Heterocyclic compounds as agonists of trigger receptor 2 expressed in myeloid cells and methods of use

Abstract

The present disclosure provides compounds of formula I that are useful for activating triggering receptor expressed on myeloid cells 2 ("TREM2"). TIFF2024545591000230.tif4551 The disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treating, for example, neurodegenerative disorders. Additionally, the disclosure provides intermediates useful in the synthesis of the compounds of formula I.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 263,814, filed November 9, 2021, and U.S. Provisional Patent Application No. 63 / 375,125, filed September 9, 2022, which are incorporated by reference herein in their entireties.

[0002] The present disclosure provides compounds useful for activating triggering receptor expressed on myeloid cells 2 ("TREM2"). The present disclosure also provides pharmaceutical compositions containing the compounds, uses of the compounds, and compositions for treating, for example, neurodegenerative disorders. Additionally, the present disclosure provides intermediates useful for synthesizing compounds of Formula I. [Background technology]

[0003] Microglia are resident innate immune cells in the brain and are important for maintaining homeostasis in the central nervous system (Hickman et al. Nat Neurosci 2018; Li and Barres, Nat Rev Immunol., 2018). These resident macrophages express various receptors that enable them to sense changes in their microenvironment and modify their phenotype to mediate responses to invading pathogens, proteotoxic stress, cellular injury, and other insults that can occur in health and disease. Ibid. Microglia reside in the parenchyma of the brain and spinal cord, where they interact with neuronal cell bodies (Cserep et al. Science, 2019), neurites (Paolicelli et al. Science, 2011, Ikegami et al. Neuropathology, 2019), as well as other glial cell types (Domingues et al. Front Cell Dev Biol, 2016; Liddelow et al. Nature, 2017; Shinozaki et al. Cell Rep., 2017), and play a role in numerous physiological processes. Given their ability to rapidly proliferate in response to stimuli, microglia characteristically exhibit myeloid cell functions, such as phagocytosis, cytokine / chemokine release, antigen presentation, and migration (Colonna and Butovsky, Annu Rev Immunol, 2017). More unique functions of microglia include their ability to sever synapses from neurons and communicate directly with highly arborized cellular processes that survey the area surrounding the neuronal cell body (Hong et al. Curr Opin Neurobiol, 2016; Sellgren et al. Nat Neurosci, 2019).

[0004] Microglial plasticity and its diverse states, as described through single-cell RNA-Seq profiling, are thought to arise through the integration of signaling from a wide variety of cell surface receptors (Hickman et al. Nat Neurosci 2013). Collectively known as the microglial "sensome," these receptors mediate activating or inhibiting intracellular signaling and include protein families such as sialic acid-binding immunoglobulin-type lectins (SIGLECs), Toll-like receptors (TLRs), Fc receptors, nucleotide-binding oligomerization domain (NOD) receptors, and purinergic G protein-coupled receptors (Doens and Fernandez 2014; Madry and Attwell 2015; Hickman and El Khoury 2019). Similar to other cells of the myeloid lineage, the composition of the microglial sensome is dynamically regulated and acts to recognize molecular patterns that direct phenotypic responses to homeostatic changes in the central nervous system (CNS). Ibid. One receptor selectively expressed by brain microglia is TREM2, which consists of a single-pass transmembrane domain, an extracellular stalk region, and an extracellular immunoglobulin variable (IgV)-like domain involved in ligand interaction (Kleinberger et al., Sci Transl Med, 2014). Because TREM2 lacks an intracellular signaling domain, biochemical analysis has shown that its interaction with the adaptor proteins DAP10 and DAP12 mediates downstream signaling following ligand recognition (Peng et al., Sci Signal, 2010; Jay et al., Mol Neurodegener, 2017). The TREM2 / DAP12 complex acts as a signaling unit that can be characterized as a promoter of activation, particularly on microglial phenotypes, in addition to peripheral macrophages and osteoclasts (Otero et al., J Immunol, 2012; Kobayashi et al., J Neurosci, 2016; Jaitin et al., Cell, 2019).In the CNS, signaling through TREM2 has been studied in the context of ligands such as phospholipids, cellular debris, apolipoproteins, and myelin (Wang et al., Cell, 2015; Kober and Brett, J Mol Biol, 2017; Shirotani et al., Sci Rep, 2019). In mice lacking functional TREM2 expression or expressing mutant forms of the receptor, a central observation is a blunted microglial response to insults such as oligodendrocyte demyelination, stroke-induced tissue damage in the brain, and proteotoxic inclusions in vivo (Cantoni et al., Acta Neuropathol, 2015; Wu et al., Mol Brain, 2017).

[0005] Coding variants at the TREM2 locus have been associated with late-onset Alzheimer's disease ("LOAD") in human genome-wide association studies linking loss of receptor function with increased disease risk (Jonsson et al. N Engl J Med 2013, Sims et al. Nat Genet 2017). Genetic variations in other genes selectively expressed by microglia in the CNS, such as CD33, PLCg2, and MS4A4A / 6A, have reached genome-wide significance for their association with LOAD risk (Hollingworth et al. Nat Genet 2011, Sims et al. Nat Genet 2017, Deming et al. Sci Transl Med 2019). Together, these genetic findings link together in a putative biochemical circuit that highlights the importance of microglial innate immune function in LOAD. Additionally, increases or elevations of the soluble form of TREM2 ("sTREM2") in the cerebrospinal fluid (CSF) of human subjects are associated with disease progression and the emergence of pathological hallmarks of LOAD, including phosphorylated tau (Suarez-Calvet et al. Mol Neurodegener 2019). Furthermore, natural history and human biology studies have shown that baseline sTREM2 levels in CSF can stratify rates of temporal lobe volume loss and episodic memory decline in longitudinally monitored cohorts (Ewers et al. Sci Transl Med 2019).

[0006] In addition to human genetic evidence supporting a role for TREM2 in LOAD, homozygous loss-of-function mutations in TREM2 are responsible for an early-onset dementia syndrome known as polycystic lipomembranous dysplasia with sclerosing leukoencephalopathy (PLOSL) or Nasu-Hakola disease (NHD) (Golde et al. Alzheimers Res Ther 2013, Dardiotis et al. Neurobiol Aging 2017). This progressive neurodegenerative disease typically manifests in the second decade and is pathologically characterized by loss of myelin in the brain accompanied by gliosis, unexplained neuroinflammation, and brain atrophy. Typical neuropsychiatric symptoms are often preceded by bone abnormalities, such as bone cysts and loss of peripheral bone density (Bianchin et al. Cell Mol Neurobiol 2004, Madry et al. Clin Orthop Relat Res 2007, Bianchin et al. Nat Rev Neurol 2010). Considering that osteoclasts of the myeloid lineage are also known to express TREM2, the PLOSL-associated symptoms of wrist and ankle pain, swelling, and fractures indicate that TREM2 may act to regulate bone homeostasis through defined signaling pathways that parallel those of microglia in the CNS (Paloneva et al. J Exp Med 2003, Otero et al. J Immunol 2012). The link between TREM2 function and PLOSL demonstrates the importance of the receptor in maintaining key physiological aspects of myeloid cell function in the human body.

[0007] In addition to the LOAD-associated TREM2 R47H loss-of-function mutation transgenic mice, efforts have been made to model TREM2 biology in mice, prompting the generation of TREM2 knockout ("KO") mice (Ulland et al. Cell, 2017; Kang et al. Hum Mol Genet, 2018). While it is not possible to recapitulate the neurological symptoms of PLOSL, TREM2 KO mice exhibit abnormalities in bone ultrastructure (Otero et al. J Immunol, 2012). When TREM2 KO or mutant mice are crossed with familial Alzheimer's disease transgenic mouse backgrounds, such as the 5XFAD amyloidogenic mutant strain, striking phenotypes have been observed (Ulrich et al. Neuron, 2017). These in vivo phenotypes of TREM2 loss of function in the CNS include elevated plaque burden and reduced levels of the secreted microglial factors SPP1 and osteopontin, hallmarks of the microglial response to amyloid pathology (Ulland et al., Cell, 2017). Other rodent studies have demonstrated that loss of TREM2 leads to reduced microglial clustering around plaques and the appearance of less compact plaque morphology in a familial AD amyloid model (Parhizkar et al., Nat Neurosci, 2019). Regarding the tau protein pathology observed in LOAD, a familial tauopathy model in mice demonstrated enhanced spread of pathological human tau aggregates from the injection point into the mouse brain in TREM2 KO mice (Leyns et al., Nat Neurosci, 2019). Furthermore, single-cell RNASeq studies using TREM2 KO mice in aging scenarios, 5XFAD familial Alzheimer's disease model mice, and amyotrophic lateral sclerosis SOD1 mutant mouse backgrounds indicate that TREM2 receptor function is important for a conserved set of phenotypic transformations within microglial populations in response to CNS pathology (Keren-Shaul et al. Cell 2017).

