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WO2024211797A1 - Pyrrolo[2,1-f][1,2,4]triazines, ainsi que leur préparation et leurs utilisations - Google Patents

Pyrrolo[2,1-f][1,2,4]triazines, ainsi que leur préparation et leurs utilisations Download PDF

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Publication number
WO2024211797A1
WO2024211797A1 PCT/US2024/023387 US2024023387W WO2024211797A1 WO 2024211797 A1 WO2024211797 A1 WO 2024211797A1 US 2024023387 W US2024023387 W US 2024023387W WO 2024211797 A1 WO2024211797 A1 WO 2024211797A1
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unsubstituted
group
disease
alkyl
cancer
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Gopi Kumar Mittapalli
Chi Ching Mak
Brian Joseph HOFILENA
Lewis Daniel TURNER
Brian Walter Eastman
Ramkrishna Reddy VAKITI
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Biosplice Therapeutics Inc
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Biosplice Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • DYRK1A a pyrrolo[2,1-f][1,2,4]triazine compound or salts or analogs thereof
  • DYRK1A e.g., cancer, Down syndrome, Alzheimer’s disease, diabetes, viral infections, and osteoarthritis.
  • Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) comprise a family of protein kinases within the CMGC group of the eukaryotic kinome.
  • protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc.
  • Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease, and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease, and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder.
  • DYRKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium) (International Journal of Molecular Sciences (2021), 22(11), 6047).
  • DYRK1A has also been identified as a critical stabilizer of EGFR (Cell Death & Disease (2019), 10, 282) which is a crucial factor contributing to the keratinization, cell hyperproliferation, abnormal differentiation and inflammatory infiltration during the progress of psoriasis.
  • the present disclosure provides methods and reagents, involving contacting a cell with an agent, such as a pyrrolo[2,1-f][1,2,4]triazine compound, in a sufficient amount to antagonize DYRK1A activity, e.g., reduce the proliferation of head and neck squamous cell carcinoma, luminal/HER2 breast cancer (Cell (2016), 164(1-2), 293–309) or pancreatic adenocarcinoma, as well as impair the self-renewal capacity of glioblastoma and compromise ovarian cancer spheroid cell viability (Molecular Cancer Research (2017), 15(4), 371–381).
  • an agent such as a pyrrolo[2,1-f][1,2,4]triazine compound
  • the present disclosure also provides methods and reagents, involving contacting a cell with an agent, such as a pyrrolo[2,1-f][1,2,4]triazine compound, in a sufficient amount to antagonize DYRK1A activity, e.g., i) to normalize prenatal and early postnatal brain development; ii) to improve cognitive function in youth and adulthood; and/or iii) to attenuate Alzheimer’s-type neurodegeneration.
  • Some embodiments disclosed herein include DYRK1A inhibitors containing a pyrrolo[2,1-f][1,2,4]triazine core.
  • Other embodiments disclosed herein include pharmaceutical compositions and methods of treatment using these compounds.
  • One embodiment disclosed herein includes a compound having the structure of Formula (I): I or a pharmaceutically acceptable salt thereof, wherein, R 1 is selected from the group consisting of H and halide; R 2 is 9-10 membered heteroaryl optionally substituted with 1-10 R 4 ; R 3 is selected from the group consisting of –heterocyclyl optionally substituted with 1-10 R 5 and –carbocyclyl optionally substituted with 1-12 R 6 ; each R 4 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), and –(C 1-5 alkylene) p carbocyclyl optionally substituted with 1-12 R 7 , wherein the –(C 1-5 alkylene) is optionally substituted with 1
  • Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of Formula (I). Some embodiments include pharmaceutically acceptable salts of a compound of Formula (I). [009] Some embodiments include pro-drugs of a compound of Formula (I). [010] Some embodiments of the present disclosure include pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient.
  • DYRK1A includes methods of inhibiting DYRK1A by administering to a patient affected by a disorder or disease in which DYRK1A overexpression is implicated, such as Alzheimer’s disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease, and additional diseases with pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor, and stroke.
  • a disorder or disease in which DYRK1A overexpression is implicated such as Alzheimer’s disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease, and additional diseases with
  • Inhibitors of DYRK1A can also be used to treat tauopathies.
  • Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The spectrum of tau pathologies expands beyond the traditionally discussed disease forms like Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease. Emerging entities and pathologies include globular glial tauopathies, primary age-related tauopathy, which includes neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and aging-related tau astrogliopathy.
  • CTE chronic traumatic encephalopathy
  • FTLD-tau frontotemporal lobar degeneration with tau inclusions
  • aging-related tau astrogliopathy aging-related tau astrogliopathy.
  • Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson syndrome, parkinsonism, pure akinesia with gait freezing and, rarely, motor neuron symptoms or cerebellar ataxia (Handbook of Clinical Neurology (2016), 145, 355-368 and Aging Cell (2019), 18(5), e13000).
  • Inhibitors of DYRK1A can also be used to treat disorders associated with abnormal folate/methionine metabolism.
  • Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetes, psoriasis, knee osteoarthritis, tendinopathy, human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), hepatitis C virus (HCV), and herpes simplex virus 1 (HSV-1).
  • HIV-1 human immunodeficiency virus type 1
  • HCMV human cytomegalovirus
  • HCV hepatitis C virus
  • HSV-1 herpes simplex virus 1
  • Some embodiments of the present disclosure include methods to prepare compounds of Formula (I).
  • compositions and methods for inhibiting DYRK1A are provided herein.
  • Some embodiments provided herein relate to a method for treating a disease including, but not limited to, neurological diseases or disorders, cancers, cognitive deficits, knee osteoarthritis, tendinopathy, viral infections, unicellular parasite infections, and motor deficits.
  • non-limiting examples of a neurological disease or disorder which can be treated with the compounds and compositions provided herein include, but are not limited to, Alzheimer’s disease, amyotrophic lateral sclerosis, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease tauopathies, and additional diseases with pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor, and stroke.
  • Alzheimer’s disease amyotrophic lateral sclerosis
  • Down syndrome frontotemporal dementia with parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease tauopathies
  • additional diseases with pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis
  • diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor
  • non-limiting examples of cancers which can be treated with the compounds and compositions provided herein include solid cancers (e.g., glioblastoma, ovarian, breast, and pancreatic cancers) and leukemias (e.g., acute lymphoblastic leukemia, acute megakaryoblastic leukemia, and chronic myeloid leukemia).
  • solid cancers e.g., glioblastoma, ovarian, breast, and pancreatic cancers
  • leukemias e.g., acute lymphoblastic leukemia, acute megakaryoblastic leukemia, and chronic myeloid leukemia.
  • pharmaceutical compositions are provided that are effective for treatment of a disease of an animal, e.g., a mammal, caused by DYRK1A overexpression.
  • the composition includes a pharmaceutically acceptable carrier and a compound as described herein.
  • alkyl means a branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl.
  • Alkyl groups can either be unsubstituted or substituted with one or more substituents.
  • alkyl groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
  • alkenyl means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
  • alkenyl groups can either be unsubstituted or substituted with one or more substituents.
  • alkenyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
  • alkynyl means a straight or branched chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, and the like.
  • alkynyl groups can either be unsubstituted or substituted with one or more substituents.
  • alkynyl groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
  • alkylene means a bivalent branched or straight chain chemical group containing only carbon and hydrogen, such as methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentylene and neo-pentylene.
  • Alkylene groups can either be unsubstituted or substituted with one or more substituents.
  • alkylene groups include 1 to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).
  • alkenylene means a bivalent branched or straight chain chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, such as ethenylene, 1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1- butenylene, 2-butenylene, and the like.
  • alkenylene groups can either be unsubstituted or substituted with one or more substituents.
  • alkenylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
  • alkynylene means a bivalent 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.
  • alkynylene groups can either be unsubstituted or substituted with one or more substituents.
  • alkynylene groups will comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).
  • alkoxy means an alkyl-O— group in which the alkyl group is as described herein.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear or branched positional isomers thereof.
  • haloalkoxy means a haloalkyl-O— group in which the haloalkyl group is as described herein.
  • haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and also the linear or branched positional isomers thereof.
  • “carbocyclyl” means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include multiple fused rings. Carbocyclyls may have any degree of saturation provided that none of the rings in the ring system are aromatic.
  • Carbocyclyl groups can either be unsubstituted or substituted with one or more substituents.
  • carbocyclyl groups include 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.
  • aryl means a mono-, bi-, tri- or polycyclic group with only carbon atoms present in the ring backbone having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic.
  • Aryl groups can either be unsubstituted or substituted with one or more substituents.
  • aryl examples include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H- indenyl, and others. In some embodiments, the aryl is phenyl.
