4-alkoxypyrrolo[2,1-f][1,2,4]triazines and their preparations and uses

Abstract

Disclosed are 4-alkoxypyrrolo[2,1-f][1,2,4]triazine compounds for treating various diseases and pathologies. More specifically, the disclosure relates to the use of 4-alkoxypyrrolo[2,1-f][1,2,4]triazine compounds or analogs thereof in the treatment of disorders characterized by overexpression of DYRK1A (e.g., cancer, Down's syndrome, Alzheimer's disease, diabetes, viral infections, and osteoarthritis).

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 355,076, filed June 23, 2022, U.S. Provisional Application No. 63 / 427,322, filed November 22, 2022, and U.S. Provisional Application No. 63 / 458,808, filed April 12, 2023, which are incorporated 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-alkoxypyrrolo[2,1-f][1,2,4]triazine compounds or salts or analogs thereof in the treatment of disorders characterized by abnormal expression and / or activity of DYRK1A (e.g., cancer, Down's syndrome, Alzheimer's disease, diabetes, viral infections, and osteoarthritis). [Background technology]

[0003] background Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) constitute 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 metabolic 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 unicellular parasites (Leishmania, Trypanosoma, Plasmodium) (International Journal of Molecular Sciences (2021), 22(11), 6047 (Non-Patent Document 1)). DYRK1A has also been identified as a key stabilizer of EGFR, a key factor in keratinization, cell hyperproliferation, abnormal differentiation, and inflammatory infiltration during the progression of psoriasis (Cell Death & Disease (2019), 10, 282 (Non-Patent Document 2)). [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

[0005] overview The present disclosure provides methods and reagents that involve contacting cells with an agent, such as a 4-alkoxypyrrolo[2,1-f][1,2,4]triazine compound, to antagonize DYRK1A activity, for example, in an amount sufficient to reduce the growth of head and neck squamous cell carcinoma, luminal / HER2 breast cancer (Cell (2016), 164(1-2), 293-309), or pancreatic adenocarcinoma, impair the self-renewal capacity of glioblastoma, and reduce the viability of ovarian cancer spheroid cells (Molecular Cancer Research (2017), 15(4), 371-381).

[0006] The disclosure also provides methods and reagents for antagonizing DYRK1A activity, including contacting a cell with an agent, such as a 4-alkoxypyrrolo[2,1-f][1,2,4]triazine compound, in an amount sufficient to: i) normalize prenatal and early postnatal brain development; ii) improve cognitive function during adolescence and adulthood; and / or III) attenuate Alzheimer's-type neurodegeneration.

[0007] Some embodiments disclosed herein include DYRK1A inhibitors containing a 4-alkoxypyrrolo[2,1-f][1,2,4]triazine core. Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.

[0008] One embodiment disclosed herein is a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 is 1 to 10 R 4 is heteroaryl optionally substituted with R 2is an unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 5 , 1 to 10 R 6 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 10 R 7 -heteroaryl optionally substituted with, and 1 to 12 R 8 may be substituted with -(C 1-5 alkylene) p carbocyclyl, wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), R 3 is H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 4 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 9 , -(C 1-5 alkylene)CN, 1 to 10 R 10 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 12 R 11 -carbocyclyl, optionally substituted with 1 to 10 R 20 may be substituted with -(C 1-5 alkylene) pHeteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2, and -C(=O)R 13 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 5 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 6 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), 1 to 10 R 16 -heterocyclyl, -(C 1-5 alkylene) p OR 21 , -SO2R 23 , and -C(=O)R 24 wherein -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Alternatively, two R attached to the same carbon atom 6 together form a carbonyl group, Each R 7 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and -OMe; Each R 8 are independently selected from halide, unsubstituted -(C1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -N(R 14 )2, -(C 1-5 alkylene) p OR 15 , 1 to 10 R 16 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, -C(=O)R 22 , and -NHC(=O)R 23 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 9 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 10 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 11 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 12 are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9haloalkyl), 1 to 12 R 17 may be substituted with -(C 1-5 alkylene) p Carbocyclyl, 1 to 10 R 18 -heterocyclyl optionally substituted with, and 1 to 10 R 19 -heteroaryl, optionally substituted with -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 13 is 1 to 10 R 18 -heterocyclyl optionally substituted by Each R 14 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 15 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 21 is selected from the group consisting of Each R 16 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 17 are independently selected from halide, -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9haloalkyl), Each R 18 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 19 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 20 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 21 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 22 are independently 1 to 10 R 18 -heterocyclyl, -N(R 12 )2, and -OR 21 is selected from the group consisting of Each R 23 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 24 are independently unsubstituted -(C 1-9 alkyl), unsubstituted -(C2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -OR 23 , and 1 to 12 R 25 -carbocyclyl optionally substituted with Each R 25 are independently selected from 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; where each H atom is independently 2 H(D) (deuterium) may be substituted.

[0009] In another embodiment disclosed herein, a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 is 1 to 10 R 4 is heteroaryl optionally substituted with R 2 is an unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 5 , 1 to 10 R 6 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 10 R 26 may be substituted with -(C 1-5 alkylene) p Aryl, 1 to 10 R 7 may be substituted with -(C1-5 alkylene) p Heteroaryl and 1 to 12 R 8 may be substituted with -(C 1-5 alkylene) p carbocyclyl, wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), R 3 is H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and 1 to 10 R 18 heterocyclyl optionally substituted with Each R 4 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 9 , -(C 1-5 alkylene) p CN, 1 to 10 R 10 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 12 R 11 -carbocyclyl, optionally substituted with 1 to 10 R 20 may be substituted with -(C 1-5 alkylene) p Heteroaryl, (C 1-5 alkylene) p C(=O)N(R 12 )2, and -C(=O)R 13 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3alkyl), Each R 5 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 6 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), 1 to 10 R 16 -heterocyclyl optionally substituted with 1 to 12 R 17 -carbocyclyl, -(C 1-5 alkylene) p OR 21 , -SO2R 23 , and -C(=O)R 24 wherein -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Alternatively, two R attached to the same carbon atom 6 together form a carbonyl group, Each R 7 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and -OMe; Each R 8 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -N(R 14 )2, -(C 1-5alkylene) p OR 15 , 1 to 10 R 16 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, -C(=O)R 22 , and -NHC(=O)R 23 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 9 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 10 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 11 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 12 are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 21 , 1 to 12 R 17 may be substituted with -(C 1-5 alkylene) pCarbocyclyl, 1 to 10 R 18 -heterocyclyl optionally substituted with, and 1 to 10 R 19 -heteroaryl, optionally substituted with -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 13 is 1 to 10 R 18 -heterocyclyl optionally substituted by Each R 14 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 15 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 21 is selected from the group consisting of Each R 16 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Alternatively, two R attached to the same carbon atom 16 together form a carbonyl group, Each R 17 are independently selected from halide, -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9haloalkyl), Each R 18 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 19 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 20 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 21 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 22 are independently 1 to 10 R 18 -heterocyclyl, -N(R 12 )2, and -OR 21 is selected from the group consisting of Each R 23 are independently 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 21 is selected from the group consisting of Each R24 are independently unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -OR 21 , and 1 to 12 R 25 -carbocyclyl optionally substituted with Each R 25 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 26 are independently selected from 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; where each H atom is independently 2 H(D) (deuterium) may be substituted.

[0010] In another embodiment disclosed herein, a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 is 1 to 10 R 4 is heteroaryl optionally substituted with R 2 is an unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene)p OR 5 , -(C 1-5 alkylene)CN, 1 to 10 R 6 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 10 R 26 may be substituted with -(C 1-5 alkylene) p Aryl, 1 to 10 R 7 may be substituted with -(C 1-5 alkylene) p Heteroaryl and 1 to 12 R 8 may be substituted with -(C 1-5 alkylene) p carbocyclyl, wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), R 3 is H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and 1 to 10 R 18 heterocyclyl optionally substituted with Each R 4 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), unsubstituted -(C 2-9 haloalkenyl), -(C 1-5 alkylene) p OR 9 , -(C 1-5 alkylene) p CN, 1 to 10 R 10 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 12 R 11-carbocyclyl, optionally substituted with 1 to 10 R 20 may be substituted with -(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2, and -C(=O)R 13 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 5 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 6 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), 1 to 10 R 16 -heterocyclyl optionally substituted with 1 to 12 R 17 -carbocyclyl, -(C 1-5 alkylene) p OR 21 , -(C 1-5 Alkylene)CN, -SO2R 23 , and -C(=O)R 24 wherein -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Alternatively, two R attached to the same carbon atom 6 together form a carbonyl group, Each R 7 are independently selected from halide, unsubstituted -(C 1-9alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and -OMe; Each R 8 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -N(R 14 )2, -(C 1-5 alkylene) p OR 15 , -CN, 1 to 10 R 16 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, -C(=O)R 22 , and -NR 14 C(=O)R 23 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 9 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 10 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 11 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C1-9 haloalkyl), Each R 12 are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 21 , 1 to 12 R 17 may be substituted with -(C 1-5 alkylene) p Carbocyclyl, 1 to 10 R 18 -heterocyclyl optionally substituted with, and 1 to 10 R 19 -heteroaryl, optionally substituted with -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 13 is 1 to 10 R 18 -heterocyclyl optionally substituted by Each R 14 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 15 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 21 is selected from the group consisting of Each R 16 are independently selected from halide, -CN, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and 1 to 12 R 27 -carbocyclyl optionally substituted with Alternatively, two R attached to the same carbon atom 16 together form a carbonyl group, Each R 17 are independently selected from halide, -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 18 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 19 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 20 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 21 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 22are independently 1 to 10 R 18 -heterocyclyl, -N(R 12 )2, and -OR 21 is selected from the group consisting of Each R 23 are independently unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 21 , and 1 to 12 R 25 -carbocyclyl optionally substituted with Each R 24 are independently unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -OR 21 , and 1 to 12 R 25 -carbocyclyl optionally substituted with Each R 25 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and —CN; Each R 26 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 27 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C1-9 haloalkyl), R 28 is independently selected from the group consisting of H and halides; each p is independently 0 or 1; where each H atom is independently 2 H(D) (deuterium) may be substituted.

[0011] In another embodiment disclosed herein, a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 is 1 to 10 R 4 is heteroaryl optionally substituted with R 2 is an unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 5 , -(C 1-5 alkylene)CN, 1 to 10 R 6 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 10 R 26 may be substituted with -(C 1-5 alkylene) p Aryl, 1 to 10 R 7 may be substituted with -(C 1-5 alkylene) p Heteroaryl and 1 to 12 R 8 may be substituted with -(C 1-5 alkylene) p carbocyclyl, wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C1-3 alkyl), R 3 is H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and 1 to 10 R 18 heterocyclyl optionally substituted with Each R 4 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), unsubstituted -(C 2-9 haloalkenyl), -(C 1-5 alkylene) p OR 9 , -(C 1-5 alkylene) p CN, 1 to 10 R 10 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 12 R 11 -carbocyclyl, optionally substituted with 1 to 10 R 20 may be substituted with -(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2, and -C(=O)R 13 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 5 are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9haloalkyl), Each R 6 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), 1 to 10 R 16 -heterocyclyl optionally substituted with 1 to 12 R 17 -carbocyclyl, -(C 1-5 alkylene) p OR 21 , -(C 1-5 Alkylene)CN, -SO2R 23 , and -C(=O)R 24 wherein -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Alternatively, two R attached to the same carbon atom 6 together form a carbonyl group, Each R 7 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and -OMe; Each R 8 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -N(R 14 )2, -(C 1-5 alkylene) p OR 15 , -CN, 1 to 10 R 16 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, -C(=O)R22 , and -NR 14 C(=O)R 23 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 9 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 10 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 11 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 12 are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 21 , 1 to 12 R 17 may be substituted with -(C 1-5 alkylene) p Carbocyclyl, 1 to 10 R 18 -heterocyclyl optionally substituted with, and 1 to 10 R 19 -heteroaryl, optionally substituted with -(C1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 alkyl), Each R 13 is 1 to 10 R 18 -heterocyclyl optionally substituted by Each R 14 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 15 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 21 is selected from the group consisting of Each R 16 are independently selected from halide, -CN, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and 1 to 12 R 27 -carbocyclyl optionally substituted with Alternatively, two R attached to the same carbon atom 16 together form a carbonyl group, Each R 17 are independently selected from halide, -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 18 are independently selected from halide, unsubstituted -(C 1-9alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 19 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 20 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 21 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 22 are independently 1 to 10 R 18 -heterocyclyl, -N(R 12 )2, and -OR 21 is selected from the group consisting of Each R 23 are independently unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 21 , and 1 to 12 R 25 -carbocyclyl optionally substituted with Each R 24 are independently unsubstituted -(C 1-9alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -OR 21 , and 1 to 12 R 25 -carbocyclyl optionally substituted with Each R 25 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and —CN; Each R 26 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), Each R 27 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), R 28a is independently selected from the group consisting of H and halides; R 28b is independently selected from the group consisting of H and D; each p is independently 0 or 1; where each H atom is independently 2 H(D) (deuterium) may be substituted.

[0012] Some embodiments include stereoisomers and pharmaceutically acceptable salts of compounds of Formula I. Some embodiments include pharmaceutically acceptable salts of compounds of Formula I.

[0013] Some embodiments include prodrugs of compounds of formula I.

[0014] Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient.

[0015] 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, such as Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency, Down's syndrome, frontotemporal dementia with parkinsonism-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.

[0016] 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).

[0017] Inhibitors of DYRK1A can also be used to treat disorders associated with malformed folate / methionine metabolism.

[0018] 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).

[0019] Some embodiments of the present disclosure include methods for preparing compounds of formula I.

[0020] 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 present disclosure, as claimed. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description Provided herein are compositions and methods for inhibiting DYRK1A.

[0022] Some embodiments provided herein relate to methods for treating diseases, including, but not limited to, neurological diseases or disorders, cancer, cognitive disorders, knee osteoarthritis, tendinopathy, viral infections, single-cell parasitic infections, and movement disorders.

[0023] In some embodiments, non-limiting examples of neurological diseases or disorders that can be treated using the compounds and compositions provided herein include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, tauopathies, and additional diseases with significant neurodegeneration, such as autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; diseases and disorders associated with acquired brain injury, such as chronic traumatic encephalopathy, traumatic brain injury, tumors, and stroke.

[0024] In some embodiments, non-limiting examples of cancers that can be treated using 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).

[0025] 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.

[0026] 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.

[0027] 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).

[0028] 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).

[0029] 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).

[0030] 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).

[0031] 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).

[0032] 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).

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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 thienyl, 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]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]dioxine, 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.

[0039] 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.

[0040] 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.

[0041] 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 O, N, and S; if the heterocycle is 5-membered, the heterocycle can have 1 or 2 heteroatoms selected from O, N, and S. Examples of heterocyclyl 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, etc. In some embodiments, heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

[0042] 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.

[0043] 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 members, and the heteroatom(s) are selected from 1 to 5 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, 2-azabicyclo[2.2.2]octane, and the like.

[0044] As used herein, "spirocyclic heterocyclyl" refers to a non-aromatic bicyclic ring system containing at least one heteroatom in the ring system backbone, with the rings bonded through only one atom. The spirocyclic heterocyclyl may be unsubstituted or substituted with one or more substituents. In some embodiments, the spirocyclic heterocycle has 5 to 11 members, with the heteroatom(s) being 1 to 5 selected from 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.

[0045] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more non-hydrogen atoms of a molecule. It is understood that "substituted" or "substituted with" is made in accordance with the substituted atom and the permissible valence of the substituent, and includes the implicit proviso that the substitution results in a stable compound, e.g., one that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, and the like. Substituents include, for example, one or more hydroxyl, -NH, -NH(C 1-3 alkyl), and -N(C 1-3 alkyl)2 optionally substituted with -(C 1-9 alkyl);-(C 1-9 haloalkyl; halide; hydroxyl; carbonyl [e.g., —C(O)OR and —C(O)R]; thiocarbonyl [e.g., —C(S)OR, —C(O)SR, and —C(S)R]; one or more of halide, hydroxyl, —NH, —NH(C 1-3 alkyl), and -N(C 1-3 alkyl)2 optionally substituted with -(C 1-9alkoxy); -OPO(OH); phosphonate [e.g., -PO(OH) and -PO(OR')]; -OPO(OR')R''; -NRR'; -C(O)NRR'; -C(NR)NR'R''; -C(NR')R''; cyano; nitro; azido; -SH; -SR; -OSO(OR); sulfonate [e.g., -SO(OH) and -SO(OR)]; -SONR'R''; and -SOR, where 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 to 4 heteroatoms independently selected from N, O, and S and optionally substituted with 1 to 3 R'"; C optionally substituted with 1 to 3 R'" 3~7 carbocyclyl; and 3- to 8-membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S and optionally substituted with 1-3 R''', wherein 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 cyano, wherein each occurrence of R and R is independently 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 and cyano, wherein each occurrence of R and R is independently selected from H and —(C 1-6 alkyl).

[0046] As used herein, when two groups are indicated as being "linked" or "bonded" to form a "ring," it is understood that the formation of a bond between the two groups may involve replacing a hydrogen atom on one or both groups with the bond to form a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. One of ordinary skill in the art will recognize that such rings can be and are readily formed by routine chemical reactions. In some embodiments, such rings have 3 to 7 members, e.g., 5 or 6 members.

[0047] 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.

[0048] 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, such as 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] The term "mammal" is used in its ordinary biological sense, and thus specifically includes humans, cows, horses, monkeys, dogs, cats, mice, rats, cattle, sheep, pigs, goats, and non-human primates, but also includes many other species.

[0053] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable diluent," and "pharmaceutically acceptable excipient" include any solvent, cosolvent, complexing agent, dispersion medium, coating, isotonicity agent, absorption delaying agent, and the like, which are not biologically or otherwise undesirable. The use of these media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is contemplated for use in therapeutic compositions, except insofar as it is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the composition. In addition, various adjuvants, such as those commonly used in the art, may be included. These and other similar compounds are described in the literature, e.g., Merck Index, Merck & Company, Rahway, NJ. Considerations for including various ingredients in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] A therapeutic effect is one that relieves to some extent one or more symptoms of the disease.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[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] 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.

[0065] 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.

[0066] In some embodiments of Formula I, R 1is 1 to 10 R 4 In some embodiments, R 1 is 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1 R 4 and heteroaryl optionally substituted with

[0067] In some embodiments of Formula I, R 1 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) R 4 may be substituted with [ka] The heteroaryl group is selected from the group consisting of:

[0068] In some embodiments of Formula I, R 1 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) R 4 may be substituted with [ka] The heteroaryl group is selected from the group consisting of:

[0069] In some embodiments of Formula I, R 1 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) R 4 may be substituted with [ka] The heteroaryl group is selected from the group consisting of:

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

[0071] In some embodiments of Formula I, R 1 is 1 to 3 (e.g., 1 to 2, 1) R 4 may be substituted with [ka] The heteroaryl group is selected from the group consisting of:

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

[0073] In some embodiments of Formula I, R 1 is 1 to 3 R 4 may be substituted with [ka] is selected from the group consisting of:

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

[0075] In some embodiments of Formula I, R 1 teeth, non-replacement [ka] is selected from the group consisting of:

[0076] In some embodiments of Formula I, R 2is an unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 5 , 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) R 6 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 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) R 7 -heteroaryl optionally substituted with, 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 8 may be substituted with -(C 1-5 alkylene) p carbocyclyl, wherein each -(C 1-5 alkylene) independently represents 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halides (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 It may be substituted with alkyl.

[0077] In some embodiments of Formula I, R 2 is an unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 5 , 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) R 6 may be substituted with -(C 1-5 alkylene) pHeterocyclyl, 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) R 26 may be substituted with -(C 1-5 alkylene) p aryl, 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) R 7 may be substituted with -(C 1-5 alkylene) p heteroaryl 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 8 may be substituted with -(C 1-5 alkylene) p carbocyclyl, wherein each -(C 1-5 alkylene) independently contains 1 to 5 halide (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 It may be substituted with alkyl.

[0078] In some embodiments of Formula I, R 2 is an unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 5 , -(C 1-5 alkylene)CN, 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) R 6 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 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) R 26 may be substituted with -(C 1-5 alkylene) paryl, 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) R 7 may be substituted with -(C 1-5 alkylene) p heteroaryl 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 8 may be substituted with -(C 1-5 alkylene) p carbocyclyl, wherein each -(C 1-5 alkylene) independently contains 1 to 5 halide (e.g., F, Cl, Br, I) and / or 1 to 3 unsubstituted -(C 1-3 It may be substituted with alkyl.

[0079] In some embodiments of Formula I, R 2 is an unsubstituted -(C 1-5 alkyl), unsubstituted -(C 1-5 haloalkyl), -(C 1-2 alkylene) p OR 5 , 1 to 3 (e.g., 1 to 2, 1) R 6 may be substituted with -(C 1-2 alkylene) p heterocyclyl and 1 to 3 (e.g., 1 to 2, 1) R 8 may be substituted with -(C 1-2 alkylene) p carbocyclyl, wherein each -(C 1-5 alkylene) may be independently substituted with 1 to 2 halides.

[0080] In some embodiments of Formula I, R 2 is an unsubstituted -(C 1-5 alkyl), unsubstituted -(C 1-5 haloalkyl), 1 to 4 R 6 -heterocyclyl optionally substituted with 1 to 2 R 26 may be substituted with -(C 1-2 alkylene) pAryl, 1-2 R 7 may be substituted with -(C 1-2 alkylene) p heteroaryl and 1 to 4 R 8 may be substituted with -(C 1-2 alkylene) p carbocyclyl, wherein each -(C 1-2 alkylene) may be independently substituted with 1 to 2 halides.

[0081] In some embodiments of Formula I, R 2 is 1 to 3 R 8 may be substituted with -(C 1-2 alkylene) p carbocyclyl, where -(C 1-5 The carbocyclyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and spiro[3.3]heptanyl.

[0082] In some embodiments of Formula I, R 2 is 1 to 3 R 8 may be substituted with -(C 1-2 alkylene) p carbocyclyl, where -(C 1-2 The carbocyclyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane, and spiro[3.3]heptanyl.

[0083] In some embodiments of Formula I, R 2 is an unsubstituted -(C 1-4 alkyl), unsubstituted -(C 2-4 alkenyl), unsubstituted -(C 2-4 alkynyl), unsubstituted -( 1-4 haloalkyl), -(C 2-4 alkylene) OR 5, -(C 2-4 alkylene)CN, 1 to 3 R 6 may be substituted with -(C 1-2 alkylene) p Heterocyclyl, 1-2 R 26 may be substituted with -(C 1-2 alkylene) p Aryl, 1-2 R 7 may be substituted with -(C 1-2 alkylene) p Heteroaryl and 1 to 3 R 8 may be substituted with -(C 1-2 alkylene) p carbocyclyl, wherein each -(C 1-2 alkylene) may be independently substituted with 1 to 2 halides (e.g., F, Cl).

[0084] In some embodiments of Formula I, R 2 is an unsubstituted -(C 1-5 haloalkyl), -(C 1-4 alkylene)OH, -(C 1-4 alkylene)OMe, and -(C 1-4 alkylene)CN.

[0085] In some embodiments of Formula I, R 2 teeth, [ka] wherein each R 8 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, -NH, -NHMe, and -NMe.

[0086] In some embodiments of Formula I, R 2 teeth, [ka] wherein each R 8 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, -CN, -NH, -NHMe, and -NMe.

[0087] In some embodiments of Formula I, R 2 teeth, [ka] wherein each R 8 is independently selected from the group consisting of F, Me, -CHF2, -CH2OMe, -OH, -OMe, -OCD3, -OCH2CHF2, and -OCH2CH2OMe.

[0088] In some embodiments of Formula I, R 2 is 1 to 3 R 6 -C( 1-2 alkylene) p heterocyclyl, where -(C 1-5 alkylene) may be optionally substituted with 1 to 2 halides, where heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxaspiro[3.3]heptanyl, and oxaspiro[3.3]heptanyl.

[0089] In some embodiments of Formula I, R 2 teeth, [ka] wherein each R 6are independently F, Me, Et, iPr, iBu, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OMe, -OH, -OMe, -OEt, -OCD3, -OCF3, -C H2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me, -C(=O)Et, -C(=O)iPr, [ka] and -SO2Me, with the proviso that F, -OH, -OMe, -OEt, -OCD3, and -OCF3 are not bonded to N.

[0090] In some embodiments of Formula I, R 2 teeth, [ka] wherein each R 6 are independently selected from the group consisting of F, Me, iBu, -OH, -OMe, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me, -C(=O)Et, and -C(=O)iPr, with the proviso that F, -OH, -OMe are not bonded to N.

[0091] In some embodiments of Formula I, R 2 is 1 to 2 R 7 and optionally substituted -heteroaryl, wherein heteroaryl is pyrazolyl.

[0092] In some embodiments of Formula I, R 2 is 1 to 2 R 7 may be substituted with -(C 1-2 alkylene)heteroaryl, where heteroaryl is pyridine.

[0093] In some embodiments of Formula I, R 2 is 1 to 2 R 7may be substituted with -(C 1-2 alkylene)aryl, where aryl is phenyl.

[0094] In some embodiments of Formula I, R 3 is H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl).

[0095] In some embodiments of Formula I, R 3 is H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and 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) R 18 -heterocyclyl optionally substituted with

[0096] In some embodiments of Formula I, R 3 is H, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 2-5 alkenyl), unsubstituted -(C 2-5 alkynyl), and unsubstituted -(C 1-5 haloalkyl).

[0097] In some embodiments of Formula I, R 3 is an unsubstituted -(C 1-5 alkyl), unsubstituted -(C 1-5 haloalkyl), and 1 to 2 R 18 -heterocyclyl optionally substituted with

[0098] In some embodiments of Formula I, R 3 is H, unsubstituted -(C 1-3 alkyl), and unsubstituted -(C 1-3haloalkyl).

[0099] In some embodiments of Formula I, R 3 is an unsubstituted -(C 1-3 alkyl).

[0100] In some embodiments of Formula I, R 3 is Me.

[0101] In some embodiments of Formula I, R 3 is an unsubstituted -(C 1-3 haloalkyl).

[0102] In some embodiments of Formula I, R 3 is selected from the group consisting of -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, and -CH2CF3.

[0103] In some embodiments of Formula I, R 3 is an unsubstituted heterocyclyl.

[0104] In some embodiments of Formula I, R 3 is unsubstituted -(3- to 4-membered heterocyclyl).

[0105] In some embodiments of Formula I, R 3 is an unsubstituted -(4-membered heterocyclyl).

[0106] In some embodiments of Formula I, each R 4 are independently selected from 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), -(C 1-5 alkylene) p OR 9 , -(C 1-5alkylene)CN, 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) R 10 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 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 11 -carbocyclyl, 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) R 20 may be substituted with -(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2, and -C(=O)R 13 wherein each -(C 1-5 alkylene) independently represents 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halides (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 It may be substituted with alkyl.

[0107] In some embodiments of Formula I, each R 4 are independently selected from halide, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 2-5 alkenyl), unsubstituted -(C 2-5 alkynyl), unsubstituted -(C 1-5 haloalkyl), -(C 1-4 alkylene) p OR 9 , -(C 1-2 alkylene) p OR 9 , -(C 1-4 alkylene)CN, -(C 1-2 alkylene)CN, 1 to 2 R 10 may be substituted with -(C 1-2 alkylene) p Heterocyclyl, 1-2 R 11-carbocyclyl, optionally substituted with 1 to 2 R 20 may be substituted with -(C 1-2 alkylene) p Heteroaryl, -(C 1-2 alkylene) p C(=O)N(R 12 )2, and -C(=O)R 13 wherein each -(C 1-2 alkylene) or -(C 1-4 alkylene) may be independently substituted with 1 to 2 halides.

[0108] In some embodiments of Formula I, each R 4 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), unsubstituted -(C 2-9 haloalkenyl), -(C 1-5 alkylene) p OR 9 , -(C 1-5 alkylene) p CN, 1 to 10 R 10 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, 1 to 12 R 11 -carbocyclyl, optionally substituted with 1 to 10 R 20 may be substituted with -(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2, and -C(=O)R 13 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 It may be substituted with alkyl.

[0109] In some embodiments of Formula I, each R4 are independently selected from 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), unsubstituted -(C 2-4 haloalkenyl), -(C 1-4 alkylene) p OR 9 , -(C 1-2 alkylene) OR 9 , -(C 1-4 alkylene)CN, -(C 1-2 alkylene)CN, 1 to 2 R 10 may be substituted with -(C 1-2 alkylene) p Heterocyclyl, 1-2 R 11 -carbocyclyl, optionally substituted with 1 to 2 R 20 may be substituted with -(C 1-2 alkylene) p Heteroaryl, -(C 1-2 alkylene) p C(=O)N(R 12 )2, and -C(=O)R 13 wherein each -(C 1-2 alkylene) or -(C 1-4 alkylene) may be independently substituted with 1 to 2 halides (e.g., F, Cl).

[0110] In some embodiments of Formula I, each R 4 are independently F, Cl, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 1-5 haloalkyl), -(C 1-4 alkylene) p OH, -(C 1-2 alkylene) p OMe, -(C 1-4 alkylene)CN, -(C 1-2 alkylene)CN, 1 to 2 R 10 may be substituted with -(CH2) p Heterocyclyl, 1-2 R11 -carbocyclyl, optionally substituted with 1 to 2 R 20 may be substituted with -(CH2) p Heteroaryl, -(CH2)C(=O)N(Me)2, and -C(=O)R 13 wherein each -(C 1-2 alkylene) or -(C 1-4 alkylene) may be independently substituted with 1 to 2 halides.

[0111] In some embodiments of Formula I, each R 4 are independently selected from halide (e.g., F, Cl, Br, I), unsubstituted -(C 1-4 alkyl), unsubstituted -(C 1-4 haloalkyl), 1 to 3 (e.g., 1 to 2, 1) R 10 -heterocyclyl optionally substituted with, and 1 to 3 (e.g., 1 to 2, 1) R 11 -carbocyclyl optionally substituted with

[0112] In some embodiments of Formula I, each R 4 are independently selected from halide, unsubstituted -(C 1-3 alkyl), unsubstituted -(C 1-3 haloalkyl), -(C 1-3 alkylene) p OR 9 , 1 to 2 R 10 -heterocyclyl optionally substituted with, and 1 to 2 R 11 -carbocyclyl, and -C(=O)R 13 is selected from the group consisting of:

[0113] In some embodiments of Formula I, each R 4 are independently selected from halide, unsubstituted -(C 1-3 alkyl), unsubstituted -(C 1-3 haloalkyl), -(C 1-3 alkylene)OH, -(C 1-3 alkylene)OMe, -CN, and -C(=O)N(R 12)2.

[0114] In some embodiments of Formula I, each R 4 is independently selected from the group consisting of chloro, methyl, ethyl, isopropyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, tetrahydropyranyl, difluorocyclobutyl, and (pyrrolidin-1-yl)methanone.

[0115] In some embodiments of Formula I, each R 5 are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl).

[0116] In some embodiments of Formula I, each R 5 are independently H, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 2-5 alkenyl), unsubstituted -(C 2-5 alkynyl), and unsubstituted -(C 1-5 haloalkyl).

[0117] In some embodiments of Formula I, each R 5 are independently H, unsubstituted -(C 1-3 alkyl), and unsubstituted -(C 1-3 haloalkyl).

[0118] In some embodiments of Formula I, each R 6 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), 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) R 16-heterocyclyl, -(C 1-5 alkylene) p OR 21 , -SO2R 23 , and -C(=O)R 24 wherein -(C 1-5 alkylene) is substituted with 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halides (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 It may be substituted with alkyl.

[0119] In some embodiments of Formula I, each R 6 are independently selected from 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 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) R 16 -heterocyclyl, 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 17 -carbocyclyl, -(C 1-5 alkylene) p OR 21 , -SO2R 23 , and -C(=O)R 24 wherein -(C 1-5 alkylene) may be 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 It may be substituted with alkyl.

[0120] In some embodiments of Formula I, each R 6 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9alkynyl), unsubstituted -(C 1-9 haloalkyl), 1 to 10 R 16 -heterocyclyl optionally substituted with 1 to 12 R 17 -carbocyclyl, -(C 1-5 alkylene) p OR 21 , -(C 1-5 Alkylene)CN, -SO2R 23 , and -C(=O)R 24 wherein -(C 1-5 alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3 It may be substituted with alkyl.

[0121] In some embodiments of Formula I, each R 6 are independently F, Cl, unsubstituted -(C 1-4 alkyl), unsubstituted -(C 1-4 haloalkyl), 1 to 2 R 16 -heterocyclyl, -(C 1-2 alkylene) p OR 21 , -(C 1-2 Alkylene)CN, -SO2R 23 , and -C(=O)R 24 wherein -(C 1-2 The alkylene may be substituted with 1 to 2 halides (eg, F, Cl).

[0122] In some embodiments of Formula I, each R 6 are independently F, Cl, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 1-5 haloalkyl), 1 to 2 R 16 -heterocyclyl, -(C 1-2 alkylene) p OR 21 , -SO2R 23 , and -C(=O)R 24 wherein -(C 1-2The alkylene) may be substituted with 1 to 2 halides.

