4-aminopyrrolo [2, 1-F] [1, 2, 4] triazine and preparation and application thereof

Abstract

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

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 422,202, filed November 3, 2022, and U.S. Provisional Application No. 63 / 494,875, filed April 7, 2023, which are incorporated by reference herein in their entirety. TECHNICAL FIELD

[0003] The present disclosure relates to inhibitors of dual-specificity tyrosine phosphorylation regulated kinase 1A, and compositions comprising the same. More particularly, the present invention relates to the use of 4-aminopyrrolo[2,1-f][1,2,4]triazine compounds or salts or analogs thereof in the treatment of disorders characterized by abnormal expression and / or activity of DYRK1A (e.g., cancer, Down syndrome disease, Alzheimer’s disease, diabetes, and osteoarthritis). BACKGROUND

[0004] Dual-specificity tyrosine phosphorylation regulated kinases (DYRK1A, 1B, 2-4) comprise a family of protein kinases within the CMGC group of eukaryotic kinases. 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, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and / or activity of some of these kinases, especially DYRK1A, is found in a variety of human neurological diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. 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, trypanosomes, plasmodia) (International Journal of Molecular Sciences (2021), 22(11), 6047). DYRK1A was also identified as a key stabilizer of EGFR (Cell Death & Disease (2019), 10, 282), which is a key factor in the development of psoriasis with keratinization, cell hyperproliferation, abnormal differentiation, and inflammatory infiltration. SUMMARY

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

[0006] The present disclosure also provides methods and reagents, including contacting a cell with an agent, such as a 4-aminopyrrolo[2,1-f][1,2,4]triazine compound, in an amount sufficient to antagonize DYRK1A activity, e.g., i) to normalize prenatal and early postnatal brain development; ii) to improve cognitive function in adolescents and adults; and / or iii) to attenuate Alzheimer’s-type neurodegeneration.

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

[0008] One embodiment disclosed herein includes a compound having the structure of Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof,

[0011] wherein,

[0012] R 1 is optionally substituted (9-10 membered heteroaryl); 4

[0013] R 2 is selected from the group consisting of -heterocyclyl optionally substituted with 1-10 R 5 6

[0014] R 3 is selected from the group consisting of H, unsubstituted -(C 1-6 alkyl), unsubstituted -(C 2-6 alkenyl), unsubstituted -(C 2-6 alkynyl), and unsubstituted -(C 1-6 haloalkyl);

[0015] each R​​​4 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl);

[0016] Each R 5 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1-10 R 7 Substituted-heterocyclyl, -(C 1-5 alkylene) p OR 8 and -C(=O)R 9 , where -(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted;

[0017] Each R 6 are independently selected from the group consisting of: halides, unsubstituted-( 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -OR 10 、-C(=O)R 11 and -NHC(=O)R 12 ;

[0018] Each R 7 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl);

[0019] Each R 8 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);

[0020] each R 9 is 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);

[0021] each R 10 is 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 8 ;

[0022] each R 11 is -N(R 13 )2;

[0023] each R 12 is 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);

[0024] each R 13 is 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);

[0025] each p is independently 0 or 1 ; and

[0026] wherein each H atom is optionally and independently replaced by 2 H(D) (deuterium).

[0027] Another embodiment disclosed herein includes compounds having the structure of Formula I:

[0028]

[0029] wherein,

[0030] R 1 is optionally substituted with 1-10 R 4Substituted (9-10 membered heteroaryl);

[0031] 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), optionally substituted by 1-10 R 5 substituted-heterocyclyl and optionally substituted by 1-12 R 6 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein the -(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted;

[0032] R 3 Selected from the group consisting of: H, unsubstituted -(C 1-6 alkyl), unsubstituted-(C 2-6 alkenyl), unsubstituted-(C 2-6 Alkynyl), unsubstituted-(C 1-6 haloalkyl) and optionally substituted by 1-10 R 16 substituted-heterocyclyl;

[0033] Each R 4 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl);

[0034] Each R 5 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1-10 R 7 Substituted -heterocyclyl, optionally substituted by 1-12 R 14 Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 8 and C(=O)R 9 wherein said-(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C1-3 alkyl) substituted;

[0035] Alternatively, two R attached to the same carbon atom 5 Together they form a carbonyl group;

[0036] Each R 6 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -CN, -(C 1-5 alkylene) p OR 10 、-C(=O)R 11 、-NHC(=O)R 12 and optionally 1-12 R 14 Substituted-carbocyclyl, wherein the-(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted;

[0037] Each R 7 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -CN and optionally 1-12 R 14 substituted-carbocyclyl;

[0038] Each R 8 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);

[0039] Each R 9 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);

[0040] Each R 10 are independently selected from the group consisting of: H, unsubstituted -(C1-9 unsubstituted -(C 2-9 unsubstituted -(C 2-9 unsubstituted -(C 1-9 unsubstituted -(C 1-5 unsubstituted -(C p unsubstituted -(C 8 unsubstituted -(C

[0041] each R 11 is -N(R 13 )2;

[0042] each R 12 is independently selected from the group consisting of unsubstituted -(C 1-9 unsubstituted -(C 2-9 unsubstituted -(C 2-9 unsubstituted -(C 1-9 unsubstituted -(C

[0043] each R 13 is independently selected from the group consisting of H, unsubstituted -(C 1-9 unsubstituted -(C 2-9 unsubstituted -(C 2-9 unsubstituted -(C 1-9 unsubstituted -(C

[0044] each R 14 is independently selected from the group consisting of halide, unsubstituted -(C 1-9 unsubstituted -(C 2-9 unsubstituted -(C 2-9 unsubstituted -(C 1-9 unsubstituted -(C

[0045] R 15 is selected from the group consisting of H and halide;

[0046] each R 16 is independently selected from the group consisting of halide, unsubstituted -(C 1-9 unsubstituted -(C 2-9 unsubstituted -(C 2-9 unsubstituted -(C 1-9 unsubstituted -(C

[0047] each p is independently 0 or 1 ; and

[0048] wherein each H atom is optionally and independently replaced with 2 H(D) (deuterium).

[0049] Another embodiment disclosed herein includes compounds having the structure of Formula I:

[0050]

[0051] in:

[0052] R 1 is optionally replaced by 1-10 R 4 Substituted (9-10 membered heteroaryl);

[0053] 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), optionally substituted by 1-10 R 5 substituted-heterocyclyl and optionally substituted by 1-12 R 6 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein the -(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted;

[0054] R 3 Selected from the group consisting of: H, unsubstituted -(C 1-6 alkyl), unsubstituted-(C 2-6 alkenyl), unsubstituted-(C 2-6 Alkynyl), unsubstituted-(C 1-6 haloalkyl) and optionally substituted by 1-10 R 16 substituted-heterocyclyl;

[0055] Each R 4 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl);

[0056] Each R 5 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1-10 R7 Substituted -heterocyclyl, optionally substituted by 1-12 R 14 Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 8 and C(=O)R 9 wherein said-(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted;

[0057] Alternatively, two R attached to the same carbon atom 5 Together they form a carbonyl group;

[0058] Each R 6 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -CN, -(C 1-5 alkylene) p OR 10 、-C(=O)R 11 、-NHC(=O)R 12 and optionally 1-12 R 14 Substituted-carbocyclyl, wherein the-(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted;

[0059] Each R 7 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -CN and optionally 1-12 R 14 substituted-carbocyclyl;

[0060] Each R 8 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);

[0061] Each R 9independently 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);

[0062] each R 10 is 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 8 ;

[0063] each R 11 is -N(R 13 )2;

[0064] each R 12 is 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);

[0065] each R 13 is 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);

[0066] each R 14 is independently selected from the group consisting of: halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl);

[0067] R 15a is selected from the group consisting of: H, D, and halide;

[0068] R 15b is selected from the group consisting of: H and D;

[0069] each R 16independently selected from the group consisting of halide, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 alkynyl), and unsubstituted-(C 1-9 haloalkyl);

[0070] each p is independently 0 or 1 ; and

[0071] wherein each H atom is optionally and independently replaced by 2 H(D) (deuterium).

[0072] Some embodiments include stereoisomers and pharmaceutically acceptable salts of the compounds of Formula (I). Some embodiments provide a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

[0073] Some embodiments include prodrugs of the compounds of Formula (I).

[0074] Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient.

[0075] Other embodiments disclosed herein include methods of inhibiting DYRK1A by administering to a patient having a disorder or disease associated with DYRK1A overexpression, such as Alzheimer’s disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down’s syndrome, Parkinson’s disease with frontotemporal dementia-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease, and other diseases with prominent 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.

[0076] DYRK1A inhibitors can also be used to treat tauopathies. Tauopathies are neurodegenerative disorders characterized by abnormal tau deposition in the brain. The tau pathology extends beyond the traditionally discussed disease forms such as Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, and agryophilic grain disease. Emerging entities and pathologies include globular glial tauopathies, primary age-related tauopathy (including neurofibrillary dementia), chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and age-related tau astrogliopathy. Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson’s syndrome, Parkinson’s disease, akinetic-rigid syndromes with freezing of gait, and rare motor neuron symptoms or cerebellar ataxia (Handbook of Clinical Neurology (2018), 145, 355-368 and Aging Cell (2019), 18(5), e13000).

[0077] DYRK1A inhibitors can also be used to treat diseases associated with abnormalities in folate / methionine metabolism.

[0078] 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).

[0079] Some embodiments of the present disclosure include methods of making a compound of Formula (I).

[0080] It should 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

[0081] Provided herein are compositions and methods of inhibiting DYRK1A.

[0082] Some embodiments provided herein relate to methods of treating diseases including, but not limited to, neurological diseases or disorders, cancer, cognitive deficits, knee osteoarthritis, tendinopathy, viral infections, unicellular parasite infections, and movement deficits.

[0083] In some embodiments, non-limiting examples of neurological diseases or disorders that can be treated with the compounds and compositions provided herein include, but are not limited to, Alzheimer’s disease, amyotrophic lateral sclerosis, Down’s syndrome, Parkinson’s disease with frontotemporal dementia-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease tauopathy, and other diseases with prominent 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.

[0084] 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).

[0085] In some embodiments, provided are pharmaceutical compositions effective to treat a disease in an animal (e.g., a mammal) caused by overexpression of DYRK1A. The compositions include a pharmaceutically acceptable carrier and a compound as described herein.

[0086] Definitions

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that any term in this document is defined differently from or is not susceptible to a meaning identical to a term as used in a patent, application, published application, or other publication, the state of the art terminology is used for purposes of this document.

[0088] “Alkyl,” as used herein, refers to a branched or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, s-pentyl, and neopentyl. Alkyl groups can be unsubstituted or substituted with one or more substituents. In some embodiments, alkyl groups include 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0089] “Alkenyl,” as used herein, refers to a straight or branched chain chemical group containing only carbon and hydrogen and at least one carbon-carbon double bond, such as ethenyl, 1- propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In various embodiments, alkenyl groups can be unsubstituted or substituted with one or more substituents. Typically, alkenyl groups contain 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0090] As used herein, "alkynyl" refers to a straight or branched 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, and the like. In various embodiments, an alkynyl group can be unsubstituted or substituted by one or more substituents. Typically, an alkynyl group contains 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0091] As used herein, "alkylene" refers to a divalent branched or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, t-butylene, n-pentylene, iso-pentylene, sec-pentylene, and neopentylene. An alkylene group can be unsubstituted or substituted by one or more substituents. In some embodiments, an alkylene group includes 1 to 9 carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

[0092] As used herein, "alkenylene" refers to a divalent branched or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenylene, 1-propenylene, 2-propenylene, 2-methyl-l- propenylene, 1-butenylene, 2-butenylene, and the like. In various embodiments, an alkenylene group can be unsubstituted or substituted by one or more substituents. Typically, an alkenylene group contains 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0093] As used herein, "alkynylene" refers to 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, and the like. In various embodiments, an alkynylene group can be unsubstituted or substituted by one or more substituents. Typically, an alkynylene group contains 2 to 9 carbon atoms (e.g., 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

[0094] As used herein, "alkoxy" refers to an alkyl-O- group, where alkyl is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, t-butyloxy, pentyloxy, hexyloxy, and heptyloxy, as well as straight chain or branched positional isomers thereof.

[0095] As used herein, "haloalkoxy" refers to a haloalkyl-O- group, where haloalkyl is as described herein. Exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and straight chain or branched positional isomers thereof.

[0096] As used herein, "carbocyclyl" refers to cyclic ring systems having only carbon atoms in the ring backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like. Carbocyclyl groups can include multiple fused rings. Carbocyclyl groups can have any degree of saturation, as long as no ring in the ring system is aromatic. Carbocyclyl groups can be unsubstituted or substituted with one or more substituents. In some embodiments, carbocyclyl groups include 3 to 10 carbon atoms, for example 3 to 6 carbon atoms.

[0097] As used herein, "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic ring group having only carbon atoms in the ring backbone, having from 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 is aromatic. Aryl groups can be unsubstituted or substituted with one or more substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-lH-indenyl, and the like. In some embodiments, aryl is phenyl.

[0098] As used herein, "arylalkylene" refers to an aryl-alkylene- group, wherein aryl and alkylene are as previously described. In some embodiments, arylalkylene contains C 1-4 alkylene moieties. Exemplary arylalkylene groups include benzyl and 2-phenylethyl.

[0099] The term "heteroaryl" as used herein refers to 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 π electrons shared in a cyclic array; wherein at least one ring is an aromatic ring, and at least one ring contains one or more heteroatoms independently selected from the group consisting of N, O, and S. The heteroaryl group can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothiophenyl, benzoxadiazolyl, benzofuranyl, benzoimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][l,4]dioxine, benzo[d][l,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][l,4]oxathiin, isoindoline, and the like. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furanyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0100] "Halo," "halide," or "halogen" as used herein refers to a chlorine, bromine, fluorine, or iodine atom group. In some embodiments, halo refers to chlorine, bromine, or fluorine. For example, the halide can be fluorine.

[0101] "Haloalkyl" as used herein refers to a hydrocarbon substituent that is a straight chain or branched alkyl, alkenyl, or alkynyl group that is substituted with one or more chlorine, bromine, fluorine, and / or iodine atoms. In some embodiments, the haloalkyl is a fluoroalkyl, wherein one or more hydrogen atoms have been replaced with fluorine. In some embodiments, the 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" refers to a di-radical version of a haloalkyl group, and such di-radical can act as a spacer between radicals, between other atoms, or between a ring and another functional group.

[0102] As used herein, "heterocyclyl" refers to a non-aromatic cyclic system comprising at least one heteroatom in the ring system backbone. Heterocyclyl groups can include multiple fused rings, such as bicyclic and spirocyclic heterocyclyl groups. Heterocyclyl groups can be substituted or unsubstituted by one or more substituents. In some embodiments, the heterocycle has 3-11 members. In a six-membered monocyclic heterocycle, the heteroatoms are selected from one to three of O, N, and S, wherein when the heterocycle is five-membered, it can have one or two heteroatoms selected from O, N, and S. Examples of heterocyclyl groups include 3-azabicyclo[3.2.1]octane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, aziridinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,4-dioxaspirodecanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, octahydrocyclopenta[c]pyrrolyl, oxazinyl, 1-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiomorpholinyl, and the like. In some embodiments, the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

[0103] As used herein, "monocyclic heterocyclyl" refers to a single non-aromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Heterocyclyl groups can be substituted or unsubstituted by one or more substituents. In some embodiments, the heterocycle has 3-7 members. In a six-membered monocyclic heterocycle, the heteroatoms are selected from one to three of O, N, and S, wherein when the heterocycle is five-membered, it can have one or two heteroatoms selected from O, N, and S. Examples of monocyclic heterocyclyl 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 the like.

[0104] As used herein, "bicyclic heterocyclyl" refers to a non-aromatic bicyclic ring system containing at least one heteroatom in the ring system backbone. The bicyclic heterocyclyl may be substituted with one or more substituents or unsubstituted. In some embodiments, the bicyclic heterocycle has 4-11 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, 3-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, and the like.

[0105] " spiro heterocyclic radical " used herein refers to a non-aromatic bicyclic system comprising at least one heteroatom in the ring system main chain and the ring being connected only by one atom. Spiro heterocyclic radical may be substituted or unsubstituted by one or more substituents. In some embodiments, spiro heterocyclic ring has 5-11 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.

[0106] The term "substituted" refers to the portion of a molecule where a hydrogen on one or more non-hydrogen atoms is replaced by a substituent. It should be understood that "substituted" or "substituted with" includes the implicit condition that the substitution is made according to the allowed valences of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Substituents may include, for example, optionally hydroxy, -NH2, -NH(C 1-3 Alkyl) and -N(C 1-3 Alkyl)2 in one or more substituted -(C 1-9 alkyl); -(C 1-9 haloalkyl); halide; hydroxy; carbonyl [such as -C(O)OR and -C(O)R]; thiocarbonyl [such as -C(S)OR, -C(O)SR and -C(S)R]; optionally substituted by halide, hydroxy, -NH2, -NH(C 1-3 Alkyl) and -N(C 1-3 Alkyl)2 substituted with one or more substituents -(C1-9 alkoxy); -OPO(OH)2; phosphonates [such as -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); sulfonates [such as -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 1-3 R"' 6-10 Aryl; 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S and optionally substituted by 1-3 R"'; C 3-7 and 3-8 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O and S and optionally substituted by 1-3 R"'; wherein each R"' is independently selected from -(C 1-6 Alkyl), -(C 1-6 haloalkyl), halide (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), halide (e.g., F), hydroxy, -C(O)OR, -C(O)R, -(C 1-6 alkoxy), -NRR', -C(O)NRR' and cyano, wherein each occurrence of R and R' is independently selected from H and -(C 1-6 alkyl).

[0107] As used herein, when two groups are indicated to be "connected" or "bonded" to form a "ring", it is understood that a bond is formed between the two groups and may involve replacing a hydrogen atom on one or both groups with the bond to form a carbocyclyl, heterocyclyl, aryl or heteroaryl ring. Those skilled in the art will recognize that such rings can and are readily formed by conventional chemical reactions. In some embodiments, such rings have 3-7 members, for example 5 or 6 members.

[0108] One skilled in the art will recognize that some of the chemical structures depicted herein can be represented on paper in one or more other resonance forms; or can exist in one or more other tautomeric forms, even though such tautomers would represent only a minor fraction of a sample of such compounds, even kinetically. Such resonance forms or tautomers, although not explicitly shown here, are nevertheless clearly encompassed by the scope of the present disclosure.

[0109] The compounds provided herein can encompass various stereochemical forms. The compounds also include diastereomers as well as optical isomers, e.g., mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers resulting from structural unsymmetry in certain of the compounds. Isolation of individual isomers or selective synthesis of individual isomers can be accomplished by various methods known to those skilled in the art. Unless otherwise indicated, when a disclosed compound is named or described in a structural formula without specifying stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0110] The present disclosure includes all pharmaceutically acceptable isotopically-labeled compounds of Formula I wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to, hydrogen isotopes such as 2 H (deuterium) and 3 H (tritium), carbon isotopes such as 11 C, 13 C and 14 C, chlorine isotopes such as 36 Cl, fluorine isotopes such as 18 F, iodine isotopes such as 123 I and 125 I, nitrogen isotopes such as 13 N and 15 N, oxygen isotopes such as 15 O, 17 O and 18 O, phosphorus isotopes such as 32 P, and sulfur isotopes such as 35 S.

[0111] The term "administering" or "administration" refers to the method of providing a dose of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method of administration is, for example, oral, subcutaneous, intravenous, intralymphatic, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, intrabody, neurotological, intraocular, subconjunctival, by injection into the anterior chamber of the eye, intravitreal, intraperitoneal, intrathecal, intracapsular, intrapleural, by irrigation into a wound, buccal, intraperitoneal, intraarticular, otic, bronchial, capsular, meningeal, by inhalation, by instillation into the trachea or bronchus, by direct instillation into the lung lumen, intraspinal, synovial, intrathoracic, by irrigation through a thoracostomy, epidural, intratympanic, intracisternal, intravascular, intraventricular, intraosseous, by irrigation of infected bone, or by application as part of a prosthetic device. The method of administration can vary depending on factors such as the components of the pharmaceutical composition, the location of the disease, the disease involved, and the severity of the disease.

[0112] As used herein, "diagnosis" is a compound, method, system, or device that aids in the identification or characterization of a health or disease state. The diagnostic method can be used in standard assays known in the art.

[0113] The term "mammal" is used in its conventional biological sense. Thus, it specifically includes humans, cows, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and non-human primates, but also includes many other species.

[0114] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable diluent," and "pharmaceutically acceptable excipient" include any and all solvents, solubilizers, complexing agents, dispersion media, coatings, isotonizing agents and absorption delaying agents, and the like that are nontoxic to the subjects. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants can be included in the compositions. Such compounds and other such compounds are described in the literature, e.g., the Merck Index, Merck & Company, Rahway, NJ. Considerations for including various components in pharmaceutical compositions are described in, e.g., Brunton et al. (eds) (2017) Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13thEd., McGraw-Hill Education, New York, NY; Goodman and Gilman’s: The Pharmacological Basis of Therapeutics 13th Edition, The McGraw-Hill Companies. , Biological Activity Evaluation General Procedure

[0115] The term "pharmaceutically acceptable salt" refers to a salt of a compound provided herein that retains its biological effectiveness and properties and does not impart biological or other adverse effects. In many cases, the compounds provided herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Many such salts are known and are described, for example, in WO 87 / 05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, 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. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0116] As used herein, "patient" means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, and any other vertebrate or invertebrate. In some embodiments, the patient is a human.

[0117] A "therapeutically effective amount" of a compound provided herein is an amount sufficient to effect a desired physiological effect, and can vary according to the nature and severity of the disease condition, and the potency of the compound. A "therapeutically effective amount" is also intended to include an amount of one or more compounds of Formula I in combination with one or more other agents effective in the treatment of the diseases and / or conditions described herein. The combination of compounds can be synergistic. Synergy is a synergistic effect of the combination of compounds when the effect is greater than additive. Generally, the effect of a combination of compounds is greater than additive when the effect of the combination is greater than the sum of the effects of the compounds when administered alone. Synergy is most often seen at sub-optimal concentrations of the compounds. It is understood that the concentrations used to prophylaxis can differ from those used for treatment of active disease. The amount also depends on the size, weight, sex, and age of the patient.

[0118] A therapeutic effect relieves to some extent one or more of the symptoms of the disease.

[0119] "Treat," "treatment," or "treating" as used herein refers to the administration of a compound or pharmaceutical composition provided herein for therapeutic purposes. The term "therapeutic treatment" refers to the treatment of a patient already suffering from a disease, in order to obtain a therapeutic benefit, such as the improvement of existing symptoms, the amelioration of the underlying metabolic causes of the symptoms, the delay or prevention of further development of the disease, and / or the amelioration of the severity of the symptoms that will or are expected to occur.

[0120] "Drug elution" and / or controlled release as used herein refers to the entry of a drug incorporated into a drug eluting material into the surrounding body tissue over time by any and all mechanisms such as diffusion, migration, osmosis, and / or desorption.

[0121] "Drug eluting material" and / or controlled release material as used herein refers to any natural, synthetic, or semi-synthetic material that is capable of assuming and maintaining a desired shape or structure, wherein one or more drugs can be incorporated, and the incorporated drug is capable of eluting therefrom over time.

[0122] "Elutable drug" as used herein refers to any drug or combination of drugs that is capable of eluting from an incorporated drug eluting material into the surrounding area of the body over time.

[0123] Compound

[0124] The compounds and compositions described herein can be used to inhibit DYRK1A for the treatment of a disorder or disease associated with DYRK1A overexpression, such as a neurological disease or disorder, cancer, cognitive deficits, knee osteoarthritis, tendinopathy, viral infection, unicellular parasite infection, and movement deficits.

[0125] Some embodiments of the present disclosure include a compound of Formula I:

[0126]

[0127] or a salt, pharmaceutically acceptable salt, or prodrug thereof.

[0128] Some embodiments of the present disclosure include a compound of Formula I:

[0129]

[0130] or a salt, pharmaceutically acceptable salt, or prodrug thereof.

[0131] Some embodiments of the present disclosure include a compound of Formula I:

[0132]

[0133] or a salt, pharmaceutically acceptable salt, or prodrug thereof.

[0134] In some embodiments of Formula I, R 1 is optionally replaced by 1-10 R 4 In some embodiments, R 1 is optionally replaced by 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1 R 4 Substituted (9-10 membered heteroaryl).

[0135] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0136] It is optionally replaced by 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 4 replace.

[0137] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of: It is optionally replaced by 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 4 replace.

[0138] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0139] It is optionally replaced by 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 4 replace.

[0140] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0141] It is optionally replaced by 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 4 replace.

[0142] In some embodiments of Formula I, R 1 Heteroaryl selected from the group consisting of:

[0143] which is optionally substituted with 1-3 (e.g., 1-2, 1) R 4 substituted.

[0144] In some embodiments of Formula I, R 1 is selected from the group consisting of:

[0145] which is optionally substituted with 1-3 (e.g., 1-2, 1) R 4 substituted.

[0146] In some embodiments of Formula I, R 1 is selected from the group consisting of:

[0147] which is optionally substituted with 1-3 R 4 substituted.

[0148] In some embodiments of Formula I, R 1 is selected from the group consisting of:

[0149] which is optionally substituted with 1-3 R 4 substituted.

[0150] In some embodiments of Formula I, R 1 is selected from the group consisting of:

[0151] which is optionally substituted with 1-2 R 4 substituted.

[0152] In some embodiments of Formula I, R 1 is selected from the group consisting of:

[0153]

[0154] In some embodiments of Formula I, R 2 is selected from the group consisting of: optionally substituted -heterocyclyl and optionally substituted -carbocyclyl. 5 substituted. 6 substituted.

[0155] In some embodiments of Formula I, R 2 is selected from the group consisting of: optionally substituted -heterocyclyl and optionally substituted -carbocyclyl. 5-substituted heterocyclyl and optionally substituted by 1-4 (e.g., 1-3, 1-2, 1) R 6 Substituted-carbocyclyl.

[0156] In some embodiments of Formula I, R 2 is optionally replaced by 1-3 R 6 Substituted-carbocyclyl, wherein the carbocyclyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0157] 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), optionally substituted by 1-10 R 5 substituted-heterocyclyl and optionally substituted by 1-12 R 6 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein -(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted;

[0158] In some embodiments of Formula I, R 2 Selected 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), optionally substituted by 1-4 R 5 substituted-heterocyclyl and optionally substituted by 1-4 R 6 Substituted-(C 1-2 alkylene) p Carbocyclic group, wherein -(C 1-2 Alkylene) is optionally substituted with 1-2 halides (eg F, Cl) and / or 1 unsubstituted -(C 1-2 alkyl) substituted.

[0159] In some embodiments of Formula I, R 2 Selected from the group consisting of: Each R 6independently selected from the group consisting of F, Me, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OMe, -OH, -OMe, -OEt, -OCD3, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2OMe, -OCH2CH2OH, -C(=O)NHMe, -C(=O)NMe2, and -NHC(=O)Me.

[0160] In some embodiments of Formula I, R 2 is selected from the group consisting of: wherein each R 8 is independently selected from the group consisting of F, Me, -CHF2, -CH2OMe, -OH, -OMe, -OCD3, -OCH2CHF2, and -OCH2CH2OMe.

[0161] In some embodiments of Formula I, R 2 is -heterocyclyl optionally substituted with 1-3 R 5 is -heterocyclyl optionally substituted with 1-3 R

[0162] In some embodiments of Formula I, R 2 is selected from the group consisting of: wherein each R 5 is 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 with the proviso that F, -OH, -OMe, -OEt, -OCD3, and -OCF3are not attached to N.

[0163] In some embodiments of Formula I, R 2 is selected from the group consisting of: wherein each R is 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 with the proviso that F, -OH, -OMe, -OEt, -OCD3, and -OCF3are not attached to N.

[0164] In some embodiments of Formula I, R 2 is selected from the group consisting of: wherein each R is 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 with the proviso that F, -OH, -OMe, -OEt, -OCD3, and -OCF3are not attached to N.

[0165] In some embodiments of Formula I, R 2 is selected from the group consisting of:

[0166] wherein each R is 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 with the proviso that F, -OH, -OMe, -OEt, -OCD3, and -OCF3are not attached to N.

[0167] In some embodiments of Formula I, R 2 is selected from the group consisting of: wherein each R is 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 with the proviso that F, -OH, -OMe, -OEt, -OCD3, and -OCF3are not attached to N.

[0168] In some embodiments of Formula I, R 5 ​independently selected from the group consisting of F, Me, iBu, -OH, -OMe, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, -CH2CH2OMe, -CH2CH2OH, -C(=O)Me, with the proviso that F, -OH, -OMe are not attached to N.

[0168] in some embodiments of formula I, R 2 is selected from the group consisting of: wherein each R 5 is independently selected from the group consisting of F, Me, -C(=O)Me, with the proviso that F is not attached to N.

[0169] in some embodiments of formula I, R 2 is selected from the group consisting of: wherein each R 5 is selected from the group consisting of Me, -C(=O)Me and .

[0170] in some embodiments of formula I, R 3 is 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).

[0171] in some embodiments of formula I, R 3 is selected from the group consisting of H, unsubstituted -(C 1-6 alkyl), unsubstituted -(C 2-6 alkenyl), unsubstituted -(C 2-6 alkynyl) and unsubstituted -(C 1-6 haloalkyl);

[0172] in some embodiments of formula I, R 3 is selected from the group consisting of H, unsubstituted -(C 1-3 alkyl) and unsubstituted -(C 1-3 haloalkyl).

[0173] in some embodiments of formula I, R 3 is selected from the group consisting of H, unsubstituted -(C 1-6 alkyl), unsubstituted -(C 2-6 alkenyl), unsubstituted -(C2-6 alkynyl), unsubstituted -(C 1-6 haloalkyl) and optionally substituted -heterocyclyl. 16 substituted -heterocyclyl.

[0174] In some embodiments of Formula I, R 3 is selected from the group consisting of H, unsubstituted -(C 1-3 alkyl), unsubstituted -(C 2-3 alkenyl), unsubstituted -(C 2-3 alkynyl), unsubstituted -(C 1-3 haloalkyl), and unsubstituted -(4-membered heterocyclyl).

[0175] In some embodiments of Formula I, R 3 is unsubstituted -(C 1-3 alkyl).

[0176] In some embodiments of Formula I, R 3 is Me.

[0177] In some embodiments of Formula I, R 3 is H.

[0178] In some embodiments of Formula I, each R 4 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl).

[0179] In some embodiments of Formula I, each R 4 is independently selected from the group consisting of halide (e.g., F, Cl), unsubstituted -(C 1-4 alkyl), and unsubstituted -(C 1-4 haloalkyl).

[0180] In some embodiments of Formula I, each R 4 is independently selected from the group consisting of fluorine, chlorine, methyl, ethyl, isopropyl, 2-fluoroethyl, and 2,2-difluoroethyl.

[0181] In some embodiments of Formula I, each R 5 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9unsubstituted -(C 1-9 haloalkyl), -heterocyclyl optionally substituted with 1-12 R 7 substituted -heterocyclyl, -(C 1-5 alkylene) p OR 8 and -C(=O)R 9 wherein -(C 1-5 alkylene) is optionally substituted with 1-5 halides (e.g., F, Cl, Br, I) and / or 1-3 (e.g., 1-2, 1) unsubstituted -(C 1-3 alkyl) groups.

[0182] In some embodiments of Formula I, each R 5 is independently selected from the group consisting of F, Cl, unsubstituted --(C 1-5 alkyl), unsubstituted -(C 2-5 alkenyl), unsubstituted -(C 2-5 alkynyl), unsubstituted -(C 1-5 haloalkyl), -heterocyclyl optionally substituted with 1-2 R 7 substituted -heterocyclyl, -(C 1-2 alkylene) p OR 8 and -C(=O)R 9 wherein -(C 1-2 alkylene) is optionally substituted with 1-2 halides (e.g., F, Cl).

[0183] In some embodiments of Formula I, each R 5 is independently selected from the group consisting of halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -heterocyclyl optionally substituted with 1-12 R 7 substituted -heterocyclyl, -carbocyclyl optionally substituted with 1-12 R 14 substituted -heterocyclyl, -(C 1-5 alkylene) p OR 8 and -C(=O)R 9 wherein -(C 1-5 alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) groups.

[0184] In some embodiments of Formula I, each R 5independently selected from the group consisting of F, Cl, unsubstituted -(C 1-5 alkyl), unsubstituted -(C 2-5 alkenyl), unsubstituted -(C 2-5 alkynyl), unsubstituted -(C 1-5 haloalkyl), -OR 7 , -C(=O)R 14 , and -NHC(=O)R 1-2 alkylene) p OR 8 and -C(=O)R 9 , wherein -(C 1-2 alkylene) is optionally substituted with 1-2 halides (e.g., F, Cl).

[0185] In some embodiments of Formula I, two R 5 attached to the same carbon atom together form a carbonyl.

[0186] In some embodiments of Formula I, each R 6 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C 1-9 haloalkyl), -OR 10 , -C(=O)R 11 , and -NHC(=O)R 12 .

[0187] In some embodiments of Formula I, each R 6 is independently selected from the group consisting of halide (e.g., F, Cl), unsubstituted -(C 1-4 alkyl), unsubstituted -(C 2-4 alkenyl), unsubstituted -(C 2-4 alkynyl), unsubstituted -(C 1-4 haloalkyl), -OR 10 , -C(=O)R 11 , and -NHC(=O)R 12 .

[0188] In some embodiments of Formula I, each R 6 is independently selected from the group consisting of halide, unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), unsubstituted -(C1-9 haloalkyl), -CN, -(C 1-5 alkylene) p OR 10 , -C(=O)R 11 , -NHC(=O)R 12 , and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 14 substituted -(C 1-5 alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl).

[0189] In some embodiments of Formula I, each R 6 is independently selected from the group consisting of halide (e.g., F, Cl), unsubstituted -(C 1-4 alkyl), unsubstituted -(C 2-4 alkenyl), unsubstituted -(C 2-4 alkynyl), unsubstituted -(C 1-4 haloalkyl), -CN, -(C 1-2 alkylene) p OR 10 , -C(=O)R 11 , -NHC(=O)R 12 , and -carbocyclyl optionally substituted with 1-2 R 14 substituted -(C 1-2 alkylene) is optionally substituted with 1-2 halides (e.g., F, Cl) and / or 1 unsubstituted -(C 1-2 alkyl).

[0190] In some embodiments of Formula I, each R 7 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl).

[0191] In some embodiments of Formula I, each R 7 is independently selected from the group consisting of halide (e.g., F, Cl), unsubstituted -(C 1-4 alkyl), unsubstituted -(C 2-4 alkenyl), unsubstituted -(C 2-4 alkynyl), and unsubstituted -(C 1-4 haloalkyl).

[0192] In some embodiments of Formula I, each R 7 is independently selected from the group consisting of halide, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 alkynyl), unsubstituted-(C 1-9 haloalkyl), -CN, and -carbocyclyl optionally substituted with 1-12 R 14 groups.

[0193] In some embodiments of Formula I, each R 7 is independently selected from the group consisting of halide (e.g., F, Cl), unsubstituted-(C 1-4 alkyl), unsubstituted-(C 2-4 alkenyl), unsubstituted-(C 2-4 alkynyl), unsubstituted-(C 1-4 haloalkyl), -CN, and -carbocyclyl optionally substituted with 1-2 R 14 groups.

[0194] In some embodiments of Formula I, each R 8 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 alkynyl), and unsubstituted-(C 1-9 haloalkyl).

[0195] In some embodiments of Formula I, each R 8 is independently selected from the group consisting of halide (e.g., F, Cl), unsubstituted-(C 1-4 alkyl), unsubstituted-(C 2-4 alkenyl), unsubstituted-(C 2-4 alkynyl), and unsubstituted-(C 1-4 haloalkyl).

