Heterocyclic compounds as DYRK1A inhibitors

Abstract

The present disclosure provides compounds and pharma- ceutically acceptable salts thereof that inhibit dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). These chemical entities are useful, for example, for treating conditions, diseases or disorders in which increased (e.g., excessive) DYRK1A activation contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., neurological disorders) in a subject (e.g., a human). The present disclosure also provides methods of use and production thereof, as well as compositions containing them. JPEG2024545132000525.jpg69164

Description

[Technical Field]

[0001] The present disclosure provides compounds and pharmaceutically acceptable salts thereof that inhibit dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These compounds are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) DYRK1A activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., neurological disorders) in a subject (e.g., a human). The present disclosure also provides methods of use and production thereof, as well as compositions containing them. [Background technology]

[0002] Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a 763-amino acid, 85-kDa serine / threonine / tyrosine kinase located on chromosome 21 (21q22.2). DYRK1A has catalytic activity regulated by autophosphorylation of the tyrosine residue (Y321), resulting in constitutively activated serine / threonine kinase activity. See Abbassi, et al., Pharmacology & Therapeutics, 151, 87-98 (2015). Because DYRK1A is constitutively active, its activity is dose-dependent. Therefore, both elevated and decreased levels of DYRK1A (compared to wild-type levels) have been shown to result in neurological disorders. See Duchon and Herault, Front Behav. Neurosci. 10, 104-104 (2016). DYRK1A is also a member of the large family of CMGC kinases, which includes cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs).

[0003] Furthermore, DYRK1A has been shown to play a role in cell cycle regulation, at least in part by phosphorylating (and thus inhibiting) the nuclear factor of activated T cells (NFAT) transcription factor family. Furthermore, over 20 substrates of DYRK1A have been identified, including those involved in cell signaling, chromatin regulation, gene expression, alternative splicing, cytoskeleton, and synaptic function. See Abassi, et al. (2016). DYRK1A dysregulation has been implicated in various disease states, such as Alzheimer's disease, autism, and Down syndrome. In some cases, novel mutations in DYRK1A have been associated with autism phenotypes. See, for example, Dang, et al., Molecular Psychiatry, 23, 747-758 (2018).

[0004] DYRK1A is also known to play an important role in brain development. For example, decreased DYRK1A activity during neurodevelopment (carrying a single copy of a loss-of-function mutation) results in an intellectual disability phenotype. Conversely, trisomy 21 in individuals with Down syndrome is associated with triploidy of the DYRK1A gene, resulting in increased DYRK1A activity. DYRK1A is located on chromosome 21, specifically within the "Down syndrome critical region," a portion of chromosome 21 that contains genes specifically associated with the development of the Down syndrome phenotype. As a result, individuals with Down syndrome have three copies of DYRK1A. Because DYRK1A is dosage-sensitive, increased DYRK1A levels in such individuals significantly affect the localization and function of the DYRK1A protein. DYRK1A expression is also elevated in the CNS of individuals with neurodegenerative diseases, such as Parkinson's disease, Pick's disease, and Alzheimer's disease.

[0005] Furthermore, approximately 50% of individuals with Down syndrome eventually develop Alzheimer's disease, with symptoms typically beginning between the ages of 40 and 60. DYRK1A phosphorylates the amyloid precursor protein (APP), promoting the production of pathogenic amyloid-β peptide (Aβ). Dyrk1A also phosphorylates tau, both directly and indirectly (see Abassi, et al., (2016)). Both Aβ and tau pathology are associated with the Down syndrome phenotype.

[0006] Normalizing DYRK1A gene dosage by crossing Ts65Dn mice (a DS model) with DYRK1A knockout mice reverses many Alzheimer's disease-like phenotypes. See Garcia-Cerro et al., 2017. DYRK1A mRNA levels, protein levels, and kinase activity are increased by approximately 50% in individuals with Down syndrome, reflecting gene copy number. See Liu et al., 2008; see also Wegiel et al., 2011.

[0007] Because there are no available treatments for these neurological disorders, for example, individuals with Alzheimer's disease have a poor prognosis. This can be particularly devastating because Alzheimer's disease causes a sharp decline in survival rates for individuals with Down's syndrome over the age of 45. Only about 25% of individuals with Down's syndrome survive beyond the age of 60, and most of them develop Alzheimer's disease.

[0008] Across all individuals, dementia remains a significant unmet medical need and poses a significant public health burden. Currently, one in three older adults will develop dementia, and approximately 70% of dementia cases are attributable to Alzheimer's disease. Approximately 11% of Americans over the age of 65 have AD, exceeding 6.2 million in 2021. This number is projected to exceed 12 million by 2050 (www.Alz.org). Currently, there is no approved therapy for treating Alzheimer's disease associated with Down syndrome, which represents a significant unmet medical need. Some DYRK1A inhibitors have been tested in vitro or in animal preclinical models for treating Alzheimer's disease or Down syndrome, but because DYRK1A is a member of the highly conserved CMGC kinase family, it has proven difficult to identify compounds that selectively target DYRK1A. Therefore, there remains a need to identify DYRK1A inhibitors for treating Down syndrome, Alzheimer's disease, Alzheimer's disease associated with Down syndrome, and other neurodegenerative and neurological diseases. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Abbassi,et al.,Pharmacology&Therapeutics,151,87-98(2015) [Non-patent document 2] Duchon and Herault,Front Behav.Neurosci.10,104-104(2016) [Non-patent document 3] Dang,et al.,Molecular Psychiatry,23,747-758(2018) Summary of the Invention [Means for solving the problem]

[0010] Some embodiments have formula (IO): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each dashed line represents a single or double bond; X 1 is CR 1 or N, X2 is CR 2 , C(=O), or N; X 3 is C or N, except that X 2 If is C(=O), X 3 is N, X 4 is CH or N, Ring A is phenyl or 5- to 6-membered heteroaryl; R 1 is hydrogen, halogen, cyano, hydroxyl, 3- to 10-membered heterocyclyl, -C(=O)C1-C6 alkyl, or -C(=O)OR A C1-C6 alkyl optionally substituted with 3- to 6-membered heterocyclyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —C(═O)-3- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl or halogen, or —OR B and R B is a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, a C-C aryl, or a C-C cycloalkyl, each of which is selected from 1 to 3 independently selected halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, cyano, hydroxy, —C(═O)OH, —C(═O)C-C alkyl, —S(O)—C-C alkyl, or —NR C R D optionally replaced by R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -C(=O)-3- to 6-membered heterocyclyl, -NH-C3-C6 cycloalkyl-C(=O)OR A or -O-C3-C6 cycloalkyl-C(=O)OR A and R 3 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, C3-C6 cycloalkyl, -XR G,or [ka] and R 4 is hydrogen or C1-C6 alkyl, R 5 is hydrogen, C1-C6 alkyl optionally substituted with 3- to 6-membered heterocyclyl, -XR E , -C3-C6 cycloalkyl-C(=O)OR A ,or [ka] or R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A together form (i) a C6-C10 aryl optionally substituted with 1-2 independently selected C1-C6 alkyl or 3-10 membered heterocyclyl optionally substituted with -C(=O)OR', (ii) a 3-6 membered heterocyclyl, or (iii) a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(=O)OR', and a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; R E is a 3- to 10-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected C1-C6 alkoxy, NR I R J or C1-C6 alkyl optionally substituted with -C(=O)OH; R Fis a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each optionally substituted with C1-C6 alkyl, or a C2-C6 alkynyl optionally substituted with hydroxy; R G is a 3- to 6-membered heterocyclyl or C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected C1-C6 alkyl, —C(═O)C1-C6 alkyl, —C(═O)OH, or NR C R D optionally replaced by R H is C1-C6 alkoxy, C1-C6 alkyl optionally substituted with hydroxy, or 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; X is -NH-, -NH(C=O)-, -NHC(=O)O-, -O-, -(C=O)- or CH2; Each R A , R C , R D , R I , and R J are independently selected from hydrogen and C1-C6 alkyl; m is 0, 1, or 2.

[0011] Some embodiments are of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each dashed line represents a single or double bond; X 1 is CR 1 or N, X 2 is CR 2 , C(=O), or N; X 3 is C or N, except that X 2 If is C(=O), X 3 is N, X 4 is CH or N, Ring A is phenyl or 5- to 6-membered heteroaryl; R 1 is hydrogen, halogen, cyano, 3- to 10-membered heterocyclyl, -C(=O)C1-C6 alkyl, or -C(=O)OR A C1-C6 alkyl optionally substituted with 3-6 membered heterocyclyl optionally substituted with C1-C6 alkoxy, -C(=O)-3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, or -OR B and R B is a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, a C-C aryl, or a C-C cycloalkyl, each of which is selected from 1 to 3 independently selected halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, cyano, hydroxy, —C(═O)OH, —C(═O)C-C alkyl, —S(O)—C-C alkyl, or —NR C R D optionally replaced by R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)-3- to 6-membered heterocyclyl, -NH-C3-C6 cycloalkyl-C(=O)OR A or -O-C3-C6 cycloalkyl-C(=O)OR A and R 3 is hydrogen, halogen, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, -XR G ,or [ka] and R 4 is hydrogen or C1-C6 alkyl, R 5 is hydrogen, C1-C6 alkyl optionally substituted with 3- to 6-membered heterocyclyl, -XR E , -C3-C6 cycloalkyl-C(=O)OR A ,or [ka] or R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A together form (i) a C6-C10 aryl optionally substituted with a 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or -C(=O)OR', (ii) a 3-6 membered heterocyclyl, or (iii) a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, a 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(=O)OR', and a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; R E is a 3- to 10-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected C1-C6 alkoxy, NR I R J or C1-C6 alkyl optionally substituted with -C(=O)OH; R F is a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each optionally substituted with C1-C6 alkyl, or a C2-C6 alkynyl optionally substituted with hydroxy; R G is a 3- to 6-membered heterocyclyl or C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected C1-C6 alkyl, —C(═O)C1-C6 alkyl, —C(═O)OH, or NR C R D optionally replaced by R H is C1-C6 alkyl optionally substituted with hydroxy or 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; X is -NH-, -NH(C=O)-, -NHC(=O)O-, -O-, -(C=O)- or CH2; Each R A , R C , R D , R I , and R J are independently selected from hydrogen and C1-C6 alkyl; m is 0, 1, or 2.

[0012] Some embodiments are of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- to 14-membered heteroaryl or a 5- to 14-membered heterocyclyl; Each R 1 are independently halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)OR A , -NR B R C , and -C(=O)NR B R C and Each R 2 are independently -C(=O)OR D , C1-C6 alkyl, C2-C6 alkynyl optionally substituted with 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl, -C(=O)-phenyl, -(C1-C6 alkyl)-phenyl, -(C1-C6 alkyl)-4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or -CO2C1-C6 alkyl, phenyl optionally substituted with cyano or fluoro, -NHC(=O)R E , 5-6 membered heteroaryl optionally substituted with C1-C6 alkoxy; m is 1, 2, or 3; n is 0, 1, 2, or 3; Each R A , R B , R C , and RD are independently hydrogen or C1-C6 alkyl, Each R E is independently C3-C6 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0013] Some embodiments are of formula (III): [ka] or a pharmaceutically acceptable salt thereof, Ring A is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R 1 is -NHC(=O)(C1-C6 alkylene) n R A , -NR F R G phenyl optionally substituted with -QR C ,or [ka] and R 2 -CO2R B C3-C6 cycloalkyl optionally substituted with, 5-10 membered heteroaryloxy, C1-C6 alkyl, cyano, or -(C1-C6 alkylene) optionally substituted with, 4-6 membered heterocyclyl p -5-10 membered heteroaryl, cyano or -NR D R E -(C1-C6 alkylene) optionally substituted with t -phenyl, 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; R 3 is a C1-C6 alkyl, R A is a 4- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, or a 5- to 10-membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl; RB is hydrogen or C1-C6 alkyl, R C is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, or -(C1-C6 alkylene)-NR D R E is phenyl optionally substituted with R D , R E , and R F are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R G is hydrogen, C1-C6 alkyl, —C(═O)—C1-C6 alkyl, or —C(═O)—C3-C6 cycloalkyl; R H is a 4- to 6-membered heterocyclyl optionally substituted with 1 to 2 independently selected C1-C6 alkyl; Q is C1-C6 alkylene, NH, or O; m is 0 or 1, n is 0 or 1, p is 0 or 1, t is 0 or 1.

[0014] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0015] Provided herein is a method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), as provided herein, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition.

[0016] Also provided herein is a method for treating a neurological disorder in a subject in need thereof, the method comprising: (a) determining that the neurological disorder is associated with dysregulation of the expression, activity, or level of the DYRK1A gene, DYRK1A protein, or any of the foregoing; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III) as provided herein, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition.

[0017] Provided herein is a method for treating a DYRK1A-associated disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a DYRK1A-associated disease or disorder a therapeutically effective amount of a compound of formula (I), (II), or (III) as provided herein, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition.

[0018] The present disclosure also provides a method of treating a DYRK1A-associated neurological disorder in a subject, the method comprising determining that the subject's neurological disorder is a DYRK1A-associated neurological disease or disorder, and administering to the subject a therapeutically effective amount of a compound of formula (I), (II), or (III) as provided herein, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition.

[0019] Further provided herein is a method for treating a DYRK1A-associated neurological disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a DYRK1A-associated neurological disorder a therapeutically effective amount of a compound of formula (I), (II), or (III) as provided herein, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition.

[0020] The present disclosure also provides a method of treating a DYRK1A-associated neuropathy in a subject, the method comprising determining that the subject's neuropathy is a DYRK1A-associated neuropathy, and administering to the subject a therapeutically effective amount of a compound of formula (I), (II), or (III) as provided herein, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition.

[0021] Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I), (II), or (III) as provided herein, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition, to a subject having medical records indicating that the subject has dysregulation of the expression or activity or level of the DYRK1A gene, DYRK1A protein, or any thereof.

[0022] The present disclosure also provides a method for inhibiting DYRK1A in a mammalian cell, the method comprising contacting the mammalian cell with a therapeutically effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing.

[0023] The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the disclosure will be apparent from the description and the claims. DETAILED DESCRIPTION OF THE INVENTION

[0024] Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a member of the dual specificity tyrosine phosphorylation-regulated kinase (DYRK) family and is also part of the larger CGMC kinase family. DYRK1A is a 763-amino acid, 85-kDa serine / threonine kinase located on chromosome 21. DYRK1A contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conserved 13 consecutive histidine repeats. Alternative splicing of DYRK1A generates several transcript variants that differ from each other in either the 5' untranslated region or the 3' coding region, resulting in at least five different isoforms.

[0025] DYRK1A has catalytic activity regulated by autophosphorylation of a tyrosine residue (Y321), resulting in constitutively activated serine / threonine kinase activity. Because DYRK1A is constitutively active, its activity is dose-dependent. Thus, both elevated and decreased levels of DYRK1A (compared to wild-type levels) have been shown to result in neuronal disorders.

[0026] DYRKIA exhibits a broad substrate spectrum (e.g., a wide range of targets), including splicing factors, synaptic proteins, and transcription factors. It is ubiquitously expressed in all mammalian tissues and cells, although its levels vary, with particularly high levels in fetal and adult brain tissue. Due to its localization in the Down syndrome critical region on chromosome 21 and its role in brain function, the human DYRKIA gene is a candidate gene for treating several characteristics of Down syndrome, including associated intellectual disability and Alzheimer's disease. In particular, Drosophila carrying deleterious mutations in the DYRKIA orthologue ("Minibrain") exhibit reduced neuron numbers in their central nervous system. Similarly, mice heterozygous for a disruptive allele of the Dyrk1a gene exhibit reduced survival, behavioral changes, and growth retardation. (Fotaki, et al., Mol Cell Biol., 22(18):6636-6647 (2014)).

[0027] The identification of hundreds of genes deregulated by DYRK1A overexpression, as well as the identification of numerous cytoplasmic, cytoskeletal, and nuclear proteins, including transcription factors, that are phosphorylated by DYRK1A, indicates that DYRK1A overexpression is important for derestricting multiple pathways in brain development and aging in individuals with Down syndrome. Identifying DYRK1A cell signaling or transduction pathways will provide a better understanding of how DYRK1A overexpression (or underexpression) leads to the various disease states in which it is known to be involved. In particular, DYRK1A is known to be active in activated PI3K / Akt signaling, a pathway critically involved in neuronal development, growth, and survival. DYRK1A is also known to be active in ASK1 / JNK1 activity, and inhibitors of DYRK1A can induce neuronal death and apoptosis. DYRK1A is also known to phosphorylate p53 during fetal brain development, and inhibitors of DYRK1A can prevent changes in neuronal proliferation. DYRK1A also phosphorylates the synaptic proteins Amph1, Dynamin1, and Synaptojanin, which are involved in regulating endocytosis. DYRK1A inhibitors may preserve synaptic plasticity by preventing changes in the number, size, and morphology of dendritic spines. DYRK1A also phosphorylates and inhibits presenilin 1, the catalytic subunit of γ-secretase. Ryu, et al., J Neurochem., 115(3):574-84(2010).

[0028] DYRK1A overexpression leads to structural and functional changes, including intellectual disability and dementia, such as Alzheimer's disease. In particular, genes involved in learning disabilities, altered synaptic plasticity, memory loss, and cell cycle abnormalities result in neuropathological symptoms similar to those of dementia associated with Alzheimer's disease. DYRK1A also affects the proliferation and differentiation of neuronal precursors, and therefore may affect neurogenesis and brain growth. It may also affect neurotransmission and dendritic spine formation through its interaction with synaptic proteins and the cytoskeleton.

[0029] One potential therapeutic area is DYRK1A inhibitors. Inhibitors that can normalize DYRK1A levels in Down syndrome may improve synaptic plasticity and delay the onset of Alzheimer's disease pathology, including tau hyperphosphorylation. Therefore, inhibiting DYRK1A activity in individuals with Down syndrome may counteract the phenotypic effects of its overexpression and provide a potential means for treating such developmental disorders and preventing and / or mitigating age-related neurodegeneration, including Alzheimer's disease associated with Down syndrome. This study demonstrated that inhibition of overexpressed DYRK1A resulted in normal DYRK1A levels and was found to ameliorate cognitive and behavioral deficits in transgenic models. See, for example, Stringer, et al., Mol Genet Genomic Med, 5, 451-465 (2017) and Feki and Hibaoui, Brain Sci, 8, 187 (2018). However, despite promising results, there is considerable variability in outcomes across studies. The differences were due to differences in model, dose, route of administration, composition of inhibitor, and timing of administration.

[0030] Epigallocatechin gallate (EGCG), the main flavonoid in green tea, has been investigated for its therapeutic benefits, including antioxidant, anti-inflammatory, anti-cancer, anti-infective, and neuroprotective activities. See Bhat, et al., "Towards the discovery of drug-like epigallocatechin gallate analogs as Hsp90 inhibitors," Bioorg Med Chem Lett, 24, 2263-2266 (2014). EGCG is a non-ATP-competitive DYRKlA inhibitor, and this study demonstrates that a green tea extract containing 41% EGCG was able to attenuate cognitive decline observed in transgenic mice overexpressing DYRKlA. EGCG has also been shown to improve memory recognition and working memory. However, EGCG is not highly selective and has numerous off-target effects, reducing the potential for its long-term use.

[0031] SM07883 is an orally bioavailable (%F of 92% in mice and 109% in monkeys), BBB-permeable DYRK1A inhibitor (IC50 1.6 nM) that also exhibits potent inhibition of DYRK1B, CLK4, and GSK3β in kinase assays. It was shown to prevent tau hyperphosphorylation in mouse models. SM07883 was tested as a treatment for Alzheimer's disease in a Phase 1 clinical trial in Australia (ACTRN12619000327189). However, according to the trial description page at www.anzctr.org.au, the last data collection date was May 2019, and the results of the trial have not yet been published.

[0032] The present disclosure provides compounds of Formulas (I), (II), and (III), as well as pharmaceutically acceptable salts of any of the foregoing, that inhibit dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These chemical entities are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) DYRK1A activation contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., neurological disorders) in a subject (e.g., a human). The present disclosure also provides methods of use and production thereof, as well as compositions containing them.

[0033] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0034] The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. A compound herein identified by name or structure as one particular tautomeric form is intended to include other tautomeric forms unless otherwise specified. For example, if quinazolin-4-ol is encompassed in a claim or embodiment, quinazolin-4(3H)-one is also encompassed by the claim or embodiment (see below). [ka]

[0035] It will be understood that certain compounds provided herein may contain one or more asymmetric centers and may therefore be prepared and isolated in a mixture of isomers, such as a racemic mixture, or in enantiomerically pure form. Unless otherwise indicated, when a disclosed compound is named or depicted by structure without specifying stereochemistry (e.g., a "flat" structure), and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0036] The term "about" when referring to a number or numerical range means that the number or numerical range referred to is an approximation, e.g., within experimental variation and / or statistical experimental error, and therefore, the number or numerical range may vary by up to ±10% of the specified number or numerical range.

[0037] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the general well-being of the subject being treated.

[0038] The term "inhibit" or "inhibition of" means to decrease by a measurable amount or to prevent completely (eg, 100% inhibition).

[0039] The term "therapeutically effective amount," as used herein, refers to a sufficient quantity of a chemical substance being administered that will alleviate to some extent one or more of the symptoms of the disease or condition being treated. Results include a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, a "therapeutically effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to produce a clinically significant reduction in disease symptoms. An appropriate "therapeutically effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0040] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material, etc. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005, Handbook of Pharmaceutical Excipients, 6th ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2009, Handbook of Pharmaceutical Additives, 3rd ed., Ash and Ash Eds., Gower Publishing. Company: 2007, Pharmaceutical Preformulation and Formulation, 2nd ed., Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

[0041] The term "pharmaceutically acceptable salt" refers to a compound formulation that does not cause significant irritation to an organism to which the formulation is administered and does not neutralize the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts can be obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form a salt, such as an ammonium salt, an alkali metal salt, such as a sodium salt or a potassium salt, an alkaline earth metal salt, such as a calcium salt or a magnesium salt, an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and an amino acid, such as arginine, lysine, etc., or by other methods previously determined. The pharmacologically acceptable salt is not particularly limited, as long as it can be used in medicine. Examples of salts that the compounds described herein form with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, salts with organic bases such as methylamine, ethylamine, and ethanolamine, salts with basic amino acids such as lysine and ornithine, and ammonium salts. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0042] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0043] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as, for example, a human.

[0044] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0045] The term "oxo" refers to a double-bonded divalent oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0046] The term "hydroxyl" refers to the --OH radical.

[0047] The term "cyano" refers to the -CN radical.

[0048] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be straight or branched, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can be either unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. The term "saturated," as used in this context, means that only single bonds exist between the constituent carbon atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein. A "C0" alkyl refers to a bond; for example, phenyl-(C0 alkyl)-OH corresponds to phenol.

[0049] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with an independently selected halogen.

[0050] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0051] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic group of 6 to 20 carbon atoms in which at least one ring in the system is aromatic. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0052] The term "cycloalkyl," as used herein, refers to a cyclic hydrocarbon group having the indicated number of carbon atoms, e.g., 3 to 20 ring carbons (C3-C20), 3 to 16 ring carbons (C3-C16), 3 to 10 ring carbons (C3-C10), or 3 to 6 ring carbons (C3-C6). Cycloalkyl groups are saturated or partially unsaturated (not aromatic). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0053] The term "heteroaryl," as used herein, means a monocyclic, bicyclic, or tricyclic group having 5 to 20 ring atoms (5-20 membered heteroaryl), e.g., 5, 6, 9, 10, or 14 ring atoms, where at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S, and at least one ring in the system is aromatic (although it need not be the ring containing the heteroatom, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and pyrido[2, 3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. Heteroaryl groups can also contain imino (=NH) groups, in addition to oxidized carbon (C=O), nitrogen (NO), and / or sulfur atoms (S=O and S(=O)2). For clarity, heteroaryl also refers to aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valencies are occupied by non-hydrogen substituents), such as pyridones (e.g., [ka] ), pyrimidones (e.g., [ka] ), pyridazinones (e.g., [ka] ), pyrazinones (e.g., [ka] ), and imidazolone (e.g., [ka] ), where each ring nitrogen adjacent to the carbonyl is tertiary (i.e., the oxo group (i.e., "=O") here is part of a heteroaryl ring).

[0054] The term "heterocyclyl" refers to a monocyclic, bicyclic, or tricyclic saturated or partially unsaturated ring system having 3 to 16 ring atoms (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 14-membered tricyclic ring system), with 1 to 3 heteroatoms in the monocyclic case, 1 to 6 heteroatoms in the bicyclic case, or 1 to 9 heteroatoms in the tricyclic case. Heteroatoms are selected from the group consisting of O, N, or S (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms in the monocyclic, bicyclic, or tricyclic rings, respectively), and, where valences allow, one or more ring atoms may be substituted by 1 to 3 oxo (e.g., to form a lactam), one or more N or S atoms may be substituted by 1 to 2 oxides (e.g., to form an N-oxide, S-oxide, or S,S-dioxide), and 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyls may include multiple fused and bridged rings.Non-limiting examples of fused / bridged heterocyclyls include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo [3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are joined through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxa ... .2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like.

[0055] As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0056] The term "saturated" as used in this context means that there are only single bonds between the constituent atoms.

[0057] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (e.g., one or more double or triple bonds between constituent ring atoms in addition to the unsaturation due to the ring itself), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0058] For the avoidance of doubt, and unless otherwise specified, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic ring systems), such rings and cyclic groups are intended to be construed as meaning that the points of fusion are (i) located on adjacent ring atoms (e.g., [xx0] ring systems (where 0 represents a zero atom bridge) (e.g., [ka] )), (ii) located on a single ring atom (spiro-fused ring systems) (e.g., [ka] ), or (iii) located on a series of consecutive ring atoms (bridged ring systems with a total bridge length >0) (e.g., [ka] ) are understood to include those having fused rings.

[0059] Additionally, atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 Contains C.

[0060] Additionally, compounds generally or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: [ka] Compounds containing the moiety: [ka] Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxyl include pyridone or pyrimidone tautomeric forms.

[0061] Dashed lines in chemical structures, e.g. [ka] represents a single or double bond. Those skilled in the art will recognize this structure [ka] For example, it is understood that the maximum number of double bonds in

[0062] Compounds of formula (I) Substituents used in this section (e.g., R 1 , R 2 etc.) refers only to groups of formula (I).

[0063] Some embodiments are of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each dashed line represents a single or double bond; X 1 is CR 1 or N, X 2 is CR 2 , C(=O), or N; X 3 is C or N, except that X 2 If is C(=O), X 3 is N, X 4 is CH or N, Ring A is phenyl or 5- to 6-membered heteroaryl; R 1 is hydrogen, halogen, cyano, 3- to 10-membered heterocyclyl, -C(=O)C1-C6 alkyl, or -C(=O)ORA C1-C6 alkyl optionally substituted with 3-6 membered heterocyclyl optionally substituted with C1-C6 alkoxy, -C(=O)-3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, or -OR B and R B is a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, a C-C aryl, or a C-C cycloalkyl, each of which is selected from 1 to 3 independently selected halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, cyano, hydroxy, —C(═O)OH, —C(═O)C-C alkyl, —S(O)—C-C alkyl, or —NR C R D optionally replaced by R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)-3- to 6-membered heterocyclyl, -NH-C3-C6 cycloalkyl-C(=O)OR A or -O-C3-C6 cycloalkyl-C(=O)OR A and R 3 is hydrogen, halogen, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, -XR G ,or [ka] and R 4 is hydrogen or C1-C6 alkyl, R 5 is hydrogen, C1-C6 alkyl optionally substituted with 3- to 6-membered heterocyclyl, -XR E , -C3-C6 cycloalkyl-C(=O)OR A ,or [ka] or R 5and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A together form (i) a C6-C10 aryl optionally substituted with a 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or -C(=O)OR', (ii) a 3-6 membered heterocyclyl, or (iii) a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, a 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(=O)OR', and a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; R E is a 3- to 10-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each of which is selected from 1 to 4 independently selected C1-C6 alkoxy, NR I R J or C1-C6 alkyl optionally substituted with -C(=O)OH; R F is a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each optionally substituted with C1-C6 alkyl, or a C2-C6 alkynyl optionally substituted with hydroxy; R G is a 3- to 6-membered heterocyclyl or C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected C1-C6 alkyl, —C(═O)C1-C6 alkyl, —C(═O)OH, or NR C R D optionally replaced by R H is C1-C6 alkyl optionally substituted with hydroxy or 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; X is -NH-, -NH(C=O)-, -NHC(=O)O-, -O-, -(C=O)- or CH2; Each R A , R C , R D , R I , and R J are independently selected from hydrogen and C1-C6 alkyl; m is 0, 1, or 2.

[0064] In some embodiments, X 1 , X 2 , X 3 , X 4 One of them is N and the other is X 1 , X 2 , X 3 , X 4 The remaining groups are C, C(=O), CH, and CR. 1 or CR 2 are independently selected from

[0065] In some embodiments, X 1 is N and X 2 is CR 2 and X 3 is C and X 4 is CH.

[0066] In some embodiments, X 2 is N and X 1 is CR 1 and X 3 is C and X 4 is CH.

[0067] In some embodiments, X 3 is N and X 1 is CR 1 and X 2 is C(=O) and X 4 is CH.

[0068] In some embodiments, X 4 is N and X 1 is CR 1 and X 2 is CR 2 and X 3 is C.

[0069] In some embodiments, X 1 , X 2 , X 3 , X 4 Each of these is C, C(=O), CH, CR 1 or CR 2 are independently selected from

[0070] In some embodiments, ring A is a 5-membered heteroaryl.

[0071] In some embodiments, ring A is [ka] where aa is X 3 represents the point of attachment to X, each dashed bond is independently a single or double bond, and X 5 , X 6 , X 7 , X 8 and X 9 are independently selected from C, (C═O), C═NH, CH, N, O, or S.

[0072] In some embodiments, Ring A is selected from the group consisting of thiazolyene, oxazolyene, imidazolyene, pyrazolyene, 1,2,4-triazolyene, 1,2,4-oxadiazolylene, and 2-imine-thiazolylene.

[0073] In some embodiments, ring A is [ka] each of which is selected from the group consisting of one or two R 5 and aa is X 3 The other wavy lines represent the bond points with R. 5 Represents the point of attachment to

[0074] In some embodiments, ring A is a 6-membered heteroaryl.

[0075] In some embodiments, ring A is [ka] wherein aa represents the point of attachment to X3.

[0076] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is cyano. In some embodiments, R 1 is halo (e.g., Cl or F). In some embodiments, R 1 is a 3- to 10-membered heterocyclyl. In some embodiments, R 1 is a 4- to 6-membered heterocyclyl. In some embodiments, R 1 is 7-10 membered heterocyclyl. In some embodiments, R 1 teeth, [ka] is.

[0077] In some embodiments, R 1 is -C(=O)C1-C6 alkyl or -C(=O)OR A In some embodiments, R is C1-C6 alkyl optionally substituted with 3-6 membered heterocyclyl optionally substituted with 1 is -C(=O)C1-C6 alkyl or -C(=O)OR A In some embodiments, R is a C1-C6 alkyl substituted with a 3-6 membered heterocyclyl optionally substituted with 1 is -C(=O)C1-C6 alkyl or -C(=O)OR A In some embodiments, R is a C1-C6 alkyl substituted with a 3-6 membered heterocyclyl substituted with R 1 is a C1-C6 alkyl substituted with a 3-6 membered heterocyclyl. 1is C1-C6 alkyl (ie, unsubstituted C1-C6 alkyl).

[0078] In some embodiments, heterocyclyl is piperidinylene, piperidinyl, piperizinylene, or piperizinyl.