[0123] In some embodiments of Formula I, each R 6 are independently F, Cl, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 1-5 haloalkyl), 1 to 2 R 16 -heterocyclyl, -OH, -OMe, -SOMe, and -C(=O)R 24 is selected from the group consisting of:

[0124] In some embodiments of Formula I, each R 6 are independently F, Cl, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 1-5 haloalkyl), 1 to 2 R 16 -heterocyclyl optionally substituted with 1 to 4 R 17 -carbocyclyl, and -C(=O)R 24 is selected from the group consisting of:

[0125] In some embodiments of Formula I, two R 6 together to form a carbonyl group.

[0126] In some embodiments of Formula I, each R 7 are independently selected from 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), and -OMe.

[0127] In some embodiments of Formula I, each R 7 is independently selected from the group consisting of F, Cl, Me, CF3, and -OMe.

[0128] In some embodiments of Formula I, each R 8are independently selected from 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), -N(R 14 )2, -(C 1-5 alkylene) p OR 15 , 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) R 16 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, -C(=O)R 22 , and -NHC(=O)R 23 wherein each -(C 1-5 alkylene) independently represents 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halides (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 It may be substituted with alkyl.

[0129] In some embodiments of Formula I, each R 8 are independently selected from halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -N(R 14 )2, -(C 1-5 alkylene) p OR 15 , -CN, 1 to 10 R 16 may be substituted with -(C 1-5 alkylene) p Heterocyclyl, -C(=O)R 22 , and -NR 14 C(=O)R 23 wherein each -(C 1-5 alkylene) independently represents 1 to 5 halide and / or 1 to 3 unsubstituted -(C 1-3It may be substituted with alkyl.

[0130] In some embodiments of Formula I, each R 8 are independently selected from 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), -N(R 14 )2, -(C 1-2 alkylene) p OR 15 , -CN, 1 to 2 R 16 may be substituted with -(C 1-2 alkylene) p Heterocyclyl, -C(=O)R 22 , and -NHC(=O)R 23 wherein each -(C 1-2 alkylene) may be independently substituted with 1 to 2 halides (e.g., F, Cl).

[0131] In some embodiments of Formula I, each R 8 are independently selected from halide, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 2-5 alkenyl), unsubstituted -(C 2-5 alkynyl), unsubstituted -(C 1-5 haloalkyl), -N(R 14 )2, -(C 1-2 alkylene) p OR 15 , 1 to 2 R 16 may be substituted with -(C 1-2 alkylene) p Heterocyclyl, -C(=O)R 22 , and -NHC(=O)R 23 wherein each -(C 1-2 alkylene) may be independently substituted with 1 to 2 halides.

[0132] In some embodiments of Formula I, each R 9are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl).

[0133] In some embodiments of Formula I, each R 10 are independently selected from 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).

[0134] In some embodiments of Formula I, each R 11 are independently selected from 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).

[0135] In some embodiments of Formula I, each R 12 are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl), 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 17 may be substituted with -(C 1-5 alkylene) p Carbocyclyl, 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 18 -heterocyclyl optionally substituted with, and 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) R19 -heteroaryl, optionally substituted with -(C 1-5 alkylene) is substituted with 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halides (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 It may be substituted with alkyl.

[0136] In some embodiments of Formula I, each R 13 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) R 18 is an optionally substituted -heterocyclyl.

[0137] In some embodiments of Formula I, each R 14 are independently H, 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 15 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 21 is selected from the group consisting of:

[0139] In some embodiments of Formula I, each R 16 are independently selected from 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).

[0140] In some embodiments of Formula I, each R 16 are independently selected from halide, -CN, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), and 1 to 12 R 27 -carbocyclyl optionally substituted with

[0141] In some embodiments of Formula I, two R 16 together to form a carbonyl group.

[0142] In some embodiments of Formula I, each R 17 are independently selected from halide (e.g., F, Cl, Br, I), -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl).

[0143] In some embodiments of Formula I, each R 18 are independently selected from 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).

[0144] In some embodiments of Formula I, each R 19 are independently selected from 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).

[0145] In some embodiments of Formula I, each R 20 are independently selected from 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).

[0146] In some embodiments of Formula I, each R 21 are independently H, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl).

[0147] In some embodiments of Formula I, each R 22 are independently 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) R 18 -heterocyclyl, -N(R 12 )2, and -OR 21 is selected from the group consisting of:

[0148] In some embodiments of Formula I, each R 23 are independently unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl).

[0149] In some embodiments of Formula I, each R 23 are independently unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -(C 1-5 alkylene)p OR 21 , and 1 to 12 R 25 -carbocyclyl optionally substituted with

[0150] In some embodiments of Formula I, each R 24 are independently unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -OR 23 , 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 25 -carbocyclyl optionally substituted with

[0151] In some embodiments of Formula I, each R 25 are independently selected from 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).

[0152] In some embodiments of Formula I, each R 26 are independently selected from 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).

[0153] In some embodiments of Formula I, each R 27 are independently selected from halide (e.g., F, Cl, Br, I), unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C1-9 haloalkyl).

[0154] In some embodiments of Formula I, R 28 is independently selected from the group consisting of H and halides (e.g., F, Cl, Br, I).

[0155] In some embodiments of Formula I, R 28 is independently selected from the group consisting of H and halides (e.g., F, Cl).

[0156] In some embodiments of Formula I, R 28 is independently selected from the group consisting of H and F.

[0157] In some embodiments of Formula I, R 28a is independently selected from the group consisting of H and halides (e.g., F, Cl, Br, I).

[0158] In some embodiments of Formula I, R 28a is independently selected from the group consisting of H and halides (e.g., F, Cl).

[0159] In some embodiments of Formula I, R 28a is independently selected from the group consisting of H and F.

[0160] In some embodiments of Formula I, R 28b is independently selected from the group consisting of H and D.

[0161] In some embodiments of Formula I, each p is independently 0 or 1.

[0162] In some embodiments of Formula I, each H atom is independently: 2 It may be replaced by H(D) (deuterium).

[0163] Exemplary compounds of Formula I are shown in Table 1.

[0164]

Table 1

[0165] 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.

[0166] The compounds provided herein may also be useful in combination (administered simultaneously or sequentially) with other known pharmaceutical agents.

[0167] Non-limiting examples of diseases that can be treated by combining a compound of Formula I with another active agent 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.

[0168] 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 / treatments: sorafenib (Nexavar®); regorafenib (Stivarga®, Regonix®), nivolumab (Opdivo®); lenvatinib (Lenvima®); pembrolizumab (Keytruda®); cabozantinib (Cometriq®, Cabometyx®); 5-fluorouracil (5-FU®); ramucirumab (Cyramza®); gemcitabine in combination with oxaliplatin (GEMOX). Other treatments that may be used in combination with the compounds of Formula I include: i) transcatheter arterial chemoembolization (TACE) in combination with doxorubicin (Doxil®), cisplatin, or mitomycin C (Mitosol®, Mutamycin®, Jelmyto®); ii) low-dose-rate brachytherapy.

[0169] 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 / treatments: transoral robotic-assisted surgery (TORS); TORS combined 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®).

[0170] 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 / treatments: induction therapy; consolidation therapy; nelarabine (Arranon®); erwinia chrysanthemi asparaginase (Erwinaze®); erwinia chrysanthemi asparaginase (recombinant)-rywn (Rylaze®); calaspargase pegol-mknl (Asparlas®); inotuzumab ozogamicin (Besponsa®); blinatumomab (Blincyto®); daunorubicin hydrochloride (Cerubidine®); clofarabine (Clolar®); cyclophosphamide; methotrexate sodium (Trexall®); cytarabine (Cytosar-U®); dasatidine nib (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.

[0171] In some embodiments, pancreatic cancer can be treated by a combination of a compound of Formula I with one or more of the following drugs / treatments: ablation and embolization treatments; 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®).

[0172] In some embodiments, brain tumors can be treated by a combination of a compound of Formula I and one or more of the following drugs / treatments: carmustine can be administered by Gliadel wafer; in glioblastoma and high-grade gliomas, radiation therapy combined with daily low-dose temozolomide (Temodar®) followed by monthly temozolomide for 6 months to 1 year after radiation therapy; lomustine (Gleostine®), procarbazine (Matulane®), and vincristine (Vincasar®) have been used in conjunction with radiation therapy; antiangiogenic treatment with bevacizumab (Avastin®, Mvasi®); and targeted treatment using larotrectinib (Vitrakvi®).

[0173] 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 / treatments: cytarabine (Cytosar-U®), etoposide (Vepesid®), and anthracycline drugs. Anthracyclines include daunorubicin (Cerubidine®), idarubicin (Idamycin®), and mitoxantrone (Novantrone®).

[0174] 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 / treatments: venetoclax and a methylation inhibitor (e.g., decitabine, azacitidine), induction chemotherapy (cytarabine and an anthracycline (e.g., daunorubicin or idarubicin), all-trans retinoic acid (ATRA) with either arsenic trioxide (ATO) as monotherapy or an anthracycline), consolidation therapy (cytarabine).

[0175] 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 / treatments: 5-azacytidine, decitabine, lenalidomide, and decitabine / cedazuridine (Inqovi®).

[0176] In some embodiments, colorectal cancer can be treated by combining a compound of Formula I with one or more of the following drugs: 5-fluorouracil (5-FU), which can be administered with the vitamin-like drug leucovorin (also known as folinic acid); capecitabine (XELODA®), irinotecan (CAMPOSTAR®), and oxaliplatin (ELOXATIN®). Examples of these drug combinations that can be further 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). For rectal cancer, chemotherapy with 5-FU or capecitabine may be combined with radiation therapy before surgery (neoadjuvant therapy).

[0177] 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®). Examples of these drug combinations that can be further combined with the compounds 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 by combining the compounds of Formula I with immune checkpoint blockade (ICB) therapy.

[0178] In some embodiments, compounds of Formula I can be used in combination with any of the following methods to treat cancer: (a) hormonal therapy, such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors; (b) ablation or embolization, such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy, and cryosurgery (cryotherapy); (c) chemotherapy using alkylating agents, such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide; (d) chemotherapy using antimetabolites, such as azathioprine and mercaptopurine; (e) chemotherapy using plant alkaloids and plant terpenoids, such as vinca alkaloids (i.e., vincristine, vinblastine, vinorelbine, and vindesine) and taxanes; (f) chemotherapy using podophyllotoxin, etoposide, teniposide, and docetaxel; (g) chemotherapy using topoisomerase inhibitors, such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) chemotherapy using cytotoxic antibiotics, such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and mitomycin;(i) tyrosine kinase inhibitors, such as 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, currently in Phase III trials), VEGF (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, such as rituximab (sold as MabThera® or Rituxan®), trastuzumab (also known as ErbB2 Herceptin), cetuximab (sold as Erbitux®), and bevacizumab (sold as Avastin®); (k) KRAS (1) chemotherapy using G12C inhibitors, such as sotorasib (Lumakras® and Lumykras®), adagrasib (MRTX849), and ARS-3248 (Wellspring Biosciences); (1) chemotherapy using checkpoint inhibitor therapeutics, such as ipilimumab (Yervoy®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), atezolizumab (Tecentriq®), avelumab (Bavencio), durvalumab (Imfinzi), cemiplimab (Libtayo®), and spartalizumab (PDR001);(m) chemotherapy using antibody-drug conjugates (ADCs), such as gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, moxetumomab pasudotox, and loncastuximab tesirin (n) chemotherapy using proteasome inhibitors, such as carfilzomib, lactacystin, disulfiram, salinosporamide A (marizomib), oprozomib, delanzomib, epoxomicin, MG132, beta-hydroxybeta-methylbutyric acid (HMB), bortezomib, ixazomib (alone or in combination with lenalidomide and dexamethasone); and (o) radiation therapy.

[0179] In some embodiments, compounds of Formula I can be used in combination with any of the following methods to treat diabetes: (a) insulin injections; (b) biguanides, such as metformin (Glucophage), phenformin (DBI), and buformin; (c) thiazolidinediones (TZDs), such as rosiglitazone (Avandia), pioglitazone (Actos), and troglitazone (yroglitazone) (Rezulin); (d) lyn kinase activators, such as glimepiride (Amaryl®) and trimidone (MLR-1023); (e) secretagogues, such as sulfonylureas (non-limiting examples include acetohexamide, carbutamide, chlorpropamide, glyceramide, etc.). (tolcyclamide), metahexamide, tolazamide, tolbutamide, glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glyclopyramide, and glimepiride) and meglitinides (non-limiting examples include repaglinide (Prandin), nateglinide (Starlix), and mitiglinide (Glufast)); (f) α-glucosidase inhibitors, such as acarbose (Glucobay, Precose, Prandase), miglitol (Glyset), and voglibose; (g) injectable incretin mimetics, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP).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 (Trulicity), and albiglutide (Tanzeum), as well as dipeptidyl peptidase-4 (DPP-4) inhibitors. Non-limiting examples 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 (in combination with pioglitazone), (h) injectable amylin analogues, such as pramlintide (Symlin); (i) glucosurics (SGLT2 inhibitors), such as canagliflozin (Invokana, Sulisent, Prominad), dapagliflozin (Forx), trelagliptin (Zafatek, Wedica), omarigliptin (MK-3102), evogliptin (Suganon, Evodine), gosogliptin (Saterex), and dutogliptin. iga, 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).

[0180] In some embodiments, the compounds of formula I can be used in combination with any of the following methods to treat osteoarthritis: (d) injections of Wnt signaling pathway inhibitors (e.g., lorexivin); (a) nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, aspirin, and acetaminophen; (b) physical therapy; (c) injections of corticosteroids; (d) injections of hyaluronic acid derivatives (e.g., Hyalgan, Synvisc); (e) narcotics such as codeine; (f) immobilizers and / or shoe inserts, or any device that can immobilize or support a joint to relieve pressure on the joint (e.g., splints, immobilizers, shoe inserts, or other medical devices); (g) bone realignment (osteectomy); (h) joint replacement (arthroplasty); and (i) in combination with chronic pain classes.

[0181] In some embodiments, the compounds of Formula I can be used in combination with aducanumab (Aduhelm™); acetylcholinesterase inhibitors such as tacrine, rivastigmine (Exelon®), galantamine (Razadyne® and GalantaMind™), and donepezil (Aricept®); and memantine (Axura®, Ebixa®, Namenda®) to treat Alzheimer's disease.

[0182] Administration of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be by any acceptable mode of administration, for example, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneally, intramuscular, intrapulmonary, vaginal, rectal, otologic, neuro-otologic, intraocular, subconjunctival, via anterior chamber injection, intravitreal, intraperitoneal, intrathecal, intracystic, intrapleural, via wound irrigation, intrabuccal, intraperitoneal In some embodiments, the method of administration includes, but is not limited to, intra-abdominally, intra-articular, intra-aural, intra-bronchial, intra-cisternal, intra-meningeal, via inhalation, via intratracheal or intra-bronchial instillation, via direct injection into the lung cavity, intraspinally, intra-synovial, intrathoracic, chest drainage lavage, epidural, intratympanic, intracisternal, intravascular, intraventricular, intraosseous, via irrigation of infected bone, or by application as part of any admixture with a prosthetic device. In some embodiments, the method of administration comprises oral or parenteral administration.

[0183] 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.

[0184] 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, such as Tween, poloxamer, or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphate, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins such as 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 can be prepared containing 0.005% to 100% of the compounds described herein, with the remainder consisting of a non-toxic carrier. Contemplated compositions may 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 the compounds provided herein. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK, 2012).

[0185] 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.

[0186] 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.).

[0187] In some embodiments, the unit dose of the compound of formula I is from about 0.25 mg / Kg to about 50 mg / Kg in humans.

[0188] In some embodiments, the unit dose of the compound of formula I is from about 0.25 mg / Kg to about 20 mg / Kg in humans.

[0189] In some embodiments, the unit dose of the compound of formula I is from about 0.50 mg / Kg to about 19 mg / Kg in humans.

[0190] In some embodiments, the unit dose of the compound of formula I is from about 0.75 mg / Kg to about 18 mg / Kg in humans.

[0191] In some embodiments, the unit dose of the compound of formula I is from about 1.0 mg / Kg to about 17 mg / Kg in humans.

[0192] In some embodiments, the unit dose of the compound of formula I is from about 1.25 mg / Kg to about 16 mg / Kg in humans.

[0193] In some embodiments, the unit dose of the compound of formula I is from about 1.50 mg / Kg to about 15 mg / Kg in humans.

[0194] In some embodiments, the unit dose of the compound of formula I is from about 1.75 mg / Kg to about 14 mg / Kg in humans.

[0195] In some embodiments, the unit dose of the compound of formula I is from about 2.0 mg / Kg to about 13 mg / Kg in humans.

[0196] In some embodiments, the unit dose of the compound of formula I is from about 3.0 mg / Kg to about 12 mg / Kg in humans.

[0197] In some embodiments, the unit dose of the compound of formula I is from about 4.0 mg / Kg to about 11 mg / Kg in humans.

[0198] In some embodiments, the unit dose of the compound of formula I is from about 5.0 mg / Kg to about 10 mg / Kg in humans.

[0199] In some embodiments, the compositions are provided in a unit dosage form suitable for single administration.

[0200] In some embodiments, the composition is provided in a unit dosage form suitable for twice-daily administration.

[0201] In some embodiments, the composition is provided in a unit dosage form suitable for administration three times daily.

[0202] Injectables can be prepared in conventional forms, such as solutions, colloids, liposomes, complexes, coacervates, or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of the compounds provided herein contained in these parenteral compositions will vary depending largely on their specific nature, as well as the activity of the compound and the patient's needs. However, percentages of active ingredient in solution of 0.01% to 10% can be used. Higher percentages are possible when the composition is a solid or suspension, which can then be diluted to the above percentages.

[0203] In some embodiments, the composition comprises about 0.1-10% of the active agent in solution.

[0204] In some embodiments, the composition comprises about 0.1-5% of the active agent in solution.

[0205] In some embodiments, the composition comprises about 0.1-4% of the active agent in solution.

[0206] In some embodiments, the composition comprises about 0.15-3% of the active agent in solution.

[0207] In some embodiments, the composition comprises about 0.2-2% of the active agent in solution.

[0208] In some embodiments, the compositions are provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 96 hours.

[0209] In some embodiments, the compositions are provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 72 hours.

[0210] In some embodiments, the compositions are provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 48 hours.

[0211] In some embodiments, the compositions are provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 24 hours.

[0212] In some embodiments, the compositions are provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 12 hours.

[0213] In some embodiments, the compositions are provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 6 hours.

[0214] In some embodiments, these compositions contain about 5 mg / m 2 ~about 300mg / m 2 It can be administered to humans by intravenous infusion at a dose of

[0215] In some embodiments, these compositions contain about 5 mg / m 2 ~about 200mg / m 2 It can be administered to humans by intravenous infusion at a dose of

[0216] In some embodiments, these compositions contain about 5 mg / m 2 ~about 100mg / m 2 It can be administered to humans by intravenous infusion at a dose of

[0217] In some embodiments, these compositions contain about 10 mg / m 2 ~about 50mg / m 2 It can be administered to humans by intravenous infusion at a dose of

[0218] In some embodiments, these compositions contain about 50 mg / m 2 ~about 200mg / m 2 It can be administered to humans by intravenous infusion at a dose of

[0219] In some embodiments, these compositions contain about 75 mg / m 2 ~about 175mg / m 2 It can be administered to humans by intravenous infusion at a dose of

[0220] In some embodiments, these compositions contain about 100 mg / m 2 ~about 150mg / m 2 It can be administered to humans by intravenous infusion at a dose of

[0221] It should also be noted that concentrations and dosage values may vary depending on the specific compound and the severity of the condition 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 compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0222] 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.

[0223] 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, an inhaled particle size of about 5 to about 100 microns is useful, with a particle size of about 10 to about 60 microns being preferred. For nasal delivery, larger inhaled particle sizes may be desirable to maximize impaction on the nasal mucosa and minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lungs are provided for inhalation through the nose or mouth. For pulmonary delivery, an aerodynamic inhaled particle size of less than about 10 μm is useful (e.g., about 1 to about 10 microns). 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 a diluent containing embedded drug nanoparticles.

[0224] 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 by liquid nebulizers using hydraulic or ultrasonic atomization, or by modified micropump systems (such as soft mist inhalers, Aerodose®, or AERx® systems). Propellant-based systems can use suitable pressurized metered dose inhalers (pMDIs). Dry powder formulations can use dry powder inhalers (DPIs) capable of effectively dispersing the drug substance. The desired particle size and particle size distribution can be achieved by selecting the appropriate device.

[0225] 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 and 6,648,873).

[0226] 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).

[0227] If desired, the formulations of the present disclosure can be incorporated into gel formulations (e.g., US Pat. Nos. 4,474,752 and 6,911,211).

[0228] In some embodiments, compounds of Formula I disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system by passing a needle directly into the middle or inner ear (cochlea), or through a cochlear implant stylet electrode channel, or alternatively provided drug delivery channels, such as, but not limited to, passing a needle through the temporal bone into the cochlea.

[0229] Other options include pump-mediated drug delivery through a thin film coated onto a multichannel electrode, or through an electrode with specially implanted drug delivery channels carved into the thin film for that purpose. In other embodiments, the solid acidic or basic compounds of Formula I can be delivered from the reservoir of an external or internal implantable pump system.

[0230] 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 No. 6,377,849 and Application Serial No. 11 / 337,815).

[0231] 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 onto the round window membrane via a surgical approach to the round window membrane that includes modification of the crista fenestrae cochleae.

[0232] In some embodiments, the compounds of formula I are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG ointment), and the like.

[0233] Suppositories for rectal administration of drugs (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, thereby melting or eroding / dissolving in the rectum to release the compounds. 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 the suppository form of the present composition, a low-melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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 the compounds 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 should be administered to a patient with cancer. In another embodiment, a kit may comprise a compound or composition described herein and a label indicating that the contents are to be administered to a patient with one or more of 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 with parkinsonism-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, autism, dementia, epilepsy, Huntington's disease, and multiple sclerosis.

[0239] Treatment method The compounds and compositions provided herein can be used as inhibitors of DYRK1A and, therefore, can be used to treat various disorders and diseases in which overexpression of DYRK1A is implicated, such as 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 with parkinsonism-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, and additional diseases with significant neurodegeneration, such as autism, dementia, epilepsy, Huntington's disease, and multiple sclerosis; diseases and disorders associated with acquired brain injury, such as chronic traumatic encephalopathy, traumatic brain injury, tumors, stroke, tauopathies (e.g., Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and globular glial tauopathy). These include 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 freezing of gait, and 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).

[0240] The gene encoding DYRK1A is located within the Down syndrome critical region (DSCR) on chromosome 21, 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 Down syndrome patients (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.

[0241] 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).

[0242] Accumulating evidence shows that DYRK1A / 1B inhibitors induce proliferation of insulin-producing pancreatic β-cells, making DYRK1A / 1B kinases 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 forms of diabetes that can be treated with DYRK inhibitors include maturity-onset diabetes of the young (MODY, monogenic diabetes), cases of diabetes caused by tissue receptors in the body that do not respond to insulin, double diabetes (when type 1 diabetes becomes insulin resistant), diabetes associated with excessive secretion of insulin-antagonist hormones, diabetes associated with nutritional disorders (ICD-10 code E12), and diabetes caused by any genetic mutation (autosomal or mitochondrial) that results in beta-cell dysfunction.

[0243] There is a wealth of literature linking DYRK1A to solid cancers 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).

[0244] Other cancers can also be treated with the compounds and compositions described herein.

[0245] More specifically, cancers that can be treated by the compounds, compositions, and methods described herein include, but are not limited to:

[0246] 1) Breast cancer, e.g., ER + breast cancer, ER - breast cancer, her2 - breast cancer, her2 + Breast cancer; stromal tumors such as fibroadenoma, phyllodes tumor, and sarcoma, and epithelial tumors such as large ductal papillomas; carcinomas of the breast, e.g., carcinoma in situ (carcinoma in situ), including ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive carcinomas (invasive carcinomas), 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), and various malignant neoplasms. Further examples of breast cancer include luminal A, luminal B, basal A, basal B, and estrogen receptor-negative (ERN) breast cancers. - ), progesterone receptor negative, and HER2 negative (HER2 - In some embodiments, the breast cancer may have a high-risk Oncotype Score.

[0247] 2) Cardiac cancers, such as sarcomas, including angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma; and teratoma.

[0248] 3) Lung cancer, for example, bronchogenic carcinoma, such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondroitin hamartoma; chemotherapy-resistant small cell lung cancer (SCLC); and mesothelioma.

[0249] 4) Gastrointestinal cancers, for example, esophageal cancer, such as squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; gastric cancer, such as carcinoma, lymphoma, and leiomyosarcoma; pancreatic cancer, such as pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and vipoma; colon cancer with APC gene mutation; small intestinal cancer, such as adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; large intestinal cancer, such as adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.

[0250] 5) Genitourinary cancers, such as cancer of the kidney, e.g., adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, and leukemia; cancer of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancer of the prostate, e.g., adenocarcinoma and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, malignant teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma.

[0251] 6) Liver cancer, for example, hepatocellular carcinoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

[0252] 7) Bone cancers, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0253] 8) Nervous system cancers, such as cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthomas, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningeal sarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma.

[0254] 9) Gynecological cancers, for example, cancer of the uterus, for example, endometrial cancer (e.g., carcinoma, endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, mixed carcinoma or undifferentiated carcinoma (including mixed Müllerian tumor), endometrial stromal sarcoma, endometrial squamous cell carcinoma, urothelial carcinoma, endometrial carcinoma with CTNNB1 mutation); cancer of the cervix, for example, cervical carcinoma and preneoplastic cervical dysplasia; cancer of the ovary, for example, BRCA-mutated ovarian cancer, superficial 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, for example, serous cystadenocarcinoma, mucinous cyst adenocarcinoma, endometrioid tumor, small cell ovarian cancer (hypercalcemic small cell ovarian cancer, pulmonary small cell ovarian cancer), unclassified carcinoma, granulosa-thecocytoma, Sertoli-Leydig cell tumor, dysgerminoma, and malignant teratoma; cancer of the vulva, such as squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, and melanoma; cancer of the vagina, such as clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancer of the fallopian tubes, such as carcinoma, primary fallopian tube carcinoma; primary peritoneal carcinoma (also known as superficial serous papillary carcinoma, primary peritoneal carcinoma, extraovarian serous carcinoma, primary papillary serous carcinoma, and psammomacarcinoma).

[0255] 10) Hematological cancers, such as cancers of the blood, such as acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndromes (refractory cytopenia with monocytic dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ringed sideroblasts, refractory cytopenia with polycytic dysplasia, refractory anemia I and II with excess blasts, childhood refractory cytopenia), and myeloproliferative neoplasms, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, myelodysplastic-myeloproliferative disorders, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Waldenstrom's macroglobulinemia.

[0256] 11) Skin cancers and disorders, such as malignant and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloids, and scleroderma.

[0257] 12) Adrenal cancer, e.g., neuroblastoma.

[0258] 13) Soft tissue sarcomas (STS), such as 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, alveolar soft part sarcoma, and infantile hemangiopericytoma.

[0259] More specifically, tumors of the central nervous system that can be treated by the compounds, compositions, and methods described herein include:

[0260] 1) Astrocytic tumors, such as diffuse astrocytoma (fibrous, protoplasmic, large round cell, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), pilocytic astrocytoma (pilocytic myxoid astrocytoma), multiform xanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosis cerebri.

[0261] 2) Oligodendroglial tumors, such as oligodendroglioma and anaplastic oligodendroglioma.

[0262] 3) Oligoastrocytic tumors, such as oligoastrocytoma and anaplastic oligoastrocytoma.

[0263] 4) Ependymal tumors, such as subependymoma, myxopapillary ependymoma, ependymoma (cellular, papillary, clear cell, elongated cell), and anaplastic (malignant) ependymoma.

[0264] 5) Choroid plexus tumors, such as choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma.

[0265] 6) Neuronal tumors and mixed neuronal-glial tumors, such as ganglioneuroma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), cerebellar dysplastic ganglioneuroma (Lhermitte-Duclos disease), desmoplastic infantile astrocytoma / ganglioma, central neurocytoma, anaplastic ganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma, papillary glioneuronal tumor, rosette-forming glioneuronal tumor of the fourth ventricle, and paraganglioma of the filum terminale.

[0266] 7) Pineal tumors, such as pineocytoma, pineoblastoma, pineal papillary tumor, and intermediate pineal parenchymal tumor.

[0267] 8) Embryonal tumors, such as medulloblastoma (medulloblastoma with extensive nodular formation, anaplastic medulloblastoma, desmoplastic, large cell, pigmented, medullomyoblastoma), medulloepithelioma, supratentorial primitive neuroectodermal tumor, and primitive neuroectodermal tumors (PNET), such as neuroblastoma, ganglioneuroblastoma, ependymoblastoma, and atypical teratoid / rhabdoid tumor.

[0268] 9) Neuroblastic tumors, such as olfactory neuroblastoma, olfactory neuroepithelioma, and adrenal-sympathetic neuroblastoma.

[0269] 10) Glial tumors, such as astroblastoma, third ventricular chordomatoid glioma, and angiocentric glioma.

[0270] 11) Tumors of the cranial nerves and paraspinal nerves, such as schwannoma, neurofibroma / perineuriomas, and malignant peripheral nerve sheath tumors.

[0271] 12) Meningeal tumors, such as tumors of meningeal epithelial cells, for example, meningiomas (atypical meningiomas and anaplastic meningiomas); mesenchymal tumors, such as lipoma, angiolipoma, brown lipoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, hemangioma, epithelioid hemangioendothelioma, hemangiopericytoma, anaplastic hemangiopericytoma, angiosarcoma, Kaposi's sarcoma, and Ewing's sarcoma; primary melanocytosis, such as diffuse melanocytosis, melanoma, malignant melanoma, meningeal melanomatosis; and hemangioblastoma.

[0272] 13) Hematopoietic tumors, such as malignant lymphoma, plasmacytoma, and granulocytic sarcoma.

[0273] 14) Germ cell tumors, such as germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumor.

[0274] 15) Sellar tumors, such as craniopharyngiomas, granular cell tumors, pituitary cell tumors, and adenohypophysial spindle cell oncocytomas.

[0275] Cancer can be a solid tumor that may or may not be metastatic.Cancer can also occur as diffuse tissue, similar to leukemia.Therefore, the term "tumor cell" provided herein includes the cell that is affected by any one of the above-identified disorders.

[0276] 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.

[0277] 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).

[0278] 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).

[0279] The compounds and compositions provided herein can be used as inhibitors and / or modulators of the enzyme DYRK1A, and therefore, to treat various 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 frontotemporal dementia with parkinsonism-17 (FTDP-17), behavioral variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (commonly known as amyotrophic lateral sclerosis) (also known as FTD-ALS), corticobasal degeneration (CBD) (also known as corticobasal ganglionic degeneration), It can be used to treat progressive supranuclear palsy, primary progressive aphasia (PPA), glioglobular tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also called Steinert's disease), myotonic dystrophy type 2 (DM2) (also called proximal myotonic myopathy), Guam complex, argyrophilic grain disease, dementia pugilistica, postencephalitic parkinsonism, dementia with Lewy bodies, Parkinson's disease, Pick's disease, and additional diseases with significant neurodegeneration, such as autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; diseases and disorders associated with acquired brain injury, such as chronic traumatic encephalopathy, traumatic brain injury, tumors, and stroke.

[0280] Non-limiting examples of neurological disorders (e.g., neurological conditions and diseases) that can be treated by the compounds and compositions provided 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 injury, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Thompson syndrome, and cerebral vasculitis. Doughson's disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compressive neuropathy, congenital bilateral 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, Demorsia syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis Inflammation, developmental apraxia, diabetic 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 disease, Fahr syndrome, familial spastic paraparesis, febrile seizures, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville syndrome, Gaucher disease, Gerstmann syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, heterotopic gray matter, Guillain-Barr syndrome Barre syndrome, HTLV-1-associated myelopathy, Hallervorden-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 disease, infantile spasms, inflammatory myopathy, intracranial cysts, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsborn syndrome, Klippel-Feil syndrome, Krabbe disease,Kugelberg-Welander disease, kuru disease, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary syndrome (Wallenberg syndrome), Leigh 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), macrocephaly, megalopsia, megalencephaly, Melkerson-Rosenthal syndrome, Meniere's disease, meningitis, Menkes disease, metachromatic leukodystrophy trophy, microcephaly, micropsia, Miller-Fisher syndrome, sound aversion, mitochondrial myopathy, Moebius syndrome, single limb muscular atrophy, motor neuron disease, motor skills disorder, moyamoya disease, mucopolysaccharidosis, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinating diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, myotubular myopathy, congenital myotonia, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, psychiatric Ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital neuralgia, sequence of latent spinal dysraphism, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus syndrome, optic neuritis, orthostatic hypotension, recurrent visual disturbances, paresthesia, Parkinson's disease, congenital paramyotonia, paraneoplastic disorders, paroxysmal 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), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive facial hemistrophy, 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 disease,Schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjögren's syndrome, snatiation, 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, trigeminal neuralgia (tic douloureux, Todd's palsy, Tourette's syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubisiosis, von Hippel-Lindau disease (VHL), Viliuisk encephalomyelitis (VE), Wallenberg syndrome, Werdnig-Hoffmann disease, West syndrome, Williams syndrome, Wilson's disease, and Zellweger syndrome.

