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WO2024249488A2 - Inhibitors of dyrk1a - Google Patents

Inhibitors of dyrk1a Download PDF

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Publication number
WO2024249488A2
WO2024249488A2 PCT/US2024/031429 US2024031429W WO2024249488A2 WO 2024249488 A2 WO2024249488 A2 WO 2024249488A2 US 2024031429 W US2024031429 W US 2024031429W WO 2024249488 A2 WO2024249488 A2 WO 2024249488A2
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Prior art keywords
alkyl
compound
independently selected
disease
haloalkyl
Prior art date
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PCT/US2024/031429
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French (fr)
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WO2024249488A3 (en
Inventor
Lijun Sun
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Beth Israel Deaconess Medical Center Inc
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Beth Israel Deaconess Medical Center Inc
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Publication of WO2024249488A2 publication Critical patent/WO2024249488A2/en
Publication of WO2024249488A3 publication Critical patent/WO2024249488A3/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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

  • This invention relates to benzimidazole carbamate compounds that are, e.g., inhibitors of DYRKIA kinase and are useful in treating, e.g., neurodegenerative diseases such as Alzheimer’s disease, autoimmune diseases such as inflammatory bowel disease,
  • neurodegenerative diseases affect a significant segment of population
  • AD Alzheimer’s disease
  • a neurodegenerative disease that affects approximately 44 million people world-wide is the sixth leading cause of death with an estimated socioeconomic burden of more than $200 billion.
  • Neurodegenerative diseases such as AD impose a substantial burden on patients, their family members, the healthcare system, and the society overall. Because of aging
  • the present disclosure is based, at least in part, on a realization that benzimidazole carbamate compounds are potent and selective inhibitors of dual
  • DYRKIA 25 specificity tyrosine-phosphorylation-regulated kinase 1 A
  • the present disclosure advantageously provides methods of using the benzimidazole carbamate compounds to treat disorders associated with DYRK.1 A, including neurodegenerative diseases, autoimmune diseases, and cancer.
  • Example embodiments of the benzimidazole carbamate compounds and related treatment methods include neurodegenerative diseases, autoimmune diseases, and cancer.
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R A is selected from moiety (i), (ii), (iii) and (iv): ( ) ( )
  • R Ia , R 2a , R 3a , and R ti are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, OR al , NR cl R dl , S(O)2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O)2OR al , wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 1 is selected from Cy 1 , OR B , NR 3 R B , CHzR 8 , and CH2R c ;
  • R c is selected from CN, NO 2 , OR 31 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • R 5 is selected from H, halo, CN, NCh, C1-3 alkyl, C1-3 haloalkyl, OR 81 , NR cl R dl , S(O) 2 R bl , S(O) 2 NR cl R dl , and S(O) 2 OR al , wherein said C1.3 alkyl is optionally substituted
  • R 6 and R 7 are each independently selected from H, halo, CN, NO 2 , C1.3 alkyl, C1-3 haloalkyl, OR 31 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR 81 , wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents
  • each Cy 1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl ;
  • each R Cyl is independently selected from halo, CN, NO2, OR al , NR el R dl , C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, OR 81 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R al , R bl , R cl , and R dl are each independently selected from H, C1.3 alkyl, and C1.3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
  • R 8a , R 8b , and R 8c are each independently selected from H, C1.3 alkyl, and C1.3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R g ; each X is independently selected from N and CR 9b , wherein one X is N and the
  • R 9a and R 9b are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R e ; and
  • each R g is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyljami.no; provided that the compound of Formula (I) is not any one of the following compounds:
  • R A is selected from moiety (i) and (ii):
  • R A is selected from moiety (iii) and (iv):
  • the compound has formula: or a pharmaceutically acceptable salt thereof.
  • the compound has formula:
  • R la , R 2a , R 3a , and R 4a are each independently selected from H, halo, CN, NOi, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R la , R 23 , R 3a , and R 4a are each independently selected from
  • the compound of Formula (I) is selected from: or a pharmaceutically acceptable salt thereof.
  • the compound has formula: or a pharmaceutically acceptable salt thereof.
  • the compound has formula:
  • the compound has formula: or a pharmaceutically acceptable salt thereof.
  • R 8a , R 8b , and R 8c are each independently selected from H
  • R 8a and R 8c are both H and R 8b is C 1-3 alkyl, such as methyl.
  • R 9a and R 9b are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said CM alkyl is optionally substituted with 1 , 2, or 3
  • R 9a and R 9b are each independently selected from H and C 1-3 alkyl.
  • R 9a and R 9b are both H.
  • the compound of Formula (I) is selected from any one of
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, ON, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR cl R dl .
  • R 5 , R 6 , and R 7 are each independently selected from H,
  • R 1 is selected from OR B and NR 3 R B .
  • R 1 is OR B .
  • R 1 is NHR B .
  • R 1 is CH2R B .
  • the compound of Formula (I) is selected from:
  • R B is selected from Cy 1 and C1-6 alkyl substituted with
  • R B is selected from Cy 1 , Ci-6 alkyl substituted with Cy 1 , and Ci -6 alkyl substituted with NR cl R dl .
  • Cy 1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • Cy 1 is Q-ioaryl, optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • Cy 1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with
  • R Cyl is selected from halo, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.
  • R Cyl is selected from halo, NO2, C 1-3 alkyl, and C 1-3 alkoxy.
  • Cy 1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected R Cyl : O
  • R B is Ci-6 alkyl substituted withNR ql R dl .
  • R B is selected from CH 2 NR ql R dl , CH 2 CH2NR cl R dl , and CH 2 CH 2 CH 2 NR cl R dl .
  • the compound of Formula (I) is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof
  • the present disclosure provides a pharmaceutical
  • composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a
  • the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager
  • AD Alzheimer’s disease
  • FAD familial AD
  • FTD frontotemporal lobar degeneration
  • AD amyotrophic lateral sclerosis
  • HD Huntington’s disease
  • HD dementia associated with HD
  • the disease or condition is a metabolic disorder selected
  • type 1 diabetes type 2 diabetes
  • hyperglycerimia hypermethioninemia
  • familial hypercholesterolemia Gaucher disease, Hunter syndrome, Krabbe disease
  • maple syrup urine disease metachromatic leukodystrophy
  • mitochondrial encephalopathy lactic acidosis
  • MELAS stroke-like episodes
  • PKU phenylketonuria
  • porphyria Tay-Sachs disease, and Wilson’s disease.
  • the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and
  • the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
  • the present disclosure provides a method of treating a
  • R A is selected from moiety (i) and (ii):
  • R Ia , R 2a , R 3a , and R 4a are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR el R dl , S(O)2R bl , C(O)NR cl R dl , S(0)2NR cl R dl , C(O)OR al ,
  • C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O)2R bl , C(O)NR cl R dl , S(O)2NR el R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 1 is selected from Cy 1 , OR B , NR 3 R S , CHaR 8 , and CH2R c ;
  • each R B is independently selected from H, Cy 1 , C1-6 alkyl, and Ci-e haloalkyl, wherein said Ci-e alkyl is optionally substituted with Cy 1 , CN, NO2, OR al , NR cl R dl , S(O)iR bl , C(O)NR cl R dl , S(O)2NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O)2NR €1 R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al ,
  • C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy 1 , CN, N0 2 , 0R al , NR cl R dl , S(O) 2 R bl , C(O)NR el R dl , S(O)iNR cl R dl , C(O)OR al , and S(O) 2 OR al ; each Cy 1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14
  • each R Cyl is independently selected from halo, CN, NO2, OR al , NR cl R dl , C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with CN, NO2, OR 11 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R al , R bl , R cl , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R 8 ; and each R s is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycaibonyl, amino, C 1-3 alkylamino, and di(C 1-3
  • the compound of Formula (la) is selected from any one of the following compounds:
  • the present disclosure provides a compound of Formula
  • R 1 is selected from OR B , NR 3 R B , and CH 2 R C ; each R B is independently selected from Cy 1 , Ci-$ haloalkyl, and Ci- ⁇ s alkyl substituted with Cy 1 , CN, NO 2 , OR’ 1 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from NOz, NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl ,
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO 2 , C 1-3 alkyl,
  • each R c>1 is independently selected from halo, CN, NO 2 , OR’ 1 , NR cl R dl , C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with CN, NO 2 , OR’ 1 , NR el R dl , S(O) 2 R bl , C(O)NR 61 R dl , S(O) 2 NR el R dl , C(O)OR al , or S(O) 2 OR al ;
  • R al , R bl , R cl , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R 8 ; and
  • each R e is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino; provided that the compound of Formula (II) is not any of the following
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR cl R dl .
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • the compound has formula: or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from OR B and NR 3 R B .
  • R* is OR B .
  • R 1 is NHR B .
  • R B is selected from Cy 1 and Ci-e alkyl substituted with Cy 1 , OR’ 1 , or NR cl R dl .
  • R B is selected from Cy 1 , Ci-e alkyl substituted with Cy 1 , and Ci-6 alkyl substituted with NR cl R dl .
  • R B is Cy 1 .
  • R B is C1-6 alkyl substituted with Cy 1 .
  • Cy 1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • Cy 1 is Ce-io aryl, optionally substituted with 1 or 2
  • Cy 1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl,
  • R Cyl is selected from halo, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.
  • R Cyl is selected from halo, NO2, C 1-3 alkyl, and C 1-3
  • Cy 1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected R Cyl :
  • R B is Ci-6 alkyl substituted with NR C1 R 41 .
  • R B is selected from CH 2 NR cl R dl , CH2CH2NR cl R dl , and
  • the compound of Formula (II) is selected from any one of the following compounds:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
  • the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager
  • AD Alzheimer’s disease
  • FAD familial AD
  • FTD frontotemporal lobar degeneration
  • ALS amyotrophic lateral sclerosis
  • the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU),
  • a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU),
  • the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
  • the present disclosure provides a method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition, the method comprising: (i) identifying a subject diagnosed with the disease or condition responsive to inhibition of DYRK1 A in a cell, a tissue, and/or an organ affected by the disease or condition; and (ii)
  • R 1 is selected from Cy 1 , OR B , NR 3 R B , CH 2 R B , and CH 2 R C ;
  • each R B is independently selected from H, Cy 1 , C1-6 haloalkyl, and Ci-e alkyl substituted with Cy', CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O)2NR cl R dl , C(O)OR at , or S(O)2OR al ;
  • R c is selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents
  • each Cy 1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl ;
  • each R Cyl is independently selected from halo, CN, NO2, OR al , NR cl R dl , C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with CN, NO2, OR al , NR tl R dl , S(O)2R bl , C(O)NR el R dl , S(O) 2 NR el R dl , C(O)OR al , or S(O) 2 OR al ;
  • R al , R bl , R cl , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
  • each R 8 is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • the compound of Formula (Ila) is selected from any one of
  • the compound of Formula (I) is selected from any one of the following compounds:
  • the present disclosure provides chemical compounds (e.g., organic heterocyclic compounds). Without being bound by any theory or speculation, it is believed that in one example, compounds of this disclosure potently and selectively inhibit kinase enzyme D YRK 1 A and/or phosphorylation of the Tau protein. Certain embodiments of these compounds
  • DYRK1 A e.g., in vitro, in vivo, or ex vivo
  • associated disorders and conditions e.g., diseases where DYRK1 A is implicated in pathology such as Alzheimer’s disease, inflammation, and cancer
  • Example embodiments of pharmaceutical compositions containing these compounds and combination treatment methods are also provided.
  • the present disclosure provides benzoimidazole (e.g., benzo[d]imidazole) compound having a substituent in the 5 -position (e.g., a substituted pyridine, a methoxy, or a substituted benzoyl moiety).
  • a substituent in the 5 -position e.g., a substituted pyridine, a methoxy, or a substituted benzoyl moiety.
  • the present disclosure provides a compound of Formula
  • the compound of Formula (la) has Formula (I):
  • R A is selected from moiety (i) and (ii):
  • R la , R 2a , R 3a , and R 4a are each independently selected from H, halo, CN, NO2, C 1-3
  • R 1 is selected from Cy 1 , OR B , NR 3 R B , CH 2 R R , and CH 2 R c ;
  • each R B is independently selected from H, Cy 1 , C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with Cy 1 , CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R di , S(O)2NR cl R dl , C(O)OR al , or S(O)2OR al ;
  • R c is selected from CN, NO 2 , OR al , NR el R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR el R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O)zOR a1 , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy 1 , CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • each Cy 1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl ;
  • each R Cvl is independently selected from halo, CN, NO2, OR al , NR cl R dl , C 1-3
  • C 1-3 alkyl is optionally substituted with CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR el R dl , C(O)OR al , or S(O) 2 OR al ;
  • R al , R bl , R cl , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R 2 ; and
  • each R 8 is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R A is selected from moiety (i) and (ii): ( ) ( )
  • R 1a R 2a , R 3b and R4S each in dependently selected from H, halo, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR el R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR el R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 1 is selected from Cy 1 , OR 8 , NR 3 R B , CHiR 8 , and CH2R c ;
  • each R B is independently selected from Cy 1 , Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy 1 , CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR el R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from CN, NO 2 , OR 31 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 is selected from H, halo, CN, NCh, C 1-3 alkyl, C 1-3 haloalkyl, OR 81 , NR cl R dl , S(O) 2 R bl , S(O) 2 NR cl R dl , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted
  • R 6 and R 7 are each independently selected from H, halo, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, OR 31 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR 81 , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents
  • each Cy 1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl ;
  • each R Cyl is independently selected from halo, CN, NO2, OR al , NR el R dl , C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with CN, NO 2 , OR 81 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R al , R bl , R cl , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
  • each R e is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R A is a moiety of formula (i). In some embodiments, R A is
  • the compound has formula:
  • the compound has formula:
  • R la is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O)iOR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • R 2a is selected from H, halo, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O)zOR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • R 3a is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • R 4a is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and
  • R la , R 23 , R 3a , and R 4a are each independently selected from
  • R la is selected from H, halo, CN, NO2, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 2a is selected from H, halo, CN, NO2, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 3a is selected from H, halo, CN, NO2, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 43 is selected from H, halo, CN, NO2, C 1-3
  • R la , R 2a , R 3a , and R 4a are each independently selected from H and C 1-3 alkyl. In some embodiments, R la is selected from H and C 1-3 alkyl. In some embodiments, R la is C 1-3 alkyl. In some embodiments, R 2a is selected from H and C 1-3 alkyl. In some embodiments, R 2a is C 1-3 alkyl. In some embodiments, R 3a is selected from
  • R 3a is C 1-3 alkyl.
  • R 43 is selected from H and C 1-3 alkyl.
  • R 43 is C 1-3 alkyl.
  • R la , R 2a , R 3a , and R 4a are each H.
  • the compound of Formula (la) or Formula (I) is selected from any one of the following compounds: R R
  • the compound of Formula (la) or Formula (I) has formula:
  • the compound of Formula (la) or Formula (I) has formula:
  • the compound of Formula (la) or Formula (I) has formula: or a pharmaceutically acceptable salt thereof.
  • R 5 , R 6 and R 7 are each independently selected from H,
  • R 5 , R 6 and R 7 are each independently selected from H,
  • R 5 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR ql R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy 1 , CN, NO2, OR al , NR ql R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • R 5 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , S(O) 2 NR ql R dl , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al .
  • R 6 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR ql R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR el R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy 1 , CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR el R dl , S(O) 2 NR ql R dl , C(O)OR al , and S(O) 2 OR al .
  • R 6 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , S(O) 2 NR cl R dl , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO 2 , OR al , NR ql R dl , S(O)2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al .
  • haloalkyl Cy 1 , OR al , NR el R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy 1 , CN, NO2, OR al , NR el R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al .
  • R 7 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3
  • haloalkyl OR al , NR cl R dl , S(O) 2 R bl , S(O) 2 NR ql R dl , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al .
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , C(O)NR cl R dl , and
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , C(O)NR el R dl , and C(O)OR al , wherein said Cua alkyl is optionally substituted with Cy 1 , CN, NO2, OR al , or NR cl R dl .
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , C(O)NR cl R dl , and C(O)OR al , wherein said C 1-3 alkyl is optionally substituted with Cy 1 , CN, NO2, OR al , or NR cl R dl .
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR cl R dl , wherein said C 1-3 alkyl is
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR cl R dl .
  • At least one of R 5 , R 6 , and R 7 is C 1-3 alkyl substituted with Cy 1 , CN, NO2, OR al , or NR cl R dl .
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.
  • R 5 , R 6 and R 7 are each H. In some embodiments, R 5 is not Cy 1 . In some embodiments, R s is not C(O)NR cl R dl . In some embodiments, R 5 is not C(O)OR al .
  • R 2 , R 3 , and R 4 are each independently selected from H and C 1-3 alkyl. In some embodiments, R 2 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 3 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 4 is selected from H, Ci .3 alkyl, and C 1-3 haloalkyl.
  • R 2 is selected from H and C 1-3 alkyl.
  • R 3 is selected from H and C 1-3 alkyl.
  • R 4 is selected from H and C 1-3 alkyl.
  • R 2 , R 3 , and R 4 are each H.
  • R 1 is selected from Cy 1 , OR B , NR 3 R B , CH2R B , and CH2R c . In some embodiments, R 1 is Cy 1 . In some embodiments, R 1 is OR B . In some
  • R 1 is NR 3 R B . In some embodiments, R 1 is CHiR B . In some embodiments, R 1 is CHaR c . In some embodiments, R 1 is selected from OR B and NR 3 R B .
  • the compound of Formula (la) or Formula (I) is selected from:
  • the compound of Formula (la) or Formula (I) has formula:
  • the compound of Formula (la) or Formula (I) has formula:
  • the compound of Formula (la) or Formula (I) has formula: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (la) or Formula (I) has formula:
  • the compound of Formula (la) or Formula (I) has formula: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (la) or Formula (I) has formula:
  • the compound of Formula (la) or Formula (I) has formula: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (la) or Formula (I) has formula: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (la) or Formula (I) has formula:
  • R B is selected from H, Cy 1 , CM alkyl (e.g., methyl, ethyl, propyl, or n-butyl), and CM haloalkyl, wherein said CM alkyl is optionally substituted with Cy 1 , CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O)zNR cl R dl , C(O)OR al ,
  • R B is selected from Cy 1 , CM haloalkyl, and CM alkyl substituted with Cy 1 , CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al .
  • R B is selected from Cy 1 , CM haloalkyl, and CM alkyl substituted with Cy 1 , CN, NO 2 , OR al , or NR cl R dl .
  • NR cl R dl is selected from Cy 1 , CM haloalkyl, and CM alkyl substituted with Cy 1 , CN, NO 2 , OR al , or NR cl R dl .
  • R B is H. In some embodiments, R B is Cy 1 . In some embodiments, R B is CM haloalkyl. In some embodiments, R B is CM alkyl optionally substituted with Cy 1 , CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O)2NR cl R dl ,
  • R B is CM alkyl substituted with Cy 1 , CN, NO2, OR al , NR cl R dl , S(O)2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al .
  • R B is CM alkyl substituted with Cy 1 , OR al , or NR cl R dl .
  • R B is selected from Cy 1 and CM alkyl substituted with Cy 1 , OR al , or NR cl R dl .
  • R B is selected from Cy 1 , CM alkyl
  • R B is a moiety of formula:
  • R B is a moiety of formula:
  • R B is CM alkyl substituted with NR ql R dl . In some embodiments, R B is selected from CH 2 NR cl R dl , CH 2 CH 2 NR cl R dl , and CH 2 CH 2 CH 2 NR cl R dl .
  • Cy 1 is selected from Ce-ioaryl and 3-10 membered
  • 10 heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3 -dioxo lanyl, tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • R Cyl is selected from halo, NCh, Ci-a alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy. In some embodiments, R Cyl is selected from halo, NO2,
  • R Cyl is C 1-3 alkyl.
  • Cy 1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected R Cyl :
  • Cy 1 is a moiety of formula:
  • Cy 1 is a moiety of formula: 5 which is optionally substituted with R Cyl .
  • Cy 1 is a moiety of formula: which is optionally substituted with R Cyl .
  • Cy 1 is a moiety of formula:
  • Cy 1 is a moiety of formula: which is optionally substituted with R Cyl .
  • Cy 1 is a moiety of formula: which is optionally substituted with R eyl .
  • Cy 1 is a moiety of formula:
  • R al , R bl , R cl , and R dl are each independently selected from
  • R al is selected from H, C 1-3 alkyl, and Ci -3 haloalkyl.
  • R bl is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R C1 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R dl is selected from H, Ci-a alkyl, and C 1-3 haloalkyl.
  • the compound of Formula (la) is selected from any one of
  • the compound of Formula (I) is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is not any one of the following compounds:
  • the present disclosure provides a compound of Formula (Ha):
  • R 10 , R 2 , R 4 , R 3 , R 6 , and R 7 e.g., as described herein for Formula Ila or Formula II.