[0196] In some embodiments of Formula I, each R 9 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 alkynyl), and unsubstituted-(C 1-9 haloalkyl).

[0197] In some embodiments of Formula I, each R9 independently selected from the group consisting of halide (e.g., F, CI), unsubstituted- (C 1-4 alkyl), unsubstituted-(C 2-4 alkenyl), unsubstituted-(C 2-4 alkynyl), and unsubstituted-(C 1-4 haloalkyl).

[0198] In certain embodiments of Formula I, each R 10 is 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 8 .

[0199] In certain embodiments of Formula I, each R 10 is independently selected from the group consisting of H, unsubstituted- (C 1-4 alkyl), unsubstituted-(C 2-4 alkenyl), unsubstituted-(C 2-4 alkynyl), unsubstituted-(C 1-4 haloalkyl), and -(C 1-2 alkylene) p OR 8 .

[0200] In certain embodiments of Formula I, each R 11 is -N(R 13 )2.

[0201] In certain embodiments of Formula I, each R 11 is -NHR 13 .

[0202] In certain embodiments of Formula I, each R 11 is -NHMe.

[0203] In certain embodiments of Formula I, each R 11 is -NHMe2.

[0204] In certain embodiments of Formula I, each R 12 is 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 1-9haloalkyl).

[0205] In some embodiments of Formula I, each R 12 is independently selected from the group consisting of unsubstituted -(C 1-4 alkyl), unsubstituted -(C 2-4 alkenyl), unsubstituted -(C 2-4 alkynyl), and unsubstituted -(C 1-4 haloalkyl).

[0206] In some embodiments of Formula I, each R 13 is 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).

[0207] In some embodiments of Formula I, each R 13 is independently selected from the group consisting of unsubstituted -(C 1-4 alkyl), unsubstituted -(C 2-4 alkenyl), unsubstituted -(C 2-4 alkynyl), and unsubstituted -(C 1-4 haloalkyl).

[0208] In some embodiments of Formula I, each R 14 is independently selected from the group consisting of halide (e.g., F, Cl, Br, I), unsubstituted -(C 1-9 alkyl), unsubstituted -(C 2-9 alkenyl), unsubstituted -(C 2-9 alkynyl), and unsubstituted -(C 1-9 haloalkyl).

[0209] In some embodiments of Formula I, each R 14 is independently selected from the group consisting of halide (e.g., F, Cl), unsubstituted -(C 1-4 alkyl), unsubstituted -(C 2-4 alkenyl), unsubstituted -(C 2-4 alkynyl), and unsubstituted -(C 1-4 haloalkyl).

[0210] In some embodiments of Formula I, R 15 is selected from the group consisting of H and halide (e.g., F, Cl, Br, I).

[0211] In some embodiments of Formula I, R 15is selected from the group consisting of H and halide (e.g., F, CI).

[0212] In some embodiments of Formula I, R 15 is H.

[0213] In some embodiments of Formula I, R 15 is F.

[0214] In some embodiments of Formula I, R 15a is selected from the group consisting of H, halide (e.g., F, CI, Br, I), and 2H(D) (deuterium).

[0215] In some embodiments of Formula I, R 15b is selected from the group consisting of H and 2 H(D) (deuterium).

[0216] In some embodiments of Formula I, R 15b is 2 H(D) (deuterium).

[0217] In some embodiments of Formula I, each R 16 is independently selected from the group consisting of halide (e.g., F, CI, Br, I), unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 alkynyl), and unsubstituted-(C 1-9 haloalkyl).

[0218] In some embodiments of Formula I, each R 16 is independently selected from the group consisting of halide (e.g., F, CI), unsubstituted-(C 1-4 alkyl), unsubstituted-(C 2-4 alkenyl), unsubstituted-(C 2-4 alkynyl), and unsubstituted-(C 1-4 haloalkyl).

[0219] In some embodiments of Formula I, each p is independently 0 or 1.

[0220] In some embodiments of Formula I, each H atom is optionally independently replaced by 2 H(D) (deuterium).

[0221] Exemplary compounds of Formula I are shown in Table 1.

[0222] Table 1.

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270] Administration and pharmaceutical compositions

[0271] Some embodiments include pharmaceutical compositions comprising: (a) a therapeutically effective amount of a compound provided herein, or a corresponding enantiomer, diastereomer, or tautomer thereof, or a pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.

[0272] The compounds provided herein can also be used in combination with other known agents (administered together or sequentially).

[0273] 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 tumor, acute megakaryoblastic leukemia (AMKL), and osteoarthritis. For example, a compound of Formula (I) can be combined with one or more chemotherapeutic compounds.

[0274] In some embodiments, hepatocellular carcinoma can be treated with a compound of Formula (I) in combination with one or more of the following drugs / therapies: sorafenib Regorafenib Nivolumab Rafavatinib Pembrolizumab Cabozantinib 5-fluorouracil Ramucirumab Gemcitabine and oxaliplatin combination (GEMOX). Other therapies that can be performed in combination with a compound of Formula (I) are i) transcatheter arterial chemoembolization (TACE) with doxorubicin cisplatin or mitomycin C ii) low-dose radiotherapy.

[0275] 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 radiotherapy; laroitinib EGFR inhibitors, such as erlotinib (Tarceva®) Osimertinib Lanatinib Gefitinib Cetuximab Panitumumab Dacomitinib Lapatinib Necitumumab (Portrazza) and Vandetanib

[0276] 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 Asparaginase Erwinia (recombinant)-rywn Calaspargase Pegol-mknl Obilfuox Blinatumomab Daunorubicin hydrochloride Clofarabine Cyclophosphamide; methotrexate sodium Cytarabine Dasatinib Dexamethasone; imatinib mesylate Pomalidomide hydrochloride Mercaptopurine Tisagenlecleucel Vincristine sulfate liposome Pegaspargase Prednisone; daunorubicin hydrochloride and vincristine sulfate.

[0277] 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 therapy; gemcitabine 5-fluorouracil Oxaliplatin Albumin-bound paclitaxel Capecitabine Cisplatin; irinotecan Liposomal irinotecan Paclitaxel and docetaxel

[0278] 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 via Gliadel wafers; for glioblastoma and high-grade gliomas, radiotherapy with daily low-dose temozolomide followed by monthly temozolomide for 6 months to 1 year after radiotherapy; lomustine Procarbazine and vincristine have been used with radiotherapy; anti-angiogenic therapy with bevacizumab has been used; and targeted therapy with larotaxifene has been used.

[0279] 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 anthracyclines. Anthracyclines include daunorubicin Idarubicin and mitoxantrone

[0280] 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 demethylating agent (e.g., decitabine, azacitidine), induction chemotherapy (cytarabine and anthracycline (e.g., daunorubicin or idarubicin), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) monotherapy or anthracycline), consolidation therapy (cytarabine).

[0281] 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-azacitidine, decitabine, lenalidomide, and decitabine / cedazuridine

[0282] 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 drug leucovorin (also known as folinic acid); capecitabine Irinotecan Oxaliplatin Examples of combinations of these drugs that can be further combined with a compound of Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan), and Ca peOx (capecitabine and oxaliplatin). For rectal cancer, 5-FU or capecitabine chemotherapy can be combined with radiation therapy before surgery (neoadjuvant therapy).

[0283] In some embodiments, ovarian cancer can be treated with a compound of Formula (I) in combination with one or more of the following drugs: topotecan, liposomal doxorubicin Gemcitabine Cyclophosphamide Vinorelbine Ifosfamide Etoposide (VP-16), hexamethylmelamine Capecitabine Irinotecan (CPT-11, ), melphalan, pemetrexed and nab-paclitaxel (nab- paclitaxel, ). Examples of combinations of these drugs that can be further combined with the compounds of formula (I) are TIP (paclitaxel [Taxol], ifosfamide and cisplatin), VeIP (vinblastine, ifosfamide and cisplatin) and VIP (etoposide [VP-16], ifosfamide and cisplatin). Ovarian cancer can also be treated with a combination of compounds of formula (I) and immune checkpoint blockade (ICB) therapy.

[0284] In some embodiments, the compounds of formula (I) can be used to treat cancer in combination with any of the following methods: (a) hormone therapy, such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, etc.; (b) ablative or embolic procedures, such as radiofrequency ablation (RFA), ethanol 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 terpenoids, such as vinca alkaloids (i.e., vinca alkaloids). (f) chemotherapy with podophyllotoxin, etoposide, teniposide, and docetaxel; (g) chemotherapy with topoisomerase inhibitors such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide; (h) chemotherapy with cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, 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 (also known as Bortezomib (sold under the trade name 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., perifocin in Phase III trials), VEGF receptor 2 inhibitors (e.g., apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g., vemurafenib), afenib), 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 (MAB or ), trastuzumab (Herceptin, also known as ErbB2), cetuximab (sold as and bevacizumab (sold under the name (k) chemotherapy with KRAS G12C inhibitors, such as sotorasib ( 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 with antibody-drug conjugates (ADCs), such as gemtuzumab ozogamicin, vibostuzumab tuxetan, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, bezlotoxumab mapfruline, moxetumomab pasudotox, and lancatuzumab transhytrel; (n) chemotherapy with proteasome inhibitors, such as carfilzomib, lactacystin, disulfiram, salinosporamide A (marizomib), onarespumab, delanzomib, epoxomicin, MG132, beta-hydroxy beta-methylbutyric acid (HMB), bortezomib, ixazomib (used alone or in combination with lenalidomide and dexamethasone); and (o) radiation therapy.

[0285] In some embodiments, the compound of Formula I can be used in combination with any of the following methods for treating diabetes: (a) injection of insulin; (b) biguanides, such as metformin (Glucophage), phenformin (DBI), and buformin; (c) thiazolidinediones (TZDs), such as rosiglitazone (Avandia), pioglitazone (Actos), and isaglitazone (Rezulin); (d) lyn kinase activators, such as glimepiride and tolimamide (MLR-1023); (e) secretagogues, such as sulfonylureas (non-limiting examples are acetohexamide, carbutamide, chlorpropamide, gliclazide (touoslazide), methyhexamine, tolazamide, tolbutamide, glibenclamide (glyburide), glibenclamide, gliclazide, glipizide, gliquidone, glipitide, glipizide, and glimepiride) and meglitinides (non-limiting examples are repaglinide (Prandin), nateglinide (Starlix), and mitiglinide (Glufast)); (f) alpha-glucosidase inhibitors, such as acarbose (Glucobay, Precose, Prandase), miglitol (Glyset), and voglibose; (g) injectable incretin mimetics, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP). Non-limiting examples of injectable glucagon-like peptide (GLP) analogues and agonists include exenatide (Exendin-4, sold under the trade name Byetta), liraglutide (Victoza, Saxenda), taspoglutide, lixisenatide (Lyxumia), semaglutide (Ozempic, Rybelsus), dulaglutide (Trulicity), albiglutide (Tanzeum). Non-limiting examples of dipeptidyl peptidase-4 (DPP-4) inhibitors include sitagliptin (Januvia), vildagliptin (Galvus), saxagliptin (Onglyza), linagliptin (Tradjenta), gemigliptin (Zemiglo), anagliptin (Suiny), teneligliptin (Tenelia), alogliptin (Nesina, Vipidia, Kazano, Vipidomet (with metformin), Oseni, Incresync (with pioglitazone)), teneligliptin (Zafatek, Wedica), omarigliptin (MK-3102), evogliptin (Suganon, Evodine), gosogliptin (Saterex), and dutogliptin; (h) injectable amylin analogues, such as pramlintide (Symlin); (i) SGLT2 inhibitors, such as canagliflozin (Invokana, Sulisent, Prominad), dapagliflozin (Forxiga, Farxiga, Edistride), empagliflozin (Jardiance, Sciampa-M), ertugliflozin (Steglatro), ipragliflozin (Suglat), luseogliflozin (Lusefi), remogliflozin etabonate (a prodrug of remogliflozin), sergliflozin etabonate (GW869682X), sotagliflozin (Zynquista), and tologliflozin (CSG452).

[0286] In some embodiments, a compound of Formula (I) can be used in combination with any of the following methods to treat osteoarthritis: (d) injection of a Wnt signaling pathway inhibitor (e.g., lorcivivint); (a) nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, aspirin, and acetaminophen; (b) physical therapy; (c) injection of corticosteroid medications; (d) injection of hyaluronic acid derivatives (e.g., Hyalgan, Synvisc); (e) anesthetics, such as codeine; (f) in combination with braces and / or shoe inserts or any device that can immobilize or support a joint to help you reduce stress (such as splints, braces, shoe inserts, or other medical devices); (g) realigning bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with chronic pain medications.

[0287] In some embodiments, a compound of Formula (I) can be used in combination with the following drugs to treat Alzheimer’s disease: aducanumab (Aduhelm TM ); acetylcholinesterase inhibitors, such as tacrine, rivastigmine galantamine and GalantaMind TM ; and donepezil and memantine

[0288] A compound disclosed herein, or a pharmaceutically acceptable salt thereof, can be administered by any acceptable mode of administration, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, intracorporeal, neurotological, intraocular, subconjunctival, by injection into the anterior chamber of the eye, intravitreal, intraperitoneal, intrathecal, intracapsular, intrapleural, by irrigation of a wound, buccal, intraperitoneal, intraarticular, otic, intrabronchial, intracapsular, intrameningeal, by inhalation, by intratracheal or intrabronchial instillation, by direct instillation into the lung lumen, intraspinal, intrasynovial, intrathoracic, by irrigation of a thoracostomy, epidural, intratympanic, intracisternal, intravascular, intraventricular, intraosseous, by irrigation of infected bone, or by application as part of a mixture with a prosthetic device. In some embodiments, the method of administration comprises oral or parenteral administration.

[0289] The compounds provided herein for pharmaceutical use can be administered in the form of a crystalline or amorphous product. Pharmaceutically acceptable compositions can include salts, solvates, and hydrates. The compounds can be administered alone or in combination with conventional pharmaceutical carriers, excipients, and the like. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) being for example d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants being for example Tweens, poloxamer or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Beta-cyclodextrin or its derivatives, such as hydroxyalkylcyclodextrins (including 2 and 3-hydroxypropyl- beta-cyclodextrin), or other solubilized derivatives can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions containing from 0.005% to 100% of the compounds described herein can be prepared; the remainder being a non-toxic carrier therefor. The contemplated compositions can contain 0.001%-100% of the compounds provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparation are known, or will be apparent, to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEd. (Pharmaceutical Press, London, UK. 2012).

[0290] The compounds can be administered alone or in combination with conventional pharmaceutical carriers, excipients, and the like. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) being for example d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants being for example Tweens, poloxamer or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Beta-cyclodextrin or its derivatives, such as hydroxyalkylcyclodextrins (including 2 and 3-hydroxypropyl- beta-cyclodextrin), or other solubilized derivatives can also be used to enhance delivery of the compounds described herein. Dosage forms or compositions containing from 0.005% to 100% of the compounds described herein can be prepared; the remainder being a non-toxic carrier therefor. The contemplated compositions can contain 0.001%-100% of the compounds provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparation are known, or will be apparent, to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEd. (Pharmaceutical Press, London, UK. 2012).

[0291] In one embodiment, the composition will take the form of unit dosage forms suitable, for example, for oral administration such as tablets or capsules, and therefore the composition can comprise a compound provided herein, as well as diluents such as lactose, sucrose, dicalcium phosphate, and the like; lubricants such as magnesium stearate, and the like; and binders such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, and the like. In another solid dosage form, a powder, pill, solution, or suspension (e.g., in propylene carbonate, vegetable oils, PEG, poloxamer 124, or triglyceride) is encapsulated in a gelatin or cellulose-based capsule. Unit dosage forms in which the compound(s) provided herein or additional active agents are physically separated are also contemplated; for example, capsules containing granules of each drug (or tablets in a capsule); bi-layer tablets; bi-compartment gel caps, and the like. Enteric or delayed release oral dosage forms are also contemplated.

[0292] Liquid pharmaceutical compositions can be prepared for administration via, for example, injection, inhalation, or oral ingestion. For example, a liquid pharmaceutical can be administered by injection, for example, by intravenous, intramuscular, subcutaneous, intraarticular (e.g., into the shoulder, elbow, or hip joint), or intradermal injection, or by infusion techniques. Liquid pharmaceutical compositions can be prepared, for example, by dissolving, dispersing, etc., a compound provided herein and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol, etc.) to form a solution, colloid, liposome, emulsion, complex, coacervate, or suspension. If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, suspending agents, surfactants, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc.).

[0293] Injectable preparations can be prepared in conventional forms, such as liquid solutions, colloids, liposomes, complexes, coacervates, or suspensions, emulsions, or in solid forms suitable for reconstitution into liquids prior to injection. The percentage of a compound provided herein contained in such parenteral compositions depends on the particular nature of the compound, its activity, and the needs of the patient. However, an active ingredient percentage of 0.01% to 10% in solution is useful, and if the composition is a solid or suspension, it can be higher, which can then be diluted to the above percentages.

[0294] It is to be noted that dosage values can also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.

[0295] In one embodiment, the composition can be administered to the respiratory tract (including the nasal cavity and the lungs) for example, by nebulizer, metered-dose inhaler, atomizer, sprayer, aerosol, dry powder inhaler, insufflator, liquid dropletizer, or other suitable device or technique.

[0296] In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavity, inhalation particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, larger inhalation particle sizes can be desirable to maximize impingement on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lungs are provided for inhalation through the nose or mouth. For delivery to the lungs, inhalation aerodynamic particle sizes of about less than 10 pm (e.g., about 1 to about 10 microns) are useful. Inhalation particles can be defined as droplets containing dissolved drug, droplets containing suspended drug particles (in the case where the drug is insoluble in the suspending medium), dry particles of pure drug substance, aggregates of drug nanoparticles mixed with excipients, liposomes, emulsions, colloidal systems, coacervates, drug nanoparticles, or dry particles containing diluents embedded with drug nanoparticles.

[0297] In some embodiments, the compounds of Formula (I) disclosed herein for respiratory delivery (systemic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants (with or without alcohol), as colloidal systems, as emulsions, coacervates, or as dry powders. Aqueous formulations can be nebulized by liquid atomizers employing hydraulic or ultrasonic energy or by improved micro-pump systems (e.g., soft mist inhalers, AERx®, or or Systems). Propellant-based systems can use suitable pressurized metered dose inhalers (pMDIs). Dry powders can use dry powder inhaler devices (DPIs) capable of effectively dispersing the drug substance. The desired particle size and distribution can be obtained by selecting the appropriate device.

[0298] In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear by various methods. For example, round window catheters can be used (e.g., U.S. Patent Nos. 6,440,102 and 6,648,873).

[0299] Alternatively, the formulation can be incorporated into a wick for use between the external ear and the middle ear (e.g., U.S. Patent No. 6,120,484) or absorbed onto a collagen sponge or other solid support (e.g., U.S. Patent No. 4,164,559).

[0300] If desired, the formulations of the disclosure can be incorporated into a gel formulation (e.g., U.S. Patent Nos. 4,474,752 and 6,911,211).

[0301] In some embodiments, the compounds of Formula (I) disclosed herein for delivery to the ear can be administered through an implanted pump and delivery system directly into the middle or inner ear (cochlea) through a needle or through a cochlear implant probe electrode channel or an alternative fabricated drug delivery channel (e.g., but not limited to, a needle through the temporal bone into the cochlea).

[0302] Other options include delivery through a pump through a thin film coated on a multi-channel electrode or an electrode engraved with special embedded drug delivery channels (passages) in the thin film. In other embodiments, acidic or basic solid compounds of Formula (I) can be delivered from an external or internal implanted pump system reservoir.

[0303] Formulations of the present disclosure can also be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Patent No. 6,377,849 and Serial No. 11 / 337,815).

[0304] Intratympanic injection of a therapeutic agent is a technique in which a therapeutic agent is injected into the middle ear and / or inner ear behind the tympanic membrane. In one embodiment, the formulations described herein are administered directly onto the round window membrane by transtympanic injection. In another embodiment, the ion channel modulator otically acceptable formulations described herein are administered onto the round window membrane of the inner ear by a non-transtympanic route. In further embodiments, the formulations described herein are administered onto the round window membrane by surgical methods to the round window membrane including modifications to the promontory.

[0305] In some embodiments, the compounds of Formula (I) are formulated as rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository base materials such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), and the like.

[0306] Suppositories (as solutions, colloids, suspensions, or complexes) for rectal administration can be prepared by mixing the compounds provided herein with suitable non-irritating excipients which are in solid form at ordinary temperatures but liquid at the temperature found in the rectum so that they will melt or erode / dissolve and release the compound in the rectum. These materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights, and polyethylene glycol fatty acid esters. In the suppository form of the composition, a low-melting point wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

[0307] The solid composition can be provided in various different types of dosage forms, depending on the physicochemical properties of the compound provided herein, the desired rate of dissolution, cost considerations, and other criteria. In one embodiment, the solid composition is a single unit. This means 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, as opposed to a multiple unit dosage form in which the individual units are incoherent.

[0308] Examples of single units that can be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafer, lyophilized matrix units, and the like. In one embodiment, the solid composition is a highly porous lyophilized form. This lyophilizate, also sometimes referred to as a wafer or lyophilized tablet, is particularly useful due to its rapid disintegration, which also allows for rapid dissolution of the compound.

[0309] On the other hand, for some applications, the solid composition can also be formed into a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. This dispersed lyophilized system comprises a large number of powder particles, each of which has an irregular, porous microstructure due to the lyophilization process used in the formation of the powder, through which the powder can very rapidly take up water and thus dissolve rapidly. Effervescent compositions are also believed to contribute to the rapid dispersion and uptake of the compound.

[0310] Another multiple particle system that enables rapid drug dissolution is a powder, granule, or pellet made of a water-soluble excipient, which is coated with the compound provided herein such that the compound is located on the outer surface of the individual particles. In this type of system, a water-soluble, low molecular weight excipient can be used to make the core of such coated particles, which can subsequently be coated with a coating composition comprising the compound and, for example, one or more additional excipients such as a binding agent, a pore-forming agent, a sugar, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.

[0311] Also provided herein are kits. Generally, a kit includes one or more compounds or compositions described herein. In certain embodiments, a kit can include one or more delivery systems (e.g., for delivering or administering a compound as provided herein) and instructions for use of the kit (e.g., instructions for treating a patient). In another embodiment, a kit can include a compound or composition as described herein and a label indicating that the contents are to be administered to a patient with cancer. In another embodiment, a kit can include a compound or composition as described herein and a label indicating that the contents are to be administered to a patient with one or more of the following: glioblastoma, ovarian cancer, breast cancer, pancreatic cancer, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, chronic myeloid leukemia, Alzheimer’s disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down’s syndrome, Parkinson’s disease with frontotemporal dementia-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease, autism, dementia, epilepsy, Huntington’s disease, and multiple sclerosis.

[0312] Methods of treatment

[0313] The compounds and compositions provided herein are useful as inhibitors of DYRK1A and, thus, are useful in treating a variety of conditions and diseases associated with DYRK1A overexpression, such as cancers and neurological conditions / disorders / diseases. Non-limiting examples of diseases that can be treated with the compounds and compositions provided herein include various cancers, Alzheimer’s disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down’s syndrome, Parkinson’s disease with frontotemporal dementia-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease, and other diseases with prominent 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, tauopathies (e.g., Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathy, primary age-related tauopathy, including neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and tau astrocytopathy associated with aging. Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson’s syndrome, Parkinson’s disease, akinetic-rigid syndrome with freezing of gait, and rare 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).

[0314] The gene encoding DYRK1A is located within the Down syndrome critical region (DSCR) on chromosome 21, and triplication of this critical region (DSCR) is responsible for most of the defects associated with Down syndrome (FEBS Journal (2011), 278, 246-256). A large body of genetic and pharmacological evidence indicates that only 1.5-fold overexpression of DYRK1A is responsible for most of the cognitive deficits observed in Down syndrome patients (Pharmacology & Therapeutics (2019), 194, 199-221 and Brain Science (2018), 8(10), 187). Genetic normalization of DYRK1A levels or pharmacological inhibition of its catalytic activity can restore cognitive function. The development of DYRK1A drug inhibitors is a major avenue for the treatment of cognitive deficits associated with Down syndrome.

[0315] DYRK1A and DYRK1B are utilized during human cytomegalovirus (HCMV) placental replication. Inhibition of DYRKs can prevent replication of various viruses, including hepatitis C virus (HCV), human cytomegalovirus (HCMV), human immunodeficiency virus type 1 (HIV-1), and herpes simplex virus type 1 (HSV-1) (Journal of Virology (2020), 94(6) and PLoS ONE (2015), 10, e0144229).

[0316] Increasing evidence suggests that DYRK1A / 1B inhibitors induce proliferation of insulin-producing pancreatic beta cells, making DYRK1A / 1B kinases attractive therapeutic targets for beta 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 can be treated with DYRK inhibitors are juvenile-onset adult diabetes (MODY, monogenic diabetes), diabetes due to a lack of response of body tissues to insulin, double diabetes (when insulin resistance occurs in a patient with type 1 diabetes), diabetes associated with excessive secretion of insulin- antagonizing hormones, malnutrition-related diabetes (ICD-10 code E12), and diabetes caused by any genetic mutation (autosomal or mitochondrial) that leads to a defect in beta cell function.

[0317] A large body of literature links 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 maternal lymphoblastic leukemia (ALL) (Journal of Clinical Investigation (2021), 131(1), e135937). Other cancers associated with DYRK1A are ovarian cancer (Frontiers in Oncology (2021), 11, 637193), head and neck squamous cell carcinoma (Scientific Reports (2016), 6, 36132), hepatocellular carcinoma (Cell Death & Disease (2021), 12, 125), DYRK1A modulates DNA damage response (Scientific Reports (2019), 9, 6014 and Scientific Reports (2019), 9, 6539). In some cases, DYRK1A seems to act as a tumor suppressor protein (Molecular & Cellular Oncology (2015), 2(1), e970048 and Nature (2016), 529, 172-177).

[0318] Other cancers can also be treated with the compounds and compositions described herein.

[0319] More specifically, cancers that can be treated by the compounds, compositions, and methods described herein include, but are not limited to, the following cancers:

[0320] 1) Breast cancer, including, for example, ER + Breast cancer, ER - Breast cancer, her2 - Breast cancer, her2 +breast cancer, stromal tumors such as fibroadenoma, phyllodes tumor, and sarcoma, and epithelial tumors such as large duct papilloma; breast cancer, including ductal carcinoma in situ (non-invasive) which includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including but not limited to invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; chemoresistant breast cancer (TNBC), and other malignancies. Further examples of breast cancer include Luminal A, Luminal B, Basal A, Basal B, and triple negative breast cancer, i.e., estrogen receptor negative (ER - ), progesterone receptor negative, and her2 negative (her2 - ). In some embodiments, the breast cancer can have a high risk Oncotype score.

[0321] 2) cancer of the cardia, including, for example, sarcomas, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma; and teratoma.

[0322] 3) lung cancer, including, for example, bronchogenic carcinoma, e.g., squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma; alveolar carcinoma and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondroid tumor; chemoresistant small cell lung cancer (SCLC); and mesothelioma.

[0323] 4) gastrointestinal cancer, including, for example, cancer of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancer of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancer of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and vasoactive intestinal peptide tumor; colon cancer with mutation in the APC gene; cancer of the small intestine, e.g., adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancer of the large intestine, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.

[0324] 5) cancer of the urinary and genital tract, including, for example, cancer of the kidney, e.g., adenocarcinoma, nephroblastoma (Wilms' tumor), lymphoma, and leukemia; cancer of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancer of the prostate, e.g., adenocarcinoma and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma.

[0325] 6) cancer of the liver, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

[0326] 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 tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastioma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.

[0327] 8) nervous system cancer, including, for example, skull cancer, such as osteoma, hemangioma, granulosa, xanthoma, and osteitis deformans; meningeal cancer, such as meningioma, meningeal sarcoma, and gliomatosis; brain cancer, such as astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumor; and spinal cord cancer, such as neurofibroma, meningioma, glioma, and sarcoma.

[0328] 9) gynecological cancer, 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 Mullerian tumor), endometrial stromal sarcoma, endometrial squamous cell carcinoma, urothelial carcinoma, endometrial carcinoma with CTNNB1 mutation); cervical cancer, such as cervical carcinoma and premalignant cervical dysplasia; ovarian cancer, such as BRCA-mutated ovarian cancer, surface epithelial-stromal tumor (epithelial ovarian cancer (type 1 (endometrioid, mucinous, clear cell, low-grade serous) or type 2 (poorly differentiated, carcinosarcoma, and high-grade serous))), ovarian cancer, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid tumor, small cell ovarian carcinoma (hypercalcemic type small cell ovarian carcinoma, lung type small cell ovarian carcinoma) unclassified carcinoma, granulosa cell tumor, Sertoli-stromal cell tumor, dysgerminoma, and malignant teratoma; vulvar cancer, such as squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; vaginal cancer, such as clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and fallopian tube cancer, such as carcinoma, primary fallopian tube carcinoma; primary peritoneal cancer (also known as serous surface papillary carcinoma, primary peritoneal carcinoma, extraovarian serous carcinoma, primary serous papillary carcinoma, and psammocarcinoma).

[0329] 10) hematologic cancers, including, for example, blood cancers, such as acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome (refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts in transformation type I and type II, childhood refractory cytopenia), and myeloproliferative neoplasms, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic disorders, multiple myeloma, myelodysplastic syndrome, myelodysplastic / myeloproliferative diseases, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma), and Waldenstrom's macroglobulinemia.

[0330] 11) skin cancers and skin diseases, including, for example, malignant melanoma and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and scleroderma.

[0331] 12) adrenal gland cancers, such as neuroblastoma.

[0332] 13) soft tissue sarcomas (STS), such as fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, Kaposi's sarcoma, lymphangiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor (also known as neurofibrosarcoma, malignant schwannoma, and neurogenic sarcoma), neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, extraskeletal mesenchymal sarcoma, embryonal sarcoma, alveolar soft part sarcoma, and infantile hemangiopericytoma.

[0333] More specifically, central nervous system tumors that can be treated by the compounds, compositions, and methods described herein include:

[0334] 1) astrocytic tumors, such as diffuse astrocytoma (fibrous, protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), pilocytic astrocytoma (pilocytic myxoid astrocytoma), pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and cerebral gliomatosis.

[0335] 2) oligodendroglial tumors, such as oligodendroglioma and anaplastic oligodendroglioma.

[0336] 3) oligoastrocytic tumors, such as oligoastrocytoma and anaplastic oligoastrocytoma.

[0337] 4) Ependymal tumors, e.g., subependymal nodule, subependymoma, myxopapillary ependymoma, ependymoma (cellular, papillary, clear cell, pronged), and anaplastic (malignant) ependymoma.

[0338] 5) Choroid plexus tumors, e.g., choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma.

[0339] 6) Neuronal and mixed neuronal-glial tumors, e.g., gangliocytoma, dysembrioplastic neuroepithelial tumor (DNET), Lhermitte-Duclos, infantile desmoplastic astrocytoma / ganglioglioma, central neurocytoma, anaplastic ganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma, papillary glioneuronal tumor, hypothalamic Ki-1 (CD99)-positive tumor, and paraganglioma of the filum terminale.

[0340] 7) Pineal tumors, e.g., pineocytoma, pineal parenchymal tumor of intermediate differentiation, and pineal parenchymal tumor of the mature type.

[0341] 8) Embryonal tumors, e.g., medulloblastoma (medulloblastoma with extensive nodularity, anaplastic medulloblastoma, desmoplastic medulloblastoma, large cell medulloblastoma, melanotic, medulloepithelioma), supratentorial primitive neuroectodermal tumor, and primitive neuroectodermal tumor (PNET) such as neuroblastoma, ganglioneuroblastoma, ependymoblastoma, and atypical teratoid / rhabdoid tumor.

[0342] 9) Neurocytoma, e.g., olfactory (olfactory neurocytoma), neuroepithelial tumor of the retina, neurocytoma of the adrenal gland and sympathetic nervous system.

[0343] 10) Glial tumors, e.g., astroblastoma, chordoid glioma of the third ventricle, and central glioma.

[0344] 11) Cranial nerves and spinal accessory nerve tumors, e.g., schwannoma, neurofibroma, neurofibromatosis, and malignant peripheral nerve sheath tumor.

[0345] 12) meningeal tumors, such as meningeal endothelial cell tumors, e.g., meningioma (atypical and anaplastic meningioma); mesenchymal tumors, such as lipoma, angiolipoma, hibernoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, hemangioma, epithelioid hemangioendothelioma, hemangiopericytoma, anaplastic hemangiopericytoma, angiosarcoma, Kaposi's sarcoma, and Ewing's sarcoma; primary melanocytic lesions, such as diffuse melanocytic hyperplasia, melanocytoma, malignant melanoma, meningeal melanocytosis; and hemangioblastoma.

[0346] 13) hematopoietic tumors, such as malignant lymphoma, plasmacytoma, and granulocytoma.

[0347] 14) germ cell tumors, such as germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumors.

[0348] 15) sellar region tumors, such as craniopharyngioma, granulosa cell tumor, pituicytoma, and spindle cell oncocytic tumors of the adenohypophysis.

[0349] The cancer can be a solid tumor that is metastatic or non-metastatic. The cancer can also appear in the form of diffuse tissue, as in leukemia. Thus, the term "tumor cell" as provided herein includes cells affected by any of the above diseases.

[0350] Methods of using the compounds or compositions described herein to treat cancer can be combined with existing methods of treating cancer, such as by chemotherapy, radiation therapy, or surgery (e.g., oophorectomy). In some embodiments, the compound or composition can be administered prior to, during, or after another anti-cancer agent or therapy.

[0351] Increasing evidence suggests that DYRK1A plays a role in the pathogenesis of Alzheimer’s disease (Future Medicinal Chemistry (2016), 8(6), 681-696 and European Journal of Medicinal Chemistry (2018), 158, 559-592). DYRK1A phosphorylates key substrates associated with Alzheimer’s disease and dementia: Tau, septin 4, amyloid precursor protein (APP), presenilin 1, neprilysin, Munc18-1, alpha-synuclein, RCAN1 and beta-tubulin. By modulating the alternative splicing of Tau exon 10, DYRK1A favors the production of 3R-Tau splice isoform over 4R-Tau isoform (a characteristic of DS / AD / tauopathies) (Journal of Biological Chemistry (2015), 290, 15219-15237).

[0352] Genome-wide association studies (GWAS) suggest that DYRK1A is a risk factor for Parkinson’s disease (The Lancet Neurology (2019), 18(12), 1091-1102). DYRK1A phosphorylates key factors of Parkinson’s disease such as parkin, septin 4 and alpha-synuclein. Upregulation of Parkinson’s disease-specific microRNAs targets DYRK1A expression. There is further evidence that DYRK1A is increased in expression in Parkinson’s disease and Pick’s disease (Neurobiology of Disease (2005), 20(2), 392-400).

[0353] The compounds and compositions provided herein can be used as inhibitors and / or modulators of the enzyme DYRK1A and thus can be used in the treatment of a variety of conditions and diseases associated with tau protein, including but not limited to Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Down’s syndrome, frontotemporal dementia (FTD), including FTD with Parkinsonism-17 (FTDP-17), behavioral variant frontotemporal dementia (bvFTD), FTD in motor neuron disease (MND) patients (usually 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 tauopathies (GGT), myotonic dystrophy type 1 (DM1) (also known as Steinert’s disease), myotonic dystrophy type 2 (DM2) (also known as proximal myotonic myopathy), Guam syndrome, argyrophilic grain disease, dementia pugilistica, postencephalitic parkinsonism, Lewy body dementia, Parkinson’s disease, Pick’s disease, and other diseases with prominent 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.