[0281] The compounds and compositions may also be useful in inhibiting invasive cancer development, tumor angiogenesis, and metastasis.

[0282] 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.

[0283] In some embodiments, the disorder or disease is cancer.

[0284] In some embodiments, the disorder or disease is metastatic melanoma.

[0285] In some embodiments, the disorder or disease is tendon regeneration.

[0286] In some embodiments, the disorder or disease is diabetes.

[0287] In some embodiments, the disorder or disease is degenerative disc disease.

[0288] In some embodiments, the disorder or disease is osteoarthritis.

[0289] In some embodiments, the disorder or disease is a viral infection.

[0290] In some embodiments, the disorder or disease is a neurological disorder.

[0291] In some embodiments, the disorder or disease is Alzheimer's disease.

[0292] In some embodiments, the disorder or disease is osteoarthritis.

[0293] In some embodiments, the patient is a human.

[0294] 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.

[0295] 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.

[0296] In some embodiments, the cancer is hepatocellular carcinoma; in some embodiments, the cancer is colon cancer; in some embodiments, the cancer is colorectal cancer; in some embodiments, the cancer is breast cancer; in some embodiments, the cancer is pancreatic cancer; in some embodiments, the cancer is chronic myeloid leukemia (CML); in some embodiments, the cancer is chronic myelomonocytic leukemia; in some embodiments, the cancer is chronic lymphocytic leukemia (CLL); in some embodiments, the cancer is acute myeloid leukemia; in some embodiments, the cancer is acute lymphocytic leukemia; in some embodiments, the cancer is Hodgkin'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 non-small cell lung cancer; in some embodiments, the cancer is small cell lung cancer; 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 basal cell / squamous cell skin cancer; 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 a gastrointestinal stromal tumor; in some embodiments, the cancer is a 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 a 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; in some embodiments, the cancer is adrenocortical carcinoma;

[0297] 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 muscle disorders.

[0298] 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 with parkinsonism-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, and additional diseases with significant neurodegeneration, such as autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; diseases and disorders associated with acquired brain injury, such as chronic traumatic encephalopathy, traumatic brain injury, tumors, and stroke.

[0299] In some embodiments, the compounds of Formula I inhibit DYRK1A.

[0300] In some embodiments, the method is for treating 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.

[0301] In some embodiments, the disease or disorder involves tumor growth, cell proliferation, or angiogenesis.

[0302] In some embodiments, the method inhibits the 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.

[0303] In some embodiments, the method is for treating 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.

[0304] 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.

[0305] In some embodiments, the method is for treating 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 compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more other medicinal agents.

[0306] 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.

[0307] For example, an in vitro assay for DYRK1A biological activity, e.g., modulation 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, e.g., 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 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).

[0308] 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).

[0309] 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]

[0310] 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.

[0311] Those skilled in the art of organic chemistry will recognize that these manipulations can be readily performed without further instruction, i.e., are well within the scope and practice of the art. These include reduction of carbonyl compounds to the corresponding alcohols, oxidation, acylation, both electrophilic and nucleophilic aromatic substitution, etherification, esterification, and saponification. These manipulations are described in standard texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Ed., John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry, 5th Ed., Springer (2007), and Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2nd Ed., John Wiley & Sons (1999), which are incorporated herein by reference in their entireties.

[0312] Those skilled in the art will readily recognize that certain reactions are best performed when other functional groups in the molecule are shielded or protected, thereby avoiding any undesired side reactions and / or improving the reaction yield. Often, those skilled in the art utilize protecting groups to achieve such improved yields or avoid undesired reactions. These reactions can be found in the literature and are well within the purview of those skilled in the art. 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), which is incorporated herein by reference in its entirety.

[0313] The trademarks used herein are merely examples and represent exemplary materials used at the time of this 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; they 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.

[0314] ( 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, 1 Measurements 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.

[0315] The following abbreviations have the indicated meanings: Ac2O = acetic anhydride Boc = tert-butyloxycarbonyl B(OiPr)3 = triisopropyl borate 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 nBuLi = n-butyllithium CDCl3 = deuterated chloroform (COCl)2 = oxalyl chloride 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 IPA = Isopropyl alcohol 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 MsCl = methanesulfonyl chloride or mesyl chloride MTBE = methyl tert-butyl ether MW = microwave irradiation NaO t Bu = sodium tert-butoxide NaHCO3 = sodium bicarbonate 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(OH)2 / C = palladium hydroxide on carbon PE = petroleum ether PPTS = pyridinium p-toluenesulfonate Prep TLC = preparative thin layer chromatography QPhos = 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene rt=room temperature TBDMSCl = tert-butyldimethylsilyl chloride 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

[0316] 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.

[0317] General Procedure Compounds of formula I of the present disclosure can be prepared as shown in Scheme 1. [ka]

[0318] Scheme 1 describes the preparation of 4-alkoxypyrrolo[2,1-f][1,2,4]triazine derivatives (VII) by first replacing the 4-chloride (I) with various alkoxy groups (II) to generate 2-chloro-5-bromo-4-alkoxypyrrolo[2,1-f][1,2,4]triazines III. Various bromides (IV) are reacted with bis(pinacolato)diboron to form various pinacol boronic acid esters, followed by Suzuki coupling with bromide (III) to generate 2-chloro-4-alkoxypyrrolo[2,1-f][1,2,4]triazines (V). The chloro group is then replaced with various amines (VI) to finally generate 4-alkoxypyrrolo[2,1-f][1,2,4]triazines (VII).

[0319] Illustrative Compound Examples The preparation of the intermediate 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) is shown below in Scheme 2. [ka]

[0320] Step 1 To a solution of methyl 3-bromo-1H-pyrrole-2-carboxylate (VIII) (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. Then, 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 N. After the addition, the reaction was allowed to warm 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 performed six times.

[0321] 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 (IX) (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).

[0322] Steps 2 and 3 To a solution of methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (IX) (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.

[0323] 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 (X) (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 actual value C7H8BrN3O3m / z 262.1 ( 79 BrM+H).

[0324] Step 4 To a solution of methyl 3-bromo-1-ureido-1H-pyrrole-2-carboxylate (X) (67 g, 255.67 mmol, 1 equiv.) in THF (4 L) was added TMSOK (65.60 g, 511.33 mmol, 2 equiv.) in several portions 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.

[0325] The filter cakes from the six reactions were combined and triturated with HO (6 L) at room temperature for 2 h, then filtered. The filter cake was dried in a vacuum oven at 60 °C for 24 h to give 5-bromopyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (XI) (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 actual value C6H4BrN3O2m / z 232.0 ( 81 BrM+H).

[0326] 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 (XI) (180 g, 782.55 mmol, 1 equiv.) in several portions at room temperature. N,N-Diethylaniline (291.95 g, 1.96 mol, 312.92 mL, 2.5 equiv.) was then added dropwise at room temperature (slightly exothermic). After the addition, the reaction was heated to 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, then heated to gentle reflux for 24 h. LCMS indicated that the majority of the intermediate remained, and approximately 11.9% of the desired product had formed. The reaction was heated at gentle reflux for an additional 4 days. LCMS indicated 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 POCl3. The residue was diluted with MeTHF (5 L), poured into ice-H2O (2 L), and 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, purity 98.96%) as a yellow solid. 1 H 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 actual value C6H2BrCl2N3m / z 266.1 ( 79 BrM+H).

[0327] Step 6 To a stirred solution of 5-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (I) (8.0 g, 29.97 mmol) in THF (10 mL) was added sodium methoxide (66 mL, 33 mmol) in MeOH dropwise at 0 °C, and the mixture was stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl, taken up in EtOAc, and washed with water and brine. The organics were separated, dried over anhydrous Na2SO4, concentrated, and dried under high vacuum to give 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (6 g, 22.86 mmol, 76.3% yield) as an off-white solid, which was used in the next step without purification. 1 H NMR (499 MHz, DMSO-d6) δ ppm 4.12 (3 H, s), 7.00 (1 H, d, J=3.01 Hz), 8.01 (1 H, d, J=3.01 Hz); ESIMS actual value C7H5BrClN3O m / z 261.1 ( 79 BrM+H).

[0328] The preparation of the intermediate 5-bromo-2-chloro-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XXII) is shown below in Scheme 3. [ka]

[0329] Step 1 To a solution of methyl 4-fluoro-1H-pyrrole-2-carboxylate (XIII) (commercially available from PharmaBlock (USA), Inc.) (1 g, 6.99 mmol) in CHCl (9 mL) was added N-bromosuccinimide (2.64 g, 14.68 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with 10% sodium thiosulfate (50 mL) and extracted with CHCl (3 × 30 mL). The organic layers were combined, washed with saturated aqueous NaCl (50 ml), and evaporated under reduced pressure to give methyl 3,5-dibromo-4-fluoro-1H-pyrrole-2-carboxylate (XIV) (2.1 g, 6.979 mmol, 99.9% yield) as a beige solid. The product was used directly without further purification. ESIMS found CHBrFNO m / z 299.9 (M+H).

[0330] Step 2 To a solution of methyl 3,5-dibromo-4-fluoro-1H-pyrrole-2-carboxylate (XIV) (2.1 g, 6.98 mmol) in dry THF (25 mL) was added NaH (0.43 g, 10.63 mmol) slowly in small portions at 0 °C under N. The suspension was stirred at 0 °C for 30 min. To the suspension was added (2-(chloromethoxy)ethyl)trimethylsilane (1.9 mL, 10.74 mmol) at 0 °C under N. The reaction mixture was stirred at 0 °C for 2 h, then quenched with ice water (20 mL) and extracted with EtOAc (3 × 30 mL). The EtOAc layer was evaporated under reduced pressure and purified by silica gel column chromatography (100% hexanes) to give methyl 3,5-dibromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (XV) (2.76 g, 6.401 mmol, 91.7% yield) as an amber liquid. 1 H NMR (499 MHz, DMSO-d6) δ ppm -0.07 (9 H, s), 0.81 (2 H, t, J=7.80 Hz), 3.50 (2 H, t, J=7.80 Hz), 3.82 (3 H, s), 5.69 (2 H, s).

[0331] Step 3 To a solution of methyl 3,5-dibromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (XV) (2.76 g, 6.4 mmol) in dry THF (60 mL) was added nBuLi (2.4 mL, 6 mmol) at −78° C. under N. The reaction mixture was stirred at −78° C. for 1 h. The mixture was carefully quenched with ice-water (20 mL), warmed to room temperature, and extracted with EtOAc (3×20 mL). The organics were dried over anhydrous NaSO, filtered, evaporated onto Celite®, and purified by silica gel column chromatography (0→6% EtOAc / hexanes) to yield methyl 3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (XVI) (760 mg, 2.157 mmol, 33.7% yield) as a clear oil. 1 H NMR (500 MHz, DMSO-d6) δ ppm -0.06 (9 H, s), 0.80 (2 H, t, J=7.96 Hz), 3.41 - 3.50 (2 H, m), 3.80 (3 H, s), 5.56 (2 H, s), 7.52 (1 H, d, J=3.29 Hz).

[0332] Step 4 To a stirred solution of methyl 3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (XVI) (881 mg, 2.5 mmol) in DCM (23 mL) was added TFA (23 mL) and the mixture was stirred at room temperature for 10 min. The solvent was concentrated and the residue was taken up in a mixture of MeOH (12 mL) / water (6 mL). To this mixture was added K2CO3 (1.75 g, 12.66 mmol) and stirred at room temperature for 4 h. Water (10 mL) was added and the solution was neutralized with 1H HCl and washed with CHCl3 (3 x 10 mL). The organic layer was stripped onto Celite® and purified by silica gel column chromatography (0→5% MeOH / CHCl3 (7N NH3)) to produce methyl 3-bromo-4-fluoro-1H-pyrrole-2-carboxylate (XVII) (450 mg, 2.027 mmol, 81.0% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 3.80 (3 H, s), 7.15 (1 H, d, J=3.56 Hz), 12.29 (1 H, br s); ESIMS actual value C6H5BrFNO2m / z 222.0 (M+H).

[0333] Step 5 To a solution of methyl 3-bromo-4-fluoro-1H-pyrrole-2-carboxylate (XVII) (500 mg, 2.25 mmol) in dry DMF (7 mL) at 0 °C, NaH (120 mg, 2.93 mmol) was added slowly. After 30 min, O-(2,4-dinitrophenyl)hydroxylamine (490 mg, 2.48 mmol) was added in one portion, and the reaction was stirred in an ice bath for 1 h and at room temperature for 1 h. LC / MS showed the reaction was incomplete, so O-(2,4-dinitrophenyl)hydroxylamine (490 mg, 2.48 mmol) was added and stirred at room temperature for 15 min. The reaction was diluted with water (100 mL) and extracted with EtOAc (3 × 75 mL). The combined extracts were stripped onto Celite® and purified by silica gel column chromatography (100% CHCl3) to produce methyl 1-amino-3-bromo-4-fluoro-1H-pyrrole-2-carboxylate (XVIII) (501 mg, 2.114 mmol, 93.9% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 3.80 (3 H, s), 6.36 (2 H, s), 7.25 (1 H, d, J=3.29 Hz); ESIMS actual value C6H6BrFN2O2m / z 237.0 (M+H).

[0334] Step 6 To a solution of methyl 1-amino-3-bromo-4-fluoro-1H-pyrrole-2-carboxylate (XVIII) (500 mg, 2.11 mmol) in DCM (10 mL) was added pyridine (210 μL, 2.6 mmol) and methyl carbonochloridate (180 μL, 2.33 mmol) dropwise. The reaction was stirred at room temperature for 20 minutes. DCM (100 mL) was added, washed with 1 N HCl (2 × 50 mL), stripped onto Celite®, and purified by silica gel column chromatography (0 → 100% EtOAc / hexanes) to give methyl 3-bromo-4-fluoro-1-((methoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (XIX) (560 mg, 1.898 mmol, 89.8% yield) as a clear oil.1 H NMR (499 MHz, DMSO-d₆) δ ppm 3.69 (3H, br s), 3.76 (3H, s), 7.48 (1H, br d, J=1.92 Hz), 10.76 (1H, br s); ESIMS found C₈H₈BrFN₂O₄ m / z 295.0 (M+H).

[0335] Step 7 To NHOH (35 mL, 263.7 mmol) in a sealed test tube was added methyl 3-bromo-4-fluoro-1-((methoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (XIX) (560 mg, 1.9 mmol). The reaction was sealed and heated to 110 °C for 16 h. The solvent was removed in vacuo and the residue was dissolved in MeCN. The solvent was stripped (three times to remove water) and placed under high vacuum for 1 h to yield 5-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (XX) (440 mg, 1.774 mmol, 93.5% yield) as a light brown solid. The product was used directly without further purification. 1 H NMR (499 MHz, DMSO-d6) δ ppm 7.04 (1 H, d, J=3.29 Hz), 7.13 (1 H, br s), 9.58 (1 H, br s); ESIMS actual value C6H3BrFN3O2m / z 247.9 (M+H).

[0336] Step 8 To a solution of neat POCl3 (3 mL, 32.19 mmol), 5-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (XX) (440 mg, 1.77 mmol) was added portionwise at room temperature. N,N-Diethylaniline (0.7 mL, 4.4 mmol) was then added dropwise at room temperature. The reaction was heated at 105 °C for 16 h. The solvent was removed in vacuo, followed by the addition of water (20 mL) and extraction with EtOAc. The organic layer was stripped onto Celite® and purified by silica gel column chromatography (0→100% EtOAc / hexanes) to yield 5-bromo-2,4-dichloro-6-fluoropyrrolo[2,1-f][1,2,4]triazine (XXI) (175 mg, 0.614 mmol, 34.6% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 7.92 (1 H, d, J=3.29 Hz); ESIMS actual value C6HBrCl2FN3m / z 283.9 (M+H).

[0337] Step 9 To a solution of 5-bromo-2,4-dichloro-6-fluoropyrrolo[2,1-f][1,2,4]triazine (XXI) (175 mg, 0.61 mmol) in MeOH (664 μL) and DCM (2 mL) was added KCO (254.1 mg, 1.84 mmol). The flask was capped and stirred at room temperature for 16 h. Water (50 mL) was added and extracted with DCM (3 × 50 mL). The organic layer was separated and washed with water (2 × 50 mL) and brine (50 mL). The solvent was removed in vacuo to yield 5-bromo-2-chloro-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XXII) (163 mg, 0.581 mmol, 94.6% yield) as a beige solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 4.12 (3 H, s), 8.34 (1 H, d, J=3.29 Hz); ESIMS actual value C7H4BrClFN3O m / z 279.95 (M+H).

[0338] The preparation of the intermediate 2,5-dichloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XXIV) is shown below in Scheme 4. [ka]

[0339] Step 1 To a stirred solution of 2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine (XXIII) (commercially available from PharmaBlock Sciences Inc.) (202 mg, 0.910 mmol) in THF (4 mL) was added dropwise sodium methoxide (2 mL, 1 mmol) in MeOH at 0 °C, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, taken up in EtOAc, and washed with brine. The organics were separated, dried over anhydrous NaSO, concentrated, and the crude mixture was purified by ISCO (0 → 100% EtOAc / hexanes). The fractions were collected, concentrated under reduced pressure, and dried under high vacuum to afford 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XXIV) (140 mg, 0.642 mmol, 70.7% yield) as a pale yellow solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 4.12 (3 H, s), 6.95 (1 H, d, J=3.01 Hz), 8.02 (1 H, d, J=3.01 Hz).

[0340] The following intermediates were prepared according to the procedure described in Scheme 4 above. [ka]

[0341] 5-Bromo-2-chloro-4-(oxetan-3-yloxy)pyrrolo[2,1-f][1,2,4]triazine (XXV): off-white solid (558.8 mg, 1.84 mmol, 98.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 4.70 (2 H, ddd, J=7.94, 4.65, 1.10 Hz), 4.95 (2 H, ddd, J=7.73, 6.37, 0.96 Hz), 5.80 (1 H, tt, J=6.09, 4.86 Hz), 7.05 (1 H, d, J=3.01 Hz), 8.05 (1 H, d, J=3.01 Hz);ESIMS actual value C9H7BrClN3O2m / z 303.95 (M+H).

[0342] The preparation of the intermediate 6-bromo-1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazole (XXX) is shown below in Scheme 5. [ka]

[0343] Step 1 To an ice-cooled suspension of sodium hydride (222 mg, 9.2 mmol) in THF (20 mL) was added 2,2-difluoroethylamine (XXVI) (746 mg, 9.32 mmol). The reaction mixture was stirred at 0 °C for 30 min, followed by the addition of an ice-cold solution of 5-bromo-1,3-difluoro-2-nitrobenzene (XXVII) (2.0 g, 8.4 mmol) in THF (20 mL). The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with water. The aqueous layer was extracted with EtOAc, and the organics were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by column chromatography (40 g silica gel) (0 → 20% EtOAc / hexanes) to afford 5-bromo-N-(2,2-difluoroethyl)-3-fluoro-2-nitroaniline (XXVIII) (500 mg, 0.836 mmol, 19.9% yield) as a yellow solid. ESIMS measured value C8H6BrF3N2O2 m / z 299.0 ( 79 BrM+H).

[0344] Step 2 A mixture of 5-bromo-N-(2,2-difluoroethyl)-3-fluoro-2-nitroaniline (XXVIII) (500 mg, 1.67 mmol), Fe (1.09 g, 16.72 mmol), and NH4Cl (1.34 g, 25.1 mmol) in a mixture of EtOH (6 mL) and water (2.5 mL) was heated to 70°C for 4 h. The reaction mixture was cooled and filtered through Celite®. The filtrate was dissolved in EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5-bromo-N 1 -(2,2-Difluoroethyl)-3-fluorobenzene-1,2-diamine (XXIX) (420 mg, 1.561 mmol, 93.4% yield) was obtained as a brown solid, which was used in the next reaction without further purification. ESIMS found C8H8BrF3N2 m / z 269.0 (M+H).

[0345] Step 3 5-Bromo-N 1 A solution of -(2,2-difluoroethyl)-3-fluorobenzene-1,2-diamine (XXIX) (420 mg, 1.56 mmol) and AcO (175 μL, 1.85 mmol) in HOAc (8 mL) was heated to 120° C. for 16 h. The reaction mixture was concentrated, the residue was partitioned between EtOAc / 1N NaOH, and the organics were separated and washed with water and brine. The organics were dried over anhydrous NaSO and concentrated to give 6-bromo-1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazole (XXX) (380 mg, 1.297 mmol, 83.1% yield) as a light brown solid. ESIMS found C 10 H 10 BrF3N2 m / z 295.0 (M+H).

[0346] The preparation of the intermediate 6-bromo-1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridine (XXXIV) is shown below in Scheme 6. [ka]

[0347] Step 1 A mixture of 2,2-difluoroethan-1-amine (XXVI) (410 mg, 5.02 mmol), 5-bromo-3-fluoro-2-nitropyridine (XXXI) (commercially available from Ark Pharma 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, and the solid was collected by filtration and dried under vacuum to give 5-bromo-N-(2,2-difluoroethyl)-2-nitropyridin-3-amine (XXXII) (1.066 g, 3.780 mmol, 83.5% yield) as a yellow solid, which was used in the next step without purification. ESIMS found C7H6BrF2N3O2 m / z 282.0 ( 79 BrM+H).

[0348] Step 2 A mixture of 5-bromo-N-(2,2-difluoroethyl)-2-nitropyridin-3-amine (XXXII) (1.32 g, 4.69 mmol), Fe (3.07 g, 46.95 mmol), and NHCl (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 to 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 NaSO, filtered, and concentrated under reduced pressure to give 5-bromo-N 3 -(2,2-Difluoroethyl)pyridine-2,3-diamine (XXXIII) (630 mg, 2.499 mmol, 53.2% yield) was obtained as a gray solid, which was used in the next reaction without further purification. ESIMS found C7H8BrF2N3 m / z 252.0 ( 79 BrM+H).

[0349] Step 3 5-Bromo-N 3A solution of -(2,2-difluoroethyl)pyridine-2,3-diamine (XXXIII) (630 mg, 2.5 mmol) and acetic anhydride (0.28 mL, 2.97 mmol) in HOAc (15 mL) was heated to 120 °C for 16 h. The reaction mixture was concentrated, the residue was partitioned between EtOAc / 1N NaOH, and the organics were separated and washed with water and brine. The organics were dried over anhydrous NaSO, and the solvent was 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 (XXXIV) (325 mg, 1.177 mmol, 47.1% yield) as a gray solid, which was used in the next step without purification. ESIMS found CHBrFN m / z 276.0 ( 79 BrM+H).

[0350] The following intermediates were prepared according to the procedures described in Scheme 6 above. [ka]

[0351] 6-Bromo-1-(3,3-difluorocyclobutyl)-2-methyl-1H-imidazo[4,5-b]pyridine (XXXV): Gray solid (1.57 g, 6.178 mmol, 68.3% yield). ESIMS found C 11 H 10 BrF2N3 m / z 302.1 (M+H). [ka]

[0352] 6-Bromo-1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazole (XXXVI): beige solid (970 mg, 3.526 mmol, 79.0% yield). ESIMS found C 10 H9BrF2N2m / z 275.0 (M+H).

[0353] The preparation of the intermediate 6-bromo-1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine (XL) is shown below in Scheme 7. [ka]

[0354] Step 1 A mixture of 2-aminopropane (XXXVII) (0.86 mL, 9.96 mmol), 5-bromo-3-fluoro-2-nitropyridine (XXXI) (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 (XXXVIII) (2.36 g, 9.074 mmol, 100.3% yield) as a yellow solid, which was used in the next step without purification. ESIMS found CH 10 BrN3O2 m / z 260.0 (M+H).

[0355] Step 2 A mixture of 5-bromo-N-isopropyl-2-nitropyridin-3-amine (XXXVIII) (2.35 g, 9.04 mmol), Fe (5.91 g, 90.35 mmol), and NHCl (7.25 g, 135.53 mmol) was taken up in a mixture of EtOH (30 mL) and water (10 mL), and the mixture was heated to 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 NaSO, filtered, and concentrated under reduced pressure to give 5-bromo-N 3 -Isopropylpyridine-2,3-diamine (XXXIX) (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. ESIMS found CH 12 BrN3 m / z 230.05 (M+H).

[0356] Step 3 5-Bromo-N 3 A solution of 1-isopropylpyridine-2,3-diamine (XXXIX) (2.08 g, 9.04 mmol) and AcO (1.05 mL, 10.84 mmol) in HOAc (20 mL) was heated to 120 °C for 16 h. The reaction mixture was concentrated, the residue was partitioned between EtOAc / 1N NaOH, and the organics were separated and washed with water and brine. The organics were dried over anhydrous NaSO, concentrated, and dried under high vacuum to give 6-bromo-1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine (XL) (1.57 g, 6.178 mmol, 68.3% yield) as a dark brown solid, which was used in the next step without purification. ESIMS found C 10 H 12 BrN3 m / z 254.0 (M+H).

[0357] The following intermediates were prepared according to the procedures described in Scheme 7 above. [ka]

[0358] 6-Bromo-2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridine (XLI): Gray solid (722 mg, 2.438 mmol, 66.3% yield). ESIMS found C 12 H 14 BrNO m / z 296.0 (M+H).

[0359] The preparation of the intermediate 6-bromo-1-(2,2-difluoroethyl)-1H-benzo[d]imidazole (XLIII) is shown below in Scheme 8. [ka]

[0360] Step 1 To a solution of 5-bromo-N1-(2,2-difluoroethyl)benzene-1,2-diamine (XLII) (3.0 g, 11.95 mmol) in triethoxymethane (60 mL) was added p-toluenesulfonic acid (0.23 g, 1.20 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 16 hours and then cooled to room temperature. The reaction mixture was concentrated. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (2×300 mL). The organic layer was concentrated, dried over Na2SO4, filtered, and concentrated. The mixture was purified by reverse-phase column chromatography (regular C18 20-40 μm, acetonitrile / 0.1% aqueous NH4HCO3, gradient: 40% → 60% MeCN) to give 6-bromo-1-(2,2-difluoroethyl)-1H-benzo[d]imidazole (XLIII) (1.5 g, 5.746 mmol, 48.1% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.8, 2 Hz, 1H), 6.46 (tt, J = 54.3, 3.0 Hz, 1H), 5.36 (td, J=16.4, 3.2 Hz, 2 H); ESIMS actual value C9H7BrF2N2m / z 260.9 (M+H).

[0361] The preparation of the intermediate 5-chloro-3-ethyl-2-methyl-3H-imidazo[4,5-b]pyridine (XLV) is shown below in Scheme 9. [ka]

[0362] Step 1 A mixture of 5-chloro-2-methyl-3H-imidazo[4,5-b]pyridine (XLIV) (commercially available from eNovation Chemicals, LLC) (0.5 g, 2.98 mmol), iodoethane (0.56 g, 3.58 mmol), and KCO (0.83 g, 5.97 mmol) in DMF (10 mL) was heated to 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 MgSO, and the solvent was concentrated under vacuum and dried to give 5-chloro-3-ethyl-2-methylimidazo[4,5-b]pyridine (XLV) (466 mg, 2.382 mmol, 79.8% yield) as a dark brown solid, which was used in the next step without purification. ESIMS found C 10 ClN3 m / z 196.05 (M+H).

[0363] The following intermediates were prepared according to the procedure described in Scheme 9 above. [ka]

[0364] 5-Chloro-3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XLVI): beige solid (830 mg, 3.583 mmol, 60.1% yield). ESIMS found C9H8ClF2N3 m / z 232.0 (M+H). [ka]

[0365] 5-Chloro-3-(2-fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XLVII): beige solid (220 mg, 1.030 mmol, 57.5% yield). ESIMS found C9H9ClFN3 m / z 214.05 (M+H). [ka]

[0366] 5-Chloro-3-(2-methoxyethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XLVIII): beige solid (195 mg, 0.864 mmol, 48.3% yield). ESIMS found C 10 H 12 ClNO m / z 226.1 (M+H). [ka]

[0367] 1-(5-Chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropan-2-ol (XLIX): 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); ESIMS actual measurement value C 11 H 14 ClNO m / z 240.1 (M+H). [ka]

[0368] 5-Chloro-3-isobutyl-2-methyl-3H-imidazo[4,5-b]pyridine (L): white solid (206.8 mg, 0.925 mmol, 38.7% yield). 1 H 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) 11 H 14ClN3 m / z 224.1 (M+H). [ka]

[0369] 5-Chloro-2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine (LI): beige solid (372 mg, 1.490 mmol, 50.0% yield). ESIMS found C9H7ClF3N3 m / z 250.0 (M+H). [ka]

[0370] 5-Chloro-2-methyl-3-(oxetan-3-ylmethyl)-3H-imidazo[4,5-b]pyridine (LII): 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) 11 H 12 ClNO m / z 238.1 (M+H). [ka]

[0371] tert-Butyl 3-((5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)azetidine-1-carboxylate (LIII): off-white amorphous solid (532.6 mg, 1.581 mmol, 52.1% yield). ESIMS found C 16 H 21 ClN4O2 m / z 337.1 (M+H). [ka]

[0372] 2-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-N,N-dimethylacetamide (LIV): off-white solid (474.4 mg, 1.877 mmol, 62.6% yield). ESIMS found C 11 H 13 ClNO m / z 253.1 (M+H). [ka]

[0373] 3-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,2-dimethylpropanenitrile (LV): off-white amorphous solid (59.1 mg, 0.238 mmol, 7.9% yield). ESIMS observed C 12 H 13 ClN4 m / z 249.1 (M+H).

[0374] The preparation of intermediate 6-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyl-1H-benzo[d]imidazole (LXII) is shown below in Scheme 10. [ka]

[0375] Step 1 A solution of 4-bromo-2-fluoro-1-nitrobenzene (LVII) (2.0 g, 9.09 mmol) in 2-aminoethanol (LVII) (2.8 mL, 46.39 mmol) was stirred at room temperature for 10 minutes. Water (50 mL) was added, and the mixture was extracted with EtOAc and dried over Celite®. The residue was purified by silica gel column chromatography (0→100% EtOAc / hexane) to give 2-((5-bromo-2-nitrophenyl)amino)ethan-1-ol (LVIII) (2.349 g, 8.998 mmol, 99.0% yield) as a yellow solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 3.41 (2 H, q, J=5.48 Hz), 3.63 (2 H, q, J=5.48 Hz), 5.00 (1 H, t, J=5.34 Hz), 6.83 (1 H, dd, J=9.17, 2.05 Hz), 7.30 (1 H, d, J=1.92 Hz), 7.98 (1 H, d, J=9.03 Hz), 8.29 (1 H, br t, J=5.06 Hz); ESIMS actual value C8H9BrN2O3m / z 260.96 (M+H).

[0376] Step 2 To a solution of 2-((5-bromo-2-nitrophenyl)amino)ethan-1-ol (LVIII) (1.31 g, 5.02 mmol) in MeOH (50 mL) was added tin(II) chloride (0.96 mL, 20.09 mmol) at room temperature. The reaction mixture was heated to 64 °C for 6 h and then cooled to room temperature. The solvent was removed in vacuo, and the residue was dissolved in water and basified to pH = 9 by adding Na2CO3. The mixture was extracted with DCM, and the combined organic phases were washed with water, brine, and dried over anhydrous Na2SO4. After the solvent was removed in vacuo, HOAc (15.6 mL, 271.49 mmol) was added. The solution was heated to reflux for 30 min. The acetic acid was removed under reduced pressure, and the residue was purified using silica gel column chromatography (0→50% 7N NH in MeOH / CHCl) to yield 2-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)ethyl acetate (LIX) and 2-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)ethan-1-ol (LX) (1.45 g, 4.880 mmol, 97.2% yield) as an 80 / 20 mixture as an off-white solid. ESIMS found C 12 H 13 BrN2O2 m / z 297.0 (M+H).

[0377] Step 3 To a solution of LiOH (3.2 mL, 9.6 mmol) in THF (27 mL) / water (6 mL) was added a mixture of 2-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)ethyl acetate (LIX) and 2-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)ethan-1-ol (LX) (1.45 g, 4.88 mmol). The reaction was stirred at room temperature for 1 hour. The solution was neutralized with 1N HCl, stripped onto Celite®, and then purified using silica gel column chromatography (0→10% 7N NH in MeOH / CHCl) to produce 2-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)ethan-1-ol (LXI) (1.02 g, 3.998 mmol, 81.9% yield) as a white solid. ESIMS found C 10 H11 BrNO m / z 255.0 (M+H).

[0378] Step 4 2-(6-Bromo-2-methyl-1H-benzo[d]imidazol-1-yl)ethan-1-ol (LXI) (1.02 g, 4 mmol) was dissolved in DCM (8 mL) under a N atmosphere. Imidazole (0.55 g, 8.1 mmol) and TBDMSCl (0.9 mL, 4.84 mmol) were then added. The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with EtOAc and washed with saturated aqueous NaHCO (400 mL). The aqueous layer was back-extracted twice with EtOAc, and the organic layer was stripped onto Celite® and then purified using silica gel column chromatography (0→5% MeOH / CHCl3) to produce 6-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyl-1H-benzo[d]imidazole (LXII) (1.44 g, 3.899 mmol, 97.5% yield) as a white solid. ESIMS found C 16 H 25 BrN2OSi m / z 369.1 (M+H).