  • arylalkylene means an aryl-alkylene- group in which the aryl and alkylene moieties are as previously described. In some embodiments, arylalkylene groups contain a C 1- 4alkylene moiety. Exemplary arylalkylene groups include benzyl and 2-phenethyl.
  • heteroaryl means a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S. Heteroaryl groups can either be unsubstituted or substituted with one or more substituents.
  • heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • halo is a chloro, bromo, fluoro, or iodo atom radical.
  • a halo is a chloro, bromo or fluoro.
  • a halide can be fluoro.
  • haloalkyl means a hydrocarbon substituent, which is a linear or branched alkyl, alkenyl or alkynyl substituted with one or more chloro, bromo, fluoro, and/or iodo atom(s).
  • a haloalkyl is a fluoroalkyl, wherein one or more of the hydrogen atoms have been substituted by fluoro.
  • haloalkyls are 1 to 3 carbons in length (e.g., 1 to 2 carbons in length or 1 carbon in length).
  • haloalkylene means a diradical variant of haloalkyl, and such diradicals may act as spacers between radicals, other atoms, or between a ring and another functional group.
  • heterocyclyl means a nonaromatic cyclic ring system comprising at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple fused rings such as bicyclic and spirocyclic heterocyclyls. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 3-11 members.
  • heteroatom(s) are selected from one to three of O, N and S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, and S.
  • heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3- dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl
  • the heterocyclyl is selected from azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.
  • “monocyclic heterocyclyl” means a single nonaromatic cyclic ring comprising at least one heteroatom in the ring system backbone. Heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, heterocycles have 3-7 members.
  • the heteroatom(s) are selected from one to three of O, N and S, and wherein when the heterocycle is five membered, it can have one or two heteroatoms selected from O, N, and S.
  • monocyclic heterocyclyls include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4- dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazo
  • bicyclic heterocyclyl means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone. Bicyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, bicyclic heterocycles have 4-11 members with the heteroatom(s) being selected from one to five of O, N and S.
  • bicyclic heterocyclyls examples include 2-azabicyclo[1.1.0]butane, 2- azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5- azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3- azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7- azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, and the like.
  • spirocyclic heterocyclyl means a nonaromatic bicyclic ring system comprising at least one heteroatom in the ring system backbone and with the rings connected through just one atom. Spirocyclic heterocyclyls may be substituted or unsubstituted with one or more substituents. In some embodiments, spirocyclic heterocycles have 5-11 members with the heteroatom(s) being selected from one to five of O, N and S.
  • spirocyclic heterocyclyls examples include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2- azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7- diazaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, and the like. [041] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more non-hydrogen atoms of the molecule.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • Substituents can include, for example, –(C 1-9 alkyl) optionally substituted with one or more of hydroxyl, -NH 2 , -NH(C 1-3 alkyl), and –N(C 1-3 alkyl) 2 ; -(C 1-9 haloalkyl); a halide; a hydroxyl; a carbonyl [such as -C(O)OR, and -C(O)R]; a thiocarbonyl [such as -C(S)OR, -C(O)SR, and -C(S)R]; –(C 1-9 alkoxy) optionally substituted with one or more of halide, hydroxyl, -NH 2 , -NH(C 1-3 alkyl), and –N(C 1-3 alkyl) 2 ; - OPO(OH) 2 ; a phosphonate [such as -PO(OH) 2 and -PO(OR’) 2 ]; -
  • the substituent is selected from –(C 1-6 alkyl), -(C 1- 6 haloalkyl), a halide (e.g., F), a hydroxyl, -C(O)OR, -C(O)R, –(C 1-6 alkoxyl), -NRR’, -C(O)NRR’, and a cyano, in which each occurrence of R and R’ is independently selected from H and –(C 1-6 alkyl).
  • a halide e.g., F
  • the compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
  • the present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of Formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include, but are not limited to, isotopes of hydrogen, such as 2 H (deuterium) and 3 H (tritium), isotopes of carbon, such as 11 C, 13 C and 14 C, isotopes of chlorine, such as 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O, 17 O and 18 O, isotopes of phosphorus, such as 32 P, and isotopes of sulfur, such as 35 S.
  • isotopes of hydrogen such as 2 H (deuterium) and 3 H (tritium
  • isotopes of carbon such as 11 C, 13 C and 14 C
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • administering refers to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method of administration is, e.g., orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro- otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation
  • a “diagnostic” as used herein is a compound, method, system, or device that assists in the identification or characterization of a health or disease state.
  • the diagnostic can be used in standard assays as is known in the art.
  • the term “mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and non- human primates, but also includes many other species.
  • pharmaceutically acceptable carrier examples include any and all solvents, co- solvents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable.
  • pharmaceutically acceptable carrier examples include any and all solvents, co- solvents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable.
  • the use of such media 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.
  • various adjuvants such as are commonly used in the art may be included.
  • salts are known in the art, for example, as described in WO 87/05297.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, 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.
  • “Patient” as used herein means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate, or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • the patient is a human.
  • a “therapeutically effective amount” of a compound as provided herein is one which is sufficient to achieve the desired physiological effect and may vary according to the nature and severity of the disease condition, and the potency of the compound.
  • “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula (I) in combination with one or more other agents that are effective to treat the diseases and/or conditions described herein.
  • the combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease.
  • a therapeutic effect relieves, to some extent, one or more of the symptoms of the disease.
  • “Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes.
  • the term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing, or preventing the further development of a disorder, and/or reducing the severity of symptoms that will or are expected to develop.
  • drug-eluting and/or controlled release refers to any and all mechanisms, e.g., diffusion, migration, permeation, and/or desorption by which the drug(s) incorporated in the drug-eluting material pass therefrom over time into the surrounding body tissue.
  • drug-eluting material and/or controlled release material as used herein refers to any natural, synthetic, or semi-synthetic material capable of acquiring and retaining a desired shape or configuration and into which one or more drugs can be incorporated and from which incorporated drug(s) are capable of eluting over time.
  • “Elutable drug” as used herein refers to any drug or combination of drugs having the ability to pass over time from the drug-eluting material in which it is incorporated into the surrounding areas of the body.
  • Compounds [058] The compounds and compositions described herein can be used to inhibit DYRK1A for treating a disorder or disease in which DYRK1A overexpression is implicated, such as in neurological diseases or disorders, cancers, cognitive deficits, knee osteoarthritis, tendinopathy, viral infections, unicellular parasite infections, and motor deficits.
  • Some embodiments of the present disclosure include compounds of Formula (I): or salts, pharmaceutically acceptable salts, or prodrugs thereof.
  • R 1 is selected from the group consisting of H and halide (e.g., F, Cl, Br, I). [061] In some embodiments of Formula (I), R 1 is H. [062] In some embodiments of Formula (I), R 1 is halide (e.g., F, Cl). [063] In some embodiments of Formula (I), R 1 is F. [064] In some embodiments of Formula (I), R 2 is 9-10 membered heteroaryl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 4 .
  • 1-10 e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1
  • R 2 is a 9-membered bicyclic heteroaryl optionally substituted with 1-3 (e.g., 1-2, 1) R 4 .
  • R 2 is a 9–membered bicyclic heteroaryl optionally substituted with 1-3 R 4 , wherein each R 4 is independently selected from the group consisting of halide (e.g., F, Cl), unsubstituted –(C 1-3 alkyl), and unsubstituted –(C 1-3 haloalkyl).
  • R 2 selected from the group consisting of: optionally substituted with 1-3 R 4 .
  • R 2 is selected from the group consisting of: , optionally substituted with 1-3 R 4 .
  • R 2 selected from the group consisting of: substituted with one halide (e.g., F, Cl), and/or one unsubstituted –(C 1-3 alkyl), and/or one unsubstituted –(C 1-3 haloalkyl).
  • R 2 selected from the group consisting
  • R 3 is selected from the group consisting of –heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R 5 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 6 .
  • R 3 is selected from the group consisting of –heterocyclyl optionally substituted with 1-3 (e.g., 1-2, 1) R 5 and –carbocyclyl optionally substituted with 1-3 (e.g., 1-2, 1) R 6 .
  • R 3 is selected from the group consisting selected from the group consisting of N, O, and S.
  • R 3 is selected from the group consisting selected from the group consisting of N and O.
  • 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), and –(C 1-5 alkylene) p 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 7 , wherein the –(C 1-5 alkylene) is optionally substituted with 1-5 halide (e.g., F, Cl, Br, I) and/or 1-3 unsubstituted –(C 1-3 alkyl).
  • halide e.g., F, Cl, Br, I
  • 1-5 halide e.g.,
  • each R 4 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), and –(C 1-2 alkylene) p carbocyclyl optionally substituted with 1-3 (e.g., 1-2, 1) R 7 , wherein the –(C 1-2 alkylene) is optionally substituted with 1-2 F and/or 1-2 Me.