[0079] In some embodiments, R 1 teeth, [ka] where the wavy line represents X 1 Represents the point of attachment to

[0080] In some embodiments, R 1 is -C(=O)-3- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0081] In some embodiments, R 1 teeth, [ka] is.

[0082] In some embodiments, R 1 -OR B is.

[0083] R 1 but, [ka] 31. The compound of claim 30 selected from the group consisting of:

[0084] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halogen (e.g., F, Cl). In some embodiments, R 2is C1-C6 alkyl (e.g., methyl). In some embodiments, R 2 is C1-C6 alkoxy (for example, methoxy, ethoxy).

[0085] In some embodiments, R 2 is -C(=O)-3 to 6-membered heterocyclyl.

[0086] In some embodiments, R 2 is -NH-C3-C6 cycloalkyl-C(=O)OR A is.

[0087] In some embodiments, R 2 is -O-C3-C6 cycloalkyl-C(=O)OR A is.

[0088] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is halogen (e.g., F or Cl). In some embodiments, R 3 is fluoro. In some embodiments, R 3 is chloro. In some embodiments, R 3 is cyano.

[0089] In some embodiments, R 3 is C1-C6 alkyl (for example, methyl, ethyl).

[0090] In some embodiments, R 3 is halogen or C1-C6 alkyl.

[0091] In some embodiments, R 3 is fluoro, chloro, or methyl.

[0092] In some embodiments, R 3 is C3-C6 cycloalkyl (for example, cyclopropyl).

[0093] In some embodiments, R 3 Ha-XR G wherein X is —NH—, —NHC(═O)O—, —O—, or CH2.

[0094] In some embodiments, R 3 teeth, [ka] The structure is selected from a list consisting of:

[0095] In some embodiments, R 3 teeth, [ka] is.

[0096] In some embodiments, R 3 teeth, [ka] is selected from the group consisting of:

[0097] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl (for example, methyl, ethyl).

[0098] In some embodiments, m is 0. In some embodiments, m is 1 or 2. In some embodiments, m is 1.

[0099] In some embodiments, R 5 is hydrogen.

[0100] In some embodiments, R 5 is C1-C6 alkyl optionally substituted with 3-6 membered heterocyclyl. In some embodiments, R 5is a C1-C6 alkyl substituted with a 3-6 membered heterocyclyl. 5 is C1-C6 alkyl (for example, methyl, ethyl).

[0101] In some embodiments, the heterocyclyl group is morpholinyl (e.g., [ka] In the formula, the wavy line represents the point of attachment to the C1 to C6 alkyl group.

[0102] In some embodiments, R 5 teeth, [ka] is.

[0103] In some embodiments, R 5 -XR E is.

[0104] In some embodiments, R 5 is -(NH)(C=O)R E , -(NH)(C=O)OR E , -NH-R E , or -(C=O)R E -It is.

[0105] In some embodiments, R 5 is -(NH)(C=O)R E In some embodiments, R 5 is -(NH)(C=O)OR E In some embodiments, R 5 is -NH-R E In some embodiments, R 5 is -(C=O)R E -It is.

[0106] In some embodiments, R 5 teeth, [ka] is selected from the group consisting of:

[0107] In some embodiments, R 5 teeth, [ka] is.

[0108] In some embodiments, R 5 teeth, [ka] is.

[0109] In some embodiments, R 5 teeth, [ka] is.

[0110] In some embodiments, R 5 is -C3~C6 cycloalkyl-C(=O)OR A is.

[0111] In some embodiments, R 5 teeth, [ka] is.

[0112] In some embodiments, R 5 teeth, [ka] is.

[0113] In some embodiments, R F is a 3-6 membered heterocyclyl optionally substituted with C2-C6 alkynyl. In some embodiments, R Fis a 3-6 membered heterocyclyl substituted with a C2-C6 alkynyl.

[0114] In some embodiments, R 5 teeth, [ka] is selected from the group consisting of:

[0115] In some embodiments, R F is a C2-C6 alkynyl optionally substituted with hydroxy. In some embodiments, R F is a C2-C6 alkynyl substituted with hydroxy.

[0116] In some embodiments, R 5 teeth, [ka] is.

[0117] In some embodiments, R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A together form (i) a C6-C10 aryl optionally substituted with a 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or -C(=O)OR', (ii) a 3-6 membered heterocyclyl, or (iii) a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, a 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(=O)OR', and a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0118] In some embodiments, R 5and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A together form a C6-C10 aryl (e.g., phenyl) optionally substituted with 1 to 2 independently selected C1-C6 alkyl or 3 to 10 membered heterocyclyl optionally substituted with -C(=O)OR'.

[0119] In some embodiments, R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A together form a phenyl ring (e.g., [ka] wherein the wavy line represents the point of attachment to ring A), which is optionally further substituted with 1 to 2 independently selected C1-C6 alkyl or 3 to 10 membered heterocyclyl optionally substituted with -C(=O)OR'.

[0120] In some embodiments, R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A are both [ka] wherein the wavy line represents the point of attachment to ring A.

[0121] In some embodiments, R 5and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A together form a 3- to 6-membered heterocyclyl.

[0122] In some embodiments, R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A together form a pyrrolidine ring (e.g., [ka] wherein the wavy line represents the point of attachment to ring A).

[0123] In some embodiments, R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A form a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3- to 10-membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(=O)OR', and 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl.

[0124] In some embodiments, R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A are both [ka] and forming a ring structure selected from the list of structures consisting of: each of which is optionally substituted with 1 to 2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3- to 10-membered heterocyclyl optionally substituted with 1 to 2 independently selected C1-C6 alkyl or C(=O)OR', and 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, and the wavy line indicates the point of attachment to ring A.

[0125] In some embodiments, R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with the adjacent carbon atom or nitrogen atom, R 5 and two adjacent carbon atoms and / or nitrogen atoms in ring A are both [ka] wherein the wavy line represents the point of attachment to ring A.

[0126] In some embodiments, R E is 1 to 4 independently selected C1-C6 alkoxy, NR I R J or a 3-10 membered heterocyclyl optionally substituted with C1-C6 alkyl optionally substituted with -C(=O)OH. In some embodiments, R E is a 3-10 membered heterocyclyl optionally substituted with 1-4 independently selected C1-C6 alkyl. In some embodiments, R E is pyridone optionally substituted with 1 to 4 independently selected C1-C6 alkyl. In some embodiments, R E is tetrahydropyran optionally substituted with 1 to 4 independently selected C1-C6 alkyl. In some embodiments, R Eis tetrahydro-2H-thiopyran 1,1-dioxide optionally substituted with 1 to 4 independently selected C1-C6 alkyl.

[0127] In some embodiments, R E is 1 to 4 independently selected C1-C6 alkoxy, NR I R J or a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl optionally substituted with -C(=O)OH.

[0128] In some embodiments, R E is 1 to 4 independently selected C1-C6 alkoxy, NR I R J or C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with -C(=O)OH.

[0129] In some embodiments, the compound is a compound of formula (I-1). [ka]

[0130] In some embodiments, the compound is a compound of formula (I-2). [ka]

[0131] In some embodiments, the compound is a compound of formula (I-3). [ka]

[0132] In some embodiments, the compound is a compound of formula (I-4). [ka]

[0133] In some embodiments, the compound is a compound of formula (I-5). [ka]

[0134] In some embodiments, the compound is a compound of formula (I-6). [ka]

[0135] In some embodiments, the compound is a compound of formula (I-7). [ka]

[0136] In some embodiments, the compound is a compound of formula (I-8). [ka]

[0137] In some embodiments, the compound is a compound of formula (I-9). [ka]

[0138] In some embodiments, the compound is a compound of formula (I-10). [ka]

[0139] In some embodiments, the compound is a compound of formula (I-11). [ka]

[0140] In some embodiments, the compound is a compound of formula (I-12). [ka]

[0141] In some embodiments, the compound is a compound of formula (I-13). [ka]

[0142] In some embodiments, the compound is a compound of formula (I-14). [ka]

[0143] In some embodiments, the compound is a compound of formula (I-15). [ka]

[0144] In some embodiments, the compound is a compound of formula (I-16). [ka]

[0145] In some embodiments, the compound is a compound of formula (I-17). [ka]

[0146] In some embodiments, the compound is a compound of formula (I-18). [ka]

[0147] In some embodiments, the compound is a compound of formula (I-19). [ka]

[0148] In some embodiments, the compound is a compound of formula (I-20). [ka]

[0149] In some embodiments, the compound is a compound of formula (I-21). [ka]

[0150] In some embodiments, the compound of formula (I) is selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0151] Compound of formula (II) Substituents used in this section (e.g., R 1 , R 2 etc.) refers only to the group of formula (II).

[0152] Some embodiments are of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- to 14-membered heteroaryl or a 5- to 14-membered heterocyclyl; Each R 1 are independently halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)OR A , -NR B R C , and -C(=O)NR B R C and Each R 2 are independently -C(=O)OR D, C1-C6 alkyl, C2-C6 alkynyl optionally substituted with 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl, -C(=O)-phenyl, -(C1-C6 alkyl)-phenyl, -(C1-C6 alkyl)-4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or -CO2C1-C6 alkyl, phenyl optionally substituted with cyano or fluoro, -NHC(=O)R E , 5-6 membered heteroaryl optionally substituted with C1-C6 alkoxy; m is 1, 2, or 3; n is 0, 1, 2, or 3; Each R A , R B , R C , and R D are independently hydrogen or C1-C6 alkyl, Each R E is independently C3-C6 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0153] In some embodiments, ring A is a monocyclic heteroaryl or a monocyclic heterocyclyl. In some embodiments, ring A is a monocyclic heteroaryl. In some embodiments, ring A is a monocyclic heterocyclyl.

[0154] In some embodiments, ring A is a 5-6 membered heteroaryl. In some embodiments, ring A is a 5 membered heteroaryl. In some embodiments, ring A is thiazole or pyrazole. In some embodiments, ring A is [ka] In some embodiments, ring A is a 6-membered heteroaryl. In some embodiments, ring A is pyridine or pyrimidin-4(3H)-one. In some embodiments, ring A is [ka] is.

[0155] In some embodiments, ring A is a bicyclic heteroaryl or bicyclic heterocyclyl. In some embodiments, ring A is a bicyclic heterocyclyl. In some embodiments, ring A is a bicyclic heteroaryl. In some embodiments, ring A is an 8-12 membered bicyclic heteroaryl or a bicyclic 8-12 membered heterocyclyl. In some embodiments, ring A is an 8-12 membered bicyclic heteroaryl. In some embodiments, ring A is a bicyclic 8-12 membered heterocyclyl.

[0156] In some embodiments, ring A is a bicyclic 9-10 membered heteroaryl or a bicyclic 9-10 membered heterocyclyl. In some embodiments, ring A is a 9-membered bicyclic heteroaryl. In some embodiments, ring A is pyrazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, pyrrolo[1,2-a]pyrazin-1(2H)-one, pyrazolo[1,5-a]pyrazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, or 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one. In some embodiments, ring A is [ka] is.

[0157] In some embodiments, ring A is a bicyclic 9-membered heterocyclyl. In some embodiments, ring A is 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, or 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. In some embodiments, ring A is [ka] is.

[0158] In some embodiments, ring A is a tricyclic heteroaryl or tricyclic heterocyclyl. In some embodiments, ring A is a tricyclic heteroaryl. In some embodiments, ring A is a tricyclic heterocyclyl. In some embodiments, ring A is a 10-14 membered tricyclic heteroaryl or a 10-14 membered tricyclic heterocyclyl. In some embodiments, ring A is a 10-14 membered tricyclic heteroaryl. In some embodiments, ring A is a 10-14 membered tricyclic heterocyclyl. In some embodiments, ring A is an 11-13 membered tricyclic heteroaryl or an 11-13 membered tricyclic heterocyclyl. In some embodiments, ring A is an 11-13 membered tricyclic heteroaryl. In some embodiments, ring A is an 11-13 membered tricyclic heterocyclyl. In some embodiments, ring A is a 11-13 membered tricyclic heteroaryl. In some embodiments, ring A is an 11-13 membered tricyclic heterocyclyl. In some embodiments, ring A is a 12 membered tricyclic heteroaryl. In some embodiments, ring A is 8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine. [ka] In some embodiments, ring A is a 12-membered tricyclic heterocyclyl. In some embodiments, ring A is 7,8,9,10-tetrahydro-pyrazolo[5,1-f][1,6]naphthyridine or 7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine. In some embodiments, ring A is [ka] is.

[0159] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0160] In some embodiments, R 1 is halogen. In some embodiments, R 1 is fluoro. In some embodiments, R1 is chloro. In some embodiments, R 1 is hydroxyl. In some embodiments, R 1 is cyano.

[0161] In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C1-C3 alkyl. In some embodiments, R 1 is methyl.

[0162] In some embodiments, R 1 is C1-C6 alkoxy. In some embodiments, R 1 is C1-C3 alkoxy. In some embodiments, R 1 is methoxy.

[0163] In some embodiments, R 1 is -C(=O)OR A In some embodiments, R 1 is -C(=O)OH, -C(=O)OCH2CH3, or -C(=O)OC(CH3)3.

[0164] In some embodiments, R 1 is -NR B R C In some embodiments, R1 is -NH2, -NHCH3, or -NH(CH3)2.

[0165] In some embodiments, R 1 is -C(=O)NR B R C In some embodiments, R 1 is -C(=O)NH2, or -C(=O)NHCH3.

[0166] In some embodiments, R 1 one of which is C1-C6 alkyl and the other R 1 is -C(=O)OR AIn some embodiments, R 1 one of which is C1-C6 alkyl and the other R 1 is —C(═O)OH or —C(═O)OCH. In some embodiments, R 1 One of the R 1 is -C(=O)OH or -C(=O)OCH3).

[0167] In some embodiments, R 1 One of the R is cyano and the other R 1 is halogen or hydroxyl. In some embodiments, R 1 One of the R is cyano and the other R 1 is C1-C6 alkoxy. In some embodiments, R 1 One of the R is cyano and the other R 1 is -OCH(CH3)2).

[0168] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2. In some embodiments, n is 3.

[0169] In some embodiments, R 2 is -C(=O)OR D In some embodiments, R 2 is -C(=O)OCH(CH3)3.

[0170] In some embodiments, R 2 is a C1-C6 alkyl.

[0171] In some embodiments, R 2 is C2-C6 alkynyl optionally substituted with 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R 2is a C2-C6 alkynyl substituted with a 4-8 membered heterocyclyl optionally substituted with a C1-C6 alkyl. 2 is a C2-C6 alkynyl substituted with a 4-8 membered heterocyclyl substituted with a C1-C6 alkyl. 2 is a C2-C6 alkynyl substituted with an unsubstituted 4-8 membered heterocyclyl. 2 is unsubstituted C2-C6 alkynyl.

[0172] In some embodiments, R 2 teeth, [ka] is.

[0173] In some embodiments, R 2 is -C(=O)-phenyl.

[0174] In some embodiments, R 2 is -(C1-C6 alkyl)-phenyl. In some embodiments, R 2 teeth, [ka] is.

[0175] In some embodiments, R 2 is -(C1-C6 alkyl)-4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R 2 is -(C1-C6 alkyl)-4-10 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R 2 is -(C1-C6 alkyl)-4-10 membered heterocyclyl substituted with methyl. In some embodiments, R 2 is -(C1-C6 alkyl)-4 to 10-membered heterocyclyl.

[0176] In some embodiments, R 2 is -(C1-C3 alkyl)-4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R 2 is -(C1-C3 alkyl)-4-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R 2 is -(C1-C3 alkyl)-4-6 membered heterocyclyl substituted with methyl. In some embodiments, R 2 is -(C1-C3 alkyl)-4-6 membered heterocyclyl.

[0177] In some embodiments, R 2 teeth, [ka] is.

[0178] In some embodiments, R 2 is a 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or -CO2C1-C6 alkyl. In some embodiments, R 2 is a 4-10 membered heterocyclyl substituted with C1-C6 alkyl or -CO2C1-C6 alkyl. In some embodiments, R 2 is a 4-10 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R 2 is a 4-10 membered heterocyclyl substituted with methyl. In some embodiments, R 2 is a 4-10 membered heterocyclyl substituted with -CO2C1-C6 alkyl. In some embodiments, R 2 is a 4-10 membered heterocyclyl substituted with -CO2CH3. In some embodiments, R 2 is an unsubstituted 4-10 membered heterocyclyl.

[0179] In some embodiments, R 2 teeth, [ka] is.

[0180] In some embodiments, R 2 is phenyl optionally substituted with cyano or fluoro. In some embodiments, R 2 is phenyl substituted with cyano or fluoro. In some embodiments, R 2 is phenyl substituted with cyano. In some embodiments, R 2 is phenyl substituted with fluoro.

[0181] In some embodiments, R 2 teeth, [ka] is.

[0182] In some embodiments, R 2 is -NHC(=O)R E is.

[0183] In some embodiments, R 2 teeth, [ka] is.

[0184] In some embodiments, R 2 is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkoxy. In some embodiments, R 2 is a 5-6 membered heteroaryl substituted with C1-C6 alkoxy. In some embodiments, R 2 is a 5-6 membered heteroaryl substituted with methoxy or ethoxy. In some embodiments, R 2 is an unsubstituted 5-6 membered heteroaryl.

[0185] In some embodiments, R 2 teeth, [ka] is.

[0186] In some embodiments, R A is hydrogen or C1-C6 alkyl. In some embodiments, R A is hydrogen or methyl. In some embodiments, R A is hydrogen. In some embodiments, R A is C1-C6 alkyl. In some embodiments, R A is methyl. In some embodiments, R B is hydrogen or C1-C6 alkyl. In some embodiments, R B is hydrogen or methyl. In some embodiments, R B is hydrogen. In some embodiments, R B is C1-C6 alkyl. In some embodiments, R B is methyl.

[0187] In some embodiments, R A and R B and are the same. In some embodiments, R A and R B In some embodiments, R A and R B One of the groups is hydrogen, and R A and R B and the other is C1-C6 alkyl. In some embodiments, R A and R B One of the groups is hydrogen, and R A and R B and the other is methyl. In some embodiments, R A and R B are each hydrogen. In some embodiments, R A and R B are each C1-C6 alkyl. In some embodiments, R A and R B are each methyl.

[0188] In some embodiments, R C is hydrogen or C1-C6 alkyl. In some embodiments, R C is hydrogen or methyl. In some embodiments, R C is hydrogen. In some embodiments, R C is C1-C6 alkyl. In some embodiments, R C is methyl. In some embodiments, R D is hydrogen or C1-C6 alkyl. In some embodiments, R D is hydrogen or methyl. In some embodiments, R D is hydrogen. In some embodiments, R D is C1-C6 alkyl. In some embodiments, R D is methyl.

[0189] In some embodiments, R C and R D and are the same. In some embodiments, R C and R D In some embodiments, R C and R D One of the groups is hydrogen, and R C and R D and the other is C1-C6 alkyl. In some embodiments, R C and R D One of the groups is hydrogen, and R C and R D and the other is methyl. In some embodiments, R C and R D are each hydrogen. In some embodiments, R C and R D are each C1-C6 alkyl. In some embodiments, R C and R D are each methyl.

[0190] In some embodiments, R E is a C3-C6 cycloalkyl.

[0191] In some embodiments, R E is a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R E is a 4-8 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R E is a 4-8 membered heterocyclyl substituted with methyl. In some embodiments, R E is an unsubstituted 4-8 membered heterocyclyl.

[0192] In some embodiments, R E is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl. In some embodiments, R E is a 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, R E is a 5-6 membered heteroaryl substituted with methyl. In some embodiments, R E is an unsubstituted 5-6 membered heteroaryl.

[0193] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-1), or a pharmaceutically acceptable salt thereof: [ka]

[0194] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-1-i), or a pharmaceutically acceptable salt thereof: [ka]

[0195] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-1-ii), or a pharmaceutically acceptable salt thereof: [ka]

[0196] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-1-iii), or a pharmaceutically acceptable salt thereof: [ka]

[0197] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-1-iv), or a pharmaceutically acceptable salt thereof: [ka]

[0198] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-2), or a pharmaceutically acceptable salt thereof: [ka]

[0199] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-3), or a pharmaceutically acceptable salt thereof: [ka]

[0200] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-4), or a pharmaceutically acceptable salt thereof: [ka]

[0201] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-5), or a pharmaceutically acceptable salt thereof: [ka]

[0202] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt thereof, is a compound of formula (II-6), or a pharmaceutically acceptable salt thereof: [ka]

[0203] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-7), or a pharmaceutically acceptable salt thereof: [ka]

[0204] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-8), or a pharmaceutically acceptable salt thereof: [ka]

[0205] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-9), or a pharmaceutically acceptable salt thereof: [ka]

[0206] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-10), or a pharmaceutically acceptable salt thereof: [ka]

[0207] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-11), or a pharmaceutically acceptable salt thereof: [ka]

[0208] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-12), or a pharmaceutically acceptable salt thereof: [ka]

[0209] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-13), or a pharmaceutically acceptable salt thereof: [ka]

[0210] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-14), or a pharmaceutically acceptable salt thereof: [ka]

[0211] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-15), or a pharmaceutically acceptable salt thereof: [ka]

[0212] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-16), or a pharmaceutically acceptable salt thereof: [ka]

[0213] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-17), or a pharmaceutically acceptable salt thereof: [ka]

[0214] In some embodiments, the compound of formula (II) is selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10]

[0215] Compound of formula (III) Substituents used in this section (e.g., R 1 , R 2 etc.) refers only to groups of formula (III).

[0216] Some embodiments are of formula (III): [ka] or a pharmaceutically acceptable salt thereof, Ring A is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R 1 is -NHC(=O)(C1-C6 alkylene) n R A , -NR F R G phenyl optionally substituted with -QR C ,or [ka] and R 2 -CO2R B C3-C6 cycloalkyl optionally substituted with, 5-10 membered heteroaryloxy, C1-C6 alkyl, cyano, or -(C1-C6 alkylene) optionally substituted with, 4-6 membered heterocyclyl p -5-10 membered heteroaryl, cyano or -NR D R E -(C1-C6 alkylene) optionally substituted with t -phenyl, 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; R 3 is a C1-C6 alkyl, R A is a 4- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, or a 5- to 10-membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl; R Bis hydrogen or C1-C6 alkyl, R C is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, or -(C1-C6 alkylene)-NR D R E is phenyl optionally substituted with R D , R E , and R F are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R G is hydrogen, C1-C6 alkyl, —C(═O)—C1-C6 alkyl, or —C(═O)—C3-C6 cycloalkyl; R H is a 4- to 6-membered heterocyclyl optionally substituted with 1 to 2 independently selected C1-C6 alkyl; Q is C1-C6 alkylene, NH, or O; m is 0 or 1, n is 0 or 1, p is 0 or 1, t is 0 or 1.

[0217] In some embodiments, R 1 is -NHC(=O)(C1-C6 alkylene) n R A In some embodiments, R 1 is -NHC(=O)(C1-C2 alkylene) n R A In some embodiments, R 1 is -NHC(=O)R A is.

[0218] In some embodiments, n is 1. In some embodiments, n is 0.

[0219] In some embodiments, R A is a 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R Ais a 4-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R A is oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, or morpholinyl, each optionally substituted with C1-C6 alkyl. A is piperidinyl, tetrahydropyranyl, or tetrahydrofuranyl, each optionally substituted with C1-C6 alkyl. A is oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with C1-C6 alkyl. A is oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, each substituted with C1-C6 alkyl. A is an unsubstituted 4- to 6-membered heterocyclyl.

[0220] In some embodiments, R A is a 5-10 membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl. In some embodiments, R A is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl. In some embodiments, R A is a 5-10 membered heteroaryl substituted with C1-C6 alkoxy or C1-C6 alkyl. In some embodiments, R A is a 5-6 membered heteroaryl substituted with C1-C6 alkoxy or C1-C6 alkyl. In some embodiments, R A is a 5-10 membered heteroaryl substituted with C1-C6 alkoxy. In some embodiments, R A is a 5-10 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, R Ais a 5-6 membered heteroaryl substituted with C1-C6 alkoxy. In some embodiments, R A is a 5-6 membered heteroaryl substituted with C1-C6 alkyl. In some embodiments, R A is pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted with C1-C6 alkoxy or C1-C6 alkyl. A is an unsubstituted 5-6 membered heteroaryl.

[0221] In some embodiments, R A teeth, [ka] is selected from the group consisting of:

[0222] In some embodiments, R 1 is -NR F R G In some embodiments, R 1 is -NR F R G is a phenyl substituted with

[0223] In some embodiments, R F is C1-C6 alkyl. In some embodiments, R F is methyl. In some embodiments, R F is C-C cycloalkyl. In some embodiments, R F is hydrogen.

[0224] In some embodiments, R G is C1-C6 alkyl. In some embodiments, R G is methyl. In some embodiments, R G is —C(═O)—C1-C6 alkyl. In some embodiments, R G is —C(═O)CH. In some embodiments, RG is —C(═O)—C-C cycloalkyl. In some embodiments, R G is hydrogen.

[0225] In some embodiments, R F and R G and are the same. In some embodiments, R F and R G In some embodiments, R F and R G are each hydrogen. In some embodiments, R F and R G are each methyl. In some embodiments, R F is hydrogen and R G is C1-C6 alkyl. In some embodiments, R F is hydrogen and R G is —C(═O)—C1 to C6 alkyl.

[0226] In some embodiments, R 1 is -QR C In some embodiments, Q is C1-C6 alkylene. In some embodiments, Q is C1-C2 alkylene. In some embodiments, Q is methylene. In some embodiments, Q is NH. In some embodiments, Q is O.

[0227] In some embodiments, R C is -(C1-C6 alkylene)-NR D R E In some embodiments, R is a 4- to 10-membered heterocyclyl optionally substituted with C is an unsubstituted 4-10 membered heterocyclyl.

[0228] In some embodiments, R C is -(C1-C6 alkylene)-NR D R E is a 5- to 10-membered heteroaryl optionally substituted with

[0229] In some embodiments, R C is -(C1-C6 alkylene)-NR D R E is phenyl optionally substituted with

[0230] In some embodiments, R 1 teeth, [ka] is.

[0231] In some embodiments, R 1 teeth, [ka] is.

[0232] In some embodiments, R H is a 4-6 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl. In some embodiments, R H is a 4-6 membered heterocyclyl substituted with 1-2 independently selected C1-C6 alkyl. In some embodiments, R H is a 4-6 membered heterocyclyl substituted with one C1-C6 alkyl. In some embodiments, R H is a 4-6 membered heterocyclyl substituted with methyl. In some embodiments, R H is a 4-6 membered heterocyclyl substituted with two independently selected C1-C6 alkyls. In some embodiments, R H is a 4-6 membered heterocyclyl substituted with two methyls. In some embodiments, R H is oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1-2 independently selected C1-C6 alkyl. H is an unsubstituted 4- to 6-membered heterocyclyl.

[0233] In some embodiments, R 2 -CO2R B In some embodiments, R 2 -CO2R B In some embodiments, R 2 is an unsubstituted C3-C6 cycloalkyl.

[0234] In some embodiments, R B is C1-C6 alkyl. In some embodiments, R B is methyl. In some embodiments, R B is hydrogen.

[0235] In some embodiments, R 2 is a 5- to 10-membered heteroaryloxy. In some embodiments, R 2 is a 5-6 membered heteroaryloxy. In some embodiments, R 2 is a 9- to 10-membered heteroaryloxy.

[0236] In some embodiments, R 2 is -(C1-C6 alkylene) optionally substituted with C1-C6 alkyl, cyano, or 4- to 6-membered heterocyclyl; p -5-10 membered heteroaryl. In some embodiments, R 2 is -(C1-C6 alkylene) substituted with C1-C6 alkyl, cyano, or 4- to 6-membered heterocyclyl p -5-10 membered heteroaryl. In some embodiments, R 2 is -(C1-C6 alkylene) substituted with C1-C6 alkyl p -5-10 membered heteroaryl. In some embodiments, R 2 is -(C1-C6 alkylene) substituted with methyl p -5-10 membered heteroaryl. In some embodiments, R 2 is a cyano-substituted -(C1-C6 alkylene)p -5-10 membered heteroaryl. In some embodiments, R 2 is a 4- to 6-membered heterocyclyl-substituted -(C1-C6 alkylene) p -5-10 membered heteroaryl. In some embodiments, R 2 is a 5- to 10-membered heteroaryl substituted with a 4- to 6-membered heterocyclyl. 2 -(C1-C6 alkylene) substituted with oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl p -5-10 membered heteroaryl. In some embodiments, R 2 is a 5-10 membered heteroaryl substituted with oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl. 2 is a 5-10 membered heteroaryl substituted with morpholinyl. In some embodiments, R 2 is unsubstituted -(C1-C6 alkylene) p -5 to 10-membered heteroaryl.

[0237] In some embodiments, p is 1. In some embodiments, p is 0.

[0238] In some embodiments, R 2 is cyano or -NR D R E -(C1-C6 alkylene) optionally substituted with t In some embodiments, R 2 is cyano or -NR D R E -(C1-C6 alkylene) substituted with t In some embodiments, R 2 is -NR D R E -(C1-C6 alkylene) substituted with t -phenyl.

[0239] In some embodiments, R D is C1-C6 alkyl. In some embodiments, R D is methyl. In some embodiments, R D is C-C cycloalkyl. In some embodiments, R D is hydrogen. In some embodiments, R E is C1-C6 alkyl. In some embodiments, R E is methyl. In some embodiments, R E is C-C cycloalkyl. In some embodiments, R E is hydrogen.

[0240] In some embodiments, t is 1. In some embodiments, t is 0.

[0241] In some embodiments, R 2 is a 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R 2 is a 4-6 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R 2 is a 4-6 membered heterocyclyl substituted with methyl. In some embodiments, R 2 is oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with C1-C6 alkyl.

[0242] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0243] In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is methyl.

[0244] In some embodiments, R C is a 4- to 10-membered heterocyclyl. In some embodiments, R C is a 4- to 6-membered heterocyclyl.

[0245] In some embodiments, R C is a 5-10 membered heteroaryl. In some embodiments, R C is a 5- to 6-membered heteroaryl.

[0246] In some embodiments, R C is -(C1-C6 alkylene)-NR D R E In some embodiments, R C is -(C1-C6 alkylene)-NR D R E In some embodiments, R C is -(C1-C2 alkylene)-NR D R E In some embodiments, R C is unsubstituted phenyl.

[0247] In some embodiments, R D is C1-C6 alkyl. In some embodiments, R D is methyl. In some embodiments, R D is C-C cycloalkyl. In some embodiments, R D is hydrogen.

[0248] In some embodiments, R E is C1-C6 alkyl. In some embodiments, R E is methyl. In some embodiments, R E is C-C cycloalkyl. In some embodiments, R E is hydrogen.

[0249] In some embodiments, m is 1. In some embodiments, m is 0.

[0250] In some embodiments, ring A is a 5-6 membered heteroaryl. In some embodiments, ring A is thiazolyl, pyrazolyl, imidazolidinon-2-yl, pyridinyl, pyrimidinyl, pyridon-2-yl, pyrimidinonyl, or oxazolidinon-2-yl.

[0251] In some embodiments, ring A is [ka] is.

[0252] In some embodiments, ring A is [ka] is.

[0253] In some embodiments, ring A is [ka] is.

[0254] In some embodiments, ring A is [ka] is.

[0255] In some embodiments, ring A is [ka] is.

[0256] In some embodiments, ring A is [ka] is.

[0257] In some embodiments, ring A is [ka] is.

[0258] In some embodiments, ring A is a 5-6 membered heterocyclyl. In some embodiments, ring A is an oxazolidinone or pyrrolidinone.

[0259] In some embodiments, ring A is [ka] is.

