), 6.40 (1 H, d, J=7.94 Hz), 7.65 (1 H, d, J=2.19 Hz), 7.93 (1 H, d, J=9.03 Hz), 8.66 (1 H, d, J=9.04 Hz), 10.28 (1 H, q, J=4.56 Hz); ESIMS found for C21H23F3N10O m / z 489.2 (M+1). 10250

[0475] 6-Fluoro-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2- fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 250. 15

[0476] Fluffy yellow solid (15 mg, 0.0300 mmol, 83.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.64 - 1.76 (1 H, m), 1.89 (1 H, qd, J=12.23, 3.83 Hz), 1.96 - 2.03 (1 H, m), 2.13 (1 H, dd, J=37.00, 12.32 Hz), 2.69 - 2.81 (1 H, m), 2.91 - 3.03 (1 H, m), 3.09 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.23 Hz), 3.71 - 3.88 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.50, 3.15 Hz), 4.89 (1 H, d, J=49.35 Hz), 5.01 (2 H, dt, 20 J=22.60, 5.04 Hz), 5.09 (2 H, s), 6.29 (1 H, d, J=7.94 Hz), 7.65 (1 H, d, J=2.19 Hz), 7.93 (1 H, d, J=8.76 Hz), 8.65 (1 H, d, J=9.03 Hz), 10.26 (1 H, q, J=4.56 Hz); ESIMS found for C22H25F3N10O m / z 503.2 (M+1).25

[0477] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-6-fluoro-5-(3-(2- fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 251.

[0478] Fluffy yellow solid (12 mg, 0.025 mmol, 89.7% yield). 1H NMR (499MHz, DMSO-d6) ppm 1.73 - 1.89 (2 H, m), 2.15 (1 H, td, J=11.16, 2.60 Hz), 2.25 (3 H, s),SMi.089PCT (BTP-002WO) 2.35 (1 H, ddd, J=26.35, 12.10, 1.40 Hz), 2.77 (1 H, br d, J=11.77 Hz), 2.98 - 3.08 (1 H, m), 3.10 (3 H, d, J=4.65 Hz), 4.12 - 4.31 (1 H, m), 5.02 (2 H, dt, J=23.85, 4.65 Hz), 5.09 (2 H, s), 6.45 (1 H, d, J=9.58 Hz), 7.66 (1 H, d, J=2.19 Hz), 7.93 (1 H, d, J=9.03 Hz), 8.65 (1 H, d, J=9.03 Hz), 10.28 (1 H, q, J=4.56 Hz); ESIMS found for C20H22F4N10m / z 479.2 (M+1). 5252

[0479] (R)-1-(3,3-Difluoro-4-((6-fluoro-5-(3-(2-fluoroethyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)piperidin-1-yl)ethan-1-one 252. 10

[0480] Fluffy yellow solid (9 mg, 0.018 mmol, 74.9% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.55 - 1.80 (1 H, m), 1.82 - 1.98 (1 H, m), 2.07 (3 H, s), 2.92 - 3.05 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.60 - 3.92 (1 H, m), 4.08 - 4.30 (1 H, m), 4.40 - 4.59 (2 H, m), 5.02 (2 H, dt, J=24.40, 4.65 Hz), 5.09 (2 H, s), 6.65 (1 H, br d, J=9.31 Hz), 7.65 (1 H, s), 7.94 (1 H, d, J=8.76 Hz), 8.66 (1 H, d, J=8.76 Hz), 10.30 (1 H, q, J=4.65 Hz); ESIMS found for 15 C21H22F4N10O m / z 507.2 (M+1).254

[0481] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-6-fluoro-5-(3-(2- fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 20 2,4-diamine 254.

[0482] Fluffy yellow solid (12 mg, 0.023 mmol, 83.6% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.73 - 1.83 (1 H, m), 1.84 - 1.90 (1 H, m), 2.08 - 2.20 (1 H, m), 2.37 (1 H, dd, J=27.40, 11.25 Hz), 2.75 (1 H, br d, J=11.77 Hz), 2.95 - 3.06 (1 H, m), 3.11 (3 H, d, J=4.65 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.21 - 4.36 (1 H, m), 4.43 (2 H, dt, J=14.78, 6.16 Hz), 25 4.55 (2 H, td, J=6.57, 3.83 Hz), 5.02 (2 H, dt, J=23.85, 4.70 Hz), 5.09 (2 H, s), 6.53 (1 H, d, J=9.31 Hz), 7.66 (1 H, d, J=2.19 Hz), 7.93 (1 H, d, J=9.03 Hz), 8.65 (1 H, d, J=8.76 Hz), 10.29 (1 H, q, J=4.80 Hz); ESIMS found for C22H24F4N10O m / z 521.2 (M+1).SMi.089PCT (BTP-002WO)

[0483] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N2- ((3R,4S)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 5 256.

[0484] Light yellow solid (22 mg, 0.045 mmol, 51.3% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.60 - 1.72 (1 H, m), 1.84 (1 H, qd, J=12.23, 3.83 Hz), 2.16 (1 H, br t, J=10.81 Hz), 2.29 (1 H, dd, J=37.85, 12.59 Hz), 2.52 (2 H, t, J=5.75 Hz), 2.89 (1 H, br d, J=12.32 Hz), 3.09 - 3.19 (1 H, m), 3.24 (3 H, s), 3.43 (2 H, t, J=5.75 Hz), 3.68 - 3.86 (1 H, m), 4.84 (1 H, d, 10 J=49.95 Hz), 5.16 (2 H, td, J=16.15, 2.19 Hz), 6.00 (1 H, d, J=7.94 Hz), 6.58 (1 H, tt, J=53.75, 2.46 Hz), 7.34 (1 H, d, J=3.29 Hz), 7.46 (1 H, d, J=3.01 Hz), 7.69 (1 H, br s), 8.09 (1 H, d, J=9.31 Hz), 8.54 (1 H, d, J=9.03 Hz), 10.46 (1 H, br s); ESIMS found for C21H25F3N10O m / z 491.2 (M+1).15 257

[0485] (1r,4r)-4-((4-Amino-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-5-yl)-6-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 257.

