4-alkoxy pyrrolo [2, 1-f] [1, 2, 4] triazines and their preparation and use

Abstract

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

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 355,076, filed on June 23, 2022, U.S. Provisional Application No. 63 / 427,322, filed on November 22, 2022, and U.S. Provisional Application No. 63 / 458,808, filed on April 12, 2023, which are incorporated herein by reference in their entireties. Background Art Technical Field

[0003] The present disclosure relates to dual-specific tyrosine phosphorylation-regulated inhibitors of 1A kinase and compositions comprising the same. More particularly, the present disclosure relates to the use of 4-alkoxypyrrolo[2,1-f][1,2,4]triazine compounds or salts or analogs thereof for treating conditions characterized by aberrant DYRK1A expression and / or activity (e.g., cancer, Down syndrome, Alzheimer's disease, diabetes, viral infections, and osteoarthritis). Background Art

[0005] Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) are a family of protein kinases within the CMGC group of the eukaryotic kinome. These protein kinases are involved in a variety of cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine / methionine / folate regulation, thermoregulation, endocrine function, neuronal development, synaptic plasticity, and the like. Aberrant expression and / or activity of some of these kinases, particularly DYRK1A, can be found in many human neurological diseases, such as cognitive deficits associated with Down syndrome, Alzheimer's disease and related disorders, tauopathies, dementia, Pick's disease, Parkinson's disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency. DYRKs are also involved in diabetes, abnormal folate / methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast cancer, and pancreatic cancer) and leukemias (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). DYRK1A has also been identified as a key stabilizer of EGFR (Cell Death & Disease (2019), 10, 282), which is a key factor in promoting keratinization, cell hyperproliferation, abnormal differentiation, and inflammatory infiltration during the progression of psoriasis. Summary of the Invention

[0006] The present disclosure provides methods and reagents, the methods comprising contacting cells with an agent, such as a 4-alkoxypyrrolo[2,1-f][1,2,4]triazine compound, in an amount sufficient to antagonize DYRK1A activity, such as to reduce the spread of head and neck squamous cell carcinoma, luminal / HER2 breast cancer (Cell (2016), 164(1-2), 293-309), or pancreatic adenocarcinoma, and to attenuate the self-renewal capacity of glioblastoma and disrupt the viability of ovarian cancer spheroid cells (Molecular Cancer Research (2017), 15(4), 371-381).

[0007] The present disclosure also provides methods and reagents, the methods involving contacting cells with an agent, e.g., a 4-alkoxypyrrolo[2,1-f][1,2,4]triazine compound, in an amount sufficient to antagonize DYRK1A activity, e.g., i) normalize prenatal and early postnatal brain development; ii) improve cognitive function in adolescents and adults; and / or iii) attenuate Alzheimer's type neurodegeneration.

[0008] 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.

[0009] One embodiment disclosed herein includes a compound having the structure of Formula I:

[0010]

[0011] or a pharmaceutically acceptable salt thereof,

[0012] in,

[0013] R 1 is optionally replaced by 1 to 10 R 4 substituted heteroaryl;

[0014] R 2 Selected from the group consisting of: 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 , optionally 1 to 10 R 6 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 10 R 7 substituted-heteroaryl and optionally substituted by 1 to 12 R 8 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0015] R 3 Selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0016] Each R 4 are independently selected from the group consisting of halogen, 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, optionally substituted by 1 to 10 R 10 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 12 R 11 Substituted-carbocyclyl, optionally substituted by 1 to 10 R 20 Substituted-(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0017] Each R 5 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0018] Each R 6 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1 to 10 R 16 Substituted-heterocyclyl, -(C 1-5 alkylene) p OR 21 、-SO2R23 and -C(=O)R 24 wherein said-(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0019] Alternatively, two R attached to the same carbon atom 6 Together they form a carbonyl group;

[0020] Each R 7 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and -OMe;

[0021] Each R 8 are independently selected from the group consisting of halogen, 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 , optionally 1 to 10 R 16 Substituted-(C 1-5 alkylene) p Heterocyclic group, -C(=O)R 22 and -NHC(=O)R 23 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0022] Each R 9 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0023] Each R 10 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0024] Each R 11 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0025] Each R 12 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1 to 12 R 17 Substituted-(C 1-5 alkylene) p Carbocyclyl, optionally substituted by 1 to 10 R 18 substituted-heterocyclyl and optionally substituted by 1 to 10 R 19 Substituted-heteroaryl, wherein the -(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0026] Each R 13 is optionally replaced by 1 to 10 R 18 substituted-heterocyclyl;

[0027] Each R 14 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0028] Each R 15 are independently selected from the group consisting of: 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 OR21 ;

[0029] Each R 16 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0030] Each R 17 are independently selected from the group consisting of halogen, -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0031] Each R 18 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0032] Each R 19 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0033] Each R 20 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0034] Each R 21 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0035] Each R 22 independently selected from the group consisting of: optionally 1 to 10 R 18 Substituted-heterocyclyl, -N(R 12 )2 and -OR 21 ;

[0036] Each R 23 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0037] Each R 24 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -OR 23 and optionally 1 to 12 R 25 substituted-carbocyclyl;

[0038] Each R 25 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl); and

[0039] Each p is independently 0 or 1;

[0040] wherein each H atom is optionally independently 2 H(D) (deuterium) instead.

[0041] In another embodiment disclosed herein, a compound having the structure of Formula I is included:

[0042]

[0043] or a pharmaceutically acceptable salt thereof,

[0044] in,

[0045] R 1 is optionally replaced by 1 to 10 R 4 substituted heteroaryl;

[0046] R 2Selected from the group consisting of: 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 , optionally 1 to 10 R 6 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 10 R 26 Substituted-(C 1-5 alkylene) p Aryl, optionally substituted with 1 to 10 R 7 Substituted-(C 1-5 alkylene) p heteroaryl and optionally substituted by 1 to 12 R 8 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0047] R 3 Selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and optionally substituted by 1 to 10 R 18 substituted heterocyclic groups;

[0048] Each R 4 are independently selected from the group consisting of halogen, 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, optionally with 1 to 10 R 10 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 12 R 11Substituted-carbocyclyl, optionally substituted by 1 to 10 R 20 Substituted-(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0049] Each R 5 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0050] Each R 6 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1 to 10 R 16 Substituted-heterocyclyl, optionally substituted by 1 to 12 R 17 Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 21 、-SO2R 23 and -C(=O)R 24 wherein said-(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0051] Alternatively, two R attached to the same carbon atom 6 Together they form a carbonyl group;

[0052] Each R 7 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and -OMe;

[0053] Each R 8 are independently selected from the group consisting of halogen, 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 , optionally 1 to 10 R 16 Substituted-(C 1-5 alkylene) p Heterocyclic group, -C(=O)R 22 and -NHC(=O)R 23 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0054] Each R 9 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0055] Each R 10 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0056] Each R 11 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0057] Each R 12 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9Alkynyl), unsubstituted-(C 1-9 haloalkyl), -(C 1-5 alkylene) p OR 21 , optionally 1 to 12 R 17 Substituted-(C 1-5 alkylene) p Carbocyclyl, optionally substituted by 1 to 10 R 18 substituted-heterocyclyl and optionally substituted by 1 to 10 R 19 Substituted-heteroaryl, wherein the -(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0058] Each R 13 is optionally replaced by 1 to 10 R 18 substituted-heterocyclyl;

[0059] Each R 14 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0060] Each R 15 are independently selected from the group consisting of: 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 ;

[0061] Each R 16 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0062] Alternatively, two R attached to the same carbon atom 16 Together they form a carbonyl group;

[0063] Each R 17are independently selected from the group consisting of halogen, -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0064] Each R 18 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0065] Each R 19 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0066] Each R 20 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0067] Each R 21 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0068] Each R 22 independently selected from the group consisting of: optionally 1 to 10 R 18 Substituted-heterocyclyl, -N(R 12 )2 and -OR 21 ;

[0069] Each R 23 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and -(C 1-5 alkylene) p OR 21 ;

[0070] Each R 24 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -OR 21 and optionally 1 to 12 R 25 substituted-carbocyclyl;

[0071] Each R 25 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0072] Each R 26 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl); and

[0073] Each p is independently 0 or 1;

[0074] wherein each H atom is optionally independently 2 H(D) (deuterium) instead.

[0075] In another embodiment disclosed herein, a compound having the structure of Formula I is included:

[0076]

[0077] or a pharmaceutically acceptable salt thereof,

[0078] in,

[0079] R 1 is optionally replaced by 1 to 10 R 4 substituted heteroaryl;

[0080] R 2Selected from the group consisting of: 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, optionally substituted by 1 to 10 R 6 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 10 R 26 Substituted-(C 1-5 alkylene) p Aryl, optionally substituted with 1 to 10 R 7 Substituted-(C 1-5 alkylene) p heteroaryl and optionally substituted by 1 to 12 R 8 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0081] R 3 Selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and optionally substituted by 1 to 10 R 18 substituted heterocyclic groups;

[0082] Each R 4 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), unsubstituted-(C 2-9 Halogenated alkenyl), -(C 1-5 alkylene) p OR 9 、-(C 1-5 alkylene) p CN, optionally with 1 to 10 R 10 Substituted-(C1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 12 R 11 Substituted-carbocyclyl, optionally substituted by 1 to 10 R 20 Substituted-(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0083] Each R 5 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0084] Each R 6 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1 to 10 R 16 Substituted-heterocyclyl, optionally substituted by 1 to 12 R 17 Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 21 、-(C 1-5 Alkylene)CN, -SO2R 23 and -C(=O)R 24 wherein said-(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0085] Alternatively, two R attached to the same carbon atom 6 Together they form a carbonyl group;

[0086] Each R 7 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and -OMe;

[0087] Each R 8 are independently selected from the group consisting of halogen, 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, optionally with 1 to 10 R 16 Substituted-(C 1-5 alkylene) p Heterocyclic group, -C(=O)R 22 and -NR 14 C(=O)R 23 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0088] Each R 9 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0089] Each R 10 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0090] Each R 11 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0091] Each R12 are independently selected from the group consisting of: 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 , optionally 1 to 12 R 17 Substituted-(C 1-5 alkylene) p Carbocyclyl, optionally substituted by 1 to 10 R 18 substituted-heterocyclyl and optionally substituted by 1 to 10 R 19 Substituted-heteroaryl, wherein the -(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0092] Each R 13 is optionally replaced by 1 to 10 R 18 substituted-heterocyclyl;

[0093] Each R 14 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0094] Each R 15 are independently selected from the group consisting of: 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 ;

[0095] Each R 16 are independently selected from the group consisting of halogen, -CN, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and optionally substituted by 1 to 12 R 27substituted-carbocyclyl;

[0096] Alternatively, two R attached to the same carbon atom 16 Together they form a carbonyl group;

[0097] Each R 17 are independently selected from the group consisting of halogen, -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0098] Each R 18 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0099] Each R 19 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0100] Each R 20 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0101] Each R 21 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0102] Each R 22 independently selected from the group consisting of: optionally 1 to 10 R 18 Substituted-heterocyclyl, -N(R 12 )2 and -OR 21 ;

[0103] Each R 23 Independently selected from the group consisting of: 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 optionally 1 to 12 R 25 substituted-carbocyclyl;

[0104] Each R 24 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -OR 21 and optionally 1 to 12 R 25 substituted-carbocyclyl;

[0105] Each R 25 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and -CN;

[0106] Each R 26 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0107] Each R 27 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0108] R 28 are independently selected from the group consisting of: H and halogen; and

[0109] Each p is independently 0 or 1;

[0110] wherein each H atom is optionally independently 2 H(D) (deuterium) instead.

[0111] In another embodiment disclosed herein, a compound having the structure of Formula I is included:

[0112]

[0113] or a pharmaceutically acceptable salt thereof,

[0114] in,

[0115] R 1 is optionally replaced by 1 to 10 R 4 substituted heteroaryl;

[0116] R 2 Selected from the group consisting of: 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, optionally substituted by 1 to 10 R 6 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 10 R 26 Substituted-(C 1-5 alkylene) p Aryl, optionally substituted with 1 to 10 R 7 Substituted-(C 1-5 alkylene) p heteroaryl and optionally substituted by 1 to 12 R 8 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0117] R 3 Selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C1-9 haloalkyl) and optionally substituted by 1 to 10 R 18 substituted heterocyclic groups;

[0118] Each R 4 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), unsubstituted-(C 2-9 Halogenated alkenyl), -(C 1-5 alkylene) p OR 9 、-(C 1-5 alkylene) p CN, optionally with 1 to 10 R 10 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 12 R 11 Substituted-carbocyclyl, optionally substituted by 1 to 10 R 20 Substituted-(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0119] Each R 5 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0120] Each R 6 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1 to 10 R 16 Substituted-heterocyclyl, optionally substituted by 1 to 12 R 17Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 21 、-(C 1-5 Alkylene)CN, -SO2R 23 and -C(=O)R 24 wherein said-(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0121] Alternatively, two R attached to the same carbon atom 6 Together they form a carbonyl group;

[0122] Each R 7 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and -OMe;

[0123] Each R 8 are independently selected from the group consisting of halogen, 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, optionally with 1 to 10 R 16 Substituted-(C 1-5 alkylene) p Heterocyclic group, -C(=O)R 22 and -NR 14 C(=O)R 23 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0124] Each R 9 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0125] Each R 10 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0126] Each R 11 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0127] Each R 12 are independently selected from the group consisting of: 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 , optionally 1 to 12 R 17 Substituted-(C 1-5 alkylene) p Carbocyclyl, optionally substituted by 1 to 10 R 18 substituted-heterocyclyl and optionally substituted by 1 to 10 R 19 Substituted-heteroaryl, wherein the -(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted;

[0128] Each R 13 is optionally replaced by 1 to 10 R 18 substituted-heterocyclyl;

[0129] Each R 14 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0130] Each R 15are independently selected from the group consisting of: 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 ;

[0131] Each R 16 are independently selected from the group consisting of halogen, -CN, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and optionally substituted by 1 to 12 R 27 substituted-carbocyclyl;

[0132] Alternatively, two R attached to the same carbon atom 16 Together they form a carbonyl group;

[0133] Each R 17 are independently selected from the group consisting of halogen, -OMe, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0134] Each R 18 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0135] Each R 19 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0136] Each R 20 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0137] Each R 21 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0138] Each R 22 independently selected from the group consisting of: optionally 1 to 10 R 18 Substituted-heterocyclyl, -N(R 12 )2 and -OR 21 ;

[0139] Each R 23 Independently selected from the group consisting of: 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 optionally 1 to 12 R 25 substituted-carbocyclyl;

[0140] Each R 24 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -OR 21 and optionally 1 to 12 R 25 substituted-carbocyclyl;

[0141] Each R 25 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and -CN;

[0142] Each R 26are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0143] Each R 27 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0144] R 28a independently selected from the group consisting of: H and halogen;

[0145] R 28b independently selected from the group consisting of: H and D; and

[0146] Each p is independently 0 or 1;

[0147] wherein each H atom is optionally independently 2 H(D) (deuterium) instead.

[0148] Some embodiments include stereoisomers and pharmaceutically acceptable salts of compounds of Formula I. Some embodiments include pharmaceutically acceptable salts of compounds of Formula I.

[0149] Some embodiments include prodrugs of compounds of Formula I.

[0150] Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient.

[0151] Other embodiments disclosed herein include methods of inhibiting DYRK1A by administering to a patient affected by a disorder or disease involving overexpression of DYRK1A, such as Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's disease, Pick's disease, and other 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.

[0152] Inhibitors of DYRK1A can also be used to treat tauopathies. Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The scope of tauopathies has expanded beyond the traditionally discussed disease forms, such as Pick's disease, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. Emerging entities and lesions include globular glial tauopathies, primary age-related tauopathies (which include neurofibrillary tangle dementia), chronic traumatic encephalopathy (CTE), frontot emporal lobar degeneration with tau inclusions (FTLD-tau), and aging-related tau astrocytopathy. Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson syndrome, Parkinsonism, pure akinesia with freezing of gait, and rarely, motor neuron symptoms or cerebellar ataxia (Handbook of Clinical Neurology (2018), 145, 355-368 and Aging Cell (2019), 18(5), e13000).

[0153] Inhibitors of DYRK1A may also be useful in treating disorders associated with abnormal folate / methionine metabolism.

[0154] Non-limiting examples of diseases that can be treated with the compounds and compositions provided herein include various cancers, diabetes, psoriasis, knee osteoarthritis, tendinopathy, human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), hepatitis C virus (HCV), and herpes simplex virus 1 (HSV-1).

[0155] Some embodiments of the present disclosure include methods of preparing compounds of Formula I.

[0156] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed. DETAILED DESCRIPTION

[0157] Provided herein are compositions and methods for inhibiting DYRK1A.

[0158] Some embodiments provided herein relate to a method for treating a disease including, but not limited to, a neurological disease or disorder, cancer, cognitive deficits, knee osteoarthritis, tendinopathy, viral infection, single cell parasitic infection, and movement deficits.

[0159] In some embodiments, non-limiting examples of neurological diseases or disorders that can be treated with the compounds and compositions provided herein include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease tauopathy, and other 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.

[0160] In some embodiments, non-limiting examples of cancers that can be treated with the compounds and compositions provided herein include solid cancers (e.g., glioblastoma, ovarian cancer, breast cancer, and pancreatic cancer) and leukemias (e.g., acute lymphoblastic leukemia, acute megakaryoblastic leukemia, and chronic myeloid leukemia).

[0161] In some embodiments, a pharmaceutical composition is provided that is effective for treating a disease caused by overexpression of DYRK1A in an animal (eg, a mammal), wherein the composition comprises a pharmaceutically acceptable carrier and a compound as described herein.

[0162] definition

[0163] 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. Unless otherwise indicated, in the event that multiple definitions exist for a term herein, the definitions in this section shall prevail.

[0164] As used herein, "alkyl" means a branched or straight-chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, and neopentyl. The alkyl group may be unsubstituted or substituted with one or more substituents. In some embodiments, the alkyl group comprises 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0165] As used herein, "alkenyl" means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. In various embodiments, alkenyl can be unsubstituted or substituted with one or more substituents. Typically, alkenyl will contain 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0166] As used herein, "alkynyl" means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, etc. In various embodiments, the alkynyl group may be unsubstituted or substituted with one or more substituents. Typically, the alkynyl group will contain 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0167] As used herein, "alkylene" means a divalent branched or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, sec-pentylene, and neopentylene. Alkylene may be unsubstituted or substituted with one or more substituents. In some embodiments, alkylene includes 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0168] As used herein, "alkenylene" means a divalent branched or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as vinylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene, 2-butenylene, etc. In various embodiments, alkenylene can be unsubstituted or substituted with one or more substituents. Typically, alkenylene will contain 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0169] As used herein, "alkynylene" means a divalent branched or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynylene, 1-propynylene, 1-butynylene, 2-butynylene, etc. In various embodiments, the alkynylene group may be unsubstituted or substituted with one or more substituents. Typically, the alkynylene group will contain 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0170] As used herein, "alkoxy" means an alkyl-O- group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and heptyloxy, and also include linear or branched positional isomers thereof.

[0171] 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 also include straight-chain or branched positional isomers thereof.

[0172] As used herein, "carbocyclyl" means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. A carbocyclyl group may include multiple fused rings. A carbocyclyl group may have any degree of saturation, provided that none of the rings 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 includes 3 to 10 carbon atoms, such as 3 to 6 carbon atoms.

[0173] As used herein, "aryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group in which carbon atoms are present only in a ring backbone having 5 to 14 ring atoms, or 5, 6, 9, or 10 ring atoms and having 6, 10, or 14 π electrons shared in a cyclic array; wherein at least one ring in the system is aromatic. Aryl groups may be unsubstituted or substituted with one or more substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, and other groups. In some embodiments, aryl is phenyl.

[0174] As used herein, "arylalkylene" means an aryl-alkylene- group in which the aryl and alkylene portions are as previously described. In some embodiments, the arylalkylene contains C 1-4 Alkylene moiety. Exemplary arylalkylene groups include benzyl and 2-phenylethyl.

[0175] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 14 ring atoms, or 5, 6, 9, or 10 ring atoms, and having 6, 10, or 14 pi electrons shared in the cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrimidinyl, In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazolyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline and others. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl and pyrimidinyl.

[0176] As used herein, "halo," "halide," or "halogen" is a chlorine, bromine, fluorine, or iodine atom. In some embodiments, the halo is chlorine, bromine, or fluorine. For example, the halogen can be fluorine.

[0177] As used herein, "haloalkyl" means a hydrocarbon substituent that is a straight or branched chain alkyl, alkenyl, or alkynyl group substituted with one or more chlorine, bromine, fluorine, and / or iodine atoms. In some embodiments, a haloalkyl group is a fluoroalkyl group in which one or more hydrogen atoms have been replaced with fluorine. In some embodiments, a haloalkyl group is 1 to 3 carbons in length (e.g., 1 to 2 carbons in length or 1 carbon in length). The term "haloalkylene" means a diradical variant of a haloalkyl group, and such diradicals can serve as spacers between radicals, other atoms, or between a ring and another functional group.

[0178] As used herein, "heterocyclyl" means a non-aromatic cyclic ring system containing at least one heteroatom in the backbone of the ring system. Heterocyclyl groups may include multiple fused rings, such as bicyclic and spirocyclic heterocyclyl groups. Heterocyclyl groups may be substituted or unsubstituted with one or more substituents. In some embodiments, the heterocycle has 3 to 11 members. In a six-membered monocyclic heterocycle, the heteroatoms are selected from one to three of O, N, and S, and when the heterocycle is five-membered, it may have one or two heteroatoms selected from O, N, and S. Examples of heterocyclic groups include aziridinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxane, 1,4-dioxane, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, oxazinyl, thiazinyl (thiazinyl / thiinyl), thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl and other groups. In some embodiments, the heterocyclic group is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl and tetrahydropyridinyl.

[0179] As used herein, "monocyclic heterocyclyl" means a single non-aromatic cyclic ring containing at least one heteroatom in the main chain of the ring system. The heterocyclyl group may be substituted or unsubstituted with one or more substituents. In some embodiments, the heterocycle has 3 to 7 members. In a six-membered monocyclic heterocycle, the heteroatoms are selected from one to three of O, N, and S, and when the heterocycle is five-membered, it may have one or two heteroatoms selected from O, N, and S. Examples of monocyclic heterocyclic groups include aziridinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, oxazinyl, thiazinyl / thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl and other groups.

[0180] As used herein, "bicyclic heterocyclyl" refers to a non-aromatic bicyclic ring system containing at least one heteroatom in the backbone of the ring system. The bicyclic heterocyclyl may be substituted with one or more substituents or unsubstituted. In some embodiments, the bicyclic heterocycle has 4 to 11 members, wherein the heteroatoms are selected from one to five of O, N, and S. Examples of bicyclic heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, and the like.

[0181] As used herein, " spiro heterocyclic radical " means a non-aromatic bicyclic system, which includes at least one heteroatom in the ring system backbone and is connected to the ring via only one atom. Spiro heterocyclic radical may be substituted or unsubstituted by one or more substituents. In some embodiments, spiro heterocyclic ring has 5 to 11 members, wherein the heteroatom is selected from one to five of O, N and S. The example of spiro heterocyclic radical includes 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 etc.

[0182] The term "substituted" refers to a moiety in which a substituent replaces a hydrogen on one or more non-hydrogen atoms of a molecule. It is understood that "substituted" or "substituted" includes the implicit proviso that such substitution is in accordance with the permitted valencies of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., one that does not spontaneously transform, e.g., by rearrangement, cyclization, elimination, etc. Substituents may include, for example, -(C 1-9 alkyl), which is optionally substituted with one or more of: hydroxy, -NH2, -NH(C 1-3 Alkyl) and -N(C 1-3 alkyl)2;-(C 1-9 haloalkyl); halogen; hydroxy; carbonyl [e.g., -C(O)OR and -C(O)R]; thiocarbonyl [e.g., -C(S)OR, -C(O)SR and -C(S)R]; -(C 1-9 alkoxy), which is optionally substituted with one or more of: halogen, hydroxy, -NH2, -NH(C 1-3 Alkyl) and -N(C 1-3alkyl)2; -OPO(OH)2; phosphonate [e.g., -PO(OH)2 and -PO(OR')2]; -OPO(OR')R"; -NRR'; -C(O)NRR'; -C(NR)NR'R"; -C(NR')R"; cyano; nitro; azido; -SH; -SR; -OSO2(OR); sulfonate [e.g., -SO2(OH) and -SO2(OR)]; -SO2NR'R"; and -SO2R; wherein R, R' and R" are independently selected at each occurrence from: H; -(C 1-9 alkyl); C optionally substituted by 1 to 3 R"' 6-10 Aryl; 5- to 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 to 4 heteroatoms independently selected from N, O and S and optionally substituted with 1 to 3 R"'; wherein each R"' is independently selected from -(C 1-6 Alkyl), -(C 1-6 haloalkyl), halogen (e.g., F), hydroxy, -C(O)OR, -C(O)R, -(C 1-6 alkoxy), -NRR', -C(O)NRR' and cyano, wherein R and R' are independently selected at each occurrence from H and -(C 1-6 In some embodiments, the substituent is selected from -(C 1-6 Alkyl), -(C 1-6 haloalkyl), halogen (e.g., F), hydroxy, -C(O)OR, -C(O)R, -(C 1-6 alkoxy), -NRR', -C(O)NRR' and cyano, wherein R and R' are independently selected at each occurrence from H and -(C 1-6 alkyl).

[0183] As used herein, when two groups are indicated as being "connected" or "bonded" to form a "ring," it is understood that the bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with a bond, thereby forming a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. One skilled in the art will recognize that such rings can and are readily formed by conventional chemical reactions. In some embodiments, such rings have 3 to 7 members, for example 5 or 6 members.

[0184] Those skilled in the art will recognize that some of the chemical structures described herein may be represented on paper by one or more other resonance forms; or may exist in one or more other tautomeric forms, even when represented kinetically, and the skilled artisan will recognize that such tautomeric forms represent only a very small fraction of the sample of such compounds. Although such resonance forms or tautomers are not explicitly represented herein, such compounds are clearly encompassed within the scope of this disclosure.

[0185] The compounds provided herein can encompass various stereochemical forms. Compounds also encompass diastereomers and optical isomers, such as mixtures of enantiomers including racemic mixtures, and individual enantiomers and diastereomers produced due to structural asymmetry in certain compounds. The separation of individual isomers or the selective synthesis of individual isomers can be achieved by applying a variety of methods well known to those skilled in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure that does not specify stereochemistry and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound.

[0186] The present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of Formula I in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. Examples of suitable isotopes for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, such as 2 H (deuterium) and 3 H (tritium); isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, e.g. 36 Cl; isotopes of fluorine, e.g. 18 F; isotopes of iodine, e.g. 123 I and 125 I; isotopes of nitrogen, e.g. 13 N and 15 N; isotopes of oxygen, e.g. 15 O. 17 O and 18 O; isotopes of phosphorus, e.g. 32 P; and isotopes of sulfur, e.g. 35 S.

[0187] The term "administration" or "administering" refers to a method of providing a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate, including mammals, birds, fish, or amphibians, wherein the method of administration is, for example, oral, subcutaneous, intravenous, intralymphatic, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, ontologically, neuro-otologically, intraocularly, subconjunctivally, or via the anterior chamber of the eye. The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of disease, the disease involved, and the severity of the disease.

[0188] As used herein, a "diagnostic" is a compound, method, system, or device that helps identify or characterize a health or disease state. Diagnostics can be used in standard assays as known in the art.

[0189] The term "mammal" is used in its common biological sense. Thus, it specifically includes humans, cows, horses, monkeys, dogs, cats, mice, rats, cattle, sheep, pigs, goats, and non-human primates, but also includes many other species.

