4-aminopyrrolo[2,1-f][1,2,4]triazine, its preparation and use

Abstract

4-aminopyrrolo[2,1-f][1,2,4]triazine compounds have been disclosed for treating various diseases and conditions. More specifically, the present invention relates to the use of 4-aminopyrrolo[2,1-f][1,2,4]triazine compounds or analogs thereof in the treatment of diseases characterized by overexpression of DYRK1A (e.g., cancer, Down's syndrome, Alzheimer's disease, diabetes, and osteoarthritis). Some embodiments disclosed herein include DYRK1A inhibitors 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. TIFF2025538866000356.tif38165

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application Nos. 63 / 422,202, filed November 3, 2022, and 63 / 494,875, filed April 7, 2023, which are incorporated herein by reference in their entireties.

[0002] Technical Field The present disclosure relates to inhibitors of dual specificity tyrosine phosphorylation-regulated 1A kinase and compositions comprising the same. More specifically, it relates to the use of 4-aminopyrrolo[2,1-f][1,2,4]triazine compounds or salts or analogs thereof in the treatment of diseases characterized by aberrant expression and / or activity of DYRK1A (e.g., cancer, Down's syndrome, Alzheimer's disease, diabetes, and osteoarthritis). [Background technology]

[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 signal transduction, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine / methionine / folate regulation, thermoregulation, endocytosis, neuronal development, and synaptic plasticity. Abnormal expression and / or activity of some of these kinases, particularly DYRK1A, is observed in many human neurological disorders, including cognitive impairment associated with Down syndrome, Alzheimer's disease and related disorders, tauopathies, dementia, Pick's disease, Parkinson's disease and other neurodegenerative disorders, Phelan-McDermid syndrome, autism, and CDKL5 deficiency. DYRK1A has also been implicated in diabetes, folate / methionine metabolism disorders, osteoarthritis, several solid cancers (glioblastoma, breast cancer, and pancreatic cancer), leukemia (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), and infections caused by single-cell parasites (Leishmania, Trypanosoma, Plasmodium) (International Journal of Molecular Sciences (2021), 22(11), 6047). DYRK1A has also been identified as a key stabilizer of EGFR, a key factor contributing to keratinization, cell hyperproliferation, abnormal differentiation, and inflammatory infiltration during the progression of psoriasis (Cell Death & Disease (2019), 10, 282). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] International Journal of Molecular Sciences(2021),22(11),6047 [Non-patent document 2] Cell Death & Disease(2019),10,282 Summary of the Invention [Means for solving the problem]

[0005] The present invention provides methods and reagents that include contacting cells with a sufficient amount of an agent (e.g., a 4-aminopyrrolo[2,1-f][1,2,4]triazine compound) to antagonize DYRK1A activity (e.g., to reduce the growth of head and neck squamous cell carcinoma, luminal / HER2 breast cancer (Cell (2016), 164(1-2), 293-309), and pancreatic adenocarcinoma, and to worsen the self-renewal capacity of glioblastoma and reduce the viability of ovarian cancer spheroid cells (Molecular Cancer Research (2017), 15(4), 371-381)). The present invention also provides methods and reagents that include contacting a cell with an agent (e.g., a 4-aminopyrrolo[2,1-f][1,2,4]triazine compound) in an amount sufficient to antagonize DYRK1A activity (e.g., i) normalize prenatal and early postnatal brain development, ii) improve cognitive function during adolescence and adulthood, and / or iii) attenuate Alzheimer's-type neurodegeneration).

[0006] Some embodiments disclosed herein include DYRK1A inhibitors 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 is a compound having the structure of Formula I: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 However, R from 1 to 10 4 (9-10 membered heteroaryl) optionally substituted with R 2 However, R from 1 to 10 5-heterocyclyl optionally substituted with R 1 to 12 6 -carbocyclyl optionally substituted with R 3 H, unsubstituted (C 1-6 alkyl), unsubstituted (C 2-6 alkenyl), unsubstituted (C 2-6 alkynyl), and unsubstituted (C 1-6 haloalkyl), Each R 4 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), Each R 5 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), R 1 to 10 7 -heterocyclyl optionally substituted with -(C 1-5 alkylene) p OR 8 , and -C(=O)R 9 -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl), Each R 6 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), -OR 10 , -C(=O)R 11 , and -NHC(=O)R 12 selected from the group consisting of Each R 7 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 8 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 9 are independently unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 10 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), and -(C 1-5 alkylene) p OR 8 selected from the group consisting of Each R 11 But -N(R 13 )2, Each R 12 are independently unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 13 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), each p is independently 0 or 1; Each H atom independently 2H(D) (deuterium)).

[0008] Another embodiment disclosed herein includes a compound having the structure of Formula I: [ka] (In the formula, R 1 However, R from 1 to 10 4 (9-10 membered heteroaryl) optionally substituted with R 2 But non-substituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), R 1 to 10 5 -heterocyclyl optionally substituted with, and R 1 to 12 6 optionally substituted with -(C 1-5 alkylene) p carbocyclyl, -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl), R 3 H, unsubstituted (C 1-6 alkyl), unsubstituted (C 2-6 alkenyl), unsubstituted (C 2-6 alkynyl), unsubstituted (C 1-6 haloalkyl), and R 1 to 10 16 -heterocyclyl optionally substituted with Each R 4 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), Each R 5 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), R 1 to 10 7 -heterocyclyl optionally substituted with R 1 to 12 14 -carbocyclyl optionally substituted with -(C 1-5 alkylene) p OR 8 , and -C(=O)R 9 -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl), Alternatively, two Rs attached to the same carbon atom 5 together to form a carbonyl group, Each R 6 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), -CN, -(C 1-5 alkylene) p OR 10 , -C(=O)R 11 , -NHC(=O)R 12 , and R from 1 to 12 14 -carbocyclyl optionally substituted with -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl), Each R 7 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), -CN, and R 1 to 12 14 -carbocyclyl optionally substituted with Each R 8 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 9 are independently unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 10 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), and -(C 1-5 alkylene) p OR 8 selected from the group consisting of Each R 11 But -N(R 13 )2, Each R 12 are independently unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 13 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 14 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), R 15 is selected from the group consisting of H and halides; Each R 16 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), each p is independently 0 or 1; Each H atom independently 2 H(D) (deuterium)).

[0009] Another embodiment disclosed herein includes a compound having the structure of Formula I: [ka] (In the formula, R 1 However, R from 1 to 10 4 (9-10 membered heteroaryl) optionally substituted with R 2 But non-substituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), R 1 to 10 5 -heterocyclyl optionally substituted with, and R 1 to 12 6 optionally substituted with -(C 1-5 alkylene) p carbocyclyl, -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl), R 3 H, unsubstituted (C 1-6 alkyl), unsubstituted (C 2-6 alkenyl), unsubstituted (C 2-6 alkynyl), unsubstituted (C 1-6 haloalkyl), and R 1 to 10 16 -heterocyclyl optionally substituted with Each R 4are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), Each R 5 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), R 1 to 10 7 -heterocyclyl optionally substituted with R 1 to 12 14 -carbocyclyl optionally substituted with -(C 1-5 alkylene) p OR 8 , and -C(=O)R 9 -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl), Alternatively, two Rs attached to the same carbon atom 5 together to form a carbonyl group, Each R 6 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), -CN, -(C 1-5 alkylene) p OR 10 , -C(=O)R 11 , -NHC(=O)R 12 , and R from 1 to 12 14 -carbocyclyl optionally substituted with -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl), Each R 7 are independently halide, unsubstituted (C1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), -CN, and R 1 to 12 14 -carbocyclyl optionally substituted with Each R 8 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 9 are independently unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 10 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), and -(C 1-5 alkylene) p OR 8 selected from the group consisting of Each R 11 But -N(R 13 )2, Each R 12 are independently unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 13 are independently H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), Each R 14 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), R 15a is selected from the group consisting of H, D, and halides; R 15b is selected from the group consisting of H and D; Each R 16 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl), each p is independently 0 or 1; Each H atom independently 2 H(D) (deuterium)).

[0010] Some embodiments include stereoisomers and pharmaceutically acceptable salts of compounds of formula (I). Some embodiments include pharmaceutically acceptable salts of compounds of formula (I).

[0011] Some embodiments include prodrugs of compounds of formula (I).

[0012] Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient.

[0013] Other embodiments disclosed herein include methods of inhibiting DYRK1A by administering to a patient suffering from a disorder or disease in which DYRK1A overexpression is implicated (e.g., Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency, Down's syndrome, frontotemporal dementia associated with Parkinson's disease-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, and additional diseases involving significant neurodegeneration (e.g., autism, dementia, epilepsy, Huntington's disease, multiple sclerosis); diseases and disorders associated with acquired brain injury (e.g., chronic traumatic encephalopathy, traumatic brain injury, tumors, and stroke)).

[0014] DYRK1A inhibitors can also be used to treat tauopathies, which are neurodegenerative disorders characterized by the accumulation of abnormal tau protein in the brain. The scope of tau pathology has expanded beyond traditionally considered disease forms such as Pick's disease, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. Emerging disease entities and pathologies include globular glial tauopathies, primary age-related tauopathies including neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and age-related tauastrogliopathy. Clinical manifestations include frontotemporal dementia, corticobasal syndrome, Richardson's syndrome, parkinsonism, pure akinesia with gait freezing, and rarely motor neuron symptoms or cerebellar ataxia (Handbook of Clinical Neurology (2018), 145, 355-368 and Aging Cell (2019), 18(5), e13000).

[0015] Inhibitors of DYRK1A can also be used to treat disorders associated with malformed folate / methionine metabolism.

[0016] Non-limiting examples of diseases that can be treated with the compounds and compositions provided herein include various cancers, diabetes, psoriasis, knee osteoarthritis, tendon disorders, human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), hepatitis C virus (HCV), and herpes simplex virus type 1 (HSV-1).

[0017] Some embodiments of the present disclosure include methods of preparing compounds of formula (I).

[0018] 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 OF THE INVENTION

[0019] Compositions and methods for inhibiting DYRK1A are provided.

[0020] Some embodiments provided herein relate to methods of treating diseases (including, but not limited to, neurological diseases or disorders, cancer, cognitive disorders, knee osteoarthritis, tendon disorders, viral infections, single-cell parasitic infections, and movement disorders).

[0021] In some embodiments, non-limiting examples of neurological diseases or disorders that can be treated with the compounds and compositions provided herein include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, frontotemporal dementia associated with Parkinson's disease-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, tauopathies, and additional diseases with significant neurodegeneration (e.g., autism, dementia, epilepsy, Huntington's disease, multiple sclerosis); diseases and disorders associated with acquired brain injury (e.g., chronic traumatic encephalopathy, traumatic brain injury, tumors, and stroke).

[0022] In some embodiments, non-limiting examples of cancers that can be treated with the compounds and compositions provided herein include solid cancers (e.g., glioblastoma, ovarian cancer, breast cancer, and pancreatic cancer) and leukemias (e.g., acute lymphoblastic leukemia, acute megakaryoblastic leukemia, and chronic myeloid leukemia).

[0023] In some embodiments, a pharmaceutical composition is provided that is effective for treating a disease in an animal, e.g., a mammal, caused by overexpression of DYRK1A, comprising a pharmaceutically acceptable carrier and a compound described herein.

[0024] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0025] As used herein, "alkyl" refers to a branched or straight-chain chemical group containing only carbon and hydrogen, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, and neopentyl. Alkyl groups can be unsubstituted or substituted with one or more substituents. In some embodiments, alkyl groups contain 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0026] As used herein, "alkenyl" refers to a straight- or branched-chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. In various embodiments, an alkenyl group can be unsubstituted or substituted with one or more substituents. Typically, an alkenyl group contains 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0027] As used herein, "alkynyl" refers to a straight- or branched-chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, e.g., ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, etc. In various embodiments, alkynyl groups can be unsubstituted or substituted with one or more substituents. Typically, alkynyl groups contain 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0028] As used herein, "alkylene" refers to a branched or straight-chain divalent chemical group containing only carbon and hydrogen, e.g., methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene, and neopentylene. An alkylene group can be unsubstituted or substituted with one or more substituents. In some embodiments, an alkylene group contains 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0029] As used herein, "alkenylene" refers to a branched or straight-chain divalent chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, e.g., ethenylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene, 2-butenylene, etc. In various embodiments, an alkenylene group can be unsubstituted or substituted with one or more substituents. Typically, an alkenylene group contains 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0030] As used herein, "alkynylene" refers to a branched or straight-chain divalent chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, e.g., ethynylene, 1-propynylene, 1-butynylene, 2-butynylene, etc. In various embodiments, alkynylene groups can be unsubstituted or substituted with one or more substituents. Typically, alkynylene groups contain 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0031] As used herein, "alkoxy" means an alkyl-O- group, wherein the alkyl 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 linear or branched positional isomers thereof.

[0032] As used herein, "haloalkoxy" means a haloalkyl-O- group in which the haloalkyl group is as described herein. Exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and linear or branched positional isomers thereof.

[0033] As used herein, "carbocyclyl" refers to a cyclic ring system containing only carbon atoms in the ring system backbone, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. A carbocyclyl may contain multiple fused rings. A carbocyclyl may have any degree of saturation, provided that no ring in the ring system is aromatic. A carbocyclyl group may be unsubstituted or substituted with one or more substituents. In some embodiments, a carbocyclyl group contains 3 to 10 carbon atoms, e.g., 3 to 6 carbon atoms.

[0034] As used herein, "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group in which only carbon atoms are present in the ring backbone, having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; 6, 10, or 14 pi electrons shared in the cyclic array; and at least one ring in the system is aromatic. Aryl groups can be unsubstituted or substituted with one or more substituents. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, and the like. In some embodiments, aryl is phenyl.

[0035] As used herein, "arylalkylene" means an aryl-alkylene- group in which the aryl and alkylene portions are as previously described. In some embodiments, an arylalkylene group is 1-4 Contains an alkylene moiety. Exemplary arylalkylene groups include benzyl and 2-phenethyl.

[0036] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in the cyclic arrangement; and 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 be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and pyrido[2,3-d] Examples include 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, chroman, 2,3-dihydrobenzo[b][1,4]dioxin, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0037] As used herein, "halo," "halide," or "halogen" is a chloro, bromo, fluoro, or iodo atom radical. In some embodiments, halo is chloro, bromo, or fluoro. For example, halide can be fluoro.

[0038] As used herein, "haloalkyl" refers to a hydrocarbon substituent that is a straight-chain 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 in which one or more hydrogen atoms are replaced with fluoro. In some embodiments, a haloalkyl is 1 to 3 carbons long (e.g., 1 to 2 carbons long or 1 carbon long). The term "haloalkylene" refers to diradical variants of haloalkyl, where such divalent groups can act as spacers between groups, other atoms, or between a ring and another functional group.

[0039] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring system containing at least one heteroatom in the ring system backbone. Heterocyclyls can include multiple fused rings, such as bicyclic and spirocyclic heterocyclyls. Heterocyclyls can be substituted or unsubstituted with one or more substituents. In some embodiments, the heterocycle has 3 to 11 members. In a 6-membered monocyclic heterocycle, the heteroatom(s) are selected from 1 to 3 of O, N, and S, and when the heterocycle is 5-membered, it can have 1 or 2 heteroatoms selected from O, N, and S. Examples of heterocyclyl include 3-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, piperyl, and the like. These include azinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, octahydrocyclopenta[c]pyrrolyl, oxazinyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl, etc. In some embodiments, heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

[0040] As used herein, "monocyclic heterocyclyl" refers to a single non-aromatic cyclic ring containing at least one heteroatom in the ring system backbone. The heterocyclyl may be substituted or unsubstituted with one or more substituents. In some embodiments, the heterocycle has 3 to 7 members. In a 6-membered monocyclic heterocycle, the heteroatom(s) are selected from 1 to 3 of O, N, and S; if the heterocycle is 5-membered, the heterocycle may have 1 or 2 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, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl, and the like.

[0041] As used herein, "bicyclic heterocyclyl" refers to a non-aromatic bicyclic ring system containing at least one heteroatom in the ring system backbone. The bicyclic heterocyclyl can be substituted or unsubstituted with one or more substituents. In some embodiments, the bicyclic heterocycle has 4 to 11 ring members, and the heteroatom(s) are selected from 1 to 5 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-azabicyclo[4.2.0]octane, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, and the like.

[0042] As used herein, "spirocyclic heterocycle" refers to a non-aromatic bicyclic ring system containing at least one heteroatom in the backbone of the ring system, and wherein the rings are bonded through exactly one atom. A spirocyclic heterocyclyl may be substituted or unsubstituted with one or more substituents. In some embodiments, the spirocyclic heterocycle has 5 to 11 members, and the heteroatom(s) are selected from 1 to 5 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.

[0043] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more non-hydrogen atoms of a molecule. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is consistent with the allowed valences of the atom and substituent being substituted, and that the substitution results in a stable compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. Substituents include, for example, hydroxyl, -NH, -NH(C 1-3 alkyl), and -N(C 1-3 -(C alkyl)2 optionally substituted with one or more of 1-9 alkyl);-(C 1-9 Haloalkyl; halide; hydroxyl; carbonyl [such as -C(O)OR and -C(O)R]; thiocarbonyl [such as -C(S)OR, -C(O)SR, and -C(S)R]; halide, hydroxyl, -NH2, -NH(C 1-3 alkyl), and -N(C 1-3 -(C alkyl)2 optionally substituted with one or more of 1-9 Alkoxy); -OPO(OH)2; Phosphonate [-PO(OH)2 and -PO(OR') 2など]; -OPO(OR')R"; -NRR'; -C(O)NRR'; -C(NR)NR'R"; -C(NR')R"; cyano; nitro; azido; -SH; -SR; -OSO2(OR); sulfonate [such as -SO2(OH) and -SO2(OR)]; -SO2NR'R" and -S02R; each occurrence of R, R', and R" independently represents H; -(C 1-9 alkyl); C optionally substituted with 1 to 3 R''' 6-10 Aryl; 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, optionally substituted with 1-3 R'"; C optionally substituted with 1-3 R'"; 3-7 carbocyclyl; and 3-8 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S, optionally substituted with 1-3 R''', where each R''' is independently -(C 1-6 alkyl), -(C 1-6 haloalkyl), halide (e.g., F), hydroxyl, -C(O)OR, -C(O)R, -(C 1-6 and each occurrence of R and R is selected from H and -(C 1-6 In some embodiments, the substituent is selected from -(C alkyl). 1-6 alkyl), -(C 1-6 haloalkyl), halide (e.g., F), hydroxyl, -C(O)OR, -C(O)R, -(C 1-6 each occurrence of R and R' is independently selected from H and -(C 1-6 alkyl).

[0044] As used herein, when two groups are shown to be "linked" or "bonded" to form a "ring," it should be understood that this may include forming a bond between the two groups and replacing a hydrogen atom on one or both groups with the bond, thereby forming a carbocyclyl ring, heterocyclyl ring, aryl ring, or heteroaryl ring. A skilled artisan will appreciate that such rings are readily formed by routine chemical reactions. In some embodiments, such rings have 3 to 7 members, e.g., 5 or 6 members.

[0045] Those skilled in the art will recognize that some chemical structures described herein may be represented on paper as one or more other resonance structures or may exist in one or more other tautomeric forms (even though one skilled in the art will recognize that kinetically, such tautomers may exist in only a small fraction of samples of such compound(s). Although such resonance structures or tautomers are not explicitly represented herein, these compounds are expressly contemplated as being within the scope of this disclosure.

[0046] The compounds provided herein may include various stereochemical forms. The compounds also include diastereomers and optical isomers resulting from structural asymmetry in a particular compound, for example, mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods known to those skilled in the art. Unless otherwise indicated, when a disclosed compound is named or depicted without specifying its stereochemistry and has one or more chiral centers, it is understood that the disclosed compound represents all possible stereoisomers of that compound.

[0047] The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of Formula I in which one or more atoms are replaced with an atom having the same atomic number but an atomic mass or atomic mass number different from the atomic mass or atomic mass number predominant in nature. Examples of isotopes suitable for inclusion in compounds of the present disclosure include:2 H (deuterium) and 3 Isotopes of hydrogen such as H (tritium), 11 C. 13 C and 14 carbon isotopes such as C, 36 chlorine isotopes such as Cl, 18 fluorine isotopes such as F, 123 I and 125 isotopes of iodine, such as I, 13 N and 15 nitrogen isotopes such as N, 15 O. 17 O and 18 isotopes of oxygen, such as O 32 Isotopes of phosphorus such as P, and 35 and isotopes of sulfur such as, but not limited to, S.

[0048] The term "administration" or "administering" refers to a method of providing a dosage form of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian, where the method of administration is, for example, oral, subcutaneous, intravenous, intralymphatic, intranasal, topical, transdermal, intraperitoneally, intramuscularly, intrapulmonary, vaginal, rectal, otologic, neuro-otologic, intraocular, subconjunctival, via anterior chamber injection, intravitreal, intraperitoneal, intrathecal, intracystic, intrapleural, "Administration" refers to administration via wound irrigation, intrabuccally, intraperitoneally, intra-articularly, intraauricularly, intrabronchially, intravesically, intrameningeally, via inhalation, via intratracheal or intrabronchial instillation, via direct injection into the lung cavity, intraspinally, intrasynovially, intrathoracically, chest drainage irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or by application as part of any admixture with a prosthetic device. The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease.

[0049] As used herein, a "diagnostic" refers to a compound, method, system, or device that aids in the identification or characterization of a health or disease state. Diagnostics can be used in standard assays known in the art.

[0050] The term "mammal" is used in its ordinary biological sense, and thus includes, among others, humans, cows, horses, monkeys, dogs, cats, mice, rats, cattle, sheep, pigs, goats, and non-human primates, but also many other species.

[0051] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable diluent," and "pharmaceutically acceptable excipient" include any and all biologically or otherwise undesirable solvents, cosolvents, complexing agents, dispersion media, coatings, isotonicity agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutical 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. Additionally, various adjuvants commonly used in the art can be included. These and other such compounds are described in the literature (e.g., Merck Index, Merck & Company, Rahway, NJ). Considerations for including various ingredients in pharmaceutical compositions are described, for example, in Brunton et al. (Eds.) (2017); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 13th Ed., The McGraw-Hill Companies.

[0052] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds provided herein and are not 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 of these salts are known in the art, for example, as described in WO 87 / 05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, 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 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, and aluminum, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0053] As used herein, a "patient" refers to a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, and any other vertebrate or invertebrate. In some embodiments, the patient is a human.

[0054] A "therapeutically effective amount" of a compound provided herein is an amount sufficient to achieve a desired physiological effect and may vary according to the nature and severity of the disease state and the efficacy of the compound. A "therapeutically effective amount" is also intended to include a combination of one or more compounds of Formula I with one or more other drugs effective in treating the diseases and / or conditions described herein. The combination of compounds may be a synergistic combination. Synergy occurs when the effect of compounds administered in combination exceeds the additive effect of the compounds administered alone as single agents, as described, for example, in Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55. Generally, synergistic effects are most evident when the concentration of the compounds is suboptimal. It will be recognized that different concentrations may be used for the prevention of active disease than for the treatment of active disease. Furthermore, this amount may depend on the patient's height, weight, sex, age, and medical history.

[0055] A therapeutic effect is one that relieves to some extent one or more symptoms of the disease.

[0056] As used herein, "treat," "treatment," or "treating" refers to the administration of a compound or pharmaceutical composition provided herein for therapeutic purposes. The term "therapeutic treatment" refers to the administration of treatment to a patient already suffering from a disease to produce a therapeutically beneficial effect, for example, ameliorating existing symptoms, ameliorating the underlying metabolic cause of symptoms, postponing or preventing further progression of the disorder, and / or reducing the severity of symptoms that have developed or are expected to develop.

[0057] As used herein, "drug elution" and / or controlled release refers to any mechanism by which a drug(s) incorporated into a drug eluting material migrates therefrom into surrounding body tissue over time, e.g., diffusion, migration, permeation, and / or desorption.

[0058] As used herein, "drug eluting material" and / or controlled release material refers to any natural, synthetic, or semi-synthetic material that is capable of acquiring and maintaining a desired shape or configuration, that can incorporate one or more drugs, and that allows the incorporated drug(s) to leach therefrom over time.

[0059] As used herein, "elutable drug" refers to any drug or combination of drugs that has the ability to migrate over time from an incorporated drug eluting material into the surrounding area of ​​the body.

[0060] compound The compounds and compositions described herein can be used to inhibit DYRK1A for the treatment of disorders or diseases in which overexpression of DYRK1A is involved, such as neurological diseases or disorders, cancer, cognitive disorders, knee osteoarthritis, tendon disorders, viral infections, single-cell parasitic infections, and movement disorders.

[0061] Some embodiments of the present disclosure include compounds of formula I: [ka] or a salt thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0062] Some embodiments of the present disclosure include compounds of formula I: [ka] or a salt thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0063] Some embodiments of the present disclosure include compounds of formula I: [ka] or a salt thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0064] In some embodiments of Formula I, R 1However, R from 1 to 10 4 In some embodiments, R 1 but 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or one R 4 is (9-10 membered heteroaryl) optionally substituted with

[0065] In some embodiments of Formula I, R 1 is selected from the heteroaryl group consisting of: R from 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 1) 4 optionally replaced with [ka]

[0066] In some embodiments of Formula I, R 1 is selected from the heteroaryl group consisting of: R from 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 1) 4 optionally replaced with [ka]

[0067] In some embodiments of Formula I, R 1 is selected from the heteroaryl group consisting of: R from 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 1) 4 optionally replaced with [ka]

[0068] In some embodiments of Formula I, R 1 is selected from the heteroaryl group consisting of: R from 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 1) 4 optionally replaced with [ka]

[0069] In some embodiments of Formula I, R 1 is selected from the heteroaryl group consisting of: 1 to 3 (e.g., 1 to 2, 1) R 4 optionally replaced with [ka]

[0070] In some embodiments of Formula I, R 1 is selected from the heteroaryl group consisting of: 1 to 3 (e.g., 1 to 2, 1) R 4 optionally replaced with [ka]

[0071] In some embodiments of Formula I, R 1 is selected from the group consisting of: 1 to 3 R 4 optionally replaced with [ka]

[0072] In some embodiments of Formula I, R 1 is selected from the group consisting of: 1 to 3 R 4 optionally replaced with [ka]

[0073] In some embodiments of Formula I, R 1 is selected from the group consisting of: 1-2 R 4 optionally replaced with [ka]

[0074] In some embodiments of Formula I, R 1 is selected from the group consisting of: [ka]

[0075] In some embodiments of Formula I, R 2 is 1 to 10 (e.g., 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 1) 5 -heterocyclyl optionally substituted with, and R 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) 6 -carbocyclyl optionally substituted with

[0076] In some embodiments of Formula I, R 2 However, there are 1 to 4 (e.g., 1 to 3, 1 to 2, 1) R 5 -heterocyclyl optionally substituted with, and 1 to 4 (e.g., 1 to 3, 1 to 2, 1) R 6 -carbocyclyl optionally substituted with

[0077] In some embodiments of Formula I, R 2 However, 1 to 3 R 6 -carbocyclyl optionally substituted with, wherein carbocyclyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0078] In some embodiments of Formula I, R 2 But non-substituted (C 1-9alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), R 1 to 10 5 -heterocyclyl optionally substituted with, and R 1 to 12 6 optionally substituted with -(C 1-5 alkylene) p carbocyclyl, -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl).

[0079] In some embodiments of Formula I, R 2 But non-substituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), unsubstituted (C 1-4 haloalkyl), 1 to 4 R 5 -heterocyclyl optionally substituted with, and 1 to 4 R 6 optionally substituted with -(C 1-2 alkylene) p carbocyclyl, -(C 1-2 alkylene) is substituted with one to two halides (e.g., F, Cl) and / or one unsubstituted (C 1-2 alkyl).

[0080] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 6 are independently selected from the group consisting of F, Me, -CHF, -CHF, -CF, -CHOH, -CHOMe, -OH, -OMe, -OEt, -OCD, -OCF, -OCHCHF, -OCHCHF, -OCHCF, -OCHCHOMe, -OCHCHOH, -C(=O)NHMe, -C(=O)NMe, and -NHC(=O)Me.

[0081] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 8 are independently selected from the group consisting of F, Me, -CHF2, -CH2OMe, -OH, -OMe, -OCD3, -OCH2CHF2, and -OCH2CH2OMe.

[0082] In some embodiments of Formula I, R 2 However, 1 to 3 R 5 and -heterocyclyl optionally substituted by, wherein 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.

[0083] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 5 are independently selected from F, Me, Et, iPr, iBu, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OMe, -OH, -OMe, -OEt, -OCD3, -OCF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me, -C(=O)Et, -C(=O)iPr, and [ka] with the proviso that F, —OH, —OMe, —OEt, —OCD3, and —OCF3 are not bonded to N.

[0084] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 5 are independently selected from F, Me, Et, iPr, iBu, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OMe, -OH, -OMe, -OEt, -OCD3, -OCF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me, -C(=O)Et, -C(=O)iPr, and [ka] with the proviso that F, —OH, —OMe, —OEt, —OCD3, and —OCF3 are not bonded to N.

[0085] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 5 are independently selected from F, Me, Et, iPr, iBu, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OMe, -OH, -OMe, -OEt, -OCD3, -OCF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me, -C(=O)Et, -C(=O)iPr, and [ka] with the proviso that F, —OH, —OMe, —OEt, —OCD3, and —OCF3 are not bonded to N.

[0086] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 5 is independently selected from the group consisting of F, Me, iBu, -OH, -OMe, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me; [ka] However, F, -OH, and -OMe are not bonded to N.

[0087] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 5 are independently selected from the group consisting of F, Me, iBu, -OH, -OMe, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me; [ka] However, F, -OH, and -OMe are not bonded to N.

[0088] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 5 is independently selected from the group consisting of F, Me, and —C(═O)Me; [ka] However, F is not bonded to N.

[0089] In some embodiments of Formula I, R 2 but, [ka] and each R is selected from the group consisting of 5 is Me, -C(=O)Me, and [ka] is selected from the group consisting of:

[0090] In some embodiments of Formula I, R 3 H, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl).

[0091] In some embodiments of Formula I, R 3 H, unsubstituted (C 1-6 alkyl), unsubstituted (C 2-6 alkenyl), unsubstituted (C 2-6 alkynyl), and unsubstituted (C 1-6 haloalkyl).

[0092] In some embodiments of Formula I, R 3 H, unsubstituted (C 1-3 alkyl), and unsubstituted (C 1-3 haloalkyl).

[0093] In some embodiments of Formula I, R 3 H, unsubstituted (C 1-6 alkyl), unsubstituted (C 2-6 alkenyl), unsubstituted (C 2-6 alkynyl), unsubstituted (C 1-6 haloalkyl), and R 1 to 10 16 -heterocyclyl optionally substituted with

[0094] In some embodiments of Formula I, R 3 H, unsubstituted (C 1-3 alkyl), unsubstituted (C 2-3 alkenyl), unsubstituted (C 2-3 alkynyl), unsubstituted (C 1-3 haloalkyl), and unsubstituted (4-membered heterocyclyl).

[0095] In some embodiments of Formula I, R 3 But non-substituted (C 1-3 alkyl).

[0096] In some embodiments of Formula I, R 3 But it's Me.

[0097] In some embodiments of Formula I, R 3 But it's H.

[0098] In some embodiments of Formula I, each R 4 are independently halide (e.g., F, Cl, Br, I), unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl).

[0099] In some embodiments of Formula I, each R 4 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), and unsubstituted (C 1-4 haloalkyl).

[0100] In some embodiments of Formula I, each R 4 is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, 2-fluoroethyl, and 2,2-difluoroethyl.

[0101] In some embodiments of Formula I, each R5 are independently halide (e.g., F, Cl, Br, I), unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 7 -heterocyclyl optionally substituted with -(C 1-5 alkylene) p OR 8 , and -C(=O)R 9 -(C 1-5 alkylene) is substituted with 1 to 5 halides (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted (C 1-3 alkyl).

[0102] In some embodiments of Formula I, each R 5 are independently F, Cl, unsubstituted (C 1-5 alkyl), unsubstituted (C 2-5 alkenyl), unsubstituted (C 2-5 alkynyl), unsubstituted (C 1-5 haloalkyl), 1 to 2 R 7 -heterocyclyl optionally substituted with -(C 1-2 alkylene) p OR 8 , and -C(=O)R 9 -(C 1-2 alkylene) is optionally substituted with one to two halides (e.g., F, Cl).

[0103] In some embodiments of Formula I, each R 5 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), R 1 to 10 7 -heterocyclyl optionally substituted with R 1 to 1214 -carbocyclyl optionally substituted with -(C 1-5 alkylene) p OR 8 , and -C(=O)R 9 -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl).

[0104] In some embodiments of Formula I, each R 5 are independently F, Cl, unsubstituted (C 1-5 alkyl), unsubstituted (C 2-5 alkenyl), unsubstituted (C 2-5 alkynyl), unsubstituted (C 1-5 haloalkyl), 1 to 2 R 7 -heterocyclyl optionally substituted with one to two R 14 -carbocyclyl optionally substituted with -(C 1-2 alkylene) p OR 8 , and -C(=O)R 9 -(C 1-2 alkylene) is optionally substituted with one to two halides (e.g., F, Cl).

[0105] In some embodiments of Formula I, two R 5 together form a carbonyl group.

[0106] In some embodiments of Formula I, each R 6 are independently halide (e.g., F, Cl, Br, I), unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), -OR 10 , -C(=O)R 11 , and -NHC(=O)R 12 is selected from the group consisting of:

[0107] In some embodiments of Formula I, each R 6 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), unsubstituted (C 1-4 haloalkyl), -OR 10 , -C(=O)R 11 , and -NHC(=O)R 12 is selected from the group consisting of:

[0108] In some embodiments of Formula I, each R 6 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), -CN, -(C 1-5 alkylene) p OR 10 , -C(=O)R 11 , -NHC(=O)R 12 , and 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 1) R 14 -carbocyclyl optionally substituted with -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C 1-3 alkyl).