[0486] Yellow solid (15 mg, 0.033 mmol, 31.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.13 (3 H, s), 1.33 - 1.48 (4 H, m), 1.53 - 1.64 (2 H, m), 1.76 - 1.88 (2 H, m), 20 3.55 - 3.69 (1 H, m), 4.21 (1 H, s), 5.19 (2 H, td, J=16.15, 2.46 Hz), 6.05 (1 H, d, J=8.21 Hz), 6.60 (2 H, tt, J=53.80, 2.75 Hz), 7.62 (1 H, br s), 7.68 (1 H, d, J=2.19 Hz), 7.93 (1 H, d, J=9.03 Hz), 8.65 (1 H, d, J=8.76 Hz), 9.64 (1 H, br s); ESIMS found for C20H22F3N9O m / z 462.2 (M+1).SMi.089PCT (BTP-002WO)

[0487] 1-((3R,4S)-4-((4-Amino-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-6-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan- 1-one 258.

[0488] Fluffy yellow solid (6 mg, 0.012 mmol, 94.8% yield).1H NMR (499 MHz, 5 DMSO-d6) ppm 1.59 - 1.69 (1 H, m), 1.71 - 1.87 (1 H, m), 1.99 (3 H, s), 2.59 - 2.73 (1 H, m), 3.09 - 3.24 (1 H, m), 3.82 - 3.96 (1 H, m), 3.98 - 4.17 (1 H, m), 4.41 - 4.72 (1 H, m), 4.93 (1 H, d, J=49.90 Hz), 5.19 (2 H, td, J=16.22, 2.33 Hz), 6.31 (1 H, d, J=8.21 Hz), 6.60 (2 H, tt, J=54.00, 2.60 Hz), 7.68 (1 H, d, J=1.92 Hz), 7.75 (1 H, br s), 7.94 (1 H, d, J=8.76 Hz), 8.67 (1 H, d, J=9.03 Hz), 9.71 (1 H, br s); ESIMS found for C20H20F4N10O m / z 493.15 (M+1). 10260

[0489] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoro- N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 260. 15

[0490] Yellow fluffy solid (10 mg, 0.0120 mmol, 18.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 (1 H, br dd, J=8.62, 3.97 Hz), 1.87 (1 H, qd, J=12.09, 3.42 Hz), 1.94 - 2.02 (1 H, m), 2.11 (1 H, dd, J=37.05, 12.59 Hz), 2.74 (1 H, br d, J=12.05 Hz), 2.90 - 3.03 (1 H, m), 3.48 (1 H, quin, J=6.43 Hz), 3.71 - 3.89 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.53 (2 H, td, J=6.50, 2.60 Hz), 4.86 (1 H, d, J=49.35 Hz), 5.19 (2 H, td, 20 J=16.08, 2.33 Hz), 6.19 (1 H, d, J=8.21 Hz), 7.68 (1 H, d, J=2.19 Hz), 7.74 (1 H, br s), 7.94 (1 H, d, J=9.03 Hz), 8.67 (1 H, d, J=9.03 Hz), 9.70 (1 H, br s); ESIMS found for C21H22F4N10O m / z 507.2 (M+1).261 25

[0491] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)- 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoropyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 261.

[0492] Fluffy yellow solid (2.8 mg, 0.006 mmol, 42.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.71 - 1.87 (2 H, m), 2.06 - 2.19 (1 H, m), 2.25 (3 H, s), 2.31 (1 H, dd,SMi.089PCT (BTP-002WO) J=26.85, 11.77 Hz), 2.78 (1 H, br d, J=12.05 Hz), 3.00 - 3.10 (1 H, m), 4.13 - 4.30 (1 H, m), 5.19 (2 H, td, J=16.08, 2.05 Hz), 6.38 (1 H, br d, J=9.58 Hz), 6.60 (1 H, tt, J=54.05, 2.55 Hz), 7.69 (1 H, d, J=1.92 Hz), 7.79 (1 H, br s), 7.94 (1 H, d, J=8.76 Hz), 8.67 (1 H, d, J=9.03 Hz), 9.73 (1 H, br s); ESIMS found for C19H19F5N10m / z 483.2 (M+1). 5262

[0493] (R)-1-(4-((4-Amino-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-5-yl)-6-fluoropyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1- yl)ethan-1-one 262. 10

[0494] Yellow fluffy solid (4 mg, 0.008 mmol, 58.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.57 - 1.79 (1 H, m), 1.81 - 1.95 (1 H, m), 2.06 (3 H, s), 2.91 - 3.03 (1 H, m), 3.64 - 3.90 (1 H, m), 4.09 - 4.28 (1 H, m), 4.41 - 4.57 (2 H, m), 5.20 (2 H, td, J=16.15, 2.46 Hz), 6.60 (1 H, tt, J=54.00, 2.74 Hz), 6.59 (1 H, d, J=8.10 Hz), 7.68 (1 H, d, J=1.92 Hz), 7.79 (1 H, br s), 7.95 (1 H, d, J=8.76 Hz), 8.68 (1 H, d, J=8.76 Hz), 9.75 (1 H, br s); ESIMS found 15 for C20H19F5N10O m / z 511.1 (M+1).264

[0495] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2- difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoropyrrolo[2,1-f][1,2,4]triazine- 20 2,4-diamine 264.

[0496] Yellow fluffy solid (7 mg, 0.013 mmol, 93.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.70 - 1.82 (1 H, m), 1.83 - 1.91 (1 H, m), 2.06 - 2.16 (1 H, m), 2.33 (1 H, dd, J=27.15, 11.23 Hz), 2.75 (1 H, br d, J=11.77 Hz), 2.96 - 3.06 (1 H, m), 3.59 (1 H, quin, J=6.23 Hz), 4.19 - 4.34 (1 H, m), 4.43 (2 H, dt, J=14.24, 6.30 Hz), 4.54 (2 H, td, J=6.57, 3.83 25 Hz), 5.19 (2 H, td, J=16.15, 2.46 Hz), 6.46 (1 H, br d, J=9.31 Hz), 6.60 (2 H, tt, J=54.00, 2.60 Hz), 7.69 (1 H, d, J=2.19 Hz), 7.78 (1 H, br s), 7.94 (1 H, d, J=9.03 Hz), 8.67 (1 H, d, J=8.76 Hz), 9.74 (1 H, br s); ESIMS found for C21H21F5N10O m / z 525.2 (M+1).SMi.089PCT (BTP-002WO)