  • 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
  • each R 4 is independently selected from the group consisting of F, unsubstituted –(C 1-3 alkyl), unsubstituted –(C 1-3 haloalkyl), and – (CH 2 ) p carbocyclyl optionally substituted with 1-2 R 7 .
  • halide e.g., F, Cl
  • unsubstituted –(C 1-4 alkyl) unsubstituted –(C 2-4
  • two R 5 attached to the same carbon atom are taken together to form a carbonyl group.
  • halide e.g., F, Cl, Br, I
  • halide e.g., F, Cl
  • 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).
  • 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
  • each R 7 is independently selected from the group consisting of F, Cl, unsubstituted –(C 1-4 alkyl), unsubstituted –(C 2-4 alkenyl), unsubstituted –(C 2-4 alkynyl), and unsubstituted –(C 1-4 haloalkyl).
  • each R 7 is independently selected from the group consisting of F, Me, Et, –CF 3 , –CHF 2 , and –CH 2 F.
  • 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).
  • 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
  • each R 8 is independently selected from the group consisting of F, Cl, unsubstituted –(C 1-4 alkyl), unsubstituted –(C 2-4 alkenyl), unsubstituted –(C 2-4 alkynyl), and unsubstituted –(C 1-4 haloalkyl).
  • each R 8 is independently selected from the group consisting of F, Me, Et, –CF 3 , –CHF 2 , and –CH 2 F.
  • 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).
  • 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
  • each R 9 is independently selected from the group consisting of F, Cl, unsubstituted –(C 1- 4 alkyl), unsubstituted –(C 2-4 alkenyl), unsubstituted –(C 2-4 alkynyl), and unsubstituted –(C 1- 4 haloalkyl).
  • each R 9 is independently selected from the group consisting of F, Me, Et, –CF 3 , –CHF 2 , and –CH 2 F.
  • 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), and unsubstituted –(C 1-9 haloalkyl).
  • 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), and unsubstituted –(C 1- 4 haloalkyl).
  • each R 10 is independently selected from the group consisting of H, Me, Et, –CF 3 , –CHF 2 , and –CH 2 F.
  • each R 11 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).
  • each R 11 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).
  • each R 11 is independently selected from the group consisting of Me, Et, –CF 3 , –CHF 2 , and –CH 2 F.
  • each R 12 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 10 , wherein the –(C 1-5 alkylene) is optionally substituted with 1-5 halide (e.g., F, Cl, Br, I) and/or 1-3 unsubstituted –(C 1- 3 alkyl).
  • 1-5 halide e.g., F, Cl, Br, I
  • each R 12 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 10 , wherein the –(C 1-2 alkylene) is optionally substituted with 1-2 F and/or 1-2 Me.
  • each R 12 is independently selected from the group consisting of H, Me, Et, –CF 3 , –CHF 2 , –CH 2 F, and –(CH 2 CH 2 ) p OR 10 .
  • 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).
  • each R 13 is independently selected from the group consisting of H, unsubstituted –(C 1- 4 alkyl), unsubstituted –(C 2-4 alkenyl), unsubstituted –(C 2-4 alkynyl), and unsubstituted –(C 1- 4 haloalkyl).
  • each R 13 is independently selected from the group consisting of H, Me, Et, –CF 3 , –CHF 2 , and –CH 2 F.
  • 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).
  • 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).
  • each R 13 is independently selected from the group consisting of Me, Et, –CF 3 , –CHF 2 , and –CH 2 F.
  • each p is independently 0 or 1.
  • each H atom is optionally, independently replaced by 2 H (D) (deuterium).
  • Illustrative compounds of Formula (I) are shown in Table 1. Table 1.
  • compositions comprising: (a) a therapeutically effective amount of a compound provided herein, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.
  • a compound provided herein or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt
  • a pharmaceutically acceptable carrier or pharmaceutically acceptable carrier.
  • Non-limiting examples of diseases which can be treated with a combination of a compound of Formula (I) and another active agent are colorectal cancer, ovarian cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, acute lymphoblastic leukemia (ALL), pancreatic cancer, brain tumors, acute megakaryoblastic leukemia (AMKL), and osteoarthritis.
  • a compound of Formula (I) can be combined with one or more chemotherapeutic compounds.
  • hepatocellular carcinoma can be treated with a combination of a compound of Formula (I) and one or more of the following drugs/therapies: sorafenib (Nexavar ® ); regorafenib (Stivarga ® , Regonix ® ), nivolumab (Opdivo ® ); lenvatinib (Lenvima ® ); pembrolizumab (Keytruda ® ); cabozantinib (Cometriq ® , Cabometyx ® ); 5-fluorouracil (5-FU ® ); ramucirumab (Cyramza ® ); combination of gemcitabine and oxaliplatin (GEMOX).
  • TACE transcatheter arterial chemoembolization
  • DOXIL ® doxorubicin
  • cisplatin doxorubicin
  • mitomycin C Mitosol ® , Mutamycin ® , Jelmyto ®
  • low-dose brachytherapy i) transcatheter arterial chemoembolization (TACE) in combination with doxorubicin (DOXIL ® ), cisplatin, or mitomycin C (Mitosol ® , Mutamycin ® , Jelmyto ® ); and ii) low-dose brachytherapy.
  • head and neck squamous cell carcinoma can be treated with a combination of a compound of Formula (I) and one or more of the following drugs/therapies: TransOral Robotic Surgery (TORS); TORS with radiation therapy; larotrectinib (Vitrakvi ® ); EGFR inhibitors, e.g., erlotinib (Tarceva ® ), osimertinib (Tagrisso ® ), neratinib (Nerlynx ® ), gefitinib (Iressa ® ), cetuximab (Erbitux ® ), panitumumab (Vectibix ® ), dacomitinib (Vizimpro ® ), lapatinib (Tykerb ® ), necitumumab (Portrazza), and vandetanib (Caprelsa ® ).
  • TORS TransOral Robotic Surgery
  • TORS with radiation therapy
  • larotrectinib
  • acute lymphoblastic leukemia can be treated with a combination of a compound of Formula (I) and one or more of the following drugs/therapies: remission induction therapy; consolidation therapy; nelarabine (Arranon ® ); asparaginase erwinia chrysanthemi (Erwinaze ® ); asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze ® ); calaspargase Pegol-mknl (Asparlas ® ); inotuzumab ozogamicin (Besponsa ® ); blinatumomab (Blincyto ® ); daunorubicin hydrochloride (Cerubidine ® ); clofarabine (Clolar ® ); cyclophosphamide; methotrexate sodium (Trexall ® ); c
  • pancreatic cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs/therapies: ablation and embolization treatment; gemcitabine (Gemzar ® ); 5-fluorouracil (5-FU ® ); oxaliplatin (Eloxatin ® ); albumin-bound paclitaxel (Abraxane ® ); capecitabine (Xeloda ® ); cisplatin; irinotecan (Camptosar ® ); liposomal Irinotecan (Onivyde ® ); paclitaxel (Taxol ® ), and docetaxel (Taxotere ® ).
  • ablation and embolization treatment gemcitabine (Gemzar ® ); 5-fluorouracil (5-FU ® ); oxaliplatin (Eloxatin ® ); albumin-bound paclitaxel (Abraxane ® ); cap
  • brain tumors can be treated with a combination of a compound of Formula (I) and one or more of the following drugs/therapies: carmustine can be administered by way of a gliadel wafer; for glioblastoma and high-grade glioma, radiation therapy with daily low-dose temozolomide (Temodar ® ) followed by monthly doses of temozolomide after radiation therapy for 6 months to 1 year; lomustine (Gleostine ® ), procarbazine (Matulane ® ), and vincristine (Vincasar ® ), have been used along with radiation therapy; anti-angiogenesis therapy with bevacizumab (Avastin ® , Mvasi ® ); and targeted therapy using larotrectinib (Vitrakvi ® ).
  • carmustine can be administered by way of a gliadel wafer; for glioblastoma and high-grade glioma, radiation therapy with daily low-dose temozolomide (
  • AKL acute megakaryoblastic leukemia
  • AKL can be treated with a combination of a compound of Formula (I) and one or more of the following drugs/therapies: cytarabine (Cytosar-U ® ), etoposide (Vepesid ® ), and anthracycline drugs.
  • Anthracyclines include daunorubicin (Cerubidine ® ), idarubicin (Idamycin ® ), and mitoxantrone (Novantrone ® ).
  • AML acute myeloid leukemia
  • venetoclax and hypomethylating agents e.g., decitabine, azacitidine
  • induction chemotherapy cytarabine and an anthracycline (e.g., daunorubicin or idarubicin)
  • ATRA all-trans-retinoic acid
  • ATO arsenic trioxide
  • consolidation therapy cytarabine
  • myelodysplastic syndrome can be treated with a combination of a compound of Formula (I) and one or more of the following drugs/therapies: 5- azacytidine, decitabine, lenalidomide, and decitabine/cedazuridine (Inqovi ® ).