[0260] In some embodiments, ring A is [ka] is.

[0261] In some embodiments, the compound has formula (III-1): [ka] is a compound of

[0262] In some embodiments, the compound has formula (III-2): [ka] is a compound of

[0263] In some embodiments, the compound of formula (III) is selected from the compounds in Table 3, or a pharmaceutically acceptable salt thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0264] Pharmaceutical Compositions and Administration overview In some embodiments, the compounds described herein (e.g., compounds of Formula (I), (II), or (III), and pharmaceutically acceptable salts of any of the foregoing) are administered as a pharmaceutical composition comprising the chemical compound and one or more pharmaceutically acceptable excipients. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the compounds may be administered in combination with one or more conventional pharmaceutical excipients, such as those described herein. Dosage forms or compositions may be prepared containing 0.005% to 100% of a chemical entity as described herein, with the remainder consisting of one or more pharmaceutically acceptable excipients. Contemplated compositions may contain 0.001% to 100%, e.g., 0.1% to 95%, 75% to 85%, or 20% to 80% of a compound provided herein (or a pharmaceutically acceptable salt thereof). Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art, and may be found, for example, in Remington: The Science and Practice of Pharmacy, 22 nd See, e.g., Pharmaceutical Press, London, UK, 2012.

[0266] Route of Administration and Composition Components In some embodiments, the compounds described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any recognized route of administration. Acceptable routes of administration include, but are not limited to, buccal, epidural, intracranial, intradural, intramedullary, intrameningeal, intramuscular, intraspinal, intravascular, intravenous, nasal, oral, parenteral, peridural, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, and transmucosal. In certain embodiments, the preferred route of administration is parenteral. In certain embodiments, the preferred route of administration is oral.

[0267] Composition can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular or subcutaneous route.Typically, such composition can be prepared as an injection, either as a solution or suspension, and can also be prepared in a solid form suitable for preparing solution or suspension when adding liquid before injection, and preparation can also be emulsified.The preparation of such preparations will be known to those skilled in the art in light of the present disclosure.

[0268] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions, formulations containing sesame oil, peanut oil, or aqueous propylene glycol, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In all cases, the form must be sterile and must be fluid to the extent that it can be easily injected.It must also be stable under the conditions of manufacture and storage, and must be protected from the contaminating action of microorganisms such as bacteria and fungi.

[0269] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0270] Sterile injectable solution is prepared by incorporating the required amount of active compound into a suitable solvent, which contains various other ingredients as listed above as necessary, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other necessary ingredients from those listed above.For the sterile powder that is intended to prepare sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which produces powder of active ingredient and any desired additional ingredients from the solution that has been previously sterilized and filtered.

[0271] In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for local delivery to the digestive or GI tract by oral administration (eg, in solid or liquid dosage form).

[0272] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In such solid dosage forms, the compound is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) moisturizers, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or The granules are mixed with tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar in addition to high molecular weight polyethylene glycols.

[0273] In some embodiments, the composition will be in the form of a unit dosage form such as a pill or tablet, and the composition may contain, together with the chemical compounds provided herein, diluents such as lactose, sucrose, dicalcium phosphate, lubricants such as magnesium stearate, and binders such as starch, acacia gum, polyvinylpyrrolidinone, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical compounds provided herein or additional active agents are physically separated are also contemplated, such as capsules (or tablets within capsules) containing granules of each drug, bilayer tablets, and bicompartment gel capsules. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[0274] Other physiologically acceptable compounds (i.e., excipients) include wetting agents, emulsifying agents, dispersing agents, or preservatives, which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0275] In certain embodiments, the excipients are sterile and generally free of undesirable materials. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not essential for excipients in various oral dosage forms, such as tablets and capsules. USP / NF standards are usually sufficient.

[0276] Ophthalmic compositions may include one or more of any of the following, but are not limited to: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol), stabilizers (e.g., Pluronic® (triblock copolymer), cyclodextrin), preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride, Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex, Allergan, Inc.)).

[0277] Dosage Dosages may vary depending on the requirements of the patient, the severity of the condition being treated, and the particular compound being used. Determination of the appropriate dosage for a particular situation can be determined by one of ordinary skill in the medical arts. The total daily dose may be divided and administered in portions throughout the day or by any means providing sustained delivery.

[0278] In some embodiments, the compounds described herein are administered at a dose of about 0.001 mg / kg to about 500 mg / kg (e.g., about 0.001 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 200 mg / kg, about 0.01 mg / kg to about 150 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.01 mg / kg to about 1 mg / kg). g / kg, about 0.01 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.1 mg / kg to about 150 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg).

[0279] Regimen The aforementioned dosages can be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, weekly, twice weekly, biweekly, monthly).

[0280] In some embodiments, the administration period of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period of time during which administration is suspended is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In one embodiment, a therapeutic compound is administered to an individual for a period of time, followed by another period of time. In another embodiment, a therapeutic compound is administered for a first period of time and a second period of time after the first period, administration is suspended during the second period, administration of the therapeutic compound is initiated for a third period of time, and then administration is suspended for a fourth period of time after the third period of time. In one aspect of this embodiment, the period of administration of a therapeutic compound followed by the period of time during which administration is suspended is repeated for a determined or indeterminate period of time. In further embodiments, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, administration is suspended for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0281] Treatment method Indications The present disclosure provides compounds of Formula (I), (II), or (III), and pharmaceutically acceptable salts of any of the foregoing, that inhibit dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These compounds are useful for treating neurological disorders, e.g., DYRK1A-associated neurological disorders. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

[0282] "Neurological disorder" refers to any disease or disorder of the nervous and / or visual system. "Neurological disease" or "neurological disorder" are used interchangeably herein and include diseases or disorders involving the central nervous system (CNS, e.g., brain, brainstem, and cerebellum), the peripheral nervous system (PNS, including the cranial nerves), and the autonomic nervous system (portions of which are located in both the CNS and PNS), including both structural and / or functional diseases and disorders (e.g., neurological syndromes).

[0283] Examples of neurological disorders include, but are not limited to, headache, stupor and coma, dementia, seizures, sleep disorders, trauma, infection, tumors, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of the peripheral nerves, muscles, and neuromuscular junction. Addiction and psychiatric disorders (including, but not limited to, bipolar disorder and schizophrenia) are also included within the definition of neurological disorders. The following is a list of some neurological disorders, conditions, signs, and syndromes that may be treated using the compositions and methods of the present invention: acquired epileptiform aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia: Aicardi syndrome, Alexander disease, Alpers disease, alternating hemiplegia, vascular dementia, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, angiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Anronl-Chiari malformation, and others. malformation), arteriovenous malformation, Asperger's syndrome, ataxia-telangiectasia, attention deficit hyperactivity disorder, autism, autonomic dysfunction, back pain, Batten disease, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal blepharospasm, muscular atrophy, benign intracranial hypertension, Binswanger's disease, blepharospasm: Bloch-Sulzberger syndrome, brachial plexus injury, brain abscess, brain injury, Brown-Séquard syndrome, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis: head injury, cerebral movement Aneurysms, cerebral arteriosclerosis: cerebral atrophy, cerebral gigantism, cerebral palsy, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chronic inflammatory demyelinating polyneuropathy, chronic pain, chronic regional pain syndrome, Coffin-Lowry syndrome, coma including persistent vegetative state, congenital bilateral facial palsy, corticobasal degeneration: cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disease, Cushing's syndrome, cytomegalic inclusion disease, cytomegalovirus infection, dancing eyes-dancing feet syndrome, Dandy-Walker syndrome, Dawson's disease, De Moisier's syndrome, Dejerine-Klumke palsypalsy), dementia, dermatomyositis, diabetic neuropathy, diffuse sclerosis, autonomic neuropathy, dysgraphia, dyslexia, dystonia, early infantile epileptic encephalopathy, empty sella syndrome, encephalitis, encephalocele, trigeminal region angiomatosis, epilepsy, Erb's palsy, essential tremor, Fabry's disease, Fahr's syndrome, syncope, familial spastic paraparesis, febrile seizures, Fisher's syndrome, Friedreich's ataxia, frontotemporal dementia, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell white matter dysplasia trophy, Guillain-Barré syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, head trauma, headache, hemifacial spasm, hereditary spastic paraplegia: hereditary polyneuropathic ataxia, otic varicella, herpes zoster, Hirayama syndrome, HIV-associated dementia and neuropathy (also neurological signs of AIDS), holoprosencephaly, Huntington's disease and other polyglutamine repeat diseases, hydranencephaly: hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, childhood phytanic acid storage disease, infantile spasms, Inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsboume syndrome, Klippel-Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral bulbar (Wallenberg) syndrome, learning disabilities, Leigh disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, dementia with Lewy bodies, lissencephaly, locked-in syndrome, Lewy body dementia, Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis), lumbar discopathy, Lyme disease - neurological sequelae, Machado-Joseph disease, megaloencephaly, megalencephaly, Melkerson-Rosenthal syndrome, Meniere's disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, migraine, Miller-Fisher syndrome, ministroke, mitochondrial myopathy, Moebius syndrome, unilateral muscular atrophy, motor neuron disease, moyamoya disease, mucopolysaccharidosis, multi-infarct dementiaDementia, multifocal motor neuropathy, multiple sclerosis and other demyelinating disorders, multiple system atrophy with postural hypotension, muscular dystrophy, myasthenia gravis, myelomatous diffuse sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, myotonia congenita, narcolepsy, neurofibroma, neuroleptic malignant syndrome, neurological manifestations of AIDS, neurological sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorders, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occult neuralgia, secondary to occult spinal dysraphism sequence), Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus, optic neuritis, orthostatic hypotension, overuse syndrome, paresthesia, neurodegenerative diseases or disorders (Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, multiple sclerosis, and other diseases and disorders involving neuronal cell death), congenital paramyotonia, paraneoplastic disorders, paroxysmal seizures, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralysis, peripheral neuropathy, painful neuropathy and neuropathic pain, persistent vegetative state, pervasive developmental disorder , photo-sneeze reflex, phytanic acid storage disease, Pick's disease, nerve compression, porencephaly, post-polio syndrome, post-herpetic neuralgia, post-infectious encephalomyelitis, post-orthostatic hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive facial hemiatrophy, progressive multifocal leukoencephalopathy, progressive sclerosing poliodystrophy, progressive supranuclear palsy, Ramsay-Hunt syndrome (types I and I1), Rasmussen encephalitis: reflex sympathetic dystrophy syndrome, Refsum's disease, repetitive movement disorder, repetitive stress injury, restless legs syndrome, retroviral-associated myelopathy, Rett syndrome, Reye's syndrome, chorea (Saint Vitus)dance), Sandhoff disease, Schilder's disease, schizencephaly, septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome, Sjogren's syndrome, Soto syndrome, spasticity, spina bifida, spinal cord injury, spinal muscular atrophy, stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, Sydenham chorea, syncope, syringomyelia, tardive dyskinesia, Tay-Sachs disease, temporal arteritis, tethered spinal cord syndrome, Thomsen's disease, thoracic outlet syndrome, painful tics, Todd's palsy, Tourette's syndrome, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trigeminal neuralgia, tropical spastic paraplegia; tuberous sclerosis, vascular dementia (multi-infarct dementia), vasculitis including temporal arteritis, von Hippel-Lindau disease (Von Hippel-Liodau disease, Wallenberg syndrome, Werdnig-Hoffman disease, West syndrome, Williams syndrome, Wildoris disease, and Zellweger syndrome.

[0284] In some embodiments, the neurological disease or disorder is Alzheimer's disease, Down's syndrome, Alzheimer's disease associated with Down's syndrome, Parkinson's disease, ALS, dementia, Huntington's disease, multiple sclerosis, proximal lateral sclerosis, stroke, stroke, or mild cognitive impairment.

[0285] In some embodiments, the dementia may be Alzheimer's disease, vascular dementia, head trauma dementia, multi-infarct dementia, mixed Alzheimer's disease and multi-infarct dementia, or alcoholic dementia.

[0286] The ability of a test compound to act as a DYRK1A inhibitor can be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as DYRK1A inhibitors can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine kinase inhibition. An alternative in vitro assay quantifies the ability of an inhibitor to bind to a protein kinase, which can be measured by either radiolabeling the compound before binding, isolating the compound / kinase complex, and determining the amount of bound radiolabel, or by performing a competition experiment in which a new compound is incubated with a kinase bound to a known radioligand.

[0287] The efficacy of DYRK1A inhibitors as provided herein is measured by EC 50 Value or IC 50 A lower EC value when determined under substantially similar conditions may be determined by the 50 Value or IC 50 Compounds with higher EC 50 Value or IC 50 In some embodiments, the substantially similar conditions include determining the level of DYRK1A-dependent phosphorylation in vitro or in vivo (e.g., in neural cells, such as neurons, astrocytes, oligodendrocytes, microglia, ependymal cells, Schwann cells, and satellite cells, that express wild-type DYRK1A, mutant DYRK1A, or a fragment of either thereof).

[0288] The efficacy of DYRK1A inhibitors as provided herein is measured by IC 50 A lower IC value when determined under substantially similar conditions may also be determined by the IC 50 Compounds with higher IC 50In some embodiments, the substantially similar conditions include determining the level of DYRK1A-dependent phosphorylation in vitro or in vivo (e.g., in neural cells, such as neurons, astrocytes, oligodendrocytes, microglia, ependymal cells, Schwann cells, and satellite cells, that express wild-type DYRK1A, mutant DYRK1A, or a fragment of either thereof).

[0289] As used herein, the term "treat" or "treatment" refers to a curative or palliative measure. Beneficial or desired clinical results include, but are not limited to, a total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, a decrease in the extent of the disease, a stabilized (i.e., not worsening) disease state, a delay or slowing of disease progression, an improvement or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete). Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0290] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented.

[0291] In some embodiments, the subject has been identified or diagnosed with a neuropathy involving dysregulation of the DYRK1A gene, DYRK1A protein, or either of their expression or activity or levels (a DYRK1A-associated neuropathy) (e.g., as determined using a regulatory-approved, e.g., FDA-approved, assay or kit). The subject may be positive for dysregulation of the DYRK1A gene, DYRK1A protein, or either of their expression or activity or levels (e.g., identified as positive using a regulatory-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject is suspected of having a DYRK1A-associated neuropathy. In some embodiments, the subject has medical records indicating that the subject has a neuropathy involving dysregulation of the DYRK1A gene, DYRK1A protein, or either of their expression or activity or levels (and optionally, the medical records indicate that the subject should be treated with any of the compositions provided herein).

[0292] In certain embodiments, compounds of Formula (I), (II), or (III), or pharmaceutically acceptable salts of any of the foregoing, are useful for preventing a neurological disorder as defined herein (e.g., Alzheimer's disease). The term "preventing," as used herein, means delaying the onset, recurrence, or spread, in whole or in part, of a disease or condition as described herein, or a symptom thereof.

[0293] The term "DYRK1A-associated neurological disorder," as used herein, refers to a disorder associated with or involving dysregulation of the expression, activity, or levels of the DYRK1A gene, the DYRK1A protein, or either (e.g., one or more) thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the DYRK1A gene, or the DYRK1A protein, or either (e.g., one or more) described herein). Non-limiting examples of DYRK1A-associated diseases or disorders include, for example, Down's syndrome, Alzheimer's disease, and Alzheimer's disease associated with Down's syndrome.

[0294] The phrase "dysregulation of the expression or activity or levels of the DYRK1A gene, DYRK1A protein, or either thereof" refers to increased expression (e.g., increased levels) of wild-type DYRK1A in mammalian cells (e.g., compared to control cells lacking abnormal signaling) due to gene duplication (or amplification) resulting in increased levels of DYRK1A in the cell, or mutations in regulatory sequences (e.g., promoters and / or enhancers) resulting in increased levels of DYRK1A in the cell, or abnormal cell signaling and / or dysregulated autocrine / paracrine signaling.

[0295] Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing.

[0296] In some embodiments, a method for treating a neurological disorder in a subject in need thereof comprises: (a) determining that the neurological disorder is associated with dysregulation of the expression, activity, or level of the DYRK1A gene, DYRK1A protein, or any of the foregoing; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing.

[0297] Some embodiments provide a method of treating a DYRK1A-associated neurological disorder in a subject, the method comprising administering to a subject who has been identified or diagnosed with a DYRK1A-associated neurological disorder a therapeutically effective amount of a compound of Formula (I), (II), or (III), or any pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or any pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the method of treating a DYRK1A-associated neurological disorder in a subject comprises: (a) determining that the subject's neurological disorder is a DYRK1A-associated neurological disorder; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing.

[0299] Some embodiments provide a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, to a subject having medical records indicating that the subject has dysregulation of the expression, activity, or levels of the DYRK1A gene, DYRK1A protein, or any of the foregoing.

[0300] In some embodiments, the method includes determining that the subject's neurological disorder is a DYRK1A-associated neurological disorder, and includes performing an assay to detect dysregulation of the expression or activity or level of the DYRK1A gene, DYRK1A protein, or either thereof, in the subject's sample.

[0301] Some embodiments provide methods of treating a neurological disorder in a subject in need thereof, the method comprising: (a) determining that the neurological disorder is associated with Down's syndrome; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing.

[0302] In some embodiments, the step of determining that the subject's neurological disorder is associated with Down's syndrome comprises performing an assay on a sample from the subject.

[0303] In some embodiments, the method further comprises obtaining a sample from the subject. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a cerebrospinal fluid (CSF) sample.

[0304] In some embodiments, the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0305] In some embodiments, the FISH is break-apart FISH analysis. In some embodiments, the sequencing is pyrosequencing or next-generation sequencing.

[0306] In some embodiments, the DYRK1A-associated neurological disorder is selected from the group consisting of Down's syndrome, Alzheimer's disease, and Alzheimer's disease associated with Down's syndrome, hi some embodiments, the DYRK1A-associated neurological disorder is Alzheimer's disease associated with Down's syndrome.

[0307] In some embodiments, the method further comprises administering to the subject an additional therapy or therapeutic agent as described herein.

[0308] Some embodiments provide a method for modulating DYRK1A in a mammalian cell, the method comprising contacting the mammalian cell with a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing.

[0309] In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vitro. In some embodiments, the mammalian cell is a mammalian neuronal cell. In some embodiments, the mammalian neuronal cell is a mammalian DYRK1A-associated neuronal cell. In some embodiments, the cell has dysregulated expression or activity or levels of the DYRK1A gene, DYRK1A protein, or any thereof. In some embodiments, the cell has a chromosomal abnormality associated with Down's syndrome.

[0310] Exemplary sequence of human dual specificity tyrosine phosphorylation-regulated kinase 1A (UniProtKB entry Q13627) (SEQ ID NO:1) MHTGGETSAC KPSSVRLAPS FSFHAAGLQM AGQMPHSHQY SDRRQPNISD QQVSALSYSD QIQQPLTNQV MPDIVMLQRR MPQTFRDPAT APLRKLSVDL IKTYKHINEV YYAKKKRRHQ QGQGDDSSHK KERKVYNDGY DDDNYDYIVK NGEKWMDRYE IDSLIGKGSF GQVVKAYDRV EQEWVAIKII KNKKAFLNQA QIEVRLLELM NKHDTEMKYY IVHLKRHFMF RNHLCLVFEM LSYNLYDLLR NTNFRGVSLN LTRKFAQQMC TALLFLATPE LSIIHCDLKP ENILLCNPKR SAIKIVDFGS SCQLGQRIYQ YIQSRFYRSP EVLLGMPYDL AIDMWSLGCI LVEMHTGEPL FSGANEVDQM NKIVEVLGIP PAHILDQAPK ARKFFEKLPD GTWNLKKTKD GKREYKPPGT RKLHNILGVE TGGPGGRRAG ESGHTVADYL KFKDLILRML DYDPKTRIQP YYALQHSFFK KTADEGTNTS NSVSTSPAME QSQSSGTTS TSSSSGGSSG TSNSGRARSD PTHQHRHSGG HFTAAVQAMD CETHSPQVRQ QFPAPLGWSG TEAPTQVTVE THPVQETTFH VAPQQNALHH HHGNSSHHHH HHHHHHHHHG QQALGNRTRP RVYNSPTNSS STQDSMEVGH SHHSMTSLSS STTSSSTSSS STGNQGNQAY QNRPVAANTL DFGQNGAMDV NLTVYSNPRQ ETGIAGHPTY QFSANTGPAH YMTEGHLTMR QGADREESPM TGVCVQQSPV ASS

[0311] In some embodiments, compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, are useful for treating neurological disorders identified as being associated with dysregulation of DYRK1A. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a neurological disorder, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing.

[0312] Also provided herein are methods for treating a subject identified or diagnosed with a DYRK1A-associated neuropathy, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the subject has been identified or diagnosed with a DYRK1A-associated neuropathy by using a regulatory-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or levels of the DYRK1A gene, DYRK1A protein, or any thereof in the subject or a biological sample (e.g., blood and / or CSF) from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the neuropathy is a DYRK1A-associated neuropathy.

[0313] The term "regulatory authority" refers to a national authority responsible for the approval of pharmaceutical products for medical use by that country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0314] Also provided are methods for inhibiting DYRK1A activity in a cell, the methods comprising contacting the cell with a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs in vivo and the method comprises administering a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, to a subject having a cell with abnormal DYRK1A activity. In some embodiments, the cell is a neuronal cell. In some embodiments, the neuronal cell is a DYRK1A-associated neuronal cell.

[0315] As used herein, the term "contacting" refers to combining the indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a DYRK1A protein with a compound provided herein includes administering a compound provided herein to an individual or subject, such as a human, having a DYRK1A protein, as well as introducing a compound provided herein into a sample containing a cell preparation or purified preparation containing a DYRK1A protein.

[0316] The phrase "therapeutically effective amount" refers to an amount of a compound sufficient, when administered to a subject in need of such treatment, to (i) treat a DYRK1A protein-associated disease or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, that would correspond to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., body weight) of the subject requiring treatment, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0317] When employed as pharmaceuticals, the compounds of Formulas (I), (II), and (III) (including any pharmaceutically acceptable salts thereof) may be administered in the form of pharmaceutical compositions as described herein.

[0318] combination In some embodiments of any of the methods described herein, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic agents.

[0319] In some embodiments, the methods described herein further comprise administering one or more additional therapies selected from typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, cholinesterase inhibitors, memantine, NSAIDs, analgesics, anti-anxiety medications, gabapentin, and pregabalin.

[0320] In some embodiments, the methods described herein further comprise providing cognitive behavioral therapy to the subject.

[0321] In some embodiments, the one or more additional therapies are standard of care for neuropathic pain. In some embodiments, the one or more additional therapies are standard of care for Alzheimer's disease. In some embodiments, the one or more additional therapies are standard of care for Alzheimer's disease associated with Down's syndrome.

[0322] In some embodiments, the one or more additional therapies are typical antipsychotics. Representative typical antipsychotics include, but are not limited to, chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, pericyazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupenthixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopenthixol.

[0323] In some embodiments, the one or more additional therapies are atypical antipsychotics. Exemplary atypical antipsychotics include, but are not limited to, aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone.

[0324] In some embodiments, the one or more additional therapies is an antidepressant, hi some embodiments, the antidepressant is an atypical antidepressant, a selective serotonin reuptake inhibitor, a selective serotonin and norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor, a selective norepinephrine reuptake inhibitor, or a tricyclic antidepressant.

[0325] In some embodiments, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, and one or more additional therapies are administered as separate doses sequentially in any order, hi some embodiments, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, and one or more additional therapies are administered as a single dosage form.

[0326] In some embodiments, the antidepressant is an atypical antidepressant. Exemplary atypical antidepressants include, but are not limited to, mirtazapine, mianserin, bupropion, trazodone, nefazodone, tianeptine, opipramol, agomelatine, vilazodone, and vortioxetine.

[0327] In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor. Representative selective serotonin reuptake inhibitors include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0328] In some embodiments, the antidepressant is a selective serotonin and norepinephrine reuptake inhibitor. Representative selective serotonin and norepinephrine reuptake inhibitors include, but are not limited to, atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine.

[0329] In some embodiments, the antidepressant is a monoamine oxidase inhibitor. Representative monoamine oxidase inhibitors include, but are not limited to, moclobemide, rasagiline, selegiline, or safinamide.

[0330] In some embodiments, the antidepressant is a selective norepinephrine reuptake inhibitor. Exemplary selective norepinephrine reuptake inhibitors include, but are not limited to, reboxetine.

[0331] In some embodiments, the antidepressant is a tricyclic antidepressant. Representative tricyclic antidepressants include, but are not limited to, amineptine, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, norclomipramine, northiaden, nortriptyline, pipramol, protriptyline, tianeptine, and trimipramine.

[0332] In some embodiments, the one or more additional therapies is a benzodiazepine. Representative benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam.

[0333] In some embodiments, one or more additional therapies are mood stabilizers. Representative mood stabilizers include, but are not limited to, lithium, valproic acid, lamotrigine, or carbamazepine. In some embodiments, one or more additional therapies are electroconvulsive therapy or transcranial magnetic stimulation.

[0334] In some embodiments, the one or more additional therapies is sertraline. In some embodiments, the one or more additional therapies is venlafaxine.

[0335] In some embodiments, the one or more additional therapies is a cholinesterase inhibitor. Representative cholinesterase inhibitors include, but are not limited to, donepezil, galantamine, and rivastigmine.

[0336] In some embodiments, the one or more additional therapies is memantine.

[0337] In some embodiments, the one or more additional therapies is an NSAID. Representative NSAIDs include, but are not limited to, clonixin, licofelone, salicylates (such as aspirin and diflunisal), propionic acid derivatives (such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, and oxaprozin), acetic acid derivatives (such as indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, and bromfenac), and COX-2 inhibitors (such as celecoxib).

[0338] In some embodiments, the one or more additional therapies is an analgesic. Exemplary analgesics include, but are not limited to, nefopam, flupiritine, ziconotide, acetaminophen, and opioids (such as morphine, oxycodone, methadone, codeine, fentanyl, hydrocodone, and tramadol).

[0339] In some embodiments, one or more additional therapies is an anti-anxiety agent. Exemplary anti-anxiety agents include, but are not limited to, alnespirone, adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, ciprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, urdazepam, and zolazepam.

[0340] In some embodiments, the one or more additional therapies is gabapentin or pregabalin.

[0341] In some embodiments, the one or more additional therapies is one additional therapy. In some embodiments, the one or more additional therapies is two, three, or four additional therapies.

[0342] Some embodiments provide a method of treating a neurological disorder, the method comprising administering to a subject in need thereof a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, and one or more additional therapies selected from a typical antipsychotic, an atypical antipsychotic, an antidepressant, electroconvulsive therapy, transcranial magnetic stimulation, a benzodiazepine, a mood stabilizer, a cholinesterase inhibitor, memantine, an NSAID, an analgesic, an anxiolytic, gabapentin, and pregabalin.

[0343] In some embodiments, the subject received one or more additional therapies before initiating treatment with a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the subject received one or more additional therapies before initiating treatment with a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, but after treatment with a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt of any of the foregoing, the subject no longer receives the one or more additional therapies for a period of time. In some embodiments of this paragraph, the period of time is from about 1 month to about 1 year, e.g., from about 1 month to about 5 months, from about 3 months to about 8 months, from about 7 months to about 1 year, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, or any value therebetween. In some embodiments, the amount of one or more additional therapies decreases over the period and reaches zero at the end of the period.

[0344] In some embodiments, the subject has previously received one or more additional therapies selected from a typical antipsychotic, an atypical antipsychotic, an antidepressant, electroconvulsive therapy, transcranial magnetic stimulation, a benzodiazepine, a mood stabilizer, a cholinesterase inhibitor, memantine, an NSAID, an analgesic, an anxiolytic, gabapentin, and pregabalin, and the subject did not respond to the prior one or more therapies.

[0345] In some embodiments, the subject has previously been administered a standard of care treatment for neuropathic pain, and the subject did not respond to the previous therapy. In some embodiments, the subject has previously been administered a standard of care treatment for Alzheimer's disease, and the subject did not respond to the previous therapy. In some embodiments, the subject has previously been administered a standard of care treatment for Alzheimer's disease associated with Down's syndrome, and the subject did not respond to the previous therapy.

[0346] In some embodiments, the subject has previously received one or more additional therapies selected from a typical antipsychotic, an atypical antipsychotic, an antidepressant, electroconvulsive therapy, transcranial magnetic stimulation, a benzodiazepine, a mood stabilizer, a cholinesterase inhibitor, memantine, an NSAID, an analgesic, an anxiolytic, gabapentin, and pregabalin, and has failed to respond to the previous therapy.

[0347] In some embodiments, the subject has previously received one or more typical antipsychotics, such as chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, pericyazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupenthixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopenthixol, and has not responded to the previous therapy.

[0348] In some embodiments, the subject has previously received one or more atypical antipsychotics, such as aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone, and has not responded to the previous therapy.

[0349] In some embodiments, the subject has previously been administered one or more antidepressants and has not responded to the previous therapy, hi some embodiments, the antidepressant is an atypical antidepressant, a selective serotonin reuptake inhibitor, a selective serotonin and norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor, a selective norepinephrine reuptake inhibitor, or a tricyclic antidepressant, and has not responded to the previous therapy.

[0350] In some embodiments, the subject has previously received one or more atypical antidepressants, such as mirtazapine, mianserin, bupropion, trazodone, nefazodone, tianeptine, opipramol, agomelatine, vilazodone, and vortioxetine, and has not responded to the previous therapy.

[0351] In some embodiments, the subject has previously received one or more selective serotonin reuptake inhibitors, such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, and has not responded to the previous therapy.

[0352] In some embodiments, the subject has previously received one or more selective serotonin and norepinephrine reuptake inhibitors, such as atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine, and has not responded to the previous therapy.

[0353] In some embodiments, the subject has previously received one or more monoamine oxidase inhibitors, such as moclobemide, rasagiline, selegiline, or safinamide, and has failed to respond to the previous therapy.

[0354] In some embodiments, the subject has previously been administered one or more selective norepinephrine reuptake inhibitors, such as reboxetine, and has failed to respond to the previous therapy.

[0355] In some embodiments, the subject has previously received one or more tricyclic antidepressants, such as amineptine, amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, norclomipramine, nosiaden, nortriptyline, pipramol, protriptyline, tianeptine, and trimipramine, and has not responded to the previous therapy.

[0356] In some embodiments, the subject has previously received one or more benzodiazepines, such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam, and has not responded to the previous therapy.

[0357] In some embodiments, the subject has previously been administered one or more mood stabilizers, such as lithium, valproate, lamotrigine, or carbamazepine, and has not responded to the previous therapy.

[0358] In some embodiments, the one or more additional therapies is electroconvulsive therapy or transcranial magnetic stimulation and have not responded to previous therapies.

[0359] In some embodiments, the subject has previously received sertraline and has not responded to the previous therapy, hi some embodiments, the subject has previously received venlafaxine and has not responded to the previous therapy.

[0360] In some embodiments, the subject has previously been administered one or more cholinesterase inhibitors, such as donepezil, galantamine, or rivastigmine, and did not respond to the previous therapy.

[0361] In some embodiments, the subject has previously received memantine and has not responded to the previous therapy.

[0362] In some embodiments, the subject has previously received one or more NSAIDs such as clonixin, licofelon, aspirin, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, bromfenac), or celecoxib, and has failed to respond to the previous therapy.

[0363] In some embodiments, the subject has previously received one or more analgesics, such as nefopam, flupiritine, ziconotide, acetaminophen, morphine, oxycodone, methadone, codeine, fentanyl, hydrocodone, or tramadol, and has not responded to the previous therapy.

[0364] In some embodiments, the subject has previously received one or more anti-anxiety medications, such as, for example, alnespirone, adinazolam, alprazolam, varazepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, ciprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, urdazepam, or zolazepam, and did not respond to the previous therapy.