[0354] Non-limiting examples of neurological conditions (e.g., neurological disorders and neurological diseases) that can be treated with the compounds and compositions provided herein include Alzheimer’s disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell’s palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, central core disease, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing’s syndrome, cytomegalic inclusion disease (CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier syndrome, Dejerine-Klumpke paralysis, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental motor disorder, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb’s palsy, erythromelalgia, essential tremor, Fabry disease, Fahr’s syndrome, familial spastic paralysis, febrile convulsions, Fisher syndrome, Friedreich’s ataxia, fibromyalgia, Foix syndrome, Gaucher disease, Gastaut syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barre syndrome, HTLV-1-associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, hereditary polyneuropathies, herpangina, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington’s disease, hydrencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile Refsum disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Kluver-Bucy syndrome, Kugelberg-Welander disease, Lambert-Eaton syndrome, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, Leigh disease, Lennox syndrome, leukodystrophy, limbic encephalitis, Lissencephaly, Locked-in syndrome, Lou Gehrig’s disease, Lubs syndrome, Machado-Joseph disease, Madelung disease, Maroteaux-Lamy syndrome, Marfan syndrome, MELAS syndrome, Meniere’s disease, meningitis, meningomyelocele, meningomyelocoele, Merskey syndrome, Miller Fisher syndrome, Miller syndrome, Miller-Dieker syndrome, Millerfisher syndrome, Miller-Fisher syndrome, Mollaret meningitis, Moebius syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome, Moeller-Barlow syndrome,disease), Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, Lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, Leukodystrophy, Lewy body dementia, Lissencephaly, Locked-in syndrome, Lou Gehrig's disease, Lumbar disc disease, Lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), Malignant cerebral edema, Macrosomia, Megalencephaly, Melkersson-Rosenthal syndrome, Meningitis, Menkes disease, Mermaid syndrome, Microcephaly, Miller Fisher syndrome, Moebius syndrome, Mollaret meningitis, Mowat-Wilson syndrome, Moyamoya disease, Multiple system atrophy, Multifocal motor neuropathy, Myasthenia gravis, Myoclonus-dystonia, Myoclonus epilepsy, Myotonic dystrophy, Narcolepsy, NARP syndrome, Neonatal adrenoleukodystrophy, Neuroacanthocytosis, Neurofibromatosis, Neuromyelitis optica, Niemann-Pick disease, Non-24 sleep-wake syndrome, Ondine's curse, Opsoclonus myoclonus syndrome, Optic neuritis, Orthostatic hypotension, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibular-limb hypogenesis syndrome, Oromandibsyndrome), Meniere's disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, microscopy, Miller-Fisher syndrome, misophonia, mitochondrial myopathy, Möbius syndrome, monosomic muscular dystrophy, motor neuron disease, motor skill impairment, moyamoya disease, mucopolysaccharidosis, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, diffuse myelin fragmentation sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, myotubular myopathy, myotonia congenita, narcolepsy, neurofibromatosis, malignant neuroleptic syndrome, Lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital neuralgia, latent myelopathy sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus syndrome, optic neuritis, orthostatic hypotension, blurred vision, paresthesias, Parkinson's disease, congenital paramyotonia, paraneoplastic disorders, paroxysmal seizures, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralysis, peripheral neuropathy, photopic sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-poliomyelitis syndrome, Postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay-Hunt syndrome type I, Ramsay-Hunt syndrome type II, Ramsay-Hunt syndrome type III, Rasmussen encephalitis, reflex vascular dystrophy, Refshum's disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, St. Vith's chorea, Sandhoff disease, schizophrenia, Schilder's disease, schizencephaly, sensory Integrative disorder, septooptic dysplasia, Shy-Drager syndrome, Sjögren's syndrome, paralysis, Sotos syndrome, spasticity, spina bifida, spinal cord tumor, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive mental disorder, Tarlov cyst, Tay-Sachs diseasetemporal arteritis, tetanus, spinal cord tethering syndrome, thomson disease, thoracic outlet syndrome, torticollis, todd's palsy, tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, osteomyelitis, von hippel-lindau disease (VHL), virgin islands spinal cord epidemmy (VE), wallenberg syndrome, wernicke-korsakoff syndrome, west syndrome, williams syndrome, wilson disease, and zellweger syndrome.

[0355] The compounds and compositions can also be used to inhibit the development of invasive cancer, tumor angiogenesis, and metastasis.

[0356] 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.

[0357] In some embodiments, the disorder or disease is cancer.

[0358] In some embodiments, the disorder or disease is metastatic melanoma.

[0359] In some embodiments, the disorder or disease is diabetes.

[0360] In some embodiments, the disorder or disease is a neurological disorder.

[0361] In some embodiments, the disorder or disease is Alzheimer's disease.

[0362] In some embodiments, the patient is a human.

[0363] 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 lymphoblastic leukemia, Hodgkin's lymphoma, lymphoma, sarcoma, and ovarian cancer.

[0364] In some embodiments, the cancer is selected from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, synovial sarcoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal cell and squamous cell, skin cancer - melanoma, small intestine cancer, stomach (gastric) cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi's sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing's tumor, esophageal cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer, and adrenal cortex cancer.

[0365] In some embodiments, the cancer is hepatocellular carcinoma; in some embodiments, the cancer is colon cancer; in some embodiments, the cancer is colorectal cancer; in some embodiments, the cancer is breast cancer; in some embodiments, the cancer is pancreatic cancer; in some embodiments, the cancer is chronic myelogenous leukemia (CML); in some embodiments, the cancer is chronic myelomonocytic leukemia; in some embodiments, the cancer is chronic lymphocytic leukemia (CLL); in some embodiments, the cancer is acute myelogenous leukemia; in some embodiments, the cancer is acute lymphoblastic leukemia; in some embodiments, the cancer is Hodgkin's lymphoma; in some embodiments, the cancer is lymphoma; in some embodiments, the cancer is sarcoma; in some embodiments, the cancer is ovarian cancer; in some embodiments, the cancer is lung cancer - non-small cell; in some embodiments, the cancer is lung cancer - small cell; in some embodiments, the cancer is multiple myeloma; in some embodiments, the cancer is nasopharyngeal 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 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 thymus 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 laryngeal or hypopharyngeal cancer; in some embodiments, the cancer is kidney cancer; in some embodiments, the cancer is Kaposi sarcoma; in some embodiments, the cancer is gestational trophoblastic disease; in some embodiments, the cancer is gastrointestinal stromal tumor; in some embodiments, the cancer is gastrointestinal carcinoid tumor; in some embodiments, the cancer is gallbladder cancer; in some embodiments, the cancer is eye cancer (melanoma and lymphoma); in some embodiments, the cancer is Ewing's tumor; in some embodiments, the cancer is esophageal cancer; in some embodiments, the cancer is endometrial cancer; in some embodiments, the cancer is colorectal cancer; in some embodiments, the cancer is cervical cancer; in some embodiments, the cancer is brain or spinal cord tumor; in some embodiments, the cancer is bone metastasis; in some embodiments, the cancer is bone cancer; in some embodiments, the cancer is bladder cancer; in some embodiments, the cancer is bile duct cancer.In some embodiments, the cancer is anal cancer; and in some embodiments, the cancer is adrenocortical carcinoma.

[0366] In some embodiments, the disorder or disease is a neurological disorder, disorder, 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 muscle disease.

[0367] In some embodiments, the disorder or disease is selected from the group consisting of: Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, Parkinson's disease with frontotemporal dementia-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.

[0368] In some embodiments, the compound of Formula (I) inhibits DYRK1A.

[0369] In some embodiments, the method treats a disease or disorder mediated by kinase activity in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.

[0371] In some embodiments, the method inhibits the activity of a protein kinase receptor, the method comprising contacting the receptor with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0372] In some embodiments, the method treats a disease or disorder associated with abnormal cell proliferation in a patient; the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, the method prevents or reduces abnormal cell proliferation in a patient; the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0374] In some embodiments, the method treats a disease or disorder associated with abnormal cell proliferation in a patient, the method comprising administering to the patient a pharmaceutical composition comprising one or more compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more other agents.

[0375] Illustrative Compound Examples

[0376] The biological activity of the compounds described herein can be tested by any suitable assay method known to those skilled in the art. For example, the activity of a compound can be tested using one or more of the following test methods.

[0377] For example, an in vitro assay of DYRK1A biological activity, such as modulation of microtubule-associated protein tau (MAPT / Tau) phosphorylation in a neuronal cell line, such as the human SH-SY5Y neuroblastoma cell line, can be used. DYRK1A modulated phosphorylation level assays can include monitoring basal pSer396 Tau levels, which can be measured, for example, by using a ten micromolar top concentration serial dilution of candidate inhibitor composition, and detected by ELISA or Western blotting. An exemplary assay of DYRK-1A modulated phosphorylation uses SH-SY5Y cells cultured in 96-well plates for a period of time sufficient to stabilize microtubules and Tau phosphorylation, typically at least 2 days, then treated overnight with 1 / 3 serial dilutions of compounds and lysed. Cell lysates are separated by SDS PAGE, then transferred to nitrocellulose and probed with a specific antibody against pSer396 Tau. Chemiluminescent signal of HRP-linked antibody for Western blots is detected using Carestream Image Station and blot density determination of pSer396 and beta-actin is analyzed using ImageJ (NIH).

[0378] In another example, activity of a candidate compound can be measured by phosphorylated Tau (Thr212) AlphaLISA, i.e., by adding the above lysate to a total Tau-coated plate and detecting with a specific pThr212 Tau antibody. Colorimetric detection of AlphaLISA signal is performed by EnVision Multi-Label Plate Reader (Perkin Elmer).

[0379] To further illustrate the disclosure, the following examples are included. Of course, these examples should not be construed as specifically limiting on the scope of the disclosure. Modifications to these examples, within the scope of the claims, are deemed to be within the scope of the disclosure as described and claimed herein. One skilled in the art will recognize that the present disclosure can be prepared and used without resorting to the details of the examples below.

[0380] EMBODIMENT

[0381] Compound Preparation

[0382] 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 one of ordinary skill in the art that methods for preparing precursors and functionalities related to the compounds claimed herein are generally described in the literature. One of ordinary skill in the art has the ability to prepare any compound according to the literature and the present disclosure.

[0383] It will be recognized that one skilled in the art of organic chemistry can readily carry out the procedures without further guidance, that is, that the procedures are well within the skill and practice of the artisan. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution (both electrophilic and nucleophilic), etherification, esterification, and saponification, among others. These procedures are discussed in standard texts, such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 7thEd., John Wiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry 5thEd., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2ndEd., John Wiley & Sons (1999) (which are incorporated by reference herein in their entirety), and the like.

[0384] One of ordinary skill in the art will readily appreciate that certain reactions can be best performed when other functional groups in the molecule are masked or protected, thereby avoiding any undesirable side reactions and / or increasing the yield of the reaction. One of ordinary skill in the art routinely utilizes protecting groups to achieve increased yield or to avoid undesirable reactions. These reactions can be found in the literature and are well within the skill of the artisan. Examples of many of these procedures can be found in, for example, P. Wuts Greene's Protective Groups in Organic Synthesis, 5thEd., John Wiley & Sons (2014), which is incorporated by reference herein in its entirety.

[0385] The trademarks used herein are by way of example only, and are illustrative of the illustrative materials used at the time of publication. One of ordinary skill in the art will recognize that variations in batches, manufacturing processes, and the like are expected. Consequently, these examples, and the trademarks used therein, are non-limiting and are not intended to limit the scope of the disclosure, but merely to illustrate how one of ordinary skill in the art can choose to perform one or more embodiments of the disclosure.

[0386] (1 H) Nuclear Magnetic Resonance Spectroscopy (NMR) was measured on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHz for1H, Avance™ DRX500, 500 MHz for1H, or Varian NMR spectrometer (Mercury 400 BB, 400 MHz for1H) in the solvent specified. Peak positions are expressed in parts per million (ppm) relative to the lower field of 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 doublets; ddd, doublet of doublet of doublets; d / ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; m, multiplet. 1 H) or Avance™ DRX500, 500 MHz for1H, 1 H) or Varian NMR spectrometer (Mercury 400 BB, 400 MHz for1H). 1 H) or Varian NMR spectrometer (Mercury 400 BB, 400 MHz for1H).

[0387] The following abbreviations have the indicated meanings:

[0388] Ac2O = acetic anhydride

[0389] Boc = tert-butyloxycarbonyl

[0390] BrettPhos = dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine

[0391] BrettPhos Pd G3 = [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0392] brine = saturated aqueous sodium chloride solution

[0393] CDCl3 = deuterated chloroform

[0394] Cs2CO3 = cesium carbonate

[0395] DCE = 1,2-dichloroethane

[0396] DCM = dichloromethane

[0397] DIPEA = N,N-diisopropylethylamine

[0398] DME = 1,2-dimethoxyethane, or glycol dimethyl ether, or monoglyme

[0399] DMF = N,N-dimethylformamide

[0400] DMPU = N,N'-dimethylpropylene urea

[0401] DMSO-d6 = Deuterated dimethyl sulfoxide

[0402] ESIMS = Electron spray mass spectrometry

[0403] EtOAc = Ethyl acetate

[0404] HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0405] HC1 = Hydrochloric acid

[0406] HOAc = Acetic acid

[0407] ISCO = Teledyne ISCO, Inc brand Rf 200

[0408] KOAc = Potassium acetate

[0409] LCMS = Liquid chromatography-mass spectrometry

[0410] LiHMDS = Lithium bis(trimethylsilyl)amide

[0411] MeCN = Acetonitrile

[0412] MeOH = Methanol

[0413] MeTHF = 2-Methyltetrahydrofuran

[0414] MgSO4 = Magnesium sulfate

[0415] MTBE = Methyl tert-butyl ether

[0416] MW = Microwave radiation

[0417] NaO t Bu = Sodium tert-butoxide

[0418] NaHC03 = Sodium bicarbonate

[0419] NaBH3CN = Sodium cyanoborohydride

[0420] NaBH(OAc)3 = Sodium triacetoxyborohydride

[0421] Na2S04 = Sodium sulfate

[0422] NMR = Nuclear magnetic resonance

[0423] ON = Overnight

[0424] Pd / C = Palladium on carbon

[0425] Pd(dppf)Cl2 = 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) chloride

[0426] Pd(OAc)2 = Palladium(II) acetate

[0427] Pd(OH)2 / C = Palladium hydroxide on carbon

[0428] PE = Petroleum ether

[0429] prep-TLC = preparative thin layer chromatography

[0430] r.t. = room temperature

[0431] TEA = triethylamine

[0432] TFA = trifluoroacetic acid

[0433] THF = tetrahydrofuran

[0434] TLC = thin layer chromatography

[0435] TMSOK = potassium trimethylsilanol

[0436] XPhos = Dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphine

[0437] The following example schemes are intended to provide guidance to the reader and collectively represent example methods of preparing the compounds provided herein. Furthermore, other methods of preparing the compounds of the present disclosure will be readily apparent to those of ordinary skill in the art in light of the following reaction schemes and examples. Those of ordinary skill in the art are fully capable of preparing these compounds by the methods given in the literature and in the present disclosure. The compound numbers used in the following synthetic schemes apply only to those particular schemes and are not to be construed as or confused with the same numbers in other sections of the present application. Unless otherwise indicated, all variables are as defined above.

[0438] Step 1

[0439] The compounds of Formula I of the present disclosure can be prepared as described in Scheme 1.

[0440]

[0441] Scheme 1 describes a method for preparing 4-alkylamino pyrrolo[2,1- f][1,2,4]triazine derivatives (VII) by first substituting 4-chloride (I) with various amines (II) to form 2-chloro-5-bromo-4-amino pyrrolo[2,1-f][1,2,4]triazine III. Various pinacol boronates are formed by reacting various bromides (IV) with bis(pinacolato)diboron, followed by Suzuki coupling with bromide (III) to form 2-chloro-4-amino pyrrolo[2,1-f][1,2,4]triazine (V). The chloro group is then substituted with various amines (VI) to form the final 4-amino pyrrolo[2,1-f][1,2,4]triazine (VII).

[0442] The compounds of Formula I of the present disclosure can also be prepared as described in Scheme 2.

[0443]

[0444] Scheme 2 describes a method for preparing 4-amino pyrrolo[2,1-f][1,2,4]triazine derivatives (VII) by first substituting 4-chloride (VIII) with various amines (II) to form 2,5-dichloro-4-amino pyrrolo[2,1-f][1,2,4]triazine IX. The 2-chloro group is then substituted with various amines (VI) to form 5-chloro-4-amino pyrrolo[2,1-f][1,2,4]triazine (X). Various pinacol boronates are formed by reacting various bromides (IV) with bis(pinacolato)diboron, followed by Suzuki coupling with chloride (X) to form the final 4-amino pyrrolo[2,1-f][1,2,4]triazine (VII).

[0445] Steps 2-3

[0446] The preparation of intermediate 5-bromo-2-chloro-N-methyl pyrrolo[2,1- f][1,2,4]triazin-4-amine (XV) is described in Scheme 3 below.

[0447]

[0448] Step 4

[0449] To a solution of methyl 3-bromo-lH-pyrrole-2-carboxylate (XI) (100 g, 490.15 mmol, 1 eq) in MeCN (2 L) was added Cs2C03(255.52 g, 784.23 mmol, 1.6 eq) in one portion at 20 °C (no exotherm). The reaction was stirred at room temperature for 5 h. Then a solution of O-(2,4-dinitrophenyl)hydroxylamine (146.40 g, 735.22 mmol, 1.5 eq) in MeCN (2 L) was added dropwise at 0-5 °C under N2. After the addition, the reaction was warmed to room temperature for 16 h. The reaction mixture was filtered, and the filtrate was diluted with MTBE (2 L) and washed with brine (2 L x 3). The above reaction was performed six times.

[0450] The combined five batches of organic were combined, dried over MgS04, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (DCM / PE = 0→ 50%, then EtOAc / PE = 20%) to give methyl l-amino-3-bromo-lH-pyrrole-2-carboxylate (XII) (380 g, 1.62 mol, 55.1% yield, 93.3% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (3H, s), 6.24 (1H, d, J = 2.8 Hz), 6.38 (2H, br s), 7.12 (1H, d, J = 2.8 Hz).

[0451] Step 5

[0452] To a solution of methyl l-amino-3-bromo-lH-pyrrole-2-carboxylate (XII) (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) dropwise at 0-5 °C, then warmed to room temperature for 1 h. Then the reaction was added dropwise to NH3 / MeOH (7 M, 1.24 L, 10 eq) at room temperature, stirred at room temperature for 1 h to give a yellow suspension. The above reaction was performed twice.

[0453] The two reactions were combined and concentrated under vacuum. The residue was triturated with MTBE (4 L) at room temperature for 30 min, filtered. The filter cake was washed with MTBE (500 mL x 3), dried under vacuum to give methyl 3-bromo-l-ureido-lH-pyrrole-2-carboxylate (XIII) (402 g, 1.53 mol, 88.2% yield, 99.78% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 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 found m / z for C7H8BrN3O3 262.1 79 BrM+H).

[0454] Step 6

[0455] To a solution of methyl 3-bromo-l-ureido-lH-pyrrole-2-carboxylate (XIII) (67 g, 255.67 mmol, 1 eq) in THF (4 L) was added TMSOK (65.60 g, 511.33 mmol, 2 eq) portion wise at 0-5 °C under N2. After stirring for 5 min, the reaction became thick slurry. The reaction mixture was stirred vigorously at room temperature for 16 h. LCMS showed about 25.8% of starting material left. 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 the reaction was complete. The reaction was concentrated. The residue was diluted with H2O (1.6 L), cooled with ice bath, added HC1 (4 m, 160 mL) drop wise to pH 2-3, filtered. The filter cake was washed with H2O (600 mL x 3). The above reaction was carried out six times.

[0456] The filter cakes of six reactions were combined, slurry with H2O (6 L) at room temperature for 2 h, then filtered. The filter cake was dried in a vacuum oven at 60 °C for 24 h to give 5-bromopyrrolo[2,l- f][l,2,4]triazine-2,4(lH,3H)-dione (XIV) (320 g, 1.28 mol, 83.4% yield, 91.95% purity) as a white solid. 1 HNMR (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 found m / z for C6H4BrN302 232.0 81 BrM+H).

[0457] Step 1

[0458] To a solution of POCl3(1500 mL) was added 5-bromo-pyrrolo[2,l- f][l,2,4]triazine-2,4(lH,3H)-dione (XIV) (180 g, 782.55 mmol, 1 eq) in portions at room temperature. Then N,N-diethylaniline (291.95 g, 1.96 mol, 312.92 mL, 2.5 eq) was added dropwise at room temperature (a small amount of exotherm). After the addition, the reaction was heated to 105 °C for 48 h. LCMS showed the starting material was consumed but there was intermediate left over, about 4.3% of desired product was formed. The reaction was cooled to 90 °C, another portion of POCl3(500 mL) was added in one portion, then gently heated to reflux for 24 h. LCMS showed most of the intermediate was left over, about 11.9% of desired product was formed. The reaction was heated to gentle reflux and continued for another 4 days. LCMS showed about 7.4% of intermediate was left over, about 55.5% of desired product was formed. The reaction was cooled to 40 °C and distilled under reduced pressure to remove most of the POCl3. The residue was diluted with MeTHF (5 L), poured into ice-H2O (2 L), added brine (1 L), and separated. The aqueous layer was extracted with MeTHF (1.5 L x 2). The combined organic phase was washed with brine (1.5 L x 2), dried over MgSO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (4 kg, 100-200 mesh, DCM / PE = 0-20%) and triturated with n-heptane (500 mL) at room temperature for 3 h, then filtered to give 5-bromo-2,4-dichloropyrrolo[2,l- f][l,2,4]triazine (I) (150 g, 556.14 mmol, 71.1% yield, 98.96% purity) as a yellow solid. 1 H NMR (400 MHz, CDC13) δ ppm 7.02 (1H, d, J=2.4 Hz), 7.79 (1H, d, J=2.4 Hz); ESIMS found m / z for C6H2BrCl2N3 266.1 (M+H). 79 BrM+H).

[0459] Step 1

[0460] To a stirred solution of 5-bromo-2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (I) (10 g, 37.47 mmol) in THF (250 mL) was added methylammonium chloride (6.33 g, 93.75 mmol) and DIPEA (22.9 mL, 131.47 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine and dried over anhydrous Na2S04. The solvent was evaporated on a rotary evaporator and the crude mixture was purified on ISCO (0→10% MeOH / CHCl3) to afford 5-bromo-2-chloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XV) (8.9 g, 34.033 mmol, 90.8% yield) as a white solid. ESIMS found for C7H6BrClN4 m / z 261.0 (M+H).

[0461] The following intermediates were prepared following the procedure described above in Scheme 3.

[0462]

[0463] 5-bromo-2-chloro-N-(oxetan-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (XVI): white solid (461 mg, 1.519 mmol, 81.1% yield). ESIMS found for C9H8BrClN4O m / z 303.0 (M+H).

[0464]

[0465] 5-bromo-2-chloro-N-ethylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XVII): beige solid (503.6 mg, 1.831 mmol, 97.6% yield). ESIMS found for C8H8BrClN4 m / z 275.0 (M+H).

[0466]

[0467] 5-bromo-2-chloro-N-isopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XVIII): white solid (453.0 g, 1.564 mmol, 83.5% yield). ESIMS found for C9H 10 BrClN4 m / z 289.0 (M+H).

[0468]

[0469]

[0470] 5-bromo-2-chloro-N-(methyl-d3)pyrrolo[2, 1 - / ] [ 1,2,4]triazin-4-amine (XIX): orange solid (647 mg, 2.446 mmol, 21.8% yield). ESIMS found C7H3D3BrClN4 m / z 264.0 (M+H).

[0471] The preparation of intermediate 5-bromo-2-chloropyrrolo[2, 1 - / ] [ 1,2,4]triazin-4-amine (XX) is described in Scheme 4 below.

[0472]

[0473] Step 1

[0474] To a stirred solution of ammonium hydroxide (4.7 mL, 37.47 mmol) in THF (10 mL) was added 5-bromo-2,4-dichloropyrrolo[2, 1 - / ] [ 1,2,4]triazine (I) (1 g, 3.75 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was extracted in DCM, washed with brine and dried over anhydrous Na2S04. The solvent was evaporated on a rotary evaporator and dried under high vacuum to give 5-bromo-2-chloropyrrolo[2, 1 - / ] [ 1,2,4]triazin-4-amine (XX) (900 mg, 3.637 mmol, 97.1 % yield) as off-white solid. ESIMS found C6H4BrClN4 m / z 246.95 (M+H).

[0475] The following intermediates were prepared following the procedure described above in Scheme 4.

[0476]

[0477] 2,5-dichloropyrrolo[2, 1 - / ] [ 1,2,4]triazin-4-amine (XXI): light orange solid (308 mg, 1.517 mmol, 16.9% yield). ESIMS found C6H4Cl2N4 m / z 203.0 (M+H).

[0478] The preparation of intermediate 2,5-dichloro-N-methylpyrrolo[2, 1 - / ] [ 1,2,4]triazin-4-amine (XXII) is described in Scheme 5 below.

[0479]

[0480] Step 2

[0481] To a stirred solution of 2,4,5-trichloropyrrolo[2,l-f][l,2,4]triazine (commercially available from PharmaBlock Sciences Inc.) (VIII) (2 g, 8.99 mmol) in THF (50 mL) was added methylammonium chloride (1.51 g, 22.36 mmol) and DIPEA (5.48 mL, 31.46 mmol) at -78 °C and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHC03solution, extracted with DCM, washed with brine and dried over anhydrous Na2S04. The solvent was evaporated on a rotary evaporator and dried under high vacuum to give 2,5-dichloro-N-methylpyrrolo[2,l-f][l,2,4]triazin-4-amine (XXII) (1.92 g, 8.846 mmol, 98.4% yield) as a yellow solid. ESIMS found for C7H6Cl2N4 m / z 217.0 (M+H).

[0482] The preparation of intermediate 6-bromo-l-(2,2-difluoroethyl)-2-methyl-lH- imidazo[4,5-b]pyridine (XXVII) is described in Scheme 6 below.

[0483]

[0484] Step 3

[0485] A mixture of 2,2-difluoroethan-l-amine (XXIV) (410 mg, 5.02 mmol), 5-bromo-3- fluoro-2-nitropyridine (XXIII) (commercially available from Ark Pharma Scientific Limited) (1.0 g, 4.53 mmol) and K2C03(1.38 g, 9.95 mmol) in MeCN (20 mL) was stirred at room temperature for 16 h. The reaction was filtered and concentrated under high vacuum. The residue was dissolved in water, stirred for 1 h, the solid was collected by filtration and dried under vacuum to give 5-bromo-N-(2,2-difluoroethyl)-2-nitropyridin-3-amine (XXV) (1.066 g, 3.780 mmol, 83.5% yield) as a yellow solid which was used in the next step without purification. ESIMS found for C7H6BrF2N3O2 m / z 282.0 (M+H). 79 BrM+H).

[0486] Step 1

[0487] A mixture of 5-bromo-N-(2,2-difluoroethyl)-2-nitropyridin-3-amine (XXV) (1.32 g, 4.69 mmol), Fe (3.07 g, 46.95 mmol) and NH4Cl (3.77 g, 70.48 mmol) was dissolved in a mixture of EtOH (18 mL) and water (6 mL), and the mixture was heated to 70°C for 4 hours. The reaction mixture was cooled and passed through 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 -(2,2-difluoroethyl)pyridine-2,3-diamine (XXVI) (630 mg, 2.499 mmol, 53.2% yield) was obtained as a gray solid which was used in the next step without further purification. ESIMS analysis of C7H8BrF2N3 showed m / z of 252.0 ( 79 BrM+H).

[0488] Step 2

[0489] 5-Bromo-N 3 A solution of -(2,2-difluoroethyl)pyridine-2,3-diamine (XXVI) (630 mg, 2.5 mmol) and acetic anhydride (0.28 mL, 2.97 mmol) in HOAc (15 mL) was heated to 120 ° C for 16 hours. 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 layer 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 (XXVII) (325 mg, 1.177 mmol, 47.1% yield) as a gray solid that was used in the next step without purification. ESIMS measured C9H8BrF2N3 m / z as 276.0 ( 79 BrM+H).

[0490] The following intermediates were prepared according to the procedure described in Scheme 6 above.

[0491]

[0492] 6-Bromo-1-(3,3-difluorocyclobutyl)-2-methyl-1H-imidazo[4,5-b]pyridine (XXVIII): gray solid (1.57 g, 6.178 mmol, 68.3% yield). ESIMS measured C 11 H 10BrF2N3 m / z is 302.1 (M+H).

[0493] The preparation of the intermediate 6-bromo-1-isopropyl-2-methyl-1H-imidazo[4,5-b]pyridine (XXXII) is described in Scheme 7 below.

[0494]

[0495] Step 3

[0496] A mixture of 2-aminopropane (XXIX) (0.86 mL, 9.96 mmol), 5-bromo-3-fluoro-2-nitropyridine (XXIII) (2 g, 9.05 mmol) and K2CO3 (2.5 g, 18.1 mmol) in MeCN (40 mL) was stirred at room temperature for 16 hours. The reaction mixture was added to water (200 mL), stirred for 1 hour, and the resulting solid was collected by filtration and dried under high vacuum to give 5-bromo-N-isopropyl-2-nitropyridine-3-amine (XXX) (2.36 g, 9.074 mmol, 100.3% yield) as a yellow solid, which was used in the next step without purification. ESIMS measured CH 10 BrN3O2 m / z is 260.0 (M+H).

[0497] Step 1

[0498] A mixture of 5-bromo-N-isopropyl-2-nitropyridin-3-amine (XXX) (2.35 g, 9.04 mmol), Fe (5.91 g, 90.35 mmol) and NH4Cl (7.25 g, 135.53 mmol) was dissolved in a mixture of EtOH (30 mL) and water (10 mL), and the mixture was heated to 70°C for 2 hours. The reaction mixture was cooled and Filter, dissolve the filtrate in EtOAc, wash with water and brine, dry over anhydrous Na2SO4, filter and concentrate under reduced pressure to give 5-bromo-N 3 -isopropylpyridine-2,3-diamine (XXXI) (2.2 g, 9.561 mmol, 105.8% yield) was obtained as a dark brown solid which was used in the next step without purification. 12 BrN3 m / z is 230.05 (M+H).

[0499] Step 1

[0500] 5-Bromo-N 3A solution of isopropylpyridine-2,3-diamine (XXXI) (2.08 g, 9.04 mmol) and Ac2O (1.05 mL, 10.84 mmol) in HO Ac (20 mL) was heated to 120 °C for 16 h. The reaction mixture was concentrated, the residue was partitioned between EtOAc / 1 N NaOH, the organics were separated, washed with water and brine. The organics were dried over anhydrous Na2S04, the solvent was concentrated and dried under high vacuum to give 6-bromo-1-isopropyl-2-methyl-1H-imidazo[4,5- b]pyridine (XXXII) (1.57 g, 6.178 mmol, 68.3% yield) as a dark brown solid which was used in the next step without purification. ESIMS found C 10 H 12 BrN3 m / z 254.0 (M+H).

[0501] The preparation of intermediate 5-chloro-3-ethyl-2-methyl-3H-imidazo[4,5- b]pyridine (XXXIV) is described in Scheme 8 below.

[0502]

[0503] Step 2

[0504] A mixture of 5-chloro-2-methyl-3H-imidazo[4,5-b]pyridine (XXXIII) (commercially available from eNovation Chemicals, LLC) (0.5 g, 2.98 mmol), iodoethane (0.56 g, 3.58 mmol) and K2C03(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 MgS04, the solvent was concentrated under vacuum and dried to give 5-chloro-3-ethyl-2-methylimidazo[4,5-b]pyridine (XXXIV) (466 mg, 2.382 mmol, 79.8% yield) as a dark brown solid which was used in the next step without purification. ESIMS found C9H 10 ClN3 m / z 196.05 (M+H).

[0505] The following intermediates were prepared following the procedure described above in Scheme 8.

[0506]

[0507] 5-Chloro-3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XXXV): beige solid (830 mg, 3.583 mmol, 60.1% yield). ESIMS found for C9H8ClF2N3 m / z 232.0 (M+H).

[0508]

[0509] 5-Chloro-3-(2-fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XXXVI): beige solid (220 mg, 1.030 mmol, 57.5% yield). ESIMS found for C9H9ClFN3 m / z 214.05 (M+H).

[0510]

[0511] 5-Chloro-3-(2-methoxyethyl)-2-methyl-3H-imidazo[4,5-b]pyridine (XXXVII): beige solid (195 mg, 0.864 mmol, 48.3% yield). ESIMS found for C10H11ClN3Om / z 226.1 (M+H). 10 H 12 ClN3Om / z 226.1 (M+H).

[0512]

[0513] 1-(5-Chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-methylpropan-2-ol (XXXVIII): white solid (229.9 mg, 0.959 mmol, 39.7% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.13 (6H, s), 2.63 (3H, s), 4.11 (2H, s), 4.80 (1H, s), 7.25 (1H, d, J=8.21 Hz), 7.96 (1H, d, J=8.21 Hz); ESIMS found for C 11 H 14 ClN3Om / z 226.1 (M+H).

[0514]

[0515] 5-Chloro-3-isobutyl-2-methyl-3H-imidazo[4,5-b]pyridine (XXXIX): white solid (206.8 mg, 0.925 mmol, 38.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.87 (6H, d, J=6.57 Hz), 2.22 (1H, d quin, J=13.89, 7.07, 7.07, 7.07, 7.07 Hz), 2.58 (3H, s), 4.01 (2H, d, J=7.67 Hz), 7.26 (1H, d, J=8.21 Hz), 7.98 (1H, d, J=8.21 Hz); ESIMS found C 11 H 14 ClN3 m / z 224.1 (M+H).

[0516]

[0517]

[0518] 5-Chloro-2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine (XL): beige solid (372 mg, 1.490 mmol, 50.0% yield). ESIMS found C9H7ClF3N3 m / z 250.0 (M+H).

[0519]

[0520] 5-Chloro-2-methyl-3-(oxetan-3-ylmethyl)-3H-imidazo[4,5-b]pyridine (XLI): light brown solid (289.7 mg, 1.219 mmol, 40.4% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 2.59 (3H, s), 3.43 - 3.56 (1H, m), 4.47 (2H, t, J=6.02 Hz), 4.52 (2H, d, J=7.67 Hz), 4.62 (2H, dd, J=7.67, 6.02 Hz), 7.27 (1H, d, J=8.21 Hz), 7.98 (1H, d, J=8.21 Hz); ESIMS found C 11 H 12 ClN3Om / z 238.1 (M+H).

[0521]

[0522] 3-((5-Chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (XLII): off-white amorphous solid (532.6 mg, 1.581 mmol, 52.1% yield). ESIMS found C 16 H 21CIN4O2 m / z 337.1 (M+H).

[0523]

[0524] 2-(5-Chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-N,N-dimethylacetamide (XLIII): off-white solid (474.4 mg, 1.877 mmol, 62.6% yield). ESIMS found C 11 H 13 CIN4O m / z 253.1 (M+H).

[0525]

[0526] 3-(5-Chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,2-dimethylpropionitrile (XLIV): off-white amorphous solid (59.1 mg, 0.238 mmol, 7.9% yield). ESIMS found C 12 H 13 CIN4 m / z 249.1 (M+H).

[0527]

[0528] 5-Chloro-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine (XLV): light yellow solid (335 mg, 1.422 mmol, 21.8% yield). ESIMS found C8H5ClF3N3 m / z 236.0 (M+H).

[0529]

[0530] 5-Chloro-3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridine (XLVI): white solid (253 mg, 1.163 mmol, 20.5% yield). ESIMS found C8H6ClF2N3 m / z 218.0 (M+H).

[0531]

[0532] 5-Chloro-3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridine (XLVII): beige solid (470 mg, 2.355 mmol, 36.2% yield). ESIMS found C8H7ClFN3 m / z 200.05 (M+H).