[0008] In a rodent model with elevated TREM2 expression levels, cerebral amyloid pathology in 5XFAD transgenic mice showed reduced plaque volume and altered morphology (Lee et al., Neuron, 2018). Changes in immunohistological markers associated with cerebral amyloid pathology were also accompanied by the presence of attenuated dystrophic neurites when TREM2 was overexpressed. Therefore, pharmacological activation of TREM2 is a promising target for treating or preventing neurological, neurodegenerative, and other diseases. Despite numerous attempts to modify disease progression by targeting the pathological hallmarks of LOAD through anti-amyloid and anti-tau therapeutics, there is a need for TREM2 activators, for example, to address neuroimmune aspects related to the genetics of LOAD. Such TREM2 activators may be suitable for use as therapeutic agents, given the significant societal burden that continues unabated from diseases such as Alzheimer's disease. Summary of the Invention

[0009] Provided herein are compounds of formula I [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 1 is an arbitrarily substituted C 1~6 Aliphatic group, OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, optionally substituted OCH2-(C 3~6cycloalkyl), or a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 5- to 12-membered saturated or partially unsaturated bridged carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a cyclic group selected from a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic ring (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted; X 1 is CR 13 , CH, or N; X 2 is CR 14 , CH, or N; Ring A, together with the six-membered ring system to which it is fused, forms a bicyclic system of the formula [ka] Forming Y is C or N when required by the bicyclic ring system formed by ring A; X 3 is CR 3 , or NR 4 and X 4 is CHR 3 , N.R. 4 , O, or S; Z 1 are each independently 2 or N, Z 2 is CR 3 or N, R 2 and R 3 each independently represents hydrogen, optionally substituted C1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 2 and R 3 together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; R 4 is hydrogen, optionally substituted C 1~6an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or R 3 and R 4 together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; Ring B is [ka] and L is a bond or an optionally substituted straight or branched chain C 1~6 is alkylene, X 5 is CH, N, or CR 5 and X 6 is CH, N, or CR 6 and However, X 5 or X 6 If one of is N, then the other is not N, R 5 and R 6 each independently represents hydrogen, optionally substituted C 1~6Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 5 and R 6 together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; X 7 is N, CH, or CR 7 and X 8 , O, NR 8 , C(R 8 )2, CHR 8 , SO2, or C=O; X 9 , O, NR9 , C(R 9 )2, CHR 9 , SO2, or C=O; X 10 , O, NR 10 , C(R 10 )2, CHR 10 , SO2, or C=O; X 11 , O, NR 11 , C(R 11 )2, CHR 11 , SO2, or C=O; X 12 is a direct bond, O, NR 12 , C(R 12 )2, CHR 12 , —CH2CH2—, —OCH2—, SO2, or C═O; R 7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, R 8 , R 9 , R 10 , R 11 , and R 12 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, C 1~6haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 any two of these, together with the intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocyclic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocyclic ring (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted; R 13 and R 14 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, R 16is an arbitrarily substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, m is 0, 1, or 2; Each R is independently hydrogen, optionally substituted C 1~6 an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or Two R groups on the same nitrogen, together with their intervening atoms, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring (having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0010] Also provided herein is a pharmaceutical composition comprising a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and a pharmaceutically acceptable excipient.

[0011] Also provided herein is a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition as described above, for use in treating or preventing a condition associated with loss of function of human TREM2.

[0012] Reference will now be made in detail to the embodiments of the present disclosure. While certain particular embodiments of the present disclosure will be described, it should be understood that they are not intended to limit the embodiments of the present disclosure to these described embodiments. On the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents, which may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0013] In one aspect, provided herein is a compound of formula I [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 1 is an arbitrarily substituted C 1~6 aliphatic group, C 1~6 Haloalkyl, optionally substituted OCH2-(C 3~6 cycloalkyl), optionally substituted O-phenyl, or a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 5- to 12-membered saturated or partially unsaturated bridged carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and 8-10-membered bicyclic aromatic rings (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and the cyclic groups are optionally substituted. X 1 is CR 13 , CH, or N; X 2is CR 14 , CH, or N; Ring A, together with the six-membered ring system to which it is fused, forms a bicyclic system of the formula [ka] and Y is C or N when required by the bicyclic ring system formed by ring A; X 3 is CHR 3 , or NR 4 and X 4 is CHR 3 , N.R. 4 , O, or S; Z 1 are each independently 2 or N, Z 2 is CR 3 or N, Z 11 is CHR 3 , C(R 3 )2, or NR 4 and Z 12 is CHR 2 , C(R 2 )2, NR 4 , or C(=NR 4 ) and R 2 and R 3 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -NR-C(O)-R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, C 1~6haloalkoxy, or a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 2 and R 3 together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; R 4 is hydrogen, optionally substituted C 1~6 an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or R 3 and R 4together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; Ring B is [ka] and L is a bond or an optionally substituted straight or branched chain C 1~6 is alkylene, X 5 is CH, N, or CR 5 and X 6 is CH, N, or CR 6 and However, X 5 or X 6 If one of is N, then the other is not N, R 5 and R 6 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C 1~6 Haloalkyl, C 1~6haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 5 and R 6 together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; X 7 is N, CH, or CR 7 and X 8 , O, NR 8 , C(R 8 )2, CHR 8 , SO2, or C=O; X 9 , O, NR 9 , C(R 9 )2, CHR 9 , SO2, or C=O; X 10 , O, NR 10, C(R 10 )2, CHR 10 , SO2, or C=O; X 11 , O, NR 11 , C(R 11 )2, CHR 11 , SO2, or C=O; X 12 is a direct bond, O, NR 12 , C(R 12 )2, CHR 12 , —CH2CH2—, —OCH2—, SO2, or C═O; R 7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, R 8 , R 9 , R 10 , R 11 , and R 12 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 7 , R8 , R 9 , R 10 , R 11 , and R 12 any two of these, together with the intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocyclic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocyclic ring (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted; R 13 and R 14 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, R 16 is an arbitrarily substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, m is 0, 1, or 2; Each R is independently hydrogen, optionally substituted C 1~6an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or Two R groups on the same nitrogen, together with their intervening atoms, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring (having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0014] Provided herein are compounds of formula I [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: R 1 is an arbitrarily substituted C 1~6 aliphatic group, C 1~6 Haloalkyl, optionally substituted OCH2-(C 3~6 cycloalkyl), or a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 5- to 12-membered saturated or partially unsaturated bridged carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- or 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic ring (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted. X1 is CR 13 , CH, or N; X 2 is CR 14 , CH, or N; Ring A, together with the six-membered ring system to which it is fused, forms a bicyclic system of the formula [ka] Forming Y is C or N when required by the bicyclic ring system formed by ring A; X 3 is CHR 3 , or NR 4 and X 4 is CHR 3 , N.R. 4 , O, or S; Z 1 are each independently 2 or N, Z 2 is CR 3 or N, R 2 and R 3 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, C 1~6haloalkoxy, or a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 2 and R 3 together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; R 4 is hydrogen, optionally substituted C 1~6 an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or R 3 and R 4together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; Ring B is [ka] and L is a bond or an optionally substituted straight or branched chain C 1~6 is alkylene, X 5 is CH, N, or CR 5 and X 6 is CH, N, or CR 6 and However, X 5 or X 6 If one of is N, then the other is not N, R 5 and R 6 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C 1~6 Haloalkyl, C 1~6haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 5 and R 6 together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; X 7 is N, CH, or CR 7 and X 8 , O, NR 8 , C(R 8 )2, CHR 8 , SO2, or C=O; X 9 , O, NR 9 , C(R 9 )2, CHR 9 , SO2, or C=O; X 10 , O, NR 10, C(R 10 )2, CHR 10 , SO2, or C=O; X 11 , O, NR 11 , C(R 11 )2, CHR 11 , SO2, or C=O; X 12 is a direct bond, O, NR 12 , C(R 12 )2, CHR 12 , —CH2CH2—, —OCH2—, SO2, or C═O; R 7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, R 8 , R 9 , R 10 , R 11 , and R 12 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or or R 7 , R8 , R 9 , R 10 , R 11 , and R 12 any two of these, together with the intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8- to 10-membered bicyclic aromatic carbocyclic ring, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocyclic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocyclic ring (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted; R 13 and R 14 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, R 16 is an arbitrarily substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 haloalkoxy, m is 0, 1, or 2; Each R is independently hydrogen, optionally substituted C 1~6an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or Two R groups on the same nitrogen, together with their intervening atoms, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring (having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0015] In some embodiments, the compound is a compound of formula IIa: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0016] In some embodiments, the compound is a compound of formula IIb: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0017] In some embodiments, the compound is a compound of formula IIc: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0018] In some embodiments, the compound is a compound of formula IIIa: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0019] In some embodiments, the compound is a compound of formula IIIb: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0020] In some embodiments, the compound is a compound of formula IIIc: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0021] In some embodiments, the compound is a compound of formula IVa: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0022] In some embodiments, the compound is a compound of formula IVb: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0023] In some embodiments, the compound is a compound of formula IVc: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0024] In some embodiments, the compound is a compound of formula Va: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0025] In some embodiments, the compound is a compound of formula Vb: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0026] In some embodiments, the compound is a compound of formula Vc: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0027] In some embodiments, the compound is a compound of formula VIa: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0028] In some embodiments, the compound is a compound of formula VIb: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0029] In some embodiments, the compound is a compound of formula VIc: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0030] In some embodiments, the compound is a compound of Formula VIIa: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0031] In some embodiments, the compound is a compound of formula VIIb: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0032] In some embodiments, the compound is a compound of Formula VIIc: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0033] In some embodiments, the compound is a compound of Formula VIIIa: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0034] In some embodiments, the compound is a compound of formula VIIIb: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0035] In some embodiments, the compound is a compound of Formula VIIIc: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0036] In some embodiments, the compound is a compound of formula VIIb-1 to VIIb-11: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0037] In some embodiments, the compound is a compound of formula VIIb'-1 to VIIb'-11: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0038] In some embodiments, the compound is a compound of formula VIIb''-1 to VIIb''-11: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and as described in the embodiments herein, both alone and in combination.