[0190] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable diluent," and "pharmaceutically acceptable excipient" include any and all solvents, cosolvents, complexing agents, dispersion media, coatings, isotonic agents, absorption delaying agents, and the like that are biologically or otherwise not adversely affected. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions. In addition, various adjuvants as are commonly used in the art may also be included. These and other such compounds are described in the literature, for example, in the Merck Index, Merck & Company, Rahway, NJ. Considerations for incorporating various components into pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (2010); Goodman and Gilman:The Pharmacological Basis of Therapeutics, 12th Edition, The McGraw-Hill Companies.

[0191] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds provided herein and has no adverse biological or other effects. In many cases, the compounds provided herein are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Many such salts are known in the art, for example, as described in WO 87 / 05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic 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, aluminum, and the like; ammonium, potassium, sodium, calcium, and magnesium salts are 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, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0192] As used herein, "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, as well as any other vertebrate or invertebrate. In some embodiments, the patient is a human.

[0193] As provided herein, a "therapeutically effective amount" of a compound is a therapeutically effective amount sufficient to achieve the desired physiological effect and may vary depending on the nature and severity of the disease condition and the potency 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 agents effective for treating the diseases and / or conditions described herein. The compound combination may be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the compound combination when administered is greater than the cumulative effect of the compound when administered alone as a single agent. In general, the synergistic effect is most clearly demonstrated at suboptimal concentrations of the compound. It will be appreciated that different concentrations may be used for prevention compared to treatment of active disease. This amount may further be determined based on the patient's height, weight, sex, age, and medical history.

[0194] The therapeutic effect alleviates one or more symptoms of the disease to some extent.

[0195] As used herein, "treat," "treatment," or "treating" refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term "therapeutic treatment" refers to administering a therapeutic agent to a patient already suffering from a disease, thereby producing a therapeutically beneficial effect, such as ameliorating existing symptoms; ameliorating potential metabolic causes of symptoms; delaying or preventing further development of the disease; and / or reducing the severity of symptoms that will or are expected to occur.

[0196] As used herein, "drug elution" and / or controlled release refers to any and all mechanisms such as diffusion, migration, permeation, and / or desorption by which a drug incorporated into a drug eluting material is delivered therefrom to surrounding body tissues over time.

[0197] As used herein, "drug eluting material" and / or controlled release material refers to any natural, synthetic, or semisynthetic material that is capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and the incorporated drugs can be eluted over time.

[0198] As used herein, "elutable drug" refers to any drug or combination of drugs that is capable of passing over time from a drug eluting material, where the drug eluting material is incorporated into the surrounding body area.

[0199] Compound

[0200] The compounds and compositions described herein can be used to inhibit DYRK1A for treating conditions or diseases involving DYRK1A overexpression, such as neurological diseases or conditions, cancer, cognitive deficits, knee osteoarthritis, tendinopathy, viral infections, unicellular parasitic infections, and movement defects.

[0201] Some embodiments of the present disclosure include compounds of Formula I:

[0202]

[0203] or a salt, pharmaceutically acceptable salt, or prodrug thereof.

[0204] Some embodiments of the present disclosure include compounds of Formula I:

[0205]

[0206] or a salt, pharmaceutically acceptable salt, or prodrug thereof.

[0207] Some embodiments of the present disclosure include compounds of Formula I:

[0208]

[0209] or a salt, pharmaceutically acceptable salt, or prodrug thereof.

[0210] In some embodiments of Formula I, R 1 is optionally replaced by 1 to 10 R 4 In some embodiments, R 1 is optionally substituted by 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 or 1 R 4 Substituted heteroaryl.

[0211] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0212] which is optionally substituted by 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 replace.

[0213] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0214] which is optionally substituted by 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 replace.

[0215] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0216] which is optionally substituted by 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 replace.

[0217] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0218] It is optionally substituted by 1 to 3 (eg, 1 to 2, 1) R 4 replace.

[0219] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0220] It is optionally substituted by 1 to 3 (eg, 1 to 2, 1) R 4 replace.

[0221] In some embodiments of Formula I, R 1 Selected from the group consisting of:

[0222] which are optionally replaced by 1 to 3 R 4 replace.

[0223] In some embodiments of Formula I, R 1 Selected from the group consisting of:

[0224] which are optionally replaced by 1 to 3 R 4 replace.

[0225] In some embodiments of Formula I, R 1 Selected from the group consisting of:

[0226] Unreplaced

[0227] In some embodiments of Formula I, R 1 Selected from the group consisting of:

[0228] Unreplaced

[0229] In some embodiments of Formula I, R 2 Selected from the group consisting of: 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 , optionally 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 Substituted-(C 1-5 alkylene) p heterocyclyl, optionally substituted by 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 7substituted -heteroaryl, and optionally substituted by 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 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halogen (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 alkyl) substituted.

[0230] In some embodiments of Formula I, R 2 Selected from the group consisting of: 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 , optionally 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 Substituted-(C 1-5 alkylene) p heterocyclyl, optionally substituted by 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 Substituted-(C 1-5 alkylene) p Aryl, optionally substituted with 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 Substituted-(C 1-5 alkylene) p heteroaryl, and optionally substituted by 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 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C1-3 alkyl) substituted.

[0231] In some embodiments of Formula I, R 2 Selected from the group consisting of: 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, optionally substituted by 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 Substituted-(C 1-5 alkylene) p heterocyclyl, optionally substituted by 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 Substituted-(C 1-5 alkylene) p Aryl, optionally substituted with 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 Substituted-(C 1-5 alkylene) p heteroaryl, and optionally substituted by 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 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogens (e.g., F, Cl, Br, I) and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted.

[0232] In some embodiments of Formula I, R 2 Selected from the group consisting of: unsubstituted -(C 1-5 alkyl), unsubstituted-(C 1-5 Haloalkyl), -(C 1-2 alkylene) p OR 5 , optionally 1 to 3 (eg, 1 to 2, 1) R 6 Substituted-(C1-2 alkylene) p heterocyclyl, and optionally substituted by 1 to 3 (e.g., 1 to 2, 1) R 8 Substituted-(C 1-2 alkylene) p Carbocyclic group, wherein each -(C 1-2 alkylene) are independently optionally substituted with 1 to 2 halogens.

[0233] In some embodiments of Formula I, R 2 Selected from the group consisting of: unsubstituted -(C 1-5 alkyl), unsubstituted-(C 1-5 haloalkyl), optionally substituted by 1 to 4 R 6 -substituted heterocyclic group, optionally substituted by 1 to 2 R 26 Substituted-(C 1-2 alkylene) p Aryl, optionally substituted with 1 to 2 R 7 Substituted-(C 1-2 alkylene) p heteroaryl, and optionally substituted by 1 to 4 R 8 Substituted-(C 1-2 alkylene) p Carbocyclic group, wherein each -(C 1-2 alkylene) are independently optionally substituted with 1 to 2 halogens.

[0234] In some embodiments of Formula I, R 2 is optionally replaced by 1 to 3 R 8 Substituted-(C 1-2 alkylene) p Carbocyclic group, wherein the -(C 1-2 alkylene) is optionally substituted with 1 to 2 halogens, and wherein the carbocyclyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and spiro[3.3]heptanyl.

[0235] In some embodiments of Formula I, R 2 is optionally replaced by 1 to 3 R 8 Substituted-(C 1-2 alkylene) p Carbocyclic group, wherein the -(C 1-2 alkylene) is optionally substituted with 1 to 2 halogens (e.g., F, Cl), and wherein 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]heptane.

[0236] In some embodiments of Formula I, R 2Selected from the group consisting of: unsubstituted -(C 1-4 alkyl), unsubstituted-(C 2-4 alkenyl), unsubstituted-(C 2-4 Alkynyl), unsubstituted-(C 1-4 haloalkyl), -(C 2-4 alkylene)OR 5 、-(C 2-4 alkylene)CN, optionally substituted by 1 to 3 R 6 Substituted-(C 1-2 alkylene) p Heterocyclic group, optionally substituted by 1 to 2 R 26 Substituted-(C 1-2 alkylene) p Aryl, optionally substituted with 1 to 2 R 7 Substituted-(C 1-2 alkylene) p heteroaryl, and optionally substituted by 1 to 3 R 8 Substituted-(C 1-2 alkylene) p Carbocyclic group, wherein each -(C 1-2 alkylene) are independently optionally substituted with 1 to 2 halogens (eg, F, Cl).

[0237] In some embodiments of Formula I, R 2 Selected from the group consisting of: unsubstituted -(C 1-5 haloalkyl), -(C 1-4 Alkylene)OH, -(C 1-4 alkylene)OMe and -(C 1-4 Alkylene)CN.

[0238] In some embodiments of Formula I, R 2 Selected from the group consisting of: Each R 8 Independently selected from the group consisting of F, Me, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OMe, -OH, -OMe, -OEt, -OCD3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2OMe, -OCH2CH2OH, -NH2, -NHMe and -NMe2.

[0239] In some embodiments of Formula I, R 2 Selected from the group consisting of: Each R 8 Independently selected from the group consisting of F, Me, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OMe, -OH, -OMe, -OEt, -OCD3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2OMe, -OCH2CH2OH, -CN, -NH2, -NHMe and -NMe2.

[0240] In some embodiments of Formula I, R 2 Selected from the group consisting of: Each R 8 Independently selected from the group consisting of F, Me, -CHF2, -CH2OMe, -OH, -OMe, -OCD3, -OCH2CHF2 and -OCH2CH2OMe.

[0241] In some embodiments of Formula I, R 2 is optionally replaced by 1 to 3 R 6 Substituted-(C 1-2 alkylene) p Heterocyclic group, wherein -(C 1-5 alkylene) is optionally substituted with 1 to 2 halogens, and wherein the heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxaspiro[3.3]heptanyl and oxaspiro[3.3]nonanyl.

[0242] In some embodiments of Formula I, R 2 Selected from the group consisting of: Each R 6 independently selected from the group consisting of F, Me, Et, iPr, iBu, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OMe, -OH, -OMe, -OEt, -OCD3, -OCF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me, -C(=O)Et, -C(=O)iPr, and -SO2Me; provided that F, -OH, -OMe, -OEt, -OCD3 and -OCF3 are not attached to N.

[0243] In some embodiments of Formula I, R 2 Selected from the group consisting of: Each R 6 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 attached to N.

[0244] In some embodiments of Formula I, R 2 is optionally replaced by 1 to 2 R 7 Substituted-heteroaryl, wherein the heteroaryl is pyrazolyl.

[0245] In some embodiments of Formula I, R 2 is optionally replaced by 1 to 2 R 7 Substituted-(C 1-2 alkylene)heteroaryl, wherein the heteroaryl is pyridine.

[0246] In some embodiments of Formula I, R 2 is optionally replaced by 1 to 2 R 7 Substituted-(C 1-2 alkylene)aryl, wherein the aryl is phenyl.

[0247] In some embodiments of Formula I, R 3 Selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl).

[0248] In some embodiments of Formula I, R 3 Selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), and is optionally substituted by 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 Substituted-heterocyclyl.

[0249] In some embodiments of Formula I, R3 Selected from the group consisting of: H, unsubstituted -(C 1-5 alkyl), unsubstituted-(C 2-5 alkenyl), unsubstituted-(C 2-5 Alkynyl) and unsubstituted-(C 1-5 haloalkyl).

[0250] In some embodiments of Formula I, R 3 Selected from the group consisting of: unsubstituted -(C 1-5 alkyl), unsubstituted-(C 1-5 haloalkyl) and optionally substituted by 1 to 2 R 18 Substituted-heterocyclyl.

[0251] In some embodiments of Formula I, R 3 Selected from the group consisting of: H, unsubstituted -(C 1-3 alkyl) and unsubstituted-(C 1-3 haloalkyl).

[0252] In some embodiments of Formula I, R 3 For unsubstituted -(C 1-3 alkyl).

[0253] In some embodiments of Formula I, R 3 For Me.

[0254] In some embodiments of Formula I, R 3 For unsubstituted -(C 1-3 haloalkyl).

[0255] In some embodiments of Formula I, R 3 Selected from the group consisting of: -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2 and -CH2CF3.

[0256] In some embodiments of Formula I, R 3 is an unsubstituted heterocyclic group.

[0257] In some embodiments of Formula I, R 3 is unsubstituted -(3- to 4-membered heterocyclic group).

[0258] In some embodiments of Formula I, R 3 is unsubstituted -(4-membered heterocyclic group).

[0259] In some embodiments of Formula I, each R 4 are independently selected from the group consisting of halogen (e.g., F, Cl, Br, I), unsubstituted -(C1-9 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, optionally substituted by 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 Substituted-(C 1-5 alkylene) p heterocyclyl, optionally substituted by 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 substituted -carbocyclyl, optionally substituted by 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 Substituted-(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halogen (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 alkyl) substituted.

[0260] In some embodiments of Formula I, each R 4 are independently selected from the group consisting of halogen, 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, optionally substituted by 1 to 2 R10 Substituted-(C 1-2 alkylene) p Heterocyclic group, optionally substituted by 1 to 2 R 11 Substituted-carbocyclyl, optionally substituted by 1 to 2 R 20 Substituted-(C 1-2 alkylene) p Heteroaryl, -(C 1-2 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-2 Alkylene) or -(C 1-4 alkylene) are independently optionally substituted with 1 to 2 halogens.

[0261] In some embodiments of Formula I, each R 4 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), unsubstituted-(C 2-9 Halogenated alkenyl), -(C 1-5 alkylene) p OR 9 、-(C 1-5 alkylene) p CN, optionally with 1 to 10 R 10 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 12 R 11 Substituted-carbocyclyl, optionally substituted by 1 to 10 R 20 Substituted-(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted.

[0262] In some embodiments of Formula I, each R 4 are independently selected from the group consisting of halogen (e.g., F, Cl), unsubstituted -(C 1-4 alkyl), unsubstituted-(C 2-4alkenyl), unsubstituted-(C 2-4 Alkynyl), unsubstituted-(C 1-4 haloalkyl), unsubstituted-(C 2-4 Halogenated alkenyl), -(C 1-4 alkylene) p OR 9 、-(C 1-2 alkylene)OR 9 、-(C 1-4 Alkylene)CN, -(C 1-2 alkylene)CN, optionally substituted by 1 to 2 R 10 Substituted-(C 1-2 alkylene) p Heterocyclic group, optionally substituted by 1 to 2 R 11 Substituted-carbocyclyl, optionally substituted by 1 to 2 R 20 Substituted-(C 1-2 alkylene) p Heteroaryl, -(C 1-2 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-2 Alkylene) or -(C 1-4 alkylene) are independently optionally substituted with 1 to 2 halogens (eg, F, Cl).

[0263] In some embodiments of Formula I, each R 4 are independently selected from the group consisting of: 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, optionally substituted by 1 to 2 R 10 Substituted -(CH2) p Heterocyclic group, optionally substituted by 1 to 2 R 11 Substituted-carbocyclyl, optionally substituted by 1 to 2 R 20 Substituted -(CH2) p Heteroaryl, -(CH2)C(=O)N(Me)2 and -C(=O)R 13 , where each -(C 1-2 Alkylene) or -(C 1-4 alkylene) are independently optionally substituted with 1 to 2 halogens.

[0264] In some embodiments of Formula I, each R 4 are independently selected from the group consisting of halogen (e.g., F, Cl, Br, I), unsubstituted -(C 1-4 alkyl), unsubstituted-(C 1-4 haloalkyl), optionally substituted by 1 to 3 (e.g., 1 to 2, 1) R 10 -substituted heterocyclyl and optionally substituted by 1 to 3 (e.g., 1 to 2, 1) R 11 Substituted-carbocyclyl.

[0265] In some embodiments of Formula I, each R 4 are independently selected from the group consisting of halogen, unsubstituted -(C 1-3 alkyl), unsubstituted-(C 1-3 Haloalkyl), -(C 1-3 alkylene) p OR 9 , optionally 1 to 2 R 10 -substituted heterocyclic group, optionally substituted by 1 to 2 R 11 Substituted-carbocyclyl and -C(=O)R 13 .

[0266] In some embodiments of Formula I, each R 4 are independently selected from the group consisting of halogen, 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.

[0267] In some embodiments of Formula I, each R 4 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.

[0268] In some embodiments of Formula I, each R 5 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl).

[0269] In some embodiments of Formula I, each R5 are independently selected from the group consisting of: H, unsubstituted -(C 1-5 alkyl), unsubstituted-(C 2-5 alkenyl), unsubstituted-(C 2-5 Alkynyl) and unsubstituted-(C 1-5 haloalkyl).

[0270] In some embodiments of Formula I, each R 5 are independently selected from the group consisting of: H, unsubstituted -(C 1-3 alkyl) and unsubstituted-(C 1-3 haloalkyl).

[0271] In some embodiments of Formula I, each R 6 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted with 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 Substituted-heterocyclyl, -(C 1-5 alkylene) p OR 21 、-SO2R 23 and -C(=O)R 24 wherein said-(C 1-5 alkylene) is optionally substituted with 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halogen (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 alkyl) substituted.

[0272] In some embodiments of Formula I, each R 6 are independently selected from the group consisting of halogen (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), optionally substituted with 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 16substituted -heterocyclyl, optionally substituted with 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 Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 21 、-SO2R 23 and -C(=O)R 24 , where -(C 1-5 Alkylene) is optionally substituted with 1 to 5 halogen (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 alkyl) substituted.

[0273] In some embodiments of Formula I, each R 6 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1 to 10 R 16 Substituted-heterocyclyl, optionally substituted by 1 to 12 R 17 Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 21 、-(C 1-5 Alkylene)CN, -SO2R 23 and -C(=O)R 24 , where -(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted.

[0274] In some embodiments of Formula I, each R 6 are independently selected from the group consisting of: F, Cl, unsubstituted -(C 1-4 alkyl), unsubstituted-(C 1-4 haloalkyl), optionally substituted by 1 to 2 R 16 Substituted-heterocyclyl, -(C 1-2 alkylene) p OR 21 、-(C 1-2 Alkylene)CN, -SO2R 23 and -C(=O)R 24 , where -(C 1-2 alkylene) is optionally substituted with 1 to 2 halogens (eg, F, Cl).

[0275] In some embodiments of Formula I, each R 6 are independently selected from the group consisting of: F, Cl, unsubstituted -(C 1-5 alkyl), unsubstituted-(C 1-5 haloalkyl), optionally substituted by 1 to 2 R 16 Substituted-heterocyclyl, -(C 1-2 alkylene) p OR 21 、-SO2R 23 and -C(=O)R 24 , where -(C 1-2 alkylene) is optionally substituted with 1 to 2 halogens.

[0276] In some embodiments of Formula I, each R 6 are independently selected from the group consisting of: F, Cl, unsubstituted -(C 1-5 alkyl), unsubstituted-(C 1-5 haloalkyl), optionally substituted by 1 to 2 R 16 Substituted-heterocyclyl, -OH, -OMe, -SO2Me and -C(=O)R 24 .

[0277] In some embodiments of Formula I, each R 6 are independently selected from the group consisting of: F, Cl, unsubstituted -(C 1-5 alkyl), unsubstituted-(C 1-5 haloalkyl), optionally substituted by 1 to 2 R 16 -substituted heterocyclic group, optionally substituted by 1 to 4 R 17 Substituted-carbocyclyl and -C(=O)R 24 .

[0278] In some embodiments of Formula I, two R 6 Together they form a carbonyl group.

[0279] In some embodiments of Formula I, each R 7 are independently selected from the group consisting of halogen (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.

[0280] In some embodiments of Formula I, each R 7Independently selected from the group consisting of: F, Cl, Me, CF3 and -OMe.

[0281] In some embodiments of Formula I, each R 8 are independently selected from the group consisting of halogen (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 , optionally 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 Substituted-(C 1-5 alkylene) p Heterocyclic group, -C(=O)R 22 and -NHC(=O)R 23 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halogen (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 alkyl) substituted.

[0282] In some embodiments of Formula I, each R 8 are independently selected from the group consisting of halogen, 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, optionally with 1 to 10 R 16 Substituted-(C 1-5 alkylene) p Heterocyclic group, -C(=O)R 22 and -NR 14 C(=O)R 23 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted.

[0283] In some embodiments of Formula I, each R 8 are independently selected from the group consisting of halogen (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, optionally 1 to 2 R 16 Substituted-(C 1-2 alkylene) p Heterocyclic group, -C(=O)R 22 and -NHC(=O)R 23 , where each -(C 1-2 alkylene) are independently optionally substituted with 1 to 2 halogens (eg, F, Cl).

[0284] In some embodiments of Formula I, each R 8 are independently selected from the group consisting of halogen, 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 , optionally 1 to 2 R 16 Substituted-(C 1-2 alkylene) p Heterocyclic group, -C(=O)R 22 and -NHC(=O)R 23 , where each -(C 1-2 alkylene) are independently optionally substituted with 1 to 2 halogens.

[0285] In some embodiments of Formula I, each R 9 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl).

[0286] In some embodiments of Formula I, each R 10 are independently selected from the group consisting of halogen (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).

[0287] In some embodiments of Formula I, each R 11 are independently selected from the group consisting of halogen (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).

[0288] In some embodiments of Formula I, each R 12 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl), optionally substituted with 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 Substituted-(C 1-5 alkylene) p carbocyclyl, optionally substituted by 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 substituted -heterocyclyl, and optionally substituted by 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 19 Substituted-heteroaryl, wherein -(C 1-5 alkylene) is optionally substituted with 1 to 5 (e.g., 1 to 4, 1 to 3, 1 to 2, 1) halogen (e.g., F, Cl, Br, I) and / or 1 to 3 (e.g., 1 to 2, 1) unsubstituted -(C 1-3 alkyl) substituted.

[0289] In some embodiments of Formula I, each R 13is optionally substituted by 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 Substituted-heterocyclyl.

[0290] In some embodiments of Formula I, each R 14 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl).

[0291] In some embodiments of Formula I, each R 15 are independently selected from the group consisting of: 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 .

[0292] In some embodiments of Formula I, each R 16 are independently selected from the group consisting of halogen (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).

[0293] In some embodiments of Formula I, each R 16 are independently selected from the group consisting of halogen, -CN, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), and optionally substituted by 1 to 12 R 27 Substituted-carbocyclyl.

[0294] In some embodiments of Formula I, two R 16 Together they form a carbonyl group.

[0295] In some embodiments of Formula I, each R 17are independently selected from the group consisting of halogen (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).

[0296] In some embodiments of Formula I, each R 18 are independently selected from the group consisting of halogen (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).

[0297] In some embodiments of Formula I, each R 19 are independently selected from the group consisting of halogen (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).

[0298] In some embodiments of Formula I, each R 20 are independently selected from the group consisting of halogen (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).

[0299] In some embodiments of Formula I, each R 21 are independently selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl).

[0300] In some embodiments of Formula I, each R 22 independently selected from the group consisting of: optionally substituted by 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 18Substituted-heterocyclyl, -N(R 12 )2 and -OR 21 .

[0301] In some embodiments of Formula I, each R 23 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl).

[0302] In some embodiments of Formula I, each R 23 Independently selected from the group consisting of: 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 optionally 1 to 12 R 25 Substituted-carbocyclyl.

[0303] In some embodiments of Formula I, each R 24 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -OR 23 and optionally 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 Substituted-carbocyclyl.

[0304] In some embodiments of Formula I, each R 25 are independently selected from the group consisting of halogen (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).

[0305] In some embodiments of Formula I, each R 26are independently selected from the group consisting of halogen (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).

[0306] In some embodiments of Formula I, each R 27 are independently selected from the group consisting of halogen (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).

[0307] In some embodiments of Formula I, R 28 are independently selected from the group consisting of: H and halogen (eg, F, Cl, Br, I).

[0308] In some embodiments of Formula I, R 28 Independently selected from the group consisting of: H and halogen (eg, F, Cl).

[0309] In some embodiments of Formula I, R 28 Independently selected from the group consisting of: H and F.

[0310] In some embodiments of Formula I, R 28a are independently selected from the group consisting of: H and halogen (eg, F, Cl, Br, I).

[0311] In some embodiments of Formula I, R 28a Independently selected from the group consisting of: H and halogen (eg, F, Cl).

[0312] In some embodiments of Formula I, R 28a Independently selected from the group consisting of: H and F.

[0313] In some embodiments of Formula I, R 28b Independently selected from the group consisting of: H and D.

[0314] In some embodiments of Formula I, each p is independently 0 or 1.

[0315] In some embodiments of Formula I, each H atom is optionally independently 2 H(D) (deuterium) instead.

[0316] Illustrative compounds of Formula I are shown in Table 1.

[0317] Table 1.

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374] Administration and pharmaceutical compositions

[0375] Some embodiments include pharmaceutical compositions comprising: (a) a therapeutically effective amount of a compound provided herein, or a corresponding enantiomer, diastereomer, or tautomer, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.

[0376] The compounds provided herein are also suitable for combination (administered together or sequentially) with other known pharmaceutical agents.

[0377] Non-limiting examples of diseases that can be treated with a combination of a compound of Formula I and another active agent are colorectal cancer, ovarian cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, acute lymphoblastic leukemia (ALL), pancreatic cancer, brain tumors, acute megakaryoblastic leukemia (AMKL) and osteoarthritis. For example, a compound of Formula I can be combined with one or more chemotherapeutic compounds.

[0378] In some embodiments, hepatocellular carcinoma can be treated with a combination of a compound of Formula I and one or more of the following drugs / therapies: sorafenib regorafenib Nivolumab Lenvatinib pembrolizumab cabozantinib 5-Fluorouracil ramucirumab Combination of gemcitabine and oxaliplatin (GEMOX). Other therapies that can be combined with the compound of formula I are i) with doxorubicin Cisplatin or mitomycin C Combined transcatheter arterial chemoembolization (TACE); ii) low-dose brachytherapy.

[0379] In some embodiments, head and neck squamous cell carcinoma can be treated with a compound of Formula I in combination with one or more of the following drugs / therapies: TransOral Robotic Surgery (TORS); TORS with radiation therapy; larotrectinib EGFR inhibitors, such as erlotinib osimertinib Neratinib Gefitinib Cetuximab panitumumab dacomitinib Lapatinib Necitumumab (Por trazza) and vandetanib

[0380] In some embodiments, acute lymphoblastic leukemia (ALL) can be treated with a compound of Formula I in combination with one or more of the following drugs / therapies: remission induction therapy; consolidation therapy; nelarabine asparaginase erwinia chrysanthemi Erwinia chrysanthemi asparaginase (recombinant)-rywn Calaspargase Pegol-mknl inotuzumab ozogamicin blinatumomab daunorubicin hydrochloride clofarabine Cyclophosphamide; methotrexate sodium Cytarabine dasatinib Dexamethasone; imatinib mesylate Ponatinib hydrochloride Mercaptopurine tisagenlecleucel vincristine sulfate liposome pegaspargase prednisone; daunorubicin hydrochloride and vincristine sulfate.

[0381] In some embodiments, pancreatic cancer can be treated with a compound of Formula I in combination with one or more of the following drugs / therapies: ablation and embolization; gemcitabine 5-Fluorouracil Oxaliplatin Albumin-bound paclitaxel Capecitabine Cisplatin; irinotecan liposomal irinotecan Pacific taxol and docetaxel

[0382] In some embodiments, brain tumors can be treated with a compound of Formula I in combination with one or more of the following drugs / therapies: carmustine can be administered in the form of a Gliadel Wafer; for glioblastomas and high-grade gliomas, daily low-dose temozolomide can be used. Radiation therapy, followed by monthly temozolomide for 6 to 1 year after radiation therapy; lomustine has been procarbazine and vincristine Used with radiation therapy; using bevacizumab antiangiogenic therapy; and larotrectinib targeted therapy.