[0533] The preparation of intermediate 5-chloro-3-(2,2-difluoroethyl)-3H- [1,2,3]triazolo[4,5-b]pyridine (LI) is described in Scheme 9 below.

[0534]

[0535] Step 3

[0536] To a solution of 2,6-dichloro-3-nitropyridine (XLVIII) (14.0 g, 73.30 mmol) in DCM (500.0 mL) cooled to 0 °C was added 2,2-difluoroethan-1 -amine (XXIV) (8.91 g, 109.95 mmol) at 0 °C. Then DIPEA (18.91 g, 146.60 mmol) was added and the reaction was warmed to room temperature for 16 h. The reaction mixture was extracted with DCM (500 mL x 2). The combined organics were washed with brine (500 mL x 3), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude was purified by silica gel column chromatography (PE / EtOAc = 10:1 → 5:1) to give 6-chloro-N-(2,2-difluoroethyl)-3-nitropyridin-2-amine (XLIX) (12.0 g, 50.507 mmol, 68.9%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.01 - 3.93 (m, 2H), 6.43 - 6.03 (m, 1H), 6.95 - 6.79 (m, 1H), 8.54 - 8.40 (m, 1H), 8.81 (t, J = 5.4 Hz, 1H).

[0537] Step 1

[0538] To a mixture of 6-chloro-N-(2,2-difluoroethyl)-3-nitropyridin-2-amine (XLIX) (12.0 g, 50.51 mmol) in NH4Cl (7.37 g, 139.00 mmol) in EtOH / H2O (300 / 100 mL, 3:1 ratio) was added. The resulting mixture was sealed and heated at 80 °C. Then Fe (12.97 g, 231.66 mmol) was added at 80 °C, sealed and heated at 80 °C for 1 h. The reaction mixture was cooled to room temperature, filtered, and diluted with EtOAc (300 mL x 2). The solution was washed with water (300 mL x 2) and the aqueous phase was extracted with EtOAc (300 mL x 2). The combined organic extracts were washed with brine (300 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10:1→3:1) to give 6-chloro-N 2 -(2,2-difluoroethyl)pyridine-2,3-diamine (L) (10.0 g, 48.167 mmol, 95.4% yield) as a purple solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.76 (d, J = 7.8 Hz, 1H), 3.76 - 3.66 (m, 2H), 4.93 (s, 2H), 6.11 (tt, J = 56.6, 4.2 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H); ESIMS found m / z for C7H8ClF2N3 208.1 (M+H).

[0539] Step 2

[0540] To a solution of 6-chloro-N 2 -(2,2-difluoroethyl)pyridine-2,3-diamine (L) (10.0 g, 48.17 mmol) in HCl (360 mL) was added a solution of NaNO2(4.00 g, 57.97 mmol) in H2O (55 mL). The mixture was stirred at room temperature under N2for 16 h. The reaction mixture was adjusted to pH = 9 with 4 m NaOH and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10:1→1:1) to give 5-chloro-3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (LI) (6.2 g, 28.364 mmol, 58.9% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 5.25 (td, J = 16.0, 3.0 Hz, 2H), 6.85 - 6.41 (m, 1H), 7.65 (d, J = 8.6 Hz, 1H), 8.72 (d, J = 8.6 Hz, 1H); ESIMS found m / z for C7H5ClF2N4 219.0 (M+H).

[0541] The following intermediates were prepared according to the procedure described above in Scheme 9.

[0542]

[0543] 5-Chloro-3-(2,2,2-trifluoroethyl)-3H-[l,2,3]triazolo[4,5-b]pyridine (LIII): yellow solid (3.1 g, 13.103 mmol, 42.2%). 1 H NMR (400 MHz, DMSO-d6) δ 5.25 (td, J = 16.0, 3.0 Hz, 2H), 6.85 - 6.41 (m, 1H), 7.65 (d, J = 8.6 Hz, 1H), 8.72 (d, J = 8.6 Hz, 1H); ESIMS found m / z for C7H5ClF2N4 219.0 (M+H).

[0544]

[0545] 5-Chloro-3-(2,2,2-trifluoroethyl)-3H-[l,2,3]triazolo[4,5-b]pyridine (LIII): yellow solid (3.1 g, 13.103 mmol, 42.2%). 1 H NMR (400 MHz, DMSO-d6) δ 5.25 (td, J = 16.0, 3.0 Hz, 2H), 6.85 - 6.41 (m, 1H), 7.65 (d, J = 8.6 Hz, 1H), 8.72 (d, J = 8.6 Hz, 1H); ESIMS found m / z for C7H5ClF2N4 219.0 (M+H).

[0546] The preparation of intermediate cis-4-(methoxy-d3)cyclohexan-l -amine (LIX) is described in Scheme 10 below.

[0547]

[0548] Step 3

[0549] To a solution of cis-4-aminocyclohexan-1-ol (LIV) (5 g, 32.9 mmol), (bromomethyl)benzene (LV) (11.25 g, 65.8 mmol) in MeCN (80 mL) was added K2CO3(13.64 g, 98.7 mmol). The mixture was stirred at 70 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove MeCN. The mixture was diluted with EtOAc and then extracted with EtOAc (100 mL x 3) and H2O. The combined organic layers were concentrated and the crude residue was purified by silica gel column chromatography (0%→30% EtOAc / PE) to give cis-4-(dibenzylamino)cyclohexan-1-ol (LVI) (8.0 g, 27.08 mmol, 82.3% yield) as a white solid. ESIMS found C 20 H 25 NO m / z 296.4 (M+H).

[0550] Step 1

[0551] To a solution of cis-4-(dibenzylamino)cyclohexan-1-ol (LVI) (8.0 g, 27.08 mmol) in DMPU (80 mL) was slowly added NaH (5.98 g, 149.7 mmol) under nitrogen atmosphere with continuous stirring. The reaction mixture was stirred at room temperature for 1 h. Then iodomethane-d3 (LVII) (10.85 g, 74.86 mmol) was added at room temperature over 10 min. After complete addition, the reaction mixture was stirred at 50 °C for 16 h. Then the reaction mixture was quenched with saturated aqueous NH4Cl solution (300 mL) and stirred for 10 min. The mixture was diluted with EtOAc and then extracted with EtOAc (300 mL x 3) and H2O. The crude residue was purified by silica gel column chromatography (0%→20% EtOAc / PE) to give cis-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine (LVIII) (6 g, 19.202 mmol, 70.9% yield) as a colorless oil. ESIMS found C 21 H 24 D3NO m / z 313.0 (M+H).

[0552] Step 2

[0553] To a solution of cis-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine (LVIII) (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 through a Celite® pad and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0%→20% EtOAc / PE) to give cis-4-(dibenzylamino)cyclohexan-1-ol (LVI) (100 mg, 0.34 mmol, 53.1% yield) as a white solid. ESIMS found C was filtered and washed with EtOH. The reaction mixture was concentrated under reduced pressure to give cis-4-(methoxy-d3)cyclohexan-l -amine (LIX) (76.4 mg, 0.578 mmol, 90.3% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.51 - 1.40 (m, 4 H), 1.67 - 1.56 (m, 4 H), 1.86 (td, J=9.8, 4.6 Hz, 2 H), 2.71 (tt, J=10.8, 5.4 Hz, 1 H), 3.34 (td, J=4.8, 2.4 Hz, 1 H); ESIMS found C7H 12 D3NO m / z 133.0 (M+H).

[0554] The following intermediates were prepared following the procedure described above in Scheme 10.

[0555]

[0556] 2-((cis-4-aminocyclohexyl)oxy)ethan-l-ol (LX): colorless oil (0.5 g, 3.14 mmol, 67.4% yield). ESIMS found C8H 17 NO2 m / z 160. (M+H).

[0557]

[0558] cis-4-(2-methoxyethoxy)cyclohexan-l -amine (LXI): colorless oil (1.5 g, 8.65 mmol, 76.6% yield). ESIMS found C9H 19 NO2 m / z 174.1 (M+H).

[0559]

[0560] cis-4-(2,2-difluoroethoxy)cyclohexan-l -amine (LXII): white solid (1.352 g, 7.54 mmol, 90.3% yield). ESIMS found C8H 15 F2NO m / z 180.1 (M+H).

[0561]

[0562] cis-4-ethoxycyclohexan-l -amine (LXIII): colorless oil (2 g, 13.96 mmol, 64.4% yield). 1H NMR (400 MHz, CDC13) δ 1.19 (t, J = 7.0 Hz, 3H), 1.49-1.44 (m, 6H), 1.62-1.55 (m, 2H), 1.86-1.79 (m, 2H), 2.4-2.723 (m, 1H), 3.49-3.41 (m, 3H).

[0563]

[0564] Cis-3-(2-methoxyethoxy)cyclobut-l-amine (LXIV): colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 1.51 (dd, J = 13.4, 5.2 Hz, 2H), 2.49-2.40 (m, 2H), 2.89-2.75 (m, 1H), 3.23 (s, 3H), 3.37-3.35 (m, 3H), 3.47 (s, 2H), 3.54-3.48 (m, 1H).

[0565]

[0566] 2-(Cis-3-aminocyclobutyloxy)ethan-l-ol (LXV): colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 1.79-1.72 (m, 2H), 2.50-2.45 (m, 2H), 3.08-2.97 (m, 1H), 3.29 (t, J = 5.4 Hz, 2H), 3.46 (t, J = 5.4 Hz, 2H), 3.73-3.57 (m, 1H).

[0567] The preparation of intermediate cis-4-(difluoromethoxy)cyclohex-l-amine (LXVIII) is described in Scheme 11 below.

[0568]

[0569] Step 1

[0570] A solution of cis-4-(dibenzylamino)cyclohexan-1-ol (LVI) (50 mg, 0.170 mmol) and CuI (6.5 mg, 0.034 mmol) in MeCN (5 mL) was heated to 45 ° C under a nitrogen atmosphere for 5 minutes. To this mixture was added a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (LXVI) (60 mg, 0.339 mmol) in MeCN (2 mL) over 10 minutes. The mixture was then stirred at 45 ° C for 1 hour. The volatile components were then removed by evaporation, and the residue was diluted with EtOAc (100 mL) and 100 mL of a 1:1 mixture of water and saturated NaHCO3 aqueous solution. 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 layer was washed with 50 mL of a 1:1 mixture of brine and water, dried over anhydrous MgSO4, filtered, and concentrated to an oil. The crude oil was purified by silica gel chromatography (100% hexane → 30% EtOAc / hexane). The fractions containing the product were combined and concentrated to give cis-N,N-dibenzyl-4-(difluoromethoxy)cyclohexane-1-amine (LXVII) (25 mg, 0.072 mmol, 42.3% yield) as an oil that solidified to an off-white solid. ESIMS measured C 21 H 25 F2NO m / z is 346.1 (M+H).

[0571] Step 2

[0572] To a solution of cis-N,N-dibenzyl-4-(difluoromethoxy)cyclohexane-1-amine (LXVII) (2.8 g, 8.11 mmol) in THF (60 mL) was added Pd(OH)2 / C (1.4 g) and Pd / C (1.4 g). The mixture was stirred at room temperature for 16 hours. The mixture was washed with water. The reaction mixture was filtered and washed with THF. The reaction mixture was concentrated under reduced pressure to give cis-4-(difluoromethoxy)cyclohexan-1-amine (LXVIII) (1.05 g, 6.36 mmol, 78.4% yield) as a colorless oil. ESIMS determined C7H 13 F2NO m / z is 166.1 (M+H).

[0573] The preparation of intermediate 1-(3,3,3-trifluoropropyl)piperidin-4-amine (LXIII) is described in Scheme 12 below.

[0574]

[0575] Step 1

[0576] tert-Butyl piperidin-4-ylcarbamate (LXIX) (commercially available from Combi-Blocks Inc.) (1 g, 4.99 mmol) and K2CO3(1.73 g, 12.52 mmol) were dissolved in DMF (15 mL), then 1-iodo-3,3,3-trifluoropropane (LXX) (878 μL, 7.49 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into EtOAc and the aqueous layer was separated. The aqueous layer was extracted with EtOAc (x 3) then the combined organic layers were acidified to pH 4.5 with 1 m citric acid. The organic layer was washed with small amounts of water three times to remove unreacted SM. There was enough product remaining in the organic layer to dry over anhydrous MgSO4, concentrated in vacuo to give the product tert-butyl N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]carbamate (LXXI) (861 mg, 2.906 mmol, 58.2% yield) as a white solid. ESIMS found C 13 H 23 F3N2O2 m / z 297.2 (M+H).

[0577] Step 1

[0578] tert-Butyl N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]carbamate (LXXI) (200 mg, 0.670 mmol) was dissolved in DCE (3.2 mL), TFA (800 μL, 10.38 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was blown dry and excess TFA was removed by high vacuum to give the crude intermediate 1-(3,3,3-trifluoropropyl)piperidin-4-amine (LXXII) (209 mg, 0.674 mmol, 99.8% yield) as a white semi-solid which was used without further purification. ESIMS found C8H 15 F3N2 m / z 197.1 (M+H).

[0579] The preparation of intermediate N-(trans-4-aminocyclohexyl)acetamide (LXXV) is described in Scheme 13 below.

[0580]

[0581] Example 1.

[0582] To a stirred solution of tert-butyl (trans-4-aminocyclohexyl)carbamate (LXXIII) (commercially available from Combi-Blocks Inc.) (0.6 g, 2.8 mmol) in DCM (6 mL) was added TEA (1.2 mL, 8.61 mmol). Acetyl chloride (LXXIV) (0.22 mL, 3.09 mmol) was then added slowly and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed and the crude material was dissolved in EtOAc, washed with 1 m NaOH, brine, dried over anhydrous MgS04and finally concentrated. The product was dissolved in EtOH (2 mL) and 4 M HC1 (1 mL). The solution was stirred at room temperature for 2 hours and then evaporated to dryness to give the HC1 salt of N-(trans-4-aminocyclohexyl)acetamide (LXXV) (480 mg, 2.49 mmol, 89.0% yield) as a white solid. ESIMS found C8H 16 N2O m / z 157.05 (M+H).

[0583] The preparation of intermediate cis-4-amino-N,N-dimethylcyclohexane-1- carboxamide (LXXVII) is described in Scheme 14 below.

[0584]

[0585]

[0586] Step 1

[0587] To a stirred solution of 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (LXXVI) (commercially available from Combi-Blocks Inc.) (0.3 g, 1.23 mmol) in DMF (6 mL) was added DIPEA (0.65 mL, 3.73 mmol) and HATU (0.7 g, 1.85 mmol). The reaction was stirred at room temperature for 5 minutes. Dimethylamine (0.92 mL, 1.84 mmol) was added and the reaction was heated to 90 °C for 16 hours. The reaction was concentrated and dissolved in EtOH (2 mL) and 4 M HC1 in dioxane (1 mL). The mixture was stirred at room temperature for 2 hours, concentrated in vacuo to give the HC1 salt of 4-amino-N,N-dimethylcyclohexane-1-carboxamide (LXXVII) (280 mg, 1.355 mmol, 109.9% yield) as a light brown sticky solid. ESIMS found C9H 18 N2O m / z 171.15 (M+H).

[0588] The following intermediates were prepared following the procedure described above in Scheme 14.

[0589] The following intermediates were prepared following the procedure described above in Scheme 14.

[0590] Trans-4-amino-N,N-dimethylcyclohexane-1-carboxamide (LXXVIII): light brown viscous solid (290 mg, 1.403 mmol, 113.8% yield). ESIMS found C9H 18 N2Om / z as 171.1 (M+H).

[0591] Step 2

[0592] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 The preparation of -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (210) is described in Scheme 15 below.

[0593]

[0594] Step 3

[0595] To a mixture of 5-bromo-2-chloro-N-methylpyrrolo[2,l- f][l,2,4]triazin-4-amine (XV) (1 g, 3.82 mmol), [3-(2,2-difluoroethyl)-2- methylimidazo[4,5-b]pyridin-5-yl]boronic acid (LXXIX) (1.01 g, 4.21 mmol), Pd(dppf)Cl2(158 mg, 0.19 mmol), and NaHCO3(1.46 g, 13.77 mmol) was added to a mixture of dry 1,4-dioxane (20 mL) and water (5 mL). The reaction mixture was purged with Ar for 5 minutes and the reaction was heated to 80 °C for 1 hour. The reaction mixture was poured into saturated aqueous NH4Cl, then extracted with DCM (x 3), dried (MgSO4) and concentrated in vacuo to give a crude orange solid. The product was purified by column chromatography (0→ 100% EtOAc / hexanes, followed by 0→ 6% MeOH / CHCl3). The product was further purified by reverse phase column chromatography (10→ 70% MeCN / H2O with 0.1% formic acid). The appropriate fractions were combined, neutralized with saturated aqueous NaHCO3, extracted with DCM (x 3), dried (MgSO4) and concentrated in vacuo to give a brown solid. The solid was triturated in MeOH, filtered and washed with MeOH. The product 2-chloro-5-[3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]-N- methylpyrrolo[2,l-f][l,2,4]triazin-4-amine (LXXI) (1.005 g, 2.660 mmol, 69.6% yield) was collected as an off-white solid. Impure fractions were combined and treated as previously described to give a second crop of product 2-chloro-5-[3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]-N- methylpyrrolo[2,l-f][l,2,4]triazin-4-amine (LXXX) (444 mg, 1.175 mmol, 30.7% yield) as an off-white solid. ESIMS found C 16 H 14 ClF2N7 m / z 378.1 (M+H).

[0596] Step 4

[0597] (3S,4R)-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5- b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3- fluoropiperidine-1-carboxylic acid (LXXXIII) was prepared from (3S,4R)-4-((5-(3-(2,2- difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (LXXXII) (167 mg, 0.298 mmol) according to the procedure described in Example 1, Step 1. The crude material was purified by reverse phase column chromatography (10→ 70% MeCN / H2O with 0.1% formic acid). The appropriate fractions were combined and neutralized with saturated aqueous NaHC03solution and extracted with DCM (x 2). The combined organic layers were dried (MgS04), concentrated in vacuo to yield (3S,4R)-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidine-1-carboxylic acid (LXXXIII) (120 mg, 0.229 mmol, 77.0% yield) as a white solid. ESIMS found C t Bu (116 mg, 1.21 mmol) was added to dry 1,4-dioxane (3 mL) in a microwave vessel. The suspension was purged with Ar for 5 minutes, then the reaction was irradiated with microwaves to 100 °C for 10 minutes. The reaction mixture was concentrated in vacuo and purified by column chromatography (0→ 100% EtOAc / hexanes, followed by 0→ 3% 7.0 M NH3in MeOH / CHCl3solution). The product was further purified by reverse phase column chromatography (10→ 70% MeCN / H2O with 0.1% formic acid). The appropriate fractions were combined and neutralized with saturated aqueous NaHC03solution and extracted with DCM (x 2). The combined organic layers were dried (MgS04), concentrated in vacuo to yield (3S,4R)-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidine-1-carboxylic acid (LXXXIII) (120 mg, 0.229 mmol, 77.0% yield) as a white solid. ESIMS found C 26 H 32 F3N9O2 m / z as 560.3 (M+H).

[0598] Example 2.

[0599] To a solution of (3S,4R)-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (LXXXII) (167 mg, 0.3 mmol) in DCE (3 mL) was added TFA (1 mL, 12.98 mmol). The reaction was stirred at room temperature for 15 min. The reaction mixture turned turquoise, the solvent was blown off, excess TFA was removed under high vacuum to give the crude intermediate (3S,4R)-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)-3-fluoropiperidin-1-ium 2,2,2-trifluoroacetate (LXXXIII) (171 mg, 0.298 mmol, 99.9% yield, assumed quantitative yield) as a greenish semi-solid, which was used without purification. ESIMS found C 21 H 24 F3N9 m / z 460.25 (M+H).

[0600] Step 1

[0601] Dissolve 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N2-((3S,4R)-3-fluoropiperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXXIII) (103 mg, 0.22 mmol) in EtOH (2 mL) and HOAc (26 μL, 0.45 mmol), add oxetan-3-one (LXXXIV) (20 μL, 0.34 mmol) and stir the reaction for 10 min. Add NaBH(OAc)3 (71 mg, 0.34 mmol) and stir the reaction at 65 °C for 30 min. Load the reaction mixture onto a SCX cartridge and purify by column chromatography (0→2% MeOH in CHCI3 with 7.0 M NH3 held). Concentrate the appropriate fractions in vacuo to give a white solid. Triturate the solid in MeOH and filter the solid, washing with minimal MeOH to give 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N2-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXXV) (103 mg, 0.22 mmol, 99.9% yield, assumed quantitative yield) as a white solid. Dissolve 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N2-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXXV) (103 mg, 0.22 mmol) in EtOH (2 mL) and HOAc (26 μL, 0.45 mmol), add oxetan-3-one (LXXXIV) (20 μL, 0.34 mmol) and stir the reaction for 10 min. Add NaBH(OAc)3 (71 mg, 0.34 mmol) and stir the reaction at 65 °C for 30 min. Load the reaction mixture onto a SCX cartridge and purify by column chromatography (0→2% MeOH in CHCI3 with 7.0 M NH3 held). Concentrate the appropriate fractions in vacuo to give a white solid. Triturate the solid in MeOH and filter the solid, washing with minimal MeOH to give 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N2-((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXXV) (103 mg, 0.22 mmol, 99.9% yield, assumed quantitative yield) as a white solid. 2 -((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (210) (64 mg, 0.124 mmol, 55.4% yield) as a white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.67-1.76 (1 H, m), 1.81-1.91 (1 H, m), 1.95-2.03 (1 H, m), 2.06-2.20 (1 H, m), 2.62 (3 H, s), 2.75 (1 H, br d, J=9.58 Hz), 2.92-3.02 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.72-3.89 (1 H, m), 4.43 (2 H, dt, J=29.30, 6.16 Hz), 4.54 (2 H, td, J=6.50, 3.15 Hz), 4.72-4.83 (2 H, m), 4.90 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.38 Hz); ESIMS found C 24 H 28 F3N9O m / z 516.3 (M+1).

[0602] Step 2

[0603] N 2 - ((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 The preparation of methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (219) and 1- ((1R,5S,6r)-6-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethan- 1-one (220) is described in Scheme 16 below.

[0604]

[0605] Step 3

[0606] To a stirred solution of 2-chloro-5-[3-(2,2-difluoroethyl)-2-methylimidazo[4,5- b]pyridin-5-yl]-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (LXXX) (100 mg, 0.26 mmol), (1R,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (LXXXV) (commercially available from Combi-Blocks Inc.) (74 mg, 0.37 mmol), NaO t A mixture of 2-chloro-5-[3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]- N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (LXXX) (100 mg, 0.26 mmol), (1R,5S,6r)-6- amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (LXXXV) (commercially available from Combi-Blocks Inc.) (74 mg, 0.37 mmol), NaO 26 H 31 F2N9O2 m / z 540.3 (M+H).

[0607] Example 3.

[0608] To a stirred solution of (1R,5S,6r)-6-((5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3- azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (LXXXVI) (130 mg, 0.24 mmol) in DCM (2 mL) was added TFA (1 mL, 12.98 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the crude was purified by ISCO (1-10% 7N NH3 MeOH / CHCl3). The pure fractions were collected, concentrated under reduced pressure, dried under high vacuum to give N 2- ((1R, 5S, 6r)-3-azabicyclo[3.1.0]hex-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (219) (65 mg, 0.148 mmol, 61.4% yield) as off-white solid. 1 HNMR (499 MHz, DMSO-d6) δ ppm 1.64 (2H, br d, J=7.12 Hz), 2.62 (3H, s), 2.88-2.92 (1H, m), 2.92-2.97 (2H, m), 2.99-3.04 (2H, m), 3.11 (3H, d, J=4.65 Hz), 4.71-4.83 (2H, m), 6.04 (1H, d, J=4.11 Hz), 6.63 (1H, tt, J=54.30, 3.00 Hz), 7.10 (1H, d, J=2.74 Hz), 7.39 (1H, d, J=2.46 Hz), 7.85 (1H, d, J=8.49 Hz), 8.00 (1H, d, J=8.49 Hz), 10.93 (1H, br q, J=4.65 Hz); ESIMS found C 21 H 23 F2N9 m / z 440.2 (M+1).

[0609] Step 1

[0610] To a solution of HOAc (5.52 μL, 0.1 mmol), HATU (34 mg, 0.09 mmol) in DMF (200 μL) was added DIPEA (38 μL, 0.22 mmol). The mixture was stirred for 5 min, and N 2 - ((1R, 5S, 6r)-3-azabicyclo[3.1.0]hex-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (219) (30 mg, 0.07 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (10 mL) was added and the solution was extracted with EtOAc. The organics were separated, concentrated, adsorbed on silica gel, purified by preparative TLC (4% MeOH / CHCl3) to give 1-((1R,5S,6r)-6-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)ethan-1- one (220) (24 mg, 0.050 mmol, 73.0% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) d ppm 1.83 (3H, s), 1.84 - 1.88 (1H, m), 1.89 - 1.95 (1H, m), 2.62 (3H, s), 2.69 (1H, td, J=6.91, 1.23 Hz), 3.12 (3H, d, J=4.65 Hz), 3.40 - 3.49 (2H, m), 3.54 (1H, d, J=10.40 Hz), 3.67 (1H, dd, J=10.40, 5.48 Hz), 4.72 - 4.83 (2H, m), 6.23 (1H, s), 6.63 (1H, tt, J=54.30, 3.00 Hz), 7.11 (1H, d, J=3.01 Hz), 7.40 (1H, d, J=2.74 Hz), 7.85 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 10.94 (1H, q, J=4.56 Hz); ESIMS found C 23 H 25 F2N9O m / z 482.2 (M+1).

[0611] Step 2

[0612] The preparation of N-(trans-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl) acetamide (187) is described in Scheme 17 below.

[0613]

[0614] Example 4.

[0615] Dichloro-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (XXII) (100 mg, 0.46 mmol), NaOEt (0.1 mL, 0.92 mmol) and 1,4-dioxane (2 mL) were added to a microwave vial and purged with Ar for 5 min. The reaction was microwave irradiated to 100 °C for 10 min. The reaction mixture was cooled, added to a mixture of saturated aqueous NH4Cl and DCM. The organic layer was separated and the aqueous layer was extracted with DCM (x 3), the combined organic layers were dried (MgSO4) and concentrated in vacuo to give a yellow oil. The crude product was purified by column chromatography (0→ 10% 7.0 M NH3in MeOH / CHCl3solution) to give N-methyl-5-oxo-5,6-dihydropyrrolo[2,1-f][1,2,4]triazine-4-carboxamide (XXIII) (50 mg, 0.22 mmol, 48.2% yield) as a yellow solid. ESIMS found C10H9N4O2, m / z 213.2 (M+H). t Bu (200 mg, 2.08 mmol), BrettPhos Pd G3 (34 mg, 0.04 mmol), BrettPhos (25 mg, 0.05 mmol) and N-(trans-4-aminocyclohexyl)acetamide (LXXV) (124 mg, 0.64 mmol) were added to a microwave vial and purged with Ar for 5 min. The reaction was microwave irradiated to 100 °C for 10 min. The reaction mixture was cooled, added to a mixture of saturated aqueous NH4Cl and DCM. The organic layer was separated and the aqueous layer was extracted with DCM (x 3), the combined organic layers were dried (MgSO4) and concentrated in vacuo to give an orange oil. The crude product was purified by column chromatography (0→ 7.0 M NH3in MeOH / CHCl3solution) to give N-(trans-4-((5-chloro-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide (LXXXVII) (87 mg, 0.258 mmol, 56.1% yield) as a beige solid. ESIMS found C21H25ClN6O m / z 337.2 (M+H). 15 H 21 ClN6O m / z 337.2 (M+H).

[0616] Step 1

[0617] N-(trans-4-((5-chloro-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide (LXXXVII) (87 mg, 0.26 mmol), [3-(2,2-difluoroethyl)-2-methylimidazo[4,5-b]pyridin-5-yl]boronic acid (LXXIX) (82 mg, 0.34 mmol), Pd(OAc)2(7 mg, 0.03 mmol), and XPhos (14 mg, 0.03 mmol) dissolved in anhydrous 1,4-dioxane (1.5 mL) were added to a microwave vial. The reaction mixture was purged with Ar for 5 min, then 2 M aqueous K2PO4(388 μL, 0.78 mmol) was added, and purged with Ar for an additional 2 min. The reaction was heated to 90 °C for 1 h. The reaction mixture was concentrated in vacuo and purified by reverse-phase column chromatography (C18 column) (0→80% MeCN / H2O with 0.1% formic acid). The corresponding fractions were lyophilized to give N-(trans-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide (187) (22 mg, 0.044 mmol, 17.1% yield) as an off-white solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.18 - 1.27 (2H, m), 1.27 - 1.37 (2H, m), 1.78 (3H, s), 1.79 - 1.83 (2H, m), 1.97 (2H, br d, J=10.68 Hz), 2.62 (3H, s), 3.10 (3H, d, J=4.65 Hz), 3.44 - 3.60 (2H, m), 4.72 - 4.83 (2H, m), 5.90 (1H, d, J=8.49 Hz), 6.63 (1H, tt, J=54.30, 3.00 Hz), 7.08 (1H, d, J=3.01 Hz), 7.37 (1H, d, J=3.01 Hz), 7.72 (1H, d, J=7.94 Hz), 7.84 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.49 Hz), 10.89 (1H, q, J=4.65 Hz); ESIMS found C 24 H 29 F2N9O m / z 498.3 (M+1).

[0618] Example 5.

[0619] N 2-((3S,4R)-1-cyclopropyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 The preparation of -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (???) is described in Scheme 18 below.

[0620]

[0621] Step 1

[0622] To 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoropiperidin-4-yl)-N 4- Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (LXXXIII) (30 mg, 0.06 mmol) and 2 tablets To a suspension of the MS beads in anhydrous DCE (0.9 mL) and ethanol (0.1 mL) were added HOAc (7 μL, 0.12 mmol) and (1-ethoxycyclopropyloxy)trimethylsilane (commercially available from AmBeed, Inc.) (27 μL, 0.13 mmol). The reaction was stirred at 65 ° C for 1 hour. The reaction mixture was cooled to room temperature, NaBH3CN (21 mg, 0.33 mmol) was added, and the reaction was stirred for 10 minutes. LCMS showed that some starting material still remained. Additional (1-ethoxycyclopropyloxy)trimethylsilane (27 μL, 0.13 mmol) was added and the reaction was heated to 65 ° C for 30 minutes. After cooling the reaction mixture, additional NaBH3CN (21 mg, 0.33 mmol) was added and the reaction was stirred for 10 minutes. LCMS confirmed that the reaction was complete. The reaction mixture was loaded onto The product was purified by column chromatography (0→4% MeOH / CHCl3). The product was further purified by HPLC (0→40% MeCN / H2O in 0.1% formic acid) and lyophilized to yield N 2 -((3S,4R)-1-cyclopropyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4- Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (377) (14 mg, 0.028 mmol, 42.9% yield) was obtained as a light yellow fluffy solid. 1HNMR (499 MHz, DMSO-d6) δ ppm 0.20-0.29 (1 H, m), 0.30-0.37 (1 H, m), 0.39-0.49 (2 H, m), 1.61-1.72 (2 H, m), 1.79 (1 H, qd, J=12.32, 3.83 Hz), 2.37 (1 H, dd, J=45.80, 13.15 Hz), 2.33-2.38 (1 H, m), 2.62 (3 H, s), 2.95 (1 H, br d, J=11.77 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.14-3.24 (1 H, m), 3.70-3.88 (1 H, m), 4.78 (2 H, td, J=16.08, 2.60 Hz), 4.87 (1 H, d, J=50.20 Hz), 5.87 (1 H, br d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.56 Hz); ESIMS found C 24 H 28 F3N9 m / z 500.3 (M+1).

[0623] Example 6.

[0624] N 2 -((3S,4R)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 The preparation of -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine (????) is described in Scheme 19 below.

[0625]

[0626] Step 1

[0627] -((3S,4R)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoropiperidin-4-yl)-N 4-Methylpyrrolo[2,l-f][l,2,4]triazine-2,4-diamine (LXXXIII) (65 mg, 0.14 mmol), K2CO3(33 mg, 0.24 mmol) and KI (30 mg, 0.18 mmol) were suspended in DMF (1 mL). 3-Bromo-l,l-difluorocyclobutane (35 mg, 0.2 mmol) was added and stirred at 115 °C for 16 h. The reaction mixture was loaded onto a silica gel column and the product was purified by column chromatography (0→4% MeOH / CHCl3). The product was further purified by HPLC (0→40% MeCN / H2O in 0.1% formic acid) to give N H NMR (499 MHz, DMSO-d6) δ ppm 1.66 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.70 Hz), 1.97 - 2.08 (1 H, m), 2.16 (1 H, dd, J=37.55, 12.32 Hz), 2.28 - 2.47 (2 H, m), 2.62 (3 H, s), 2.64 - 2.77 (3 H, m), 2.83 (1 H, br d, J=10.13 Hz), 3.02 - 3.09 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.73 - 3.89 (1 H, m), 4.78 (2 H, td, J=15.74, 2.19 Hz), 4.91 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.98 (1 H, q, J=4.56 Hz); ESIMS found C 2 -((3S,4R)-l-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2- difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 Methylpyrrolo[2,l-f][l,2,4]triazine-2,4-diamine (380) (6 mg, 0.011 mmol, 7.7% yield) as an off-white fluffy solid. 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.66 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.70 Hz), 1.97 - 2.08 (1 H, m), 2.16 (1 H, dd, J=37.55, 12.32 Hz), 2.28 - 2.47 (2 H, m), 2.62 (3 H, s), 2.64 - 2.77 (3 H, m), 2.83 (1 H, br d, J=10.13 Hz), 3.02 - 3.09 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.73 - 3.89 (1 H, m), 4.78 (2 H, td, J=15.74, 2.19 Hz), 4.91 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.98 (1 H, q, J=4.56 Hz); ESIMS found C 25 H 28 F5N9 m / z 550.3 (M+l).

[0628] Step 2

[0629] The preparation of (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol (986) is described in Scheme 20 below.

[0630]

[0631] Step 3

[0632] 2,5-Dichloropyrrolo[2,1-f][1,2,4]triazine-4-amine (XXI) (100 mg, 0.49 mmol), di-tert-butyl dicarbonate (162 mg, 0.74 mmol) and DMAP (8 mg, 0.07 mmol) were dissolved in DCM (4 mL). TEA (103 μL, 0.74 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was loaded onto The product was purified by silica gel column chromatography (EtOAc / hexane = 0→10) to give tert-butyl (2,5-dichloropyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (LXXXVIII) (107 mg, 0.353 mmol, 71.7% yield) as an off-white solid. ESIMS analysis revealed that C 11 H 12 Cl2N4O2 m / z is 303.05 (M+H).

[0633] ​

[0634] Tert-butyl (2,5-dichloropyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (LXXXVIII) (200 mg, 0.66 mmol), LiHMDS (1.0 M in THF) (1.26 mL, 1.26 mmol), BrettPhos Pd G3 (30 mg, 0.03 mmol), BrettPhos (54 mg, 0.1 mmol) and trans-4-amino-1-methylcyclohexanol (LXXXIX) (94 mg, 0.73 mmol) were added to a microwave vessel. Anhydrous 1,4-dioxane (4 mL) was added and the suspension was purged with Ar for 5 minutes. The reaction was heated at 50 °C for 45 minutes. The reaction mixture was loaded into was added to this mixture, followed by TFA (1 mL) and stirred at room temperature for 16 h. The reaction solvent was blown off with N2 stream, and the residue was purified by silica gel column chromatography (MeOH / CHCl3= 0→ 10%) and the solvent was removed from the fractions containing the product, and re-purified by C18 prep-HPLC (MeCN / water (0.1% formic acid) = 0→ 50%). The fractions containing the product were frozen and lyophilized to give (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-1 -methylcyclohexan-1 -ol (986) (8 mg, 0.018 mmol, 26.5% yield) as a white solid. ESIMS found C 18 H 26 ClN5O3 m / z 396.2 (M + 1).