[0109] In some embodiments of Formula I, each R 6 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), unsubstituted (C 1-4 haloalkyl), -CN, -(C 1-2 alkylene) p OR 10 , -C(=O)R 11 , -NHC(=O)R 12, and 1 to 2 R 14 -carbocyclyl optionally substituted with -(C 1-2 alkylene) is substituted with one to two halides (e.g., F, Cl) and / or one unsubstituted (C 1-2 alkyl).

[0110] In some embodiments of Formula I, each R 7 are independently halide (e.g., F, Cl, Br, I), unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl).

[0111] In some embodiments of Formula I, each R 7 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), and unsubstituted (C 1-4 haloalkyl).

[0112] In some embodiments of Formula I, each R 7 are independently halide, unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), -CN, and R 1 to 12 14 -carbocyclyl optionally substituted with

[0113] In some embodiments of Formula I, each R 7 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), unsubstituted (C 1-4haloalkyl), -CN, and one to two R 14 -carbocyclyl optionally substituted with

[0114] In some embodiments of Formula I, each R 8 are independently halide (e.g., F, Cl, Br, I), unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl).

[0115] In some embodiments of Formula I, each R 8 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), and unsubstituted (C 1-4 haloalkyl).

[0116] In some embodiments of Formula I, each R 9 are independently halide (e.g., F, Cl, Br, I), unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl).

[0117] In some embodiments of Formula I, each R 9 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), and unsubstituted (C 1-4 haloalkyl).

[0118] In some embodiments of Formula I, each R 10 are independently H, unsubstituted (C 1-9alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), unsubstituted (C 1-9 haloalkyl), and -(C 1-5 alkylene) p OR 8 is selected from the group consisting of:

[0119] In some embodiments of Formula I, each R 10 are independently H, unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), unsubstituted (C 1-4 haloalkyl), and -(C 1-2 alkylene) p OR 8 is selected from the group consisting of:

[0120] In some embodiments of Formula I, each R 11 But -N(R 13 )2.

[0121] In some embodiments of Formula I, each R 11 But, -NHR 13 is.

[0122] In some embodiments of Formula I, each R 11 is -NHMe.

[0123] In some embodiments of Formula I, each R 11 is -NHMe2.

[0124] In some embodiments of Formula I, each R 12 are independently unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl).

[0125] In some embodiments of Formula I, each R 12are independently unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), and unsubstituted (C 1-4 haloalkyl).

[0126] In some embodiments of Formula I, each R 13 are independently unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl).

[0127] In some embodiments of Formula I, each R 13 are independently unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), and unsubstituted (C 1-4 haloalkyl).

[0128] In some embodiments of Formula I, each R 14 are independently halide (e.g., F, Cl, Br, I), unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl).

[0129] In some embodiments of Formula I, each R 14 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4 alkynyl), and unsubstituted (C 1-4 haloalkyl).

[0130] In some embodiments of Formula I, R 15is selected from the group consisting of H and halides (e.g., F, Cl, Br, I).

[0131] In some embodiments of Formula I, R 15 is selected from the group consisting of H and halides (e.g., F, Cl).

[0132] In some embodiments of Formula I, R 15 But it's H.

[0133] In some embodiments of Formula I, R 15 But it is F.

[0134] In some embodiments of Formula I, R 15a H, halides (e.g., F, Cl, Br, I), and 2 H(D) (deuterium).

[0135] In some embodiments of Formula I, R 15b But H and 2 H(D) (deuterium).

[0136] In some embodiments of Formula I, R 15b but, 2 H(D) (deuterium).

[0137] In some embodiments of Formula I, each R 16 are independently halide (e.g., F, Cl, Br, I), unsubstituted (C 1-9 alkyl), unsubstituted (C 2-9 alkenyl), unsubstituted (C 2-9 alkynyl), and unsubstituted (C 1-9 haloalkyl).

[0138] In some embodiments of Formula I, each R 16 are independently halide (e.g., F, Cl), unsubstituted (C 1-4 alkyl), unsubstituted (C 2-4 alkenyl), unsubstituted (C 2-4alkynyl), and unsubstituted (C 1-4 haloalkyl).

[0139] In some embodiments of Formula I, each p is independently 0 or 1.

[0140] In some embodiments of Formula I, each H atom is independently: 2 Optionally substituted with H(D) (deuterium).

[0141] Exemplary compounds of Formula I are shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 [Table 1-47]

[0142] Administration and Pharmaceutical Compositions Some embodiments include a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound provided herein, or its corresponding enantiomer, diastereoisomer, or tautomer, or a pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.

[0143] The compounds provided herein may also be useful in combination (administered together or sequentially) with other known pharmaceutical agents.

[0144] Non-limiting examples of diseases that can be treated using a combination of a compound of formula (I) and other active agents include colorectal cancer, ovarian cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck, acute lymphoblastic leukemia (ALL), pancreatic cancer, brain tumors, acute megakaryoblastic leukemia (AMKL), and osteoarthritis. For example, a compound of formula (I) can be combined with one or more chemotherapeutic compounds.

[0145] 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: sorafenib (Nexavar®); regorafenib (Stivarga®, Regonix®), nivolumab (Opdivo®); lenvatinib (Lenvima®); pembrolizumab (Keytruda®); cabozantinib (Cometriq®, Cabometyx®); 5-fluorouracil (5-FU®); ramucirumab (Cyramza®); a combination of gemcitabine and oxaliplatin (GEMOX). Other therapies that may be performed in combination with the compounds of formula (I) are: i) transcatheter arterial chemoembolization (TACE) in combination with doxorubicin (DOXIL®), cisplatin, or mitomycin C (Mitosol®, Mutamycin®, Jelmyto®); ii) low-dose brachytherapy.

[0146] 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 drugs / therapies: transoral robotic surgery (TORS), TORS with radiation therapy, larotrectinib (Vitrakvi®), EGFR inhibitors such as erlotinib (Tarceva®), osimertinib (Tagrisso®), neratinib (Nerlynx®), gefitinib (Iressa®), cetuximab (Erbitux®), panitumumab (Vectibix®), dacomitinib (Vizimpro®), lapatinib (Tykerb®), necitumumab (Portrazza), and vandetanib (Caprelsa®).

[0147] 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 chrysanthimy (Erwinaze®); asparaginase erwinia chrysanthimy (recombinant)-rywn (Rylaze®); calaspargaspegol-mknl (Asparlas®); inotuzumab ozogamicin (Besponsa®); blinatumomab (Blincyto®); daunorubicin hydrochloride (Cerubidine®); clofarabine (Clol ar®); 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; daunorubicin hydrochloride (Rubidomycin®); and vincristine sulfate.

[0148] 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: gemcitabine (Gemzar®); 5-fluorouracil (5-FU®); oxaliplatin (Eloxatin®); albumin-bound paclitaxel (Abraxane®); capecitabine (Xeloda®); cisplatin; irinotecan (Camptosar®); liposomal irinotecan (Onivyde®); paclitaxel (Taxol®), and docetaxel (Taxotere®).

[0149] 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, which can be administered with Gliadel wafers; in the case of glioblastoma and high-grade gliomas, radiation therapy with daily low-dose temozolomide (Temodar®) followed by monthly temozolomide after six months to one year of radiation therapy; lomustine (Gleostine®), procarbazine (Matulane®), and vincristine (Vincasar®) (used in conjunction with radiation therapy); anti-angiogenic therapy with bevacizumab (Avastin®, Mvasi®); and targeted therapy with larotrectinib (Vitrakvi®).

[0150] 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 drugs / therapies: cytarabine (Cytosar-U®), etoposide (Vepesid®), and anthracycline drugs. Anthracyclines include daunorubicin (Cerubidine®), idarubicin (Idamycin®), and mitoxantrone (Novantrone®).

[0151] 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: venetoclax and a hypomethylating agent (e.g., decitabine, azacitidine), induction chemotherapy (cytarabine and an anthracycline (e.g., daunorubicin or idarubicin), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) either as monotherapy or an anthracycline), consolidation therapy (cytarabine).

[0152] In some embodiments, myelodysplastic syndromes (MDS) can be treated 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®).

[0153] 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), which can be administered with the vitamin-like drug leucovorin (also called folic acid); capecitabine (XELODA®), irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Further examples of combinations in which these drugs can be combined with a compound of Formula (I) include: FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan), and CapeOx (capecitabine and oxaliplatin). In the case of rectal cancer, chemotherapy with 5-FU or capecitabine combined with radiation therapy may be administered before surgery (neoadjuvant treatment).

[0154] 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®), 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®). Further examples of drug combinations that can be combined with the compound of formula (I) include TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin), and VIP (etoposide [VP-16], ifosfamide, and cisplatin). Ovarian cancer can also be treated using a combination of the compound of formula (I) and immune checkpoint inhibitor (ICB) therapy.

[0155] In some embodiments, compounds of formula (I) can be used in combination with any of the following methods to treat cancer: (a) hormonal therapy (e.g., aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, etc.); b) ablation or embolization (e.g., radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy, and cryotherapy (cryotherapy); (c) chemotherapy using alkylating agents (cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide); (d) chemotherapy using antimetabolites (azathioprine and mercaptopurine); (e) chemotherapy using plant alkaloids and terpenoids (e.g., vinca alkaloids (i.e., vincristine, vinblastine, vinorelbine, and vindesine) and taxanes); (f) chemotherapy using podophyllotoxin, etoposide, teniposide, and docetaxel; (g) chemotherapy using topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide); (h) chemotherapy using cytotoxic antibiotics (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and mitomycin);(i) tyrosine kinase inhibitors (e.g., imatinib mesylate (GLEEVEC®, also known as STI-571), gefitinib (Iressa, also known as ZD1839), erlotinib (sold 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 Phase III trials), VEGF inhibitors (j) chemotherapy using 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; (k) chemotherapy using monoclonal antibodies (e.g., rituximab (sold as MABTHERA® or RITUXAN®), trastuzumab (also known as Herceptin, ErbB2), cetuximab (sold as ERBITUX®), and bevacizumab (sold as AVASTIN®)); (k) chemotherapy using KRAS (l) chemotherapy using G12C inhibitors (e.g., sotorasib (e.g., Lumakras® and Lumykras®), adagrasib (MRTX849), and ARS-3248 (Wellspring Biosciences); (l) chemotherapy using checkpoint inhibitors (e.g., ipilimumab (Yervoy®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), atezolizumab (Tecentriq®), avelumab (Bavencio), durvalumab (Imfinzi), cemiplimab (Libtayo®), and spartalizumab (PDR001);(m) Antibody-drug conjugates (ADCs) (e.g., gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, moxetumomab pasudotoxin, and loncastuximab tesirine) (n) proteasome inhibitors (e.g., carfilzomib, lactacystin, disulfiram, salinosporamide A (marizomib), oprozomib, delanzomib, epoxomicin, MG132, β-hydroxyβ-methylbutyrate (HMB), bortezomib, ixazomib (alone or in combination with lenalidomide and dexamethasone); and (o) chemotherapy using radiation therapy.

[0156] In some embodiments, compounds of Formula I can be used to treat diabetes in combination with any of the following methods: (a) insulin injections; (b) biguanides (e.g., metformin (Glucophage), phenformin (DBI), and buformin); (c) thiazolidinediones (TZDs) (e.g., rosiglitazone (Avandia), pioglitazone (Actos), and iroglitazone (Rezulin)); (d) lyn kinase activators (e.g., glimepiride (Amaryl®) and trimidone (MLR-1023)); (e) secretagogues (e.g., sulfonylureas (non-limiting examples include , acetohexamide, carbutamide, chlorpropamide, glycclamide (tolcyclamide), metahexamide, tolazamide, tolbutamide, glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glyclopyramide, and glimepiride) and meglitinides (non-limiting examples are repaglinide (Prandin), nateglinide (Starlix), and mitiglinide (Glufast)); (f) α-glucosidase inhibitors (e.g., acarbose (Glucobay, Precose, Prandase), miglitol (Glyset), and voglibose);(g) injectable incretin mimetics (e.g., glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptides (glucose-dependent insulinotropic peptide, GIP)). Non-limiting examples of injectable glucagon-like peptide (GLP) analogs and agonists include exenatide (Exendin-4, sold as Byetta), liraglutide (Victoza, Saxenda), taspoglutide, lixisenatide (Lyxumia), semaglutide (Ozempic, Rybelsus), dulaglutide (Trul icity), albiglutide (Tanzeum), and non-limiting examples of dipeptidyl peptidase-4 (DPP-4) inhibitors include sitagliptin (Januvia), vildagliptin (Galvus), saxagliptin (Onglyza), linagliptin (Tradjenta), gemigliptin (Zemiglo), anagliptin (Suiny), teneligliptin (Tenelia), alogliptin (Nesina, Vipidia, Kazano, Vipidomet (in combination with metformin) , Oseni, Incresync (combined with pioglitazone), trelagliptin (Zafatek, Wedica), omarigliptin (MK-3102), evogliptin (Suganon, Evodine), gosogliptin (Saterex), and dutogliptin; (h) injectable amylin analogs (e.g., pramlintide (Symlin)); (i) glucose metabolism improvers (SGLT2 inhibitors) (e.g., canagliflozin (Invokana, Sulisent, Prominad), Dapagliflozin (Forxiga, Farxiga, Edistride), empagliflozin (Jardiance, Sciampa-M), ertugliflozin (Steglatro), ipragliflozin (Suglat), luseogliflozin (Lusefi), remogliflozin etabonate (prodrug of remogliflozin), sergliflozin etabonate (GW869682X), sotagliflozin (Zynquista), and tofogliflozin (CSG452);

[0157] In some embodiments, the compounds of formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (d) injections of Wnt signaling pathway inhibitors (e.g., loresivivin); (a) nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, aspirin, and acetaminophen; (b) physical therapy; (c) injections of corticosteroids; (d) injections of hyaluronic acid derivatives (e.g., Hyalgan, Synvisc); (e) narcotics (e.g., codeine); (f) in combination with braces and / or shoe insoles, or any device that helps to immobilize or support the joint and relieve pressure (e.g., splints, braces, shoe insoles, or other medical devices); (g) bone repositioning (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with chronic pain medications.

[0158] In some embodiments, compounds of formula (I) can be used to treat Alzheimer's disease in combination with aducanumab (Aduhelm™); acetylcholinesterase inhibitors (e.g., tacrine, rivastigmine (Exelon®), galantamine (Razadyne® and GalantaMind™), and donepezil (Aricept®); and memantine (Axura®, Ebixa®, Namenda®).

[0159] Administration of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be via any of the accepted modes of administration, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, intravaginal, intrarectal, ontological, neuro-otological, intraocular, subconjunctival, via anterior chamber injection, intravitreal, intraperitoneal, intrathecal, intracystic, intrapleural, via wound irrigation, intrabuccal, intraperitoneal, intra-articular, intra-auricular, intrabronchial, intraocular capsule, intrameningeal, via inhalation, via intratracheal or intrabronchial injection, via direct injection into the lung cavity, intraspinal, intrasynovial, intrapleural, via pleural lavage, epidural, intratympanic, intracisternal, intravascular, intraventricular, intraosseous, via irrigation of infected bone, or via application as part of any combination with a prosthetic device. In some embodiments, the method of administration comprises oral or parenteral administration.

[0160] The compounds provided herein for pharmaceutical use can be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions can include solids, semisolids, liquids, solutions, colloids, liposomes, emulsions, suspensions, complexes, coacervates, and aerosols. Dosage forms include, for example, tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, implants, and controlled-release dosage forms. Dosage forms can be obtained, for example, as solid plugs, powders, or films, by methods such as precipitation, crystallization, milling, pulverization, 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 compounds may also be administered in sustained- or controlled-release forms, including depot injections, osmotic pumps, pills (tablets and / or capsules), transdermal patches (including electrotransport), implantable tablets, and the like, for prolonged and / or timed pulse administration at a predetermined rate.

[0161] The compounds can be administered alone or in combination with conventional pharmaceutical carriers, excipients, etc. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms (e.g., Tween®, poloxamer, or other similar polymeric delivery matrices, serum proteins (e.g., human serum albumin)), buffer substances (e.g., phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water), salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, etc.). Examples of suitable cyclodextrins include cyclodextrins, polyethylene-polyoxypropylene block polymers, and wool fat. Cyclodextrins (e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives), or hydroxyalkyl cyclodextrins (e.g., 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives) can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions containing compounds described herein in the range of 0.005% to 100%, with the balance being made up of a non-toxic carrier, can be prepared. Contemplated compositions can contain 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80%, of a compound provided herein. Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 22 nd Edition(Pharmaceutical Press,London,UK.2012).

[0162] In one embodiment, the composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain a compound provided herein together with a diluent such as lactose, sucrose, or dicalcium phosphate; a lubricant such as magnesium stearate; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, or a cellulose derivative. In another solid dosage form, a powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglyceride) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated, such as capsules with granules (or tablets within capsules) of each drug; bilayer tablets; two-compartment gel capsules, etc. Enteric-coated oral dosage forms or delayed-release oral dosage forms are also contemplated.

[0163] Pharmaceutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, etc., a compound provided herein and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution, colloid, liposome, emulsion, complex, coacervate, or suspension. If desired, the pharmaceutical compositions may also contain minor amounts of nontoxic auxiliary substances, such as wetting agents, emulsifiers, cosolvents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc.).

[0164] Injectables can be prepared in conventional forms, such as liquid solutions, colloids, liposomes, complexes, coacervates, or suspensions, as emulsions, or in solid forms suitable for reconstitution with a liquid prior to injection. The percentage of the compound provided herein contained in these parenteral compositions will vary depending on the specific nature of the composition, as well as the activity of the compound and the patient's needs. However, percentages of active ingredient in solution (0.01% to 10%) can be used, and may be higher if the composition is a solid or suspension, which can then be diluted to the above percentages.

[0165] It should be noted that concentration and dosage values ​​may also vary depending on the specific compound and the severity of the symptoms to be alleviated.It should 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 composition, and that the concentration ranges described herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0166] In one embodiment, the compositions can be administered to the respiratory tract (including the nose and lungs) by, for example, a nebulizer, metered dose inhaler, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid drops, or other suitable device or technique.

[0167] In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavity, inhaled particle sizes (about 5 to about 100 microns) are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, larger inhaled particle sizes may be desirable to maximize adhesion to the nasal mucosa and minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for pulmonary delivery are provided for inhalation through the nose or mouth. For pulmonary delivery, inhaled aerodynamic particle sizes (less than about 10 μm, e.g., about 1 to about 10 microns) are useful. Inhaled particles may be defined as droplets containing dissolved drug, droplets containing suspended drug particles (when the drug is insoluble in the suspension medium), dry particles of pure drug substance, drug substance with incorporated excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of diluent containing embedded drug nanoparticles.

[0168] In some embodiments, compounds of Formula (I) disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, non-aqueous solutions or suspensions, suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, colloidal systems, emulsions, coacervates, or dry powders. Aqueous formulations can be aerosolized with liquid nebulizers using either hydraulic or ultrasonic atomization, or with modified micropump systems (such as soft mist inhalers, Aerodose®, or AERx® systems). Propellant-based systems may use suitable pressurized metered dose inhalers (pMDIs). Dry powders may use dry powder inhalers (DPIs) capable of effectively dispersing the drug component. The desired particle size and distribution can be obtained by selecting the appropriate device.

[0169] In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear in a variety of ways, for example, using a round window catheter (e.g., U.S. Patent Nos. 6,440,102, 6,648,873).

[0170] Alternatively, the formulations can be incorporated into wicks for use between the outer and middle ear (e.g., U.S. Patent No. 6,120,484) or absorbed onto collagen sponges or other solid supports (e.g., U.S. Patent No. 4,164,559).

[0171] If desired, the formulations of the present disclosure can be incorporated into gel formulations (e.g., U.S. Patent Nos. 4,474,752 and 6,911,211).

[0172] In some embodiments, compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered through a needle directly into the middle or inner ear (cochlea) via an implantable pump and delivery system, or through a cochlear implant stylet electrode channel or an alternative prepared drug delivery channel (such as, but not limited to, a needle that penetrates through the temporal bone into the cochlea).

[0173] Other options include pump delivery via a thin film coated on a multichannel electrode, or an electrode with drug delivery channels (pathways) specifically embedded in the thin film for this purpose. In other embodiments, the solid acidic or basic compounds of Formula (I) can be delivered from the reservoir of an externally or internally implanted pump system.

[0174] The formulations of the present disclosure can also be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Patent Nos. 6,377,849 and Ser. 11 / 337,815).

[0175] Intratympanic injection of a therapeutic agent is a technique for injecting a therapeutic agent into the middle and / or inner ear from behind the tympanic membrane. In one embodiment, the formulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the auris-acceptable formulations of ion channel modulating agents described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In a further embodiment, the formulations described herein are administered to the round window membrane via a surgical approach to the round window membrane that includes modification of the crista fenestrae.

[0176] In some embodiments, the compounds of formula (I) are formulated in rectal compositions (e.g., enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas) containing conventional suppository bases (e.g., cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), and the like).

[0177] Suppositories for rectal administration of drugs (either as solutions, colloids, suspensions, or complexes) can be prepared by mixing the compounds provided herein with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and therefore melt or erode / dissolve in the rectum, releasing the compound. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. In suppository forms of the present compositions, a low-melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0178] The solid composition can be provided in various dosage forms according to the physicochemical properties of the compound provided herein, the desired dissolution rate, cost considerations, and other criteria.In one embodiment, the solid composition is a single-unit type.This means that a single unit dose of the compound is contained in a solid form or article with a single physical shape.In other words, the solid composition is consistent, which is in contrast to the multiple-unit type, in which the unit is inconsistent.

[0179] Examples of single-unit dosage forms that can be used for the solid composition include tablets such as compressed tablets, film units, foil units, wafers, freeze-dried matrix units, etc. In one embodiment, the solid composition is a highly porous freeze-dried form. Such freeze-dried products, sometimes called wafers or freeze-dried tablets, are particularly useful for rapid disintegration, which also allows for rapid dissolution of the compound.

[0180] On the other hand, in some applications, the solid composition may be formed as a multiple-unit dosage form as defined above. Examples of multiple-unit forms include powders, granules, microparticles, pellets, minitablets, beads, freeze-dried powders, etc. In one embodiment, the solid composition is a freeze-dried powder. This dispersion freeze-dried system contains a large number of powder particles, and due to the freeze-drying process used to form the powder, each particle has an irregular and porous microstructure, through which the powder can absorb water very quickly, resulting in rapid dissolution. In addition, effervescent compositions are also contemplated to aid in the rapid dispersion and absorption of the compound.

[0181] Another type of multiparticulate system that can also achieve rapid drug dissolution is a multiparticulate system of powders, granules, or pellets derived from water-soluble excipients coated with the compounds provided herein, such that the compounds are located on the outer surface of each particle. In this type of system, water-soluble low-molecular-weight excipients can be used to prepare the core of these coated particles, which can then be coated with a coating composition comprising the compounds and one or more additional excipients, such as binders, pore-forming agents, sugars, sugar alcohols, film-forming polymers, plasticizers, or other excipients used in pharmaceutical coating compositions.

[0182] Also provided herein is a kit. Typically, the kit includes one or more compounds or compositions described herein. In certain embodiments, the kit may include one or more delivery systems, such as a delivery system for delivering or administering a compound provided herein, and instructions for using the kit (e.g., instructions for treating a patient). In another embodiment, the kit may include a compound or composition described herein and a label indicating that the contents are to be administered to a cancer patient. In another embodiment, a kit may include a compound or composition described herein and a label indicating that the contents are for administration to a patient with one or more of the following: glioblastoma, ovarian cancer, breast cancer, pancreatic cancer, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, chronic myeloid leukemia, Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency, Down syndrome, frontotemporal dementia associated with Parkinson's disease-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, autism, dementia, epilepsy, Huntington's disease, and multiple sclerosis.

[0183] Treatment method The compounds and compositions provided herein can be used as inhibitors of DYRK1A, and thereby can be used to treat various disorders and diseases in which overexpression of DYRK1A is implicated (e.g., cancer and neurological conditions / disorders / diseases). Non-limiting examples of diseases that can be treated with the compounds and compositions provided herein include various cancers, Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency, Down's syndrome, frontotemporal dementia associated with Parkinson's disease-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, and additional diseases with significant neurodegeneration (e.g., autism, dementia, epilepsy, Huntington's disease, multiple sclerosis); diseases and disorders associated with acquired brain injury (e.g., chronic traumatic encephalopathy, traumatic brain injury, tumors, stroke, tauopathies (e.g., Pick's disease, progressive supranuclear palsy, corticobasal degeneration, addiction), and other conditions and disorders. Argyrgia disease, glioglobular tauopathy, primary age-related tauopathies (including neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and age-related tauastrogliopathy). Clinical manifestations include frontotemporal dementia, corticobasal syndrome, Richardson syndrome, Parkinson's disease, pure akinesia with freezing of gait, rarely motor neuron syndrome or cerebellar ataxia, diabetes, psoriasis, knee osteoarthritis, tendinopathy, human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), hepatitis C virus (HCV), and herpes simplex virus type 1 (HSV-1).

[0184] The gene encoding DYRK1A is located on chromosome 21 within the Down syndrome critical region (DSCR), and triploidy of the DSCR is believed to be responsible for most Down syndrome-related disorders (FEBS Journal (2011), 278, 246-256). There is substantial genetic and pharmacological evidence that a mere 1.5-fold overexpression of DYRK1A accounts for most cognitive impairment observed in individuals with Down syndrome (Pharmacology & Therapeutics (2019), 194, 199-221 and Brain Science (2018), 8(10), 187). Genetic normalization of DYRK1A levels or pharmacological inhibition of its catalytic activity restores cognitive function. The development of pharmacological inhibitors of DYRK1A is a major avenue for the treatment of cognitive impairment associated with Down syndrome.

[0185] DYRK1A and DYRK1B are utilized during placental replication of human cytomegalovirus (HCMV). Inhibition of DYRKs prevents the replication of various viruses, including hepatitis C virus (HCV), human cytomegalovirus (HCMV), human immunodeficiency virus type 1 (HIV-1), and herpes simplex virus type 1 (HSV-1) (Journal of Virology (2020), 94(6) and PLoS ONE (2015), 10, e0144229).

[0186] Increasing evidence shows that DYRK1A / 1B inhibitors induce proliferation of insulin-producing pancreatic β-cells, making DYRK1A / 1B kinase an attractive therapeutic target for β-cell regeneration in both type 1 and type 2 diabetes and gestational diabetes (Nature Communications (2015), 6 (8372); Diabetes (2016), 65 (6), 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 types of diabetes that can be treated with DYRK inhibitors are maturity-onset diabetes of the young (MODY, monogenic diabetes), diabetes caused by receptors in body tissues that do not respond to insulin, double diabetes (when type 1 diabetes patients become insulin resistant), diabetes associated with excessive secretion of insulin-antagonist hormones, malnutrition-related diabetes (ICD-10 code E12), and diabetes caused by genetic mutations (autosomal or mitochondrial) that lead to defective beta-cell function.

[0187] There is a wealth of literature linking DYRK1A to solid tumors and leukemia (Pharmacology & Therapeutics (2015), 151, 87-98; Cancers (2020), 12 (8), 2106; and Cellular and Molecular Life Sciences (2021), 78, 603-619). The most notable examples include 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), 948-962), and acute lymphoblastic leukemia (ALL) (Journal of Clinical Investigation (2021), 131 (1), e135937). Other cancers associated with DYRK1A include ovarian cancer (Frontiers in Oncology (2021), 11, 637193), head and neck squamous cell carcinoma (Scientific Reports (2016), 6, 36132), and hepatocellular carcinoma (Cell Death & Disease (2021), 12, 125). DYRK1A regulates the 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).

[0188] Other cancers can also be treated with the compounds and compositions described herein.

[0189] More specifically, cancers that may be treated by the compounds, compositions, and methods described herein include, but are not limited to:

[0190] 1) Breast cancer (e.g., ER) + breast cancer, ER - breast cancer, her2 - breast cancer, her2 + Breast cancer, as well as stromal tumors (e.g., fibroadenoma, phyllodes tumor, and sarcoma), and epithelial tumors (e.g., large ductal papillomas); breast cancer (e.g., non-invasive (non-invasive) carcinoma, including ductal carcinoma in situ (e.g., Paget's disease) and lobular carcinoma in situ, and invasive ductal carcinoma (including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma); chemotherapy-resistant breast cancer (TNBC), as well as other malignancies. Further examples of breast cancer include luminal A, luminal B, versal A, versal B, and estrogen receptor-negative (ER) breast cancers. - ), progesterone receptor negative, and HER2 negative (HER2 - In some embodiments, the breast cancer may have a high-risk Oncotype Score.

[0191] 2) Cardiac cancers (e.g., including sarcomas, such as angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma; and teratoma).

[0192] 3) Lung cancer (e.g., bronchogenic carcinomas, such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondroitinous hamartoma; chemotherapy-resistant small cell lung cancer (SCLC), and mesothelioma).

[0193] 4) Gastrointestinal cancers (e.g., esophageal cancer, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; gastric cancer, e.g., carcinoma, lymphoma, and leiomyosarcoma; pancreatic cancer, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and vipoma; colorectal cancer with APC gene mutation; small intestinal cancer, e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; colon cancer, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma).

[0194] 5) Genitourinary cancers (e.g., kidney cancer, e.g., adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, and leukemia; bladder and urethral cancer, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; prostate cancer, e.g., adenocarcinoma and sarcoma; testicular cancer, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenooid tumor, and lipoma).

[0195] 6) Liver cancer (e.g., hepatocellular carcinoma, including hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma).

[0196] 7) Bone cancer (including, for example, osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor).

[0197] 8) Nervous system cancers (e.g., skull cancers, such as osteoma, hemangioma, granuloma, xanthomas, and osteitis deformans; meningeal cancers, such as meningioma, meningeal sarcoma, and gliomatosis; brain cancers, such as astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and spinal cancers, such as neurofibroma, meningioma, glioma, and sarcoma).

[0198] 9) Gynecological cancers (e.g., uterine cancer, e.g., endometrial cancer (e.g., carcinoma, endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, mixed carcinoma or undifferentiated carcinoma (including mixed Müllerian tumors)), endometrial stromal sarcoma, endometrial squamous cell carcinoma, urothelial carcinoma, endometrial carcinoma with CTNNB1 mutation; cancer of the cervix, e.g., cervical carcinoma and preneoplastic cervical dysplasia; cancer of the ovary, e.g., BRCA-mutated ovarian cancer, surface epithelial stromal tumors (epithelial ovarian cancer (type 1 (endometrioid, mucinous, clear cell, low-grade serous) or type 2 (poorly differentiated, carcinosarcoma, and high-grade serous))), ovarian cancer, e.g., serous Cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid tumor, small cell ovarian cancer (hypercalcemic small cell ovarian cancer, pulmonary type small cell ovarian cancer), unclassified carcinoma, granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, and malignant teratoma; cancer of the vulva, e.g., squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, and melanoma; cancer of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma), and cancer of the fallopian tube, e.g., carcinoma, primary fallopian tube carcinoma; primary peritoneal carcinoma (also called serous surface papillary carcinoma, primary peritoneal carcinoma, extraovarian serous carcinoma, primary serous papillary carcinoma, and psammoma carcinoma).

[0199] 10) Hematopoietic cancers, such as blood cancers, for example, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndromes (refractory cytopenia with monolineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess type I and type II blasts, pediatric refractory cytopenia), and myeloproliferative neoplasms, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, myelodysplastic myeloproliferative disorders, Hodgkin's lymphoma, non-Hodgkin's lymphoma, (malignant lymphoma), and Waldenstrom's macroglobulinemia.

[0200] 11) Skin cancers and disorders (including, for example, malignant and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigines, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, and scleroderma).

[0201] 12) Adrenal cancer (including, for example, neuroblastoma).

[0202] 13) Soft tissue sarcomas (STS) (e.g., fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, Kaposi's sarcoma, lymphangiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor (also called neurofibrosarcoma, malignant schwannoma, and neurogenic sarcoma), neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, extraskeletal mesenchymal, embryonal, and alveolar soft part sarcoma, and infantile hemangiopericytoma).

[0203] More specifically, tumors of the central nervous system that may be treated with the compounds, compositions, and methods described herein include:

[0204] 1) Astrocytic tumors (e.g., diffuse astrocytoma (fibrous, protoplasmic, astrocytic, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), pilocytic astrocytoma (pilomyxoid astrocytoma), pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosis cerebri).

[0205] 2) Oligodendroglial tumors (eg, oligodendroglioma and anaplastic oligodendroglioma).

[0206] 3) Oligoastrocytic tumors (e.g., oligoastrocytoma and anaplastic oligoastrocytoma).

[0207] 4) Ependymal tumors (e.g., subependymoma, myxopapillary ependymoma, ependymoma (cellular, papillary, clear cell, tanycytic), and undifferentiated (malignant) ependymoma).

[0208] 5) Choroid plexus tumors (e.g., choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma).

[0209] 6) Neuronal and mixed glial tumors (e.g., ganglioneuroma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplastic ganglioneuroma of the cerebellum (Lhermitte-Duclos), desmoplastic infantile astrocytoma / ganglioma, central neurocytoma, anaplastic ganglioneuroma, extraventricular neurocytoma, cerebellar liponeurocytoma, papillary glioneuronal tumor, rosette-forming glioneuronal tumor of the fourth ventricle, and paraganglioma of the filum terminale).

[0210] 7) Pineal tumors (e.g., pineocytoma, pineoblastoma, papillary tumor of the pineal region, and intermediately differentiated pineal parenchymal tumor).

[0211] 8) Embryonal tumors (e.g., medulloblastoma (widespread nodular medulloblastoma, anaplastic medulloblastoma, desmoplastic large cell melanotic medulloblastoma), medulloepithelioma, supratentorial primitive neuroectodermal tumor, and primitive neuroectodermal tumor (PNET) (e.g., neuroblastoma, ganglioneuroblastoma, ependymoblastoma, and atypical teratoid / rhabdoid tumor)).