[0383] In some embodiments, acute megakaryoblastic leukemia (AMKL) can be treated with a compound of Formula I in combination with one or more of the following drugs / therapies: cytarabine Etoposide and anthracycline drugs. Anthracyclines include daunomycin Idarubicin and mitoxantrone

[0384] In some embodiments, acute myeloid leukemia (AML) can be treated with a compound of Formula I in combination with one or more of the following drugs / therapies: venetoclax and a hypomethylating agent (e.g., decitabine, azacitidine), induction chemotherapy (cytarabine and anthracycline (e.g., daunomycin or edamicin), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) monotherapy or anthracycline), consolidation therapy (cytarabine).

[0385] In some embodiments, myelodysplastic syndrome (MDS) can be treated with a compound of Formula I in combination with one or more of the following drugs / therapies: 5-azacytidine, decitabine, lenalidomide, and decitabine / cedazuridine

[0386] In some embodiments, colorectal cancer can be treated with a compound of Formula I in combination 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; Irinotecan Oxaliplatin Examples of combinations of these drugs that can be further combined with compounds of formula I are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan), and CapeOx (capecitabine and oxaliplatin). For rectal cancer, chemotherapy using a combination of 5-FU or capecitabine with radiation can be given before surgery (neoadjuvant treatment).

[0387] In some embodiments, ovarian cancer can be treated with a compound of Formula I in combination with one or more of the following: topotecan, liposomal doxorubicin, Gemcitabine Cyclophosphamide Vinorelbine Ifosfamide Etoposide (VP-16), altretamine (HEXAL ), Capecitabine Irinotecan (CPT-11, ), melphalan, pemetrexed and albumin-bound paclitaxel (nab-paclitaxel, ). Examples of combinations of these drugs that can be further combined with compounds of Formula I are TIP (paclitaxel [paclitaxel], ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin), and VIP (etoposide [VP-16], ifosfamide, and cisplatin). Ovarian cancer can also be treated with a combination of compounds of Formula I and immune checkpoint blockade (ICB) therapy.

[0388] In some embodiments, the compounds of Formula I can be used in combination with any of the following methods for treating cancer: (a) hormone therapy, such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) ablative or embolic procedures, such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy, and cryosurgery (cryotherapy); (c) chemotherapy with alkylating agents, such as cisplatin and carboplatin, oxaliplatin, nitrogen mustard, cyclophosphamide, chlorambucil, and ifosfamide; (d) chemotherapy with antimetabolites, such as azathioprine and mercaptopurine; (e) chemotherapy with plant alkaloids and terpenes, such as vinca alkaloids (i.e., vincristine, vinblastine, vinorelbine, and vindesine) and taxanes; (f) chemotherapy with podophyllotoxin, etoposide, teniposide, and docetaxel; (g) chemotherapy with oxaliplatin, chlorambucil, and cyclophosphamide; Chemotherapy with topoisomerase inhibitors, such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) chemotherapy with cytotoxic antibiotics, such as actinomycin, anthracyclines, doxorubicin, daunomycin, valrubicin, edamamycin, epirubicin, bleomycin, plicamycin, and mitomycin; (i) chemotherapy with tyrosine kinase inhibitors, such as imatinib mesylate ( Also known as STI-571), gefitinib (Iressa, also known as ZD1839), erlotinib ( Bortezomib Tamoxifen, tofacitinib, crizotinib, Bcl-2 inhibitors (e.g., obatoclax, navitoclax (ABT-263), oblimersen (G3139), venetoclax (ABT-199), Gossypol), PARP inhibitors (e.g., iniparib, olaparib, rucaparib, niraparib, talazoparib), PI3K inhibitors (e.g., perifosine in phase III trials), (e.g., rituximab), VEGF receptor 2 inhibitors (e.g., apatinib), AN-152, (AEZS-108), BRAF inhibitors (e.g., vemurafenib, dabrafenib, and LGX818), MEK inhibitors (e.g., trametinib and MEK162), CDK inhibitors (e.g., PD-0332991), salinomycin, and sorafenib; (j) chemotherapy with monoclonal antibodies, such as rituximab ( or sold), trastuzumab (Herceptin, also known as ErbB2), cetuximab ( Sold) and bevacizumab (sold as (k) chemotherapy with KRAS G12C inhibitors, such as sotora sib ( and ), adagrasib (MRTX849), and ARS-3248 (Wellspring Biosciences); (l) chemotherapy with checkpoint inhibitor therapy, such as ipilimumab Nivolumab Pembrolizumab Atezolizumab avelumab (Bavencio), durvalumab (Imfinzi), cemiplimab and spartalizumab (PDR001); (m) chemotherapy using antibody-drug conjugates (ADCs), such as gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, ituzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, moxetumomab vedotin, and spartalizumab (PDR001). (n) chemotherapy with proteasome inhibitors, such as carfilzomib, lactacystin, disulfiram, salinosporamide A (marizomib), oprozomib, delanzomib, epoxomicin, MG132, β-hydroxyβ-methylbutyrate (HMB), bortezomib, ixazomib (alone or in combination with lenalidomide and dexamethasone); and (o) radiation therapy.

[0389] In some embodiments, the compounds of Formula I can be used in combination with any of the following methods for treating 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 (Rezulin); (d) lyn kinase activators such as glimepiride (Amar ) and tolimidone (MLR-1023); (e) secretagogues, such as sulfonylureas (non-limiting examples are acetohexamide, carbutamide, chlorpropamide, glycyclamide (tolcyclamide), metahexamide, tolazamide, tolbutamide, glibenclamide (glyburide), glibornuride, gliclazide, glipizide, (f) alpha-glucosidase inhibitors such as acarbose (Glucobay, Precose, Prandase), miglitol (Glyset), and voglibose;(g) Injectable insulinotropic 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 are exenatide (incretin analog-4 (Exendin-4), sold as Byetta), liraglutide (Victoza, Saxenda), taspoglutide, lixisenatide (Lixisenatide), and taspoglutide. Non-limiting examples of dipeptidyl peptidase-4 (DPP-4) inhibitors are sitagliptin (Januvia), vildagliptin (Galvus), saxagliptin (Saxavar), and saxagliptin (Valveolar). gliptin (Onglyza), linagliptin (Tradjenta), gemigliptin (Zemiglo), anagliptin (Suiny), teneligliptin (Tenelia), alogliptin (Nesina, Vipidia, Kazano, Vipidomet (with metformin), Oseni, Incresync (with pioglitazone)), trelagliptin (Zafatek, Wedica), omarigliptin (MK-3102), evogliptin (Suganon, Evodine), gosogliptin (Saterex), and dutogliptin; (h) injectable amyloid analogs, such as pramlintide (Symlin);(i) Glycosurics (SGLT2 inhibitors), such as canagliflozin (Invokana, Sulisent, Prominad), dapagliflozin (Forxiga, Farxiga, Edistride), empagliflozin (Jardiance, Sciampa-M), ertugliflozin (Steglatro), ipragliflozin (Suglat), luseogliflozin (Lusefi), remogliflozine tabonate (a prodrug of remogliflozin), sergliflozin etabonate (GW869682X), sotagliflozin (Zynquista), and tofogliflozin (CSG452).

[0390] In some embodiments, the compound 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., lorecivivint); (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) anesthetics, such as codeine; (f) in combination with braces and / or footpads or any device that can immobilize or support a joint to help avoid pressure (e.g., splints, braces, footpads, or other medical devices); (g) realignment of bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with chronic pain categories.

[0391] In some embodiments, the compound of Formula I can be used in combination with aducanumab (Aduhelm TM ); acetylcholinesterase inhibitors, such as tacrine and rivastigmine Galantamine ( and GalantaMind TM ) and donepezil and memantine

[0392] Administration of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be via any of the acceptable modes of administration, including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally, otically, intraneurally, intraocularly, subconjunctivally, via anterior chamber injection, intravitreally, intraperitoneally, intrathecally, intracapsularly, intrapleurally, via wound irrigation, intrabuccally, intraabdominally, intraarticularly, intraauricularly, intrabronchially, intracapsularly, intrameningeally, via inhalation, via intratracheal or intrabronchial instillation, via direct instillation into a lung cavity, intraspinally, intrasynovially, intrathoracically, via thoracotomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intracerebroventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic device. In some embodiments, the method of administration includes oral or parenteral administration.

[0393] The compound provided herein for medical use can be applied in the form of crystallization or amorphous product.Pharmaceutically acceptable compositions may include solid, semisolid, liquid, solution, colloid, liposome, emulsion, suspension, complex, coagulation and aerosol. Dosage form, such as tablet, capsule, powder, liquid, suspension, suppository, aerosol, implant, controlled release dosage form etc. It can be obtained in the form of solid plug, powder or film by, for example, precipitation, crystallization, grinding, grinding, supercritical fluid processing, coagulation, complex coagulation, encapsulation, emulsification, compound, freeze drying, spray drying or evaporative drying. Microwave or radio frequency drying can be used for this purpose. Compounds can also be applied in a continuous or controlled release dosage form, including reservoir injection, osmotic pump, pill (tablet and or capsule), transdermal (including electromigration) patch, implant etc., for long-term and / or timed pulse application at a predetermined rate.

[0394] 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-tocopheryl polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tweens, poloxamers, 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 silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin) or chemically modified derivatives (such as hydroxyalkylcyclodextrin, including 2-hydroxypropyl-β-cyclodextrin and 3-hydroxypropyl-β-cyclodextrin) or other dissolved derivatives can also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing compounds as described herein in the range of 0.005% to 100% and the remainder consisting of non-toxic carriers can be prepared. The compositions contemplated may contain 0.001% to 100% of the compounds provided herein, in one embodiment 0.1% to 95%, in another embodiment 75% to 85%, in another embodiment 20% to 80%. The actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK. 2012).

[0395] In one embodiment, the composition will be in the form of a unit dosage form such as a pill or tablet, and thus, in addition to containing the compound provided herein, the composition may also contain a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; and a binder such as starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, a spherical particle (marume), a solution or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglyceride) is encapsulated in a capsule (gelatin or cellulose capsule). Also contemplated are physically separated unit dosage forms of one or more compounds or other active agents provided herein; for example, capsules with granules of each drug (or tablets in a capsule); double-layer tablets; double-chamber capsules, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0396] Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, etc., the compounds provided herein and optional pharmaceutical adjuvants in a carrier (e.g., water, physiological saline, aqueous dextrose solution, glycerol, glycol, ethanol, etc.) to form a solution, colloid, liposome, emulsion, complex, aggregate, or suspension. If necessary, the pharmaceutical composition may also contain a small amount of non-toxic auxiliary substances, such as wetting agents, emulsifiers, cosolvents, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc.).

[0397] In some embodiments, the unit dosage of the compound of Formula I in humans is from about 0.25 mg / Kg to about 50 mg / Kg.

[0398] In some embodiments, the unit dosage of the compound of Formula I in humans is from about 0.25 mg / Kg to about 20 mg / Kg.

[0399] In some embodiments, the unit dosage of the compound of Formula I in humans is from about 0.50 mg / Kg to about 19 mg / Kg.

[0400] In some embodiments, the unit dose of the compound of Formula I in humans is from about 0.75 mg / Kg to about 18 mg / Kg.

[0401] In some embodiments, the unit dose of the compound of Formula I in humans is from about 1.0 mg / Kg to about 17 mg / Kg.

[0402] In some embodiments, the unit dosage of the compound of Formula I in humans is from about 1.25 mg / Kg to about 16 mg / Kg.

[0403] In some embodiments, the unit dosage of the compound of Formula I in humans is from about 1.50 mg / Kg to about 15 mg / Kg.

[0404] In some embodiments, the unit dose of the compound of Formula I in humans is from about 1.75 mg / Kg to about 14 mg / Kg.

[0405] In some embodiments, the unit dose of the compound of Formula I in humans is from about 2.0 mg / Kg to about 13 mg / Kg.

[0406] In some embodiments, the unit dose of the compound of Formula I in humans is from about 3.0 mg / Kg to about 12 mg / Kg.

[0407] In some embodiments, the unit dose of the compound of Formula I in humans is from about 4.0 mg / Kg to about 11 mg / Kg.

[0408] In some embodiments, the unit dosage of the compound of Formula I in humans is from about 5.0 mg / Kg to about 10 mg / Kg.

[0409] In some embodiments, the composition is provided in unit dosage form suitable for single administration.

[0410] In some embodiments, the composition is provided in a unit dosage form suitable for twice-a-day administration.

[0411] In some embodiments, the composition is provided in a unit dosage form suitable for three times a day administration.

[0412] Injectables can be prepared in conventional forms, in the form of liquid solutions, colloids, liposomes, complexes, aggregates or suspensions, in the form of emulsions, or in any of the solid forms suitable for reconstitution in liquids before injection. The percentage of the compound provided herein contained in such parenteral compositions depends primarily on its specific properties, as well as the activity of the compound and the needs of the patient. However, 0.01% to 10% active ingredient percentages in solution are useful, and may be higher if the composition can be subsequently diluted to a solid or suspension of the above percentages.

[0413] In some embodiments, the composition comprises about 0.1% to 10% active agent in solution.

[0414] In some embodiments, the composition comprises about 0.1% to 5% active agent in solution.

[0415] In some embodiments, the composition comprises about 0.1% to 4% active agent in solution.

[0416] In some embodiments, the composition comprises about 0.15% to 3% active agent in solution.

[0417] In some embodiments, the composition comprises about 0.2% to 2% active agent in solution.

[0418] In some embodiments, the composition is provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 96 hours.

[0419] In some embodiments, the composition is provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 72 hours.

[0420] In some embodiments, the composition is provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 48 hours.

[0421] In some embodiments, the composition is provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 24 hours.

[0422] In some embodiments, the composition is provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 12 hours.

[0423] In some embodiments, the composition is provided in a dosage form suitable for continuous administration by intravenous infusion over a period of about 1 to 6 hours.

[0424] In some embodiments, these compositions may be administered by intravenous infusion at a dose of about 5 mg / m 2 to about 300 mg / m 2 administration to humans at doses of .

[0425] In some embodiments, these compositions may be administered by intravenous infusion at a dose of about 5 mg / m 2 to about 200 mg / m 2 administration to humans at doses of .

[0426] In some embodiments, these compositions may be administered by intravenous infusion at a dose of about 5 mg / m 2 to about 100 mg / m 2 administration to humans at doses of .

[0427] In some embodiments, these compositions may be administered by intravenous infusion at a dose of about 10 mg / m 2 Up to 50 mg / m 2 administration to humans at doses of .

[0428] In some embodiments, these compositions may be administered by intravenous infusion at a dose of about 50 mg / m 2 to about 200 mg / m 2 administration to humans at doses of .

[0429] In some embodiments, these compositions may be administered by intravenous infusion at a dose of about 75 mg / m 2 Up to 175 mg / m 2 administration to humans at doses of .

[0430] In some embodiments, these compositions may be administered by intravenous infusion at a dose of about 100 mg / m 2 Up to about 150 mg / m 2 administration to humans at doses of .

[0431] It should be noted that concentrations and dosage values ​​may also vary depending on the particular compound and the severity of the condition to be alleviated. It should be further understood that for any particular patient, the specific dosage regimen should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.

[0432] In one embodiment, the composition may be administered to the respiratory tract (including nasal and pulmonary), for example, via a nebulizer, metered dose inhaler, atomizer, sprayer, aerosol, dry powder inhaler, insufflator, liquid instillation, or other suitable device or technique.

[0433] In some embodiments, an aerosol is provided for delivery to the nasal mucosa for inhalation via the nose. For optimal delivery to the nasal cavity, an inhalation particle size of about 5 to about 100 microns is applicable, wherein a particle size of about 10 to about 60 microns is preferred. For nasal delivery, a larger inhalation particle size may be required to maximize the effect on the nasal mucosa and minimize or prevent the lung deposition of the administered preparation. In some embodiments, an aerosol is provided for delivery to the lungs for inhalation via the nose or mouth. For delivery to the lungs, an inhalation aerodynamic particle size of approximately less than 10 μm is applicable (e.g., about 1 to about 10 microns). Inhaled particles can be defined as droplets containing dissolved drugs, droplets containing suspended drug particles (when the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substances merged with excipients, liposomes, emulsions, colloidal systems, agglomerates, aggregates of drug nanoparticles, or dry particles containing a diluent for embedding drug nanoparticles.

[0434] In some embodiments, the compounds of Formula I disclosed herein for respiratory delivery (systemic or topical) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as colloidal systems, as emulsion aggregates, or as dry powders. Aqueous formulations can be administered by liquid nebulizers using hydraulic or ultrasonic atomization or by modified micropump systems (e.g., soft mist inhalers, or Systems) can be aerosolized. Propellant-based systems can use a suitable pressurized metered dose inhaler (pMDI). Dry powders can be aerosolized using a dry powder inhaler device (DPI), which can effectively disperse the drug substance. The desired particle size and distribution can be obtained by selecting an appropriate device.

[0435] In some embodiments, the compositions of Formula I disclosed herein can be administered to the ear by various methods. For example, a round window catheter can be used (e.g., U.S. Patent Nos. 6,440,102 and 6,648,873).

[0436] Alternatively, the formulation can be incorporated into a wick for use between the outer and middle ear (eg, US Patent No. 6,120,484) or absorbed into a collagen sponge or other solid carrier (eg, US Patent No. 4,164,559).

[0437] If desired, the formulations of the present disclosure can be incorporated into gel formulations (eg, US Pat. Nos. 4,474,752 and 6,911,211).

[0438] In some embodiments, the compounds of Formula I disclosed herein for delivery to the ear can be administered via an implanted pump and delivery system, directly into the middle or inner ear (cochlea) through a needle, or into the cochlea through a cochlear implant probe electrode channel or alternatively prepared drug delivery channel such as, but not limited to, a needle through the temporal bone.

[0439] Other options include delivery via a pump through a film coated on a multi-channel electrode or an electrode with specially embedded drug delivery channels (pathways) engraved in the film for this purpose. In other embodiments, the acidic or basic solid compound of Formula I can be delivered from a reservoir of an external or internally implanted pumping system.

[0440] The formulations of the present disclosure may also be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (eg, US Patent No. 6,377,849 and Serial No. 11 / 337,815).

[0441] Intratympanic injection of therapeutic agent is the technology that therapeutic agent is injected into middle ear and / or inner ear behind eardrum.In one embodiment, preparation described herein is directly applied on round window membrane via transtympanic injection.In another embodiment, the acceptable preparation of ion channel modulator ear described herein is applied on round window membrane via the non-transtympanic method leading to inner ear.In other embodiments, preparation described herein is applied on round window membrane via the surgical method leading to the round window membrane of the modification comprising cochlear window ridge (cristafenestrae cochleae).

[0442] In some embodiments, the compounds of Formula I are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides and synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), and the like.

[0443] For the suppository (in solution, colloid, suspension or complex form) of the drug for rectal administration, the compound provided herein can be prepared by mixing with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt or corrode / dissolve in the rectum and release the compound. Such materials include mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In the suppository form of the composition, a low melting point wax is first melted, such as, but not limited to, a mixture of fatty acid glycerides optionally in combination with cocoa butter.

[0444] Depending on the physicochemical properties of the compound provided herein, the desired dissolution rate, cost considerations and other criteria, the solid composition can be provided in a variety of different types of dosage forms. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the compound is contained in a single physically formed solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, the units of which are discontinuous.

[0445] Examples of single units that can be used as dosage forms for solid compositions include tablets (e.g., compressed tablets), film-type units, foil-type units, powder tablets, freeze-dried matrix units, and the like. In one embodiment, the solid composition is in the form of a highly porous freeze-dried product. Such freeze-dried products (sometimes also referred to as powder tablets or freeze-dried tablets) are particularly suitable for rapid disintegration, which also allows for rapid dissolution of the compound.

[0446] On the other hand, for some applications, the solid composition can also be formed as a multi-unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, aggregates, microtablets, beads, freeze-dried powders, etc. In one embodiment, the solid composition is a freeze-dried powder. Such a dispersed freeze-dried system comprises a plurality of powder particles, and due to the freeze-drying process used to form the powder, each particle has an irregular porous microstructure through which the powder can absorb water very quickly, thereby resulting in rapid dissolution. Foaming compositions are also contemplated to facilitate rapid dispersion and absorption of the compound.

[0447] Another type of multiparticulate system that can also achieve rapid drug dissolution is a powder, granule, or pellet formed from a water-soluble excipient that is coated with a compound as provided herein so that the compound is located at the outer surface of the individual particles. In this type of system, a water-soluble low molecular weight excipient can be suitable for preparing the core of such coated particles, which can then be coated with a coating composition comprising the compound and, for example, one or more other excipients (e.g., a binder, a pore former, a sugar, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions).

[0448] Kits are also provided herein. Typically, kits include one or more compounds or compositions as described herein. In certain embodiments, the kit may include one or more delivery systems (e.g., for delivering or administering a delivery system for a compound as 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 as described herein and a label indicating that the contents are to be administered to a patient suffering from cancer. In another embodiment, the kit may include a compound or composition as described herein and a label indicating that the contents are to be administered to a patient suffering from one or more of the following: glioblastoma, ovarian cancer, breast cancer, pancreatic cancer, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, chronic myeloid leukemia, Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency, Down syndrome, frontotemporal dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's disease, Pick's disease, autism, dementia, epilepsy, Huntington's disease, and multiple sclerosis.

[0449] Treatment

[0450] The compounds and compositions provided herein can be used as inhibitors of DYRK1A and are therefore useful in treating various conditions and diseases involving overexpression of DYRK1A, such as cancer and neurological disorders / conditions / 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 syndrome, frontotemporal dementia with Parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson's disease, Pick's disease, and other diseases with significant neurodegeneration such as autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; diseases and conditions associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumors, stroke, tauopathy (e.g., Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, Primary age-related tauopathies (which include neurofibrillary tangle dementia), chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and aging-related tauogliopathy. Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson syndrome, Parkinsonism, pure akinesia with freezing of gait and rarely motor neuron symptoms 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 1 (HSV-1).

[0451] The gene encoding DYRK1A is located on chromosome 21, within the Down syndrome critical region (DSCR), and its triploidy is responsible for most Down syndrome-associated defects (FEBS Journal (2011), 278, 246-256). There is considerable genetic and pharmacological evidence showing that just 1.5-fold overexpression of DYRK1A is responsible for most of the cognitive deficits observed in patients with Down syndrome. (Pharmacology & Therapeutics (2019), 194, 199-221 and Brain Science (2018), 8(10), 187). Genetic normalization of DYRK1A levels or pharmacological inhibition of its catalytic activity restores cognitive function. The development of pharmacological inhibitors of DYRK1A is a major approach for treating cognitive deficits associated with Down syndrome.

[0452] DYRK1A and DYRK1B are utilized during human cytomegalovirus (HCMV) placental replication. Inhibition of DYRKs blocks the replication of various viruses, including hepatitis C virus (HCV), human cytomegalovirus (HCMV), human immunodeficiency virus type 1 (HIV-1), and herpes simplex virus 1 (HSV-1) (Journal of Virology (2020), 94(6) and PLoS ONE (2015), 10, e0144229).

[0453] 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 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 may be treated with DYRK inhibitors are maturity-onset diabetes of the young (MODY, monogenic diabetes), cases of diabetes caused by the body's tissue receptors not responding to insulin, dual diabetes (when type 1 diabetes becomes insulin-resistant), diabetes associated with overproduction of insulin-resistant hormones, malnutrition-related diabetes (ICD-10 code E12), and diabetes caused by any genetic mutation (autosomal or mitochondrial) that results in defective beta-cell function.

[0454] There is a large body of literature linking DYRK1A to solid cancers and leukemias (Pharmacology & Therapeutics (2015), 151, 87-98; Cancers (2020), 12(8), 2106; and Cellular and Molecular Life Sciences (2021), 78, 603-619). The most prominent examples are pancreatic cancer (Gut (2019), 68(8), 1465-1476 and Gene (2020), 758, 144960), brain tumors, glioblastoma (Journal of Clinical Investigation (2013), 123(6), 2475-2487), acute megakaryoblastic leukemia (AMKL) (Journal of Clinical Investigation (2012), 122(3), 948-962) 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, 637-193), head and neck squamous cell carcinoma (Scientific Reports (2016), 6, 36-132), 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 cases, DYRK1A appears to act as a tumor suppressor protein (Molecular & Cellular Oncology (2015), 2(1), e970048 and Nature (2016), 529, 172-177).

[0455] Other cancers may also be treated with the compounds and compositions described herein.

[0456] More particularly, cancers treatable by the compounds, compositions, and methods described herein include, but are not limited to, the following:

[0457] 1) Breast cancer, including ER + Breast cancer, ER - Breast cancer, HER2 - Breast cancer, HER2 +Breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors and sarcomas, and epithelial tumors such as large duct papilloma; breast carcinomas, including: in situ (non-invasive) carcinomas, including ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) 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 mixed malignant neoplasms. Other examples of breast cancer may include luminal cell A type, luminal cell B type, basal cell A type, basal cell B type and triple-negative breast cancer, which is estrogen receptor negative (ER - ), progesterone receptor negative and HER2 negative (HER2 - In some embodiments, a breast cancer may have a high-risk Oncotype score.

[0458] 2) Cardiac cancers, including, for example, sarcomas, such as angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyomas; fibromas; lipomas, and teratomas.

[0459] 3) Lung cancer, including, for example, bronchogenic carcinomas, such as squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinomas; alveolar and bronchiolar carcinomas; bronchial adenomas; sarcomas; lymphomas; enchondroma, hamartomas; chemotherapy-resistant small cell lung cancer (SCLC), and mesothelioma.

[0460] 4) Gastrointestinal cancers, including, 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 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; and colorectal cancer, such as adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.

[0461] 5) Genitourinary tract cancers, including, for example, renal cancer, such as adenocarcinoma, Wilm's tumor (Nephroblastoma), lymphoma, and leukemia; bladder and urethral cancer, such as squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; prostate cancer, such as adenocarcinoma and sarcoma; testicular cancer, such as seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma.

[0462] 6) Liver cancer, including, for example, liver cancer, such as hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

[0463] 7) Bone cancer, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochrondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0464] 8) Cancers of the nervous system, including, for example, skull cancers, such as osteomas, hemangiomas, granulomas, xanthomas, and osteitis deformans; meningeal cancers, such as meningiomas, meningiosarcomas, and gliomatosis; brain cancers, such as astrocytomas, medulloblastomas, gliomas, ependymomas, blastomas (pinealomas), glioblastomas multiforme, oligodendrogliomas, oligodendrocytomas, schwannomas, retinoblastomas, and congenital tumors; and spinal cord cancers, such as neurofibromas, meningiomas, gliomas, and sarcomas.

[0465] 9) Gynecological cancers, including, for example, uterine cancer, such as endometrial cancer (e.g., carcinoma, endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, mixed or undifferentiated carcinoma (including mixed Müllerian tumor), endometrial stromal sarcoma, endometrial squamous cell carcinoma, urothelial carcinoma, endometrial carcinoma with CTNNB1 mutation); cervical cancer, such as cervical cancer and preneoplastic cervical dysplasia; ovarian cancer, such as BRCA mutant ovarian cancer, surface epithelial stromal tumor (epithelial ovarian cancer (type 1 (endometrioid, mucinous, clear cell, low-grade serous) or type 2 (dysdifferentiated, carcinosarcoma and high-grade serous))), ovarian cancer, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid tumor, small cell ovarian cancer (small cell ovarian cancer hypercalcemic type, small cell ovarian cancer pulmonary type) unclassified carcinoma, granulosa cell tumor, Sertoli cell carcinoma Leydig cell tumors, dysgerminomas, and malignant teratomas; vulvar cancers, such as squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; vaginal cancers, such as clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and fallopian tube cancers, such as carcinoma, primary fallopian tube carcinoma; primary peritoneal carcinoma (also known as serous superficial papillary carcinoma, primary peritoneal carcinoma, extraovarian serous carcinoma, primary serous papillary carcinoma, and psammomacarcinoma).