[0039] As generally defined above, R 1 is an arbitrarily substituted C 1~6 aliphatic group, C 1~6 Haloalkyl, optionally substituted OCH2-(C 3~6 cycloalkyl), or a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 6- to 12-membered saturated or partially unsaturated bridged carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), In some embodiments, R is a cyclic group selected from a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic ring (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted. 1 is optionally substituted O-phenyl.

[0040] In some embodiments, R 1 is an arbitrarily substituted C 1~6 In some embodiments, R 1 is -OR. In some embodiments, R 1 is -NR2. In some embodiments, R 1 is —C(═O)R. In some embodiments, R 1 is —C(═O)OR. In some embodiments, R 1 is —C(═O)NR. In some embodiments, R 2is -SO2R. In some embodiments, R 1 is -SO2NR2. In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is an optionally substituted -OCH2-(C 3~6 In some embodiments, R 1 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is an optionally substituted 5- to 12-membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 1 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 1 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0041] In some embodiments, R 1is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 6- to 12-membered saturated or partially unsaturated bridged carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic ring (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted.

[0042] In some embodiments, R 1 are independently halogen, C 1~6 Aliphatic, -OR°, or C 1~6 In some embodiments, R is phenyl optionally substituted with 1 to 3 substituents selected from haloalkyl. 1 is phenyl optionally substituted with 1 to 3 halogens. In some embodiments, R 1 are independently halogen, C 1~6 Aliphatic, -OR°, or C 1~6 haloalkyl. 1 are independently halogen, C 1~6 Aliphatic, -OR°, or C 1~6 C optionally substituted with 1 to 3 substituents selected from haloalkyl 5~8 In some embodiments, R 1 are independently halogen, C 1~6 Aliphatic, -OR°, or C 1~6In some embodiments, R is a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 substituents selected from haloalkyl. 1 is a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) optionally substituted with 1-3 halogens.

[0043] In some embodiments, R 1 is an arbitrarily substituted C 3~6 cycloalkyl, optionally substituted spiro[3.3]heptanyl, optionally substituted spiro[5.2]octanyl, optionally substituted [ka] optionally substituted cyclopent-1-en-1-yl, optionally substituted cyclohex-1-en-1-yl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted aziridin-1-yl, optionally substituted pyrrolidin-1-yl, optionally substituted azabicyclo[3.1.0]hexan-3-yl, optionally substituted piperidin-1-yl, or optionally substituted -OCH2-(C 3~4 In some embodiments, R 1 is an arbitrarily substituted C 3~6 In some embodiments, R 1 is an optionally substituted spiro[3.3]heptanyl. In some embodiments, R 1 is an optionally substituted spiro[5.2]octanyl. In some embodiments, R 1 is an arbitrarily substituted [ka] In some embodiments, R 1 is optionally substituted cyclopent-1-en-1-yl. In some embodiments, R 1is optionally substituted cyclohex-1-en-1-yl. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted pyridinyl. In some embodiments, R 1 is an optionally substituted aziridin-1-yl. In some embodiments, R 1 is an optionally substituted pyrrolidin-1-yl. In some embodiments, R 1 is an optionally substituted azabicyclo[3.1.0]hexan-3-yl. In some embodiments, R 1 is optionally substituted piperidin-1-yl. In some embodiments, R 1 is an optionally substituted -OCH2-(C 3~4 cycloalkyl).

[0044] In some embodiments, R 1 are independently halogen, -(CH2) 0-6 R°, -(CH2) 0-6 OR, °-O(CH2) 0-6 R o , -O-(CH2) 0-6 C(O)OR°, -(CH2) 0-6 CH(OR°)2, -(CH2) 0-6 SR, °-(CH2) 0-6 Ph (Ph may be substituted with R°), —(CH2) 0-46 O(CH2) 0-1 Ph (Ph may be substituted with R°), -CH=CHPh (Ph may be substituted with R°), -(CH2) 0-6 O(CH2) 0-1 -pyridyl (pyridyl is R°, -NO2, -CN, -N3, -(CH2) 0-6 N(R°)2, -(CH2) 0-6 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-6 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0-6N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0-6 C(O)R°, -C(S)R°, -(CH2) 0-6 C(O)OR°, -(CH2) 0-6 C(O)SR°, -(CH2) 0-6 C(O)OSiR°3, -(CH2) 0-6 OC(O)R°, -OC(O)(CH2) 0-6 SR°, -(CH2) 0-6 SC(O)R°, -(CH2) 0-6 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-6 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0-6 SSR°, -(CH2) 0-6 S(O)2R°, -(CH2) 0-6 S(O)2OR°, -(CH2) 0-6 OS(O)2R°, -S(O)2NR°2, -(CH2) 0-6 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -P(O)(OR°)2, -OP(O)(R°)OR°, -OP(O)R°2, -OP(O)(OR°)2, SiR°3, -(C 1-4 linear or branched alkylene)ON(R°)2, or -(C 1-4 and optionally substituted with 1 to 3 groups which are straight or branched chain alkylene)C(O)ON(R°)2), where each R° is optionally substituted as defined elsewhere herein and independently is hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or, notwithstanding the above definitions, two independently occurring R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is optionally substituted with one or more -SF5 groups.