  • colorectal cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: 5-fluorouracil (5-FU), which can be administered with the vitamin-like drug leucovorin (also called folinic acid); capecitabine (XELODA ® ), irinotecan (CAMPOSTAR ® ), oxaliplatin (ELOXATIN ® ).
  • 5-fluorouracil 5-FU
  • XELODA ® irinotecan
  • CAMPOSTAR ® irinotecan
  • ELOXATIN ® oxaliplatin
  • Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are FOLFOX (5- FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin).
  • FOLFOX 5- FU, leucovorin, and oxaliplatin
  • FOLFIRI 5-FU, leucovorin, and irinotecan
  • FOLFOXIRI leucovorin, 5-FU, oxaliplatin, and irinotecan
  • CapeOx CapeOx
  • chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).
  • ovarian cancer can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: topotecan, liposomal doxorubicin (DOXIL ® ), gemcitabine (GEMZAR ® ), cyclophosphamide (CYTOXAN ® ), vinorelbine (NAVELBINE ® ), ifosfamide (IFEX ® ), etoposide (VP-16), altretamine (HEXALEN ® ), capecitabine (XELODA ® ), irinotecan (CPT-11, CAMPTOSAR ® ), melphalan, pemetrexed (ALIMTA ® ) and albumin-bound paclitaxel (nab-paclitaxel, ABRAXANE ® ).
  • topotecan liposomal doxorubicin (DOXIL ® ), gemcitabine (GEMZAR ® ), cyclophospham
  • Examples of combinations of these drugs which could be further combined with a compound of Formula (I) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP (etoposide [VP-16], ifosfamide, and cisplatin).
  • TIP paclitaxel [Taxol], ifosfamide, and cisplatin
  • VeIP vinblastine, ifosfamide, and cisplatin
  • VIP etoposide [VP-16], ifosfamide, and cisplatin
  • Ovarian cancer can also be treated with a combination of a compound of Formula (I) and immune checkpoint blockade (ICB) therapy.
  • IRB immune checkpoint blockade
  • a compound of Formula (I) can be used to treat cancer in combination with any of the following methods: (a) hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy and cryosurgery (cryotherapy); (c) chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide; (d) chemotherapy using anti-metabolites such as azathioprine and mercaptopurine; (e) chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (e.g., vincristine, vinblastine, vinorelbine, and vindesine) and taxanes; (f) chemotherapy
  • hormone therapy such as aromat
  • BRAF inhibitors e.g., vemurafenib, dabrafenib, and LGX818, BRAF inhibitors (e.g., vemurafenib, dabrafenib, and LGX818), MEK inhibitors (e.g., trametinib and MEK162), CDK inhibitors (e.g., PD-0332991), salinomycin, and sorafenib; (j) chemotherapy using monoclonal antibodies such as rituximab (marketed as MABTHERA ® or RITUXAN ® ), trastuzumab (Herceptin also known as ErbB2), cetuximab (marketed as ERBITUX ® ), and bevacizumab (marketed as AVASTIN ® ); (k) chemotherapy using KRAS G12C inhibitors such as sotorasib (Lumakras ® and Lumykras ® ), adagrasib (MRT
  • a compound of Formula (I) can be used to treat diabetes mellitus in combination with any of the following methods: (a) injections of insulin; (b) biguanides such as metformin (Glucophage), phenformin (DBI), and buformin; (c) thiazolidinediones (TZDs) such as rosiglitazone (Avandia), pioglitazone (Actos), and yroglitazone (Rezulin); (d) lyn kinase activators such as glimepiride (Amaryl ® ) and tolimidone (MLR-1023); (e) secretagogues such as sulfonylureas (non-limiting examples are acetohexamide, carbutamide, chlorpropamide, glycyclamide (tolcyclamide), metahexamide, tolazamide, tolbutamide, glibenclamide (glyburide), glibornuri
  • TGDs rosi
  • a compound of Formula (I) can be used to treat osteoarthritis in combination with any of the following methods: (d) injections of a Wnt signaling pathway inhibitor (e.g. lorecivivint); (a) nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin, and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Hyalgan, Synvisc Hyalgan, Synvisc
  • narcotics like codeine
  • f in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices);
  • splints e.g., splints, braces, shoe inserts or other medical devices
  • realigning bones osteotomy
  • arthroplasty joint replacement
  • i) in combination with a chronic pain class a chronic pain class.
  • a compound of Formula (I) can be used to treat Alzheimer’s disease in combination with aducanumab (Aduhelm TM ); acetylcholinesterase inhibitors, e.g., tacrine, rivastigmine (Exelon ® ), galantamine (Razadyne ® and GalantaMind TM ), and donepezil (Aricept ® ); and memantine (Axura ® , Ebixa ® , Namenda ® ).
  • aducanumab Aduhelm TM
  • acetylcholinesterase inhibitors e.g., tacrine, rivastigmine (Exelon ® ), galantamine (Razadyne ® and GalantaMind TM ), and donepezil (Aricept ® ); and memantine (Axura ® , Ebixa ® , Namenda ® ).
  • Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration, including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro- otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intrac
  • the administration method includes oral or parenteral administration.
  • Compounds provided herein intended for pharmaceutical use may be administered as crystalline or amorphous products.
  • Pharmaceutically acceptable compositions may include solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, complexes, coacervates and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release, or the like.
  • the compounds may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compounds can be administered either alone or in combination with a conventional pharmaceutical carrier, excipient, or the like.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self- emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers 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 carboxymethyl cellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.
  • Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared.
  • the contemplated compositions may contain 0.001%-100% of a compound provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.
  • the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, or the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or the like
  • a lubricant such as magnesium stearate or the like
  • a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, or the like.
  • a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEGs, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule).
  • Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated, e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc.
  • a compound provided herein and optional pharmaceutical adjuvants in a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol, or the like
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol, or the like
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
  • the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 50 mg/Kg in humans. [0136] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.25 mg/Kg to about 20 mg/Kg in humans. [0137] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.50 mg/Kg to about 19 mg/Kg in humans. [0138] In some embodiments, the unit dosage of compounds of Formula (I) is about 0.75 mg/Kg to about 18 mg/Kg in humans. [0139] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.0 mg/Kg to about 17 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 1.25 mg/Kg to about 16 mg/Kg in humans. [0141] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.50 mg/Kg to about 15 mg/Kg in humans. [0142] In some embodiments, the unit dosage of compounds of Formula (I) is about 1.75 mg/Kg to about 14 mg/Kg in humans. [0143] In some embodiments, the unit dosage of compounds of Formula (I) is about 2.0 mg/Kg to about 13 mg/Kg in humans. [0144] In some embodiments, the unit dosage of compounds of Formula (I) is about 3.0 mg/Kg to about 12 mg/Kg in humans.
  • the unit dosage of compounds of Formula (I) is about 4.0 mg/Kg to about 11 mg/Kg in humans. [0146] In some embodiments, the unit dosage of compounds of Formula (I) is about 5.0 mg/Kg to about 10 mg/Kg in humans. [0147] In some embodiments, the compositions are provided in unit dosage forms suitable for single administration. [0148] In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration. [0149] In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration.
  • Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection.
  • the percentage of a compound provided herein contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the patient. However, percentages of active ingredient of 0.01% to 10% in solution are employable and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.
  • the composition comprises about 0.1-10% of the active agent in solution.
  • the composition comprises about 0.1-5% of the active agent in solution. [0153] In some embodiments, the composition comprises about 0.1-4% of the active agent in solution. [0154] In some embodiments, the composition comprises about 0.15-3% of the active agent in solution. [0155] In some embodiments, the composition comprises about 0.2-2% of the active agent in solution. [0156] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-96 hours. [0157] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-72 hours.
  • the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-48 hours. [0159] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-24 hours. [0160] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-12 hours. [0161] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of about 1-6 hours. [0162] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 300 mg/m 2 .
  • these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 200 mg/m 2 . [0164] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 5 mg/m 2 to about 100 mg/m 2 . [0165] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 10 mg/m 2 to about 50 mg/m 2 . [0166] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of about 50 mg/m 2 to about 200 mg/m 2 .
  • these compositions can be administered by intravenous infusion to humans at doses of about 75 mg/m 2 to about 175 mg/m 2 .
  • these compositions can be administered by intravenous infusion to humans at doses of about 100 mg/m 2 to about 150 mg/m 2 .
  • concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated.
  • compositions can be administered to the respiratory tract (including nasal and pulmonary), e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique.
  • aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose.