[0212] 9) Neuroblastic tumors, such as olfactory nerve (neuroepithelioma), olfactory neuroepithelioma, and neuroblastoma of the adrenal and sympathetic nervous system.

[0213] 10) Glial tumors (e.g., astroblastoma, chordal glioma of the third ventricle, and angiocentric glioma).

[0214] 11) Cranial and paraspinal nerves (e.g., schwannoma, neurofibroma, perineurioma, and malignant peripheral nerve sheath tumors).

[0215] 12) Tumors of the meninges (e.g., tumors of meningeal epithelial cells, such as meningiomas (atypical meningiomas and anaplastic meningiomas), mesenchymal tumors (e.g., lipoma, angiolipoma, pheochromocytoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, hemangioma, epithelioid granulomatous hemangioendothelioma, hemangiopericytoma, anaplastic hemangiopericytoma, angiosarcoma, Kaposi's sarcoma, and Ewing's sarcoma; primary pigment cell lesions (e.g., diffuse melanocytosis, pheochromocytoma, malignant melanoma, meningeal melanomatosis); and hemangioblastoma).

[0216] 13) Hematopoietic tumors, such as malignant lymphoma, plasmacytoma, and granulocytic sarcoma.

[0217] 14) Germ cell tumors, such as germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumor.

[0218] 15) Sellar tumors (e.g., craniopharyngiomas, granular cell tumors, pituitary cell tumors, and spindle cell tumors of the anterior pituitary gland).

[0219] Cancer may be a solid tumor (which may or may not metastasize). Cancer may also occur as a diffuse tissue, similar to leukemia. Thus, the term "tumor cell" as provided herein includes a cell affected by any one of the above-identified disorders.

[0220] Methods of treating cancer using the compounds or compositions described herein may be combined with existing methods of treating cancer, such as chemotherapy, radiation, or surgery (e.g., oophorectomy). In some embodiments, the compounds or compositions may be administered before, during, or after another anti-cancer agent or treatment.

[0221] Accumulating evidence supports the role of DYRK1A in the pathogenesis of 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, α-synuclein, RCAN1, and β-tubulin. By regulating alternative splicing of exon 10 of tau, DYRK1A preferentially produces the 3R-tau splice isoform (characteristic of DS / AD / tauopathy) over the 4R-tau isoform (Journal of Biological Chemistry (2015), 290, 15219-15237).

[0222] 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 in Parkinson's disease, such as parkin, septin 4, and α-synuclein. Upregulation of Parkinson's disease-specific microRNAs targets DYRK1A expression. Furthermore, there is evidence that DYRK1A expression is increased in Parkinson's disease and Pick's disease (Neurobiology of Disease (2005), 20 (2), 392-400).

[0223] The compounds and compositions provided herein can be used as inhibitors and / or modulators of the enzyme DYRK1A, thereby treating a variety of disorders and diseases associated with tau protein, including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Down's syndrome, frontotemporal dementia (FTD) (including FTD-17 associated with Parkinson's disease (FTDP-17)), behavioral variant frontotemporal dementia (bvFTD), FTD associated with motor neuron disease (MND) (also commonly referred to as amyotrophic lateral sclerosis, FTD-ALS), corticobasal degeneration (CBD) (also referred to as corticobasal degeneration), progressive supranuclear palsy, primary progressive encephalopathy (RPA), and rheumatoid arthritis (RP). and disorders associated with acquired brain injury (e.g., chronic traumatic encephalopathy, ...

[0224] Non-limiting examples of neurological disorders (e.g., neurological conditions and diseases) that can be treated with the compounds and compositions described herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia-telangiectasia, attention-deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, head disease, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Maestro syndrome, and cerebral vasculitis. Lea-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compressive neuropathy, congenital facial nerve palsy, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson's disease, de Morsia syndrome, Déjerine-Krampke palsy, Déjerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental coordination disorder, diabetes Neuropathy, diffuse sclerosis, Dravet syndrome, autonomic dysfunction, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, trigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial spastic paraparesis, febrile seizures, Fisher's syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globular cell leukodystrophy, heterotopic gray matter, Guillain-Barré syndrome, HTLV-1-associated myelopathy, Haller's syndrome Levorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, hereditary polyneuropathic ataxia, otic varicella, herpes zoster, 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's disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsborn syndrome, Klippel-Feil syndrome, Krabbe disease, Kugelberg-Welander disease,Kuru, Lafora's disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, dementia with Lewy bodies, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (spinocerebellar ataxia type 3), megalencephalopathy, macropsia, megalencephalopathy, Melkerson-Rosenthal syndrome, Meniere's disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, Miller-Frank syndrome Fisher syndrome, misophonia, mitochondrial myopathy, Moebius syndrome, unilateral upper limb muscular atrophy, motor neuron disease, motor disability, moyamoya disease, mucopolysaccharidosis, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, diffuse myodestructive sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, myotubular myopathy, myotonia congenita, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscin Swinton syndrome, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital neuralgia, latent spinal dysraphism, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus syndrome, optic neuritis, orthostatic hypotension, recurrent vision, paresthesia, Parkinson's disease, congenital paramyotonia, paraneoplastic disorders, seizures, Parry-Romberg syndrome, Pelizaeus-Merzbach disease, periodic paralysis, peripheral neuropathy, photophobia, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), orthostatic hysteresis pressure, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive hemiface 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's disease, restless legs syndrome, retrovirus-associated myelopathy, Rett's syndrome, Reye's syndrome, rhythmic movement disorder, Romberg's syndrome, chorea, Sandhoff's disease, schizophrenia, Schilder's syndrome, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome,Sjögren's syndrome, sunaschiasis, Sotos syndrome, spasticity, spina bifida, spinal cord tumor, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dyspnea, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus , tethered spinal cord syndrome, Thomsen's disease, thoracic outlet syndrome, pain tics, Todd's palsy, Tourette's syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraplegia, trypanosomiasis, tuberous sclerosis, ubiquitosis, von Hippel-Lindau disease (VHL), Vilyuyske encephalomyelitis (VE), Wallenberg syndrome, Werdnig-Hoffmann disease, West syndrome, Williams syndrome, Wilson's disease, and Zellweger syndrome.

[0225] The compounds and compositions may also be useful in inhibiting invasive cancer, tumor angiogenesis, and the development of metastases.

[0226] 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.

[0227] In some embodiments, the disorder or disease is cancer.

[0228] In some embodiments, the disorder or disease is metastatic melanoma.

[0229] In some embodiments, the disorder or disease is diabetes.

[0230] In some embodiments, the disorder or disease is a neurological disorder.

[0231] In some embodiments, the disorder or disease is Alzheimer's disease.

[0232] In some embodiments, the patient is a human.

[0233] In some embodiments, the cancer is selected 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's lymphoma, lymphoma, sarcoma, and ovarian cancer.

[0234] In some embodiments, the cancer is selected from non-small cell lung cancer, small cell lung cancer, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, synovial sarcoma, rhabdomyosarcoma, salivary gland cancer, basal cell and squamous cell skin cancer, skin cancer (melanoma), small intestine cancer, gastric cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi's sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing's tumor, esophageal cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer, and adrenocortical carcinoma.

[0235] 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 myelogenous leukemia (CML), in 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, and in some embodiments, In embodiments, the cancer is acute lymphocytic leukemia, in some embodiments, the cancer is Hodgkin's lymphoma, in some embodiments, the cancer is lymphoma, in some embodiments, the cancer is sarcoma, in some embodiments, the cancer is ovarian cancer, in some embodiments, the cancer is lung cancer (non-small cell carcinoma), in some embodiments, the cancer is multiple myeloma, in some embodiments, the cancer is nasopharyngeal carcinoma, in some 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 a pituitary tumor, in some embodiments, the cancer is prostate cancer, in some embodiments, the cancer is retinoblastoma, in some embodiments, the cancer is rhabdomyosarcoma, in some embodiments, the cancer is salivary gland cancer, in some embodiments, the cancer is skin cancer (basal cell carcinoma and squamous cell carcinoma), in some embodiments, the cancer is skin cancer (melanoma), in some embodiments, the cancer is small intestine cancer, in some embodiments, the cancer is gastric cancer, in some embodiments, the cancer is testicular cancer, in some embodiments, the cancer is thymic carcinoma, in some embodiments, the cancer is thyroid cancer, 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's sarcoma,In some embodiments, the cancer is gestational trophoblastic disease, in some 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's tumor, in some embodiments, the cancer is esophageal cancer, in some embodiments, the cancer is endometrial cancer, in some embodiments, the 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 cholangiocarcinoma, in some embodiments, the cancer is anal cancer, and in some embodiments, the cancer is adrenocortical carcinoma.

[0236] In some embodiments, the disorder or disease is a neurological condition, disorder, or disease, and the neurological disease is selected from: Alzheimer's disease, frontotemporal dementia, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, and degenerative myopathy.

[0237] In some embodiments, the disorder or disease is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, frontotemporal dementia associated with Parkinson's disease-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, and additional diseases with significant neurodegeneration (e.g., autism, dementia, epilepsy, Huntington's disease, multiple sclerosis); diseases and disorders associated with acquired brain injury (e.g., chronic traumatic encephalopathy, traumatic brain injury, tumors, and stroke).

[0238] In some embodiments, the compounds of Formula (I) inhibit DYRK1A.

[0239] In some embodiments, the method treats a disease or disorder mediated by kinase activity in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound(s) of Formula (I) or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the disease or disorder involves tumor growth, cell proliferation, or angiogenesis.

[0241] In some embodiments, the method inhibits activity of a protein kinase receptor, the method comprising contacting the receptor with an effective amount of a compound(s) of Formula (I) or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the method treats a disease or disorder associated with abnormal cell proliferation in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound(s) of formula (I) or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the method prevents or reduces abnormal cell proliferation in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound(s) of Formula (I) or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the method treats a disease or disorder associated with abnormal cell proliferation in a patient, the method comprising 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.

[0245] Assessment of biological activity The biological activity of the compounds described herein can be tested using any suitable assay known to those skilled in the art. For example, the activity of the compounds can be tested using one or more of the test methods outlined below.

[0246] For example, an in vitro assay for DYRK1A biological activity, such as the regulation of microtubule-associated protein tau (MAPT / Tau) phosphorylation in a neuronal cell line, such as the human SH-SY5Y neuroblastoma cell line, can be used. Assays for DYRK1A-regulated phosphorylation levels can include monitoring basal pSer396 Tau levels, which can be measured by serial dilution of a candidate inhibitor composition, for example, using a top concentration of 10 micromolar, and detected by ELISA or Western blotting. In an exemplary assay for DYRK-1A-regulated phosphorylation, SH-SY5Y cells are cultured in a 96-well plate format for a period sufficient to stabilize microtubule and Tau phosphorylation, typically at least two days, and then treated overnight with 1 / 3 serial dilutions of compounds, lysed, and used. Cell lysates are separated by SDS-PAGE, transferred to nitrocellulose, and probed with an antibody specific for pSer396 Tau. The chemiluminescent signals of the HRP-conjugated antibodies used in Western blotting are detected using a Carestream Image Station, and blot densitometry of pSer396 and β-actin is analyzed using ImageJ (NIH).

[0247] In a further example, the activity of candidate compounds can be measured by phosphorylated Tau (Thr212) AlphaLISA by adding the above-mentioned lysate onto a whole Tau-coated plate and detecting with a specific pThr212 Tau antibody. Colorimetric detection of the AlphaLISA signal is performed using an EnVision multilabel plate reader (Perkin Elmer).

[0248] The following examples are included to further illustrate the present disclosure. Of course, the examples should not be construed as specifically limiting the present disclosure. Variations of these examples within the scope of the claims are within the skill of one of ordinary skill in the art and are considered to be within the scope of the present disclosure as described and claimed herein. The reader will recognize that one of ordinary skill in the art, armed with this disclosure and the skills in the art, will be able to prepare and use the present disclosure even without the exhaustive examples. [Example]

[0249] Preparation of compounds The starting materials used in preparing the compounds of the present disclosure are known, can be made by known methods, or are commercially available.It will be clear to those skilled in the art that methods for preparing precursors and functional groups related to the compounds claimed herein are generally described in the literature.Given the literature and this disclosure, those skilled in the art are fully capable of preparing any compound.

[0250] It will be recognized that those skilled in the art of organic chemistry can readily perform these manipulations without further instruction, i.e., it is well within the scope and practice of the art to perform these manipulations. These include reduction of carbonyl compounds to the corresponding alcohols, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic substitution, etherification, esterification, saponification, and the like. These manipulations are well known and are well documented in standard texts (e.g., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7). th Ed.,John Wiley & Sons(2013),Carey and Sundberg,Advanced Organic Chemistry 5 th Ed., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2 ndEd., John Wiley & Sons (1999) (incorporated by reference in its entirety).

[0251] A skilled artisan will readily appreciate that certain reactions are best performed when other functional groups within the molecule are masked or protected, thereby avoiding any undesired side reactions and / or increasing the yield of the reaction. Often, those skilled in the art utilize protecting groups to achieve such improved yields or avoid undesired reactions. These reactions are found in the literature and are well within the purview 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.

[0252] The trademarks used herein are merely examples and reflect the descriptive materials used at the time of disclosure. One skilled in the art will recognize that variations in lots, manufacturing processes, etc. are to be expected. Therefore, the examples and the trademarks used in the examples are non-limiting and are not intended to be limiting, but merely illustrative of methods that one skilled in the art may choose to implement one or more embodiments of the present disclosure.

[0253] ( 1 H) Nuclear magnetic resonance spectra (NMR) were measured in the solvents indicated on a Bruker NMR spectrometer (Avance™ DRX300, 1 300MHz for H, or Avance™ DRX500, 1 500 MHz for H) or a Varian NMR spectrometer (Mercury 400BB, 1Measurements were performed at a frequency of 400 MHz for H. Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. Peak multiplicities are expressed 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.

[0254] The following abbreviations have the indicated meanings: Ac2O = acetic anhydride 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 Brine = saturated aqueous sodium chloride solution CDCl3 = deuterated chloroform Cs2CO3 = Cesium carbonate DCE = 1,2-dichloroethane DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DME = 1,2-dimethoxyethane, or glyme, or monoglyme DMF = N,N-dimethylformamide DMPU = N,N'-dimethylpropylene urea DMSO-d6 = deuterated dimethyl sulfoxide ESIMS = Electrospray Mass Spectrometry EtOAc = ethyl acetate HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl = Hydrochloric acid HOAc = acetic acid ISCO = Teledyne ISCO, Inc. brand CombiFlash® Rf 200 KOAc = potassium acetate LCMS = Liquid Chromatography Mass Spectrometry LiHMDS = lithium bis(trimethylsilyl)amide MeCN = acetonitrile MeOH = methanol MeTHF = 2-methyltetrahydrofuran MgSO4 = Magnesium sulfate MTBE = methyl tert-butyl ether MW = microwave irradiation NaO t Bu = sodium tert-butoxide NaHCO3 = sodium bicarbonate NaBH3CN = sodium cyanoborohydride NaBH(OAc)3 = sodium triacetoxyborohydride Na2SO4 = sodium sulfate NMR=nuclear magnetic resonance ON = overnight Pd / C = palladium on carbon Pd(dppf)Cl2 = 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride Pd(OAc)2 = Palladium(II) acetate Pd(OH)2 / C = palladium hydroxide on carbon PE = petroleum ether Prep TLC = preparative thin layer chromatography rt=room temperature TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMSOK = potassium trimethylsilanolate XPhos = dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane

[0255] The following exemplary schemes are provided as a guide to the reader and summarize exemplary methods for making the compounds provided herein. Additionally, other methods for preparing the compounds of the present disclosure will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Given the literature and this disclosure, those skilled in the art are fully equipped to prepare these compounds by these methods. The numbering of compounds used in the synthetic schemes set forth below refers only to those particular schemes and should not be construed as or confused with the same numbering in other sections of this application. Unless otherwise indicated, all variables are as defined above.

[0256] General Procedure Compounds of formula I of the present disclosure can be prepared as shown in Scheme 1. [ka]

[0257] Scheme 1 describes the preparation of 4-alkylaminopyrrolo[2,1-f][1,2,4]triazine derivatives (VII) by first displacing the 4-chloride (I) with various amines (II) to generate 2-chloro-5-bromo-4-aminopyrrolo[2,1-f][1,2,4]triazine III. Various bromides (IV) were reacted with bis(pinacolato)diboron to form various pinacol boronic acid esters, followed by Suzuki coupling with bromide (III) to generate 2-chloro-4-aminopyrrolo[2,1-f][1,2,4]triazine (V). The chloro was then displaced with various amines (VI) to yield the final 4-aminopyrrolo[2,1-f][1,2,4]triazine (VII).

[0258] Compounds of formula I of the present disclosure can also be prepared as shown in Scheme 2. [ka]

[0259] Scheme 2 describes the preparation of 4-aminopyrrolo[2,1-f][1,2,4]triazine derivatives (VII) by first displacing the 4-chloride (VIII) with various amines (II) to generate 2,5-dichloro-4-aminopyrrolo[2,1-f][1,2,4]triazine IX. The 2-chloro group is then displaced with various amines (VI) to obtain 5-chloro-4-aminopyrrolo[2,1-f][1,2,4]triazine (X). Various bromides (IV) are reacted with bis(pinacolato)diboron to form various pinacol boronic acid esters, followed by Suzuki coupling with chloride (X) to finally generate 4-aminopyrrolo[2,1-f][1,2,4]triazine (VII).

[0260] Illustrative Compound Examples The preparation of the intermediate 5-bromo-2-chloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XV) is shown in Scheme 3 below. [ka]

[0261] Step 1 To a solution of methyl 3-bromo-1H-pyrrole-2-carboxylate (XI) (100 g, 490.15 mmol, 1 equiv.) in MeCN (2 L) was added CsCO (255.52 g, 784.23 mmol, 1.6 equiv.) in one portion at 20 °C (no exotherm). The reaction was stirred at room temperature for 5 h. Next, a solution of O-(2,4-dinitrophenyl)hydroxylamine (146.40 g, 735.22 mmol, 1.5 equiv.) in MeCN (2 L) was added dropwise at 0–5 °C under N2. After the 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 × 3). The above reaction was carried out six times.

[0262] The five batches of combined organics were combined, dried over MgSO, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (DCM / PE = 0 to 50%, then EtOAc / PE = 20%) to give 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. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (3 H, s), 6.24 (1 H, d, J=2.8 Hz), 6.38 (2 H, br s), 7.12 (1 H, d, J=2.8 Hz).

[0263] Steps 2 and 3 To a solution of methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (XII) (190 g, 867.44 mmol, 1 equiv.) in THF (1900 mL), 2,2,2-trichloroacetyl isocyanate (179.76 g, 954.18 mmol, 113.06 mL, 1.1 equiv.) was added dropwise at 0-5 °C and then warmed to room temperature for 1 h. The reaction was then added dropwise to NH3 / MeOH (7 M, 1.24 L, 10 equiv.) at room temperature and stirred for 1 h at room temperature to give a yellow suspension. The above reaction was performed twice.

[0264] The two reactions were combined and concentrated in vacuo. The residue was triturated with MTBE (4 L) at room temperature for 30 minutes and filtered. The filter cake was washed with MTBE (500 mL × 3) and dried in vacuo 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. 1 H NMR (400 MHz, DMSO-d6) δ 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 observed m / z 262.1 ( 79 BrM+H).

[0265] Step 4 To a solution of methyl 3-bromo-1-ureido-1H-pyrrole-2-carboxylate (XIII) (67 g, 255.67 mmol, 1 equiv.) in THF (4 L) was added TMSOK (65.60 g, 511.33 mmol, 2 equiv.) portionwise at 0–5 °C under N. After stirring for 5 min, the reaction became a thick slurry. The reaction mixture was stirred vigorously at room temperature for 16 h. LCMS indicated that approximately 25.8% of the starting material remained. An additional amount of TMSOK (16.40 g, 127.83 mmol, 0.5 equiv.) was added at room temperature and stirred for 3 h. LCMS indicated the reaction was complete. The reaction was concentrated. The residue was diluted with HO (1.6 L), cooled in an ice bath, and adjusted to pH 2–3 by dropwise addition of HCl (4 M, 160 mL) and filtered. The filter cake was washed with H2O (600 mL x 3). The above reaction was carried out six times.

[0266] The filter cakes from the six reactions were combined and triturated with HO (6 L) at room temperature for 2 hours, then filtered. The filter cake was dried in a vacuum drying oven at 60 °C for 24 hours 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.1 H NMR (400 MHz, DMSO-d6) δ 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 observed m / z 232.0 ( 81 BrM+H).

[0267] Step 5 To a solution of POCl3 (1500 mL) was added 5-bromopyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (XIV) (180 g, 782.55 mmol, 1 equiv.) in 1500 mL of POCl3 at room temperature. Next, N,N-diethylaniline (291.95 g, 1.96 mol, 312.92 mL, 2.5 equiv.) was added dropwise at room temperature (slightly exothermic). After the addition, the reaction was heated at 105 °C for 48 h. LCMS indicated that the starting material had been consumed, but the intermediate remained, and approximately 4.3% of the desired product had formed. The reaction was cooled to 90 °C, and additional POCl3 (500 mL) was added in one portion. The reaction was heated to gentle reflux for 24 h. LCMS indicated that most of the intermediate remained, and approximately 11.9% of the desired product had formed. The reaction was heated to gentle reflux for an additional 4 days. LCMS showed that approximately 7.4% of the intermediate remained and approximately 55.5% of the desired product had formed. The reaction was cooled to 40 °C and distilled under reduced pressure to remove most of the POCl. The residue was diluted with MeTHF (5 L), poured into ice H2O (2 L), brine (1 L) was added, and separated. The aqueous layer was extracted with MeTHF (1.5 L x 2). The combined organics were washed with brine (1.5 L x 2), dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (4 kg, 100–200 mesh, DCM / PE=0–20%), triturated with n-heptane (500 mL) at room temperature for 3 h, and then filtered to give 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) δ ppm 7.02 (1 H, d, J = 2.4 Hz), 7.79 (1 H, d, J = 2.4 Hz); ESIMS observed m / z 266.1 ( 79 BrM+H).

[0268] Step 6 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 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 with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated on a rotary evaporator, and the crude mixture was purified by ISCO (0→10% MeOH / CHCl3) to give 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 solid. ESIMS observed m / z 261.0 (M+H) for C7H6BrClN4.

[0269] The following intermediates were prepared according to the procedure described in Scheme 3 above. [ka]

[0270] 5-Bromo-2-chloro-N-(oxetan-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (XVI): white solid (461 mg, 1.519 mmol, 81.1% yield). ESIMS m / z 303.0 (M+H) for CHBrClNO. [ka]

[0271] 5-Bromo-2-chloro-N-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XVII): beige solid (503.6 mg, 1.831 mmol, 97.6% yield). ESIMS m / z 275.0 (M+H) for C8H8BrClN4. [ka]

[0272] 5-Bromo-2-chloro-N-isopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XVIII): White solid (453.0 g, 1.564 mmol, 83.5% yield). CH 10 ESIMS observed m / z 289.0 (M+H) for BrClN4. [ka]

[0273] 5-Bromo-2-chloro-N-(methyl-d)pyrrolo[2,1-f][1,2,4]triazin-4-amine (XIX): orange solid (647 mg, 2.446 mmol, 21.8% yield). ESIMS m / z 264.0 (M+H) for CHDBrClN.

[0274] The preparation of the intermediate 5-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (XX) is shown in Scheme 4 below. [ka]

[0275] Step 1 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 with DCM, washed with brine, and dried over anhydrous NaSO. The solvent was evaporated on a rotary evaporator and dried under high vacuum to give 5-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-amine (XX) (900 mg, 3.637 mmol, 97.1% yield) as an off-white solid. ESIMS m / z 246.95 (M+H) for CHBrClN.

[0276] The following intermediates were prepared according to the procedure described in Scheme 4 above. [ka]

[0277] 2,5-Dichloropyrrolo[2,1-f][1,2,4]triazin-4-amine (XXI): pale orange solid (308 mg, 1.517 mmol, 16.9% yield). ESIMS m / z 203.0 (M+H) for C6H4Cl2N4.

[0278] The synthesis of the intermediate 2,5-dichloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XXII) is shown in Scheme 5 below. [ka]

[0279] Step 1 To a 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 mL) was added methylammonium chloride (1.51 g, 22.36 mmol) and DIPEA (5.48 mL, 31.46 mmol) at −78° C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO solution, extracted with DCM, washed with brine, and dried over anhydrous NaSO. The solvent was evaporated on a rotary evaporator and dried under high vacuum to give 2,5-dichloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XXII) (1.92 g, 8.846 mmol, 98.4% yield) as a yellow solid. ESIMS observed m / z 217.0 (M+H) for C7H6Cl2N4.

[0280] The preparation of the intermediate 6-bromo-1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridine (XXVII) is shown in Scheme 6 below. [ka]

[0281] Step 1 A mixture of 2,2-difluoroethan-1-amine (XXIV) (410 mg, 5.02 mmol), 5-bromo-3-fluoro-2-nitropyridine (XXIII) (commercially available from ArkPharma Scientific Limited) (1.0 g, 4.53 mmol), and K2CO3 (1.38 g, 9.95 mmol) in MeCN (20 mL) was stirred at room temperature for 16 hours. The reaction was filtered and concentrated under high vacuum. The residue was taken up in water and stirred for 1 hour. The solid was collected by filtration and dried under vacuum to give 5-bromo-N-(2,2-difluoroethyl)-2-nitropyridin-3-amine (XXV) (1.066 g, 3.780 mmol, 83.5% yield) as a yellow solid, which was used in the next step without purification. ESIMS found m / z 282.0 ( 79 BrM+H).

[0282] Step 2 A mixture of 5-bromo-N-(2,2-difluoroethyl)-2-nitropyridin-3-amine (XXV) (1.32 g, 4.69 mmol), Fe (3.07 g, 46.95 mmol), and NH4Cl (3.77 g, 70.48 mmol) was taken up in a mixture of EtOH (18 mL) and water (6 mL), and the mixture was heated at 70°C for 4 h. The reaction mixture was cooled and filtered through Celite®. The filtrate was taken up in EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5-bromo-N 3 -(2,2-Difluoroethyl)pyridine-2,3-diamine (XXVI) (630 mg, 2.499 mmol, 53.2% yield) was obtained as a grey solid, which was used in the next reaction without further purification. ESIMS found m / z 252.0 ( 79 BrM+H).

[0283] Step 3 5-Bromo-N 3 A solution of -(2,2-difluoroethyl)pyridine-2,3-diamine (XXVI) (630 mg, 2.5 mmol) and acetic anhydride (0.28 mL, 2.97 mmol) in HOAc (15 mL) was heated at 120 °C for 16 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc / 1N NaOH. The organics were separated and washed with water and brine. The organics were dried over anhydrous NaSO and concentrated under high vacuum. The residue was triturated with diethyl ether, sonicated, and the solid was collected by filtration and dried under high vacuum to give 6-bromo-1-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridine (XXVII) (325 mg, 1.177 mmol, 47.1% yield) as a gray solid, which was used in the next step without purification. ESIMS found m / z 276.0 ( 79 BrM+H).

[0284] The following intermediates were prepared according to the procedure described in Scheme 6 above. [ka]

[0285] 6-Bromo-1-(3,3-difluorocyclobutyl)-2-methyl-1H-imidazo[4,5-b]pyridine (XXVIII): Gray solid (1.57 g, 6.178 mmol, 68.3% yield). 11 H 10 ESIMS observed m / z 302.1 (M+H) for BrF2N3.

[0286] The preparation of the intermediate 6-bromo-1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine (XXXII) is shown below in Scheme 7. [ka]

[0287] Step 1 A mixture of 2-aminopropane (XXIX) (0.86 mL, 9.96 mmol), 5-bromo-3-fluoro-2-nitropyridine (XXIII) (2 g, 9.05 mmol), and K2CO3 (2.5 g, 18.1 mmol) in MeCN (40 mL) was stirred at room temperature for 16 hours. The reaction mixture was added to water (200 mL) and stirred for 1 hour. The resulting solid was collected by filtration and dried under high vacuum to give 5-bromo-N-isopropyl-2-nitropyridin-3-amine (XXX) (2.36 g, 9.074 mmol, 100.3% yield) as a yellow solid, which was used in the next step without purification. CH 10 ESIMS observed m / z 260.0 (M+H) for BrN3O2.

[0288] Step 2 A mixture of 5-bromo-N-isopropyl-2-nitropyridin-3-amine (XXX) (2.35 g, 9.04 mmol), Fe (5.91 g, 90.35 mmol), and NH4Cl (7.25 g, 135.53 mmol) was taken up in EtOH (30 mL) and water (10 mL), and the mixture was heated at 70° C. for 2 h. The reaction mixture was cooled and filtered through Celite®, and the filtrate was taken up in EtOAc, washed with water, then brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5-bromo-N 3 C8H-isopropylpyridine-2,3-diamine (XXXI) (2.2 g, 9.561 mmol, 105.8% yield) was obtained as a dark brown solid, which was used in the next step without purification. 12 ESIMS observed m / z 230.05 (M+H) for BrN3.

[0289] Step 3 5-Bromo-N 3 A solution of 1-isopropylpyridine-2,3-diamine (XXXI) (2.08 g, 9.04 mmol) and AcO (1.05 mL, 10.84 mmol) in HOAc (20 mL) was heated at 120 °C for 16 h. The reaction mixture was concentrated, the residue partitioned between EtOAc / 1N NaOH, and the organics separated and washed with water and brine. The organics were dried over anhydrous NaSO, the solvent concentrated, and dried under high vacuum to give 6-bromo-1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine (XXXII) (1.57 g, 6.178 mmol, 68.3% yield) as a dark brown solid, which was used in the next step without purification. 10 H 12 ESIMS observed m / z 254.0 (M+H) for BrN3.

[0290] The preparation of the intermediate 5-chloro-3-ethyl-2-methyl-3H-imidazo[4,5-b]pyridine (XXXIV) is shown below in Scheme 8. [ka]

[0291] Step 1 A mixture of 5-chloro-2-methyl-3H-imidazo[4,5-b]pyridine (XXXIII) (commercially available from eNovation Chemicals, LLC) (0.5 g, 2.98 mmol), iodoethane (0.56 g, 3.58 mmol), and K2CO3 (0.83 g, 5.97 mmol) in DMF (10 mL) was heated at 70 °C overnight. The reaction mixture was cooled, the solvent was concentrated, and the residue was partitioned between EtOAc / water. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, and the solvent was concentrated in vacuo and dried to afford 5-chloro-3-ethyl-2-methylimidazo[4,5-b]pyridine (XXXIV) (466 mg, 2.382 mmol, 79.8% yield) as a dark brown solid, which was used in the next step without purification. CH 10 ESIMS observed m / z 196.05 (M+H) for ClN3.

[0292] The following intermediates were prepared according to the procedure described in Scheme 8 above. [ka]

[0293] 5-Chloro-3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XXXV): beige solid (830 mg, 3.583 mmol, 60.1% yield). ESIMS m / z 232.0 (M+H) for C9H8ClF2N3. [ka]

[0294] 5-Chloro-3-(2-fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XXXVI): beige solid (220 mg, 1.030 mmol, 57.5% yield). ESIMS m / z 214.05 (M+H) for C9H9ClFN3. [ka]

[0295] 5-Chloro-3-(2-methoxyethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XXXVII): beige solid (195 mg, 0.864 mmol, 48.3% yield). 10 H 12 ESIMS observed m / z 226.1 (M+H) for ClNO. [ka]

[0296] 1-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropan-2-ol (XXXVIII): white solid (229.9 mg, 0.959 mmol, 39.7% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.13 (6 H, s), 2.63 (3 H, s), 4.11 (2 H, s), 4.80 (1 H, s), 7.25 (1 H, d, J=8.21 Hz), 7.96 (1 H, d, J=8.21 Hz);C 11 H 14 ESIMS observed m / z 240.1 (M+H) for ClNO. [ka]

[0297] 5-Chloro-3-isobutyl-2-methyl-3H-imidazo[4,5-b]pyridine (XXXIX): white solid (206.8 mg, 0.925 mmol, 38.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.87 (6 H, d, J=6.57 Hz), 2.22 (1 H, dquin, J=13.89, 7.07, 7.07, 7.07, 7.07 Hz), 2.58 (3 H, s), 4.01 (2 H, d, J=7.67 Hz), 7.26 (1 H, d, J=8.21 Hz), 7.98 (1 H, d, J=8.21 Hz);C 11 H 14 ESIMS observed m / z 224.1 (M+H) for ClN3. [ka]

[0298] 5-Chloro-2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine (XL): beige solid (372 mg, 1.490 mmol, 50.0% yield). ESIMS m / z 250.0 (M+H) for C9H7ClF3N3. [ka]

[0299] 5-Chloro-2-methyl-3-(oxetan-3-ylmethyl)-3H-imidazo[4,5-b]pyridine (XLI): light brown solid (289.7 mg, 1.219 mmol, 40.4% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 2.59 (3 H, s), 3.43 - 3.56 (1 H, m), 4.47 (2 H, t, J=6.02 Hz), 4.52 (2 H, d, J=7.67 Hz), 4.62 (2 H, dd, J=7.67, 6.02 Hz), 7.27 (1 H, d, J=8.21 Hz), 7.98 (1 H, d, J=8.21 Hz);C 11 H 12 ESIMS observed m / z 238.1 (M+H) for ClNO. [ka]

[0300] tert-Butyl 3-((5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)azetidine-1-carboxylate (XLII): off-white amorphous solid (532.6 mg, 1.581 mmol, 52.1% yield). 16 H 21 ESIMS observed m / z 337.1 (M+H) for ClN4O2. [ka]

[0301] 2-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-N,N-dimethylacetamide (XLIII): off-white solid (474.4 mg, 1.877 mmol, 62.6% yield). 11 H 13 ESIMS observed m / z 253.1 (M+H) for ClNO. [ka]

[0302] 3-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,2-dimethylpropanenitrile (XLIV): off-white amorphous solid (59.1 mg, 0.238 mmol, 7.9% yield). 12 H 13 ESIMS observed m / z 249.1 (M+H) for ClN4. [ka]

[0303] 5-Chloro-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine (XLV): Pale yellow solid (335 mg, 1.422 mmol, 21.8% yield). ESIMS m / z 236.0 (M+H) for C8H5ClF3N3. [ka]

[0304] 5-Chloro-3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridine (XLVI): White solid (253 mg, 1.163 mmol, 20.5% yield). ESIMS m / z 218.0 (M+H) for C8H6ClF2N3. [ka]

[0305] 5-Chloro-3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridine (XLVII): beige solid (470 mg, 2.355 mmol, 36.2% yield). ESIMS m / z 200.05 (M+H) for C8H7ClFN3.