[0379] The preparation of the intermediate 6-bromo-1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazole (LXV) is shown below in Scheme 11. [ka]

[0380] Step 1 A solution of 4-bromo-2-fluoro-1-nitrobenzene (LVI) (20.0 g, 98.03 mmol) in THF (500.0 mL) was cooled to 0 °C. CsCO (63.9 g, 196.06 mmol) was added, followed by 2,2-difluoroethan-1-amine (LXIII) (36.6 g, 183.81 mmol) at 0 °C. The reaction was warmed to 40 °C for 16 h. The reaction mixture was extracted with EtOAc (500 L × 3). The combined organics were washed with brine (500 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give the crude product. The crude material was purified by column chromatography on silica gel (10% EtOAc / PE→20% EtOAc / PE) to give 5-bromo-N-(2,2-difluoroethyl)-2-nitroaniline (LXIV) (23 g, 81.83 mmol, 83.5% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 3.99 (tdd, J = 15.6, 6.6, 3.8 Hz, 2H), 6.29 (tt, J = 55.4, 3.7 Hz, 1H), 6.96 (dd, J = 9.2, 2.0 Hz, 1H), 7.51 (d, ESIMS actual value C8H7BrF2N2O2m / z 280.9 (M+H).

[0381] Step 2 To a solution of 5-bromo-N-(2,2-difluoroethyl)-2-nitroaniline (LXIV) (12.0 g, 42.86 mmol) in HOAc / HCl (500 / 50 mL) was added Fe (30.0 g, 428.62 mmol). The reaction mixture was stirred at 50 °C for 30 min, then cooled to room temperature and filtered. Next, NaNO (3.0 g, 53.58 mmol) in water (20 mL) was added dropwise to the above acid solution at 0 °C. The reaction solution was stirred at 0 °C for 1 h. The reaction mixture was concentrated to dryness, and the reaction mixture was poured into EtOAc (300 mL) and H O (300 mL). The pH was adjusted to >7 with NaHCO. The reaction mixture was extracted with EtOAc (500 mL × 3). The combined organics were washed with brine (500 mL × 3). The organic layer was concentrated, dried over Na SO, filtered, and concentrated to give the crude product. The crude material was purified by column chromatography on silica gel (10% EtOAc / PE to 50% EtOAc / PE) to afford 6-bromo-1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazole (LXV) (5 g, 19.08 mmol, 44.5%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 5.41 - 5.29 (m, 2H), 6.61 (tt, J = 54.2, 3.2 Hz, 1H), 7.60 (dd, J = 8.8, 1.7 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 1.0 Hz, 1H); ESIMS measured value C8H6BrF2N3m / z 261.9 (M+H).

[0382] The following intermediates were prepared according to the procedure described in Scheme 11 above. [ka]

[0383] 6-Bromo-1-ethyl-1H-benzo[d][1,2,3]triazole (LXVI): white solid (4.112 g, 18.188 mmol). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 1.6 Hz, 1H), 8.00 (dd, J = 8.8, 3.2 Hz, 1H), 7.54 (dd, J = 8.8, 3.2 Hz, 1H), 4.74 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H); ESIMS measured m / z 225.9 (M+H) for C8H8BrN3.

change

[0384] 6-ブロモ-1-(2-フルオロエチル)-1H-ベンゾ[d][1,2,3]トリアゾール (LXVII): white solid (4.163g, 17.057mmol). 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 1.6 Hz, 1H), 5.11 (dt, J = 28, 4 Hz, 2H), 4.92 (dt, J = 48, 4 Hz, 2H); ESIMS measured m / z 244.0 (M+H) for C8H7BrFN3.

change

[0385] 6-Torono-1-(2,2,2-Torotron)-1H-Toro[d][1,2,3]Torotron (LXVIII): white solid (5.05 g, 18.032 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.63 (dd, J = 8.4, 1.6 Hz, 1H), 5.90 (q, J = 9.2 Hz, 2H); ESIMS measured C8H5BrF3N3 m / z 280.0 (M+H).

change

[0386] 6-Bromo-1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazole (LXIX): white solid (4.112 g, 14.683 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s 1H), 7.61 (d, J = 10.0 Hz, 1H), 6.60 (tt, J = 54.3, 3.0 Hz, 1H), 5.36 (td, J=15.81, 2.87 Hz, 2 H);ESIMS actual value C8H5BrF3N3m / z 280.0 (M+H). [ka]

[0387] 6-Bromo-1-isopropyl-1H-benzo[d][1,2,3]triazole (LXX): white solid (10.58 g, 44.065 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 1.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.54 (dd, J = 8.4, 1.6 Hz, 1H), 5.26 (sep, J = 6.8 Hz, 1H), 5.26 (d, J = 6.8 Hz, 6H); ESIMS actual value C9H 10 BrN3 m / z 240.1 (M+H).

[0388] The preparation of the intermediate 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (LXXIII) is shown below in Scheme 12. [ka]

[0389] Step 1 A mixture of 5-bromo-3-fluoropyridin-2-amine (LXXI) (2 g, 10.47 mmol), 1-bromo-2,2-dimethoxypropane (LXXII) (2.11 g, 11.53 mmol), and PPTS (260 mg, 1.05 mmol) in IPA (25 mL) was heated to 80 °C overnight. The reaction mixture was cooled to room temperature, and water (200 mL) was added and stirred for 1 h. The resulting solid was collected and dried under high vacuum to give 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (LXXIII) (2.61 g, 11.40 mmol, 108.8% yield) as a beige solid, which was used in the next step without further purification. ESIMS found CHBrFN m / z 229.0 (M+H).

[0390] The following intermediates were prepared according to the procedure described in Scheme 12 above. [ka]

[0391] 6-Bromo-8-fluoroimidazo[1,2-a]pyridine (LXXIV): Beige solid (909.0 mg, 4.228 mmol, 80.7% yield). ESIMS found C7H4BrFN2 m / z 214.9 (M+H).

[0392] The preparation of the intermediate (6-bromoimidazo[1,2-a]pyridin-3-yl)(pyrrolidin-1-yl)methanone (LXXVII) is shown below in Scheme 13. [ka]

[0393] Step 1 A mixture of 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (LXXV) (0.5 g, 2.07 mmol), DIPEA (0.9 mL, 5.17 mmol), and HATU (0.79 g, 2.07 mmol) in DMF (4 mL) was stirred for 5 min. Pyrrolidine (LXXVI) (0.32 mL, 3.18 mmol) was then added, and the reaction mixture was continued to stir at room temperature for 4 h. The solvent was concentrated, and the residue was partitioned between EtOAc and saturated aqueous NaHCO. The organic layer was separated and washed with water and brine. The organic layer was dried over anhydrous NaSO, concentrated, and dried under high vacuum to give (6-bromoimidazo[1,2-a]pyridin-3-yl)-pyrrolidin-1-ylmethanone (LXXVII) (577 mg, 1.962 mmol, 94.6% yield) as a beige solid. ESIMS found C 12 H 12 BrNO m / z 294.0 (M+H).

[0394] The following intermediates were prepared according to the procedures described in Scheme 13 above. [ka]

[0395] 6-Bromo-N-methylimidazo[1,2-a]pyridine-3-carboxamide (LXXVIII): off-white solid (530 mg, 2.086 mmol, 83.8% yield). ESIMS found C9H8BrNO m / z 254.0 (M+H). [ka]

[0396] 5-Bromo-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (LXXIX): Off-white solid (290 mg, 1.141 mmol, 91.7% yield). ESIMS found C9H8BrNO m / z 253.95 (M+H).

[0397] The preparation of the intermediate imidazo[1,2-a]pyrimidin-6-ylboronic acid (LXXXII) is shown below in Scheme 14. [ka]

[0398] Step 1 A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (LXXX) (1 g, 4.52 mmol) and chloroacetaldehyde (LXXXI) (0.92 mL, 5.39 mmol) was dissolved in 1,4-dioxane (20 mL) and heated to 110 °C over the weekend. The reaction mixture was cooled, and the solid was collected by filtration and dried under high vacuum to give imidazo[1,2-a]pyrimidin-6-ylboronic acid (LXXXII) (650 mg, 3.989 mmol, 88.2% yield) as a brown solid, which was used in the next step without purification. ESIMS found CHBNO m / z 164.1 (M+H).

[0399] The preparation of the intermediate 6-bromo-3-methylimidazo[1,2-a]pyrimidine (LXXXVII) is shown below in Scheme 15. [ka]

[0400] Step 1 To a mixture of propionaldehyde (LXXXIII) (5 g, 70 mmol) in EtO (150 mL) was added 5,5-dibromopyrimidine-2,4,6(1H,3H,5H)-trione (LXXXIV) (9.91 g, 35 mmol), and the resulting mixture was stirred at room temperature for 16 h. After completion, the mixture was washed with petroleum ether (80 mL × 2). The organic layer was filtered and concentrated to give 2-bromopropanal (LXXXV) (2.0 g, 14.6 mmol, 20.9% yield) as a yellow oil.

[0401] Step 2 To a solution of 2-bromopropanal (LXXXV) (0.7 g, 5.11 mol) in DMF (20 mL) was added 5-bromopyrimidin-2-amine (LXXXVI) (0.97 g, 5.56 mmol) at room temperature under Ar. The mixture was stirred at 100 °C for 16 h. Upon completion, the mixture was diluted with EtOAc and washed with brine (20 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0% → 20% EtOAc / petroleum ether) to give 6-bromo-3-methylimidazo[1,2-a]pyrimidine (LXXXVII) (80 mg, 0.377 mmol, 7.4% yield) as a white solid. ESIMS found C7H6BrN3 m / z 212.1 (M+H).

[0402] The following intermediates were prepared according to the procedure described in Scheme 15 above. [ka]

[0403] 6-Bromo-3-ethylimidazo[1,2-a]pyrimidine (LXXXVIII): White solid (200 mg, 0.885 mmol, 19.1% yield). ESIMS found C8H8BrN3 m / z 226.0 (M+H).

[0404] The preparation of the intermediate (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)boronic acid (XCII) is shown below in Scheme 16. [ka]

[0405] Step 1 To a solution of 5-azaindole (LXXXIX) (commercially available from Combi-Blocks Inc.) (2.0 g, 16.93 mmol) in DMF (20 mL) was added NaH (0.81 g, 20.18 mmol) under N2. The mixture was stirred at 0 °C for 1 h. Next, (2-(chloromethoxy)ethyl)trimethylsilane (XC) (commercially available from Combi-Blocks Inc.) (3.6 mL, 20.34 mmol) was added, and the mixture was stirred at 0 °C for 4 h. After concentration in vacuo to remove DMF, ice-cold saturated aqueous NH3Cl was added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, and the solvent was concentrated in vacuo onto Celite®. The crude product was purified using column chromatography (0→100% EtOAc / hexanes) to yield 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (XCI) (2.32 g, 9.340 mmol, 55.2% yield) as an amber liquid. 1 H NMR (499 MHz, DMSO-d6) δ ppm -0.11 (9 H, s), 0.75 - 0.84 (2 H, m), 3.40 - 3.48 (2 H, m), 5.58 (2 H, s), 6.64 (1 H, dd, J=3.29, 0.82 Hz), 7.55 - 7.60 (2 H, m), 8.23 (1 H, d, J=5.75 Hz), 8.84 (1 H, d, J=0.82 Hz);ESIMS actual value C 13 H 20 N2OSi m / z 249.1 (M+H).

[0406] Step 2 To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (XCI) (0.5 g, 2.01 mmol) in dry THF (4.0 mL) was slowly added a solution of n-butyllithium (1.21 mL, 3.02 mmol) in hexanes at −78° C. under N 2 . The mixture was stirred at −46° C. for 2 hours. Triisopropyl borate (0.93 mL, 4.03 mmol) was added, and the mixture was stirred overnight while warming to room temperature. The reaction mixture was quenched with 1 M aqueous HLC and neutralized to pH 8 with 4 N NaOH. The solvent was evaporated onto Celite®, and the residue was purified by reverse-phase (C18) silica gel column chromatography (0→40% MeCN / water (0.1% formic acid as a modifier)). LC / MS shows a 40 / 60 mixture of starting material and [1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-2-yl]boronic acid (XCII) (200 mg, 0.684 mmol, 34.0% yield) as an off-white solid. The mixture was used directly without further purification. ESIMS found C 13 H 21 BN2O3Si m / z 293.1 (M+H).

[0407] The following intermediates were prepared according to the procedures described in Scheme 16 above. [ka]

[0408] (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)boronic acid (XCIII): tan solid (796 mg, 2.861 mmol, 71.1% yield). ESIMS found C 13 H 21 BN2O3Si m / z 293.15 (M+H). [ka]

[0409] (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)boronic acid (XCIV): tan solid (831 mg, 2.844 mmol, 70.6% yield). ESIMS found C 13 H 21 BN2O3Si m / z 293.1 (M+H).

[0410] The preparation of intermediate cis-4-(methoxy-d3)cyclohexan-1-amine (C) is shown below in Scheme 17. [ka]

[0411] Step 1 To a solution of cis-4-aminocyclohexan-1-ol (XCV) (5 g, 32.9 mmol), (bromomethyl)benzene (XCVI) (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 layer was 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 (XCVII) (8.0 g, 27.08 mmol, 82.3% yield) as a white solid. ESIMS found C 20 H 25 NO m / z 296.4 (M+H).

[0412] Step 2 To a solution of cis-4-(dibenzylamino)cyclohexan-1-ol (XCVII) (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 hour. Then, iodomethane-d3 (XCVIII) (10.85 g, 74.86 mmol) was added over 10 minutes at room temperature. After the addition was complete, the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was then quenched with saturated aqueous NH4Cl (300 mL) and stirred for 10 minutes. The mixture was diluted with EtOAc and then extracted with EtOAc (300 mL x 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 (XCIX) (6 g, 19.202 mmol, 70.9% yield) as a colorless oil. ESIMS found C 21 H 24 D3NO m / z 313.0 (M+H).

[0413] Step 3 To a solution of cis-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine (XCIX) (200 mg, 0.64 mmol) in EtOH (5 mL) was added Pd(OH)2 / C (50 mg) and Pd / C (50 mg). 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 (C) (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);ESIMS actual value C7H 12D3NO m / z 133.0 (M+H).

[0414] The following intermediates were prepared according to the procedures described in Scheme 17 above. [ka]

[0415] 2-((cis-4-aminocyclohexyl)oxy)ethan-1-ol (CI): Colorless oil (0.5 g, 3.14 mmol, 67.4% yield). ESIMS found C8H 17 NO2 m / z 160. (M+H). [ka]

[0416] cis-4-(2-Methoxyethoxy)cyclohexan-1-amine (CII): Colorless oil (1.5 g, 8.65 mmol, 76.6% yield). ESIMS found C9H 19 NO2 m / z 174.1 (M+H). [ka]

[0417] cis-4-(2,2-Difluoroethoxy)cyclohexan-1-amine (CIII): White solid (1.352 g, 7.54 mmol, 90.3% yield). ESIMS found C8H 15 F2NO m / z 180.1 (M+H). [ka]

[0418] cis-4-Ethoxycyclohexan-1-amine (CIV): colorless oil (2 g, 13.96 mmol, 64.4% yield). 1H 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]

[0419] cis-3-(2-Methoxyethoxy)cyclobutan-1-amine (CV): 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]

[0420] 2-(cis-3-aminocyclobutoxy)ethan-1-ol (CVI): 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).

[0421] The preparation of the intermediate cis-4-(difluoromethoxy)cyclohexan-1-amine (CIX) is shown below in Scheme 18. [ka]

[0422] Step 1 A solution of cis-4-(dibenzylamino)cyclohexan-1-ol (XCVII) (50 mg, 0.170 mmol) and CuI (6.5 mg, 0.034 mmol) in MeCN (5 mL) was heated to 45 °C for 5 min under a nitrogen atmosphere. To this mixture was added a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (CVII) (60 mg, 0.339 mmol) in MeCN (2 mL) 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 100 mL of EtOAc and a 1:1 mixture of water and saturated aqueous NaHCO3. 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 (CVIII) (25 mg, 0.072 mmol, 42.3% yield) as an oil that solidified to an off-white solid. ESIMS found C 21 H 25 F2NO m / z 346.1 (M+H).

[0423] Step 2 To a solution of cis-N,N-dibenzyl-4-(difluoromethoxy)cyclohexan-1-amine (CVIII) (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 (CIX) (1.05 g, 6.36 mmol, 78.4% yield) as a colorless oil. ESIMS found CH 13F2NO m / z 166.1 (M+H).

[0424] The preparation of the intermediate trans-4-amino-1-ethylcyclohexan-1-ol (CXIV) is shown below in Scheme 19. [ka]

[0425] Step 1 To a solution of trans-4-aminocyclohexan-1-ol (CX) (25 g, 0.217 mmol) and benzyl bromide (XCVI) (74.2 g, 0.434 mmol) in MeCN (500 mL) was added K2CO3 (90 g, 0.6512 mmol). The mixture was stirred at 90 °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 × 3) and H2O. The organic layer was dried over anhydrous Na2SO4 and evaporated under high vacuum to produce trans-4-(dibenzylamino)cyclohexan-1-ol (CXI) (32 g, 108.3 mmol, 49.9% yield) as a white solid. The product was used directly in the next step without further purification. ESIMS found C 20 H 25 NO m / z 296.3 (M+H).

[0426] Step 2 To a solution of (COCl) (12.89 g, 101.55 mmol) in DCM (150 mL) was slowly added a solution of DMSO (10.6 g, 135.4 mmol) in DCM (50 mL) at −70° C. under N. A solution of trans-4-(dibenzylamino)cyclohexan-1-ol (CXI) (20.0 g, 67.7 mmol) in DMF (50 mL) was added at −70° C. under N and stirred for 30 min. TEA (21.92 g, 216.64 mmol) was then added, and the mixture was stirred at −70° C. over 3 h while warming to room temperature. The reaction mixture was diluted with HO (800 mL) and extracted with DCM (800 mL). The combined organic layers were dried over anhydrous NaSO and concentrated to give a residue. The residue was purified by column chromatography on silica gel (9→25% EtOAc / PE) to give 4-(dibenzylamino)cyclohexan-1-one (CXII) (18.0 g, 61.3 mmol, 90.6% yield) as a white solid. ESIMS found C 20 H 23 NO m / z 294.2 (M+H).

[0427] Step 3 4-(Dibenzylamino)cyclohexan-1-one (CXII) (5.0 g, 17.04 mmol) was added to THF (50 mL) at −78 °C under N and stirred for 1 h. Ethylmagnesium bromide (17 mL, 34.08 mmol) was added, and the reaction was stirred at −78 °C and allowed to warm to room temperature over 16 h. The reaction mixture was diluted with NHCl (100 mL), filtered, and extracted with EtOAc (200 mL × 3 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under high vacuum to give a residue. LC / MS showed two products. The residue was purified by column chromatography on silica gel (2→3% EtOAc / PE) to give only trans-4-(dibenzylamino)-1-ethylcyclohexan-1-ol (CXIII) (1.5 g, 4.637 mmol, 27.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.80 (t, J = 7.4 Hz, 3H), 1.17 - 1.10 (m, 2H), 1.47 - 1.37 (m, 4H), 1.65 (t, J = 11.4 Hz, 4H), 2.41 (s, 1H), 3.57 (s, 4H), 3.91 (s, 1H), 7.21 - 7.17 (m, 2H), 7.34 - 7.27 (m, 8H); ESIMS actual value C 22 H 29 NO m / z 324.2 (M+H).

[0428] Step 4 To a solution of trans-4-(dibenzylamino)-1-ethylcyclohexan-1-ol (CXIII) (1.5 g, 4.6 mmol) in 50.0 mL of EtOAc, 0.4 g of 10% Pd / C and 0.4 g of 20% Pd(OH) / C were added and purged with H. The mixture was stirred at room temperature under an atmosphere of H for 16 hours. The reaction mixture was filtered through Celite® and concentrated under high vacuum to give trans-4-amino-1-ethylcyclohexan-1-ol (CXIV) (390 mg, 2.723 mmol, 58.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 0.80 (t, J = 7.4 Hz, 3H), 1.14 - 1.03 (m, 2H), 1.29 - 1.20 (m, 2H), 1.40 (q, J = 7.4 Hz, 2H), 1.59 - 1.49 (m, 2H), 1.67-1.61 (m, 2H), 2.70 - 2.61 (m, 1H), 3.84 (br s, 1H); ESIMS actual value C8H 17 NO m / z 144.1 (M+H).

[0429] The preparation of intermediate 1-(3,3,3-trifluoropropyl)piperidin-4-amine (CXVIII) is shown below in Scheme 20. [ka]

[0430] Step 1 tert-Butyl piperidin-4-ylcarbamate (CXV) (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 (CXVI) (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 starting material (SM). A sufficient amount of product remained in the organic layer, which was dried using anhydrous MgSO4 and reduced in vacuo to give the product tert-butyl N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]carbamate (CXVII) (861 mg, 2.906 mmol, 58.2% yield) as a white solid. ESIMS found C 13 H 23 F3N2O2m / z 297.2 (M+H).

[0431] Step 2 tert-Butyl N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]carbamate (CXVII) (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 by high vacuum to give the crude intermediate 1-(3,3,3-trifluoropropyl)piperidin-4-amine (CXVIII) (209 mg, 0.674 mmol, 99.8% yield) as a white semi-solid, which was used without further purification. ESIMS found CH 15 F3N2 m / z 197.1 (M+H).

[0432] The preparation of the intermediate N-(trans-4-aminocyclohexyl)acetamide (CXXI) is shown below in Scheme 21. [ka]

[0433] Step 1 To a stirred solution of tert-butyl N-(4-aminocyclohexyl)carbamate (CXIX) (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). Acetyl chloride (CXX) (0.22 mL, 3.09 mmol) was then slowly added, and the reaction mixture was stirred at room temperature for 16 h. 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 h and then evaporated to dryness to give the HCl salt of N-(4-aminocyclohexyl)acetamide (CXXI) (480 mg, 2.49 mmol, 89.0% yield) as a white solid. ESIMS found CH 16 N2O m / z 157.05 (M+H).

[0434] The preparation of the intermediate cis-4-amino-N,N-dimethylcyclohexane-1-carboxamide (CXXIII) is shown below in Scheme 22. [ka]

[0435] Step 1 To a stirred solution of 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (CXXII) (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 to 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 (CXXIII) (280 mg, 1.355 mmol, 109.9% yield) as a light brown sticky solid. ESIMS found CH 18 N2O m / z 171.15 (M+H).

[0436] The following intermediates were prepared according to the procedure described in Scheme 22 above. [ka]

[0437] trans-4-Amino-N,N-dimethylcyclohexane-1-carboxamide (CXXIV): Light brown viscous solid (290 mg, 1.403 mmol, 113.8% yield). ESIMS found C9H 18 N2O m / z 171.1 (M+H).

[0438] The preparation of the intermediate 3-amino-N-methylbicyclo[1.1.1]pentane-1-carboxamide (CXXVII) is shown below in Scheme 23. [ka]

[0439] Step 1 To a solution of 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (CXXV) (commercially available from AmBeed, Inc.) (0.5 g, 2.2 mmol) and HATU (0.8 g, 2.09 mmol) in DMF, DIPEA (0.8 mL, 4.59 mmol) was added, and the mixture was stirred for 5 min. Then, methanamine HCl (1.49 g, 22.07 mmol) was added at −78° C., followed by additional DIPEA (4 mL). The reaction mixture was stirred at room temperature overnight. The solvent was concentrated, and the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3, water, and brine. The organics were dried over anhydrous NaSO, concentrated, and the residue was dried under high vacuum to give tert-butyl (3-(methylcarbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (CXXVI) (244 mg, 1.015 mmol, 46.2% yield) as an off-white solid. ESIMS found C 12 H 20 N2O3 m / z 241.1 (M+H).

[0440] Step 2 A solution of tert-butyl (3-(methylcarbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (CXXVI) (240 mg, 1.0 mmol) in 4 M HCl in dioxane (1.25 mL, 5.0 mmol) was stirred at room temperature for 1 h. The solvent was concentrated and dried under high vacuum overnight to give 3-amino-N-methylbicyclo[1.1.1]pentane-1-carboxamide HCl (CXXVII) (177 mg, 1.002 mmol, 100.3% yield), which was used in the next step without purification. ESIMS found CH 12 N2O m / z 141.15 (M+H).

[0441] Example 1 The preparation of N-(cis-4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide (17) is shown below in Scheme 24. [ka]

[0442] Steps 1 and 2 A mixture of 5-bromopyrazolo[1,5-a]pyridine (CXXVIII) (1.8 g, 9.14 mmol), Pd(dppf)Cl (311 mg, 0.380 mmol), bis(pinacolato)diboron (2.9 g, 11.42 mmol), and KOAc (2.24 g, 22.82 mmol) in 1,4-dioxane (15 mL) in a sealed test tube was degassed with N and heated to 90 °C for 3 h. The reaction was cooled to room temperature, and 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (2 g, 7.62 mmol), Pd(dppf)Cl (311 mg, 0.380 mmol), NaCO (15 mL, 15 mmol), and DME (15 mL) were added. The reaction was then degassed with N2 and heated to 85 °C for 16 h. Water (100 mL) was added and extracted with EtOAc (100 mL x 3). The organic layer was evaporated onto Celite® and purified on a silica gel column (0 → 100% EtOAc / hexane). The test tube containing the pure sample was collected and the solvent was removed under vacuum. The impure fractions were combined and re-purified on a silica gel column (0 → 100% EtOAc / hexane). The test tube containing the pure sample was collected and the solvent was removed under vacuum. The impure fractions were combined and re-purified on a silica gel column (0 → 100% EtOAc / hexane). The three pure fractions were combined and placed under high vacuum to give 2-chloro-4-methoxy-5-pyrazolo[1,5-a]pyridin-5-ylpyrrolo[2,1-f][1,2,4]triazine (CXXIX) (660 mg, 2.202 mmol, 28.9% yield) as a beige solid. ESIMS observed C 14 H 10 ClNO m / z 300.1 (M+H).

[0443] Step 3 To a stirred solution of 2-chloro-4-methoxy-5-pyrazolo[1,5-a]pyridin-5-ylpyrrolo[2,1-f][1,2,4]triazine (CXXIX) (100 mg, 0.330 mmol) in 1,4-dioxane (2 mL), BrettPhos (19 mg, 0.040 mmol), BrettPhos PD G3 (25 mg, 0.030 mmol), DIPEA (0.13 mL, 0.720 mmol), tert-butyl N-(4-aminocyclohexyl)carbamate (CXXX) (commercially available from Combi-Blocks Inc.) (90 mg, 0.420 mmol), and LiHMDS (1 mL, 1 mmol) were added at room temperature. The mixture was purged with N and stirred at 100 °C for 1 h. The reaction mixture was concentrated and purified by ISCO (0->6% 7N NH3MeOH / CHCl3). The pure fractions were collected, concentrated under reduced pressure, and dried under high vacuum to give cis-N 1 -(4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclohexane-1,4-diamine (CXXXI) (70 mg, 0.186 mmol, 55.6% yield) was obtained as an off-white gummy solid. ESIMS found C 20 H 23 N7O m / z 378.2 (M+H).

[0444] Step 4 To a solution of HOAc (11 μL, 0.190 mmol) and HATU (79 mg, 0.210 mmol) in DMF (0.2 mL), DIPEA (85 μL, 0.490 mmol) was added, and the mixture was stirred for 5 min. Then, cis-N 1N-(4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclohexane-1,4-diamine (CXXXI) (60 mg, 0.160 mmol) 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 give N-(cis-4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide (17) (22 mg, 0.052 mmol, 33.0% yield) as a yellow solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.50 - 1.59 (2 H, m), 1.60 - 1.72 (4 H, m), 1.74 - 1.81 (2 H, m), 1.81 (3 H, s), 3.64 - 3.71 (2 H, m), 3.99 (3 H, s), 6.47 (1 H, d, J=6.30 Hz), 6.58 (1 H, d, J=1.64 Hz), 6.76 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.26, 1.78 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.70 (1 H, br d, J=6.84 Hz), 7.81 (1H, s), 7.97 (1H, d, J=2.19 Hz), 8.62 (1H, d, J=7.12 Hz); ESIMS observed value C 22 H 25 N7O2 m / z 420.2 (M+1).

[0445] Example 2. The preparation of 4-methoxy-5-pyrazolo[1,5-a]pyridin-5-yl-N-(3R,4S)-3-fluoropiperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-2-amine (29) and N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (31) is shown below in Scheme 25. [ka]

[0446] Steps 1 and 2 A mixture of 5-bromopyrazolo[1,5-a]pyridine (CXXVIII) (1.8 g, 9.14 mmol), Pd(dppf)Cl (311 mg, 0.380 mmol), bis(pinacolato)diboron (2.9 g, 11.42 mmol), and KOAc (2.24 g, 22.82 mmol) in 1,4-dioxane (15 mL) in a sealed test tube was degassed with N and heated to 90 °C for 3 h. The reaction was cooled to room temperature, and 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (2 g, 7.62 mmol), Pd(dppf)Cl (311 mg, 0.380 mmol), NaCO (15 mL, 15 mmol), and DME (15 mL) were added. The reaction was then degassed with N2 and heated to 85 °C for 16 h. Water (100 mL) was added and extracted with EtOAc (100 mL x 3). The organic layer was evaporated onto Celite® and purified on a silica gel column (0 → 100% EtOAc / hexane). The test tube containing the pure sample was collected and the solvent was removed under vacuum. The impure fractions were combined and re-purified on a silica gel column (0 → 100% EtOAc / hexane). The test tube containing the pure sample was collected and the solvent was removed under vacuum. The impure fractions were combined and re-purified on a silica gel column (0 → 100% EtOAc / hexane). The three pure fractions were combined and placed under high vacuum to give 2-chloro-4-methoxy-5-pyrazolo[1,5-a]pyridin-5-ylpyrrolo[2,1-f][1,2,4]triazine (CXXIX) (660 mg, 2.202 mmol, 28.9% yield) as a beige solid. ESIMS observed C 14 H 10 ClNO m / z 300.1 (M+H).

[0447] Step 3 To a stirred solution of 2-chloro-4-methoxy-5-pyrazolo[1,5-a]pyridin-5-ylpyrrolo[2,1-f][1,2,4]triazine (CXXIX) (100 mg, 0.330 mmol) in 1,4-dioxane (3 mL), BrettPhos (19 mg, 0.040 mmol), BrettPhos PD G3 (25 mg, 0.030 mmol), DIPEA (0.13 mL, 0.720 mmol), 2-methyl-2-propanyl(3S,4R)-4-amino-3-fluoro-1-piperidinecarboxylate (CXXXII) (100 mg, 0.460 mmol), and LiHMDS (1 mL, 1 mmol) were added at room temperature. The mixture was purged with N and stirred at 100 °C for 1 h. The reaction mixture was concentrated and purified by ISCO (0→100% EtOAc / hexanes). Pure fractions were collected, concentrated under reduced pressure, and dried under high vacuum to give tert-butyl (3R,4S)-3-fluoro-4-[(4-methoxy-5-pyrazolo[1,5-a]pyridin-5-ylpyrrolo[2,1-f][1,2,4]triazin-2-yl)amino]piperidine-1-carboxylate (CXXXIII) (65 mg, 0.135 mmol, 40.5% yield) as a white solid. ESIMS found C 24 H 28 FN7O3 m / z 482.25 (M+H).

[0448] Step 4 To a stirred solution of tert-butyl (3R,4S)-3-fluoro-4-[(4-methoxy-5-pyrazolo[1,5-a]pyridin-5-ylpyrrolo[2,1-f][1,2,4]triazin-2-yl)amino]piperidine-1-carboxylate (CXXXIII) (65 mg, 0.130 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.49 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, treated with 7N NH3 / MeOH, absorbed onto silica gel, and purified by ISCO (0→100% CHCl3 / MeOH). The pure fractions were collected, concentrated under reduced pressure, and dried under high vacuum to give 4-methoxy-5-pyrazolo[1,5-a]pyridin-5-yl-N-(3R,4S)-3-fluoropiperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-2-amine (29) (45 mg, 0.118 mmol, 87.4% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.58 - 1.65 (1 H, m), 1.73 (1 H, qd, J=12.37, 4.24 Hz), 2.56 (1 H, br t, J=12.46 Hz), 2.70 (1 H, dd, J=38.70, 14.30 Hz), 2.96 (1 H, br d, J=13.14 Hz), 3.13 (1 H, br t, J=11.50 Hz), 3.78 - 3.93 (1 H, m), 4.00 (3 H, s), 4.80 (1 H, d, J=50.75 Hz), 6.59 (1 H, d, J=1.64 Hz), 6.64 (1 H, d, J=7.94 Hz), 6.78 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.39, 1.92 Hz), 7.63 (1 H, d, J=2.46 Hz), 7.81 (1 H, d, J=1.10 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.63 (1 H, d, J=7.12 Hz) ;ESIMS actual value C 19 H 20 FN7O m / z 382.2 (M+H).