[0497] (1r,3r)-3-((5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol 266. 5

[0498] Yellow solid (16 mg, 0.037 mmol, 35.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.27 (3 H, s), 1.92 - 2.01 (2 H, m), 2.24 - 2.33 (2 H, m), 3.12 (3 H, d, J=4.65 Hz), 4.28 (1 H, sxt, J=7.56 Hz), 4.74 (1 H, s), 5.26 (2 H, td, J=16.08, 2.60 Hz), 6.51 (1 H, d, J=7.12 Hz), 6.72 (1 H, tt, J=54.00, 2.87 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=2.74 Hz), 8.10 (1 H, d, J=9.31 Hz), 8.54 (1 H, d, J=9.04 Hz), 10.87 (1 H, q, J=4.56 Hz); ESIMS 10 found for C19H21F2N9O m / z 430.2 (M+1).

[0499] (1r,3s)-3-((5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol 267. 15

[0500] Yellow solid (32 mg, 0.072 mmol, 54.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 0.81 (3 H, t, J=7.39 Hz), 1.50 (2 H, q, J=7.39 Hz), 1.86 - 1.97 (2 H, m), 2.17 - 2.26 (2 H, m), 3.12 (3 H, d, J=4.65 Hz), 4.32 (1 H, sxt, J=7.67 Hz), 4.57 (1 H, s), 5.26 (2 H, td, J=15.88, 2.46 Hz), 6.50 (1 H, d, J=7.12 Hz), 6.72 (1 H, tt, J=54.00, 2.87 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 8.10 (1 H, d, J=9.31 Hz), 8.54 (1 H, d, J=9.04 Hz), 10.87 20 (1 H, q, J=4.65 Hz); ESIMS found for C20H23F2N9O m / z 444.2 (M+1).

[0501] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N2-(1- (2,2-difluoroethyl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 270.SMi.089PCT (BTP-002WO)

[0502] Yellow solid (54 mg, 0.110 mmol, 96.4% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.46 - 1.59 (2 H, m), 1.87 (2 H, br d, J=9.86 Hz), 2.19 - 2.30 (2 H, m), 2.71 (2 H, td, J=15.74, 4.38 Hz), 2.89 (2 H, br d, J=11.77 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.53 - 3.64 (1 H, m), 5.25 (2 H, td, J=16.08, 2.60 Hz), 6.13 (1 H, tt, J=55.95, 4.38 Hz), 6.17 (1 H, d, J=8.21 5 Hz), 6.72 (1 H, tt, J=54.00, 2.87 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.10 (1 H, d, J=9.03 Hz), 8.54 (1 H, d, J=9.03 Hz), 10.87 (1 H, q, J=4.47 Hz); ESIMS found for C21H24F4N10m / z 493.2 (M+1).271 10

[0503] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4- methyl-N2-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 271.

[0504] Yellow solid (5 mg, 0.010 mmol, 27.6% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.45 - 1.59 (2 H, m), 1.81 - 1.87 (2 H, m), 1.89 (2 H, br d, J=11.77 Hz), 2.68 (2 H, br d, J=10.95 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.54 - 3.65 (1 H, m), 4.42 (2 H, t, J=6.16 15 Hz), 4.52 (2 H, t, J=6.57 Hz), 5.25 (2 H, td, J=16.02, 2.46 Hz), 6.19 (1 H, d, J=8.21 Hz), 6.71 (1 H, tt, J=54.05, 2.87 Hz), 7.31 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 8.10 (1 H, d, J=9.31 Hz), 8.54 (1 H, d, J=9.03 Hz), 10.87 (1 H, q, J=4.65 Hz); ESIMS found for C22H26F2N10O m / z 485.2 (M+1). 20

[0505] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N2- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 272.

[0506] Yellow solid (30 mg, 0.065 mmol, 34.6% yield).1H NMR (499 MHz, 25 DMSO-d6) ppm 1.63 - 1.74 (1 H, m), 1.90 (1 H, qd, J=12.23, 3.83 Hz), 2.02 - 2.14 (1 H, m), 2.22 (1 H, dd, J=37.85, 13.14 Hz), 2.21 (3 H, s), 2.82 (1 H, br d, J=11.50 Hz), 3.02 - 3.10 (1 H, m), 3.13 (3 H, d, J=4.93 Hz), 3.69 - 3.85 (1 H, m), 4.89 (1 H, d, J=49.90 Hz), 5.26 (2 H, td, J=16.02, 2.46 Hz), 6.11 (1 H, d, J=7.67 Hz), 6.72 (1 H, tt, J=54.30, 2.88 Hz), 7.34 (1 H, d,SMi.089PCT (BTP-002WO) J=2.74 Hz), 7.44 (1 H, d, J=2.74 Hz), 8.11 (1 H, d, J=8.76 Hz), 8.55 (1 H, d, J=8.76 Hz), 10.92 (1 H, q, J=4.56 Hz); ESIMS found for C20H23F3N10m / z 461.2 (M+1).5

[0507] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N2- ((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 273.

[0508] Yellow solid (4 mg, 0.009 mmol, 38.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.62 - 1.74 (1 H, m), 1.89 (1 H, qd, J=12.23, 3.83 Hz), 2.04 (1 H, br t, J=10.95 10 Hz), 2.16 (1 H, dd, J=37.30, 12.87 Hz), 2.18 (3 H, s), 2.79 (1 H, br d, J=10.68 Hz), 2.97 - 3.08 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.68 - 3.84 (1 H, m), 4.88 (1 H, d, J=49.90 Hz), 5.26 (2 H, td, J=16.08, 2.60 Hz), 6.09 (1 H, d, J=7.94 Hz), 6.72 (1 H, tt, J=54.05, 2.87 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.11 (1 H, d, J=9.03 Hz), 8.55 (1 H, d, J=9.04 Hz), 10.92 (1 H, q, J=4.65 Hz); ESIMS found for C20H23F3N10m / z 461.2 (M+1). 15