[0306] The preparation of the intermediate 5-chloro-3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (LI) is shown below in Scheme 9. [ka]

[0307] Step 1 To a solution of 2,6-dichloro-3-nitropyridine (XLVIII) (14.0 g, 73.30 mmol) in DCM (500.0 mL) cooled to 0 °C, 2,2-difluoroethan-1-amine (XXIV) (8.91 g, 109.95 mmol) was added at 0 °C. DIPEA (18.91 g, 146.60 mmol) was then added, and the reaction was allowed to warm to room temperature for 16 h. The reaction mixture was extracted with DCM (500 mL × 2). The combined organics were washed with brine (500 mL × 3), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc=10:1→5:1) to give 6-chloro-N-(2,2-difluoroethyl)-3-nitropyridin-2-amine (XLIX) (12.0 g, 50.507 mmol, 68.9%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0308] Step 2 6-Chloro-N-(2,2-difluoroethyl)-3-nitropyridin-2-amine (XLIX) (12.0 g, 50.51 mmol) was added to a mixture of NH4Cl (7.37 g, 139.00 mmol) in EtOH / HO (300 / 100 mL, 3:1 ratio). The resulting mixture was sealed and heated at 80 °C. Then, Fe (12.97 g, 231.66 mmol) was added at 80 °C, sealed, and heated at 80 °C for 1 h. The reaction mixture was cooled to room temperature, filtered, and diluted with EtOAc (300 mL × 2). The solution was washed with water (300 mL × 2), and the aqueous layer was extracted with EtOAc (300 mL × 2). The combined organic extracts were washed with brine (300 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10:1 → 3:1) to give 6-chloro-N 2-(2,2-Difluoroethyl)pyridine-2,3-diamine (L) (10.0 g, 48.167 mmol, 95.4% yield) was obtained as a purple solid. 1 H NMR (400 MHz, DMSO-d6) δ 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 actual value m / z 208.1(M+H) for C7H8ClF2N3.

[0309] Step 3 6-Chloro-N at 0°C 2 To a solution of -(2,2-difluoroethyl)pyridine-2,3-diamine (L) (10.0 g, 48.17 mmol) in HCl (360 mL) was added NaNO (4.00 g, 57.97 mmol) in HO (55 mL). The mixture was stirred under N at room temperature for 16 hours. The reaction mixture was adjusted to pH 9 with 4 M NaOH and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, 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 give 5-chloro-3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (LI) (6.2 g, 28.364 mmol, 58.9% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 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 actual value m / z 219.0(M+H) for C7H5ClF2N4.

[0310] The following intermediates were prepared according to the procedure described in Scheme 9 above. [ka]

[0311] 5-Chloro-3-(2-fluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (LII): yellow solid (2.7 g, 13.460 mmol, 39.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 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 actual value m / z 201.1(M+H) for C7H6ClFN4. [ka]

[0312] 5-Chloro-3-(2,2,2-trifluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (LIII): yellow solid (3.1 g, 13.103 mmol, 42.2%). 1 H NMR (400 MHz, DMSO-d6) δ 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 measured value m / z 237.0(M+H) for C7H4ClF3N4.

[0313] The preparation of the intermediate cis-4-(methoxy-d3)cyclohexan-1-amine (LIX) is shown below in Scheme 10. [ka]

[0314] Step 1 To a solution of cis-4-aminocyclohexan-1-ol (LIV) (5 g, 32.9 mmol) and (bromomethyl)benzene (LV) (11.25 g, 65.8 mmol) in MeCN (80 mL) was added K2CO3 (13.64 g, 98.7 mmol). The mixture was stirred at 70 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove MeCN. The mixture was diluted with EtOAc and then extracted with EtOAc (100 mL x 3) and H2O. The combined organic layers were concentrated, and the crude residue was purified by silica gel column chromatography (0% to 30% EtOAc / PE) to give cis-4-(dibenzylamino)cyclohexan-1-ol (LVI) (8.0 g, 27.08 mmol, 82.3% yield) as a white solid. 20 H 25 ESIMS observed m / z 296.4 (M+H) for NO.

[0315] Step 2 To a solution of cis-4-(dibenzylamino)cyclohexan-1-ol (LVI) (8.0 g, 27.08 mmol) in DMPU (80 mL) was added NaH (5.98 g, 149.7 mmol) slowly under nitrogen atmosphere with continuous stirring. The reaction mixture was stirred at room temperature for 1 h. Next, iodomethane-d3 (LVII) (10.85 g, 74.86 mmol) was added over 10 min at room temperature. After the addition was complete, the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (300 mL) and stirred for 10 min. The mixture was then diluted with EtOAc and extracted with EtOAc (300 mL × 3) and HO. The crude residue was purified by silica gel column chromatography (0% to 20% EtOAc / PE) to give cis-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine (LVIII) (6 g, 19.202 mmol, 70.9% yield) as a colorless oil. 21 H 24 ESIMS observed m / z 313.0 (M+H) for D3NO.

[0316] Step 3 To a solution of cis-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine (LVIII) (200 mg, 0.64 mmol) in EtOH (5 mL), Pd(OH)2 / C (50 mg) and Pd / C (50 mg) were added. The mixture was stirred at room temperature for 16 hours. The mixture was filtered through Celite® and washed with EtOH. The reaction mixture was concentrated under reduced pressure to give cis-4-(methoxy-d3)cyclohexan-1-amine (LIX) (76.4 mg, 0.578 mmol, 90.3% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.51 - 1.40 (m, 4H), 1.67 - 1.56 (m, 4H), 1.86 (td, J = 9.8, 4.6 Hz, 2H), 2.71 (tt, J = 10.8, 5.4 Hz, 1H), 3.34 (td, J = 4.8, 2.4 Hz, 1H);C7H 12 ESIMS observed m / z 133.0 (M+H) for D3NO.

[0317] The following intermediates were prepared according to the procedure described in Scheme 10 above. [ka]

[0318] 2-((cis-4-aminocyclohexyl)oxy)ethan-1-ol (LX): Colorless oil (0.5 g, 3.14 mmol, 67.4% yield). CH 17 ESIMS observed m / z 160 for NO2. (M+H). [ka]

[0319] cis-4-(2-methoxyethoxy)cyclohexane-1-amine (LXI): Colorless oil (1.5 g, 8.65 mmol, 76.6% yield). 19 ESIMS observed m / z 174.1 (M+H) for NO2. [ka]

[0320] cis-4-(2,2-difluoroethoxy)cyclohexane-1-amine (LXII): White solid (1.352 g, 7.54 mmol, 90.3% yield). 15 ESIMS observed m / z 180.1 (M+H) for F2NO. [ka]

[0321] Cis-4-ethoxycyclohexan-1-amine (LXIII): colorless oil (2 g, 13.96 mmol, 64.4% yield). 1 H NMR (400 MHz, CDCl3) δ 1.19 (t, J = 7.0 Hz, 3H), 1.49 - 1.44 (m, 6H), 1.62 - 1.55 (m, 2H), 1.86 - 1.79 (m, 2H), 2.4 - 2.723 (m, 1H), 3.49 - 3.41 (m, 3H). [ka]

[0322] cis-3-(2-methoxyethoxy)cyclobutan-1-amine (LXIV): colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 1.51 (dd, J = 13.4, 5.2 Hz, 2H), 2.49 - 2.40 (m, 2H), 2.89 - 2.75 (m, 1H), 3.23 (s, 3H), 3.37 - 3.35 (m, 3H), 3.47 (s, 2H), 3.54 - 3.48 (m, 1H). [ka]

[0323] 2-(cis-3-aminocyclobutoxy)ethan-1-ol (LXV): colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 1.79-1.72 (m, 2H), 2.50 - 2.45 (m, 2H), 3.08 - 2.97 (m, 1H), 3.29 (t, J = 5.4 Hz, 2H), 3.46 (t, J = 5.4 Hz, 2H), 3.73 - 3.57 (m, 1H).

[0324] The preparation of the intermediate cis-4-(difluoromethoxy)cyclohexan-1-amine (LXVIII) is shown below in Scheme 11. [ka]

[0325] Step 1 A solution of cis-4-(dibenzylamino)cyclohexan-1-ol (LVI) (50 mg, 0.170 mmol) and CuI (6.5 mg, 0.034 mmol) in MeCN (5 mL) was heated at 45 °C for 5 min under a nitrogen atmosphere. To this mixture was added a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (LXVI) (60 mg, 0.339 mmol) over 10 min. The mixture was then stirred at 45 °C for 1 h. The volatile components were then removed by evaporation, and the residue was diluted with EtOAc (100 mL) and a 1:1 mixture of water and saturated aqueous NaHCO3 (100 mL). The resulting biphasic mixture containing solids was filtered through a sintered glass Buchner funnel. The filtrate layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined EtOAc layers were washed with 50 mL of a 1:1 mixture of brine and water, dried over anhydrous MgSO4, filtered, and concentrated to an oil. The crude oil was purified by silica gel chromatography (100% hexanes → 30% EtOAc / hexanes). The product-containing fractions were combined and concentrated to give cis-N,N-dibenzyl-4-(difluoromethoxy)cyclohexan-1-amine (LXVII) (25 mg, 0.072 mmol, 42.3% yield) as an oil, which solidified to an off-white solid.21 H 25 ESIMS observed m / z 346.1 (M+H) for F2NO.

[0326] Step 2 To a solution of cis-N,N-dibenzyl-4-(difluoromethoxy)cyclohexan-1-amine (LXVII) (2.8 g, 8.11 mmol) in THF (60 mL) was added Pd(OH)2 / C (1.4 g) and Pd / C (1.4 g). The mixture was stirred at room temperature for 16 hours. The mixture was filtered through Celite® and washed with THF. The reaction mixture was concentrated under reduced pressure to give cis-4-(difluoromethoxy)cyclohexan-1-amine (LXVIII) (1.05 g, 6.36 mmol, 78.4% yield) as a colorless oil. CH 13 ESIMS observed m / z 166.1 (M+H) for F2NO.

[0327] The preparation of intermediate 1-(3,3,3-trifluoropropyl)piperidin-4-amine (LXIII) is shown below in Scheme 12. [ka]

[0328] Step 1 tert-Butyl piperidin-4-ylcarbamate (LXIX) (commercially available from Combi-Blocks Inc.) (1 g, 4.99 mmol) and K2CO3 (1.73 g, 12.52 mmol) were dissolved in DMF (15 mL), 1-iodo-3,3,3-trifluoropropane (LXX) (878 μL, 7.49 mmol) was added, and the reaction was stirred at room temperature for 16 h. The reaction mixture was poured into EtOAc, and the aqueous layer was separated. The aqueous layer was extracted with EtOAc (×3), and the combined organic layers were then acidified to pH 4.5 with 1 M citric acid. The organic layer was washed three times with small amounts of water to remove unreacted SM. A sufficient amount of product remained in the organic layer. This was dried over anhydrous MgSO4 and reduced in vacuo to give tert-butyl N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]carbamate (LXXI) (861 mg, 2.906 mmol, 58.2% yield) as a white solid. 13 H 23 ESIMS observed m / z 297.2 (M+H) for F3N2O2.

[0329] Step 2 tert-Butyl N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]carbamate (LXXI) (200 mg, 0.670 mmol) was dissolved in DCE (3.2 mL), TFA (800 μL, 10.38 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was blown dry and excess TFA was removed under high vacuum to give the crude intermediate 1-(3,3,3-trifluoropropyl)piperidin-4-amine (LXXII) (209 mg, 0.674 mmol, 99.8% yield) as a white semi-solid, which was used without further purification. CH 15 ESIMS observed m / z 197.1 (M+H) for F3N2.

[0330] The preparation of the intermediate N-(trans-4-aminocyclohexyl)acetamide (LXXV) is shown below in Scheme 13. [ka]

[0331] Step 1 To a stirred solution of tert-butyl(trans-4-aminocyclohexyl)carbamate (LXXIII) (commercially available from Combi-Blocks Inc.) (0.6 g, 2.8 mmol) in DCM (6 mL) was added TEA (1.2 mL, 8.61 mmol). Next, acetyl chloride (LXXIV) (0.22 mL, 3.09 mmol) was added slowly, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed, and the crude material was dissolved in EtOAc, washed with 1 M NaOH, brine, dried over anhydrous MgSO4, and finally concentrated. The product was dissolved in EtOH (2 mL) and 4 M HCl (1 mL). The solution was stirred at room temperature for 2 hours and then evaporated to dryness to give the HCl salt of N-(trans-4-aminocyclohexyl)acetamide (LXXV) (480 mg, 2.49 mmol, 89.0% yield) as a white solid. CH 16 ESIMS observed m / z 157.05 (M+H) for N2O.

[0332] The preparation of the intermediate cis-4-amino-N,N-dimethylcyclohexane-1-carboxamide (LXXVII) is shown below in Scheme 14. [ka]

[0333] Step 1 To a solution of 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (LXXVI) (commercially available from Combi-Blocks Inc.) (0.3 g, 1.23 mmol) in DMF (6 mL) was added DIPEA (0.65 mL, 3.73 mmol) and HATU (0.7 g, 1.85 mmol). The reaction was stirred at room temperature for 5 minutes. Dimethylamine (0.92 mL, 1.84 mmol) was added, and the reaction was heated at 90° C. for 16 hours. The reaction was concentrated and dissolved in EtOH (2 mL) and 4 M HCl in dioxane (1 mL). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo to give the HCl salt of 4-amino-N,N-dimethylcyclohexane-1-carboxamide (LXXVII) (280 mg, 1.355 mmol, 109.9% yield) as a light brown sticky solid. CH 18 ESIMS observed m / z 171.15 (M+H) for N2O.

[0334] The following intermediates were prepared according to the procedure described in Scheme 14 above. [ka]

[0335] trans-4-amino-N,N-dimethylcyclohexane-1-carboxamide (LXXVIII): Light brown viscous solid (290 mg, 1.403 mmol, 113.8% yield). 18 ESIMS observed m / z 171.1 (M+H) for NO.

[0336] Example 1 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 The preparation of -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (210) is shown in Scheme 15 below. [ka]

[0337] Step 1 5-Bromo-2-chloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XV) (1 g, 3.82 mmol), [3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]boronic acid (LXXIX) (1.01 g, 4.21 mmol), Pd(dppf)Cl (158 mg, 0.19 mmol), and NaHCO (1.46 g, 13.77 mmol) were added to a mixture of dry 1,4-dioxane (20 mL) and water (5 mL). The reaction mixture was purged with Ar for 5 minutes, and the reaction was heated at 80 °C for 1 hour. The reaction mixture was poured into saturated aqueous NH Cl, then extracted with DCM (x3), dried (MgSO), and reduced in vacuo to give a crude orange solid. The product was purified by column chromatography (0→100% EtOAc / hexanes, followed by 0→6% MeOH / CHCl). The product was further purified by reverse-phase column chromatography (10→70% MeCN / H2O in 0.1% formic acid). The appropriate fractions were combined, neutralized with saturated aqueous NaHCO3, extracted with DCM (×3), dried (MgSO4), and reduced in vacuo to give a brown solid. The solid was triturated with methanol and filtered, washing with methanol. The product, 2-chloro-5-[3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (LXXI) (1.005 g, 2.660 mmol, 69.6% yield), was collected as an off-white solid. The impure fractions were combined and worked up as described above to give a second batch of product, 2-chloro-5-[3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (LXXX) (444 mg, 1.175 mmol, 30.7% yield) as an off-white solid. 16 H 14 ESIMS observed m / z 378.1 (M+H) for ClF2N7.

[0338] Step 2 2-chloro-5-[3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (LXXX) (150 mg, 0.4 mmol), tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (LXXXI) (commercially available from Advanced ChemBlocks Inc.) (104 mg, 0.48 mmol), BrettPhos Pd G3 (30 mg, 0.03 mmol), BrettPhos (20 mg, 0.04 mmol), and NaO t Bu (116 mg, 1.21 mmol) was added to dry 1,4-dioxane (3 mL) in a microwave vial. The suspension was purged with Ar for 5 min, and then the reaction was microwaved to 100 °C for 10 min. The reaction mixture was reduced in vacuo and purified by column chromatography (0 → 100% EtOAc / hexanes, then 0 → 3% 7.0 M NH in MeOH / CHCl). The product was further purified by reverse-phase column chromatography (10 → 70% MeCN / H2O in 0.1% formic acid). The appropriate fractions were collected, neutralized with saturated aqueous NaHCO3, and extracted with DCM (x2). The combined organic phases were dried (MgSO4) and reduced in vacuo to give tert-butyl (3S,4R)-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-fluoropiperidine-1-carboxylate (LXXXII) (167 mg, 0.298 mmol, 75.2% yield) as a pale yellow solid. 26 H 32 ESIMS observed m / z 560.3 (M+H) for F3N9O2.

[0339] Step 3 To a solution of tert-butyl (3S,4R)-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-fluoropiperidine-1-carboxylate (LXXXII) (167 mg, 0.3 mmol) in DCE (3 mL) was added TFA (1 mL, 12.98 mmol). The reaction was stirred at room temperature for 15 minutes. The reaction mixture turned emerald green. The solvent was blown dry and excess TFA was removed under high vacuum to give the crude intermediate (3S,4R)-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-ium 2,2,2-trifluoroacetate (LXXXIII) (171 mg, 0.298 mmol, 99.9% yield assumed quantitative) as a green semi-solid, which was used without purification. 21 H 24 ESIMS observed m / z 460.25 (M+H) for F3N9.

[0340] Step 4 5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N2-((3S,4R)-3-fluoropiperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXXIII) (103 mg, 0.22 mmol) was dissolved in EtOH (2 mL), HOAc (26 μL, 0.45 mmol) and oxetan-3-one (LXXXIV) (20 μL, 0.34 mmol) were added, and the reaction was stirred for 10 min. NaBH(OAc)3 (71 mg, 0.34 mmol) was added, and the reaction was stirred at 65 °C for 30 min. The reaction mixture was loaded onto Celite® and purified by column chromatography (7.0 M NH with 0 to 2% retention in MeOH / CHCl). The appropriate fractions were reduced in vacuo to give a white solid. The solid was triturated with MeOH, filtered, and washed with minimal MeOH to give 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 4-Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (210) (64 mg, 0.124 mmol, 55.4% yield) was obtained as a white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 - 1.76 (1 H, m), 1.81 - 1.91 (1 H, m), 1.95 - 2.03 (1 H, m), 2.06 - 2.20 (1 H, m), 2.62 (3 H, s), 2.75 (1 H, br d, J=9.58 Hz), 2.92 - 3.02 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.72 - 3.89 (1 H, m), 4.43 (2 H, dt, J=29.30, 6.16 Hz), 4.54 (2H, td, J=6.50, 3.15 Hz), 4.72 - 4.83 (2 H, m), 4.90 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 C 24 H 28 ESIMS observed m / z 516.3 (M+1) for F3N9O.

[0341] Example 2. N 2 -((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4The preparation of 1-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (219) and 1-((1R,5S,6r)-6-((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-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one (220) is shown in Scheme 16 below. [ka]

[0342] Step 1 2-Chloro-5-[3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (LXXX) (100 mg, 0.26 mmol), tert-butyl (1R,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (LXXXV) (commercially available from Combi-Blocks Inc.) (74 mg, 0.37 mmol), NaO in 1,4-dioxane (2 mL). t A mixture of Bu (70 mg, 0.73 mmol), BrettPhos Pd G3 (20 mg, 0.02 mmol), and BrettPhos (14 mg, 0.03 mmol) was purged with N2. The reaction was heated at 100 °C for 10 min under microwave irradiation. The reaction mixture was filtered and concentrated, and the crude product was purified by ISCO (0 to 10% MeOH / CHCl3). The fractions were collected and concentrated under reduced pressure, and the residue was triturated with MTBE. The resulting solid was filtered and dried under high vacuum to give tert-butyl (1R,5S,6r)-6-((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-azabicyclo[3.1.0]hexane-3-carboxylate (LXXXVI) (132 mg, 0.245 mmol, 92.4% yield) as an off-white solid. 26H 31 ESIMS observed m / z 540.3 (M+H) for F2N9O2.

[0343] Step 2 To a stirred solution of tert-butyl (1R,5S,6r)-6-((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-azabicyclo[3.1.0]hexane-3-carboxylate (LXXXVI) (130 mg, 0.24 mmol) in DCM (2 mL) was added TFA (1 mL, 12.98 mmol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, and the crude product was purified by ISCO (1-10% 7N NH3MeOH / CHCl3). Pure fractions were collected, concentrated under reduced pressure, dried under high vacuum, and purified with N 2 -((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 4-Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (219) (65 mg, 0.148 mmol, 61.4% yield) was obtained as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.64 (2 H, br d, J=7.12 Hz), 2.62 (3 H, s), 2.88 - 2.92 (1 H, m), 2.92 - 2.97 (2 H, m), 2.99 - 3.04 (2 H, m), 3.11 (3 H, d, J=4.65 Hz), 4.71 - 4.83 (2 H, m), 6.04 (1 H, d, J=4.11 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=2.74 Hz), 7.39 (1 H, d, J=2.46 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.93 (1 H, br q, J=4.65 Hz);C21 H 23 ESIMS observed m / z 440.2 (M+1) for F2N9.

[0344] Step 3 To a solution of HOAc (5.52 μL, 0.1 mmol) and HATU (34 mg, 0.09 mmol) in DMF (200 μL) was added DIPEA (38 μL, 0.22 mmol). The mixture was stirred for 5 min. N in DMF (300 μL) 2 -((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 30 mg (0.07 mmol) of 2,1-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (219) was added, and the reaction mixture was stirred at room temperature for 16 h. Water (10 mL) was added, and the solution was extracted with EtOAc. The organics were separated, concentrated, absorbed onto silica gel, and purified by preparative TLC (4% MeOH / CHCl) to afford 1-((1R,5S,6r)-6-((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-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one (220) (24 mg, 0.050 mmol, 73.0% yield) as an off-white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.83 (3 H, s), 1.84 - 1.88 (1 H, m), 1.89 - 1.95 (1 H, m), 2.62 (3 H, s), 2.69 (1 H, td, J=6.91, 1.23 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.40 - 3.49 (2 H, m), 3.54 (1 H, d, J=10.40 Hz), 3.67 (1 H, dd, J=10.40, 5.48 Hz), 4.72 - 4.83 (2 H, m), 6.23 (1 H, s), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.40 (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), 10.94 (1 H, q, J=4.56 Hz);C 23 H 25 ESIMS observed m / z 482.2 (M+1) for F2N9O.

[0345] Example 3 The preparation of N-(trans-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)cyclohexyl)acetamide (187) is shown in Scheme 17 below. [ka]

[0346] Step 1 2,5-Dichloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XXII) (100 mg, 0.46 mmol) dissolved in dry 1,4-dioxane (2 mL), NaO tBu (200 mg, 2.08 mmol), BrettPhos Pd G3 (34 mg, 0.04 mmol), BrettPhos (25 mg, 0.05 mmol), and N-(trans-4-aminocyclohexyl)acetamide (LXXV) (124 mg, 0.64 mmol) were added to a microwave vessel and purged with Ar for 5 minutes. The reaction was microwaved at 100 °C for 10 minutes. The reaction mixture was cooled and added to a mixture of saturated aqueous NH4Cl and DCM. The organic layer was separated, the aqueous layer extracted with DCM (x3), and the combined organic layers were dried (MgSO4) and reduced in vacuo to give an orange oil. The crude product was purified by column chromatography (0% 7.0 M NH in MeOH / CHCl) to give N-(trans-4-((5-chloro-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide (LXXXVII) (87 mg, 0.258 mmol, 56.1% yield) as a beige solid. 15 H 21 ESIMS observed m / z 337.2 (M+H) for ClNO.

[0347] Step 2 N-(trans-4-((5-chloro-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide (LXXXVII) (87 mg, 0.26 mmol), [3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]boronic acid (LXXIX) (82 mg, 0.34 mmol), Pd(OAc) (7 mg, 0.03 mmol), and XPhos (14 mg, 0.03 mmol) were dissolved in dry 1,4-dioxane (1.5 mL) and added to a microwave vial. The reaction mixture was purged with Ar for 5 min. 2 M aqueous KPO (388 μL, 0.78 mmol) was added and purged with Ar for an additional 2 min. The reaction was heated to 90 °C for 1 h. The reaction mixture was reduced in vacuo and purified by reverse-phase column chromatography (C18 column) (0→80% MeCN / HO in 0.1% formic acid). The corresponding fractions were lyophilized to give N-(trans-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)cyclohexyl)acetamide (187) (22 mg, 0.044 mmol, 17.1% yield) as an off-white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.18 - 1.27 (2 H, m), 1.27 - 1.37 (2 H, m), 1.78 (3 H, s), 1.79 - 1.83 (2 H, m), 1.97 (2 H, br d, J=10.68 Hz), 2.62 (3 H, s), 3.10 (3 H, d, J=4.65 Hz), 3.44 - 3.60 (2 H, m), 4.72 - 4.83 (2 H, m), 5.90 (1 H, d, J=8.49 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), C 24 H 29 ESIMS observed m / z 498.3 (M+1) for F2N9O.

[0348] Example 4. N 2 -((3S,4R)-1-cyclopropyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 The preparation of -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (???) is shown in Scheme 18 below. [ka]

[0349] Step 1 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N in dry DCE (0.9 mL) and ethanol (0.1 mL) 2 -((3S,4R)-3-fluoropiperidin-4-yl)-N 4To a suspension of 30 mg (0.06 mmol) of 1-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXXIII) and two beads of 3 Å MS was added HOAc (7 μL, 0.12 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (commercially available from AmBeed, Inc.) (27 μL, 0.13 mmol). The reaction was stirred at 65° C. for 1 h. The reaction mixture was cooled to room temperature, NaBHCN (21 mg, 0.33 mmol) was added, and the reaction was stirred for 10 min. LCMS indicated starting material remained. Additional (1-ethoxycyclopropoxy)trimethylsilane (27 μL, 0.13 mmol) was added, and the reaction was heated at 65° C. for 30 min. The reaction mixture was cooled, and additional NaBHCN (21 mg, 0.33 mmol) was added, and the reaction was stirred for 10 minutes. LCMS confirmed the reaction was complete. The reaction mixture was loaded onto Celite®, and the product was purified by column chromatography (0->4% MeOH / CHCl). The product was further purified by HPLC (0->40% MeCN / H2O in 0.1% formic acid) and, after lyophilization, was purified by N 2 -((3S,4R)-1-cyclopropyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 4-Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (377) (14 mg, 0.028 mmol, 42.9% yield) was obtained as a pale yellow fluffy solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 0.20 - 0.29 (1 H, m), 0.30 - 0.37 (1 H, m), 0.39 - 0.49 (2 H, m), 1.61 - 1.72 (2 H, m), 1.79 (1 H, qd, J=12.32, 3.83 Hz), 2.37 (1 H, dd, J=45.80, 13.15 Hz), 2.33 - 2.38 (1 H, m), 2.62 (3 H, s), 2.95 (1 H, br d, J=11.77 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.14 - 3.24 (1 H, m), 3.70 - 3.88 (1 H, m), 4.78 (2 H, td, J=16.08, 2.60 Hz), 4.87 (1 H, d, J=50.20 Hz), 5.87 (1 H, br d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 C 24 H 28 ESIMS observed m / z 500.3 (M+1) for F3N9.

[0350] Example 5. N 2 -((3S,4R)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 The preparation of -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (???) is shown in Scheme 19 below. [ka]

[0351] Step 1 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoropiperidin-4-yl)-N 4 1-Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXXIII) (65 mg, 0.14 mmol), K2CO3 (33 mg, 0.24 mmol), and KI (30 mg, 0.18 mmol) were suspended in DMF (1 mL). 3-Bromo-1,1-difluorocyclobutane (35 mg, 0.2 mmol) was added and stirred at 115 °C for 16 h. The reaction mixture was loaded onto Celite®, and the product was purified by column chromatography (0 → 4% MeOH / CHCl3). The product was further purified by HPLC (0 → 40% MeCN / HO in 0.1% formic acid) and, after lyophilization, N 2 -((3S,4R)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 4-Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (380) (6 mg, 0.011 mmol, 7.7% yield) was obtained as an off-white fluffy solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.66 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.70 Hz), 1.97 - 2.08 (1 H, m), 2.16 (1 H, dd, J=37.55, 12.32 Hz), 2.28 - 2.47 (2 H, m), 2.62 (3 H, s), 2.64 - 2.77 (3 H, m), 2.83 (1 H, br d, J=10.13 Hz), 3.02 - 3.09 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.73 - 3.89 (1 H, m), 4.78 (2 H, td, J=15.74, 2.19 Hz), 4.91 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 C 25 H 28 ESIMS observed m / z 550.3 (M+1) for F5N9.

[0352] Example 6 The preparation of (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (986) is shown in Scheme 20 below. [ka]

[0353] Step 1 2,5-Dichloropyrrolo[2,1-f][1,2,4]triazin-4-amine (XXI) (100 mg, 0.49 mmol), di-tert-butyl decarbonate (162 mg, 0.74 mmol), and DMAP (8 mg, 0.07 mmol) were dissolved in DCM (4 mL). TEA (103 μL, 0.74 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was loaded onto Celite® and purified by silica gel column chromatography (EtOAc / hexane = 0 → 10) to afford tert-butyl (2,5-dichloropyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (LXXVIII) (107 mg, 0.353 mmol, 71.7% yield) as an off-white solid. 11 H 12 ESIMS observed m / z 303.05 (M+H) for Cl2N4O2.

[0354] Step 2 tert-Butyl (2,5-dichloropyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (LXXXVIII) (200 mg, 0.66 mmol), LiHMDS (1.0 M in THF) (1.26 mL, 1.26 mmol), BrettPhos Pd G3 (30 mg, 0.03 mmol), BrettPhos (54 mg, 0.1 mmol), and trans-4-amino-1-methylcyclohexanol (LXXXIX) (94 mg, 0.73 mmol) were added to a microwave vial. Dry 1,4-dioxane (4 mL) was added, and the suspension was purged with Ar for 5 minutes. The reaction was heated at 50 °C for 45 minutes. The reaction mixture was loaded onto Celite® and purified by silica gel column chromatography (EtOAc / hexane = 0 → 45%) to give tert-butyl (5-chloro-2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (XC) (81 mg, 0.205 mmol, 31.0% yield) as an off-white solid. 18 H 26 ESIMS observed m / z 396.2 (M+1) for ClN5O3.

[0355] Step 3 tert-Butyl (5-chloro-2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (XC) (27 mg, 0.07 mmol), [3-(2,2-difluoroethyl)imidazo[4,5-b]pyridin-5-yl]boronic acid (XCI) (22 mg, 0.1 mmol), Pd(OAc) (1.6 mg, 0.01 mmol), and XPhos (5.1 mg, 0.01 mmol) were suspended in dry 1,4-dioxane (1 mL). 2 M aqueous KPO (104.1 μL, 0.21 mmol) was then added, and the reaction was sonicated and purged with Ar for 5 min. The reaction was heated at 100 °C for 45 min. To this mixture, DCE (2 mL) and then TFA (1 mL) were added and stirred at room temperature for 16 hours. The reaction solvent was blown off with a stream of N2, and the residue was purified by silica gel column chromatography (MeOH / CHCl3 = 0 → 10%). The product-containing fractions were stripped of solvent and repurified by C18 preparative HPLC (MeCN / water (0.1% formic acid) = 0 → 50%). The product-containing fractions were frozen and lyophilized to give (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (986) (8 mg, 0.018 mmol, 26.5% yield) as a white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.34 - 1.46 (4 H, m), 1.51 - 1.62 (2 H, m), 1.77 - 1.89 (2 H, m), 3.62 (1 H, dt, J=8.08, 3.90 Hz), 4.20 (1 H, br s), 4.74 (2 H, td, J=16.50, 2.33 Hz), 5.77 (1 H, d, J=8.21 Hz), 6.47 (1 H, tt, J=54.45, 2.75 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=3.01 Hz), 7.45 (1 H, br s), 7.87 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.49 Hz), 8.39 (1 H, s), 10.49 (1 H, br s);C 21 H 24 ESIMS observed m / z 443.2 (M+1) for F2N8O.

[0356] The following compounds were prepared according to the procedures described in Schemes 1-20 above. [ka]

[0357] trans-4-((4-amino-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 1.

[0358] Beige solid (1.3 mg, 0.003 mmol, 1.0% yield). 1H NMR (499 MHz, METHANOL-d4) δ ppm 1.27 (3 H, s), 1.44 - 1.55 (2 H, m), 1.56 - 1.65 (2 H, m), 1.67 - 1.76 (2 H, m), 1.98 - 2.08 (2 H, m), 3.15 - 3.23 (1 H, m), 3.73 (1 H, tt, J=8.73, 4.14 Hz), 4.60 (2 H, br s), 6.57 (1 H, d, J=2.46 Hz), 6.62 (1 H, d, J=1.64 Hz), 7.02 (1 H, dd, J=7.12, 1.92 Hz), 7.39 (1 H, d, J=2.46 Hz), 7.68 (1 H, d, J=1.09 Hz), 7.97 (1 H, d, J=2.46 Hz), 8.57 (1 H, d, J=7.39 Hz) 20 H 23 ESIMS observed m / z 378.2 (M+1) for N7O. [ka]

[0359] N 4 -methyl-N 2 -(1-(oxetan-3-yl)piperidin-4-yl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 2.