[0449] Step 5 4-Methoxy-5-pyrazolo[1,5-a]pyridin-5-yl-N-(3R,4S)-3-fluoropiperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-2-amine (29) (40 mg, 0.100 mmol) was dissolved in EtOH (1 mL), HOAc (15 μL, 0.260 mmol) and formaldehyde (18 μL, 0.320 mmol) were added, and the reaction was stirred at room temperature for 20 min. NaBH(OAc) (56 mg, 0.260 mmol) was added, and the reaction was stirred for 2 h. TLC indicated completion of starting material. The reaction mixture was absorbed onto silica gel and purified by ISCO (0→8% 7N NHMeOH / CHCl). The pure fractions were concentrated, and the residue was dried under high vacuum to give N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (31) (30 mg, 0.076 mmol, 72.3% yield) as an off-white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.68 (1 H, br dd, J=12.59, 3.01 Hz), 1.92 (1 H, qd, J=12.23, 3.56 Hz), 2.01 - 2.09 (1 H, m), 2.17 (1 H, dd, J=37.55, 13.20 Hz), 2.19 (3 H, s), 2.79 (1 H, br d, J=11.23 Hz), 3.00 - 3.09 (1 H, m), 3.67 - 3.83 (1 H, m), 4.00 (3 H, s), 4.91 (1 H, d, J=50.20 Hz), 6.59 (1 H, d, J=1.64 Hz), 6.64 (1 H, d, J=7.67 Hz), 6.78 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.12, 1.92 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.81 (1 H, d, J=0.82 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.63 (1 H, d, J=7.39 Hz) 20 H 22 FN7O m / z 396.2 (M+1).

[0450] Example 3. The preparation of 6-(2-((trans-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)imidazo[1,2-a]pyridine-3-carboxamide (104) and 6-(2-((trans-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)imidazo[1,2-a]pyridine-3-carbonitrile (103) is shown below in Scheme 26. [ka]

[0451] Steps 1 and 2 A mixture of 6-bromoimidazo[1,2-a]pyridine-3-carbonitrile (CXXXIV) (commercially available from Combi-Blocks Inc.) (888 mg, 4.0 mmol), bis(pinacolato)diboron (1.016 g, 4.0 mmol), KOAc (1.18 g, 12.02 mmol), and Pd(dppf)Cl (123 mg, 0.15 mmol) was dissolved in 1,4-dioxane (12 mL), and the reaction mixture was purged with N gas for 5 minutes. The vial was sealed and heated at 95 °C for 3 hours. To the above reaction mixture was added a solution of 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (525 mg, 2.0 mmol), QPhos (143 mg, 0.2 mmol), and NaCO (1.27 g, 12 mmol) in water (3 mL). The reaction mixture was purged with N gas for 5 minutes, the vial was sealed, and heated to 80 °C for 1 hour. The organic layer was separated, absorbed onto silica, and purified on an ISCO (0→20% MeOH / CHCl) to give 6-(2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)imidazo[1,2-a]pyridine-3-carbonitrile (CXXXV) (116 mg, 0.357 mmol, 17.9% yield) as a beige solid. ESIMS found C 15 H9ClNO m / z 325.1 (M+H).

[0452] Step 3 To a stirred solution of 6-(2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)imidazo[1,2-a]pyridine-3-carbonitrile (CXXXV) (116 mg, 0.36 mmol), trans-4-amino-1-methylcyclohexan-1-ol (CXXXVI) (commercially available from PharmaBlock (USA), Inc.) (56 mg, 0.43 mmol), BrettPhos Pd G3 (24 mg, 0.03 mmol), and BrettPhos (19 mg, 0.04 mmol) in 1,4-dioxane (3 mL) was added NaO. tBu (110 mg, 1.14 mmol) was added at room temperature. The reaction mixture was purged with N for 5 min and then heated to 100 °C for 5 h. The reaction mixture was concentrated and purified by ISCO (0 → 20% 7N NH in MeOH / CHCl) to give two products. 6-(2-((trans-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)imidazo[1,2-a]pyridine-3-carbonitrile (103) (12 mg, 0.029 mmol, 8.0% yield) was obtained as a beige solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.38 - 1.53 (4 H, m), 1.56 - 1.66 (3 H, m), 1.83 - 1.93 (2 H, m), 3.60 - 3.71 (1 H, m), 4.01 (3 H, s), 4.23 (1 H, s), 6.56 (1 H, d, J=7.94 Hz), 6.89 (1 H, d, J=2.74 Hz), 7.67 (1 H, d, J=2.74 Hz), 7.81 - 7.92 (2 H, m), 8.44 (1 H, s), 8.77 - 8.86 (1 H, m); ESIMS actual value C 22 H 23 N7O2 m / z 418.2 (M+1)) and 6-(2-((trans-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)imidazo[1,2-a]pyridine-3-carboxamide (104) (2.2 mg, 0.005 mmol, 1.4% yield) as a beige solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.39 - 1.48 (4 H, m), 1.57 - 1.63 (2 H, m), 1.85 - 1.91 (2 H, m), 3.60 - 3.72 (1 H, m), 3.99 (3 H, s), 4.23 (1 H, s), 6.49 (1 H, d, J=7.94 Hz), 6.75 (1 H, d, J=2.46 Hz), 7.34 (1 H, br s), 7.65 (1 H, d, J=2.74 Hz), 7.69 (2 H, s), 7.95 (1 H, br s), 8.33 (1 H, s), 9.84 (1 H, s); ESIMS measured value C 22 H 25 N7O3 m / z 436.25 (M+1)).

[0453] Example 4. The preparation of 1-(7-((5-(1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (173) is shown below in Scheme 27. [ka]

[0454] Steps 1 and 2 A mixture of 6-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyl-1H-benzo[d]imidazole (CXXXVII) (950 mg, 2.57 mmol), Pd(dppf)Cl (99 mg, 0.12 mmol), bis(pinacolato)diboron (960 mg, 3.78 mmol), and KOAc (748 mg, 7.62 mmol) in 1,4-dioxane (10 mL) in a sealed tube was purged with N, sealed, and then heated to 90 °C for 2 h. LCMS indicated a mixture of boronic acid and boronic ester.

[0455] The reaction was cooled to room temperature, and then to this mixture was added 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (660 mg, 2.51 mmol), QPhos (178 mg, 0.25 mmol), Pd(OAc) (28 mg, 0.12 mmol), and aqueous NaCO (5 mL, 5.0 mmol). The reaction was purged with N, sealed, and then heated to 80 °C for 20 min. Water (100 mL) was added and extracted with EtOAc (3 × 100 mL). The solvent was reduced onto Celite® and purification by silica gel column chromatography (0→100% EtOAc / hexanes) afforded 5-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (CXXXVIII) (460 mg, 0.975 mmol, 38.8% yield) as an off-white solid. ESIMS found C 23 H 30 ClN5O2Si m / z 472.2 (M+H).

[0456] Step 3 To a stirred solution of tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate HCl (CXXXIX) (commercially available from J&W Pharmlab, LLC) (70 mg, 0.25 mmol), 5-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (CXXXVIII) (100 mg, 0.21 mmol), BrettPhos (12 mg, 0.02 mmol), and BrettPhos PD G3 (10 mg, 0.01 mmol) in dioxane (1.6 mL) was added NaO. tBu (62 mg, 0.65 mmol) was added. The solution was purged with N, sealed, and then heated at 100 °C for 30 min. The solvent reaction was reduced onto Celite® and purified by silica gel column chromatography (0 → 30% 7N NH in MeOH / CHCl) to yield tert-butyl 7-((5-(1-(2-((tert)-butyldimethylsilyl)oxy)ethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylate (CXL) (17 mg, 0.025 mmol, 11.9% yield) as an off-white solid. ESIMS found C 36 H 53 N7O4Si m / z 676.4 (M+H).

[0457] Step 4 To a solution of tert-butyl 7-((5-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylate (CXL) (17 mg, 0.03 mmol) in CHCl (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (0→15% 7N NH in MeOH / CHCl) to give 2-(6-(2-((2-azaspiro[3.5]nonan-7-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)ethan-1-ol (CXLI) (11 mg, 0.024 mmol, 94.8% yield) as an amber glass. ESIMS found C 25 H 31 N7O2 m / z 462.3 (M+H).

[0458] Step 5 A solution of HATU (10 mg, 0.03 mmol), HOAc (1.5 μL, 0.03 mmol), and DIPEA (12 μL, 0.07 mmol) in DCM (2 mL) was stirred at room temperature for 30 min, then 2-(6-(2-((2-azaspiro[3.5]nonan-7-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)ethan-1-ol (CXLI) (11 mg, 0.024 mmol) was added, and the solution was stirred at room temperature for 16 h. The solvent was reduced onto Celite® and purified by silica gel column chromatography (0→10% 7N NH in MeOH / CHCl) to give 1-(7-((5-(1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (173) (6 mg, 0.012 mmol, 50.0% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.28 - 1.39 (2 H, m), 1.48 - 1.60 (2 H, m), 1.72 - 1.79 (3 H, m), 1.83 - 1.94 (4 H, m), 2.60 (3 H, s), 3.47 (1 H, s), 3.52 (1 H, s), 3.57 (1 H, dt, J=10.20, 6.95 Hz), 3.74 (1 H, s), 3.75 - 3.79 (2 H, m), 3.80 (1 H, s), 3.93 (3 H, d, J=1.10 Hz), 4.28 (2 H, br t, J=5.20 Hz), 4.99 (1 H, t, J=5.48 Hz), 6.43 (1 H, dd, J=16.43, 7.94 Hz), 6.62 (1 H, d, J=2.46 Hz), 7.37 (1 H, dd, J=8.21, 1.37 Hz), 7.51 (1 H, d, J=8.49 Hz), 7.58 (1 H, t, J=2.74 Hz), 7.69 (1 H, s);ESIMS actual value C 27 H33 N7O3 m / z 504.3 (M+1).

[0459] Example 5. trans-N 1 The preparation of -(4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine (203) and 1-(trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)pyrrolidin-2-one (223) is shown below in Scheme 28. [ka]

[0460] Steps 1 and 2 A mixture of 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole (CXLII) (commercially available from Combi-Blocks Inc.) (0.93 g, 4.39 mmol), Pd(dppf)Cl (0.17 g, 0.21 mmol), bis(pinacolato)diboron (1.68 g, 6.62 mmol), and KOAc (1.3 g, 13.25 mmol) in 1,4-dioxane (11 mL) in a sealed tube was purged with N, sealed, and heated to 90 °C for 1 h. LCMS indicated a mixture of boronic acid and boronic ester.

[0461] The reaction was cooled to room temperature, and then to this mixture was added 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (1.15 g, 4.38 mmol), Pd(OAc) (0.05 g, 0.22 mmol), QPhos (0.32 g, 0.45 mmol), aqueous NaCO (9.2 mL, 9.2 mmol), and 1,4-dioxane (11 mL). The reaction was purged with N, sealed, and heated to 80 °C for 20 min. Water (100 mL) was added and extracted with EtOAc (3 × 100 mL). The solvent was reduced onto Celite® and purification by silica gel column chromatography (0→100% EtOAc / hexanes) afforded 6-(2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-methyl-1H-benzo[d][1,2,3]triazole (CXLIII) (0.763 g, 2.424 mmol, 55.3% yield) as an off-white solid. ESIMS found C 14 H 11 ClNO m / z 315.1 (M+H).

[0462] Step 3 To a stirred solution of 6-(2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-methyl-1H-benzo[d][1,2,3]triazole (CXLIII) (212 mg, 0.67 mmol), tert-butyl (trans-3-amino-1-methylcyclobutyl)carbamate (CXLIV) (commercially available from PharmaBlock (USA), Inc.) (160 mg, 0.8 mmol), BrettPhos PD G3 (46 mg, 0.05 mmol), and BrettPhos (37 mg, 0.07 mmol) in 1,4-dioxane (4 mL) was added NaO. tBu (195 mg, 2.03 mmol) was added. The reaction mixture was purged for 5 min and then heated to 100 °C for 30 min. The reaction mixture was concentrated and purified on an ISCO (0→10% MeOH / CHCl3) to afford tert-butyl (trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)carbamate (CXLV) (188 mg, 0.393 mmol, 58.3% yield) as a colorless gum. ESIMS found C 24 H 30 N8O3m / z 479.3 (M+H).

[0463] Step 4 To a stirred solution of tert-butyl (trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)carbamate (CXLV) (188 mg, 0.39 mmol) in DCM (2 mL) was added TFA (1.2 mL, 15.58 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, treated with saturated aqueous NaCO, washed with EtOAc, dried over anhydrous NaSO, concentrated in vacuo, and then absorbed onto silica gel and purified by ISCO (0→20% 7N NH in MeOH / CHCl) to give the trans-N 1 -(4-Methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine (203) (110 mg, 0.291 mmol, 74.0% yield) was obtained as an off-white foam. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.22 (3 H, s), 1.80 (2 H, br s), 1.88 - 1.98 (2 H, m), 2.13 - 2.22 (2 H, m), 3.95 (3 H, s), 4.23 - 4.33 (1 H, m), 4.31 (3 H, s), 6.74 (1 H, d, J=2.46 Hz), 6.90 (1 H, d, J=7.12 Hz), 7.60 (1 H, dd, J=8.76, 1.37 Hz), 7.63 (1 H, d, J=2.46 Hz), 7.93 (1 H, s), 7.95 - 8.00 (1 H, m); ESIMS measured value C 19 H 22 N8O m / z 379.2 (M+1).

[0464] Step 5 To a solution of 4-chlorobutyric acid (CXLVI) (16 μL, 0.16 mmol) and HATU (70 mg, 0.18 mmol) in DMF (0.5 mL) was added DIPEA (74 μL, 0.42 mmol), and the mixture was stirred for 10 min. 1 -(4-Methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine (203) (50 mg, 0.13 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, concentrated, absorbed onto silica gel, and purified by ISCO (0→10% MeOH / CHCl3) to give 4-chloro-N-(trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)butanamide (CXLVII) (53 mg, 0.110 mmol, 83.1% yield) as an off-white solid. ESIMS found C 23 H 27 ClN8O2 m / z 483.2 (M+H).

[0465] Step 6 To a solution of 4-chloro-N-(trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)butanamide (CXLVII) (53 mg, 0.11 mmol) in THF (5 mL), KO t Bu (37 mg, 0.33 mmol) was added, and the reaction mixture was heated at 60 °C for 12 h. The reaction mixture was quenched with saturated aqueous NaHCO and extracted with EtOAc. The organic layer was separated, concentrated, absorbed onto silica gel, and purified by ISCO (0→10% MeOH / CHCl) to afford 1-(trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)pyrrolidin-2-one (223) (23 mg, 0.052 mmol, 46.9% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.36 (3 H, s), 1.92 (2 H, quin, J=7.53 Hz), 2.00 - 2.08 (2 H, m), 2.23 (2 H, t, J=8.08 Hz), 2.82 - 2.92 (2 H, m), 3.40 (2 H, t, J=6.84 Hz), 3.96 (3 H, s), 4.04 - 4.12 (1 H, m), 4.31 (3 H, s), 6.74 (1 H, d, J=2.46 Hz), 7.06 (1 H, d, J=6.30 Hz), 7.60 (1 H, dd, J=8.62, 1.51 Hz), 7.64 (1 1H, d, J=2.46 Hz), 7.94 (1H, s), 7.97 (1H, d, J=8.76 Hz); ESIMS measured value C 23 H 26 N8O2m / z 447.3 (M+1).

[0466] Example 6 cis-N 3 -(4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N 1 ,N 1 The preparation of 1,1-trimethylcyclobutane-1,3-diamine (204) is shown below in Scheme 29. [ka]

[0467] Step 1 (cis-N) in EtOH (1 mL) and DCE (4 mL) 1 To a stirred solution of -(4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine (CXLVIII) (prepared by the method described in Steps 1-4 of Example 5) (25 mg, 0.07 mmol) was added formaldehyde (13 μL, 0.17 mmol). The reaction was stirred at room temperature for 30 minutes, after which NaBH(OAc) (70 mg, 0.33 mmol) was added. The reaction was further stirred at room temperature for 16 hours. Saturated aqueous NaCO was added and extracted with DCM. The organic layer was separated and dried over anhydrous NaSO. The solvent was removed under reduced pressure, and the residue was purified by ISCO silica gel column chromatography (0→20% 7N NH in MeOH / CHCl) to give the cis-N 3 -(4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N 1 ,N 1 ,1-trimethylcyclobutane-1,3-diamine (204) (18 mg, 0.044 mmol, 67.0% yield) was obtained as a white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.06 (3 H, s), 1.82 - 1.92 (2 H, m), 2.03 (6 H, s), 2.19 (2 H, td, J=8.15, 2.60 Hz), 3.91 - 4.01 (1 H, m), 3.95 (3 H, s), 4.31 (3 H, s), 6.74 (1 H, d, J=2.46 Hz), 6.95 (1 H, d, J=7.12 Hz), 7.60 (1 H, dd, J=8.62, 1.51 Hz), 7.64 (1 H, d, J=2.74 Hz), 7.93 (1 H, s), 7.97 (1 H, d, J = 8.76 Hz); ESIMS measured value C 21 H 26 N8O m / z 407.3 (M+1).

[0468] Example 7 The preparation of (trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)(pyrrolidin-1-yl)methanone (222) is shown below in Scheme 30. [ka]

[0469] Steps 1-3 A microwave vial was charged with methyl trans-3-{[(tert-butoxy)carbonyl]amino}-1-methylcyclobutane-1-carboxylate (CXLIX) (255.1 mg, 1.05 mmol), MeOH (5 mL), and a 4 M solution of HCl in dioxane (0.5 mL, 2 mmol). The vial was sealed, and the solution was stirred at room temperature for 16 h. The solvent was blown off with a stream of N2 while heating to 50 °C. The residue was dissolved in MeCN (5 mL), and the solvent was blown off with a stream of N2 while heating to 50 °C. This was repeated two more times to produce methyl trans-3-amino-1-methylcyclobutane-1-carboxylate (CL) as a white solid.

[0470] The white residue was dissolved in 6-(2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-methyl-1H-benzo[d][1,2,3]triazole (CXLIII) (300 mg, 0.95 mmol), 1,4-dioxane (4.8 mL), BrettPhos (50 mg, 0.09 mmol), and NaO. t Bu (366.4 mg, 3.81 mmol), BrettPhos PD G3 (44 mg, 0.05 mmol) were added. The reaction mixture was purged with N, the vial was sealed, and heated to 100 °C for 30 min. LC / MS showed a mixture of the methyl ester and the acid.

[0471] To the above solution was added water (2 mL), followed by 2 M aqueous LiOH (0.48 mL, 0.96 mmol). The reaction was heated at 50° C. for 1 h. The reaction was poured into water (5 mL), neutralized with 1 N HCl, and extracted with DCM (3×50 mL). The DCM layer was reduced onto Celite® and purified by silica gel column chromatography (0→50% EtOAc / hexanes) to yield 3-[[4-methoxy-5-(3-methylbenzotriazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl]amino]-1-methylcyclobutane-1-carboxylic acid (CLI) (104 mg, 0.2553 mmol, 26.779% yield) as an off-white solid. ESIMS found C 20 H 21 N7O3 m / z 408.2 (M+H).

[0472] Step 4 A solution of HATU (34.5 mg, 0.09 mmol), trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxylic acid (CLI) (34 mg, 0.08 mmol), and DIPEA (30.9 μL, 0.18 mmol) in DCM (2 mL) was stirred at room temperature for 30 min, followed by the addition of pyrrolidine (CLII) (10 μL, 0.12 mmol). The reaction was stirred at room temperature for 16 h. The solvent was reduced onto Celite® and purified by silica gel column chromatography (0→10% 7N NH in MeOH / CHCl) to give (trans-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)(pyrrolidin-1-yl)methanone (222) (36 mg, 0.078 mmol, 93.7% yield) as a white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.38 (3 H, s), 1.73 - 1.80 (2 H, m), 1.81 - 1.87 (2 H, m), 1.91 - 1.99 (2 H, m), 2.86 - 2.93 (2 H, m), 3.30 - 3.34 (4 H, m), 3.87 - 3.94 (1 H, m), 3.96 (3 H, s), 4.31 (3 H, s), 6.74 (1 H, d, J=2.46 Hz), 7.07 (1 H, d, J=6.57 Hz), 7.60 (1 H, dd, J=8.62, 1.51 Hz), 7.64 (1 H, d, J=2.74 Hz), 7.93 (1 H, s), 7.97 (1 H, d, J=8.76 Hz); ESIMS measured value C 24 H 28 N8O2m / z 461.3 (M+1).

[0473] Example 8 The preparation of 2-(((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)amino)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (265) is shown below in Scheme 31. [ka]

[0474] Step 1 2-chloro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazine (CLIII) (prepared by the method described in Example 3, Steps 1-2) (200 mg, 0.67 mmol), tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (CLIV) (commercially available from PharmaBlock (USA), Inc.) (177 mg, 0.87 mmol), BrettPhos Pd G3 (51 mg, 0.06 mmol), BrettPhos (31 mg, 0.06 mmol), and NaO tBu (192 mg, 2.0 mmol) was suspended in dry 1,4-dioxane (4 mL). The mixture was purged with Ar for 5 min, followed by heating at 100 °C for 10 min. The reaction mixture was added to saturated aqueous NH4Cl and DCM, and the organic layer was separated. The aqueous layer was extracted with DCM (x2), and the combined organic layers were dried (anhydrous MgSO4) and reduced in vacuo to give the product tert-butyl (3S,4R)-3-fluoro-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidine-1-carboxylate (CLV) (220 mg, 0.470 mmol). , 70.6% yield) and tert-butyl (3S,4R)-3-fluoro-4-((4-hydroxy-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidine-1-carboxylate (CLVI) (91 mg, 0.200 mmol, 30.1% yield) were obtained as an orange fluffy solid, which was used without purification. Amounts and yields were calculated by LCMS. ESIMS found C 22 H 25 FN8O3 m / z 469.3 (M+H) and C 21 H 23 FN8O3 m / z 455.2 (M+H).

[0475] Step 2 A mixture of tert-butyl (3S,4R)-3-fluoro-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidine-1-carboxylate (CLV) (220 mg, 0.470 mmol) and tert-butyl (3S,4R)-3-fluoro-4-((4-hydroxy-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidine-1-carboxylate (CLVI) (91 mg, 0.200 mmol) was dissolved in DCE (9 mL) at 0° C. TFA (1 mL) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was evaporated and excess TFA was removed by high vacuum. The crude product was purified by column chromatography (0 to 8% 7.0 NH in MeOH / CHCl) followed by (8 to 20% 7.0 NH in MeOH / CHCl) to recover two compounds, N-((3R,4S)-4-fluoropyrrolidin-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (CLVII) (100 mg, 0.272 mmol, 57.8% yield) as a pale yellow semi-solid. ESIMS observed C 17 H 17 FN8O m / z 369.2 (M+H). The product 2-(((3R,4S)-4-fluoropyrrolidin-3-yl)amino)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (CLVIII) (171 mg, 0.483 mmol, 102.8% yield) was recovered as a yellow solid. ESIMS found C 16 H 15 FN8O m / z 355.2 (M+H). Additional demethylation was performed during TFA Boc deprotection.

[0476] Step 3 2-(((3R,4S)-4-Fluoropyrrolidin-3-yl)amino)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (CLVIII) (40 mg, 0.11 mmol) was suspended in EtOH (1 mL) and DCE (1 mL). HOAc (19 μL, 0.33 mmol) and oxetan-3-one (CIX) (33 μL, 0.56 mmol) were then added and the reaction was stirred at 65° C. for 15 min. NaBH(OAc) (48 mg, 0.23 mmol) was added and the reaction was stirred for an additional 10 min. LC / MS showed unreacted starting material, so additional oxetan-3-one (23 μL, 0.36 mmol) was added and stirred at 65° C. for 10 minutes, followed by additional NaBH(OAc) (48 mg, 0.23 mmol). The reaction was stirred at 65° C. for 10 minutes. LC / MS showed a small amount of starting material, so the reaction was stopped. The reaction mixture was loaded onto Celite® and purified by silica column chromatography (0→9% 7.0 M NH in MeOH / CHCl). The product was further purified by HPLC (0→15% MeCN / HO (0.1% formic acid)) to yield 2-(((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)amino)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (265) (4 mg, 0.010 mmol, 8.6% yield) as an off-white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 2.56 (1 H, t, J=8.49 Hz), 2.79 - 2.91 (1 H, m), 2.96 - 3.09 (1 H, m), 2.98 - 3.03 (1 H, m), 3.76 (1 H, quin, J=6.09 Hz), 4.22 - 4.37 (1 H, m), 4.46 (2 H, t, J=6.02 Hz), 4.58 (2 H, t, J=6.57 Hz), 5.25 (1 H, dtd, J=55.95, 4.65, 4.65, 1.00 Hz), 6.29 (1 H, br d, J=6.30 Hz), 6.81 (1 H, d, J=2.74 Hz), 7.48 (1 H, d, J=2.74 Hz), 7.71 (1 H, d, J=1.10 Hz), 7.93 (1 H, d, J=1.09 Hz), 8.90 (1 H, d, J=2.46 Hz), 9.41 (1 H, d, J=2.19 Hz), 10.78 (1 H, br s); ESIMS actual value C 19 H 19 FN8O2 m / z 411.2 (M+1).

[0477] Example 9. The preparation of (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (725) and (1r,4r)-4-((5-(1-((E)-2-fluorovinyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (672) is shown below in Scheme 32. [ka]

[0478] Steps 1 and 2 6-Bromo-1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazole (LXV) (500 mg, 1.91 mmol), bis(pinacolato)diboron (650 mg, 2.56 mmol), Pd(dppf)Cl (75 mg, 0.09 mmol), and KOAc (500 mg, 5.09 mmol) were suspended in dry 1,4-dioxane (12 mL). The reaction was sonicated and degassed for 5 minutes before heating at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, and a 2 M aqueous solution of KPO (2.52 mL, 5.04 mmol) was added, and the reaction was stirred for 5 minutes. 5-Bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (443 mg, 1.69 mmol), Pd(OAc) (19 mg, 0.08 mmol), and QPhos (84 mg, 0.12 mmol) were added, and the reaction was purged with Ar for 5 minutes. The reaction was heated to 80 °C for 1 hour. The reaction mixture was reduced in vacuo, and the crude product was purified by column chromatography (100% CHCl). The product was further purified by column chromatography (0→50% EtOAc / hexanes, followed by 50→100% EtOAc / hexanes) to give a solid that was triturated with MeOH, washed with MeOH, and filtered to give 6-(2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazole (CLX) (295 mg, 0.809 mmol, 47.9% yield) as a beige solid. ESIMS found C 15 H 11 ClF2N6O m / z 365.1 (M+H).

[0479] Step 3 6-(2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazole (CLX) (25 mg, 0.07 mmol), trans-4-amino-1-methylcyclohexan-1-ol (CXXXVI) (commercially available from PharmaBlock (USA), Inc.) (9 mg, 0.07 mmol), BrettPhos PD G3 (5 mg, 0.01 mmol), BrettPhos (4 mg, 0.01 mmol), and NaO t Bu (21 mg, 0.22 mmol) was dissolved in dry 1,4-dioxane (0.7 mL) in a microwave vial. The suspension was purged with Ar for 5 minutes, and then the reaction was heated to 100° C. for 3 hours. The reaction was reduced in vacuo, loaded onto Celite®, and purified by column chromatography (0 to 90% EtOAc / hexanes). The isolated product was further purified by HPLC (holding at 0 to 35%, then increasing in 5% increments to 80% MeOH / HO in 0.1% formic acid). The appropriate fractions were collected, neutralized with saturated aqueous NaHCO3, and extracted with DCM (×2). The combined organic layers were dried over anhydrous MgSO and reduced in vacuo to give (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (725) as a yellow solid (3 mg, 0.007 mmol, 9.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.15 (3 H, s), 1.40 - 1.50 (4 H, m), 1.57 - 1.65 (2 H, m), 1.84 - 1.92 (2 H, m), 3.60 - 3.69 (1 H, m), 3.94 (3 H, s), 4.23 (1 H, s), 5.30 (2 H, td, J=15.81, 2.87 Hz), 6.50 (1 H, d, J=7.94 Hz), 6.60 (1 H, tt, J=54.30, 3.00 Hz), 6.72 (1 H, d, J=2.46 Hz), 7.62 - 7.65 (1 H, m), 7.65 (1H, d, J=2.74 Hz), 8.00 - 8.05 (2H, m); ESIMS observed value C 22 H 25 F2N7O2 m / z 458.2 (M+1). The elimination by-product (1r,4r)-4-((5-(1-((E)-2-fluorovinyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (672) (7 mg, 0.016 mmol, 23.3% yield) was also obtained as a yellow solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.15 (3 H, s), 1.38 - 1.51 (4 H, m), 1.57 - 1.66 (2 H, m), 1.82 - 1.93 (2 H, m), 3.59 - 3.71 (1 H, m), 3.94 (3 H, s), 4.23 (1 H, s), 6.51 (1 H, d, J=7.94 Hz), 6.74 (1 H, d, J=2.74 Hz), 7.34 (1 H, dd, J=60.90, 4.10 Hz), 7.45 (1 H, dd, J=18.62, 3.83 Hz), 7.65 (1 H, d, J=2.46 Hz), 7.69 (1H, d, J=9.03 Hz), 7.92 (1H, s), 8.08 (1H, d, J=8.76 Hz); ESIMS observed value C 22 H 24FN7O2 m / z 438.2 (M+1).

[0480] Example 10. The preparation of N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (688) and 3-((3R,4S)-3-fluoro-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile (690) is shown below in Scheme 33. [ka]

[0481] Steps 1 and 2 Using the procedure described in Example 9, Scheme 32, Steps 1-2, 6-(2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-isopropyl-1H-benzo[d][1,2,3]triazole (CLXI) (1.022 g, 2.982 mmol, 97.8% yield) was produced as a fluffy red solid. ESIMS observed C 16 H 15 ClNO m / z 343.1 (M+H).

[0482] Step 3 The procedure described in Example 9, Scheme 32, Step 3 was used to produce tert-butyl (3R,4S)-3-fluoro-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidine-1-carboxylate (CLXIII) (184 mg, 0.351 mmol, 100.19% yield) as a brown semi-solid. ESIMS found C 26 H 33FN8O3 m / z 525.15 (M+H).

[0483] Step 4 The procedure described in Example 8, Scheme 31, Step 2 was used to produce N-((3R,4S)-3-fluoropiperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (CLXIV) (148 mg, 0.349 mmol, 99.4% yield) as a brown solid. ESIMS found C 21 H 25 FN8O m / z 425.2 (M+H).

[0484] Steps 5a and 5b N-((3R,4S)-3-fluoropiperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (CLXIV) (40 mg, 0.09 mmol) was suspended in dry DCE (0.9 mL), followed by the addition of EtOH (0.1 mL) to aid dissolution. After the addition of acetic acid (16 μL, 0.28 mmol), oxetan-3-one (CIX) (17 μL, 0.29 mmol), and 3Å MS (5 beads), the reaction was heated to 65 °C for 1 h. The reaction was cooled to room temperature, and 400 μL of the reaction mixture was removed (leaving 600 μL) and added to another vial, both of which were heated to 65 °C. To the first vial was added NaBH(OAc)3 (41 mg, 0.19 mmol), and the reaction was stirred for 10 minutes. To the second vial was added trimethylsilyl cyanide (24 μL, 0.19 mmol), and the reaction was stirred for 10 minutes. Both reactions were separately loaded onto Celite® and purified by column chromatography (0→2% MeOH / CHCl3). Compound 688 was further purified by HPLC (0→50% MeCN / H2O with 0.1% formic acid). Compound 690 was further purified by HPLC (0→80% MeCN / H2O with 0.1% formic acid). N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (688) (11 mg, 0.023 mmol, 24.3% yield) was obtained as a fluffy white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 (6 H, d, J=6.57 Hz), 1.70 - 1.77 (1 H, m), 1.88 - 1.97 (1 H, m), 1.99 - 2.06 (1 H, m), 2.16 (1 H, dd, J=37.00, 12.59 Hz), 2.71 - 2.80 (1 H, m), 2.95 - 3.04 (1 H, m), 3.49 (1 H, quin, J=6.37 Hz), 3.74 - 3.90 (1 H, m), 3.96 (3 H, s), 4.40 (1 H, t, J=6.16 Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.43, 3.01 Hz), 4.94 (1 H, d, J=49.90 Hz), 5.24 (1 H, spt, J=6.75 Hz), 6.69 (1 H, d, J=7.94 Hz), 6.77 (1 H, d, ESIMS actual measurement value C 24 H 29 FN8O2 m / z 481.25 (M+1) and 3-((3R,4S)-3-fluoro-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile (690) (10 mg, 0.020 mmol, 21.0% yield) were obtained as fluffy white solids. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 (6 H, d, J=6.84 Hz), 1.82 (1 H, br dd, J=12.32, 3.01 Hz), 2.00 (1 H, qd, J=12.37, 3.70 Hz), 2.09 - 2.18 (1 H, m), 2.26 (1 H, dd, J=36.20, 12.32 Hz), 2.78 - 2.86 (1 H, m), 3.00 - 3.11 (1 H, m), 3.79 - 3.95 (1 H, m), 3.97 (3 H, s), 4.52 (1 H, d, J=6.84 Hz), 4.65 (1 H, d, J=7.12 Hz), 4.76 (2 H, t, J=6.84 Hz), 5.04 (1 H, d, J=49.35 Hz), 5.24 (1 H, spt, J=6.75 Hz), 6.78 (1 H, d, J=2.46 Hz), 6.81 (1 H, d, J=7.67 ESIMS actual value C 25 H 28 FN9O2 m / z 506.2 (M+1).