[0365] In some embodiments, the subject has previously received gabapentin or pregabalin and did not respond to the previous therapy.

[0366] In some embodiments, the one or more additional therapies previously administered to the subject are one to three additional therapies. In some embodiments, the one or more additional therapies previously administered to the subject are one additional therapy. In some embodiments, the one or more additional therapies previously administered to the subject are two additional therapies. In some embodiments, the one or more additional therapies previously administered to the subject are three additional therapies.

[0367] Subjects who "failed to respond" to previous therapy include those for whom the previous therapy lacked sufficient clinical benefit, those who experienced an unacceptable number and / or severity of side effects from the previous therapy (sufficient to require discontinuation of treatment), and those who experienced both of the foregoing. Side effects include, but are not limited to, weight gain, flat affect, tardive dyskinesia, drowsiness, nausea, vomiting, constipation, dry mouth, restlessness, dizziness, decreased libido, erectile dysfunction, insomnia, and blurred vision.

[0368] Embodiment Exemplary Embodiments of Compounds of Formula (I) Embodiment 1: Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: Each dashed line represents a single or double bond; X 1 is CR 1 or N, X 2 is CR 2 , C(=O), or N; X 3 is C or N, except that X 2 If is C(=O), X 3 is N, X 4 is CH or N, Ring A is phenyl or 5- to 6-membered heteroaryl; R 1 is hydrogen, halogen, cyano, 3- to 10-membered heterocyclyl, -C(=O)C1-C6 alkyl, or -C(=O)OR A C1-C6 alkyl optionally substituted with 3-6 membered heterocyclyl optionally substituted with C1-C6 alkoxy, -C(=O)-3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, or -OR B and R Bis a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, a C-C aryl, or a C-C cycloalkyl, each of which is selected from 1 to 3 independently selected halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, cyano, hydroxy, —C(═O)OH, —C(═O)C-C alkyl, —S(O)—C-C alkyl, or —NR C R D optionally replaced by R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)-3- to 6-membered heterocyclyl, -NH-C3-C6 cycloalkyl-C(=O)OR A or -O-C3-C6 cycloalkyl-C(=O)OR A and R 3 is hydrogen, halogen, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, -XR G ,or [ka] and R 4 is hydrogen or C1-C6 alkyl, R 5 is hydrogen, C1-C6 alkyl optionally substituted with 3- to 6-membered heterocyclyl, -XR E , -C3-C6 cycloalkyl-C(=O)OR A ,or [ka] or R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5and the two adjacent carbon atoms and / or nitrogen atoms in ring A together form (i) a C6-C10 aryl optionally substituted with a 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or -C(=O)OR', (ii) a 3-6 membered heterocyclyl, or (iii) a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, a 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(=O)OR', and a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; R E is a 3- to 10-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected C1-C6 alkoxy, NR I R J or C1-C6 alkyl optionally substituted with -C(=O)OH; R F is a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each optionally substituted with C1-C6 alkyl, or a C2-C6 alkynyl optionally substituted with hydroxy; R G is a 3- to 6-membered heterocyclyl or C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected C1-C6 alkyl, —C(═O)C1-C6 alkyl, —C(═O)OH, or NR C R D optionally replaced by R H is C1-C6 alkyl optionally substituted with hydroxy or 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; X is -NH-, -NH(C=O)-, -NHC(=O)O-, -O-, -(C=O)- or CH2; Each R A , R C , R D , R I , and R Jare independently selected from hydrogen and C1-C6 alkyl; The compound or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

[0369] Embodiment 2: X 1 , X 2 , X 3 , X 4 One of them is N and the other is X 1 , X 2 , X 3 , X 4 The remaining groups are C, C(=O), CH, and CR. 1 or CR 2 The compound of embodiment 1, independently selected from:

[0370] Embodiment 3: X 1 is N and X 2 is CR 2 and X 3 is C and X 4 The compound of embodiment 1 or 2, wherein is CH.

[0371] Embodiment 4: X 2 is N and X 1 is CR 1 and X 3 is C and X 4 The compound of embodiment 1 or 2, wherein is CH.

[0372] Embodiment 5: X 3 is N and X 1 is CR 1 and X 2 is C(=O) and X 4 The compound of embodiment 1 or 2, wherein is CH.

[0373] Embodiment 6: X 4 is N and X 1 is CR 1 and X 2 is CR 2 and X 3 The compound of embodiment 1 or 2, wherein

[0374] Embodiment 7:X 1 , X 2 , X 3 , X 4 Each of these is C, C(=O), CH, CR 1 or CR 2 The compound of embodiment 1, independently selected from:

[0375] Embodiment 8: The compound of embodiment 1, wherein Ring A is a 5-membered heteroaryl.

[0376] Embodiment 9: Ring A is [ka] where aa is X 3 represents the point of attachment to X, each dashed bond is independently a single or double bond, and X 5 , X 6 , X 7 , X 8 and X 9 is independently selected from C, (C=O), C=NH, CH, N, O, or S.

[0377] Embodiment 10: The compound of any one of embodiments 1-9, wherein Ring A is selected from the group consisting of thiazoliene, oxazoliene, imidazoliene, pyrazoliene, 1,2,4-triazoliene, 1,2,4-oxadiazolylene, and 2-imine-thiazolylene.

[0378] Embodiment 11: Ring A is [ka] each of which is selected from the group consisting of one or two R 5 and aa is X 3 The other wavy lines represent the bond points with R. 5 The compound of any one of embodiments 1-9, wherein R represents a point of attachment to R.

[0379] Embodiment 12: The compound of any one of embodiments 1-7, wherein Ring A is a 6-membered heteroaryl.

[0380] Embodiment 13: Ring A is [ka] wherein aa is X 3 13. The compound of any one of embodiments 1-7 or 12, wherein:

[0381] Embodiment 14:R 1 The compound of any one of embodiments 1-13, wherein is hydrogen.

[0382] Embodiment 15:R 1 The compound of any one of embodiments 1-13, wherein is cyano.

[0383] Embodiment 16:R 1 The compound of any one of embodiments 1-13, wherein is halo (e.g., Cl or F).

[0384] Embodiment 17:R 1 The compound of any one of embodiments 1-13, wherein is 3-10 membered heterocyclyl.

[0385] Embodiment 18:R 1 teeth, [ka] 18. The compound of embodiment 17, wherein

[0386] Embodiment 19:R 1 is -C(=O)C1-C6 alkyl or -C(=O)OR A The compound of any one of embodiments 1-13, wherein the aryl is C1-C6 alkyl optionally substituted with 3-6 membered heterocyclyl optionally substituted with

[0387] Embodiment 20:R 1The compound of any of embodiments 1-13 or 19, wherein is C1-C6 alkyl (e.g., methyl).

[0388] Embodiment 21:R 1 The compound of any one of embodiments 1-13 or 19, wherein is C1-C6 alkyl substituted with 3-6 membered heterocyclyl.

[0389] Embodiment 22:R 1 is C(=O)OR A 22. The compound of any one of embodiments 1-13 or 21, wherein the compound is C1-C6 alkyl substituted with 3-6 membered heterocyclyl substituted with

[0390] Embodiment 23:R 1 The compound of any one of embodiments 1-13 or 21, wherein is C1-C6 alkyl substituted with a 3-6 membered heterocyclyl substituted with -C(=O)C1-C6 alkyl.

[0391] Embodiment 24: The compound of any one of embodiments 21-23, wherein the heterocyclyl is piperidinylene, piperidinyl, piperizinylene, or piperizinyl.

[0392] Embodiment 25:R 1 teeth, [ka] where the wavy line represents X 1 23. The compound of embodiment 22, wherein the compound represents a point of attachment to

[0393] Embodiment 26:R 1 teeth, [ka] where the wavy line represents X 1 The compound of embodiment 23, wherein the compound represents a point of attachment to

[0394] Embodiment 27:R 1 The compound of any one of embodiments 1-13, wherein is C1-C6 alkoxy (eg, methoxy).

[0395] Embodiment 28:R 1 The compound of any one of embodiments 1-13, wherein is -C(=O)-3- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0396] Embodiment 29:R 1 teeth, [ka] 29. The compound of embodiment 28, wherein

[0397] Embodiment 30:R 1 -OR B 14. The compound of embodiments 1-13, wherein

[0398] Embodiment 31:R 1 teeth, [ka] 31. The compound of embodiment 30, selected from the group consisting of:

[0399] Embodiment 32:R 2 The compound of any one of embodiments 1-31, wherein is hydrogen.

[0400] Embodiment 33:R 2 The compound of any one of embodiments 1-31, wherein is halogen (e.g., F, Cl).

[0401] Embodiment 34:R 2 The compound of any one of embodiments 1-31, wherein is C1-C6 alkyl (e.g., methyl).

[0402] Embodiment 35:R 2The compound of any one of embodiments 1-31, wherein is C1-C6 alkoxy (eg, methoxy, ethoxy).

[0403] Embodiment 36:R 2 The compound of any one of embodiments 1-31, wherein is -C(=O)-3- to 6-membered heterocyclyl.

[0404] Embodiment 37:R 2 is -NH-C3-C6 cycloalkyl-C(=O)OR A 32. The compound of any one of embodiments 1-31, wherein:

[0405] Embodiment 38:R 2 is -O-C3-C6 cycloalkyl-C(=O)OR A 32. The compound of any one of embodiments 1-31, wherein:

[0406] Embodiment 39:R 3 The compound of any one of embodiments 1-38, wherein is hydrogen.

[0407] Embodiment 40:R 3 The compound of any one of embodiments 1-38, wherein is halogen (e.g., F or Cl).

[0408] Embodiment 41:R 3 The compound of any one of embodiments 1-38, wherein is cyano.

[0409] Embodiment 42:R 3 The compound of any one of embodiments 1-38, wherein is C1-C6 alkyl (eg, methyl, ethyl).

[0410] Embodiment 43:R 3 The compound of any one of embodiments 1-38, wherein is C3-C6 cycloalkyl (e.g., cyclopropyl).

[0411] Embodiment 44:R 3 Ha-XR G39. The compound of any one of embodiments 1-38, wherein X is —NH—, —NHC(═O)O—, —O—, or CH 2 .

[0412] Embodiment 45:R 3 teeth, [ka] The compound of embodiment 44, selected from the list of structures consisting of:

[0413] Embodiment 46:R 3 teeth, [ka] The compound of any one of embodiments 1-38, wherein

[0414] Embodiment 47:R 3 teeth, [ka] 47. The compound of embodiment 46, selected from the group consisting of:

[0415] Embodiment 48:R 4 The compound of any one of embodiments 1-47, wherein is hydrogen.

[0416] Embodiment 49:R 4 The compound of any one of embodiments 1-47, wherein is C1-C6 alkyl (eg, methyl, ethyl).

[0417] Embodiment 50: The compound of any one of embodiments 1 to 49, wherein m is 0.

[0418] Embodiment 51: A compound of any one of embodiments 1 to 49, wherein m is 1 or 2.

[0419] Embodiment 52: The compound of any one of embodiments 1-49 or 51, wherein m is 1.

[0420] Embodiment 53:R 5 The compound of embodiment 52, wherein

[0421] Embodiment 54:R 5 Compounds according to embodiment 52, wherein is C1-C6 alkyl optionally substituted with 3-6 membered heterocyclyl.

[0422] Embodiment 55:R 5 is C1-C6 alkyl (e.g., methyl, ethyl).

[0423] Embodiment 56:R 5 The compound of embodiment 54, wherein is C1-C6 alkyl substituted with a 3-6 membered heterocyclyl.

[0424] Embodiment 57: The heterocyclyl group is morpholinyl, e.g., [ka] 55. The compound according to 54, wherein the wavy line represents the point of attachment to the C1-C6 alkyl group.

[0425] Embodiment 58:R 5 teeth, [ka] 58. The compound of any one of embodiments 54, 56, or 57, wherein

[0426] Embodiment 59:R 5 -XR E 53. The compound of any one of embodiments 1-49, 51, or 52, wherein

[0427] Embodiment 60:R 5 is -(NH)(C=O)R E , -(NH)(C=O)OR E , -NH-R E , or -(C=O)R E60. The compound of embodiment 59, wherein

[0428] Embodiment 61:R 5 teeth, [ka] 61. The compound of embodiment 59 or 60, selected from the group consisting of:

[0429] Embodiment 62:R 5 teeth, [ka] 61. The compound of embodiment 59 or 60, wherein

[0430] Embodiment 63:R 5 teeth, [ka] 61. The compound of embodiment 59 or 60, wherein

[0431] Embodiment 64:R 5 teeth, [ka] 61. The compound of embodiment 59 or 60, wherein

[0432] Embodiment 65:R 5 is -C3~C6 cycloalkyl-C(=O)OR A 53. The compound of any one of embodiments 1-49, 51, or 52, wherein

[0433] Embodiment 66:R 5 teeth, [ka] 66. The compound of embodiment 65, wherein

[0434] Embodiment 67:R 5 teeth, [ka] 53. The compound of any one of embodiments 1-49, 51, or 52, wherein

[0435] Embodiment 68:R F The compound of embodiment 67, wherein is a 3-6 membered heterocyclyl optionally substituted with C2-C6 alkynyl.

[0436] Embodiment 69:R 5 teeth, [ka] 69. The compound of embodiment 67 or 68, selected from the group consisting of:

[0437] Embodiment 70:R F The compound of embodiment 67, wherein is C2-C6 alkynyl optionally substituted with hydroxy.

[0438] Embodiment 71:R 5 teeth, [ka] The compound of embodiment 67 or 70, wherein

[0439] Embodiment 72:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5and the two adjacent carbon atoms and / or nitrogen atoms in Ring A together form (i) a C-C aryl optionally substituted with a 3-10 membered heterocyclyl optionally substituted with one to two independently selected C-C alkyl or —C(═O)OR′; (ii) a 3-6 membered heterocyclyl; or (iii) a 5-6 membered heteroaryl optionally substituted with one to two substituents independently selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, 3-10 membered heterocyclyl optionally substituted with one to two independently selected C-C alkyl or C(═O)OR′, and a 5-6 membered heteroaryl optionally substituted with C-C alkyl.

[0440] Embodiment 73:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5 and two of said adjacent carbon and / or nitrogen atoms in ring A together form a C-C aryl (e.g., phenyl) optionally substituted with one to two independently selected C-C alkyl or 3-10 membered heterocyclyl optionally substituted with -C(=O)OR'.

[0441] Embodiment 74:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5 and the two adjacent carbon atoms and / or nitrogen atoms in ring A are both phenyl rings (e.g., [ka] wherein the wavy line represents the point of attachment to ring A), which is optionally further substituted with 1 to 2 independently selected C1-C6 alkyl or 3-10 membered heterocyclyl optionally substituted with -C(=O)OR'.

[0442] Embodiment 75:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5 and the two adjacent carbon atoms and / or nitrogen atoms in ring A are both [ka] The compound of any one of embodiments 72-74, wherein the compound forms a structure selected from the group consisting of:

[0443] Embodiment 76:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5 and the two adjacent carbon and / or nitrogen atoms in ring A together form a 3- to 6-membered heterocyclyl.

[0444] Embodiment 77:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5 and the two adjacent carbon atoms and / or nitrogen atoms in ring A together form a pyrrolidine ring (e.g., [ka] wherein the wavy line represents the point of attachment to ring A.

[0445] Embodiment 78:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5 and two of the adjacent carbon and / or nitrogen atoms in ring A form a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(═O)OR′, and 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl.

[0446] Embodiment 79:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5 and the two adjacent carbon atoms and / or nitrogen atoms in ring A are both [ka] and C(═O)OR′, each of which is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3- to 10-membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(═O)OR′, and 5- to 6-membered heteroaryl optionally substituted with C1-C6 alkyl, and the wavy line indicates the point of attachment to Ring A.

[0447] Embodiment 80:R 5 and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R 5 and the two adjacent carbon atoms and / or nitrogen atoms in ring A are both [ka] The compound of any one of embodiments 72, 78, or 79, wherein the compound forms a ring structure selected from the list of structures consisting of: wherein the wavy line represents the point of attachment to ring A.

[0448] Embodiment 81: The compound of embodiment 1, wherein the compound is a compound of formula (I-1), or a pharmaceutically acceptable salt thereof: [ka]

[0449] Embodiment 82: The compound of embodiment 1, wherein the compound is a compound of formula (I-2), or a pharmaceutically acceptable salt thereof: [ka]

[0450] Embodiment 83: The compound of embodiment 1, wherein the compound is a compound of formula (I-3), or a pharmaceutically acceptable salt thereof: [ka]

[0451] Embodiment 84: The compound of embodiment 1, wherein the compound is a compound of formula (I-4), or a pharmaceutically acceptable salt thereof: [ka]

[0452] Embodiment 85: The compound of embodiment 1, wherein the compound is a compound of formula (I-5), or a pharmaceutically acceptable salt thereof: [ka]

[0453] Embodiment 86: The compound of embodiment 1, wherein the compound is a compound of formula (I-6), or a pharmaceutically acceptable salt thereof: [ka]

[0454] Embodiment 87: The compound of embodiment 1, wherein the compound is a compound of formula (I-7), or a pharmaceutically acceptable salt thereof: [ka]

[0455] Embodiment 88: The compound of embodiment 1, wherein the compound is a compound of formula (I-8), or a pharmaceutically acceptable salt thereof: [ka]

[0456] Embodiment 89: The compound of embodiment 1, wherein the compound is a compound of formula (I-9), or a pharmaceutically acceptable salt thereof: [ka]

[0457] Embodiment 90: The compound of embodiment 1, wherein the compound is a compound of formula (I-10), or a pharmaceutically acceptable salt thereof: [ka]

[0458] Embodiment 91: The compound of embodiment 1, wherein the compound is a compound of formula (I-11), or a pharmaceutically acceptable salt thereof: [ka]

[0459] Embodiment 92: The compound of embodiment 1, wherein the compound is a compound of formula (I-12), or a pharmaceutically acceptable salt thereof: [ka]

[0460] Embodiment 93: The compound of embodiment 1, wherein the compound is a compound of formula (I-13), or a pharmaceutically acceptable salt thereof: [ka]

[0461] Embodiment 94: The compound of embodiment 1, wherein the compound is a compound of formula (I-14), or a pharmaceutically acceptable salt thereof: [ka]

[0462] Embodiment 95: The compound of embodiment 1, wherein the compound is a compound of formula (I-15), or a pharmaceutically acceptable salt thereof: [ka]

[0463] Exemplary embodiments of compounds of formula (II) Embodiment 1: Formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- to 14-membered heteroaryl or a 5- to 14-membered heterocyclyl; Each R 1 are independently halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)OR A , -NR B R C , and -C(=O)NR B RC and Each R 2 are independently -C(=O)OR D , C1-C6 alkyl, C2-C6 alkynyl optionally substituted with 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl, -C(=O)-phenyl, -(C1-C6 alkyl)-phenyl, -(C1-C6 alkyl)-4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or -CO2C1-C6 alkyl, phenyl optionally substituted with cyano or fluoro, -NHC(=O)R E , 5-6 membered heteroaryl optionally substituted with C1-C6 alkoxy; m is 1, 2, or 3; n is 0, 1, 2, or 3; Each R A , R B , R C , and R D are independently hydrogen or C1-C6 alkyl, Each R E are independently C3-C6 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0464] Embodiment 2: A compound of embodiment 1, wherein ring A is a monocyclic heteroaryl or monocyclic heterocyclyl.

[0465] Embodiment 3: The compound of embodiment 1 or 2, wherein ring A is a 5-6 membered heteroaryl.

[0466] Embodiment 4: The compound of any one of embodiments 1-3, wherein Ring A is a 5-membered heteroaryl.

[0467] Embodiment 5: The compound of any one of embodiments 1-4, wherein ring A is thiazole or pyrazole.

[0468] Embodiment 6: Ring A is [ka] The compound of any one of embodiments 1 to 4, wherein

[0469] Embodiment 7: The compound of embodiment 1 or 2, wherein Ring A is a 6-membered heteroaryl.

[0470] Embodiment 8: The compound of any one of embodiments 1-2 or 7, wherein Ring A is pyridine or pyrimidin-4(3H)-one.

[0471] Embodiment 9: Ring A is [ka] The compound of any one of embodiments 1-2 or 7, wherein

[0472] Embodiment 10: A compound of embodiment 1, wherein ring A is a bicyclic heteroaryl or bicyclic heterocyclyl.

[0473] Embodiment 11: The compound of embodiment 1 or 10, wherein ring A is an 8- to 12-membered bicyclic heteroaryl or an 8- to 12-membered bicyclic heterocyclyl.

[0474] Embodiment 12: A compound of any one of embodiments 1 or 10-11, wherein ring A is a 9-10 membered bicyclic heteroaryl or a 9-10 membered bicyclic heterocyclyl.

[0475] Embodiment 13: The compound of any one of embodiments 1 or 10-12, wherein Ring A is a 9-membered bicyclic heteroaryl.

[0476] Embodiment 14: The compound of any one of embodiments 1 or 10-13, wherein Ring A is pyrazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, pyrrolo[1,2-a]pyrazin-1(2H)-one, pyrazolo[1,5-a]pyrazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, or 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one.

[0477] Embodiment 15: Ring A is [ka] 14. The compound of any one of embodiments 1 or 10-13, wherein

[0478] Embodiment 16: The compound of any one of embodiments 1 or 10-12, wherein Ring A is a 9-membered bicyclic heterocyclyl.

[0479] Embodiment 17: The compound of any one of embodiments 1, 10-12, or 16, wherein Ring A is 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, or 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one.

[0480] Embodiment 18: Ring A is [ka] 17. The compound of any one of embodiments 1, 10-12, or 16, wherein

[0481] Embodiment 19: A compound of embodiment 1, wherein ring A is a tricyclic heteroaryl or tricyclic heterocyclyl.

[0482] Embodiment 20: The compound of embodiment 1 or 19, wherein ring A is a 10-14 membered tricyclic heteroaryl or a 10-14 membered tricyclic heterocyclyl.

[0483] Embodiment 21: A compound of any one of embodiments 1 or 19-20, wherein ring A is an 11-13 membered tricyclic heteroaryl or an 11-13 membered tricyclic heterocyclyl.

[0484] Embodiment 22: The compound of any one of embodiments 1 or 19-21, wherein ring A is a 12-membered tricyclic heteroaryl.

[0485] Embodiment 23: The compound of any one of embodiments 1 or 19-22, wherein Ring A is 8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine.

[0486] Embodiment 24: Ring A is [ka] 23. The compound of any one of embodiments 1 or 19-22, wherein

[0487] Embodiment 25: A compound of any one of embodiments 1 or 19-21, wherein ring A is a 12-membered tricyclic heterocyclyl.

[0488] Embodiment 26: The compound of any one of embodiments 1, 19-21, or 25, wherein Ring A is 7,8,9,10-tetrahydro-pyrazolo[5,1-f][1,6]naphthyridine or 7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine.

[0489] Embodiment 27: Ring A is [ka] 26. The compound of embodiment 1, 19-21, or 25, wherein

[0490] Embodiment 28: The compound of any one of embodiments 1 to 27, wherein m is 1 or 2.

[0491] Embodiment 29: The compound of any one of embodiments 1 to 28, wherein m is 1.

[0492] Embodiment 30:R 1 The compound of any one of embodiments 1-29, wherein is halogen.

[0493] Embodiment 31:R 1 The compound of any one of embodiments 1-29, wherein is hydroxyl.

[0494] Embodiment 32:R 1 The compound of any one of embodiments 1-29, wherein is cyano.

[0495] Embodiment 33:R 1 The compound of any one of embodiments 1-29, wherein is C1-C6 alkyl.

[0496] Embodiment 34:R 1 The compound of any one of embodiments 1-29, wherein is C1-C6 alkoxy.

[0497] Embodiment 35:R 1 is -C(=O)OR A 30. The compound of any one of embodiments 1-29, wherein

[0498] Embodiment 36:R 1 is —C(═O)OH, —C(═O)OCH2CH3, or —C(═O)OC(CH3)3.

[0499] Embodiment 37:R 1 is -NR B R C 30. The compound of any one of embodiments 1-29, wherein

[0500] Embodiment 38:R 1 is -C(=O)NR B R C 30. The compound of any one of embodiments 1-29, wherein

[0501] Embodiment 39:R1 The compound of embodiment 38, wherein is —C(═O)NH 2 or —C(═O)NHCH 3 .

[0502] Embodiment 40: The compound of any one of embodiments 1 to 28, wherein m is 2.

[0503] Embodiment 41:R 1 one of which is C1-C6 alkyl and the other R 1 is -C(=O)OR A (e.g., —C(═O)OH or —C(═O)OCH 3 ).

[0504] Embodiment 42:R 1 The compound of any one of embodiments 1-28 or 40, wherein one of is cyano.

[0505] Embodiment 43: The other R 1 The compound of embodiment 42, wherein is halo.

[0506] Embodiment 44: The other R 1 is hydroxy.

[0507] Embodiment 45: The other R 1 The compound of embodiment 42, wherein is C1-C6 alkoxy.

[0508] Embodiment 46: The compound of any one of embodiments 1 to 45, wherein n is 0.

[0509] Embodiment 47: The compound of any one of embodiments 1 to 45, wherein n is 1, 2, or 3.

[0510] Embodiment 48: The compound of any one of embodiments 1 to 45 or 47, wherein n is 1.

[0511] Embodiment 49:R 2 is -C(=O)OR D49. The compound of embodiment 48, wherein

[0512] Embodiment 50:R 2 The compound of embodiment 58 or 49, wherein is —C(═O)OCH(CH 3 ) 3 .

[0513] Embodiment 51:R 2 is C1-C6 alkyl.

[0514] Embodiment 52:R 2 Compounds according to embodiment 48, wherein is C2-C6 alkynyl optionally substituted with 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0515] Embodiment 53:R 2 teeth, [ka] 53. The compound of embodiment 52, wherein

[0516] Embodiment 54:R 2 The compound of embodiment 48, wherein is —C(═O)-phenyl.

[0517] Embodiment 55:R 2 The compound of embodiment 48, wherein is -(C1-C6 alkyl)-phenyl.

[0518] Embodiment 56:R 2 teeth, [ka] 56. The compound of embodiment 55, wherein

[0519] Embodiment 57:R 2 Compounds according to embodiment 48, wherein is -(C1-C6 alkyl)-4 to 10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0520] Embodiment 58:R 2teeth, [ka] 58. The compound of embodiment 57, wherein

[0521] Embodiment 59:R 2 Compounds according to embodiment 48, wherein is 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or —CO2C1-C6 alkyl.

[0522] Embodiment 60:R 2 teeth, [ka] 60. The compound of embodiment 59, wherein

[0523] Embodiment 61:R 2 The compound of embodiment 48, wherein is phenyl optionally substituted with cyano or fluoro.

[0524] Embodiment 62:R 2 teeth, [ka] 62. The compound of embodiment 61, wherein

[0525] Embodiment 63:R 2 is -NHC(=O)R E 49. The compound of embodiment 48, wherein

[0526] Embodiment 64:R 2 teeth, [ka] 64. The compound of embodiment 63, wherein

[0527] Embodiment 65:R 2 The compound of embodiment 48, wherein is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkoxy.

[0528] Embodiment 66:R 2 teeth, [ka] 66. The compound of embodiment 65, wherein

[0529] Embodiment 67: The compound has formula (II-1): [ka] 2. The compound of embodiment 1, wherein the compound is

[0530] Embodiment 68: The compound has formula (II-2): [ka] or a pharmaceutically acceptable salt thereof.

[0531] Embodiment 69: The compound has formula (II-3): [ka] or a pharmaceutically acceptable salt thereof.

[0532] Embodiment 70: The compound has formula (II-4): [ka] 2. The compound of embodiment 1, wherein the compound is

[0533] Embodiment 71: The compound has formula (II-5): [ka] or a pharmaceutically acceptable salt thereof.

[0534] Embodiment 72: The compound has formula (II-6): [ka] or a pharmaceutically acceptable salt thereof.

[0535] Embodiment 73: The compound has formula (II-7): [ka] or a pharmaceutically acceptable salt thereof.

[0536] Embodiment 74: The compound has formula (II-8): [ka] or a pharmaceutically acceptable salt thereof.

[0537] Embodiment 75: The compound has formula (II-9): [ka] 2. The compound of embodiment 1, wherein the compound is

[0538] Embodiment 76: The compound has formula (II-10): [ka] or a pharmaceutically acceptable salt thereof.

[0539] Embodiment 77: The compound has formula (II-11): [ka] or a pharmaceutically acceptable salt thereof.

[0540] Embodiment 78: The compound has formula (II-12): [ka] or a pharmaceutically acceptable salt thereof.

[0541] Embodiment 79: The compound has formula (II-13): [ka] or a pharmaceutically acceptable salt thereof.

[0542] Embodiment 80: The compound has formula (II-14): [ka] or a pharmaceutically acceptable salt thereof.

[0543] Embodiment 81: The compound has formula (I-I15): [ka] or a pharmaceutically acceptable salt thereof.

[0544] Embodiment 82: The compound has formula (II-16): [ka] or a pharmaceutically acceptable salt thereof.

[0545] Embodiment 83: The compound has formula (II-17): [ka] or a pharmaceutically acceptable salt thereof.

[0546] Exemplary embodiments of compounds of formula (III) Embodiment 1: Formula (III): [ka] or a pharmaceutically acceptable salt thereof, Ring A is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R 1 is -NHC(=O)(C1-C6 alkylene) n R A , -NR F R G phenyl optionally substituted with -QR C ,or [ka] and R 2 -CO2R B C3-C6 cycloalkyl optionally substituted with, 5-10 membered heteroaryloxy, C1-C6 alkyl, cyano, or -(C1-C6 alkylene) optionally substituted with, 4-6 membered heterocyclyl p -5-10 membered heteroaryl, cyano or -NR D R E -(C1-C6 alkylene) optionally substituted with t -phenyl, 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; R 3 is a C1-C6 alkyl, R A is a 4- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, or a 5- to 10-membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl; R B is hydrogen or C1-C6 alkyl, R C is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, or -(C1-C6 alkylene)-NR D R E is phenyl optionally substituted with R D , R E , and R Fare independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R G is hydrogen, C1-C6 alkyl, —C(═O)—C1-C6 alkyl, or —C(═O)—C3-C6 cycloalkyl; R H is a 4- to 6-membered heterocyclyl optionally substituted with 1 to 2 independently selected C1-C6 alkyl; Q is C1-C6 alkylene, NH, or O; m is 0 or 1, n is 0 or 1, p is 0 or 1, The compound or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1.

[0547] Embodiment 2: R 1 is -NHC(=O)(C1-C6 alkylene) n R A 2. The compound of embodiment 1, wherein

[0548] Embodiment 3: R 1 is -NHC(=O)(C1-C2 alkylene) n R A 3. The compound of embodiment 1 or 2, wherein

[0549] Embodiment 4: The compound of any one of embodiments 1-3, wherein n is 1.

[0550] Embodiment 5: The compound of any one of embodiments 1-3, wherein n is 0.

[0551] Embodiment 6: R A The compound of any one of embodiments 1-5, wherein is 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0552] Embodiment 7: R AThe compound of any one of embodiments 1-6, wherein is oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with C1-C6 alkyl.

[0553] Embodiment 8: R A The compound of any one of embodiments 1-7, wherein is 4-6 membered heterocyclyl substituted with C1-C6 alkyl.

[0554] Embodiment 9:R A The compound of any one of embodiments 1-7, wherein is unsubstituted 4-6 membered heterocyclyl.

[0555] Embodiment 10:R A The compound of any one of embodiments 1-5, wherein is a 5-10 membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl.