[0360] Off-white solid (34 mg, 0.081 mmol, 50.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.46 - 1.57 (2 H, m), 1.80 - 1.94 (4 H, m), 2.67 (2 H, br d, J=11.22 Hz), 2.86 (3 H, d, J=4.65 Hz), 3.35 - 3.42 (1 H, m), 3.52 - 3.63 (1 H, m), 4.42 (2 H, t, J=5.89 Hz), 4.53 (2 H, t, J=6.43 Hz), 6.02 (1 H, br d, J=8.21 Hz), 6.26 (1 H, br q, J=4.65 Hz), 6.48 (1 H, d, J=2.46 Hz), 6.59 (1 H, d, J=1.64 Hz), 6.89 (1 H, dd, J=7.39, 1.92 Hz), 7.39 (1 H, d, J=2.74 Hz), 7.61 (1 H, d, J=1.09 Hz), 7.99 (1 H, d, J=2.19 Hz), 8.66 (1 H, d, J=7.39 Hz);C 22 H 26 ESIMS observed m / z 419.3 (M+1) for NO. [ka]

[0361] trans-1-methyl-4-((4-(methylamino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol 20.

[0362] Beige solid (24 mg, 0.061 mmol, 12.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.37 - 1.49 (4 H, m), 1.54 - 1.64 (2 H, m), 1.79 - 1.90 (2 H, m), 3.10 (3 H, d, J=4.65 Hz), 3.63 (1 H, br s), 4.21 (1 H, s), 6.05 (1 H, d, J=7.94 Hz), 6.69 (1 H, d, J=1.92 Hz), 7.30 (1 H, d, J=3.01 Hz), 7.42 (1 H, d, J=3.01 Hz), 7.54 (1 H, d, J=7.67 Hz), 8.15 (1 H, d, J=2.19 Hz), 9.01 (1 H, d, J=7.67 Hz), 11.43 (1 H, q, J=4.65 Hz);C 20 H 24 ESIMS observed value m / z 393.25 (M+1) for NO. [ka]

[0363] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-N 4 -Methyl-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (44).

[0364] Yellow fluffy solid (13 mg, 0.031 mmol, 83.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.73 - 1.88 (2 H, m), 2.16 (1 H, br s), 2.26 (3 H, s), 2.31 - 2.45 (1 H, m), 2.78 (1 H, br d, J=10.40 Hz), 3.05 (1 H, br s), 3.13 (3 H, d, J=4.38 Hz), 4.16 - 4.32 (1 H, m), 6.34 (1 H, br d, J=9.31 Hz), 6.71 (1 H, d, J=2.19 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 7.56 (1 H, d, J=7.67 Hz), 8.17 (1 H, d, J=1.92 Hz), 9.03 (1 H, d, J=7.67 Hz), 11.53 (1 H, q, J=4.65 Hz);C 19 H 21 ESIMS observed m / z 414.2 (M+1) for F2N9. [ka]

[0365] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -Methyl-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (46).

[0366] Yellow fluffy solid (14 mg, 0.031 mmol, 64.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.74 - 1.83 (1 H, m), 1.84 - 1.91 (1 H, m), 2.14 (1 H, br t, J=10.68 Hz), 2.37 (1 H, ddd, J=27.15, 11.80, 1.35 Hz), 2.75 (1 H, br d, J=11.23 Hz), 2.95 - 3.06 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.59 (1 H, quin, J=6.30 Hz), 4.21 - 4.37 (1 H, m), 4.44 (2 H, dt, J=14.65, 6.09 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 6.42 (1 H, d, J=9.58 Hz), 6.72 (1 H, d, J=2.19 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 7.56 (1 H, d, J=7.67 Hz), 8.17 (1 H, d, J=2.19 Hz), 9.03 (1 H, d, J=7.67 Hz), 11.54 (1 H, q, J=4.56 Hz);C 21 H 23 ESIMS observed m / z 456.2 (M+1) for F2N9O. [ka]

[0367] trans-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (58).

[0368] Beige solid (47 mg, 0.120 mmol, 23.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.36 - 1.48 (4 H, m), 1.53 - 1.63 (2 H, m), 1.79 - 1.90 (2 H, m), 2.84 (3 H, d, J=4.65 Hz), 3.54 - 3.66 (1 H, m), 4.20 (1 H, s), 5.83 (1 H, d, J=8.21 Hz), 6.21 (1 H, q, J=4.47 Hz), 6.41 (1 H, d, J=2.46 Hz), 7.23 (1 H, dd, J=9.31, 1.64 Hz), 7.39 (1 H, d, J=2.46 Hz), 7.58 (1 H, br d, J=9.03 Hz), 7.58 (1 H, s), 7.94 (1 H, s), 8.53 (1 H, s);C 21 H 25 ESIMS observed m / z 392.3 (M+1) for N7O. [ka]

[0369] 5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N 4 -methyl-N 2 -(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (114).

[0370] Off-white solid (8 mg, 0.017 mmol, 11.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.43 - 1.54 (2 H, m), 1.57 (6 H, d, J=6.84 Hz), 1.81 - 1.93 (3 H, m), 1.96 - 2.03 (1 H, m), 2.63 (3 H, s), 2.67 (2 H, br dd, J=6.57, 2.46 Hz), 2.82 (3 H, d, J=4.65 Hz), 3.34 - 3.42 (1 H, m), 3.53 - 3.64 (1 H, m), 4.42 (2 H, br s), 4.53 (2 H, br s), 4.78 (1 H, quin, J=6.98 Hz), 5.98 (1 H, br d, J=7.67 Hz), 6.06 (1 H, br d, J=1.37 Hz), 6.48 (1 H, s), 7.40 (1 H, d, J=2.46 Hz), 7.99 (1 H, d, J=1.92 Hz), 8.37 (1 H, d, J=1.92 Hz);C 25 H 33 ESIMS observed m / z 476.3 (M+1) for NO. [ka]

[0371] trans-4-((5-(3-isopropyl-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-1-ol (132).

[0372] Off-white solid (62 mg, 0.138 mmol, 73.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.36 - 1.50 (4 H, m), 1.54 - 1.62 (2 H, m), 1.67 (6 H, d, J=7.12 Hz), 1.81 - 1.90 (2 H, m), 2.65 (3 H, s), 3.12 (3 H, d, J=4.65 Hz), 3.62 (1 H, br s), 4.21 (1 H, s), 4.92 (1 H, dt, J=14.03, 7.08 Hz), 5.87 (1 H, d, J=8.21 Hz), 7.01 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, C 24 H 32 ESIMS observed m / z 449.3 (M+1) for NO. [ka]

[0373] trans-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol (170).

[0374] Off-white solid (13 mg, 0.029 mmol, 16.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.27 (3 H, s), 1.92 - 2.00 (2 H, m), 2.25 - 2.33 (2 H, m), 2.63 (3 H, s), 2.82 (3 H, d, J=4.65 Hz), 4.25 (1 H, sxt, J=7.45 Hz), 4.73 (1 H, s), 4.77 - 4.90 (2 H, m), 5.95 (1 H, q, J=4.38 Hz), 6.32 (1 H, d, J=7.12 Hz), 6.47 (1 H, tt, J=54.60, 3.00 Hz), 6.44 (1 H, d, J=2.46 Hz), 7.40 (1 H, d, J=2.46 Hz), 7.98 (1 H, d, J=1.92 Hz), 8.40 (1 H, d, J=1.92 Hz);C 21 H 24 ESIMS observed m / z 443.25 (M+1) for F2N8O. [ka]

[0375] trans-4-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (171).

[0376] Beige solid (7 mg, 0.015 mmol, 8.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.38 - 1.49 (4 H, m), 1.54 - 1.62 (2 H, m), 1.80 - 1.88 (2 H, m), 2.63 (4 H, s), 2.82 (3 H, d, J=4.65 Hz), 3.62 (1 H, br d, J=4.38 Hz), 4.20 (1 H, s), 4.77 - 4.89 (2 H, m), 5.83 (1 H, d, J=8.21 Hz), 5.94 (1 H, q, J=4.65 Hz), 6.47 (1 H, tt, J=54.60, 3.00 Hz), 6.44 (1 C 23 H 28 ESIMS observed m / z 471.3 (M+1) for F2N8O. [ka]

[0377] 2-(cis-3-((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)cyclobutoxy)ethan-1-ol (172).

[0378] White solid (35 mg, 0.074 mmol, 56.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.84 (2 H, qd, J=8.49, 2.74 Hz), 2.57 - 2.61 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.29 - 3.33 (2 H, m), 3.48 (2 H, q, J=5.38 Hz), 3.69 (1 H, quin, J=7.19 Hz), 3.78 (1 H, dq, J=16.02, 8.08 Hz), 4.59 (1 H, t, J=5.61 Hz), 4.72 - 4.82 (2 H, m), 6.42 (1 H, d, J=7.67 Hz), 6.63 (1 H, tt, J=54.35, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.34 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.92 (1 H, q, J=4.47 Hz);C 22 H 26 ESIMS observed m / z 473.2 (M+1) for F2N8O2. [ka]

[0379] cis-3-((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)-1-methylcyclobutan-1-ol (174).

[0380] Beige solid (30 mg, 0.068 mmol, 51.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.25 (3 H, s), 1.98 (2 H, td, J=8.90, 2.19 Hz), 2.28 - 2.36 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.93 Hz), 3.72 (1 H, sxt, J=7.78 Hz), 4.77 (2 H, td, J=16.00, 2.20 Hz), 4.86 (1 H, s), 6.28 (1 H, d, J=6.84 Hz), 6.63 (1 H, tt, J=54.60, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.90 (1 H, q, J=4.56 Hz);C 21 H 24 ESIMS observed m / z 443.2 (M+1) for F2N8O. [ka]

[0381] N 2 -(4,4-difluorocyclohexyl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (182).

[0382] Off-white solid (15 mg, 0.032 mmol, 19.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.54 - 1.69 (2 H, m), 1.83 - 2.01 (4 H, m), 2.01 - 2.14 (2 H, m), 2.62 (3 H, s), 3.12 (3 H, d, J=4.65 Hz), 3.70 - 3.84 (1 H, m), 4.71 - 4.84 (2 H, m), 6.15 (1 H, d, J=7.67 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.09 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.84 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.92 (1 H, q, J=4.56 Hz);C 22 H 24 ESIMS observed m / z 477.2 (M+1) for F4N8. [ka]

[0383] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(cis-4-methoxycyclohexyl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (183).

[0384] White solid (6 mg, 0.013 mmol, 9.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.52 (2 H, m), 1.53 - 1.62 (2 H, m), 1.63 - 1.71 (2 H, m), 1.79 - 1.88 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.22 (3 H, s), 3.29 - 3.32 (1 H, m), 3.57 - 3.68 (1 H, m), 4.71 - 4.83 (2 H, m), 5.90 (1 H, d, J=7.94 Hz), 6.63 (1 H, tt, J=54.20, 3.00 Hz), 7.07 (1 H, d, C 23 H 28 ESIMS observed m / z 471.3 (M+1) for F2N8O. [ka]

[0385] 2-((cis-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)cyclohexyl)oxy)ethan-1-ol (184).

[0386] Off-white solid (16 mg, 0.03 mmol, 24.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.55 (2 H, m), 1.58 - 1.73 (4 H, m), 1.76 - 1.87 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.39 (2 H, t, J=5.50 Hz), 3.46 (1 H, br s), 3.50 (2 H, q, J=5.48 Hz), 3.56 - 3.67 (1 H, m), 4.51 (1 H, t, J=5.61 Hz), 4.70 - 4.82 (2 H, m), 5.86 (1 H, d, J=7.67 Hz), 6.63 (1 H, tt, J=54.30, 2.75 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=2.74 Hz), 7.83 (1 H, d, J=8.76 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.88 (1 H, br q, J=4.65 Hz);C 24 H 30 ESIMS observed m / z 501.3 (M+1) for F2N8O2. [ka]

[0387] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(cis-4-(2-methoxyethoxy)cyclohexyl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (185).

[0388] White solid (29 mg, 0.056 mmol, 30.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.54 (2 H, m), 1.57 - 1.72 (4 H, m), 1.75 - 1.87 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.27 (3 H, s), 3.43 - 3.47 (3 H, m), 3.47 - 3.52 (2 H, m), 3.56 - 3.68 (1 H, m), 4.71 - 4.84 (2 H, m), 5.90 (1 H, d, J=7.67 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.07 (1 H, d, C 25 H 32 ESIMS observed m / z 515.3 (M+1) for F2N8O2. [ka]

[0389] N-(cis-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)cyclohexyl)acetamide (186).

[0390] Off-white solid (17 mg, 0.034 mmol, 74.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.49 - 1.58 (2 H, m), 1.58 - 1.69 (4 H, m), 1.71 - 1.79 (2 H, m), 1.81 (3 H, s), 2.62 (3 H, s), 3.12 (3 H, d, J=4.65 Hz), 3.29 - 3.32 (1 H, m), 3.68 (2 H, br s), 4.72 - 4.84 (2 H, m), 5.72 (1 H, d, J=6.57 Hz), 6.63 (1 H, tt, J=54.30, 2.75 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, C 24 H 29 ESIMS observed m / z 498.3 (M+1) for F2N9O. [ka]

[0391] N-(trans-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)cyclohexyl)acetamide (187).

[0392] Off-white solid (22 mg, 0.044 mmol, 17.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.18 - 1.27 (2 H, m), 1.27 - 1.37 (2 H, m), 1.78 (3 H, s), 1.79 - 1.83 (2 H, m), 1.97 (2 H, br d, J=10.68 Hz), 2.62 (3 H, s), 3.10 (3 H, d, J=4.65 Hz), 3.44 - 3.60 (2 H, m), 4.72 - 4.83 (2 H, m), 5.90 (1 H, d, J=8.49 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), C 24 H 29 ESIMS observed m / z 498.3 (M+1) for F2N9O. [ka]

[0393] cis-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)-1-methylcyclohexan-1-ol (188).

[0394] Beige solid (27 mg, 0.057 mmol, 43.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.12 (3 H, s), 1.35 (2 H, td, J=13.14, 3.83 Hz), 1.57 (2 H, br d, J=12.05 Hz), 1.59 - 1.66 (2 H, m), 1.66 - 1.72 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.45 - 3.56 (1 H, m), 3.98 (1 H, s), 4.70 - 4.83 (2 H, m), 5.81 (1 H, d, J=7.94 Hz), 6.63 (1 H, tt, J=54.60, 3.00 C 23 H 28 ESIMS observed m / z 471.3 (M+1) for F2N8O. [ka]

[0395] trans-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)-1-methylcyclohexan-1-ol (189).

[0396] Off-white solid (20 mg, 0.043 mmol, 26.3% yield). 1H NMR (499 MHz, METHANOL-d4) δ ppm 1.28 (3 H, s), 1.46 - 1.56 (2 H, m), 1.57 - 1.66 (2 H, m), 1.69 - 1.77 (2 H, m), 2.04 (2 H, dq, J=13.18, 4.19 Hz), 2.68 (3 H, s), 3.14 - 3.19 (3 ​​H, m), 3.70 - 3.80 (1 H, m), 4.59 (1 H, s), 4.75 (2 H, td, J=15.26, 3.15 Hz), 5.49 (1 H, s), 6.44 (1 H, tt, J=54.60, 3.05 Hz), 7.00 (1 H, d, J=3.01 Hz), 7.28 (1 H, d, J=2.74 Hz), 7.83 (1 H, d, J=8.76 Hz), 7.94 (1 H, d, J=8.49 Hz), 10.87 - 10.94 (1 H, m); 23 H 28 ESIMS observed m / z 471.3 (M+1) for F2N8O. [ka]

[0397] N 2 -(adamantan-1-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (196).

[0398] Off-white solid (25 mg, 0.062 mmol, 24.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.66 (6 H, br s), 2.06 (3 H, br s), 2.09 (6 H, s), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 4.77 (2 H, td, J=15.95, 2.33 Hz), 5.36 (1 H, s), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=2.74 Hz), 7.32 (1 H, d, J=2.74 Hz), 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.84 (1H, q, J=4.29 Hz);C 26 H 30 ESIMS observed m / z 493.3 (M+1) for F2N8. [ka]

[0399] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (197).

[0400] White solid (34 mg, 0.074 mmol, 43.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.31 (3 H, s), 2.53 - 2.59 (2 H, m), 2.62 (3 H, s), 2.91 (1 H, t, J=8.08 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.11 - 3.22 (1 H, m), 4.22 - 4.36 (1 H, m), 4.78 (2 H, td, J=16.20, 2.75 Hz), 5.08 - 5.26 (1 H, m), 6.05 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.60, 3.00 Hz), 7.12 (1 H, d, C 21 H 24 ESIMS observed m / z 460.25 (M+1) for F3N9. [ka]

[0401] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (198).

[0402] White solid (41 mg, 0.089 mmol, 59.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.31 (3 H, s), 2.56 (1 H, br d, J=7.67 Hz), 2.62 (3 H, s), 2.91 (1 H, t, J=8.21 Hz), 3.09 - 3.22 (2 H, m), 3.12 (3 H, d, J=4.65 Hz), 4.22 - 4.36 (1 H, m), 4.78 (2 H, td, J=16.18, 2.75 Hz), 5.08 - 5.25 (1 H, m), 6.05 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 C 21 H 24 ESIMS observed m / z 460.2 (M+1) for F3N9. [ka]

[0403] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (199).

[0404] Off-white solid (64 mg, 0.128 mmol, 41.5% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1H NMR (499 MHz, DMSO-d6) δ ppm 2.59 - 2.66 (1 H, m), 2.62 (3 H, s), 2.74 (1 H, ddd, J=30.45, 12.05, 1.37 Hz), 3.00 (1 H, t, J=8.21 Hz), 3.09 - 3.24 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.75 - 3.82 (1 H, m), 4.25 - 4.39 (1 H, m), 4.46 (2 H, t, J=6.02 Hz), 4.59 (2 H, t, J=6.57 Hz), 4.78 (2 H, td, J=15.95, 2.60 Hz), 5.20 (1 H, dtd, J=55.95, 4.52, 4.52, 1.37 Hz), 6.12 (1 H, d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 H, d, J=3.01 C 23 H 26 ESIMS observed m / z 502.3 (M+1) for F3N9O. [ka]

[0405] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (200).

[0406] Off-white solid (72 mg, 0.144 mmol, 49.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.59 - 2.66 (1 H, m), 2.62 (3 H, s), 2.74 (1 H, ddd, J=30.45, 12.05, 1.37 Hz), 3.00 (1 H, t, J=8.21 Hz), 3.08 - 3.25 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.74 - 3.83 (1 H, m), 4.24 - 4.38 (1 H, m), 4.46 (2 H, t, J=5.89 Hz), 4.59 (2 H, t, J=6.57 Hz), 4.78 (2 H, td, J=15.88, 2.46 Hz), 5.20 (1 H, dtd, J=55.95, 4.52, 4.52, 1.37 Hz), 6.12 (1 H, d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 H, d, J=3.01 C 23 H 26 ESIMS observed m / z 502.3 (M+1) for F3N9O. [ka]

[0407] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-(2,2-difluoroethyl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (201).

[0408] White solid (43 mg, 0.085 mmol, 53.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.57 (2 H, m), 1.87 (2 H, br d, J=10.13 Hz), 2.20 - 2.28 (2 H, m), 2.62 (3 H, s), 2.71 (2 H, td, J=15.74, 4.38 Hz), 2.89 (2 H, br d, J=11.77 Hz), 3.11 (3 H, d, J=4.65 Hz), 3.51 - 3.62 (1 H, m), 4.72 - 4.83 (2 H, m), 5.98 (1 H, d, J=8.21 Hz), 6.13 (1 H, tt, J=55.95, 4.35 Hz), 6.63 (1 H, tt, J=54.60, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.91 (1 H, q, J=4.65 Hz);C 23 H 27 ESIMS observed m / z 506.3 (M+1) for F4N9. [ka]

[0409] 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)piperidin-1-yl)ethan-1-one (202).

[0410] Beige solid (20 mg, 0.041 mmol, 15.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.78 - 1.86 (1 H, m), 1.87 - 1.97 (1 H, m), 2.35 - 2.42 (1 H, m), 2.42 - 2.48 (1 H, m), 2.50 (3 H, s), 3.12 (3 H, s), 3.17 - 3.27 (1 H, m), 3.61 (3 H, d, J=4.93 Hz), 4.11 (1 H, dtd, J=13.21, 6.54, 6.54, 3.83 Hz), 4.26 - 4.34 (2 H, m), 4.77 (1 H, br d, J=14.24 Hz), 5.27 (2 H, td, J=15.88, 2.46 Hz), 6.60 (1 H, d, J=8.21 Hz), 7.13 (1 H, tt, J=54.30, 3.00 Hz), 7.59 (1 H, d, J=2.74 Hz), 7.87 (1 H, d, J=3.01 Hz), 8.34 (1 H, d, J=8.76 Hz), 8.50 (1 H, d, J=8.49 Hz), 11.42 (1 H, q, J=4.29 Hz);C 23 H 27 ESIMS observed m / z 484.3 (M+1) for F2N9O. [ka]

[0411] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (203).

[0412] Off-white solid (51 mg, 0.103 mmol, 49.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.57 (2 H, m), 1.81 - 1.87 (2 H, m), 1.89 (2 H, br d, J=11.23 Hz), 2.62 (3 H, s), 2.67 (2 H, br d, J=10.95 Hz), 3.11 (3 H, d, J=4.65 Hz), 3.35 - 3.41 (1 H, m), 3.52 - 3.64 (1 H, m), 4.42 (2 H, t, J=6.02 Hz), 4.52 (2 H, t, J=6.43 Hz), 4.71 - 4.83 (2 H, m), 6.00 (1 H, d, J=8.21 Hz), 6.63 (1 H, tt, J=54.45, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.91 (1 H, br q, J=4.70 Hz);C 24 H 29 ESIMS observed m / z 498.3 (M+1) for F2N9O. [ka]

[0413] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (204).

[0414] White solid (35 mg, 0.074 mmol, 38.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.68 (1 H, br dd, J=12.59, 3.01 Hz), 1.87 (1 H, qd, J=12.23, 3.56 Hz), 2.00 - 2.07 (1 H, m), 2.10 - 2.22 (1 H, m), 2.18 (3 H, s), 2.79 (1 H, br d, J=10.95 Hz), 3.04 (1 H, br t, J=10.95 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.66 - 3.82 (1 H, m), 4.78 (2 H, td, J=15.90, 2.20 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.87 (1 H, d, J=7.94 Hz), 6.64 (1 H, tt, J=54.60, 2.75 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.65 Hz);C 22 H 26 ESIMS observed m / z 474.25 (M+1) for F3N9. [ka]

[0415] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (205).

[0416] White solid (40 mg, 0.085 mmol, 44.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.64 - 1.72 (1 H, m), 1.87 (1 H, qd, J=12.23, 3.83 Hz), 2.04 (1 H, br t, J=10.95 Hz), 2.10 - 2.22 (1 H, m), 2.18 (3 H, s), 2.62 (3 H, s), 2.79 (1 H, br d, J=10.40 Hz), 3.04 (1 H, br t, J=11.23 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.66 - 3.81 (1 H, m), 4.73 - 4.81 (2 H, m), 4.88 (1 H, d, J=49.65 Hz), 5.87 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 2.75 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.76 Hz), 10.97 (1 H, q, J=4.65 Hz);C 22 H 26 ESIMS observed m / z 474.3 (M+1) for F3N9. [ka]

[0417] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (210).

[0418] White solid (64 mg, 0.124 mmol, 55.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 - 1.76 (1 H, m), 1.81 - 1.91 (1 H, m), 1.95 - 2.03 (1 H, m), 2.06 - 2.20 (1 H, m), 2.62 (3 H, s), 2.75 (1 H, br d, J=9.58 Hz), 2.92 - 3.02 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.72 - 3.89 (1 H, m), 4.43 (2 H, dt, J=29.30, 6.16 Hz), 4.54 (2H, td, J=6.50, 3.15 Hz), 4.72 - 4.83 (2 H, m), 4.90 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 C 24 H 28 ESIMS observed m / z 516.3 (M+1) for F3N9O. [ka]

[0419] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (211).

[0420] Light yellow solid (22 mg, 0.043 mmol, 65.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.57 (1 H, m), 1.94 (1 H, td, J=11.57, 2.05 Hz), 2.00 (2 H, td, J=9.65, 5.34 Hz), 2.62 (3 H, s), 2.62 - 2.67 (1 H, m), 2.98 - 3.06 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.51 (1 H, quin, J=6.30 Hz), 3.78 - 3.91 (1 H, m), 4.42 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.50 - 4.66 (1 H, m), 4.54 (2 H, t, J=6.60 Hz), 4.78 (2 H, td, J=16.20, 2.75 Hz), 6.32 (1 H, d, J=8.76 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), C 24 H 28 ESIMS observed m / z 516.3 (M+1) for F3N9O. [ka]

[0421] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (212).

[0422] Light yellow solid (23 mg, 0.045 mmol, 66.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.57 (1 H, m), 1.91 - 1.96 (1 H, m), 2.00 (2 H, td, J=9.58, 5.48 Hz), 2.60 - 2.67 (1 H, m), 2.62 (3 H, s), 2.98 - 3.05 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.51 (1 H, quin, J=6.30 Hz), 3.78 - 3.91 (1 H, m), 4.42 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.50 - 4.66 (1 H, m), 4.54 (2 H, t, J=6.57 Hz), 4.78 (2 H, td, J=15.81, 2.60 Hz), 6.32 (1 H, d, J=8.76 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.09 (1 H, d, C 24 H 28 ESIMS observed m / z 516.3 (M+1) for F3N9O. [ka]

[0423] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (213).

[0424] White solid (48 mg, 0.093 mmol, 44.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 - 1.76 (1 H, m), 1.87 (1 H, qd, J=12.09, 3.42 Hz), 1.96 - 2.05 (1 H, m), 2.06 - 2.22 (1 H, m), 2.62 (3 H, s), 2.75 (1 H, br d, J=10.40 Hz), 2.97 (1 H, br t, J=10.27 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.71 - 3.89 (1 H, m), 4.43 (2 H, dt, J=29.35, 6.16 Hz), 4.54 (2 H, td, J=6.50, 3.15 Hz), 4.72 - 4.82 (2 H, m), 4.90 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.47 Hz);C 24 H 28 ESIMS observed m / z 516.3 (M+1) for F3N9O. [ka]

[0425] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (214).

[0426] Yellow solid (7 mg, 0.014 mmol, 32.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.89 (2 H, m), 2.11 - 2.21 (1 H, m), 2.26 (3 H, br s), 2.32 - 2.46 (1 H, m), 2.62 (3 H, s), 2.74 - 2.84 (1 H, m), 2.98 - 3.10 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.16 - 4.31 (1 H, m), 4.73 - 4.84 (2 H, m), 6.12 (1 H, br d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, C 22 H 25 ESIMS observed m / z 492.3 (M+1) for F4N9. [ka]

[0427] (S)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (215).

[0428] Yellow solid (8 mg, 0.016 mmol, 37.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.88 (2 H, m), 2.10 - 2.22 (1 H, m), 2.27 (3 H, br s), 2.36 (1 H, br s), 2.62 (3 H, s), 2.75 - 2.85 (1 H, m), 2.99 - 3.10 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.18 - 4.34 (1 H, m), 4.78 (2 H, td, J=15.74, 2.19 Hz), 6.13 (1 H, br d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), C 22 H 25 ESIMS observed m / z 492.3 (M+1) for F4N9. [ka]

[0429] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (216).

[0430] Yellow solid (12 mg, 0.023 mmol, 27.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.82 (1 H, m), 1.88 (1 H, br dd, J=9.03, 4.38 Hz), 2.14 (1 H, br t, J=10.54 Hz), 2.32 - 2.44 (1 H, m), 2.62 (3 H, s), 2.74 (1 H, br d, J=11.77 Hz), 2.95 - 3.06 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.22 - 4.36 (1 H, m), 4.44 (2 H, dt, J=14.24, 6.30 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 4.73 - 4.85 (2 H, m), 6.19 (1 H, d, J=9.58 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, C 24 H 27 ESIMS observed m / z 534.3 (M+1) for F4N9O. [ka]

[0431] (S)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (217).

[0432] Yellow solid (11 mg, 0.021 mmol, 29.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.82 (1 H, m), 1.88 (1 H, br dd, J=9.17, 4.52 Hz), 2.14 (1 H, br t, J=10.68 Hz), 2.32 - 2.44 (1 H, m), 2.62 (3 H, s), 2.75 (1 H, br d, J=11.50 Hz), 2.95 - 3.05 (1 H, m), 3.14 (3 H, d, J=4.93 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.21 - 4.36 (1 H, m), 4.44 (2 H, dt, J=14.31, 6.26 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 4.72 - 4.85 (2 H, m), 6.19 (1 H, d, J=9.58 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, C 24 H 27 ESIMS observed m / z 534.3 (M+1) for F4N9O. [ka]

[0433] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(4-Methyltetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (218).

[0434] White solid (4.0 mg, 0.009 mmol, 4.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.43 (3 H, s), 1.54 - 1.65 (2 H, m), 2.26 (2 H, br d, J=13.69 Hz), 2.62 (3 H, s), 3.12 (3 H, d, J=4.65 Hz), 3.55 - 3.60 (2 H, m), 3.61 - 3.66 (2 H, m), 4.72 - 4.83 (2 H, m), 5.61 (1 H, s), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.09 (1 H, d, J=3.01 Hz), 7.34 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.84 - 10.93 (1 H, m);C 22 H 26 ESIMS observed m / z 457.2 (M+1) for F2N8O. [ka]

[0435] N 2 -((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (219).

[0436] Off-white solid (65 mg, 0.148 mmol, 61.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.64 (2 H, br d, J=7.12 Hz), 2.62 (3 H, s), 2.88 - 2.92 (1 H, m), 2.92 - 2.97 (2 H, m), 2.99 - 3.04 (2 H, m), 3.11 (3 H, d, J=4.65 Hz), 4.71 - 4.83 (2 H, m), 6.04 (1 H, d, J=4.11 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=2.74 Hz), 7.39 (1 H, d, J=2.46 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.93 (1 H, br q, J=4.65 Hz);C 21 H 23 ESIMS observed m / z 440.2 (M+1) for F2N9. [ka]

[0437] 1-((1R,5S,6r)-6-((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-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one (220).

[0438] Off-white solid (24 mg, 0.050 mmol, 73.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.83 (3 H, s), 1.84 - 1.88 (1 H, m), 1.89 - 1.95 (1 H, m), 2.62 (3 H, s), 2.69 (1 H, td, J=6.91, 1.23 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.40 - 3.49 (2 H, m), 3.54 (1 H, d, J=10.40 Hz), 3.67 (1 H, dd, J=10.40, 5.48 Hz), 4.72 - 4.83 (2 H, m), 6.23 (1 H, s), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.40 (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), 10.94 (1 H, q, J=4.56 Hz);C 23 H 25 ESIMS observed m / z 482.2 (M+1) for F2N9O. [ka]

[0439] N 2 -((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (221).

[0440] Off-white solid (12 mg, 0.027 mmol, 14.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.81 (2 H, s), 2.40 (1 H, q, J=2.46 Hz), 2.62 (3 H, s), 3.10 (3 H, d, J=4.65 Hz), 3.64 (2 H, d, J=8.21 Hz), 3.86 (2 H, d, J=8.21 Hz), 4.77 (2 H, td, J=15.95, 2.33 Hz), 6.42 (1 H, d, J=3.29 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=2.74 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.93 (1 H, q, J=4.56 Hz) 21 H 22 ESIMS observed m / z 441.2 (M+1) for F2N8O. [ka]

[0441] N 2 -((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (222).

[0442] Off-white solid (38 mg, 0.086 mmol, 32.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.96 (2 H, br d, J=6.57 Hz), 2.62 (3 H, s), 2.91 (1 H, td, J=6.84, 4.11 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.81 - 3.88 (4 H, m), 4.72 - 4.83 (2 H, m), 5.64 (1 H, d, J=4.11 Hz), 6.64 (1 H, tt, J=54.18, 2.75 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.94 (1 H, q, J=4.65 Hz);C 21 H 22 ESIMS observed m / z 441.1 (M+1) for F2N8O. [ka]

[0443] 1-(2-((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)-7-azaspiro[3.5]nonan-7-yl)ethan-1-one (223).

[0444] Off-white solid (45 mg, 0.086 mmol, 90.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.40 - 1.45 (1 H, m), 1.46 - 1.54 (2 H, m), 1.55 - 1.61 (1 H, m), 1.76 (2 H, br t, J=8.76 Hz), 1.97 (3 H, d, J=8.76 Hz), 2.23 (2 H, br dd, J=9.58, 8.21 Hz), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.26 - 3.31 (2 H, m), 3.36 - 3.44 (2 H, m), 4.13 - 4.25 (1 H, m), 4.72 - 4.83 (2 H, m), 6.40 (1 H, t, J=7.26 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.84 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.91 (1 H, q, J=4.47 Hz);C 26 H 31 ESIMS observed m / z 524.3 (M+1) for F2N9O. [ka]

[0445] 1-(7-((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)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (224).

[0446] Off-white solid (48 mg, 0.092 mmol, 84.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.94 (4 H, d, J=6.57 Hz), 1.22 - 1.38 (2 H, m), 1.46 - 1.59 (2 H, m), 1.75 (3 H, d, J=9.03 Hz), 1.82 - 1.92 (4 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.11 Hz), 3.46 (1 H, s), 3.51 (1 H, s), 3.55 (1 H, br d, J=8.49 Hz), 3.74 (1 H, s), 3.79 (1 H, s), 4.77 (2 H, td, J=15.95, 2.33 Hz), 5.88 (1 H, dd, J=19.16, 8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, t, J=2.74 Hz), 7.81 - 7.86 (1 H, m), 8.00 (1 H, d, J=8.49 Hz), 10.87 - 10.93 (1 H, m);C 26 H 31 ESIMS observed m / z 524.3 (M+1) for F2N9O. [ka]

[0447] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (225).