[0045] In some embodiments, R 1 is -CH2CH2CF3, [ka] is.

[0046] In some embodiments, R 1 teeth, [ka] is.

[0047] In some embodiments, R 1 is a substituent selected from those shown below. [ka]

[0048] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is selected from those shown in Table A below. In some embodiments, R 1 is selected from those shown in Table A2 below.

[0049] Generally as defined above, X 1 is CR 13 , CH, or N. In some embodiments, X 1 is CH or N. In some embodiments, X 1 is CH. In some embodiments, X 1 is CR 13 In some embodiments, X 1 is N. In some embodiments, X 1 is selected from those shown in Table A below. In some embodiments, X 1 is selected from those shown in Table A2 below.

[0050] Generally as defined above, X 2 is CR 14 , CH, or N. In some embodiments, X 2 is CH or N. In some embodiments, X 2 is CH. In some embodiments, X 2 is CR 14 In some embodiments, X 2 is N. In some embodiments, X 2 is selected from those shown in Table A below. In some embodiments, X 2 is selected from those shown in Table A2 below.

[0051] As generally defined above, R 13 , and R14 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 It is haloalkoxy.

[0052] In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is an arbitrarily substituted C 1~6 In some embodiments, R 13 is halogen. In some embodiments, R 13 is -OR. In some embodiments, R 13 is -CN. In some embodiments, R 13 is -NR2. In some embodiments, R 13 is —C(═O)R. In some embodiments, R 13 is —C(═O)OR. In some embodiments, R 13 is —C(═O)NR. In some embodiments, R 13 is -SO2R. In some embodiments, R 13 is -SO2NR2. In some embodiments, R 13 is C 1~6 In some embodiments, R 13 is C 1~6 In some embodiments, R 13 is methyl.

[0053] In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is an arbitrarily substituted C 1~6 In some embodiments, R 14 is halogen. In some embodiments, R 14 is -OR. In some embodiments, R 14is -CN. In some embodiments, R 14 is -NR2. In some embodiments, R 14 is —C(═O)R. In some embodiments, R 14 is —C(═O)OR. In some embodiments, R 14 is —C(═O)NR. In some embodiments, R 14 is -SO2R. In some embodiments, R 14 is -SO2NR2. In some embodiments, R 14 is C 1~6 In some embodiments, R 14 is C 1~6 In some embodiments, R 14 is methyl.

[0054] As generally defined above, ring A, together with the six-membered ring system to which it is fused, forms a bicyclic ring system of the formula [ka] Form.

[0055] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, forms a bicyclic ring system of the formula: [ka] Forming

[0056] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0057] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0058] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0059] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0060] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0061] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0062] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0063] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0064] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0065] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0066] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0067] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0068] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0069] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of

[0070] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, has the formula [ka] wherein Z forms a bicyclic ring system of the formula 11 is CHR3 , C(R 3 )2, or NR 4 and Z 12 is CHR 2 , C(R 2 )2, NR 4 , or C(=NR 4 ), where each variable is independently as defined herein and described in the embodiments herein.

[0071] In some embodiments, ring A, together with the 6-membered ring system to which it is fused, is a bicyclic ring system selected from: [ka] Form.

[0072] In some embodiments, ring A, together with the six-membered ring system to which it is fused, forms a bicyclic ring system selected from those shown in Table A below. In some embodiments, ring A, together with the six-membered ring system to which it is fused, forms a bicyclic ring system selected from those shown in Table A2 below.

[0073] Generally as defined above, X 3 is CHR 3 , or NR 4 In some embodiments, X 3 is CHR 3 In some embodiments, X 3 is NR 4 In some embodiments, X 3 is NH. In some embodiments, X 3 is NMe. In some embodiments, X 3 is NCH(CH3)2.

[0074] Generally as defined above, X 4 is CHR 3 , N.R. 4 , O, or S. In some embodiments, X 4 is CHR 3 In some embodiments, X4 is NR 4 In some embodiments, X 4 is O. In some embodiments, X 4 is S. In some embodiments, X 4 is NH. In some embodiments, X 4 is NMe. In some embodiments, X 4 is NCH(CH3)2.

[0075] Generally, as defined above, each Z 1 is an independent CR 2 or N. In some embodiments, Z 1 is CR 2 In some embodiments, Z 1 is N.

[0076] Generally, as defined above, each Z 2 is an independent CR 3 or N. In some embodiments, Z 2 is CR 3 In some embodiments, Z 1 is N.

[0077] Generally as defined above, Z 11 is CHR 3 , C(R 3 )2, or NR 4 In some embodiments, Z 11 is CHR 3 In some embodiments, Z 11 is C(R 3 )2. In some embodiments, Z 11 is NR 4 is.

[0078] Generally as defined above, Z 12 is CHR 2 , C(R 2 )2, NR 4 , or C(=NR 4 In some embodiments, Z12 is CHR 2 In some embodiments, Z 12 is C(R 2 )2. In some embodiments, Z 12 is NR 4 In some embodiments, Z12 is C(=NR 4 )

[0079] As generally defined above, R 2 and R 3 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); R 2 and R 3 When at least one of R is not hydrogen, the cyclic group is optionally substituted or 2 and R 3together with their intervening atoms form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted. In some embodiments, R 2 and R 3 are each independently -NR-C(O)-R.

[0080] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is an arbitrarily substituted C 1~6 In some embodiments, R 2 is halogen. In some embodiments, R 2 is -OR. In some embodiments, R 2 is -NR2. In some embodiments, R 2 is —C(═O)R. In some embodiments, R 2 is —C(═O)OR. In some embodiments, R 2 is —C(═O)NR. In some embodiments, R 2 is -SO2R. In some embodiments, R 2 is -SO2NR2. In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is C 1~6 In some embodiments, R 2is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 2 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 2 is optionally substituted phenyl. In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 2 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 2 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is selected from those shown in Table A below. In some embodiments, R 2 is selected from those shown in Table A2 below.

[0081] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an arbitrarily substituted C 1~6 In some embodiments, R 3is halogen. In some embodiments, R 3 is -OR. In some embodiments, R 3 is -NR2. In some embodiments, R 3 is —NR—C(O)—R. In some embodiments, R 3 is —C(═O)R. In some embodiments, R 3 is —C(═O)OR. In some embodiments, R 3 is —C(═O)NR. In some embodiments, R 3 is -SO2R. In some embodiments, R 3 is -SO2NR2. In some embodiments, R 3 is C 1~6 In some embodiments, R 3 is C 1~6 In some embodiments, R 3 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 3 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 3 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 3 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R3 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is selected from those shown in Table A below. In some embodiments, R 3 is selected from those shown in Table A2 below.

[0082] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is methyl. In some embodiments, R 2 is Cl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is C 1~3 In some embodiments, R 2 is a 3-8 membered saturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is an azetidinyl group. In some embodiments, R 2 is optionally substituted ethyl. In some embodiments, R 2 is methoxy. In some embodiments, R 2 is -CHF. In some embodiments, R 2 is -OCH2F. In some embodiments, R 2 is -CD3.

[0083] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is methyl. In some embodiments, R 3 is Cl. In some embodiments, R 3 is isopropyl. In some embodiments, R3 is C 1~3 In some embodiments, R 3 is a 3-8 membered saturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is an azetidinyl group. In some embodiments, R 3 is optionally substituted ethyl. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is -CHF. In some embodiments, R 3 is -OCH2F. In some embodiments, R 3 is -CD3. In some embodiments, R 3 is —N(CH)—C(O)—CH. In some embodiments, R 3 is —N(CH). In some embodiments, R 3 is —NH(CH). In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0084] In some embodiments, R 2 and R 3together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted.

[0085] In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted phenyl. In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 and R 3together with their intervening atoms form an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted 5-6 membered monocyclic aromatic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 and R 3 together with their intervening atoms form an optionally substituted 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0086] In some embodiments, R 2 and R 3 together with their intervening atoms form a cyclopentane ring. In some embodiments, R 2 and R 3 together with their intervening atoms form a pyrrolidine ring.