[0556] Embodiment 11:R A The compound of any one of embodiments 1-5 or 10, wherein is a 5-10 membered heteroaryl substituted with C1-C6 alkoxy.

[0557] Embodiment 12:R A The compound of any one of embodiments 1-5 or 10, wherein is a 5-10 membered heteroaryl substituted with C1-C6 alkyl.

[0558] Embodiment 13:R A The compound of any one of embodiments 1-5 or 10, wherein is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl.

[0559] Embodiment 14:R AThe compound of any one of embodiments 1-5, 10, or 13, wherein is pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted with C1-C6 alkoxy or C1-C6 alkyl.

[0560] Embodiment 15:R A The compound of any one of embodiments 1-5, 10, or 13-14, wherein is a 5-6 membered heteroaryl substituted with C1-C6 alkoxy.

[0561] Embodiment 16:R A The compound of any one of embodiments 1-5, 10, or 13-14, wherein is a 5-6 membered heteroaryl substituted with C1-C6 alkyl.

[0562] Embodiment 17:R A The compound of any one of embodiments 1-5, 10, or 13-14, wherein is unsubstituted 5-6 membered heteroaryl.

[0563] Embodiment 18:R 1 teeth, -NR F R G The compound of embodiment 1, wherein R is phenyl optionally substituted with R.

[0564] Embodiment 19:R 1 teeth, -NR F R G The compound of embodiment 1, wherein N is phenyl substituted with N.

[0565] Embodiment 20:R F The compound of embodiment 1 or 19, wherein is C1-C6 alkyl.

[0566] Embodiment 21:R F The compound of any one of embodiments 1 or 19-20, wherein is methyl.

[0567] Embodiment 22:R FThe compound of embodiment 1 or 19, wherein is C3-C6 cycloalkyl.

[0568] Embodiment 23:R F The compound of embodiment 1 or 19, wherein is hydrogen.

[0569] Embodiment 24:R G The compound of any one of embodiments 1 or 19-23, wherein is C1-C6 alkyl.

[0570] Embodiment 25:R G The compound of any one of embodiments 1 or 19-24, wherein is methyl.

[0571] Embodiment 26:R G The compound of any one of embodiments 1 or 19-23, wherein is —C(═O)—C1-C6 alkyl.

[0572] Embodiment 27:R G The compound of any one of embodiments 1, 19-23, or 26, wherein is —C(═O)CH 3 .

[0573] Embodiment 28:R G The compound of any one of embodiments 1 or 19-23, wherein is —C(═O)—C3-C6 cycloalkyl.

[0574] Embodiment 29:R G The compound of any one of embodiments 1 or 19-23, wherein is hydrogen.

[0575] Embodiment 30:R F and R G and n are the same.

[0576] Embodiment 31:R F and R G and n is different.

[0577] Embodiment 32:RF and R G and n is 0 or 1. The compound of embodiment 1 or 19, wherein each is hydrogen.

[0578] Embodiment 33:R F and R G and R are each methyl.

[0579] Embodiment 34:R F is hydrogen and R G is C1-C6 alkyl.

[0580] Embodiment 35:R F is hydrogen and R G The compound of embodiment 1 or 19, wherein is —C(═O)—C1-C6 alkyl.

[0581] Embodiment 36:R 1 is -QR C 2. The compound of embodiment 1, wherein

[0582] Embodiment 37: The compound of embodiment 1 or 36, wherein Q is C1-C6 alkylene.

[0583] Embodiment 38: A compound of any one of embodiments 1 or 36-37, wherein Q is C1-C2 alkylene.

[0584] Embodiment 39: The compound of any one of embodiments 1 or 36-38, wherein Q is methylene.

[0585] Embodiment 40: The compound of embodiment 1 or 36, wherein Q is NH.

[0586] Embodiment 41: The compound of embodiment 1 or 36, wherein Q is O.

[0587] Embodiment 42:R 1 teeth, [ka] 2. The compound of embodiment 1, wherein

[0588] Embodiment 43:R H The compound of embodiment 1 or 42, wherein is a 4-6 membered heterocyclyl substituted with 1-2 independently selected C1-C6 alkyl.

[0589] Embodiment 44:R H The compound of any one of embodiments 1 or 42-43, wherein is a 4-6 membered heterocyclyl substituted with one C1-C6 alkyl.

[0590] Embodiment 45:R H The compound of any one of embodiments 1 or 42-44, wherein is 4-6 membered heterocyclyl substituted with methyl.

[0591] Embodiment 46:R H The compound of any one of embodiments 1 or 42-43, wherein is a 4-6 membered heterocyclyl substituted with two independently selected C1-C6 alkyl.

[0592] Embodiment 47:R H The compound of any one of embodiments 1, 42-43, or 46, wherein is a 4-6 membered heterocyclyl substituted with two methyl.

[0593] Embodiment 48:R H The compound of any one of embodiments 1 or 42, wherein is oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1-2 independently selected C1-C6 alkyl.

[0594] Embodiment 49:R 2 -CO2R B The compound of any one of embodiments 1-48, wherein R is C3-C6 cycloalkyl optionally substituted with R.

[0595] Embodiment 50:R 2 -CO2R B The compound of any one of embodiments 1-49, wherein the compound is C3-C6 cycloalkyl substituted with

[0596] Embodiment 51:R B The compound of any one of embodiments 1-50, wherein is C1-C6 alkyl.

[0597] Embodiment 52:R B The compound of any one of embodiments 1-51, wherein is methyl.

[0598] Embodiment 53:R B The compound of any one of embodiments 1-50, wherein is hydrogen.

[0599] Embodiment 54:R 2 The compound of any one of embodiments 1-49, wherein is unsubstituted C3-C6 cycloalkyl.

[0600] Embodiment 55:R 2 The compound of any one of embodiments 1-48, wherein is 5-10 membered heteroaryloxy.

[0601] Embodiment 56:R 2 The compound of any one of embodiments 1-48 or 55, wherein is 9-10 membered heteroaryloxy.

[0602] Embodiment 57:R 2 The compound of any one of embodiments 1-48 or 55, wherein is 5-6 membered heteroaryloxy.

[0603] Embodiment 58:R 2 is -(C1-C6 alkylene) optionally substituted with C1-C6 alkyl, cyano, or 4- to 6-membered heterocyclyl; p The compound of any one of embodiments 1-48, wherein: -5-10 membered heteroaryl.

[0604] Embodiment 59:R 2 is -(C1-C6 alkylene) substituted with C1-C6 alkyl, cyano, or 4- to 6-membered heterocyclyl p The compound of any one of embodiments 1-48 or 58, wherein: -5-10 membered heteroaryl.

[0605] Embodiment 60:R 2 is -(C1-C6 alkylene) substituted with C1-C6 alkyl p The compound of any one of embodiments 1-48 or 58-59, wherein: -5-10 membered heteroaryl.

[0606] Embodiment 61:R 2 is -(C1-C6 alkylene) substituted with methyl p The compound of any one of embodiments 1-48 or 58-60, wherein: -5-10 membered heteroaryl.

[0607] Embodiment 62:R 2 is a cyano-substituted -(C1-C6 alkylene) p The compound of any one of embodiments 1-48 or 58-59, wherein: -5-10 membered heteroaryl.

[0608] Embodiment 63:R 2 is a 4- to 6-membered heterocyclyl-substituted -(C1-C6 alkylene) p The compound of any one of embodiments 1-48 or 58-59, wherein: -5-10 membered heteroaryl.

[0609] Embodiment 64:R 2 -(C1-C6 alkylene) substituted with oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl p The compound of any one of embodiments 1-48, 58-59, or 63, wherein: -5-10 membered heteroaryl.

[0610] Embodiment 65:R 2is unsubstituted -(C1-C6 alkylene) p The compound of any one of embodiments 1-48 or 58, wherein: -5-10 membered heteroaryl.

[0611] Embodiment 66: The compound of any one of embodiments 1-48 or 58-65, wherein p is 1.

[0612] Embodiment 67: The compound of any one of embodiments 1-48 or 58-65, wherein p is 0.

[0613] Embodiment 68:R 2 is cyano or -NR D R E -(C1-C6 alkylene) optionally substituted with t -phenyl.

[0614] Embodiment 69:R 2 is cyano or -NR D R E -(C1-C6 alkylene) substituted with t The compound of any one of embodiments 1-48 or 68, wherein N is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,

[0615] Embodiment 70:R 2 is -NR D R E -(C1-C6 alkylene) substituted with t The compound of any one of embodiments 1-48 or 68-69, wherein N is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,

[0616] Embodiment 71:R D The compound of any one of embodiments 1-48 or 68-70, wherein is C1-C6 alkyl.

[0617] Embodiment 72:R D The compound of any one of embodiments 1-48 or 68-71, wherein is methyl.

[0618] Embodiment 73:RD The compound of any one of embodiments 1-48 or 68-70, wherein is C3-C6 cycloalkyl.

[0619] Embodiment 74:R D The compound of any one of embodiments 1-48 or 68-70, wherein is hydrogen.

[0620] Embodiment 75:R E The compound of any one of embodiments 1-48 or 68-74, wherein is C1-C6 alkyl.

[0621] Embodiment 76:R E The compound of any one of embodiments 1-48 or 68-75, wherein is methyl.

[0622] Embodiment 77:R E The compound of any one of embodiments 1-48 or 68-74, wherein is C3-C6 cycloalkyl.

[0623] Embodiment 78:R E The compound of any one of embodiments 1-48 or 68-74, wherein is hydrogen.

[0624] Embodiment 79: The compound of any one of embodiments 1 to 48 or 68 to 78, wherein t is 1.

[0625] Embodiment 80: The compound of any one of embodiments 1-48 or 68-78, wherein t is 0.

[0626] Embodiment 81:R 2 The compound of any one of embodiments 1-48, wherein is 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0627] Embodiment 82:R 2 The compound of any one of embodiments 1-48 or 81, wherein is 4-6 membered heterocyclyl substituted with C1-C6 alkyl.

[0628] Embodiment 83:R 2 The compound of any one of embodiments 1-48 or 81-82, wherein is 4-6 membered heterocyclyl substituted with methyl.

[0629] Embodiment 84:R 2 82. The compound of any one of embodiments 1-48 or 81, wherein is oxetanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with C1-C6 alkyl.

[0630] Embodiment 85:R 3 The compound of any one of embodiments 1-84, wherein is C1-C3 alkyl.

[0631] Embodiment 86:R 3 The compound of any one of embodiments 1-85, wherein is methyl.

[0632] Embodiment 87:R C The compound of any one of embodiments 1-86, wherein is 4-10 membered heterocyclyl.

[0633] Embodiment 88:R C The compound of any one of embodiments 1-87, wherein is 4-6 membered heterocyclyl.

[0634] Embodiment 89:R C The compound of any one of embodiments 1-86, wherein is 5-10 membered heteroaryl.

[0635] Embodiment 90:R C The compound of any one of embodiments 1-86 or 89, wherein is a 5-6 membered heteroaryl.

[0636] Embodiment 91:R C is -(C1-C6 alkylene)-NR D R EThe compound of any one of embodiments 1-86, wherein R is phenyl optionally substituted with R.

[0637] Embodiment 92:R C is -(C1-C6 alkylene)-NR D R E The compound of any one of embodiments 1-86 or 91, wherein the compound is phenyl substituted with

[0638] Embodiment 93:R C is -(C1-C2 alkylene)-NR D R E The compound of any one of embodiments 1-86 or 91-92, wherein the compound is phenyl substituted with

[0639] Embodiment 94:R D The compound of any one of embodiments 91-93, wherein is C1-C6 alkyl.

[0640] Embodiment 95:R D The compound of any one of embodiments 91-94, wherein is methyl.

[0641] Embodiment 96:R D The compound of any one of embodiments 91-93, wherein is C3-C6 cycloalkyl.

[0642] Embodiment 97:R D The compound of any one of embodiments 91-93, wherein is hydrogen.

[0643] Embodiment 98:R E The compound of any one of embodiments 91-97, wherein is C1-C6 alkyl.

[0644] Embodiment 99:R E The compound of any one of embodiments 91-98, wherein is methyl.

[0645] Embodiment 100:R EThe compound of any one of embodiments 91-97, wherein is C3-C6 cycloalkyl.

[0646] Embodiment 101:R E The compound of any one of embodiments 91-97, wherein is hydrogen.

[0647] Embodiment 102:R C The compound of any one of embodiments 1-86 or 91, wherein is unsubstituted phenyl.

[0648] Embodiment 103: A compound according to any one of embodiments 1 to 102, wherein m is 1.

[0649] Embodiment 104: A compound according to any one of embodiments 1 to 102, wherein m is 0.

[0650] Embodiment 105: A compound of any one of embodiments 1 to 102, wherein ring A is a 5-6 membered heteroaryl.

[0651] Embodiment 106: A compound according to any one of embodiments 1 to 102, wherein Ring A is thiazolyl, pyrazolyl, imidazolidinon-2-yl, pyridinyl, pyrimidinyl, pyridon-2-yl, pyrimidinonyl, or oxazolidinon-2-yl.

[0652] Embodiment 107: Ring A is [ka] The compound of any one of embodiments 1-102 or 105, wherein

[0653] Embodiment 108: Ring A is [ka] The compound of any one of embodiments 1-102 or 105, wherein

[0654] Embodiment 109: Ring A is [ka] The compound of any one of embodiments 1-102 or 105, wherein

[0655] Embodiment 110: Ring A is [ka] The compound of any one of embodiments 1-102 or 105, wherein

[0656] Embodiment 111: Ring A is [ka] The compound of any one of embodiments 1-102 or 105, wherein

[0657] Embodiment 112: Ring A is [ka] The compound of any one of embodiments 1-102 or 105, wherein

[0658] Embodiment 113: Ring A is [ka] The compound of any one of embodiments 1-102 or 105, wherein

[0659] Embodiment 114: A compound according to any one of embodiments 1 to 102, wherein ring A is a 5- to 6-membered heterocyclyl.

[0660] Embodiment 115: A compound of any one of embodiments 1 to 102 or 114, wherein Ring A is an oxazolidinone or pyrrolidinone.

[0661] Embodiment 116: Ring A is [ka] 115. The compound of any one of embodiments 1-102 or 114, wherein

[0662] Embodiment 117: Ring A is [ka] 115. The compound of any one of embodiments 1-102 or 114, wherein

[0663] Further exemplary embodiments of compounds of Formulas (I), (II), and (III): Embodiment 1: A compound selected from a compound of Table 1, Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutically acceptable salt thereof.

[0664] Embodiment 2: A pharmaceutical composition comprising a compound of embodiment 1 or any one of the embodiments of a compound of Formula (I), (II), and (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0665] Embodiment 3: A method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of embodiment 1 or any one of the embodiments of a compound of Formula (I), (II), and (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 2.

[0666] Embodiment 4: The method of embodiment 3, wherein the neurological disorder is selected from the group consisting of Down's syndrome, Alzheimer's disease, and Alzheimer's disease associated with Down's syndrome.

[0667] Embodiment 5: The method of embodiment 3 or 4, wherein the neurological disorder is selected from Alzheimer's disease associated with Down's syndrome.

[0668] Embodiment 6: A method for treating a subject, comprising administering a therapeutically effective amount of a compound described in embodiment 1 or any one of the embodiments of the compounds of formulae (I), (II), and (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 2, to a subject having medical records indicating that the subject has dysregulation of the expression, activity, or level of the DYRK1A gene, DYRK1A protein, or any of them.

[0669] Embodiment 7: A method for treating a DYRK1A-associated neurological disorder in a subject, comprising administering to a subject who has been identified or diagnosed with a DYRK1A-associated neurological disorder a therapeutically effective amount of a compound described in embodiment 1 or any one of the embodiments of the compounds of formulae (I), (II), and (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 2.

[0670] Embodiment 8: A method of treating a DYRK1A-associated neurological disorder in a subject, comprising: determining that the neurological disorder in the subject is a DYRK1A-associated neurological disorder; and administering to the subject a therapeutically effective amount of a compound of any one of Embodiment 1 or any one of the foregoing embodiments of a compound of Formula (I), (II), and (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 2. The method comprising:

[0671] Embodiment 9: A method for treating a neurological disorder in a subject in need thereof, comprising: (a) determining that the neurological disorder is associated with dysregulation of the expression, activity, or level of the DYRK1A gene, DYRK1A protein, or any of them; and (b) administering to the subject a therapeutically effective amount of a compound described in embodiment 1 or any one of the embodiments of a compound of Formulae (I), (II), and (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 2.

[0672] Embodiment 10: The method of embodiment 8 or 9, wherein the step of determining that the subject's neuropathy is a DYRK1A-associated neuropathy comprises performing an assay to detect dysregulation of the expression or activity or level of the DYRK1A gene, DYRK1A protein, or any of them, in a sample from the subject.

[0673] Embodiment 11: A method of treating a neurological disorder in a subject in need thereof, comprising: (a) determining that the neurological disorder is associated with Down's syndrome; and (b) administering to the subject a therapeutically effective amount of a compound of embodiment 1 or any one of the embodiments of a compound of Formula (I), (II), and (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 2.

[0674] Embodiment 12: The method of embodiment 11, wherein said step of determining that said neurological disorder in said subject is associated with Down syndrome comprises performing an assay on a sample from said subject.

[0675] Embodiment 13: The method of any one of embodiments 8 to 12, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

[0676] Embodiment 14: The method of any one of embodiments 7, 8, or 305, wherein the DYRK1A-associated neurological disorder is selected from the group consisting of Down's syndrome, Alzheimer's disease, and Alzheimer's disease associated with Down's syndrome.

[0677] Embodiment 15: The method of any one of embodiments 7, 8, 305, or 309, wherein the DYRK1A-associated neurological disorder is Alzheimer's disease associated with Down's syndrome.

[0678] Embodiment 16: A method for modulating DYRK1A in a mammalian cell, comprising contacting the mammalian cell with a therapeutically effective amount of a compound of embodiment 1 or any one of the embodiments of the compounds of Formulae (I), (II), and (III), or a pharmaceutically acceptable salt thereof.

[0679] Embodiment 17: The method of embodiment 16, wherein said contacting occurs in vivo.

[0680] Embodiment 18: The method of embodiment 16, wherein said contacting is performed in vitro.

[0681] Embodiment 19: The method of any one of embodiments 16 to 18, wherein the mammalian cell is a mammalian neuronal cell.

[0682] Embodiment 20: The method of embodiment 19, wherein the mammalian neuronal cell is a mammalian DYRK1A-associated neuronal cell.

[0683] Embodiment 21: The method of any one of embodiments 16 to 20, wherein the cell has dysregulated expression or activity or levels of the DYRK1A gene, DYRK1A protein, or either thereof.

[0684] Embodiment 22: The method of any one of embodiments 16 to 21, wherein the cell has a chromosomal abnormality associated with Down's syndrome. [Example]

[0685] Preparation of compounds The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing any standard synthetic methods and procedures known to those skilled in the art or in light of the teachings herein. Synthesis of the compounds disclosed herein can be achieved generally by following the schemes provided herein, with modifications to specific desired substituents.

[0686] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the art. Any one or several sources, including but not limited to, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994), Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001, and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference texts on organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are designed to illustrate, but not limit, general procedures for preparing compounds of the present disclosure.

[0687] The synthetic processes disclosed herein can tolerate a wide variety of functional groups, allowing the use of variously substituted starting materials. Although the processes generally provide the desired final compound at or near the end of the overall process, in certain cases it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0688] Example overview 1 1 H NMR spectra were recorded on a Bruker Avance 400 MHz.

[0689] Unless otherwise indicated, LCMS was performed on a Shimadzu LCMS 2010 quadrupole mass spectrometer (column: Shim-pack XR-ODS (3.0 × 30 mm, 2.2 m)) operating in ESI (+) ionization mode, flow rate: 0.8 mL / min, acquisition time: 2 or 3 min, wavelength: UV220, oven temperature: 50 °C.

[0690] Preparative HPLC was performed under the following conditions: Method A: Column: Fuji C18 (300 × 25), YMC 250 × 20, Wavelength: 220 nm, Mobile phase: A CH3CN (0.05% FA), B water (0.05% FA), Flow rate: 25 mL / min, Injection volume: 2 mL, Run time: 20 min, Equilibration: 3 min. Method B: Column: Fuji C18 (300 × 25), YMC 250 × 20, Wavelength: 220 nm, Mobile phase: A CH3CN (0.05% NH3·H2O as additive), B Water (0.05% NH3·H2O as additive), Flow rate: 25 mL / min, Injection volume: 2 mL, Run time: 20 min, Equilibration: 3 min. Method C: Column: Phenomenex luna C18 (100 × 25), YMC (250 × 20), wavelength: 220 nm, mobile phase: A CHCN, B water (0.225% FA), flow rate: 25 mL / min, injection volume: 2 mL, run time: 10 minutes, equilibration: 3 minutes. Method D: Column: Fuji C18 (300 × 25), YMC 250 × 20, Wavelength: 220 nm, Mobile phase: A CH3CN (0.05% HCOONH4 as additive), B Water (0.05% HCOONH4 as additive), Flow rate: 25 mL / min, Injection volume: 2 mL, Run time: 20 min, Equilibration: 3 min. Method E: Preparative HPLC (0.04%NH3H2O+10mM NH4HCO3 Method F: Phenomenex luna C18 (100 × 25), YMC (250 × 20), wavelength: 220 nm, mobile phase: A CH3CN, B water (0.04% HCl), flow rate: 25 mL / min, injection volume: 2 mL, run time: 10 minutes, equilibration: 3 minutes.

[0691] Abbreviation The following abbreviations have the indicated meanings: Acac = acetylacetone AcCl = acetyl chloride ACE-Cl = 1-chloroethyl chloroformate ACN = acetonitrile BINAP = (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene Bis-Pin = Bis(pinacolato)diboron BnBr = (bromomethyl)benzene BPO = Benzoyl Peroxide Boc = t-butyloxycarbonyl Boc2O = di-tert-butyl dicarbonate BocNH2 = tert-butyl carbamate BrettPhos Pd G3 = Methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) BrettPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl CbzCl = benzyl carbonochloridate Cbz = carbobenzyloxy CDI = 1,1'-carbonyldiimidazole CuCN = copper(I) cyanide CuI = copper(I) iodide CPME = cyclopentyl methyl ether CyJohnphos = (2-biphenyl)dicyclohexylphosphine DAST = diethylaminosulfur trifluoride DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene DCE = 1,2-dichloroethane DCM = dichloromethane DEAD = diethyl azodicarboxylate DIEA = N,N-diisopropylethylamine DIPEA = N,N-diisopropylethylamine DIAD = diisopropyl azodicarboxylate DME = dimethoxyethane DMEDA = N,N'-dimethylethylenediamine DMF = N,N-dimethylformamide DMAP = N,N-dimethylpyridin-4-amine DMSO = dimethyl sulfoxide Dioxane = 1,4-dioxane DPPA = diphenylphosphoryl azide DPPP = 1,3-bis(diphenylphosphino)propane Dtbpy = 4,4'-di-tert-butyl-2,2'-bipyridine EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtI = ethyl iodide EtOAc = ethyl acetate FA = formic acid Second-generation Grubbs catalyst = benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium HATU = N,N,N,N-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HBPin = 4,4,5,5-tetramethyl-1,3,2-dioxaborolane HF / Py = hydrogen fluoride-pyridine HOAc = acetic acid HOBt = 1-hydroxybenzotriazole hydrate HPLC = High-Performance Liquid Chromatography [Ir(OMe)(COD)]2 = bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) KOAc = potassium acetate LAH / THF = 1M THF solution of lithium aluminum hydride LDA = lithium diisopropylamide LiHMDS = lithium bis(trimethylsilyl)amide LC-MS = Liquid Chromatography Mass Spectrometry M-CPBA = 3-chloroperbenzoic acid Me = methyl MeOH = methanol MeCN = acetonitrile Me2SO4 = dimethyl sulfate MsCl = methanesulfonyl chloride NaBH3CN = sodium cyanoborohydride NaOAc = sodium acetate NBS = N-bromosuccinimide n-BuLi = butyllithium n-Bu3SnH = tributyltin hydride NCS = N-chlorosuccinimide NIS = N-iodosuccinimide NMI = 1-methylimidazole NMO = N-methylmorpholine N-oxide NMP = N-methylpyrrolidone NMR=nuclear magnetic resonance PCy3 = tricyclohexylphosphine Pd2(dba)3-CHCl3 = Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct Pd(dppf)Cl2-CH2Cl2 = 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex Pd / C = palladium(0) activated carbon Pd(dtbpf)Cl2 = [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2 = palladium(II) acetate Pd(PCy3)2Cl2 = dichlorobis(tricyclohexylphosphine)palladium(ii) Pd(PPh3)2Cl2 = bis(triphenylphosphine)palladium chloride Pd(PPh3)4 = Tetrakis-(triphenylphosphine)-palladium PE = petroleum ether PPA = polyphosphate PPh3 = triphenylphosphine PPTS = pyridinium p-toluenesulfonate PtO2=platinum(IV) oxide Pre-HPLC = Preparative High Performance Liquid Chromatography RT=room temperature Ruphos-Pd-G2 = Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) Ruphos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl Sat.=saturated SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride Sodium phosphate buffer solution = sodium phosphate Speedvac=Savant SC250EXP SpeedVac concentrator Sulfolane = 1λ 6 -Thiolan-1,1-dione T3P = propanephosphonic cyclic anhydride Trt = trityl protecting group TABF = tetrabutylammonium fluoride trihydrate TBAB = tetrabutylammonium bromide TBHP = tert-butyl hydroperoxide TBSCl = tert-butyldimethylsilyl chloride TCFH = chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate TMAD = N,N,N',N'-tetramethylazodicarboxamide TMEDA = tetramethylethylenediamine TsCl = 4-toluenesulfonyl chloride t-BuOK = potassium tert-butoxide t-BuONO = tert-butyl nitrite t-Bu3PHBF4 = Tri-tert-butylphosphonium tetrafluoroborate TCFH = N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate TEA = trimethylamine TEMPO = 2,2,6,6-tetramethylpiperidinooxy TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran TLC = thin layer chromatography TMAD = tetramethylazodicarboxamide TMSCHNH2 = Trimethylsilyldiazomethane TMSCN = trimethylsilyl cyanide UV=ultraviolet light XantPhos Pd G2 = chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2-amino-1,1-biphenyl)]palladium(II) XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Xphos Pd G3 = Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct X3 = 3 times X2=2 times

[0692] Intermediates of formula (I) Intermediate 1 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline [ka] A mixture of 6-bromoisoquinoline (500 mg, 2.40 mmol), Bis-pin (1.83 g, 7.21 mmol), KOAc (710 mg, 7.23 mmol), and Pd(dppf)Cl.CHCl (294 mg, 0.360 mmol) in anhydrous dioxane (6 mL) was degassed and purged with N three times. The reaction mixture was then stirred at 80 °C under a N atmosphere for 2 h. The mixture was concentrated to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (415 mg, crude) as a black solid, which was used directly in the subsequent step.

[0693] Intermediate 2 6-Bromo-4-iodoisoquinoline [ka] A mixture of 6-bromoisoquinoline (14.0 g, 67.3 mmol), I (34.2 g, 132 mmol), and TBHP (18.2 g, 202 mmol) in DCE (200 mL) was stirred at 120 °C for 24 h. The reaction mixture was quenched with a saturated solution of Na SO (300 mL) at 20 °C, then diluted with HO (100 mL) and extracted with DCM (300 mL × 3). The combined organic layers were washed with brine (700 mL), dried over anhydrous Na SO , filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 120 g SepaFlash® silica flash column, 0–22% ethyl acetate / petroleum ether gradient elution at 75 mL / min) to give 6-bromo-4-iodoisoquinoline (19.0 g, 85% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.73-7.83 (2H, m), 8.22 (1H, s), 8.97 (1H, s), 9.12 (1H, s).

[0694] Intermediate 3 6-Bromoisoquinolin-4-ol [ka] Step 1. Synthesis of N-(4-bromobenzyl)-4-methylbenzenesulfonamide To a solution of (4-bromophenyl)methanamine (10.0 g, 53.8 mmol) and 4-methylbenzenesulfonyl chloride (12.3 g, 64.5 mmol) in DCM (120 mL) was added EtN (16.3 g, 161 mmol), and the mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with saturated aqueous NaHCO (120 mL) and separated. The aqueous phase was extracted with DCM (120 mL × 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, 28-42% ethyl acetate / petroleum ether gradient eluent at 60 mL / min) to give N-(4-bromobenzyl)-4-methylbenzenesulfonamide (16.5 g, 90% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 2.45 (3H, s), 4.09 (2H, d, J = 6.4 Hz), 4.70 (1H, t, J = 6.0 Hz), 7.06-7.12 (2H, m), 7.28-7.35 (2H, m), 7.38-7.43 (2H, m), 7.71-7.78 (2H, m).

[0695] Step 2. Synthesis of ethyl N-(4-bromobenzyl)-N-tosylglycinate To a solution of N-(4-bromobenzyl)-4-methylbenzenesulfonamide (15.4 g, 45.3 mmol) in THF (100 mL), NaH (1.90 g, 47.5 mmol, 60% mineral oil dispersion) was added at 0 °C, and the mixture was stirred at 20 °C for 2 h. Ethyl 2-bromoacetate (11.3 g, 67.9 mmol) was added to the above mixture at 0 °C, and the mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched with HO (200 mL) and extracted with DCM (200 mL × 3). The combined organic layers were washed with brine (250 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, 14-90% ethyl acetate / petroleum ether gradient eluent at 65 mL / min) to give ethyl N-(4-bromobenzyl)-N-tosylglycinate (18.9 g, 98% yield) as a pale yellow solid.

[0696] Step 3. Synthesis of N-(4-bromobenzyl)-N-tosylglycine To a solution of ethyl N-(4-bromobenzyl)-N-tosylglycinate (18.9 g, 44.3 mmol) in THF (150 mL), HO (75 mL), and MeOH (150 mL) was added LiOH.HO (5.58 g, 133 mmol), and the mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated, and the residue was diluted in HO (260 mL), then acidified to pH = 2 with 1 N aqueous HCl and extracted with DCM (230 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give N-(4-bromobenzyl)-N-tosylglycine (17.5 g, crude) as a white solid, which was used in the next step without further purification.

[0697] Step 4. Synthesis of N-(4-bromobenzyl)-N-tosylglycinoyl chloride A solution of N-(4-bromobenzyl)-N-tosylglycine (17.5 g, 43.9 mmol) in SOCl (100 mL) was stirred for 2 h at 80° C. The reaction mixture was concentrated to give N-(4-bromobenzyl)-N-tosylglycinoyl chloride (18.5 g, crude) as a pale yellow solid, which was used in the next step without further purification.

[0698] Step 5. Synthesis of 6-bromo-2-tosyl-2,3-dihydroisoquinolin-4(1H)-one To a solution of N-(4-bromobenzyl)-N-tosylglycinoyl chloride (18.5 g, 44.4 mmol) in DCM (600 mL) was added AlCl (23.7 g, 178 mmol) in small portions at 0 °C, and the mixture was stirred at 20 °C under a N atmosphere for 3 h. The reaction mixture was quenched with 2 N aqueous NaOH to pH = 14, diluted with HO (400 mL), and then separated. The aqueous phase was extracted with DCM (400 mL × 2), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, 22–45% ethyl acetate / petroleum ether gradient elution at 60 mL / min) to give 6-bromo-2-tosyl-2,3-dihydroisoquinolin-4(1H)-one (9.00 g, 47% yield over three steps) as a pale yellow solid.