  • the compound of Formula (Ila) has Formula (II): or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from Cy 1 , OR B , NR 3 R B , CH 2 R B . and CHiR c ;
  • each R B is independently selected from H, Cy 1 , Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy 1 , CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR el R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O>2NR cl R dl , C(O)OR al , and
  • each R Cyl is independently selected from halo, CN, NO2, OR al , NR cl R dl , C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with CN, NO2, OR' 1 , NR €1 R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R al , R bl , R €1 , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3
  • each R s is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycatbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R 1 is selected from OR B , NR 3 R B , and CH 2 R c ; each R B is independently selected from Cy 1 , C1-6 haloalkyl, and C1-6 alkyl substituted with Cy’, CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O)2NR cl R dl , C(O)OR aI , or S(O)2OR al ;
  • R c is selected from NOa, NR el R dl , S(O)aR bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , S(O) 2 OR al , and Ci-6 alkyl substituted with NO 2 , NR cl R dl , S(O) 2 R bl , C(O)NR CI R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R 2 , R ⁇ and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O)2NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • each Cy 1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl ; each R Cyl is independently selected from halo, CN, NO2, OR al , NR el R dl , C 1-3
  • R al , R bl , R cl , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R 8 ; and
  • each R e is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycaibonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR el R dl , S(O) 2 R bl , C(O)NR el R dl ,
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , S(O) 2 NR cl R dl , and
  • R 5 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and
  • R 5 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , S(O) 2 NR cl R dl , and S(O) 2 OR al , wherein said C 1-3
  • 10 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO 2J OR al , NR el R dl , S(O)iR bl , C(O)NR 61 R dl , S(O) 2 NR el R dl , C(O)OR al , and S(O) 2 OR al .
  • R 6 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents
  • R 6 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , S(O) 2 NR ql R dl , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN,
  • R 7 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy 1 , CN, NO2, OR al , NR ql R dl , S(O) 2 R bl , C(O)NR el R dl ,
  • R 7 is selected from H, halo, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , S(O) 2 NR cl R dl , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al .
  • R 3 , R 6 and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , C(O)NR cl R dl , and
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , C(O)NR cl R dl , and
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR el R dl , C(O)NR cl R dl , and C(O)OR al , wherein said C 1-3 alkyl is optionally substituted with Cy 1 , CN, NO2, OR al , or NR cl R dl .
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NOs, C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR cl R dl , wherein said C 1-3 alkyl is optionally substituted with Cy 1 , CN, NO 2 , OR al , or NR cl R dl .
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR el R dl .
  • At least one of R 5 , R 6 , and R 7 is C 1-3 alkyl substituted with Cy 1 , CN, NO2, OR al , or NR cl R dl .
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.
  • R 5 , R 6 and R 7 are each H. In some embodiments, R 5 is not Cy 1 . In some embodiments, R 5 is not C(O)NR cl R dl . In some embodiments, R 5 is not C(O)OR al .
  • R 2 , R 3 , and R 4 are each independently selected from H and Ci.3 alkyl.
  • R 2 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 3 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 4 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R 2 is selected from H and C 1-3 alkyl.
  • R 3 is selected
  • R 4 is selected from H and C 1-3 alkyl.
  • R 2 , R 3 , and R 4 are each H.
  • the compound of Formula (Ila) or Formula (II) has formula: or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from Cy 1 , OR B , NR 3 R B , CH 2 R B , and CH 2 R c In some embodiments, R 1 is Cy 1 . In some embodiments, R 1 is OR B . In some embodiments, R 1 is NR 3 R B . In some embodiments, R 1 is NHR B . In some embodiments, R 1 is CH 2 R B . In some embodiments, R 1 is CH 2 R C . In some embodiments, R 1 is selected from OR B and NR 3 R B . In some embodiments, R 1 is selected from OR B and NHR B .
  • R B is selected from H, Cy 1 , Cw alkyl (e.g., methyl, ethyl, propyl, or zi-butyl), and Ci-6 haloalkyl, wherein said Ci-6 alkyl is optionally substituted with Cy 1 , CN, NO2, OR al , NR cl R dl , S(O)2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O)zOR al .
  • Cw alkyl e.g., methyl, ethyl, propyl, or zi-butyl
  • Ci-6 haloalkyl wherein said Ci-6 alkyl is optionally substituted with Cy 1 , CN, NO2, OR al , NR cl R dl , S(O)2R bl , C(O)NR cl R dl ,
  • R B is selected from Cy 1 , Ci-e haloalkyl, and CM alkyl
  • R B is selected from Cy 1 , CM haloalkyl, and Ci -6 alkyl substituted with Cy 1 , CN, NOz, OR al , or NR cl R dl .
  • R B is selected from Cy 1 , CM haloalkyl, and CM alkyl substituted with Cy 1 , OR al , or NR ⁇ 1 R dl .
  • R B is H. In some embodiments, R B is Cy 1 . In some embodiments, R B is CM haloalkyl. In some embodiments, R B is CM alkyl optionally substituted with Cy 1 , CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR at , or S(O) 2 OR al . In some embodiments.
  • R B is CM alkyl substituted with Cy 1 , CN, NO2, OR al , NR cl R dl , S(O)2R bl , C(O)NR cl R dl , S(O) 2 NR el R dl , C(O)OR al , or
  • R B is CM alkyl substituted with Cy 1 , OR 81 , or NR cl R dt . In some embodiments, R B is selected from Cy 1 and CM alkyl substituted with Cy 1 , OR 81 , orNR ⁇ R 111 . In some embodiments, R B is selected from Cy 1 , CM alkyl substituted with Cy 1 , and CM alkyl substituted with NR cl R dl . In some embodiments, R B B is R B is CM alkyl substituted with Cy 1 .
  • R B is a moiety of formula:
  • R B is a moiety of formula:
  • R B is Ci-e alkyl substituted with NR cl R dl . In some embodiments, R B is selected from CH 2 NR cl R dl , CH 2 CH 2 NR cl R dl , and CH 2 CH 2 CH 2 NR cJ R d1 .
  • R c is selected from CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cI R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al .
  • R c is selected from CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cI R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al .
  • R c is
  • R c is OR al or NR cl R dl . In some embodiments, R c is OR al . In some embodiments, R c is NR cl R dl . In some embodiments, R c is S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al .
  • Cy 1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents
  • Cy 1 is Ce-io aryl, optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • Cy 1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl,
  • R Cyl is selected from halo, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy. In some embodiments, R Cyl is selected from halo, NO 2 , C 1-3 alkyl, and C 1-3 alkoxy. In some embodiments, R Cyl is C 1-3 alkyl.
  • Cy 1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected R Cyl :
  • Cy 1 is a moiety of formula:
  • Cy 1 is a moiety of formula: which is optionally substituted with R Cyl .
  • Cy 1 is a moiety of formula:
  • Cy 1 is a moiety of formula: which is optionally substituted with R Cyl .
  • Cy 1 is a moiety of formula:
  • Cy 1 is a moiety of formula:
  • Cy 1 is a moiety of formula: O which is optionally substituted with R Cyl .
  • Cy 1 is a moiety of formula: which is optionally substituted with R Cyl .
  • R al , R bl , R el , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl. In some embodiments, R al is selected from H, C 1-3 alkyl,
  • R bl is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R C1 is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R dl is selected from H, C 1-3 alkyl, and C 1-3 haloalkyl.
  • the compound of Formula (Ila) is selected from any one of the following compounds:
  • the compound of Formula (II) is selected from any one of the following compounds:
  • the compound of Formula (II) is not any of the following compounds:
  • the present disclosure provides a compound of Formula
  • R A is selected from moiety (iii) and (iv): (iii)
  • R 1 is selected from Cy 1 , OR 3 , NR 3 R B , CHiR 8 , and CHiR c ; ()
  • each R B is independently selected from Cy 1 , Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy 1 , CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR el R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from CN, NO 2 , OR 31 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl ,
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 is selected from H, halo, CN, NCh, C 1-3 alkyl, C 1-3 haloalkyl, OR 81 , NR cl R dl , S(O) 2 R bl , S(O) 2 NR cl R dl , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted
  • R 6 and R 7 are each independently selected from H, halo, CN, NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, OR 31 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR 81 , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents
  • each Cy 1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl ;
  • each R Cyl is independently selected from halo, CN, NO2, OR al , NR el R dl , C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with CN, NO2, OR 81 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R Sa , R Sb , and R Sc are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
  • each X is independently selected from N and CR 9b , wherein one X is N and the other X is CR 9b ;
  • R 9a and R 9b are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently
  • each R g is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • the compound has formula:
  • the compound has formula: or a pharmaceutically acceptable salt thereof.
  • the compound has formula: or a pharmaceutically acceptable salt thereof.
  • the compound has formula:
  • R 8a , R 8b , and R 8c are each independently selected from H and Ci -3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
  • R Sa , R 8b , and R Se are each independently selected from H and Ci.3 alkyl.
  • R 8a and R 8e are both H and R 8b is C 1-3 alkyl, such as methyl.
  • R 9a and R 9b are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R s .
  • R 9a and R 9b are each independently selected from H and C 1-3 alkyl.
  • R 9a and R 9b are both H.
  • the compound of Formula (I) is selected from any one of the following compounds: R
  • R 3 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR cl R dl .
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R 1 is selected from OR B and NR 3 R B .
  • R 1 is OR B .
  • R 1 is NHR B .
  • R 1 is CH;R R .
  • the compound of Formula (I) is selected from:
  • R B is selected from Cy 1 and Ci-e alkyl substituted with Cy 1 , OR al , or NR cl R dl .
  • R B is selected from Cy 1 , C1-6 alkyl substituted with Cy 1 ,
  • R B is Cy 1 .
  • R B is C1-6 alkyl substituted with Cy 1 .
  • Cy 1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents
  • Cy 1 is Ce-io aryl, optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • Cy 1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl,
  • R Cyl is selected from halo, NOz, C 1-3 alkyl, C 1-3 haloalkyl, Ci -3 alkoxy, and C 1-3 haloalkoxy.
  • R Cyl is selected from halo, NCh, C 1-3 alkyl, and C 1-3 alkoxy.
  • Cy 1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected R Cyl :
  • R B is C1-6 alkyl substituted with NR cl R dl .
  • R B is selected from CH2NR cl R dl , CH2CH2NR cl R dl , and CH2CH2CH2NR cl R dl .
  • the compound of Formula (I) is selected from any one of the following compounds:
  • a salt of a compound of this disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • acids commonly employed to form pharmaceutically acceptable salts of the compounds of this disclosure include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid,
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic
  • bases commonly employed to form pharmaceutically acceptable salts of the compounds of this disclosure include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc;
  • organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or trialkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as
  • the compounds, or pharmaceutically acceptable salts thereof, are substantially isolated.
  • Protein phosphorylation catalyzed by protein kinases, is one of the major intracellular mechanisms which cells use to regulate their structural and enzymatic
  • DYRK1 A dualspecificity tyrosine phosphorylation-regulated kinase 1A
  • DYRK kinases belong to the CMGC group which includes cyclin-dependent kinases (CDK), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK), and Ccd2-like kinases (CLK).
  • CDK cyclin-dependent kinases
  • MAP kinases mitogen-activated protein kinases
  • GSK glycogen synthase kinases
  • CLK Ccd2-like kinases
  • DYRK1 A is involved in cell cycle and differentiation regulation, P-cell regeneration, T cell regulation, cytoskeleton stabilization, brain neurodevelopment, and synaptic activities. See Nguyen, Expert Opin. Then Pat., 2017, 11,
  • the present disclosure provides compounds as described herein, or pharmaceutically acceptable salts thereof, that modulate (e.g., inhibit) DYRK1A in a cell.
  • the present disclosure provides a method of modulating (e.g., inhibiting) DYRK.1A in a cell, the method comprising contacting the
  • the method includes contacting the cell in vitro, in vivo, or ex vivo.
  • the compound modulates DYRK1A selectively (e.g., the compound is at least about 2x ? about 5x, about 10x, about 100x, or about l,000x selective to DYRK1 A as compared to DYRK1B, DYRK2, DYRK3, and/or DYRK4,
  • DYRK1A is involved in pathology of numerous debilitating conditions (e.g., the disease or condition may include overexpression, abnormal function, persistent activation, etc, of DYRK1A, e.g., in a cell or tissue affected by the disease). See, for example, J. Med. Chem., 2021, 64, 11709-11728, attesting to the fact that DYRK1A
  • DYRK1A is useful in treating Down syndrome and Alzheimer’s disease, among other neurodegenerative conditions. Inhibition of DYRK1 A is also clinically relevant in treatment of metabolic disorders (e.g., diabetes), myocardial Infarction, inflammatory disorders (e.g., inflammatory
  • cancer e.g, glioblastoma, leukemia, because DYRKlA’s function mediates cancer cell cycle
  • other conditions e.g., Ini. J. Mol. Sei., 2021, 22, 6047 and Young e/ a/., Circulation Research, 2022, 130, 1345-1361, among others, all of which are incorporated herein by reference in their entirety.
  • the method provides a method of treating
  • DYRK1A is implicated in pathology of the disease or condition (e.g., the disease or condition responsive to inhibition of DYRK1 A in a cell, a
  • the method comprising administering to a subject (e.g., in need thereof) a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • a subject e.g., in need thereof
  • a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof e.g., the subject is human. In some embodiments, the subject is male or
  • tire method includes a step of identifying a mammal in need of treatment.
  • the step includes identifying a subject diagnosed with the disease or condition (e.g., by diagnosing the subject with the disease
  • the diagnosis can be performed by a lab technician, a diagnostician, a treating physician, a primary care physician, or a specialty physician such as an oncologist or a memory care specialist.
  • the diagnosis can be performed on the basis of laboratory tests (e.g., MRI imaging or testing a specimen obtained from the mammal for
  • this disclosure provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease, disorder, or condition. In some embodiments, this disclosure provides a use of a compound as described herein, or a pharmaceutically acceptable salt thereof, for
  • this disclosure provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use (or a use of a compound as described herein, or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disease, disorder, or condition.
  • a compound as described herein, or a pharmaceutically acceptable salt thereof for use (or a use of a compound as described herein, or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disease, disorder, or condition.
  • neurodegeneration is often featured by accumulation in brain cells and intracellular spaces of insoluble protein aggregates, such as a-synuclein fibrils, amyloid-p plaques, and tau tangles, as well as by marked neuroinflammation.
  • Parkinson 10 Parkinson’s, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder, among others.
  • the disease or disorder treatable by a compound of this disclosure is a neurodegenerative disorder.
  • Suitable examples of neurodegenerative disorders include synucleinopathies, amyloidopathies, and/or
  • synucleinopathies include dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF) ; PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, and Bradbury-Eggleston syndrome.
  • PD Parkinson’s disease
  • MSA multiple system atrophy
  • PAF pure autonomic failure
  • PD with dementia olivopontocerebellar atrophy
  • SND striatonigral degeneration
  • neuroaxonal dystrophy Shy-Drager syndrome
  • Hallervorden-Spatz syndrome Hallervorden-Spatz syndrome
  • Bradbury-Eggleston syndrome Suitable examples of amyloidopathies include
  • AD Alzheimer’s disease
  • FAD familial AD
  • FAD frontotemporal lobar degeneration
  • ALS amyotrophic lateral sclerosis
  • HD Huntington’s disease
  • tauopathies include Pick’s disease, progressive supranuclear palsy,
  • argyrophilic grain disease 25 corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
  • CTE chronic traumatic encephalopathy
  • aging-related tau astrogliopathy Richardson syndrome
  • cerebellar ataxia globular glial tauopathy
  • argyrophilic grain disease 25 corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
  • CTE chronic traumatic encephalopathy
  • the disease or disorder treatable by a compound of this disclosure is a metabolic disorder selected from type 1 diabetes,
  • metabolic disorders include familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann- Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
  • An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non- infectious causes.
  • the disease or disorder treatable by a compound of this disclosure is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple
  • sclerosis 30 sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease. Additional examples of inflammatory disorders include atherosclerosis, arteriosclerosis, polymyalgia
  • PMR rheumatics
  • gouty arthritis degenerative arthritis, tendonitis, bursitis, cystic fibrosis, arthrosteitis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, myasthenia gravis, sclerosing cholangitis, Crohn’s disease,
  • hypersensitivity reactions e.g., poison ivy dermatitis
  • pneumonia respiratory tract inflammation
  • ARDS Adult Respiratory Distress Syndrome
  • encephalitis immediate hypersensitivity reactions
  • asthma hayfever
  • allergies acute anaphylaxis
  • rheumatic fever glomerulonephritis
  • pyelonephritis cellulitis
  • cystitis chronic cholecystitis
  • ischemia ischemic injury
  • reperfusion injury allograft rejection
  • host-versus-graft host-versus-graft
  • parotitis pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.
  • the disease or disorder treatable by a compound of this disclosure is an autoimmune disease selected from autoimmune thyroiditis, glomerulonephritis, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosis, systemic sclerosis, deployatomyositis/polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, uveitis, Reiter’s
  • autoimmune disease selected from autoimmune thyroiditis, glomerulonephritis, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosis, systemic sclerosis, deployatomyositis/polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, uveitis, Reiter’s
  • cancers See, e.g., PLoS ONE, 8, 11, e81803, which is incorporated herein by reference in its entirety, among many other publications discussing DYRK1 A’s involvement in the pathology of cancer, such as brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g, B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
  • brain cancer e.g., glioblastoma, neuroblastoma
  • leukemia e.g, B cell acute lymphoblastic leukemia
  • breast cancer e.g., and pancreatic cancer.
  • pancreatic cancer e.g., acoustic neuroma,
  • adenocarcinoma 10 adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangi ⁇ carcinoma), bladder cancer, breast cancer (e.g, adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer), brain cancer (e.g., meningioma, glioblastomas,
  • angiosarcoma e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma
  • appendix cancer benign monoclonal gammopathy
  • biliary cancer e.g., cholangi ⁇ carcinoma
  • bladder cancer e.g.,
  • glioma e.g., astrocytoma, oligodendroglioma), medulloblastoma
  • bronchus cancer carcinoid tumor, cervical cancer (e.g via cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorecta 1 cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), connective tissue cancer, epithelial carcinoma, ependymoma, endothel iosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic
  • hemorrhagic sarcoma 20 hemorrhagic sarcoma
  • endometrial cancer e.g., uterine cancer, uterine sarcoma
  • esophageal cancer e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma
  • Ewing’s sarcoma ocular cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), germ cell cancer,
  • head and neck cancer e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)
  • heavy chain disease e.g., alpha chain disease, gamma chain disease, mu chain disease, hemangioblastoma, hypopharynx cancer, inflammatory my of ibroblastic tumors. inununocytic
  • kidney cancer e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), muscle cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g.,
  • PV polycythemia vera
  • EMT essential thrombocytosis
  • AMM agnogenic myeloid metaplasia
  • MF myelofibrosis
  • CML chronic myelocytic leukemia
  • CTL chronic neutrophilic leukemia
  • HES hypereosinophilic syndrome
  • neuroblastoma e.g, neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • NF neurofibromatosis
  • schwannomatosis neuroendocrine cancer
  • GEP-NET gastroenteropancreatic neuroendoctrine tumor
  • carcinoid tumor carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic andenocarcinoma intraductal papillary mucinous neoplasm (IPMN), islet cell tumors
  • penile cancer e.g., Paget’s disease of the penis
  • pinealoma e.g., pinealoma, primitive neuroectodermal tumor (PNT), plasma cell neoplasia, paraneoplastic syndromes, intraepithelial neoplasms, prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer),
  • SCC squamous cell carcinoma
  • KA keratoacanthoma
  • BCC basal cell carcinoma
  • small bowel cancer e.g., appendix cancer
  • soft tissue sarcoma e.g., malignant fibrous histiocytoma (MFH), eposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, small intestine cancer, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid
  • PTC carcinoma
  • medullary thyroid cancer medullary thyroid cancer
  • urethral cancer urethral cancer
  • vaginal cancer e.g., Paget’s disease of the vulva
  • compositions comprising, formulations, and routes of administration
  • compositions comprising an effective amount of a compound of the present disclosure disclosed herein, or a
  • composition may also comprise any one of the additional therapeutic
  • the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein.
  • the carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a
  • compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human
  • serum albumin buffer substances such as phosphates, 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
  • compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients.
  • compositions of the present application include those suitable for any acceptable route of administration.
  • Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal,
  • intracerebral intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal,
  • compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example,
  • compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets,
  • granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches.
  • Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, 6) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, ⁇ V)
  • disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as
  • paraffin paraffin,/) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and t) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
  • absorption accelerators such as quaternary ammonium compounds
  • wetting agents such as, for example, cetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
  • useful diluents include lactose and dried com starch.
  • the active ingredient is combined with emulsifying and suspending agents.
  • certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and
  • acacia or tragacanth 10 acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of
  • aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5%
  • injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • 25 preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a non-toxic parenterally-acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any blandness of the diluent or solvent for example, as a solution in 1,3-butanediol.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils solutions or suspensions may also contain a long- chain alcohol diluent or dispersant
  • compositions of the present application may be administered
  • compositions can be prepared by mixing a compound of the present application with a suitable non- irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non- irritating excipient include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
  • compositions of the present application may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents
  • topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel,
  • Topical compositions of the present application is especially useful when the desired treatment involves areas or organs
  • the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding
  • silicones for silicones, skin-identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners.
  • Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
  • an effective amount of the compound can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g,, from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 500 mg/kg (e.g, from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to
  • an effective amount of a compound is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg.
  • the foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g, once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two
  • the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).
  • Ci-6 alkyl is specifically intended to individually disclose methyl, ethyl, Cs alkyl, Ca alkyl, C5 alkyl, and Ce alkyl.
  • a pyridine ring or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3- yl, or pyridin-4-yl ring.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (z.e., having (4n + 2) delocalized it (pi)
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • the phrase “optionally substituted” means unsubstituted or substituted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position.
  • substituted means that a
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.
  • Cn-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons.
  • CM complementary metal-oxide-semiconductor
  • CI -6 complementary metal-oxide-semiconductor
  • Cn-m alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, isopropyl, //-butyl, /cr/-butyl,
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or I to 2 carbon atoms.
  • halogen atom refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms.
  • the haloalkyl group is fluorinated only.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • Cn-m alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons.
  • Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., zz-propoxy and isopropoxy), butoxy (e.g., « -butoxy and ter? -butoxy), and the like.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • Cn-m haloalkoxy refers to a group of formula -O-haloalkyl having n to m carbon atoms.
  • An example haloalkoxy group is OCFs.
  • the haloalkoxy group is fluorinated only.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • amino refers to a group of formula -NH2.
  • C n -m alkylamino refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N- propylamino (e.g., N-(rt-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(zz-
  • di(Cn-m-alkyl)amino refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • Cn-m alkoxycarbonyl refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl
  • carboxy refers to a -C(O)OH group.
  • halo refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.
  • Cn-m aryl refers to an aryl group having from n to m ring carbon atoms.
  • Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring- forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are
  • cycloalkyl ring 25 moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons
  • the cycloalkyl is a C3-10 monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, adamantyl, and the like.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heteroaryl refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen.
  • the heteroaryl ring has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl
  • a five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g. , 1, 2, or 3) ring atoms are independently selected from N, 0, and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazo lyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl,
  • a six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (eg., 1 , 2, or 3) ring atoms are independently selected from N, 0, and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heterocycloalkyl refers to non-aromatic monocyclic or
  • heterocycloalkyl 25 polycyclic heterocycles having one or more ring-forming heteroatoms selected from 0, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles.
  • Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin- 2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino,
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), 8(0), C(S), or S(O)2, etc.).
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring- forming heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (z.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered
  • heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
  • the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded.
  • rings e.g., an azetidine ring, a pyridine ring, etc.
  • an azetidine ring may be attached at any position of the ring, whereas a pyridin- 3-yl ring is attached at the 3 -position.
  • the compounds described herein can be asymmetric (e.g., having one or more
  • 78 asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms.
  • Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Cis and trans geometric isomers of the compounds of die present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • the compound has the ( ⁇ -configuration.
  • the compound has the (S)-
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” the DYRKI A with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having DYRKI A, as
  • the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the
  • disease for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the
  • preventing or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a
  • disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and/or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring.
  • Step b to 2-nitro-4-aniline intermediate (1.0 eq.) in MeOH (0.1 M), Pd/C (1.0 equiv. 10 wt.% Pd/C, pre-wetted) was added and then a Ha-filled balloon attached to a 3- way valve was attached. The flask’s atmosphere was repeatedly evacuated under vacuum and back-filled with Hz. The reaction was stirred for 24 h then filtered through Celite,
  • Step c benzene- 1,2-diamine compound (1.0 eq.) was dissolved in MeOH (0.5 M) and l,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.1 eq.) was added.
  • MeOH 0.5 M
  • l,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea 1.1 eq.
  • Step d in a flame dried glassware, a methyl carbamate (1.0 eq.) was dissolved in
  • Compound was further purified by Prep-LC using a 5-100% gradient of MeCN in water 0.1% formic acid as the mobile phase. Collected fractions were dried in a Speed-Vac concentrator to yield >95 % purity.
  • DYRK1A dual-specificity tyrosine phosphorylation-regulated kinase- 1 A
  • DYRK1 A catalyzes the phosphorylation of the amyloid precursor and tau proteins, two major pathological effectors involved in the formation of amyloid plaques and neurofibrillary tangle, and consequentially
  • DYRK1 A protein including a number of highly active DYRK1 A inhibitors.
  • five (5) compounds were shown to bind to DYRK1A with KD of ⁇ 1 nM: 2 (KD: 720 pM), 11 (KD: 330 pM), 5 (KD: 330 pM), 1 (KD: 170 pM), and 12 (KD: 140 pM).
  • compound 1 showed 15 to 90-fold selectivity over DYRK1B/2 and CLK1-4 kinases, and potently inhibited Tau
  • T-cell Inflammation Inhibition Assay Protocol Day 1, High binding plates were coated with anti-CD3 (clone UCHT-1, 2 pg/niL) and isotype IgGl using PBS lx and incubated overnight at 4 °C. Day 2: Cryopreserved PBMCs were drip thawed and diluted to the appropriate density and seeded into U bottom 96-well polypropylene plates
  • test compounds were solubilized in DMSO and further diluted to 20 x with cell culture medium.
  • Cytokine levels in each sample were determined using Luminex methodology, per the manufacturer’s protocol. Luminex assessment of cytokine levels in cell culture supernatants in tissue culture medium, was performed per manufacturer's protocol using the Human Cytokine/Chemokine Magnetic
  • E. coll host derived from the BL21 strain 10 an E. coll host derived from the BL21 strain. E. coh were grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin- coated magnetic beads were treated with biotinylated small molecule ligands for 30
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1 x binding buffer (20% SeaBlock, 0.17*
  • Test compounds were prepared as 11 lx stocks in 100% DMSO. Kds were determined using an 11 -point 3-fold compound dilution series with three DMSO control points. All compounds for Ka measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All
  • the kinase concentration in the eluates was measured by qPCR.
  • HEK293 human embryonic kidney cells were transiently co-transfected with vectors encoding full-length human DYRK1A and Tau. Cells were dispensed into 96-well plates at a number previously determined by cell titration and signal optimization for the DYRK1 A assay. Compounds were diluted to 200* final assay
  • the experimental results show that the 5-pyridyl group-containing compounds show high binding affinity in the kinase assays. These compounds are highly active at about 0.1 pM, about 1 pM, or about 10 p.M concentration.
  • R A is selected from moiety (i) and (ii):
  • R la , R 2a , R 3a , and R 4a are each independently selected from H. halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR 31 , NR cl R dl , S(O)2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 1 is selected from Cy 1 , OR B , NR 3 R B , CH 2 R B , and CH2R c ; each R B is independently selected from Cy 1 , C1-6 haloalkyl, and C1-6 alkyl substituted with Cy 1 , CN, NO 2 , OR al , NR el R dl , S(O) 2 R bl , C(O)NR el R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 is selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR el R dl , S(O) 2 R bl , S(O) 2 NR cl R dl , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O)2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 6 and R 7 are each independently selected from H, halo, CN, NCh, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR el R dl , S(O)£NR cl R dl , C(O)OR al , and S(O) 2 OR al ; each Cy 1 is independently selected from C ⁇ - 10 aryl.
  • each R Cy1 is independently selected from halo, CN, NO 2 , OR al , NR cl R dl , C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with CN, NO 2 , OR al , NR cl R dl , S(O)2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R al , R bl , R cl , andR dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R e ; and each R 8 is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino; provided that the compound of Formula (I) is not any one of the following compounds:
  • R la , R 2a , R 3a , and R 43 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, and C 1-3 haloalkyl.
  • R la , R 2a , R 3a , and R 4a are each independently selected from H and C 1-3 alkyl.
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR cl R dl .
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, NO2, C 1-3 alkyl, C 1-3 haloalkyl, Ci- 3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R B is selected from Cy 1 and Ci -e alkyl substituted with Cy 1 , OR al , or NR cl R dl .
  • R B is selected from Cy 1 , C 1-3 alkyl substituted with Cy 1 , and Ci ⁇ alkyl substituted with NR el R dl .
  • Cy 1 is selected from Ce- io aryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R Cyl .
  • R Cyl is selected from halo, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.
  • R Cyl is selected from halo, NO2, C 1-3 alkyl, and C 1-3 alkoxy.
  • R B is selected from CH2NR el R dl , CHiCH2NR cl R dl , and CH 2 CH 2 CH2NR el R dl .
  • a pharmaceutical composition comprising a compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any
  • the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle
  • the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup mine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
  • a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup mine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
  • the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease.
  • an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis,
  • the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
  • a method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition comprising:
  • R A is selected from moiety (i) and (ii):
  • R la , R 2 ", R 3a , and R 4a are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR" 1 , NR cl R dl , S(O)zR bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR el R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl > C(O)OR al , and S(O) 2 OR al ;
  • R 1 is selected from Cy 1 , OR 8 , NR 3 R B , CH 2 R B , and CH 2 R c ;
  • each R B is independently selected from H, Cy 1 , Ci-6 alkyl, and Ci-6 haloalkyl, wherein said Ci-e alkyl is optionally substituted with Cy 1 , CN, NO2, 0R al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from CN, NO 2 , 0R al , NR cl R dl , S(0)2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 , R 6 and R 7 are each independently selected from H, halo, CN, NCb, C 1-3 alkyl, C 1-3 haloalkyl, Cy 1 , OR al , NR cl R dl , S(0>2R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy 1 , CN, N0 2 , 0R al , NR el R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ; each Cy 1 is independently selected from Cs-ioaryl, C3-10 cyclo
  • R al , R bl , R cl , andR dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R 8 ; and each R 8 is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di (C 1-3 alkyl)amino.
  • R 7 or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is selected from OR B , NR 3 R B , and CH 2 R c ; each R B is independently selected from Cy 1 , Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy 1 , CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from NO 2 , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , S(O) 2 OR al , and C1-6 alkyl substituted with NO2, NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, CJ-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR ai , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ; each Cy 1 is independently selected from Cs-ioaryl, C3-10 cycloalkyl, 5-14 membere
  • R al , R bl , R cl , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R g ; and
  • each R e is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino; provided that the compound of Formula (II) is not any of the following compounds:
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , and NR cl R dl .
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, OH, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.
  • R B is selected from Cy 1 , Ci-6 alkyl substituted with Cy 1 , and Ci-e alkyl substituted with NR cl R dl .
  • R Cyl is selected from halo, NO2, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.
  • R Cvl is selected from halo, NO2, C 1-3 alkyl, and C 1-3 alkoxy.
  • R B is selected from CH 2 NR cl R dl , CH2CH 2 NR el R dl , and CH 2 CH 2 CH 2 NR el R dl .
  • a pharmaceutical composition comprising a compound of any one of embodiments 36-56, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 36-56, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 57.
  • the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary
  • the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
  • a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
  • the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease.
  • an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis,
  • the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
  • brain cancer e.g., glioblastoma, neuroblastoma
  • leukemia e.g., B cell acute lymphoblastic leukemia
  • a method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition comprising:
  • R 1 is selected from Cy 1 , OR B , NR 3 R B , CH2R B , and CH 2 R c ; each R B is independently selected from H, Cy 1 , C1-6 haloalkyl, and C1-6 alkyl substituted with Cy 1 , CN, NO 2 , OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , or S(O) 2 OR al ;
  • R c is selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ;
  • R 2 , R 3 , and R 4 are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl;
  • R 5 , R 6 , and R 7 are each independently selected from H, halo, CN, NO2, C 1-3 alkyl, C 1-3 haloalkyl, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al , wherein said C 1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR al , NR cl R dl , S(O) 2 R bl , C(O)NR cl R dl , S(O) 2 NR cl R dl , C(O)OR al , and S(O) 2 OR al ; each Cy 1 is independently selected from Ce-ioaryl, C3-1Q cycloalkyl, 5-14 membered heteroaryl
  • R al , R bl , R el , and R dl are each independently selected from H, C 1-3 alkyl, and C 1-3 haloalkyl, wherein said C 1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R g ; and each R s is independently selected from halo, CN, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, carboxy, C 1-3 alkoxycarbonyl, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.

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Abstract

The present disclosure provides chemical compounds such as benzimidazole carbamates that are inhibitors of DYRK1A kinase and are useful in treating, e.g., neurodegenerative diseases such as Alzheimer's disease, autoimmune diseases such as inflammatory bowel disease, osteoarthritis, and type-1 diabetes, and cancer (including brain tumors such as glioblastoma and neuroblastoma).

Description

INHIBITORS OF DYRKIA
CLAIM OF PRIORITY
This application claims priority under 35 USC §119(e) to U.S. Patent Application Serial No. 63/504,910, filed on May 30, 2024. The entire contents of the foregoing are
5 hereby incorporated by reference.
TECHNICAL FIELD
This invention relates to benzimidazole carbamate compounds that are, e.g., inhibitors of DYRKIA kinase and are useful in treating, e.g., neurodegenerative diseases such as Alzheimer’s disease, autoimmune diseases such as inflammatory bowel disease,
10 osteoarthritis, and type-1 diabetes, and cancer (including brain tumors such as glioblastoma and neuroblastoma).
BACKGROUND
There are numerous deadly diseases affecting current human population. For example, neurodegenerative diseases affect a significant segment of population,
15 especially the elderly. As one example, Alzheimer’s disease (“AD”), a neurodegenerative disease that affects approximately 44 million people world-wide, is the sixth leading cause of death with an estimated socioeconomic burden of more than $200 billion. Neurodegenerative diseases such as AD impose a substantial burden on patients, their family members, the healthcare system, and the society overall. Because of aging
20 population worldwide, neurodegenerative disorders pose an increasing threat to public health.
SUMMARY
The present disclosure is based, at least in part, on a realization that benzimidazole carbamate compounds are potent and selective inhibitors of dual
25 specificity tyrosine-phosphorylation-regulated kinase 1 A (DYRKIA). Without being bound by any particular theory, and as discussed in this disclosure, numerous peer- reviewed scientific publications provide credible evidence that DYRKIA is implicated in pathology of various disorders. For example, as a kinase, DYRKIA promotes phosphorylation of the Tau protein, and hyperphosphorylation of Tciu is a pathological
30 factor in the development of neurodegenerative disorders, including Alzheimer’s disease.
1 Attorney Docket No. 13681.0050W01
As such, the present disclosure advantageously provides methods of using the benzimidazole carbamate compounds to treat disorders associated with DYRK.1 A, including neurodegenerative diseases, autoimmune diseases, and cancer. Example embodiments of the benzimidazole carbamate compounds and related treatment methods
5 are described herein.
In one general aspect, the present disclosure provides a compound of Formula (I):
Figure imgf000003_0002
or a pharmaceutically acceptable salt thereof, wherein: RA is selected from moiety (i), (ii), (iii) and (iv):
Figure imgf000003_0001
( ) ( )
10 RIa, R2a, R3a, and Rti are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
16 R1 is selected from Cy1, ORB, NR3RB, CHzR8, and CH2Rc;
2 each RB is independently selected from Cy1, Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, OR31, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
5 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5 is selected from H, halo, CN, NCh, C1-3 alkyl, C1-3 haloalkyl, OR81, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said C1.3 alkyl is optionally substituted
10 with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R6 and R7 are each independently selected from H, halo, CN, NO2, C1.3 alkyl, C1-3 haloalkyl, OR31, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2OR81, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents
15 independently selected from CN, NO2, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl;
20 each RCyl is independently selected from halo, CN, NO2, ORal, NRelRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1.3 alkyl, and C1.3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
25 independently selected from Rg;
R8a, R8b, and R8c are each independently selected from H, C1.3 alkyl, and C1.3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from Rg; each X is independently selected from N and CR9b, wherein one X is N and the
30 other X is CR9b;
3 R9a and R9b are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Re; and
5 each Rg is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyljami.no; provided that the compound of Formula (I) is not any one of the following compounds:
Figure imgf000005_0001
10
In some embodiments of the compound of Formula (I), RA is selected from moiety (i) and (ii):
Figure imgf000005_0002
In some embodiments of the compound of Formula (I), RA is selected from moiety (iii) and (iv):
Figure imgf000005_0003
4
Figure imgf000006_0001
In some embodiments, the compound has formula:
Figure imgf000006_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound has formula:
5
Figure imgf000006_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, Rla, R2a, R3a, and R4a are each independently selected from H, halo, CN, NOi, C1-3 alkyl, and C1-3 haloalkyl.
In some embodiments, Rla, R23, R3a, and R4a are each independently selected from
10 H and C1-3 alkyl.
In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:
Figure imgf000006_0004
5
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I) is selected from:
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof.
6 In some embodiments, the compound has formula:
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound has formula:
5
Figure imgf000008_0002
or a pharmaceutically acceptable salt thereof
In some embodiments, the compound has formula:
Figure imgf000008_0003
or a pharmaceutically acceptable salt thereof.
10 In some embodiments, the compound has formula:
Figure imgf000008_0004
or a pharmaceutically acceptable salt thereof.
7 In some embodiments, RSa, R8b, and R8e are each independently selected from H and Ci -s alkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rs.
In some embodiments, R8a, R8b, and R8c are each independently selected from H
5 and Ci -3 alkyl.
In some embodiments, R8a and R8c are both H and R8b is C1-3 alkyl, such as methyl.
In some embodiments, R9a and R9b are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said CM alkyl is optionally substituted with 1 , 2, or 3
10 substituents independently selected from Rg.
In some embodiments, R9a and R9b are each independently selected from H and C1-3 alkyl.
In some embodiments, R9a and R9b are both H.
In some embodiments, the compound of Formula (I) is selected from any one of
15 the following compounds:
Figure imgf000009_0001
8 or a pharmaceutically acceptable salt thereof.
In some embodiments, R5, R6, and R7 are each independently selected from H, halo, ON, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl.
In some embodiments, R5, R6, and R7 are each independently selected from H,
5 halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
In some embodiments, R1 is selected from ORB and NR3RB.
In some embodiments, R1 is ORB.
In some embodiments, R1 is NHRB.
10 In some embodiments, R1 is CH2RB.
In some embodiments, the compound of Formula (I) is selected from:
Figure imgf000010_0001
9
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, RB is selected from Cy1 and C1-6 alkyl substituted with
Cy1, ORal, or NRclRdl.
10 In some embodiments, RB is selected from Cy1, Ci-6 alkyl substituted with Cy1, and Ci -6 alkyl substituted with NRclRdl.
In some embodiments, RB is Cy1.
In some embodiments, RB is Ci-6 alkyd substituted with Cy1.
5 In some embodiments, Cy1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
In some embodiments, Cy1 is Q-ioaryl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
10 In some embodiments, Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
In some embodiments, the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with
15 1 or 2 substituents independently selected from RCy1.
In some embodiments, RCyl is selected from halo, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
In some embodiments, RCyl is selected from halo, NO2, C1-3 alkyl, and C1-3 alkoxy.
20 In some embodiments, Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000012_0001
O
In some embodiments, RB is Ci-6 alkyl substituted withNRqlRdl.
In some embodiments, RB is selected from CH2NRqlRdl, CH2CH2NRclRdl, and CH2CH2CH2NRclRdl.
11 In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof
In another general aspect, the present disclosure provides a pharmaceutical
5 composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another general aspect, the present disclosure provides a method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a
10 therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
12 In some embodiments, the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager
5 syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease,
10 progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
In some embodiments, the disease or condition is a metabolic disorder selected
15 from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
20 In some embodiments, the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and
25 Grave’s disease.
In some embodiments, the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
In another general aspect, the present disclosure provides a method of treating a
30 disease or condition where overexpression and/or enhanced activity of DYRK1A is implicated in pathology of the disease or condition, the method comprising: (i)
13 identifying a subject diagnosed with the disease or condition responsive to inhibition of DYRK 1 A in a cell, a tissue, and/or an organ affected by the disease or condition; and (ii) after (i), administering to the subject a therapeutically effective amount of a compound of Formula (la):
5
Figure imgf000015_0002
or a pharmaceutically acceptable salt thereof, wherein: RA is selected from moiety (i) and (ii):
Figure imgf000015_0001
RIa, R2a, R3a, and R4a are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(0)2NRclRdl, C(O)ORal,
10 and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal;
Rw is selected from H, C1-3 alkyl, C1-3 haloalkyl, and C(=O)R1;
R1 is selected from Cy1, ORB, NR3RS, CHaR8, and CH2Rc;
15 each RB is independently selected from H, Cy1, C1-6 alkyl, and Ci-e haloalkyl, wherein said Ci-e alkyl is optionally substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)iRbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NR€1Rdl, C(O)ORal, and S(O)2ORal;
20 R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal,
14 and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, N02, 0Ral, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)iNRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14
5 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each RCyl is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, OR11, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
10 Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R8; and each Rs is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycaibonyl, amino, C1-3 alkylamino, and di(C1-3
15 alkyl)amino.
In some embodiments, the compound of Formula (la) is selected from any one of the following compounds:
Figure imgf000016_0001
15
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof.