[0448] White solid (31 mg, 0.064 mmol, 20.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.17 - 1.30 (2 H, m), 1.51 (2 H, td, J=12.94, 3.42 Hz), 1.85 (2 H, br dd, J=12.87, 3.01 Hz), 2.05 (2 H, br d, J=13.14 Hz), 2.62 (3 H, s), 3.10 (3 H, d, J=4.65 Hz), 3.47 - 3.59 (1 H, m), 4.23 (2 H, s), 4.31 (2 H, s), 4.77 (2 H, td, J=15.81, 2.05 Hz), 5.86 (1 H, d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=3.01 Hz), 7.83 (1 H, d, J=8.76 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.89 (1 H, q, J=4.29 Hz);C 24 H 28 ESIMS observed m / z 483.3 (M+1) for F2N8O. [ka]

[0449] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -((4r,7r)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (226).

[0450] Beige solid (15.6 mg, 0.032 mmol, 10.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (3 H, td, J=12.53, 3.30 Hz), 1.85 - 1.95 (2 H, m), 2.04 (2 H, br d, J=12.23 Hz), 2.31 - 2.37 (3 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.52 Hz), 3.49 - 3.62 (2 H, m), 4.37 (2 H, t, J=7.70 Hz), 4.69 - 4.86 (2 H, m), 5.90 (1 H, br d, J=8.07 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), C 24 H 28 ESIMS observed m / z 483.1 (M+1) for F2N8O. [ka]

[0451] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -((4s,7s)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (227).

[0452] Off-white solid (8.77 mg, 0.018 mmol, 5.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88 - 2.02 (2 H, m), 2.03 - 2.18 (1 H, m), 2.10 (3 H, br t, J=6.72 Hz), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.43 - 3.55 (2 H, m), 3.70 - 3.84 (1 H, m), 4.40 (1 H, t, J=5.32 Hz), 4.77 (2 H, td, J=15.93, 2.14 Hz), 5.36 (1 H, br s), 5.91 (1 H, d, J=8.31 ​​Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.06 Hz), 7.36 (1 H, d, J=2.93 Hz), 7.84 (1 H, d, J=8.68 Hz), 8.00 (1 H, d, J=8.56 Hz), 10.90 (1 H, q, J=4.28 Hz);C 24 H 28 ESIMS observed m / z 483.1 (M+1) for F2N8O. [ka]

[0453] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(3-Methyl-3-azabicyclo[3.2.1]octan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (228).

[0454] White solid (25.0 mg, 0.052 mmol, 24.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.54 - 1.67 (4 H, m), 1.75 (2 H, br s), 1.94 - 2.02 (2 H, m), 2.24 (3 H, br s), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.12 - 3.16 (2 H, m), 3.88 - 4.01 (1 H, m), 4.71 - 4.83 (2 H, m), 5.88 (1 H, br d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.33 (1 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.76 Hz), 10.86 - 10.94 (1 H, m);C 24 H 29 ESIMS observed m / z 482.3 (M+1) for F2N9. [ka]

[0455] (R)-N 2 -(3,3-difluoropiperidin-4-yl)-N 4 -Methyl-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (339).

[0456] Yellow solid (38 mg, 0.095 mmol, 86.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.66 (1 H, qd, J=11.82, 4.24 Hz), 1.78 - 1.89 (1 H, m), 2.57 (1 H, br t, J=11.50 Hz), 2.78 (1 H, dd, J=29.30, 13.70 Hz), 2.91 (1 H, br d, J=13.42 Hz), 3.06 - 3.12 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 4.24 - 4.41 (1 H, m), 6.35 (1 H, d, J=9.58 Hz), 6.68 - 6.74 (1 H, m), 7.33 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 7.56 (1 H, d, J=7.67 Hz), 8.17 (1 H, d, J=2.19 Hz), 9.00 - 9.08 (1 H, m), 11.52 (1 H, q, J=4.56 Hz);C 18 H 19 ESIMS observed m / z 400.2 (M+1) for F2N9. [ka]

[0457] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (351).

[0458] Off-white solid (6 mg, 0.012 mmol, 20.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.82 (1 H, m), 1.83 - 1.91 (1 H, m), 2.09 - 2.22 (1 H, m), 2.37 (1 H, dd, J=27.05, 11.85 Hz), 2.74 (1 H, br d, J=11.77 Hz), 2.94 - 3.04 (1 H, m), 3.10 (3 H, d, J=4.65 Hz), 3.59 (1 H, quin, J=6.30 Hz), 4.21 - 4.36 (1 H, m), 4.44 (2 H, dt, J=14.24, 6.16 Hz), 4.55 (2H, td, J=6.57, 3.29 Hz), 4.89 (2 H, td, J=16.08, 2.60 Hz), 6.17 (1 H, d, J=9.58 Hz), 6.49 (1 H, tt, J=54.30, 3.00 Hz), 7.15 (1 H, d, J=3.01 C 23 H 25 ESIMS observed m / z 520.2 (M+1) for F4N9O. [ka]

[0459] 2-(trans-3-((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)cyclobutyl)propan-2-ol (355).

[0460] Brown solid (33 mg, 0.070 mmol, 35.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.04 (6 H, s), 1.88 - 1.98 (2 H, m), 2.15 - 2.23 (1 H, m), 2.24 - 2.33 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 4.08 (1 H, dq, J=14.03, 7.00 Hz), 4.14 (1 H, s), 4.72 - 4.83 (2 H, m), 6.33 (1 H, d, J=7.12 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=3.01 Hz), 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.88 (1 H, q, J=4.56 Hz);C 23 H 28 ESIMS observed m / z 471.3 (M+1) for F2N8O. [ka]

[0461] (S)-N 2 -(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (363).

[0462] Off-white solid (29 mg, 0.061 mmol, 38.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.27 (3 H, s), 2.39 (1 H, t, J=9.03 Hz), 2.55 (1 H, dt, J=15.13, 3.80 Hz), 2.62 (3 H, s), 3.13 (3 H, d, J=4.65 Hz), 3.19 - 3.25 (2 H, m), 4.53 - 4.69 (1 H, m), 4.73 - 4.85 (2 H, m), 6.39 (1 H, d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=3.01Hz), 7.86 (1H, d, J=8.49Hz), 8.01 (1H, d, J=8.49Hz), 11.02 (1H, q, J=4.38Hz) 21 H 23 ESIMS observed m / z 478.2 (M+1) for F4N9. [ka]

[0463] (R)-N 2 -(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (364).

[0464] Off-white solid (19 mg, 0.040 mmol, 37.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.27 (3 H, s), 2.39 (1 H, t, J=9.03 Hz), 2.52 - 2.61 (1 H, m), 2.62 (3 H, s), 3.13 (3 H, d, J=4.65 Hz), 3.18 - 3.26 (2 H, m), 4.55 - 4.68 (1 H, m), 4.78 (2 H, td, J=16.02, 2.74 Hz), 6.39 (1 H, d, J=9.31 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.38 (1 H, C 21 H 23 ESIMS observed m / z 478.2 (M+1) for F4N9. [ka]

[0465] (S)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-ethyl-4,4-difluoropyrrolidin-3-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (365).

[0466] Light yellow fluffy solid (12 mg, 0.024 mmol, 15.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.03 (3 H, t, J=7.26 Hz), 2.35 - 2.41 (1 H, m), 2.41 - 2.48 (2 H, m), 2.56 (1 H, ddd, J=18.69, 15.40, 11.09 Hz), 2.62 (3 H, s), 3.13 (3 H, d, J=4.65 Hz), 3.27 (2 H, br t, J=8.62 Hz), 4.60 (1 H, dt, J=15.19, 7.73 Hz), 4.78 (2 H, td, J=16.08, 2.60 Hz), 6.38 (1 H, d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.38 (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=4.65 Hz);C 22 H 25 ESIMS observed m / z 492.2 (M+1) for F4N9. [ka]

[0467] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-ethyl-4,4-difluoropyrrolidin-3-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (366).

[0468] Light yellow solid (11 mg, 0.022 mmol, 33.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.03 (3 H, t, J=7.12 Hz), 2.35 - 2.41 (1 H, m), 2.41 - 2.48 (2 H, m), 2.51 - 2.61 (1 H, m), 2.62 (3 H, s), 3.13 (3 H, d, J=4.65 Hz), 3.27 (2 H, br t, J=8.62 Hz), 4.53 - 4.68 (1 H, m), 4.78 (2 H, td, J=16.02, 2.46 Hz), 6.38 (1 H, d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), C 22 H 25 ESIMS observed m / z 492.2 (M+1) for F4N9. [ka]

[0469] (S)-N 2 -(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (367).

[0470] Yellow solid (5 mg, 0.010 mmol, 9.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.44 - 2.49 (1 H, m), 2.63 (3 H, s), 2.65 - 2.75 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 3.27 (2 H, br t, J=8.76 Hz), 3.68 (1 H, quin, J=6.09 Hz), 4.46 - 4.52 (2 H, m), 4.58 (2 H, q, J=6.84 Hz), 4.61 - 4.71 (1 H, m), 4.78 (2 H, td, J=15.95, 2.60 Hz), 6.43 (1 H, d, J=9.31 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.86 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.03 (1 H, q, J=4.56 Hz);C 23 H 25 ESIMS observed m / z 520.2 (M+1) for F4N9O. [ka]

[0471] (R)-N 2 -(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (368).

[0472] Light orange (6 mg, 0.012 mmol, 7.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.45 - 2.49 (1 H, m), 2.63 (3 H, s), 2.65 - 2.75 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 3.22 - 3.30 (2 H, m), 3.68 (1 H, quin, J=6.02 Hz), 4.46 - 4.53 (2 H, m), 4.58 (2 H, q, J=6.75 Hz), 4.61 - 4.71 (1 H, m), 4.79 (2 H, td, J=15.88, 2.74 Hz), 6.43 (1 H, d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.86 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.03 (1 H, q, J=4.65 Hz);C 23 H 25 ESIMS observed m / z 520.2 (M+1) for F4N9O. [ka]

[0473] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-(2-fluoroethyl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (369).

[0474] Light yellow fluffy solid (29 mg, 0.060 mmol, 79.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.50 (2 H, qd, J=11.73, 3.42 Hz), 1.83 - 1.93 (2 H, m), 2.04 - 2.15 (2 H, m), 2.60 (2 H, dt, J=28.25, 4.93 Hz), 2.62 (3 H, s), 2.87 (2 H, br d, J=11.77 Hz), 3.11 (3 H, d, J=4.65 Hz), 3.50 - 3.62 (1 H, m), 4.52 (2 H, dt, J=48.00, 4.95 Hz), 4.77 (2 H, td, J=16.02, 2.74 Hz), 5.96 (1 H, d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.90 (1 H, q, J=4.56 Hz);C 23 H 28 ESIMS observed m / z 488.3 (M+1) for F3N9. [ka]

[0475] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (370).

[0476] Light yellow fluffy solid (2 mg, 0.004 mmol, 5.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.60 (2 H, m), 1.83 - 1.92 (2 H, m), 2.42 (2 H, br t, J=10.54 Hz), 2.62 (3 H, s), 2.92 (2 H, br d, J=12.05 Hz), 3.11 (3 H, d, J=4.65 Hz), 3.15 (2 H, q, J=10.15 Hz), 3.53 - 3.62 (1 H, m), 4.69 - 4.85 (2 H, m), 5.99 (1 H, d, J=7.94 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 C 23 H 26 ESIMS observed m / z 524.3 (M+1) for F5N9. [ka]

[0477] N 2 -(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (371).

[0478] Light yellow solid (5 mg, 0.009 mmol, 5.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.43 - 1.55 (2 H, m), 1.84 - 1.94 (4 H, m), 2.31 - 2.44 (2 H, m), 2.62 (3 H, s), 2.63 - 2.72 (3 H, m), 2.78 (2 H, br d, J=10.95 Hz), 3.11 (3 H, d, J=4.65 Hz), 3.51 - 3.65 (1 H, m), 4.71 - 4.83 (2 H, m), 6.00 (1 H, d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=2.74 C 25 H 29 ESIMS observed m / z 532.3 (M+1) for F4N9. [ka]

[0479] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (372).

[0480] Light yellow fluffy solid (4 mg, 0.008 mmol, 12.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.00 (3 H, t, J=7.12 Hz), 1.64 - 1.74 (1 H, m), 1.85 (1 H, qd, J=12.27, 3.97 Hz), 1.98 - 2.08 (1 H, m), 2.17 (1 H, dd, J=38.15, 12.32 Hz), 2.36 (2 H, q, J=7.21 Hz), 2.62 (3 H, s), 2.88 (1 H, br d, J=11.50 Hz), 3.09 - 3.16 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.67 - 3.87 (1 H, m), 4.78 (2 H, td, J=15.81, 2.33 Hz), 4.89 (1 H, d, J=50.50 Hz), 5.87 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, C 23 H 28 ESIMS observed m / z 488.3 (M+1) for F3N9. [ka]

[0481] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-1-ethyl-3-fluoropiperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (373).

[0482] Light yellow fluffy solid (6 mg, 0.012 mmol, 18.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.00 (3 H, t, J=7.12 Hz), 1.64 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.42 Hz), 1.99 - 2.08 (1 H, m), 2.17 (1 2.36 (2 H, q, J=7.12 Hz), 2.62 (3 H, s), 2.88 (1 H, br d, J=10.95 Hz), 3.08 - 3.16 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.68 - 3.85 (1 H, m), 4.78 (2 H, td, J=15.95, 2.33 Hz), 4.89 (1 H, d, J=50.50 Hz), 5.87 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, C 23 H 28 ESIMS observed m / z 488.3 (M+1) for F3N9. [ka]

[0483] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (374).

[0484] Light yellow fluffy solid (29 mg, 0.057 mmol, 87.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.63 - 1.74 (1 H, m), 1.82 - 1.93 (1 H, m), 2.23 (1 H, br t, J=11.09 Hz), 2.37 (1 H, dd, J=37.85, 12.60 Hz), 2.62 (3 H, s), 2.63 - 2.73 (2 H, m), 2.92 (1 H, br d, J=10.95 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.17 (1 H, br t, J=10.54 Hz), 3.70 - 3.88 (1 H, m), 4.54 (2H, dt, J=47.70, 4.93 Hz), 4.78 (2 H, td, J=16.08, 2.60 Hz), 4.89 (1 H, d, J=49.90 Hz), 5.91 (1 H, br d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), C 23 H 27 ESIMS observed m / z 506.25 (M+1) for F4N9. [ka]

[0485] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (375).

[0486] White solid (28 mg, 0.055 mmol, 84.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.63 - 1.73 (1 H, m), 1.87 (1 H, qd, J=12.27, 3.42 Hz), 2.23 (1 H, br t, J=11.09 Hz), 2.37 (1 H, dd, J=37.85, 12.90 Hz), 2.62 (3 H, s), 2.67 (2 H, dt, J=28.50, 4.95 Hz), 2.92 (1 H, br d, J=11.50 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.13 - 3.20 (1 H, m), 3.69 - 3.87 (1 H, m), 4.54 (2 H, dt, J=48.00, 4.95 Hz), 4.78 (2 H, td, J=15.74, 2.46 Hz), 4.89 (1 H, d, J=50.15 Hz), 5.90 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.29 Hz);C 23 H 27 ESIMS observed m / z 506.3 (M+1) for F4N9. [ka]

[0487] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-isopropylpiperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (376).

[0488] Light yellow fluffy solid (25 mg, 0.050 mmol, 76.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.96 (3 H, d, J=5.20 Hz), 0.98 (3 H, d, J=5.20 Hz), 1.66 - 1.73 (1 H, m), 1.81 (1 H, qd, J=11.96, 3.83 Hz), 2.25 (1 H, br t, J=10.95 Hz), 2.39 (1 H, dd, J=37.05, 12.35 Hz), 2.62 (3 H, s), 2.73 (1 H, dt, J=13.07, 6.47 Hz), 2.77 - 2.82 (1 H, m), 3.01 - 3.08 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.67 - 3.83 (1 H, m), 4.78 (2 H, td, J=15.95, 2.60 Hz), 4.88 (1 H, d, J=50.15 Hz), 5.85 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.76 Hz), 10.97 (1 H, q, J=4.38 Hz);C 24 H 30 ESIMS observed m / z 502.3 (M+1) for F3N9. [ka]

[0489] N 2 -((3S,4R)-1-cyclopropyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (377).

[0490] Light yellow fluffy solid (14 mg, 0.028 mmol, 42.9% yield).1 H NMR (499 MHz, DMSO-d6) δ ppm 0.20 - 0.29 (1 H, m), 0.30 - 0.37 (1 H, m), 0.39 - 0.49 (2 H, m), 1.61 - 1.72 (2 H, m), 1.79 (1 H, qd, J=12.32, 3.83 Hz), 2.37 (1 H, dd, J=45.80, 13.15 Hz), 2.33 - 2.38 (1 H, m), 2.62 (3 H, s), 2.95 (1 H, br d, J=11.77 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.14 - 3.24 (1 H, m), 3.70 - 3.88 (1 H, m), 4.78 (2 H, td, J=16.08, 2.60 Hz), 4.87 (1 H, d, J=50.20 Hz), 5.87 (1 H, br d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 C 24 H 28 ESIMS observed m / z 500.3 (M+1) for F3N9. [ka]

[0491] N 2 -((3R,4S)-1-Cyclopropyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (378).

[0492] Yellow solid (12 mg, 0.024 mmol, 36.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.21 - 0.28 (1 H, m), 0.30 - 0.37 (1 H, m), 0.43 (2 H, br d, J=6.30 Hz), 1.61 - 1.72 (2 H, m), 1.78 (1 H, qd, J=12.18, 3.70 Hz), 2.29 - 2.44 (2 H, m), 2.62 (3 H, s), 2.95 (1 H, br d, J=11.50 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.17 (1 H, br t, J=10.95 Hz), 3.70 - 3.88 (1 H, m), 4.73 - 4.81 (2 H, m), 4.87 (1 H, d, J=50.45 Hz), 5.86 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.37 (1 7.85 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.65 Hz) 24 H 28 ESIMS observed m / z 500.3 (M+1) for F3N9. [ka]

[0493] N2-((3R,4S)-1-Cyclobutyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (379).

[0494] Light yellow fluffy solid (24 mg, 0.047 mmol, 71.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.58 - 1.65 (2 H, m), 1.66 - 1.89 (5 H, m), 1.92 - 2.07 (3 H, m), 2.62 (3 H, s), 2.74 (1 H, quin, J=7.94 Hz), 2.80 (1 H, br d, J=9.58 Hz), 2.99 - 3.07 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.69 - 3.84 (1 H, m), 4.77 (2 H, td, J=15.88, 2.46 Hz), 4.88 (1 H, d, J=50.15 Hz), 5.88 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.56 Hz);C 25 H 30 ESIMS observed m / z 514.3 (M+1) for F3N9. [ka]

[0495] N 2 -((3S,4R)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (380).

[0496] Off-white fluffy solid (6 mg, 0.011 mmol, 7.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.66 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.70 Hz), 1.97 - 2.08 (1 H, m), 2.16 (1 H, dd, J=37.55, 12.32 Hz), 2.28 - 2.47 (2 H, m), 2.62 (3 H, s), 2.64 - 2.77 (3 H, m), 2.83 (1 H, br d, J=10.13 Hz), 3.02 - 3.09 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.73 - 3.89 (1 H, m), 4.78 (2 H, td, J=15.74, 2.19 Hz), 4.91 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 C 25 H 28 ESIMS observed m / z 550.3 (M+1) for F5N9. [ka]

[0497] N 2 -((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (381).

[0498] Light yellow solid (9 mg, 0.016 mmol, 25.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 - 1.74 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.97 Hz), 1.98 - 2.06 (1 H, m), 2.16 (1 H, dd, J=37.30, 13.15 Hz), 2.28 - 2.46 (2 H, m), 2.62 (3 H, s), 2.66 - 2.77 (3 H, m), 2.83 (1 H, br d, J=10.13 Hz), 3.06 (1 H, br t, J=10.95 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.73 - 3.89 (1 H, m), 4.72 - 4.82 (2 H, m), 4.91 (1 H, d, J=49.05 Hz), 5.94 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=2.74 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.98 (1 H, q, J=4.53 Hz);C 25 H 28 ESIMS observed m / z 550.3 (M+1) for F5N9. [ka]

[0499] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -(Methyl-d3)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (382).

[0500] Off-white solid (9 mg, 0.018 mmol, 43.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.81 (1 H, m), 1.81 - 1.88 (1 H, m), 2.10 - 2.21 (1 H, m), 2.25 (3 H, s), 2.36 (1 H, ddd, J=27.20, 11.91, 1.12 Hz), 2.62 (3 H, s), 2.77 (1 H, br d, J=11.77 Hz), 2.98 - 3.10 (1 H, m), 4.16 - 4.30 (1 H, m), 4.78 (2 H, td, J=15.95, 2.60 Hz), 6.12 (1 H, d, J=9.31 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, s);C 22 H 22 ESIMS observed m / z 495.3 (M+1) for [2H3]F4N9. [ka]

[0501] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-ethyl-3,3-difluoropiperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (383).

[0502] Off-white solid (19 mg, 0.038 mmol, 59.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.01 (3 H, t, J=7.12 Hz), 1.74 (1 H, qd, J=11.96, 3.56 Hz), 1.85 (1 H, br dd, J=8.76, 4.11 Hz), 2.16 (1 H, br t, J=10.54 Hz), 2.36 (1 H, dd, J=27.70, 12.35 Hz), 2.44 (2 H, q, J=7.12 Hz), 2.62 (3 H, s), 2.86 (1 H, br d, J=11.77 Hz), 3.06 - 3.13 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.18 - 4.32 (1 H, m), 4.78 (2 H, td, J=16.02, 2.74 Hz), 6.12 (1 H, d, J=9.31 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, C 23 H 27 ESIMS observed m / z 506.3 (M+1) for F4N9. [ka]

[0503] (S)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-ethyl-3,3-difluoropiperidin-4-yl)-N 4- Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (384).

[0504] Off-white solid (13 mg, 0.026 mmol, 40.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.01 (3 H, t, J=7.12 Hz), 1.69 - 1.79 (1 H, m), 1.85 (1 H, br dd, J=8.90, 4.24 Hz), 2.16 (1 H, br t, J=10.81 Hz), 2.36 (1 H, dd, J=27.70, 11.75 Hz), 2.44 (2 H, q, J=7.03 Hz), 2.62 (3 H, s), 2.86 (1 H, br d, J=11.50 Hz), 3.06 - 3.12 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.17 - 4.32 (1 H, m), 4.78 (2 H, td, J=15.95, 2.60 Hz), 6.11 (1 H, d, J=9.58 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.38 (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);C 23 H 27 ESIMS observed m / z 506.3 (M+1) for F4N9. [ka]

[0505] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-ethyl-3,3-difluoropiperidin-4-yl)-N 4 -(Methyl-d3)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (385).

[0506] White solid (6 mg, 0.012 mmol, 18.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.01 (3 H, t, J=7.26 Hz), 1.66 - 1.80 (1 H, m), 1.80 - 1.90 (1 H, m), 2.16 (1 H, br t, J=10.95 Hz), 2.36 (1 H, dd, J=27.45, 12.05 Hz), 2.44 (2 H, q, J=6.84 Hz), 2.62 (3 H, s), 2.86 (1 H, br d, J=11.77 Hz), 3.05 - 3.17 (1 H, m), 4.16 - 4.33 (1 H, m), 4.73 - 4.84 (2 H, m), 6.12 (1 H, d, J=9.58 Hz), 6.64 (1 H, tt, J=54.18, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, s);C 23 H 24 ESIMS observed m / z 509.2 (M+1) for [2H3]F4N9. [ka]

[0507] (R)-N 2 -(1-cyclopropyl-3,3-difluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (386).

[0508] Light yellow semi-solid (2 mg, 0.004 mmol, 18.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.27 - 0.33 (1 H, m), 0.33 - 0.39 (1 H, m), 0.46 (2 H, br d, J=6.30 Hz), 1.64 - 1.74 (1 H, m), 1.76 - 1.86 (2 H, m), 2.45 (1 H, br t, J=10.54 Hz), 2.62 (3 H, s), 2.63 - 2.71 (1 H, m), 2.94 (1 H, br d, J=11.50 Hz), 3.10 - 3.19 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.19 - 4.36 (1 H, m), 4.70 - 4.84 (2 H, m), 6.12 (1 H, d, J=9.58 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 H, d, J=2.74 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.86 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.00 (1 H, q, J=4.38 Hz);C 24 H 27 ESIMS observed m / z 518.3 (M+1) for F4N9. [ka]

[0509] (S)-N 2 -(1-cyclopropyl-3,3-difluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (387).

[0510] Light yellow semi-solid (1.3 mg, 0.003 mmol, 12.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.27 - 0.33 (1 H, m), 0.33 - 0.39 (1 H, m), 0.46 (2 H, br d, J=6.30 Hz), 1.64 - 1.74 (1 H, m), 1.76 - 1.87 (1 H, m), 1.97 - 2.04 (1 H, m), 2.45 (1 H, br t, J=10.40 Hz), 2.62 (3 H, s), 2.63 - 2.72 (1 H, m), 2.94 (1 H, br d, J=11.50 Hz), 3.10 - 3.18 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.19 - 4.36 (1 H, m), 4.71 - 4.86 (2 H, m), 6.12 (1 H, d, J=9.31 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.38 (1 7.86 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 - 11.03 (1 H, m);C 24 H 27 ESIMS observed m / z 518.3 (M+1) for F4N9. [ka]

[0511] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -(Methyl-d3)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (388).

[0512] White solid (12 mg, 0.022 mmol, 43.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.83 (1 H, m), 1.76 - 1.76 (1 H, m), 1.88 (1 H, br dd, J=9.03, 4.38 Hz), 2.14 (1 H, br t, J=10.54 Hz), 2.38 (1 H, dd, J=26.05, 11.50 Hz), 2.74 (1 H, br d, J=11.23 Hz), 2.95 - 3.06 (1 H, m), 3.60 (1 H, quin, J=6.30 Hz), 4.22 - 4.37 (1 H, m), 4.44 (2 H, dt, J=14.37, 6.23 Hz), 4.55 (2 H, td, J=6.57, 3.29 Hz), 4.78 (2 H, td, J=15.88, 2.19 Hz), 6.20 (1 H, d, J=9.58 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.98 (1 H, s);C 24 H 24 ESIMS observed m / z 537.3 (M+1) for [2H3]F4N9O. [ka]

[0513] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(1,4-Dioxaspiro[4.5]decan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (389).

[0514] Off-white solid (72 mg, 0.144 mmol, 72.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.49 - 1.63 (4 H, m), 1.72 (2 H, br dd, J=7.67, 3.83 Hz), 1.83 - 1.94 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.64 (1 H, br d, J=3.56 Hz), 3.83 - 3.90 (4 H, m), 4.77 (2 H, td, J=15.81, 2.60 Hz), 5.99 (1 H, d, J=7.94 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, C 24 H 28 ESIMS observed m / z 499.3 (M+1) for F2N8O2. [ka]

[0515] (1s,4s)-1-Methyl-4-((5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol (441).

[0516] Beige solid (7 mg, 0.014 mmol, 11.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.12 (3 H, s), 1.35 (2 H, td, J=13.21, 3.97 Hz), 1.51 - 1.64 (4 H, m), 1.64 - 1.73 (2 H, m), 2.64 (3 H, s), 3.10 (3 H, d, J=4.65 Hz), 3.43 - 3.56 (1 H, m), 3.97 (1 H, s), 5.29 (2 H, q, J=9.31 Hz), 5.86 (1 H, d, J=7.94 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=3.01 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.03 (1 H, d, J=8.49 Hz), 10.78 (1 H, q, J=4.56 Hz);C 23 H 27 ESIMS observed m / z 489.3 (M+1) for F3N8O. [ka]

[0517] 1-((3R,4S)-3-Fluoro-4-((5-(2-methyl-3-(2,2,2-trifluoroethyl)-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 (449).

[0518] White solid (10 mg, 0.019 mmol, 38.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.60 - 1.72 (1 H, m), 1.74 - 1.87 (1 H, m), 1.98 - 2.07 (3 H, m), 2.66 - 2.96 (1 H, m), 3.12 (3 H, d, J=4.93 Hz), 3.89 (1 H, br d, J=11.50 Hz), 3.93 - 4.06 (1 H, m), 4.07 - 4.17 (1 H, m), 4.40 - 4.75 (1 H, m), 4.97 (1 H, d, J=49.35 Hz), 5.30 (2 H, q, J=9.13 Hz), 6.12 (1 H, dd, J=7.94, 3.01 Hz), 7.14 (1 H, d, J=3.29 Hz), 7.38 (1 H, d, J=3.29 Hz), 7.91 (1 H, d, J=8.76 Hz), 8.04 (1 H, d, J=8.76 Hz), 10.89 (1 H, q, J=4.93 Hz);C 23 H 25 ESIMS observed m / z 520.25 (M+1) for F4N9O. [ka]

[0519] (1r,4r)-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)-1-methylcyclohexan-1-ol (465).

[0520] Orange fluffy solid (19 mg, 0.042 mmol, 64.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.34 - 1.49 (4 H, m), 1.53 - 1.65 (2 H, m), 1.79 - 1.91 (2 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.63 (1 H, br s), 4.22 (1 H, s), 5.25 (2 H, td, J=15.95, 2.60 Hz), 6.04 (1 H, d, J=8.21 Hz), 6.72 (1 H, tt, J=54.30, 3.00 Hz), 7.31 (1 H, d, J=3.29 Hz), 7.44 (1 H, d, 8.10 (1 H, d, J=9.04 Hz), 8.54 (1 H, d, J=9.03 Hz), 10.85 (1 H, q, J=4.56 Hz);C 21 H 25 ESIMS observed m / z 458.2 (M+1) for F2N9O. [ka]

[0521] 5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (469).

[0522] Yellow solid (32 mg, 0.066 mmol, 63.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.64 (1 H, t, J=9.31 Hz), 2.75 (1 H, ddd, J=30.20, 12.05, 1.10 Hz), 3.00 (1 H, t, J=8.21 Hz), 3.14 (3 H, d, J=4.93 Hz), 3.18 (1 H, ddd, J=32.90, 12.05, 4.38 Hz), 3.78 (1 H, quin, J=6.16 Hz), 4.24 - 4.41 (1 H, m), 4.47 (2 H, t, J=5.75 Hz), 4.59 (2 H, t, J=6.57 Hz), 5.13 - 5.27 (1 H, m), 5.27 (2 H, td, J=16.45, 2.75 Hz), 6.32 (1 H, d, J=7.67 Hz), 6.72 (1 H, tt, J=54.30, 3.00 Hz), 7.35 (1 H, d, J=2.74 Hz), 7.43 - 7.48 (1 H, m), 8.12 (1 H, d, J=9.31 Hz), 8.56 (1 H, d, J=8.76 Hz), 10.95 (1 H, q, J=4.38 Hz);C 21 H 23 F3N 10 ESIMS observed m / z 489.2 (M+1) for O. [ka]

[0523] 1-((3R,4S)-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-fluoropiperidin-1-yl)ethan-1-one (472).

[0524] Yellow solid (12 mg, 0.025 mmol, 49.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.61 - 1.72 (1 H, m), 1.72 - 1.89 (1 H, m), 1.97 - 2.07 (3 H, m), 2.80 - 2.96 (1 H, m), 3.14 (3 H, d, J=4.38 Hz), 3.89 (1 H, br d, J=14.24 Hz), 3.94 - 4.06 (1 H, m), 4.07 - 4.16 (1 H, m), 4.40 - 4.75 (1 H, m), 4.97 (1 H, d, J=48.80 Hz), 5.27 (2 H, td, J=16.02, 2.46 Hz), 6.28 (1 H, d, J=7.67 Hz), 6.72 (1 H, tt, J=53.70, 3.00 Hz), 7.35 (1 H, d, J=2.74 Hz), 7.44 (1 H, d, J=3.29 Hz), 8.12 (1 H, d, J=9.31 Hz), 8.56 (1 H, d, J=8.76 Hz), 10.94 (1 H, q, J=4.38 Hz);C 21 H 23 F3N 10 ESIMS observed m / z 489.2 (M+1) for O. [ka]

[0525] 5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (474).

[0526] Yellow fluffy solid (16 mg, 0.032 mmol, 56.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 (1 H, br d, J=10.13 Hz), 1.88 (1 H, qd, J=12.18, 3.42 Hz), 1.96 - 2.04 (1 H, m), 2.13 (1 H, dd, J=36.75, 12.32 Hz), 2.75 (1 H, br d, J=9.58 Hz), 2.98 (1 H, br t, J=10.40 Hz), 3.13 (3 H, d, J=4.65 Hz), 3.49 (1 H, quin, J=6.30 Hz), 3.74 - 3.92 (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=6.50, 3.15 Hz), 4.90 (1 H, d, J=49.35 Hz), 5.26 (2 H, td, J=16.08, 2.60 Hz), 6.17 (1 H, d, J=8.21 Hz), 6.72 (1 H, tt, J=54.05, 3.00 Hz), 7.34 (1 H, d, J=3.01 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=9.03 Hz), 10.93 (1 H, q, J=4.56 Hz);C 22 H 25 F3N 10 ESIMS observed m / z for O: 503.2 (M+1). [ka]

[0527] (R)-N 2 -(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (479).