  • inhaled particle sizes For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size may be desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation.
  • aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth.
  • inhaled aerodynamic particle sizes of about less than 10 ⁇ m are useful (e.g., about 1 to about 10 microns).
  • Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.
  • compounds of Formula (I) disclosed herein intended for respiratory delivery can be administered as aqueous formulations, as non-aqueous solutions, or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates, or as dry powders.
  • Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose ® or the AERx ® systems).
  • Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs).
  • Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.
  • DPIs dry powder inhaler devices
  • the compositions of Formula (I) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat. Nos.6,440,102 and 6,648,873) can be used.
  • formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).
  • formulations of the disclosure can be incorporated into a gel formulation (e.g., U.S. Pat. Nos.4,474,752 and 6,911,211).
  • compounds of Formula (I) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.
  • Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose.
  • the acidic or basic solid compound of Formula (I) can be delivered from the reservoir of an external or internal implanted pumping system.
  • Formulations of the disclosure also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No.6,377,849 and Ser. No.11/337,815).
  • Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear.
  • the formulations described herein are administered directly onto the round window membrane via transtympanic injection.
  • the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear.
  • the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
  • the compounds of Formula (I) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.
  • Suppositories for rectal administration of the drug can be prepared by mixing a compound provided herein with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the compound.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
  • Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the compound provided herein, the desired dissolution rate, cost considerations, and other criteria.
  • the solid composition is a single unit. This implies that one unit dose of the compound is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.
  • Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like.
  • the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the compound.
  • the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like.
  • the solid composition is a lyophilized powder.
  • a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution.
  • Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound.
  • Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with a compound provided herein so that the compound is located at the outer surface of the individual particles.
  • the water-soluble low molecular weight excipient may be useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the compound and, for example, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
  • a kit includes one or more compounds or compositions as described herein.
  • a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided herein, and directions for use of the kit (e.g., instructions for treating a patient).
  • the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer.
  • the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of glioblastoma, ovarian, breast, pancreatic cancers, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, chronic myeloid leukemia, Alzheimer’s disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease, autism, dementia, epilepsy, Huntington’s disease, and multiple sclerosis.
  • glioblastoma ovarian, breast, pancreatic cancers
  • acute lymphoblastic leukemia acute megakaryoblastic leukemia
  • chronic myeloid leukemia Alzheimer’s disease
  • Alzheimer’s disease amyotrophic lateral sclerosis
  • CDKL5 deficiency disorder Down syndrome
  • the compounds and compositions provided herein can be used as inhibitors of DYRK1A, and thus can be used to treat a variety of disorders and diseases in which over expression of DYRK1A is implicated, such as cancer and neurological conditions/disorders/diseases.
  • Non- limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, Alzheimer’s disease, amyotrophic lateral sclerosis, CDKL5 deficiency disorder, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease, and additional diseases with pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor, stroke, tauopathies (e.g., Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathies, primary age-related tauopathy, which includes neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration with tau inclusions (FTLD- tau), and aging-related tau a
  • Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson syndrome, parkinsonism, pure akinesia with gait freezing and, rarely, motor neuron symptoms or cerebellar ataxia, diabetes, psoriasis, knee osteoarthritis, tendinopathy, human immunodeficiency virus type 1 (HIV-1), human cytomegalovirus (HCMV), hepatitis C virus (HCV), and herpes simplex virus 1 (HSV-1).
  • HAV-1 human immunodeficiency virus type 1
  • HCMV human cytomegalovirus
  • HCV hepatitis C virus
  • HSV-1 herpes simplex virus 1
  • DYRK1A and DYRK1B are utilized during human cytomegalovirus (HCMV) placental replication.
  • HCV hepatitis C virus
  • HMV human cytomegalovirus
  • HAV-1 human immunodeficiency virus type 1
  • HSV-1 herpes simplex virus 1
  • diabetes Other forms of diabetes that may be treated with DYRK inhibitors are maturity onset diabetes of the young (MODY, monogenic diabetes), cases of diabetes that are caused by the body’s tissue receptors not responding to insulin, double diabetes (when a type 1 diabetic becomes insulin resistant), diabetes associated with excessive secretion of insulin-antagonistic hormones, malnutrition-related diabetes mellitus (ICD-10 code E12), and diabetes caused by any genetic mutations (autosomal or mitochondrial) that leads to defects in beta cell function.
  • MODY monogenic diabetes
  • cases of diabetes that are caused by the body’s tissue receptors not responding to insulin double diabetes (when a type 1 diabetic becomes insulin resistant)
  • diabetes associated with excessive secretion of insulin-antagonistic hormones e.g., malnutrition-related diabetes mellitus (ICD-10 code E12)
  • diabetes e.g., diabetes caused by any genetic mutations (autosomal or mitochondrial) that leads to defects in beta cell function.
  • pancreatic cancer (Gut (2019), 68(8), 1465–1476 and Gene (2020), 758, 144960), brain tumors, glioblastoma (Journal of Clinical Investigation (2013), 123(6), 2475-2487), acute megakaryoblastic leukemia (AMKL) (Journal of Clinical Investigation (2012), 122(3), 948–962), and acute lymphoblastic leukemia (ALL) (Journal of Clinical Investigation (2021), 131(1), e135937).
  • ANKL acute megakaryoblastic leukemia
  • ALL acute lymphoblastic leukemia
  • DYRK1A ovarian (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 regulates DNA damage response (Scientific Reports (2019), 9, 6014 and Scientific Reports (2019), 9, 6539). In some situations, DYRK1A appears to function as a tumor-suppressor protein (Molecular & Cellular Oncology (2015), 2(1), e970048 and Nature (2016), 529, 172–177). [0192] Other cancers can also be treated with the compounds and compositions described herein.
  • cancers that may be treated by the compounds, compositions and methods described herein include, but are not limited to, the following: [0194] 1) Breast cancers, including, for example ER + breast cancer, ER- breast cancer, her2- breast cancer, her2 + breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget’s disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; chemoresistant breast cancers (TNBC), and miscellaneous malignant neoplasms.
  • TNBC chemoresistant breast cancers
  • breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER-), progesterone receptor negative, and her2 negative (her2-).
  • the breast cancer may have a high risk Oncotype score.
  • Cardiac cancers including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma.
  • Lung cancers including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; chemoresistant small cell lung cancer (SCLC), and mesothelioma.
  • bronchogenic carcinoma e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma
  • alveolar and bronchiolar carcinoma bronchial adenoma
  • sarcoma sarcoma
  • lymphoma chondromatous hamartoma
  • SCLC chemoresistant small cell lung cancer
  • Gastrointestinal cancer including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; colon cancers with APC gene mutations; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocar
  • Genitourinary tract cancers including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm’s tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma.
  • adenocarcinoma Wilm’s tumor (nephroblastoma), lymphoma, and leukemia
  • Liver cancers including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.
  • hepatoma e.g., hepatocellular carcinoma
  • cholangiocarcinoma e.g., hepatocellular carcinoma
  • hepatoblastoma hepatoblastoma
  • angiosarcoma hepatocellular adenoma
  • hemangioma hemangioma
  • Bone cancers 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, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing’s sarcoma malignant lymphoma (reticulum cell sarcoma)
  • multiple myeloma malignant giant cell tumor chordoma
  • Nervous system cancers including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, oligodendrocytoma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma; pediatric brain cancer, e.g., neurofibroma
  • Gynecological cancers including, for example, cancers of the uterus, e.g., endometrial cancers (e.g., carcinoma, endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinomas, mixed or undifferentiated carcinoma (including mixed Müllerian tumor), endometrial stromal sarcoma, squamous cell carcinoma of the endometrium, urothelial carcinoma, endometrial cancer with CTNNB1 mutations); cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., BRCA-mutant ovarian cancer, surface epithelial-stromal tumors (epithelial ovarian cancer (Type 1 (endometroid, mucinous, clear cell, low grade serous) or Type 2 (poorly differentiated, carcinosarcoma, and high grade serous))
  • Hematologic cancers including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndromes (refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemias with excess blasts I and II, refractory cytopenia of childhood), and myeloproliferative neoplasms, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, myelodysplastic–myeloproliferative diseases, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (mal
  • Skin cancers and skin disorders including, for example, malignant melanoma and metastatic melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and scleroderma.
  • Adrenal gland cancers including, for example, neuroblastoma.
  • Soft-tissue sarcomas such as fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, Kaposi’s sarcoma, lymphangiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors (also called neurofibrosarcomas, malignant schwannomas, and neurogenic sarcomas), neurofibrosarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, extraskeletal mesenchymal, embryonal, alveolar soft part sarcoma, and infantile hemangio-pericytoma.