16 In another general aspect, the present disclosure provides a compound of Formula
(H):
Figure imgf000018_0001
or a pharmaceutically acceptable salt thereof, wherein:
5 R 1 is selected from ORB, NR3RB, and CH2RC; each RB is independently selected from Cy1, Ci-$ haloalkyl, and Ci-<s alkyl substituted with Cy1, CN, NO2, OR’1, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from NOz, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl,
10 C(O)ORal, S(O)2ORal, and C i-6 alkyl substituted with NO2, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl,
15 C1-3 haloalkyl, OR’1, NR61Rdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR’1, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14
20 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each Rc>1 is independently selected from halo, CN, NO2, OR’1, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, OR’1, NRelRdl, S(O)2Rbl, C(O)NR61Rdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal;
25 Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
17 each Re is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; provided that the compound of Formula (II) is not any of the following
5 compounds:
Figure imgf000019_0001
In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl. In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
10 In some embodiments, the compound has formula:
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, R1 is selected from ORB and NR3RB.
In some embodiments, R* is ORB.
15 In some embodiments, R1 is NHRB.
In some embodiments, RB is selected from Cy1 and Ci-e alkyl substituted with Cy1, OR’1, or NRclRdl.
In some embodiments, RB is selected from Cy1, Ci-e alkyl substituted with Cy1, and Ci-6 alkyl substituted with NRclRdl.
20 In some embodiments, RB is Cy1.
In some embodiments, RB is C1-6 alkyl substituted with Cy1.
18 In some embodiments, Cy1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
In some embodiments, Cy1 is Ce-io aryl, optionally substituted with 1 or 2
5 substituents independently selected from RCyl.
In some embodiments, Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
In some embodiments, the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl,
10 morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
In some embodiments, RCyl is selected from halo, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
In some embodiments, RCyl is selected from halo, NO2, C1-3 alkyl, and C1-3
15 alkoxy.
In some embodiments, Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000020_0001
In some embodiments, RB is Ci-6 alkyl substituted with NRC1R41.
In some embodiments, RB is selected from CH2NRclRdl, CH2CH2NRclRdl, and
20 CH2CH2CH2NRciRd3.
In some embodiments, the compound of Formula (II) is selected from any one of the following compounds:
19
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof.
In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6 In another general aspect, the present disclosure provides a method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.
10 In some embodiments, the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager
20 syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s
5 disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
10 In some embodiments, the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU),
15 porphyria, Tay-Sachs disease, and Wilson’s disease.
In some embodiments, the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis,
20 dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease.
In some embodiments, the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
25 In another general aspect, the present disclosure provides a method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition, the method comprising: (i) identifying a subject diagnosed with the disease or condition responsive to inhibition of DYRK1 A in a cell, a tissue, and/or an organ affected by the disease or condition; and (ii)
30 after (i), administering to the subject a therapeutically effective amount of a compound of Formula (Ha):
21
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof, wherein:
R10 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and C(=O)R1;
R1 is selected from Cy1, ORB, NR3RB, CH2RB, and CH2RC;
5 each RB is independently selected from H, Cy1, C1-6 haloalkyl, and Ci-e alkyl substituted with Cy', CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORat, or S(O)2ORal;
Rc is selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
10 R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents
15 independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl;
20 each RCyl is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, ORal, NRtlRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
25 independently selected from R8; and
22 each R8 is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
In some embodiments, the compound of Formula (Ila) is selected from any one of
5 the following compounds: o
Figure imgf000024_0001
23
Figure imgf000025_0002
In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:
5
Figure imgf000025_0001
35 or a pharmaceutically acceptable salt thereof.
10 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be
15 limiting. All publications, patent applications, patents, sequences, database entries, and
24 other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.
5 DETAILED DESCRIPTION
The present disclosure provides chemical compounds (e.g., organic heterocyclic compounds). Without being bound by any theory or speculation, it is believed that in one example, compounds of this disclosure potently and selectively inhibit kinase enzyme D YRK 1 A and/or phosphorylation of the Tau protein. Certain embodiments of these
10 compounds, methods of using these compounds to inhibit DYRK1 A (e.g., in vitro, in vivo, or ex vivo) and to treat associated disorders and conditions (e.g., diseases where DYRK1 A is implicated in pathology such as Alzheimer’s disease, inflammation, and cancer) are described herein. Example embodiments of pharmaceutical compositions containing these compounds and combination treatment methods are also provided.
15 Therapeutic compounds
In a general aspect, the present disclosure provides benzoimidazole (e.g., benzo[d]imidazole) compound having a substituent in the 5 -position (e.g., a substituted pyridine, a methoxy, or a substituted benzoyl moiety). Example embodiments of these compounds are provided herein.
20 Pyridine-containing benzonnidazole compounds
In some embodiments, the present disclosure provides a compound of Formula
(la):
Figure imgf000026_0001
( ), or a pharmaceutically acceptable salt thereof, wherein R10, R2, R4, R5, R6, R7, and
25 RA (e.g, as described herein for Formula la or Formula I).
25 In some embodiments, R10 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and C(=O)R*. In some embodiments, R10 is H. In some embodiments, R10 is C1-3 alkyl. In some embodiments, R10 is haloalkyl. In some embodiments, R10 is C(=O)R*.
In some embodiments, the compound of Formula (la) has Formula (I):
5
Figure imgf000027_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments of Formula (la) or Formula (I):
RA is selected from moiety (i) and (ii):
Figure imgf000027_0002
Rla, R2a, R3a, and R4a are each independently selected from H, halo, CN, NO2, C1-3
10 alkyl, C1-3 haloalkyl, ORal, NRelRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)zNR<1Rdl, C(O)ORal, and S(O)2ORal;
R1 is selected from Cy1, ORB, NR3RB, CH2RR, and CH2Rc;
15 each RB is independently selected from H, Cy1, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdi, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
20 R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
26 R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, and S(O)zORa1, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
5 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each RCvl is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3
10 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R2; and
15 each R8 is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
In some embodiments of Formula (la) or Formula (I):
RA is selected from moiety (i) and (ii):
Figure imgf000028_0001
( ) ( )
20 R1a R2a, R3b and R4S each in dependently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal;
25 R1 is selected from Cy1, OR8, NR3RB, CHiR8, and CH2Rc;
27 each RB is independently selected from Cy1, Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, OR31, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
5 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5 is selected from H, halo, CN, NCh, C1-3 alkyl, C1-3 haloalkyl, OR81, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted
10 with 1 or 2 substituents independently selected from CN, NCh, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, OR31, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2OR81, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents
15 independently selected from CN, NCh, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl;
20 each RCyl is independently selected from halo, CN, NO2, ORal, NRelRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
25 independently selected from Rg; and each Re is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
In some embodiments, RA is a moiety of formula (i). In some embodiments, RA is
30 a moiety of formula (ii).
In some embodiments, the compound has formula:
28
Figure imgf000030_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound has formula:
Figure imgf000030_0002
5 or a pharmaceutically acceptable salt thereof
In some embodiments, Rla is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)iORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
10 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R2a is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)zORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
15 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R3a is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
20 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R4a is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and
29 S(O)iORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)iNRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, Rla, R23, R3a, and R4a are each independently selected from
5 H, halo, CN, NO2, C1-3 alkyl, and C1-3 haloalkyl.
In some embodiments, Rla is selected from H, halo, CN, NO2, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R2a is selected from H, halo, CN, NO2, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3a is selected from H, halo, CN, NO2, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R43 is selected from H, halo, CN, NO2, C1-3
10 alkyl, and C1-3 haloalkyl.
In some embodiments, Rla, R2a, R3a, and R4a are each independently selected from H and C1-3 alkyl. In some embodiments, Rla is selected from H and C1-3 alkyl. In some embodiments, Rla is C1-3 alkyl. In some embodiments, R2a is selected from H and C1-3 alkyl. In some embodiments, R2a is C1-3 alkyl. In some embodiments, R3a is selected from
15 H and C1 -3 alkyl. In some embodiments, R3a is C1-3 alkyl. In some embodiments, R43 is selected from H and C1-3 alkyl. In some embodiments, R43 is C1-3 alkyl. In some embodiments, Rla, R2a, R3a, and R4a are each H.
In some embodiments, the compound of Formula (la) or Formula (I) is selected from any one of the following compounds:
Figure imgf000031_0001
R R
20 or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
30
Figure imgf000032_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
Figure imgf000032_0002
6 or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
Figure imgf000032_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, R5, R6 and R7 are each independently selected from H,
10 halo, CN, NO2, CI-3 alkyl, C1-3 haloalkyl, Cy1, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NCh, ORal, NRtlRdi, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R5, R6 and R7 are each independently selected from H,
15 halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, OR81, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NCh, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
31 In some embodiments, R5 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRqlRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NO2, ORal, NRqlRdl, S(O)2Rbl, C(O)NRclRdl,
5 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R5 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, S(O)2NRqlRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
10 In some embodiments, R6 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRqlRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRqlRdl, C(O)ORal, and S(O)2ORal.
15 In some embodiments, R6 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRqlRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R7 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3
20 haloalkyl, Cy1, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R7 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3
25 haloalkyl, ORal, NRclRdl, S(O)2Rbl, S(O)2NRqlRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, C(O)NRclRdl, and
30 C(O)ORaI, wherein said C1-3 alkyl is optionally substituted with Cy1, CN, NCh, ORal, or NRclRdl.
32 In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, C(O)NRelRdl, and C(O)ORal, wherein said Cua alkyl is optionally substituted with Cy1, CN, NO2, ORal, or NRclRdl.
5 In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, C(O)NRclRdl, and C(O)ORal, wherein said C1-3 alkyl is optionally substituted with Cy1, CN, NO2, ORal, or NRclRdl.
In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl, wherein said C1-3 alkyl is
10 optionally substituted with Cy1, CN, NO2, ORal, or NRelRdl.
In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl.
In some embodiments, at least one of R5, R6, and R7 is C1-3 alkyl substituted with Cy1, CN, NO2, ORal, or NRclRdl.
15 In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
20 In some embodiments, R5, R6 and R7 are each H. In some embodiments, R5 is not Cy1. In some embodiments, Rs is not C(O)NRclRdl. In some embodiments, R5 is not C(O)ORal.
In some embodiments, R2, R3, and R4 are each independently selected from H and C1-3 alkyl. In some embodiments, R2 is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In
25 some embodiments, R3 is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R4 is selected from H, Ci .3 alkyl, and C1-3 haloalkyl. In some embodiments, R2 is selected from H and C1-3 alkyl. In some embodiments, R3 is selected from H and C1-3 alkyl. In some embodiments, R4 is selected from H and C1-3 alkyl. In some embodiments, R2, R3, and R4 are each H.
30 In some embodiments, R1 is selected from Cy1, ORB, NR3RB, CH2RB, and CH2Rc. In some embodiments, R1 is Cy1. In some embodiments, R1 is ORB. In some
33 embodiments, R1 is NR3RB. In some embodiments, R1 is CHiRB. In some embodiments, R1 is CHaRc. In some embodiments, R1 is selected from ORB and NR3RB.
In some embodiments, the compound of Formula (la) or Formula (I) is selected from:
Figure imgf000035_0001
5 or a pharmaceutically acceptable salt thereof
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
34
Figure imgf000036_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
Figure imgf000036_0002
5 or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
Figure imgf000036_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
10
Figure imgf000036_0004
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
Figure imgf000036_0005
or a pharmaceutically acceptable salt thereof.
35 In some embodiments, the compound of Formula (la) or Formula (I) has formula:
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
5
Figure imgf000037_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (la) or Formula (I) has formula:
Figure imgf000037_0003
or a pharmaceutically acceptable salt thereof.
10 In some embodiments, the compound of Formula (la) or Formula (I) has formula:
Figure imgf000037_0004
or a pharmaceutically acceptable salt thereof.
In some embodiments the compound of Formula (la) or Formula (I) has formula:
Figure imgf000037_0005
36 or a pharmaceutically acceptable salt thereof.
In some embodiments, RB is selected from H, Cy1, CM alkyl (e.g., methyl, ethyl, propyl, or n-butyl), and CM haloalkyl, wherein said CM alkyl is optionally substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)zNRclRdl, C(O)ORal,
5 or S(O)2ORal.
In some embodiments, RB is selected from Cy1, CM haloalkyl, and CM alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal. In some embodiments, RB is selected from Cy1, CM haloalkyl, and CM alkyl substituted with Cy1, CN, NO2, ORal, or NRclRdl. In some embodiments,
10 RB is selected from Cy1, CM haloalkyl, and CM alkyl substituted with Cy1, ORal, or NR^R".
In some embodiments, RB is H. In some embodiments, RB is Cy1. In some embodiments, RB is CM haloalkyl. In some embodiments, RB is CM alkyl optionally substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl,
15 C(O)ORaI, or S(O)2ORal. In some embodiments, RB is CM alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal. In some embodiments, RB is CM alkyl substituted with Cy1, ORal, or NRclRdl. In some embodiments, RB is selected from Cy1 and CM alkyl substituted with Cy1, ORal, or NRclRdl. In some embodiments, RB is selected from Cy1, CM alkyl
20 substituted with Cy1, and CM alkyl substituted with NR61Rdl. In some embodiments, RB is RB is CM alkyl substituted with Cy1.
In some embodiments, RB is a moiety of formula:
Figure imgf000038_0001
In some embodiments, RB is a moiety of formula:
26
Figure imgf000038_0002
In some embodiments, RB is CM alkyl substituted with NRqlRdl. In some embodiments, RB is selected from CH2NRclRdl, CH2CH2NRclRdl, and CH2CH2CH2NRclRdl.
In some embodiments, Rc is selected from CN, NO2, 0Ral, NRclRdl, S(O)2Rbl,
30 C(O)NRCIRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal. In some embodiments, Rc is
37 CN or NO2. In some embodiments, Rc is ORal or NRelRdl. In some embodiments, Rc is ORal. In some embodiments, Rc is NRclRdl. In some embodiments, Rc is S(O)aRbl, C(O)NRc,Rdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal.
In some embodiments, Cy1 is selected from Ce-ioaryl and 3-10 membered
5 heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl. In some embodiments, Cy1 is Ce-io aryl, optionally substituted with 1 or 2 substituents independently selected from RCyl. In some embodiments, Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl. In some embodiments, the 3-10 membered
10 heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3 -dioxo lanyl, tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
In some embodiments, RCyl is selected from halo, NCh, Ci-a alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments, RCyl is selected from halo, NO2,
15 C1-3 alkyl, and C1-3 alkoxy. In some embodiments, RCyl is C1-3 alkyl.
In some embodiments, Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000039_0001
In some embodiments, Cy1 is a moiety of formula:
Figure imgf000039_0003
20 In some embodiments, Cy1 is a moiety of formula:
Figure imgf000039_0002
5 which is optionally substituted with RCyl.
38 In some embodiments, Cy1 is a moiety of formula:
Figure imgf000040_0004
which is optionally substituted with RCyl.
In some embodiments, Cy1 is a moiety of formula:
5 <>
Figure imgf000040_0003
which is optionally substituted with RCyl.
In some embodiments, Cy1 is a moiety of formula:
Figure imgf000040_0001
which is optionally substituted with RCyl.
10 In some embodiments, Cy1 is a moiety of formula:
Figure imgf000040_0002
which is optionally substituted with Reyl.
In some embodiments, Cy1 is a moiety of formula:
Figure imgf000040_0005
15 which is optionally substituted with RCyl.
In some embodiments, Cy1 is a moiety of formula:
Figure imgf000040_0006
which is optionally substituted with RCyl.
In some embodiments, Ral, Rbl, Rcl, and Rdl are each independently selected from
20 H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, Ral is selected from H, C1-3 alkyl, and Ci -3 haloalkyl. In some embodiments, Rbl is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, RC1 is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, Rdl is selected from H, Ci-a alkyl, and C1-3 haloalkyl.
In some embodiments, the compound of Formula (la) is selected from any one of
25 the following compounds:
39
Figure imgf000041_0001
40
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof.
Figure imgf000042_0002
In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:
Figure imgf000042_0003
or a pharmaceutically acceptable salt thereof.
5 In some embodiments, the compound of Formula (I) is not any one of the following compounds:
41
Figure imgf000043_0001
Methoxv-containine benzoimidazole compounds
In some embodiments, the present disclosure provides a compound of Formula (Ha):
Figure imgf000043_0002
6 or a pharmaceutically acceptable salt thereof, wherein R10, R2, R4, R3, R6, and R7 (e.g., as described herein for Formula Ila or Formula II).
In some embodiments, R10 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and C(=O)R1. In some embodiments, R10 is H. In some embodiments, R10 is C1-3 alkyl. In some embodiments, R10 is haloalkyl. In some embodiments, R10 is C(=O)R1.
10 In some embodiments, the compound of Formula (Ila) has Formula (II):
Figure imgf000043_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments of Formula (Ila) or Formula (II):
R1 is selected from Cy1, ORB, NR3RB, CH2RB. and CHiRc;
42 each RB is independently selected from H, Cy1, Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
5 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O>2NRclRdl, C(O)ORal, and
10 S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally
15 substituted with 1 or 2 substituents independently selected from RCy1 ; each RCyl is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, OR'1, NR€1Rdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, R€1, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3
20 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and each Rs is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycatbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
25 In some embodiments of Formula (Ila) or Formula (II):
R1 is selected from ORB, NR3RB, and CH2Rc; each RB is independently selected from Cy1, C1-6 haloalkyl, and C1-6 alkyl substituted with Cy’, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORaI, or S(O)2ORal;
43 Rc is selected from NOa, NRelRdl, S(O)aRbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, S(O)2ORal, and Ci-6 alkyl substituted with NO2, NRclRdl, S(O)2Rbl, C(O)NRCIRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
R2, R\ and R4 are each independently selected from H, C1-3 alkyl, and C1-3
5 haloalky 1;
R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
10 S(O)2NRelRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each RCyl is independently selected from halo, CN, NO2, ORal, NRelRdl, C1-3
15 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, OR11, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and
20 each Re is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycaibonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRelRdl, S(O)2Rbl, C(O)NRelRdl,
25 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and
30 S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents
44 independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R5 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and
5 S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R5 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said C1-3
10 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2J ORal, NRelRdl, S(O)iRbl, C(O)NR61Rdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R6 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents
15 independently selected from Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R6 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, S(O)2NRqlRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN,
20 NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRqlRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R7 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NO2, ORal, NRqlRdl, S(O)2Rbl, C(O)NRelRdl,
25 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
In some embodiments, R7 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal.
30 In some embodiments, R3, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, C(O)NRclRdl, and
45 C(O)ORal, wherein said C1-3 alkyl is optionally substituted with Cy1, ON, NO2, ORal, or NRelRdl.
In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, C(O)NRclRdl, and
5 C(O)ORal, wherein said C1-3 alkyl is optionally substituted with Cy1, CN, NO2, ORal, or NRelRdI.
In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRelRdl, C(O)NRclRdl, and C(O)ORal, wherein said C1-3 alkyl is optionally substituted with Cy1, CN, NO2, ORal, or NRclRdl.
10 In some embodiments, R5, R6 and R7 are each independently selected from H, halo, CN, NOs, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl, wherein said C1-3 alkyl is optionally substituted with Cy1, CN, NO2, ORal, or NRclRdl.
In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRelRdl.
15 In some embodiments, at least one of R5, R6, and R7 is C1-3 alkyl substituted with Cy1, CN, NO2, ORal, or NRclRdl.
In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
20 In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
In some embodiments, R5, R6 and R7 are each H. In some embodiments, R5 is not Cy1. In some embodiments, R5 is not C(O)NRclRdl. In some embodiments, R5 is not C(O)ORal.
25 In some embodiments, R2, R3, and R4 are each independently selected from H and Ci.3 alkyl. In some embodiments, R2 is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3 is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R4 is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R2 is selected from H and C1-3 alkyl. In some embodiments, R3 is selected
30 from H and C1-3 alkyl. In some embodiments, R4 is selected from H and C1-3 alkyl. In some embodiments, R2, R3, and R4 are each H.
46 In some embodiments, the compound of Formula (Ila) or Formula (II) has formula:
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof.
5 In some embodiments, R1 is selected from Cy1, ORB, NR3RB, CH2RB, and CH2Rc In some embodiments, R1 is Cy1. In some embodiments, R1 is ORB. In some embodiments, R1 is NR3RB. In some embodiments, R1 is NHRB. In some embodiments, R1 is CH2RB. In some embodiments, R1 is CH2RC. In some embodiments, R1 is selected from ORB and NR3RB. In some embodiments, R1 is selected from ORB and NHRB.
10 In some embodiments, RB is selected from H, Cy1, Cw alkyl (e.g., methyl, ethyl, propyl, or zi-butyl), and Ci-6 haloalkyl, wherein said Ci-6 alkyl is optionally substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)zORal.
In some embodiments, RB is selected from Cy1, Ci-e haloalkyl, and CM alkyl
15 substituted with Cy1, CN, NO2, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal. In some embodiments, RB is selected from Cy1, CM haloalkyl, and Ci -6 alkyl substituted with Cy1, CN, NOz, ORal, or NRclRdl. In some embodiments, RB is selected from Cy1, CM haloalkyl, and CM alkyl substituted with Cy1, ORal, or NR<1Rdl.