[0635] ​

[0636] was added to this mixture, followed by TFA (1 mL) and stirred at room temperature for 16 h. The reaction solvent was blown off with N2 stream, and the residue was purified by silica gel column chromatography (MeOH / CHCl3= 0→ 10%) and the solvent was removed from the fractions containing the product, and re-purified by C18 prep-HPLC (MeCN / water (0.1% formic acid) = 0→ 50%). The fractions containing the product were frozen and lyophilized to give (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-1 -methylcyclohexan-1 -ol (986) (8 mg, 0.018 mmol, 26.5% yield) as a white solid. ESIMS found C 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3 H, s), 1.34 - 1.46 (4 H, m), 1.51 - 1.62 (2 H, m), 1.77 - 1.89 (2 H, m), 3.62 (1 H, dt, J=8.08, 3.90 Hz), 4.20 (1 H, br s), 4.74 (2 H, td, J=16.50, 2.33 Hz), 5.77 (1 H, d, J=8.21 Hz), 6.47 (1 H, tt, J=54.45, 2.75 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=3.01 Hz), 7.45 (1 H, br s), 7.87 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.49 Hz), 8.39 (1 H, s), 10.49 (1 H, br s); ESIMS found C 21 H 24 F2N8O m / z 443.2 (M+1).

[0637] The following compounds were prepared according to the procedures described above in Scheme 1-20.

[0638]

[0639] Trans-4-((4-amino-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)-1-methylcyclohexan-1-ol 1.

[0640] Beige solid (1.3 mg, 0.003 mmol, 1.0% yield). 1 H NMR (499 MHz, METHANOL-d4) δ ppm 1.27 (3 H, s), 1.44 - 1.55 (2 H, m), 1.56 - 1.65 (2 H, m), 1.67 - 1.76 (2 H, m), 1.98 - 2.08 (2 H, m), 3.15 - 3.23 (1 H, m), 3.73 (1 H, tt, J=8.73, 4.14 Hz), 4.60 (2 H, br s), 6.57 (1 H, d, J=2.46 Hz), 6.62 (1 H, d, J=1.64 Hz), 7.02 (1 H, dd, J=7.12, 1.92 Hz), 7.39 (1 H, d, J=2.46 Hz), 7.68 (1 H, d, J=1.09 Hz), 7.97 (1 H, d, J=2.46 Hz), 8.57 (1 H, d, J=7.39 Hz); ESIMS found C 20 H 23 N7O m / z 378.2 (M+1).

[0641]

[0642] N 4 - methyl-N 2 - (1-(oxetan-3-yl)piperidin-4-yl)-5-(pyrazolo[1,5-a]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazine-2,4-diamine 2.

[0643] Off-white solid (34 mg, 0.081 mmol, 50.7% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.46 - 1.57 (2H, m), 1.80 - 1.94 (4H, m), 2.67 (2H, br d, J=11.22 Hz), 2.86 (3H, d, J=4.65 Hz), 3.35 - 3.42 (1H, m), 3.52 - 3.63 (1H, m), 4.42 (2H, t, J=5.89 Hz), 4.53 (2H, t, J=6.43 Hz), 6.02 (1H, br d, J=8.21 Hz), 6.26 (1H, br q, J=4.65 Hz), 6.48 (1H, d, J=2.46 Hz), 6.59 (1H, d, J=1.64 Hz), 6.89 (1H, dd, J=7.39, 1.92 Hz), 7.39 (1H, d, J=2.74 Hz), 7.61 (1H, d, J=1.09 Hz), 7.99 (1H, d, J=2.19 Hz), 8.66 (1H, d, J=7.39 Hz); ESIMS found C 22 H 26 N8O m / z 419.3 (M+1).

[0644]

[0645] Trans-1-methyl-4-((4-(methylamino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)cyclohexan-1-ol 20.

[0646] Beige solid (24 mg, 0.061 mmol, 12.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3H, s), 1.37 - 1.49 (4H, m), 1.54 - 1.64 (2H, m), 1.79 - 1.90 (2H, m), 3.10 (3H, d, J=4.65 Hz), 3.63 (1H, br s), 4.21 (1H, s), 6.05 (1H, d, J=7.94 Hz), 6.69 (1H, d, J=1.92 Hz), 7.30 (1H, d, J=3.01 Hz), 7.42 (1H, d, J=3.01 Hz), 7.54 (1H, d, J=7.67 Hz), 8.15 (1H, d, J=2.19 Hz), 9.01 (1H, d, J=7.67 Hz), 11.43 (1H, q, J=4.65 Hz); ESIMS found C 20 H 24 N8O m / z 393.25 (M+1).

[0647]

[0648] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-N 4 -methyl-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 44.

[0649] Fluffy yellow solid (13 mg, 0.031 mmol, 83.7% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3H, s), 1.37 - 1.49 (4H, m), 1.54 - 1.64 (2H, m), 1.79 - 1.90 (2H, m), 3.10 (3H, d, J=4.65 Hz), 3.63 (1H, br s), 4.21 (1H, s), 6.05 (1H, d, J=7.94 Hz), 6.69 (1H, d, J=1.92 Hz), 7.30 (1H, d, J=3.01 Hz), 7.42 (1H, d, J=3.01 Hz), 7.54 (1H, d, J=7.67 Hz), 8.15 (1H, d, J=2.19 Hz), 9.01 (1H, d, J=7.67 Hz), 11.43 (1H, q, J=4.65 Hz); ESIMS found C 19 H 21 F2N9 m / z 414.2 (M+1).

[0650]

[0651] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4 -methyl-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 46.

[0652] Off-white solid (14 mg, 0.031 mmol, 64.6% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.74 - 1.83 (1 H, m), 1.84 - 1.91 (1 H, m), 2.14 (1 H, br t, J=10.68 Hz), 2.37 (1 H, ddd, J=27.15, 11.80, 1.35 Hz), 2.75 (1 H, br d, J=11.23 Hz), 2.95 - 3.06 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.59 (1 H, quin, J=6.30 Hz), 4.21 - 4.37 (1 H, m), 4.44 (2 H, dt, J=14.65, 6.09 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 6.42 (1 H, d, J=9.58 Hz), 6.72 (1 H, d, J=2.19 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.43 (1 H, d, J=3.01 Hz), 7.56 (1 H, d, J=7.67 Hz), 8.17 (1 H, d, J=2.19 Hz), 9.03 (1 H, d, J=7.67 Hz), 11.54 (1 H, q, J=4.56 Hz); ESIMS found C 21 H 23 F2N9O m / z 456.2 (M+1).

[0653]

[0654] Trans-4-((5-(imidazo[1,2-a]pyridin-6-yl)-4-(methylamino)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 58.

[0655] Off-white solid (47 mg, 0.120 mmol, 23.9% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 1.14 (3H, s), 1.36 - 1.48 (4H, m), 1.53 - 1.63 (2H, m), 1.79 - 1.90 (2H, m), 2.84 (3H, d, J=4.65 Hz), 3.54 - 3.66 (1H, m), 4.20 (1H, s), 5.83 (1H, d, J=8.21 Hz), 6.21 (1H, q, J=4.47 Hz), 6.41 (1H, d, J=2.46 Hz), 7.23 (1H, dd, J=9.31, 1.64 Hz), 7.39 (1H, d, J=2.46 Hz), 7.58 (1H, br d, J=9.03 Hz), 7.58 (1H, s), 7.94 (1H, s), 8.53 (1H, s) ESIMS found C 21 H 25 N7O m / z 392.3 (M+1).

[0656]

[0657] 5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N 4 -methyl-N 2 -(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 114.

[0658] Off-white solid (8 mg, 0.017 mmol, 11.3% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.14 (3H, s), 1.36 - 1.48 (4H, m), 1.53 - 1.63 (2H, m), 1.79 - 1.90 (2H, m), 2.84 (3H, d, J=4.65 Hz), 3.54 - 3.66 (1H, m), 4.20 (1H, s), 5.83 (1H, d, J=8.21 Hz), 6.21 (1H, q, J=4.47 Hz), 6.41 (1H, d, J=2.46 Hz), 7.23 (1H, dd, J=9.31, 1.64 Hz), 7.39 (1H, d, J=2.46 Hz), 7.58 (1H, br d, J=9.03 Hz), 7.58 (1H, s), 7.94 (1H, s), 8.53 (1H, s) ESIMS found C 25 H 33N9O m / z 476.3 (M+1).

[0659]

[0660] Trans-4-((5-(3-isopropyl-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 132.

[0661] Off-white solid (62 mg, 0.138 mmol, 73.4% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3H, s), 1.36 - 1.50 (4H, m), 1.54 - 1.62 (2H, m), 1.67 (6H, d, J=7.12 Hz), 1.81 - 1.90 (2H, m), 2.65 (3H, s), 3.12 (3H, d, J=4.65 Hz), 3.62 (1H, br s), 4.21 (1H, s), 4.92 (1H, dt, J=14.03, 7.08 Hz), 5.87 (1H, d, J=8.21 Hz), 7.01 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=3.01 Hz), 7.75 (1H, d, J=8.49 Hz), 7.95 (1H, d, J=8.49 Hz), 10.50 (1H, br d, J=4.65 Hz); ESIMS found C 24 H 32 N8O m / z 449.3 (M+1).

[0662]

[0663] Trans-3-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol 170.

[0664] Off-white solid (13 mg, 0.029 mmol, 16.1% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 1.27 (3H, s), 1.92-2.00 (2H, m), 2.25-2.33 (2H, m), 2.63 (3H, s), 2.82 (3H, d, J=4.65 Hz), 4.25 (1H, sxt, J=7.45 Hz), 4.73 (1H, s), 4.77-4.90 (2H, m), 5.95 (1H, q, J=4.38 Hz), 6.32 (1H, d, J=7.12 Hz), 6.47 (1H, tt, J=54.60, 3.00 Hz), 6.44 (1H, d, J=2.46 Hz), 7.40 (1H, d, J=2.46 Hz), 7.98 (1H, d, J=1.92 Hz), 8.40 (1H, d, J=1.92 Hz); ESIMS found C 21 H 24 F2N8O m / z 443.25 (M+1).

[0665]

[0666] Trans-4-((5-(1-(2,2-difluoroethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 171.

[0667] Off-white solid (7 mg, 0.015 mmol, 8.1% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.27 (3H, s), 1.92-2.00 (2H, m), 2.25-2.33 (2H, m), 2.63 (3H, s), 2.82 (3H, d, J=4.65 Hz), 4.25 (1H, sxt, J=7.45 Hz), 4.73 (1H, s), 4.77-4.90 (2H, m), 5.95 (1H, q, J=4.38 Hz), 6.32 (1H, d, J=7.12 Hz), 6.47 (1H, tt, J=54.60, 3.00 Hz), 6.44 (1H, d, J=2.46 Hz), 7.40 (1H, d, J=2.46 Hz), 7.98 (1H, d, J=1.92 Hz), 8.40 (1H, d, J=1.92 Hz); ESIMS found C 23 H 28 F2N8O m / z 471.3 (M+1).

[0668]

[0669] 2-(cis-3-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutoxy)ethan-1-ol 172.

[0670] White solid (35 mg, 0.074 mmol, 56.0% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.84 (2H, qd, J=8.49, 2.74 Hz), 2.57-2.61 (2H, m), 2.62 (3H, s), 3.11 (3H, d, J=4.65 Hz), 3.29-3.33 (2H, m), 3.48 (2H, q, J=5.38 Hz), 3.69 (1H, quin, J=7.19 Hz), 3.78 (1H, dq, J=16.02, 8.08 Hz), 4.59 (1H, t, J=5.61 Hz), 4.72-4.82 (2H, m), 6.42 (1H, d, J=7.67 Hz), 6.63 (1H, tt, J=54.35, 3.00 Hz), 7.08 (1H, d, J=3.01 Hz), 7.34 (1H, d, J=2.74 Hz), 7.84 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.49 Hz), 10.92 (1H, q, J=4.47 Hz); ESIMS found C 22 H 26 F2N8O2 m / z 473.2 (M+1).

[0671]

[0672] cis-3-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclobutan-1-ol 174.

[0673] Beige solid (30 mg, 0.068 mmol, 51.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.25 (3H, s), 1.98 (2H, td, J=8.90, 2.19 Hz), 2.28 - 2.36 (2H, m), 2.62 (3H, s), 3.11 (3H, d, J=4.93 Hz), 3.72 (1H, sxt, J=7.78 Hz), 4.77 (2H, td, J=16.00, 2.20 Hz), 4.86 (1H, s), 6.28 (1H, d, J=6.84 Hz), 6.63 (1H, tt, J=54.60, 3.00 Hz), 7.08 (1H, d, J=3.01 Hz), 7.37 (1H, d, J=3.01 Hz), 7.84 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.49 Hz), 10.90 (1H, q, J=4.56 Hz); ESIMS found C 21 H 24 F2N8O m / z 443.2 (M+1).

[0674]

[0675] N 2 -(4,4-difluorocyclohexyl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5- b]pyridin-5-yl)-N 4- Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 182.

[0676] Off-white solid (15 mg, 0.032 mmol, 19.8% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.25 (3H, s), 1.98 (2H, td, J=8.90, 2.19 Hz), 2.28 - 2.36 (2H, m), 2.62 (3H, s), 3.11 (3H, d, J=4.93 Hz), 3.72 (1H, sxt, J=7.78 Hz), 4.77 (2H, td, J=16.00, 2.20 Hz), 4.86 (1H, s), 6.28 (1H, d, J=6.84 Hz), 6.63 (1H, tt, J=54.60, 3.00 Hz), 7.08 (1H, d, J=3.01 Hz), 7.37 (1H, d, J=3.01 Hz), 7.84 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.49 Hz), 10.90 (1H, q, J=4.56 Hz); ESIMS found C 22 H 24 F4N8 m / z 477.2 (M+1).

[0677]

[0678] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(cis-4-methoxycyclohexyl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 183.

[0679] White solid (6 mg, 0.013 mmol, 9.6% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.52 (2 H, m), 1.53 - 1.62 (2 H, m), 1.63 - 1.71 (2 H, m), 1.79 - 1.88 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.22 (3 H, s), 3.29 - 3.32 (1 H, m), 3.57 - 3.68 (1 H, m), 4.71 - 4.83 (2 H, m), 5.90 (1 H, d, J=7.94 Hz), 6.63 (1 H, tt, J=54.20, 3.00 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=2.74 Hz), 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.88 (1 H, br q, J=4.65 Hz); ESIMS found C 23 H 28 F2N8O m / z 471.3 (M+1).

[0680]

[0681] 2-((cis-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)oxy)ethan-1-ol 184.

[0682] Off-white solid (16 mg, 0.03 mmol, 24.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.55 (2 H, m), 1.58 - 1.73 (4 H, m), 1.76 - 1.87 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.39 (2 H, t, J=5.50 Hz), 3.46 (1 H, br s), 3.50 (2 H, q, J=5.48 Hz), 3.56 - 3.67 (1 H, m), 4.51 (1 H, t, J=5.61 Hz), 4.70 - 4.82 (2 H, m), 5.86 (1 H, d, J=7.67 Hz), 6.63 (1 H, tt, J=54.30, 2.75 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=2.74 Hz), 7.83 (1 H, d, J=8.76 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.88 (1 H, br q, J=4.65 Hz); ESIMS found C 24 H 30 F2N8O2 m / z 501.3 (M + 1).

[0683]

[0684] 5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(cis-4-(2-methoxyethoxy)cyclohexyl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 185.

[0685] White solid (29 mg, 0.056 mmol, 30.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.54 (2 H, m), 1.57 - 1.72 (4 H, m), 1.75 - 1.87 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.27 (3 H, s), 3.43 - 3.47 (3 H, m), 3.47 - 3.52 (2 H, m), 3.56 - 3.68 (1 H, m), 4.71 - 4.84 (2 H, m), 5.90 (1 H, d, J=7.67 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=2.74 Hz), 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.88 (1 H, q, J=4.38 Hz); ESIMS found C 25 H 32 F2N8O2 m / z 515.3 (M+l).

[0686]

[0687] N-(cis-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide 186.

[0688] Off-white solid (17 mg, 0.034 mmol, 74.1% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.49 - 1.58 (2 H, m), 1.58 - 1.69 (4 H, m), 1.71 - 1.79 (2 H, m), 1.81 (3 H, s), 2.62 (3 H, s), 3.12 (3 H, d, J=4.65 Hz), 3.29 - 3.32 (1 H, m), 3.68 (2 H, br s), 4.72 - 4.84 (2 H, m), 5.72 (1 H, d, J=6.57 Hz), 6.63 (1 H, tt, J=54.30, 2.75 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.68 (1 H, br d, J=7.12 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.91 (1 H, q, J=4.38 Hz); ESIMS found C 24 H 29F2N9O m / z 498.3 (M+1).

[0689]

[0690] N-(trans-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclohexyl)acetamide 187.

[0691] Off-white solid (22 mg, 0.044 mmol, 17.1% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.18 - 1.27 (2 H, m), 1.27 - 1.37 (2 H, m), 1.78 (3 H, s), 1.79 - 1.83 (2 H, m), 1.97 (2 H, br d, J=10.68 Hz), 2.62 (3 H, s), 3.10 (3 H, d, J=4.65 Hz), 3.44 - 3.60 (2 H, m), 4.72 - 4.83 (2 H, m), 5.90 (1 H, d, J=8.49 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.72 (1 H, d, J=7.94 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.89 (1 H, q, J=4.65 Hz); ESIMS found C 24 H 29 F2N9O m / z 498.3 (M+1).

[0692]

[0693] Cis-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 188.

[0694] Beige solid (27 mg, 0.057 mmol, 43.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.12 (3H, s), 1.35 (2H, td, J=13.14, 3.83 Hz), 1.57 (2H, br d, J=12.05 Hz), 1.59 - 1.66 (2H, m), 1.66 - 1.72 (2H, m), 2.62 (3H, s), 3.11 (3H, d, J=4.65 Hz), 3.45 - 3.56 (1H, m), 3.98 (1H, s), 4.70 - 4.83 (2H, m), 5.81 (1H, d, J=7.94 Hz), 6.63 (1H, tt, J=54.60, 3.00 Hz), 7.07 (1H, d, J=3.01 Hz), 7.34 (1H, d, J=2.74 Hz), 7.83 (1H, d, J=8.76 Hz), 7.99 (1H, d, J=8.49 Hz), 10.87 (1H, q, J=4.38 Hz); ESIMS found C 23 H 28 F2N8O m / z 471.3 (M+1).

[0695]

[0696] Trans-4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 189.

[0697] Off-white solid (20 mg, 0.043 mmol, 26.3% yield). 1 H NMR (499 MHz, METHANOL-d4) δ ppm 1.28 (3H, s), 1.46 - 1.56 (2H, m), 1.57 - 1.66 (2H, m), 1.69 - 1.77 (2H, m), 2.04 (2H, dq, J=13.18, 4.19 Hz), 2.68 (3H, s), 3.14 - 3.19 (3H, m), 3.70 - 3.80 (1H, m), 4.59 (1H, s), 4.75 (2H, td, J=15.26, 3.15 Hz), 5.49 (1H, s), 6.44 (1H, tt, J=54.60, 3.05 Hz), 7.00 (1H, d, J=3.01 Hz), 7.28 (1H, d, J=2.74 Hz), 7.83 (1H, d, J=8.76 Hz), 7.94 (1H, d, J=8.49 Hz), 10.87 - 10.94 (1H, m); ESIMS found C 23 H 28F2N8 m / z 471.3 (M+1).

[0698]

[0699] N 2 -(adamantan-1-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 196.

[0700] off-white solid (25 mg, 0.062 mmol, 24.0% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.66 (6 H, br s), 2.06 (3 H, br s), 2.09 (6 H, s), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 4.77 (2 H, td, J=15.95, 2.33 Hz), 5.36 (1 H, s), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=2.74 Hz), 7.32 (1 H, d, J=2.74 Hz), 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.84 (1 H, q, J=4.29 Hz) ESIMS m / z 471.3 (M+1). 26 H 30 F2N8 m / z 493.3 (M+1).

[0701]

[0702] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 197.

[0703] white solid (34 mg, 0.074 mmol, 43.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.31 (3H, s), 2.53-2.59 (2H, m), 2.62 (3H, s), 2.91 (1H, t, J=8.08 Hz), 3.12 (3H, d, J=4.65 Hz), 3.11-3.22 (1H, m), 4.22-4.36 (1H, m), 4.78 (2H, td, J=16.20, 2.75 Hz), 5.08-5.26 (1H, m), 6.05 (1H, d, J=8.21 Hz), 6.64 (1H, tt, J=54.60, 3.00 Hz), 7.12 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=3.01 Hz), 7.85 (1H, d, J=8.49 Hz), 8.01 (1H, d, J=8.49 Hz), 10.99 (1H, q, J=4.38 Hz); ESIMS found C 21 H 24 F3N9 m / z 460.25 (M+1).

[0704]

[0705] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 198.

[0706] White solid (41 mg, 0.089 mmol, 59.3% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 2.31 (3H, s), 2.53-2.59 (2H, m), 2.62 (3H, s), 2.91 (1H, t, J=8.08 Hz), 3.12 (3H, d, J=4.65 Hz), 3.11-3.22 (1H, m), 4.22-4.36 (1H, m), 4.78 (2H, td, J=16.20, 2.75 Hz), 5.08-5.26 (1H, m), 6.05 (1H, d, J=8.21 Hz), 6.64 (1H, tt, J=54.60, 3.00 Hz), 7.12 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=3.01 Hz), 7.85 (1H, d, J=8.49 Hz), 8.01 (1H, d, J=8.49 Hz), 10.99 (1H, q, J=4.38 Hz); ESIMS found C 21 H24 F3N9 m / z 460.2 (M+1).

[0707]

[0708] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 199.

[0709] off-white solid (64 mg, 0.128 mmol, 41.5% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1 H NMR (499 MHz, DMSO-d6) δ ppm 2.59-2.66 (1 H, m), 2.62 (3 H, s), 2.74 (1 H, ddd, J=30.45, 12.05, 1.37 Hz), 3.00 (1 H, t, J=8.21 Hz), 3.09-3.24 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.75-3.82 (1 H, m), 4.25-4.39 (1 H, m), 4.46 (2 H, t, J=6.02 Hz), 4.59 (2 H, t, J=6.57 Hz), 4.78 (2 H, td, J=15.95, 2.60 Hz), 5.20 (1 H, dtd, J=55.95, 4.52, 4.52, 1.37 Hz), 6.12 (1 H, d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.86 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.00 (1 H, q, J=4.56 Hz); ESIMS found C 23 H 26 F3N9O m / z 502.3 (M+1).

[0710]

[0711] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-N 4-Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 200.

[0712] Off-white solid (72 mg, 0.144 mmol, 49.9% yield). 1 H NMR(499MHz,DMSO-d6)δppm 2.59-2.66(1H,m),2.62(3H,s),2.74(1H,ddd,J=30.45,12.05,1.37Hz),3.00(1H,t,J=8.21Hz),3.08-3.25(1H,m),3.13( 3H,d,J=4.65Hz), 3.74-3.83(1H,m), 4.24-4.38(1H,m), 4.46(2H,t,J=5.89Hz), 4.59(2H,t,J=6.57Hz), 4.78(2H,td,J=15. 88,2.46Hz),5.20(1H,dtd,J=55.95,4.52,4.52,1.37Hz),6.12(1H,d,J=7.94Hz),6.64(1H,tt,J=54.30,3.00Hz),7.12(1H,d,J=3.01Hz),7.38(1H,d,J=2.74Hz),7.86(1H,d,J=8.76Hz),8.01(1H,d,J=8.49Hz),11.00(1H,q,J=4.47Hz); ESIMS measured C 23 H 26 F3N9O m / z is 502.3 (M+1).

[0713]

[0714] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-(2,2-difluoroethyl)piperidin-4-yl)-N 4- Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 201.

[0715] White solid (43 mg, 0.085 mmol, 53.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.57 (2H, m), 1.87 (2H, br d, J=10.13 Hz), 2.20 - 2.28 (2H, m), 2.62 (3H, s), 2.71 (2H, td, J=15.74, 4.38 Hz), 2.89 (2H, br d, J=11.77 Hz), 3.11 (3H, d, J=4.65 Hz), 3.51 - 3.62 (1H, m), 4.72 - 4.83 (2H, m), 5.98 (1H, d, J=8.21 Hz), 6.13 (1H, tt, J=55.95, 4.35 Hz), 6.63 (1H, tt, J=54.60, 3.00 Hz), 7.08 (1H, d, J=3.01 Hz), 7.36 (1H, d, J=2.74 Hz), 7.84 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.49 Hz), 10.91 (1H, q, J=4.65 Hz); ESIMS found C 23 H 27 F4N9 m / z 506.3 (M + 1).

[0716]

[0717] 1-(4-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one 202.

[0718] Off-white solid (20 mg, 0.041 mmol, 15.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.78 - 1.86 (1 H, m), 1.87 - 1.97 (1 H, m), 2.35 - 2.42 (1 H, m), 2.42 - 2.48 (1 H, m), 2.50 (3 H, s), 3.12 (3 H, s), 3.17 - 3.27 (1 H, m), 3.61 (3 H, d, J=4.93 Hz), 4.11 (1 H, dtd, J=13.21, 6.54, 6.54, 3.83 Hz), 4.26 - 4.34 (2 H, m), 4.77 (1 H, br d, J=14.24 Hz), 5.27 (2 H, td, J=15.88, 2.46 Hz), 6.60 (1 H, d, J=8.21 Hz), 7.13 (1 H, tt, J=54.30, 3.00 Hz), 7.59 (1 H, d, J=2.74 Hz), 7.87 (1 H, d, J=3.01 Hz), 8.34 (1 H, d, J=8.76 Hz), 8.50 (1 H, d, J=8.49 Hz), 11.42 (1 H, q, J=4.29 Hz); ESIMS found C 23 H 27 F2N9O m / z 484.3 (M + 1).

[0719]

[0720] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4- methyl-N 2 -(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 203.

[0721] Off-white solid (51 mg, 0.103 mmol, 49.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.57 (2H, m), 1.81 - 1.87 (2H, m), 1.89 (2H, br d, J=11.23 Hz), 2.62 (3H, s), 2.67 (2H, br d, J=10.95 Hz), 3.11 (3H, d, J=4.65 Hz), 3.35 - 3.41 (1H, m), 3.52 - 3.64 (1H, m), 4.42 (2H, t, J=6.02 Hz), 4.52 (2H, t, J=6.43 Hz), 4.71 - 4.83 (2H, m), 6.00 (1H, d, J=8.21 Hz), 6.63 (1H, tt, J=54.45, 3.00 Hz), 7.08 (1H, d, J=3.01 Hz), 7.36 (1H, d, J=2.74 Hz), 7.84 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.49 Hz), 10.91 (1H, br q, J=4.70 Hz); ESIMS found C 24 H 29 F2N9O m / z 498.3 (M + 1).

[0722]

[0723] 5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 204.

[0724] White solid (35 mg, 0.074 mmol, 38.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.68 (1 H, br dd, J=12.59, 3.01 Hz), 1.87 (1 H, qd, J=12.23, 3.56 Hz), 2.00 - 2.07 (1 H, m), 2.10 - 2.22 (1 H, m), 2.18 (3 H, s), 2.79 (1 H, br d, J=10.95 Hz), 3.04 (1 H, br t, J=10.95 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.66 - 3.82 (1 H, m), 4.78 (2 H, td, J=15.90, 2.20 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.87 (1 H, d, J=7.94 Hz), 6.64 (1 H, tt, J=54.60, 2.75 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.65 Hz); ESIMS found C 22 H 26 F3N9 m / z 474.25 (M+1).

[0725]

[0726] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 205.

[0727] White solid (40 mg, 0.085 mmol, 44.0% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 1.64 - 1.72 (1 H, m), 1.87 (1 H, qd, J=12.23, 3.83 Hz), 2.04 (1 H, br t, J=10.95 Hz), 2.10 - 2.22 (1 H, m), 2.18 (3 H, s), 2.62 (3 H, s), 2.79 (1 H, br d, J=10.40 Hz), 3.04 (1 H, br t, J=11.23 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.66 - 3.81 (1 H, m), 4.73 - 4.81 (2 H, m), 4.88 (1 H, d, J=49.65 Hz), 5.87 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 2.75 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.76 Hz), 10.97 (1 H, q, J=4.65 Hz); ESIMS found C 22 H 26 F3N9 m / z 474.3 (M+1).

[0728]

[0729] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 210.

[0730] White solid (64 mg, 0.124 mmol, 55.4% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.67 - 1.76 (1 H, m), 1.81 - 1.91 (1 H, m), 1.95 - 2.03 (1 H, m), 2.06 - 2.20 (1 H, m), 2.62 (3 H, s), 2.75 (1 H, br d, J=9.58 Hz), 2.92 - 3.02 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.72

[0731] -3.89 (1H, m), 4.43 (2H, dt, J = 29.30, 6.16 Hz), 4.54 (2H, td, J = 6.50, 3.15 Hz), 4.72-4.83 (2H, m), 4.90 (1H, d, J = 49.90 Hz), 5.95 (1H, d, J = 8.21 Hz), 6.64 (1H, tt, J = 54.30, 3.00 Hz), 7.10 (1H, d, J = 3.01 Hz), 7.36 (1H, d, J = 2.74 Hz), 7.85 (1H, d, J = 8.49 Hz), 8.00 (1H, d, J = 8.49 Hz), 10.97 (1H, q, J = 4.38 Hz); ESIMS found C 24 H 28 F3N9O m / z 516.3 (M + 1).

[0732]

[0733] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4R)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 211.

[0734] pale yellow solid (22 mg, 0.043 mmol, 65.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.57 (1 H, m), 1.94 (1 H, td, J=11.57, 2.05 Hz), 2.00 (2 H, td, J=9.65, 5.34 Hz), 2.62 (3 H, s), 2.62 - 2.67 (1 H, m), 2.98 - 3.06 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.51 (1 H, quin, J=6.30 Hz), 3.78 - 3.91 (1 H, m), 4.42 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.50 - 4.66 (1 H, m), 4.54 (2 H, t, J=6.60 Hz), 4.78 (2 H, td, J=16.20, 2.75 Hz), 6.32 (1 H, d, J=8.76 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.09 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.96 (1 H, q, J=4.56 Hz); ESIMS found C 24 H 28 F3N9O m / z 516.3 (M + 1).

[0735]

[0736] 5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4- Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 212.

[0737] Light yellow solid (23 mg, 0.045 mmol, 66.1 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.45 - 1.57 (1 H, m), 1.91 - 1.96 (1 H, m), 2.00 (2 H, td, J=9.58, 5.48 Hz), 2.60 - 2.67 (1 H, m), 2.62 (3 H, s), 2.98 - 3.05 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.51 (1 H, quin, J=6.30 Hz), 3.78 - 3.91 (1 H, m), 4.42 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.50 - 4.66 (1 H, m), 4.54 (2 H, t, J=6.57 Hz), 4.78 (2 H, td, J=15.81, 2.60 Hz), 6.32 (1 H, d, J=8.76 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.09 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.96 (1 H, q, J=4.65 Hz); ESIMS found C 24 H 28 F3N9O m / z 516.3 (M + 1).

[0738]

[0739] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 213.

[0740] White solid (48 mg, 0.093 mmol, 44.1 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 - 1.76 (1 H, m), 1.87 (1 H, qd, J=12.09, 3.42 Hz), 1.96 - 2.05 (1 H, m), 2.06 - 2.22 (1 H, m), 2.62 (3 H, s), 2.75 (1 H, br d, J=10.40 Hz), 2.97 (1 H, br t, J=10.27 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.48 (1 H, quin, J=6.37 Hz), 3.71 - 3.89 (1 H, m), 4.43 (2 H, dt, J=29.35, 6.16 Hz), 4.54 (2 H, td, J=6.50, 3.15 Hz), 4.72 - 4.82 (2 H, m), 4.90 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.47 Hz); ESIMS found C 24 H 28 F3N9O m / z 516.3 (M + 1).

[0741]

[0742] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 214.

[0743] Yellow solid (7 mg, 0.014 mmol, 32.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.89 (2 H, m), 2.11 - 2.21 (1 H, m), 2.26 (3 H, br s), 2.32 - 2.46 (1 H, m), 2.62 (3 H, s), 2.74 - 2.84 (1 H, m), 2.98 - 3.10 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.16 - 4.31 (1 H, m), 4.73 - 4.84 (2 H, m), 6.12 (1 H, br d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.99 (1 H, q, J=4.47 Hz); ESIMS found C 22 H 25 F4N9 m / z 492.3 (M+1).

[0744]

[0745] (S)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 215.

[0746] Yellow solid (8 mg, 0.016 mmol, 37.0% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.89 (2 H, m), 2.11 - 2.21 (1 H, m), 2.26 (3 H, br s), 2.32 - 2.46 (1 H, m), 2.62 (3 H, s), 2.74 - 2.84 (1 H, m), 2.98 - 3.10 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.18 - 4.34 (1 H, m), 4.78 (2 H, td, J=15.74, 2.19 Hz), 6.13 (1 H, br d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.00 (1 H, q, J=4.56 Hz); ESIMS found C22 H 25 F4N9 m / z 492.3 (M+1).

[0747]

[0748] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)-N 4 - methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 216.

[0749] Yellow solid (12 mg, 0.023 mmol, 27.2% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.82 (1 H, m), 1.88 (1 H, br dd, J = 9.03, 4.38 Hz), 2.14 (1 H, br t, J = 10.54 Hz), 2.32 - 2.44 (1 H, m), 2.62 (3 H, s), 2.74 (1 H, br d, J = 11.77 Hz), 2.95 - 3.06 (1 H, m), 3.14 (3 H, d, J = 4.65 Hz), 3.60 (1 H, quin, J = 6.30 Hz), 4.22 - 4.36 (1 H, m), 4.44 (2 H, dt, J = 14.24, 6.30 Hz), 4.55 (2 H, td, J = 6.64, 3.42 Hz), 4.73 - 4.85 (2 H, m), 6.19 (1 H, d, J = 9.58 Hz), 6.64 (1 H, tt, J = 54.30, 3.00 Hz), 7.11 (1 H, d, J = 2.74 Hz), 7.37 (1 H, d, J = 2.74 Hz), 7.85 (1 H, d, J = 8.49 Hz), 8.01 (1 H, d, J = 8.49 Hz), 11.00 (1 H, q, J = 4.47 Hz); ESIMS found C 24 H 27 F4N9O m / z 534.3 (M+1).

[0750]

[0751] (S)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo [2, 1-f] [1, 2, 4] triazine-2, 4-diamine 217.

[0752] Yellow solid (11 mg, 0.021 mmol, 29.7% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.82 (1 H, m), 1.88 (1 H, br dd, J = 9.17, 4.52 Hz), 2.14 (1 H, br t, J = 10.68 Hz), 2.32 - 2.44 (1 H, m), 2.62 (3 H, s), 2.75 (1 H, br d, J = 11.50 Hz), 2.95 - 3.05 (1 H, m), 3.14 (3 H, d, J = 4.93 Hz), 3.60 (1 H, quin, J = 6.30 Hz), 4.21 - 4.36 (1 H, m), 4.44 (2 H, dt, J = 14.31, 6.26 Hz), 4.55 (2 H, td, J = 6.64, 3.42 Hz), 4.72 - 4.85 (2 H, m), 6.19 (1 H, d, J = 9.58 Hz), 6.64 (1 H, tt, J = 54.30, 3.00 Hz), 7.11 (1 H, d, J = 3.01 Hz), 7.37 (1 H, d, J = 2.74 Hz), 7.85 (1 H, d, J = 8.76 Hz), 8.01 (1 H, d, J = 8.49 Hz), 11.00 (1 H, q, J = 4.75 Hz); ESIMS found C 24 H 27 F4N9O m / z 534.3 (M + 1).