[0087] As generally defined above, R 4 is hydrogen, optionally substituted C 1~6 an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5- to 6-membered heteroaryl ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or R 3 and R 4are, together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic heteroaromatic ring (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic heteroaromatic ring (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted.

[0088] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is an arbitrarily substituted C 1~6 In some embodiments, R 4 is optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 4 is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 is an optionally substituted 5- to 6-membered aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0089] In some embodiments, R 3 and R 4 together with their intervening atoms form an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 and R 4 together with their intervening atoms form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 3 and R4 together with their intervening atoms form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 3 and R 4 together with their intervening atoms form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 4 together with their intervening atoms form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 and R 4 together with their intervening atoms form an optionally substituted 5-6 membered monocyclic aromatic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 and R 4 together with their intervening atoms form an optionally substituted 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0090] In some embodiments, R 3 and R 4 together with their intervening atoms form a cyclopentane ring. In some embodiments, R 3 and R 4 together with their intervening atoms form a pyrrolidine ring.

[0091] Ring B, as generally defined above, is [ka] is.

[0092] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0093] As generally defined above, L is a bond or an optionally substituted straight or branched chain C 1~6 In some embodiments, L is an alkylene. In some embodiments, L is a bond. In some embodiments, L is an optionally substituted straight or branched C 1~6 In some embodiments, L is alkylene. In some embodiments, L is optionally substituted ethylene. In some embodiments, L is optionally substituted methylene. In some embodiments, L is selected from those shown in Table A below. In some embodiments, L is selected from those shown in Table A2 below.

[0094] Generally as defined above, X 5 is CH, N, or CR 5 In some embodiments, X 5 is CH. In some embodiments, X 5 is N. In some embodiments, X 5 is CR 5 In some embodiments, X 5 is selected from those shown in Table A below. In some embodiments, X 5 is selected from those shown in Table A2 below.

[0095] Generally as defined above, X 6 is CH, N, or CR 6 In some embodiments, X6 is CH. In some embodiments, X 6 is N. In some embodiments, X 6 is CR 6 In some embodiments, X 6 is selected from those shown in Table A below. In some embodiments, X 6 is selected from those shown in Table A2 below.

[0096] In some embodiments, X 5 is N and X 6 is CH. In some embodiments, X 5 is N and X 6 is CR 6 In some embodiments, X 5 is CH and X 6 is N. In some embodiments, X 5 is CR 5 and X 6 is N. In some embodiments, X 5 is CH and X 6 is CH. In some embodiments, X 5 is CH and X 6 is CR 6 In some embodiments, X 5 is CR 5 and X 6 is CH.

[0097] As generally defined above, R 16 is an arbitrarily substituted C 1~6 Aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 In some embodiments, R 16 is hydrogen. In some embodiments, R 16 is an arbitrarily substituted C 1~6 In some embodiments, R 16is halogen. In some embodiments, R 13 is -OR. In some embodiments, R 16 is -CN. In some embodiments, R 16 is -NR2. In some embodiments, R 16 is —C(═O)R. In some embodiments, R 16 is —C(═O)OR. In some embodiments, R 16 is —C(═O)NR. In some embodiments, R 16 is -SO2R. In some embodiments, R 16 is -SO2NR2. In some embodiments, R 16 is C 1~6 In some embodiments, R 16 is C 1~6 In some embodiments, R 16 is -CD3. In some embodiments, R 16 is selected from those shown in Table A below. In some embodiments, R 16 is selected from those shown in Table A2 below.

[0098] As generally defined above, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0099] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0100] As generally defined above, R 5 and R 6 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or is selected from R 5 and R 6together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted.

[0101] In some embodiments, R 5 is an arbitrarily substituted C 1~6 In some embodiments, R 5 is -OR. In some embodiments, R 5 is -NR2. In some embodiments, R 5 is —C(═O)R. In some embodiments, R 5 is —C(═O)OR. In some embodiments, R 5 is —C(═O)NR. In some embodiments, R 5 is -SO2R. In some embodiments, R 5 is -SO2NR2. In some embodiments, R 5 is halogen. In some embodiments, R 5 is C 1~6 In some embodiments, R 5 is C 1~6 In some embodiments, R 5 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 5is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 5 is optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 5 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0102] In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is -OCF3. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is selected from those shown in Table A below. In some embodiments, R 5 is selected from those shown in Table A2 below.

[0103] In some embodiments, R 6 is an arbitrarily substituted C 1~6 In some embodiments, R6 is -OR. In some embodiments, R 6 is -NR2. In some embodiments, R 6 is —C(═O)R. In some embodiments, R 6 is —C(═O)OR. In some embodiments, R 6 is —C(═O)NR. In some embodiments, R 6 is -SO2R. In some embodiments, R 6 is -SO2NR2. In some embodiments, R 6 is halogen. In some embodiments, R 6 is C 1~6 In some embodiments, R 6 is C 1~6 In some embodiments, R 6 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 6 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 6 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 6 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 6 is an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 6 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 6is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 6 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0104] In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is -OCF3. In some embodiments, R 6 is cyclopropyl. In some embodiments, R 6 is cyclobutyl. In some embodiments, R 6 is an optionally substituted pyrazolyl. In some embodiments, R 6 is an optionally substituted pyridinyl. In some embodiments, R 6 is an optionally substituted pyrimidinyl. In some embodiments, R 6 is an optionally substituted pyridazinyl. In some embodiments, R 6 is an optionally substituted imidazolyl. In some embodiments, R 6 is an optionally substituted triazolyl. In some embodiments, R 6 is an optionally substituted oxazolyl. In some embodiments, R 6 is an optionally substituted thiazolyl. In some embodiments, R 6 is an optionally substituted oxadiazolyl. In some embodiments, R 6 is an optionally substituted thiadiazolyl. In some embodiments, R 6 is an optionally substituted oxetanyl. In some embodiments, R 6 is an optionally substituted azetidinyl. In some embodiments, R 6 is optionally substituted piperidinyl. In some embodiments, R 6is an optionally substituted piperazinyl. In some embodiments, R 6 is selected from those shown in Table A below. In some embodiments, R 6 is selected from those shown in Table A2 below.

[0105] In some embodiments, R 5 and R 6 are independently hydrogen and substituents selected from those shown below. [ka]

[0106] In some embodiments, R 5 and R 6 together with their intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted.

[0107] In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 5 and R 6together with their intervening atoms form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted phenyl. In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted 6- to 12-membered saturated or partially unsaturated bridged heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted 5-6 membered monocyclic aromatic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 5 and R 6 together with their intervening atoms form an optionally substituted 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0108] In some embodiments, R 5 and R 6 together with their intervening atoms form a dioxole ring.

[0109] Generally as defined above, X 7 is N, CH, or CR 7 In some embodiments, X 7 is N. In some embodiments, X 7 is CH. In some embodiments, X 7 is CR 7 In some embodiments, X 7 is CCH3. In some embodiments, X 7 is COH. In some embodiments, X 7 is CF. In some embodiments, X 7 is selected from those shown in Table A below. In some embodiments, X 7 is selected from those shown in Table A2 below.

[0110] Generally as defined above, X 8 , O, NR 8 , C(R 8 )2, CHR 8 , SO, or C=O. In some embodiments, X 8 is O. In some embodiments, X 8 is NR 8 In some embodiments, X 8 is C(R 8 )2. In some embodiments, X 8 is CHR 8 In some embodiments, X 8 is SO. In some embodiments, X 8 is CH. In some embodiments, X 8 is C=O. In some embodiments, X 8 is selected from those shown in Table A below. In some embodiments, X 8 is selected from those shown in Table A2 below.