20 In some embodiments, RB is H. In some embodiments, RB is Cy1. In some embodiments, RB is CM haloalkyl. In some embodiments, RB is CM alkyl optionally substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORat, or S(O)2ORal. In some embodiments. RB is CM alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, or
25 S(O)2ORal. In some embodiments, RB is CM alkyl substituted with Cy1, OR81, or NRclRdt. In some embodiments, RB is selected from Cy1 and CM alkyl substituted with Cy1, OR81, orNR^R111. In some embodiments, RB is selected from Cy1, CM alkyl substituted with Cy1, and CM alkyl substituted with NRclRdl. In some embodiments, R BB is RB is CM alkyl substituted with Cy1.
47 In some embodiments, RB is a moiety of formula:
Figure imgf000049_0001
In some embodiments, RB is a moiety of formula:
Figure imgf000049_0002
5 In some embodiments, RB is Ci-e alkyl substituted with NRclRdl. In some embodiments, RB is selected from CH2NRclRdl, CH2CH2NRclRdl, and CH2CH2CH2NRcJRd1.
In some embodiments, Rc is selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRcIRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal. In some embodiments, Rc is
10 CN or NO2, In some embodiments, Rc is ORal or NRclRdl. In some embodiments, Rc is ORal. In some embodiments, Rc is NRclRdl. In some embodiments, Rc is S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal.
In some embodiments, Cy1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents
15 independently selected from RCyl. In some embodiments, Cy1 is Ce-io aryl, optionally substituted with 1 or 2 substituents independently selected from RCyl. In some embodiments, Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl. In some embodiments, the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl,
20 tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCy1.
In some embodiments, RCyl is selected from halo, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments, RCyl is selected from halo, NO2, C1-3 alkyl, and C1-3 alkoxy. In some embodiments, RCyl is C1-3 alkyl.
48 In some embodiments, Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000050_0001
In some embodiments, Cy1 is a moiety of formula:
Figure imgf000050_0002
6 In some embodiments, Cy1 is a moiety of formula:
Figure imgf000050_0003
which is optionally substituted with RCyl.
In some embodiments, Cy1 is a moiety of formula:
Figure imgf000050_0004
10 which is optionally substituted with RCyl.
In some embodiments, Cy1 is a moiety of formula:
Figure imgf000050_0005
which is optionally substituted with RCyl.
In some embodiments, Cy1 is a moiety of formula:
15
Figure imgf000050_0006
which is optionally substituted with RCyl.
In some embodiments, Cy1 is a moiety of formula:
Figure imgf000050_0007
49 which is optionally substituted with RCyl.
In some embodiments, Cy1 is a moiety of formula: O
Figure imgf000051_0001
which is optionally substituted with RCyl.
5 In some embodiments, Cy1 is a moiety of formula:
Figure imgf000051_0002
which is optionally substituted with RCyl.
In some embodiments, Ral, Rbl, Rel, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, Ral is selected from H, C1-3 alkyl,
10 and C1-3 haloalkyl. In some embodiments, Rbl is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, RC1 is selected from H, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, Rdl is selected from H, C1-3 alkyl, and C1-3 haloalkyl.
In some embodiments, the compound of Formula (Ila) is selected from any one of the following compounds:
Figure imgf000051_0003
50
Figure imgf000052_0001
Figure imgf000052_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (II) is selected from any one of the following compounds:
Figure imgf000052_0003
51
Figure imgf000053_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (II) is not any of the following compounds:
Figure imgf000053_0002
5-membered heteroaryl-containing benzoimidazole compounds
5 In some embodiments, the present disclosure provides a compound of Formula
(I):
Figure imgf000053_0003
or a pharmaceutically acceptable salt thereof, wherein: RA is selected from moiety (iii) and (iv):
Figure imgf000053_0004
(iii)
Figure imgf000053_0005
10 R1 is selected from Cy1, OR3, NR3RB, CHiR8, and CHiRc; ()
52 each RB is independently selected from Cy1, Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, OR31, NRclRdl, S(O)2Rbl, C(O)NRclRdl,
5 S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5 is selected from H, halo, CN, NCh, C1-3 alkyl, C1-3 haloalkyl, OR81, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted
10 with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, OR31, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2OR81, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents
15 independently selected from CN, NO2, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl;
20 each RCyl is independently selected from halo, CN, NO2, ORal, NRelRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
RSa, RSb, and RSc are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
25 independently selected from Rg; each X is independently selected from N and CR9b, wherein one X is N and the other X is CR9b;
R9a and R9b are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently
30 selected from Rg; and
53 each Rg is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
In some embodiments, the compound has formula:
5
Figure imgf000055_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound has formula:
Figure imgf000055_0001
or a pharmaceutically acceptable salt thereof.
10 In some embodiments, the compound has formula:
Figure imgf000055_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound has formula:
54
or a pharma
Figure imgf000056_0001
ceutically acceptable salt thereof.
In some embodiments, R8a, R8b, and R8c are each independently selected from H and Ci -3 alkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents
5 independently selected from R6.
In some embodiments, RSa, R8b, and RSe are each independently selected from H and Ci.3 alkyl.
In some embodiments, R8a and R8e are both H and R8b is C1-3 alkyl, such as methyl.
10 In some embodiments, R9a and R9b are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from Rs.
In some embodiments, R9a and R9b are each independently selected from H and C1-3 alkyl.
15 In some embodiments, R9a and R9b are both H.
In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:
Figure imgf000056_0002
R
55
Figure imgf000057_0001
or a pharmaceutically acceptable salt thereof.
5 In some embodiments, R3, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl.
In some embodiments, R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
10 In some embodiments, R1 is selected from ORB and NR3RB.
In some embodiments, R1 is ORB.
In some embodiments, R1 is NHRB.
In some embodiments, R1 is CH;RR.
In some embodiments, the compound of Formula (I) is selected from:
Figure imgf000057_0002
56
Figure imgf000058_0001
Figure imgf000059_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, RB is selected from Cy1 and Ci-e alkyl substituted with Cy1, ORal, or NRclRdl.
In some embodiments, RB is selected from Cy1, C1-6 alkyl substituted with Cy1,
5 and C1-6 alkyl substituted with NRclRdl.
In some embodiments, RB is Cy1.
In some embodiments, RB is C1-6 alkyl substituted with Cy1.
In some embodiments, Cy1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents
10 independently selected from RCyl.
In some embodiments, Cy1 is Ce-io aryl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
In some embodiments, Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
15 In some embodiments, the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl,
58 morpholinyl, pyrrolidlnyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
In some embodiments, RCyl is selected from halo, NOz, C1-3 alkyl, C1-3 haloalkyl, Ci -3 alkoxy, and C1-3 haloalkoxy.
5 In some embodiments, RCyl is selected from halo, NCh, C1-3 alkyl, and C1-3 alkoxy.
In some embodiments, Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000060_0001
In some embodiments, RB is C1-6 alkyl substituted with NRclRdl.
10 In some embodiments, RB is selected from CH2NRclRdl, CH2CH2NRclRdl, and CH2CH2CH2NRclRdl.
In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:
15
Figure imgf000060_0002
59
Figure imgf000061_0001
or a pharmaceutically acceptable salt thereof.
6 Pharmaceutically acceptable salts
In some embodiments, a salt of a compound of this disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.
10 In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of this disclosure include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid,
15 gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
20 monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
25 phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate,
60 phenylbutyrate, citrate, lactate, /i-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2 -sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic
5 acid, and especially those formed with organic acids such as maleic acid.
In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of this disclosure include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc;
10 ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or trialkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as
15 arginine, lysine, and the like. In some embodiments, the compounds, or pharmaceutically acceptable salts thereof, are substantially isolated.
Methods of use
Protein phosphorylation, catalyzed by protein kinases, is one of the major intracellular mechanisms which cells use to regulate their structural and enzymatic
20 proteins. Reversible phosphorylation/dephosphorylation is involved in essentially all physiological events, and abnormal phosphorylations and kinase activities have been observed under many pathological situations. Among the 518 human kinases, dualspecificity tyrosine phosphorylation-regulated kinase 1A (DYRK1 A) is a conserved eukaryotic serine/threonine protein kinase that belongs to the DYRK family (which
25 includes also DYRK IB, DYRK2, DYRK3, and DYRK4). DYRK kinases belong to the CMGC group which includes cyclin-dependent kinases (CDK), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK), and Ccd2-like kinases (CLK). Like many members of the CMGC group, the phosphorylation/dephosphorylation of a conserved tyrosine regulates the catalytic activity of the kinase. In DYRK 1 A, the Tyr321
30 residue has been described to be autophosphorylated in the activation loop allowing stabilization of the active conformation of DYRK1 A. In its mature form, DYRK1 A is then
61 able to phosphorylate various protein targets (involved in various physiological functions) on their serine or threonine residues. DYRK1 A is involved in cell cycle and differentiation regulation, P-cell regeneration, T cell regulation, cytoskeleton stabilization, brain neurodevelopment, and synaptic activities. See Nguyen, Expert Opin. Then Pat., 2017, 11,
5 1183- 1199, and references discussed therein.
Accordingly, in some embodiments, the present disclosure provides compounds as described herein, or pharmaceutically acceptable salts thereof, that modulate (e.g., inhibit) DYRK1A in a cell. In some embodiments, the present disclosure provides a method of modulating (e.g., inhibiting) DYRK.1A in a cell, the method comprising contacting the
10 cell with a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes contacting the cell in vitro, in vivo, or ex vivo. In some embodiments, the compound modulates DYRK1A selectively (e.g., the compound is at least about 2x? about 5x, about 10x, about 100x, or about l,000x selective to DYRK1 A as compared to DYRK1B, DYRK2, DYRK3, and/or DYRK4,
15 CLK1, CLK2, CLK3, CLK4, or any other kinase or protein target). As discussed herein, DYRK1A is involved in pathology of numerous debilitating conditions (e.g., the disease or condition may include overexpression, abnormal function, persistent activation, etc, of DYRK1A, e.g., in a cell or tissue affected by the disease). See, for example, J. Med. Chem., 2021, 64, 11709-11728, attesting to the fact that DYRK1A
20 regulates the proliferation and differentiation of neuronal progenitor cells during brain development, and as such, inhibitors of DYRK1A are useful in treating Down syndrome and Alzheimer’s disease, among other neurodegenerative conditions. Inhibition of DYRK1 A is also clinically relevant in treatment of metabolic disorders (e.g., diabetes), myocardial Infarction, inflammatory disorders (e.g., inflammatory
25 bowel disease), cancer (e.g, glioblastoma, leukemia, because DYRKlA’s function mediates cancer cell cycle), as well as other conditions. See, e.g., Ini. J. Mol. Sei., 2021, 22, 6047 and Young e/ a/., Circulation Research, 2022, 130, 1345-1361, among others, all of which are incorporated herein by reference in their entirety.
Accordingly, in some embodiments, the method provides a method of treating
30 a disease or condition where DYRK1A is implicated in pathology of the disease or condition (e.g., the disease or condition responsive to inhibition of DYRK1 A in a cell, a
62 tissue, and/or an organ affected by the disease or condition), the method comprising administering to a subject (e.g., in need thereof) a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is human. In some embodiments, the subject is male or
5 female. In some embodiments, the subject is from about 18 to about 75 years old, or from 35 to about 75 years old, or from about 45 to about 75 years old, or from about 55 to about 75 years old. In some embodiments, tire method includes a step of identifying a mammal in need of treatment. In one example, the step includes identifying a subject diagnosed with the disease or condition (e.g., by diagnosing the subject with the disease
10 or by identifying the subject that was already diagnosed with disease by another person). For example, the diagnosis can be performed by a lab technician, a diagnostician, a treating physician, a primary care physician, or a specialty physician such as an oncologist or a memory care specialist. The diagnosis can be performed on the basis of laboratory tests (e.g., MRI imaging or testing a specimen obtained from the mammal for
15 a disease biomarker), a clinical observation, or both.
In some embodiments, this disclosure provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease, disorder, or condition. In some embodiments, this disclosure provides a use of a compound as described herein, or a pharmaceutically acceptable salt thereof, for
20 treating a disease, disorder, or condition. In some embodiments, this disclosure provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use (or a use of a compound as described herein, or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a disease, disorder, or condition. Example embodiments of diseases, disorders, or conditions
25 are described herein.
Nenrodegenerative diseases
In neuropathology, neurodegeneration is often featured by accumulation in brain cells and intracellular spaces of insoluble protein aggregates, such as a-synuclein fibrils, amyloid-p plaques, and tau tangles, as well as by marked neuroinflammation. Together,
30 these pathologies lead to a reduction of brain volume and brain cell number, degeneration of neurons, dysfunction of microglia, and the development of various neurodegenerative
63 disorders. Numerous scientific publications attest to the well-established principle that modulating (e.g., inhibiting) DYRK1 A in cells (e.g., brain cells such as neurons and/or glia) is an art-accepted model that is well-known to reliably correlate with the clinical treatment of neurodegenerative disorders. See, for example, J. Neurochem, 2015, 133,
5 440-451, which is incorporated herein by reference in its entirety, and which shows that DYRK1A is implicated in the generation of Tau and amyloid aggregates and related pathologies and is associated with onset of, e.g., Down Syndrome, Alzheimer’s disease, and other synucleinopathies, amyloidopathies, and/or tauopathies. See also Front. Behav. Neurosci., 10, 104 (discussing treatment of, e.g., dementia, Pick’s disease,
10 Parkinson’s, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder, among others).
Accordingly, in some embodiments, the disease or disorder treatable by a compound of this disclosure is a neurodegenerative disorder. Suitable examples of neurodegenerative disorders include synucleinopathies, amyloidopathies, and/or
15 tauopathies. For example, synucleinopathies include dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF); PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, and Bradbury-Eggleston syndrome. Suitable examples of amyloidopathies include
20 premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), and dementia associated with HD. Suitable examples of tauopathies include Pick’s disease, progressive supranuclear palsy,
25 corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
Metabolic diseases
30 Numerous scientific publications attest to the well-established principle that modulating (e.g., inhibiting) DYRK1A in cells (e.g., insulin-producing p-cells) is an
64 art-accepted model that is well-known to reliably correlate with the clinical treatment of metabolic disorders. See, for example, J. Med. Chem., 2021, 64, 2901-2922, and J. Med. Chem., 2020, 63, 2958-2973, which are incorporated herein by reference in their entirety, and which show that inhibition of DYRK1 A promotes regeneration of
5 functional insulin-producing human P-cells in people with diabetes (e.g., type 1 diabetes, type 2 diabetes) and/or hyperglycerimia. See also Ini. J. Mol. Set, 2021, 22, 6047 (discussing treatment of, e.g., abnormal folate/methionine metabolism-related disorders). Accordingly, in some embodiments, the disease or disorder treatable by a compound of this disclosure is a metabolic disorder selected from type 1 diabetes,
10 type 2 diabetes, hyperglycerimia, and hypermethioninemia. Additional examples of metabolic disorders include familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann- Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
15 Autoimmune and inflammatory conditions
Numerous scientific publications attest to the well-established principle that modulating (e.g., inhibiting) DYRK1A in immune cells (e.g., T-cells) is an art-accepted model that is well-known to reliably correlate with the clinical treatment of inflammatory and autoimmune diseases (e.g., systemic autoimmunity, mucosal inflammation,
20 osteoarthritis). See, for example, eLife, 2015, 4, e05920, which is incorporated herein by reference in its entirety, and which shows that inhibition of DYRK1 A enhances T«g differentiation and impairs Th 17 differentiation. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non- infectious causes.
25 Accordingly, in some embodiments, the disease or disorder treatable by a compound of this disclosure is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple
30 sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease. Additional examples of inflammatory disorders include atherosclerosis, arteriosclerosis, polymyalgia
65 rheumatics (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, cystic fibrosis, arthrosteitis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, myasthenia gravis, sclerosing cholangitis, Crohn’s disease,
5 ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis, inflammatory dermatoses, delayed-type
10 hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft
15 rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis,
20 parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.
25 Accordingly, in some embodiments, the disease or disorder treatable by a compound of this disclosure is an autoimmune disease selected from autoimmune thyroiditis, glomerulonephritis, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosis, systemic sclerosis, dennatomyositis/polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, uveitis, Reiter’s
30 syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, and cardiomyopathy.
66 Cancer
Numerous scientific publications attest to the well-established principle that modulating (e.g., inhibiting) DYRK1 A in cells (e.g., cancer cells) is an art-accepted model that is well-known to reliably correlate with the clinical treatment of various
5 cancer types. See, e.g., PLoS ONE, 8, 11, e81803, which is incorporated herein by reference in its entirety, among many other publications discussing DYRK1 A’s involvement in the pathology of cancer, such as brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g, B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer. Additional exemplary cancers include acoustic neuroma,
10 adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangi ©carcinoma), bladder cancer, breast cancer (e.g, adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer), brain cancer (e.g., meningioma, glioblastomas,
15 glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g„ cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorecta 1 cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), connective tissue cancer, epithelial carcinoma, ependymoma, endothel iosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic
20 hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma), Ewing’s sarcoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), germ cell cancer,
25 head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease, hemangioblastoma, hypopharynx cancer, inflammatory my of ibroblastic tumors. inununocytic
30 amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma),
67 lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), muscle cancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g.,
5 polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) aka. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g, neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer
10 (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma (e.g., bone cancer), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors), penile cancer (e.g., Paget’s disease of the penis
15 and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), plasma cell neoplasia, paraneoplastic syndromes, intraepithelial neoplasms, prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer),
20 soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), eposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, small intestine cancer, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid
25 carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget’s disease of the vulva).
Compositions, formulations, and routes of administration
The present application also provides pharmaceutical compositions comprising an effective amount of a compound of the present disclosure disclosed herein, or a
30 pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic
68 agents described herein. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a
5 pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human
10 serum albumin, buffer substances such as phosphates, 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
15 carboxymethylcellulose, polyaciylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.
The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated
20 compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients.
25 Routes of administration and dosage forms
The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal,
30 intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal,
69 intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal,
5 respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.
Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example,
10 Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid
15 carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets,
20 granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In
25 the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, 6) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, <V)
30 disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as
70 paraffin,/) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and t) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral
5 administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and
10 acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
Compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of
15 the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5%
20 dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable
25 preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland
30 fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are
71 natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant
The pharmaceutical compositions of the present application may be administered
5 in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present application with a suitable non- irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.
10 The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents
15 known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L„ Ear J Pham Set 11:1-18, 2000.
The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel,
20 hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and/or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs
25 readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents/pigments, emollients (moisturizers), emulsifiers, film-forming/holding
30 agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents,
72 silicones, skin-identical/repairing agents, slip agents, sunscreen actives, surfactants/detergent cleansing agents, penetration enhancers, and thickeners.
Dosages and regimens
In the pharmaceutical compositions of the present application, a compound of the
5 present disclosure is present in an effective amount (e.g., a therapeutically effective amount). Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
10 In some embodiments, an effective amount of the compound can range, for example, from about 0.001 mg/kg to about 500 mg/kg (e.g,, from about 0.001 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 200 mg/kg; from about 0.01 mg/kg to about 150 mg/kg; from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to
15 about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0.1 mg/kg to about 200 mg/kg; from about 0. 1 mg/kg to about 150 mg/kg; from about 0.1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about 0.1 mg/kg to about 10 mg/kg; from about 0.1 mg/kg to about 5 mg/kg; from about 0.1 mg/kg to about 2 mg/kg;
20 from about 0.1 mg/kg to about 1 mg/kg; or from about 0.1 mg/kg to about 0.5 mg/kg). In some embodiments, an effective amount of a compound is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, or about 5 mg/kg. The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g, once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two
25 days, every three days, once weekly, twice weekly, once every two weeks, once a month).
Selected definitions
As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).
At various places in the present specification, substituents of compounds of the
30 invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such
73 groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, Cs alkyl, Ca alkyl, C5 alkyl, and Ce alkyl.
At various places in the present specification various aiyl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be
5 attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3- yl, or pyridin-4-yl ring.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in
10 combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (z.e., having (4n + 2) delocalized it (pi)
15 electrons where n is an integer).
The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered
20 heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a
25 hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.
Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples
30 include CM, CI -6, and the like.
74 As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, isopropyl, //-butyl, /cr/-butyl,
5 isobutyl, sec-butyl; higher homologs such as 2 -methyl- 1 -butyl, n-pentyl, 3-pentyl, zz- hexyl, 1,2,2-trimethylpropyI, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or I to 2 carbon atoms.
As used herein, the term “Cn-mhaloalkyl”, employed alone or in combination with
10 other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
15 As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., zz-propoxy and isopropoxy), butoxy (e.g., « -butoxy and ter? -butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
20 As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCFs. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “amino” refers to a group of formula -NH2.
25 As used herein, the term “Cn-m alkylamino” refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N- propylamino (e.g., N-(rt-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(zz-
30 butyl)amino and N-(/er/-butyl)amino), and the like.
75 As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
5 As used herein, the term “Cn-m alkoxycarbonyl” refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl
10 (e.g., n -butoxy carbonyl and tert-butoxycarbonyl), and the like.
As used herein, the term “carboxy” refers to a -C(O)OH group.
As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.
As used herein, the term “aryl,” employed alone or in combination with other
15 terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g. , having 2, 3 or 4 fused rings). The term “Cn-m aryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl.
20 As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring- forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are
25 moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons
30 (Cs-io). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl.