[0753]

[0754] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 - methyl-N 2 -(4-methyltetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 218.

[0755] White solid (4.0 mg, 0.009 mmol, 4.1% yield). 1H NMR(499MHz,DMSO-d6)δppm 1.43(3H,s),1.54-1.65(2H,m),2.26(2H,br d,J=13.69Hz),2.62(3H,s),3.12(3H,d,J=4.65Hz),3.55-3.60(2H,m) ,3.61-3.66(2H,m),4.72-4.83(2H,m),5.61(1H,s),6.64(1H,tt,J=54 C 22 H 26 F2N8O m / z is 457.2 (M+1).

[0756]

[0757] N 2 -((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4- Methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 219.

[0758] Off-white solid (65 mg, 0.148 mmol, 61.4% yield). 1 H NMR(499MHz,DMSO-d6)δppm 1.64(2H,br d,J=7.12Hz),2.62(3H,s),2.88-2.92(1H,m),2.92-2.97(2H,m),2.99-3 .04(2H,m),3.11(3H,d,J=4.65Hz),4.71-4.83(2H,m),6.04(1H,d,J=4.1 1Hz),6.63(1H,tt,J=54.30,3.00Hz),7.10(1H,d,J=2.74Hz),7.39(1H,d ,J=2.46Hz),7.85(1H,d,J=8.49Hz),8.00(1H,d,J=8.49Hz),10.93(1H,br q, J=4.65Hz); C measured by ESIMS 21 H 23 F2N9 m / z is 440.2 (M+1).

[0759]

[0760] 1-((1R,5S,6r)-6-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-azabicyclo[3.1.0]hex-3-yl)ethan-1- one 220.

[0761] Off-white solid (24 mg, 0.050 mmol, 73.0% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.83 (3H, s), 1.84 - 1.88 (1H, m), 1.89 - 1.95 (1H, m), 2.62 (3H, s), 2.69 (1H, td, J=6.91, 1.23 Hz), 3.12 (3H, d, J=4.65 Hz), 3.40 - 3.49 (2H, m), 3.54 (1H, d, J=10.40 Hz), 3.67 (1H, dd, J=10.40, 5.48 Hz), 4.72 - 4.83 (2H, m), 6.23 (1H, s), 6.63 (1H, tt, J=54.30, 3.00 Hz), 7.11 (1H, d, J=3.01 Hz), 7.40 (1H, d, J=2.74 Hz), 7.85 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 10.94 (1H, q, J=4.56 Hz); ESIMS found C 23 H 25 F2N9O m / z 482.2 (M+l).

[0762]

[0763] N 2 -((1R,5S,6r)-3-oxabicyclo[3.1.0]hex-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 221.

[0764] Off-white solid (12 mg, 0.027 mmol, 14.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.81 (2H, s), 2.40 (1H, q, J=2.46 Hz), 2.62 (3H, s), 3.10 (3H, d, J=4.65 Hz), 3.64 (2H, d, J=8.21 Hz), 3.86 (2H, d, J=8.21 Hz), 4.77 (2H, td, J=15.95, 2.33 Hz), 6.42 (1H, d, J=3.29 Hz), 6.63 (1H, tt, J=54.30, 3.00 Hz), 7.10 (1H, d, J=2.74 Hz), 7.39 (1H, d, J=3.01 Hz), 7.85 (1H, d, J=8.49 Hz), 8.00 (1H, d, J=8.49 Hz), 10.93 (1H, q, J=4.56 Hz); ESIMS found C 21 H 22 F2N8O m / z 441.2 (M+1).

[0765]

[0766] N 2 -((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 222.

[0767] Off-white solid (38 mg, 0.086 mmol, 32.6% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.96 (2H, br d, J=6.57 Hz), 2.62 (3H, s), 2.91 (1H, td, J=6.84, 4.11 Hz), 3.12 (3H, d, J=4.65 Hz), 3.81-3.88 (4H, m), 4.72-4.83 (2H, m), 5.64 (1H, d, J=4.11 Hz), 6.64 (1H, tt, J=54.18, 2.75 Hz), 7.10 (1H, d, J=3.01 Hz), 7.39 (1H, d, J=3.01 Hz), 7.85 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.49 Hz), 10.94 (1H, q, J=4.65 Hz); ESIMS found C 21 H 22 F2N8O m / z 441.1 (M+1).

[0768]

[0769] 1-(2-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-7-azaspiro[3.5]non-7-yl)ethan-1- one223.

[0770] Off-white solid (45 mg, 0.086 mmol, 90.0% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.40 - 1.45 (1 H, m), 1.46 - 1.54 (2 H, m), 1.55 - 1.61 (1 H, m), 1.76 (2 H, br t, J = 8.76 Hz), 1.97 (3 H, d, J = 8.76 Hz), 2.23 (2 H, br dd, J = 9.58, 8.21 Hz), 2.62 (3 H, s), 3.11 (3 H, d, J = 4.65 Hz), 3.26 - 3.31 (2 H, m), 3.36 - 3.44 (2 H, m), 4.13 - 4.25 (1 H, m), 4.72 - 4.83 (2 H, m), 6.40 (1 H, t, J = 7.26 Hz), 6.63 (1 H, tt, J = 54.30, 3.00 Hz), 7.08 (1 H, d, J = 3.01 Hz), 7.36 (1 H, d, J = 3.01 Hz), 7.84 (1 H, d, J = 8.49 Hz), 8.00 (1 H, d, J = 8.49 Hz), 10.91 (1 H, q, J = 4.47 Hz); ESIMS found C 26 H 31 F2N9O m / z 524.3 (M + 1).

[0771]

[0772] 1-(7-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-2-azaspiro[3.5]non-2-yl)ethan-1- one224.

[0773] Off-white solid (48 mg, 0.092 mmol, 84.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.94 (4H, d, J=6.57 Hz), 1.22 - 1.38 (2H, m), 1.46 - 1.59 (2H, m), 1.75 (3H, d, J=9.03 Hz), 1.82 - 1.92 (4H, m), 2.62 (3H, s), 3.11 (3H, d, J=4.11 Hz), 3.46 (1H, s), 3.51 (1H, s), 3.55 (1H, br d, J=8.49 Hz), 3.74 (1H, s), 3.79 (1H, s), 4.77 (2H, td, J=15.95, 2.33 Hz), 5.88 (1H, dd, J=19.16, 8.21 Hz), 6.63 (1H, tt, J=54.30, 3.00 Hz), 7.08 (1H, d, J=3.01 Hz), 7.36 (1H, t, J=2.74 Hz), 7.81 - 7.86 (1H, m), 8.00 (1H, d, J=8.49 Hz), 10.87 - 10.93 (1H, m); ESIMS found C 26 H 31 F2N9O m / z 524.3 (M + 1).

[0774]

[0775]

[0776] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(2-oxaspiro[3.5]non-7-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 225.

[0777] White solid (31 mg, 0.064 mmol, 20.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.17 - 1.30 (2H, m), 1.51 (2H, td, J=12.94, 3.42 Hz), 1.85 (2H, br dd, J=12.87, 3.01 Hz), 2.05 (2H, br d, J=13.14 Hz), 2.62 (3H, s), 3.10 (3H, d, J=4.65 Hz), 3.47 - 3.59 (1H, m), 4.23 (2H, s), 4.31 (2H, s), 4.77 (2H, td, J=15.81, 2.05 Hz), 5.86 (1H, d, J=8.21 Hz), 6.63 (1H, tt, J=54.30, 3.00 Hz), 7.07 (1H, d, J=3.01 Hz), 7.35 (1H, d, J=3.01 Hz), 7.83 (1H, d, J=8.76 Hz), 7.99 (1H, d, J=8.49 Hz), 10.89 (1H, q, J=4.29 Hz); ESIMS found C 24 H 28 F2N8O m / z 483.3 (M + 1).

[0778]

[0779] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -((4r,7r)-1-oxaspiro[3.5]non-7-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 226.

[0780] Off-white solid (15.6 mg, 0.032 mmol, 10.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (3H, td, J=12.53, 3.30 Hz), 1.85 - 1.95 (2H, m), 2.04 (2H, br d, J=12.23 Hz), 2.31 - 2.37 (3H, m), 2.62 (3H, s), 3.11 (3H, d, J=4.52 Hz), 3.49 - 3.62 (2H, m), 4.37 (2H, t, J=7.70 Hz), 4.69 - 4.86 (2H, m), 5.90 (1H, br d, J=8.07 Hz), 6.63 (1H, tt, J=54.30, 3.00 Hz), 7.08 (1H, d, J=2.93 Hz), 7.37 (1H, d, J=2.81 Hz), 7.84 (1H, d, J=8.68 Hz), 8.00 (1H, d, J=8.44 Hz), 10.89 (1H, q, J=3.99 Hz); ESIMS found C 24 H 28 F2N8O m / z 483.1 (M + 1).

[0781]

[0782] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -((4s,7s)-1-oxaspiro[3.5]non-7-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 227.

[0783] Off-white solid (8.77 mg, 0.018 mmol, 5.7% yield). 1H NMR (400 MHz, DMSO-c / 6) δ ppm 1.88 - 2.02 (2 H, m), 2.03 - 2.18 (1 H, m), 2.10 (3 H, br t, J=6.72 Hz), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.43 - 3.55 (2 H, m), 3.70 - 3.84 (1 H, m), 4.40 (1 H, t, J=5.32 Hz), 4.77 (2 H, td, J=15.93, 2.14 Hz), 5.36 (1 H, br s), 5.91 (1 H, d, J=8.31 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.06 Hz), 7.36 (1 H, d, J=2.93 Hz), 7.84 (1 H, d, J=8.68 Hz), 8.00 (1 H, d, J=8.56 Hz), 10.90 (1 H, q, J=4.28 Hz); ESIMS found C 24 H 28 F2N8O m / z 483.1 (M + 1).

[0784]

[0785] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(3-methyl-3-azabicyclo[3.2.1]octan-8-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 228.

[0786] White solid (25.0 mg, 0.052 mmol, 24.5% yield). 1 H NMR (499 MHz, DMSO-c / 6) δ ppm 1.54 - 1.67 (4 H, m), 1.75 (2 H, br s), 1.94 - 2.02 (2 H, m), 2.24 (3 H, br s), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.12 - 3.16 (2 H, m), 3.88 - 4.01 (1 H, m), 4.71 - 4.83 (2 H, m), 5.88 (1 H, br d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.33 (1 H, d, J=2.74 Hz), 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.76 Hz), 10.86 - 10.94 (1 H, m); ESIMS found C24 H 29 F2N9 m / z 482.3 (M+1).

[0787]

[0788] (R)-N 2 -(3,3-difluoropiperidin-4-yl)-N 4 -methyl-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 339.

[0789] Yellow solid (38 mg, 0.095 mmol, 86.4% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.66 (1H, qd, J=11.82, 4.24 Hz), 1.78 - 1.89 (1H, m), 2.57 (1H, br t, J=11.50 Hz), 2.78 (1H, dd, J=29.30, 13.70 Hz), 2.91 (1H, br d, J=13.42 Hz), 3.06 - 3.12 (1H, m), 3.13 (3H, d, J=4.65 Hz), 4.24 - 4.41 (1H, m), 6.35 (1H, d, J=9.58 Hz), 6.68 - 6.74 (1H, m), 7.33 (1H, d, J=3.01 Hz), 7.43 (1H, d, J=3.01 Hz), 7.56 (1H, d, J=7.67 Hz), 8.17 (1H, d, J=2.19 Hz), 9.00 - 9.08 (1H, m), 11.52 (1H, q, J=4.56 Hz); ESIMS found C 18 H 19 F2N9 m / z 400.2 (M+1).

[0790]

[0791] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 351.

[0792] Yellowish white solid (6 mg, 0.012 mmol, 20.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.82 (1 H, m), 1.83 - 1.91 (1 H, m), 2.09 - 2.22 (1 H, m), 2.37 (1 H, dd, J=27.05, 11.85 Hz), 2.74 (1 H, br d, J=11.77 Hz), 2.94 - 3.04 (1 H, m), 3.10 (3 H, d, J=4.65 Hz), 3.59 (1 H, quin, J=6.30 Hz), 4.21 - 4.36 (1 H, m), 4.44 (2 H, dt, J=14.24, 6.16 Hz), 4.55 (2 H, td, J=6.57, 3.29 Hz), 4.89 (2 H, td, J=16.08, 2.60 Hz), 6.17 (1 H, d, J=9.58 Hz), 6.49 (1 H, tt, J=54.30, 3.00 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.94 (1 H, d, J=8.76 Hz), 8.18 (1 H, d, J=8.76 Hz), 8.48 (1 H, s), 12.24 (1 H, q, J=4.29 Hz); ESIMS found C 23 H 25 F4N9O m / z 520.2 (M + 1).

[0793]

[0794] 2-(trans-3-((5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)cyclobutyl)propan-2-ol 355.

[0795] Brown solid (33 mg, 0.070 mmol, 35.3% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 1.04 (6 H, s), 1.88 - 1.98 (2 H, m), 2.15 - 2.23 (1 H, m), 2.24 - 2.33 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 4.08 (1 H, dq, J=14.03, 7.00 Hz), 4.14 (1 H, s), 4.72 - 4.83 (2 H, m), 6.33 (1 H, d, J=7.12 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=3.01 Hz), 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.88 (1 H, q, J=4.56 Hz); ESIMS found C 23 H 28 F2N8O m / z 471.3 (M+1).

[0796]

[0797] (S)-N 2 -(4,4-difluoro-1-methylpyrrolidin-3-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 363.

[0798] off-white solid (29 mg, 0.061 mmol, 38.2% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.04 (6 H, s), 1.88 - 1.98 (2 H, m), 2.15 - 2.23 (1 H, m), 2.24 - 2.33 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 4.08 (1 H, dq, J=14.03, 7.00 Hz), 4.14 (1 H, s), 4.72 - 4.83 (2 H, m), 6.33 (1 H, d, J=7.12 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.07 (1 H, d, J=3.01 Hz), 7.35 (1 H, d, J=3.01 Hz), 7.83 (1 H, d, J=8.49 Hz), 7.99 (1 H, d, J=8.49 Hz), 10.88 (1 H, q, J=4.56 Hz); ESIMS found C 21 H 23 F4N9 m / z 478.2 (M+1).

[0799]

[0800] (R)-N 2 -(4,4-difluoro-l-methylpyrrolidin-3-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- Methylpyrrolo[2,l-f][l,2,4]triazine-2,4-diamine 364.

[0801] Off-white solid (19 mg, 0.040 mmol, 37.6% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 2.27 (3H, s), 2.39 (1H, t, J=9.03 Hz), 2.52-2.61 (1H, m), 2.62 (3H, s), 3.13 (3H, d, J=4.65 Hz), 3.18-3.26 (2H, m), 4.55-4.68 (1H, m), 4.78 (2H, td, J=16.02, 2.74 Hz), 6.39 (1H, d, J=9.31 Hz), 6.64 (1H, tt, J=54.30, 3.00 Hz), 7.13 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=2.74 Hz), 7.86 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 11.02 (1H, q, J=4.47 Hz); ESIMS found C 21 H 23 F4N9 m / z 478.2 (M+l).

[0802]

[0803] (S)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(l-ethyl-4,4-difluoropyrrolidin-3-yl)-N 4- Methylpyrrolo[2,l-f][l,2,4]triazine-2,4-diamine 365.

[0804] Light yellow fluffy solid (12 mg, 0.024 mmol, 15.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.03 (3H, t, J=7.26 Hz), 2.35 - 2.41 (1H, m), 2.41 - 2.48 (2H, m), 2.56 (1H, ddd, J=18.69, 15.40, 11.09 Hz), 2.62 (3H, s), 3.13 (3H, d, J=4.65 Hz), 3.27 (2H, br t, J=8.62 Hz), 4.60 (1H, dt, J=15.19, 7.73 Hz), 4.78 (2H, td, J=16.08, 2.60 Hz), 6.38 (1H, d, J=9.03 Hz), 6.64 (1H, tt, J=54.30, 3.00 Hz), 7.13 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=3.01 Hz), 7.86 (1H, d, J=8.49 Hz), 8.01 (1H, d, J=8.49 Hz), 11.02 (1H, q, J=4.65 Hz); ESIMS found C 22 H 25 F4N9 m / z 492.2 (M + 1).

[0805]

[0806] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-ethyl-4,4-difluoropyrrolidin-3-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 366.

[0807] pale yellow solid (11 mg, 0.022 mmol, 33.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.03 (3H, t, J=7.12 Hz), 2.35 - 2.41 (1H, m), 2.41 - 2.48 (2H, m), 2.51 - 2.61 (1H, m), 2.62 (3H, s), 3.13 (3H, d, J=4.65 Hz), 3.27 (2H, br t, J=8.62 Hz), 4.53 - 4.68 (1H, m), 4.78 (2H, td, J=16.02, 2.46 Hz), 6.38 (1H, d, J=9.03 Hz), 6.64 (1H, tt, J=54.30, 3.00 Hz), 7.13 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=3.01 Hz), 7.86 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 11.02 (1H, q, J=4.75 Hz); ESIMS found C 22 H 25 F4N9 m / z 492.2 (M+1).

[0808]

[0809] (S)-N 2 -(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(3-(2,2-difluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 367.

[0810] Yellow solid (5 mg, 0.010 mmol, 9.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.44 - 2.49 (1 H, m), 2.63 (3 H, s), 2.65 - 2.75 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 3.27 (2 H, br t, J=8.76 Hz), 3.68 (1 H, quin, J=6.09 Hz), 4.46 - 4.52 (2 H, m), 4.58 (2 H, q, J=6.84 Hz), 4.61 - 4.71 (1 H, m), 4.78 (2 H, td, J=15.95, 2.60 Hz), 6.43 (1 H, d, J=9.31 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.86 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.03 (1 H, q, J=4.56 Hz); ESIMS found C 23 H 25 F4N9O m / z 520.2 (M+1).

[0811]

[0812] (R)-N 2 -(4,4-difluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(3-(2,2-difluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 368.

[0813] Light orange solid (6 mg, 0.012 mmol, 7.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.45 - 2.49 (1 H, m), 2.63 (3 H, s), 2.65 - 2.75 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 3.22 - 3.30 (2 H, m), 3.68 (1 H, quin, J=6.02 Hz), 4.46 - 4.53 (2 H, m), 4.58 (2 H, q, J=6.75 Hz), 4.61 - 4.71 (1 H, m), 4.79 (2 H, td, J=15.88, 2.74 Hz), 6.43 (1 H, d, J=9.03 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.86 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.03 (1 H, q, J=4.65 Hz); ESIMS found C 23 H 25 F4N9O m / z 520.2 (M + 1).

[0814]

[0815] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-(2-fluoroethyl)piperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 369.

[0816] pale yellow fluffy solid (29 mg, 0.060 mmol, 79.6 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.50 (2 H, qd, J=11.73, 3.42 Hz), 1.83 - 1.93 (2 H, m), 2.04 - 2.15 (2 H, m), 2.60 (2 H, dt, J=28.25, 4.93 Hz), 2.62 (3 H, s), 2.87 (2 H, br d, J=11.77 Hz), 3.11 (3 H, d, J=4.65 Hz), 3.50 - 3.62 (1 H, m), 4.52 (2 H, dt, J=48.00, 4.95 Hz), 4.77 (2 H, td, J=16.02, 2.74 Hz), 5.96 (1 H, d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.90 (1 H, q, J=4.56 Hz); ESIMS found C 23 H 28 F3N9 m / z 488.3 (M+1).

[0817]

[0818] 5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 370.

[0819] Light yellow fluffy solid (2 mg, 0.004 mmol, 5.1 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.44 - 1.60 (2 H, m), 1.83 - 1.92 (2 H, m), 2.42 (2 H, br t, J=10.54 Hz), 2.62 (3 H, s), 2.92 (2 H, br d, J=12.05 Hz), 3.11 (3 H, d, J=4.65 Hz), 3.15 (2 H, q, J=10.15 Hz), 3.53 - 3.62 (1 H, m), 4.69 - 4.85 (2 H, m), 5.99 (1 H, d, J=7.94 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.84 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.91 (1 H, q, J=4.80 Hz); ESIMS found C 23 H 26 F5N9 m / z 524.3 (M + 1).

[0820]

[0821] N 2 -(1-(3,3-difluorocyclobutyl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 371.

[0822] pale yellow solid (5 mg, 0.009 mmol, 5.9% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.43 - 1.55 (2 H, m), 1.84 - 1.94 (4 H, m), 2.31 - 2.44 (2 H, m), 2.62 (3 H, s), 2.63 - 2.72 (3 H, m), 2.78 (2 H, br d, J=10.95 Hz), 3.11 (3 H, d, J=4.65 Hz), 3.51 - 3.65 (1 H, m), 4.71 - 4.83 (2 H, m), 6.00 (1 H, d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=2.74 Hz), 7.36 (1 H, d, J=2.74 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.91 (1 H, q, J=4.38 Hz); ESIMS found C 25 H29 F4N9 m / z 532.3 (M+1).

[0823]

[0824] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 372.

[0825] pale yellow fluffy solid (4 mg, 0.008 mmol, 12.6% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.00 (3H, t, J=7.12 Hz), 1.64 - 1.74 (1H, m), 1.85 (1H, qd, J=12.27, 3.97 Hz), 1.98 - 2.08 (1H, m), 2.17 (1H, dd, J=38.15, 12.32 Hz), 2.36 (2H, q, J=7.21 Hz), 2.62 (3H, s), 2.88 (1H, br d, J=11.50 Hz), 3.09 - 3.16 (1H, m), 3.12 (3H, d, J=4.65 Hz), 3.67 - 3.87 (1H, m), 4.78 (2H, td, J=15.81, 2.33 Hz), 4.89 (1H, d, J=50.50 Hz), 5.87 (1H, d, J=8.21 Hz), 6.64 (1H, tt, J=54.30, 3.00 Hz), 7.10 (1H, d, J=3.01 Hz), 7.37 (1H, d, J=3.01 Hz), 7.85 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 10.97 (1H, q, J=4.38 Hz); ESIMS found C 23 H 28 F3N9 m / z 488.3 (M+1).

[0826]

[0827] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-1-ethyl-3-fluoropiperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 373.

[0828] Light yellow fluffy solid (6 mg, 0.012 mmol, 18.8% yield). 1 H NMR (499 MHz, DMSO-d6) ppm 1.00 (3 H, t, J=7.12 Hz), 1.64 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.42 Hz), 1.99 - 2.08 (1 H, m), 2.17 (1 H, dd, J=37.85, 12.59 Hz), 2.36 (2 H, q, J=7.12 Hz), 2.62 (3 H, s), 2.88 (1 H, br d, J=10.95 Hz), 3.08 - 3.16 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.68 - 3.85 (1 H, m), 4.78 (2 H, td, J=15.95, 2.33 Hz), 4.89 (1 H, d, J=50.50 Hz), 5.87 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.10 (1 H, d, J=2.74 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.47 Hz); ESIMS found C 23 H 28 F3N9 m / z 488.3 (M+1).

[0829]

[0830] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3S,4R)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 374.

[0831] Light yellow fluffy solid (29 mg, 0.057 mmol, 87.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.63 - 1.74 (1 H, m), 1.82 - 1.93 (1 H, m), 2.23 (1 H, br t, J=11.09 Hz), 2.37 (1 H, dd, J=37.85, 12.60 Hz), 2.62 (3 H, s), 2.63 - 2.73 (2 H, m), 2.92 (1 H, br d, J=10.95 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.17 (1 H, br t, J=10.54 Hz), 3.70 - 3.88 (1 H, m), 4.54 (2 H, dt, J=47.70, 4.93 Hz), 4.78 (2 H, td, J=16.08, 2.60 Hz), 4.89 (1 H, d, J=49.90 Hz), 5.91 (1 H, br d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.38 Hz); ESIMS found C 23 H 27 F4N9 m / z 506.25 (M+1).

[0832]

[0833] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(2-fluoroethyl)piperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 375.

[0834] White solid (28 mg, 0.055 mmol, 84.8 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.63 - 1.73 (1 H, m), 1.87 (1 H, qd, J=12.27, 3.42 Hz), 2.23 (1 H, br t, J=11.09 Hz), 2.37 (1 H, dd, J=37.85, 12.90 Hz), 2.62 (3 H, s), 2.67 (2 H, dt, J=28.50, 4.95 Hz), 2.92 (1 H, br d, J=11.50 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.13 - 3.20 (1 H, m), 3.69 - 3.87 (1 H, m), 4.54 (2 H, dt, J=48.00, 4.95 Hz), 4.78 (2 H, td, J=15.74, 2.46 Hz), 4.89 (1 H, d, J=50.15 Hz), 5.90 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.29 Hz); ESIMS found C 23 H 27 F4N9 m / z 506.3 (M + 1).

[0835]

[0836] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-isopropylpiperidin-4-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 376.

[0837] Light yellow fluffy solid (25 mg, 0.050 mmol, 76.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.96 (3H, d, J=5.20 Hz), 0.98 (3H, d, J=5.20 Hz), 1.66 - 1.73 (1H, m), 1.81 (1H, qd, J=11.96, 3.83 Hz), 2.25 (1H, br t, J=10.95 Hz), 2.39 (1H, dd, J=37.05, 12.35 Hz), 2.62 (3H, s), 2.73 (1H, dt, J=13.07, 6.47 Hz), 2.77 - 2.82 (1H, m), 3.01 - 3.08 (1H, m), 3.12 (3H, d, J=4.65 Hz), 3.67 - 3.83 (1H, m), 4.78 (2H, td, J=15.95, 2.60 Hz), 4.88 (1H, d, J=50.15 Hz), 5.85 (1H, d, J=8.21 Hz), 6.64 (1H, tt, J=54.30, 3.00 Hz), 7.10 (1H, d, J=3.01 Hz), 7.36 (1H, d, J=3.01 Hz), 7.85 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.76 Hz), 10.97 (1H, q, J=4.38 Hz); ESIMS found C 24 H 30 F3N9 m / z 502.3 (M+1).

[0838]

[0839] N 2 -((3S,4R)-1-cyclopropyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 377.

[0840] pale yellow fluffy solid (14 mg, 0.028 mmol, 42.9 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.20 - 0.29 (1 H, m), 0.30 - 0.37 (1 H, m), 0.39 - 0.49 (2 H, m), 1.61 - 1.72 (2 H, m), 1.79 (1 H, qd, J=12.32, 3.83 Hz), 2.37 (1 H, dd, J=45.80, 13.15 Hz), 2.33 - 2.38 (1 H, m), 2.62 (3 H, s), 2.95 (1 H, br d, J=1 1.77 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.14 - 3.24 (1 H, m), 3.70 - 3.88 (1 H, m), 4.78 (2 H, td, J=16.08, 2.60 Hz), 4.87 (1 H, d, J=50.20 Hz), 5.87 (1 H, br d, J=7.94 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.1 1 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, q, J=4.56 Hz); ESIMS found C 24 H 28 F3N9 m / z 500.3 (M + 1 ).

[0841]

[0842] N 2 -((3R,4S)-1 -cyclopropyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 378.

[0843] Yellow solid (12 mg, 0.024 mmol, 36.8% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 0.21 - 0.28 (1 H, m), 0.30 - 0.37 (1 H, m), 0.43 (2 H, br d, J = 6.30 Hz), 1.61 - 1.72 (2 H, m), 1.78 (1 H, qd, J = 12.18, 3.70 Hz), 2.29 - 2.44 (2 H, m), 2.62 (3 H, s), 2.95 (1 H, br d, J = 11.50 Hz), 3.12 (3 H, d, J = 4.65 Hz), 3.17 (1 H, br t, J = 10.95 Hz), 3.70 - 3.88 (1 H, m), 4.73 - 4.81 (2 H, m), 4.87 (1 H, d, J = 50.45 Hz), 5.86 (1 H, d, J = 8.21 Hz), 6.64 (1 H, tt, J = 54.30, 3.00 Hz), 7.10 (1 H, d, J = 3.01 Hz), 7.37 (1 H, d, J = 2.74 Hz), 7.85 (1 H, d, J = 8.49 Hz), 8.01 (1 H, d, J = 8.49 Hz), 10.97 (1 H, q, J = 4.65 Hz); ESIMS found C 24 H 28 F3N9 m / z 500.3 (M + 1 ).

[0844]

[0845] N2-((3R,4S)-1 -cyclobutyl-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 379.

[0846] pale yellow fluffy solid (24 mg, 0.047 mmol, 71.6 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.58 - 1.65 (2H, m), 1.66 - 1.89 (5H, m), 1.92 - 2.07 (3H, m), 2.62 (3H, s), 2.74 (1H, quin, J=7.94 Hz), 2.80 (1H, br d, J=9.58 Hz), 2.99 - 3.07 (1H, m), 3.12 (3H, d, J=4.65 Hz), 3.69 - 3.84 (1H, m), 4.77 (2H, td, J=15.88, 2.46 Hz), 4.88 (1H, d, J=50.15 Hz), 5.88 (1H, d, J=8.21 Hz), 6.64 (1H, tt, J=54.30, 3.00 Hz), 7.10 (1H, d, J=3.01 Hz), 7.36 (1H, d, J=2.74 Hz), 7.85 (1H, d, J=8.76 Hz), 8.00 (1H, d, J=8.49 Hz), 10.97 (1H, q, J=4.56 Hz); ESIMS found C 25 H 30 F3N9 m / z 514.3 (M+1).

[0847]

[0848] N 2 -((3S,4R)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2- difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 - methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 380.

[0849] Off-white fluffy solid (6 mg, 0.011 mmol, 7.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.66 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.70 Hz), 1.97 - 2.08 (1 H, m), 2.16 (1 H, dd, J=37.55, 12.32 Hz), 2.28 - 2.47 (2 H, m), 2.62 (3 H, s), 2.64 - 2.77 (3 H, m), 2.83 (1 H, br d, J=10.13 Hz), 3.02 - 3.09 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.73 - 3.89 (1 H, m), 4.78 (2 H, td, J=15.74, 2.19 Hz), 4.91 (1 H, d, J=49.90 Hz), 5.95 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.98 (1 H, q, J=4.56 Hz); ESIMS found C 25 H 28 F5N9 m / z 550.3 (M+1).

[0850]

[0851] N 2 -((3R,4S)-1-(3,3-difluorocyclobutyl)-3-fluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 381.

[0852] pale yellow solid (9 mg, 0.016 mmol, 25.1 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 - 1.74 (1 H, m), 1.85 (1 H, qd, J=12.18, 3.97 Hz), 1.98 - 2.06 (1 H, m), 2.16 (1 H, dd, J=37.30, 13.15 Hz), 2.28 - 2.46 (2 H, m), 2.62 (3 H, s), 2.66 - 2.77 (3 H, m), 2.83 (1 H, br d, J=10.13 Hz), 3.06 (1 H, br t, J=10.95 Hz), 3.12 (3 H, d, J=4.65 Hz), 3.73 - 3.89 (1 H, m), 4.72 - 4.82 (2 H, m), 4.91 (1 H, d, J=49.05 Hz), 5.94 (1 H, d, J=8.21 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=2.74 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.85 (1 H, d, J=8.76 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.98 (1 H, q, J=4.53 Hz); ESIMS found C 25 H 28 F5N9 m / z 550.3 (M+1).

[0853]

[0854] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 (methyl-d3)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 382.

[0855] Off-white solid (9 mg, 0.018 mmol, 43.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.81 (1 H, m), 1.81 - 1.88 (1 H, m), 2.10 - 2.21 (1 H, m), 2.25 (3 H, s), 2.36 (1 H, ddd, J=27.20, 11.91, 1.12 Hz), 2.62 (3 H, s), 2.77 (1 H, br d, J=11.77 Hz), 2.98 - 3.10 (1 H, m), 4.16 - 4.30 (1 H, m), 4.78 (2 H, td, J=15.95, 2.60 Hz), 6.12 (1 H, d, J=9.31 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.85 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 (1 H, s); ESIMS found C 22 H 22 [2H3]F4N9 m / z 495.3 (M+1).

[0856]

[0857] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -1-ethyl-3,3-difluoropiperidin-4-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 383.

[0858] Off-white solid (19 mg, 0.038 mmol, 59.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.01 (3H, t, J=7.12 Hz), 1.74 (1H, qd, J=11.96, 3.56 Hz), 1.85 (1H, br dd, J=8.76, 4.11 Hz), 2.16 (1H, br t, J=10.54 Hz), 2.36 (1H, dd, J=27.70, 12.35 Hz), 2.44 (2H, q, J=7.12 Hz), 2.62 (3H, s), 2.86 (1H, br d, J=11.77 Hz), 3.06 - 3.13 (1H, m), 3.14 (3H, d, J=4.65 Hz), 4.18 - 4.32 (1H, m), 4.78 (2H, td, J=16.02, 2.74 Hz), 6.12 (1H, d, J=9.31 Hz), 6.64 (1H, tt, J=54.30, 3.00 Hz), 7.11 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=3.01 Hz), 7.85 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 11.00 (1H, q, J=4.56 Hz); ESIMS found C 23 H 27 F4N9 m / z 506.3 (M+1).

[0859]

[0860] (S)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-ethyl-3,3-difluoropiperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 384.

[0861] off-white solid (13 mg, 0.026 mmol, 40.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.01 (3H, t, J=7.12 Hz), 1.69 - 1.79 (1H, m), 1.85 (1H, br dd, J=8.90, 4.24 Hz), 2.16 (1H, br t, J=10.81 Hz), 2.36 (1H, dd, J=27.70, 11.75 Hz), 2.44 (2H, q, J=7.03 Hz), 2.62 (3H, s), 2.86 (1H, br d, J=11.50 Hz), 3.06 - 3.12 (1H, m), 3.14 (3H, d, J=4.65 Hz), 4.17 - 4.32 (1H, m), 4.78 (2H, td, J=15.95, 2.60 Hz), 6.11 (1H, d, J=9.58 Hz), 6.64 (1H, tt, J=54.30, 3.00 Hz), 7.11 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=2.74 Hz), 7.85 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 10.99 (1H, q, J=4.47 Hz); ESIMS found C 23 H 27 F4N9 m / z 506.3 (M + 1).

[0862]

[0863] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(1-ethyl-3,3-difluoropiperidin-4-yl)-N 4 (methyl-d3)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 385.

[0864] White solid (6 mg, 0.012 mmol, 18.9% yield). 1H NMR(499MHz, DMSO-d6)δppm 1.01(3H,t,J=7.26Hz),1.66-1.80(1H,m),1.80-1.90(1H,m),2.16(1H,br t,J=10.95Hz),2.36(1H,dd,J=27.45,12.05Hz),2.44(2H,q,J=6.84Hz),2.62(3H,s),2.86(1H,br d,J=11.77Hz),3.05-3.17(1H,m),4.16-4.33(1H,m),4.73-4.84(2H,m),6.12(1H,d,J=9.58Hz),6.64(1H,tt,J=54.18,3.00 Hz), 7.11 (1H, d, J = 3.01Hz), 7.38 (1H, d, J = 2.74Hz), 7.85 (1H, d, J = 8.49Hz), 8.01 (1H, d, J = 8.49Hz), 10.97 (1H, s); ESIMS measured C 23 H 24 [2H3]F4N9 m / z is 509.2 (M+1).

[0865]

[0866] (R)-N 2 -(1-cyclopropyl-3,3-difluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 386.

[0867] Light yellow semisolid (2 mg, 0.004 mmol, 18.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.27 - 0.33 (1 H, m), 0.33 - 0.39 (1 H, m), 0.46 (2 H, br d, J=6.30 Hz), 1.64 - 1.74 (1 H, m), 1.76 - 1.86 (2 H, m), 2.45 (1 H, br t, J=10.54 Hz), 2.62 (3 H, s), 2.63 - 2.71 (1 H, m), 2.94 (1 H, br d, J=11.50 Hz), 3.10 - 3.19 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.19 - 4.36 (1 H, m), 4.70 - 4.84 (2 H, m), 6.12 (1 H, d, J=9.58 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 H, d, J=2.74 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.86 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 11.00 (1 H, q, J=4.38 Hz); ESIMS found C 24 H 27 F4N9 m / z 518.3 (M + 1).