[0466] 10) Hematologic cancers, including, for example, hematologic cancers such as acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome (refractory cytopenia with single lineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts I and II, refractory cytopenia in children) and myeloproliferative neoplasms, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, myelodysplastic-myeloproliferative disorders, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), and Waldenstrom's macroglobulinemia ( macroglobulinemia).

[0467] 11) Skin cancers and skin disorders, including, for example, malignant and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, and scleroderma.

[0468] 12) Adrenal cancer, including, for example, neuroblastoma.

[0469] 13) Soft tissue sarcomas (STS), such as fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangioendothelioma, Kaposi's sarcoma, lymphangiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor (also known as neurofibrosarcoma, malignant schwannoma, and neurosarcoma), neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, extraskeletal mesenchymal, embryonal, alveolar soft part sarcoma, and infantile hemangio-pericytoma.

[0470] More particularly, central nervous system tumors treatable by the compounds, compositions, and methods described herein include:

[0471] 1) Astrocytic tumors, such as diffuse astrocytomas (fibrous, protoplasmic, feeder cell, mixed), anaplastic (malignant) astrocytomas, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), piloastrocytomas (pilomyxoid astrocytoma), pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma and gliomatosis cerebri.

[0472] 2) Oligodendroglial tumors, such as oligodendroglioma and anaplastic oligodendroglioma.

[0473] 3) Oligoastrocytic tumors, such as oligoastrocytoma and anaplastic oligoastrocytoma.

[0474] 4) Ependymal tumors, such as subependymoma, myxopapillary ependymoma, ependymoma (cellular, papillary, clear cell, subependymoma) and anaplastic (malignant) ependymoma.

[0475] 5) Choroid plexus tumors, such as choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma.

[0476] 6) Neuronal and mixed neuronal-glial tumors, such as gangliocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplastic cerebellar gangliocytoma (Lhermitte-Duclos), desmoplastic infantile astrocytoma / ganglioglioma, central neurocytoma, degenerative ganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma, papillary glioneuronal tumor, rosette-forming glioneuronal tumor of the fourth ventricle, and paraganglioma of the filum terminale.

[0477] 7) Pineal tumors, such as pineocytoma, pineoblastoma, pineal region papillary tumor and moderately differentiated pineal parenchymal tumor.

[0478] 8) Embryonal tumors, such as medulloblastoma (generalized nodular medulloblastoma, anaplastic medulloblastoma, desmoplastic, large cell, melanotic, medulloblastoma), medulloepithelioma, supratentorial primitive neuroectodermal tumor, and primitive neuroectodermal tumors (PNETs), such as neuroblastoma, ganglioblastoma, ependymoma, and atypical teratoid / rhabdoid tumor.

[0479] 9) Neuroblastomas, such as olfactory (sensitive neuroblastoma), olfactory neuroepithelioma, and neuroblastomas of the adrenal glands and sympathetic nervous system.

[0480] 10) Glial tumors, such as astroblastoma, third ventricular chordoid glioma, and angiocentric glioma.

[0481] 11) Cranial nerve and paraspinal nerve tumors, such as schwannoma, neurofibromatosis, perineurioma, and malignant peripheral nerve sheath tumor.

[0482] 12) Meningeal tumors, such as meningeal epithelial cell tumors, such as meningiomas (atypical meningiomas and degenerative meningiomas); mesenchymal tumors, such as lipoma, angiolipoma, dormant lipoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, hemangioma, epithelioid hemangioendothelioma, hemangiopericyoma, degenerative hemangiopericyoma, angiosarcoma, Kaposi's sarcoma, and Ewing's sarcoma; primary melanocytic lesions, such as diffuse melanocytosis, melanocytoma, malignant melanoma, meningeal melanomatosis; and hemangioblastoma.

[0483] 13) Tumors of the hematopoietic system, such as malignant lymphocytoma, plasmacytoma and granulocytic sarcoma.

[0484] 14) Germ cell tumors, such as blastoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma and mixed germ cell tumor.

[0485] 15) Tumors of the sellar region, such as craniopharyngioma, granular cell tumor, pituicytoma, and adenohypophyseal spindle cell oncocytoma.

[0486] Cancer can be a solid tumor, which may or may not be metastatic. Cancer can also occur as a spread of tissue, such as in leukemia. Thus, the term "tumor cell" as provided herein includes cells afflicted by any of the above-identified conditions.

[0487] Methods of treating cancer using compounds or compositions as described herein can be combined with existing methods of treating cancer, for example, by chemotherapy, radiation or surgery (e.g., oophorectomy). In some embodiments, the compounds or compositions can be administered before, during, or after another anticancer agent or treatment.

[0488] There is increasing evidence for a role for DYRK1A in the onset of Alzheimer's disease (Future Medicinal Chemistry (2016), 8(6), 681-696 and European Journal of Medicinal Chemistry (2018), 158, 559-592). DYRK1A phosphorylates the following 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 Tau exon 10, DYRK1A favors the production of the 3R-Tau splice isoform (specific for DS / AD / tauopathy) over the 4R-Tau isoform (Journal of Biological Chemistry (2015), 290, 15219-15237).

[0489] 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 microRNAs specific for Parkinson's disease targets DYRK1A expression. There is additional evidence that DYRK1A expression is increased in Parkinson's disease and Pick's disease (Neurobiology of Disease (2005), 20 (2), 392-400).

[0490] The compounds and compositions provided herein are useful as inhibitors and / or modulators of the enzyme DYRK1A and, therefore, are useful in treating a variety of tau-related conditions and diseases, including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Down syndrome, frontotemporal dementia (FTD) (including FTD with parkinsonism-17 (FTDP-17)), behavioral variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis, also known as FTD-ALS), corticobasal degeneration (CBD) (also known as corticobasal ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), globular glial tauopathy (GGT), myotonic dystrophy type 1 (DM1) (also known as Steinert disease), myotonic dystrophy type 2 (DM2) (also known as proximal myotonic myopathy), Guam complex (Guam complex), and other tau-related diseases. complex), argyrophilic grain disease, dementia pugilistica, postencephalitic parkinsonism, dementia with Lewy bodies, Parkinson's disease, Pick's disease, and additional disorders with significant neurodegeneration such as autism, dementia, epilepsy, Huntington's disease, and multiple sclerosis; and diseases and conditions associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumors, and stroke.

[0491] Non-limiting examples of neurological disorders (e.g., neurological conditions and neurological diseases) that can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnitis, telangiectasia disorder, 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 disorders, cerebral aneurysms, cerebral arteriosclerosis, brain atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical stenosis, Charcot-Marie-Tooth disease, 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 palsy, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalovirus inclusion disease (CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease disease), delayed sleep phase syndrome, dementia, dermatomyositis, developmental movement disorder, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dysarithmia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, cerebral trigeminal angiomatosis, fecal incontinence, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr syndrome, familial spastic paralysis, febrile cramps, Fisher syndrome, Friedreich's ataxia, myalgia, Foville syndrome, Gaucher's disease disease), Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, cerebral gray matter shift, cerebral gray matter heterotopia, Guillain-Barré syndrome, HTLV-1-associated myelopathy, Hallervorden-Spatz diseasedisease), hemifacial spasm, hereditary spastic paraplegia, polyneuritic movement disorders, herpes zoster virus ototoxicity, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington disease, hydrocephalus, hydrocortisoneuria, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel-Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease disease), Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, Wallenberg syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, dementia with Lewy bodies, flat brain, locked-in syndrome, Lou Gehrig's disease, intervertebral disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (spinocerebellar disorder type 3), megalencephaly, macrocephaly, megalencephaly, Melkersson-Rosenthal syndrome, Meniere's disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, macrocephaly, Miller's disease Fisher syndrome, misophonia, mitochondrial myopathy, Mobius syndrome, monomelic muscular dystrophy, motor neuron disease, motor skill impairment, Moyamoya diseasedisease), mucopolysaccharidosis, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, diffuse demyelinating sclerosis, infantile spastic encephalopathy, myoclonus, myopathy, myotubular myopathy, myotonia congenita, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital neuralgia, occult spinal dysraphism sequence, Ohtahara syndrome syndrome), olivopontocerebellar atrophy, opsoclonus-myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesias, Parkinson disease, paramyotonia congenita, paraneoplastic disorders, paroxysmal seizures, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralysis, peripheral neuropathy, photosensitivity sneeze reflex, phytanic acid storage disease, Pick disease, polymicrogyria (PMG), polymyositis, pyreneal malformation, postpoliomyelitis syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, cerebral pseudotumor, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration disorder, ventricular septal defect with optic nerve hypoplasia, Shy-Drager syndrome, syndrome, postprandial sneezing, Sotos syndrome, spasticity, spina bifida, spinal cord tumor, spinal muscular atrophy, spinocerebellar disorder, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive neuropathy, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered cord syndrome, Thomsen disease, thoracic outlet syndrome, trigeminal neuralgia (tic douloureux), Todd palsy, Tourette syndrome 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 disease, Hoffman disease, West syndrome, Williams syndrome, Wilson's disease, and Zellweger syndrome.

[0492] The compounds and compositions may also be useful in inhibiting the development of aggressive cancers, tumor angiogenesis, and cancer metastasis.

[0493] 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.

[0494] In some embodiments, the disorder or disease is cancer.

[0495] In some embodiments, the disorder or disease is metastatic melanoma.

[0496] In some embodiments, the disorder or disease is tendon regeneration.

[0497] In some embodiments, the condition or disease is diabetes.

[0498] In some embodiments, the condition or disease is degenerative disc disease.

[0499] In some embodiments, the condition or disease is osteoarthritis.

[0500] In some embodiments, the condition or disease is a viral infection.

[0501] In some embodiments, the disorder or disease is a neurological disorder.

[0502] In some embodiments, the condition or disease is Alzheimer's disease.

[0503] In some embodiments, the condition or disease is osteoarthritis.

[0504] In some embodiments, the patient is a human.

[0505] In some embodiments, the cancer is selected from the group consisting of hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma, and ovarian cancer.

[0506] In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, synovial sarcoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer - melanoma, small intestine cancer, stomach (gastric) cancer, testicular cancer, thymic 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 tumor, esophageal cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumors, bone cancer metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer, and adrenocortical carcinoma.

[0507] 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 lymphoma; in some embodiments, the cancer is a lymphoma; in some embodiments, the cancer is a 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 skin cancer - basal and squamous cell; in some embodiments, the cancer is skin cancer - melanoma; in some embodiments, the cancer is small intestine cancer; in some embodiments, the cancer is stomach (gastric) cancer; in some embodiments, the cancer is testicular cancer; in some embodiments, the cancer is thymic cancer; 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 a laryngeal or hypopharyngeal cancer; in some embodiments, the cancer is renal 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 an eye cancer (melanoma and lymphoma); in some embodiments, the cancer is Ewing's tumor; in some embodiments, the cancer is esophageal cancer; in some embodiments, the cancer is endometrial cancer;In some embodiments, the cancer is colorectal cancer; in some embodiments, the cancer is cervical cancer; in some embodiments, the cancer is a brain or spinal cord tumor; in some embodiments, the cancer is a bone cancer metastasis; in some embodiments, the cancer is bone cancer; in some embodiments, the cancer is bladder cancer; in some embodiments, the cancer is bile duct cancer; in some embodiments, the cancer is anal cancer; and in some embodiments, the cancer is adrenocortical carcinoma.

[0508] In some embodiments, the condition or disease is a neurological disorder, condition or disease, wherein the neurological disease is selected from the group consisting of: 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, degenerative myopathy.

[0509] In some embodiments, the condition or disease is selected from the group consisting of: Alzheimer's disease, amyotrophic lateral sclerosis, Down 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 conditions associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumors, and stroke.

[0510] In some embodiments, the compound of Formula I inhibits DYRK1A.

[0511] In some embodiments, the method treats a disease or condition in a patient mediated by kinase activity, comprising administering to the patient a therapeutically effective amount of a compound of Formula I (or compounds of Formula I) or a pharmaceutically acceptable salt thereof.

[0512] In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.

[0513] In some embodiments, the method inhibits the activity of a protein kinase receptor, comprising contacting the receptor with an effective amount of a compound of Formula I (or multiple compounds of Formula I) or a pharmaceutically acceptable salt thereof.

[0514] In some embodiments, the method treats a disease or condition associated with abnormal cell proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound of Formula I (or compounds of Formula I) or a pharmaceutically acceptable salt thereof.

[0515] In some embodiments, the method prevents or reduces abnormal cell proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound of Formula I (or compounds of Formula I) or a pharmaceutically acceptable salt thereof.

[0516] In some embodiments, the method treats a disease or condition associated with abnormal cell proliferation in a patient, comprising administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more additional agents.

[0517] Evaluation of biological activity

[0518] 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 assays outlined below.

[0519] For example, an in vitro assay for DYRK1A biological activity can be used, such as for the regulation of microtubule-associated protein tau (MAPT / Tau) phosphorylation in a neuronal cell line (e.g., a human SH-SY5Y neuroblastoma cell line). Assays for DYRK1A-regulated phosphorylation levels can include monitoring basal pSer396 Tau levels, which can be measured, for example, by using serial dilutions of a candidate inhibitor composition at a ten-micromolar maximum concentration and detected by ELISA or Western blotting. An exemplary assay for DYRK-1A-regulated phosphorylation utilizes SH-SY5Y cells cultured in a 96-well plate format for a period sufficient to stabilize microtubule and Tau phosphorylation, typically at least 2 days, followed by overnight treatment with 1 / 3 serial dilutions of the compound and lysis. Cell lysates are resolved by SDS PAGE, then transferred to nitrocellulose and probed with an antibody specific for pSer396 Tau. Chemiluminescent signals of HRP-linked antibodies used in Western blots were detected using Carestream Image Station, and blot densitometry for pSer396 and β-actin was analyzed using ImageJ (NIH).

[0520] In another example, the activity of the candidate compound can be measured by adding the above-mentioned lysate to a plate coated with total Tau and detecting it with a specific pThr212Tau antibody by phosphoTau (Thr212) AlphaLISA. Colorimetric detection of the AlphaLISA signal is performed by an EnVision multi-label plate reader (Perkin Elmer).

[0521] 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 those skilled 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 those skilled in the art who are familiar with the present disclosure and the art will be able to prepare and use the present disclosure without the need for detailed examples.

[0522] Example

[0523] Compound preparation

[0524] The starting materials used to prepare the compounds of the present disclosure are known, prepared by known methods, or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and functional groups related to the compounds claimed herein are generally described in the literature. The skilled artisan, armed with the literature and this disclosure, is fully prepared to prepare any of the compounds described.

[0525] It will be appreciated that those skilled in the art of organic chemistry can readily perform the operations without further guidance, i.e., it is well within the scope and practice of those skilled in the art to perform these operations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, electrophilic and nucleophilic aromatic substitutions, etherifications, esterifications, and saponifications, etc. These operations are discussed in standard texts, such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7th Edition, John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5th Edition, Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2nd Edition, John Wiley & Sons (1999) (incorporated herein by reference in its entirety), etc.

[0526] The skilled artisan will readily appreciate that certain reactions are best performed when other functional groups in the molecule are masked or protected, thereby avoiding any undesirable side reactions and / or improving the reaction yield. The skilled artisan typically utilizes protecting groups to achieve such yield improvements or avoid undesirable reactions. These reactions are found in the literature and are well within the skill of the skilled artisan. Examples of many of these procedures can be found, for example, in P. Wuts Greene's Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons (2014), which is incorporated herein by reference in its entirety.

[0527] The trademarks used herein are examples only and reflect the illustrative material used in this disclosure. A skilled artisan will recognize that variations in batches, manufacturing processes, etc. can be expected. Therefore, the examples and the trademarks used therein are non-limiting, and they are not intended to be limiting, but are merely illustrative of how a skilled artisan may choose to implement one or more of the embodiments of the present disclosure.

[0528] ( 1 H) Nuclear magnetic resonance spectroscopy (NMR) was performed on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHz, 1 H, or Avance™ DRX500, 500MHz, 1 H) or Varian NMR spectrometer (Mercury 400BB, 400 MHz, 1 H) were measured in the indicated solvents. Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. Peak multiplicities are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublet; ddd, doublet of doublet of doublet; d / ABq, doublet of AB quartet; dt, doublet of triplet; td, triplet of doublet; dq, doublet of quartet; m, multiplet.

[0529] The following abbreviations have the designated meanings:

[0530] Ac2O = acetic anhydride

[0531] Boc = tert-butyloxycarbonyl

[0532] B(OiPr)3=triisopropyl borate

[0533] BrettPhos = dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine

[0534] BrettPhos Pd G3 = [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) methanesulfonate

[0535] Brine = saturated sodium chloride aqueous solution

[0536] nBuLi = n-butyllithium

[0537] CDCl3=deuterated chloroform

[0538] (COCl)2=oxalyl chloride

[0539] Cs2CO3=cesium carbonate

[0540] DCE = 1,2-dichloroethane

[0541] DCM = dichloromethane

[0542] DIPEA=N,N-diisopropylethylamine

[0543] DME = 1,2-dimethoxyethane, or ethylene glycol dimethyl ether, or monoethylene glycol dimethyl ether

[0544] DMF=N,N-dimethylformamide

[0545] DMPU=N,N'-dimethylpropyleneurea

[0546] DMSO-d6 = deuterated dimethyl sulfoxide

[0547] ESIMS = Electrospray Mass Spectrometry

[0548] EtOAc = ethyl acetate

[0549] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0550] HCl = hydrochloric acid

[0551] HOAc = acetic acid

[0552] IPA = Isopropyl alcohol

[0553] ISCO=Teledyne ISCO, Inc., brand Rf 200

[0554] KOAc = potassium acetate

[0555] LCMS = Liquid Chromatography-Mass Spectrometry

[0556] LiHMDS = Lithium Bis(trimethylsilyl)amide

[0557] MeCN = acetonitrile

[0558] MeOH = methanol

[0559] MeTHF = 2-methyltetrahydrofuran

[0560] MgSO4 = magnesium sulfate

[0561] MsCl = methanesulfonyl chloride / mesyl chloride

[0562] MTBE = methyl tert-butyl ether

[0563] MW = microwave irradiation

[0564] NaO t Bu = sodium tert-butoxide

[0565] NaHCO3 = Sodium bicarbonate

[0566] NaBH(OAc)3=sodium triacetoxyborohydride

[0567] Na2SO4=Sodium sulfate

[0568] NMR = Nuclear Magnetic Resonance

[0569] ON=Overnight

[0570] Pd / C = Palladium / Carbon

[0571] Pd(dppf)Cl2=1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride

[0572] Pd(OH)2 / C=Palladium hydroxide / carbon

[0573] PE = Petroleum Ether

[0574] PPTS = Pyridinium p-toluenesulfonate

[0575] Preparative TLC = Preparative Thin Layer Chromatography

[0576] QPhos=1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene

[0577] rt = room temperature

[0578] TBDMSCl = tert-butyldimethylsilyl chloride

[0579] TEA = triethylamine

[0580] TFA = trifluoroacetic acid

[0581] THF = Tetrahydrofuran

[0582] TLC = Thin Layer Chromatography

[0583] TMSOK = Potassium trimethylsilanolate

[0584] XPhos = dicyclohexyl[2',4',6'-tri(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphane

[0585] The following examples are provided to guide the reader and generally represent the example methods for making the compounds provided herein. In addition, according to the following reaction schemes and examples, other methods for preparing the disclosed compounds will be readily apparent to those of ordinary skill in the art. Skilled artisans are fully prepared to prepare these compounds by those methods of the literature and the present disclosure. The compound numbers used in the synthetic schemes described below are only used for those specific schemes and should not be considered as identical numbers in other parts of the application or confused with identical numbers in other parts of the application. Unless otherwise indicated, all variables are as defined above.

[0586] General Procedures

[0587] Compounds of Formula I of the present disclosure can be prepared as depicted in Scheme 1.

[0588]

[0589] Scheme 1 describes a method for preparing 4-alkoxypyrrolo[2,1-f][1,2,4]triazine derivatives (VII) by first displacing the 4-chloride ion (I) with various alkyl oxides (II) to produce 2-chloro-5-bromo-4-alkoxypyrrolo[2,1-f][1,2,4]triazine III. Various bromides (IV) are reacted with bis(pinacolato)diboron, followed by Suzuki coupling with bromide (III) to form various pinacol boronic acid esters, thereby producing 2-chloro-4-alkoxypyrrolo[2,1-f][1,2,4]triazine (V). The chloride is then displaced with various amines (VI) to produce the final 4-alkoxypyrrolo[2,1-f][1,2,4]triazine (VII).

[0590] Illustrative Compound Examples

[0591] The preparation of the intermediate 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) is depicted in Scheme 2 below.

[0592]

[0593] Step 1

[0594] To a solution of 3-bromo-1H-pyrrole-2-carboxylic acid methyl ester (VIII) (100 g, 490.15 mmol, 1 eq.) in MeCN (2 L) was added Cs2CO3 (255.52 g, 784.23 mmol, 1.6 eq.) (no exotherm) at 20 ° C. The reactant was stirred at room temperature for 5 h. A solution of O-(2,4-dinitrophenyl)hydroxylamine (146.40 g, 735.22 mmol, 1.5 eq.) in MeCN (2 L) was then added dropwise at 0 to 5 ° C under N2. After addition, the reactant 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 x 3). The above reaction was carried out six times.

[0595] The combined organics of the five batches were combined, dried over MgSO 4 , filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (DCM / PE = 0 to 50%, then EtOAc / PE = 20%) to give 1-amino-3-bromo-1H-pyrrole-2-carboxylic acid methyl ester (IX) (380 g, 1.62 mol, 55.1% yield, 93.3% purity) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 3.84 (3H, s), 6.24 (1H, d, J = 2.8Hz), 6.38 (2H, br s), 7.12 (1H, d, J = 2.8Hz).

[0596] Steps 2 to 3

[0597] To a solution of 1-amino-3-bromo-1H-pyrrole-2-carboxylic acid methyl ester (IX) (190 g, 867.44 mmol, 1 eq.) in THF (1900 mL) was added 2,2,2-trichloroacetyl isocyanate (179.76 g, 954.18 mmol, 113.06 mL, 1.1 eq.) at 0 to 5 ° C., and then warmed to room temperature for 1 hour. The reaction was then added dropwise to NH3 / MeOH (7 M, 1.24 L, 10 eq) at room temperature and stirred at room temperature for 1 hour to give a yellow suspension. The above reaction was carried out twice.

[0598] The two reactants are merged and concentrated in vacuo. In room temperature, MTBE (4L) is used to grind residue 30min, filter.Filter cake is washed with MTBE (500mLx3), vacuum dried, obtains 3-bromo-1-urea groups-1H-pyrroles-2-methyl-formiate (X) (402g, 1.53mol, 88.2% yield, 99.78% purity) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.75 (3H, s), 6.27 (2H, br s), 6.28 (1H, d, J = 2.8 Hz), 7.10 (1H, d, J = 2.8 Hz), 9.27 (1H, br s); ESIMS experimental value of C7H8BrN3O3 m / z 262.1 ( 79 BrM+H).

[0599] Step 4

[0600] To a solution of 3-bromo-1-ureido-1H-pyrrole-2-carboxylic acid methyl ester (X) (67 g, 255.67 mmol, 1 eq.) in THF (4 L) was added TMSOK (65.60 g, 511.33 mmol, 2 eq.) in portions at 0 to 5 ° C under N2. After stirring for 5 min, the reactant became a viscous slurry. The reaction mixture was vigorously stirred at room temperature for 16 h. LCMS showed that approximately 25.8% of the starting material remained. Another portion of TMSOK (16.40 g, 127.83 mmol, 0.5 eq.) was added at room temperature and stirred for 3 h. LCMS showed that the reaction was complete. The reactant was concentrated. The residue was diluted with H2O (1.6 L), cooled with an ice bath, and HCl (4 M, 160 mL) was added dropwise to a pH of 2 to 3, and filtered. The filter cake was washed with H2O (600 mL x 3). The above reaction was carried out six times.

[0601] The filter cakes from the six reactions were combined, triturated with H2O (6 L) at room temperature for 2 h, and then filtered. The filter cake was dried in a vacuum oven at 60°C for 24 h to afford 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 (1H, d, J = 2.8 Hz), 7.17 (1H, d, J = 2.8 Hz), 11.30 (1H, br s); ESIMS experimental value of C6H4BrN3O2 m / z 232.0 ( 81 BrM+H).

[0602] Step 5

[0603] 5-Bromopyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (XI) (180 g, 782.55 mmol, 1 eq.) was added portionwise to a POCl solution (1500 mL) at room temperature. N,N-diethylaniline (291.95 g, 1.96 mol, 312.92 mL, 2.5 eq.) was then added dropwise at room temperature (minimal exotherm). After addition, the reaction was heated to 105°C for 48 h. LCMS showed that the starting material was consumed, but the intermediate remained, with approximately 4.3% of the desired product formed. The reaction was cooled to 90°C, and POCl (500 mL) was added once more, then gently heated to reflux for 24 h. LCMS showed that most of the intermediate remained, with approximately 11.9% of the desired product formed. The reaction was gently heated to reflux for another 4 days. LCMS shows that about 7.4% intermediate remains, forming about 55.5% desired product. The reactant is cooled to 40 ° C and distilled under reduced pressure to remove most of POCl 3. The residue is diluted with MeTHF (5L), poured into ice H2O (2L), salt water (1L) is added, and separated. The aqueous layer is extracted with MeTHF (1.5Lx2). The combined organic matter is washed with salt water (1.5Lx2), dried over MgSO4, filtered and concentrated in vacuo to obtain a crude product. The crude product is purified by silica gel column chromatography (4kg, 100 to 200 mesh, DCM / PE=0 to 20%) and wet-milled with n-heptane (500mL) for 3h at room temperature, then filtered to obtain 5- bromo-2,4- dichloropyrrolo [2,1-f] [1,2,4] triazine (I) (150g, 556.14mmol, 71.1% yield, 98.96% purity) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.02 (1H, d, J = 2.4 Hz), 7.79 (1H, d, J = 2.4 Hz); ESIMS experimental value of C6H2BrCl2N3 m / z 266.1 ( 79 BrM+H).

[0604] Step 6

[0605] 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 dropwise MeOH containing sodium methoxide (66 mL, 33 mmol) at 0 ° C. and the mixture was stirred for 2 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl, dissolved in EtOAc, washed with water and brine. The organic matter was 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 (3H, s), 7.00 (1H, d, J = 3.01 Hz), 8.01 (1H, d, J = 3.01 Hz); ESIMS experimental value of C7H5BrClN3O m / z 261.1 ( 79 BrM+H).

[0606] The preparation of the intermediate 5-bromo-2-chloro-6-fluoro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XXII) is depicted in Scheme 3 below.

[0607]

[0608] Step 1

[0609] To a solution of 4-fluoro-1H-pyrrole-2-formic acid methyl ester (XIII) (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 mixture was quenched with 10% sodium thiosulfate (50 mL) and extracted with CHCl (3x30 mL). The organic layers were combined and washed with a saturated aqueous solution of NaCl (50 ml) and evaporated under reduced pressure to produce 3,5-dibromo-4-fluoro-1H-pyrrole-2-formic acid methyl ester (XIV) (2.1 g, 6.979 mmol, 99.9% yield) as a beige solid. The product was used as is without further purification. The ESIMS experimental value of C6H4Br2FNO2 was m / z 299.9 (M+H).