[0485] Example 11 The preparation of 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (1145) is shown below in Scheme 34. [ka]

[0486] Step 1 2,5-dichloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (700 mg, 3.21 mmol), tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (CLXII) (commercially available from Advanced ChemBlocks Inc.) (771 mg, 3.53 mmol), BrettPhos Pd G3 (146 mg, 0.16 mmol), BrettPhos (86 mg, 0.16 mmol), and t BuONa (770 mg, 8.01 mmol) was placed in a microwave vial and dry 1,4-dioxane (20 mL) was added. 3A MS (8 beads) was added and the reaction was stirred at room temperature for 1 h. The sieves were quickly removed, the reaction was sealed, and purged with Ar for 5 min, followed by microwave irradiation at 115 °C for 3 min. The reaction mixture was poured into DCM and water, and the organic layer was separated. The aqueous layer was extracted with DCM (×2), and the combined organic layers were dried (MgSO) and reduced in vacuo to afford the crude product tert-butyl (3R,4S)-4-((5-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidine-1-carboxylate (CLXV) (1.284 g, 3.211 mmol, 100.0% yield, assuming quantitative yield) as a brown semi-solid, which was used without further purification. ESIMS measured value C 17 H 23 ClFN5O3 m / z 344.10 (M+H- t Bu).

[0487] Step 2 The procedure described in Example 8, Scheme 31, Step 2 was used to produce 5-chloro-N-((3R,4S)-3-fluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (CLXVI) (381 mg, 1.271 mmol, 39.6% yield) as a pale yellow solid. ESIMS found C 12 H 15 ClFN5O m / z 300.1 (M+H).

[0488] Step 3 K2CO3 (115 mg, 0.83 mmol) and MsCl (45 mg, 0.39 mmol) were suspended in DMF (1 mL), 5-chloro-N-((3R,4S)-3-fluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (CLXVI) (50 mg, 0.17 mmol) was added, and the reaction was heated to 80 °C for 16 h. The reaction was loaded onto Celite® and purified by column chromatography (0→45% EtOAc / hexanes) to afford 5-chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (CLXVII) (13 mg, 0.034 mmol, 20.6% yield) as an iridescent white solid. ESIMS found C 13 H 17 ClFN5O3S m / z 378.1 (M+H).

[0489] Step 4 6-Bromo-1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazole (LXV) (5.16 g, 19.69 mmol), bis(pinacolato)diboron (7.51 g, 29.57 mmol), Pd(dppf)Cl (803 mg, 0.98 mmol), and KOAc (5.8 g, 59.1 mmol) were suspended in dry 1,4-dioxane (100 mL). The reaction was sonicated and degassed for 5 min before being heated at 100 °C for 2.5 h. The reaction mixture was loaded onto Celite® and purified by column chromatography (0→50% EtOAc / hexanes) to yield 1-(2,2-difluoroethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (CLXVIII) (5.654 g, 18.291 mmol, 92.9% yield) as a fluffy pale orange solid. ESIMS found C 14 H 18 BF2N3O2 m / z 310.15 (M+H).

[0490] Step 5 5-Chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (CLXVII) (13 mg, 0.03 mmol), 1-(2,2-difluoroethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (CLXVIII) (17 mg, 0.05 mmol), Pd(OAc) (2 mg, 0.01 mmol), and XPhos (3 mg, 0.01 mmol) were suspended in dry 1,4-dioxane (0.5 mL). KPO (52 μL, 0.1 mmol) was added, and the reaction was sonicated and bubbled with Ar for 5 min. The reaction was then heated to 90° C. for 30 minutes. The reaction mixture was loaded onto Celite® and purified by column chromatography (0→1.5% MeOH / CHCl). The product was further purified by HPLC (0→35% MeCN / HO with 0.1% formic acid) to afford, after lyophilization, 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine (1145) (6 mg, 0.011 mmol, 33.2% yield) as a fluffy white solid. 1H NMR (499 MHz, DMSO-d6) δ ppm 1.77 - 1.88 (1 H, m), 1.96 (1 H, qd, J=12.50, 4.38 Hz), 2.93 (3 H, s), 3.02 (1 H, td, J=12.25, 2.60 Hz), 3.20 (1 H, dd, J=37.55, 12.59 Hz), 3.61 - 3.70 (1 H, m), 3.80 - 3.89 (1 H, m), 3.90 - 4.04 (1 H, m), 3.96 (3 H, s), 5.05 (1 H, d, J=49.10 Hz), 5.30 (2H, td, J=15.95, 2.87 Hz), 6.61 (1 H, tt, J=54.30, 3.00 Hz), 6.76 (1 H, d, J=2.74 Hz), 6.88 (1 H, d, J=7.94 Hz), 7.63 (1 H, d, J=2.46 Hz), 7.64 - 7.66 (1 H, m), 8.02 - 8.05 (2 H, m); ESIMS measured value C 21 H 23 F3N8O3S m / z 525.15 (M+1).

[0491] The following compounds were prepared according to the procedures described above in Schemes 1-34. [ka]

[0492] cis-4-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 1.

[0493] Beige solid (2.8 mg, 0.005 mmol, 2.5% yield). 1H NMR (499 MHz, chloroform-d) δ ppm 1.29 (3 H, s), 1.58 - 1.68 (4 H, m), 1.75 (2 H, br d, J=10.68 Hz), 1.99 - 2.06 (2 H, m), 2.72 (3 H, s), 3.66 - 3.74 (1 H, m), 3.95 (3 H, s), 4.50 (2 H, td, J=14.80, 2.50 Hz), 6.12 (1 H, tt, J=54.60, 3.00 Hz), 6.60 (1 H, d, J=2.46 Hz), 7.47 (1 H, d, J=2.19 Hz), 7.81 (1 H, br s), 8.73 (1 H, br s); ESIMS observed value C 23 H 27 F2N7O2 m / z 472.2 (M+1). [ka]

[0494] trans-4-((4-Methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 3.

[0495] Beige solid (10 mg, 0.025 mmol, 10.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.15 (3 H, s), 1.38 - 1.53 (4 H, m), 1.56 - 1.65 (2 H, m), 1.84 - 1.93 (2 H, m), 3.59 - 3.71 (1 H, m), 3.95 (3 H, s), 4.24 (1 H, s), 4.31 (3 H, s), 6.48 (1 H, d, J=7.94 Hz), 6.73 (1 H, d, J=2.74 Hz), 7.61 (1 H, dd, J=8.49, 1.37 Hz), 7.64 (1 H, d, J=2.74 Hz), 7.93 (1 H, s), 7.97 (1 H, d, J = 8.76 Hz); ESIMS measured value C 21 H 25 N7O2 m / z 408.25 (M+1). [ka]

[0496] cis-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 4.

[0497] Off-white solid (15 mg, 0.038 mmol, 22.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.12 (3 H, s), 1.36 (2 H, td, J=13.00, 4.11 Hz), 1.58 (2 H, br d, J=12.32 Hz), 1.61 - 1.75 (4 H, m), 3.45 - 3.60 (1 H, m), 3.97 (3 H, s), 4.00 (1 H, s), 6.57 (1 H, d, J=7.94 Hz), 6.76 (1 H, d, J=2.46 Hz), 7.64 (1 H, d, J=2.46 Hz), 7.72 (1 H, d, J=1.37 Hz), 7.93 (1 H, d, J=1.37 Hz), 8.73 (1 H, d, J=2.46 Hz), 9.08 (1 H, d, J=2.46 Hz); ESIMS actual value C 20 H 23 N7O2 m / z 394.2 (M+1). [ka]

[0498] 2-(cis-3-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol 6.

[0499] White solid (28 mg, 0.071 mmol, 35.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.82 - 1.93 (2 H, m), 2.60 - 2.69 (2 H, m), 3.30 - 3.33 (2 H, m), 3.48 (2 H, q, J=5.48 Hz), 3.68 - 3.74 (1 H, m), 3.74 - 3.81 (1 H, m), 3.98 (3 H, s), 4.60 (1 H, t, J=5.61 Hz), 6.58 (1 H, d, J=1.92 Hz), 6.77 (1 H, d, J=2.46 Hz), 7.04 (1 H, d, J=7.39 Hz), 7.10 (1 H, dd, J=7.26, 1.78 (Hz), 7.60 (1 H, d, J=2.46 Hz), 7.80 (1 H, d, J=0.82 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.12 Hz) 20 H 22 N6O3 m / z 395.2 (M+1). [ka]

[0500] cis-3-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol 7.

[0501] Off-white solid (53 mg, 0.145 mmol, 54.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.27 (3 H, s), 2.02 (2 H, td, J=8.90, 2.19 Hz), 2.31 - 2.41 (2 H, m), 3.72 (1 H, dq, J=15.16, 7.72 Hz), 3.98 (3 H, s), 4.92 (1 H, s), 6.58 (1 H, d, J=1.64 Hz), 6.76 (1 H, d, J=2.74 Hz), 6.95 (1 H, d, J=6.57 Hz), 7.10 (1 H, dd, J=7.39, 1.92 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.80 (1 H, d, J=1.10 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.39 Hz); ESIMS actual value C 19 H 20 N6O2 m / z 365.2 (M+1). [ka]

[0502] trans-3-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol 8.

[0503] White solid (16 mg, 0.044 mmol, 16.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.28 (3 H, s), 1.93 - 2.05 (2 H, m), 2.27 - 2.35 (2 H, m), 3.98 (3 H, s), 4.25 (1 H, sxt, J=7.34 Hz), 4.79 (1 H, s), 6.58 (1 H, d, J=1.92 Hz), 6.76 (1 H, d, J=2.74 Hz), 6.95 (1 H, d, J=6.57 Hz), 7.10 (1 H, dd, J=7.12, 1.92 Hz), 7.62 (1 H, d, J=2.46 Hz), 7.80 (1 H, d, J=0.82 Hz), 7.97 (1H, d, J=2.19 Hz), 8.62 (1H, d, J=7.39 Hz); ESIMS observed value C 19 H 20 N6O2 m / z 365.2 (M+1). [ka]

[0504] 4-Methoxy-N-(cis-4-methoxycyclohexyl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 9.

[0505] Off-white solid (25 mg, 0.064 mmol, 31.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.54 (2 H, m), 1.55 - 1.65 (2 H, m), 1.65 - 1.73 (2 H, m), 1.80 - 1.88 (2 H, m), 3.22 (3 H, s), 3.34 (1 H, br d, J=2.19 Hz), 3.59 - 3.70 (1 H, m), 3.98 (3 H, s), 6.56 - 6.58 (1 H, m), 6.58 (1 H, s), 6.75 (1 H, d, J=2.46 Hz), 7.10 (1 H, dd, J=7.26, 2.05 Hz), 7.61 (1 H, d, ESIMS actual value C 21 H 24 N6O2 m / z 393.2 (M+1). [ka]

[0506] 4-Methoxy-N-(trans-4-methoxycyclohexyl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 10.

[0507] Off-white solid (40 mg, 0.102 mmol, 50.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 - 1.26 (2 H, m), 1.27 - 1.40 (2 H, m), 2.01 (4 H, br t, J=10.81 Hz), 3.12 (1 H, tt, J=10.23, 3.73 Hz), 3.24 (3 H, s), 3.51 - 3.63 (1 H, m), 3.98 (3 H, s), 6.57 (1 H, d, J=7.94 Hz), 6.58 (1 H, d, J=1.64 Hz), 6.75 (1 H, d, J=2.46 Hz), 7.10 (1 H, dd, J=7.39, 1.92 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.80 (1 H, d, J=0.82 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.12 Hz) 21 H 24 N6O2 m / z 393.2 (M+1). [ka]

[0508] 2-((cis-4-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol 13.

[0509] Off-white semi-solid (10 mg, 0.024 mmol, 14.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.55 (2 H, m), 1.60 - 1.73 (4 H, m), 1.78 - 1.88 (2 H, m), 3.38 - 3.42 (2 H, m), 3.47 (1 H, br s), 3.50 (2 H, q, J=5.48 Hz), 3.57 - 3.69 (1 H, m), 3.98 (3 H, s), 4.51 (1 H, t, J=5.48 Hz), 6.55 (1 H, d, J=7.67 Hz), 6.58 (1 H, d, J=1.37 Hz), 6.75 (1 H, d, J=2.46 Hz), 7.10 (1 H, dd, J=7.39, 1.64 Hz), 7.61 (1 H, d, J=2.74 Hz), 7.80 (1 H, s), 7.97 (1 H, d, J=1.92 Hz), 8.62 (1 H, d, J=7.39 Hz);ESIMS actual value C 22 H 26 N6O3 m / z 423.3 (M+1). [ka]

[0510] 4-Methoxy-N-(cis-4-(2-methoxyethoxy)cyclohexyl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 15.

[0511] Fluffy off-white solid (33 mg, 0.0756 mmol, 45.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.55 (2 H, m), 1.59 - 1.73 (4 H, m), 1.78 - 1.88 (2 H, m), 3.27 (3 H, s), 3.43 - 3.46 (2 H, m), 3.46 - 3.48 (1 H, m), 3.48 - 3.52 (2 H, m), 3.57 - 3.69 (1 H, m), 3.98 (3 H, s), 6.58 (1 H, d, J=2.19 Hz), 6.59 (1 H, d, J=7.85 Hz), 6.75 (1 H, d, J=2.46 Hz), 7.10 (1 H, dd, J=7.39, ESIMS actual measurement value C 23 H 28 N6O3 m / z 437.25 (M+1). [ka]

[0512] 4-Methoxy-N-(trans-4-(2-methoxyethoxy)cyclohexyl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 16.

[0513] White solid (31 mg, 0.071 mmol, 35.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.18 - 1.37 (4 H, m), 2.00 (4 H, br d, J=10.95 Hz), 3.20 - 3.27 (1 H, m), 3.25 (3 H, s), 3.40 - 3.45 (2 H, m), 3.53 (2 H, t, J=4.93 Hz), 3.54 - 3.60 (1 H, m), 3.97 (3 H, s), 6.56 (1 H, d, J=8.21 Hz), 6.58 (1 H, d, J=1.64 Hz), 6.75 (1 H, d, J=2.46 Hz), 7.10 (1 H, dd, J=7.39, 1.64 (Hz), 7.63 (1 H, d, J=2.74 Hz), 7.80 (1 H, s), 7.96 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.12 Hz) 23 H 28 N6O3 m / z 437.2 (M+1). [ka]

[0514] N-(cis-4-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide 17.

[0515] White solid (22 mg, 0.052 mmol, 33.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.50 - 1.59 (2 H, m), 1.60 - 1.72 (4 H, m), 1.74 - 1.81 (2 H, m), 1.81 (3 H, s), 3.64 - 3.71 (2 H, m), 3.99 (3 H, s), 6.47 (1 H, d, J=6.30 Hz), 6.58 (1 H, d, J=1.64 Hz), 6.76 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.26, 1.78 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.70 (1 H, br d, J=6.84 Hz), 7.81 (1H, s), 7.97 (1H, d, J=2.19 Hz), 8.62 (1H, d, J=7.12 Hz); ESIMS observed value C 22 H 25 N7O2 m / z 420.2 (M+1). [ka]

[0516] N-(trans-4-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide 18.

[0517] White solid (2 mg, 0.005 mmol, 2.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.19 - 1.29 (2 H, m), 1.30 - 1.40 (2 H, m), 1.78 (3 H, s), 1.81 (2 H, br d, J=11.50 Hz), 1.99 (2 H, br d, J=10.13 Hz), 3.45 - 3.51 (1 H, m), 3.52 - 3.59 (1 H, m), 3.97 (3 H, s), 6.56 (1 H, d, J=8.21 Hz), 6.58 (1 H, d, J=1.64 Hz), 6.76 (1 H, d, J=2.74 Hz), 7.10 (1 H, dd, J=7.26, 2.05 Hz), 7.63 (1 H, d, J=2.46 Hz), 7.74 (1 H, d, J=7.67 Hz), 7.80 (1 H, d, J=1.09 Hz), 7.97 (1 H, d, J=2.46 Hz), 8.62 (1 H, d, J=7.39 Hz); ESIMS actual measurement value C 22 H 25 N7O2 m / z 420.2 (M+1). [ka]

[0518] cis-4-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 19.

[0519] Off-white solid (20 mg, 0.051 mmol, 42.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.12 (3 H, s), 1.36 (2 H, td, J=13.00, 4.38 Hz), 1.58 (2 H, br d, J=12.05 Hz), 1.61 - 1.68 (2 H, m), 1.69 - 1.75 (2 H, m), 3.45 - 3.59 (1 H, m), 3.98 (3 H, s), 3.99 (1 H, s), 6.52 (1 H, d, J=7.94 Hz), 6.58 (1 H, d, J=1.64 Hz), 6.74 (1 H, d, J=2.74 Hz), 7.10 (1H, dd, J=7.12, ESIMS actual measurement value C 21 H 24 N6O2 m / z 393.2 (M+1). [ka]

[0520] trans-4-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 20.

[0521] Beige solid (5 mg, 0.013 mmol, 8.3% yield). 1H NMR (499 MHz, chloroform-d) δ ppm 1.32 (3 H, s), 1.47 - 1.58 (2 H, m), 1.60 - 1.68 (2 H, m), 1.71 - 1.79 (2 H, m), 2.09 - 2.18 (2 H, m), 3.86 (1 H, br d, J=3.83 Hz), 4.01 (3 H, s), 4.12 (1 H, s), 6.53 (1 H, br s), 6.64 (1 H, d, J=2.46 Hz), 7.04 (1 H, br d, J=5.75 Hz), 7.47 (1 H, d, J=2.46 Hz), 7.71 (1H, br s), 7.96 (1 H, br s), 8.50 (1 H, br d, J=6.57 Hz); ESIMS measured value C 21 H 24 N6O2 m / z 393.2 (M+1). [ka]

[0522] N-(1-(2-Fluoroethyl)piperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 24.

[0523] Off-white solid (17 mg, 0.042 mmol, 20.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.46 - 1.60 (2 H, m), 1.85 - 1.96 (2 H, m), 2.11 (2 H, br t, J=11.09 Hz), 2.61 (2 H, dt, J=28.25, 4.95 Hz), 2.84 - 2.93 (2 H, m), 3.53 - 3.66 (1 H, m), 3.98 (3 H, s), 4.53 (2 H, dt, J=47.70, 4.95 Hz), 6.58 (1 H, d, J=1.64 Hz), 6.62 (1 H, d, J=7.94 Hz), 6.76 (1 H, d, J=2.74 Hz), 7.10 (1 H, dd, J=7.39, 1.92 Hz), 7.62 (1 H, d, J=2.46 Hz), 7.81 (1 H, d, J=1.10 Hz), 7.97 (1 H, d, J=2.46 Hz), 8.62 (1 H, d, J=7.39 Hz); ESIMS actual measurement value C 21 H 24 FN7O m / z 410.2 (M+1). [ka]

[0524] 4-Methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 26.

[0525] Off-white solid (2 mg, 0.005 mmol, 1.2% yield). 1H NMR (499 MHz, METHANOL-d4) δ ppm 1.57 - 1.70 (2 H, m), 2.06 (2 H, br t, J=11.77 Hz), 2.09 - 2.15 (2 H, m), 2.80 (2 H, br d, J=11.77 Hz), 3.53 (1 H, quin, J=6.43 Hz), 3.67 - 3.77 (1 H, m), 4.03 (3 H, s), 4.62 (2 H, t, J=6.30 Hz), 4.69 - 4.75 (2 H, m), 6.54 - 6.61 (1 H, m), 6.70 (1 H, d, J=2.46 Hz), 7.14 (1 H, dd, ESIMS actual measurement value C 22 H 25 N7O2 m / z 420.2 (M+1). [ka]

[0526] 1-(4-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one 27.

[0527] Beige solid (11 mg, 0.027 mmol, 13.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.27 - 1.39 (1 H, m), 1.40 - 1.52 (1 H, m), 1.87 - 1.94 (1 H, m), 1.94 - 2.00 (1 H, m), 2.01 (3 H, s), 2.70 - 2.81 (1 H, m), 3.12 - 3.19 (1 H, m), 3.78 - 3.87 (2 H, m), 3.99 (3 H, s), 4.24 - 4.34 (1 H, m), 6.59 (1 H, dd, J=2.19, 0.82 Hz), 6.73 (1 H, d, J=7.94 Hz), 6.77 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.12, 1.92 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.81 (1 H, d, J=1.10 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.12 Hz); ESIMS actual measurement value C 21 H 23 N7O2 m / z 406.2 (M+1). [ka]

[0528] N-((3S,4R)-3-Fluoropiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 29.

[0529] Off-white solid (45 mg, 0.118 mmol, 87.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.57 - 1.65 (1 H, m), 1.73 (1 H, qd, J=12.37, 4.24 Hz), 2.56 (1 H, br t, J=12.46 Hz), 2.71 (1 H, dd, J=39.25, 14.30 Hz), 2.96 (1 H, br d, J=13.14 Hz), 3.13 (1 H, br t, J=11.50 Hz), 3.77 - 3.94 (1 H, m), 4.00 (3 H, s), 4.80 (1 H, d, J=50.75 Hz), 6.59 (1 H, d, J=1.64 Hz), 6.64 (1 H, d, J=7.94 Hz), 6.78 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.39, 1.92 Hz), 7.63 (1 H, d, J=2.46 Hz), 7.81 (1 H, d, J=1.10 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.63 (1 H, d, J=7.12 Hz);ESIMS actual value C 19 H 20 FN7O m / z 382.2 (M+1). [ka]

[0530] N-((3R,4S)-3-Fluoropiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 30.

[0531] Brown solid (109 mg, 0.286 mmol, 99.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.89 - 1.96 (1 H, m), 2.07 (1 H, qd, J=13.23, 4.11 Hz), 2.75 (1 H, s), 3.11 - 3.18 (1 H, m), 3.27 - 3.38 (1 H, m), 3.58 - 3.66 (1 H, m), 4.01 (3 H, s), 4.05 - 4.18 (1 H, m), 5.20 (1 H, d, J=47.45 Hz), 6.60 (1 H, d, J=1.92 Hz), 6.81 (1 H, d, J=2.46 Hz), 7.06 (1 H, d, J=7.39 Hz), 7.11 (1 H, dd, J=7.12, 1.92 Hz), 7.59 (1 H, d, J=2.74 Hz), 7.82 (1 H, d, J=1.37 Hz), 7.98 (1 H, d, J=2.19 Hz), 8.64 (1 H, br d, J=7.39 Hz); ESIMS actual measurement value C 19 H 20 FN7O m / z 382.2 (M+1). [ka]

[0532] N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 31.

[0533] Off-white solid (30 mg, 0.076 mmol, 72.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.68 (1 H, br dd, J=12.59, 3.01 Hz), 1.92 (1 H, qd, J=12.23, 3.56 Hz), 2.01 - 2.09 (1 H, m), 2.17 (1 H, dd, J=37.55, 13.20 Hz), 2.19 (3 H, s), 2.79 (1 H, br d, J=11.23 Hz), 3.00 - 3.09 (1 H, m), 3.67 - 3.83 (1 H, m), 4.00 (3 H, s), 4.91 (1 H, d, J=50.20 Hz), 6.59 (1 H, d, J=1.64 Hz), 6.64 (1 H, d, J=7.67 Hz), 6.78 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.12, 1.92 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.81 (1 H, d, J=0.82 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.63 (1 H, d, J=7.39 Hz) 20 H 22 FN7O m / z 396.2 (M+1). [ka]

[0534] N-((3R,4S)-3-Fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 34.

[0535] Off-white solid (43 mg, 0.109 mmol, 38.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.65 - 1.72 (1 H, m), 1.92 (1 H, qd, J=12.27, 3.70 Hz), 2.01 - 2.09 (1 H, m), 2.17 (1 H, dd, J=37.55, 13.20 Hz), 2.19 (3 H, s), 2.80 (1 H, br d, J=11.77 Hz), 3.01 - 3.07 (1 H, m), 3.67 - 3.83 (1 H, m), 4.00 (3 H, s), 4.91 (1 H, d, J=49.90 Hz), 6.59 (1 H, d, J=1.37 Hz), 6.65 (1 H, d, J=7.67 Hz), 6.78 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.26, 2.05 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.81 (1 H, d, J=1.10 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.63 (1 H, d, J=7.12 Hz); ESIMS actual value C 20 H 22 FN7O m / z 396.3 (M+1). [ka]

[0536] 4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 36.

[0537] Off-white solid (8 mg, 0.022 mmol, 6.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.47 - 1.60 (2 H, m), 1.89 (2 H, br dd, J=12.46, 2.05 Hz), 3.36 - 3.45 (2 H, m), 3.73 - 3.85 (1 H, m), 3.85 - 3.92 (2 H, m), 3.99 (3 H, s), 6.58 (1 H, d, J=1.92 Hz), 6.71 (1 H, d, J=7.94 Hz), 6.76 (1 H, d, J=2.46 Hz), 7.10 (1 H, dd, J=7.26, 1.78 Hz), 7.63 (1 H, d, J=2.74 Hz), 7.81 (1 H, d, J=0.82 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.12 Hz);ESIMS actual value C 19 H 20 N6O2 m / z 365.2 (M+1). [ka]

[0538] 1-(6-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)ethan-1-one 37.

[0539] White solid (28 mg, 0.067 mmol, 38.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.69 - 1.76 (3 H, m), 2.13 - 2.25 (2 H, m), 2.52 - 2.60 (2 H, m), 3.77 (1 H, s), 3.89 (1 H, s), 3.98 (3 H, s), 4.04 - 4.11 (1 H, m), 4.05 (1 H, s), 4.17 (1 H, s), 6.58 (1 H, d, J=1.92 Hz), 6.77 (1 H, d, J=2.46 Hz), 7.03 (1 H, t, J=6.98 Hz), 7.10 (1 H, dd, J=7.39, 1.92 Hz), 7.62 (1 7.80 (1 H, d, J=0.82 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.39 Hz) 22 H 23 N7O2 m / z 418.2 (M+1). [ka]

[0540] 1-(2-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-7-azaspiro[3.5]nonan-7-yl)ethan-1-one 39.

[0541] Off-white solid (50 mg, 0.112 mmol, 79.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.40 - 1.46 (1 H, m), 1.49 - 1.56 (2 H, m), 1.57 - 1.64 (1 H, m), 1.74 - 1.84 (2 H, m), 1.95 - 2.01 (3 H, m), 2.26 (2 H, br dd, J=9.86, 8.21 Hz), 3.26 - 3.30 (1 H, m), 3.30 - 3.32 (1 H, m), 3.35 - 3.39 (1 H, m), 3.39 - 3.44 (1 H, m), 3.98 (3 H, s), 4.14 - 4.25 (1 H, m), 6.58 (1 H, d, J=1.64 Hz), 6.76 (1 H, d, J=2.74 Hz), 7.02 (1 H, t, J=7.12 Hz), 7.10 (1 H, dd, J=7.12, 1.92 Hz), 7.59 - 7.66 (1 H, m), 7.80 (1 H, d, J=1.09 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.39 Hz) 24 H 27 N7O2 m / z 446.2 (M+1). [ka]

[0542] 1-(7-((4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one 40.

[0543] Off-white solid (75 mg, 0.168 mmol, 95.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.26 - 1.39 (2 H, m), 1.48 - 1.60 (2 H, m), 1.73 - 1.78 (3 H, m), 1.83 - 1.93 (4 H, m), 3.47 (1 H, s), 3.52 (1 H, s), 3.57 (1 H, br dd, J=7.53, 3.15 Hz), 3.74 (1 H, s), 3.80 (1 H, s), 3.98 (3 H, d, J=1.10 Hz), 6.54 (1 H, dd, J=16.15, 7.94 Hz), 6.58 (1 H, d, J=1.64 Hz), 6.76 (1 H, d, J=2.74 Hz), 7.10 (1 H, dd, J=7.39, 1.92 Hz), 7.62 (1 H, t, J=2.87 Hz), 7.80 (1 H, d, J=1.09 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J=7.39 Hz); ESIMS actual measurement value C 24 H 27 N7O2 m / z 446.2 (M+1). [ka]

[0544] cis-3-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol 43.

[0545] White solid (19 mg, 0.052 mmol, 31.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.27 (3 H, s), 1.96 - 2.07 (2 H, m), 2.31 - 2.41 (2 H, m), 3.71 (1 H, dq, J=15.16, 7.72 Hz), 3.96 (3 H, s), 4.91 (1 H, s), 6.67 (1 H, d, J=2.74 Hz), 6.92 (1 H, d, J=6.84 Hz), 7.43 (1 H, dd, J=9.31, 1.64 Hz), 7.54 (1 H, d, J=9.31 Hz), 7.56 (1 H, d, J=0.82 Hz), 7.62 (1 H, d, J = 2.46 Hz), 7.95 (1 H, s), 8.68 (1 H, s); ESIMS measured value C 19 H 20 N6O2 m / z 365.2 (M+1). [ka]

[0546] trans -3-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol 44 .

[0547] Off-white semi-solid (10 mg, 0.027 mmol, 16.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.28 (3 H, s), 1.94 - 2.03 (2 H, m), 2.28 - 2.35 (2 H, m), 3.96 (3 H, s), 4.25 (1 H, sxt, J=7.39 Hz), 4.78 (1 H, br s), 6.68 (1 H, d, J=2.74 Hz), 6.93 (1 H, d, J=6.84 Hz), 7.43 (1 H, dd, J=9.31, 1.64 Hz), 7.54 (1 H, d, J=9.58 Hz), 7.56 (1 H, s), 7.61 (1 H, d, J=2.74 Hz), 7.95 (1 H, s), 8.68 (1 H, s); ESIMS observed value C 19 H 20 N6O2 m / z 365.2 (M+1). [ka]

[0548] 5-(Imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(cis-4-methoxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 45.

[0549] Off-white solid (2.6 mg, 0.007 mmol, 4.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.54 (2 H, m), 1.55 - 1.65 (2 H, m), 1.69 (2 H, dt, J=8.35, 4.04 Hz), 1.80 - 1.88 (2 H, m), 3.22 (3 H, s), 3.29 - 3.37 (1 H, m), 3.56 - 3.71 (1 H, m), 3.96 (3 H, s), 6.54 (1 H, d, J=7.67 Hz), 6.67 (1 H, d, J=2.46 Hz), 7.43 (1 H, dd, J=9.31, 1.37 Hz), 7.54 (1 H, d, J=9.31 Hz), 7.56 (1 H, s), 7.61 (1 H, d, J=2.46 Hz), 7.95 (1 H, s), 8.68 (1 H, s); ESIMS observed C 21 H 24 N6O2 m / z 393.2 (M+1). [ka]

[0550] 2-((cis-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol 49.

[0551] Orange semi-solid (6 mg, 0.014 mmol, 6.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.56 (2 H, m), 1.60 - 1.74 (4 H, m), 1.78 - 1.88 (2 H, m), 3.38 - 3.42 (2 H, m), 3.47 (1 H, br s), 3.50 (2 H, q, J=5.20 Hz), 3.58 - 3.70 (1 H, m), 3.96 (3 H, s), 4.51 (1 H, br t, J=5.34 Hz), 6.52 (1 H, d, J=7.67 Hz), 6.67 (1 H, d, J=2.46 Hz), 7.47 (1 H, br d, J=9.03 Hz), 7.56 (1H, br d, J=9.03 Hz), 7.58 - 7.60 (1H, m), 7.61 (1H, d, J=2.46 Hz), 7.98 (1H, br s), 8.70 (1H, br s); ESIMS observed value C 22 H 26 N6O3 m / z 423.25 (M+1). [ka]

[0552] 5-(Imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(cis-4-(2-methoxyethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 51.

[0553] White solid (3 mg, 0.007 mmol, 4.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.56 (2 H, m), 1.58 - 1.74 (4 H, m), 1.77 - 1.88 (2 H, m), 3.27 (3 H, s), 3.43 - 3.46 (2 H, m), 3.47 (1 H, br s), 3.48 - 3.52 (2 H, m), 3.62 (1 H, ddt, J=12.53, 8.56, 4.52, 4.52 Hz), 3.96 (3 H, s), 6.56 (1 H, d, J=7.67 Hz), 6.67 (1 H, d, J=2.46 Hz), 7.43 (1H, dd, J=9.45, ESIMS actual measurement value C 23 H 28 N6O3 m / z 437.2 (M+1). [ka]

[0554] 5-(Imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(trans-4-(2-methoxyethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 52.

[0555] White solid (5 mg, 0.012 mmol, 5.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.18 - 1.26 (2 H, m), 1.27 - 1.36 (2 H, m), 2.00 (4 H, br d, J=10.95 Hz), 3.20 - 3.26 (1 H, m), 3.25 (3 H, s), 3.42 (2 H, dd, J=5.75, 3.83 Hz), 3.53 (2 H, dd, J=5.75, 3.83 Hz), 3.55 - 3.60 (1 H, m), 3.95 (3 H, s), 6.52 (1 H, d, J=7.94 Hz), 6.67 (1 H, d, J=2.46 Hz), 7.43 (1 H, dd, J=9.45, 1.78 Hz), 7.54 (1 H, d, J=9.31 Hz), 7.56 (1 H, d, J=1.09 Hz), 7.63 (1 H, d, J=2.46 Hz), 7.95 (1 H, s), 8.64 - 8.70 (1 H, m);ESIMS actual measurement value C 23 H 28 N6O3 m / z 437.2 (M+1). [ka]

[0556] N-(cis-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide 53.