76 Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
5 As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1 , 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some
10 embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl
15 ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g. , 1, 2, or 3) ring atoms are independently selected from N, 0, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazo lyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl,
20 1,3,4-triazolyl, 1,3,4-thiadiazolyI, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (eg., 1 , 2, or 3) ring atoms are independently selected from N, 0, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or
25 polycyclic heterocycles having one or more ring-forming heteroatoms selected from 0, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin- 2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino,
30 piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, hnidazolidinyl, azepanyl,
77 benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), 8(0), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring- forming heteroatom. In some
5 embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (z.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a
10 fused aromatic ring can be attached through any ring-forming atom including a ringforming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered
15 heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For
20 example, an azetidine ring may be attached at any position of the ring, whereas a pyridin- 3-yl ring is attached at the 3 -position.
As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group.
25 The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
The compounds described herein can be asymmetric (e.g., having one or more
30 stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain
78 asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N
5 double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of die present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (^^-configuration. In some embodiments, the compound has the (S)-
10 configuration.
Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total
15 charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by
20 appropriate substitution.
As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as
25 a mammal.
As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” the DYRKI A with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having DYRKI A, as
30 well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the DYRKI A.
79 As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
5 As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
As used herein the term “treating” or “treatment” refers to 1) inhibiting the
10 disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the
15 disease, condition or disorder (z.e., reversing the pathology and/or symptomatology).
As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a
20 disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and/or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring.
EXAMPLES
25 Materials and methods
General. All reagents and solvents were purchased from commercially available sources and used without further purification. All reactions were carried out according to the indicated procedures and conditions. Flash Chromatography was performed on an Interchim PufiFlash 430 with cartridges filled with Silica gel 15 pm (PF-50SIHC).
30 Agilent 1200 was used for Prep LC purification with Thermo Scientific C18 column,
80 particle size 5 pm, dimensions 250 mm x 21.2 mm. Reactions were monitored by HPLC analysis and/or thin-layer chromatography (TLC) on silica-coated glass with the indicated eluent. The compounds were visualized by UV light (254 nm). LC/MS analysis was performed on an Agilent 1260 HPLC/UV (X = 220 nm and/or 254 nm) system coupled
5 with Agilent 6130 Single Quadrupole Mass Spectrometer. High-resolution mass spectrometry (HRMS) was performed on an Agilent 6530 QTOF Mass Spectrometer with 1290 Infinity Binary LC (mass accuracy 1 ppm with internal calibrant) in the positive mode that utilizes electrospray ionization (ESI). Compounds for analysis were dissolved in 100% DMSO and separated on Cis cartridge (particle size 2.6 pm, dimensions: 100
10 mm x 2.1 mm, 0.3 mL/min flow rate, 5 pL injection volume) using acetonitrile/water mobile phase with 0.1% formic acid as a modifier. The gradient started at 0% acetonitrile, held for 1 min, and linearly increased to 97% acetonitrile over 10 min, with 2 min hold at 97% acetonitrile and subsequent re-equilibration to the original conditions in a total of 17 min. All compounds reported were obtained in a purity of > 95% at 254 nm
15 wavelength. Nuclear magnetic resonance ( 1 H NMR) spectra were recorded on a Varian Mercury plus NMR spectrometer operating at 400 MHz frequencies for ‘H, using a 5 mm ASW PEG probe capable of detecting 1H and 13C nuclei. The proton chemical shifts (ppm) were referenced to the DMSO-c/o residual solvent peaks and indicated in parts per million (ppm). The splitting patterns are abbreviated as follows: s (singlet), d (doublet),
20 dd (doublet of doublets), t (triplet), q (quartet), quin (quintet), sxt (sextet), br (broad), and m (multiplet).
Example 1 - preparation of exemplified pyridine-based compounds
Figure imgf000082_0001
Scheme 1: reagents and conditions: (a) 4-pyridinylboronic acid, PdCh(dppf),
25 NasCOs, dioxane:H2O = 5:2, 8 h, 95 °C; (b) H2, 10% Pd/C (wet), MeOH, 8 h, rt; (c) 1,3- bis(methoxycarbonyl)-2-methyl -2 -thiopseudourea, MeOH, MW, 80 W, 5 min x 10; (d) R3-R2-H (R2: O, NH, N(CI-3 alkyl)), anhydrous pyridine, o/n, 95 °C.
Procedure For The Synthesis of Methyl Carbamates
81 Step b: to 2-nitro-4-aniline intermediate (1.0 eq.) in MeOH (0.1 M), Pd/C (1.0 equiv. 10 wt.% Pd/C, pre-wetted) was added and then a Ha-filled balloon attached to a 3- way valve was attached. The flask’s atmosphere was repeatedly evacuated under vacuum and back-filled with Hz. The reaction was stirred for 24 h then filtered through Celite,
5 rinsing with additional MeOH. The solvent was removed under reduced pressure and the product was placed under high vacuum to yield benzene- 1,2-diamine intermediates as an off-white solid (quantitative yield) for the next step without further purification.
Step c: benzene- 1,2-diamine compound (1.0 eq.) was dissolved in MeOH (0.5 M) and l,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.1 eq.) was added. The
10 mixture was exposed to microwave irradiation (80 W) for 5 min, 10 times (5 min cooling interval). Once the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure and residual oil was triturated with MeCN three times, filtered, and dried in vacuo to give the desired compound.
Step d: in a flame dried glassware, a methyl carbamate (1.0 eq.) was dissolved in
15 anhydrous pyridine (0.2 M). To this solution, corresponding alcohol (10 eq.) was added as indicated in Scheme 1 and the reaction proceeded at 95 °C for o/n under argon. Once the reaction was completed (monitored by HPLC), the solvent was removed in vacuo utilizing toluene as an azeotrope. The residual oil was purified by silica gel chromatography with 10% MeOH in DCM and dried in vacuo to give the desired
20 compound. Compound was further purified by Prep-LC using a 5-100% gradient of MeCN in water 0.1% formic acid as the mobile phase. Collected fractions were dried in a Speed-Vac concentrator to yield >95 % purity.
Methyl (5-(pyndin-4-yl)-lH-benzo[djimidazol-2-yl)carbaTnate (cmpd 4)
Figure imgf000083_0001
25 Product was obtained as an off-white solid; Rf = 0.51 (10% MeOH/DCM); HPLC analysis (Cl 8 reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): ZR = 7.9 min; *H NMR (400 MHz, 25 °C, DMSO-t/e) 6 11.22 (br s, 2H), 8.6-8.45 (m, 3H), 7.8-
82 7.65 (m, 3H), 7.54 (t, 2H, J= 1.4 Hz), 3.8 (s, 3H); HRMS (ESI) m/z; [M+H]+ calcd for C14H13N4O2269.1033; found 269.1018.
Methyl (5-(2-methylpyridin-4-yl)-lH-benzo[d]imidazol-2-yl)carbamate (cmpd 2)
Figure imgf000084_0001
5 Product was obtained using general methods (scheme 1) as an off-white solid; Rf = 0.53 (10% MeOHZDCM); HPLC analysis (CIS reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): IR = 8.4 min; *H NMR (400 MHz, 25 °C, DMSO-Jc) 5 11.71 (s, 2H), 8.44 (d, 1H, J = 53 Hz), 7.78 (d, 1H, J= 1.3 Hz), 7.55 (s, 1H), 7.50 (s, 2H), 7.47 (dd, 1H, J= 5.3, 1.8 Hz), 3.77 (s, 3H), 2.53 (s, 3H).; HRMS (ESI) m/z; [M +
10 H]+ calcd for C15H14N4O2283.1190; found 283.1185.
Methyl (5-(pyridin-3-yl)-lH-benzo[d]imidazol-2-yl)carbamate (cmpd 3)
Figure imgf000084_0002
Product was obtained as an off- white solid; Rf = 0,52 (10% MeOH/DCM); HPLC analysis (CIS reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 7.8
15 min; NMR (400 MHz, 25 °C, DMSO-^e) 5 10.75 (d, 2H, J= 10.8 Hz), 8.82 (d, 1H, J= 2.4 Hz), 8.51 (d, 1H, J = 4.8 Hz), 7.99 (dt, 1H, J= 7.9, 1.9 Hz), 7.44 (dd, 1H, J= 8.O, 4.8 Hz), 7.28 (dd, 1H, J= 8.1, 1.8 Hz), 7.21 (d, 1H, J= 1.6 Hz), 7.04 (d, 1H, J= 8.0 Hz), 3.35 (s, 3H); HRMS (ESI) m/z; [M+H]+ calcd for C14H13N4O2269.1033; found 269.1023.
83 2-(dimethylamino)ethyl (5-(pyridin-4-yl)-lH-benzo[d]imidazol-2-yl)carbamate (cmpd 13)
Figure imgf000085_0001
Compound was obtained following the general procedure as an off-white solid; Rr
5 = 0.36 (10% MeOHZDCM); HPLC analysis (C18 reverse phase, 17 min, 0-97% H2O/ACN with 0.1% formic acid): ft = 8.3 min; ’HNMR (400 MHz, 25 °C, DMSCM,) 5 8.57 (d, 2H, J= 5.0 Hz), 7.79 (s, 1H), 7.66 (d, 2H, J= 4.7 Hz), 7.50 (s, 2H), 4.27 (t, 2H, J= 5.7 Hz), 2.62 (t, 2H, J= 5.7 Hz), 2.52 (s, 6H); HRMS (ESI) m/z\ [M+H]+ calcd for C17H20N5O2 326.1612; found 326.1604.
10 5-(pyndin-4-yl)-lH-benzo[d]lmidazol-2-amme (cmpd 14)
Figure imgf000085_0002
Compound was isolated as a minor product of step d reaction (scheme 1) by Prep- LC using a 5-100% gradient of MeCN in water 0.1% formic acid as the mobile phase. Title compound was obtained as an off-white solid; Rf = 0.33 (10% MeOH/DCM); HPLC
15 analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 7.6 min; *H NMR (400 MHz, 25 °C, DMSO-Js) 5 10.81 (s, 2H), 8.57 (m, 2H), 7.63 (m, 2H), 7.39 (dd, *H, J= 8.0, 1.8 Hz), 7.3 (d, ’H, J= 1.6 Hz), 7.05 (d, *H, J= 8.2 Hz); HRMS (ESI) m/z: [M+H]+ calcd for C12H10N3O 212.0818; found 212.0820.
5-(Pyridm-4-yl)-lH-benzo[d]imidazol-2-ol (cmpd 15)
20
Figure imgf000085_0003
Compound was isolated as a minor product of step d reaction (scheme 1), and further purified by Prep-LC using a 5-100% gradient of MeCN in water 0.1% formic acid
84 as the mobile phase. Product was obtained as an off-white solid; Rr = 0.33 (10% MeOH/DCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97 % H2O/ACN with 0.1% formic acid): to = 7.6 min; 'HNMR (400 MHz, 25 °C, DMSO-tfc) 8 10.81 (s, 2H), 8.57 (m, 2H), 7.63 (m, 2H), 7.39 (dd, 1H, J= 8.0, 1.8 Hz), 7.3 (d, 1H, J= 1.6 Hz), 7.05 (d,
5 1H, J= 8.2 Hz); HRMS (ESI) m/z: [M+H]+ calcd for C12H10N3O 212.0818; found 212.0820.
(3-methyloxetan-3-yl)methyl (5-(pyridin-4-yl)-lH-benzo[d]imidazol-2- yl)carbamate (cmpd I )
Figure imgf000086_0001
10 Compound was obtained using general methods and further purified by Prep-LC using a 5-100% gradient of MeCN in water 0,1% formic acid as the mobile phase. Product was obtained as an off-white solid; Rr = 0.39 (10% MeOH/DCM); HPLC analysis (Cu reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 9.6 min; *H NMR (400 MHz, 25 °C, DMSO-r/e) 8 11.74 (br s, 2H) 8.59 (d, 2H, J= 6.3 Hz),
15 7.81 (s, 1H), 7.68 (d, 2H, J= 5.9 Hz), 7.52 (s, 2H), 4.48 (d, 2H, J= 5.9 Hz), 4.37 - 4.18 (m, 4H), 1.33 (s, 3H); HRMS (ESI) m/z: [M + H]+ calcd for C18H19N4O3 339.1452; found 339.1468.
0xetan-3-ylmethyl (5-(2-methylpyridin-4-yl)-lH-benzo[d]imidazol-2- yl)carbamate (cmpd 5)
20
Figure imgf000086_0002
Product was obtained using general methods (scheme 1) as an off-white solid; Rr = 0.57 (10% MeOH/DCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): fe = 9.0 min; *H NMR (400 MHz, 25 °C, DMSO-tifc) 8 11.74 (s, 2H), 8.45 (d, 1H, J= 5.2 Hz), 7.79 (d, 1H, J= 1.3 Hz), 7.54 (d, 1H, J= 1.8 Hz),
85 7.50 (d, 2H, J= 1.2 Hz), 7.46 (dd, 1H, J= 5.3, 1.8 Hz), 4.68 (dd, 2H, J= 7.9, 6.1 Hz), 4.42 (t, 4H, J= 5.9 Hz), 3.35 (dd, 1H, J = 7.8, 6.3 Hz), 2.52 (s, 3H); HRMS (ESI) m/z: [M+H]+ calcd for CisHisN-tCh 339.1452; found 339.1455.
(3-methyloxeian-3-yl)methyl (5-(2-methylpyridin-4-yl)-lH-benzo[d]imidazol-2-
5 yl)carbamate (cmpd 12)
Figure imgf000087_0001
Product was obtained using general methods (scheme 1) as an off-white solid;
HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): fit = 9.2 min; *H NMR (400 MHz, 25 °C, DMSO</6) 3 11.75 (s, 3H), 8.45 (d, 1H, J= 5.3
10 Hz), 7.78 (d, 1H, J= 1.2 Hz), 7.55 - 7.45 (m, 4H), 4.48 (d, 2H, J= 5.8 Hz), 4.30 -4.27 (m, 4H), 2.53 (s, 3H), 1.33 (s, 3H); HRMS (ESI) m/z: [M+H]4 calcd for C19H21N4O3 353.1608; found 353.1610. l-((3-Methyloxetan-3-yl)methyl)-3-(5-(2-methylpyridin-4-yl)-lH- benzo[d]imidazol-2-yl)urea (cmpd 6)
15
Figure imgf000087_0002
Product was obtained using general methods (scheme 1) as an off-white solid; Ry = 0.34 (10% MeOHZDCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97% HzO/ACN with 0.1% formic acid): fit = 9.5 min; *H NMR (400 MHz, 25 °C, DMSO-J(,) 5 12.12 (br s, 1H), 8.44 (t, 1H, J= 4.7 Hz), 7.83 (d, 1H, J= 21.2 Hz), 7.57 - 7.40 (m, 6H),
20 4.43 - 4.23 (m, 2H), 3.94 - 3.83 (m, 2H), 3.37 (s, 2H), 2.52 (s, 3H), 1.02 (s, 3H); HRMS (ESI) m/z: [M+H]4 calcd for C19H22N5O2352.1768; found 352.1771.
86 Oxetan-3-ylmethyl (5-(pyridin-3-yl)-lH-benzo[d]imidazol-2-yl)carbamate (cmpd
7)
Figure imgf000088_0001
Product was obtained using general methods (scheme 1) as an off-white solid; Ry
5 = 0.35 (10% MeOH/DCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 9.1 min; *H NMR (400 MHz, 25 °C, DMSOtZe) 8 11.74 (s, 2H), 8.87 (d, 1H, J= 2.4 Hz), 8.52 (d, 1H, J= 4.7 Hz), 8.03 (d, 1H, J= 8.0 Hz), 7.71 (s, 1H), 7.52 - 7.42 (m, 3H), 4.70 -4.66 (m, 2H), 4.42 (t, 4H, J = 5.9 Hz), 3.37 - 3.30 (m, 1H); HRMS (ESI) m/z: [M+H]+ calcd for C17H17N4O3 325.1295; found
10 325.1288.
(3-methyloxetan-3-yl)methyl (5-(pyridin-3-yl)-lH-benzo[d]iinidazol-2- yl)carbamate (cmpd 8)
Figure imgf000088_0002
Product was obtained using general methods (scheme 1) as an off-white solid; Rf
15 = 0.56 (10% MeOH/DCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): tr - 8.7 min; *H NMR (400 MHz, 25 °C, DMSO-tfc) 8 12.05 (s, 2H), 8.91 (d, 1H, J= 2.4 Hz), 8.56 (d, 1H, J= 4.7 Hz), 8.14 - 8.10 (m, 1H), 7.74 (d, 1H, J= 1.7 Hz), 7.55 - 7.45 (m, 3H), 4.48 (d, 2H, J= 5.9 Hz), 4.30 - 4.27 (m, 4H), 1.33 (s, 3H); HRMS (ESI) m/z: [M+H]+ calcd for C18H19N4O3 339.1452; found
20 339.1454.
87 l-((3-methyloxetan-3-yl)methyl)-3 -( 5-(pyridin-3-yl)-lH-benzo[d] imidazol-2- yl)urea (cmpd 9)
Figure imgf000089_0001
Product was obtained using general methods (scheme 1) as an off-white solid; Rf
5 = 0.40 (10% MeOH/DCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): IR = 9.0 min; *H NMR (400 MHz, 25 °C, DMSO-tfc) 8 12.10 (br s, 1H), 8.87 (s, 1H), 8.52 (s, 1H), 8,20 (br s, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.76 (s, 1H), 7.53 - 7.39 (m, 4H), 3.95 - 3.84 (m, 2H), 3.38 (s, 2H), 3.15 (d, 1H, J= 11.7 Hz), 2.94 (d, 1H, J = 11.6 Hz), 1.02 (s, 3H); HRMS (ESI) m/z: [M + HJ* calcd for C18H20N5O2
10 338.1612; found 338.1611.
Oxetan-3-ylmethyl (5-(pyridin-4-yl)-IH-benzo[d]imidazol-2-yl)carbamate (cmpd
10)
Figure imgf000089_0002
Product was obtained as an off-white solid; Rf = 0.43 (10% MeOH/DCM); HPLC
15 analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 8.8 min; *H NMR (400 MHz, 25 °C, DMSO-A) 5 11.72 (s, 2H), 8.60- 8.58 (m, 3H), 7.81 (t, 1H, J = 1.2 Hz), 7.69 - 7.67 (m, 2H), 7.52 (t, 2H, J = 1.5 Hz), 4.68 (dd, 2H, J = 7.9, 6.1 Hz), 4.42 (t, 4H, J= 6.1 Hz), 3.35 (dt, 1H, J= 8.1 , 6.3 Hz); HRMS (ESI) m/z: [M + H]+ calcd for C17H17N4O3 325.1295; found 325.1301.
20 l-((3-Methyloxetan-3-yl)methyl)-3-(5-(pyridin-4-yl)-lH-benzo[d]imidazol-2- yl)urea (cmpd II)
Figure imgf000089_0003
88 Product was obtained as an off-white solid; R/= 0.38 (10% MeOH/DCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): fit = 9.1 min; *H NMR (400 MHz, 25 °C, DMSCWe) 5 11.72 (br s, 1H), 9.96 (br s, 1H), 8.59 - 8.57 (m, 2H), 7.79 (s, 1H), 7.67 (s, 2H), 7.49 (br s, 3H), 4.41 (d, 2H, J= 5.8 Hz), 4.24 (d,
5 2H, J= 5.8 Hz), 3.42 (d, 2H, J= 6.0 Hz), 1.27 (s, 3H).; HRMS (ESI) m/z; [M + H]+ calcd for C18H20N5O2338.1612; found 338.1614.
Compounds 1-15 described in Example 1 can also be prepared using method and procedures generically depicted in Scheme 2, below, using 4-bromobenzene-l,2-diamine as the starting material
10
Figure imgf000090_0001
Scheme 2: reagents and conditions: (a) R1-B(OH)2 (R1 is Ar, Het, Ar(C=O), or Het(C=O)), Pd(dppf)Ch, Na2CO3, dioxane:H2O=5:2, 8h, 115 °C; (b) 1,3- bis(methoxycarbonyl)-2-methyl-2 -thiopseudourea, acetic acid, glacial, 50 °C, 1 h; (c) R3- R2-H (R2: 0, NH, N(CI-3 alkyl)), anhydrous pyridine, 8 h, 95 °C.
15 Example 2a - preparation of exemplified 5-methoxy-based compounds
The following benzo[d]imidazole compounds having a methoxy substituent in position 5 on the phenyl ring were prepared according to the methods and procedures similar to those provided for pyridine-containing compounds in Example 1.
Methyl (5-methoxy-IH-benzo[d]imidazol-2-yl)carbamate (cmpd 17)
20
Figure imgf000090_0002
Compound was obtained as an off-white solid; R/= 0.57 (10% MeOH/DCM);
HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): fit = 8.4 min; *H NMR (400 MHz, 25 °C, DMSCMO 8 11.53 (br s, 2H), 7.25 (d, 1H, J= 8.6 Hz), 6.94 (d, 1H, J= 2.3 Hz), 6.67 (dd, 1H, J= 8.6, 2.3 Hz), 3.72 (s, 6H); HRMS (ESI)
25 m/z: [M + H]+ calcd for C10H12N3O3 222.0873; found 222.0873.