[0699] Step 6. Synthesis of 6-bromoisoquinolin-4-ol To a solution of 6-bromo-2-tosyl-2,3-dihydroisoquinolin-4(1H)-one (9.00 g, 23.7 mmol) in EtOH (150 mL) was added EtONa (6.44 g, 94.7 mmol) at 0 °C, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with 1 N aqueous HCl to pH = 6 and extracted with EtOAc (200 mL × 5). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, 5–10% MeOH / DCM gradient elution at 60 mL / min) to give 6-bromoisoquinolin-4-ol (4.20 g, 73% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (1H, dd, J = 8.8, 2.0 Hz), 8.02 (1H, d, J = 8.8 Hz), 8.10 (1H, s), 8.26 (1H, d, J = 1.6 Hz), 8.82 (1H, s), 10.64 (1H, brs).

[0700] Intermediate 4 5-(Isoquinolin-6-yl)thiazol-2-amine [ka] Step 1. Synthesis of (E)-6-(2-ethoxyvinyl)isoquinoline A mixture of 6-bromoisoquinoline (1.00 g, 4.81 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.50 g, 7.57 mmol), Pd(dppf)Cl (352 mg, 0.481 mmol), and NaCO (1.53 g, 14.4 mmol) in dioxane (8 mL) and HO (2 mL) was degassed and purged with N three times. The mixture was then stirred at 90 °C under a N atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, 0-30% ethyl acetate / petroleum ether gradient eluent at 40 mL / min) to afford Int-4c (900 mg, yield: 94%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 1.29 (3H, t, J = 6.8 Hz), 3.98 (2H, q, J = 6.8 Hz), 6.04 (1H, d, J = 12.8 Hz), 7.53 (1H, d, J = 12.8 Hz), 7.65 (1H, d, J = 6.0 Hz), 7.69 (1H, s), 7.74 (1H, dd, J = 8.8, 1.6 Hz), 7.97 (1H, d, J = 8.8 Hz), 8.40 (1H, d, J = 6.0 Hz), 9.16 (1H, s).

[0701] Step 2. Synthesis of 5-(isoquinolin-6-yl)thiazol-2-amine To a solution of (E)-6-(2-ethoxyvinyl)isoquinoline (1.10 g, 5.52 mmol) in dioxane (10 mL) and HO (10 mL), NBS (1.08 g, 6.07 mmol) was added portionwise at 0 °C. After the addition, the mixture was stirred at 25 °C for 30 min, and then thiourea (462 mg, 6.07 mmol) was added at 25 °C. The resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, 0–15% MeOH / DCM eluent at 25 mL / min), followed by trituration with MeOH (10 mL) to give 5-(isoquinolin-6-yl)thiazol-2-amine (500 mg, 40% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 7.67 (2H, brs), 7.81-7.91 (2H, m), 8.00 (1H, d, J = 6.0 Hz), 8.07 (1H, dd, J = 8.8, 1.6 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.49 (1H, d, J = 6.0 Hz), 9.39 (1H, s).

[0702] Intermediate 5 6-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,5,6,7,8-hexahydro-2,6-naphthyridine-4-carboxylic acid [ka] Step 1. Synthesis of (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile To a solution of 3-methylisonicotinonitrile (4.66 g, 39.4 mmol) in anhydrous DMF (50 mL) was added DMF-DMA (9.40 g, 78.9 mmol) at 20° C. The mixture was stirred at 145° C. for 16 hours. The reaction mixture was concentrated to give (£)-3-(2-(dimethylamino)vinyl)isonicotinonitrile (6.80 g, yield: 99%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 2.92 (6H, s), 5.03 (1H, d, J = 13.2 Hz), 7.45 (1H, dd, J = 5.2, 0.8 Hz), 7.64 (1H, d, J = 13.2 Hz), 8.08 (1H, d, J = 5.2 Hz), 8.87-8.95 (1H, m).

[0703] Step 2. Synthesis of 2,6-naphthyridin-1(2H)-one To a solution of (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile (6.80 g, 39.3 mmol) in EtOH (70 mL) was added HBr (46.3 g, 274 mmol, 48% aqueous solution) at 20 °C. The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated, then diluted with DCM (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 100% EtOAc in PE) to give 2,6-naphthyridin-1(2H)-one (4.32 g, yield: 75%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.67 (1H, d, J = 7.2 Hz), 7.32 (1H, d, J = 7.2 Hz), 7.96 (1H, d, J = 5.6 Hz), 8.61 (1H, d, J = 5.2 Hz), 9.06 (1H, d, J = 0.8 Hz), 11.63 (1H, brs).

[0704] Step 3. Synthesis of 2-methyl-2,6-naphthyridin-1(2H)-one To a solution of 2,6-naphthyridin-1(2H)-one (4.32 g, 29.6 mmol) in anhydrous DMF (50 mL) was added NaH (4.73 g, 118 mmol, 60% mineral oil dispersion) and MeI (9.44 g, 66.5 mmol) at 0°C. The mixture was stirred at 0°C for 4 h and then at 20°C for 18 h. The reaction mixture was quenched at 0°C by the addition of MeOH (30 mL) and then concentrated. The residue was purified by Combi Flash (0% to 100% EtOAc in PE) to give 2-methyl-2,6-naphthyridin-1(2H)-one (1.60 g, 33% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 3.53 (3H, s), 6.73 (1H, d, J = 7.2 Hz), 7.62 (1H, d, J = 7.2 Hz), 8.00 (1H, d, J = 5.2 Hz), 8.63 (1H, d, J = 5.2 Hz), 9.06 (1H, d, J = 0.8 Hz).

[0705] Step 4. Synthesis of 2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one A mixture of 2-methyl-2,6-naphthyridin-1(2H)-one (1.60 g, 9.99 mmol) and PtO (1.13 g, 4.99 mmol) in absolute EtOH (20 mL) was degassed and purged with H three times, and then the mixture was stirred under H atmosphere (50 psi) at 20° C. for 18 h. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated to give 2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (1.63 g, 99% yield) as a pale gray solid. 1 H NMR (400 MHz, DMSO-d6) δ 2.27 (2H, t, J = 5.2 Hz), 2.84 (2H, t, J = 5.6 Hz), 3.38 (3H, s), 3.57 (2H, s), 5.92 (1H, d, J = 7.2 Hz), 7.42 (1H, d, J = 6.8 Hz).

[0706] Step 5. Synthesis of tert-butyl 6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxylate To a solution of 2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (1.63 g, 9.93 mmol) in anhydrous DCM (20 mL) was added TEA (3.01 g, 29.8 mmol) and BocO (2.38 g, 10.9 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 80% EtOAc in PE) to give tert-butyl 6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxylate (2.49 g, 91% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 1.41 (9H, s), 2.41 (2H, t, J = 5.6 Hz), 3.39 (3H, s), 3.49 (2H, t, J = 5.6 Hz), 4.28 (2H, s), 6.06 (1H, d, J = 6.8 Hz), 7.51 (1H, d, J = 7.2 Hz).

[0707] Step 6. Synthesis of tert-butyl 8-bromo-6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxylate To a solution of tert-butyl 6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxylate (2.49 g, 9.42 mmol) in MeCN (30 mL) was added NBS (1.84 g, 10.4 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated. The residue was diluted with water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 60% EtOAc in PE) to give compound 7, tert-butyl 8-bromo-6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxylate (3.09 g, 93% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.42 (9H, s), 2.39-2.48 (2H, t, J = 5.6 Hz), 3.36 (3H, s), 3.50 (2H, t, J = 5.6 Hz), 4.25 (2H, s), 7.99 (1H, s).

[0708] Step 7. Synthesis of 2-(tert-butyl) 8-ethyl 6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2,8(1H)-dicarboxylate A mixture of tert-butyl 8-bromo-6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2(1H)-carboxylate (1.00 g, 2.91 mmol), Pd(OAc) (131 mg, 0.582 mmol), KCO (805 mg, 5.83 mmol), and dppp (480 mg, 1.17 mmol) in anhydrous DMF (2 mL) and EtOH (10 mL) was degassed and purged with CO three times, and then the mixture was stirred under a CO atmosphere (50 psi) at 80 °C for 18 h. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated. The residue was purified by Combi Flash (0% to 50% EtOAc in PE) to give 2-(tert-butyl)-8-ethyl 6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2,8(1H)-dicarboxylate (860 mg, yield: 56%) as a pale yellow oil.

[0709] Step 8. Synthesis of 6-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,5,6,7,8-hexahydro-2,6-naphthyridine-4-carboxylic acid To a solution of 2-(tert-butyl)-8-ethyl 6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridine-2,8(1H)-dicarboxylate (860 mg, 2.56 mmol) in THF (10 mL) and HO (2.5 mL) was added LiOH.HO (214 mg, 5.11 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with HO (25 mL) and washed with EtOAc (25 mL × 2). The aqueous layer was acidified to pH = 5 with 1 N aqueous HCl and then extracted with EtOAc (30 mL × 2) and DCM / MeOH (30 mL × 3, 10 / 1). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 6-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,5,6,7,8-hexahydro-2,6-naphthyridine-4-carboxylic acid (200 mg, yield: 24%) as a white solid.

[0710] Intermediate 6 5-(4-chloroisoquinolin-6-yl)thiazol-2-amine [ka] Step 1. Synthesis of 6-bromo-4-chloroisoquinoline A solution of 6-bromoisoquinoline (500 mg, 2.40 mmol) in SO2Cl2 (5 mL) was stirred at 40 °C under a N2 atmosphere for 16 h. The reaction mixture was added dropwise to saturated aqueous Na2CO3 (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, 0–7% ethyl acetate / petroleum ether gradient elution at 30 mL / min) to give 6-bromo-4-chloroisoquinoline (270 mg, 46% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.80 (1H, dd, J = 8.4, 1.6 Hz), 7.90 (1H, d, J = 8.4 Hz), 8.41 (1H, s), 8.63 (1H, s), 9.14 (1H, s).

[0711] Step 2. Synthesis of (E)-4-chloro-6-(2-ethoxyvinyl)isoquinoline A mixture of 6-bromo-4-chloroisoquinoline (270 mg, 1.11 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (331 mg, 1.67 mmol), Pd(dppf)Cl (81 mg, 0.11 mmol), and NaCO (354 mg, 3.34 mmol) in dioxane (4 mL) and HO (1 mL) was degassed and purged with N three times. The mixture was then stirred at 90 °C under a N atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, 0-15% ethyl acetate / petroleum ether gradient elution at 40 mL / min) to give (£)-4-chloro-6-(2-ethoxyvinyl)isoquinoline (140 mg, 54% yield) as a yellow solid.

[0712] Step 3. Synthesis of 5-(4-chloroisoquinolin-6-yl)thiazol-2-amine To a solution of (E)-4-chloro-6-(2-ethoxyvinyl)isoquinoline (140 mg, 0.599 mmol) in dioxane (5 mL) and HO (5 mL) was added NBS (117 mg, 0.659 mmol) at 0° C. The mixture was stirred at 25° C. for 30 minutes. Then, thiourea (50 mg, 0.66 mmol) was added at 25° C. The resulting mixture was stirred at 100° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. The residue was triturated with MeOH (2 mL) to give 5-(4-chloroisoquinolin-6-yl)thiazol-2-amine (100 mg, yield: 64%) as a yellow solid.

[0713] Intermediate 7 5-(4-methylisoquinolin-6-yl)thiazol-2-amine [ka] Step 1. Synthesis of 6-bromo-4-methylisoquinoline A mixture of compound Int-2 (827 mg, 3.29 mmol), trimethylboroxine (1.10 g, 3.29 mmol), Pd(dppf)Cl (241 mg, 0.329 mmol), and KPO (1.40 g, 6.59 mmol) in 1,4-dioxane (30 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under N atmosphere for 12 h. The reaction mixture was concentrated, and the residue was diluted with water (25 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 15% EtOAc in PE) to give 6-bromo-4-methylisoquinoline (250 mg, yield: 34%) as a yellow oil.

[0714] Step 2. Synthesis of (E)-6-(2-ethoxyvinyl)-4-methylisoquinoline A mixture of 6-bromo-4-methylisoquinoline (250 mg, 1.13 mmol), (E)-1-ethoxyethene-2-boronic acid pinacol ester (267 mg, 1.35 mmol), NaCO (239 mg, 2.25 mmol), and Pd(dppf)Cl (83 mg, 0.11 mmol) in 1,4-dioxane (10 mL) and HO (1 mL) was degassed and purged with N three times, and then the mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The reaction mixture was concentrated, and the residue was purified by Combi Flash (0% to 30% EtOAc in PE) to give (E)-6-(2-ethoxyvinyl)-4-methylisoquinoline (200 mg, yield: 83%) as a yellow oil.

[0715] Step 3. Synthesis of 5-(4-methylisoquinolin-6-yl)thiazol-2-amine To a solution of (E)-6-(2-ethoxyvinyl)-4-methylisoquinoline (200 mg, 937.76 μmol) in 1,4-dioxane (3 mL) and HO (3 mL) was added NBS (184 mg, 1.03 mmol) at 0° C. The reaction mixture was then stirred at 25° C. for 0.5 h. Thiourea (79 mg, 1.0 mmol) was added, and the resulting reaction mixture was stirred at 100° C. for 1.5 h. The reaction mixture was concentrated, and the crude product was triturated with MeOH (10 mL) to give 5-(4-methylisoquinolin-6-yl)thiazol-2-amine (150 mg, yield: 66%) as a yellow solid.

[0716] Intermediate 8 6-Bromo-4-methoxyisoquinoline [ka] To a solution of compound Int-3 (300 mg, 1.34 mmol) in anhydrous DMF (4 mL), NaH (64 mg, 1.6 mmol, 60% mineral oil dispersion) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. MeI (247 mg, 1.74 mmol) was added to the above reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, 20% to 25% ethyl acetate / petroleum ether gradient elution at 25 mL / min) to give 6-bromo-4-methoxyisoquinoline (60 mg, yield: 19%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.05 (3H, s), 7.85 (1H, dd, J = 8.8, 2.0 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.21-8.28 (2H, m), 8.97 (1H, s).

[0717] Intermediate 9 5-(4-Methoxyisoquinolin-6-yl)thiazol-2-amine [ka] Step 1. Synthesis of tert-butyl (5-bromothiazol-2-yl)(4-methoxybenzyl)carbamate To a mixture of tert-butyl (5-bromothiazol-2-yl)carbamate (2.00 g, 7.16 mmol), PMBOH (1.98 g, 14.3 mmol), and PPh (4.13 g, 15.8 mmol) in THF (20 mL) was added DIAD (3.19 g, 15.8 mmol) at 0 °C, and the mixture was stirred at 0 °C for 15 min and then at 20 °C for 2 h under a N atmosphere. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, 0–2% ethyl acetate / petroleum ether gradient elution at 35 mL / min) to give tert-butyl (5-bromothiazol-2-yl)(4-methoxybenzyl)carbamate (2.20 g, 77% yield) as a white solid.

[0718] Step 2. Synthesis of tert-butyl (4-methoxybenzyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate To a solution of tert-butyl (5-bromothiazol-2-yl)(4-methoxybenzyl)carbamate (1.70 g, 4.26 mmol) in anhydrous THF (20 mL), n-BuLi (1.7 mL, 4.25 mmol, 2.5 M in hexane) was added dropwise at −78 °C under a N atmosphere, and the mixture was stirred at −78 °C for 0.5 h. Bis-Pin (1.41 g, 5.53 mmol) in anhydrous THF (5 mL) was added to the reaction mixture, and the mixture was stirred at −78 °C under a N atmosphere for an additional 1.5 h. The reaction mixture was quenched with saturated aqueous NH Cl (20 mL), diluted with HO (20 mL), and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, 8-40% ethyl acetate / petroleum ether gradient elution at 45 mL / min) to afford tert-butyl (4-methoxybenzyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (1.30 g, 68% yield) as a pale yellow solid.

[0719] Step 3. Synthesis of tert-butyl (4-methoxybenzyl)(5-(4-methoxyisoquinolin-6-yl)thiazol-2-yl)carbamate To a solution of tert-butyl (4-methoxybenzyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (120 mg, 0.504 mmol) and compound Int-8 (450 mg, 1.01 mmol) in 1,4-dioxane (6 mL) and HO (1.2 mL) was added Pd(dppf)Cl (55 mg, 0.076 mmol) and NaCO (107 mg, 1.01 mmol) under a N atmosphere, and the mixture was stirred at 90 °C under a N atmosphere for 12 hours. The reaction mixture was concentrated to remove the solvent. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, 55-58% ethyl acetate / petroleum ether gradient elution at 25 mL / min) to afford tert-butyl (4-methoxybenzyl)(5-(4-methoxyisoquinolin-6-yl)thiazol-2-yl)carbamate (160 mg, 67% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 1.56 (9H, s), 3.80 (3H, s), 4.09 (3H, s), 5.30 (2H, s), 6.81-6.88 (2H, m), 7.30-7.39 (2H, m), 7.82-7.88 (2H, m), 7.93 (1H, d, J = 8.4 Hz), 8.07 (1H, s), 8.31 (1H, s), 8.85 (1H, s).

[0720] Step 4. Synthesis of 5-(4-methoxyisoquinolin-6-yl)thiazol-2-amine A solution of tert-butyl (4-methoxybenzyl)(5-(4-methoxyisoquinolin-6-yl)thiazol-2-yl)carbamate (160 mg, 0.335 mmol) in TFA (5 mL) was stirred at 60 °C for 16 h. The reaction mixture was concentrated, and the residue was basified with 2 N aqueous NaOH to pH = 10, diluted with HO (30 mL), and extracted with DCM / MeOH (30 mL × 3, 10 / 1). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, 6–7% MeOH / DCM gradient elution at 25 mL / min) to give 5-(4-methoxyisoquinolin-6-yl)thiazol-2-amine (54 mg, 63% yield) as a yellow solid.

[0721] Intermediate 10 5-(5-chloroisoquinolin-6-yl)thiazol-2-amine [ka] Step 1. Synthesis of 6-bromo-5-chloroisoquinoline To a mixture of 6-bromoisoquinoline (500 mg, 2.40 mmol) in concentrated HSO (10 mL) was added NCS (1.80 g, 13.5 mmol) at 0 °C, and then the mixture was stirred at 50 °C under a N atmosphere for 24 h. The reaction mixture was slowly poured into saturated aqueous NaCO (100 mL) at 0 °C and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give 6-bromo-5-chloroisoquinoline (580 mg, yield: >99%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.76-7.80 (1H, m), 7.80-7.85 (1H, m), 8.06 (1H, d, J = 6.0 Hz), 8.68 (1H, d, J = 6.0 Hz), 9.26 (1H, s).

[0722] Step 2. Synthesis of (E)-5-chloro-6-(2-ethoxyvinyl)isoquinoline A mixture of 6-bromo-5-chloroisoquinoline (300 mg, 1.24 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (368 mg, 1.86 mmol), Pd(dppf)Cl (91 mg, 0.12 mmol), and NaCO (393 mg, 3.71 mmol) in dioxane (4 mL) and HO (1 mL) was degassed and purged with N three times. The mixture was then stirred at 90 °C under a N atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, 0-16% ethyl acetate / petroleum ether gradient eluent at 40 mL / min) to give (£)-5-chloro-6-(2-ethoxyvinyl)isoquinoline (240 mg, 83% yield) as a yellow solid.

[0723] Step 3. Synthesis of 5-(5-chloroisoquinolin-6-yl)thiazol-2-amine To a solution of (E)-5-chloro-6-(2-ethoxyvinyl)isoquinoline (240 mg, 1.03 mmol) in dioxane (3 mL) and HO (3 mL) was added NBS (201 mg, 1.13 mmol) at 0° C. The mixture was stirred at 25° C. for 30 minutes. Then, thiourea (86 mg, 1.1 mmol) was added at 25° C. The resulting mixture was stirred at 100° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. The residue was triturated with EtOAc (3 mL) to give 5-(5-chloroisoquinolin-6-yl)thiazol-2-amine (210 mg, yield: 78%) as a yellow solid.

[0724] Intermediate 11 6-Bromo-5-methylisoquinoline [ka] Step 1. Synthesis of (3-bromo-2-methylphenyl)methanol To a solution of 3-bromo-2-methylbenzoic acid (10.0 g, 46.5 mmol) in anhydrous THF (100 mL) was added BH3.Me2S (6.98 mL, 10 M) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with 1 N aqueous HCl (30 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give (3-bromo-2-methylphenyl)methanol (9.00 g, yield: 96%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 2.45 (3H, s), 4.74 (2H, s), 7.08 (1H, t, J = 7.6 Hz), 7.34 (1H, d, J = 7.2 Hz), 7.53 (1H, d, J = 8.0 Hz).

[0725] Step 2. Synthesis of 1-bromo-3-(bromomethyl)-2-methylbenzene To a solution of (3-bromo-2-methylphenyl)methanol (9.00 g, 44.8 mmol) in DCM (100 mL) was added PBr (12.1 g, 44.8 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with saturated aqueous NaCO (70 mL) at 25 °C and extracted with EtOAc (70 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 1 / 0 to 10 / 1) to give 1-bromo-3-(bromomethyl)-2-methylbenzene (10.0 g, yield: 85%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 2.40 (3H, s), 4.44 (2H, s), 6.94 (1H, t, J = 7.6 Hz), 7.17 (1H, d, J = 6.4 Hz), 7.44 (1H, d, J = 8.0 Hz).

[0726] Step 3. Synthesis of 2-(3-bromo-2-methylphenyl)acetonitrile To a solution of 1-bromo-3-(bromomethyl)-2-methylbenzene (10.0 g, 37.9 mmol) in MeOH (100 mL) was added KF (11.0 g, 189 mmol) and TMSCN (18.8 g, 189 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated, and the residue was diluted with water (40 mL) and extracted with EtOAc (70 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 10 / 1 to 5 / 1) to give 2-(3-bromo-2-methylphenyl)acetonitrile (6.50 g, yield: 82%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 2.45 (3H, s), 3.74 (2H, s), 7.09 (1H, t, J = 7.6 Hz), 7.33 (1H, d, J = 7.6 Hz), 7.57 (1H, d, J = 8.0 Hz).

[0727] Step 4. Synthesis of 2-(3-bromo-2-methylphenyl)ethan-1-amine To a solution of 2-(3-bromo-2-methylphenyl)acetonitrile (6.00 g, 28.6 mmol) in anhydrous THF (100 mL) was added BH3.Me2S (5.71 mL, 10 M) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with 1 N aqueous HCl (20 mL) at 25 °C and concentrated. The mixture was then basified with 2 N aqueous NaOH to pH = 10 and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 2-(3-bromo-2-methylphenyl)ethan-1-amine (5.00 g, yield: 82%) as a colorless oil.

[0728] Step 5. Synthesis of N-(3-bromo-2-methylphenethyl)formamide To a solution of HCOOH (2.24 g, 46.7 mmol) in THF (100 mL) was added CDI (7.57 g, 46.7 mmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. Then, 2-(3-bromo-2-methylphenyl)ethan-1-amine (5.00 g, 23.4 mmol) was added to the reaction mixture at 0 °C and stirred at 25 °C for another 0.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (PE / EtOAc = 3 / 1 to 1 / 1) to give N-(3-bromo-2-methylphenethyl)formamide (3.20 g, yield: 57%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 2.45 (3H, s), 2.94 (2H, t, J = 7.2 Hz), 3.54 (2H, t, J = 6.8 Hz), 5.64 (1H, brs), 6.95-7.05 (1H, m), 7.08-7.13 (1H, m), 7.48 (1H, d, J = 7.2 Hz), 8.18 (1H, s).

[0729] Step 6. Synthesis of 6-bromo-5-methyl-3,4-dihydroisoquinoline A solution of N-(3-bromo-2-methylphenethyl)formamide (1.00 g, 4.13 mmol) in PPA (5 mL) was stirred at 120 °C for 12 h. The reaction mixture was quenched with 30% aqueous NH3.HO until pH = 9 and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 6-bromo-5-methyl-3,4-dihydroisoquinoline (800 mg, yield: 86%) as a yellow oil.

[0730] Step 7. Synthesis of 6-bromo-5-methylisoquinoline To a solution of 6-bromo-5-methyl-3,4-dihydroisoquinoline (800 mg, 3.57 mmol) in toluene (10 mL) was added MnO (931 mg, 10.7 mmol) at 25 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 6-bromo-5-methylisoquinoline (500 mg, yield: 59%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 2.70 (3H, s), 7.53-7.76 (3H, m), 8.52 (1H, d, J = 6.0 Hz), 9.13 (1H, s).

[0731] Intermediate 12 5-(3-methylisoquinolin-6-yl)thiazol-2-amine [ka] Step 1. Synthesis of 6-bromo-3-methylisoquinoline To a solution of (4-bromophenyl)methanamine (10.0 g, 53.8 mmol) in DCM (100 mL) were added 1,1-dimethoxypropan-2-one (6.98 g, 59.1 mmol) and MgSO (20.0 g, 166 mmol). The mixture was stirred at 40 °C for 12 h. The reaction mixture was cooled to 25 °C, and NaBHCN (4.05 g, 64.5 mmol) was added and stirred at 25 °C for 5 h. The mixture was filtered, and the filtrate was concentrated. The residue was cooled to -10 °C, and ClSO H (52.5 g, 451 mmol) was added dropwise at -10 °C. The reaction mixture was heated at 100 °C for 10 min and poured into ice. The mixture was basified to pH = 10 with 2 N aqueous NaOH and extracted with DCM (100 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 30% EtOAc in PE) to give 6-bromo-3-methylisoquinoline (2.30 g, yield: 19%) as a white solid.

[0732] Step 2. Synthesis of (E)-6-(2-ethoxyvinyl)-3-methylisoquinoline A mixture of 6-bromo-3-methylisoquinoline (500 mg, 2.25 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (535 mg, 2.70 mmol), Pd(dppf)Cl (165 mg, 0.225 mmol), and NaCO (477 mg, 4.50 mmol) in 1,4-dioxane (10 mL) and HO (1 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was diluted with HO (25 mL) and extracted with EtOAc (25 mL × 2). The combined organic layers were washed with brine (25 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 30% EtOAc in PE) to give (E)-6-(2-ethoxyvinyl)-3-methylisoquinoline (370 mg, yield: 77%) as a yellow solid.

[0733] Step 3. Synthesis of 5-(3-methylisoquinolin-6-yl)thiazol-2-amine To a solution of (E)-6-(2-ethoxyvinyl)-3-methylisoquinoline (170 mg, 0.797 mmol) in 1,4-dioxane (2 mL) and HO (2 mL) was added NBS (156 mg, 0.877 mmol) at 0° C. After the addition, the mixture was stirred at 25° C. for 30 min. Thiourea (67 mg, 0.88 mmol) was added, and the resulting mixture was stirred at 100° C. for 3.5 h. The reaction was concentrated, and the crude product was triturated with MeOH (10 mL) to give 5-(3-methylisoquinolin-6-yl)thiazol-2-amine (80 mg, 42% yield) as a yellow solid.

[0734] Intermediate 13 6-Bromo-1-methylisoquinoline [ka] To a mixture of 6-bromo-1-chloroisoquinoline (3.00 g, 12.4 mmol), TMEDA (719 mg, 6.19 mmol), and Fe(acac) (437 mg, 1.24 mmol) in anhydrous THF (5 mL) was added MeMgBr (5.4 mL, 3 M in EtO) at 0 °C under N. The mixture was then stirred at 25 °C for 16 h under N. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, 0–7% ethyl acetate / petroleum ether gradient elution at 45 mL / min) to give 6-bromo-1-methylisoquinoline (1.90 g, 69% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 2.87 (3 H, s), 7.34 (1H, d, J = 6.0 Hz), 7.59 (1H, dd, J = 8.8, 2.0 Hz), 7.85-7.95 (2H, m), 8.33 (1H, d, J = 6.0 Hz).

[0735] Intermediate 14 1-Methyl-N-(thiazol-2-yl)piperidine-4-carboxamide [ka] To a suspension of thiazol-2-amine (2.00 g, 20.0 mmol), 1-methylpiperidine-4-carboxylic acid (4.29 g, 30.0 mmol) in pyridine (20 mL) was added EtN (4.04 g, 39.9 mmol) and T3P (38.1 g, 59.9 mmol (50% in EtOAc)) at 10-15 °C. The reaction mixture was then stirred at 50 °C for 16 h. The reaction mixture changed from a suspension to a yellow solution. The reaction mixture was concentrated, and the residue was basified with 1 N aqueous NaOH to pH = 11 and then extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was triturated with PE / EtOAc (20 mL 1 / 1) to give 1-methyl-N-(thiazol-2-yl)piperidine-4-carboxamide (3.60 g, yield: 80%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 1.55-1.70 (2H, m), 1.70-1.80 (2H, m), 1.81-1.91 (2H, m), 2.16 (3 H, s), 2.40-2.46 (1H, m), 2.75-2.85 (2H, m), 7.19 (1H, d, J = 3.6 Hz), 7.46 (1H, d, J = 3.6 Hz), 12.07 (1H, brs).

[0736] Intermediate 15 5-(1,6-naphthyridin-2-yl)thiazol-2-amine [ka] Step 1. Synthesis of 2-chloro-1,6-naphthyridine A mixture of 1,6-naphthyridin-2(1H)-one (500 mg, 3.42 mmol) in POCl3 (8.25 g, 53.8 mmol) was stirred at 120 °C for 3 h. After cooling to 25 °C, the resulting solution was concentrated, and the residue was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by Combi Flash (0% to 30% EtOAc in PE) to give 2-chloro-1,6-naphthyridine (120 mg, yield: 21%) as a pale yellow solid.

[0737] Step 2. Synthesis of (E)-2-(2-ethoxyvinyl)-1,6-naphthyridine A mixture of 2-chloro-1,6-naphthyridine (120 mg, 0.730 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (173 mg, 0.875 mmol), Pd(dppf)Cl (53 mg, 0.073 mmol), and NaCO (155 mg, 1.46 mmol) in 1,4-dioxane (10 mL) and HO (1 mL) was degassed and purged with N three times, and then the mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (25 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 100% EtOAc in PE) to give (E)-2-(2-ethoxyvinyl)-1,6-naphthyridine (70 mg, yield: 48%) as a brown oil.

[0738] Step 3. Synthesis of 5-(1,6-naphthyridin-2-yl)thiazol-2-amine To a solution of (E)-2-(2-ethoxyvinyl)-1,6-naphthyridine (70 mg, 0.35 mmol) in 1,4-dioxane (3 mL) and HO (3 mL) was added NBS (68 mg, 0.39 mmol) at 0 °C. After the addition, the mixture was stirred at 25 °C for 30 min. Thiourea (29 mg, 0.39 mmol) was added, and the resulting mixture was stirred at 100 °C for 4.5 h. The reaction was concentrated, and the residue was purified by Combi Flash (0% to 5% MeOH in DCM) to give 5-(1,6-naphthyridin-2-yl)thiazol-2-amine (50 mg, 63% yield) as a yellow solid.

[0739] Intermediate 16 3-chloro-1,7-naphthyridine [ka] Step 1. Synthesis of 3-bromo-5-chloro-2-methylpyridine To a solution of 5-bromo-6-methylpyridin-3-amine (2.40 g, 12.8 mmol) in CH3CN (25 mL) was added isoamyl nitrite (3.01 g, 25.7 mmol) and CuCl2 (4.31 g, 32.1 mmol) at 25 °C. The mixture was stirred at 70 °C for 2 h. The reaction mixture was quenched with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 3-bromo-5-chloro-2-methylpyridine (2.20 g, yield: 83%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 2.64 (3H, s), 7.83 (1H, d, J = 2.0 Hz, 1H), 8.40 (1H, d, J = 2.0 Hz).

[0740] Step 2. Synthesis of 3-bromo-2-(bromomethyl)-5-chloropyridine To a solution of 3-bromo-5-chloro-2-methylpyridine (1.00 g, 4.84 mmol) in DCE (20 mL) were added NBS (1.29 g, 7.27 mmol) and BPO (235 mg, 0.969 mmol) at 25 °C. The mixture was stirred at 70 °C for 12 h. The mixture was concentrated, and the residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 3-bromo-2-(bromomethyl)-5-chloropyridine (1.10 g, yield: 72%) as a colorless oil.