[0557] Off-white solid (8 mg, 0.019 mmol, 37.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.50 - 1.59 (2 H, m), 1.60 - 1.71 (4 H, m), 1.73 - 1.81 (2 H, m), 1.81 (3 H, s), 3.67 (2 H, br d, J=3.56 Hz), 3.97 (3 H, s), 6.43 (1 H, d, J=6.30 Hz), 6.68 (1 H, d, J=2.74 Hz), 7.44 (1 H, dd, J=9.31, 1.64 Hz), 7.54 (1 H, d, J=9.31 Hz), 7.57 (1 H, s), 7.62 (1 H, d, J=2.46 Hz), 7.70 (1H, br d, J=7.12 Hz), 7.95 (1H, s), 8.68 (1H, s); ESIMS observed C 22 H 25 N7O2 m / z 420.2 (M+1). [ka]

[0558] N-(trans-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide 54.

[0559] Off-white solid (17 mg, 0.041 mmol, 24.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.19 - 1.29 (2 H, m), 1.29 - 1.39 (2 H, m), 1.78 (3 H, s), 1.79 - 1.85 (2 H, m), 1.99 (2 H, br d, J=10.95 Hz), 3.44 - 3.59 (2 H, m), 3.95 (3 H, s), 6.53 (1 H, d, J=8.21 Hz), 6.67 (1 H, d, J=2.46 Hz), 7.43 (1 H, dd, J=9.45, 1.51 Hz), 7.54 (1 H, d, J=9.31 Hz), 7.56 (1 H, s), 7.63 (1 1H, d, J=2.46 Hz), 7.74 (1H, d, J=7.67 Hz), 7.95 (1H, s), 8.68 (1H, s); ESIMS observed value C 22 H 25 N7O2 m / z 420.2 (M+1). [ka]

[0560] cis-4-((5-(Imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 55.

[0561] Off-white solid (7.9 mg, 0.020 mmol, 14.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.12 (3 H, s), 1.36 (2 H, td, J=13.00, 4.11 Hz), 1.58 (2 H, br d, J=12.32 Hz), 1.60 - 1.68 (2 H, m), 1.68 - 1.74 (2 H, m), 3.45 - 3.57 (1 H, m), 3.96 (3 H, s), 4.00 (1 H, s), 6.49 (1 H, d, J=7.94 Hz), 6.66 (1 H, d, J=2.46 Hz), 7.43 (1 H, dd, J=9.58, 1.64 Hz), 7.54 (1 H, d, J=9.31 Hz), 7.56 (1 H, d, J=0.82 Hz), 7.60 (1 H, d, J=2.74 Hz), 7.95 (1 H, s), 8.68 (1 H, s); ESIMS observed value C 21 H 24 N6O2 m / z 393.2 (M+1). [ka]

[0562] trans -4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 56.

[0563] Beige solid (16 mg, 0.041 mmol, 20.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.37 - 1.52 (4 H, m), 1.56 - 1.64 (2 H, m), 1.81 - 1.93 (2 H, m), 3.57 - 3.70 (1 H, m), 3.96 (3 H, s), 4.24 (1 H, s), 6.47 (1 H, d, J=7.94 Hz), 6.67 (1 H, d, J=2.46 Hz), 7.43 (1 H, dd, J=9.31, 1.64 Hz), 7.54 (1 H, d, J=9.31 Hz), 7.56 (1 H, s), 7.62 (1 H, d, J=2.46 Hz), 7.95 (1H, s), 8.68 (1H, s); ESIMS measured C 21 H 24 N6O2 m / z 393.2 (M+1). [ka]

[0564] N-(1-(2,2-difluoroethyl)piperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine 61.

[0565] White solid (5 mg, 0.012 mmol, 5.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.48 - 1.62 (2 H, m), 1.89 (2 H, br d, J=10.95 Hz), 2.22 - 2.31 (2 H, m), 2.72 (2 H, td, J=15.74, 4.38 Hz), 2.90 (2 H, br d, J=11.77 Hz), 3.53 - 3.65 (1 H, m), 3.96 (3 H, s), 6.13 (1 H, tt, J=55.95, 4.40 Hz), 6.59 (1 H, d, J=7.94 Hz), 6.68 (1 H, d, J=2.74 Hz), 7.43 (1 H, dd, J=9.45, 1.78 Hz), 7.54 (1 H, d, J=9.58 Hz), 7.56 (1 H, d, J=0.82 Hz), 7.62 (1 H, d, J=2.74 Hz), 7.95 (1 H, s), 8.65 - 8.70 (1 H, m);ESIMS actual measurement value C 21 H 23 F2N7O m / z 428.2 (M+1). [ka]

[0566] 5-(Imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 62.

[0567] Colorless semi-solid (10 mg, 0.024 mmol, 14.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.48 - 1.61 (2 H, m), 1.84 - 1.98 (4 H, m), 2.71 (2 H, br d, J=11.22 Hz), 3.41 (1 H, br s), 3.54 - 3.65 (1 H, m), 3.96 (3 H, s), 4.43 (2 H, t, J=6.16 Hz), 4.54 (2 H, t, J=6.57 Hz), 6.63 (1 H, d, J=7.94 Hz), 6.68 (1 H, d, J=2.46 Hz), 7.44 (1 H, dd, J=9.31, 1.37 Hz), 7.55 (1 H, br d, J=9.31 Hz), 7.57 (1 H, br s), 7.62 (1 H, d, J=2.46 Hz), 7.96 (1 H, s), 8.68 (1 H, s); ESIMS observed value C 22 H 25 N7O2 m / z 420.2 (M+1). [ka]

[0568] 1-(4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one 63.

[0569] Beige solid (9 mg, 0.022 mmol, 13.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.29 - 1.38 (1 H, m), 1.39 - 1.50 (1 H, m), 1.88 - 1.95 (1 H, m), 1.97 (1 H, br d, J=13.14 Hz), 2.01 (3 H, s), 2.69 - 2.82 (1 H, m), 3.11 - 3.20 (1 H, m), 3.77 - 3.87 (2 H, m), 3.97 (3 H, s), 4.28 (1 H, br d, J=12.59 Hz), 6.68 - 6.72 (2 H, m), 7.47 (1 H, d, J=9.31 Hz), 7.56 (1 H, d, J=9.31 Hz), 7.59 (1 H, s), 7.63 (1 H, d, J=2.46 Hz), 7.97 (1 H, s), 8.70 (1 H, s); ESIMS observed value C 21 H 23 N7O2 m / z 406.2 (M+1). [ka]

[0570] N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine 67.

[0571] White solid (5.5 mg, 0.014 mmol, 10.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.63 - 1.74 (1 H, m), 1.92 (1 H, qd, J=12.27, 3.70 Hz), 2.06 (1 H, br t, J=11.09 Hz), 2.11 - 2.24 (1 H, m), 2.19 (3 H, s), 2.80 (1 H, br d, J=10.95 Hz), 3.00 - 3.07 (1 H, m), 3.66 - 3.83 (1 H, m), 3.98 (3 H, s), 4.91 (1 H, d, J=49.90 Hz), 6.61 (1 H, d, J=7.94 Hz), 6.70 (1 H, d, J=2.74 Hz), 7.44 (1 H, dd, J=9.45, 1.78 Hz), 7.55 (1 H, d, J=9.31 Hz), 7.57 (1 H, s), 7.62 (1 H, d, J=2.46 Hz), 7.95 (1 H, s), 8.69 (1 H, s);ESIMS actual measurement value C 20 H 22 FN7O m / z 396.2 (M+1). [ka]

[0572] 5-(Imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(2-oxaspiro[3.3]heptan-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 74.

[0573] White solid (4.0 mg, 0.011 mmol, 4.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.12 - 2.23 (2 H, m), 2.61 (2 H, ddd, J=9.86, 7.53, 2.87 Hz), 3.95 - 4.04 (1 H, m), 3.97 (3 H, s), 4.51 (2 H, s), 4.63 (2 H, s), 6.58 (1 H, d, J=1.92 Hz), 6.76 (1 H, d, J=2.46 Hz), 7.00 (1 H, d, J=7.12 Hz), 7.10 (1 H, dd, J=7.26, 1.78 Hz), 7.61 (1 H, d, J=2.74 Hz), 7.80 (1 H, s), 7.97 (1H, d, J=1.92 Hz), 8.62 (1H, d, J=7.39 Hz); ESIMS observed value C 20 H 20 N6O2m / z 377.2 (M+1). [ka]

[0574] N-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 80.

[0575] Off-white solid (16 mg, 0.044 mmol, 13.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.95 - 2.04 (2 H, m), 2.86 (1 H, td, J=6.78, 3.15 Hz), 3.81 - 3.88 (4 H, m), 4.00 (3 H, s), 6.39 (1 H, d, J=3.01 Hz), 6.59 (1 H, d, J=1.64 Hz), 6.78 (1 H, d, J=2.74 Hz), 7.11 (1 H, dd, J=7.39, 1.92 Hz), 7.65 (1 H, d, J=2.46 Hz), 7.82 (1 H, d, J=0.82 Hz), 7.97 (1 H, d, J=2.19 Hz), 8.62 (1 H, d, J = 7.12 Hz); ESIMS measured value C 19 H 18 N6O2 m / z 363.2 (M+1). [ka]

[0576] 2-(cis-3-((4-ethoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol 91.

[0577] Off-white solid (4 mg, 0.010 mmol, 4.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.33 (3 H, t, J=7.12 Hz), 1.87 (2 H, qd, J=8.53, 2.87 Hz), 2.58 - 2.68 (2 H, m), 3.30 - 3.33 (2 H, m), 3.48 (2 H, q, J=5.20 Hz), 3.68 - 3.73 (1 H, m), 3.74 - 3.81 (1 H, m), 4.47 (2 H, q, J=7.12 Hz), 4.60 (1 H, t, J=5.48 Hz), 6.57 (1 H, d, J=1.37 Hz), 6.78 (1 H, d, J=2.46 Hz), 6.98 (1 H, d, J...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: 【Chemical 1】 During the ceremony, R １ is 1 to 10 R ４ is heteroaryl optionally substituted with R ２ is an unsubstituted -(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), -(C １－５ alkylene) ｐ OR ５ , -(C １－５ alkylene)CN, 1 to 10 R ６ -(C １－５ alkylene) ｐ heterocyclyl, 1 to 10 R ２６ -(C １－５ alkylene) ｐ aryl, 1 to 10 R ７ -(C １－５ alkylene) ｐ heteroaryl, and 1 to 12 R ８ -(C １－５ alkylene) ｐ carbocyclyl, wherein each —(C １－５ alkylene) independently contains 1 to 5 halide and / or 1 to 3 unsubstituted -(C １－３ alkyl), R ３ is H, unsubstituted -(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), and 1 to 10 R １８ heterocyclyl optionally substituted with Each R ４ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), unsubstituted -(C ２－９ haloalkenyl), -(C １－５ alkylene) ｐ OR ９ , -(C １－５ alkylene) ｐ CN, 1 to 10 R １０ -(C １－５ alkylene) ｐ heterocyclyl, 1 to 12 R １１ -carbocyclyl, 1 to 10 R ２０ -(C １－５ alkylene) ｐ Heteroaryl, -(C １－５ alkylene) ｐ C(=O)N(R １２ ) ２ and -C(=O)R １３ wherein each -(C １－５ alkylene) independently contains 1 to 5 halide and / or 1 to 3 unsubstituted -(C １－３ alkyl), Each R ５ 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 ６ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), 1 to 10 R １６ -heterocyclyl, 1 to 12 R １７ -carbocyclyl, -(C １－５ alkylene) ｐ OR ２１ , -(C １－５ alkylene)CN, -SO ２ R ２３ and -C(=O)R ２４ wherein -(C １－５ alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C １－３ alkyl), Alternatively, two R ６ together form a carbonyl group, Each R ７ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), and -OMe; Each R ８ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), -N(R １４ ) ２ , -(C １－５ alkylene) ｐ OR １５ , -CN, 1 to 10 R １６ -(C １－５ alkylene) ｐ Heterocyclyl, —C(═O)R ２２ , and -NR １４ C(=O)R ２３ wherein each -(C １－５ alkylene) independently contains 1 to 5 halide and / or 1 to 3 unsubstituted -(C １－３ alkyl), Each R ９ 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 １０ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), and unsubstituted -(C １－９ haloalkyl); Each R １１ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), and unsubstituted -(C １－９ haloalkyl); Each R １２ are independently H, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), -(C １－５ alkylene) ｐ OR ２１ , 1 to 12 R １７ -(C １－５ alkylene) ｐ Carbocyclyl, 1 to 10 R １８ -heterocyclyl optionally substituted with, and 1 to 10 R １９ -heteroaryl optionally substituted with -(C １－５ alkylene) is 1 to 5 halide and / or 1 to 3 unsubstituted -(C １－３ alkyl), Each R １３ is 1 to 10 R １８ -heterocyclyl optionally substituted by Each R １４ 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 １５ 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 ２１ is selected from the group consisting of Each R １６ are independently selected from halide, —CN, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), and 1 to 12 R ２７ -carbocyclyl, optionally substituted with Alternatively, two R １６ together form a carbonyl group, Each R １７ are independently selected from halide, —OMe, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), and unsubstituted -(C １－９ haloalkyl); Each R １８ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), and unsubstituted -(C １－９ haloalkyl); Each R １９ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), and unsubstituted -(C １－９ haloalkyl); Each R ２０ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), and unsubstituted -(C １－９ haloalkyl); Each R ２１ 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 ２２ are independently 1 to 10 R １８ -heterocyclyl, -N(R １２ ) ２ , and -OR ２１ is selected from the group consisting of Each R ２３ are independently unsubstituted -(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), -(C １－５ alkylene) ｐ OR ２１ , and 1 to 12 R ２５ -carbocyclyl, optionally substituted with Each R ２４ are independently unsubstituted -(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), -OR ２１ , and 1 to 12 R ２５ -carbocyclyl, optionally substituted with Each R ２５ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), unsubstituted -(C １－９ haloalkyl), and —CN; Each R ２６ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), and unsubstituted -(C １－９ haloalkyl); Each R ２７ are independently selected from halide, unsubstituted —(C １－９ alkyl), unsubstituted -(C ２－９ alkenyl), unsubstituted -(C ２－９ alkynyl), and unsubstituted -(C １－９ haloalkyl); R ２８ is independently selected from the group consisting of H and halides; and each p is independently 0 or 1; wherein each H atom is independently ２ It may be replaced by H(D) (deuterium).

2. R １ but, 1 to 10 R ４ may be substituted with 【Chemistry 2】 2. The compound of claim 1 selected from the group consisting of:

3. R １ but, 1 to 3 R ４ may be substituted with 【Chemistry 3】 The compound according to any one of claims 1 to 2, selected from the group consisting of:

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

6. R １ but, non-replacement 【Chemistry 6】 The compound according to any one of claims 1 to 5, selected from the group consisting of:

7. R ４ is a halide, unsubstituted -(C １－３ alkyl), unsubstituted -(C １－３ haloalkyl), -(C １－３ alkylene)OH, -(C １－３ alkylene)OMe, —CN, and —C(═O)N(R １２ ) ２ The compound according to any one of claims 1 to 5, selected from the group consisting of:

8. R ２ But 1 to 3 R ５ -heterocyclyl optionally substituted with 1 to 3 R ８ -(C １－２ alkylene) ｐ carbocyclyl and one to two R ７ -(C １－２ wherein each —(C １－２ The compound of any one of claims 1 to 7, wherein each of the alkylenes is independently optionally substituted with 1 to 2 halides.

9. R ３ is unsubstituted -(C １－５ alkyl), unsubstituted -(C １－５ haloalkyl), and 1 to 2 R １８ The compound of any one of claims 1 to 8, wherein the heterocyclyl is selected from the group consisting of -heterocyclyl, optionally substituted with:

10. R ３ is unsubstituted -(C １－３ alkyl) and unsubstituted -(C １－３ 10. The compound of any one of claims 1 to 9, selected from the group consisting of: alkyl, alkyl haloalkyl.

11. R ３ The compound according to any one of claims 1 to 10, wherein is methyl.

12. The compound of formula I is (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol[1]; (1r,4r)-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol[2]; (1r,4r)-4-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol[3]; (1s,4s)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol[4]; 1-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-methylpropan-2-ol[5]; 2-(cis-3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol[6]; (1s,3s)-3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [7]; (1r,3r)-3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [8]; 4-Methoxy-N-(cis-4-methoxycyclohexyl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[9]; 4-Methoxy-N-(trans-4-methoxycyclohexyl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[10]; N-(cis-4-(difluoromethoxy)cyclohexyl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[11]; N-(trans-4-(difluoromethoxy)cyclohexyl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[12]; 2-((cis-4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [13]; 2-((trans-4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [14]; 4-Methoxy-N-(cis-4-(2-methoxyethoxy)cyclohexyl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[15]; 4-Methoxy-N-(trans-4-(2-methoxyethoxy)cyclohexyl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[16]; N-(cis-4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [17]; N-(trans-4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [18]; (1s,4s)-4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [19]; (1r,4r)-4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [20]; 1-(3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)azetidin-1-yl)ethan-1-one [21]; N-((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[22]; N-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [23]; N-(1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[24]; N-(1-(2,2-difluoroethyl)piperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[25]; 4-Methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[26]; 1-(4-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [27]; 4-Methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[28]; N-((3S,4R)-3-fluoropiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [29]; N-((3R,4S)-3-fluoropiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [30]; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [31]; N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [32]; N-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [33]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [34]; (S)-5-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [35]; 4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [36]; 1-(6-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)ethan-1-one [37]; 4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)-N-(2-oxaspiro[3.3]heptan-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [38]; 1-(2-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-7-azaspiro[3.5]nonan-7-yl)ethan-1-one [39]; 1-(7-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [40]; 1-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-methylpropan-2-ol [41]; 2-(cis-3-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [42]; (1s,3s)-3-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [43]; (1r,3r)-3-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [44]; 5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(cis-4-methoxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [45]; 5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(trans-4-methoxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [46]; N-(cis-4-(difluoromethoxy)cyclohexyl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [47]; N-(trans-4-(difluoromethoxy)cyclohexyl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [48]; 2-((cis-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [49]; 2-((trans-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [50]; 5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(cis-4-(2-methoxyethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [51]; 5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(trans-4-(2-methoxyethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [52]; N-(cis-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [53]; N-(trans-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [54]; (1s,4s)-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [55]; (1r,4r)-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [56]; 1-(3-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)azetidin-1-yl)ethan-1-one [57]; N-((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [58]; N-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [59]; N-(1-(2-fluoroethyl)piperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [60]; N-(1-(2,2-difluoroethyl)piperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [61]; 5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [62]; 1-(4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [63]; 5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [64]; N-((3S,4R)-3-fluoropiperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [65]; N-((3R,4S)-3-fluoropiperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [66]; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [67]; N-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [68]; N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [69]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [70]; (S)-5-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [71]; 5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [72]; 1-(6-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)ethan-1-one [73]; 5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxy-N-(2-oxaspiro[3.3]heptan-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [74]; 1-(2-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-7-azaspiro[3.5]nonan-7-yl)ethan-1-one [75]; 1-(7-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [76]; 1-((1R,5S,6s)-6-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one [77]; 1-((1R,5S,6r)-6-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one [78]; N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [79]; N-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [80]; 1-((1R,5S,6s)-6-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one [81]; 1-((1R,5S,6r)-6-((5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one [82]; N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [83]; N-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(imidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [84]; N-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [85]; N-((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [86]; (1s,4s)-4-((4-(difluoromethoxy)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [87]; (1r,4r)-4-((4-(difluoromethoxy)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [88]; (1s,4s)-4-((4-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [89]; (1r,4r)-4-((4-(difluoromethoxy)-5-(imidazo[1,2-a]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [90]; 2-(cis-3-((4-ethoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [91]; tert-Butyl 6-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate [92]; (R)-4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)-N-(1-(pyridin-2-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [93]; (1r, 3r)-N １ -(4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine [94]; (1s,3s)-N １ -(4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine [95]; N-((1r,3r)-3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [96]; N-((1s,3s)-3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [97]; tert-Butyl ((1r,3r)-3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)carbamate [98]; 1-(6-((4-ethoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)ethan-1-one [99]; and 5-(2-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide [100] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

13. The compound of formula I is 5-(2-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)pyrazolo[1,5-a]pyridine-3-carboxamide [101]; 5-(2-((2-oxaspiro[3.5]nonan-7-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [102]; 6-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)imidazo[1,2-a]pyridine-3-carbonitrile [103]; 6-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)imidazo[1,2-a]pyridine-3-carboxamide [104]; 6-(2-((4,4-difluorocyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [105]; 6-(2-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [106]; 6-(2-((2-oxaspiro[3.5]nonan-7-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [107]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [108]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,N,1-trimethylcyclobutane-1-carboxamide [109]; Azetidin-1-yl((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)methanone [110]; ((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)(pyrrolidin-1-yl)methanone [111]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [112]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [113]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [114]; 1-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [115]; 1-((3S,4R)-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [116]; (S)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [117]; (R)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [118]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(1-(2-fluoroethyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [119]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-(1-(2,2-difluoroethyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [120]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxy-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [121]; 1-(4-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [122]; N-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [123]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [124]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [125]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [126]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [127]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-1-ethyl-3-fluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [128]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [129]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4R)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [130]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [131]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [132]; N-((3R,4S)-1-cyclopropyl-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [133]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [134]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [135]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [136]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [137]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [138]; (S)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [139]; (R)—N-(1-cyclobutyl-3,3-difluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [140]; (S)—N-(1-cyclobutyl-3,3-difluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [141]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [142]; (S)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [143]; 1-((4s,6r)-6-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-azaspiro[3.3]heptan-1-yl)ethan-1-one [144]; 1-((4r,6s)-6-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-azaspiro[3.3]heptan-1-yl)ethan-1-one [145]; 1-(7-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [146]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxy-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [147]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [148]; N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [149]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [150]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [151]; (S)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [152]; (R)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [153]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [154]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [155]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [156]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [157]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [158]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [159]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [160]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [161]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [162]; (S)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [163]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [164]; (S)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [165]; 1-((4s,6r)-6-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-azaspiro[3.3]heptan-1-yl)ethan-1-one [166]; 1-((4r,6s)-6-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-azaspiro[3.3]heptan-1-yl)ethan-1-one [167]; (1r,4r)-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [168]; (1s,3s)-3-((5-(1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [169]; (1r,3r)-3-((5-(1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [170]; N-((1r,3r)-3-((5-(1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [171]; (1r,4r)-4-((5-(1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [172]; 1-(7-((5-(1-(2-hydroxyethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [173]; 2-(6-(2-((2-oxaspiro[3.5]nonan-7-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)ethan-1-ol [174]; 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [175]; 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [176]; 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [177]; 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [178]; 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [179]; 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((3R,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [180]; 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [181]; 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [182]; (R)-5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [183]; (S)-5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [184]; (R)-5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [185]; (S)-5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [186]; (1r,4r)-4-((5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [187]; 5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-methoxy-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [188]; (1s,3s)-N １ -(5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine [189]; (1r, 3r)-N １ -(5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine [190]; N-((1s,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [191]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [192]; 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(4,4-difluorocyclohexyl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [193]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [194]; 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxy-N-(2-azaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [195]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [196]; tert-Butyl 7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonane-2-carboxylate [197]; 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxy-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [198]; (1s,3s)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [199]; and (1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [200] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

14. The compound of formula I is 2-(cis-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [201]; (1s,3s)-N １ -(4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine [202]; (1r, 3r)-N １ -(4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine [203]; (1s,3s)-N ３ -(4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N １ , N １ , 1-trimethylcyclobutane-1,3-diamine [204]; N-((1s,3s)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [205]; N-((1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [206]; N-((1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)propionamide [207]; 2-Methoxy-N-((1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [208]; (1s,3s)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [209]; (1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [210]; (1s,3s)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,N,1-trimethylcyclobutane-1-carboxamide [211]; (1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,N,1-trimethylcyclobutane-1-carboxamide [212]; (1s,3s)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N-(2-methoxyethyl)-1-methylcyclobutane-1-carboxamide [213]; (1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N-(2-methoxyethyl)-1-methylcyclobutane-1-carboxamide [214]; (1r,3r)-N-(2-fluoroethyl)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [215]; (1r,3r)-N-(2,2-difluoroethyl)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [216]; (1s,3s)-N-cyclopropyl-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [217]; (1r,3r)-N-cyclopropyl-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [218]; (1r,3r)-N-cyclobutyl-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [219]; (1r,3r)-N-(3,3-difluorocyclobutyl)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [220]; (1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methyl-N-(oxetan-3-yl)cyclobutane-1-carboxamide [221]; ((1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)(pyrrolidin-1-yl)methanone [222]; 1-((1r,3r)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)pyrrolidin-2-one [223]; (1s,4s)-4-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [224]; (1s,4s)-4-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclohexane-1-carboxamide [225]; 3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N-methylbicyclo[1.1.1]pentane-1-carboxamide [226]; 1-(2-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-7-azaspiro[3.5]nonan-7-yl)ethan-1-one [227]; 1-((3aR,5r,6aS)-5-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one [228]; 1-(7-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [229]; 4-Methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [230]; (R)-N-(1-cyclopropylethyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [231]; (S)—N-(1-cyclopropylethyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [232]; (R)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(1-phenylethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [233]; (R)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(1-(pyridin-2-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [234]; (S)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(1-(pyridin-2-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [235]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(cis-3-methoxycyclobutyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [236]; N-((1R,2S)-2-fluorocyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [237]; N-((1S,2R)-2-fluorocyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [238]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(cis-4-(trifluoromethyl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [239]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(trans-4-(trifluoromethyl)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [240]; 2-(cis-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)propan-2-ol [241]; 2-(trans-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)propan-2-ol [242]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(cis-4-methoxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [243]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(trans-4-methoxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [244]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(cis-4-(methoxy-d ３ )cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [245]; N-(cis-4-ethoxycyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [246]; N-(trans-4-ethoxycyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [247]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-N-(cis-4-isopropoxycyclohexyl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [248]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-N-(trans-4-isopropoxycyclohexyl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [249]; N-(cis-4-(difluoromethoxy)cyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine[250]; N-(trans-4-(difluoromethoxy)cyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [251]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(cis-4-(trifluoromethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [252]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(trans-4-(trifluoromethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [253]; N-(4,4-difluorocyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [254]; (R)-N-(2,2-difluorocyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [255]; (S)—N-(2,2-difluorocyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [256]; (1r,4r)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [257]; (1r,4r)-1-ethyl-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [258]; 1-(3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)azetidin-1-yl)ethan-1-one [259]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [260]; 2-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol [261]; N-((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [262]; 1-((3S,4R)-3-fluoro-4-((4-hydroxy-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [263]; 1-((3S,4R)-3-fluoro-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [264]; 2-(((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)amino)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol [265]; N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [266]; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [267]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [268]; N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [269]; N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [270]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [271]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(2-oxaspiro[3.3]heptan-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [272]; 1-(7-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [273]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-((4s,7s)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [274]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-((4r,7r)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [275]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [276]; (1s,3s)-3-((4-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [277]; (1r,3r)-3-((4-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [278]; (1s,4s)-4-((4-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [279]; (1r,4r)-4-((4-methoxy-5-(1H-pyrrolo[3,2-b]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [280]; (1s,3s)-3-((4-methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [281]; (1r,4r)-4-((4-methoxy-5-(1H-pyrrolo[3,2-c]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [282]; (1s,3s)-3-((4-methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [283]; (1r,4r)-4-((4-methoxy-5-(1H-pyrrolo[2,3-c]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [284]; (R)-4-Methoxy-N-(1-(pyridin-2-yl)ethyl)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [285]; 2-((1s,3s)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutyl)propan-2-ol [286]; 2-((1r,3r)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutyl)propan-2-ol [287]; N-((1s,3s)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [288]; N-((1s,3s)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-N-methylacetamide [289]; (1r,3r)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,N,1-trimethylcyclobutane-1-carboxamide [290]; Azetidin-1-yl((1r,3r)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)methanone [291]; ((1r,3r)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)(pyrrolidin-1-yl)methanone [292]; (1s,4s)-4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [293]; (1r,4r)-4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [294]; N-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [295]; N-((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [296]; 1-((3R,4S)-3-fluoro-4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [297]; 1-((3S,4R)-3-fluoro-4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [298]; N-((3S,4R)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [299]; and N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [300] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

15. The compound of formula I is (S)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [301]; (R)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [302]; N-(1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [303]; N-(1-(2,2-difluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [304]; 4-Methoxy-5-(quinolin-6-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [305]; N-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [306]; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [307]; N-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [308]; N-((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [309]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [310]; N-((3S,4R)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [311]; N-((3R,4R)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [312]; N-((3S,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [313]; N-((3R,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [314]; N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [315]; N-((3R,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [316]; N-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [317]; N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [318]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [319]; (S)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [320]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [321]; (S)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [322]; 1-((4s,6r)-6-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-azaspiro[3.3]heptan-1-yl)ethan-1-one [323]; 1-((4r,6s)-6-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-azaspiro[3.3]heptan-1-yl)ethan-1-one [324]; 1-(7-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [325]; 4-Methoxy-5-(quinolin-6-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [326]; 2-(cis-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutyl)propan-2-ol [327]; 2-(trans-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutyl)propan-2-ol [328]; 2-(cis-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [329]; (1r,3r)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [330]; (1r,3r)-3-((4-(methoxy-d ３ )-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [331]; (1s,3s)-N １ -(4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-3-methylcyclobutane-1,3-diamine [332]; N-((1s,3s)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [333]; N-((1r,3r)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [334]; N-((1s,3s)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)propionamide [335]; 2-Methoxy-N-((1s,3s)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [336]; tert-butyl((1s,3s)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)carbamate [337]; (1r,3r)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [338]; (1r,3r)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,N,1-trimethylcyclobutane-1-carboxamide [339]; ((1r,3r)-3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)(pyrrolidin-1-yl)methanone [340]; 2-(cis-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)propan-2-ol [341]; 2-(trans-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)propan-2-ol [342]; 2-((cis-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [343]; N-(trans-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [344]; (1s,4s)-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [345]; 2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol [346]; (1r,4r)-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [347]; (1r,4r)-4-((4-(methoxy-d ３ )-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [348]; (1r,4r)-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-(trifluoromethyl)cyclohexan-1-ol [349]; N-((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [350]; N-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [351]; 1-((3S,4R)-3-fluoro-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [352]; 1-((3S,4R)-3-fluoro-4-((4-(methoxy-d ３ )-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [353]; 1-((3R,4S)-3-fluoro-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [354]; N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [355]; N-((3S,4R)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [356]; (R)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [357]; (S)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [358]; (R)—N-(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [359]; (S)—N-(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [360]; N-(1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [361]; N-(1-(2,2-difluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [362]; 4-Methoxy-5-(quinoxalin-6-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [363]; N-(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [364]; 4-Methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [365]; 4-Methoxy-5-(quinoxalin-6-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [366]; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [367]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [368]; N-((3S,4R)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [369]; N-((3R,4R)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [370]; N-((3S,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [371]; N-((3R,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [372]; N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [373]; N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [374]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [375]; (S)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [376]; (R)—N-(1-cyclobutyl-3,3-difluoropiperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [377]; (S)—N-(1-cyclobutyl-3,3-difluoropiperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [378]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [379]; (S)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [380]; N １ -(4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)bicyclo[1.1.1]pentane-1,3-diamine [381]; N-(3-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[1.1.1]pentan-1-yl)acetamide [382]; 1-((4s,6r)-6-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-azaspiro[3.3]heptan-1-yl)ethan-1-one [383]; 1-((4r,6s)-6-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-azaspiro[3.3]heptan-1-yl)ethan-1-one [384]; 4-Methoxy-5-(quinoxalin-6-yl)-N-(2-oxaspiro[3.3]heptan-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [385]; 1-(2-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-7-azaspiro[3.5]nonan-7-yl)ethan-1-one [386]; 1-((3aR,5s,6aS)-5-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one [387]; 1-((3aR,5r,6aS)-5-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)ethan-1-one [388]; 1-(7-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [389]; 4-Methoxy-5-(quinoxalin-6-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [390]; (1s,3s)-1-methyl-3-((4-(oxetan-3-yloxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutan-1-ol [391]; (1r,4r)-1-methyl-4-((4-(oxetan-3-yloxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [392]; (S)-4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)-N-(1-(pyridin-2-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [393]; 1-cyano-N-((1s,3s)-3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)cyclopropane-1-carboxamide [394]; 4-Methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [395]; (R)-5-(4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [396]; (S)-5-(4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [397]; 5-(2-(cyclohexylamino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [398]; 5-(4-methoxy-2-(((1s,4s)-4-methoxycyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [399]; and 5-(2-((4,4-dimethylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [400] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