[0610] Step 2

[0611] To a solution of 3,5-dibromo-4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester (XIV) (2.1 g, 6.98 mmol) in anhydrous THF (25 mL) was added NaH (0.43 g, 10.63 mmol) in small portions at 0 ° C under N2. The suspension was stirred for 30 min at 0 ° C. To the suspension was added (2-(chloromethoxy)ethyl)trimethylsilane (1.9 mL, 10.74 mmol) at 0 ° C under N2. The reaction mixture was stirred for 2 h at 0 ° C, then quenched with ice water (20 mL) and extracted with EtOAc (3x30 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 HNMR (499MHz, DMSO-d6) δppm-0.07 (9H, s), 0.81 (2H, t, J = 7.80Hz), 3.50 (2H, t, J = 7.80Hz), 3.82 (3H, s), 5.69 (2H, s).

[0612] Step 3

[0613] 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 anhydrous THF (60 mL) was added nBuLi (2.4 mL, 6. mmol) at -78 ° C under N2. 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 (3x20 mL). The organics were dried over anhydrous Na2SO4, filtered and evaporated to The product was added to the above-mentioned column and purified by silica gel column chromatography (0→6% EtOAc / hexanes) to give 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 (500MHz, DMSO-d6) δppm-0.06 (9H, s), 0.80 (2H, t, J = 7.96Hz), 3.41-3.50 (2H, m), 3.80 (3H, s), 5.56 (2H, s), 7.52 (1H, d, J = 3.29Hz).

[0614] Step 4

[0615] 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 dissolved in a mixture of MeOH (12 mL) / water (6 mL). To this mixture was added KCO (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 CHCl (3x10 mL). The organic layer was stripped to The product was purified by silica gel column chromatography (0→5% MeOH / CHCl 3 (7N NH 3 )) to give methyl 3-bromo-4-fluoro-1H-pyrrole-2-carboxylate (XVII) as an off-white solid (450 mg, 2.027 mmol, 81.0% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 3.80 (3H, s), 7.15 (1H, d, J=3.56 Hz), 12.29 (1H, br s); ESIMS experimental value of C6H5BrFNO2 m / z 222.0 (M+H).

[0616] Step 5

[0617] To a solution of 3-bromo-4-fluoro-1H-pyrrole-2-formic acid methyl ester (XVII) (500mg, 2.25mmol) in anhydrous DMF (7mL) was slowly added NaH (120mg, 2.93mmol) at 0°C. After 30min, O-(2,4-dinitrophenyl)hydroxylamine (490mg, 2.48mmol) was added once and the reactant was stirred in an ice bath for 1h and stirred at room temperature for 1h. LC / MS showed that the reaction was incomplete, so O-(2,4-dinitrophenyl)hydroxylamine (490mg, 2.48mmol) was added and stirred at room temperature for 15min. The reactant was diluted with water (100mL) and extracted with EtOAc (3x75 mL). The combined extracts were stripped to 4% ethanol. The product was added to the above-mentioned solid and purified by silica gel column chromatography (100% CHCl 3 ) to give 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. 1H NMR (499 MHz, DMSO-d6) δ ppm 3.80 (3H, s), 6.36 (2H, s), 7.25 (1H, d, J = 3.29 Hz); ESIMS experimental value of C6H6BrFN2O2 m / z 237.0 (M+H).

[0618] Step 6

[0619] To a solution of 1-amino-3-bromo-4-fluoro-1H-pyrrole-2-carboxylic acid methyl ester (XVIII) (500 mg, 2.11 mmol) in DCM (10 mL) was added pyridine (210 μL, 2.6 mmol) and methyl chloroformate (180 μL, 2.33 mmol). The reaction was stirred at room temperature for 20 min. DCM (100 mL) was added and washed with 1N HCl (2x50 mL), which was stripped to 4% HCl. The product was 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 experimental value of C8H8BrFN2O4 m / z 295.0 (M+H).

[0620] Step 7

[0621] 3-Bromo-4-fluoro-1-((methoxycarbonyl)amino)-1H-pyrrole-2-carboxylic acid methyl ester (XIX) (560 mg, 1.9 mmol) was added to NH4OH (35 mL, 263.7 mmol) in a sealed tube. 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 (3 times to remove water) and placed on high vacuum for 1 h to produce 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 as is without further purification. 1H NMR (499 MHz, DMSO-d6) δ ppm 7.04 (1H, d, J = 3.29 Hz), 7.13 (1H, br s), 9.58 (1H, br s); ESIMS experimental value of C6H3BrFN3O2 m / z 247.9 (M+H).

[0622] Step 8

[0623] To a solution of pure POCl3 (3 mL, 32.19 mmol) was added 5-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazine-2,4(1H,3H)-dione (XX) (440 mg, 1.77 mmol) in portions 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, and water (20 mL) was added and extracted with EtOAc. The organic layer was stripped to The product was added to the supernatant and purified by silica gel column chromatography (0→100% EtOAc / hexanes) to give 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 (1H, d, J = 3.29 Hz); ESIMS experimental value of C6HBrCl2FN3 m / z 283.9 (M+H).

[0624] Step 9

[0625] 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 the reactant was stirred at room temperature for 16 h. Water (50 mL) was added and extracted with DCM (3x50 mL). The organic layer was separated and washed with water (2x50 mL) and brine (50 mL). The solvent was removed in vacuo to produce 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 (3H, s), 8.34 (1H, d, J = 3.29 Hz); ESIMS experimental value of C7H4BrClFN3O m / z 279.95 (M+H).

[0626] The preparation of the intermediate 2,5-dichloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XXIV) is depicted in Scheme 4 below.

[0627]

[0628] Step 1

[0629] To a stirred solution of 2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine (XXIII) (available from PharmaBlockSciences Inc.) (202 mg, 0.910 mmol) in THF (4 mL) was added dropwise MeOH containing sodium methoxide (2 mL, 1 mmol) at 0 ° C, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, dissolved in EtOAc and washed with brine. The organic matter was separated, dried over anhydrous Na2SO4, concentrated, and the crude mixture was purified by ISCO (0 → 100% EtOAc / hexane). The fractions were collected and concentrated under reduced pressure and dried under high vacuum to give 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XXIV) (140 mg, 0.642 mmol, 70.7% yield) as a light yellow solid. 1 H NMR (499MHz, DMSO-d6) δppm 4.12 (3H, s), 6.95 (1H, d, J = 3.01Hz), 8.02 (1H, d, J = 3.01Hz).

[0630] The following intermediates were prepared according to the procedure described in Scheme 4 above.

[0631]

[0632] 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). 1 H NMR (499 MHz, DMSO-d6) δ ppm 4.70 (2H, ddd, J = 7.94, 4.65, 1.10 Hz), 4.95 (2H, ddd, J = 7.73, 6.37, 0.96 Hz), 5.80 (1H, tt, J = 6.09, 4.86 Hz), 7.05 (1H, d, J = 3.01 Hz), 8.05 (1H, d, J = 3.01 Hz); ESIMS experimental value of C9H7BrClN3O2 is m / z 303.95 (M+H).

[0633] The preparation of intermediate 6-bromo-1-(2,2-difluoroethyl)-4-fluoro-2-methyl-1H-benzo[d]imidazole (XXX) is depicted in Scheme 5 below.

[0634]

[0635] Step 1

[0636] To an ice-cold 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, and then an ice-cold solution of 5-bromo-1,3-difluoro-2-nitrobenzene (XXVII) (2.0 g, 8.4 mmol) in THF (20 mL) was added. The reaction mixture was stirred for 2 h at 0 ° C. The reactant was quenched with water. The aqueous layer was extracted with EtOAc, the organic matter was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (40 g silica gel) (0 → 20% EtOAc / hexane) to obtain 5-bromo-N-(2,2-difluoroethyl)-3-fluoro-2-nitroaniline (XXVIII) (500 mg, 0.836 mmol, 19.9% ​​yield) as a yellow solid. The ESIMS experimental value of C8H6BrF3N2O2 is m / z 299.0 ( 79 BrM+H).

[0637] Step 2

[0638] 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 stirred for 2 hours. 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-[3-(2-bromo-3-oxo-4-yl)-1,2-dimethyl-1,2-dihydro ... 1 -(2,2-Difluoroethyl)-3-fluorobenzene-1,2-diamine (XXIX) (420 mg, 1.561 mmol, 93.4% yield) was used in the next reaction without further purification. ESIMS observed value of C8H8BrF3N2: m / z 269.0 (M+H).

[0639] Step 3

[0640] 5-Bromo-N 1A solution of 6-bromo-1-(2,2-difluoroethyl)-3-fluorobenzene-1,2-diamine (XXIX) (420 mg, 1.56 mmol) and Ac2O (175 μL, 1.85 mmol) in HOAc (8 mL) was heated to 120 °C for 16 h. The reaction mixture was concentrated and 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 Na2SO4 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. 10 H 10 ESIMS experimental value of BrF3N2 is m / z 295.0 (M+H).

[0641] The preparation of the intermediate 6-bromo-1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridine (XX XIV) is depicted in Scheme 6 below.

[0642]

[0643] Step 1

[0644] A mixture of 2,2-difluoroethane-1-amine (XXVI) (410 mg, 5.02 mmol), 5-bromo-3-fluoro-2-nitropyridine (XXXI) (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 h. The reactants were filtered and concentrated under high vacuum. The residue was dissolved in water, stirred for 1 hour and the solid was collected by filtration and dried under vacuum to give 5-bromo-N-(2,2-difluoroethyl)-2-nitropyridine-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. The ESIMS experimental value of m / z 282.0 ( 79 BrM+H).

[0645] Step 2

[0646] 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 NH4Cl (3.77 g, 70.48 mmol) was dissolved 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 stirred via 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-[3-(2-bromo-4-oxo-2-yl)-1-oxo-5-nitropropane]propane as a gray solid. 3 -(2,2-difluoroethyl)pyridine-2,3-diamine (XXXIII) (630 mg, 2.499 mmol, 53.2% yield), which was used in the next reaction without further purification. ESIMS experimental value of C7H8BrF2N3 m / z 252.0 ( 79 BrM+H).

[0647] Step 3

[0648] 5-Bromo-N 3 -(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) were heated to 120 ° C for 16 h. The reaction mixture was concentrated, the residue was partitioned between EtOAc / 1 N NaOH, the organic matter was separated, and washed with water and brine. The organic matter was dried over anhydrous Na2SO4, 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 experimental value of C9H8BrF2N3 m / z 276.0 ( 79 BrM+H).

[0649] The following intermediates were prepared according to the procedure described in Scheme 6 above.

[0650]

[0651] 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). 11 H 10ESIMS experimental value of BrF2N3 is m / z 302.1 (M+H).

[0652]

[0653] 6-Bromo-1-(2,2-difluoroethyl)-2-methyl-1H-benzo[d]imidazole (XXXVI): beige solid (970 mg, 3.526 mmol, 79.0% yield). 10 ESIMS experimental value of H9BrF2N2 is m / z 275.0 (M+H).

[0654] The preparation of the intermediate 6-bromo-1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine (XL) is depicted in Scheme 7 below.

[0655]

[0656] Step 1

[0657] 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 KCO (2.5 g, 18.1 mmol) in MeCN (40 mL) was stirred at room temperature for 16 h. The reaction mixture was added to water (200 mL), stirred for 1 h and the resulting solid was collected by filtration and dried under high vacuum to give 5-bromo-N-isopropyl-2-nitropyridine-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. CH 10 The ESIMS experimental value of BrN3O2 is m / z 260.0 (M+H).

[0658] Step 2

[0659] 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 NH4Cl (7.25 g, 135.53 mmol) was dissolved 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 stirred for 2 h via Filter, dissolve the filtrate in EtOAc, wash with water, then brine, dry over anhydrous Na2SO4, filter and concentrate under reduced pressure to give 5-bromo-N-[3-(2-bromo-3-oxo-4-yl)-1-oxo-4-nitropropane]-2-nitropropane as a dark brown solid. 3-isopropylpyridine-2,3-diamine (XXXIX) (2.2 g, 9.561 mmol, 105.8% yield), which was used in the next step without purification. 12 The ESIMS experimental value of BrN3 is m / z 230.05 (M+H).

[0660] Step 3

[0661] 5-Bromo-N 3 A solution of -isopropylpyridine-2,3-diamine (XXXIX) (2.08 g, 9.04 mmol) and Ac2O (1.05 mL, 10.84 mmol) in HOAc (20 mL) was heated to 120 ° C for 16 h. The reaction mixture was concentrated and the residue was partitioned between EtOAc / 1N NaOH. The organic matter was separated and washed with water and brine. The organic matter was dried over anhydrous Na2SO4, 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. C 10 H 12 ESIMS experimental value of BrN3 is m / z 254.0 (M+H).

[0662] The following intermediates were prepared according to the procedure described in Scheme 7 above.

[0663]

[0664] 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). 12 H 14 ESIMS experimental value of BrN3O: m / z 296.0 (M+H).

[0665] The preparation of intermediate 6-bromo-1-(2,2-difluoroethyl)-1H-benzo[d]imidazole (XLIII) is depicted in Scheme 8 below.

[0666]

[0667] Step 1

[0668] 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 h 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 20-4 μm, acetonitrile / 0.1% NH4HCO3 aqueous solution, 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, 2H); ESIMS experimental value of C9H7BrF2N2 m / z 260.9 (M+H).

[0669] The preparation of the intermediate 5-chloro-3-ethyl-2-methyl-3H-imidazo[4,5-b]pyridine (XLV) is depicted in Scheme 9 below.

[0670]

[0671] Step 1

[0672] 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 K2CO3 (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, the residue was partitioned between EtOAc / water, the organic layer was separated, washed with brine, dried over anhydrous MgSO4 and the solvent was concentrated in vacuo and dried to 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. C9H 10ESIMS experimental value of ClN3: m / z 196.05 (M+H).

[0673] The following intermediates were prepared according to the procedure described in Scheme 9 above.

[0674]

[0675] 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 observed value of C9H8ClF2N3: m / z 232.0 (M+H).

[0676]

[0677] 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 observed value of C9H9ClFN3: m / z 214.05 (M+H).

[0678]

[0679] 5-Chloro-3-(2-methoxyethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XLVIII): beige solid (195 mg, 0.864 mmol, 48.3% yield). 10 H 12 ESIMS experimental value of ClN3O: m / z 226.1 (M+H).

[0680]

[0681] 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 C 11 H 14 ESIMS experimental value of ClN3O: m / z 240.1 (M+H).

[0682]

[0683] 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 (499MHz, DMSO-d6) δppm0.87 (6H, d, J = 6.57Hz), 2.22 (1H, dquin, J = 13.89, 7.07, 7.07, 7.07, 7.07Hz), 2.58 (3H,s), 4.01 (2H, d, J = 7.67Hz), 7.26 (1H, d, J = 8.21Hz), 7.98 (1H, d, J = 8.21Hz); C 11 H 14 ESIMS experimental value of ClN3: m / z 224.1 (M+H).

[0684]

[0685] 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 observed value of C9H7ClF3N3: m / z 250.0 (M+H).

[0686]

[0687] 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(499MHz,DMSO-d6)δppm 2.59(3H,s),3.43-3.56(1H,m),4.47(2H,t,J=6.02Hz), 4.52(2H,d,J=7.67Hz), 4.62(2H,dd,J=7.67,6.02Hz),7.27(1H,d,J=8.21Hz),7.98(1H,d,J=8.21Hz);C 11 H 12 ESIMS experimental value of ClN3O is m / z 238.1 (M+H).

[0688]

[0689] 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). 16 H 21 ESIMS experimental value of ClN4O2 is m / z 337.1 (M+H).

[0690]

[0691] 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). 11 H 13 ESIMS experimental value of ClN4O: m / z 253.1 (M+H).

[0692]

[0693] 3-(5-Chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,2-dimethylpropionitrile (LV): off-white amorphous solid (59.1 mg, 0.238 mmol, 7.9% yield). 12 H 13 ESIMS experimental value of ClN4 is m / z 249.1 (M+H).

[0694] The preparation of the intermediate 6-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methyl-1H-benzo[d]imidazole (LXII) is depicted in Scheme 10 below.

[0695]

[0696] Step 1

[0697] A solution of 4-bromo-2-fluoro-1-nitrobenzene (LVI) (2.0 g, 9.09 mmol) dissolved in 2-aminoethanol (LVII) (2.8 mL, 46.39 mmol) was stirred at room temperature for 10 min. Water (50 mL) was added and extracted with EtOAc and the mixture was stirred for 10 min. The residue was purified by silica gel column chromatography (0→100% EtOAc / hexanes) 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. 1H NMR (499 MHz, DMSO-d6) δ ppm 3.41 (2H, q, J = 5.48 Hz), 3.63 (2H, q, J = 5.48 Hz), 5.00 (1H, t, J = 5.34 Hz), 6.83 (1H, dd, J = 9.17, 2.05 Hz), 7.30 (1H, d, J = 1.92 Hz), 7.98 (1H, d, J = 9.03 Hz), 8.29 (1H, br t, J = 5.06 Hz); ESIMS experimental value of C8H9BrN2O3: m / z 260.96 (M+H).

[0698] Step 2

[0699] 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. The solvent was removed in vacuo, and HOAc (15.6 mL, 271.49 mmol) was added. The solution was heated to reflux for 30 min. 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 of off-white solids. 12 H 13 The ESIMS experimental value of BrN2O2 is m / z 297.0 (M+H).

[0700] Step 3

[0701] 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 h. The solution was neutralized with 1 N HCl and stripped to 4% by volume. The mixture was then purified using silica gel column chromatography (0→10% 7N NH3 in MeOH / CHCl3) 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. 10 H 11 ESIMS experimental value of BrN2O: m / z 255.0 (M+H).

[0702] Step 4

[0703] 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 N2 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 h. The solution was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3 (400 mL). The aqueous layer was stripped to 4% by volume using EtOAc. The reaction mixture was then purified using silica gel column chromatography (0→5% MeOH / CHCl 3 ) 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. 16 H 25 The ESIMS experimental value of BrN2OSi is m / z 369.1 (M+H).

[0704] The preparation of the intermediate 6-bromo-1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazole (LXV) is depicted in Scheme 11 below.

[0705]

[0706] Step 1

[0707] 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 and 2,2-difluoroethane-1-amine (LXIII) (36.6 g, 183.81 mmol) was added at 0 ° C. The reactant was allowed to warm to 40 ° C for 16 h. The reaction mixture was extracted with EtOAc (500 L x 3). The combined organic matter was washed with brine (500 mL x 3). The combined organic layer was dried over NaSO, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (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, J = 1.6 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 8.33 (t, J = 6.4 Hz, 1H); ESIMS experimental value of C8H7BrF2N2O2 m / z 280.9 (M+H).

[0708] Step 2

[0709] 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 minutes, then cooled to room temperature and filtered. Water (20 mL) containing NaNO2 (3.0 g, 53.58 mmol) was then 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 poured into EtOAc (300 mL) and H2O (300 mL). The pH was adjusted to >7 with NaHCO3. The reaction mixture was extracted with EtOAc (500 mL x 3). The combined organics were washed with brine (500 mL x 3). The organic layer was concentrated, dried over Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (10% EtOAc / PE→50% EtOAc / PE) to give 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 experimental value of C8H6BrF2N3 m / z 261.9 (M+H).

[0710] The following intermediates were prepared according to the procedure described in Scheme 11 above.

[0711]

[0712] 6-Bromo-1-ethyl-1H-benzo[d][1,2,3]triazole (LXVI): white solid (4.112 g, 18.188 mmol). 1 H NMR (400 MHz, DMSO-d6) δ8.30 (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 experimental value of C8H8BrN3 is m / z 225.9 (M+H).

[0713]

[0714] 6-Bromo-1-(2-fluoroethyl)-1H-benzo[d][1,2,3]triazole (LXVII): white solid (4.163 g, 17.057 mmol). 1 H NMR (400 MHz, DMSO-d6) δ8.29 (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 experimental value of C8H7BrFN3 m / z 244.0 (M+H).

[0715]

[0716] 6-Bromo-1-(2,2,2-trifluoroethyl)-1H-benzo[d][1,2,3]triazole (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 experimental value of C8H5BrF3N3 m / z 280.0 (M+H).

[0717]

[0718] 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) δ8.19 (s1H), 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, 2H); ESIMS experimental value of C8H5BrF3N3 m / z 280.0 (M+H).

[0719]

[0720] 6-Bromo-1-isopropyl-1H-benzo[d][1,2,3]triazole (LXX): white solid (10.58 g, 44.065 mmol). 1HNMR (400MHz, DMSO-d6) δ8.32(d,J=1.2Hz,1H),8.03(d,J=9.2Hz,1H),7.54(dd,J=8.4,1.6Hz,1H),5.26(sep,J=6.8Hz,1H),5.26(d,J=6.8Hz,6H); C9H 10 The ESIMS experimental value of BrN3 is m / z 240.1 (M+H).

[0721] The preparation of the intermediate 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (LXXIII) is depicted in Scheme 12 below.

[0722]

[0723] Step 1

[0724] A mixture of 5-bromo-3-fluoropyridine-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, added to water (200 mL) 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 experimental value m / z 229.0 (M+H) for C8H6BrFN2.

[0725] The following intermediates were prepared according to the procedure described in Scheme 12 above.

[0726]

[0727] 6-Bromo-8-fluoroimidazo[1,2-a]pyridine (LXXIV): beige solid (909.0 mg, 4.228 mmol, 80.7% yield). ESIMS observed value for C7H4BrFN2: m / z 214.9 (M+H).

[0728] The preparation of intermediate (6-bromoimidazo[1,2-a]pyridin-3-yl)(pyrrolidin-1-yl)methanone (LXXVII) is depicted in Scheme 13 below.

[0729]

[0730] Step 1

[0731] 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 distributed between EtOAc and a saturated aqueous solution of NaHCO3, the organic layer was separated, and the mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, 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. 12 H 12 The ESIMS experimental value of BrN3O is m / z 294.0 (M+H).

[0732] The following intermediates were prepared according to the procedure described in Scheme 13 above.

[0733]

[0734] 6-Bromo-N-methylimidazo[1,2-a]pyridine-3-carboxamide (LXXVIII): off-white solid (530 mg, 2.086 mmol, 83.8% yield). ESIMS observed value for C9H8BrN3O: m / z 254.0 (M+H).

[0735]

[0736] 5-Bromo-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (LXXIX): off-white solid (290 mg, 1.141 mmol, 91.7% yield). ESIMS observed value of C9H8BrN3O: m / z 253.95 (M+H).

[0737] The preparation of the intermediate imidazo[1,2-a]pyrimidin-6-ylboronic acid (LXXXII) is depicted in Scheme 14 below.

[0738]

[0739] Step 1

[0740] 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 afford 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 observed m / z for CHBNO: 164.1 (M+H).

[0741] The preparation of the intermediate 6-bromo-3-methylimidazo[1,2-a]pyrimidine (LXXXVII) is depicted in Scheme 15 below.

[0742]

[0743] Step 1

[0744] To a mixture of propanal (LXXXIII) (5 g, 70 mmol) in Et o (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 x 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.

[0745] Step 2

[0746] To a solution of 2-bromopropanal (LXXXV) (0.7 g, 5.11 mol) in DMF (20 mL) was added 5-bromopyrimidine-2-amine (LXXXVI) (0.97 g, 5.56 mmol) under Ar at room temperature. The mixture was stirred at 100 ° C for 16 h. After completion, the mixture was diluted with EtOAc and washed with brine (20 mLx3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0% → 20% EtOAc / petroleum ether) to obtain 6- bromo-3-methylimidazo [1,2-a] pyrimidine (LXXXVII) (80 mg, 0.377 mmol, 7.4% yield) as a white solid. The ESIMS experimental value of C7H6BrN3 was m / z 212.1 (M+H).

[0747] The following intermediates were prepared according to the procedure described in Scheme 15 above.

[0748]

[0749] 6-Bromo-3-ethylimidazo[1,2-a]pyrimidine (LXXXVIII): white solid (200 mg, 0.885 mmol, 19.1% yield). ESIMS observed value for C8H8BrN3: m / z 226.0 (M+H).

[0750] The preparation of intermediate (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)boronic acid (XCII) is depicted in Scheme 16 below.

[0751]

[0752] Step 1

[0753] To a solution of 5-azaindole (LXXXIX) (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. (2-(chloromethoxy)ethyl)trimethylsilane (XC) (available from Combi-Blocks Inc.) (3.6 mL, 20.34 mmol) was then added and the mixture was stirred at 0°C for 4 h. After vacuum concentration to remove DMF, an ice-cold saturated aqueous solution of NH3Cl was added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, and the solvent was concentrated to 5% by volume under vacuum. 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(499MHz, DMSO-d6)δppm-0.11(9H,s),0.75-0.84(2H,m),3.40-3.48(2H,m),5.58(2H,s),6. 64(1H,dd,J=3.29,0.82Hz),7.55-7.60(2H,m),8.23(1H,d,J=5.75Hz),8.84(1H,d,J=0.82Hz);C 13 H 20 The ESIMS experimental value of N2OSi is m / z 249.1 (M+H).

[0754] Step 2

[0755] Under N2, a hexane solution of n-butyllithium (1.21 mL, 3.02 mmol) was slowly added to a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (XCI) (0.5 g, 2.01 mmol) in anhydrous THF (4.0 mL) at -78 ° C. The mixture was stirred for 2 h at -46 ° C. Triisopropyl borate (0.93 mL, 4.03 mmol) was added, and the mixture was stirred overnight and warmed to room temperature. The reaction mixture was quenched with 1 M HCl aqueous solution and neutralized to pH 8 with 4 N NaOH. The solvent was evaporated to 40 ° C. The product was added to a 5-[[(1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridin-2-yl]boronic acid (XCII)]) solution and purified by reverse phase (C18) silica gel column chromatography (0→40% MeCN / water (0.1% formic acid as a modifier). LC / MS showed a 40 / 60 mixture of the 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 as is without further purification. 13 H 21 The ESIMS experimental value of BN2O3Si is m / z 293.1 (M+H).

[0756] The following intermediates were prepared according to the procedure described in Scheme 16 above.

[0757]

[0758] (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). 13 H 21 The ESIMS experimental value of BN2O3Si is m / z 293.15 (M+H).

[0759]

[0760] (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). 13 H 21 The ESIMS experimental value of BN2O3Si is m / z 293.1 (M+H).

[0761] The preparation of the intermediate cis-4-(methoxy-d3)cyclohexan-1-amine (C) is depicted in Scheme 17 below.

[0762]

[0763] Step 1

[0764] 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 KCO (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 H O. The combined organic layers were concentrated and the crude residue was purified by silica gel column chromatography (0% → 30% EtOAc / PE) to give cis-4-(diphenylmethylamino)cyclohexan-1-ol (XCVII) (8.0 g, 27.08 mmol, 82.3% yield) as a white solid. 20 H 25 The ESIMS experimental value of NO is m / z 296.4 (M+H).

[0765] Step 2

[0766] Under nitrogen atmosphere, under continuous stirring, NaH (5.98g, 149.7mmol) is slowly added to a solution of cis-4-(benzhydrylamino) hexamethylene-1-ol (XCVII) (8.0g, 27.08mmol) in DMPU (80mL). The reaction mixture is stirred at room temperature for 1h. Then iodomethane-d3 (XCVIII) (10.85g, 74.86mmol) is added at room temperature over a period of 10min. After addition, the reaction mixture is stirred at 50°C for 16h. The reaction mixture is then quenched with NH4Cl saturated aqueous solution (300mL) and stirred for 10min. The mixture is diluted with EtOAc and then extracted with EtOAc (300mLx3) and H2O. The crude residue was purified by silica gel column chromatography (0%→20% EtOAc / PE) to afford cis-N,N-diphenylmethyl-4-(methoxy-d3)cyclohexan-1-amine (XCIX) (6 g, 19.202 mmol, 70.9% yield) as a colorless oil. 21 H 24 ESIMS experimental value of D3NO: m / z 313.0 (M+H).