[0741] Step 3. Synthesis of 3-bromo-5-chloropicolinaldehyde To a solution of 3-bromo-2-(bromomethyl)-5-chloropyridine (1.10 g, 3.85 mmol) in CH3CN (12 mL) was added NMO (903 mg, 7.71 mmol) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 3-bromo-5-chloropicolinaldehyde (500 mg, yield: 56%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.00 (1H, d, J = 2.0 Hz), 8.64 (1H, d, J = 2.0 Hz), 10.12 (1H, s).

[0742] Step 4. Synthesis of 5-chloro-3-((trimethylsilyl)ethynyl)picolinaldehyde To a solution of 3-bromo-5-chloropicolinaldehyde (400 mg, 1.81 mmol) in THF (5 mL) was added CuI (35 mg, 0.18 mmol), EtN (918 mg, 9.07 mmol), Pd(PPh)Cl (127 mg, 0.181 mmol), and ethynyl(trimethyl)silane (267 mg, 2.72 mmol) under a N atmosphere at 25 °C. The mixture was stirred under a N atmosphere at 25 °C for 1 h. The reaction mixture was quenched with HO (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 5-chloro-3-((trimethylsilyl)ethynyl)picolinaldehyde (250 mg, yield: 58%) as a yellow gum. 1 H NMR (400MHz, CDCl3) δ 0.31 (9H, s), 7.92 (1H, d, J = 2.0 Hz), 8.66 (1H, d, J = 2.0 Hz), 10.36 (1H, s).

[0743] Step 5. Synthesis of 3-chloro-1,7-naphthyridine A solution of 5-chloro-3-((trimethylsilyl)ethynyl)picolinaldehyde (250 mg, 1.05 mmol) in 7N NH3 / MeOH (20 mL) was stirred in a sealed tube at 80 °C for 12 h. The reaction mixture was concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 3-chloro-1,7-naphthyridine (50 mg, yield: 29%) as a brown solid. 1 H NMR (400MHz, CDCl3) δ 7.56 (1H, d, J = 5.6 Hz), 8.10 (1H, d, J = 2.0 Hz), 8.60 (1H, d, J = 5.6 Hz), 8.88 (1H, d, J = 2.4 Hz), 9.46 (1H, s).

[0744] Intermediate 17 8-Bromo-4H-quinolizin-4-one [ka] Step 1. Synthesis of ethyl 8-bromo-4-oxo-4H-quinolizine-3-carboxylate To a solution of LDA (1.9 mL, 3.80 mmol, 2 M in THF) in 20 mL of THF was added dropwise 4-bromo-2-methylpyridine (500 mg, 2.91 mmol) in 4 mL of THF over 10 min at -65 °C. After stirring at 65 °C for 40 min, a solution of diethyl 2-(ethoxymethylene)propanedioate (755 mg, 3.49 mmol) in 2 mL of THF was added dropwise to the reaction mixture over 20 min. The mixture was slowly warmed to 25 °C and stirred for an additional 2.5 h. The reaction was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in toluene (4 mL) and stirred at 60 °C for 12 h. The reaction mixture was concentrated, and the residue was purified by Combi Flash (0% to 60% EtOAc in PE) to give compound 2 (230 mg, yield: 27%) as a yellow solid.

[0745] Step 2. Synthesis of 8-bromo-4H-quinolizin-4-one A mixture of ethyl 8-bromo-4-oxo-4H-quinolizine-3-carboxylate (330 mg, 1.11 mmol) in 6 N aqueous HCl (6 mL) was stirred at 100 °C for 12 h under a N atmosphere. The reaction mixture was neutralized with 1 N aqueous NaOH at 0 °C and extracted with EtOAc (25 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 60% EtOAc in PE) to give 8-bromo-4H-quinolizin-4-one (70 mg, yield: 28%) as a yellow solid.

[0746] Intermediate 18 6-Bromo-3-iodopyrazolo[1,5-a]pyridine [ka] To a solution of 6-bromopyrazolo[1,5-a]pyridine (200 mg, 1.02 mmol) in DMF (4 mL) was added NIS (251 mg, 1.12 mmol), and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was poured into water (20 mL) and filtered. The solid was washed with water (10 mL × 2) and dried to give 6-bromo-3-iodopyrazolo[1,5-a]pyridine (300 mg, yield: 91%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.40-7.55 (2H, m), 8.15 (1H, s), 9.12-9.21 (1H, m).

[0747] Intermediate 19 7-Bromo-3-iodoimidazo[1,2-a]pyridine [ka] To a solution of 7-bromoimidazo[1,2-a]pyridine (900 mg, 4.57 mmol) in DMF (10 mL) was added NIS (1.39 g, 6.17 mmol), and the mixture was stirred at 100° C. for 1 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc = 10 / 1) to give compound 2 (850 mg, yield: 58%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.06 (1H, dd, J = 7.2, 1.6 Hz), 7.69 (1H, s), 7.84 (1H, d, J = 1.2 Hz), 8.01 (1H, d, J = 7.6 Hz).

[0748] Intermediate 20 3-Iodo-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine [ka] Step 1. Synthesis of 6-iodopyrazolo[1,5-a]pyridine A mixture of 6-bromopyrazolo[1,5-a]pyridine (2.00 g, 10.2 mmol), CuI (193 mg, 1.02 mmol), NaI (4.56 g, 30.5 mmol), and DMEDA (358 mg, 4.06 mmol) in 1,4-dioxane (30 mL) was degassed and purged with N at 0 °C three times. The resulting mixture was then stirred at 110 °C under a N atmosphere for 2.5 days. The reaction mixture was filtered, and the filtrate was cooled to 0 °C. CuI (193 mg, 1.02 mmol), NaI (4.56 g, 30.5 mmol), and DMEDA (358 mg, 4.06 mmol) were then added. The resulting mixture was degassed and purged with N at 0 °C three times, and then stirred at 110 °C under a N atmosphere for 4 days. The reaction mixture was filtered, and the filter cake was washed with EtOAc (20 mL × 2). The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give 6-iodopyrazolo[1,5-a]pyridine (2.10 g, yield: 68%, purity: 80%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 6.58-6.66 (1H, m), 7.36 (1H, dd, J = 8.8, 1.2 Hz), 7.54 (1H, d, J = 9.2 Hz), 7.93 (1H, d, J = 2.0 Hz), 9.03-9.08 (1H, m).

[0749] Step 2. Synthesis of 6-(trifluoromethyl)pyrazolo[1,5-a]pyridine A mixture of 6-iodopyrazolo[1,5-a]pyridine (2.10 g, 6.88 mmol, purity: 80%), CuI (5.24 g, 27.5 mmol) in DMF (30 mL) was degassed and purged with N three times, then FSOCFCOMe (5.29 g, 27.5 mmol) was added via syringe. The resulting mixture was stirred at 110 °C under a N atmosphere for 40 h. The reaction mixture was filtered and the filter cake was washed with DMF (15 mL × 2). CuI (5.24 g, 27.5 mmol) was then added to the combined filtrate. The mixture was degassed and purged with N three times, then FSOCFCOMe (5.29 g, 27.5 mmol) was added via syringe. The resulting mixture was stirred at 110 °C under a N atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was neutralized with saturated aqueous NaHCO to adjust the pH to 7, then diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give 6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (7.20 g, crude) as a brown oil.

[0750] Step 3. Synthesis of 3-iodo-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine A solution of 6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (7.20 g, 7.32 mmol) and NIS (1.81 g, 8.05 mmol) in DMF (30 mL) was stirred at 25 °C for 16 h. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 10 / 1) to give 3-iodo-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (100 mg, yield: 4%) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.34 (1H, dd, J = 9.2, 1.2 Hz), 7.60 (1H, d, J = 9.2 Hz), 8.10 (1H, s), 8.81 (1H, s).

[0751] Intermediate 21 Ethyl 4-((6-bromoisoquinolin-4-yl)oxy)cyclohexane-1-carboxylate [ka] A mixture of compound Int-3 (500 mg, 2.23 mmol), ethyl 4-hydroxycyclohexane-1-carboxylate (769 mg, 4.46 mmol), TMAD (1.15 g, 6.69 mmol), and n-Bu3P (1.35 g, 6.69 mmol) in anhydrous toluene (40 mL) was stirred at 110 °C for 16 h under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash (0% to 100% EtOAc in PE) to give ethyl 4-((6-bromoisoquinolin-4-yl)oxy)cyclohexane-1-carboxylate (770 mg, yield: 91%) as a colorless oil.

[0752] Intermediate 22 2-Chloro-8-cyclobutoxy-1,6-naphthyridine [ka] Step 1. Synthesis of 4-bromo-3-cyclobutoxypyridine To a solution of 4-bromopyridin-3-ol (500 mg, 2.87 mmol) in DMF (5 mL) were added K2CO3 (794 mg, 5.75 mmol) and bromocyclobutane (776 mg, 5.75 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (0% to 18% EtOAc in PE) to give 4-bromo-3-cyclobutoxypyridine (450 mg, 69% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.68-1.81 (1H, m), 1.89-1.99 (1H, m), 2.24-2.36 (2H, m), 2.49-2.59 (1H, m), 2.53-2.53 (1H, m), 4.74-4.87 (1H, m), 7.53 (1H, d, J = 4.8 Hz), 8.05 (1H, d, J = 5.2 Hz), 8.10 (1H, s).

[0753] Step 2. Synthesis of tert-butyl (3-cyclobutoxypyridin-4-yl)carbamate A mixture of 4-bromo-3-cyclobutoxypyridine (600 mg, 2.63 mmol), BocNH (339 mg, 2.89 mmol), Pd(dba) (241 mg, 0.263 mmol), Xantphos (304 mg, 0.526 mmol), and CsCO (2.57 g, 7.89 mmol) in dioxane (10 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under N for 3 h. The reaction mixture was suspended in CHOH (50 mL) and filtered. The filtrate was concentrated, and the residue was purified by silica gel column (0% to 15% EtOAc in PE) to give tert-butyl (3-cyclobutoxypyridin-4-yl)carbamate (600 mg, 74% yield) as a yellow solid.

[0754] Step 3. Synthesis of 3-cyclobutoxypyridin-4-amine To a solution of tert-butyl (3-cyclobutoxypyridin-4-yl)carbamate (500 mg, 1.89 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated, and the residue was diluted with DCM (100 mL), washed with saturated aqueous NaHCO (50 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give 3-cyclobutoxypyridin-4-amine (350 mg, yield: 94%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.68 (1H, m), 1.72-1.82 (1H, m), 1.99-2.15 (2H, m), 2.35-2.45 (2H, m), 4.61-4.73 (1H, m), 5.61 (2H, brs), 6.53 (1H, d, J = 4.8 Hz), 7.66-7.74 (2H, m).

[0755] Step 4. Synthesis of 3-bromo-5-cyclobutoxypyridin-4-amine To a solution of 3-cyclobutoxypyridin-4-amine (300 mg, 1.83 mmol) in CHCN (5 mL) was added NBS (358 mg, 2.01 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated, and the residue was diluted with DCM (100 mL), washed with saturated aqueous NaSO (30 mL × 2), saturated aqueous NaHCO (30 mL × 2), water (30 mL × 2), brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give 3-bromo-5-cyclobutoxypyridin-4-amine (350 mg, yield: 79%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 1.57-1.68 (1H, m), 1.74-1.84 (1H, m), 2.04-2.16 (2H, m), 2.37-2.47 (2H, m), 4.69-4.81 (1H, m), 5.97 (2H, brs), 7.72 (1H, s), 7.99 (1H, s).

[0756] Step 5. Synthesis of ethyl (E)-3-(4-amino-5-cyclobutoxypyridin-3-yl)acrylate A mixture of 3-bromo-5-cyclobutoxypyridin-4-amine (350 mg, 1.44 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (391 mg, 1.73 mmol), XPhos-Pd-G (122 mg, 0.144 mmol) and KCO (398 mg, 2.88 mmol) in dioxane (10 mL) and HO (1 mL) was degassed and purged with N three times, then the mixture was stirred at 90 °C under N atmosphere for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (0% to 50% EtOAc in PE) to give ethyl (E)-3-(4-amino-5-cyclobutoxypyridin-3-yl)acrylate (300 mg, yield: 72%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.27 (3H, t, J = 7.2 Hz), 1.56-1.69 (1H, m), 1.73-1.85 (1H, m), 2.03-2.16 (2H, m), 2.37-2.45 (2H, m), 4.19 (2H, q, J = 7.2 Hz), 4.67-4.80 (1H, m), 6.17 (2H, brs), 6.47 (1H, d, J = 16.0 Hz), 7.68 (1H, s), 7.88 (1H, d, J = 16.0 Hz), 8.20 (1H, s).

[0757] Step 6. Synthesis of 8-cyclobutoxy-1,6-naphthyridin-2(1H)-one To a solution of (E)-ethyl 3-(4-amino-5-cyclobutoxypyridin-3-yl)acrylate (200 mg, 0.762 mmol) in HOAc (4 mL) was added n-Bu3P (154 mg, 0.762 mmol). The mixture was stirred at 110° C. for 1 hour. The reaction mixture was concentrated, and the residue was triturated with EtOAc (5 mL) to give 8-cyclobutoxy-1,6-naphthyridin-2(1H)-one (200 mg, 81% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.72 (1H, m), 1.77-1.89 (1H, m), 2.17-2.29 (2H, m), 2.41-2.49 (2H, m), 4.85-4.99 (1H, m), 6.60 (1H, d, J = 9.2 Hz), 7.99 (1H, d, J = 9.6 Hz), 8.08 (1H, s), 8.48 (1H, s), 11.52 (1H, brs).

[0758] Step 7. Synthesis of 2-chloro-8-cyclobutoxy-1,6-naphthyridine A mixture of 8-cyclobutoxy-1,6-naphthyridin-2(1H)-one (130 mg, 0.601 mmol) in POCl (3 mL) was stirred for 4 h at 80° C. The reaction mixture was concentrated and the residue was diluted with DCM (80 mL), washed with saturated aqueous NaHCO (30 mL × 2), dried over anhydrous NaSO, filtered and concentrated to give 2-chloro-8-cyclobutoxy-1,6-naphthyridine (150 mg, yield: 92%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.64-1.79 (1H, m), 1.83-1.93 (1H, m), 2.17-2.28 (2H, m), 2.55-2.67 (2H, m), 5.01-5.10 (1H, m), 7.92 (1H, d, J = 8.4 Hz), 8.37 (1H, s), 8.75 (1H, d, J = 8.4 Hz), 9.26 (1H, s).

[0759] Intermediate 23 6-(2-methyloxazol-5-yl)isoquinolin-5-amine [ka] Step 1. Synthesis of 6-bromo-5-nitroisoquinoline To concentrated H2SO4 (13 mL) was added 6-bromoisoquinoline (2.00 g, 9.61 mmol) slowly at 0 °C. After stirring for 6 minutes, KNO3 (1.02 g, 10.1 mmol) was added in portions, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was added dropwise to ice water (150 mL). Then, 28% aqueous ammonia hydrate was added slowly to adjust the pH to 9. The precipitate was collected by filtration and dried to give 6-bromo-5-nitroisoquinoline (2.40 g, yield: 88%) as a yellow solid.

[0760] Step 2. Synthesis of 1-(5-nitroisoquinolin-6-yl)ethan-1-one To a solution of 6-bromo-5-nitroisoquinoline (3.00 g, 11.9 mmol) and tributyl(1-ethoxyvinyl)stannane (6.42 g, 17.8 mmol) in anhydrous toluene (40 mL), Pd(PPh)Cl (832 mg, 1.19 mmol) was added under a N atmosphere, and the mixture was stirred at 100 °C for 16 h under a N atmosphere. THF (30 mL) and 3 N aqueous HCl (30 mL) were added to the reaction mixture, which was then stirred at 50 °C for 5 h. The reaction mixture was concentrated, and the residue was quenched with saturated aqueous KF (40 mL), basified with 2 N aqueous NaOH to pH = 9, and then extracted with EtOAc (80 mL × 2). The combined organic layers were washed with brine (100 mL) and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, approximately 55% ethyl acetate / petroleum ether gradient eluent at 50 mL / min) to give 1-(5-nitroisoquinolin-6-yl)ethan-1-one (1.90 g, yield: 63%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 2.70 (3H, s), 7.82 (1H, d, J = 8.4 Hz), 7.89 (1H, d, J = 6.0 Hz), 8.29 (1H, d, J = 8.4 Hz), 8.79 (1H, d, J = 6.0 Hz), 9.43 (1H, s).

[0761] Step 3. Synthesis of 2-methyl-5-(5-nitroisoquinolin-6-yl)oxazole To a solution of TfOH (5.61 g, 37.4 mmol) and 1-(5-nitroisoquinolin-6-yl)ethan-1-one (1.90 g, 7.47 mmol), iodosylbenzene (4.11 g, 18.7 mmol) in MeCN (20 mL) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 6 min and at 25 °C for 1 h. The reaction mixture was stirred at 85 °C for 24 h. After cooling to room temperature, the reaction mixture was concentrated, and the residue was diluted with HO (20 mL), neutralized with saturated aqueous NaHCO at 0 °C, and extracted with EtOAc (70 mL × 2). The combined organic layers were concentrated, and the residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, approximately 50% EtOAc / PE gradient eluent at 45 mL / min) to give 2-methyl-5-(5-nitroisoquinolin-6-yl)oxazole (2.00 g, yield: 63%) as a yellow solid.

[0762] Step 4. Synthesis of 6-(2-methyloxazol-5-yl)isoquinolin-5-amine A mixture of 2-methyl-5-(5-nitroisoquinolin-6-yl)oxazole (2.00 g, 4.72 mmol), NHCl (1.01 g, 18.9 mmol), and Fe powder (1.05 g, 18.9 mmol) in EtOH (30 mL) and HO (30 mL) was stirred at 75 °C for 2 h. The reaction mixture was filtered through a celite pad, and the solid was washed with DCM / MeOH (20 mL x 3, 10 / 1). The filtrate was concentrated, and the residue was purified by flash silica gel chromatography (ISCO®, 40 g SepaFlash® silica flash column, 2–3% DCM / MeOH (1% NH₃ / HO as additive) gradient elution at 40 mL / min) to give 6-(2-methyloxazol-5-yl)isoquinolin-5-amine (400 mg, 37% yield) as a yellow solid.

[0763] Intermediate 24 Ethyl 3-((6-bromoisoquinolin-5-yl)amino)cyclobutane-1-carboxylate [ka] Step 1. Synthesis of 6-bromoisoquinolin-5-amine A mixture of 6-bromo-5-nitroisoquinoline (3.00 g, 11.9 mmol) and NH4Cl (2.54 g, 47.4 mmol) in EtOH (30 mL) and HO (30 mL) was added with stirring to Fe powder (2.65 g, 47.4 mmol), followed by stirring at 75 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column (PE / EtOAc = 1 / 1) to give 6-bromoisoquinolin-5-amine (2.15 g, yield: 81%) as a pink solid. 1 H NMR (400MHz, DMSO-d6) δ 6.15 (2H, brs), 7.23 (1H, d, J = 8.8 Hz), 7.62 (1H, d, J = 8.4 Hz), 8.10 (1H, d, J = 6.0 Hz), 8.45 (1H, d, J = 6.0 Hz), 9.15 (1H, s).

[0764] Step 2. Synthesis of ethyl 3-((6-bromoisoquinolin-5-yl)amino)cyclobutane-1-carboxylate To a solution of 6-bromoisoquinolin-5-amine (500 mg, 2.24 mmol) and ethyl 3-oxocyclobutane-1-carboxylate (574 mg, 4.03 mmol) in DCM (20 mL) was added TiCl (3.40 g, 17.9 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 5 h. NaBHCN (423 mg, 6.72 mmol) was added to the reaction mixture at 0 °C, and the resulting reaction mixture was stirred at 10 °C for 16 h. The reaction mixture was quenched with MeOH (80 mL), then basified with saturated aqueous NaHCO to pH = 8 and filtered. The filtrate was concentrated, and the residue was diluted with HO (50 mL), then extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc=2 / 1) to give ethyl 3-((6-bromoisoquinolin-5-yl)amino)cyclobutane-1-carboxylate (270 mg, yield: 29%) as a yellow gum. 1 H NMR (400MHz, DMSO-d6) δ 1.15-1.18 (3H, m), 2.26-2.37 (2H, m), 2.37-2.48 (2H, m), 2.58-2.81 (1H, m), 3.86-3.98 (1H, m), 4.01-4.10 (3H, m), 7.59 (1H, d, J = 8.8 Hz), 7.75 (1H, d, J = 8.4 Hz), 7.89-8.00 (1H, m), 8.47-8.58 (1H, m), 9.24 (1H, s).

[0765] Intermediate 25 Methyl (1s,3s)-3-((6-bromoisoquinolin-5-yl)oxy)cyclobutane-1-carboxylate [ka] Step 1. Synthesis of 6-bromoisoquinolin-5-ol To a solution of isoquinolin-5-ol (1.00 g, 6.89 mmol) in CHCl (18 mL) and MeOH (2 mL) was added dropwise a solution of 2,4,4,6-tetrabromocyclohexa-2,5-dien-1-one (2.82 g, 6.89 mmol) in CHCl (54 mL) and MeOH (6 mL) over 2 h with stirring at 0 °C, followed by stirring at 25 °C for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc = 0 / 1) to give 6-bromoisoquinolin-5-ol (1.00 g, yield: 39%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 7.58 (1H, d, J = 8.8 Hz), 7.75 (1H, d, J = 8.8 Hz), 8.04 (1H, d, J = 6.0 Hz), 8.53 (1H, d, J = 6.0 Hz), 9.26 (1H, s), 10.49 (1H, brs).

[0766] Step 2. Synthesis of methyl (1s,3s)-3-((6-bromoisoquinolin-5-yl)oxy)cyclobutane-1-carboxylate To a mixture of 6-bromoisoquinolin-5-ol (900 mg, 4.02 mmol) and methyl (1r,3r)-3-hydroxycyclobutane-1-carboxylate (627 mg, 4.82 mmol) in toluene (15 mL), n-BuP (1.63 g, 8.03 mmol) and TMAD (1.38 g, 8.03 mmol) were added, followed by stirring under a N atmosphere at 110° C. for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc = 2 / 1) to give methyl (1s,3s)-3-((6-bromoisoquinolin-5-yl)oxy)cyclobutane-1-carboxylate (600 mg, yield: 30%) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ 2.53-2.60 (2H, m), 2.61-2.72 (3H, m), 3.63 (3H, s), 4.47-4.72 (1H, m), 7.85-7.89 (3H, m), 8.60 (1H, d, J = 5.6 Hz), 9.36 (1H, s).

[0767] Intermediate 26 tert-Butyl 3-((6-bromo-3-methylisoquinolin-4-yl)oxy)azetidine-1-carboxylate [ka] Step 1. Synthesis of methyl tosylalaninate To a mixture of methyl alaninate (5.00 g, 35.8 mmol, HCl salt) and EtN (10.9 g, 108 mmol) in DCM (150 mL) was added TsCl (6.83 g, 35.8 mmol) in small portions at 20 °C. After the addition, the mixture was stirred at 20 °C under a N atmosphere for 14 h. The reaction mixture was acidified with 1 N aqueous HCl to pH = 2 and extracted with DCM (40 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel column (PE / EtOAc = 3 / 1) to give methyl tosylalaninate (7.77 g, yield: 84%) as a colorless oil.

[0768] Step 2. Synthesis of methyl N-(4-bromobenzyl)-N-tosylalaninate A mixture of methyl tosylalaninate (1.06 g, 4.11 mmol), 4-bromobenzyl bromide (1.03 g, 4.11 mmol), and KCO (1.14 g, 8.22 mmol) in CHCN (20 mL) was stirred at 30 °C under a N atmosphere for 14 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel column (PE / EtOAc = 5 / 1) to give methyl N-(4-bromobenzyl)-N-tosylalaninate (1.70 g, yield: 97%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.27 (3H, d, J = 6.4 Hz), 2.44 (3H, s), 3.45 (3H, s), 4.37 (1H, d, J = 16.4 Hz), 4.53 (1H, d, J = 16.4 Hz), 4.67 (1H, q, J = 7.2 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.69 (2H, d, J = 8.4 Hz).

[0769] Step 3. Synthesis of N-(4-bromobenzyl)-N-tosylalanine To a solution of methyl N-(4-bromobenzyl)-N-tosylalaninate (1.70 g, 3.99 mmol) in MeOH (10 mL), HO (5 mL), and THF (10 mL) was added LiOH.HO (502 mg, 12.0 mmol). The mixture was stirred at 20 °C for 1 h, acidified with 1 N aqueous HCl to pH = 2-3, and then extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give N-(4-bromobenzyl)-N-tosylalanine (1.38 g, 84% yield) as a white solid.

[0770] Step 4. Synthesis of 6-bromo-3-methyl-2-tosyl-2,3-dihydroisoquinolin-4(1H)-one A solution of N-(4-bromobenzyl)-N-tosylalanine (2.00 g, 4.85 mmol) in SOCl (24.6 g, 207 mmol) was stirred at 80 °C for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in anhydrous toluene (15 mL), followed by concentration to remove remaining SOCl. The residue was dissolved in anhydrous DCM (20 mL), and AlCl (2.48 g, 18.6 mmol) was added portionwise at 0 °C. The resulting reaction mixture was stirred at 10 °C under a N atmosphere for 16 hours. The reaction mixture was poured into ice water (50 mL) and then extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel column (PE / EtOAc=3 / 1) to give 6-bromo-3-methyl-2-tosyl-2,3-dihydroisoquinolin-4(1H)-one (160 mg, yield: 9%) as a yellow solid.

[0771] Step 5. Synthesis of 6-bromo-3-methylisoquinolin-4-ol To a solution of 6-bromo-3-methyl-2-tosyl-2,3-dihydroisoquinolin-4(1H)-one (160 mg, 0.406 mmol) in EtOH (4 mL) was added EtONa (110 mg, 1.62 mmol) at 0 °C, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with 1 N aqueous HCl to pH = 7, diluted with water (10 mL), and then extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by flash silica gel column (PE / EtOAc = 1 / 1) to give 6-bromo-3-methylisoquinolin-4-ol (60 mg, yield: 62%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 2.54 (3H, s), 7.68 (1H, dd, J = 8.8, 1.6 Hz), 7.98 (1H, d, J = 8.8 Hz), 8.37 (1H, d, J = 1.2 Hz), 8.78 (1H, s), 9.58 (1H, brs).

[0772] Step 6. Synthesis of tert-butyl 3-((6-bromo-3-methylisoquinolin-4-yl)oxy)azetidine-1-carboxylate A mixture of 6-bromo-3-methylisoquinolin-4-ol (400 mg, 1.68 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (873 mg, 5.04 mmol), TMAD (868 mg, 5.04 mmol) and n-Bu3P (1.02 g, 5.04 mmol) in toluene (15 mL) was degassed and purged with N2 three times, then the mixture was stirred at 110 °C under N2 atmosphere for 12 h.

[0773] The reaction mixture was concentrated, and the residue was diluted with water (20 mL) and then extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel column (PE / EtOAc = 1 / 1) to give tert-butyl 3-((6-bromo-3-methylisoquinolin-4-yl)oxy)azetidine-1-carboxylate (1.04 g, crude) as a yellow oil.

[0774] Intermediate 27 tert-Butyl 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-4-yl)oxy)piperidine-1-carboxylate [ka] Step 1. Synthesis of tert-butyl 4-((6-bromoisoquinolin-4-yl)oxy)piperidine-1-carboxylate A mixture of compound Int-3 (1.00 g, 4.46 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.80 g, 8.93 mmol), TMAD (2.31 g, 13.4 mmol), and tributylphosphane (2.71 g, 13.4 mmol) in toluene (40 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 100 °C for 14 hours. The reaction mixture was concentrated and diluted with water (40 mL), then extracted with EtOAc (60 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel column (PE / EtOAc = 1 / 2) to give tert-butyl 4-((6-bromoisoquinolin-4-yl)oxy)piperidine-1-carboxylate (2.42 g, crude material) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 1.47 (9H, s), 1.90-2.00 (2H, m), 2.07-2.14 (2H, m), 2.95-3.10 (2H, m), 3.39-3.49 (2H, m), 4.75-4.85 (1H, m), 7.78-7.86 (1H, m), 7.88-7.95 (1H, m), 8.12 (1H, s), 8.43 (1H, s), 8.91 (1H, s).

[0775] Step 2. Synthesis of tert-butyl 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-4-yl)oxy)piperidine-1-carboxylate A mixture of tert-butyl 4-((6-bromoisoquinolin-4-yl)oxy)piperidine-1-carboxylate (60 mg, 0.15 mmol), Bis-Pin (75 mg, 0.29 mmol), Pd(dppf)Cl (11 mg, 0.015 mmol), and KOAc (36 mg, 0.37 mmol) in dioxane (4 mL) was degassed and purged with N three times, then the mixture was stirred under a N atmosphere at 110 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give tert-butyl 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-4-yl)oxy)piperidine-1-carboxylate (66 mg, crude) as a black gum.

[0776] Intermediate 28 6-Bromoisoquinoline-4-carbaldehyde [ka] Step 1. Synthesis of (6-bromoisoquinolin-4-yl)methanol A mixture of compound Int-2 (2.50 g, 7.49 mmol), (tributylstannyl)methanol (3.61 g, 11.2 mmol), LiCl (952 mg, 22.4 mmol), and Pd(PPh)Cl (525 mg, 0.749 mmol) in anhydrous dioxane (20 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 100 °C for 12 h. The reaction mixture was concentrated and diluted with saturated aqueous KF solution (50 mL) and DCM (50 mL), then extracted with DCM (50 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 100% EtOAc in PE) to give (6-bromoisoquinolin-4-yl)methanol (1.23 g, yield: 70%) as a pale yellow solid.

[0777] Step 2. Synthesis of 6-bromoisoquinoline-4-carbaldehyde To a solution of (6-bromoisoquinolin-4-yl)methanol (1.23 g, 5.17 mmol) in anhydrous DCM (10 mL) was added Dess-Martin (4.38 g, 10.3 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was basified with saturated aqueous NaHCO to pH = 8 and then extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by Combi Flash (0% to 100% EtOAc in PE) to give 6-bromoisoquinoline-4-carbaldehyde (1.20 g, yield: 79%) as a pale yellow solid.

[0778] Intermediate 29 5-ethynyl-1-methylpyridin-2(1H)-one [ka] Step 1. Synthesis of 1-methyl-5-((trimethylsilyl)ethynyl)pyridin-2(1H)-one A mixture of 5-bromo-1-methylpyridin-2(1H)-one (2.00 g, 10.6 mmol), Pd(PPh)Cl (746 mg, 1.06 mmol), CuI (405 mg, 2.13 mmol), and EtN (5.38 g, 53.19 mmol) in THF (20 mL) was degassed and purged with N three times at 0 °C. Ethynyltrimethylsilane (2.09 g, 21.3 mmol) was then added to the reaction mixture, and the mixture was stirred at 70 °C under a N atmosphere for 16 h. The reaction mixture was concentrated, and the residue was purified by flash silica gel chromatography (PE / EtOAc = 1 / 1) to give 1-methyl-5-((trimethylsilyl)ethynyl)pyridin-2(1H)-one (1.60 g, yield: 73%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 0.23 (9H, s), 3.53 (3H, s), 6.50 (1H, d, J = 9.6 Hz), 7.35 (1H, dd, J = 9.6, 2.4 Hz), 7.53 (1H, d, J = 2.4 Hz).