  • STS Soft-tissue sarcomas
  • tumors of the central nervous system that may be treated by the compounds, compositions and methods described herein include: [0208] 1) Astrocytic tumors, e.g., diffuse astrocytoma (fibrillary, protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastoma and gliosarcoma), pilocytic astrocytoma (pilomyxoid astrocytoma), pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and gliomatosis cerebri.
  • Astrocytic tumors e.g., diffuse astrocytoma (fibrillary, protoplasmic, gemistocytic, mixed), anaplastic (malignant) astrocytoma, glioblastoma multiforme (giant cell glioblastom
  • Oligodendroglial tumors e.g., oligodendroglioma and anaplastic oligodendroglioma.
  • Oligoastrocytic tumors e.g., oligoastrocytoma and anaplastic oligoastrocytoma.
  • Ependymal tumors e.g., subependymoma, myxopapillary ependymoma, ependymoma, (cellular, papillary, clear cell, tanycytic), and anaplastic (malignant) ependymoma.
  • Neuronal and mixed neuronal-glial tumors e.g., gangliocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplastic infantile astrocytoma/ganglioglioma, central neurocytoma, anaplastic ganglioglioma, extraventricular neurocytoma, cerebellar liponeurocytoma, Papillary glioneuronal tumor, Rosette-forming glioneuronal tumor of the fourth ventricle, and paraganglioma of the filum terminale.
  • gangliocytoma e.g., gangliocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor (DNET), dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos), desmoplastic infantile
  • Pineal tumors e.g., pineocytoma, pineoblastoma, papillary tumors of the pineal region, and pineal parenchymal tumor of intermediate differentiation.
  • Embryonal tumors e.g., medulloblastoma (medulloblastoma with extensive nodularity, anaplastic medulloblastoma, desmoplastic, large cell, melanotic, medullomyoblastoma), medulloepithelioma, supratentorial primitive neuroectodermal tumors, and primitive neuroectodermal tumors (PNETs) such as neuroblastoma, ganglioneuroblastoma, ependymoblastoma, and atypical teratoid/rhabdoid tumor.
  • PNETs neuroectodermal tumors
  • Neuroblastic tumors e.g., olfactory (esthesioneuroblastoma), olfactory neuroepithelioma, and neuroblastomas of the adrenal gland and sympathetic nervous system.
  • Glial tumors e.g., astroblastoma, chordoid glioma of the third ventricle, and angiocentric glioma.
  • Tumors of cranial and paraspinal nerves e.g., schwannoma, neurofibroma Perineurioma, and malignant peripheral nerve sheath tumor.
  • Tumors of the meninges such as tumors of meningothelial cells, e.g., meningioma (atypical meningioma and anaplastic meningioma); mesenchymal tumors, e.g., lipoma, angiolipoma, hibernoma, liposarcoma, solitary fibrous tumor, fibrosarcoma, malignant fibrous histiocytoma, leiomyoma, leiomyosarcoma, rhabdomyoma, rhabdomyosarcoma, chondroma, chondrosarcoma, osteoma, osteosarcoma, osteochondroma, haemangioma, epithelioid hemangioendothelioma, haemangiopericytoma, anaplastic haemangiopericytoma, angiosarcoma, Kaposi sarcoma, and Ewing
  • Tumors of the hematopoietic system e.g., malignant lymphomas, plasmocytoma, and granulocytic sarcoma.
  • Germ cell tumors e.g., germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, and mixed germ cell tumors.
  • Tumors of the sellar region e.g., craniopharyngioma, granular cell tumor, pituicytoma, and spindle cell oncocytoma of the adenohypophysis.
  • Cancers may be solid tumors that may or may not be metastatic.
  • cancers may also occur, as in leukemia, as a diffuse tissue.
  • tumor cell includes a cell afflicted by any one of the above identified disorders.
  • a method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy).
  • a compound or composition can be administered before, during, or after another anticancer agent or treatment.
  • DYRK1A phosphorylates key substrates involved in Alzheimer’s disease and dementia: Tau, septin 4, amyloid precursor protein (APP), presenilin 1, neprilysin, Munc18-1, ⁇ -synuclein, RCAN1, and ⁇ -tubulin.
  • DYRK1A By modulating alternative splicing of Tau exon 10, DYRK1A favors the production of the 3R-Tau splice isoform (characteristic for DS/AD/tauopathy) over the 4R-Tau isoform (Journal of Biological Chemistry (2015), 290, 15219– 15237).
  • GWAS Genome-wide association studies
  • DYRK1A phosphorylates key factors for Parkinson’s disease such as parkin, septin 4, and ⁇ -synuclein. Upregulation of micro-RNAs specific for Parkinson’s disease targets DYRK1A expression.
  • DYRK1A expression is increased in Parkinson’s disease and in Pick’s disease (Neurobiology of Disease (2005), 20(2), 392–400).
  • the compounds and compositions provided herein can be used as inhibitors and/or modulators of the enzyme DYRK1A, and thus can be used to treat a variety of disorders and diseases associated with tau protein, including, but not limited to, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Down syndrome, frontotemporal dementia (FTD) including FTD with parkinsonism-17 (FTDP-17), behavioral variant frontotemporal dementia (bvFTD), FTD in patients with motor neuron disease (MND) (typically amyotrophic lateral sclerosis, also called FTD-ALS), corticobasal degeneration (CBD) (also called corticobasal ganglionic degeneration), progressive supranuclear palsy, primary progressive aphasia (PPA), globular glial tauopathy (GGT), myo
  • Non-limiting examples of neurological disorders which can be treated with the compounds and compositions provided herein include Alzheimer’s disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell’s palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin–Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia,
  • CIDP chronic inflammatory demyelinating polyn
  • 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.
  • the disorder or disease is cancer.
  • the disorder or disease is metastatic melanoma.
  • the disorder or disease is tendon regeneration.
  • the disorder or disease is diabetes.
  • the disorder or disease is degenerative disc disease.
  • the disorder or disease is osteoarthritis.
  • the disorder or disease is a viral infection.
  • the disorder or disease is a neurological disorder.
  • the disorder or disease is Alzheimer’s disease.
  • the disorder or disease is osteoarthritis.
  • the patient is a human.
  • the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma, and ovarian cancer.
  • CML chronic myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • acute myeloid leukemia acute lymphocytic leukemia
  • Hodgkin lymphoma lymphoma
  • lymphoma lymphoma
  • sarcoma sarcoma
  • the cancer is chosen from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, synovial sarcoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer – melanoma, small intestine cancer, stomach (gastric) cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor,
  • the cancer is hepatocellular carcinoma; in some embodiments, the cancer is colon cancer; in some embodiments, the cancer is colorectal cancer; in some embodiments, the cancer is breast cancer; in some embodiments, the cancer is pancreatic cancer; in some embodiments, the cancer is chronic myeloid leukemia (CML); in some embodiments, the cancer is chronic myelomonocytic leukemia; in some embodiments, the cancer is chronic lymphocytic leukemia (CLL); in some embodiments, the cancer is acute myeloid leukemia; in some embodiments, the cancer is acute lymphocytic leukemia; in some embodiments, the cancer is Hodgkin lymphoma; in some embodiments, the cancer is 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
  • the disorder or disease is a neurological condition, disorder, or disease, wherein the neurological disease is selected from: Alzheimer’s disease, frontotemporal dementias, Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies.
  • the neurological disease is selected from: Alzheimer’s disease, frontotemporal dementias, Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies.
  • the disorder or disease is selected from the group consisting of: Alzheimer’s disease, amyotrophic lateral sclerosis, Down syndrome, frontotemporal dementia with parkinsonism-17 (FTDP-17), Lewy body dementia, Parkinson’s disease, Pick’s disease, and additional diseases with pronounced neurodegeneration such as autism, dementia, epilepsy, Huntington’s disease, multiple sclerosis; diseases and disorders associated with acquired brain injury such as chronic traumatic encephalopathy, traumatic brain injury, tumor, and stroke.
  • a compound of Formula (I) inhibits DYRK1A.
  • the method treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.
  • the method inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the method treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprises administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharmaceutically acceptable carrier and one or more other agents.
  • Evaluation of Biological Activity [0254] The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art. For example, the activity of a compound may be tested using one or more of the test methods outlined below.
  • in vitro assays for DYRK1A biological activity may be used, e.g., regulation of microtubule-associated protein tau (MAPT/Tau) phosphorylation in neuronal cell lines such as the human SH-SY5Y neuroblastoma cell line.
  • Assays for DYRK1A-regulated level of phosphorylation can include monitoring levels of basal pSer396 Tau, which can be measured, for example, by serial dilutions of a candidate inhibitor composition using a ten micromolar top concentration and detected by ELISA or Western Blotting.