[0767] Step 3

[0768] To a solution of cis-N,N-diphenylmethyl-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 h. The mixture was filtered 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(400MHz,DMSO-d6)δppm C7H 12 ESIMS experimental value of D3NO: m / z 133.0 (M+H).

[0769] The following intermediates were prepared according to the procedure described in Scheme 17 above.

[0770]

[0771] 2-((cis-4-aminocyclohexyl)oxy)ethan-1-ol (CI): colorless oil (0.5 g, 3.14 mmol, 67.4% yield). C8H 17 ESIMS experimental value of NO2: m / z 160. (M+H).

[0772]

[0773] cis-4-(2-methoxyethoxy)cyclohexan-1-amine (CII): colorless oil (1.5 g, 8.65 mmol, 76.6% yield). 19 The ESIMS experimental value of NO2 is m / z 174.1 (M+H).

[0774]

[0775] cis-4-(2,2-difluoroethoxy)cyclohexan-1-amine (CIII): white solid (1.352 g, 7.54 mmol, 90.3% yield). 15 The ESIMS experimental value of F2NO is m / z 180.1 (M+H).

[0776]

[0777] cis-4-Ethoxycyclohexan-1-amine (CIV): colorless oil (2 g, 13.96 mmol, 64.4% yield). 1 H NMR (400MHz, CDCl3) δ1.19(t,J=7.0Hz,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).

[0778]

[0779] cis-3-(2-Methoxyethoxy)cyclobutan-1-amine (CV): colorless oil. 1 H NMR (400MHz, DMSO-d6) δ1.51 (dd, J=13.4, 5.2Hz, 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).

[0780]

[0781] 2-(cis-3-Aminocyclobutoxy)ethan-1-ol (CVI): colorless oil. 1 H NMR (400MHz, DMSO-d6) δ1.79-1.72(m,2H), 2.50-2.45(m,2H), 3.08-2.97(m,1H), 3.29(t,J=5.4Hz,2H), 3.46(t,J=5.4Hz,2H), 3.73-3.57(m,1H).

[0782] The preparation of the intermediate cis-4-(difluoromethoxy)cyclohexan-1-amine (CIX) is depicted in Scheme 18 below.

[0783]

[0784] Step 1

[0785] Under a nitrogen atmosphere, a solution of cis-4-(benzhydrylamino)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. To this mixture was added a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (CVII) (60 mg, 0.339 mmol) in (2 mL) MeCN 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 a 1:1 mixture of EtOAc (100 mL) and water and a saturated aqueous solution of NaHCO 3. The resulting two-phase 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 MgSO 4 , filtered, and concentrated to an oil. The crude oil was purified by silica gel chromatography (100% hexane → 30% EtOAc / hexane). The fractions containing the product were combined and concentrated to give cis-N,N-diphenylmethyl-4-(difluoromethoxy)cyclohexan-1-amine (CVIII) (25 mg, 0.072 mmol, 42.3% yield) as an oil, which solidified into an off-white solid. C 21 H 25 The ESIMS experimental value of F2NO is m / z 346.1 (M+H).

[0786] Step 2

[0787] To a solution of cis-N,N-diphenylmethyl-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 h. The mixture was filtered 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. 13 The ESIMS experimental value of F2NO is m / z 166.1 (M+H).

[0788] The preparation of the intermediate trans-4-amino-1-ethylcyclohexan-1-ol (CXIV) is depicted in Scheme 19 below.

[0789]

[0790] Step 1

[0791] To a solution of trans-4-aminocyclohexan-1-ol (CX) (25 g, 0.217 mmol) and bromotoluene (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 x 3) and H2O. The organic layer was dried over anhydrous Na2SO4 and evaporated under high vacuum to produce trans-4-(diphenylmethylamino)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. 20 H 25 The ESIMS experimental value of NO is m / z 296.3 (M+H).

[0792] Step 2

[0793] To a solution of (COCl) (12.89 g, 101.55 mmol) in DCM (150 mL) was slowly added DCM (50 mL) containing DMSO (10.6 g, 135.4 mmol) at -70 ° C under N2. DMF (50 mL) containing trans-4-(benzhydrylamino)cyclohexan-1-ol (CXI) (20.0 g, 67.7 mmol) was added at -70 ° C under N2 and stirred for 30 min. TEA (21.92 g, 216.64 mmol) was then added and the mixture was stirred at -70 ° C and warmed to room temperature over 3 h. The reaction mixture was diluted with H2O (800 mL) and extracted with DCM (800 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by silica gel column chromatography (9→25% EtOAc / PE) to give 4-(benzhydrylamino)cyclohexan-1-one (CXII) (18.0 g, 61.3 mmol, 90.6% yield) as a white solid. 20 H 23 The ESIMS experimental value of NO is m / z 294.2 (M+H).

[0794] Step 3

[0795] 4-(Benzhydrylamino)cyclohexan-1-one (CXII) (5.0 g, 17.04 mmol) was added to THF (50 mL) at -78 ° C under N2 and stirred for 1 h. Ethylmagnesium bromide (17 mL, 34.08 mmol) was added and the reactant was stirred at -78 ° C and warmed to room temperature over 16 h. The reaction mixture was diluted with NH4Cl (100 mL), filtered and extracted with EtOAc (200 mL x 3 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under high vacuum to give a residue. LC / MS showed two products. The residue was purified by silica gel column chromatography (2 → 3% EtOAc / PE) to give only trans-4-(benzhydrylamino)-1-ethylcyclohexan-1-ol (CXIII) (1.5 g, 4.637 mmol, 27.2% yield) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ0.80(t,J=7.4Hz,3H),1.17-1.10(m,2H),1.47-1.37(m,4H),1.65(t, J=11.4Hz,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); C 22 H 29 The ESIMS experimental value of NO is m / z 324.2 (M+H).

[0796] Step 4

[0797] A solution of trans-4-(benzhydrylamino)-1-ethylcyclohexan-1-ol (CXIII) (1.5 g, 4.6 mmol) in EtOAc (50.0 mL), 10% Pd / C (0.4 g), 20% Pd(OH)2 / C (0.4 g) was purged with H2. The mixture was stirred at room temperature for 16 h under H2 atmosphere. The reaction mixture was filtered and concentrated under high vacuum to afford trans-4-amino-1-ethylcyclohexan-1-ol (CXIV) (390 mg, 2.723 mmol, 58.7% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ0.80(t,J=7.4Hz,3H),1.14-1.03(m,2H),1.29-1.20(m,2H),1 .40(q,J=7.4Hz,2H),1.59-1.49(m,2H),1.67-1.61(m,2H),2.70-2.61(m,1H),3.84(br s,1H);C8H 17The ESIMS experimental value of NO is m / z 144.1 (M+H).

[0798] The preparation of intermediate 1-(3,3,3-trifluoropropyl)piperidin-4-amine (CXVIII) is depicted in Scheme 20 below.

[0799]

[0800] Step 1

[0801] By piperidin-4-ylcarbamic acid tert-butyl ester (CXV) (available from Combi-Blocks Inc.) (1g, 4.99mmol) and K cO (1.73g, 12.52mmol) be dissolved in DMF (15mL) and add 1-iodo-3,3,3-trifluoropropane (CXVI) (878 μ L, 7.49mmol), and reactant is stirred at room temperature 16h.Reactant mixture is poured in EtOAc, and separated aqueous layer.With EtOAc (× 3) aqueous layer extracted, and then with 1M citric acid, the organic layer through merging is acidified to pH 4.5.With small volume water washing organic layer three times to remove unreacted SM. Sufficient product remained in the organic layer, which was dried over 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. 13 H 23 The ESIMS experimental value of F3N2O2 is m / z 297.2 (M+H).

[0802] Step 2

[0803] By N- [1- (3,3,3- trifluoropropyl) piperidin-4-yl] tert-butyl carbamate (CXVII) (200mg, 0.670mmol) is dissolved in DCE (3.2mL) and TFA (800 μL, 10.38mmol) is added, and the reactant is stirred at room temperature for 30 minutes. The reaction mixture is blown dry and excess TFA is removed by high vacuum to obtain the crude intermediate 1- (3,3,3- trifluoropropyl) piperidin-4-amine (CXVIII) (209mg, 0.674mmol, 99.8% yield) in a white semi-solid, which is used without further purification. C8H 15 The ESIMS experimental value of F3N2 is m / z 197.1 (M+H).

[0804] The preparation of intermediate N-(trans-4-aminocyclohexyl)acetamide (CXXI) is depicted in Scheme 21 below.

[0805]

[0806] Step 1

[0807] To N- (4- aminocyclohexyl) tert-butyl carbamate (CXIX) (available from Combi-Blocks Inc.) (0.6g, 2.8mmol) in DCM (6mL) through stirring solution, add TEA (1.2mL, 8.61mmol). Then slowly add acetyl chloride (CXX) (0.22mL, 3.09mmol) and the reaction mixture is stirred at room temperature for 16h. Remove solvent, and make crude material be dissolved in EtOAc, use 1M NaOH, salt water washing, and through anhydrous MgSO4 dry and finally concentrate. Product is dissolved in EtOH (2mL) and 4M HCl (1mL). The solution is stirred at room temperature for 2h, then evaporated to dryness, obtain the HCl salt (CXXI) (480mg, 2.49mmol, 89.0% yield) of N- (4- aminocyclohexyl) acetamide as white solid. CH 16 The ESIMS experimental value of N2O is m / z 157.05 (M+H).

[0808] The preparation of the intermediate cis-4-amino-N,N-dimethylcyclohexane-1-carboxamide (CXXIII) is depicted in Scheme 22 below.

[0809]

[0810] Step 1

[0811] To a stirred solution of 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (CXXII) (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 min. Dimethylamine (0.92 mL, 1.84 mmol) was added and the reaction was heated to 90 ° C for 16 h. The reaction was concentrated and dissolved in EtOH (2 mL) and 4M HCl / dioxane (1 mL). The mixture was stirred at room temperature for 2 h 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. 18 The ESIMS experimental value of N2O is m / z 171.15 (M+H).

[0812] The following intermediates were prepared according to the procedure described in Scheme 22 above.

[0813]

[0814] trans-4-amino-N,N-dimethylcyclohexane-1-carboxamide (CXXIV): light brown sticky solid (290 mg, 1.403 mmol, 113.8% yield). 18 The ESIMS experimental value of N2O is m / z 171.1 (M+H).

[0815] The preparation of the intermediate 3-amino-N-methylbicyclo[1.1.1]pentane-1-carboxamide (CXXVII) is depicted in Scheme 23 below.

[0816]

[0817] Step 1

[0818] To a solution of 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (CXXV) (available from AmBeed, Inc.) (0.5 g, 2.2 mmol) and HATU (0.8 g, 2.09 mmol) in DMF was added DIPEA (0.8 mL, 4.59 mmol) and the mixture was stirred for 5 min. Methylamine HCL (1.49 g, 22.07 mmol) was then 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 a saturated aqueous solution of NaHCO 3 , water, and brine. The organics were dried over anhydrous Na2SO4, concentrated, and the residue was dried under high vacuum to afford 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. 12 H 20 The ESIMS experimental value of N2O3 is m / z 241.1 (M+H).

[0819] Step 2

[0820] A solution of tert-butyl (3-(methylcarbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (CXXVI) (240 mg, 1.0 mmol) in 4M HCl / 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. 12 The ESIMS experimental value of N2O is m / z 141.15 (M+H).

[0821] Example 1.

[0822] 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 depicted in Scheme 24 below.

[0823]

[0824] Steps 1 to 2

[0825] A mixture of 5-bromopyrazolo[1,5-a]pyridine (CXXVIII) (1.8 g, 9.14 mmol), Pd(dppf)Cl2 (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) was degassed with N2 and heated to 90°C for 3 h in a sealed tube. 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)Cl2 (311 mg, 0.380 mmol), Na2CO3 (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. Add water (100 mL) and extract with EtOAc (100 mL x 3). Evaporate the organic layer to The mixture was concentrated to 400 μg / ml and purified by silica gel column (0→100% EtOAc / hexane). The test tube containing the pure sample was collected and the solvent was removed in vacuo. The impure fractions were combined and repurified by silica gel column (0→100% EtOAc / hexane). The test tube containing the pure sample was collected and the solvent was removed in vacuo, the impure fractions were combined and repurified by silica gel column (0→100% EtOAc / hexane). The three pure fractions were combined and placed under high vacuum to produce 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. 14 H 10 ESIMS experimental value of ClN5O: m / z 300.1 (M+H).

[0826] Step 3

[0827] 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) was added 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) (available from Combi-Blocks Inc.) (90 mg, 0.420 mmol) and LiHMDS (1 mL, 1 mmol) at room temperature. The mixture was purged with N2 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 afford 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). 20 H 23 The ESIMS experimental value of N7O is m / z 378.2 (M+H).

[0828] Step 4

[0829] To a solution of HOAc (11 μL, 0.190 mmol), HATU (79 mg, 0.210 mmol) in DMF (0.2 mL) was added DIPEA (85 μL, 0.490 mmol) and the mixture was stirred for 5 min. 1 -(4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)cyclohexane-1,4-diamine (CXXXI) (60 mg, 0.160 mmol) in DMF (0.3 mL) 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 organic matter was separated, concentrated, absorbed on 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]triazine-2-yl)amino)cyclohexyl)acetamide (17) (22 mg, 0.052 mmol, 33.0% yield) as a yellow solid. 1 H NMR(499MHz,DMSO-d6)δppm 1.50-1.59(2H,m),1.60-1.72(4H,m),1.74-1.81(2H,m),1.81(3H,s),3.64-3.71(2H,m),3.99(3H,s),6.47(1H,d,J=6.3 0Hz),6.58(1H,d,J=1.64Hz),6.76(1H,d,J=2.74Hz),7.11(1H,dd,J=7.26,1.78Hz),7.63(1H,d,J=2.74Hz),7.70(1H,br d,J=6.84Hz),7.81(1H,s),7.97(1H,d,J=2.19Hz),8.62(1H,d,J=7.12Hz); C 22 H 25 The ESIMS experimental value of N7O2 is m / z 420.2 (M+1).

[0830] Example 2.

[0831] 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 depicted in Scheme 25 below.

[0832]

[0833] Steps 1 to 2

[0834] A mixture of 5-bromopyrazolo[1,5-a]pyridine (CXXVIII) (1.8 g, 9.14 mmol), Pd(dppf)Cl2 (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) was degassed with N2 and heated to 90°C for 3 h in a sealed tube. 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)Cl2 (311 mg, 0.380 mmol), Na2CO3 (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. Add water (100 mL) and extract with EtOAc (100 mL x 3). Evaporate the organic layer to The mixture was concentrated to 4% 4-nitropropane and purified by silica gel column (0→100% EtOAc / hexane). The test tube containing the pure sample was collected and the solvent was removed in vacuo. The impure fractions were combined and repurified by silica gel column (0→100% EtOAc / hexane). The test tube containing the pure sample was collected and the solvent was removed in vacuo, the impure fractions were combined and repurified by silica gel column (0→100% EtOAc / hexane). The three pure fractions were combined and placed under high vacuum to produce 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. 14 H 10 ESIMS experimental value of ClN5O is m / z 300.1 (M+H).

[0835] Step 3

[0836] 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) was added BrettPhos (19 mg, 0.040 mmol), BrettPhos PD G3 (25 mg, 0.030 mmol), DIPEA (0.13 mL, 0.720 mmol), (3S,4R)-2-methyl-2-propane-4-amino-3-fluoro-1-piperidincarboxylate (CXXXII) (100 mg, 0.460 mmol) and LiHMDS (1 mL, 1 mmol) at room temperature. The mixture was purged with N2 and stirred at 100 °C for 1 h. The reaction mixture was concentrated and purified by ISCO (0→100% EtOAc / hexane). The pure fractions were collected, concentrated under reduced pressure and dried under high vacuum to afford 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. 24 H 28 The ESIMS experimental value of FN7O3 is m / z 482.25 (M+H).

[0837] Step 4

[0838] 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 afford 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. 1H NMR (499MHz, DMSO-d6) δppm 1.58-1.65 (1H, m), 1.73 (1H, qd, J = 12.37, 4.24Hz), 2.56 (1H, br t,J=12.46Hz),2.70(1H,dd,J=38.70,14.30Hz),2.96(1H,br d,J=13.14Hz),3.13(1H,br t,J=11.50Hz),3.78-3.93(1H,m),4.00(3H,s),4.80(1H,d,J=50.75Hz),6.59(1H,d,J=1.64Hz),6.64(1H,d,J=7.94Hz),6.78(1H,d,J=2 C 19 H 20 The ESIMS experimental value of FN7O is m / z 382.2 (M+H).

[0839] Step 5

[0840] 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) and 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) 3 (56 mg, 0.260 mmol) was added and the reaction was stirred for 2 h. TLC showed that the starting material was complete. The reaction mixture was absorbed onto silica gel and purified by ISCO (0→8% 7N NH 3 MeOH / CHCl 3). Pure fractions were concentrated and the residue was dried under high vacuum to afford 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(499MHz,DMSO-d6)δppm 1.68(1H,br dd,J=12.59,3.01Hz),1.92(1H,qd,J=12.23,3.56Hz),2.01-2.09(1H,m),2.17(1H,dd,J=37.55,13.20Hz),2.19(3H,s),2.79(1H,br d,J=11.23Hz),3.00-3.09(1H,m),3.67-3.83(1H,m),4.00(3H,s),4.91( 1H,d,J=50.20Hz),6.59(1H,d,J=1.64Hz),6.64(1H,d,J=7.67Hz),6.78( C 20 H 22 The ESIMS experimental value of FN7O is m / z 396.2 (M+1).

[0841] Example 3.

[0842] 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 depicted in Scheme 26 below.

[0843]

[0844] Steps 1 to 2

[0845] A mixture of 6-bromoimidazo[1,2-a]pyridine-3-carbonitrile (CXXXIV) (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)Cl2 (123 mg, 0.15 mmol) was dissolved in 1,4-dioxane (12 mL), and the reaction mixture was purged with N2 for 5 min. The vial was sealed and heated at 95 ° C. for 3 h. To the above reaction mixture was added 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 a solution of Na2CO3 (1.27 g, 12. mmol) in water (3 mL). The reaction mixture was purged with N2 gas for 5 min, the vial was sealed and heated at 80°C for 1 h. The organic layer was separated, absorbed onto silica, and purified by ISCO (0→20% MeOH / CHCl3) to afford 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. 15 ESIMS experimental value of H9ClN6O: m / z 325.1 (M+H).

[0846] Step 3

[0847] 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, 0.36mmol), trans-4-amino-1-methylcyclohexan-1-ol (CXXXVI) (available from PharmaBlock (USA), Inc.) (56.mg, 0.43mmol), BrettPhos Pd G3 (24.mg, 0.03mmol) and BrettPhos (19.mg, 0.04mmol) in 1,4-dioxane (3mL) was added NaO at room temperature. tTo the mixture of 4-nitro-2-nitro-1-oxo-2-nitro-4-nitro-2 ... 1 H NMR(499MHz,DMSO-d6)δppm 1.14(3H,s),1.38-1.53(4H,m),1.56-1.66(3H,m),1.83-1.93(2H,m),3.60-3.71(1H,m),4.01(3H,s),4.23(1H,s),6.5 C 22 H 23 ESIMS experimental value of N7O2 was 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) was obtained as a beige solid. 1 HNMR(499MHz,DMSO-d6)δppm 1.14(3H,s),1.39-1.48(4H,m),1.57-1.63(2H,m),1.85-1.91(2H,m),3.60-3.72(1H,m ),3.99(3H,s),4.23(1H,s),6.49(1H,d,J=7.94Hz),6.75(1H,d,J=2.46Hz),7.34(1H,br s),7.65(1H,d,J=2.74Hz),7.69(2H,s),7.95(1H,br s),8.33(1H,s),9.84(1H,s);C 22 H 25 The ESIMS experimental value of N7O3 is m / z 436.25 (M+1).

[0848] Example 4.

[0849] 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 depicted in Scheme 27 below.

[0850]

[0851] Steps 1 to 2

[0852] 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) was purged with N in a sealed tube, sealed, and then heated to 90° C. for 2 h. LCMS showed a mixture of boronic acid and boronate ester.

[0853] The reaction was cooled to room temperature and then 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) 2 (28 mg, 0.12 mmol) and Na 2 CO 3 aqueous solution (5 mL, 5.0 mmol) were added to the mixture. The reaction was purged with N 2 , sealed, and then heated to 80 ° C for 20 min. Water (100 mL) was added and extracted with EtOAc (3x100 mL). The solvent was stirred at 4 ° C for 10 min. The reaction mixture was reduced in volume and purified by silica gel column chromatography (0→100% EtOAc / hexanes) to yield 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. 23 H 30 The ESIMS experimental value of ClN5O2Si is m / z 472.2 (M+H).

[0854] Step 3

[0855] To a stirred solution of tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate HCl (CXXXIX) (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 t Bu (62 mg, 0.65 mmol). The solution was purged with N2, sealed, and then heated at 100°C for 30 min. The solvent reactants were The reaction mixture was reduced in volume 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. 36 H 53 The ESIMS experimental value of N7O4Si is m / z 676.4 (M+H).

[0856] Step 4

[0857] 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. 25 H31 The ESIMS experimental value of N7O2 is m / z 462.3 (M+H).

[0858] Step 5

[0859] 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 added at room temperature. The reaction mixture was reduced in volume and purified by silica gel column chromatography (0→10% 7N NH in MeOH / CHCl) to afford 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(499MHz,DMSO-d6)δppm 1.28-1.39(2H,m),1.48-1.60(2H,m),1.72-1.79(3H,m),1.83-1.94(4H,m),2.60(3H,s),3.47(1H,s),3.52(1H,s) ,3.57(1H,dt,J=10.20,6.95Hz),3.74(1H,s),3.75-3.79(2H,m),3.80(1H,s),3.93(3H,d,J=1.10Hz),4.28(2H,br t,J=5.20Hz),4.99(1H,t,J=5.48Hz),6.43(1H,dd,J=16.43,7.94Hz),6.62(1H,d,J=2.46Hz) ,7.37(1H,dd,J=8.21,1.37Hz),7.51(1H,d,J=8.49Hz),7.58(1H,t,J=2.74Hz),7.69(1H,s);C 27 H 33 The ESIMS experimental value of N7O3 is m / z 504.3 (M+1).

[0860] Example 5.

[0861] Anti-N 1 The preparation of 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) 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 depicted in Scheme 28 below.

[0862]

[0863] Steps 1 to 2

[0864] A mixture of 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole (CXLII) (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) was purged with N in a sealed tube, sealed, and heated to 90° C. for 1 h. LCMS showed a mixture of boronic acid and boronate ester.

[0865] The reactants were cooled to room temperature and then 5-bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (1.15 g, 4.38 mmol), Pd(OAc) 2 (0.05 g, 0.22 mmol), QPhos (0.32 g, 0.45 mmol), an aqueous solution of Na 2 CO 3 (9.2 mL, 9.2 mmol) and 1,4-dioxane (11 mL) were added to the mixture. The reactants were purged with N 2 , sealed, and heated to 80 ° C for 20 min. Water (100 mL) was added and extracted with EtOAc (3x100 mL). The solvent was stirred at 40 ° C for 10 min. The reaction mixture was reduced in volume and purified by silica gel column chromatography (0→100% EtOAc / hexanes) to yield 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. 14 H 11 ESIMS experimental value of ClN6O: m / z 315.1 (M+H).

[0866] Step 3

[0867] 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) (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 t Bu (195 mg, 2.03 mmol). The reaction mixture was purged for 5 min and then heated to 100 ° C for 30 min. The reaction mixture was concentrated and purified by ISCO (0→10% MeOH / CHCl 3) to give 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. 24 H 30 The ESIMS experimental value of N8O3 is m / z 479.3 (M+H).

[0868] Step 4

[0869] 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 Na2CO3, washed with EtOAc, dried over anhydrous Na2SO4, concentrated in vacuo, then absorbed onto silica gel and purified by ISCO (0→20% 7N NH3 in MeOH / CHCl3) to afford trans-N-((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) as an off-white foam. 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). 1 H NMR(499MHz,DMSO-d6)δppm1.22(3H,s),1.80(2H,br s),1.88-1.98(2H,m),2.13-2.22(2H,m),3.95(3H,s),4.23-4.33(1H,m),4.31(3H,s),6.74(1H,d,J=2.46Hz), 6.90(1H,d,J=7.12Hz),7.60(1H,dd,J=8.76,1.37Hz),7.63(1H,d,J=2.46Hz),7.93(1H,s),7.95-8.00(1H,m);C 19 H 22 The ESIMS experimental value of N8O is m / z 379.2 (M+1).

[0870] Step 5

[0871] 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) in DMF (0.5 mL) 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 afford 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. 23 H 27 ESIMS experimental value of ClN8O2 is m / z 483.2 (M+H).

[0872] Step 6

[0873] 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) was added KO t To the mixture of 4-nitro-2-nitro-1- pyrrolidone (223) (23 mg, 0.052 mmol) and 4-nitro-2- pyrrolidone (223) (23 mg, 0.052 mmol, 46.9% yield) was obtained. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.36(3H,s),1.92(2H,quin,J=7.53Hz),2.00-2.08(2H,m),2.23(2H,t,J=8.0 8Hz),2.82-2.92(2H,m),3.40(2H,t,J=6.84Hz),3.96(3H,s),4.04-4.12(1H,m ),4.31(3H,s),6.74(1H,d,J=2.46Hz),7.06(1H,d,J=6.30Hz),7.60(1H,dd,J =8.62,1.51Hz),7.64(1H,d,J=2.46Hz),7.94(1H,s),7.97(1H,d,J=8.76Hz); C 23 H 26 The ESIMS experimental value of N8O2 is m / z 447.3 (M+1).

[0874] Example 6.

[0875] Shun-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-trimethylcyclobutane-1,3-diamine (204) is depicted in Scheme 29 below.

[0876]

[0877] Step 1

[0878] Towards (N 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]triazine-2-yl)-3-methylcyclobutane-1,3-diamine (CXLVIII) (prepared by the method shown in Example 5, steps 1 to 4) (25 mg, 0.07 mmol) in EtOH (1 mL) and DCE (4 mL) was added formaldehyde (13 μL, 0.17 mmol). The reaction was stirred at room temperature for 30 min, then NaBH(OAc)3 (70 mg, 0.33 mmol) was added. The reaction was further stirred at room temperature for 16 h. A saturated aqueous solution of Na2CO3 was added and extracted with DCM. The organic layer was separated and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by ISCO silica gel column chromatography (0→20% 7N NH3 in MeOH / CHCl3) to give cis-N-(4-methoxy-5-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)-3-methylcyclobutane-1,3-diamine 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). 1 H NMR(499MHz,DMSO-d6)δppm 1.06(3H,s),1.82-1.92(2H,m),2.03(6H,s),2.19(2H,td,J=8.15,2.60Hz),3.91-4.01(1H,m),3.95(3H,s),4.31(3H,s),6.74(1H, C 21 H 26 The ESIMS experimental value of N8O is m / z 407.3 (M+1).

[0879] Example 7.

[0880] 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 depicted in Scheme 30 below.

[0881]

[0882] Steps 1 to 3

[0883] To a microwave vial was added trans-3-{[(tert-butoxy)carbonyl]amino}-1-methylcyclobutane-1-carboxylic acid methyl ester (CXLIX) (255.1 mg, 1.05 mmol), MeOH (5 mL) and a solution of 4M HCl in dioxane (0.5 mL, 2. mmol). The vial was sealed and the solution was stirred at room temperature for 16 h. While heating to 50 ° C, the solvent was removed with a stream of N2. The residue was dissolved in MeCN (5 mL) and while heating to 50 ° C, the solvent was removed with a stream of N2. This was repeated two more times to produce trans-3-amino-1-methylcyclobutane-1-carboxylic acid methyl ester (CL) as a white solid.