[0779] Step 2. Synthesis of 5-ethynyl-1-methylpyridin-2(1H)-one A mixture of 1-methyl-5-((trimethylsilyl)ethynyl)pyridin-2(1H)-one (1.50 g, 7.31 mmol) in THF (20 mL) was added with TBAF (14.6 mL, 14.6 mmol, 1 M in THF) at 20 °C and stirred at 20 °C for 6 h. The reaction mixture was quenched by the addition of saturated aqueous NH Cl (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated aqueous NaHCO (50 mL), HO (50 mL), and brine (50 mL), dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by flash silica gel chromatography (EtOAc as eluent) to give 5-ethynyl-1-methylpyridin-2(1H)-one (600 mg, yield: 58%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 3.02 (1H, s), 3.54 (3H, s), 6.52 (1H, d, J = 9.6 Hz), 7.36 (1H, dd, J = 9.2, 2.4 Hz), 7.55 (1H, d, J = 2.4 Hz).

[0780] Intermediate 30 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline [ka] Step 1. Synthesis of 6-bromo-4-methoxyisoquinoline To a solution of compound Int-3 (50 mg, 0.22 mmol) in DCM (3 mL) and MeOH (0.75 mL) was added TMSCHN (0.9 mL, 0.45 mmol, 2 M in hexane). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by flash silica gel column chromatography (PE / EtOAc = 1 / 2) to give 6-bromo-4-methoxyisoquinoline (25 mg, yield: 31%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 4.06 (3H, s), 7.84-7.88 (1H, m), 8.09 (1H, d, J = 8.8 Hz), 8.22-8.31 (2H, m), 8.98 (1H, s).

[0781] Step 2. Synthesis of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline A mixture of 6-bromo-4-methoxyisoquinoline (100 mg, 0.420 mmol), Bis-Pin (213 mg, 0.840 mmol), KOAc (103 mg, 1.05 mmol), and Pd(dppf)Cl (31 mg, 0.042 mmol) in dioxane (8 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 90 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (390 mg, crude) as a black oil.

[0782] Intermediate 31 tert-Butyl 4-((6-bromoisoquinolin-3-yl)oxy)piperidine-1-carboxylate [ka] A mixture of 6-bromoisoquinolin-3-ol (1.00 g, 4.46 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.80 g, 8.93 mmol), TMAD (2.31 g, 13.4 mmol), and n-BuP (2.71 g, 13.4 mmol) in toluene (20 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 110° C. for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc=5 / 1) to give tert-butyl 4-((6-bromoisoquinolin-3-yl)oxy)piperidine-1-carboxylate (1.35 g, yield: 74%) as a yellow solid.

[0783] Intermediate 32 6-Bromoisoquinoline-3-carboxylic acid methyl ester [ka] Step 1. Synthesis of 6-bromoisoquinoline-3-carboxylic acid A solution of 6-bromoisoquinoline-3-carboxylic acid (800 mg, 3.17 mmol) in DCM (24 mL) and MeOH (6 mL) was slowly added with TMSCHN (3.2 mL, 6.40 mmol, 2 M in hexane) and stirred under N atmosphere at 25° C. for 16 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc = 1 / 1) to give 6-bromoisoquinoline-3-carboxylic acid (800 mg, yield: 76%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 3.93 (3H, s), 8.00 (1H, dd, J = 8.4, 2.0 Hz), 8.22 (1H, d, J = 8.8 Hz), 8.55 (1H, d, J = 1.6 Hz), 8.64 (1H, s), 9.43 (1H, s).

[0784] Step 2. Synthesis of methyl 6-bromoisoquinoline-3-carboxylate To a solution of methyl 6-bromoisoquinoline-3-carboxylate (800 mg, 3.01 mmol) in anhydrous toluene (18 mL) was added DIBAL-H (6.0 mL, 6.00 mmol, 1 M in toluene) dropwise at −78 °C. After the addition was complete, the reaction mixture was stirred at −78 °C for 0.25 h under a N atmosphere. The reaction mixture was quenched dropwise with MeOH (8 mL) at −78 °C and stirred at −78 °C for 0.5 h under a N atmosphere. The mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 3 / 1) to give methyl 6-bromoisoquinoline-3-carboxylate (300 mg, yield: 42%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (1H, dd, J = 8.8, 2.0 Hz), 8.25 (1H, d, J = 8.8 Hz), 8.50 (1H, s), 8.59 (1H, d, J = 1.6 Hz), 9.53 (1H, s), 10.16 (1H, s).

[0785] Intermediate 33 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)oxy)cyclohexan-1-one [ka] Step 1. Synthesis of 3-((1,4-dioxaspiro[4.5]decan-8-yl)oxy)-6-bromoisoquinoline A mixture of 6-bromoisoquinolin-3-ol (1.00 g, 4.46 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (1.06 g, 6.69 mmol), and PPh (1.76 g, 6.69 mmol) in THF (10 mL) was degassed and purged with N three times, and then DIAD (1.35 g, 6.69 mmol) was added to the reaction mixture at 0 °C and stirred at 80 °C under N atmosphere for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc = 5 / 1) to give 3-((1,4-dioxaspiro[4.5]decan-8-yl)oxy)-6-bromoisoquinoline (1.20 g, yield: 74%) as a white solid.

[0786] Step 2. Synthesis of 4-((6-bromoisoquinolin-3-yl)oxy)cyclohexan-1-one To a solution of 3-((1,4-dioxaspiro[4.5]decan-8-yl)oxy)-6-bromoisoquinoline (1.10 g, 3.02 mmol) in dioxane (12 mL) was added 6 N aqueous HCl (5 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated, and the residue was diluted with HO (30 mL), then extracted with DCM (40 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 5 / 1) to give 4-((6-bromoisoquinolin-3-yl)oxy)cyclohexan-1-one (900 mg, yield: 93%) as a white solid.

[0787] Step 3. Synthesis of 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)oxy)cyclohexan-1-one A mixture of 4-((6-bromoisoquinolin-3-yl)oxy)cyclohexan-1-one (460 mg, 1.44 mmol), Bis-Pin (730 mg, 2.87 mmol), Pd(dppf)Cl (105 mg, 0.144 mmol), and KOAc (282 mg, 2.87 mmol) in dioxane (7 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 90 °C for 1.5 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc = 2 / 1) to give 4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)oxy)cyclohexan-1-one (510 mg, yield: 97%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.34 (12H, s), 2.02-2.14 (2H, m), 2.16-2.29 (2H, m), 2.40-2.46 (4H, m), 5.39-5.50 (1H, m), 7.34 (1H, s), 7.62 (1H, d, J = 8.0 Hz), 8.01 (1H, d, J = 8.0 Hz), 8.21 (1H, s), 9.10 (1H, s).

[0788] Intermediate 34 3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline [ka] A mixture of 6-bromo-3-chloro-1,2-dihydroisoquinoline (1.00 g, 4.12 mmol), Bis-Pin (1.26 g, 4.95 mmol), Pd(dppf)Cl (302 mg, 0.410 mmol), and KOAc (809 mg, 8.25 mmol) in 1,4-dioxane (10 mL) was degassed and purged with N three times. The reaction mixture was then stirred at 110 °C under a N atmosphere for 5 h. The reaction mixture was concentrated and purified using a silica gel column (PE / EtOAc = 5 / 1) to give 3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (1.14 g, yield: 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.34 (12H, s), 7.88 (1H, dd, J = 8.4 Hz, 0.8 Hz), 8.14-8.16 (2H, m), 8.36 (1H, s), 9.24 (1H, s).

[0789] Intermediate 35 3-Cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline [ka] Step 1. Synthesis of 2-(cyclopropylethynyl)-4-methoxybenzaldehyde A mixture of 2-bromo-4-methoxybenzaldehyde (3.80 g, 17.7 mmol), Pd(PPh)Cl (1.24 g, 1.77 mmol), CuI (1.01 g, 5.30 mmol), and EtN (12.30 mL) in THF (100 mL) was degassed and purged with N three times, then cyclopropylacetylene (5.13 mL, 61.9 mmol) was added, and the reaction mixture was stirred under N at 60 °C for 12 h. The reaction mixture was concentrated, and the residue was purified by silica gel column (PE / EtOAc = 10 / 1) to give 2-(cyclopropylethynyl)-4-methoxybenzaldehyde (2.60 g, yield: 34%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 0.81-0.87 (2H, m), 0.92-0.98 (2H, m), 1.53-1.72 (1H, m), 3.85 (3H, s), 7.01-7.07 (2H, m), 7.73-7.78 (1H, m), 10.20 (1H, s).

[0790] Step 2. Synthesis of 3-cyclopropyl-6-methoxyisoquinoline To a solution of 2-(cyclopropylethynyl)-4-methoxybenzaldehyde (1.60 g, 7.99 mmol) in EtOH (20 mL) was added K2CO3 (11.0 g, 80.0 mmol) and 28% aqueous NH3.H2O (5.60 g, 160 mmol). The mixture was stirred at 78 °C for 32 h. The reaction mixture was concentrated, and the residue was diluted with water (30 mL) and then extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 5 / 1) to give 3-cyclopropyl-6-methoxyisoquinoline (440 mg, yield: 28%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 0.93-1.00 (4H, m), 2.11-2.21 (1H, m), 3.89 (3H, s), 7.15 (1H, dd, J = 8.8, 2.0 Hz), 7.19 (1H, d, J = 1.6 Hz), 7.56 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 8.99 (1H, s).

[0791] Step 3. Synthesis of 3-cyclopropylisoquinolin-6-ol A mixture of 3-cyclopropyl-6-methoxyisoquinoline (560 mg, 2.81 mmol) and pyridine hydrochloride (15 g, 126 mmol) was stirred at 200 °C for 3 h. The reaction mixture was basified with 2 N aqueous NaOH to pH = 10, diluted with water (30 mL), and then extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc = 1 / 1) to give 3-cyclopropylisoquinolin-6-ol (370 mg, yield: 71%) as a yellow solid.

[0792] Step 4. Synthesis of 3-cyclopropylisoquinolin-6-yl trifluoromethanesulfonate To a solution of 3-cyclopropylisoquinolin-6-ol (370 mg, 2.00 mmol) in DMF (8 mL) were added DIPEA (2.09 mL) and PhNTf2 (856 mg, 2.40 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1) to give 3-cyclopropylisoquinolin-6-yl trifluoromethanesulfonate (600 mg, yield: 76%) as a yellow oil.

[0793] Step 5. Synthesis of 3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline A mixture of 3-cyclopropylisoquinolin-6-yl trifluoromethanesulfonate (500 mg, 1.58 mmol), Bis-Pin (480 mg, 1.89 mmol), Pd(dppf)Cl (115 mg, 0.158 mmol), and KOAc (464 mg, 4.73 mmol) in 1,4-dioxane (15 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 90 °C for 16 h. The reaction mixture was diluted with dioxane (35 mL), filtered, and the filtrate was concentrated to give 3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (1.00 g, crude) as a black solid.

[0794] Intermediate 36 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinoline [ka] A mixture of 6-bromo-3-chloroisoquinoline (1.00 g, 4.12 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.03 g, 4.95 mmol), Pd(dppf)Cl (301 mg, 0.412 mmol), and NaCO (874 mg, 8.25 mmol) in 1,4-dioxane (20 mL) and HO (2 mL) was degassed and purged with N three times. The resulting mixture was then stirred at 100 °C under a N atmosphere for 20 h. The reaction mixture was diluted with HO (50 mL) and extracted with DCM (70 mL × 3). The combined organic layers were washed with brine (70 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (PE / EtOAc=1 / 1) to give 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinoline (701 mg, yield: 69%) as a yellow gum.

[0795] Compounds of formula (I) Example 1 6-(imidazo[1,2-a]pyridin-3-yl)isoquinoline [ka] A mixture of compound Int-1 (416 mg, 2.40 mmol), 3-bromoimidazo[1,2-a]pyridine (450 mg, 2.28 mmol), Pd(dppf)Cl.CHCl (98 mg, 0.12 mmol), and KCO (997 mg, 7.21 mmol) in dioxane (4 mL) and HO (1 mL) was degassed and purged with N three times. The reaction mixture was then stirred at 100 °C under a N atmosphere for 10 h. The reaction mixture was filtered through a celite pad, and the filtrate was diluted with water (20 mL) and then extracted with EtOAc (10 mL × 5). The combined organic layers were washed with brine (10 mL × 6), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (0.05% HCOONH4 as additive, Method D) and then lyophilized to give the title compound (8.0 mg, yield: 1.4%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 6.79-7.06 (1H, m), 7.28-7.38 (1H, m), 7.43-8.26 (6H, m), 8.45-8.70 (2H, m), 9.31 (1H, s).

[0796] The following compounds were synthesized in the same manner as in Example 1. [Table 5-1] [Table 5-2]

[0797] Example 2 6-(1-methyl-1H-pyrazol-4-yl)-4-phenoxyisoquinoline [ka] Step 1. Synthesis of 6-bromo-4-phenoxyisoquinoline To a solution of 6-bromo-4-iodoisoquinoline (100 mg, 0.299 mmol) and phenol (28 mg, 0.30 mmol) in DMSO (2 mL) was added CuI (6 mg, 0.03 mmol), KPO (127 mg, 0.599 mmol), and 2-picolinic acid (7 mg, 0.06 mmol) under a N atmosphere. The mixture was stirred at 80 °C for 18 h under a N atmosphere. The reaction mixture was diluted with EtOAc (20 mL) and saturated aqueous NaHCO (20 mL) and separated. The aqueous phase was extracted with EtOAc (20 mL × 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , 0-23% ethyl acetate / petroleum ether gradient eluent) to afford 6-bromo-4-phenoxyisoquinoline (58 mg, yield: 65%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.07-7.13 (2H, m), 7.17-7.24 (1H, m), 7.36-7.45 (2H, m), 7.73-7.79 (1H, m), 7.90 (1H, d, J = 8.8 Hz), 8.12 (1H, s), 8.40 (1H, s), 8.93-9.11 (1H, m).

[0798] Step 2. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-4-phenoxyisoquinoline A mixture of 6-bromo-4-phenoxyisoquinoline (133 mg, 0.443 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (67 mg, 0.53 mmol), Pd(PPh) (51 mg, 0.044 mol), and NaCO (94 mg, 0.89 mmol) in 1,4-dioxane (2 mL) and HO (0.5 mL) was degassed and purged with N three times. The mixture was then stirred at 100 °C under a N atmosphere for 16 h. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (0.04% NH3H2O+10 mM NH4HCO3 as additive) and lyophilized to give the title compound (40 mg, yield: 30%) as a pale yellow oil. 1 H NMR (400 MHz, CD3OD) δ 3.94 (3H, s), 7.10-7.16 (2H, m), 7.18-7.25 (1H, m), 7.40-7.47 (2H, m), 7.85 (1H, s), 7.93-7.98 (2H, m), 8.12 (1H, d, J = 8.8 Hz), 8.15 (1H, s), 8.26 (1H, s), 8.92 (1H, s).

[0799] The following compounds were synthesized in the same manner as in Example 2. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7]

[0800] Example 5 3-((6-(imidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)oxy)phenol [ka] Example 4 (60 mg, 0.16 mmol) was dissolved in dry DCM (2 mL). BBr (614 mg, 2.45 mmol) was added dropwise to the mixture at 0 °C. The solution was stirred at 0 °C for 2 hours. The reaction mixture was quenched with MeOH (3 mL), poured into water (15 mL), and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (0.04% NHH0 + 10 mM NHHCO as additive) and lyophilized to give the title compound (8 mg, yield: 3% for two steps) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.45-6.49 (1H, m), 6.53 (1H, dd, J = 7.6, 1.6 Hz), 6.60 (1H, dd, J = 8.4, 2.0 Hz), 6.90-6.97 (1H, m), 7.16-7.24 (1H, m), 7.33-7.39 (1H, m), 7.68-7.73 (1H, m), 8.00 (1H, s), 8.06 (1H, dd, J = 8.8, 2.0 Hz), 8.12 (1H, s), 8.28 (1H, s), 8.34-8.40 (2H, m), 9.24 (1H, s), 9.67 (1H, brs).

[0801] Example 6 3-((6-(imidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)oxy)benzonitrile [ka] Step 1. Synthesis of 3-((6-(imidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)oxy)phenyl trifluoromethanesulfonate To a solution of Example 5 (90 mg, crude) and EtN (129 mg, 1.27 mmol) in DCM (3 mL) was added TfO (180 mg, 0.637 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into water (15 mL) and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, 0–3% methanol / dichloromethane gradient eluent at 20 mL / min) to give 3-((6-(imidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)oxy)phenyl trifluoromethanesulfonate (110 mg, 80% yield over two steps) as a yellow solid.

[0802] Step 2. Synthesis of 3-((6-(imidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)oxy)benzonitrile To a solution of 3-((6-(imidazo[1,2-a]pyridin-3-yl)isoquinolin-4-yl)oxy)phenyl trifluoromethanesulfonate (90 mg, 0.19 mmol) and Zn(CN) (120 mg, 1.02 mmol) in DMF (2 mL) was added Pd(PPh) (21 mg, 0.019 mol) under N. The mixture was stirred at 100 °C under N for 16 h. The reaction mixture was poured into HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (0.05% NH3H2O+10 mM NH4HCO3 as additive), and then further purified by preparative TLC (DCM / MeOH=10 / 1) to give the title compound (14 mg, yield: 20%) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 6.97-7.03 (1H, m), 7.39-7.47 (2H, m), 7.54-7.57 (1H, m), 7.57-7.64 (2H, m), 7.65-7.70 (1H, m), 7.90 (1H, s), 8.07 (1H, dd, J = 8.4, 1.2 Hz), 8.19 (1H, s), 8.30 (1H, s), 8.39 (1H, d, J = 8.4 Hz), 8.49 (1H, d, J = 7.2 Hz), 9.19 (1H, s).

[0803] Example 10 6-(1-methyl-1H-pyrazol-4-yl)-4-((1-methylpiperidin-3-yl)oxy)isoquinoline [ka] To a solution of Example 9 (260 mg, 0.843 mmol) and 37% aqueous formaldehyde (342 mg, 4.22 mmol) in MeOH (5 mL), HOAc (152 mg, 2.53 mmol) was added, and the mixture was stirred at 20 °C for 1 h. NaBHCN (159 mg, 2.53 mmol) was added to the above reaction mixture, and the mixture was stirred at 45 °C for 11 h. The reaction mixture was diluted with HO (40 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (0.05% NHHO + 10 mM NHHCO as additive) and lyophilized to give the title compound (106 mg, 41% yield over two steps) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 1.53-1.74 (2H, m), 1.87-1.98 (1H, m), 2.09-2.35 (3H, m), 2.36 (3H, s), 2.69-2.78 (1H, m), 3.13-3.21 (1H, m), 4.00 (3H, s), 4.61-4.71 (1H, m), 7.73 (1H, dd, J = 8.4, 1.6 Hz), 7.81 (1H, s), 7.88-7.94 (2H, m), 8.16 (1H, s), 8.23 ​​(1H, s) 8.83 (1H, s).

[0804] Example 11 N-(5-(isoquinolin-6-yl)thiazol-2-yl)-1-methylpiperidine-4-carboxamide [ka] Step 1. Synthesis of N-(5-bromothiazol-2-yl)-1-methylpiperidine-4-carboxamide A mixture of 5-bromothiazol-2-amine (200 mg, 1.12 mmol), 1-methylpiperidine-4-carboxylic acid (208 mg, 1.45 mmol), T3P (2.13 g, 3.35 mmol, 50% in EtOAc), Et3N (226 mg, 2.23 mmol) in pyridine (2 mL) was stirred for 16 h at 50° C. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (30 mL × 3), brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, 0-12% MeOH / DCM eluent at 25 mL / min) to afford N-(5-bromothiazol-2-yl)-1-methylpiperidine-4-carboxamide (200 mg, yield: 59%) as a yellow solid. 1 H NMR (400MHz, CD3OD) δ 1.90-2.06 (4H, m), 2.40-2.49 (2H, m), 2.50 (3H, s), 2.55-2.65 (1H, m), 3.10-3.20 (2H, m), 7.40 (1H, s).

[0805] Step 2. Synthesis of N-(5-(isoquinolin-6-yl)thiazol-2-yl)-1-methylpiperidine-4-carboxamide A mixture of N-(5-bromothiazol-2-yl)-1-methylpiperidine-4-carboxamide (100 mg, 0.329 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (101 mg, 0.394 mmol), Pd(dppf)Cl (24 mg, 0.033 mmol), and NaHCO (83 mg, 0.99 mmol) in dioxane (3 mL) and water (1 mL) was degassed and purged with N three times. The mixture was then stirred at 90 °C under a N atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, 0-15% MeOH / DCM eluent at 25 mL / min), then further purified by preparative HPLC (0.225% FA as additive, Method C) to give the title compound (7.95 mg, 12% yield, FA salt) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 1.61-1.74 (2H, m), 1.77-1.86 (2H, m), 1.85-1.95 (2H, m), 2.18 (3H, s), 2.40-2.45 (1H, m), 2.80-2.90 (2H, m), 7.84 (1H, d, J = 6.0 Hz), 8.03 (1H, dd, J = 8.4, 1.6 Hz), 8.11-8.17 (3H, m), 8.27 (1H, s), 8.50 (1H, d, J = 5.6 Hz), 9.28 (s, 1H, brs).

[0806] The following compounds were synthesized in the same manner as in Example 11. [Table 7]

[0807] Example 12 N-(5-(isoquinolin-6-yl)thiazol-2-yl)-1-methylazetidine-3-carboxamide [ka] Step 1. Synthesis of tert-butyl 3-((5-(isoquinolin-6-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate A mixture of compound Int-4 (100 mg, 0.440 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (133 mg, 0.660 mmol), T3P (840 mg, 1.32 mmol, 50% in EtOAc), and Et3N (145 mg, 1.44 mmol) in pyridine (2 mL) was stirred at 50 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, 0–14% MeOH / DCM eluent at 25 mL / min) to afford tert-butyl 3-((5-(isoquinolin-6-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (180 mg, yield: >99%) as a yellow solid.

[0808] Step 2. Synthesis of N-(5-(isoquinolin-6-yl)thiazol-2-yl)azetidine-3-carboxamide A mixture of tert-butyl 3-((5-(isoquinolin-6-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (200 mg, 0...

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: Each dashed line represents a single or double bond; X １ is CR １ or N, X ２ is CR ２ , C(═O), or N; X ３ is C or N, with the proviso that X ２ When is C(=O), X ３ is N, X ４ is CH or N, Ring A is phenyl or 5-6 membered heteroaryl; R １ is hydrogen, halogen, cyano, 3- to 10-membered heterocyclyl, —C(═O)C1-C6 alkyl, or —C(═O)OR Ａ C1-C6 alkyl optionally substituted with 3- to 6-membered heterocyclyl optionally substituted with C1-C6 alkoxy, —C(═O)-3- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, or —OR Ｂ and R Ｂ is a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, a C6-C10 aryl, or a C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, hydroxy, —C(═O)OH, —C(═O)C1-C6 alkyl, —S(O ２ ) —C1-C6 alkyl, or —NR Ｃ R Ｄ optionally replaced by R ２ is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, —C(═O)-3- to 6-membered heterocyclyl, —NH—C3-C6 cycloalkyl-C(═O)OR Ａ or —O—C3-C6 cycloalkyl-C(═O)OR Ａ and R ３ is hydrogen, halogen, C1-C6 alkyl, cyano, C3-C6 cycloalkyl, -X-R Ｇ ,or 【Chemistry 2】 and R ４ is hydrogen or C1-C6 alkyl, R ５ is hydrogen, C1-C6 alkyl optionally substituted with 3- to 6-membered heterocyclyl, -X-R Ｅ , —C3-C6 cycloalkyl-C(═O)OR Ａ ,or 【Transformation 3】 or R ５ and the carbon atom and / or nitrogen atom to which it is attached replaces a hydrogen atom on an adjacent carbon atom or nitrogen atom to form a bond with said adjacent carbon atom or nitrogen atom, R ５ and the two adjacent carbon atoms and / or nitrogen atoms in ring A together form (i) a C6-C10 aryl optionally substituted with 1-2 independently selected C1-C6 alkyl or 3-10 membered heterocyclyl optionally substituted with -C(=O)OR', (ii) a 3-6 membered heterocyclyl, or (iii) a 5-6 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, 3-10 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl or C(=O)OR', and a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; R Ｅ is a 3- to 10-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each of which is selected from 1 to 3 independently selected C1-C6 alkoxy, NR Ｉ R Ｊ or C1-C6 alkyl optionally substituted with —C(═O)OH; R Ｆ is a 3- to 6-membered heterocyclyl, a 5- to 6-membered heteroaryl, or a C3-C6 cycloalkyl, each optionally substituted with C1-C6 alkyl, or a C2-C6 alkynyl optionally substituted with hydroxy; R Ｇ is a 3- to 6-membered heterocyclyl or C3-C6 cycloalkyl, each of which is 1 to 3 independently selected C1-C6 alkyl, —C(═O)C1-C6 alkyl, —C(═O)OH, or NR Ｃ R Ｄ optionally replaced by R Ｈ is C1-C6 alkyl optionally substituted with hydroxy or 3-6 membered heterocyclyl optionally substituted with C1-C6 alkyl; X is -NH-, -NH(C=O)-, -NHC(=O)O-, -O-, -(C=O)- or CH ２ and Each R Ａ , R Ｃ , R Ｄ , R Ｉ , and R Ｊ are independently selected from hydrogen and C1-C6 alkyl; The compound or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

2. X １ , X ２ , X ３ , X ４ One of them is N and X １ , X ２ , X ３ , X ４ The remainder of each is C, C(=O), CH, CR １ or CR ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, independently selected from:

3. X １ is N and X ２ is CR ２ and X ３ is C and X ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

4. X ２ is N and X １ is CR １ and X ３ is C and X ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

5. X ３ is N and X １ is CR １ and X ２ is C(=O), and X ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

6. X ４ is N and X １ is CR １ and X ２ is CR ２ and X ３ 3. The compound of claim 1 or 2, wherein is C, or a pharmaceutically acceptable salt thereof.

7. Ring A is 【Transformation 5】 each of which is selected from the group consisting of one or two R ５ and aa is optionally substituted with X ３ The other wavy lines represent the bond points with R ５ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

8. Formula (II): 【Transformation 7】 or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- to 14-membered heteroaryl or a 5- to 14-membered heterocyclyl; Each R １ are independently halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, —C(═O)OR Ａ , -NR Ｂ R Ｃ and —C(═O)NR Ｂ R Ｃ and each R ２ are independently —C(═O)OR Ｄ , C1-C6 alkyl, C2-C6 alkynyl optionally substituted with 4-8-membered heterocyclyl optionally substituted with C1-C6 alkyl, -C(=O)-phenyl, -(C1-C6 alkyl)-phenyl, -(C1-C6 alkyl)-4-10-membered heterocyclyl optionally substituted with C1-C6 alkyl, C1-C6 alkyl or -CO ２ 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, phenyl optionally substituted with cyano or fluoro, —NHC(═O)R Ｅ , 5-6 membered heteroaryl optionally substituted with C1-C6 alkoxy; m is 1, 2, or 3; n is 0, 1, 2, or 3; Each R Ａ , R Ｂ , R Ｃ , and R Ｄ are independently hydrogen or C1-C6 alkyl; Each R Ｅ are independently C3-C6 cycloalkyl, 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl, or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8, wherein ring A is pyrazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, pyrrolo[1,2-a]pyrazin-1(2H)-one, pyrazolo[1,5-a]pyrazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, or 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein ring A is 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, or 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one.

11. The compound according to claim 8, wherein ring A is 8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein ring A is 7,8,9,10-tetrahydro-pyrazolo[5,1-f][1,6]naphthyridine or 7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine.

13. Formula (III): 【Transformation 8】 or a pharmaceutically acceptable salt thereof, Ring A is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclyl; R １ is -NHC(=O)(C1-C6 alkylene) ｎ R Ａ , -NR Ｆ R Ｇ phenyl optionally substituted with -QR Ｃ ,or 【Chemistry 9】 and R ２ is -CO ２ R Ｂ C3-C6 cycloalkyl optionally substituted with 5-10 membered heteroaryloxy, C1-C6 alkyl, cyano, or —(C1-C6 alkylene) optionally substituted with 4-6 membered heterocyclyl ｐ -5 to 10-membered heteroaryl, cyano or -NR Ｄ R Ｅ -(C1-C6 alkylene) optionally substituted with ｔ -phenyl, 4-6 membered heterocyclyl optionally substituted with C1-C6 alkyl, R ３ is C1-C6 alkyl, R Ａ is a 4- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, or a 5- to 10-membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl; R Ｂ is hydrogen or C1-C6 alkyl, R Ｃ is a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, or -(C1-C6 alkylene)-NR Ｄ R Ｅ is phenyl optionally substituted with R Ｄ , R Ｅ , and R Ｆ are independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; R Ｇ is hydrogen, C1-C6 alkyl, —C(═O)—C1-C6 alkyl, or —C(═O)—C3-C6 cycloalkyl; R Ｈ is a 4-6 membered heterocyclyl optionally substituted with 1-2 independently selected C1-C6 alkyl; Q is C1-C6 alkylene, NH, or O; m is 0 or 1; n is 0 or 1; p is 0 or 1; The compound or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1.

14. Ring A is 【Chemistry 10】 14. The compound of claim 13, wherein:

15. Ring A is 【Chemistry 11】 14. The compound of claim 13, wherein:

16. Ring A is 【Chemistry 12】 14. The compound of claim 13, wherein:

17. Ring A is 【Chemistry 13】 14. The compound of claim 13, wherein:

18. Ring A is 【Chemistry 14】 14. The compound of claim 13, wherein:

19. Ring A is 【Chemistry 15】 14. The compound of claim 13, wherein:

20. Ring A is 【Chemistry 16】 14. The compound of claim 13, wherein:

21. Ring A is 【Chemistry 17】 14. The compound of claim 13, wherein:

22. Ring A is [Chemistry 18] 14. The compound of claim 13, wherein:

23. The compound of formula (III) represented by formula (III-1): 【Chemistry 19】 14. The compound of claim 13, which is a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein: R 2 is -(C1-C6 alkylene) p -5-10 membered heteroaryl optionally substituted with C1-C6 alkyl, cyano, or 4-6 membered heterocyclyl; p is 0, The compound or a pharmaceutically acceptable salt thereof, wherein R A is 4- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, or 5- to 10-membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R A is 4- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl.

25. The compound of formula (III) represented by formula (III-2): 【Chemistry 20】 24. The compound of claim 23, which is a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein: The compound or a pharmaceutically acceptable salt thereof, wherein R A is 4- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, or 5- to 10-membered heteroaryl optionally substituted with C1-C6 alkoxy or C1-C6 alkyl.

26. R A is 【Chemistry 21】 26. The compound according to any one of claims 23 to 25, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

27. A compound selected from the compounds of Table 1, Table 2, Table 3, or Table 4, or a pharmaceutically acceptable salt of any of the foregoing.

28. 30. A pharmaceutical composition comprising a compound according to any one of claims 1, 8, 13 and 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

29. 30. Use of a compound of any one of claims 1, 8, 13 and 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a neurological disorder in a subject in need thereof.

30. Use of a compound according to any one of claims 1, 8, 13 and 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a DYRK1A-associated neurological disorder in a subject in need of such treatment.

31. A composition for treating a neurological disorder in a subject in need thereof, comprising a compound according to any one of claims 1, 8, 13 and 27, or a pharmaceutically acceptable salt thereof.

32. A composition for treating a DYRK1A-associated neuropathy in a subject in need of such treatment, comprising a compound described in any one of claims 1, 8, 13 and 27, or a pharmaceutically acceptable salt thereof.

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