[0509] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N2- ((3R,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 274. 20

[0510] Yellow solid (55 mg, 0.112 mmol, 93.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.64 - 1.74 (1 H, m), 1.89 (1 H, qd, J=12.23, 4.38 Hz), 2.18 - 2.28 (1 H, m), 2.37 (1 H, dd, J=37.45, 12.59 Hz), 2.67 (2 H, dt, J=28.55, 4.93 Hz), 2.92 (1 H, br d, J=9.86 Hz), 3.13 (3 H, d, J=4.38 Hz), 3.14 - 3.20 (1 H, m), 3.71 - 3.87 (1 H, m), 4.54 (2 H, dt, J=48.30, 4.93 Hz), 4.89 (1 H, d, J=49.50 Hz), 5.26 (2 H, td, J=16.15, 2.74 Hz), 6.11 (1 H, d, J=8.21 Hz), 25 6.72 (1 H, tt, J=53.75, 2.88 Hz), 7.34 (1 H, d, J=3.29 Hz), 7.44 (1 H, d, J=3.29 Hz), 8.11 (1 H, d, J=9.31 Hz), 8.55 (1 H, d, J=9.31 Hz), 10.93 (1 H, q, J=4.38 Hz); ESIMS found for C21H24F4N10m / z 493.2 (M+1).SMi.089PCT (BTP-002WO)

[0511] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N2- ((3R,4S)-3-fluoro-1-(2-methoxyethyl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 5 2,4-diamine 275.

[0512] Yellow solid (7 mg, 0.014 mmol, 75.6% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.68 (1 H, br d, J=6.02 Hz), 1.80 - 1.94 (1 H, m), 2.10 - 2.21 (1 H, m), 2.23 - 2.36 (1 H, m), 2.51 - 2.55 (2 H, m), 2.86 - 2.95 (1 H, m), 3.13 (3 H, d, J=4.38 Hz), 3.13 - 3.19 (1 H, m), 3.25 (3 H, s), 3.44 (2 H, br s), 3.72 - 3.87 (1 H, m), 4.87 (1 H, d, J=50.50 Hz), 5.26 10 (2 H, td, J=15.88, 2.74 Hz), 6.02 - 6.14 (1 H, m), 6.72 (1 H, tt, J=54.00, 2.87 Hz), 7.34 (1 H, d, J=3.29 Hz), 7.44 (1 H, d, J=2.74 Hz), 8.11 (1 H, d, J=9.31 Hz), 8.55 (1 H, d, J=8.76 Hz), 10.93 (1 H, q, J=4.65 Hz); ESIMS found for C22H27F3N10O m / z 505.2 (M+1).15

[0513] (R)-1-(4-((5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-2- hydroxyethan-1-one 276.

[0514] Fluffy yellow solid (27 mg, 0.052 mmol, 74.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.57 - 1.81 (1 H, m), 1.84 - 1.98 (1 H, m), 3.06 (1 H, br t, J=11.36 Hz), 20 3.16 (3 H, d, J=4.65 Hz), 3.56 - 3.84 (1 H, m), 4.03 - 4.25 (3 H, m), 4.41 - 4.51 (1 H, m), 4.51 - 4.61 (1 H, m), 4.77 - 4.86 (1 H, m), 5.27 (2 H, td, J=16.02, 2.19 Hz), 6.56 (1 H, br d, J=9.58 Hz), 6.72 (1 H, tt, J=54.00, 2.74 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.13 (1 H, d, J=9.31 Hz), 8.56 (1 H, d, J=9.04 Hz), 10.97 (1 H, q, J=4.65 Hz); ESIMS found for C21H22F4N10O2m / z 523.15 (M+1).SMi.089PCT (BTP-002WO)286

[0515] (1r,4r)-4-((5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-6-fluoro-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1- 5 ol 286.

[0516] Fluffy yellow solid (2 mg, 0.004 mmol, 40.1% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.14 (3 H, s), 1.38 - 1.48 (4 H, m), 1.55 - 1.63 (2 H, m), 1.80 - 1.87 (2 H, m), 3.08 (3 H, d, J=4.93 Hz), 3.56 - 3.69 (1 H, m), 4.22 (1 H, s), 5.26 (2 H, td, J=16.15, 2.74 Hz), 6.16 (1 H, d, J=8.21 Hz), 6.71 (1 H, tt, J=53.75, 2.87 Hz), 7.67 (1 H, d, J=1.92 Hz), 7.95 (1 H, 10 d, J=9.03 Hz), 8.66 (1 H, d, J=8.76 Hz), 10.14 (1 H, q, J=4.47 Hz); ESIMS found for C21H24F3N9O m / z 476.2 (M+1).

[0517] 1-((3R,4S)-4-((5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-15 5-yl)-6-fluoro-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1- yl)ethan-1-one 288.

[0518] Fluffy yellow solid (4 mg, 0.008 mmol, 91.7% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.60 - 1.72 (1 H, m), 1.73 - 1.88 (1 H, m), 1.97 - 2.06 (3 H, m), 2.60 - 2.73 (1 H, m), 2.87 (1 H, dd, J=39.25, 13.96 Hz), 3.10 (3 H, d, J=4.65 Hz), 3.84 - 3.97 (1 H, m), 20 4.00 - 4.17 (1 H, m), 4.40 - 4.72 (1 H, m), 4.95 (1 H, d, J=49.35 Hz), 5.27 (2 H, td, J=16.02, 2.74 Hz), 6.42 (1 H, d, J=7.94 Hz), 6.72 (2 H, tt, J=54.00, 2.87 Hz), 7.65 (1 H, d, J=2.19 Hz), 7.96 (1 H, d, J=9.03 Hz), 8.68 (1 H, d, J=9.03 Hz), 10.16 - 10.27 (1 H, m); ESIMS found for C21H22F4N10O m / z 507.2 (M+1).SMi.089PCT (BTP-002WO) 290

[0519] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoro- N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 290. 5

[0520] Fluffy yellow solid (13 mg, 0.025 mmol, 72.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.63 - 1.76 (1 H, m), 1.88 (1 H, qd, J=12.05, 3.56 Hz), 1.95 - 2.04 (1 H, m), 2.13 (1 H, dd, J=37.30, 12.59 Hz), 2.75 (1 H, br d, J=9.31 Hz), 2.90 - 3.03 (1 H, m), 3.09 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.43 Hz), 3.72 - 3.89 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.57, 3.01 Hz), 4.89 (1 H, d, J=49.60 Hz), 5.27 10 (2 H, td, J=16.08, 2.87 Hz), 6.30 (1 H, d, J=7.94 Hz), 6.72 (1 H, tt, J=54.05, 2.87 Hz), 7.65 (1 H, d, J=2.19 Hz), 7.95 (1 H, d, J=9.03 Hz), 8.67 (1 H, d, J=8.76 Hz), 10.20 (1 H, q, J=4.56 Hz) ESIMS found for C22H24F4N10O m / z 521.2 (M+1).291 15

[0521] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)- 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoro-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 291.