[0884] To the white residue were added 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), NaO t Bu (366.4 mg, 3.81 mmol), BrettPhos PD G3 (44 mg, 0.05 mmol). The reaction mixture was purged with N2, the vial was sealed and heated to 100°C for 30 min. LC / MS showed a mixture of methyl ester and acid.

[0885] To the above solution was added water (2 mL) followed by 2M aqueous LiOH solution (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 1N HCl and extracted with DCM (3 x 50 mL). The DCM layer was separated and the mixture was stirred for 2 h. The reaction mixture was reduced in volume 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) as an off-white solid (104 mg, 0.2553 mmol, 26.779% yield).20 H 21 The ESIMS experimental value of N7O3 is m / z 408.2 (M+H).

[0886] Step 4

[0887] 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, then pyrrolidine (CLII) (10 μL, 0.12 mmol) was added. The reaction was stirred at room temperature for 16 h. The solvent was added at room temperature. The reaction mixture was reduced in volume and purified by silica gel column chromatography (0→10% 7N NH3 in MeOH / CHCl3) to afford (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(499MHz,DMSO-d6)δppm 1.38(3H,s),1.73-1.80(2H,m),1.81-1.87(2H,m),1.91-1.99(2H,m),2. 86-2.93(2H,m),3.30-3.34(4H,m),3.87-3.94(1H,m),3.96(3H,s),4.31( 3H,s),6.74(1H,d,J=2.46Hz),7.07(1H,d,J=6.57Hz),7.60(1H,dd,J=8.6 2,1.51Hz),7.64(1H,d,J=2.74Hz),7.93(1H,s),7.97(1H,d,J=8.76Hz); C 24 H 28 The ESIMS experimental value of N8O2 is m / z 461.3 (M+1).

[0888] Example 8.

[0889] 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 depicted in Scheme 31 below.

[0890]

[0891] Step 1

[0892] 2-Chloro-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazine (CLIII) (prepared by the method presented in Steps 1 to 2 of Example 3) (200 mg, 0.67 mmol), tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (CLIV) (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 were added. t Bu (192 mg, 2.0 mmol) was suspended in anhydrous 1,4-dioxane (4 mL). The mixture was purged with Ar for 5 min and then heated at 100 ° C for 10 min. The reaction mixture was added to a saturated aqueous solution of NH4Cl and DCM, and the organic layer was separated. The aqueous layer was extracted with DCM (× 2), and the combined organic layers were dried (anhydrous MgSO4) and reduced in vacuo to give the product (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-carboxylic acid tert-butyl ester (CLV) (220 mg) as an orange fluffy solid A mixture of 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) was used without purification. The amount and yield were calculated by LCMS. 22 H 25 The ESIMS experimental values ​​of FN8O3 are m / z 469.3 (M+H) and C 21 H 23 The ESIMS experimental value of FN8O3 is m / z 455.2 (M+H).

[0893] Step 2

[0894] 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 h. The reaction mixture was evaporated and the excess TFA was removed via high vacuum. The crude product was purified by column chromatography (0→8% 7.0 NH3 in MeOH / CHCl3) followed by (8→20% 7.0 NH3 in MeOH / CHCl3) to separate the two compounds, collecting 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 light yellow semisolid. 17 H 17 ESIMS experimental value of FN8O was 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 collected as a yellow solid. 16 H 15 ESIMS experimental value of FN8O is m / z 355.2 (M+H). Demethylation is further carried out during TFA Boc deprotection.

[0895] Step 3

[0896] 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 (CLIX) (33 μL, 0.56 mmol) were then added and the reaction was stirred at 65° C. for 15 min. NaBH(OAc) 3 (48 mg, 0.23 mmol) was added and the reaction was stirred for an additional 10 min. LC / MS showed unreacted starting material, so more oxetan-3-one (23 μL, 0.36 mmol) was added and stirred at 65° C. for 10 min, followed by more NaBH(OAc) 3 (48 mg, 0.23 mmol). The reaction was stirred at 65° C. for 10 min. LC / MS showed a small amount of starting material and the reaction was stopped. The reaction mixture was loaded onto a The product was purified by silica column chromatography (0→9% 7.0 M NH in MeOH / CHCl). The product was further purified by HPLC (0→15% MeCN / H2O (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. 1 HNMR(499MHz,DMSO-d6)δppm 2.56(1H,t,J=8.49Hz),2.79-2.91(1H,m),2.96-3.09(1H,m),2.98-3.03(1H,m),3.76(1H,quin,J=6.09Hz),4.22-4 .37(1H,m),4.46(2H,t,J=6.02Hz),4.58(2H,t,J=6.57Hz),5.25(1H,dtd,J=55.95,4.65,4.65,1.00Hz),6.29(1H,br d,J=6.30Hz),6.81(1H,d,J=2.74Hz),7.48(1H,d,J=2.74Hz),7.71(1H,d,J=1.10Hz) ,7.93(1H,d,J=1.09Hz),8.90(1H,d,J=2.46Hz),9.41(1H,d,J=2.19Hz),10.78(1H,br s);C 19 H 19The ESIMS experimental value of FN8O2 is m / z 411.2 (M+1).

[0897] Example 9.

[0898] 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 depicted in Scheme 32 below.

[0899]

[0900] Steps 1 to 2

[0901] 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)Cl2 (75 mg, 0.09 mmol) and KOAc (500 mg, 5.09 mmol) were suspended in anhydrous 1,4-dioxane (12 mL). The reaction was sonicated and degassed for 5 min, then heated at 100°C for 2 h. The reaction mixture was cooled to room temperature and 2M aqueous K3PO4 (2.52 mL, 5.04 mmol) was added and stirred for 5 min. 5-Bromo-2-chloro-4-methoxypyrrolo[2,1-f][1,2,4]triazine (XII) (443 mg, 1.69 mmol), Pd(OAc)2 (19 mg, 0.08 mmol) and QPhos (84 mg, 0.12 mmol) were added and the reaction was purged with Ar for 5 min. The reaction was heated to 80 ° C for 1 h. The reaction mixture was reduced in vacuo and the crude product was purified by column chromatography (100% CHCl3). The product was further purified by column chromatography (maintaining 0→50% EtOAc / hexanes, then 50→100% EtOAc / hexanes) to give a solid, which was triturated with MeOH and filtered, washing with MeOH 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.15 H 11 ESIMS experimental value of ClF2N6O is m / z 365.1 (M+H).

[0902] Step 3

[0903] In a microwave vial, 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) (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 were added. t Bu (21 mg, 0.22 mmol) was dissolved in anhydrous 1,4-dioxane (0.7 mL). The suspension was purged with Ar for 5 min, and then the reaction was heated to 100 °C for 3 h. The reaction was reduced in vacuo and loaded into The product was purified by column chromatography (0 → 90% EtOAc / hexane). The isolated product was further purified by HPLC (maintaining 0 → 35%, then increasing stepwise from 5% to 80% MeOH / H2O in 0.1% formic acid). The appropriate fractions were collected and neutralized with a saturated aqueous solution of NaHCO3 and extracted with DCM (×2). The combined organic layers were dried over anhydrous MgSO4 and reduced in vacuo to afford (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) (3 mg, 0.007 mmol, 9.6% yield) as a yellow solid. 1H NMR(499MHz,DMSO-d6)δppm 1.15(3H,s),1.40-1.50(4H,m),1.57-1.65(2H,m),1.84-1.92(2H,m),3. 60-3.69(1H,m),3.94(3H,s),4.23(1H,s),5.30(2H,td,J=15.81,2.87Hz ),6.50(1H,d,J=7.94Hz),6.60(1H,tt,J=54.30,3.00Hz),6.72(1H,d,J= 2.46Hz),7.62-7.65(1H,m),7.65(1H,d,J=2.74Hz),8.00-8.05(2H,m);C 22 H 25 The ESIMS experimental value of F2N7O2 was m / z 458.2 (M+1). The elimination byproduct (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) was also obtained as a yellow solid (7 mg, 0.016 mmol, 23.3% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.15(3H,s),1.38-1.51(4H,m),1.57-1.66(2H,m),1.82-1.93(2H,m),3.59-3 .71(1H,m),3.94(3H,s),4.23(1H,s),6.51(1H,d,J=7.94Hz),6.74(1H,d,J=2. 74Hz),7.34(1H,dd,J=60.90,4.10Hz),7.45(1H,dd,J=18.62,3.83Hz),7.65(1 H,d,J=2.46Hz),7.69(1H,d,J=9.03Hz),7.92(1H,s),8.08(1H,d,J=8.76Hz); C 22 H 24 The ESIMS experimental value of FN7O2 is m / z 438.2 (M+1).

[0904] Example 10.

[0905] 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 depicted in Scheme 33 below.

[0906]

[0907] Steps 1 to 2

[0908] Using the procedure described in Example 9, Scheme 32, Steps 1 to 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. 16 H 15 ESIMS experimental value of ClN6O: m / z 343.1 (M+H).

[0909] Step 3

[0910] Using the procedure described in Example 9, Scheme 32, Step 3, 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) was produced as a brown semisolid. 26 H 33 The ESIMS experimental value of FN8O3 is m / z 525.15 (M+H).

[0911] Step 4

[0912] Using the procedure described in Example 8, Scheme 31, Step 2, 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) was produced as a brown solid (148 mg, 0.349 mmol, 99.4% yield).21 H 25 The ESIMS experimental value of FN8O is m / z 425.2 (M+H).

[0913] Steps 5a and 5b

[0914] 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 anhydrous DCE (0.9 mL) followed by EtOH (0.1 mL) to aid dissolution. Acetic acid (16 μL, 0.28 mmol), oxetan-3-one (CLIX) (17 μL, 0.29 mmol) and MS (5 beads), then 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 taken out (leaving 600 μL), and added to separate vials, and both were heated to 65 ° C. To the first vial, NaBH (OAc) 3 (41 mg, 0.19 mmol) was added and the reaction was stirred for 10 minutes. To the second vial, trimethylsilyl cyanide (24 μL, 0.19 mmol) was added and the reaction was stirred for 10 minutes. The two reactants were loaded into The product was purified by column chromatography (0→2% MeOH / CHCl). Compound 688 was further purified by HPLC (0→50% MeCN / HO containing 0.1% formic acid). Compound 690 was further purified by HPLC (0→80% MeCN / HO containing 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(499MHz,DMSO-d6)δppm 1.67(6H,d,J=6.57Hz),1.70-1.77(1H,m),1.88-1.97(1H,m),1.99-2.06(1H,m),2.16(1H,dd,J=37.00,12.59Hz),2.71- 2.80(1H,m),2.95-3.04(1H,m),3.49(1H,quin,J=6.37Hz),3.74-3.90(1H,m),3.96(3H,s),4.40(1H,t,J=6.16Hz),4.46 (1H,t,J=6.16Hz),4.54(2H,td,J=6.43,3.01Hz),4.94(1H,d,J=49.90Hz),5.24(1H,spt,J=6.75Hz),6.69(1H,d,J=7.94 Hz), 6.77 (1H, d, J = 2.74Hz), 7.59 (1H, dd, J = 8.76, 1.37Hz), 7.64 (1H, d, J = 2.46Hz), 7.99 (1H, d, J = 8.76Hz), 8.02 (1H, s); C 24 H 29 ESIMS experimental value of FN8O2 was 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) as a fluffy white solid. 1H NMR (499MHz, DMSO-d6) δppm 1.67 (6H, d, J = 6.84Hz), 1.82 (1H, br dd,J=12.32,3.01Hz),2.00(1H,qd,J=12.37,3.70Hz),2.09-2.18(1H,m),2.26(1H,dd,J=36.20,12.32Hz),2. 78-2.86(1H,m),3.00-3.11(1H,m),3.79-3.95(1H,m),3.97(3H,s),4.52(1H,d,J=6.84Hz),4.65(1H,d,J=7.12 Hz), 4.76 (2H, t, J = 6.84Hz), 5.04 (1H, d, J = 49.35Hz), 5.24 (1H, spt, J = 6.75Hz), 6.78 (1H, d, J = 2.46Hz), 6.81 ( C 25 H 28 The ESIMS experimental value of FN9O2 is m / z 506.2 (M+1).

[0915] Example 11.

[0916] 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 depicted in Scheme 34 below.

[0917]

[0918] Step 1

[0919] 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) (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 tBuONa (770 mg, 8.01 mmol) was placed in a microwave vial and anhydrous 1,4-dioxane (20 mL) was added. 3AMS (8 beads) was added and the reaction was stirred at room temperature for 1 h. The sieve was quickly removed, and the reaction was sealed and purged with Ar for 5 min, followed by microwave irradiation to 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 (MgSO4) and reduced in vacuo to give the crude product (3R, 4S) -4- ((5- chloro-4-methoxypyrrolo [2,1-f] [1,2,4] triazine-2-yl) amino) -3-fluoropiperidine -1- carboxylic acid tert-butyl ester (CLXV) (1,284 g, 3.211 mmol, 100.0% yield) (assuming quantitative yield) as a brown semi-solid, which was used without further purification. 17 H 23 The ESIMS experimental value of ClFN5O3 is m / z 344.10 (M+H- t Bu).

[0920] Step 2

[0921] Using the procedure described in Example 8, Scheme 31, Step 2, 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) was produced as a light yellow solid. 12 H 15 ESIMS experimental value of ClFN5O: m / z 300.1 (M+H).

[0922] Step 3

[0923] KCO (115 mg, 0.83 mmol) and MsCl (45 mg, 0.39 mmol) were suspended in DMF (1 mL) and 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 The mixture was added to a suspension 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 a pearly white solid.13 H 17 The ESIMS experimental value of ClFN5O3S is m / z 378.1 (M+H).

[0924] Step 4

[0925] 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)Cl2 (803 mg, 0.98 mmol) and KOAc (5.8 g, 59.1 mmol) were suspended in anhydrous 1,4-dioxane (100 mL). The reaction was sonicated and degassed for 5 minutes and then heated at 100°C for 2.5 h. The reaction mixture was loaded into The mixture was added to a 5-[[(4-(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)]-1-[[[(4-(2,2-difluoroethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (CLXVIII)]) 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)) as a fluffy light orange solid. 14 H 18 The ESIMS experimental value of BF2N3O2 is m / z 310.15 (M+H).

[0926] Step 5

[0927] 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 (2 mg, 0.01 mmol) and XPhos (3 mg, 0.01 mmol) were suspended in anhydrous 1,4-dioxane (0.5 mL). K2PO4 (52 μL, 0.1 mmol) was added and the reaction was sonicated and sparged with Ar for 5 min. The reaction was then heated to 90°C for 30 min. The product was purified by column chromatography (0→1.5% MeOH / CHCl). The product was further purified by HPLC (0→35% MeCN / HO containing 0.1% formic acid) to give 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 after lyophilization. 1 H NMR(499MHz,DMSO-d6)δppm 1.77-1.88(1H,m),1.96(1H,qd,J=12.50,4.38Hz),2.93(3H,s),3.02(1H,td,J=12.25,2.60Hz),3.2 0(1H,dd,J=37.55,12.59Hz),3.61-3.70(1H,m),3.80-3.89(1H,m),3.90-4.04(1H,m),3.96(3H,s), 5.05(1H,d,J=49.10Hz), 5.30(2H,td,J=15.95,2.87Hz), 6.61(1H,tt,J=54.30,3.00Hz), 6.76(1H,d ,J=2.74Hz),6.88(1H,d,J=7.94Hz),7.63(1H,d,J=2.46Hz),7.64-7.66(1H,m),8.02-8.05(2H,m); 21 H 23 The ESIMS experimental value of F3N8O3S is m / z 525.15 (M+1).

[0928] The following compounds were prepared according to the procedures described in Schemes 1 to 34 above.

[0929]

[0930] 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.

[0931] Beige solid (2.8 mg, 0.005 mmol, 2.5% yield). 1H NMR (499MHz, chloroform-d) δppm 1.29(3H,s),1.58-1.68(4H,m),1.75(2H,br d,J=10.68Hz),1.99-2.06(2H,m),2.72(3H,s),3.66-3.74(1H,m),3.95(3H,s),4.50(2H,td,J=14.80 ,2.50Hz),6.12(1H,tt,J=54.60,3.00Hz),6.60(1H,d,J=2.46Hz),7.47(1H,d,J=2.19Hz),7.81(1H,br s),8.73(1H,brs);C 23 H 27 The ESIMS experimental value of F2N7O2 is m / z 472.2 (M+1).

[0932]

[0933] 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.

[0934] Beige solid (10 mg, 0.025 mmol, 10.0% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.15(3H,s),1.38-1.53(4H,m),1.56-1.65(2H,m),1.84-1.93(2H,m),3.59-3.71(1H,m),3.95(3H,s),4.24(1H,s),4.31(3H,s),6.48( C 21 H 25 The ESIMS experimental value of N7O2 is m / z 408.25 (M+1).

[0935]

[0936] 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.

[0937] Off-white solid (15 mg, 0.038 mmol, 22.9% yield). 1 H NMR (499MHz, DMSO-d6) δppm 1.12 (3H, s), 1.36 (2H, td, J = 13.00, 4.11Hz), 1.58 (2H, br d,J=12.32Hz),1.61-1.75(4H,m),3.45-3.60(1H,m),3.97(3H,s),4.00(1H,s),6.57(1H,d,J=7.94Hz),6.76(1H,d,J=2.46H z), 7.64 (1H, d, J = 2.46Hz), 7.72 (1H, d, J = 1.37Hz), 7.93 (1H, d, J = 1.37Hz), 8.73 (1H, d, J = 2.46Hz), 9.08 (1H, d, J = 2.46Hz); C 20 H 23 The ESIMS experimental value of N7O2 is m / z 394.2 (M+1).

[0938]

[0939] 2-(cis-3-((4-methoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutyloxy)ethan-1-ol 6.

[0940] White solid (28 mg, 0.071 mmol, 35.5% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.82-1.93(2H,m),2.60-2.69(2H,m),3.30-3.33(2H,m),3.48(2H,q,J=5.48Hz),3.68-3 .74(1H,m),3.74-3.81(1H,m),3.98(3H,s),4.60(1H,t,J=5.61Hz),6.58(1H,d,J=1.92Hz ),6.77(1H,d,J=2.46Hz),7.04(1H,d,J=7.39Hz),7.10(1H,dd,J=7.26,1.78Hz),7.60(1 H,d,J=2.46Hz),7.80(1H,d,J=0.82Hz),7.97(1H,d,J=2.19Hz),8.62(1H,d,J=7.12Hz); 20 H 22 The ESIMS experimental value of N6O3 is m / z 395.2 (M+1).

[0941]

[0942] 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.

[0943] Off-white solid (53 mg, 0.145 mmol, 54.5% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.27(3H,s),2.02(2H,td,J=8.90,2.19Hz),2.31-2.41(2H,m),3.72(1H,dq,J=1 5.16,7.72Hz),3.98(3H,s),4.92(1H,s),6.58(1H,d,J=1.64Hz),6.76(1H,d,J= 2.74Hz),6.95(1H,d,J=6.57Hz),7.10(1H,dd,J=7.39,1.92Hz),7.63(1H,d,J=2 .74Hz), 7.80 (1H, d, J = 1.10Hz), 7.97 (1H, d, J = 2.19Hz), 8.62 (1H, d, J = 7.39Hz); C 19 H 20 The ESIMS experimental value of N6O2 is m / z 365.2 (M+1).

[0944]

[0945] 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.

[0946] White solid (16 mg, 0.044 mmol, 16.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.28(3H,s),1.93-2.05(2H,m),2.27-2.35(2H,m),3.98(3H,s),4.25(1H,s xt,J=7.34Hz),4.79(1H,s),6.58(1H,d,J=1.92Hz),6.76(1H,d,J=2.74Hz), 6.95(1H,d,J=6.57Hz),7.10(1H,dd,J=7.12,1.92Hz),7.62(1H,d,J=2.46H z), 7.80 (1H, d, J = 0.82Hz), 7.97 (1H, d, J = 2.19Hz), 8.62 (1H, d, J = 7.39Hz); C 19 H 20 The ESIMS experimental value of N6O2 is m / z 365.2 (M+1).

[0947]

[0948] 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.

[0949] Off-white solid (25 mg, 0.064 mmol, 31.8% yield). 1 H NMR (499MHz, DMSO-d6) δppm 1.45-1.54(2H,m),1.55-1.65(2H,m),1.65-1.73(2H,m),1.80-1.88(2H,m),3.22(3H,s),3.34(1H,br d,J=2.19Hz),3.59-3.70(1H,m),3.98(3H,s),6.56-6.58(1H,m),6.58(1H,s),6.75(1H,d,J=2.46Hz),7.10(1H,dd C 21 H 24 The ESIMS experimental value of N6O2 is m / z 393.2 (M+1).

[0950]

[0951] 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.

[0952] Off-white solid (40 mg, 0.102 mmol, 50.9% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.14-1.26(2H,m),1.27-1.40(2H,m),2.01(4H,br t,J=10.81Hz),3.12(1H,tt,J=10.23,3.73Hz),3.24(3H,s),3.51-3.63( 1H,m),3.98(3H,s),6.57(1H,d,J=7.94Hz),6.58(1H,d,J=1.64Hz),6.75 C 21 H 24 The ESIMS experimental value of N6O2 is m / z 393.2 (M+1).

[0953]

[0954] 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.

[0955] Off-white semisolid. (10 mg, 0.024 mmol, 14.2% yield). 1H NMR (499MHz, DMSO-d6) δppm1.45-1.55(2H,m),1.60-1.73(4H,m),1.78-1.88(2H,m),3.38-3.42( 2H,m),3.47(1H,brs),3.50(2H,q,J=5.48Hz),3.57-3.69(1H,m),3.98(3H,s),4.51(1H,t,J=5.4 8Hz), 6.55 (1H, d, J = 7.67Hz), 6.58 (1H, d, J = 1.37Hz), 6.75 (1H, d, J = 2.46Hz), 7.10 (1H, dd, J = 7.3 9,1.64Hz),7.61(1H,d,J=2.74Hz),7.80(1H,s),7.97(1H,d,J=1.92Hz),8.62(1H,d,J=7.39Hz);C 22 H 26 The ESIMS experimental value of N6O3 is m / z 423.3 (M+1).

[0956]

[0957] 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.

[0958] Fluffy off-white solid (33 mg, 0.0756 mmol, 45.3% yield). 1 H NMR (499MHz, DMSO-d6) δppm1.45-1.55(2H,m),1.59-1.73(4H,m),1.78-1.88(2H,m),3.27(3H,s) ,3.43-3.46(2H,m),3.46-3.48(1H,m),3.48-3.52(2H,m),3.57-3.69(1H,m),3.98(3H,s),6.58( 1H,d,J=2.19Hz), 6.59(1H,d,J=7.85Hz), 6.75(1H,d,J=2.46Hz), 7.10(1H,dd,J=7.39,1.92Hz), 7.61(1H,d,J=2.74Hz), 7.80(1H,d,J=0.82Hz), 7.97(1H,d,J=2.19Hz), 8.62(1H,d,J=7.12Hz); C 23 H 28 The ESIMS experimental value of N6O3 is m / z 437.25 (M+1).

[0959]

[0960] 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.

[0961] White solid (31 mg, 0.071 mmol, 35.5% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.18-1.37(4H,m),2.00(4H,br d,J=10.95Hz),3.20-3.27(1H,m),3.25(3H,s),3.40-3.45(2H,m),3.53(2H,t ,J=4.93Hz),3.54-3.60(1H,m),3.97(3H,s),6.56(1H,d,J=8.21Hz),6.58(1H ,d,J=1.64Hz),6.75(1H,d,J=2.46Hz),7.10(1H,dd,J=7.39,1.64Hz),7.63(1 H,d,J=2.74Hz),7.80(1H,s),7.96(1H,d,J=2.19Hz),8.62(1H,d,J=7.12Hz); C 23 H 28 The ESIMS experimental value of N6O3 is m / z 437.2 (M+1).

[0962]

[0963] 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.

[0964] White solid (22 mg, 0.052 mmol, 33.0% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.50-1.59(2H,m),1.60-1.72(4H,m),1.74-1.81(2H,m),1.81(3H,s),3.64-3.71(2H,m),3.99(3H,s),6.47(1H,d,J=6.3 0Hz),6.58(1H,d,J=1.64Hz),6.76(1H,d,J=2.74Hz),7.11(1H,dd,J=7.26,1.78Hz),7.63(1H,d,J=2.74Hz),7.70(1H,br d,J=6.84Hz),7.81(1H,s),7.97(1H,d,J=2.19Hz),8.62(1H,d,J=7.12Hz); C 22 H 25 The ESIMS experimental value of N7O2 is m / z 420.2 (M+1).

[0965]

[0966] 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.

[0967] White solid (2 mg, 0.005 mmol, 2.9% yield). 1 H NMR (499MHz, DMSO-d6) δppm 1.19-1.29(2H,m),1.30-1.40(2H,m),1.78(3H,s),1.81(2H,br d,J=11.50Hz),1.99(2H,br d,J=10.13Hz),3.45-3.51(1H,m),3.52-3.59(1H,m),3.97(3H,s),6.56 (1H,d,J=8.21Hz),6.58(1H,d,J=1.64Hz),6.76(1H,d,J=2.74Hz),7.10( C 22 H 25 The ESIMS experimental value of N7O2 is m / z 420.2 (M+1).

[0968]

[0969] 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.

[0970] Off-white solid (20 mg, 0.051 mmol, 42.4% yield). 1 H NMR (499MHz, DMSO-d6) δppm 1.12 (3H, s), 1.36 (2H, td, J = 13.00, 4.38Hz), 1.58 (2H, br d,J=12.05Hz),1.61-1.68(2H,m),1.69-1.75(2H,m),3.45-3.59(1H,m),3 .98(3H,s),3.99(1H,s),6.52(1H,d,J=7.94Hz),6.58(1H,d,J=1.64Hz),6. 74(1H,d,J=2.74Hz),7.10(1H,dd,J=7.12,1.92Hz),7.60(1H,d,J=2.74Hz ),7.80(1H,d,J=1.09Hz),7.96(1H,d,J=2.19Hz),8.62(1H,d,J=7.39Hz);C 21 H 24 The ESIMS experimental value of N6O2 is m / z 393.2 (M+1).

[0971]

[0972] 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.

[0973] Beige solid (5 mg, 0.013 mmol, 8.3% yield). 1H NMR (499MHz, chloroform-d) δppm 1.32(3H,s),1.47-1.58(2H,m),1.60-1.68(2H,m),1.71-1.79(2H,m),2.09- 2.18(2H,m),3.86(1H,brd,J=3.83Hz),4.01(3H,s),4.12(1H,s),6.53(1H,br C 21 H 24 The ESIMS experimental value of N6O2 is m / z 393.2 (M+1).

[0974]

[0975] 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.

[0976] Off-white solid (17 mg, 0.042 mmol, 20.7% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.46-1.60(2H,m),1.85-1.96(2H,m),2.11(2H,br t,J=11.09Hz),2.61(2H,dt,J=28.25,4.95Hz),2.84-2.93(2H,m),3.53-3.66(1H, m),3.98(3H,s),4.53(2H,dt,J=47.70,4.95Hz),6.58(1H,d,J=1.64Hz),6.62(1H, d,J=7.94Hz),6.76(1H,d,J=2.74Hz),7.10(1H,dd,J=7.39,1.92Hz),7.62(1H,d,J =2.46Hz),7.81(1H,d,J=1.10Hz),7.97(1H,d,J=2.46Hz),8.62(1H,d,J=7.39Hz); C 21 H 24 The ESIMS experimental value of FN7O is m / z 410.2 (M+1).

[0977]

[0978] 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.