89 5-Methoxy-lH-benzo[d]imidazol-2-amine (cmpd 18)
Figure imgf000091_0001
Compound was isolated as a minor by-product, and purified by Prep-LC using a 5-100% gradient of MeCN in water 0.1% formic acid as the mobile phase. Product was
5 obtained as an off-white solid; Rf = 0.18 (EtOAc:MeOH:H2O = 7:2:1); HPLC analysis (CIS reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 9.7 min; ’H NMR (400 MHz, 25 °C, DMSO-tfc) 6 6.99 (d, 1H, J= 8.6 Hz), 6.72 (d, 1H, J= 2.7 Hz), 6.50 (dd, 1H, J = 8.6, 2.3 Hz), 6.39 (hr s, 2H), 3.7 (s, 3H); HRMS (ESI) m/z: [M + H]+ calcd for QH10N3O 164.0818; found 164.0817.
10 2-(Dlmethylamino)ethyl (5-methoxy-lH-benzo[d] imidazol-2-yl)carbamate (cmpd
19)
Figure imgf000091_0002
Compound was further purified by Prep-LC using a 5-100% gradient of MeCN in water 0.1% formic acid as the mobile phase. Product was obtained as a brown solid; Rf =
15 0.55 (10% MeOH/DCM); HPLC analysis (C18 reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): = 9.4 min; 'H NMR (400 MHz, 25 °C, DMSO-d6) 5 7.26 (d, 1H, J= 8.6 Hz), 6.95 (d, 1H, J= 2.7 Hz), 6.69 (dd, 1H, J= 8.8, 2.5 Hz), 4.25 (t, 2H, J = 5.9 Hz), 3.74 (s, 3H), 2.62 (t, 2H, J= 5.7 Hz), 2.27 (s, 6H); HRMS (ESI) m/z; [M + H]+ calcd for C13H19N4O3 279.1452; found 279.1455.
20 (3-Methyloxetan-3-yl)methyl (5-methoxy-lH-benzo[d]imidazol-2-yl)carbamate
(cmpd 20)
Figure imgf000091_0003
90 Compound was further purified by Prep-LC using a 5- 100% gradient of MeCN in water 0.1% formic acid as the mobile phase. Product was obtained as an off-white solid; Rf = 0.57 (10% MeOH/DCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 9.0 min; *H NMR (400 MHz, 25 °C, DMSO-tifc) 3
5 11.71 (m, 2H), 7.26 (d, 1H, J= 8.6 Hz), 6.95 (d, 1H, J= 2.7 Hz), 6.69 (dd, 1H, J= 8.6, 2.7 Hz), 4.46 (d, 2H, J= 5.9 Hz), 4.26 (m, 4H), 3.74 (s, 3H), 1.31 (s, 3H); HRMS (ESI) m/z; [M+H]+ calcd for C14H18N3O4 292.1292; found 292.1295.
3-Fluorobenzyl (5 -methoxy- lH-benzo[d]imidazol-2-yl)carbamate (cmpd 21)
Figure imgf000092_0001
10 Compound was obtained as an off-white solid; Rf= 0.57 (10% MeOH/DCM);
HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 9.1 min; *H NMR (400 MHz, 25 °C, DMSO</a) 3 11.62 (br s, 2H, J= Hz), 7.44 (m, 1H), 7.27 (t, 3H, J= 8.6 Hz), 7.18 (m, 1H), 6.95 (d, 1H, J= 2.3 Hz), 6.69 (dd, 1H, J= 8.8, 2.5 Hz), 5.23 (s, 2H), 3.73 (s, 3H); HRMS (ESI) m/z; [M+H]+ calcd for C16H15FN3O3
15 316.1092; found 316.1091.
2-(Pyrrolidin-l-yl)ethyl (5-methoxy-lH-benzo[d]imidazol-2-yl)carbamate (cmpd
22)
Figure imgf000092_0002
Product was obtained as an off-white solid; Rf = 0.25 (10% MeOH/DCM); HPLC
20 analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 8.0 min; *H NMR (400 MHz, 25 °C, DMSO-) d6) 8 7.26 (d, 1H, J= 8.6 Hz), 6.94 (d, 2H, J= 2.5 Hz), 6.68 (dd, 1H, J= 8.6, 2.5 Hz), 4.26 (t, 2H, J= 5.8 Hz), 3.74 (s, 3H), 2.77 (t, 2H,
91 J= 5.8 Hz), 2.60 - 2.56 (m, 4H), 1.72 - 1.69 (m, 4H); HRMS (ESI) m/z: [M + H]+ calcd for C15H21N4O3305.1608; found 305.1611.
2-(Piperidin-l-yl)ethyl (5-methoxy-lH-benzo[d]imidazol-2-yl)carbamate (cmpd
23)
5
Figure imgf000093_0001
Product was obtained as an off-white solid; R∫= 0.28 (10% MeOH/DCM); HPLC analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1 % formic acid): fit = 8.4 min; *H NMR (400 MHz, 25 °C, DMSO-rfe) 5 7.26 (d, 1H, J = 8.6 Hz), 6.95 (d, 1H, J= 2.4 Hz), 6.69 (dd, 1H, J= 8.6, 2.4 Hz), 4.27 (t, 2H, J= 5.8 Hz), 3.74 (s, 3H), 2.68 (t, 2H,
10 J= 5.8 Hz), 2.53 (d, 4H, J= 5.0 Hz), 1.52 (p, 4H, J = 5.6 Hz), 1.40 (q, 2H, J= 6.1 Hz); HRMS (ESI) m/z: [M + H]+ calcd for C16H23N4O3319.1765; found 319.1764.
2-Morpholinoethyl (5-methoxy-lH-benzo[d]imidazol-2-yl)carbamate (cmpd 24)
Figure imgf000093_0002
Product was obtained as an off-white solid; Rf = 0.67 (10% MeOH/DCM); HPLC
16 analysis (Cis reverse phase, 17 mins, 0-97% HiO/ACN with 0.1% formic acid): fit = 7.9 min; *H NMR (400 MHz, 25 °C, DMSO-A) 57.26 (d, 1H, J= 8.6 Hz), 6.95 (d, 1H, J= 2.4 Hz), 6.68 (dd, 1H, J= 8.6, 2.4 Hz), 4.26 (t, 2H, J= 5.8 Hz), 3.74 (s, 3H), 3.58 - 3.55 (m, 4H), 2.60 (t, 2H, J= 5.7 Hz), 2.45 (t, 4H, J= 4.8 Hz); HRMS (ESI) m/z: [M + H]+ calcd for C15H21N4O4321.1557; found 321.1565.
92 (T ?trahydro-2H-pyran-4-yl)melhyl (5-methoxy-iH-benzo[d] tmidazol-2- yl)carbcimate (cmpd 25)
Figure imgf000094_0001
Product was obtained as an off-white solid; Rj= 0.67 (10% MeOH/DCM); HPLC
6 analysis (Cis reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): fe = 9.4 min; *H NMR (400 MHz, 25 °C, DMSO-t/e) 8 11.44 (s, 2H), 7.26 (d, 1H, J= 8.6 Hz), 6.95 (d, 1H, J = 2.4 Hz), 6.68 (dd, 1H, J= 8.6, 2.4 Hz), 3.86 (ddd, 2H, J= 11.5, 4.5, 1.8 Hz), 3.74 (s, 3H), 3.34 — 3.27 (m, 4H), 1.92 (ddt, 1H, 11.5, 8.5, 4.3 Hz), 1.60 (ddd,
2H J= 12.9, 4.1, 1.9 Hz), 1.29 (qd, 2H, J = 12.5, 4.9 Hz).; HRMS (ESI) m/z: [M + H]+
10 calcd for C15H20N3O4306.1448; found 306.1447.
Oxetan-3-ylmethyl (5-methoxy-lH-benzo[d] imidazol-2-yl)ccirbarnate (cmpd 26)
Figure imgf000094_0002
Product was obtained as a brown solid; Rf= 0.67 (10% MeOH/DCM); HPLC analysis (Cig reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): /R = 8.9
15 min; *H NMR (400 MHz, 25 °C, DMSO- d6) 8 7.26 (d, 1H, J= 8.7 Hz), 6.95 (d, 1H, J= 2.4 Hz), 6.69 (dd, 1H, J- 8.7, 2.4 Hz), 4.67 (dd, 2H, J- 7.9, 6.0 Hz), 4.42 - 4.36 (m, 4H), 3.74 (s, 3H), 3.31 (ddq, 1H, J= 14.4, 8.0, 6.5 Hz); HRMS (ESI) m/z: M + H]+ calcd for C13H16N3O4278.1135; found 278.1134.
Example 2b - 5-(5-membered heteroaryl)-based compounds
20
Figure imgf000094_0003
93 Methyl (5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-2-yl)carbamate (31) (101.3 mg, 88%). HPLC analysis (CIS reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): to = 5.21 min; ]H NMR (400 MHz, CD3OD) 8 11.54 (br s, 2H), 8.02 (s, 1H), 7.76 (s, 1H), 7.52 (s, 1H), 7.35 (d, J= 8.2 Hz, 1H), 7.27 (d, ./ = 8.2 Hz, 1H), 3.86
5 (s, 3H), 3.75 (s, 3H).
Figure imgf000095_0001
Methyl (5-(isothiazol-5-yl)-lH-benzo[d]imidazol-2-yl)carbamate (32) (25.5 mg, 75%).
HPLC analysis (Cl 8 reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid):
10 = 5.83 min; *H NMR (400 MHz, DMSO-<) 8 11.74 (br s, 3H), 8.54 (d, J= 1.8 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J= 1.8 Hz, 1H), 7.52 - 7.43 (m, 2H), 3.77 (s, 3H). HRMS (ESI) m/z\ [M + H]+ calcd for C12H10N4O2S 275.0597; found 275.0595.
Figure imgf000095_0002
15 Methyl (5-(thiazol-5-yl)-lH-benzo[d]imidazol-2-yl)carbamate (33) (16.3 mg, 23%).
HPLC analysis (C18 reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): tR = 5.48 min; *H NMR (400 MHz, DM S 0-d6 ) 8 11.66 (br s, 2H), 9.00 (s, 1H), 8.19 (s, 1H), 7.67 (s, 1H), 7.45 (d, J= 8.3 Hz, 1H), 7.41 (dd, J= 8.3, 1.6 Hz, 1H), 3.77 (s, 3H). HRMS (ESI) m/z; [M + H]~ calcd for C12H10N4O2S 275.0597; found 275.0595.
20
Figure imgf000095_0003
94 l-(5-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-2-yl)-3-((3-methyloxetan-3- yl)methyl)urea (34) was obtained as an off-white solid (99.3 mg, 0.36 mmol). Rf = 0.31 (7% MeOH/DCM); HPLC analysis (C18 reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): fc = 5.46 min; ]H NMR (400 MHz, DMSO-tk) 8 11.42 (br s, 1H),
5 9.81 (br s, 1H), 8,00 (s, 1H), 7.75 (s, 1H), 7.66 (br s, 1H), 7.50 (d, J= 1.2 Hz, 1H), 7.32 (d, J= 8.2 Hz, 1H), 7.23 (d, J = 9.6 Hz, 1H), 4.41 (d, J= 5.8 Hz, 2H), 4.24 (d, J = 5.8 Hz, 2H), 3.85 (s, 3H), 3.41 (d, J= 6.1 Hz, 2H), 1 .27 (s, 3H). HRMS (ESI) m/z; [M + H]+ calcd for C17H20N6O2 341.1271; found 341.1271.
10
Figure imgf000096_0001
l-((3-methyloxetan-3-yl)methyl)-3-(5-(thiftzol-5-yl)-lH-benzo[d]imidazo]-2-yl)urea
(35) (15.7 mg, 84%). Rr = 0.49 (10% MeOHDCM): HPLC analysis (C18 reverse phase, 17 mins, 0-97% H2O/ACN with 0.1% formic acid): to = 5.64 min; JH NMR (400 MHz, CD3OD) 8 8.89 (s, 1H), 8.10 (d, J = 10.1 Hz, 3H), 7.67 (s, 1H), 7.44 (s, 2H), 4.58 (d, J =
15 6.0 Hz, 2H), 4.39 (d, J= 6.0 Hz, 2H), 3.50 (s, 2H), 1.36 (s, 3H). HRMS (ESI) m/z: [M + H]+ calcd for C16H217N5O2S 344.1176; found 344.1175.
All compounds disclosed herein can be prepared in a manner analogous to the one disclosed above in the Examples.
20 Example 3 - benzimidazole carbamates as high affinity DYRK1A kinase inhibitors - inhibition of Tait phosphorylation
Introduction: the dual-specificity tyrosine phosphorylation-regulated kinase- 1 A (DYRK1A) is implicated in the pathology of AD. DYRKlAis upregulated in the brain tissue of AD patients, and as a trisomy gene it is the underlying cause of Down Syndrome
26 with increased risk of developing AD. DYRK1 A catalyzes the phosphorylation of the amyloid precursor and tau proteins, two major pathological effectors involved in the formation of amyloid plaques and neurofibrillary tangle, and consequentially
95 neuro inflammation in AD. The experimental data provided in the examples provides credible evidence thatDYRKlA inhibitors of this disclosure are useful as therapeutics for neurodegenerative disorders such as tauopathies, including AD.
Methods: a competitive binding assay was used as the primary screen to measure
5 the binding affinity (Ko) to DYRK1A. Selectivity against DYRK1B/2 as well as the related CLK1-4 was determined by comparison of the KD in each of the enzymes. Cellular activity of representative compounds was obtained by measuring the p-Tau levels in HEK293 cells expressing human full-length DYRK1 A and Tau.
Results: a exemplified benzimidazole carbamates were synthesized as described
10 in the examples and tested for their Ko to the DYRK1 A protein, including a number of highly active DYRK1 A inhibitors. Among them, five (5) compounds were shown to bind to DYRK1A with KD of < 1 nM: 2 (KD: 720 pM), 11 (KD: 330 pM), 5 (KD: 330 pM), 1 (KD: 170 pM), and 12 (KD: 140 pM). Furthermore, compound 1 showed 15 to 90-fold selectivity over DYRK1B/2 and CLK1-4 kinases, and potently inhibited Tau
15 phosphorylation in the HEK293 cellular assay (ICso: 26 nM).
T-cell Inflammation Inhibition Assay Protocol: Day 1, High binding plates were coated with anti-CD3 (clone UCHT-1, 2 pg/niL) and isotype IgGl using PBS lx and incubated overnight at 4 °C. Day 2: Cryopreserved PBMCs were drip thawed and diluted to the appropriate density and seeded into U bottom 96-well polypropylene plates
20 (1.2x105 cells per well) with 228 pL per well of culture medium (RPMI 1640, 10% heat- inactivated FBS, 1% penicillin/ streptomycin, 2 mM L-glutamine). Cells were incubated at 37 °C, 5% COa for 1 hour prior to the addition of test compounds. Test compounds were solubilized in DMSO and further diluted to 20 x with cell culture medium.
Compounds were added to the PBMCs in volumes of 12 pL (lx) in triplicate and
25 incubated for 1 hour at 37 °C, 5% CO2. For reference compound, 12 pL of dexamethasone (100 nM) was added to the control wells according to the plate map and incubated for 1 hour at 37 °C, 5% CO2. After 1 hour incubation, 200 pL of cells (lx105) treated with test compounds or controls were transferred to the anti-CD3 coated plates and incubated for 24 hours at 37 °C, 5% CO2. For positive and negative controls,
30 transferred 200 pL (1 x 105) of cells to the coated plate with anti-CD3 or isotype IgGl. Plates were centrifuged at 200 xg for 10 minutes. Cell culture supernatants were collected
96 and stored at -80 °C until needed for analysis. Cytokine levels in each sample were determined using Luminex methodology, per the manufacturer’s protocol. Luminex assessment of cytokine levels in cell culture supernatants in tissue culture medium, was performed per manufacturer's protocol using the Human Cytokine/Chemokine Magnetic
5 bead panel from Millipore Sigma (catalogue No. HCYTOMAG-60K) with standards range 3.2, 16, 80, 400, 2,000, 10,000 pg/mL, Cytokines Measured: The following cytokines were measured for a complete cytokine response profile. Human panel, T cell (neat): IL-2, IL-17, IFNv.
Kinase assays. For most assays, kinase-tagged T7 phage strains were prepared in
10 an E. coll host derived from the BL21 strain. E. coh were grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin- coated magnetic beads were treated with biotinylated small molecule ligands for 30
15 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1 x binding buffer (20% SeaBlock, 0.17*
20 PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 11 lx stocks in 100% DMSO. Kds were determined using an 11 -point 3-fold compound dilution series with three DMSO control points. All compounds for Ka measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All
25 reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1 x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1 * PBS, 0.05% Tween 20, 0.5 pM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30
30 minutes. The kinase concentration in the eluates was measured by qPCR.
97 Kinase Cellular Assay: HEK293 human embryonic kidney cells were transiently co-transfected with vectors encoding full-length human DYRK1A and Tau. Cells were dispensed into 96-well plates at a number previously determined by cell titration and signal optimization for the DYRK1 A assay. Compounds were diluted to 200* final assay
5 concentration in DMSO. Eight 3-fold or 4-fold serial dilutions were prepared for each compound in 100% DMSO. Compounds were then diluted in tissue culture medium to 10* final assay concentration and 5% DMSO. Compounds were added to the cells in 96- well plates (10-fold dilution in medium) for a final concentration of 1 * compound and 0.5% DMSO. For positive (high signal) controls, cells were treated with 0.5% DMSO
10 alone. For negative (low signal) controls, cells were treated with 20 pM harmine including 0.5% DMSO final concentration. Cells were incubated with compound at 37 °C for 2 hours. Cells were lysed, and lysates were transferred to an ELISA plate that had been previously coated with antibody to capture the substrate (human Tau). Plates were washed then incubated with an antibody to detect phosphorylation of Tau. Plates were
15 washed then incubated with HRP-linked secondary antibody. Plates were washed, then HRP substrate was added. Absorbance was read at 450 nm. Per cent inhibition values were calculated from absorbance readings based on positive and negative control values, and according to the following formula: (%INH = ((positive control - sample)/(positive control - negative control))* 100. Z’ values were calculated based on the following
20 formula: l-[(3*standard deviation of positives + 3* standard deviation of negatives )/(average positive - average negative)]. Per cent inhibition values were plotted vs. the log of compound concentrations utilizing GraphPad Prism software. ICsos were determined after utilizing sigmoidal dose response curve fitting to generate the curves.
Figure imgf000099_0001
98
Figure imgf000100_0001
99
Figure imgf000101_0001
100
Figure imgf000102_0001
101
Figure imgf000103_0001
102 NT: not tested
The experimental results show that the 5-pyridyl group-containing compounds show high binding affinity in the kinase assays. These compounds are highly active at about 0.1 pM, about 1 pM, or about 10 p.M concentration.
5 Exemplary embodiments:
I. A compound of Formula (I):
Figure imgf000104_0001
or a pharmaceutically acceptable salt thereof, wherein:
RA is selected from moiety (i) and (ii):
Figure imgf000104_0002
Rla, R2a, R3a, and R4a are each independently selected from H. halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, OR31, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R1 is selected from Cy1, ORB, NR3RB, CH2RB, and CH2Rc; each RB is independently selected from Cy1, C1-6 haloalkyl, and C1-6 alkyl substituted with Cy1, CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
103 R5 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRelRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R6 and R7 are each independently selected from H, halo, CN, NCh, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)£NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from C<- 10 aryl. C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each RCy1 is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, andRdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from Re; and each R8 is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; provided that the compound of Formula (I) is not any one of the following compounds:
Figure imgf000105_0001
104
Figure imgf000106_0001
2. The compound of embodiment 1, having formula:
Figure imgf000106_0002
or a pharmaceutically acceptable salt thereof
3. The compound of embodiment 1 , having formula:
Figure imgf000106_0003
or a pharmaceutically acceptable salt thereof.
4. The compound of any one of embodiments 1-3, wherein Rla, R2a, R3a, and R43 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, and C1-3 haloalkyl.
5. The compound of any one of embodiments 1-3, wherein Rla, R2a, R3a, and R4a are each independently selected from H and C1-3 alkyl.
6. The compound of embodiment 1, wherein the compound of Formula (I) is selected from any one of the following compounds:
105
Figure imgf000107_0001
or a pharmaceutically acceptable salt thereof.
7. The compound of any one of embodiments 1-6, wherein R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl.
8. The compound of any one of embodiments 1-6, wherein R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, Ci- 3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3alkyl)amino.
9. The compound of any one of embodiments 1-8, wherein R1 is selected from OR8 and NR3RB.
10. The compound of embodiment 9, wherein R1 is OR8.
11. The compound of embodiment 9, wherein R1 is NHRB.
12. The compound of any one of embodiments 1-8, wherein R1 is ClfcRB.
13. The compound of any one of embodiments 1-8, wherein the compound of Formula (I) is selected from:
Figure imgf000107_0002
106
Figure imgf000108_0001
or a pharmaceutically acceptable salt thereof.
14. The compound of any one of embodiments 1-13, wherein RB is selected from Cy1 and Ci -e alkyl substituted with Cy1, ORal, or NRclRdl.
15. The compound of embodiment 14, wherein RB is selected from Cy1, C1-3 alkyl substituted with Cy1, and Ci^ alkyl substituted with NRelRdl.