  • An exemplary assay for DYRK-1A-regulated phosphorylation uses the SH-SY5Y cells cultured in a 96 well plate format for a period of time sufficient to stabilize microtubules and Tau phosphorylation, usually at least 2 days, then treated with a 1/3 serial dilution of compounds overnight and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with an antibody specific for pSer396 Tau. The chemiluminescence signal for HRP-linked antibodies used in western blotting is detected using a Carestream Image Station and blot densitometry for pSer396 and beta-actin are analyzed using ImageJ (NIH).
  • the activity of a candidate compound can be measured by phosphoTau (Thr212) AlphaLISA by adding the lysate mentioned above onto total Tau-coated plates and detected with a specific pThr212Tau antibody. Colorimetric detection of AlphaLISA signal is performed by EnVision Multilabel Plate Reader (Perkin Elmer).
  • Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane.
  • the peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; dq, doublet of quartets; m, multiplet.
  • Scheme 1 describes a method for preparation of pyrrolo[2,1-f][1,2,4]triazine derivatives (VI) by first coupling the chloride (I) with a variety of amines (II) to produce bromo pyrrolo[2,1-f][1,2,4]triazine III. Formation of a variety of boronic acid pinacol esters by reacting various bromides (IV) with bis(pinacolato)diboron followed by Suzuki coupling with bromide (IV) produces the final pyrrolo[2,1-f][1,2,4]triazine (VI).
  • Scheme 2 describes a method for preparation of pyrrolo[2,1-f][1,2,4]triazine derivatives (VI) by oxidizing sulfide VII to the sulfone VIII. Sulfone VIII can then be coupled with a variety of amines (II) to produce bromo pyrrolo[2,1-f][1,2,4]triazine III followed by Suzuki coupling with a variety of boronic acids (IX) to produce the final pyrrolo[2,1-f][1,2,4]triazine (VI).
  • Steps 2-3 To a solution of methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (XII) (190 g, 867.44 mmol, 1 eq.) in THF (1900 mL) was added dropwise 2,2,2-trichloroacetyl isocyanate (179.76 g, 954.18 mmol, 113.06 mL, 1.1 eq.) at 0 ⁇ 5°C, then warmed to room temperature for 1 h. The reaction was then added dropwise to NH 3 /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.
  • Step 4 To a solution of methyl 3-bromo-1-ureido-1H-pyrrole-2-carboxylate (XIII) (67 g, 255.67 mmol, 1 eq.) in THF (4 L) was added TMSOK (65.60 g, 511.33 mmol, 2 eq.) in portions at 0 ⁇ 5°C under N 2 . After stirring for 5 min, the reaction became a thick slurry. The reaction mixture was stirred vigorously at room temperature for 16 h. LCMS showed ⁇ 25.8% of starting material remained. An additional portion of TMSOK (16.40 g, 127.83 mmol, 0.5 eq.) was added at room temperature and stirred for 3 h.
  • Step 5 To a solution of POCl 3 (1500 mL) was added 5-bromopyrrolo[2,1- f][1,2,4]triazine-2,4(1H,3H)-dione (XIV) (180 g, 782.55 mmol, 1 eq.) in portions at room temperature. N,N-Diethylaniline (291.95 g, 1.96 mol, 312.92 mL, 2.5 eq.) was then added dropwise at room temperature (a little exothermic). After addition, the reaction was heated to 105°C for 48 h. LCMS showed the starting material was consumed but the intermediate remained, ⁇ 4.3% of desired product was formed.
  • the reaction was cooled to 90°C, added an additional POCl 3 (500 mL) in one portion, then heated to reflux gently for 24 h.
  • LCMS showed most of intermediate remained, ⁇ 11.9% of desired product was formed.
  • the reaction was heated to reflux gently for another 4 days.
  • LCMS showed ⁇ 7.4% of intermediate remained, ⁇ 55.5% of desired product was formed.
  • the reaction was cooled to 40°C and distilled under reduced pressure to remove most of POCl 3 .
  • the residue was diluted with MeTHF (5 L), poured into ice-H 2 O (2 L), the added brine (1 L), and separated.
  • the aqueous layer was extracted with MeTHF (1.5 L x 2).
  • the reaction mixture was filtered, and the filter cake was washed with THF (30 mL x 3). The filtrate was concentrated, and the residue was dissolved in DCM (10 mL) before adding DDQ (1.45 g, 6.38 mmol) in portions. The reaction was stirred at room temperature under N 2 for 1 h. The reaction mixture was filtered, and the filtrate was washed with saturated aqueous NaHCO 3 (500 mL), separated. The aqueous layer was extracted with DCM (500 mL x 2).
  • Step 2 To a solution of methyl 3,5-dibromo-4-fluoro-1H-pyrrole-2-carboxylate (XVIII) (2.1 g, 6.98 mmol) in dry THF (25 mL) at 0°C under N 2 was added slowly NaH (0.43 g, 10.63 mmol) in small portions. The suspension was stirred at 0°C for 30 min. To the suspension was added (2-(chloromethoxy)ethyl)trimethylsilane (1.9 mL, 10.74 mmol) at 0°C under N 2 .
  • XVIII 3,5-dibromo-4-fluoro-1H-pyrrole-2-carboxylate
  • reaction mixture was stirred at 0°C for 2 h before quenching with ice-water (20 mL) and extracted with EtOAc (3 x 30 mL).
  • EtOAc 3 x 30 mL
  • the EtOAc layer was evaporated under reduced pressure and purified by silica gel column chromatography (100% hexanes) to produce methyl 3,5-dibromo-4-fluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylate (XIX) (2.76 g, 6.401 mmol, 91.7% yield) as an amber liquid.
  • Step 6 To a solution of methyl 1-amino-3-bromo-4-fluoro-1H-pyrrole-2-carboxylate (XXII) (500 mg, 2.11 mmol) in DCM (10 mL) was added pyridine (210 ⁇ L, 2.6 mmol) and methyl carbonochloridate (180 ⁇ L, 2.33 mmol) dropwise. The reaction was stirred at room temperature for 20 min.
  • N,N-Diethylaniline (0.7 mL, 4.4 mmol) was then added dropwise at room temperature. The reaction was heated at 105°C for 16 h. The solvent was removed under vacuum before adding water (20 mL) and extracting with EtOAc. The organic layer was stripped onto Celite ® and purified by silica gel column chromatography (0 ⁇ 100% EtOAc/hexanes) to produce 5-bromo-2,4-dichloro-6-fluoropyrrolo[2,1-f][1,2,4]triazine (XXV) (175 mg, 0.614 mmol, 34.6% yield) as an off-white solid.
  • XXV 5-bromo-2,4-dichloro-6-fluoropyrrolo[2,1-f][1,2,4]triazine
  • the LC/MS shows 5-bromo-2-chloro-6-fluoro-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine (ESIMS found for C 6 H 4 BrClFN 3 m/z 251.9 (M+1)).
  • the reaction mixture was filtered. The filter cake was washed with THF (3 x 30 mL). The filtrate was concentrated, and the residue was dissolved in DCM (1 mL). DDQ (60 mg, 0.26 mmol) was then added in portions at room temperature. After addition, the reaction was stirred at room temperature under N 2 for 1 h. The reaction mixture was filtered and to the filtrate was added aqueous saturated NaHCO 3 (500 mL).
  • Step 2 To a solution of 5-bromo-N-(2,2-difluoroethyl)-2-nitroaniline (XXIX) (12.0 g, 42.86 mmol) in HOAc/HCl (500/50 mL) was added Fe (30.0 g, 428.62 mmol). The reaction mixture was stirred at 50°C for 30 minutes, then cooled to room temperature and filtered. NaNO 2 (3.0 g, 53.58 mmol) in water (20 mL) was then added dropwise into the above acid solution at 0°C. The reaction solution was stirred for 1 h at 0°C.
  • reaction mixture was concentrated to dryness, the reaction mixture was poured into EtOAc (300 mL) and H 2 O (300 mL). The pH was adjusted >7 with NaHCO 3 .
  • the reaction mixture was extracted with EtOAc (3 x 500 mL). The combined organics were washed with brine (3 x 500 mL). The organic layers was concentrated, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude.
  • XXXVII 5-Chloro-3-(2,2-difluorocyclopropyl)-2-methyl-3H-imidazo[4,5-b]pyridine
  • XXXVII White solid (836 mg, 3.431 mmol, 63.9% yield).
  • XXXIX 5-Chloro-3-(cyclopropylmethyl)-2-methyl-3H-imidazo[4,5-b]pyridine
  • XXXIX Amber viscous solid (300 mg, 1.353 mmol, 22.7% yield).
  • trans-4- (dibenzylamino)cyclohexan-1-ol (XLV) (20.0 g, 67.7 mmol) in DMF (50 mL) was added at -70°C under N 2 and stirred for 30 min.