[0111] Generally as defined above, X 9 , O, NR 9 , C(R9 )2, CHR 9 , SO, or C=O. In some embodiments, X 9 is O. In some embodiments, X 9 is NR 9 In some embodiments, X 9 is C(R 9 )2. In some embodiments, X 9 is CHR 9 In some embodiments, X 9 is SO. In some embodiments, X 9 is CH. In some embodiments, X 9 is C=O. In some embodiments, X 9 is selected from those shown in Table A below. In some embodiments, X 9 is selected from those shown in Table A2 below.

[0112] Generally as defined above, X 10 , O, NR 10 , C(R 10 )2, CHR 10 , SO, or C=O. In some embodiments, X 10 is O. In some embodiments, X 10 is NR 10 In some embodiments, X 10 is C(R 10 )2. In some embodiments, X 10 is CHR 10 In some embodiments, X 10 is SO. In some embodiments, X 10 is C=O. In some embodiments, X 10 is CH, CF, or O. In some embodiments, X 10 is CH. In some embodiments, X 10 is NR 10 or O. In some embodiments, X 10 is NMe, NH, or O. In some embodiments, X10 is selected from those shown in Table A below. In some embodiments, X 10 is selected from those shown in Table A2 below.

[0113] Generally as defined above, X 11 , O, NR 11 , C(R 11 )2, CHR 11 , SO, or C=O. In some embodiments, X 11 is O. In some embodiments, X 11 is NR 11 In some embodiments, X 11 is C(R 11 )2. In some embodiments, X 11 is CHR 11 In some embodiments, X 11 is SO. In some embodiments, X 11 is CH. In some embodiments, X 11 is C=O. In some embodiments, X 11 is selected from those shown in Table A below. In some embodiments, X 11 is selected from those shown in Table A2 below.

[0114] Generally as defined above, X 12 is a direct bond, O, NR 12 , C(R 12 )2, CHR 12 , —CH2CH2—, —OCH2—, SO2, or C═O. In some embodiments, X 12 is O. In some embodiments, X 12 is NR 12 In some embodiments, X 12 is C(R 12 )2. In some embodiments, X 12 is CHR 12 In some embodiments, X 12 is CH. In some embodiments, X 12is SO. In some embodiments, X 12 is C=O. In some embodiments, X 12 is -CHCH-. In some embodiments, X 12 is —OCH—. In some embodiments, X 12 is a direct bond. In some embodiments, X 12 is selected from those shown in Table A below. In some embodiments, X 12 is selected from those shown in Table A2 below.

[0115] In some embodiments, X 7 , X 8 , X 9 , X 10 , X 11 , or X 12 is N, O, or SO2, then neither of the adjacent positions in ring B is N, O, or SO2.

[0116] In some embodiments, X 8 , X 9 , X 10 , X 11 , or X 12 When any one of is C=O, then neither of the adjacent positions in ring B is C=O or SO2.

[0117] As generally defined above, R 7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, or C 1~6 In some embodiments, R 7 is an optionally substituted aliphatic group. In some embodiments, R 7 is halogen. In some embodiments, R 7 is -OR. In some embodiments, R 7 is -NR2. In some embodiments, R 7is —C(═O)R. In some embodiments, R 7 is —C(═O)OR. In some embodiments, R 7 is —C(═O)NR. In some embodiments, R 7 is -SO2R. In some embodiments, R 7 is -SO2NR2. In some embodiments, R 7 is C 1~6 In some embodiments, R 7 is C 1~6 In some embodiments, R 7 is methyl. In some embodiments, R 7 is OH. In some embodiments, R 7 is F. In some embodiments, R 7 is selected from those shown in Table A below. In some embodiments, R 7 is selected from those shown in Table A2 below.

[0118] As generally defined above, R 8 , R 9 , R 10 , R 11 , and R 12 each independently represents hydrogen, optionally substituted C 1~6 Aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C 1~6 Haloalkyl, C 1~6haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or is selected from R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 any two of these, together with the intervening atoms, form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted.

[0119] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is an arbitrarily substituted C 1~6 In some embodiments, R 8 is -OR. In some embodiments, R 8 is -NR2. In some embodiments, R 8is —C(═O)R. In some embodiments, R 8 is —C(═O)OR. In some embodiments, R 8 is —C(═O)NR. In some embodiments, R 8 is -SO2R. In some embodiments, R 8 is -SO2NR2. In some embodiments, R 8 is C 1~6 In some embodiments, R 8 is C 1~6 In some embodiments, R 8 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 8 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 8 is optionally substituted phenyl. In some embodiments, R 8 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 8 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 8 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 8 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 8 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 8 is methyl. In some embodiments, R 8 is —OH. In some embodiments, R 8 is F. In some embodiments, R 8is methoxy. In some embodiments, R 8 is -CH2OH. X 8 is C(R 8 In some embodiments, each R 8 is independently selected from any of the aforementioned substituents. 8 is C(R 8 In some embodiments, both R 8 are the same. In some embodiments, R 8 is selected from those shown in Table A below. In some embodiments, R 8 is selected from those shown in Table A2 below.

[0120] In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is an arbitrarily substituted C 1~6 In some embodiments, R 9 is -OR. In some embodiments, R 9 is -NR2. In some embodiments, R 9 is —C(═O)R. In some embodiments, R 9 is —C(═O)OR. In some embodiments, R 9 is —C(═O)NR. In some embodiments, R 9 is -SO2R. In some embodiments, R 9 is -SO2NR2. In some embodiments, R 9 is C 1~6 In some embodiments, R 9 is C 1~6 In some embodiments, R 9 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 9 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 9 is optionally substituted phenyl. In some embodiments, R9 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 9 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is methyl. In some embodiments, R 9 is —OH. In some embodiments, R 9 is F. In some embodiments, R 9 is methoxy. In some embodiments, R 9 is -CH2OH. X 9 is C(R 9 In some embodiments, each R 9 is independently selected from any of the aforementioned substituents. 9 is C(R 9 In some embodiments, both R 9 are the same. In some embodiments, R 9 is selected from those shown in Table A below. In some embodiments, R 9 is selected from those shown in Table A2 below.

[0121] In some embodiments, R 9 is an optionally substituted pyrazolyl. In some embodiments, R 9 is an optionally substituted pyridinyl. In some embodiments, R9 is an optionally substituted pyrimidinyl. In some embodiments, R 9 is an optionally substituted pyridazinyl. In some embodiments, R 9 is an optionally substituted imidazolyl. In some embodiments, R 9 is an optionally substituted triazolyl. In some embodiments, R 9 is an optionally substituted oxazolyl. In some embodiments, R 9 is an optionally substituted thiazolyl. In some embodiments, R 9 is an optionally substituted oxadiazolyl. In some embodiments, R 9 is an optionally substituted thiadiazolyl. In some embodiments, R 9 is an optionally substituted oxetanyl. In some embodiments, R 9 is an optionally substituted azetidinyl. In some embodiments, R 9 is optionally substituted piperidinyl. In some embodiments, R 9 is an optionally substituted piperazinyl.

[0122] In some embodiments, R 9 is substituted with an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 9 is substituted with an optionally substituted 5-8 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 9 is substituted with an optionally substituted 3-6 membered saturated or partially unsaturated monocyclic heterocycle. In some embodiments, R 9 is an arbitrarily substituted C 1~6 In some embodiments, R 9 is substituted with a methyl group. In some embodiments, R 9 is substituted with a -CD group. In some embodiments, R 9 is substituted with a methoxy group. In some embodiments, R 9 is substituted with a cyclopropyl group. In some embodiments, R9 is an arbitrarily substituted [ka] is.

[0123] In some embodiments, R 9 is —OR, where R is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is —NHR, where R is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is —N(CH)R, where R is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is —C(═O)N(CH)R, where R is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is —C(═O)NHR, where R is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0124] In some embodiments, R 9 is a substituent selected from those shown below. [ka]

[0125] In some embodiments, R 9 is methyl, tetrahydrofuran-3-yl, [ka] is.

[0126] In some embodiments, R 9 is methyl, tetrahydrofuran-3-yl, [ka] is.

[0127] In some embodiments, R 9 teeth, [ka] is.

[0128] In some embodiments, R 9 teeth, [ka] is.

[0129] In some embodiments, R 9 teeth, [ka] is.