16. The compound of embodiment 15, wherein RB is Cy1.
17. The compound of embodiment 15, wherein RB is C1-6 alkyl substituted with Cy1.
18. The compound of any one of embodiments 1-17, wherein Cy1 is selected from Ce- io aryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
107 19. The compound of embodiment 18, wherein Cy1 is Ce-ioaryl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
20. The compound of embodiment 18, wherein Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
21. The compound of embodiment 20, wherein the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
22. The compound of any one of embodiments 1-21, wherein RCyl is selected from halo, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
23. The compound of any one of embodiments 1-21, wherein RCyl is selected from halo, NO2, C1-3 alkyl, and C1-3 alkoxy.
24. The compound of any one of embodiments 1-23, wherein Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000109_0001
25. The compound of any one of embodiments 1-13, wherein RB is C1-6 alkyl substituted with NRclRdl.
108 26. The compound of embodiment 25, wherein RB is selected from CH2NRelRdl, CHiCH2NRclRdl, and CH2CH2CH2NRelRdl.
27. The compound of embodiment 1, wherein the compound of Formula (I) is selected from any one of the following compounds:
Figure imgf000110_0001
or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising a compound of any one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
29. A method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any
109 one of embodiments 1-28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 29.
30. The method of embodiment 30, wherein the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
31. The method of embodiment 30, wherein the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup mine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
32. The method of embodiment 30, wherein the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease.
110 33. The method of embodiment 30, wherein the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
34. A method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition, the method comprising:
(0 identifying a subject diagnosed with the disease or condition responsive to inhibition of DYRKlAin a cell, a tissue, and/or an organ affected by the disease or condition; and
(ii) after (i), administering to the subject a therapeutically effective amount of a compound of Formula (la):
Figure imgf000112_0001
or a pharmaceutically acceptable salt thereof, wherein:
RA is selected from moiety (i) and (ii):
Figure imgf000112_0002
Rla, R2", R3a, and R4a are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, OR"1, NRclRdl, S(O)zRbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl > C(O)ORal, and S(O)2ORal;
R10 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and C(=O)R*;
R1 is selected from Cy1, OR8, NR3RB, CH2RB, and CH2Rc;
111 each RB is independently selected from H, Cy1, Ci-6 alkyl, and Ci-6 haloalkyl, wherein said Ci-e alkyl is optionally substituted with Cy1, CN, NO2, 0Ral, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, 0Ral, NRclRdl, S(0)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6 and R7 are each independently selected from H, halo, CN, NCb, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRclRdl, S(0>2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, N02, 0Ral, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Cs-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCv1; each RCyi is independently selected from halo, CN, N02, 0Ral, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, N02J ORal, NRqlRdl, S(0)2Rbl, C(O)NRqlRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, andRdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R8; and each R8 is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di (C1-3 alkyl)amino.
35. The method of embodiment 35, wherein the compound of Formula (la) is selected from any one of the following compounds:
Figure imgf000113_0001
112
Figure imgf000114_0001
H or a pharmaceutically acceptable salt thereof.
113 36. A compound of Formula (II):
R7
Figure imgf000115_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from ORB, NR3RB, and CH2Rc; each RB is independently selected from Cy1, Ci-6 haloalkyl, and Ci-6 alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from NO2, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, S(O)2ORal, and C1-6 alkyl substituted with NO2, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, CJ-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORai, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Cs-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCvl; each RCyl is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
114 each Re is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; provided that the compound of Formula (II) is not any of the following compounds:
Figure imgf000116_0001
37. The compound of embodiment 36, wherein R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl.
38. The compound of embodiment 36, wherein R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
39. The compound of embodiment 36, wherein the compound has formula:
Figure imgf000116_0002
or a pharmaceutically acceptable salt thereof.
40. The compound of any one of embodiments 36-39, wherein R1 is selected from ORB and NR3RB.
41. The compound of embodiment 40, wherein R1 is ORB.
42. The compound of embodiment 40, wherein R1 is NHRB.
115 43. The compound of any one of embodiments 36-42 wherein RB is selected from Cy1 and Ci -6 alkyl substituted with Cy1, ORal, or NRclRdl.
44. The compound of embodiment 43, wherein RB is selected from Cy1, Ci-6 alkyl substituted with Cy1, and Ci-e alkyl substituted with NRclRdl.
45. The compound of embodiment 44, wherein RB is Cy1.
46. The compound of embodiment 44, wherein RB is Ci-6 alkyl substituted with Cy1.
47. The compound of any one of embodiments 36-46, wherein Cy1 is selected from Ce-ioaryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
48. The compound of embodiment 47, wherein Cy1 is Cts-io aryl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
49. The compound of embodiment 47, wherein Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
50. The compound of embodiment 49, wherein the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
51. The compound of any one of embodiments 36-50, wherein RCyl is selected from halo, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
52. The compound of any one of embodiments 36-50, wherein RCvl is selected from halo, NO2, C1-3 alkyl, and C1-3 alkoxy.
116 53. The compound of any one of embodiments 36-46, wherein Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000118_0001
54. The compound of any one of embodiments 36-46, wherein RB is Ci-e alkyl substituted with NRclRdl.
55. The compound of embodiment 54, wherein RB is selected from CH2NRclRdl, CH2CH2NRelRdl, and CH2CH2CH2NRelRdl.
56. The compound of embodiment 36, wherein the compound of Formula (II) is selected from any one of the following compounds:
Figure imgf000118_0002
117
Figure imgf000119_0001
or a pharmaceutically acceptable salt thereof.
57. A pharmaceutical composition comprising a compound of any one of embodiments 36-56, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
58. A method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 36-56, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 57.
59. The method of embodiment 58, wherein the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson
118 syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
60. The method of embodiment 58, wherein the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
61. The method of embodiment 58, wherein the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease.
62. The method of embodiment 58, wherein the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
63. A method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition, the method comprising:
(i) identifying a subject diagnosed with the disease or condition responsive to inhibition of DYRK1A in a cell, a tissue, and/or an organ affected by the disease or condition; and
119 (ii) after (i), administering to the subject a therapeutically effective amount of a compound of Formula (Ila): 7
Figure imgf000121_0001
or a pharmaceutically acceptable salt thereof, wherein:
R10 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and C(=O)R*;
R1 is selected from Cy1, ORB, NR3RB, CH2RB, and CH2Rc; each RB is independently selected from H, Cy1, C1-6 haloalkyl, and C1-6 alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-ioaryl, C3-1Q cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each RCyl is independently selected from halo, CN, NO2, ORal, NRelRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
120 Ral, Rbl, Rel, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from Rg; and each Rs is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
64. The method of embodiment 63, wherein the compound of Formula (Ha) is selected from any one of the following compounds:
Figure imgf000122_0001
121
Figure imgf000123_0001
or a pharmaceutically acceptable salt thereof.
OTHER EMBODIMENTS
It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to
5 illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
122

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I):
Figure imgf000124_0001
or a pharmaceutically acceptable salt thereof, wherein: RA is selected from moiety (i), (ii), (iii) and (iv):
Figure imgf000124_0002
Rla, R2a, R3a, and R4a are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORaI, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R1 is selected from Cy1, ORB, NR3RB, CH2RB, and CH2Rc; each RB is independently selected from Cy1, Ci-$ haloalkyl, and C1-6 alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, OR81, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal;
123 R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5 is selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, S(O)2NRclRdl, and S(O)2ORal, wherein said CM alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdi, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ce-io aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each RCvi is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C 1.3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg;
R8a, R8b, and RSc are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8; each X is independently selected from N and CR9b, wherein one X is N and the other X is CR9b;
R9a and R9b are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Rg; and
124 each Re is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; provided that the compound of Formula (I) is not any one of the following compounds:
Figure imgf000126_0003
2. The compound of claim 1, having formula:
Figure imgf000126_0001
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, having formula:
Figure imgf000126_0002
R or a pharmaceutically acceptable salt thereof.
4. The compound of any one of claims 1-3, wherein Rla, R2a, R3a, and R43 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, and C1-3 haloalkyl.
125
5. The compound of any one of claims 1-3, wherein Rla, R2a, R3a, and R4® are each independently selected from H and Ci -3 alkyl.
6. The compound of claim 1, wherein the compound of Formula (I) is selected from any one of the following compounds:
Figure imgf000127_0001
or a pharmaceutically acceptable salt thereof.
7. The compound of any one of claims 1-6, wherein R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl.
8. The compound of any one of claims 1-6, wherein R3, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, Ci- 3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3alkyl)amino.
9. The compound of any one of claims 1-8, wherein R1 is selected from OR8 and NR3RB.
10. The compound of claim 9, wherein R1 is OR8.
11. The compound of claim 9, wherein R1 is NHR8.
12. The compound of any one of claims 1-8, wherein R1 is CH2R8.
13. The compound of any one of claims 1-8, wherein the compound of Formula (I) is selected from:
126
Figure imgf000128_0001
or a pharmaceutically acceptable salt thereof.
14. The compound of any one of claims 1-13, wherein RB is selected from Cy1 and Cb6 alkyl substituted with Cy1, 0Ral, or NRclRdl.
15. The compound of claim 14, wherein RB is selected from Cy1, Ci-6 alkyl substituted with Cy1, and Ci-e alkyl substituted with NR61Rdl.
16. The compound of claim 15, wherein RB is Cy1.
127
17. The compound of claim 15, wherein RB is Ci-6 alkyl substituted with Cy1.
18. The compound of any one of claims 1-17, wherein Cy1 is selected from Ct- 10 aryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
19. The compound of claim 18, wherein Cy1 is Ce-ioaryl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
20. The compound of claim 18, wherein Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
21. The compound of claim 20, wherein the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
22. The compound of any one of claims 1-21, wherein RCyl is selected from halo, NO:, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
23. The compound of any one of claims 1-21, wherein RCyl is selected from halo, NO2, C1-3 alkyl, and C1-3 alkoxy.
24. The compound of any one of claims 1-23, wherein Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000129_0001
128
25. The compound of any one of claims 1-13, wherein RB is Ci-6 alkyl substituted with NRelRdl.
26. The compound of claim 25, wherein RB is selected from CH2NRclRdl, CH2CH2NRclRdl, and CH2CH2CH2NRclRdl.
27. The compound of claim 1, wherein the compound of Formula (I) is selected from any one of the following compounds:
Figure imgf000130_0001
or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising a compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
129
29. A method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 29.
30. The method of claim 30, wherein the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (GTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
31. The method of claim 30, wherein the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
32. The method of claim 30, wherein the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis,
130 systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease.
33. The method of claim 30, wherein the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (eg., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
34. A method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition, the method comprising:
0) identifying a subject diagnosed with the disease or condition responsive to inhibition of DYRK1 A in a cell, a tissue, and/or an organ affected by the disease or condition; and
(ii) after (i), administering to the subject a therapeutically effective amount of a compound of Formula (la):
Figure imgf000132_0001
or a pharmaceutically acceptable salt thereof, wherein:
RA is selected from moiety (i) and (ii):
Figure imgf000132_0002
Rla, R2a, R3a, andR4a are each independently selected from H, halo, CN, NO:, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, OR91, NRqlRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdL, C(O)ORal, and S(O)2ORal;
R10 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and C(=O)R*;
131 R1 is selected from Cy1, ORB, NR3RB, CH2RB, and CH2Rc; each RB is independently selected from H, Cy1, Ci-e alkyl, and Ci-6 haloalkyl, wherein said Ci-6 alkyl is optionally substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRelRdl, C(O)ORal, and S(0)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6 and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, Cy1, ORal, NRelRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRelRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Cs-ioaryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each RCy! is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8; and each R8 is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
35. The method of claim 35, wherein the compound of Formula (la) is selected from any one of the following compounds:
132
Figure imgf000134_0001
133
Figure imgf000135_0001
or a pharmaceutically acceptable salt thereof.
36. A compound of Formula (II):
Figure imgf000135_0002
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from ORB, NR3RB, and CH2Rc; each RB is independently selected from Cy1, Ci-6 haloalkyl, and Ci-e alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from NO2, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, S(O)2ORal, and CM alkyl substituted with NO2, NRclRdl, S(O)2Rbl, C(O)NRelRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from Ct- 10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCvl; each RCyi is independently selected from halo, CN, NO2, ORal, NRclRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with
134 CN, NO2, ORal, NRelRdl, S(O)2Rbl, C(O)NRelRdl, S(0)2NRelRdl, C(O)ORal, or S(O)2ORal;
Ral, Rbl, Rcl, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from R8; and each Rg is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; provided that the compound of Formula (II) is not any of the following compounds:
Figure imgf000136_0001
37. The compound of claim 36, wherein R3, R6, and R7 are each independently selected fiom H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl.
38. The compound of claim 36, wherein R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
39. The compound of claim 36 wherein the compound has formula:
Figure imgf000136_0002
or a pharmaceutically acceptable salt thereof.
135
40. The compound of any one of claims 36-39, wherein R1 is selected from ORB and NR3RB.
41. The compound of claim 40, wherein R1 is ORB.
42. The compound of claim 40, wherein R1 is NHRB.
43. The compound of any one of claims 36-42 wherein RB is selected from Cy1 and C1-6 alkyl substituted with Cy1, ORal, or NRclRdl.
44. The compound of claim 43, wherein RB is selected from Cy1, CH> alkyl substituted with Cy1, and Ci-« alkyl substituted with NRclRdl.
45. The compound of claim 44, wherein RB is Cy1.
46. The compound of claim 44, wherein RB is Ci-e alkyl substituted with Cy1.
47. The compound of any one of claims 36-46, wherein Cy1 is selected from Ce-io aryl and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
48. The compound of claim 47, wherein Cy1 is Ce-io aryl, optionally substituted with 1 or 2 substituents independently selected from RCy1.
49. The compound of claim 47, wherein Cy1 is 3-10 membered heterocycloalkyl, optionally substituted with 1 or 2 substituents independently selected from RCyl.
50. The compound of claim 49, wherein the 3-10 membered heterocycloalkyl is selected from oxiranyl, oxetanyl, tetrahydrofhranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,3-dioxanyl, morpholinyl, pyrrolidinyl, and oxazolidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl.
51. The compound of any one of claims 36-50, wherein RCyl is selected from halo, NO2, Ci -3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.
52. The compound of any one of claims 36-50, wherein RCyl is selected from halo, NO2, C1-3 alkyl, and C1-3 alkoxy.
136
53. The compound of any one of claims 36-46, wherein Cy1 is selected from any one of the following moieties, each of which is optionally substituted with 1 or 2 independently selected RCyl:
Figure imgf000138_0001
54. The compound of any one of claims 36-46, wherein RB is C1-6 alkyl substituted with NRclRdl.
55. The compound of claim 54, wherein RB is selected from CH2NRclRdl, CH2CH2NRelRdl, and CH2CH2CH2NRelRdl.
56. The compound of claim 36, wherein the compound of Formula (II) is selected from any one of the following compounds:
Figure imgf000138_0002
137
Figure imgf000139_0001
or a pharmaceutically acceptable salt thereof.
57. A pharmaceutical composition comprising a compound of any one of claims 36- 56, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
58. A method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 36-56, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57,
59. The method of claim 58, wherein the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic
138 encephalopathy (CTE), aging-related tan astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
60. The method of claim 58, wherein the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
61. The method of claim 58, wherein the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease.
62. The method of claim 58, wherein the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
63. A method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition, the method comprising:
(i) identifying a subject diagnosed with the disease or condition responsive to inhibition of DYRK1A in a cell, a tissue, and/or an organ affected by the disease or condition; and
139 (ii) after (i), administering to the subject a therapeutically effective amount of a compound of Formula (Ila): 7
Figure imgf000141_0001
or a pharmaceutically acceptable salt thereof, wherein:
R10 is selected from H, C1-3 alkyl, C1-3 haloalkyl, and C(=O)R*;
R1 is selected from Cy1, ORB, NR3RB, CH2RB, and CH2Rc; each RB is independently selected from H, Cy1, C1-6 haloalkyl, and C1-6 alkyl substituted with Cy1, CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
Rc is selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal;
R2, R3, and R4 are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;
R5, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal, wherein said C1-3 alkyl is optionally substituted with 1 or 2 substituents independently selected from CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, and S(O)2ORal; each Cy1 is independently selected from C6-10 aryl, C3-1Q cycloalkyl, 5-14 membered heteroaryl, and 3-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from RCyl; each RCyl is independently selected from halo, CN, NO2, ORal, NRelRdl, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with CN, NO2, ORal, NRclRdl, S(O)2Rbl, C(O)NRclRdl, S(O)2NRclRdl, C(O)ORal, or S(O)2ORal;
140 Ral, Rbl, Rel, and Rdl are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from Rg; and each Rs is independently selected from halo, CN, OH, C1-3 alkoxy, C1-3 haloalkoxy, carboxy, C1-3 alkoxycarbonyl, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino.
64. The method of claim 63, wherein the compound of Formula (Ha) is selected from any one of the following compounds:
Figure imgf000142_0001
141
Figure imgf000143_0001
or a pharmaceutically acceptable salt thereo
Figure imgf000143_0002
f.
65. The compound of claim 1, wherein RA is selected from moiety (iii) and (iv):
Figure imgf000143_0003
66. The compound of claim 65, wherein the compound has the formula
Figure imgf000143_0004
or a pharmaceutically acceptable salt thereof.
67. The compound of claim 65, wherein the compound has the formula
Figure imgf000143_0005
or a pharmaceutically acceptable salt thereof.
142
68. The compound of claim 67, wherein the compound has the formula
Figure imgf000144_0001
or a pharmaceutically acceptable salt thereof.
69. The compound of claim 67, wherein the compound has the formula
Figure imgf000144_0002
or a pharmaceutically acceptable salt thereof.
70. The compound of claim 66, wherein R8a, R8b, and R80 are each independently selected from H and C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
71. The compound of claim 66, wherein R8a, R8b, and R80 are each independently selected from H and C1-3 alkyl.
72. The compound of claim 66, wherein R8a and RSc are both H and R8b is C1-3 alkyl.
73. The compound of claim 67, wherein R9a and R9b are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R8.
143
74. The compound of claim 67, wherein R9a and R9b are each independently selected from H and C1-3 alkyl.
75. The compound of claim 67, wherein R9a and R9b are both H.
76. The compound of claim 65, wherein the compound is selected from any one of the following compounds:
Figure imgf000145_0001
or a pharmaceutically acceptable salt thereof.
77. The compound of claim 65, wherein R3, R6, and R7 are each independently selected from H, halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, ORal, and NRclRdl.
144
78. The compound of claim 65, wherein R5, R6, and R7 are each independently selected from H, halo, CN, OH, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di (C 1.3 alkyl)amino.
79. The compound of claim 65, wherein R1 is selected from ORB and NR3RB.
80. The compound of claim 65, wherein R1 is ORB.
81. The compound of claim 65, wherein R1 is NHRB.
82. The compound of claim 65, wherein R1 is CH:RD.
83. The compound of claim 65, wherein the compound of Formula (I) is selected from:
Figure imgf000146_0001
145
Figure imgf000147_0001
Figure imgf000148_0001
or a pharmaceutically acceptable salt thereof.
84 The compound of claim 65, wherein the compound is selected from any one of the following compounds:
Figure imgf000148_0002
or a pharmaceutically acceptable salt thereof.
85. A pharmaceutical composition comprising a compound of any one of claims 65- 84, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
147
86. A method of treating a disease or condition where DYRK1 A is implicated in pathology of the disease or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 65-84, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 85.
87. The method of claim 86, wherein the disease or condition is a neurodegenerative disease selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Hallervorden-Spatz syndrome, Bradbury-Eggleston syndrome, premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), dementia associated with AD or FAD, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), dementia associated with HD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (GTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and argyrophilic grain disease.
88. The method of claim 86, wherein the disease or condition is a metabolic disorder selected from type 1 diabetes, type 2 diabetes, hyperglycerimia, hypermethioninemia, familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tay-Sachs disease, and Wilson’s disease.
89. The method of claim 86, wherein the disease or condition is an inflammatory disorder selected from arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory arthritis, inflammatory bowel disease, osteoarthritis, inflammatory joint disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis,
148 systemic autoimmunity, sepsis, dermatomyositis, multiple sclerosis, myasthenia gravis, Hashimoto thyroiditis, and Grave’s disease.
90. The method of claim 86, wherein the disease or condition is a cancer selected from brain cancer (e.g., glioblastoma, neuroblastoma), leukemia (e.g., B cell acute lymphoblastic leukemia), breast cancer, and pancreatic cancer.
91. A method of treating a disease or condition where overexpression and/or enhanced activity of DYRK1 A is implicated in pathology of the disease or condition, the method comprising:
(i) identifying a subject diagnosed with the disease or condition responsive to inhibition of DYRK1A in a cell, a tissue, and/or an organ affected by the disease or condition; and
(ii) after (i), administering to the subject a therapeutically effective amount of a compound of any one of claims 65-84, or a pharmaceutically acceptable salt thereof.
92 The method of claim 91, wherein the compound is selected from any one of the following compounds:
Figure imgf000150_0001
149 and or a p
Figure imgf000151_0001
harmaceutically acceptable salt thereof.
150
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