  • TEA 21.92 g, 216.64 mmol was then added and the mixture was stirred at -70°C warming to room temperature over 3 h.
  • the reaction mixture was diluted with H 2 O (800 mL) and extracted with DCM (800 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated to give a residue.
  • Step 4 To a solution of trans-4-(dibenzylamino)-1-ethylcyclohexan-1-ol (XLVII) (1.5 g, 4.6 mmol) in EtOAc (50.0 mL), 10% Pd/C (0.4 g), 20% Pd(OH) 2 /C (0.4 g) was purged with H 2 . The mixture was stirred under a H 2 atm at room temperature for 16 h. The reaction mixture was filter through Celite ® and concentrated under high vacuum to give trans-4-amino-1- ethylcyclohexan-1-ol (XLVIII) (390 mg, 2.723 mmol, 58.7% yield) as a white solid.
  • XLVIII trans-4-amino-1- ethylcyclohexan-1-ol
  • Step 2 [0309] 5-Bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine (I) (commercially available from Advanced ChemBlocks Inc.) (1.5 g, 6.45 mmol), [3-(2,2-difluoroethyl)-2-methylimidazo[4,5- b]pyridin-5-yl]boronic acid (XLIX) (1.63 g, 6.78 mmol), Pd(OAc) 2 (45 mg, 0.2 mmol) and QPhos (270 mg, 0.38 mmol) were dissolved in dry1,4-dioxane (35 mL) and purged with Ar for 5 min.
  • XLIX [3-(2,2-difluoroethyl)-2-methylimidazo[4,5- b]pyridin-5-yl]boronic acid
  • Pd(OAc) 2 45 mg, 0.2 mmol
  • QPhos 270 mg, 0.38 mmol
  • Step 3 [0310] 5-(2-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-(2,2-difluoroethyl)-2- methylimidazo [4,5-b]pyridine (L) (150 mg, 0.43 mmol) and tert-butyl (3R,4R)-4-amino-3- fluoropiperidine-1-carboxylate (LI) (123 mg, 0.56 mmol) were dissolved in DMSO (1 mL). DIPEA (200 ⁇ L, 1.15 mmol) was added and the reaction was stirred at 120°C for 16 h. The reaction mixture was added to water (15 mL) and stirred at room temperature for 1 h.
  • DIPEA 200 ⁇ L, 1.15 mmol
  • Step 4 [0311] tert-Butyl (3R,4R)-4-((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-fluoropiperidine-1-carboxylate (LII) (228 mg, 0.43 mmol) was dissolved in DCM (2 mL). TFA (1 mL, 12.98 mmol) was added, and the reaction was stirred at room temperature for 1 h.
  • Step 5 A mixture of 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5- yl)-N-((3R,4R)-3-fluoropiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (LIII) (80 mg, 0.19 mmol), 2-bromoethyl methyl ether (LIV) (32.mg, 0.23 mmol) and K 2 CO 3 (65 mg, 0.47 mmol) were taken in DMF (1 mL) and the reaction mixture was heated to 65°C for 16 h.
  • LIII 5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5- yl)-N-((3R,4R)-3-fluoropiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin
  • Steps 2-3 [0315] To a mixture of 7-bromo-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5- b]pyridin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (LVI) (25 mg, 0.05 mmol) and palladium (9 mg, 0.01 mmol) in degassed MeOH-d 4 (2 ml) was added NaBD 4 (2 mg, 0.05 mmol).
  • LVI 7-bromo-5-(3-(2,2-difluoroethyl)-2-methyl-3H-imidazo[4,5- b]pyridin-5-yl)-N-(1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine
  • reaction mixture was concentrated, the residue partitioned between DCM/water, organic layer separated, washed with brine, dried over anhydrous Na 2 SO 4 , the solvent was stripped onto Celite ® and purified by silica gel column chromatography (0 ⁇ 100% EtOAc/hexanes) to produce tert-butyl (3R,4S)-4-((5-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl-4- d)amino)-3-fluoropiperidine-1-carboxylate (LVII) (136 mg, 0.328 mmol, 38.2% yield) as a beige solid.
  • reaction mixture was purged with N 2 for 5 min and then heated to 110°C for 40 min.
  • the reaction mixture was reduced in vacuo and purified by column chromatography (0-100% EtOAc/hexanes) to give tert-butyl (3R,4S)-4-((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-4-d)amino)-3- fluoropiperidine-1-carboxylate (LVIII) (116 mg, 0.218 mmol, 66.6% yield) as a yellow solid.
  • reaction was cooled to room temperature and 1.1 mL of the reaction mixture was removed (leaving 1.1 mL behind) and was added to a separate vial.
  • NaBH(OAc) 3 60 mg, 0.28 mmol was added, and the reaction was stirred for 10 min.
  • the CHCl 3 layer was stripped onto Celite ® and purified by column chromatography (0 ⁇ 6% 7 N NH 3 in MeOH/CHCl 3 ) to produce 5-(3-(2,2-Difluoroethyl)-2-methyl- 3H-imidazo[4,5-b]pyridin-5-yl)-N-((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-d-2-amine (131) (15 mg, 0.031 mmol, 22.1% yield) as a yellow solid.
  • the DYRK1A kinase assay was run using the Ser/Thr 18 peptide Z-lyte assay kit according to manufacturer’s instructions (Life Technologies- a Division of Thermo-Fisher). This is a non-radioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity which is represented as a ratio of coumarin emission/fluorescein emission.
  • FRET fluorescence resonance energy transfer
  • Emission ratio was calculated as a ratio of the coumarin (C) emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm).
  • the percent phosphorylation was then calculated using the following formula: [1 - ((Em ratio X F100%)-C100%)/ ((C0%-C100%) + (Em ratio X (F100% - F0%))].
  • Dose-response curves were generated, and inhibitory concentration (IC 50 ) values were calculated using non-linear regression curve fit in the Dotmatics’ Studies Software (Bishops Stortford, UK).
  • Table 2 shows the measured activity for representative compounds of Formula (I) as described herein. Table 2.
  • Example 5 Representative compounds were screened using the assay procedure for tau phosphorylation activity described below.
  • HEK293T cells ATCC, CRL3216
  • DMEM Thermo Fisher Scientific, 10566024
  • FBS FBS
  • Penicillin/Streptomycin Thermo Fisher Scientific, 15140163
  • the HEK293T cells were then transiently transfected with 5 ⁇ g DYRK1A (NM_001396) human untagged clone (OriGene, SC314641) and 2.5 ⁇ g MAPT (441 a.a. Tau gene) (NM_005910) human untagged clone (OriGene, TP313312) using Lipofectamine 3000 (Thermo Fisher Scientific, L30000015) and incubated for 20-30 hours in a humidified incubator at 37°C and 5% CO 2 .
  • HEK293T cells transfected with the DYRK1A and MAPT expression vectors were harvested and seeded in BioCoat poly-D lysine coated 96-well plates (Corning, 354461) at 3 x 10 4 cells/well.
  • the above synthesized compounds were screened using the cell assay procedure to assess decreased Tau phosphorylation at Thr212 (pThr212) described below.
  • DMSO Sigma-Aldrich, D8418-100 mL
  • Lysates were spun down at 12,000g for 10 min to remove any cellular debris and 5 ⁇ L of lysates were dispensed into a 384-well Opti-Plate (Perkin Elmer, 6007290) for the measurement of Tau phosphorylation in the phosphoTau (Thr212) AlphaLISA assay.
  • Donor antibody, biotinylated HT7Tau (Thermo Fisher Scientific, MN1000B), and acceptor antibody, pThr212Tau (Thermo Fisher Scientific, 44740G) were both added to the cell lysates at a final concentration of 3 nM and incubated for 1 hour at room temperature.
  • anti-rabbit IgG(Fc specific) AlphaLISA acceptor beads (Perkin Elmer, AL104C) were added at a 10 ug/mL final concentration and incubated for 1 hour at room temperature protected from light.
  • AlphaScreen streptavidin donor beads (PerkinElmer, 6760002) were added at 40 ug/mL final concentration and incubated for 1 hour at room temperature protected from light.

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Abstract

L'invention concerne des composés pyrrolo[2,1-f][1,2,4]triazines pour le traitement de diverses maladies et pathologies. Plus particulièrement, la présente invention concerne l'utilisation de composés pyrrolo[2,1-f][1,2,4]triazines ou d'analogues de ceux-ci, dans le traitement de troubles caractérisés par la surexpression de DYRK1A (par exemple, le cancer, le syndrome de Down, la maladie d'Alzheimer, le diabète, les infections virales et l'arthrose).
PCT/US2024/023387 2023-04-07 2024-04-05 Pyrrolo[2,1-f][1,2,4]triazines, ainsi que leur préparation et leurs utilisations Pending WO2024211797A1 (fr)

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