[0130] In some embodiments, R 9 teeth, [ka] is.

[0131] In some embodiments, R 9 teeth, [ka] is.

[0132] In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is an arbitrarily substituted C 1~6 In some embodiments, R 10is -OR. In some embodiments, R 10 is -NR2. In some embodiments, R 10 is —C(═O)R. In some embodiments, R 10 is —C(═O)OR. In some embodiments, R 10 is —C(═O)NR. In some embodiments, R 10 is -SO2R. In some embodiments, R 10 is -SO2NR2. In some embodiments, R 10 is C 1~6 In some embodiments, R 10 is C 1~6 In some embodiments, R 10 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 10 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 10 is optionally substituted phenyl. In some embodiments, R 10 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 10 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 10 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 10 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 10 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 10 is methyl. In some embodiments, R 10is —OH. In some embodiments, R 10 is F. In some embodiments, R 10 is methoxy. In some embodiments, R 10 is -CH2OH. X 10 is C(R 10 In some embodiments, each R 10 is independently selected from any of the aforementioned substituents. 10 is C(R 10 In some embodiments, both R 10 are the same. In some embodiments, R 10 is selected from those shown in Table A below. In some embodiments, R 10 is selected from those shown in Table A2 below.

[0133] In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is an arbitrarily substituted C 1~6 In some embodiments, R 11 is -OR. In some embodiments, R 11 is -NR2. In some embodiments, R 11 is —C(═O)R. In some embodiments, R 11 is —C(═O)OR. In some embodiments, R 11 is —C(═O)NR. In some embodiments, R 11 is -SO2R. In some embodiments, R 11 is -SO2NR2. In some embodiments, R 11 is C 1~6 In some embodiments, R 11 is C 1~6 In some embodiments, R 11 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 11is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 11 is optionally substituted phenyl. In some embodiments, R 11 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 11 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 11 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 11 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 11 is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 11 is methyl. In some embodiments, R 11 is —OH. In some embodiments, R 11 is F. In some embodiments, R 11 is methoxy. In some embodiments, R 11 is -CH2OH. X 11 is C(R 11 In some embodiments, each R 11 is independently selected from any of the aforementioned substituents. 11 is C(R 11 In some embodiments, both R 11 are the same. In some embodiments, R 11 is selected from those shown in Table A below. In some embodiments, R 11 is selected from those shown in Table A2 below.

[0134] In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is an arbitrarily substituted C 1~6 In some embodiments, R 12 is -OR. In some embodiments, R 12 is -NR2. In some embodiments, R 12 is —C(═O)R. In some embodiments, R 12 is —C(═O)OR. In some embodiments, R 12 is —C(═O)NR. In some embodiments, R 12 is -SO2R. In some embodiments, R 12 is -SO2NR2. In some embodiments, R 12 is C 1~6 In some embodiments, R 12 is C 1~6 In some embodiments, R 12 is an optionally substituted 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 12 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocycle. In some embodiments, R 12 is optionally substituted phenyl. In some embodiments, R 12 is an optionally substituted 8-10 membered bicyclic aromatic carbocycle. In some embodiments, R 12 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 12 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 12 is an optionally substituted 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 12is an optionally substituted 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 12 is methyl. In some embodiments, R 12 is —OH. In some embodiments, R 12 is F. In some embodiments, R 12 is methoxy. In some embodiments, R 12 is -CH2OH. X 12 is C(R 12 In some embodiments, each R 12 is independently selected from any of the aforementioned substituents. 12 is C(R 12 In some embodiments, both R 12 are the same. In some embodiments, R 12 is selected from those shown in Table A below. In some embodiments, R 12 is selected from those shown in Table A2 below.

[0135] In some embodiments, Ring B is a substituent selected from those shown below. [ka]

[0136] In some embodiments, ring B is [ka] is.

[0137] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0138] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0139] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0140] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0141] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is [ka] is.

[0142] In some embodiments, at least one hydrogen atom of the compound is a deuterium atom. In some embodiments, at least one C1-C6 aliphatic group of the compound is substituted with at least one deuterium atom. In some embodiments, at least one C1-C6 alkyl group of the compound is substituted with at least one deuterium atom. In some embodiments, R 2 is -CD3. In some embodiments, R 3 is -CD3. In some embodiments, R 2 and R 3 and R are both -CD3. In some embodiments, R 4 is -CD3.

[0143] Exemplary compounds of the invention are set forth below in Table A. In some embodiments, the compound is a compound set forth in Table A, or a pharmaceutically acceptable salt thereof. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7] [Table A-8]

[0144] Exemplary compounds of the invention are set forth below in Table A2: In some embodiments, the compound is a compound set forth in Table A2, or a pharmaceutically acceptable salt thereof. [Table A2-1] [Table A2-2] [Table A2-3] [Table A2-4] [Table A2-5] [Table A2-6] [Table A2-7] [Table A2-8] [Table A2-9] [Table A2-10] [Table A2-11] [Table A2-12] [Table A2-13] [Table A2-14] [Table A2-15] [Table A2-16]

[0145] The foregoing merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.

[0146] Formulation and route of administration In the uses described herein, it may be possible to administer the compound disclosed herein alone, but the compound that is usually administered will be present as an active ingredient in a pharmaceutical composition.Therefore, in one embodiment, the present invention provides pharmaceutical compositions that include the compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants, etc., and optionally other active ingredients. See, for example, Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by G. D. Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0147] The compounds disclosed herein can be administered by any suitable route in the form of a pharmaceutical composition adapted for such a route, in a dose effective for the intended treatment. The compounds and compositions presented herein can be administered orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally, or by infusion techniques, for example, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0148] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drops, infusion, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. Pharmaceutical compositions are typically made in the form of a dosage unit containing a particular amount of the active ingredient.

[0149] In one aspect, the invention provides a pharmaceutical composition comprising a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, and a pharmaceutically acceptable excipient.

[0150] In another aspect, the present invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition comprising said compound or said tautomer, or said salt, for use as a medicament.

[0151] Pharmaceutically acceptable compositions According to some embodiments, the present disclosure provides a composition comprising a compound of the present disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present disclosure is an amount effective to measurably activate TREM2 protein or a variant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present disclosure is an amount effective to measurably activate TREM2 protein or a variant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present disclosure is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0152] The compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present disclosure may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques well known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media.

[0153] For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially their polyoxyethylated versions, are useful for preparing injections, as are natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0154] The pharmaceutically acceptable composition of the present disclosure can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, active ingredients are combined with emulsifiers and suspending agents.If necessary, certain sweeteners, flavors, or coloring agents can also be added.

[0155] Alternatively, the pharmaceutically acceptable compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0156] The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0157] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0158] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0159] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, either with or without preservatives such as benzyl alkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated into an ointment such as petrolatum.

[0160] The pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0161] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0162] The amount of the compounds of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the provided compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0163] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of a compound of the present disclosure in a composition will also depend on the particular compound in the composition.

[0164] How to use As discussed herein (see the section entitled "Definitions"), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing, or solvates of any of the foregoing. Accordingly, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses employing all such forms.

[0165] In addition to being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs, and cats may be treated with the compounds provided herein.