[0522] Fluffy yellow solid (4 mg, 0.008 mmol, 38.9% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.69 - 1.88 (2 H, m), 2.15 (1 H, td, J=10.95, 2.46 Hz), 2.25 (3 H, s), 2.35 (1 20 H, dd, J=26.85, 11.77 Hz), 2.77 (1 H, br d, J=12.05 Hz), 2.97 - 3.07 (1 H, m), 3.10 (3 H, d, J=4.93 Hz), 4.13 - 4.31 (1 H, m), 5.27 (2 H, td, J=16.08, 2.60 Hz), 6.47 (1 H, d, J=9.31 Hz), 6.72 (2 H, tt, J=54.30, 2.87 Hz), 7.67 (1 H, d, J=2.19 Hz), 7.96 (1 H, d, J=9.03 Hz), 8.67 (1 H, d, J=8.76 Hz), 10.22 (1 H, q, J=4.65 Hz); ESIMS found for C20H21F5N10m / z 497.2 (M+1).25 293

[0523] (R)-1-(4-((5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5- yl)-6-fluoro-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1- yl)ethan-1-one 293.SMi.089PCT (BTP-002WO)

[0524] Fluffy yellow solid (12 mg, 0.023 mmol, 96.4% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.54 - 1.81 (1 H, m), 1.82 - 1.99 (1 H, m), 2.07 (3 H, s), 2.98 (1 H, br t, J=11.50 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.60 - 3.91 (1 H, m), 4.06 - 4.28 (1 H, m), 4.40 - 4.60 (2 H, m), 5.28 (2 H, td, J=16.02, 2.46 Hz), 6.72 (1 H, tt, J=54.00, 2.74 Hz), 6.67 (1 H, br d, 5 J=9.58 Hz), 7.66 (1 H, s), 7.97 (1 H, d, J=9.03 Hz), 8.69 (1 H, d, J=9.03 Hz), 10.24 (1 H, q, J=4.65 Hz); ESIMS found for C21H21F5N10O m / z 525.2 (M+1).295

[0525] (R)-N2-(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-10 difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-6-fluoro-N4-methylpyrrolo[2,1- f][1,2,4]triazine-2,4-diamine 295.

[0526] Fluffy yellow solid (10 mg, 0.019 mmol, 64.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.73 - 1.83 (1 H, m), 1.84 - 1.91 (1 H, m), 2.09 - 2.18 (1 H, m), 2.37 (1 H, dd, J=26.60, 11.50 Hz), 2.75 (1 H, br d, J=11.50 Hz), 2.93 - 3.06 (1 H, m), 3.11 (3 H, d, 15 J=4.65 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.19 - 4.36 (1 H, m), 4.43 (2 H, dt, J=14.92, 6.09 Hz), 4.55 (2 H, td, J=6.64, 3.70 Hz), 5.27 (2 H, td, J=16.08, 2.60 Hz), 6.55 (1 H, d, J=9.31 Hz), 6.72 (1 H, tt, J=54.00, 2.87 Hz), 7.66 (1 H, d, J=2.19 Hz), 7.96 (1 H, d, J=9.03 Hz), 8.68 (1 H, d, J=8.76 Hz), 10.23 (1 H, q, J=4.56 Hz); ESIMS found for C22H23F5N10O m / z 539.2 (M+1).20 333

[0527] N2-((3R,4S)-3-Fluoro-1-methylpiperidin-4-yl)-5-(3-(3-fluoropropyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 333.

[0528] Light yellow solid (10 mg, 0.022 mmol, 57.0% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.62 - 1.73 (1 H, m), 1.89 (1 H, qd, J=12.27, 3.97 Hz), 2.05 (1 H, br t, J=10.81 25 Hz), 2.17 (1 H, dd, J=37.85, 12.32 Hz), 2.18 (3 H, s), 2.43 (2 H, dquin, J=27.15, 6.30, 6.30, 6.30, 6.30 Hz), 2.79 (1 H, br d, J=11.23 Hz), 3.04 (1 H, br t, J=10.81 Hz), 3.13 (3 H, d, J=4.65 Hz), 3.65 - 3.86 (1 H, m), 4.54 (2 H, dt, J=47.20, 5.48 Hz), 4.82 (2 H, t, J=6.98 Hz), 4.88 (1 H, d, J=49.35 Hz), 6.08 (1 H, d, J=7.94 Hz), 7.31 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz),SMi.089PCT (BTP-002WO) 8.07 (1 H, d, J=9.03 Hz), 8.51 (1 H, d, J=9.04 Hz), 11.06 (1 H, q, J=4.56 Hz); ESIMS found for C21H26F2N10m / z 457.2 (M+1).5

[0529] 1-((3R,4S)-3-Fluoro-4-((5-(3-(3-fluoropropyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1- one 335.