[0979] Off-white solid (2 mg, 0.005 mmol, 1.2% yield). 1 H NMR (499MHz, METHANOL-d4) δppm1.57-1.70(2H,m),2.06(2H,br t,J=11.77Hz),2.09-2.15(2H,m),2.80(2H,br d,J=11.77Hz),3.53(1H,quin,J=6.43Hz),3.67-3.77(1H,m),4.03(3H,s),4.62(2H,t,J=6.30Hz),4.69-4.75(2H,m),6.54-6.61(1H,m),6.70(1 C 22 H 25 The ESIMS experimental value of N7O2 is m / z 420.2 (M+1).

[0980]

[0981] 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.

[0982] Beige solid (11 mg, 0.027 mmol, 13.6% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.27-1.39(1H,m),1.40-1.52(1H,m),1.87-1.94(1H,m),1.94-2.00(1H,m),2.01(3H,s),2.70- 2.81(1H,m),3.12-3.19(1H,m),3.78-3.87(2H,m),3.99(3H,s),4.24-4.34(1H,m),6.59(1H,dd, J=2.19,0.82Hz),6.73(1H,d,J=7.94Hz),6.77(1H,d,J=2.74Hz),7.11(1H,dd,J=7.12,1.92Hz), 7.63(1H,d,J=2.74Hz), 7.81(1H,d,J=1.10Hz), 7.97(1H,d,J=2.19Hz), 8.62(1H,d,J=7.12Hz); C 21 H 23 The ESIMS experimental value of N7O2 is m / z 406.2 (M+1).

[0983]

[0984] 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.

[0985] Off-white solid (45 mg, 0.118 mmol, 87.4% yield). 1 H NMR (499MHz, DMSO-d6) δppm 1.57-1.65 (1H, m), 1.73 (1H, qd, J = 12.37, 4.24Hz), 2.56 (1H, br t,J=12.46Hz),2.71(1H,dd,J=39.25,14.30Hz),2.96(1H,br d,J=13.14Hz),3.13(1H,br t,J=11.50Hz),3.77-3.94(1H,m),4.00(3H,s),4.80(1H,d,J=50.75Hz),6.59(1H,d,J=1.64Hz),6.64(1H,d,J=7.94Hz),6.78(1H,d,J=2 C19 H 20 The ESIMS experimental value of FN7O is m / z 382.2 (M+1).

[0986]

[0987] 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.

[0988] Brown solid (109 mg, 0.286 mmol, 99.0% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.89-1.96(1H,m),2.07(1H,qd,J=13.23,4.11Hz),2.75(1H,s),3.11-3.18(1H,m),3.27-3 .38(1H,m),3.58-3.66(1H,m),4.01(3H,s),4.05-4.18(1H,m),5.20(1H,d,J=47.45Hz),6.6 0(1H,d,J=1.92Hz),6.81(1H,d,J=2.46Hz),7.06(1H,d,J=7.39Hz),7.11(1H,dd,J=7.12,1 .92Hz),7.59(1H,d,J=2.74Hz),7.82(1H,d,J=1.37Hz),7.98(1H,d,J=2.19Hz),8.64(1H,br d,J=7.39Hz); C 19 H 20 The ESIMS experimental value of FN7O is m / z 382.2 (M+1).

[0989]

[0990] 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.

[0991] Off-white solid (30 mg, 0.076 mmol, 72.3% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.68(1H,br dd,J=12.59,3.01Hz),1.92(1H,qd,J=12.23,3.56Hz),2.01-2.09(1H,m),2.17(1H,dd,J=37.55,13.20Hz),2.19(3H,s),2.79(1H,br d,J=11.23Hz),3.00-3.09(1H,m),3.67-3.83(1H,m),4.00(3H,s),4.91( 1H,d,J=50.20Hz),6.59(1H,d,J=1.64Hz),6.64(1H,d,J=7.67Hz),6.78( C 20 H 22 The ESIMS experimental value of FN7O is m / z 396.2 (M+1).

[0992]

[0993] 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.

[0994] Off-white solid (43 mg, 0.109 mmol, 38.1% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.65-1.72(1H,m),1.92(1H,qd,J=12.27,3.70Hz),2.01-2.09(1H,m),2.17(1H,dd,J=37.55,13.20Hz),2.19(3H,s),2.80(1H,br d,J=11.77Hz),3.01-3.07(1H,m),3.67-3.83(1H,m),4.00(3H,s),4.91( 1H,d,J=49.90Hz),6.59(1H,d,J=1.37Hz),6.65(1H,d,J=7.67Hz),6.78( C 20 H 22 The ESIMS experimental value of FN7O is m / z 396.3 (M+1).

[0995]

[0996] 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.

[0997] Off-white solid (8 mg, 0.022 mmol, 6.6% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.47-1.60(2H,m),1.89(2H,br dd,J=12.46,2.05Hz),3.36-3.45(2H,m),3.73-3.85(1H,m),3.85-3.92( 2H,m),3.99(3H,s),6.58(1H,d,J=1.92Hz),6.71(1H,d,J=7.94Hz),6.76 C 19 H 20 The ESIMS experimental value of N6O2 is m / z 365.2 (M+1).

[0998]

[0999] 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.

[1000] White solid (28 mg, 0.067 mmol, 38.7% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.69-1.76(3H,m),2.13-2.25(2H,m),2.52-2.60(2H,m),3.77(1H,s),3.89(1H,s),3.9 8(3H,s),4.04-4.11(1H,m),4.05(1H,s),4.17(1H,s),6.58(1H,d,J=1.92Hz),6.77(1H ,d,J=2.46Hz),7.03(1H,t,J=6.98Hz),7.10(1H,dd,J=7.39,1.92Hz),7.62(1H,dd,J=4 .79, 2.60Hz), 7.80 (1H, d, J = 0.82Hz), 7.97 (1H, d, J = 2.19Hz), 8.62 (1H, d, J = 7.39Hz); C 22 H 23 The ESIMS experimental value of N7O2 is m / z 418.2 (M+1).

[1001]

[1002] 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.

[1003] Off-white solid (50 mg, 0.112 mmol, 79.4% yield). 1H NMR (499MHz, DMSO-d6) δppm 1.40-1.46(1H,m),1.49-1.56(2H,m),1.57-1.64(1H,m),1.74-1.84(2H,m),1.95-2.01(3H,m),2.26(2H,br dd,J=9.86,8.21Hz),3.26-3.30(1H,m),3.30-3.32(1H,m),3.35-3.39(1H,m),3. 39-3.44(1H,m),3.98(3H,s),4.14-4.25(1H,m),6.58(1H,d,J=1.64Hz),6.76(1H ,d,J=2.74Hz),7.02(1H,t,J=7.12Hz),7.10(1H,dd,J=7.12,1.92Hz),7.59-7.66 (1H,m),7.80(1H,d,J=1.09Hz),7.97(1H,d,J=2.19Hz),8.62(1H,d,J=7.39Hz);C 24 H 27 The ESIMS experimental value of N7O2 is m / z 446.2 (M+1).

[1004]

[1005] 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.

[1006] Off-white solid (75 mg, 0.168 mmol, 95.7% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.26-1.39(2H,m),1.48-1.60(2H,m),1.73-1.78(3H,m),1.83-1.93(4H,m),3.47(1H,s),3.52(1H,s),3.57(1H,br dd,J=7.53,3.15Hz),3.74(1H,s),3.80(1H,s),3.98(3H,d,J=1.10Hz),6.54(1H,dd,J=16.15,7.94Hz),6.58(1H,d,J=1.64Hz),6.76(1H,d, C 24 H 27 The ESIMS experimental value of N7O2 is m / z 446.2 (M+1).

[1007]

[1008] 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.

[1009] White solid (19 mg, 0.052 mmol, 31.3% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.27(3H,s),1.96-2.07(2H,m),2.31-2.41(2H,m),3.71(1H,dq,J=15.1 6,7.72Hz),3.96(3H,s),4.91(1H,s),6.67(1H,d,J=2.74Hz),6.92(1H, C 19 H 20 The ESIMS experimental value of N6O2 is m / z 365.2 (M+1).

[1010]

[1011] 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.

[1012] Off-white semisolid (10 mg, 0.027 mmol, 16.5% yield). 1 H NMR (499MHz, DMSO-d6) δppm1.28(3H,s),1.94-2.03(2H,m),2.28-2.35(2H,m),3.96(3H,s),4.25(1H,sxt,J=7.39Hz),4.78(1H,br s), 6.68 (1H, d, J = 2.74Hz), 6.93 (1H, d, J = 6.84Hz), 7.43 (1H, dd, J = 9.31, 1.64Hz), 7. 54(1H,d,J=9.58Hz),7.56(1H,s),7.61(1H,d,J=2.74Hz),7.95(1H,s),8.68(1H,s);C 19 H 20 The ESIMS experimental value of N6O2 is m / z 365.2 (M+1).

[1013]

[1014] 5-(Imidazolo[1,2-a]pyridin-6-yl)-4-methoxy-N-(cis-4-methoxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-2-amine 45.

[1015] Off-white solid (2.6 mg, 0.007 mmol, 4.7% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.45-1.54(2H,m),1.55-1.65(2H,m),1.69(2H,dt,J=8.35,4.04Hz),1.80-1.88 (2H,m),3.22(3H,s),3.29-3.37(1H,m),3.56-3.71(1H,m),3.96(3H,s),6.54(1 H,d,J=7.67Hz),6.67(1H,d,J=2.46Hz),7.43(1H,dd,J=9.31,1.37Hz),7.54(1H ,d,J=9.31Hz),7.56(1H,s),7.61(1H,d,J=2.46Hz),7.95(1H,s),8.68(1H,s);C 21 H 24The ESIMS experimental value of N6O2 is m / z 393.2 (M+1).

[1016]

[1017] 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.

[1018] Orange semisolid. (6 mg, 0.014 mmol, 6.1% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.45-1.56(2H,m),1.60-1.74(4H,m),1.78-1.88(2H,m),3.38-3.42(2H,m),3.47(1H,br s),3.50(2H,q,J=5.20Hz),3.58-3.70(1H,m),3.96(3H,s),4.51(1H,br t,J=5.34Hz),6.52(1H,d,J=7.67Hz),6.67(1H,d,J=2.46Hz),7.47(1H,br d,J=9.03Hz),7.56(1H,br d,J=9.03Hz),7.58-7.60(1H,m),7.61(1H,d,J=2.46Hz),7.98(1H,br s),8.70(1H,br s);C 22 H 26 The ESIMS experimental value of N6O3 is m / z 423.25 (M+1).

[1019]

[1020] 5-(Imidazolo[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.

[1021] White solid (3 mg, 0.007 mmol, 4.1% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.44-1.56(2H,m),1.58-1.74(4H,m),1.77-1.88(2H,m),3.27(3H,s),3.43-3.46(2H,m),3. 47(1H,brs),3.48-3.52(2H,m),3.62(1H,ddt,J=12.53,8.56,4.52,4.52Hz),3.96(3H,s),6. 56(1H,d,J=7.67Hz), 6.67(1H,d,J=2.46Hz), 7.43(1H,dd,J=9.45,1.78Hz), 7.54(1H,d,J=9. 31Hz),7.56(1H,d,J=1.09Hz),7.61(1H,d,J=2.74Hz),7.95(1H,s),8.68(1H,d,J=1.64Hz);C 23 H 28 The ESIMS experimental value of N6O3 is m / z 437.2 (M+1).

[1022]

[1023] 5-(Imidazolo[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.

[1024] White solid (5 mg, 0.012 mmol, 5.7% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.18-1.26(2H,m),1.27-1.36(2H,m),2.00(4H,br d,J=10.95Hz),3.20-3.26(1H,m),3.25(3H,s),3.42(2H,dd,J=5.75,3.83Hz),3. 53(2H,dd,J=5.75,3.83Hz),3.55-3.60(1H,m),3.95(3H,s),6.52(1H,d,J=7.94H z),6.67(1H,d,J=2.46Hz),7.43(1H,dd,J=9.45,1.78Hz),7.54(1H,d,J=9.31Hz) ,7.56(1H,d,J=1.09Hz),7.63(1H,d,J=2.46Hz),7.95(1H,s),8.64-8.70(1H,m);C 23 H 28 The ESIMS experimental value of N6O3 is m / z 437.2 (M+1).

[1025]

[1026] 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.

[1027] Off-white solid (8 mg, 0.019 mmol, 37.9% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.50-1.59(2H,m),1.60-1.71(4H,m),1.73-1.81(2H,m),1.81(3H,s),3.67(2H,br d,J=3.56Hz),3.97(3H,s),6.43(1H,d,J=6.30Hz),6.68(1H,d,J=2.74Hz),7.44(1H,dd,J=9.31,1.64Hz),7.5 4(1H,d,J=9.31Hz),7.57(1H,s),7.62(1H,d,J=2.46Hz),7.70(1H,brd,J=7.12Hz),7.95(1H,s),8.68(1H,s);C 22 H 25 The ESIMS experimental value of N7O2 is m / z 420.2 (M+1).

[1028]

[1029] 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.

[1030] Off-white solid (17 mg, 0.041 mmol, 24.3% yield). 1H NMR (499MHz, DMSO-d6) δppm 1.19-1.29(2H,m),1.29-1.39(2H,m),1.78(3H,s),1.79-1.85(2H,m),1.99(2H,br d,J=10.95Hz),3.44-3.59(2H,m),3.95(3H,s),6.53(1H,d,J=8.21Hz),6.67(1H,d,J=2.46Hz),7.43(1H,dd,J=9.45,1. C 22 H 25 The ESIMS experimental value of N7O2 is m / z 420.2 (M+1).

[1031]

[1032] 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.

[1033] Off-white solid (7.9 mg, 0.020 mmol, 14.4% yield). 1 H NMR (499MHz, DMSO-d6) δppm 1.12 (3H, s), 1.36 (2H, td, J = 13.00, 4.11Hz), 1.58 (2H, br d,J=12.32Hz),1.60-1.68(2H,m),1.68-1.74(2H,m),3.45-3.57(1H,m),3.96(3H,s),4.00(1H,s),6.49(1H,d,J=7.94Hz),6.66(1H,d,J=2 C 21 H 24 The ESIMS experimental value of N6O2 is m / z 393.2 (M+1).

[1034]

[1035] 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.

[1036] Beige solid (16 mg, 0.041 mmol, 20.4% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.14(3H,s),1.37-1.52(4H,m),1.56-1.64(2H,m),1.81-1.93(2H,m), 3.57-3.70(1H,m),3.96(3H,s),4.24(1H,s),6.47(1H,d,J=7.94Hz),6 C 21 H 24 The ESIMS experimental value of N6O2 is m / z 393.2 (M+1).

[1037]

[1038] 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.

[1039] White solid (5 mg, 0.012 mmol, 5.8% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.48-1.62(2H,m),1.89(2H,br d,J=10.95Hz),2.22-2.31(2H,m),2.72(2H,td,J=15.74,4.38Hz),2.90(2H,br d,J=11.77Hz),3.53-3.65(1H,m),3.96(3H,s),6.13(1H,tt,J=55.95,4.40Hz),6.59(1H,d,J=7.94Hz),6.68(1H,d,J=2.74Hz),7.4 C 21 H 23 The ESIMS experimental value of F2N7O is m / z 428.2 (M+1).

[1040]

[1041] 5-(Imidazolo[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.

[1042] Colorless semisolid. (10 mg, 0.024 mmol, 14.3% yield). 1 H NMR (499MHz, DMSO-d6) δppm1.48-1.61(2H,m),1.84-1.98(4H,m),2.71(2H,br d,J=11.22Hz),3.41(1H,br s),3.54-3.65(1H,m),3.96(3H,s),4.43(2H,t,J=6.16Hz),4.54(2H,t,J=6.57Hz),6.6 3(1H,d,J=7.94Hz),6.68(1H,d,J=2.46Hz),7.44(1H,dd,J=9.31,1.37Hz),7.55(1H,br d,J=9.31Hz),7.57(1H,br s),7.62(1H,d,J=2.46Hz),7.96(1H,s),8.68(1H,s);C 22 H 25 The ESIMS experimental value of N7O2 is m / z 420.2 (M+1).

[1043]

[1044] 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.

[1045] Beige solid (9 mg, 0.022 mmol, 13.3% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.29-1.38(1H,m),1.39-1.50(1H,m),1.88-1.95(1H,m),1.97(1H,br d,J=13.14Hz),2.01(3H,s),2.69-2.82(1H,m),3.11-3.20(1H,m),3.77-3.87(2H,m),3.97(3H,s),4.28(1H,br d,J=12.59Hz),6.68-6.72(2H,m),7.47(1H,d,J=9.31Hz),7.56(1H,d,J= 9.31Hz),7.59(1H,s),7.63(1H,d,J=2.46Hz),7.97(1H,s),8.70(1H,s);C 21 H 23 The ESIMS experimental value of N7O2 is m / z 406.2 (M+1).

[1046]

[1047] 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.

[1048] White solid (5.5 mg, 0.014 mmol, 10.6% yield). 1H NMR (499MHz, DMSO-d6) δppm 1.63-1.74 (1H, m), 1.92 (1H, qd, J = 12.27, 3.70Hz), 2.06 (1H, br t,J=11.09Hz),2.11-2.24(1H,m),2.19(3H,s),2.80(1H,br d,J=10.95Hz),3.00-3.07(1H,m),3.66-3.83(1H,m),3.98(3H,s),4.91(1H,d,J=49.90Hz),6.61(1H,d,J=7.94Hz),6.70(1H,d,J =2.74Hz),7.44(1H,dd,J=9.45,1.78Hz),7.55(1H,d,J=9.31Hz),7.57(1H,s),7.62(1H,d,J=2.46Hz),7.95(1H,s),8.69(1H,s); C 20 H 22 The ESIMS experimental value of FN7O is m / z 396.2 (M+1).

[1049]

[1050] 5-(Imidazolo[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.

[1051] White solid (4.0 mg, 0.011 mmol, 4.0% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 2.12-2.23(2H,m),2.61(2H,ddd,J=9.86,7.53,2.87Hz),3.95-4.04(1H,m) ,3.97(3H,s),4.51(2H,s),4.63(2H,s),6.58(1H,d,J=1.92Hz),6.76(1H,d, J=2.46Hz),7.00(1H,d,J=7.12Hz),7.10(1H,dd,J=7.26,1.78Hz),7.61(1H, d,J=2.74Hz),7.80(1H,s),7.97(1H,d,J=1.92Hz),8.62(1H,d,J=7.39Hz); C 20 H 20 The ESIMS experimental value of N6O2 is m / z 377.2 (M+1).

[1052]

[1053] 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.

[1054] Off-white solid (16 mg, 0.044 mmol, 13.2% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.95-2.04(2H,m),2.86(1H,td,J=6.78,3.15Hz),3.81-3.88(4H,m),4.00(3H,s),6.39(1H,d,J=3.01Hz),6.59(1H,d,J=1.64Hz),6.78(1H,d C 19 H 18 The ESIMS experimental value of N6O2 is m / z 363.2 (M+1).

[1055]

[1056] 2-(cis-3-((4-ethoxy-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutyloxy)ethan-1-ol 91.

[1057] Off-white solid (4 mg, 0.010 mmol, 4.9% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.33(3H,t...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: R 1 is optionally replaced by 1 to 10 R 4 substituted heteroaryl; R 2 Selected from the group consisting of: 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, optionally substituted by 1 to 10 R 6 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 10 R 26 Substituted-(C 1-5 alkylene) p Aryl, optionally substituted with 1 to 10 R 7 Substituted-(C 1-5 alkylene) p heteroaryl and optionally substituted by 1 to 12 R 8 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted; R 3 Selected from the group consisting of: H, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and optionally substituted by 1 to 10 R 18 substituted heterocyclic groups; Each R 4 are independently selected from the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), unsubstituted-(C 2-9 Halogenated alkenyl), -(C 1-5 alkylene) p OR 9 、-(C 1-5 alkylene) p CN, optionally with 1 to 10 R 10 Substituted-(C 1-5 alkylene) p Heterocyclyl, optionally substituted by 1 to 12 R 11 Substituted-carbocyclyl, optionally substituted by 1 to 10 R 20 Substituted-(C 1-5 alkylene) p Heteroaryl, -(C 1-5 alkylene) p C(=O)N(R 12 )2 and -C(=O)R 13 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted; Each R 5 are independently selected from the group consisting of: 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 the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1 to 10 R 16 Substituted-heterocyclyl, optionally substituted by 1 to 12 R 17 Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 21 、-(C 1-5 Alkylene)CN, -SO2R 23 and -C(=O)R 24 wherein said-(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted; Alternatively, two R attached to the same carbon atom 6 Together they form a carbonyl group; Each R 7 are independently selected from the group consisting of halogen, 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 the group consisting of halogen, 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, optionally with 1 to 10 R 16 Substituted-(C 1-5 alkylene) p Heterocyclic group, -C(=O)R 22 and -NR 14 C(=O)R 23 , where each -(C 1-5 alkylene) are independently optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted; Each R 9 are independently selected from the group consisting of: 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 the group consisting of halogen, 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 the group consisting of halogen, 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 selected from the group consisting of: 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 , optionally 1 to 12 R 17 Substituted-(C 1-5 alkylene) p Carbocyclyl, optionally substituted by 1 to 10 R 18 substituted-heterocyclyl and optionally substituted by 1 to 10 R 19 Substituted-heteroaryl, wherein the -(C 1-5 alkylene) is optionally substituted with 1 to 5 halogen and / or 1 to 3 unsubstituted -(C 1-3 alkyl) substituted; Each R 13 is optionally replaced by 1 to 10 R 18 substituted-heterocyclyl; Each R 14 are independently selected from the group consisting of: 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 selected from the group consisting of: 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 ; Each R 16 are independently selected from the group consisting of halogen, -CN, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl) and optionally substituted by 1 to 12 R 27 substituted-carbocyclyl; Alternatively, two R attached to the same carbon atom 16 Together they form a carbonyl group; Each R 17 are independently selected from the group consisting of halogen, -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 the group consisting of halogen, 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 the group consisting of halogen, 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 the group consisting of halogen, 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 selected from the group consisting of: 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 independently selected from the group consisting of: optionally 1 to 10 R 18 Substituted-heterocyclyl, -N(R 12 )2 and -OR 21 ; Each R 23 Independently selected from the group consisting of: 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 optionally 1 to 12 R 25 substituted-carbocyclyl; Each R 24 Independently selected from the group consisting of: unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -OR 21 and optionally 1 to 12 R 25 substituted-carbocyclyl; Each R 25 are independently selected from the group consisting of halogen, 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 the group consisting of halogen, 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 the group consisting of halogen, unsubstituted -(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl); R 28 are independently selected from the group consisting of: H and halogen; and Each p is independently 0 or 1; wherein each H atom is optionally independently 2 H(D) (deuterium) instead.

2. The compound of claim 1, wherein R 1 Selected from the group consisting of: It is optionally replaced by 1 to 10 R 4 replace.

3. The compound according to any one of claims 1 to 2, wherein R 1 Selected from the group consisting of: It is optionally replaced by 1 to 3 R 4 replace.

4. The compound according to any one of claims 1 to 3, wherein R 1 Selected from the group consisting of: It is optionally replaced by 1 to 3 R 4 replace.

5. The compound according to any one of claims 1 to 4, wherein R 1 Selected from the group consisting of: It is optionally replaced by 1 to 3 R 4 replace.

6. The compound according to any one of claims 1 to 5, wherein R 1 Selected from the group consisting of: Unreplaced 7. The compound according to any one of claims 1 to 5, wherein R 4 Selected from the group consisting of halogen, 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.

8. A compound according to any one of claims 1 to 7, wherein R 2 Selected from the group consisting of: optionally 1 to 3 R 5 Substituted-heterocyclyl, optionally substituted by 1 to 3 R 8 Substituted-(C 1-2 alkylene) p carbocyclyl and optionally 1 to 2 R 7 Substituted-(C 1-2 alkylene)aryl, wherein each -(C 1-2 alkylene) are independently optionally substituted with 1 to 2 halogens.

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

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

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

12. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: (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)cyclobutyloxy)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]heptane-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)cyclobutyloxy)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]heptane-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)cyclobutyloxy)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]; or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: 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-(oxetane-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]; or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: 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)cyclobutyloxy)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-d3)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-(oxetane-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]heptane-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]; or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: (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)cyclobutyloxy)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-d3)-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-d3)-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-d3)-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-(oxetane-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]heptane-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]; or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: 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] heptane-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] heptane-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] heptane-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]; or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: 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)cyclobutyloxy)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-d3[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-d3[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-d3[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-d3[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-d3[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]; or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: 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-d3[602]; N-((1r,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d3)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-d3)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutyl)acetamide-2,2,2-d3[604]; (1s,3r)-3-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(methoxy-d3)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-d3)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-d3)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-d3)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-d3)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-d3)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-d3)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one-2,2,2-d3[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-d3[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-d3[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)cyclobutyloxy)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)cyclobutyloxy)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)cyclobutyloxy)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-dimethylpropionitrile[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)cyclobutyloxy)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]; or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: (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-d3[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-d3[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-dimethylpropionitrile[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-dimethylpropionitrile[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-ethynyloxetane-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-isopropyloxetane-3-yl)piperidin-4-yl)-4-methoxypyrrolo[2,1-f][1,2,4]triazin-2-amine[767]; N-((3R,4S)-1-(3-cyclopropyloxetane-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-d3[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-d3[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-d2)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-d3)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-dimethylpropionitrile[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-d3[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-d3[800]; or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: 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)cyclobutyloxy)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)cyclobutyloxy)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)cyclobutyloxy)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)cyclobutyloxy)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-d3)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutyloxy)ethan-1-ol[884]; N-((1s,3s)-3-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d3)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-d3)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-d3)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-d3)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-d3)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-d3)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-d3)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-d3)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-d3)-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-d3)-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-d3)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-d3)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-d3)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-d3)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-d3)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-d3)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile[900]; or a pharmaceutically acceptable salt thereof.

21. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: (R)-1-(4-((5-(1-(2,2-difluoroethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-4-(methoxy-d3)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-d3)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-d3)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)cyclobutyloxy)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-(Imidazolo[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-(Imidazolo[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-(Imidazolo[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-(oxetane-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-d3[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]triazine-7-d-2-amine[989]; 5-(Imidazolo[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]triazine-7-d-2-amine[990]; 5-(Imidazolo[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]triazine-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]; or a pharmaceutically acceptable salt thereof.

22. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: 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-d3[1009]; 2-(trans-4-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d3)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-d3)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-d3)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-d3)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-d3)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol[1014]; (R)-N-(3,3-difluoro-1-(oxetane-3-yl)piperidin-4-yl)-5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d3)pyrrolo[2,1-f][1,2,4]triazin-2-amine[1015]; 1-(7-((5-(imidazo[1,2-a]pyrimidin-6-yl)-4-(methoxy-d3)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-d3)-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-d3)-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-d3)-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]; or a pharmaceutically acceptable salt thereof.

23. The compound according to any one of claims 1 to 11, wherein the compound of formula I is selected from the group consisting of: 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-(Oxetane-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-(Oxetane-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-dimethylpropionitrile[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]; or a pharmaceutically acceptable salt thereof.

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. A method of treating a condition or disease in a patient, wherein the condition or disease is selected from the group consisting of a neurological disorder, diabetes, and cancer, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 23, or a pharmaceutical composition according to claim 24.

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

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

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

29. The method of any one of claims 25-26, 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 method of any one of claims 25 and 28, wherein the condition or disease is a neurological condition, wherein the neurological condition is selected from the group consisting of: Alzheimer's disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), dementia with Lewy bodies, Parkinson's disease, Pick's disease, and other diseases with significant neurodegeneration such as autism, dementia, epilepsy, Huntington's disease, multiple sclerosis; diseases and conditions associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumors, 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 aging-associated tau astrogliopathy.

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

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

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