[0868]

[0869] (S)-N 2 -(1- cyclopropyl-3,3-difluoropiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 387.

[0870] pale yellow semi-solid (1.3 mg, 0.003 mmol, 12.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 0.27 - 0.33 (1 H, m), 0.33 - 0.39 (1 H, m), 0.46 (2 H, br d, J=6.30 Hz), 1.64 - 1.74 (1 H, m), 1.76 - 1.87 (1 H, m), 1.97 - 2.04 (1 H, m), 2.45 (1 H, br t, J=10.40 Hz), 2.62 (3 H, s), 2.63 - 2.72 (1 H, m), 2.94 (1 H, br d, J=11.50 Hz), 3.10 - 3.18 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.19 - 4.36 (1 H, m), 4.71 - 4.86 (2 H, m), 6.12 (1 H, d, J=9.31 Hz), 6.64 (1 H, tt, J=54.30, 3.00 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=3.01 Hz), 7.86 (1 H, d, J=8.49 Hz), 8.01 (1 H, d, J=8.49 Hz), 10.97 - 11.03 (1 H, m); ESIMS found C 24 H 27 F4N9 m / z 518.3 (M+1).

[0871]

[0872] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 -(methyl-d3)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 388.

[0873] White solid (12 mg, 0.022 mmol, 43.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.83 (1 H, m), 1.76 - 1.76 (1 H, m), 1.88 (1 H, br dd, J = 9.03, 4.38 Hz), 2.14 (1 H, br t, J = 10.54 Hz), 2.38 (1 H, dd, J = 26.05, 11.50 Hz), 2.74 (1 H, br d, J = 11.23 Hz), 2.95 - 3.06 (1 H, m), 3.60 (1 H, quin, J = 6.30 Hz), 4.22 - 4.37 (1 H, m), 4.44 (2 H, dt, J = 14.37, 6.23 Hz), 4.55 (2 H, td, J = 6.57, 3.29 Hz), 4.78 (2 H, td, J = 15.88, 2.19 Hz), 6.20 (1 H, d, J = 9.58 Hz), 6.64 (1 H, tt, J = 54.30, 3.00 Hz), 7.11 (1 H, d, J = 3.01 Hz), 7.37 (1 H, d, J = 3.01 Hz), 7.85 (1 H, d, J = 8.76 Hz), 8.01 (1 H, d, J = 8.49 Hz), 10.98 (1 H, s); ESIMS found C 24 H 24 [2H3]F4N9O m / z 537.3 (M + 1).

[0874]

[0875] 5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methyl-N 2 -(1,4-dioxaspiro[4.5]dec-8-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 389.

[0876] Off-white solid (72 mg, 0.144 mmol, 72.7% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.49 - 1.63 (4 H, m), 1.72 (2 H, br dd, J=7.67, 3.83 Hz), 1.83 - 1.94 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.64 (1 H, br d, J=3.56 Hz), 3.83 - 3.90 (4 H, m), 4.77 (2 H, td, J=15.81, 2.60 Hz), 5.99 (1 H, d, J=7.94 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.89 (1 H, q, J=4.56 Hz); ESIMS found C 24 H 28 F2N8O2 m / z 499.3 (M + 1).

[0877]

[0878] (1s,4s)-1 -Methyl-4-((5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2- yl)amino)cyclohexan-1 -ol 441.

[0879] Off-white solid (7 mg, 0.014 mmol, 11.3% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.49 - 1.63 (4 H, m), 1.72 (2 H, br dd, J=7.67, 3.83 Hz), 1.83 - 1.94 (2 H, m), 2.62 (3 H, s), 3.11 (3 H, d, J=4.65 Hz), 3.64 (1 H, br d, J=3.56 Hz), 3.83 - 3.90 (4 H, m), 4.77 (2 H, td, J=15.81, 2.60 Hz), 5.99 (1 H, d, J=7.94 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.08 (1 H, d, J=3.01 Hz), 7.36 (1 H, d, J=3.01 Hz), 7.84 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.89 (1 H, q, J=4.56 Hz); ESIMS found C 23 H 27 F3N8O m / z 489.3 (M + 1).

[0880]

[0881]

[0882] 1-((3R,4S)-3-Fluoro-4-((5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one 449.

[0883] White solid (10 mg, 0.019 mmol, 38.6% yield). 1 H NMR (499MHz, DMSO-d6) δppm 1.60-1.72(1H,m),1.74-1.87(1H,m),1.98-2.07(3H,m),2.66-2.96(1H,m),3.12(3H,d,J=4.93Hz),3.89(1H,br d,J=11.50Hz),3.93-4.06(1H,m),4.07-4.17(1H,m),4.40-4.75(1H,m),4.97(1H,d,J=49.35Hz),5.30(2H,q,J=9.13Hz),6.12(1H,dd,J=7.9 C 23 H 25 F4N9O m / z is 520.25 (M+1).

[0884]

[0885] (1r,4r)-4-((5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4-(methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-ol 465.

[0886] Fluffy orange solid (19 mg, 0.042 mmol, 64.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3H, s), 1.34 - 1.49 (4H, m), 1.53 - 1.65 (2H, m), 1.79 - 1.91 (2H, m), 3.12 (3H, d, J=4.65 Hz), 3.63 (1H, br s), 4.22 (1H, s), 5.25 (2H, td, J=15.95, 2.60 Hz), 6.04 (1H, d, J=8.21 Hz), 6.72 (1H, tt, J=54.30, 3.00 Hz), 7.31 (1H, d, J=3.29 Hz), 7.44 (1H, d, J=3.01 Hz), 8.10 (1H, d, J=9.04 Hz), 8.54 (1H, d, J=9.03 Hz), 10.85 (1H, q, J=4.56 Hz); ESIMS found C 21 H 25 F2N9O m / z 458.2 (M + 1).

[0887]

[0888] 5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 469.

[0889] Yellow solid (32 mg, 0.066 mmol, 63.0% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 2.64 (1 H, t, J = 9.31 Hz), 2.75 (1 H, ddd, J = 30.20, 12.05, 1.10 Hz), 3.00 (1 H, t, J = 8.21 Hz), 3.14 (3 H, d, J = 4.93 Hz), 3.18 (1 H, ddd, J = 32.90, 12.05, 4.38 Hz), 3.78 (1 H, quin, J = 6.16 Hz), 4.24 - 4.41 (1 H, m), 4.47 (2 H, t, J = 5.75 Hz), 4.59 (2 H, t, J = 6.57 Hz), 5.13 - 5.27 (1 H, m), 5.27 (2 H, td, J = 16.45, 2.75 Hz), 6.32 (1 H, d, J = 7.67 Hz), 6.72 (1 H, tt, J = 54.30, 3.00 Hz), 7.35 (1 H, d, J = 2.74 Hz), 7.43 - 7.48 (1 H, m), 8.12 (1 H, d, J = 9.31 Hz), 8.56 (1 H, d, J = 8.76 Hz), 10.95 (1 H, q, J = 4.38 Hz); ESIMS found C 21 H 23 F3N 10 O m / z 489.2 (M + 1).

[0890]

[0891] 1-((3R,4S)-4-((5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one 472.

[0892] Yellow solid (12 mg, 0.025 mmol, 49.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.61 - 1.72 (1 H, m), 1.72 - 1.89 (1 H, m), 1.97 - 2.07 (3 H, m), 2.80 - 2.96 (1 H, m), 3.14 (3 H, d, J=4.38 Hz), 3.89 (1 H, br d, J=14.24 Hz), 3.94 - 4.06 (1 H, m), 4.07 - 4.16 (1 H, m), 4.40 - 4.75 (1 H, m), 4.97 (1 H, d, J=48.80 Hz), 5.27 (2 H, td, J=16.02, 2.46 Hz), 6.28 (1 H, d, J=7.67 Hz), 6.72 (1 H, tt, J=53.70, 3.00 Hz), 7.35 (1 H, d, J=2.74 Hz), 7.44 (1 H, d, J=3.29 Hz), 8.12 (1 H, d, J=9.31 Hz), 8.56 (1 H, d, J=8.76 Hz), 10.94 (1 H, q, J=4.38 Hz); ESIMS found C 21 H 23 F3N 10 O m / z 489.2 (M + 1).

[0893]

[0894] 5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 474.

[0895] Fluffy yellow solid (16 mg, 0.032 mmol, 56.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 (1H, br d, J=10.13 Hz), 1.88 (1H, qd, J=12.18, 3.42 Hz), 1.96 - 2.04 (1H, m), 2.13 (1H, dd, J=36.75, 12.32 Hz), 2.75 (1H, br d, J=9.58 Hz), 2.98 (1H, br t, J=10.40 Hz), 3.13 (3H, d, J=4.65 Hz), 3.49 (1H, quin, J=6.30 Hz), 3.74 - 3.92 (1H, m), 4.40 (1H, t, J=6.16 Hz), 4.46 (1H, t, J=6.16 Hz), 4.54 (2H, td, J=6.50, 3.15 Hz), 4.90 (1H, d, J=49.35 Hz), 5.26 (2H, td, J=16.08, 2.60 Hz), 6.17 (1H, d, J=8.21 Hz), 6.72 (1H, tt, J=54.05, 3.00 Hz), 7.34 (1H, d, J=3.01 Hz), 7.44 (1H, d, J=2.74 Hz), 8.11 (1H, d, J=9.31 Hz), 8.55 (1H, d, J=9.03 Hz), 10.93 (1H, q, J=4.56 Hz); ESIMS found C 22 H 25 F3N 10 O m / z 503.2 (M+1).

[0896]

[0897] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 479.

[0898] Fluffy yellow solid (11 mg, 0.023 mmol, 47.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.90 (2 H, m), 2.09 - 2.20 (1 H, m), 2.25 (3 H, s), 2.36 (1 H, dd, J=28.00, 11.77 Hz), 2.78 (1 H, br d, J=10.13 Hz), 2.97 - 3.08 (1 H, m), 3.14 (3 H, d, J=4.65 Hz), 4.15 - 4.32 (1 H, m), 5.27 (2 H, td, J=16.02, 2.46 Hz), 6.33 (1 H, d, J=9.58 Hz), 6.72 (1 H, tt, J=54.00, 3.00 Hz), 7.35 (1 H, d, J=3.29 Hz), 7.45 (1 H, d, J=3.01 Hz), 8.12 (1 H, d, J=9.03 Hz), 8.56 (1 H, d, J=9.04 Hz), 10.95 (1 H, q, J=4.65 Hz); ESIMS found C 20 H 22 F4N 10 m / z 479.2 (M + 1).

[0899]

[0900] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H- [1,2,3] triazolo [4,5-b] pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 480.

[0901] Fluffy yellow solid (11 mg, 0.021 mmol, 43.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.73 - 1.83 (1 H, m), 1.84 - 1.91 (1 H, m), 2.14 (1 H, br t, J=10.54 Hz), 2.38 (1 H, dd, J=25.50, 12.05 Hz), 2.75 (1 H, br d, J=12.59 Hz), 2.95 - 3.07 (1 H, m), 3.15 (3 H, d, J=4.65 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.21 - 4.37 (1 H, m), 4.44 (2 H, dt, J=14.51, 6.16 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 5.27 (2 H, td, J=16.02, 2.46 Hz), 6.41 (1 H, d, J=9.58 Hz), 6.72 (1 H, tt, J=54.00, 3.00 Hz), 7.35 (1 H, d, J=3.29 Hz), 7.44 (1 H, d, J=3.01 Hz), 8.12 (1 H, d, J=9.04 Hz), 8.56 (1 H, d, J=9.03 Hz), 10.96 (1 H, q, J=4.65 Hz); ESIMS found C 22 H 24 F4N 10 O m / z 521.2 (M+1).

[0902]

[0903] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(3,3-difluoropiperidin-4-yl)-N 4 -ethylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 482.

[0904] White solid (100 mg, 0.204 mmol, 43.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.24 (3H, t, J=6.98 Hz), 1.65 (1H, qd, J=11.96, 3.56 Hz), 1.78 - 1.88 (1H, m), 2.54 - 2.61 (1H, m), 2.63 (3H, s), 2.77 (1H, dd, J=29.35, 13.75 Hz), 2.92 (1H, br d, J=12.87 Hz), 3.05 - 3.17 (1H, m), 3.67 (2H, quin, J=6.78 Hz), 4.25 - 4.40 (1H, m), 4.75 (2H, td, J=15.74, 2.74 Hz), 6.13 (1H, d, J=9.58 Hz), 6.62 (1H, tt, J=54.30, 3.00 Hz), 7.09 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=2.74 Hz), 7.84 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 10.93 (1H, t, J=6.16 Hz); ESIMS found C 22 H 25 F4N9 m / z 492.25 (M+1).

[0905]

[0906] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 -ethylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 483.

[0907] Off-white solid (2 mg, 0.004 mmol, 3.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.24 (3H, t, J=6.98 Hz), 1.72 - 1.81 (1H, m), 1.81 - 1.88 (1H, m), 2.10 - 2.19 (1H, m), 2.25 (3H, s), 2.29 - 2.40 (1H, m), 2.63 (3H, s), 2.78 (1H, br d, J=11.23 Hz), 3.00 - 3.11 (1H, m), 3.66 (2H, quin, J=7.05 Hz), 4.15 - 4.31 (1H, m), 4.69 - 4.81 (2H, m), 6.12 (1H, d, J=9.31 Hz), 6.62 (1H, tt, J=54.30, 3.00 Hz), 7.09 (1H, d, J=3.01 Hz), 7.38 (1H, d, J=2.74 Hz), 7.84 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 10.94 (1H, t, J=6.16 Hz); ESIMS found C 23 H 27 F4N9 m / z 506.2 (M+1).

[0908]

[0909] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(3,3-difluoropiperidin-4-yl)-N 4- Isopropylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 484.

[0910] White solid (118 mg, 0.233 mmol, 81.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.32 (6 H, dd, J=6.57, 1.64 Hz), 1.59 - 1.73 (1 H, m), 1.79 - 1.89 (1 H, m), 2.57 (1 H, br t, J=11.77 Hz), 2.63 (3 H, s), 2.77 (1 H, dd, J=28.80, 13.69 Hz), 2.92 (1 H, br d, J=12.32 Hz), 3.06 - 3.16 (1 H, m), 4.24 - 4.40 (1 H, m), 4.51 - 4.63 (1 H, m), 4.82 (2 H, td, J=15.19, 3.29 Hz), 6.16 (1 H, d, J=9.31 Hz), 6.55 (1 H, tt, J=54.30, 3.00 Hz), 6.94 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.73 (1 H, d, J=8.49 Hz), 8.03 (1 H, d, J=8.21 Hz), 9.45 (1 H, d, J=8.21 Hz); ESIMS found C 23 H 27 F4N9 m / z 506.3 (M + 1).

[0911]

[0912] (R)-N 2 -(3,3-difluoro-l-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl-3H- imidazo[4,5-b]pyridin-5-yl)-N 4 -isopropylpyrrolo[2,l-f][l,2,4]triazine-2,4-diamine 485.

[0913] Off-white solid (31 mg, 0.060 mmol, 60.3% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.32 (6 H, dd, J=6.71, 1.51 Hz), 1.74 - 1.81 (1 H, m), 1.81 - 1.87 (1 H, m), 2.15 (1 H, br t, J=10.54 Hz), 2.25 (3 H, s), 2.29 - 2.39 (1 H, m), 2.63 (3 H, s), 2.73 - 2.82 (1 H, m), 2.98 - 3.10 (1 H, m), 4.15 - 4.31 (1 H, m), 4.51 - 4.59 (1 H, m), 4.82 (2 H, td, J=15.19, 3.29 Hz), 6.15 (1 H, d, J=9.31 Hz), 6.55 (1 H, tt, J=54.30, 3.00 Hz), 6.94 (1 H, d, J=2.74 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.73 (1 H, d, J=8.49 Hz), 8.03 (1 H, d, J=8.49 Hz), 9.46 (1 H, d, J=8.21 Hz); ESIMS found C 24 H 29 F4N9 m / z 520.3 (M+1).

[0914]

[0915] (R)-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -(3,3-difluoropiperidin-4-yl)-N 4 -(oxetan-3-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 486.

[0916] White solid (18 mg, 0.035 mmol, 32.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.67 - 1.81 (1 H, m), 1.87 (1 H, br d, J=11.23 Hz), 2.55 - 2.63 (1 H, m), 2.59 (3 H, s), 2.72 - 2.89 (1 H, m), 2.94 (1 H, br d, J=12.05 Hz), 3.07 - 3.20 (1 H, m), 3.41 - 3.56 (1 H, m), 3.57 - 3.68 (1 H, m), 3.70 - 3.97 (1 H, m), 3.98 - 4.19 (1 H, m), 4.23 - 4.42 (2 H, m), 4.75 (2 H, br t, J=13.96 Hz), 4.82 - 4.95 (1 H, m), 6.16 - 6.35 (1 H, m), 6.42 - 6.68 (1 H, m), 7.02 (1 H, br s), 7.22 (1 H, br d, J=1.92 Hz), 7.87 (1 H, br s), 8.82 - 8.97 (1 H, m); ESIMS found C 23 H 25 F4N9O m / z 520.2 (M + 1).

[0917]

[0918] (R)-N2-(3,3-difluoro-l-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)-N4-(oxetan-3-yl)pyrrolo[2,l-f][l,2,4]triazine- 2,4-diamine 487.

[0919] Brown solid (4.1 mg, 0.008 mmol, 8.7% yield). 1H NMR(499MHz, DMSO-d6)δppm 1.72-1.85(2H,m),2.15(1H,br t,J=11.09Hz),2.25(3H,s),2.31-2.42(1H,m),2.62(3H,s),2.77(1H,br d,J=11.50Hz),2.99-3.09(1H,m),4.16-4.33(1H,m),4.67(1H,t,J=6.30Hz),4.70(1H,br t,J=6.43Hz),4.78(2H,br t,J=14.92Hz),4.94(2H,t,J=6.98Hz),5.20-5.29(1H,m),6.28(1H,br d, J = 9.31 Hz), 6.53 (1H, tt, J = 54.30, 3.00 Hz), 7.05 (1H, d, J = 3.01 Hz), 7.44 (1H, d, J = 2.74 Hz), 7.81 (1H, d, J = 8.49 Hz), 8.04 (1H, d, J = 8.49 Hz), 10.50 (1H, d, J = 6.02 Hz); ESIMS measured C 24 H 27 F4N9O m / z is 534.2 (M+1).

[0920]

[0921] (1r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexane-1-ol 692.

[0922] White solid (20 mg, 0.044 mmol, 74.9% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 1.14 (3H, s), 1.33 - 1.46 (4H, m), 1.51 - 1.62 (2H, m), 1.78 - 1.87 (2H, m), 2.60 (3H, s), 3.61 (1H, br d, J=8.21, 3.83 Hz), 4.21 (1H, s), 4.70 (2H, td, J=16.45, 1.65 Hz), 5.74 (1H, d, J=8.21 Hz), 6.46 (1H, tt, J=54.00, 2.75 Hz), 7.07 (1H, d, J=2.74 Hz), 7.38 (1H, d, J=2.74 Hz), 7.42 (1H, br s), 7.80 (1H, d, J=8.76 Hz), 7.99 (1H, d, J=8.21 Hz), 10.52 (1H, br s); ESIMS found C 22 H 26 F2N8O m / z 457.2 (M+1).

[0923]

[0924] 1-((3R,4S)-3-((4-amino-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1-yl)ethan-1-one 700.

[0925] White solid (20 mg, 0.042 mmol, 34.8% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.92 - 2.00 (3H, m), 2.60 (3H, s), 3.41 - 3.58 (1H, m), 3.62 - 3.73 (1H, m), 3.75 - 3.86 (1H, m), 3.91 (1H, t, J=9.03 Hz), 4.26 - 4.56 (1H, m), 4.71 (2H, td, J=16.45, 1.65 Hz), 5.20 - 5.43 (1H, m), 6.33 (1H, dd, J=11.77, 7.67 Hz), 6.47 (1H, tt, J=54.30, 2.20 Hz), 7.13 (1H, dd, J=3.01, 1.92 Hz), 7.41 (1H, dd, J=4.24, 2.87 Hz), 7.58 - 7.68 (1H, m), 7.83 (1H, d, J=8.76 Hz), 8.01 (1H, d, J=8.49 Hz), 10.67 (1H, br s); ESIMS found C 21 H22 F3N9O m / z 474.2 (M+l).

[0926]

[0927] 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4- diamine 701.

[0928] White solid (29 mg, 0.060 mmol, 46.3% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 2.60 (3H, s), 2.60-2.64 (1H, m), 2.76 (1H, ddd, J = 30.15, 12.35, 1.35 Hz), 2.99 (1H, t, J = 8.21 Hz), 3.15 (1H, ddd, J = 33.75, 12.10, 4.40 Hz), 3.78 (1H, quin, J = 6.23 Hz), 4.22-4.37 (1H, m), 4.46 (2H, t, J = 6.02 Hz), 4.59 (2H, t, J = 6.57 Hz), 4.71 (2H, td, J = 16.75, 1.90 Hz), 5.19 (1H, dtd, J = 55.70, 4.60, 4.60, 1.35 Hz), 6.02 (1H, d, J = 7.94 Hz), 6.47 (1H, tt, J = 54.40, 2.20 Hz), 7.11 (1H, d, J = 3.01 Hz), 7.41 (1H, d, J = 2.74 Hz), 7.61 (1H, br s), 7.82 (1H, d, J = 8.49 Hz), 8.00 (1H, d, J = 8.49 Hz), 10.62 (1H, br s); ESIMS found C 22 H 24 F3N9O m / z 488.2 (M+l).

[0929]

[0930] 1-((3R,4S)-4-((4-amino-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one 715.

[0931] Fluffy off-white solid (8 mg, 0.016 mmol, 26.8% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.57 - 1.70 (1 H, m), 1.73 - 1.84 (1 H, m), 1.97 - 2.06 (3 H, m), 2.60 (3 H, s), 2.67 (1 H, td, J=12.80, 3.42 Hz), 2.86 (1 H, dd, J=40.05, 13.96 Hz), 3.83 - 3.98 (1 H, m), 4.00 - 4.17 (1 H, m), 4.38 - 4.48 (1 H, m), 4.66 - 4.79 (2 H, m), 4.95 (1 H, d, J=49.90 Hz), 5.96 (1 H, dd, J=8.21, 5.75 Hz), 6.47 (1 H, tt, J=54.00, 2.75 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.56 (1 H, br s), 7.82 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.63 (1 H, br s); ESIMS found C 22 H 24 F3N9O m / z 244.65 (M / 2 + 1).

[0932]

[0933] 5-(3-(2,2-Difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 718.

[0934] Fluffy off-white solid (3 mg, 0.006 mmol, 14.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.64 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.05, 3.56 Hz), 1.94 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.00, 12.59 Hz), 2.60 (3 H, s), 2.69 - 2.79 (1 H, m), 2.97 (1 H, br t, J=10.81 Hz), 3.48 (1 H, dt, J=12.66, 6.40 Hz), 3.73 - 3.91 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.43, 2.74 Hz), 4.64 - 4.76 (2 H, m), 4.88 (1 H, d, J=49.40 Hz), 5.83 (1 H, d, J=8.21 Hz), 6.46 (1 H, tt, J=54.00, 2.75 Hz), 7.10 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.55 (1 H, br s), 7.81 (1 H, d, J=8.49 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.61 (1 H, br s); ESIMS found C 23 H 26 F3N9O m / z 251.65 (M / 2 + 1).

[0935]

[0936] (R)-1-(4-((4-amino-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one 729.

[0937] Fluffy light yellow solid (3 mg, 0.006 mmol, 17.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.52 - 1.80 (1 H, m), 1.81 - 1.97 (1 H, m), 2.02 - 2.08 (3 H, m), 2.60 (3 H, s), 2.98 (1 H, br t, J=11.36 Hz), 3.57 - 3.91 (1 H, m), 4.09 - 4.27 (1 H, m), 4.42 - 4.58 (2 H, m), 4.63 - 4.79 (2 H, m), 6.20 - 6.31 (1 H, m), 6.47 (1 H, tt, J=54.00, 2.75 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.39 (1 H, dd, J=2.87, 1.51 Hz), 7.60 (1 H, br s), 7.83 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.67 (1 H, br s); ESIMS found C 22 H 23 F4N9O m / z 506.2 (M + 1).

[0938]

[0939] (R)-N 2 (R)-N

[0940] Off-white fluffy solid (14 mg, 0.027 mmol, 48.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.69 - 1.81 (1 H, m), 1.81 - 1.90 (1 H, m), 2.06 - 2.18 (1 H, m), 2.34 (1 H, ddd, J=26.60, 12.05, 1.35 Hz), 2.60 (3 H, s), 2.74 (1 H, br d, J=11.23 Hz), 2.95 - 3.06 (1 H, m), 3.59 (1 H, quin, J=6.30 Hz), 4.20 - 4.36 (1 H, m), 4.43 (2 H, dt, J=13.89, 6.19 Hz), 4.55 (2 H, td, J=6.57, 3.56 Hz), 4.65 - 4.79 (2 H, m), 6.12 (1 H, d, J=9.58 Hz), 6.47 (1 H, tt, J=54.05, 2.20 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.60 (1 H, br s), 7.82 (1 H, d, J=8.76 Hz), 8.00 (1 H, d, J=8.49 Hz), 10.66 (1 H, br s); ESIMS found C 23 H 25 F4N9O m / z 520.2 (M + 1).

[0941]

[0942] (1 r,4r)-4-((4-amino-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5- b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1 -methylcyclohexan-1 -ol 754.

[0943] White solid (10 mg, 0.021 mmol, 30.9% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 1.14 (3H, s), 1.33 - 1.46 (4H, m), 1.50 - 1.62 (2H, m), 1.77 - 1.88 (2H, m), 2.62 (3H, s), 3.62 (1H, dt, J=7.94, 3.97 Hz), 4.21 (1H, br s), 5.15 (2H, q, J=9.22 Hz), 5.74 (1H, d, J=8.21 Hz), 7.08 (1H, d, J=2.74 Hz), 7.39 (1H, d, J=2.74 Hz), 7.54 (1H, br s), 7.84 (1H, d, J=8.76 Hz), 8.02 (1H, d, J=8.49 Hz), 10.31 (1H, br s); ESIMS found C 22 H 25 F3N8Om / z as 475.2 (M+1).

[0944]

[0945] 1-((3R,4S)-3-((4-amino-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-4- fluoropyrrolidin-1-yl)ethan-1-one 762.

[0946] White solid (19 mg, 0.039 mmol, 31.8% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.92 - 2.01 (3H, m), 2.63 (3H, s), 3.49 - 3.61 (1H, m), 3.62 - 3.74 (1H, m), 3.75 - 3.86 (1H, m), 3.91 (1H, t, J=9.03 Hz), 4.27 - 4.56 (1H, m), 5.16 (2H, q, J=8.94 Hz), 5.20 - 5.42 (1H, m), 6.33 (1H, dd, J=10.40, 7.67 Hz), 7.14 (1H, dd, J=2.87, 2.05 Hz), 7.43 (1H, dd, J=4.38, 3.01 Hz), 7.70 - 7.82 (1H, m), 7.87 (1H, d, J=8.49 Hz), 8.04 (1H, d, J=8.49 Hz), 10.46 (1H, br s); ESIMS found C 21 H 21 F4N9O m / z as 492.2 (M+1).

[0947]

[0948] N 2 -((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 763.

[0949] White solid (20 mg, 0.040 mmol, 30.8% yield). 1 H NMR(499MHz,DMSO-d6)δppm 2.60-2.64(1H,m),2.63(3H,s),2.76(1H,ddd,J=30.20,12.18,1.23Hz),3.00(1H,t,J=8.21H z),3.15(1H,ddd,J=33.75,12.05,4.38Hz),3.74-3.83(1H,m),4.23-4.38(1H,m),4.46(2H,t, J=5.89Hz),4.59(2H,t,J=6.57Hz),5.19(1H,dtd,J=55.40,4.65,4.65,1.10Hz),5.16(2H,q,J =9.22Hz),6.01(1H,d,J=7.94Hz),7.12(1H,d,J=3.01Hz),7.42(1H,d,J=2.74Hz),7.73(1H,br s), 7.86 (1H, d, J = 8.49Hz), 8.03 (1H, d, J = 8.49Hz), 10.41 (1H, br s); C measured by ESIMS 22 H 23 F4N9O m / z is 506.2 (M+1).

[0950]

[0951] 1-((3R,4S)-4-((4-amino-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1-one 777.

[0952] Fluffy light yellow solid (5 mg, 0.010 mmol, 16.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.56 - 1.70 (1 H, m), 1.73 - 1.85 (1 H, m), 1.97 - 2.07 (3 H, m), 2.63 (3 H, s), 2.67 (1 H, td, J=12.87, 3.29 Hz), 2.86 (1 H, dd, J=39.80, 14.24 Hz), 3.92 - 4.06 (1 H, m), 4.37 - 4.49 (1 H, m), 4.61 - 4.76 (1 H, m), 4.94 (1 H, d, J=49.90 Hz), 5.16 (2 H, q, J=9.13 Hz), 5.96 (1 H, dd, J=8.08, 5.61 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.69 (1 H, br s), 7.86 (1 H, d, J=8.76 Hz), 8.03 (1 H, d, J=8.49 Hz), 10.42 (1 H, br s); ESIMS found C 22 H 23 F4N9O m / z 253.7 (M / 2 + 1).

[0953]

[0954] N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(2-methyl-3-(2,2,2- trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 780.

[0955] Fluffy light yellow solid (10 mg, 0.019 mmol, 46.9% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.66 - 1.76 (1 H, m), 1.85 (1 H, qd, J=12.14, 3.29 Hz), 1.95 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.55, 12.59 Hz), 2.62 (3 H, s), 2.74 (1 H, br d, J=10.40 Hz), 2.91 - 3.02 (1 H, m), 3.48 (1 H, quin, J=6.23 Hz), 3.72 - 3.89 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.43, 2.74 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.15 (2 H, q, J=9.22 Hz), 5.83 (1 H, d, J=8.21 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=3.01 Hz), 7.68 (1 H, br s), 7.85 (1 H, d, J=8.76 Hz), 8.03 (1 H, d, J=8.49 Hz), 10.40 (1 H, br s); ESIMS found C 23 H 25 F4N9O m / z 260.7 (M+1).

[0956]

[0957] (R)-1-(4-((4-amino-5-(2-methyl-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one 791.

[0958] Fluffy light yellow solid (2 mg, 0.004 mmol, 11.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.52 - 1.80 (1 H, m), 1.81 - 1.98 (1 H, m), 2.02 - 2.09 (3 H, m), 2.63 (3 H, s), 2.91 - 3.03 (1 H, m), 3.59 - 3.93 (1 H, m), 4.07 - 4.30 (1 H, m), 4.42 - 4.59 (2 H, m), 5.16 (2 H, q, J=8.94 Hz), 6.20 - 6.30 (1 H, m), 7.13 (1 H, d, J=3.01 Hz), 7.40 (1 H, dd, J=2.74, 1.64 Hz), 7.72 (1 H, br s), 7.87 (1 H, d, J=8.49 Hz), 8.04 (1 H, d, J=8.49 Hz), 10.46 (1 H, br s); ESIMS found C 22 H 22 F5N9O m / z 524.15 (M + 1).

[0959]

[0960] (R)-N 2 (R)-N

[0961] Fluffy white solid (11 mg, 0.021 mmol, 48.9 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.81 (1 H, m), 1.82 - 1.90 (1 H, m), 2.05 - 2.17 (1 H, m), 2.34 (1 H, dd, J=26.60, 11.77 Hz), 2.74 (1 H, br d, J=10.68 Hz), 2.95 - 3.06 (1 H, m), 3.59 (1 H, quin, J=6.16 Hz), 4.21 - 4.36 (1 H, m), 4.43 (2 H, dt, J=14.10, 6.09 Hz), 4.55 (2 H, td, J=6.57, 3.56 Hz), 5.15 (2 H, q, J=9.13 Hz), 6.12 (1 H, br d, J=9.58 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.72 (1 H, br s), 7.86 (1 H, d, J=8.76 Hz), 8.03 (1 H, d, J=8.49 Hz), 10.45 (1 H, br s); ESIMS found C 23 H 24 F5N9O m / z 538.2 (M+1).

[0962]

[0963] (1 r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-1 -methylcyclohexan-1 -ol 816.

[0964] Fluffy yellow solid (3.5 mg, 0.008 mmol, 9.7% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.81 (1 H, m), 1.82 - 1.90 (1 H, m), 2.05 - 2.17 (1 H, m), 2.34 (1 H, dd, J=26.60, 11.77 Hz), 2.74 (1 H, br d, J=10.68 Hz), 2.95 - 3.06 (1 H, m), 3.59 (1 H, quin, J=6.16 Hz), 4.21 - 4.36 (1 H, m), 4.43 (2 H, dt, J=14.10, 6.09 Hz), 4.55 (2 H, td, J=6.57, 3.56 Hz), 5.15 (2 H, q, J=9.13 Hz), 6.12 (1 H, br d, J=9.58 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.72 (1 H, br s), 7.86 (1 H, d, J=8.76 Hz), 8.03 (1 H, d, J=8.49 Hz), 10.45 (1 H, br s); ESIMS found C 20 H23 F2N9O m / z 444.2 (M+1).

[0965]

[0966] 5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1- f][1,2,4]triazine-2,4-diamine 842.

[0967] Fluffy yellow solid (7 mg, 0.014 mmol, 48.8% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.64 - 1.77 (1 H, m), 1.86 (1 H, qd, J=12.09, 3.97 Hz), 1.95 - 2.03 (1 H, m), 2.12 (1 H, dd, J=37.50, 12.32 Hz), 2.74 (1 H, br d, J=11.23 Hz), 2.90 - 3.05 (1 H, m), 3.48 (1 H, quin, J=6.23 Hz), 3.72 - 3.90 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.57, 2.74 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.16 (2 H, td, J=16.22, 2.60 Hz), 6.07 (1 H, d, J=8.21 Hz), 6.58 (2 H, tt, J=54.00, 2.75 Hz), 7.34 (1 H, d, J=3.01 Hz), 7.46 (1 H, d, J=3.01 Hz), 7.69 (1 H, br s), 8.09 (1 H, d, J=9.03 Hz), 8.55 (1 H, d, J=9.03 Hz), 10.46 (1 H, br s); ESIMS found C 21 H 23 F3N 10 O m / z 489.2 (M+1).

[0968]

[0969] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 850.

[0970] Fluffy yellow solid (20 mg, 0.043 mmol, 52.5% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.70 - 1.87 (2H, m), 2.07 - 2.17 (1H, m), 2.25 (3H, s), 2.33 (1H, dd, J = 27.40, 11.66 Hz), 2.78 (1H, br d, J = 12.05 Hz), 2.98 - 3.10 (1H, m), 4.15 - 4.32 (1H, m), 5.16 (2H, td, J = 16.15, 2.46 Hz), 6.25 (1H, d, J = 9.58 Hz), 6.58 (1H, tt, J = 54.05, 2.75 Hz), 7.36 (1H, d, J = 3.01 Hz), 7.47 (1H, d, J = 3.01 Hz), 7.74 (1H, br s), 8.10 (1H, d, J = 9.31 Hz), 8.55 (1H, d, J = 9.03 Hz), 10.49 (1H, br s); ESIMS found C 19 H 20 F4N 10 m / z 465.2 (M+1).

[0971]

[0972] (R)-1-(4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one 853.