[0530] Light yellow solid (13 mg, 0.027 mmol, 69.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.60 - 1.90 (2 H, m), 1.97 - 2.06 (3 H, m), 2.61 - 2.77 (1 H, m), 2.88 (1 H, 10 dd, J=39.50, 14.23 Hz), 3.14 (3 H, d, J=4.65 Hz), 3.85 - 4.00 (1 H, m), 4.02 - 4.19 (1 H, m), 4.55 (2 H, dt, J=47.20, 5.48 Hz), 4.63 - 4.76 (1 H, m), 4.82 (2 H, t, J=6.84 Hz), 4.96 (1 H, d, J=49.35 Hz), 6.28 (1 H, br d, J=7.94 Hz), 7.32 (1 H, d, J=3.29 Hz), 7.43 (1 H, d, J=3.01 Hz), 8.07 (1 H, d, J=9.04 Hz), 8.52 (1 H, d, J=9.03 Hz), 11.08 (1 H, q, J=4.47 Hz); ESIMS found for C22H26F2N10O m / z 485.2 (M+1). 15

[0531] N2-((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(3- fluoropropyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 337. 20

[0532] Light yellow solid (7 mg, 0.014 mmol, 36.5% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.66 - 1.77 (1 H, m), 1.88 (1 H, qd, J=12.00, 3.42 Hz), 1.96 - 2.06 (1 H, m), 2.13 (1 H, dd, J=37.30, 12.87 Hz), 2.43 (2 H, dquin, J=27.15, 6.18, 6.18, 6.18, 6.18 Hz), 2.75 (1 H, br d, J=10.40 Hz), 2.91 - 3.04 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 3.49 (1 H, quin, J=6.30 Hz), 3.74 - 3.90 (1 H, m), 4.40 (1 H, t, J=6.16 Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, dt, 25 J=47.15, 5.48 Hz), 4.54 (2 H, td, J=6.50, 3.15 Hz), 4.82 (2 H, t, J=6.84 Hz), 4.90 (1 H, d, J=49.35 Hz), 6.15 (1 H, d, J=7.94 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 8.07 (1 H, d, J=9.03 Hz), 8.51 (1 H, d, J=9.04 Hz), 11.07 (1 H, q, J=4.38 Hz); ESIMS found for C23H28F2N10O m / z 499.3 (M+1).SMi.089PCT (BTP-002WO)

[0533] (R)-N2-(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(3-fluoropropyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 338. 5

[0534] Light yellow solid (23 mg, 0.049 mmol, 69.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.72 - 1.88 (2 H, m), 2.10 - 2.20 (1 H, m), 2.25 (3 H, s), 2.36 (1 H, dd, J=27.80, 11.70 Hz), 2.43 (2 H, dquin, J=27.15, 6.00, 6.00, 6.00, 6.00 Hz), 2.77 (1 H, br d, J=11.77 Hz), 2.97 - 3.10 (1 H, m), 3.15 (3 H, d, J=4.65 Hz), 4.17 - 4.34 (1 H, m), 4.54 (2 H, dt, J=47.20, 5.61 Hz), 4.83 (2 H, t, J=6.98 Hz), 6.32 (1 H, d, J=9.31 Hz), 7.33 (1 H, d, J=3.01 Hz), 10 7.44 (1 H, d, J=3.01 Hz), 8.07 (1 H, d, J=9.03 Hz), 8.52 (1 H, d, J=8.76 Hz), 11.09 (1 H, q, J=4.47 Hz); ESIMS found for C21H25F3N10m / z 475.2 (M+1).

[0535] (R)-1-(3,3-Difluoro-4-((5-(3-(3-fluoropropyl)-3H-[1,2,3]triazolo[4,5-b]15 pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1- one 339.

[0536] Light yellow solid (28 mg, 0.056 mmol, 80.2% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.55 - 1.81 (1 H, m), 1.82 - 1.96 (1 H, m), 2.07 (3 H, s), 2.43 (2 H, dquin, J=27.15, 5.75, 5.75, 5.75, 5.75 Hz), 2.99 (1 H, br t, J=11.09 Hz), 3.16 (3 H, d, J=4.65 Hz), 3.60 20 - 3.90 (1 H, m), 4.08 - 4.27 (1 H, m), 4.43 - 4.57 (2 H, m), 4.55 (2 H, dt, J=47.15, 5.61 Hz), 4.83 (2 H, t, J=6.98 Hz), 6.54 (1 H, d, J=4.38 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=2.74 Hz), 8.08 (1 H, d, J=9.31 Hz), 8.52 (1 H, d, J=9.03 Hz), 11.11 (1 H, q, J=4.47 Hz); ESIMS found for C22H25F3N10O m / z 503.2 (M+1).SMi.089PCT (BTP-002WO)

[0537] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-ethyl- N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 5 403.

[0538] Fluffy yellow solid (2 mg, 0.004 mmol, 7.8% yield).1H NMR (499 MHz, DMSO-d6) ppm 1.25 (3 H, t, J=7.12 Hz), 1.68 - 1.75 (1 H, m), 1.88 (1 H, qd, J=12.05, 3.56 Hz), 1.96 - 2.04 (1 H, m), 2.13 (1 H, dd, J=37.30, 12.59 Hz), 2.75 (1 H, br d, J=9.58 Hz), 2.94 - 3.05 (1 H, m), 3.49 (1 H, quin, J=6.43 Hz), 3.67 (2 H, quin, J=6.84 Hz), 3.75 - 3.90 (1 H, m), 10 4.40 (1 H, t, J=6.16 Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.57, 3.01 Hz), 4.90 (1 H, d, J=49.65 Hz), 5.21 (2 H, td, J=15.74, 2.74 Hz), 6.16 (1 H, d, J=8.21 Hz), 6.72 (1 H, tt, J=54.05, 3.15 Hz), 7.33 (1 H, d, J=3.01 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.11 (1 H, d, J=9.31 Hz), 8.56 (1 H, d, J=8.76 Hz), 10.89 (1 H, t, J=5.89 Hz); ESIMS found for C23H27F3N10O m / z 517.2 (M+1). 15

[0539] 5-(3-(2,2-Difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N2- ((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-isopropylpyrrolo[2,1-f][1,2,4]triazine- 2,4-diamine 411.