16. The compound of formula I is 5-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [401]; 5-(2-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [402]; 5-(2-(((1r,4r)-4-ethyl-4-hydroxycyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [403]; 5-(4-methoxy-2-(((1s,4s)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [404]; 5-(4-methoxy-2-(((1r,4r)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [405]; 5-(2-(((1s,4s)-4-cyano-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [406]; 5-(2-(((1r,4r)-4-cyano-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [407]; 5-(2-(bicyclo[3.1.0]hexan-3-ylamino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [408]; 5-(2-((4-hydroxybicyclo[2.2.1]heptan-1-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [409]; 5-(4-methoxy-2-(spiro[2.5]octan-6-ylamino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [410]; (R)-5-(6-fluoro-4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [411]; (S)-5-(6-fluoro-4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [412]; 5-(2-(cyclohexylamino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [413]; 5-(6-fluoro-4-methoxy-2-((cis-4-methoxycyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [414]; 5-(2-((4,4-dimethylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [415]; 5-(6-fluoro-2-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [416]; 5-(6-fluoro-2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [417]; 5-(2-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [418]; 5-(2-(((1r,4r)-4-ethyl-4-hydroxycyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [419]; 5-(6-fluoro-4-methoxy-2-(((1s,4s)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [420]; 5-(6-fluoro-4-methoxy-2-(((1r,4r)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [421]; 5-(2-(((1s,4s)-4-cyano-4-methylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [422]; 5-(2-(((1r,4r)-4-cyano-4-methylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [423]; 5-(2-(bicyclo[3.1.0]hexan-3-ylamino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [424]; 5-(6-fluoro-2-((4-hydroxybicyclo[2.2.1]heptan-1-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [425]; 5-(6-fluoro-4-methoxy-2-(spiro[2.5]octan-6-ylamino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [426]; 5-(2-((2-oxaspiro[3.5]nonan-7-yl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide [427]; N-((1s,3s)-3-((5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [428]; N-((1r,3r)-3-((5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [429]; (1s,4s)-4-((5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [430]; (1r,4r)-4-((5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [431]; (1s,4s)-1-ethyl-4-((5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [432]; (1r,4r)-1-ethyl-4-((5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [433]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [434]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(8-fluoroimidazo[1,2-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [435]; (R)-6-(4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [436]; (S)-6-(4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [437]; 6-(2-(cyclohexylamino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [438]; 6-(4-methoxy-2-((cis-4-methoxycyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [439]; 6-(2-((4,4-dimethylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [440]; 6-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [441]; 6-(2-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [442]; 6-(2-(((1r,4r)-4-ethyl-4-hydroxycyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [443]; 6-(4-methoxy-2-(((1s,4s)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [444]; 6-(4-methoxy-2-(((1r,4r)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [445]; 6-(2-(((1s,4s)-4-cyano-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [446]; 6-(2-(((1r,4r)-4-cyano-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [447]; 6-(2-(bicyclo[3.1.0]hexan-3-ylamino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [448]; 6-(2-((4-hydroxybicyclo[2.2.1]heptan-1-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [449]; 6-(4-methoxy-2-(spiro[2.5]octan-6-ylamino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [450]; (R)-8-fluoro-6-(4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [451]; (S)-8-Fluoro-6-(4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [452]; 6-(2-(cyclohexylamino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [453]; 8-fluoro-6-(4-methoxy-2-((cis-4-methoxycyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [454]; 6-(2-((4,4-dimethylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [455]; 8-fluoro-6-(2-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [456]; 8-fluoro-6-(2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [457]; 6-(2-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [458]; 6-(2-(((1r,4r)-4-ethyl-4-hydroxycyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [459]; 8-fluoro-6-(4-methoxy-2-(((1s,4s)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [460]; 8-fluoro-6-(4-methoxy-2-(((1r,4r)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [461]; 6-(2-(((1s,4s)-4-cyano-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [462]; 6-(2-(((1r,4r)-4-cyano-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [463]; 6-(2-(bicyclo[3.1.0]hexan-3-ylamino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [464]; 8-fluoro-6-(2-((4-hydroxybicyclo[2.2.1]heptan-1-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [465]; 8-fluoro-6-(4-methoxy-2-(spiro[2.5]octan-6-ylamino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [466]; 6-(2-((2-oxaspiro[3.5]nonan-7-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [467]; (R)-6-(6-fluoro-4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [468]; (S)-6-(6-fluoro-4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [469]; 6-(2-(cyclohexylamino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [470]; 6-(6-fluoro-4-methoxy-2-((cis-4-methoxycyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [471]; 6-(2-((4,4-dimethylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [472]; 6-(6-fluoro-2-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [473]; 6-(6-fluoro-2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [474]; 6-(2-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [475]; 6-(2-(((1r,4r)-4-ethyl-4-hydroxycyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [476]; 6-(6-fluoro-4-methoxy-2-(((1s,4s)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [477]; 6-(6-fluoro-4-methoxy-2-(((1r,4r)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [478]; 6-(2-(((1s,4s)-4-cyano-4-methylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [479]; 6-(2-(((1r,4r)-4-cyano-4-methylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [480]; 6-(2-(bicyclo[3.1.0]hexan-3-ylamino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [481]; 6-(6-fluoro-2-((4-hydroxybicyclo[2.2.1]heptan-1-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [482]; 6-(6-fluoro-4-methoxy-2-(spiro[2.5]octan-6-ylamino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [483]; 6-(2-((2-oxaspiro[3.5]nonan-7-yl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [484]; (R)-8-fluoro-6-(6-fluoro-4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [485]; (S)-8-Fluoro-6-(6-fluoro-4-methoxy-2-((1-(oxetan-3-yl)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [486]; 6-(2-(cyclohexylamino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [487]; 8-fluoro-6-(6-fluoro-4-methoxy-2-((cis-4-methoxycyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [488]; 6-(2-((4,4-dimethylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [489]; 8-fluoro-6-(6-fluoro-2-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [490]; 8-fluoro-6-(6-fluoro-2-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [491]; 6-(2-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [492]; 6-(2-(((1r,4r)-4-ethyl-4-hydroxycyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [493]; 8-fluoro-6-(6-fluoro-4-methoxy-2-(((1s,4s)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [494]; 8-fluoro-6-(6-fluoro-4-methoxy-2-(((1r,4r)-4-methoxy-4-methylcyclohexyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [495]; 6-(2-(((1s,4s)-4-cyano-4-methylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [496]; 6-(2-(((1r,4r)-4-cyano-4-methylcyclohexyl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [497]; 6-(2-(bicyclo[3.1.0]hexan-3-ylamino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [498]; 8-fluoro-6-(6-fluoro-2-((4-hydroxybicyclo[2.2.1]heptan-1-yl)amino)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [499]; and 8-Fluoro-6-(6-fluoro-4-methoxy-2-(spiro[2.5]octan-6-ylamino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide [500] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

17. The compound of formula I is 6-(2-((2-oxaspiro[3.5]nonan-7-yl)amino)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-8-fluoro-N-methylimidazo[1,2-a]pyridine-3-carboxamide [501]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [502]; (1r,3r)-N-cyclopropyl-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [503]; (1r,3r)-N-(3,3-difluorocyclobutyl)-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [504]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [505]; 5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [506]; 5-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [507]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-(oxetan-3-yloxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [508]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [509]; (1s,3r)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [510]; (1r,3s)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [511]; N-((1s,4s)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [512]; 1-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [513]; 1-((3S,4R)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [514]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [515]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [516]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropyrrolidin-1-yl)ethan-1-one [517]; (R)—N-(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [518]; 2-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-ol [519]; 1-((3S,4R)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [520]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [521]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [522]; 5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [523]; 3-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile [524]; (R)-2-(4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-ol [525]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [526]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [527]; (S)-5-((5-(1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [528]; N-((1s,3s)-3-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [529]; N-((1r,3r)-3-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [530]; (1s,3r)-1-ethyl-3-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutan-1-ol [531]; (1r,3s)-1-ethyl-3-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutan-1-ol [532]; N-((1s,4s)-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [533]; (1s,4s)-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [534]; 1-((3S,4R)-3-fluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [535]; 1-((3R,4S)-3-fluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [536]; N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [537]; N-((3S,4R)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [538]; (R)-1-(3,3-difluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [539]; (R)—N-(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [540]; 5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [541]; 2-((3R,4S)-3-fluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-ol [542]; 1-((3S,4R)-3-fluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [543]; 1-((3R,4S)-3-fluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [544]; N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [545]; N-((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [546]; N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [547]; 3-((3R,4S)-3-fluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile [548]; (R)-2-(3,3-difluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-ol [549]; (R)-1-(3,3-difluoro-4-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [550]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [551]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [552]; (S)-5-((5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [553]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [554]; 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(cis-3-ethoxycyclobutyl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [555]; 2-(cis-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [556]; (1s,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [557]; (1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [558]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide-2,2,2-d ３ [559]; N-((1s,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-N-methylacetamide [560]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-N-methylacetamide [561]; N-((1s,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-1-cyanocyclopropane-1-carboxamide [562]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-1-cyanocyclopropane-1-carboxamide [563]; (1s,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [564]; (1r,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [565]; 2-((cis-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [566]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [567]; (1s,4s)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-carbonitrile [568]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-carbonitrile [569]; (R)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpyrrolidin-2-one [570]; (S)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpyrrolidin-2-one [571]; 1-(4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [572]; 1-(4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidine-1-carbonyl)cyclopropane-1-carbonitrile [573]; 1-((3R,4S)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidine-1-carbonyl)cyclopropane-1-carbonitrile [574]; (R)-5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(3,3-difluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [575]; (R)-5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [576]; (R)-5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(1-ethyl-3,3-difluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [577]; (R)-5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [578]; (R)-1-(4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidine-1-carbonyl)cyclopropane-1-carbonitrile [579]; (R)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [580]; (S)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [581]; 4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [582]; 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(bicyclo[3.1.0]hexan-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [583]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d ３ [584]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [585]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide-2,2,2-d ３ [586]; (1s,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [587]; (1r,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [588]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [589]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [590]; 1-(4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [591]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [592]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d ３ [593]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutyl)acetamide [594]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutyl)acetamide-2,2,2-d ３ [595]; (1s,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-ethylcyclobutan-1-ol [596]; (1r,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-ethylcyclobutan-1-ol [597]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclohexan-1-ol [598]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-ethylcyclohexan-1-ol [599]; and 1-(4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)piperidin-1-yl)ethan-1-one [600] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

18. The compound of formula I is 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [601]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d ３ [602]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [603]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide-2,2,2-d ３ [604]; (1s,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [605]; (1r,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [606]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [607]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [608]; 1-(4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [609]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [610]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d ３ [611]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [612]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide-2,2,2-d ３ [613]; (1s,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [614]; (1r,3s)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [615]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [616]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [617]; 1-(4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [618]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [619]; 1-(7-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(2,2-difluoroethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d ３ [620]; (1r,4r)-4-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(oxetan-3-yloxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [621]; (1r,4r)-4-((4-methoxy-5-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [622]; (S)-4-Methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [623]; N-(cis-3-ethoxycyclobutyl)-4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [624]; 1-cyano-N-((1s,3s)-3-((4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)cyclopropane-1-carboxamide [625]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [626]; (R)—N-(1-ethyl-3,3-difluoropiperidin-4-yl)-4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [627]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [628]; (1r,4r)-4-((6-fluoro-4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [629]; 6-fluoro-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [630]; (1r,4r)-1-methyl-4-((5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-(oxetan-3-yloxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [631]; 2-(cis-3-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [632]; N-((1s,3s)-3-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [633]; N-((1r,3r)-3-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [634]; (1s,3s)-3-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [635]; (1r,3r)-3-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [636]; 2-((cis-4-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [637]; (1s,4s)-4-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [638]; (1r,4r)-4-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [639]; 1-((3R,4S)-3-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [640]; 5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [641]; 5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [642]; 5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [643]; 1-((3R,4S)-4-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [644]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [645]; 5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [646]; 5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [647]; 3-((3R,4S)-4-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile [648]; (R)-1-(4-((5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [649]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [650]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-ethyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [651]; 2-(cis-3-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [652]; N-((1s,3s)-3-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [653]; N-((1r,3r)-3-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [654]; (1s,3s)-3-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [655]; (1r,3r)-3-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [656]; 2-((cis-4-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [657]; (1s,4s)-4-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [658]; (1r,4r)-4-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [659]; 1-((3S,4R)-3-fluoro-4-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [660]; 5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [661]; 5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [662]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [663]; 1-((3R,4S)-3-fluoro-4-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [664]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [665]; N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [666]; N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [667]; 3-((3R,4S)-3-fluoro-4-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile [668]; (R)-1-(3,3-difluoro-4-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [669]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [670]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [671]; (1r,4r)-4-((5-(1-((E)-2-fluorovinyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [672]; (E)-5-((5-(1-(2-fluorovinyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [673]; 2-(cis-3-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [674]; N-((1s,3s)-3-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [675]; N-((1r,3r)-3-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [676]; (1s,3s)-3-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [677]; (1r,3r)-3-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [678]; 2-((cis-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [679]; (1s,4s)-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [680]; (1r,4r)-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [681]; 1-((3S,4R)-3-fluoro-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [682]; 5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [683]; 5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [684]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [685]; 1-((3R,4S)-3-fluoro-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [686]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [687]; N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [688]; N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [689]; 3-((3R,4S)-3-fluoro-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile [690]; (R)-1-(3,3-difluoro-4-((5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [691]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [692]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-isopropyl-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [693]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-(2-fluoro-2-methylpropyl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [694]; 3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2,2-dimethylpropanenitrile [695]; 1-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-methylpropan-2-ol [696]; (R)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [697]; (S)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [698]; 2-(cis-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [699]; and (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [700] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

19. The compound of formula I is (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [701]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [702]; N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [703]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-N-methylacetamide [704]; N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-N-methylacetamide [705]; 1-cyano-N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)cyclopropane-1-carboxamide [706]; 1-cyano-N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)cyclopropane-1-carboxamide [707]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carbonitrile [708]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carbonitrile [709]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [710]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [711]; (1s,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [712]; (1r,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclobutan-1-ol [713]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-(trifluoromethyl)cyclobutan-1-ol [714]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-(trifluoromethyl)cyclobutan-1-ol [715]; 2-(trans-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)propan-2-ol [716]; N-(cis-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [717]; cis-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [718]; trans-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [719]; 2-((cis-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [720]; 4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-carbonitrile [721]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-carbonitrile [722]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-carbonitrile [723]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [724]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [725]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [726]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [727]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-(trifluoromethyl)cyclohexan-1-ol [728]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-(trifluoromethyl)cyclohexan-1-ol [729]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [730]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [731]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-1-ethyl-4-fluoropyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [732]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3S,4R)-1-ethyl-4-fluoropyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [733]; 1-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [734]; 1-((3S,4R)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [735]; 1-((3S,4R)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one-2,2,2-d ３ [736]; 1-((3S,4R)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)propan-1-one [737]; N-((3S,4R)-1-cyclopropyl-4-fluoropyrrolidin-3-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [738]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [739]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3S,4R)-4-fluoro-1-(3-methyloxetan-3-yl)pyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [740]; 3-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)oxetane-3-carbonitrile [741]; (R)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [742]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropyrrolidin-1-yl)ethan-1-one [743]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropyrrolidin-1-yl)ethan-1-one-2,2,2-d ３ [744]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropyrrolidin-1-yl)propan-1-one [745]; (R)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpyrrolidin-2-one [746]; (S)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpyrrolidin-2-one [747]; 2-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-ol [748]; 3-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)-2,2-dimethylpropanenitrile [749]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [750]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [751]; 3-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile [752]; 1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidine-1-carbonyl)cyclopropane-1-carbonitrile [753]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [754]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-1-ethyl-3-fluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [755]; 2-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-ol [756]; 3-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)-2,2-dimethylpropanenitrile [757]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)-2-methylpropan-2-ol [758]; N-((3R,4S)-1-cyclopropyl-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [759]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [760]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [761]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [762]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [763]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [764]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-1-(3-ethyloxetan-3-yl)-3-fluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [765]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-1-(3-ethynyloxetan-3-yl)-3-fluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [766]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(3-isopropyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [767]; N-((3R,4S)-1-(3-cyclopropyloxetan-3-yl)-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [768]; 3-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile [769]; 1-((3S,4R)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [770]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [771]; 1-((3S,4R)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)propan-1-one [772]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)propan-1-one [773]; 1-((3S,4R)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one-2,2,2-d ３ [774]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one-2,2,2-d ３ [775]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidine-1-carbonyl)cyclopropane-1-carbonitrile [776]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [777]; (R)—N-(3,3-difluoro-1-(methyl-d ２ )piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [778]; (R)—N-(3,3-difluoro-1-(methyl-d ３ )piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [779]; (R)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-(1-ethyl-3,3-difluoropiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [780]; (R)-2-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-ol [781]; (R)-3-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-2,2-dimethylpropanenitrile [782]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-2-methylpropan-2-ol [783]; (R)—N-(1-cyclopropyl-3,3-difluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [784]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [785]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [786]; (R)-3-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)oxetane-3-carbonitrile [787]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [788]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one-2,2,2-d ３ [789]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)propan-1-one [790]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidine-1-carbonyl)cyclopropane-1-carbonitrile [791]; (S)-1-(5-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [792]; 5-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [793]; (S)-5-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [794]; (R)-5-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [795]; (R)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [796]; (S)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [797]; 4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [798]; 1-(7-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [799]; and 1-(7-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d ３ [800] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

20. The compound of formula I is 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [801]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-((4r,7r)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [802]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-((4s,7s)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [803]; 2-(cis-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [804]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [805]; N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [806]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [807]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [808]; 2-((cis-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [809]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [810]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [811]; 1-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [812]; 5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [813]; 5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [814]; 5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [815]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [816]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [817]; 5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [818]; 5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [819]; 3-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile [820]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [821]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [822]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [823]; 2-(cis-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)cyclobutoxy)ethan-1-ol [824]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutyl)acetamide [825]; N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutyl)acetamide [826]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutan-1-ol [827]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutan-1-ol [828]; 2-((cis-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)cyclohexyl)oxy)ethan-1-ol [829]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclohexan-1-ol [830]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclohexan-1-ol [831]; 1-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [832]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [833]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [834]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [835]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-3-fluoropiperidin-1-yl)ethan-1-one [836]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [837]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [838]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [839]; 3-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile [840]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [841]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [842]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [843]; 2-(cis-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [844]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [845]; N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [846]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [847]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [848]; 2-((cis-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [849]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [850]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [851]; 1-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [852]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [853]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [854]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [855]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [856]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [857]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [858]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [859]; 3-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile [860]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [861]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [862]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [863]; 2-(cis-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)cyclobutoxy)ethan-1-ol [864]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutyl)acetamide [865]; N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutyl)acetamide [866]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutan-1-ol [867]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclobutan-1-ol [868]; 2-((cis-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)cyclohexyl)oxy)ethan-1-ol [869]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclohexan-1-ol [870]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclohexan-1-ol [871]; 1-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [872]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [873]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [874]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [875]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-3-fluoropiperidin-1-yl)ethan-1-one [876]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [877]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [878]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [879]; 3-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile [880]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [881]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [882]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [883]; 2-(cis-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [884]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [885]; N-((1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [886]; (1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [887]; (1r,3r)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [888]; 2-((cis-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [889]; (1s,4s)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [890]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [891]; 1-((3R,4S)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one [892]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ )-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [893]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ )-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [894]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-amine [895]; 1-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [896]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-amine [897]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-amine [898]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-amine [899]; and 3-((3R,4S)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile [900] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

21. The compound of formula I is (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [901]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-amine [902]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-amine [903]; 2-(cis-3-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol [904]; N-((1s,3s)-3-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [905]; N-((1r,3r)-3-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [906]; (1s,3s)-3-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [907]; (1r,3r)-3-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol [908]; 2-((cis-4-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol [909]; (1s,4s)-4-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [910]; (1r,4r)-4-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [911]; 1-((3S,4R)-3-fluoro-4-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)pyrrolidin-1-yl)ethan-1-one [912]; 4-Methoxy-N-(1-(oxetan-3-yl)piperidin-4-yl)-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [913]; 4-Methoxy-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [914]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [915]; 1-((3R,4S)-3-fluoro-4-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [916]; N-((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [917]; N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [918]; N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [919]; 3-((3R,4S)-3-fluoro-4-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile [920]; (R)-1-(3,3-difluoro-4-((4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [921]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [922]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [923]; N-(2-fluoro-2-methylpropyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [924]; (R)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(1,1,1-trifluoropropan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [925]; (R)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(4-methoxybutan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [926]; (R)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [927]; (S)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(1-(oxetan-3-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [928]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-((1R,2S)-2-methoxycyclobutyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [929]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-((1R,2R)-2-methoxycyclobutyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [930]; N-(cis-3-ethoxycyclobutyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [931]; (1s,3s)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [932]; (1r,3r)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [933]; N-((1s,3s)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [934]; N-((1r,3r)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [935]; N-((1s,3s)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-N-methylacetamide [936]; N-((1r,3r)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)-N-methylacetamide [937]; 1-cyano-N-((1s,3s)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)cyclopropane-1-carboxamide [938]; 1-cyano-N-((1r,3r)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)cyclopropane-1-carboxamide [939]; (1s,3r)-1-ethyl-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutan-1-ol [940]; (1r,3s)-1-ethyl-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutan-1-ol [941]; (1S,2R)-2-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclopentan-1-ol [942]; (R)-N-(3,3-difluorocyclopentyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [943]; N-cyclohexyl-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [944]; 2-(trans-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)propan-2-ol [945]; N-(cis-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [946]; N-(4,4-dimethylcyclohexyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [947]; 4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-carbonitrile [948]; (1s,4s)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-carbonitrile [949]; (1r,4r)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-carbonitrile [950]; (1s,4s)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [951]; (1s,4s)-1-ethyl-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [952]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-((1s,4s)-4-methoxy-4-methylcyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [953]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-((1r,4r)-4-methoxy-4-methylcyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [954]; (R)—N-(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [955]; (R)-N-(1-ethyl-4,4-difluoropyrrolidin-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [956]; (R)—N-(1-cyclopropyl-4,4-difluoropyrrolidin-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [957]; (R)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpyrrolidin-2-one [958]; (S)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpyrrolidin-2-one [959]; 1-(4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [960]; 1-(4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidine-1-carbonyl)cyclopropane-1-carbonitrile [961]; 1-((3R,4S)-3-fluoro-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [962]; 1-((3R,4S)-3-fluoro-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidine-1-carbonyl)cyclopropane-1-carbonitrile [963]; (R)—N-(3,3-difluoropiperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [964]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [965]; (R)—N-(1-ethyl-3,3-difluoropiperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [966]; (R)—N-(1-cyclopropyl-3,3-difluoropiperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [967]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [968]; (R)-1-(3,3-difluoro-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [969]; (R)-1-(3,3-difluoro-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidine-1-carbonyl)cyclopropane-1-carbonitrile [970]; (S)-5-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [971]; (R)-5-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [972]; (R)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [973]; (S)-3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [974]; (R)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [975]; N-(bicyclo[3.1.0]hexan-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [976]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(spiro[2.5]octan-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [977]; 4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [978]; 1-(7-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d ３ [979]; Cyclopropyl(7-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)methanone [980]; (1-Fluorocyclopropyl)(7-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)methanone [981]; 2-(trans-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)cyclohexyl)propan-2-ol [982]; (1s,4s)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclohexan-1-ol [983]; (1r,4r)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-1-methylcyclohexan-1-ol [984]; (1s,4s)-1-ethyl-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)cyclohexan-1-ol [985]; (1r,4r)-1-ethyl-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)cyclohexan-1-ol [986]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [987]; 1-(7-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl-7-d)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [988]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [989]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-((4r,7r)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [990]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-((4s,7s)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-7-d-2-amine [991]; N-((1s,3s)-3-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [992]; N-((1r,3r)-3-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [993]; 2-(trans-4-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)propan-2-ol [994]; (1s,4s)-4-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [995]; (1r,4r)-4-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [996]; (1s,4s)-1-ethyl-4-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [997]; (1r,4r)-1-ethyl-4-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [998]; 6-fluoro-N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [999]; and 1-(4-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1000] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

22. The compound of formula I is 6-fluoro-N-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1001]; 6-fluoro-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1002]; 6-fluoro-N-((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1003]; 6-fluoro-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1004]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1005]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1006]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1007]; 1-(7-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [1008]; 1-(7-((6-fluoro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d ３ [1009]; 2-(trans-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)propan-2-ol [1010]; (1s,4s)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1011]; (1r,4r)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1012]; (1s,4s)-1-ethyl-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1013]; (1r,4r)-1-ethyl-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1014]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-amine [1015]; 1-(7-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ ) pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [1016]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ )-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1017]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ )-N-((4r,7r)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1018]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d ３ )-N-((4s,7s)-1-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1019]; (1s,4s)-4-((4-(difluoromethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1020]; (1r,4r)-4-((4-(difluoromethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1021]; (1s,4s)-4-((4-(difluoromethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [1022]; (1r,4r)-4-((4-(difluoromethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [1023]; 1-(7-((4-(difluoromethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [1024]; 4-(difluoromethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[1025]; (1s,4s)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1026]; (1r,4r)-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1027]; (1s,4s)-1-ethyl-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1028]; (1r,4r)-1-ethyl-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1029]; 1-(7-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [1030]; 5-(imidazo[1,2-a]pyrimidin-6-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1031]; (1s,4s)-4-((4-(2,2-difluoroethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1032]; (1r,4r)-4-((4-(2,2-difluoroethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1033]; (1s,4s)-4-((4-(2,2-difluoroethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [1034]; (1r,4r)-4-((4-(2,2-difluoroethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-ethylcyclohexan-1-ol [1035]; 1-(7-((4-(2,2-difluoroethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one [1036]; 4-(2,2-difluoroethoxy)-5-(imidazo[1,2-a]pyrimidin-6-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1037]; (1r,3r)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-N,1-dimethylcyclobutane-1-carboxamide [1038]; (1r,3r)-N-cyclopropyl-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [1039]; (1r,3r)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methyl-N-(1-methylcyclobutyl)cyclobutane-1-carboxamide [1040]; (1r,3r)-N-(3,3-difluorocyclobutyl)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutane-1-carboxamide [1041]; (1r,3r)-3-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methyl-N-(3-methyloxetan-3-yl)cyclobutane-1-carboxamide [1042]; (1s,3s)-N ３ -(4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N １ , N １ , 1-trimethylcyclobutane-1,3-diamine [1043]; N-(cis-4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1044]; 1-((3R,4S)-3-fluoro-4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol [1045]; N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1046]; 1-((3R,4S)-3-fluoro-4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1047]; (R)-1-(3,3-difluoro-4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1048]; (R)-5-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [1049]; (R)-4-Methoxy-5-(quinolin-6-yl)-N-(tetrahydro-2H-pyran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1050]; 4-((4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [1051]; N-((1s,3s)-3-((6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [1052]; N-((1r,3r)-3-((6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [1053]; N-(cis-4-((6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1054]; (1s,4s)-4-((6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1055]; (1r,4r)-4-((6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1056]; 6-fluoro-N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1057]; 1-((3R,4S)-3-fluoro-4-((6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol [1058]; 6-fluoro-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1059]; 6-fluoro-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1060]; 1-((3R,4S)-3-fluoro-4-((6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1061]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1062]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1063]; (R)-1-(3,3-difluoro-4-((6-fluoro-4-methoxy-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1064]; N-(cis-4-((4-(difluoromethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1065]; (1s,4s)-4-((4-(difluoromethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1066]; (1r,4r)-4-((4-(difluoromethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1067]; 1-((3R,4S)-4-((4-(difluoromethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)-2-methylpropan-2-ol [1068]; 4-(difluoromethoxy)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1069]; 1-((3R,4S)-4-((4-(difluoromethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [1070]; (R)-1-(4-((4-(difluoromethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [1071]; 4-((4-(difluoromethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [1072]; N-(cis-4-((5-(quinolin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1073]; (1s,4s)-1-methyl-4-((5-(quinolin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1074]; (1r,4r)-1-methyl-4-((5-(quinolin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1075]; 1-((3R,4S)-3-fluoro-4-((5-(quinolin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol [1076]; N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(quinolin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1077]; 1-((3R,4S)-3-fluoro-4-((5-(quinolin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1078]; (R)-1-(3,3-difluoro-4-((5-(quinolin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1079]; 4-((5-(quinolin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [1080]; N-(cis-4-((4-(2,2-difluoroethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1081]; (1s,4s)-4-((4-(2,2-difluoroethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1082]; (1r,4r)-4-((4-(2,2-difluoroethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1083]; 1-((3R,4S)-4-((4-(2,2-difluoroethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)-2-methylpropan-2-ol [1084]; 4-(2,2-difluoroethoxy)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1085]; 1-((3R,4S)-4-((4-(2,2-difluoroethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [1086]; (R)-1-(4-((4-(2,2-difluoroethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [1087]; 4-((4-(2,2-difluoroethoxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [1088]; (1r,4r)-1-methyl-4-((4-(oxetan-3-yloxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1089]; N-((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-4-(oxetan-3-yloxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1090]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-(oxetan-3-yloxy)-5-(quinolin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1091]; N-(cis-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1092]; (3S,4R)-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)tetrahydrofuran-3-ol [1093]; 1-((3R,4S)-3-fluoro-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol [1094]; (R)—N-(1-ethyl-3,3-difluoropiperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1095]; (R)-1-(3,3-difluoro-4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1096]; (R)-5-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylpiperidin-2-one [1097]; 4-((4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [1098]; N-((4s,6r)-1-(2,2-difluoroethyl)-1-azaspiro[3.3]heptan-6-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1099]; and 4-Methoxy-5-(quinoxalin-6-yl)-N-(7-oxaspiro[3.5]nonan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1100] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

23. The compound of formula I is N-((1s,3s)-3-((6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [1101]; N-((1r,3r)-3-((6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide [1102]; N-(cis-4-((6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1103]; (1s,4s)-4-((6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1104]; 1-((3R,4S)-3-fluoro-4-((6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol [1105]; 6-fluoro-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1106]; 6-fluoro-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1107]; 1-((3R,4S)-3-fluoro-4-((6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1108]; (R)—N-(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1109]; (R)—N-(3,3-difluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine[1110]; (R)-1-(3,3-difluoro-4-((6-fluoro-4-methoxy-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1111]; N-(cis-4-((4-(difluoromethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1112]; (1s,4s)-4-((4-(difluoromethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1113]; (1r,4r)-4-((4-(difluoromethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1114]; 1-((3R,4S)-4-((4-(difluoromethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)-2-methylpropan-2-ol [1115]; 4-(difluoromethoxy)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1116]; 1-((3R,4S)-4-((4-(difluoromethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [1117]; (R)-1-(4-((4-(difluoromethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [1118]; 4-((4-(difluoromethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [1119]; N-(cis-4-((5-(quinoxalin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1120]; (1s,4s)-1-methyl-4-((5-(quinoxalin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1121]; (1r,4r)-1-methyl-4-((5-(quinoxalin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol [1122]; 1-((3R,4S)-3-fluoro-4-((5-(quinoxalin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol [1123]; N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(quinoxalin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1124]; 1-((3R,4S)-3-fluoro-4-((5-(quinoxalin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1125]; (R)-1-(3,3-difluoro-4-((5-(quinoxalin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one [1126]; 4-((5-(quinoxalin-6-yl)-4-(trifluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [1127]; N-(cis-4-((4-(2,2-difluoroethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide [1128]; (1s,4s)-4-((4-(2,2-difluoroethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1129]; (1r,4r)-4-((4-(2,2-difluoroethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1130]; 1-((3R,4S)-4-((4-(2,2-difluoroethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)-2-methylpropan-2-ol [1131]; 4-(2,2-difluoroethoxy)-N-((3R,4S)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1132]; 1-((3R,4S)-4-((4-(2,2-difluoroethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one [1133]; (R)-1-(4-((4-(2,2-difluoroethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [1134]; 4-((4-(2,2-difluoroethoxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)bicyclo[2.2.1]heptan-1-ol [1135]; (R)—N-(3,3-difluoro-1-methylpiperidin-4-yl)-4-(oxetan-3-yloxy)-5-(quinoxalin-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1136]; 4-(oxetan-3-yloxy)-5-(quinoxalin-6-yl)-N-(7-oxaspiro[3.5]nonan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1137]; 4-(oxetan-3-yloxy)-5-(quinoxalin-6-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1138]; (1r,4r)-4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol [1139]; (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one [1140]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d]imidazol-6-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1141]; N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1142]; 1-((3R,4S)-3-fluoro-4-((5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)propan-1-one [1143]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxy-N-((3-methyloxetan-3-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1144]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1145]; 3-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2,2-dimethylpropanenitrile [1146]; (R)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxy-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1147]; N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1148]; N-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1149]; N-(8-oxabicyclo[3.2.1]octan-3-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine[1150]; N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1151]; 5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-N-((3S,4R)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine [1152]; N-((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-4-methoxy-5-(1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine [1153] 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

24. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. 26. 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, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24.

26. 26. The method of claim 25, wherein the disease or disorder is cancer.

27. 26. The method of claim 25, wherein the disease or disorder is diabetes.

28. 26. The method of claim 25, wherein the disease or disorder is a neurological disorder.

29. 27. The method of any one of claims 25 to 26, 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.

30. the disorder or disease is a neurological disorder, the neurological disorder being Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency, Down's syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, and additional diseases with significant neurodegeneration, such as autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; diseases and disorders associated with acquired brain injury; The method of any one of claims 25 and 28, wherein the disease 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.

31. 31. The method of any one of claims 25, 28, and 30, wherein the disorder or disease is Alzheimer's disease.

32. The method of any one of claims 25 to 31, wherein the patient is a human.

Images