[0973] Fluffy yellow solid (1.3 mg, 0.003 mmol, 6.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.53 - 1.80 (1 H, m), 1.82 - 1.99 (1 H, m), 2.02 - 2.08 (3 H, m), 2.88 - 3.02 (1 H, m), 3.57 - 3.93 (1 H, m), 4.05 - 4.31 (1 H, m), 4.41 - 4.59 (2 H, m), 5.17 (2 H, td, J=16.22, 2.33 Hz), 6.59 (1 H, tt, J=54.00, 2.75 Hz), 6.68 (1 H, s), 7.37 (1 H, d, J=3.01 Hz), 7.47 (1 H, dd, J=2.74, 1.37 Hz), 7.73 (1 H, br s), 8.11 (1 H, d, J=9.03 Hz), 8.56 (1 H, d, J=9.03 Hz), 10.52 (1 H, br s); ESIMS found C 20 H 20 F4N 10 O m / z 493.15 (M + 1).

[0974]

[0975] (R)-N 2 (R)-N

[0976] Fluffy yellow solid (9 mg, 0.018 mmol, 42.5% yield). 1H NMR (499 MHz, DMSO-d6) d ppm 1.71 - 1.81 (1 H, m), 1.86 (1 H, br dd, J = 8.62, 4.52 Hz), 2.06 - 2.17 (1 H, m), 2.35 (1 H, dd, J = 26.35, 11.77 Hz), 2.74 (1 H, br d, J = 11.23 Hz), 2.95 - 3.06 (1 H, m), 3.59 (1 H, quin, J = 6.37 Hz), 4.20 - 4.36 (1 H, m), 4.43 (2 H, dt, J = 14.24, 6.30 Hz), 4.55 (2 H, td, J = 6.64, 3.70 Hz), 5.17 (2 H, td, J = 16.15, 2.19 Hz), 6.34 (1 H, br d, J = 9.31 Hz), 6.59 (1 H, tt, J = 54.05, 2.75 Hz), 7.36 (1 H, d, J = 3.01 Hz), 7.47 (1 H, d, J = 3.01 Hz), 7.73 (1 H, br s), 8.10 (1 H, d, J = 9.03 Hz), 8.55 (1 H, d, J = 9.03 Hz), 10.50 (1 H, br s) ESIMS found C 21 H 22 F4N 10 O m / z 507.2 (M + 1).

[0977]

[0978] (R)-N 2 -(3,3-difluoro-l-methylpiperidin-4-yl)-5-(3-(2-fluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,l-f][l,2,4]triazine-2,4-diamine 985.

[0979] White solid (15 mg, 0.034 mmol, 50.8 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.79 (1 H, m), 1.80 - 1.85 (1 H, m), 2.13 (1 H, br t, J=10.40 Hz), 2.25 (3 H, s), 2.32 (1 H, ddd, J=27.10, 12.30, 1.65 Hz), 2.77 (1 H, br d, J=11.50 Hz), 2.98 - 3.10 (1 H, m), 4.13 - 4.31 (1 H, m), 4.58 (2 H, dt, J=27.70, 4.65 Hz), 4.82 (2 H, dt, J=47.15, 4.65 Hz), 6.07 (1 H, d, J=9.31 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=3.01 Hz), 7.65 (1 H, br s), 7.88 (1 H, d, J=8.49 Hz), 8.13 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 10.81 (1 H, br s); ESIMS found C 20 H 22 F3N9 m / z 446.1 (M+1).

[0980]

[0981] (1 r,4r)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-1 -methylcyclohexan-1 -ol 986.

[0982] White solid (8 mg, 0.018 mmol, 26.5% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.79 (1 H, m), 1.80 - 1.85 (1 H, m), 2.13 (1 H, br t, J=10.40 Hz), 2.25 (3 H, s), 2.32 (1 H, ddd, J=27.10, 12.30, 1.65 Hz), 2.77 (1 H, br d, J=11.50 Hz), 2.98 - 3.10 (1 H, m), 4.13 - 4.31 (1 H, m), 4.58 (2 H, dt, J=27.70, 4.65 Hz), 4.82 (2 H, dt, J=47.15, 4.65 Hz), 6.07 (1 H, d, J=9.31 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=3.01 Hz), 7.65 (1 H, br s), 7.88 (1 H, d, J=8.49 Hz), 8.13 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 10.81 (1 H, br s); ESIMS found C 21 H24 F2N8O m / z 443.2 (M+1).

[0983]

[0984] 1-((3R,4S)-3-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-4-fluoropyrrolidin-1 -yl)ethan-1 -one 987.

[0985] White solid (15 mg, 0.033 mmol, 26.9% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.98 (3H, s), 3.41 - 3.60 (1H, m), 3.62 - 3.73 (1H, m), 3.75 - 3.87 (1H, m), 3.91 (1H, t, J=9.03 Hz), 4.25 - 4.55 (1H, m), 4.75 (2H, td, J=16.45, 2.20 Hz), 5.18 - 5.43 (1H, m), 6.36 (1H, dd, J=11.50, 7.67 Hz), 6.48 (1H, tt, J=54.30, 2.45 Hz), 7.17 (1H, dd, J=3.01, 1.64 Hz), 7.43 (1H, dd, J=4.24, 2.87 Hz), 7.62 - 7.70 (1H, m), 7.90 (1H, d, J=8.76 Hz), 8.16 (1H, d, J=8.76 Hz), 8.41 (1H, s), 10.63 (1H, br s); ESIMS found C 20 H 20 F3N9O m / z 460.2 (M+1).

[0986]

[0987] 5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-4-fluoro-1-(oxetan-3-yl)pyrrolidin-3-yl)pyrrolo[2,1- f][1,2,4]triazin-2,4-diamine 988.

[0988] White solid (21 mg, 0.044 mmol, 34.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 2.62 (1 H, t, J=9.03 Hz), 2.76 (1 H, ddd, J=30.15, 12.05, 1.10 Hz), 2.99 (1 H, t, J=8.21 Hz), 3.16 (1 H, ddd, J=33.75, 12.18, 4.52 Hz), 3.78 (1 H, quin, J=6.16 Hz), 4.22 - 4.37 (1 H, m), 4.46 (2 H, t, J=6.02 Hz), 4.59 (2 H, t, J=6.57 Hz), 4.75 (2 H, td, J=16.43, 2.19 Hz), 5.19 (1 H, dtd, J=55.95, 4.40, 4.40, 1.40 Hz), 6.05 (1 H, d, J=8.21 Hz), 6.48 (1 H, tt, J=54.55, 2.60 Hz), 7.16 (1 H, d, J=2.74 Hz), 7.42 (1 H, d, J=2.74 Hz), 7.64 (1 H, br s), 7.89 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.49 Hz), 8.41 (1 H, s), 10.58 (1 H, br s); ESIMS found C 21 H 22 F3N9O m / z 474.2 (M + 1).

[0989]

[0990] 1-((3R,4S)-4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1 -yl)ethan-1 -one 989.

[0991] Fluffy light yellow solid (10 mg, 0.021 mmol, 34.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.58 - 1.72 (1 H, m), 1.73 - 1.85 (1 H, m), 1.97 - 2.05 (3 H, m), 2.67 (1 H, td, J=12.66, 3.70 Hz), 2.86 (1 H, dd, J=39.75, 13.96 Hz), 3.92 - 4.05 (1 H, m), 4.07 - 4.16 (1 H, m), 4.43 (1 H, br dd, J=11.22, 2.19 Hz), 4.70 - 4.82 (2 H, m), 4.94 (1 H, d, J=49.90 Hz), 6.00 (1 H, dd, J=7.94, 5.20 Hz), 6.48 (1 H, tt, J=54.00, 2.75 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.59 (1 H, br s), 7.89 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.49 Hz), 8.40 (1 H, s), 10.59 (1 H, br s); ESIMS found C 21 H 22 F3N9O m / z 474.2 (M + 1).

[0992]

[0993] 5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 990.

[0994] Fluffy light yellow solid (14 mg, 0.029 mmol, 69.9 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.64 - 1.75 (1 H, m), 1.85 (1 H, qd, J=12.09, 3.70 Hz), 1.95 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.30, 12.59 Hz), 2.74 (1 H, br d, J=10.68 Hz), 2.90 - 3.03 (1 H, m), 3.48 (1 H, quin, J=6.30 Hz), 3.73 - 3.87 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.53 (2 H, td, J=6.57, 2.74 Hz), 4.74 (2 H, td, J=16.48, 2.20 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.87 (1 H, d, J=8.21 Hz), 6.48 (1 H, tt, J=54.00, 2.75 Hz), 7.14 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.58 (1 H, br s), 7.88 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.76 Hz), 8.40 (1 H, s), 10.58 (1 H, br s); ESIMS found C 22 H 24 F3N9O m / z 488.2 (M + 1).

[0995]

[0996] (R)-N 2 (R)-N

[0997] White solid (20 mg, 0.043 mmol, 65.1 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.79 (1 H, m), 1.79 - 1.86 (1 H, m), 2.08 - 2.19 (1 H, m), 2.25 (3 H, s), 2.32 (1 H, ddd, J=26.85, 12.05, 1.37 Hz), 2.77 (1 H, br d, J=11.50 Hz), 3.00 - 3.10 (1 H, m), 4.15 - 4.29 (1 H, m), 4.75 (2 H, td, J=16.36, 2.05 Hz), 6.07 (1 H, d, J=9.58 Hz), 6.48 (1 H, tt, J=54.30, 2.50 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.41 (1 H, d, J=2.74 Hz), 7.63 (1 H, br s), 7.89 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.76 Hz), 8.40 (1 H, s), 10.61 (1 H, br s); ESIMS found C 20 H 21 F4N9 m / z 464.1 (M + 1).

[0998]

[0999] (R)-1-(4-((4-amino-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one992.

[1000] Fluffy light yellow solid (8 mg, 0.016 mmol, 46.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.53 - 1.78 (1 H, m), 1.80 - 1.98 (1 H, m), 2.02 - 2.08 (3 H, m), 2.91 - 3.04 (1 H, m), 3.65 (1 H, dd, J=28.00, 14.24 Hz), 4.07 - 4.27 (1 H, m), 4.41 - 4.59 (2 H, m), 4.75 (2 H, td, J=16.50, 2.33 Hz), 6.29 (1 H, dd, J=9.31, 6.02 Hz), 6.48 (1 H, tt, J=54.00, 2.75 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.41 (1 H, dd, J=2.87, 1.51 Hz), 7.62 (1 H, br s), 7.89 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.49 Hz), 8.41 (1 H, s), 10.64 (1 H, br s); ESIMS found C 21 H 21 F4N9O m / z 492.2 (M + 1).

[1001]

[1002] (R)-N 2 (R)-N

[1003] Fluffy white solid (13 mg, 0.026 mmol, 61.5% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.81 (1 H, m), 1.82 - 1.89 (1 H, m), 2.06 - 2.17 (1 H, m), 2.35 (1 H, dd, J=26.60, 11.23 Hz), 2.74 (1 H, br d, J=11.77 Hz), 2.95 - 3.05 (1 H, m), 3.59 (1 H, quin, J=6.37 Hz), 4.19 - 4.35 (1 H, m), 4.43 (2 H, dt, J=14.10, 6.09 Hz), 4.55 (2 H, td, J=6.64, 3.70 Hz), 4.75 (2 H, td, J=16.45, 2.20 Hz), 6.15 (1 H, br d, J=9.58 Hz), 6.48 (1 H, tt, J=54.00, 2.75 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.40 (1 H, d, J=2.74 Hz), 7.62 (1 H, br s), 7.89 (1 H, d, J=8.76 Hz), 8.15 (1 H, d, J=8.76 Hz), 8.40 (1 H, s), 10.62 (1 H, br s); ESIMS found C 22 H 23 F4N9O m / z 506.25 (M + 1).

[1004]

[1005] (R)-N 2 -(3,3-difluoro-l-methylpiperidin-4-yl)-5-(3-(2,2,2-trifluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,l-f][l,2,4]triazine-2,4-diamine 994.

[1006] White solid (18 mg, 0.037 mmol, 56.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.79 (1 H, m), 1.80 - 1.86 (1 H, m), 2.08 - 2.19 (1 H, m), 2.25 (3 H, s), 2.32 (1 H, ddd, J=26.35, 12.59, 1.64 Hz), 2.77 (1 H, br d, J=11.50 Hz), 2.98 - 3.09 (1 H, m), 4.14 - 4.31 (1 H, m), 5.20 (2 H, q, J=9.22 Hz), 6.07 (1 H, d, J=9.58 Hz), 7.17 (1 H, d, J=3.01 Hz), 7.42 (1 H, d, J=2.74 Hz), 7.72 (1 H, br s), 7.93 (1 H, d, J=8.76 Hz), 8.18 (1 H, d, J=8.49 Hz), 8.48 (1 H, s), 10.48 (1 H, br s); ESIMS found C 20 H 20 F5N9 m / z 482.2 (M+1).

[1007]

[1008] (1 r,4r)-4-((4-amino-5-(3-(2-fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-1 -methylcyclohexan-1 -ol 995.

[1009] White solid (2 mg, 0.005 mmol, 6.7% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.71 - 1.79 (1 H, m), 1.80 - 1.86 (1 H, m), 2.08 - 2.19 (1 H, m), 2.25 (3 H, s), 2.32 (1 H, ddd, J=26.35, 12.59, 1.64 Hz), 2.77 (1 H, br d, J=11.50 Hz), 2.98 - 3.09 (1 H, m), 4.14 - 4.31 (1 H, m), 5.20 (2 H, q, J=9.22 Hz), 6.07 (1 H, d, J=9.58 Hz), 7.17 (1 H, d, J=3.01 Hz), 7.42 (1 H, d, J=2.74 Hz), 7.72 (1 H, br s), 7.93 (1 H, d, J=8.76 Hz), 8.18 (1 H, d, J=8.49 Hz), 8.48 (1 H, s), 10.48 (1 H, br s); ESIMS found C 22 H 27 FN8O m / z 439.25 (M+1).

[1010]

[1011] 1 -((3R,4S)-4-((4-amino-5-(3-(2-fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5- yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1 -yl)ethan-1 -one 996.

[1012] Fluffy light yellow solid (3 mg, 0.006 mmol, 10.4% yield). 1 H NMR (499 MHz, DMSO-d6) d ppm 1.58 - 1.71 (1 H, m), 1.73 - 1.85 (1 H, m), 1.96 - 2.07 (3 H, m), 2.59 (3 H, s), 2.67 (1 H, td, J = 12.73, 3.29 Hz), 2.86 (1 H, dd, J = 40.05, 13.96 Hz), 3.91 - 4.04 (1 H, m), 4.38 - 4.47 (1 H, m), 4.55 (2 H, dt, J = 27.40, 4.65 Hz), 4.64 - 4.72 (1 H, m), 4.78 (2 H, dt, J = 47.20, 4.65 Hz), 4.94 (1 H, d, J = 49.90 Hz), 5.96 (1 H, dd, J = 8.08, 5.61 Hz), 7.12 (1 H, d, J = 3.01 Hz), 7.38 (1 H, d, J = 3.01 Hz), 7.60 (1 H, br s), 7.81 (1 H, d, J = 8.49 Hz), 7.98 (1 H, d, J = 8.49 Hz), 10.81 (1 H, br s); ESIMS found C 22 H 25 F2N9O m / z 235.65 (M / 2 + 1).

[1013]

[1014] N 2 -((3R,4S)-3-fluoro-1 -(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-2,4-diamine 997.

[1015] Fluffy light yellow solid (4 mg, 0.008 mmol, 20.1 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.65 - 1.76 (1 H, m), 1.85 (1 H, qd, J=12.23, 3.83 Hz), 1.94 - 2.02 (1 H, m), 2.12 (1 H, dd, J=37.60, 12.59 Hz), 2.59 (3 H, s), 2.74 (1 H, br d, J=11.23 Hz), 2.91 - 3.04 (1 H, m), 3.48 (1 H, dt, J=12.80, 6.33 Hz), 3.69 - 3.90 (1 H, m), 4.39 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.50 - 4.60 (4 H, m), 4.78 (2 H, dt, J=46.90, 4.73 Hz), 4.88 (1 H, d, J=49.90 Hz), 5.83 (1 H, d, J=8.21 Hz), 7.11 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.59 (1 H, br s), 7.80 (1 H, d, J=8.76 Hz), 7.98 (1 H, d, J=8.49 Hz), 10.80 (1 H, br s); ESIMS found C 23 H 27 F2N9Om / z as 242.7 (M / 2+1).

[1016]

[1017] (R)-1-(4-((4-amino-5-(3-(2-fluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrrolo[2,1- f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one 998.

[1018] Fluffy yellow solid (0.31 mg, 0.0006 mmol, 1.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.52 - 1.78 (1 H, m), 1.81 - 1.96 (1 H, m), 2.02 - 2.08 (3 H, m), 2.59 (3 H, s), 2.90 - 3.03 (1 H, m), 3.84 (1 H, br d, J=13.69 Hz), 4.07 - 4.26 (1 H, m), 4.42 - 4.52 (2 H, m), 4.55 (2 H, dt, J=27.75, 4.65 Hz), 4.78 (2 H, dt, J=46.90, 4.65 Hz), 6.26 (1 H, dd, J=9.58, 6.57 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.39 (1 H, dd, J=2.74, 1.64 Hz), 7.63 (1 H, br s), 7.81 (1 H, d, J=8.76 Hz), 7.99 (1 H, d, J=8.49 Hz), 8.50 (3 H, s), 10.85 (1 H, br s); ESIMS found C 22 H 24 F3N9O m / z 488.2 (M + 1).

[1019]

[1020] (R)-N 2 (R)-N

[1021] Fluffy white solid (6 mg, 0.012 mmol, 28.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.70 - 1.80 (1 H, m), 1.82 - 1.89 (1 H, m), 2.06 - 2.17 (1 H, m), 2.34 (1 H, dd, J=26.35, 12.05 Hz), 2.59 (3 H, s), 2.69 - 2.79 (1 H, m), 2.93 - 3.05 (1 H, m), 3.59 (1 H, quin, J=6.30 Hz), 4.18 - 4.35 (1 H, m), 4.43 (2 H, dt, J=13.83, 6.23 Hz), 4.50 - 4.56 (2 H, m), 4.55 (2 H, dt, J=27.45, 4.65 Hz), 4.78 (2 H, dt, J=47.20, 4.73 Hz), 6.12 (1 H, br d, J=9.58 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.63 (1 H, br s), 7.81 (1 H, d, J=8.49 Hz), 7.98 (1 H, d, J=8.49 Hz), 10.85 (1 H, br s); ESIMS found C 23 H 26 F3N9O m / z 251.7 (M / 2 + 1).

[1022]

[1023] 5-(3-(2,2-Difluoroethyl)-3H-[l,2,3]triazolo[4,5-b]pyridin-5-yl)-N 2 -(cis-4-(Difluoromethoxy)cyclohexyl)pyrrolo[2,l-f][l,2,4]triazine-2,4-diamine 1000.

[1024] Fluffy yellow solid (15 mg, 0.031 mmol, 49.4 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.57 - 1.68 (4 H, m), 1.70 - 1.78 (2 H, m), 1.82 - 1.90 (2 H, m), 3.60 - 3.72 (1 H, m), 4.27 (1 H, br s), 5.16 (2 H, td, J=16.22, 2.33 Hz), 6.13 (1 H, d, J=7.94 Hz), 6.58 (1 H, tt, J=54.00, 2.75 Hz), 6.72 (1 H, t, J=77.05 Hz), 7.32 (1 H, d, J=3.01 Hz), 7.45 (1 H, d, J=2.74 Hz), 7.57 (1 H, br s), 8.08 (1 H, d, J=9.03 Hz), 8.53 (1 H, d, J=9.03 Hz), 10.40 (1 H, br s); ESIMS found C 20 H 21 F4N9O m / z 480.2 (M+1).

[1025]

[1026] N 2 - (4, 4-difluorocyclohexyl)-5- (3- (2-fluoroethyl)-3H-imidazo [4, 5-b] pyridin-5-yl)-N 4 - methylpyrrolo [2, 1-f] [1, 2, 4] triazine-2, 4-diamine 1001.

[1027] Off-white solid (10 mg, 0.023 mmol, 54.6% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.55 - 1.68 (2 H, m), 1.82 - 2.00 (4 H, m), 2.01 - 2.14 (2 H, m), 3.10 (3 H, d, J=4.65 Hz), 3.78 (1 H, q, J=8.30 Hz), 4.65 (2 H, dt, J=27.45, 4.79 Hz), 4.93 (2 H, dt, J=46.90, 4.79 Hz), 6.16 (1 H, d, J=7.94 Hz), 7.12 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.88 (1 H, d, J=8.76 Hz), 8.13 (1 H, d, J=8.49 Hz), 8.45 (1 H, s), 11.11 (1 H, q, J=4.65 Hz); ESIMS found C 21 H 23 F3N8 m / z 223.2 (M / 2+1).

[1028]

[1029] 1 -((3R,4S)-3-fluoro-4-((5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1 -yl)ethan-1 -one 1002.

[1030] Off-white fluffy solid (10 mg, 0.021 mmol, 56.4% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.61 -1.71 (1 H, m), 1.73-1.86 (1 H, m), 1.98-2.05 (3H, m), 2.60-2.93 (1 H, m), 3.11 (3H, d, J=4.65 Hz), 3.83-3.92 (1 H, m), 3.93-4.05 (1 H, m), 4.07-4.18 (1 H, m), 4.40-4.49 (1 H, m), 4.66 (2H, dt, J=27.45, 4.93 Hz), 4.93 (2H, dt, J=46.90, 4.79 Hz), 4.97 (1 H, d, J=49.10 Hz), 6.09 (1 H, dd, J=7.94, 4.11 Hz), 7.14 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=2.74 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.49 Hz), 8.45 (1 H, s), 11.17 (1 H, q, J=4.29 Hz); ESIMS found C 22 H 25 F2N90 m / z 235.65 (M / 2+1 ).

[1031]

[1032] N 2 -((3R,4S)-3-Fluoro-1 -(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)-N4-methylpyrrolo[2,1 -f][1,2,4]triazin-2,4-diamine 1003.

[1033] Off-white fluffy solid (10 mg, 0.021 mmol, 56.4% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.65 - 1.76 (1 H, m), 1.87 (1 H, qd, J=12.09, 3.70 Hz), 1.96 - 2.03 (1 H, m), 2.13 (1 H, dd, J=37.00, 12.59 Hz), 2.74 (1 H, br d, J=12.05 Hz), 2.97 (1 H, br t, J=10.54 Hz), 3.11 (3 H, d, J=4.93 Hz), 3.48 (1 H, quin, J=6.43 Hz), 3.71 - 3.90 (1 H, m), 4.40 (1 H, t, J=6.16 Hz), 4.45 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.50, 3.15 Hz), 4.65 (2 H, dt, J=27.45, 3.79 Hz), 4.90 (1 H, d, J=49.90 Hz), 4.93 (2 H, dt, J=46.90, 3.79 Hz), 5.96 (1 H, d, J=7.94 Hz), 7.13 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.88 (1 H, d, J=8.49 Hz), 8.14 (1 H, d, J=8.76 Hz), 8.45 (1 H, s), 11.15 (1 H, q, J=4.56 Hz); ESIMS found C 23 H 27 F2N9O m / z 242.7 (M / 2 + 1).

[1034]

[1035] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2-fluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 1004.

[1036] Fluffy white solid (13 mg, 0.028 mmol, 72.0 % yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.81 (1 H, m), 1.81 - 1.88 (1 H, m), 2.11 - 2.20 (1 H, m), 2.25 (3 H, s), 2.36 (1 H, dd, J=27.15, 12.34 Hz), 2.77 (1 H, br d, J=11.77 Hz), 2.97 - 3.08 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 4.14 - 4.31 (1 H, m), 4.66 (2 H, dt, J=27.40, 4.79 Hz), 4.93 (2 H, dt, J=46.90, 4.79 Hz), 6.12 (1 H, d, J=9.58 Hz), 7.14 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.49 Hz), 8.45 (1 H, s), 11.17 (1 H, q, J=4.65 Hz); ESIMS found C 21 H 24 F3N9 m / z 230.65 (M / 2 + 1).

[1037]

[1038] (R)-N 2 -(3,3-difluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-(3-(2-fluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 1005.

[1039] Fluffy off-white solid (e (10 mg, 0.020 mmol, 57.2% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.82 (1 H, m), 1.83 - 1.91 (1 H, m), 2.14 (1 H, br t, J=10.68 Hz), 2.38 (1 H, dd, J=26.30, 11.77 Hz), 2.74 (1 H, br d, J=11.50 Hz), 2.95 - 3.05 (1 H, m), 3.13 (3 H, d, J=4.65 Hz), 3.60 (1 H, quin, J=6.30 Hz), 4.20 - 4.35 (1 H, m), 4.44 (2 H, dt, J=14.31, 6.26 Hz), 4.55 (2 H, td, J=6.64, 3.42 Hz), 4.66 (2 H, dt, J=27.40, 4.79 Hz), 4.94 (2 H, dt, J=46.90, 4.79 Hz), 6.21 (1 H, d, J=9.31 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.38 (1 H, d, J=2.74 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.49 Hz), 8.45 (1 H, s), 11.18 (1 H, q, J=4.65 Hz); ESIMS found C 23 H 26 F3N9Om / z 251.70 (M / 2+1).

[1040]

[1041] (R)-1-(3,3-difluoro-4-((5-(3-(2-fluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)piperidin-1-yl)ethan-1-one 1006.

[1042] Fluffy white solid (7 mg, 0.014 mmol, 46.8% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.56 - 1.80 (1 H, m), 1.82 - 1.99 (1 H, m), 2.02 - 2.08 (3 H, m), 3.00 (1 H, br t, J=10.81 Hz), 3.13 (3 H, d, J=4.65 Hz), 3.61 - 3.90 (1 H, m), 4.08 - 4.28 (1 H, m), 4.41 - 4.57 (2 H, m), 4.66 (2 H, dt, J=27.45, 4.79 Hz), 4.94 (2 H, dt, J=47.20, 4.95 Hz), 6.35 (1 H, dd, J=9.45, 6.43 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.38 (1 H, dd, J=2.74, 1.64 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.76 Hz), 8.46 (1 H, s), 11.20 (1 H, q, J=4.38 Hz); ESIMS found C 22 H 24 F3N9O m / z 244.65 (M / 2 + 1).

[1043]

[1044] N 2 -(4,4-difluorocyclohexyl)-5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 4 -methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 1007.

[1045] Off-white solid (12 mg, 0.026 mmol, 63.0% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.56 - 1.80 (1 H, m), 1.82 - 1.99 (1 H, m), 2.02 - 2.08 (3 H, m), 3.00 (1 H, br t, J=10.81 Hz), 3.13 (3 H, d, J=4.65 Hz), 3.61 - 3.90 (1 H, m), 4.08 - 4.28 (1 H, m), 4.41 - 4.57 (2 H, m), 4.66 (2 H, dt, J=27.45, 4.79 Hz), 4.94 (2 H, dt, J=47.20, 4.95 Hz), 6.35 (1 H, dd, J=9.45, 6.43 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.38 (1 H, dd, J=2.74, 1.64 Hz), 7.89 (1 H, d, J=8.76 Hz), 8.14 (1 H, d, J=8.76 Hz), 8.46 (1 H, s), 11.20 (1 H, q, J=4.38 Hz); ESIMS found C 21 H 22F4N8 m / z 232.1 (M / 2 + 1).

[1046]

[1047] (1r,4r)-4-((5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-1-methylcyclohexan-1-ol 1008.

[1048] Off-white fluffy solid (12 mg, 0.026 mmol, 54.3% yield). 1 H NMR (499 MHz, DMSO-d6) δ ppm 1.14 (3H, s), 1.35 - 1.49 (4H, m), 1.53 - 1.65 (2H, m), 1.78 - 1.90 (2H, m), 3.11 (3H, d, J=4.65 Hz), 3.62 (1H, br dd, J=8.35, 3.97 Hz), 4.21 (1H, s), 4.82 (2H, td, J=16.08, 2.60 Hz), 5.86 (1H, d, J=8.21 Hz), 6.62 (1H, tt, J=54.30, 3.00 Hz), 7.12 (1H, d, J=2.74 Hz), 7.38 (1H, d, J=3.01 Hz), 7.90 (1H, d, J=8.76 Hz), 8.14 (1H, d, J=8.76 Hz), 8.41 (1H, s), 10.95 (1H, q, J=4.38 Hz); ESIMS found C 22 H 26 F2N8 Om / z 457.2 (M + 1).

[1049]

[1050] 5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-N 2 -((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-N4-methylpyrrolo[2,1- f][1,2,4]triazine-2,4-diamine 1009.

[1051] Off-white fluffy solid (7 mg, 0.014 mmol, 33.0% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.65 - 1.76 (1 H, m), 1.87 (1 H, qd, J=12.05, 3.56 Hz), 1.95 - 2.04 (1 H, m), 2.13 (1 H, dd, J=37.30, 12.59 Hz), 2.75 (1 H, br d, J=11.23 Hz), 2.92 - 3.03 (1 H, m), 3.12 (3 H, d, J=4.65 Hz), 3.49 (1 H, quin, J=6.37 Hz), 3.73 - 3.90 (1 H, m), 4.40 (1 H, t, J=6.02 Hz), 4.46 (1 H, t, J=6.16 Hz), 4.54 (2 H, td, J=6.50, 3.15 Hz), 4.83 (2 H, td, J=16.20, 2.60 Hz), 4.91 (1 H, d, J=47.45 Hz), 5.97 (1 H, d, J=8.21 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.15 (1 H, d, J=3.01 Hz), 7.37 (1 H, d, J=3.01 Hz), 7.91 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 11.04 (1 H, q, J=4.56 Hz); ESIMS found C 23 H 26 F3N9O m / z 502.2 (M + 1).

[1052]

[1053] (R)-1-(4-((5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1- one 1010.

[1054] White solid (14 mg, 0.028 mmol, 32.1% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.53 - 1.81 (1 H, m), 1.82 - 1.98 (1 H, m), 2.01 - 2.09 (3 H, m), 2.92 - 3.05 (1 H, m), 3.15 (3 H, d, J=4.65 Hz), 3.58 - 3.91 (1 H, m), 4.08 - 4.27 (1 H, m), 4.41 - 4.61 (2 H, m), 4.84 (2 H, td, J=16.08, 2.60 Hz), 6.37 (1 H, dd, J=9.31, 5.75 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.17 (1 H, d, J=3.01 Hz), 7.38 (1 H, dd, J=2.87, 1.51 Hz), 7.92 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.76 Hz), 8.43 (1 H, s), 11.09 (1 H, q, J=4.56 Hz); ESIMS found C 22 H 23 F4N9O m / z 506.2 (M + 1).

[1055]

[1056] (R)-N 2 -(3,3-difluoro-1-methylpiperidin-4-yl)-5-(3-(2,2-difluoroethyl)-3H- imidazo[4,5-b]pyridin-5-yl)-N 4- methylpyrrolo[2,1-f][1,2,4]triazine-2,4-diamine 1011.

[1057] Fluffy off-white solid (14 mg, 0.029 mmol, 74.6% yield). 1H NMR (499 MHz, DMSO-d6) δ ppm 1.72 - 1.81 (1 H, m), 1.81 - 1.87 (1 H, m), 2.16 (1 H, br t, J=10.13 Hz), 2.25 (3 H, s), 2.36 (1 H, dd, J=27.15, 11.77 Hz), 2.77 (1 H, br d, J=11.77 Hz), 2.99 - 3.08 (1 H, m), 3.13 (3 H, d, J=4.93 Hz), 4.15 - 4.32 (1 H, m), 4.83 (2 H, td, J=16.45, 2.75 Hz), 6.14 (1 H, d, J=9.58 Hz), 6.63 (1 H, tt, J=54.30, 3.00 Hz), 7.16 (1 H, d, J=3.01 Hz), 7.39 (1 H, d, J=2.74 Hz), 7.92 (1 H, d, J=8.76 Hz), 8.16 (1 H, d, J=8.76 Hz), 8.42 (1 H, s), 11.06 (1 H, q, J=4.38 Hz); ESIMS found C 21 H 23 F4N9 m / z 239.65 (M / 2 + 1).

[1058]

[1059] 1-((3R,4S)-4-((5-(3-(2,2-difluoroethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-4- (methylamino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)amino)-3-fluoropiperidin-1-yl)ethan-1- one 1012.

[1060] pale yellow solid (...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: R 1 is optionally replaced by 1-10 R 4 Substituted (9-10 membered 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), optionally substituted by 1-10 R 5 substituted-heterocyclyl and optionally substituted by 1-12 R 6 Substituted-(C 1-5 alkylene) p Carbocyclic group, wherein the -(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted; R 3 Selected from the group consisting of: H, unsubstituted -(C 1-6 alkyl), unsubstituted-(C 2-6 alkenyl), unsubstituted-(C 2-6 Alkynyl), unsubstituted-(C 1-6 haloalkyl) and optionally substituted by 1-10 R 16 substituted-heterocyclyl; Each R 4 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl); Each R 5 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), optionally substituted by 1-10 R 7 Substituted -heterocyclyl, optionally substituted by 1-12 R 14 Substituted-carbocyclyl, -(C 1-5 alkylene) p OR 8 and C(=O)R 9 wherein said-(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted; Alternatively, two R attached to the same carbon atom 5 Together they form a carbonyl group; Each R 6 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -CN, -(C 1-5 alkylene) p OR 10 、-C(=O)R 11 、-NHC(=O)R 12 and optionally 1-12 R 14 Substituted-carbocyclyl, wherein the-(C 1-5 Alkylene) is optionally substituted with 1-5 halides and / or 1-3 unsubstituted -(C 1-3 alkyl) substituted; Each R 7 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl), unsubstituted-(C 1-9 haloalkyl), -CN and optionally 1-12 R 14 substituted-carbocyclyl; Each R 8 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 9 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); Each R 10 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 8 ; Each R 11 -N(R 13 )2; Each R 12 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); Each R 13 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 14 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl); R 15 selected from the group consisting of H and halides; Each R 16 are independently selected from the group consisting of: halides, unsubstituted-(C 1-9 alkyl), unsubstituted-(C 2-9 alkenyl), unsubstituted-(C 2-9 Alkynyl) and unsubstituted-(C 1-9 haloalkyl); Each p is independently 0 or 1; and wherein each H atom is optionally independently 2 H(D) (deuterium) substitution.

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

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

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 1-10 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 1-3 R 4 replace.

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

7. The compound according to any one of claims 1 to 6, wherein R 1 Selected from the group consisting of: It is optionally replaced by 1-3 R 4 replace.

8. A compound according to any one of claims 1 to 7, wherein R 4 Selected from halides, unsubstituted-(C 1-4 alkyl) and unsubstituted-(C 1-4 a group consisting of a halogenated alkyl group.

9. The compound according to any one of claims 1 to 8, wherein R 1 Selected from the group consisting of:

10. The compound according to any one of claims 1 to 9, wherein R 1 Selected from the group consisting of:

11. The compound according to any one of claims 1 to 10, wherein R 2 Selected from the group consisting of: optionally 1-4 R 5 substituted-heterocyclyl, and optionally substituted by 1-4 R 6 Substituted-carbocyclyl.

12. The compound according to any one of claims 1 to 11, wherein R 2 Selected from the group consisting of: Each R 5 Selected from Me, -C(=O)Me and The group composed of.

13. A compound according to any one of claims 1 to 12, wherein R 3 Selected from H and unsubstituted -(C 1-3 alkyl).

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

15. A compound according to any one of claims 1 to 13, wherein R 3 It is a methyl group.

16. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

21. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

22. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

23. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

24. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

25. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

26. The compound according to any one of claims 1 to 15, wherein the compound of formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

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

28. 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 according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27.

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

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

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

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

33. The method of any one of claims 28 and 31, 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, Down syndrome, Parkinson's disease with frontotemporal dementia-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 cell tauopathy, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and tau astrocytopathy associated with aging.

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

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

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