[0540] Fluffy yellow solid (2 mg, 0.004 mmol, 7.6% yield).1H NMR (499 MHz, 20 DMSO-d6) ppm 1.34 (3 H, d, J=3.01 Hz), 1.35 (3 H, d, J=3.01 Hz), 1.71 (1 H, br dd, J=13.14, 3.29 Hz), 1.88 (1 H, qd, J=12.09, 3.42 Hz), 1.95 - 2.05 (1 H, m), 2.13 (1 H, dd, J=37.30, 12.59 Hz), 2.71 - 2.81 (1 H, m), 2.93 - 3.05 (1 H, m), 3.49 (1 H, quin, J=6.30 Hz), 3.71 - 3.90 (1 H, m), 4.40 (1 H, t, J=6.16 Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.43, 3.01 Hz), 4.61 (1 H, dq, J=14.10, 6.80 Hz), 4.89 (1 H, d, J=49.65 Hz), 5.21 (2 H, td, J=15.06, 3.29 Hz), 6.18 (1 25 H, d, J=8.21 Hz), 6.73 (1 H, tt, J=54.30, 3.42 Hz), 7.23 (1 H, d, J=3.01 Hz), 7.46 (1 H, d, J=3.01 Hz), 8.07 (1 H, d, J=9.03 Hz), 8.57 (1 H, d, J=9.03 Hz), 9.62 (1 H, d, J=8.21 Hz); ESIMS found for C24H29F3N10O m / z 531.3 (M+1).SMi.089PCT (BTP-002WO)419

[0541] N4-Cyclopropyl-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5- b]pyridin-5-yl)-N2-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1- 5 f][1,2,4]triazine-2,4-diamine 419.

[0542] Fluffy yellow solid (2 mg, 0.004 mmol, 7.6% yield).1H NMR (499 MHz, DMSO-d6) ppm 0.69 - 0.78 (2 H, m), 0.82 - 0.93 (2 H, m), 1.68 - 1.77 (1 H, m), 1.90 (1 H, qd, J=12.14, 3.56 Hz), 1.96 - 2.03 (1 H, m), 2.13 (1 H, dd, J=37.60, 12.59 Hz), 2.73 - 2.80 (1 H, m), 2.80 - 2.87 (1 H, m), 2.94 - 3.05 (1 H, m), 3.49 (1 H, quin, J=6.50 Hz), 3.76 - 3.94 (1 H, 10 m), 4.40 (1 H, t, J=6.16 Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.43, 3.29 Hz), 4.94 (1 H, d, J=49.90 Hz), 5.23 (2 H, td, J=15.40, 3.15 Hz), 6.19 (1 H, br d, J=7.94 Hz), 6.73 (1 H, tt, J=54.30, 3.29 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.46 (1 H, d, J=2.74 Hz), 8.11 (1 H, d, J=9.03 Hz), 8.55 (1 H, d, J=8.76 Hz), 10.96 (1 H, s); ESIMS found for C24H27F3N10O m / z 529.2 (M+1). 15 Example 6.

[0543] Representative compounds were screened using the assay procedure for DYRK1A kinase activity as described below.

[0544] Each compound was dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 11-point dose-response curves from 10 20 μM to 0.00016 μM) and compound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Corning).

[0545] The DYRK1A kinase assay was run using the Ser / Thr 18 peptide Z-lyte assay kit according to manufacturer’s instructions (Life Technologies- a Division of Thermo- Fisher). This is a non-radioactive assay using fluorescence resonance energy transfer (FRET) 25 between coumarin and fluorescein to detect kinase activity which is represented as a ratio of coumarin emission / fluorescein emission.

[0546] Briefly, recombinant DYRK1A kinase, ATP and Ser / Thr peptide 18 were prepared in 1X Kinase buffer to final concentrations of 0.25 μg / mL, 15 μM, and 4 μM respectively. The mixture was allowed to incubate with the representative compounds for one 30 hour at room temperature. All reactions were performed in duplicate. Unphosphorylated (“0% Control”) and phosphorylated (“100% control”) forms of Ser / Thr 18 served as controlSMi.089PCT (BTP-002WO) reactions. Additionally, an 11-point dose-response curve of Staurosporine (1uM top) was run to serve as a positive compound control.

[0547] After incubation, Development Reagent A was diluted in Development Buffer then added to the reaction and allowed to further incubate for one hour at room 5 temperature. The plate was read at Ex 400 Em 455 to detect the coumarin signal and Ex 400 Em 520 to measure the signal (EnVision Multilabel Plate Reader, PerkinElmer).

[0548] The Emission ratio (Em) was calculated as a ratio of the coumarin (C) emission signal (at 445 nm) / Fluorescein (F) emission signal (at 520 nm). The percent phosphorylation was then calculated using the following formula: [1 - ((Em ratio X F100%)- 10 C100%) / ((C0%-C100%) + (Em ratio X (F100% - F0%)))]. Dose-response curves were generated, and inhibitory concentration (IC50) values were calculated using non-linear regression curve fit in the Dotmatics’ Studies Software (Bishops Stortford, UK).

[0549] Table 3 shows the measured activity for representative compounds of Formula I as described herein. 15 Table 3.

Claims

SMi.089PCT (BTP-002WO) CLAIMS WHAT IS CLAIMED IS:

1. A compound, or a pharmaceutically acceptable salt thereof, of Formula I:5 I wherein: A1, A2, A3, A4, and A5are independently selected from the group consisting of carbon and nitrogen with the proviso that at least two of A1, A2, A3, A4, and A5are nitrogen; if A1and A3are both nitrogen then R2bis absent; if A1and A4are both nitrogen then 10 R3is absent; if A1and A5are both nitrogen then R2ais absent; if A1, A3, and A4are all nitrogen then R2band R3are absent; if A1, A4, and A5are all nitrogen then R2aand R3are absent; if A1, A3, and A5are all nitrogen then R2aand R2bare absent; if A1, A3, A4, and A5are all nitrogen then R2a, R2b, and R3are all absent; if A2and A3are both nitrogen then R2bis absent; if A2and A4are both nitrogen then R3is absent; if A2and A5are both nitrogen then R2ais absent; if A2, 15 A3, and A4are all nitrogen then R2band R3are absent; if A2, A4, and A5are all nitrogen then R2aand R3are absent; if A2, A3, and A5are all nitrogen then R2aand R2bare absent; if A2, A3, A4, and A5are all nitrogen then R2a, R2b, and R3are all absent; R1is selected from the group consisting of H and halide; R2ais selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted 20 –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), and unsubstituted –(C1-9haloalkyl); R2bis selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), unsubstituted –(C1-9haloalkyl), and – C(=O)N(R6)2; R3is selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted 25 –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), and unsubstituted –(C1-9haloalkyl); R4is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), unsubstituted –(C1-6haloalkyl), and –carbocyclyl optionally substituted with 1-10 R7; R5is selected from the group consisting of –heterocyclyl optionally substituted with 1- 30 10 R8and –carbocyclyl optionally substituted with 1-12 R9;SMi.089PCT (BTP-002WO) each R6is independently selected from the group consisting of H, unsubstituted –(C1-9alkyl), unsubstituted –(C2-9alkenyl), and unsubstituted –(C2-9alkynyl); each R7is halide; each R8is independently selected from the group consisting of halide, unsubstituted – 5 (C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), unsubstituted –(C1-9haloalkyl), –heterocyclyl optionally substituted with 1-10 R10, –(C1-5alkylene)OR11, –SO2R12, and –C(=O)R13, wherein the –(C1-5alkylene) is optionally substituted with 1-5 halide and / or 1- 3 unsubstituted –(C1-3alkyl); each R9is independently selected from the group consisting of halide, unsubstituted – 10 (C1-9alkyl), unsubstituted –(C2-9alkenyl), unsubstituted –(C2-9alkynyl), unsubstituted –(C1-9haloalkyl), –OR14, and –NR15C(=O)R16; each R10is halide; R11is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); 15 R12is selected from the group consisting of unsubstituted –(C1-6alkyl), unsubstituted – (C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); R13is selected from the group consisting of unsubstituted –(C1-6alkyl), unsubstituted – (C2-6 alkenyl), unsubstituted –(C2-6 alkynyl), unsubstituted –(C1-6 haloalkyl), and –(C1-5 alkylene)OR17, wherein the –(C1-5alkylene) is optionally substituted with 1-5 halide and / or 1- 20 3 unsubstituted –(C1-3alkyl); R14is selected from the group consisting of H, unsubstituted –(C1-6 alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl), and –(C1-5alkylene)OR18, wherein the –(C1-5alkylene) is optionally substituted with 1-5 halide and / or 1- 3 unsubstituted –(C1-3alkyl); 25 R15is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); R16is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); R17is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted 30 –(C2-6 alkenyl), unsubstituted –(C2-6 alkynyl), and unsubstituted –(C1-6 haloalkyl); R18is selected from the group consisting of H, unsubstituted –(C1-6alkyl), unsubstituted –(C2-6alkenyl), unsubstituted –(C2-6alkynyl), and unsubstituted –(C1-6haloalkyl); and wherein each H atom is optionally, independently replaced by2H (D) (deuterium).

2. The compound of claim 1, wherein R1is H. 35 3. The compound of claim 1, wherein R1is F.

4. The compound according to any one of claims 1-3, wherein A1and A5are nitrogen, and A2, A3, and A4are carbon.SMi.089PCT (BTP-002WO) 5. The compound according to any one of claims 1-3, wherein A2and A5are nitrogen, and A1, A3, and A4are carbon.

6. The compound according to any one of claims 1-3, wherein A3and A5are nitrogen, and A1, A2, and A4are carbon. 5 7. The compound according to any one of claims 1-3, wherein A3, A4, and A5are nitrogen, and A1and A2are carbon.

8. The compound according to any one of claims 1-5, wherein R2bis selected from the group consisting of H, unsubstituted –(C1-3haloalkyl), and –C(=O)NHMe; and R3is H.

9. The compound according to any one of claims 1-3 and 6, wherein R2bis 10 selected from the group consisting of unsubstituted –(C1-3alkyl) and unsubstituted –(C1-3haloalkyl); and R3is selected from the group consisting of H and Me.

10. The compound according to any one of claims 1-3 and 7, wherein R2bis selected from the group consisting of unsubstituted –(C1-3alkyl) and unsubstituted –(C1-3haloalkyl). 15 11. The compound according to any one of claims 1-10, wherein R4is H.

12. The compound according to any one of claims 1-10, wherein R4is Me.

13. The compound according to any one of claims 1-12, wherein R5is selected from the group consisting of –heterocyclyl optionally substituted with 1-4 R8and – carbocyclyl optionally substituted with 1-4 R9. 20 14. The compound according to any one of claims 1-13, wherein each R8is selected from the group consisting of Me, –C(=O)Me, –C(=O)CH2OH, –SO2Me, and .

15. The compound according to any one of claims 1-13, wherein each R9is independently selected from the group consisting of F, Me, –OH, –OMe, and –OCH2CH2OH. 25 16. The compound of claim 1, wherein the compound of Formula I is selected from the group consisting of: , ,SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)17. The compound of claim 1, wherein the compound of Formula I is selected from the group consisting of:SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound of Formula I is selected from the group consisting of: , , , ,SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO) 5SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)19. The compound of claim 1, wherein the compound of Formula I is selected fromSMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)SMi.089PCT (BTP-002WO)pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a therapeutically effective amount of 5 a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A method of treating a disorder or disease in a patient, wherein the disorder or disease is selected from the group consisting of: a neurological disorder, diabetes, and cancer, the method comprising administering to the patient a therapeutically effective amount of a 10 compound according to any one of claims 1-19, or a pharmaceutically acceptable salt.

22. The method of claim 21, wherein the cancer is selected from the group consisting of: brain tumors, glioblastoma, ovarian, breast, head and neck squamous cell carcinoma, hepatocellular carcinoma, pancreatic cancer, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, and chronic myeloid leukemia. 15 23. The method of claim 21, wherein the disorder or disease is a neurological disorder, wherein the neurological disorder is selected from the group consisting of: Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, CDKL5 Deficiency Disorder, Down Syndrome, Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Pick's Disease, and additional diseases with pronounced 20 neurodegeneration such as Autism, Dementia, Epilepsy, Huntington’s Disease, Multiple Sclerosis; diseases and disorders associated with acquired brain injury such as Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, Stroke, Pick disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glialSMi.089PCT (BTP-002WO) tauopathies, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and aging-related tau astrogliopathy.

24. The method of claim 23, wherein the disorder or disease is Alzheimer’s disease. 5 25. The method according to any one of claims 21-24, wherein the patient is a human.

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