[0528] Yellow fluffy solid (11 mg, 0.023 mmol, 47.5% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.90 (2 H, m), 2.09 - 2.20 (1 H, m), 2.25 (3 H, s), 2.36 (1 H, dd, J=28.00, 11.77 Hz), 2.78 (1 H, br d, J=10.13 Hz), 2.97 - 3.08 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.15 - 4.32 (1 H, m), 5.27 (2 H, td, J=16.02, 2.46 Hz), 6.33 (1 H, d, J=9.58 Hz), 6.72 (1H, tt, J=54.00, 3.00 Hz), 7.35 (1 H, d, J=3.29 Hz), 7.45 (1 H, d, J=3.01 Hz), 8.12 (1 H, d, J=9.03 Hz), 8.56 (1 H, d, J=9.04 Hz), 10.95 (1 H, q, J=4.65 Hz);C 20 H 22 F4N 10 The ESIMS observed value for m / z 479.2 (M+1). [ka]

[0529] (R)-N 2 -(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)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (480).

[0530] Yellow fluffy solid (11 mg, 0.021 mmol, 43.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.73 - 1.83 (1 H, m), 1.84 - 1.91 (1 H, m), 2.14 (1 H, br t, J=10.54 Hz), 2.38 (1 H, dd, J=25.50, 12.05 Hz), 2.75 (1 H, br d, J=12.59 Hz), 2.95 - 3.07 (1 H, m), 3.15 (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, J=14.51, 6.16 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 5.27 (2 H, td, J=16.02, 2.46 Hz), 6.41 (1 H, d, J=9.58 Hz), 6.72 (1 H, tt, J=54.00, 3.00 Hz), 7.35 (1 H, d, C 22 H 24 F4N 10 ESIMS observed m / z for O: 521.2 (M+1). [ka]

[0531] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(3,3-difluoropiperidin-4-yl)-N 4 -Ethylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (482).

[0532] White solid (100 mg, 0.204 mmol, 43.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.24 (3 H, t, J=6.98 Hz), 1.65 (1 H, qd, J=11.96, 3.56 Hz), 1.78 - 1.88 (1 H, m), 2.54 - 2.61 (1 H, m), 2.63 (3 H, s), 2.77 (1 H, dd, J=29.35, 13.75 Hz), 2.92 (1 H, br d, J=12.87 Hz), 3.05 - 3.17 (1 H, m), 3.67 (2 H, quin, J=6.78 Hz), 4.25 - 4.40 (1 H, m), 4.75 (2 H, td, J=15.74, 2.74 Hz), 6.13 (1 H, d, J=9.58 Hz), 6.62 (1 H, tt, J=54.30, 3.00 Hz), 7.09 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.93 (1 H, t, J=6.16 Hz);C 22 H 25 ESIMS observed m / z 492.25 (M+1) for F4N9. [ka]

[0533] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Ethylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (483).

[0534] Off-white solid (2 mg, 0.004 mmol, 3.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.24 (3 H, t, J=6.98 Hz), 1.72 - 1.81 (1 H, m), 1.81 - 1.88 (1 H, m), 2.10 - 2.19 (1 H, m), 2.25 (3 H, s), 2.29 - 2.40 (1 H, m), 2.63 (3 H, s), 2.78 (1 H, br d, J=11.23 Hz), 3.00 - 3.11 (1 H, m), 3.66 (2 H, quin, J=7.05 Hz), 4.15 - 4.31 (1 H, m), 4.69 - 4.81 (2 H, m), 6.12 (1 H, d, J=9.31 Hz), 6.62 (1 H, tt, J=54.30, 3.00 Hz), 7.09 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.94 (1 H, t, J=6.16 Hz);C 23 H 27 ESIMS observed m / z 506.2 (M+1) for F4N9. [ka]

[0535] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(3,3-difluoropiperidin-4-yl)-N 4 -Isopropylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (484).

[0536] White solid (118 mg, 0.233 mmol, 81.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.32 (6 H, dd, J=6.57, 1.64 Hz), 1.59 - 1.73 (1 H, m), 1.79 - 1.89 (1 H, m), 2.57 (1 H, br t, J=11.77 Hz), 2.63 (3 H, s), 2.77 (1 H, dd, J=28.80, 13.69 Hz), 2.92 (1 H, br d, J=12.32 Hz), 3.06 - 3.16 (1 H, m), 4.24 - 4.40 (1 H, m), 4.51 - 4.63 (1 H, m), 4.82 (2 H, td, J=15.19, 3.29 Hz), 6.16 (1 H, d, J=9.31 Hz), 6.55 (1 H, tt, J=54.30, 3.00 Hz), 6.94 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.73 (1 H, d, J=8.49 Hz), 8.03 (1 H, d, J=8.21 Hz), 9.45 (1 H, d, J=8.21 Hz);C 23 H 27 ESIMS observed m / z 506.3 (M+1) for F4N9. [ka]

[0537] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Isopropylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (485).

[0538] Off-white solid (31 mg, 0.060 mmol, 60.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.32 (6 H, dd, J=6.71, 1.51 Hz), 1.74 - 1.81 (1 H, m), 1.81 - 1.87 (1 H, m), 2.15 (1 H, br t, J=10.54 Hz), 2.25 (3 H, s), 2.29 - 2.39 (1 H, m), 2.63 (3 H, s), 2.73 - 2.82 (1 H, m), 2.98 - 3.10 (1 H, m), 4.15 - 4.31 (1 H, m), 4.51 - 4.59 (1 H, m), 4.82 (2 H, td, J=15.19, 3.29 Hz), 6.15 (1 H, d, J=9.31 Hz), 6.55 (1 H, tt, J=54.30, 3.00 Hz), 6.94 (1 H, d, J=2.74 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.73 (1 H, d, J=8.49 Hz), 8.03 (1 H, d, J=8.49 Hz), 9.46 (1 H, d, J=8.21 Hz);C 24 H 29 ESIMS observed m / z 520.3 (M+1) for F4N9. [ka]

[0539] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(3,3-difluoropiperidin-4-yl)-N 4 -(Oxetan-3-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (486).

[0540] White solid (18 mg, 0.035 mmol, 32.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 - 1.81 (1 H, m), 1.87 (1 H, br d, J=11.23 Hz), 2.55 - 2.63 (1 H, m), 2.59 (3 H, s), 2.72 - 2.89 (1 H, m), 2.94 (1 H, br d, J=12.05 Hz), 3.07 - 3.20 (1 H, m), 3.41 - 3.56 (1 H, m), 3.57 - 3.68 (1 H, m), 3.70 - 3.97 (1 H, m), 3.98 - 4.19 (1 H, m), 4.23 - 4.42 (2H, m), 4.75 (2H, br t, J=13.96 Hz), 4.82 - 4.95 (1 H, m), 6.16 - 6.35 (1 H, m), 6.42 - 6.68 (1 H, m), 7.02 (1 H, br s), 7.22 (1 H, br d, J=1.92 Hz), 7.87 (1 H, br s), 8.82 - 8.97 (1 H, m);C 23 H 25 ESIMS observed m / z 520.2 (M+1) for F4N9O. [ka]

[0541] (R)—N2-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N4-(oxetan-3-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (487).

[0542] Tan solid (4.1 mg, 0.008 mmol, 8.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.85 (2 H, m), 2.15 (1 H, br t, J=11.09 Hz), 2.25 (3 H, s), 2.31 - 2.42 (1 H, m), 2.62 (3 H, s), 2.77 (1 H, br d, J=11.50 Hz), 2.99 - 3.09 (1 H, m), 4.16 - 4.33 (1 H, m), 4.67 (1 H, t, J=6.30 Hz), 4.70 (1 H, br t, J=6.43 Hz), 4.78 (2 H, br t, J=14.92 Hz), 4.94 (2 H, t, J=6.98 Hz), 5.20 - 5.29 (1 H, m), 6.28 (1 H, br d, J=9.31 Hz), 6.53 (1 H, tt, J=54.30, 3.00 Hz), 7.05 (1 H, d, J=3.01 Hz), 7.44 (1 H, d, J=2.74 Hz), 7.81 (1 H, d, J=8.49 Hz), 8.04 (1 H, d, J=8.49 Hz), 10.50 (1 H, d, J=6.02 Hz) 24 H 27 ESIMS observed m / z 534.2 (M+1) for F4N9O. [ka]

[0543] (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-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 (692).

[0544] White solid (20 mg, 0.044 mmol, 74.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.33 - 1.46 (4 H, m), 1.51 - 1.62 (2 H, m), 1.78 - 1.87 (2 H, m), 2.60 (3 H, s), 3.61 (1 H, br dd, J=8.21, 3.83 Hz), 4.21 (1 H, s), 4.70 (2 H, td, J=16.45, 1.65 Hz), 5.74 (1 H, d, J=8.21 Hz), 6.46 (1 H, tt, J=54.00, 2.75 Hz), 7.07 (1 H, d, J=2.74 Hz), 7.38 (1 H, C 22 H 26 ESIMS observed m / z 457.2 (M+1) for F2N8O. [ka]

[0545] 1-((3R,4S)-3-((4-amino-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one (700).

[0546] White solid (20 mg, 0.042 mmol, 34.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.92 - 2.00 (3 H, m), 2.60 (3 H, s), 3.41 - 3.58 (1 H, m), 3.62 - 3.73 (1 H, m), 3.75 - 3.86 (1 H, m), 3.91 (1 H, t, J=9.03 Hz), 4.26 - 4.56 (1 H, m), 4.71 (2 H, td, J=16.45, 1.65 Hz), 5.20 - 5.43 (1 H, m), 6.33 (1 H, dd, J=11.77, 7.67 Hz), 6.47 (1 H, tt, J=54.30, 2.20 Hz), 7.13 (1 H, dd, J=3.01, 1.92 Hz), 7.41 (1 H, dd, J=4.24, 2.87 Hz), 7.58 - 7.68 (1 H, m), 7.83 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.67 (1 H, br s);C 21 H 22 ESIMS observed value m / z 474.2 (M+1) for F3N9O. [ka]

[0547] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-Fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (701).

[0548] White solid (29 mg, 0.060 mmol, 46.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.60 (3 H, s), 2.60 - 2.64 (1 H, m), 2.76 (1 H, ddd, J=30.15, 12.35, 1.35 Hz), 2.99 (1 H, t, J=8.21 Hz), 3.15 (1 H, ddd, J=33.75, 12.10, 4.40 Hz), 3.78 (1 H, quin, J=6.23 Hz), 4.22 - 4.37 (1 H, m), 4.46 (2 H, t, J=6.02 Hz), 4.59 (2 H, t, J=6.57 Hz), 4.71 (2 H, td, J=16.75, 1.90 Hz), 5.19 (1 H, dtd, J=55.70, 4.60, 4.60, 1.35 Hz), 6.02 (1 H, d, J=7.94 Hz), 6.47 (1 H, tt, J=54.40, 2.20 Hz), 7.11 (1 H, d, C 22 H 24 ESIMS observed value m / z 488.2 (M+1) for F3N9O. [ka]

[0549] 1-((3R,4S)-4-((4-amino-5-(3-(2,2-difluoroethyl)-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 (715).

[0550] Light yellow fluffy solid (8 mg, 0.016 mmol, 26.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.57 - 1.70 (1 H, m), 1.73 - 1.84 (1 H, m), 1.97 - 2.06 (3 H, m), 2.60 (3 H, s), 2.67 (1 H, td, J=12.80, 3.42 Hz), 2.86 (1 H, dd, J=40.05, 13.96 Hz), 3.83 - 3.98 (1 H, m), 4.00 - 4.17 (1 H, m), 4.38 - 4.48 (1 H, m), 4.66 - 4.79 (2 H, m), 4.95 (1 H, d, J=49.90 Hz), 5.96 (1 H, dd, J=8.21, 5.75 Hz), 6.47 (1 H, tt, J=54.00, 2.75 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.56 (1 H, br s), 7.82 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.63 (1 H, br s);C 22 H 24 ESIMS observed m / z 244.65 (M / 2+1) for F3N9O. [ka]

[0551] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (718).

[0552] Light yellow fluffy solid (3 mg, 0.006 mmol, 14.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.64 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.05, 3.56 Hz), 1.94 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.00, 12.59 Hz), 2.60 (3 H, s), 2.69 - 2.79 (1 H, m), 2.97 (1 H, br t, J=10.81 Hz), 3.48 (1 H, dt, J=12.66, 6.40 Hz), 3.73 - 3.91 (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), 4.64 - 4.76 (2 H, m), 4.88 (1 H, d, J=49.40 Hz), 5.83 (1 H, d, J=8.21 Hz), 6.46 (1 H, tt, J=54.00, 2.75 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.55 (1 H, br s), 7.81 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.61 (1 H, br s);C 23 H 26 ESIMS observed m / z 251.65 (M / 2+1) for F3N9O. [ka]

[0553] (R)-1-(4-((4-amino-5-(3-(2,2-difluoroethyl)-2-methyl-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 (729).

[0554] Light yellow fluffy solid (3 mg, 0.006 mmol, 17.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.52 - 1.80 (1 H, m), 1.81 - 1.97 (1 H, m), 2.02 - 2.08 (3 H, m), 2.60 (3 H, s), 2.98 (1 H, br t, J=11.36 Hz), 3.57 - 3.91 (1 H, m), 4.09 - 4.27 (1 H, m), 4.42 - 4.58 (2 H, m), 4.63 - 4.79 (2 H, m), 6.20 - 6.31 (1 H, m), 6.47 (1 H, tt, J=54.00, 2.75 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.39 (1 H, dd, J=2.87, 1.51 Hz), 7.60 (1 H, br s), 7.83 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.67 (1 H, br s) 22 H 23 ESIMS observed m / z 506.2 (M+1) for F4N9O. [ka]

[0555] (R) -N2- (3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine(??).

[0556] Off-white fluffy solid (14 mg, 0.027 mmol, 48.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.69 - 1.81 (1 H, m), 1.81 - 1.90 (1 H, m), 2.06 - 2.18 (1 H, m), 2.34 (1 H, ddd, J=26.60, 12.05, 1.35 Hz), 2.60 (3 H, s), 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 - 4.36 (1 H, m), 4.43 (2 H, dt, J=13.89, 6.19 Hz), 4.55 (2H, td, J=6.57, 3.56 Hz), 4.65 - 4.79 (2 H, m), 6.12 (1 H, d, J=9.58 Hz), 6.47 (1 H, tt, J=54.05, 2.20 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.39 (1 H, C 23 H 25 ESIMS observed m / z 520.2 (M+1) for F4N9O. [ka]

[0557] (1r,4r)-4-((4-amino-5-(2-methyl-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 (754).

[0558] White solid (10 mg, 0.021 mmol, 30.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.33 - 1.46 (4 H, m), 1.50 - 1.62 (2 H, m), 1.77 - 1.88 (2 H, m), 2.62 (3 H, s), 3.62 (1 H, dt, J=7.94, 3.97 Hz), 4.21 (1 H, br s), 5.15 (2 H, q, J=9.22 Hz), 5.74 (1 H, d, J=8.21 Hz), 7.08 (1 H, d, J=2.74 Hz), 7.39 (1 H, d, J=2.74 Hz), 7.54 (1 H, br s), 7.84 (1 H, d, J=8.76 Hz), 8.02 (1 H, d, J=8.49 Hz), 10.31 (1 H, br s);C 22 H 25 ESIMS observed m / z 475.2 (M+1) for F3N8O. [ka]

[0559] 1-((3R,4S)-3-((4-amino-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one (762).

[0560] White solid (19 mg, 0.039 mmol, 31.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.92 - 2.01 (3 H, m), 2.63 (3 H, s), 3.49 - 3.61 (1 H, m), 3.62 - 3.74 (1 H, m), 3.75 - 3.86 (1 H, m), 3.91 (1 H, t, J=9.03 Hz), 4.27 - 4.56 (1 H, m), 5.16 (2 H, q, J=8.94 Hz), 5.20 - 5.42 (1 H, m), 6.33 (1 H, dd, J=10.40, 7.67 Hz), 7.14 (1 H, dd, J=2.87, 2.05 Hz), 7.43 (1 H, dd, 7.70 - 7.82 (1 H, m), 7.87 (1 H, d, J=8.49 Hz), 8.04 (1 H, d, J=8.49 Hz), 10.46 (1 H, br s);C 21 H 21 ESIMS observed m / z 492.2 (M+1) for F4N9O. [ka]

[0561] N 2 -((3R,4S)-4-Fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (763).

[0562] White solid (20 mg, 0.040 mmol, 30.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.60 - 2.64 (1 H, m), 2.63 (3 H, s), 2.76 (1 H, ddd, J=30.20, 12.18, 1.23 Hz), 3.00 (1 H, t, J=8.21 Hz), 3.15 (1 H, ddd, J=33.75, 12.05, 4.38 Hz), 3.74 - 3.83 (1 H, m), 4.23 - 4.38 (1 H, m), 4.46 (2 H, t, J=5.89 Hz), 4.59 (2 H, t, J=6.57 Hz), 5.19 (1 H, dtd, J=55.40, 4.65, 4.65, 1.10 Hz), 5.16 (2 H, q, J=9.22 Hz), 6.01 (1 H, d, J=7.94 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.42 (1 H, d, J=2.74 Hz), 7.73 (1 H, br s), 7.86 (1 H, d, J=8.49 Hz), 8.03 (1 H, d, J=8.49 Hz), 10.41 (1 H, br s);C 22 H 23 ESIMS observed m / z 506.2 (M+1) for F4N9O. [ka]

[0563] 1-((3R,4S)-4-((4-amino-5-(2-methyl-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 (777).

[0564] Light yellow fluffy solid (5 mg, 0.010 mmol, 16.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.56 - 1.70 (1 H, m), 1.73 - 1.85 (1 H, m), 1.97 - 2.07 (3 H, m), 2.63 (3 H, s), 2.67 (1 H, td, J=12.87, 3.29 Hz), 2.86 (1 H, dd, J=39.80, 14.24 Hz), 3.92 - 4.06 (1 H, m), 4.37 - 4.49 (1 H, m), 4.61 - 4.76 (1 H, m), 4.94 (1 H, d, J=49.90 Hz), 5.16 (2 H, q, J=9.13 Hz), 5.96 (1 H, dd, J=8.08, 5.61 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.69 (1 H, br s), 7.86 (1 H, d, J=8.76 Hz), 8.03 (1 H, d, J=8.49 Hz), 10.42 (1 H, br s);C 22 H 23 ESIMS observed m / z 253.7 (M / 2+1) for F4N9O. [ka]

[0565] N 2 -((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (780).

[0566] Light yellow fluffy solid (10 mg, 0.019 mmol, 46.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.66 - 1.76 (1 H, m), 1.85 (1 H, qd, J=12.14, 3.29 Hz), 1.95 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.55, 12.59 Hz), 2.62 (3 H, s), 2.74 (1 H, br d, J=10.40 Hz), 2.91 - 3.02 (1 H, m), 3.48 (1 H, quin, J=6.23 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=6.43, 2.74 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.15 (2 H, q, J=9.22 Hz), 5.83 (1 H, d, J=8.21 Hz), 7.11 (1 H, d, J=3.01 ESIMS found for C 23 H 25 ESIMS observed m / z 260.7 (M+1) for F4N9O. [ka]

[0567] (R)-1-(4-((4-amino-5-(2-methyl-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 (791).

[0568] Light yellow fluffy solid (2 mg, 0.004 mmol, 11.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.52 - 1.80 (1 H, m), 1.81 - 1.98 (1 H, m), 2.02 - 2.09 (3 H, m), 2.63 (3 H, s), 2.91 - 3.03 (1 H, m), 3.59 - 3.93 (1 H, m), 4.07 - 4.30 (1 H, m), 4.42 - 4.59 (2 H, m), 5.16 (2 H, q, J=8.94 Hz), 6.20 - 6.30 (1 H, m), 7.13 (1 H, d, J=3.01 Hz), 7.40 (1 H, dd, J=2.74, 1.64 Hz), 7.72 (1 H, br s), 7.87 (1 H, d, J=8.49 Hz), 8.04 (1 H, d, J=8.49 Hz), 10.46 (1 H, br s); 22 H 22 ESIMS observed m / z 524.15 (M+1) for F5N9O. [ka]

[0569] (R)-N 2 -(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (792).

[0570] White fluffy solid (11 mg, 0.021 mmol, 48.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.81 (1 H, m), 1.82 - 1.90 (1 H, m), 2.05 - 2.17 (1 H, m), 2.34 (1 H, dd, J=26.60, 11.77 Hz), 2.74 (1 H, br d, J=10.68 Hz), 2.95 - 3.06 (1 H, m), 3.59 (1 H, quin, J=6.16 Hz), 4.21 - 4.36 (1 H, m), 4.43 (2 H, dt, J=14.10, 6.09 Hz), 4.55 (2 H, td, J=6.57, 3.56 Hz), 5.15 (2 H, q, J=9.13 Hz), 6.12 (1 H, br d, J=9.58 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.72 (1 H, br s), 7.86 (1 H, d, J=8.76 Hz), 8.03 (1 H, d, J=8.49 Hz), 10.45 (1 H, br s);C 23 H 24 ESIMS observed m / z 538.2 (M+1) for F5N9O. [ka]

[0571] (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (816).

[0572] Yellow fluffy solid (3.5 mg, 0.008 mmol, 9.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.33 - 1.47 (4 H, m), 1.52 - 1.63 (2 H, m), 1.76 - 1.88 (2 H, m), 3.55 - 3.68 (1 H, m), 4.22 (1 H, br s), 5.16 (2 H, td, J=16.15, 2.46 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.58 (2 H, tt, J=54.10, 2.75 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.46 (1 H, d, J=3.01 Hz), 7.56 (1 H, br s), 8.08 (1 H, d, J=9.31 Hz), 8.53 (1 H, d, J=8.76 Hz), 10.39 (1 H, br s);C 20 H 23 ESIMS observed m / z 444.2 (M+1) for F2N9O. [ka]

[0573] 5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (842).

[0574] Yellow fluffy solid (7 mg, 0.014 mmol, yield) 48.8%. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.64 - 1.77 (1 H, m), 1.86 (1 H, qd, J=12.09, 3.97 Hz), 1.95 - 2.03 (1 H, m), 2.12 (1 H, dd, J=37.50, 12.32 Hz), 2.74 (1 H, br d, J=11.23 Hz), 2.90 - 3.05 (1 H, m), 3.48 (1 H, quin, J=6.23 Hz), 3.72 - 3.90 (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, 2.74 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.16 (2 H, td, J=16.22, 2.60 Hz), 6.07 (1 H, d, J=8.21 Hz), 6.58 (2 H, tt, J=54.00, 2.75 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.46 (1 H, d, J=3.01 Hz), 7.69 (1 H, br s), 8.09 (1 H, d, J=9.03 Hz), 8.55 (1 H, d, J=9.03 Hz), 10.46 (1 H, br s);C 21 H 23 F3N 10 ESIMS observed m / z 489.2 (M+1) for O. [ka]

[0575] (R)-N 2 -(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (850).

[0576] Yellow fluffy solid (20 mg, 0.043 mmol, 52.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.87 (2 H, m), 2.07 - 2.17 (1 H, m), 2.25 (3 H, s), 2.33 (1 H, dd, J=27.40, 11.66 Hz), 2.78 (1 H, br d, J=12.05 Hz), 2.98 - 3.10 (1 H, m), 4.15 - 4.32 (1 H, m), 5.16 (2 H, td, J=16.15, 2.46 Hz), 6.25 (1 H, d, J=9.58 Hz), 6.58 (1 H, tt, J=54.05, 2.75 Hz), 7.36 (1 H, d, C 19 H 20 F4N 10 The ESIMS observed value for m / z 465.2 (M+1). [ka]

[0577] (R)-1-(4-((4-amino-5-(3-(2,2-difluoroethyl)-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 (853).

[0578] Yellow fluffy solid (1.3 mg, 0.003 mmol, 6.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.53 - 1.80 (1 H, m), 1.82 - 1.99 (1 H, m), 2.02 - 2.08 (3 H, m), 2.88 - 3.02 (1 H, m), 3.57 - 3.93 (1 H, m), 4.05 - 4.31 (1 H, m), 4.41 - 4.59 (2 H, m), 5.17 (2 H, td, J=16.22, 2.33 Hz), 6.59 (1 H, tt, J=54.00, 2.75 Hz), 6.68 (1 H, s), 7.37 (1 H, d, J=3.01 Hz), 7.47 (1 H, dd, C 20 H 20 F4N 10 ESIMS observed m / z for O: 493.15 (M+1). [ka]

[0579] (R)-N 2 -(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)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (854).

[0580] Yellow fluffy solid (9 mg, 0.018 mmol, 42.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.81 (1 H, m), 1.86 (1 H, br dd, J=8.62, 4.52 Hz), 2.06 - 2.17 (1 H, m), 2.35 (1 H, dd, J=26.35, 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=6.37 Hz), 4.20 - 4.36 (1 H, m), 4.43 (2 H, dt, J=14.24, 6.30 Hz), 4.55 (2 H, td, J=6.64, 3.70 Hz), 5.17 (2 H, td, J=16.15, 2.19 Hz), 6.34 (1 H, br d, J=9.31 Hz), 6.59 (1 H, tt, J=54.05, 2.75 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.47 (1 C 21 H 22 F4N 10 ESIMS observed m / z for O: 507.2 (M+1). [ka]

[0581] (R)-N 2 -(3,3-Difluoro-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 (985).

[0582] White solid (15 mg, 0.034 mmol, 50.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.79 (1 H, m), 1.80 - 1.85 (1 H, m), 2.13 (1 H, br t, J=10.40 Hz), 2.25 (3 H, s), 2.32 (1 H, ddd, J=27.10, 12.30, 1.65 Hz), 2.77 (1 H, br d, J=11.50 Hz), 2.98 - 3.10 (1 H, m), 4.13 - 4.31 (1 H, m), 4.58 (2 H, dt, J=27.70, 4.65 Hz), 4.82 (2 H, dt, J=47.15, 4.65 Hz), 6.07 (1 H, d, J=9.31 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=3.01 Hz), 7.65 (1 H, br s), 7.88 (1 H, d, J=8.49 Hz), 8.13 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 10.81 (1 H, br s);C 20 H 22 ESIMS observed m / z 446.1 (M+1) for F3N9. [ka]

[0583] (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (986).

[0584] White solid (8 mg, 0.018 mmol, 26.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.34 - 1.46 (4 H, m), 1.51 - 1.62 (2 H, m), 1.77 - 1.89 (2 H, m), 3.62 (1 H, dt, J=8.08, 3.90 Hz), 4.20 (1 H, br s), 4.74 (2 H, td, J=16.50, 2.33 Hz), 5.77 (1 H, d, J=8.21 Hz), 6.47 (1 H, tt, J=54.45, 2.75 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=3.01 Hz), 7.45 (1 H, br s), 7.87 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.49 Hz), 8.39 (1 H, s), 10.49 (1 H, br s);C 21 H 24 ESIMS observed m / z 443.2 (M+1) for F2N8O. [ka]

[0585] 1-((3R,4S)-3-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one (987).

[0586] White solid (15 mg, 0.033 mmol, 26.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.98 (3 H, s), 3.41 - 3.60 (1 H, m), 3.62 - 3.73 (1 H, m), 3.75 - 3.87 (1 H, m), 3.91 (1 H, t, J=9.03 Hz), 4.25 - 4.55 (1 H, m), 4.75 (2 H, td, J=16.45, 2.20 Hz), 5.18 - 5.43 (1 H, m), 6.36 (1 H, dd, J=11.50, 7.67 Hz), 6.48 (1 H, tt, J=54.30, 2.45 Hz), 7.17 (1H, dd, J=3.01, 1.64 Hz), 7.43 (1 H, dd, J=4.24, 2.87 Hz), 7.62 - 7.70 (1 H, m), 7.90 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.76 Hz), 8.41 (1 H, s), 10.63 (1 H, br s);C 20 H 20 ESIMS observed value m / z 460.2 (M+1) for F3N9O. [ka]

[0587] 5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-Fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (988).

[0588] White solid (21 mg, 0.044 mmol, 34.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.62 (1 H, t, J=9.03 Hz), 2.76 (1 H, ddd, J=30.15, 12.05, 1.10 Hz), 2.99 (1 H, t, J=8.21 Hz), 3.16 (1 H, ddd, J=33.75, 12.18, 4.52 Hz), 3.78 (1 H, quin, J=6.16 Hz), 4.22 - 4.37 (1 H, m), 4.46 (2 H, t, J=6.02 Hz), 4.59 (2 H, t, J=6.57 Hz), 4.75 (2 H, td, J=16.43, 2.19 Hz), 5.19 (1 H, dtd, J=55.95, 4.40, 4.40, 1.40 Hz), 6.05 (1 H, d, J=8.21 Hz), 6.48 (1 H, tt, J=54.55, 2.60 Hz), 7.16 (1 H, d, J=2.74 Hz), C 21 H 22 ESIMS observed value m / z 474.2 (M+1) for F3N9O. [ka]

[0589] 1-((3R,4S)-4-((4-amino-5-(3-(2,2-difluoroethyl)-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 (989).

[0590] Light yellow fluffy solid (10 mg, 0.021 mmol, 34.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.58 - 1.72 (1 H, m), 1.73 - 1.85 (1 H, m), 1.97 - 2.05 (3 H, m), 2.67 (1 H, td, J=12.66, 3.70 Hz), 2.86 (1 H, dd, J=39.75, 13.96 Hz), 3.92 - 4.05 (1 H, m), 4.07 - 4.16 (1 H, m), 4.43 (1 H, br dd, J=11.22, 2.19 Hz), 4.70 - 4.82 (2 H, m), 4.94 (1 H, d, J=49.90 Hz), 6.00 (1 H, dd, J=7.94, 5.20 Hz), 6.48 (1 H, tt, J=54.00, 2.75 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.59 (1 H, br s), 7.89 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.49 Hz), 8.40 (1 H, s), 10.59 (1 H, br s);C 21 H 22 ESIMS observed value m / z 474.2 (M+1) for F3N9O. [ka]

[0591] 5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (990).

[0592] Light yellow fluffy solid (14 mg, 0.029 mmol, 69.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.64 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.09, 3.70 Hz), 1.95 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.30, 12.59 Hz), 2.74 (1 H, br d, J=10.68 Hz), 2.90 - 3.03 (1 H, m), 3.48 (1 H, quin, J=6.30 Hz), 3.73 - 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=6.57, 2.74 Hz), 4.74 (2 H, td, J=16.48, 2.20 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.87 (1 H, d, J=8.21 Hz), 6.48 (1 H, tt, J=54.00, 2.75 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=8.76 Hz), 8.40 (1 H, s), 10.58 (1 H, br s);C 22 H 24 ESIMS observed value m / z 488.2 (M+1) for F3N9O. [ka]

[0593] (R)-N 2 -(3,3-Difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (991).

[0594] White solid (20 mg, 0.043 mmol, 65.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.79 (1 H, m), 1.79 - 1.86 (1 H, m), 2.08 - 2.19 (1 H, m), 2.25 (3 H, s), 2.32 (1 H, ddd, J=26.85, 12.05, 1.37 Hz), 2.77 (1 H, br d, J=11.50 Hz), 3.00 - 3.10 (1 H, m), 4.15 - 4.29 (1 H, m), 4.75 (2 H, td, J=16.36, 2.05 Hz), 6.07 (1 H, d, J=9.58 Hz), 6.48 (1 H, tt, J=54.30, 2.50 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.41 (1 H, d, J=2.74 Hz), 7.63 (1 H, br s), 7.89 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.76 Hz), 8.40 (1 H, s), 10.61 (1 H, br s);C 20 H 21 ESIMS observed m / z 464.1 (M+1) for F4N9. [ka]

[0595] (R)-1-(4-((4-amino-5-(3-(2,2-difluoroethyl)-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 (992).

[0596] Light yellow fluffy solid (8 mg, 0.016 mmol, 46.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.53 - 1.78 (1 H, m), 1.80 - 1.98 (1 H, m), 2.02 - 2.08 (3 H, m), 2.91 - 3.04 (1 H, m), 3.65 (1 H, dd, J=28.00, 14.24 Hz), 4.07 - 4.27 (1 H, m), 4.41 - 4.59 (2 H, m), 4.75 (2 H, td, J=16.50, 2.33 Hz), 6.29 (1 H, dd, J=9.31, 6.02 Hz), 6.48 (1 H, tt, J=54.00, 2.75 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.41 (1 H, dd, J=2.87, 1.51 Hz), 7.62 (1 H, br s), 7.89 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.49 Hz), 8.41 (1 H, s), 10.64 (1 H, br s);C 21 H 21 ESIMS observed m / z 492.2 (M+1) for F4N9O. [ka]

[0597] (R)-N 2 -(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (993).

[0598] White fluffy solid (13 mg, 0.026 mmol, 61.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.81 (1 H, m), 1.82 - 1.89 (1 H, m), 2.06 - 2.17 (1 H, m), 2.35 (1 H, dd, J=26.60, 11.23 Hz), 2.74 (1 H, br d, J=11.77 Hz), 2.95 - 3.05 (1 H, m), 3.59 (1 H, quin, J=6.37 Hz), 4.19 - 4.35 (1 H, m), 4.43 (2 H, dt, J=14.10, 6.09 Hz), 4.55 (2 H, td, J=6.64, 3.70 Hz), 4.75 (2 H, td, J=16.45, 2.20 Hz), 6.15 (1 H, br d, J=9.58 Hz), 6.48 (1 H, tt, J=54.00, 2.75 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 C 22 H 23 ESIMS observed m / z 506.25 (M+1) for F4N9O. [ka]

[0599] (R)-N 2 -(3,3-Difluoro-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 (994).

[0600] White solid (18 mg, 0.037 mmol, 56.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.79 (1 H, m), 1.80 - 1.86 (1 H, m), 2.08 - 2.19 (1 H, m), 2.25 (3 H, s), 2.32 (1 H, ddd, J=26.35, 12.59, 1.64 Hz), 2.77 (1 H, br d, J=11.50 Hz), 2.98 - 3.09 (1 H, m), 4.14 - 4.31 (1 H, m), 5.20 (2 H, q, J=9.22 Hz), 6.07 (1 H, d, J=9.58 Hz), 7.17 (1 H, d, J=3.01 Hz), 7.42 C 20 H 20 ESIMS observed m / z 482.2 (M+1) for F5N9. [ka]

[0601] (1r,4r)-4-((4-amino-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 (995).

[0602] White solid (2 mg, 0.005 mmol, 6.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.33 - 1.45 (4 H, m), 1.50 - 1.61 (2 H, m), 1.74 - 1.86 (2 H, m), 2.59 (3 H, s), 3.54 - 3.68 (1 H, m), 4.21 (1 H, br s), 4.54 (2 H, dt, J=27.45, 4.52 Hz), 4.78 (2 H, dt, J=46.90, 4.65 Hz), 5.74 (1 H, d, J=8.21 Hz), 7.08 (1 H, d, J=2.74 Hz), 7.38 (1 H, d, J=2.74 C 22 H 27 ESIMS observed m / z 439.25 (M+1) for FN8O. [ka]

[0603] 1-((3R,4S)-4-((4-amino-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 (996).

[0604] Light yellow fluffy solid (3 mg, 0.006 mmol, 10.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.58 - 1.71 (1 H, m), 1.73 - 1.85 (1 H, m), 1.96 - 2.07 (3 H, m), 2.59 (3 H, s), 2.67 (1 H, td, J=12.73, 3.29 Hz), 2.86 (1 H, dd, J=40.05, 13.96 Hz), 3.91 - 4.04 (1 H, m), 4.38 - 4.47 (1 H, m), 4.55 (2 H, dt, J=27.40, 4.65 Hz), 4.64 - 4.72 (1 H, m), 4.78 (2H, dt, J=47.20, 4.65 Hz), 4.94 (1 H, d, J=49.90 Hz), 5.96 (1 H, dd, J=8.08, 5.61 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=3.01 Hz), 7.60 (1 H, br s), 7.81 (1 H, d, J=8.49 Hz), 7.98 (1 H, d, J=8.49 Hz), 10.81 (1 H, br s);C 22 H 25 ESIMS observed m / z 235.65 (M / 2+1) value for F2N9O. [ka]

[0605] N 2 -((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 (997).

[0606] Light yellow fluffy solid (4 mg, 0.008 mmol, 20.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.65 - 1.76 (1 H, m), 1.85 (1 H, qd, J=12.23, 3.83 Hz), 1.94 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.60, 12.59 Hz), 2.59 (3 H, s), 2.74 (1 H, br d, J=11.23 Hz), 2.91 - 3.04 (1 H, m), 3.48 (1 H, dt, J=12.80, 6.33 Hz), 3.69 - 3.90 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.50 - 4.60 (4 H, m), 4.78 (2 H, dt, J=46.90, 4.73 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.83 (1 H, d, J=8.21 Hz), 7.11 (1 H, d, C 23 H 27 ESIMS observed m / z 242.7 (M / 2+1) for F2N9O. [ka]

[0607] (R)-1-(4-((4-amino-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)-3,3-difluoropiperidin-1-yl)ethan-1-one (998).

[0608] Yellow fluffy solid (0.31 mg, 0.0006 mmol, 1.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.52 - 1.78 (1 H, m), 1.81 - 1.96 (1 H, m), 2.02 - 2.08 (3 H, m), 2.59 (3 H, s), 2.90 - 3.03 (1 H, m), 3.84 (1 H, br d, J=13.69 Hz), 4.07 - 4.26 (1 H, m), 4.42 - 4.52 (2 H, m), 4.55 (2 H, dt, J=27.75, 4.65 Hz), 4.78 (2 H, dt, J=46.90, 4.65 Hz), 6.26 (1 H, dd, J=9.58, 6.57 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.39 (1 H, dd, J=2.74, 1.64 Hz), 7.63 (1 H, br s), 7.81 (1 H, d, J=8.76 Hz), 7.99 (1 H, d, J=8.49 Hz), 8.50 (3 H, s), 10.85 (1 H, br s);C 22 H 24 ESIMS observed value m / z 488.2 (M+1) for F3N9O. [ka]

[0609] (R)-N 2 -(3,3-Difluoro-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 (999).

[0610] White fluffy solid (6 mg, 0.012 mmol, 28.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.80 (1 H, m), 1.82 - 1.89 (1 H, m), 2.06 - 2.17 (1 H, m), 2.34 (1 H, dd, J=26.35, 12.05 Hz), 2.59 (3 H, s), 2.69 - 2.79 (1 H, m), 2.93 - 3.05 (1 H, m), 3.59 (1 H, quin, J=6.30 Hz), 4.18 - 4.35 (1 H, m), 4.43 (2 H, dt, J=13.83, 6.23 Hz), 4.50 - 4.56 (2 H, m), 4.55 (2 H, dt, J=27.45, 4.65 Hz), 4.78 (2 H, dt, J=47.20, 4.73 Hz), 6.12 (1 H, br d, J=9.58 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.63 (1 H, br s), 7.81 (1 H, d, J=8.49 Hz), 7.98 (1 H, d, J=8.49 Hz), 10.85 (1 H, br s);C 23 H 26 ESIMS observed m / z 251.7 (M / 2+1) for F3N9O. [ka]

[0611] 5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N 2 -(cis-4-(difluoromethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1000).

[0612] Yellow fluffy solid (15 mg, 0.031 mmol, 49.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.57 - 1.68 (4 H, m), 1.70 - 1.78 (2 H, m), 1.82 - 1.90 (2 H, m), 3.60 - 3.72 (1 H, m), 4.27 (1 H, br s), 5.16 (2 H, td, J=16.22, 2.33 Hz), 6.13 (1 H, d, J=7.94 Hz), 6.58 (1 H, tt, J=54.00, 2.75 Hz), 6.72 (1 H, t, J=77.05 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.45 (1 H, d, J=2.74 Hz), 7.57 (1 H, br s), 8.08 (1 H, d, J=9.03 Hz), 8.53 (1 H, d, J=9.03 Hz), 10.40 (1 H, br s);C 20 H 21 ESIMS observed m / z 480.2 (M+1) for F4N9O. [ka]

[0613] N 2 -(4,4-difluorocyclohexyl)-5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1001).

[0614] Off-white solid (10 mg, 0.023 mmol, 54.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.55 - 1.68 (2 H, m), 1.82 - 2.00 (4 H, m), 2.01 - 2.14 (2 H, m), 3.10 (3 H, d, J=4.65 Hz), 3.78 (1 H, q, J=8.30 Hz), 4.65 (2 H, dt, J=27.45, 4.79 Hz), 4.93 (2 H, dt, J=46.90, 4.79 Hz), 6.16 (1 H, d, J=7.94 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.88 (1 H, d, J=8.76 Hz), 8.13 (1 H, d, J=8.49 Hz), 8.45 (1 H, s), 11.11 (1 H, q, J=4.65 Hz);C 21 H 23 ESIMS observed m / z 223.2 (M / 2+1) for F3N8. [ka]

[0615] 1-((3R,4S)-3-fluoro-4-((5-(3-(2-fluoroethyl)-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 (1002).

[0616] White fluffy solid (11 mg, 0.023 mmol, 61.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.61 - 1.71 (1 H, m), 1.73 - 1.86 (1 H, m), 1.98 - 2.05 (3 H, m), 2.60 - 2.93 (1 H, m), 3.11 (3 H, d, J=4.65 Hz), 3.83 - 3.92 (1 H, m), 3.93 - 4.05 (1 H, m), 4.07 - 4.18 (1 H, m), 4.40 - 4.49 (1 H, m), 4.66 (2 H, dt, J=27.45, 4.93 Hz), 4.93 (2 H, dt, J=46.90, 4.79 Hz), 4.97 (1 H, d, J=49.10 Hz), 6.09 (1 H, dd, J=7.94, 4.11 Hz), 7.14 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.49 Hz), 8.45 (1 H, s), 11.17 (1 H, q, J=4.29 Hz);C 22 H 25 ESIMS observed m / z 235.65 (M / 2+1) for F2N9O. [ka]

[0617] N 2 -((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1003).

[0618] Off-white fluffy solid (10 mg, 0.021 mmol, 56.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.65 - 1.76 (1 H, m), 1.87 (1 H, qd, J=12.09, 3.70 Hz), 1.96 - 2.03 (1 H, m), 2.13 (1 H, dd, J=37.00, 12.59 Hz), 2.74 (1 H, br d, J=12.05 Hz), 2.97 (1 H, br t, J=10.54 Hz), 3.11 (3 H, d, J=4.93 Hz), 3.48 (1 H, quin, J=6.43 Hz), 3.71 - 3.90 (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=6.50, 3.15 Hz), 4.65 (2 H, dt, J=27.45, 3.79 Hz), 4.90 (1 H, d, J=49.90 Hz), 4.93 (2 H, dt, J=46.90, 3.79 Hz), 5.96 (1 H, d, J=7.94 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.88 (1 H, d, J=8.49 Hz), 8.14 (1 H, d, J=8.76 Hz), 8.45 (1 H, s), 11.15 (1H, q, J=4.56 Hz);C 23 H 27 ESIMS observed m / z 242.7 (M / 2+1) for F2N9O. [ka]

[0619] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1004).

[0620] White fluffy solid (13 mg, 0.028 mmol, 72.0% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.81 (1 H, m), 1.81 - 1.88 (1 H, m), 2.11 - 2.20 (1 H, m), 2.25 (3 H, s), 2.36 (1 H, dd, J=27.15, 12.34 Hz), 2.77 (1 H, br d, J=11.77 Hz), 2.97 - 3.08 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 4.14 - 4.31 (1 H, m), 4.66 (2 H, dt, J=27.40, 4.79 Hz), 4.93 (2 H, dt, J=46.90, 4.79 Hz), 6.12 (1 H, d, J=9.58 Hz), 7.14 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.49 Hz), 8.45 (1 H, s), 11.17 (1 H, q, J=4.65 Hz);C 21 H 24 ESIMS observed m / z 230.65 (M / 2+1) for F3N9. [ka]

[0621] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1005).

[0622] An off-white fluffy solid (e) (10 mg, 0.020 mmol, 57.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.82 (1 H, m), 1.83 - 1.91 (1 H, m), 2.14 (1 H, br t, J=10.68 Hz), 2.38 (1 H, dd, J=26.30, 11.77 Hz), 2.74 (1 H, br d, J=11.50 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), 4.20 - 4.35 (1 H, m), 4.44 (2 H, dt, J=14.31, 6.26 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 4.66 (2 H, dt, J=27.40, 4.79 Hz), 4.94 (2 H, dt, J=46.90, 4.79 Hz), 6.21 (1 H, d, J=9.31 Hz), 7.15 (1 H, d, C 23 H 26 ESIMS observed m / z 251.70 (M / 2+1) for F3N9O. [ka]

[0623] (R)-1-(3,3-difluoro-4-((5-(3-(2-fluoroethyl)-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 (1006).

[0624] White fluffy solid (7 mg, 0.014 mmol, 46.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.56 - 1.80 (1 H, m), 1.82 - 1.99 (1 H, m), 2.02 - 2.08 (3 H, m), 3.00 (1 H, br t, J=10.81 Hz), 3.13 (3 H, d, J=4.65 Hz), 3.61 - 3.90 (1 H, m), 4.08 - 4.28 (1 H, m), 4.41 - 4.57 (2 H, m), 4.66 (2 H, dt, J=27.45, 4.79 Hz), 4.94 (2 H, dt, J=47.20, 4.95 Hz), 6.35 (1 H, dd, J=9.45, 6.43 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.38 (1 H, dd, J=2.74, 1.64 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.76 Hz), 8.46 (1 H, s), 11.20 (1 H, q, J=4.38 Hz);C 22 H 24 ESIMS observed m / z 244.65 (M / 2+1) for F3N9O. [ka]

[0625] N 2 -(4,4-difluorocyclohexyl)-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1007).

[0626] Off-white solid (12 mg, 0.026 mmol, 63.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.55 - 1.69 (2 H, m), 1.82 - 2.00 (4 H, m), 2.01 - 2.14 (2 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.73 - 3.84 (1 H, m), 4.83 (2 H, td, J=16.08, 2.60 Hz), 6.17 (1 H, d, J=7.94 Hz), 6.62 (1 H, tt, J=54.60, 3.01 Hz), 7.13 (1 H, d, J=2.74 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.91 (1 H, d, J=8.49 Hz), 8.15 (1 H, d, J=8.49 Hz), 8.43 (1 H, s), 10.99 (1 H, q, J=4.56 Hz);C 21 H 22 ESIMS observed m / z 232.1 (M / 2+1) for F4N8. [ka]

[0627] (1r,4r)-4-((5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (1008).

[0628] Off-white fluffy solid (12 mg, 0.026 mmol, 54.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.35 - 1.49 (4 H, m), 1.53 - 1.65 (2 H, m), 1.78 - 1.90 (2 H, m), 3.11 (3 H, d, J=4.65 Hz), 3.62 (1 H, br dd, J=8.35, 3.97 Hz), 4.21 (1 H, s), 4.82 (2 H, td, J=16.08, 2.60 Hz), 5.86 (1 H, d, J=8.21 Hz), 6.62 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 H, d, J=2.74 Hz), 7.38 (1 H, d, J=3.01 Hz), 7.90 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.76 Hz), 8.41 (1 H, s), 10.95 (1 H, q, J=4.38 Hz); 22 H 26 ESIMS observed m / z 457.2 (M+1) for F2N8O. [ka]

[0629] 5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1009).

[0630] Off-white fluffy solid (7 mg, 0.014 mmol, 33.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.65 - 1.76 (1 H, m), 1.87 (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=11.23 Hz), 2.92 - 3.03 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.49 (1 H, quin, J=6.37 Hz), 3.73 - 3.90 (1 H, m), 4.40 (1 H, t, J=6.02 Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.50, 3.15 Hz), 4.83 (2 H, td, J=16.20, 2.60 Hz), 4.91 (1 H, d, J=47.45 Hz), 5.97 (1 H, d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.91 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 11.04 (1 H, q, J=4.56 Hz);C 23 H 26 ESIMS observed m / z 502.2 (M+1) for F3N9O. [ka]

[0631] (R)-1-(4-((5-(3-(2,2-difluoroethyl)-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)ethan-1-one (1010).

[0632] White solid (14 mg, 0.028 mmol, 32.1% yield).1 H NMR (499 MHz, DMSO-d6) δ ppm 1.53 - 1.81 (1 H, m), 1.82 - 1.98 (1 H, m), 2.01 - 2.09 (3 H, m), 2.92 - 3.05 (1 H, m), 3.15 (3 H, d, J=4.65 Hz), 3.58 - 3.91 (1 H, m), 4.08 - 4.27 (1 H, m), 4.41 - 4.61 (2 H, m), 4.84 (2 H, td, J=16.08, 2.60 Hz), 6.37 (1 H, dd, J=9.31, 5.75 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.17 (1 H, d, J=3.01 Hz), 7.38 (1 H, dd, J=2.87, 1.51 Hz), 7.92 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.76 Hz), 8.43 (1 H, s), 11.09 (1 H, q, J=4.56 Hz);C 22 H 23 ESIMS observed m / z 506.2 (M+1) for F4N9O. [ka]

[0633] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1011).

[0634] Off-white fluffy solid (14 mg, 0.029 mmol, 74.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.81 (1 H, m), 1.81 - 1.87 (1 H, m), 2.16 (1 H, br t, J=10.13 Hz), 2.25 (3 H, s), 2.36 (1 H, dd, J=27.15, 11.77 Hz), 2.77 (1 H, br d, J=11.77 Hz), 2.99 - 3.08 (1 H, m), 3.13 (3 H, d, J=4.93 Hz), 4.15 - 4.32 (1 H, m), 4.83 (2 H, td, J=16.45, 2.75 Hz), 6.14 (1 H, d, J=9.58 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=2.74 Hz), 7.92 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 11.06 (1 H, q, J=4.38 Hz);C 21 H 23 ESIMS observed m / z 239.65 (M / 2+1) for F4N9. [ka]

[0635] 1-((3R,4S)-4-((5-(3-(2,2-difluoroethyl)-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 (1012).

[0636] Light yellow solid (21 mg, 0.043 mmol, 54.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.59 - 1.71 (1 H, m), 1.73 - 1.89 (1 H, m), 1.97 - 2.06 (3 H, m), 2.66 - 2.95 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.84 - 3.92 (1 H, m), 3.93 - 4.06 (1 H, m), 4.07 - 4.17 (1 H, m), 4.37 - 4.73 (1 H, m), 4.83 (2 H, td, J=16.29, 2.74 Hz), 4.97 (1 H, d, J=49.65 Hz), 6.11 (1 H, dd, J=8.08, 3.70 Hz), 6.63 (1 H, tt, J=54.55, 3.05 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=3.01 Hz), 7.92 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.49 Hz), 8.43 (1 H, s), 11.05 (1 H, q, J=4.38 Hz);C 22 H 24 ESIMS observed value m / z 488.2 (M+1) for F3N9O. [ka]

[0637] (R)-N 2 -(3,3-Difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (1013).

[0638] Off-white solid (5 mg, 0.010 mmol, 11.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.82 (1 H, m), 1.85 - 1.92 (1 H, m), 2.09 - 2.20 (1 H, m), 2.32 - 2.44 (1 H, m), 2.74 (1 H, br d, J=11.50 Hz), 2.93 - 3.04 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.22 - 4.36 (1 H, m), 4.44 (2 H, dt, J=14.44, 6.19 Hz), 4.55 (2 H, td, J=6.57, 3.29 Hz), 4.75 - 4.90 (2 H, m), 6.23 (1 H, d, J=9.58 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=3.01 Hz), 7.92 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.49 Hz), 8.41 - 8.45 (1 H, m), 11.04 - 11.12 (1 H, m);C 23 H 25 ESIMS observed m / z 520.2 (M+1) for F4N9O. [ka]

[0639] N 2 -(4,4-difluorocyclohexyl)-N 4 -methyl-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 (1014).

[0640] White fluffy solid (11 mg, 0.023 mmol, 55.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.53 - 1.68 (2 H, m), 1.81 - 2.00 (4 H, m), 2.01 - 2.14 (2 H, m), 3.11 (3 H, d, J=4.65 Hz), 3.70 - 3.85 (1 H, m), 5.35 (2 H, q, J=9.49 Hz), 6.21 (1 H, d, J=7.94 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.96 (1 H, d, J=8.76 Hz), 8.18 (1 H, d, J=8.76 Hz), 8.49 (1 H, s), 10.91 (1 H, q, J=4.38 Hz);C 21 H 21 ESIMS observed m / z 481.2 (M+1) for F5N8. [ka]

[0641] 1-((3R,4S)-3-Fluoro-4-((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)piperidin-1-yl)ethan-1-one (1015).

[0642] Off-white fluffy solid (15 mg, 0.030 mmol, 77.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.61 - 1.71 (1 H, m), 1.72 - 1.86 (1 H, m), 1.98 - 2.05 (3 H, m), 2.66 - 2.96 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.83 - 3.92 (1 H, m), 3.92 - 4.05 (1 H, m), 4.06 - 4.17 (1 H, m), 4.39 - 4.76 (1 H, m), 4.97 (1 H, d, J=49.35 Hz), 5.36 (2 H, q, J=9.22 Hz), 6.15 (1 H, dd, J=7.94, 3.29 Hz), 7.19 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=2.74 Hz), 7.97 (1 H, d, J=8.76 Hz), 8.19 (1 H, d, J=8.76 Hz), 8.49 (1 H, s), 10.97 (1 H, q, J=4.56 Hz);C 22 H 23 ESIMS observed m / z 506.2 (M+1) for F4N9O. [ka]

[0643] N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -methyl-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 (1016).

[0644] Off-white fluffy solid (15 mg, 0.029 mmol, 78.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.65 - 1.76 (1 H, m), 1.88 (1 H, qd, J=12.14, 3.83 Hz), 1.95 - 2.05 (1 H, m), 2.13 (1 H, dd, J=37.60, 12.87 Hz), 2.74 (1 H, br d, J=10.40 Hz), 2.91 - 3.03 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.72 - 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=6.50, 3.15 Hz), 4.90 (1 H, d, J=49.90 Hz), 5.35 (2 H, q, J=9.22 Hz), 6.02 (1 H, d, J=7.94 Hz), 7.18 (1 H, C 23 H 25 ESIMS observed m / z 260.70 (M / 2+1) for F4N9O. [ka]

[0645] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-N 4 -methyl-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 (1017).

[0646] Off-white fluffy solid (13 mg, 0.026 mmol, 66.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.69 - 1.90 (2 H, m), 2.08 - 2.19 (1 H, m), 2.25 (3 H, s), 2.35 (1 H, dd, J=26.90, 12.32 Hz), 2.71 - 2.82 (1 H, m), 2.97 - 3.08 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 4.14 - 4.31 (1 H, m), 5.36 (2 H, q, J=9.22 Hz), 6.18 (1 H, d, J=9.58 Hz), 7.19 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, C 21 H 22 ESIMS observed m / z 248.65 (M / 2+1) for F5N9. [ka]

[0647] (R)-1-(3,3-difluoro-4-((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)piperidin-1-yl)ethan-1-one (1018).

[0648] Off-white fluffy solid (15 mg, 0.029 mmol, 79.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.55 - 1.80 (1 H, m), 1.82 - 1.98 (1 H, m), 2.02 - 2.08 (3 H, m), 2.99 (1 H, br t, J=10.95 Hz), 3.14 (3 H, d, J=4.65 Hz), 3.62 - 3.89 (1 H, m), 4.09 - 4.28 (1 H, m), 4.42 - 4.60 (2 H, m), 5.36 (2 H, q, J=9.22 Hz), 6.41 (1 H, dd, J=9.31, 5.48 Hz), 7.20 (1 H, d, J=3.01 Hz), 7.39 (1 H, C 22 H 22 ESIMS observed m / z 524.2 (M+1) for F5N9O. [ka]

[0649] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -methyl-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 (1019).

[0650] Off-white fluffy solid (4 mg, 0.007 mmol, 21.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.73 - 1.82 (1 H, m), 1.84 - 1.91 (1 H, m), 2.14 (1 H, br t, J=10.68 Hz), 2.38 (1 H, dd, J=26.85, 11.77 Hz), 2.74 (1 H, br d, J=11.23 Hz), 2.95 - 3.05 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.60 (1 H, quin, J=6.23 Hz), 4.20 - 4.36 (1 H, m), 4.44 (2 H, dt, J=14.44, 6.19 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 5.36 (2 H, q, J=9.13 Hz), 6.26 (1 H, d, J=9.31 Hz), 7.19 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.97 (1 H, d, J=8.76 Hz), 8.19 (1 H, d, J=8.49 Hz), 8.49 (1 H, s), 10.98 (1 H, q, J=4.38 Hz);C 23 H 24 ESIMS observed m / z 269.65 (M / 2+1) for F5N9O. [ka]

[0651] 1-((3R,4S)-3-Fluoro-4-((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 (1020).

[0652] White solid (13 mg, 0.027 mmol, 53.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.56 - 1.72 (1 H, m), 1.72 - 1.87 (1 H, m), 1.98 - 2.07 (3 H, m), 2.61 (3 H, s), 2.78 - 2.96 (1 H, m), 3.11 (3 H, d, J=4.65 Hz), 3.84 - 3.92 (1 H, m), 3.93 - 4.06 (1 H, m), 4.07 - 4.16 (1 H, m), 4.34 - 4.49 (1 H, m), 4.61 (2 H, dt, J=26.60, 4.79 Hz), 4.90 (2 H, dt, J=46.90, 4.93 Hz), 4.97 (1 H, d, J=49.65 Hz), 6.06 (1 H, dd, J=8.08, 4.79 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=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 11.13 (1 H, q, J=4.47 Hz);C 23 H 27 ESIMS observed m / z 484.2 (M+1) for F2N9O. [ka]

[0653] (R)-1-(3,3-difluoro-4-((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 (1021).

[0654] White solid (11 mg, 0.022 mmol, 43.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.54 - 1.80 (1 H, m), 1.82 - 2.00 (1 H, m), 2.02 - 2.09 (3 H, m), 2.62 (3 H, s), 3.00 (1 H, br t, J=10.95 Hz), 3.13 (3 H, d, J=4.93 Hz), 3.60 - 3.90 (1 H, m), 4.08 - 4.27 (1 H, m), 4.40 - 4.55 (2 H, m), 4.61 (2 H, dt, J=26.90, 4.79 Hz), 4.90 (2 H, dt, J=46.65, 4.93 Hz), 6.33 (1 H, dd, J=9.45, 6.71 Hz), 7.11 (1 H, d, J=2.74 Hz), 7.36 (1 H, dd, J=2.74, 1.64 Hz), 7.82 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 11.16 (1 H, q, J=4.56 Hz);C 23 H 26 ESIMS observed m / z 502.2 (M+1) for F3N9O. [ka]

[0655] 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)ethan-1-one (1022).

[0656] White solid (17 mg, 0.034 mmol, 68.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.58 - 1.71 (1 H, m), 1.73 - 1.87 (1 H, m), 1.97 - 2.06 (3 H, m), 2.80 - 2.96 (1 H, m), 3.13 (3 H, d, J=4.93 Hz), 3.89 (1 H, br d, J=13.69 Hz), 3.93 - 4.06 (1 H, m), 4.11 (1 H, ddd, J=12.05, 9.86, 2.46 Hz), 4.39 - 4.71 (1 H, m), 4.78 (2 H, td, J=16.02, 2.46 Hz), 4.97 (1 H, d, J=49.40 Hz), 6.08 (1 H, dd, J=8.08, 4.24 Hz), 6.64 (1 H, tt, J=54.60, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.99 (1 H, q, J=4.65 Hz);C 23 H 26 ESIMS observed m / z 502.2 (M+1) for F3N9O. [ka]

[0657] (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)ethan-1-one (1023).

[0658] White solid (11 mg, 0.021 mmol, 42.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.54 - 1.80 (1 H, m), 1.82 - 1.98 (1 H, m), 2.03 - 2.08 (3 H, m), 2.63 (3 H, s), 2.95 - 3.05 (1 H, m), 3.15 (3 H, d, J=4.65 Hz), 3.62 - 3.90 (1 H, m), 4.08 - 4.28 (1 H, m), 4.42 - 4.60 (2 H, m), 4.78 (2 H, td, J=15.88, 2.46 Hz), 6.34 (1 H, dd, J=9.45, 6.43 Hz), 6.64 (1 H, tt, J=54.30, 3.05 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.37 (1 H, dd, J=2.74, 1.64 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...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: 【Chemistry 245】 (In the formula, R １ But R from 1 to 10 ４ (9-10 membered heteroaryl) optionally substituted with R ２ is unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), unsubstituted (C １－９ haloalkyl), R 1 to 10 ５ -heterocyclyl optionally substituted with, and R ６ -(C １－５ alkylene) ｐ carbocyclyl, wherein -(C １－５ alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C １－３ alkyl), R ３ is H, unsubstituted (C １－６ alkyl), unsubstituted (C ２－６ alkenyl), unsubstituted (C ２－６ alkynyl), unsubstituted (C １－６ haloalkyl), and R 1 to 10 １６ -heterocyclyl optionally substituted with Each R ４ are independently halide, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), unsubstituted (C １－９ haloalkyl); Each R ５ are independently halide, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), unsubstituted (C １－９ haloalkyl), R 1 to 10 ７ -heterocyclyl optionally substituted with R 1 to 12 １４ -carbocyclyl optionally substituted with -(C １－５ alkylene) ｐ OR ８ and -C(=O)R ９ wherein -(C １－５ alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C １－３ alkyl), Alternatively, two R groups bonded to the same carbon atom ５ together to form a carbonyl group, Each R ６ are independently halide, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), unsubstituted (C １－９ haloalkyl), -CN, -(C １－５ alkylene) ｐ OR １０ , -C(=O)R １１ , -NHC(=O)R １２ , and R 1 to 12 １４ -carbocyclyl optionally substituted with -(C １－５ alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted (C １－３ alkyl), Each R ７ are independently halide, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), unsubstituted (C １－９ haloalkyl), —CN, and R 1 to 12 １４ -carbocyclyl optionally substituted with Each R ８ are independently H, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), and unsubstituted (C １－９ haloalkyl); Each R ９ are independently unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), and unsubstituted (C １－９ haloalkyl); Each R １０ are independently H, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), unsubstituted (C １－９ haloalkyl), and -(C １－５ alkylene) ｐ OR ８ selected from the group consisting of Each R １１ But -N(R １３ ) ２ and Each R １２ are independently unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), and unsubstituted (C １－９ haloalkyl); Each R １３ are independently H, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), and unsubstituted (C １－９ haloalkyl); Each R １４ are independently halide, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), and unsubstituted (C １－９ haloalkyl); R １５ is selected from the group consisting of H and halides; Each R １６ are independently halide, unsubstituted (C １－９ alkyl), unsubstituted (C ２－９ alkenyl), unsubstituted (C ２－９ alkynyl), and unsubstituted (C １－９ haloalkyl); each p is independently 0 or 1; Each H atom independently ２ H(D) (deuterium)).

2. R １５ The compound of claim 1 , wherein is H.

3. R １５ The compound of claim 1 , wherein is F.

4. R １ but, R from 1 to 10 ４ optionally replaced with 【Chemistry 246】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

5. R １ but, 1 to 3 R ４ optionally replaced with 【Chemistry 247】 The compound according to any one of claims 1 to 4, selected from the group consisting of:

6. R １ but, 1 to 3 R ４ optionally replaced with 【Chemistry 248】 The compound according to any one of claims 1 to 5, selected from the group consisting of:

7. R １ but, 1 to 3 R ４ optionally replaced with 【Chemistry 249】 The compound according to any one of claims 1 to 6, selected from the group consisting of:

8. R ４ is halide, unsubstituted (C １－４ alkyl), and unsubstituted (C １－４ The compound of any one of claims 1 to 7, selected from the group consisting of: (a) alkyl, alkyl haloalkyl;

9. R １ but, [Chemical 250] The compound according to any one of claims 1 to 8, selected from the group consisting of:

10. R １ but, 【Chemistry 251】 The compound according to any one of claims 1 to 9, selected from the group consisting of:

11. R ２ However, 1 to 4 R ５ -heterocyclyl optionally substituted with, and 1 to 4 R ６ 11. The compound of any one of claims 1 to 10, wherein the compound is selected from the group consisting of -carbocyclyl optionally substituted with

12. R ２ but, 【Chemistry 252】 and each R ５ is Me, —C(═O)Me, and 【Chemistry 253】 The compound according to any one of claims 1 to 11, selected from the group consisting of:

13. R ３ is H and unsubstituted (C １－３ The compound of any one of claims 1 to 12, wherein the compound is selected from the group consisting of:

14. R ３ The compound according to any one of claims 1 to 13, wherein is H.

15. R ３ The compound according to any one of claims 1 to 13, wherein is methyl.

16. The compound of formula I is 【Chemistry 254-1】 【Chemistry 254-2】 【Chemistry 254-3】 【Chemistry 254-4】 【Chemistry 254-5】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

17. The compound of formula I is 【Chemistry 255-1】 【Chemistry 255-2】 【Chemistry 255-3】 【Chemistry 255-4】 【Chemistry 255-5】 【Chemistry 255-6】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. The compound of formula I is 【Chemistry 256-1】 【Chemistry 256-2】 【Chemistry 256-3】 【Chemistry 256-4】 【Chemistry 256-5】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. The compound of formula I is 【Chemistry 257-1】 【Chemistry 257-2】 【Chemistry 257-3】 【Chemistry 257-4】 【Chemistry 257-5】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

20. The compound of formula I is 【Chemistry 258-1】 【Chemistry 258-2】 【Chemistry 258-3】 【Chemistry 258-4】 【Chemistry 258-5】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

21. The compound of formula I is 【Chemistry 259-1】 【Chemistry 259-2】 【Chemistry 259-3】 【Chemistry 259-4】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

22. The compound of formula I is 【Chemistry 260-1】 【Chemistry 260-2】 【Chemistry 260-3】 【Chemistry 260-4】 【Chemistry 260-5】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

23. The compound of formula I is 【Chemistry 261-1】 【Chemistry 261-2】 【Chemistry 261-3】 【Chemistry 261-4】 【Chemistry 261-5】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

24. The compound of formula I is 【Chemistry 262-1】 【Chemistry 262-2】 【Chemistry 262-3】 【Chemistry 262-4】 【Chemistry 262-5】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

25. The compound of formula I is 【Chemistry 263-1】 【Chemistry 263-2】 【Chemistry 263-3】 【Chemistry 263-4】 【Chemistry 263-5】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

26. The compound of formula I is 【Chemistry 264-1】 【Chemistry 264-2】 16. The compound according to any one of claims 1 to 15, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

27. 27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

28. 28. A method of treating a disorder or disease in a patient, wherein the disorder or disease is selected from the group consisting of neuropathy, diabetes, and cancer, said method comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, or a pharmaceutical composition according to claim 27.

29. 29. The method of claim 28, wherein the disorder or disease is cancer.

30. 29. The method of claim 28, wherein the disorder or disease is diabetes.

31. 29. The method of claim 28, wherein the disorder or disease is a neurological disorder.

32. 30. The method of any one of claims 28 to 29, wherein the cancer is selected from the group consisting of brain tumor, glioblastoma, ovarian cancer, breast cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, pancreatic cancer, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, and chronic myeloid leukemia.

33. The disorder or disease is a neurological disorder, and the neurological disorder is Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency, Down's syndrome, frontotemporal dementia with Parkinson's disease 17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, and further diseases with significant neurodegeneration (e.g., autism, dementia, epilepsy, Huntington's disease, multiple sclerosis); diseases and disorders associated with acquired brain injury (e.g., The method according to any one of claims 28 to 31, wherein the tauopathy is selected from the group consisting of chronic traumatic encephalopathy, traumatic brain injury, tumor, stroke, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and age-related tauastrogliopathy.

34. 34. The method of any one of claims 28, 31, and 33, wherein the disorder or disease is Alzheimer's disease.

35. The method of any one of claims 28 to 34, wherein the patient is a human.

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