[0166] Without intending to be bound by any particular theory, it is noted that TREM2 is involved in several myeloid cell processes, including phagocytosis, proliferation, survival, and regulation of inflammatory cytokine production (Ulrich and Holtzman 2016). In recent years, TREM2 has been associated with several diseases. For example, mutations in both TREM2 and DAP12 are associated with Nasu-Hakola disease, an autosomal recessive disorder characterized by bone cysts, muscle wasting, and a demyelinating phenotype (Guerreiro et al. 2013). More recently, variants in the TREM2 gene have been associated with an increased risk of Alzheimer's disease (AD) and other forms of dementia, including frontotemporal dementia (FTD). Jonsson et al. 2013, Guerreiro, Lohmann et al. 2013, and Jay, Miller et al. 2015. In particular, the R47H variant has been associated with an increased risk of late-onset AD in genome-wide studies, with an overall adjusted odds ratio (for all age groups) of 2.3, second only to the strong genetic association between ApoE and Alzheimer's disease. The R47H mutation resides in the extracellular lg V-set domain of the TREM2 protein and has been shown to affect lipid binding and the uptake of apoptotic cells and Abeta (Wang et al. 2015; Yeh et al. 2016), suggesting a disease-related loss of function. Furthermore, postmortem comparison of brains from AD patients with and without the R47H mutation supports the loss of novel microbarrier function in mutation carriers, showing that microglia in R47H carriers have a reduced ability to compact plaques and limit their spread. Yuan et al. 2016. Impaired microgliosis has been reported in animal models of prion disease, multiple sclerosis, and stroke, suggesting that TREM2 may play an important role in supporting microgliosis in response to central nervous system pathology or injury. Ulrich and Holtzman 2016.Furthermore, knockdown of TREM2 has been shown to exacerbate a-syn-induced inflammatory responses in vitro and dopaminergic neuron loss in response to AAV-SYN (a model of Parkinson's disease) in vivo, suggesting that impaired microglial TREM2 signaling exacerbates neurodegeneration by regulating the activation state of microglia (Guo et al. 2019). Various animal models also suggest that Toll-like receptor (TLR) signaling is important in the pathogenesis of rheumatoid arthritis (RA) through the sustained expression of proinflammatory cytokines by macrophages. Signaling through TREM2 / DAP12 inhibits TLR responses by reducing MAPK (Erk1 / 2) activation, suggesting that TREM2 activation may act as a negative regulator of TLR-driven RA pathogenesis (Huang and Pope 2009).

[0167] In view of data showing that loss of TREM2 activity affects macrophage and microglial function, the compounds disclosed herein are particularly useful in, for example, the disorders described in the embodiments above and below, as well as in neurodegenerative disorders generally.

[0168] In one aspect, the invention provides a compound of the disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in treating or preventing a condition associated with loss of function of human TREM2.

[0169] In one aspect, the invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0170] In one aspect, the invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating or preventing a condition associated with loss of function of human TREM2.

[0171] In one aspect, the invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0172] In another aspect, there is provided a method of treating or preventing a condition associated with loss of function of human TREM2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.

[0173] In another aspect, the present invention provides a method of treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.

[0174] CSF1R CSF1R is the cell surface receptor for the cytokine colony-stimulating factor 1 (CSF-1), which until recently was also known as macrophage colony-stimulating factor (M-CSF), and it regulates the survival, proliferation, differentiation, and function of mononuclear phagocytes, including microglia, in the central nervous system. CSF1R consists of a highly glycosylated extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Binding of CSF-1 to CSF1R leads to the formation of receptor homodimers and subsequent autophosphorylation of several tyrosine residues in the cytoplasmic domain, particularly Syk. In the brain, CSF1R is primarily expressed in microglial cells. Microglia in CSF1R± patients have been found to be depleted and exhibit increased apoptosis (Oosterhof et al., 2018).

[0175] The present invention relates to the unexpected discovery that administration of a TREM2 agonist can rescue microglia loss in cells harboring mutations in CSF1R. It has previously been shown that the TREM2 agonist antibody 4D9 increases ATP luminescence (a measure of cell number and activity) in a dose-dependent manner when M-CSF levels in the culture medium are reduced to 5 ng / mL (Schlepckow et al., EMBO Mol Med., 2020), and that the TREM2 agonist AL002c increases ATP luminescence when M-CSF is completely removed from the culture medium (Wang et al., J. Exp. Med.; 2020, 217(9):e20200785). This finding suggests that TREM2 agonism can compensate for defects in CSF1R signaling caused by a decrease in the concentration of its ligand. In the 5xFAD mouse Alzheimer's disease model of amyloid pathology, doses of CSF1R inhibitors that nearly completely eliminate microglia in the brains of wild-type animals exhibit surviving microglia clustered around amyloid plaques (Spangenberg et al., Nature Communications, 2019). Plaque amyloid has previously been demonstrated to be a ligand for TREM2, and microglial engagement with amyloid has been shown to be TREM2-dependent (Condello et al., Nat Comm., 2015). The present invention relates to the unexpected discovery that it is TREM2 activation that rescues microglia in the presence of CSF1R inhibitors, an effect also observed in patients with microglial loss due to CSF1R mutations. This discovery has not previously been taught or suggested in the available art.

[0176] Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously recognized as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmented orthochromatic leukodystrophy (POLD), is an autosomal dominant central nervous system disorder that manifests as fluctuating behavioral, cognitive, and motor changes in affected individuals. ALSP is characterized by patchy cerebral white matter abnormalities visible on magnetic resonance imaging. However, clinical symptoms and MRI changes are not specific for ALSP and are shared with other neurological conditions, including Nasu-Hakola disease (NHD) and AD, making the diagnosis and treatment of ALSP extremely challenging.

[0177] Recent studies have discovered that ALSP is a Mendelian disorder in which patients carry heterozygous loss-of-function mutations in the kinase domain of CSF1R, suggesting reduced levels of signaling in the macrophage colony-stimulating factor (M-CSF) / CSF1R axis (Rademakers et al., Nat Genet 2012; Konno et al., Neurology 2018). In one aspect, the present invention relates to the surprising discovery that activation of the TREM2 pathway rescues microglial loss and prevents microglial apoptosis in CSF1R+ / - ALSP patients, thereby treating the ALSP condition.

[0178] In one aspect, the invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in the treatment or prevention of a condition associated with dysfunction of colony-stimulating factor 1 receptor (CSF1R, also known as macrophage colony-stimulating factor receptor / M-CSFR, or cluster of differentiation 115 / CD115).

[0179] In one aspect, the present invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof, for use in the treatment or prevention of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS).

[0180] In one aspect, the invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating or preventing a condition associated with dysfunction of CSF1R.

[0181] In one aspect, the invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS).

[0182] In another aspect, a method of treating or preventing a disease or disorder associated with dysfunction of CSF1R in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof. In some embodiments, the subject is selected for treatment based on a diagnosis comprising the presence of a mutation in the CSF1R gene that affects CSF1R function. In some embodiments, the mutation in the CSF1R gene is a mutation that causes reduced or abolished CSF1R activity. In some embodiments, the disease or disorder is caused by a heterozygous CSF1R mutation. In some embodiments, the disease or disorder is caused by a homozygous CSF1R mutation. In some embodiments, the disease or disorder is caused by a splice mutation in the csf1r gene. In some embodiments, the disease or disorder is caused by a missense mutation in the csf1r gene. In some embodiments, the disease or disorder is caused by a mutation in the catalytic kinase domain of CSF1R. In some embodiments, the disease or disorder is caused by a mutation in the immunoglobulin domain of CSF1R. In some embodiments, the disease or disorder is caused by a mutation in the ectodomain of CSF1R. In some embodiments, the disease or disorder is a disease or disorder resulting from an alteration (e.g., an increase, decrease, or abolition) in the activity of CSF1R. In some embodiments, the disease or disorder is a disease or disorder resulting from a decrease or abolition in the activity of CSF1R. CSF1R-associated activities that are altered in a disease or disorder include, but are not limited to, a decrease or loss of microglial function, an increase in microglial apoptosis, a decrease in Src signaling, a decrease in Syk signaling, a decrease in microglial proliferation, a decrease in microglial response to cellular debris, a decrease in phagocytosis, and a decrease in cytokine release in response to stimuli. In some embodiments, the disease or disorder is caused by a loss-of-function mutation in CSF1R. In some embodiments, the loss-of-function mutation results in a complete abolition of CSF1R function.In some embodiments, the loss-of-function mutation results in a partial loss of CSF1R function or a decrease in CSF1R activity.

[0183] In another aspect, the present invention provides a method of treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof. In some embodiments, the method treats or prevents ALSP, which encompasses and replaces both HDLS and POLD. In some embodiments, the disease or disorder is a homozygous mutation in CSF1R. In some embodiments, the method treats or prevents childhood-onset leukoencephalopathy. In some embodiments, the method treats or prevents congenital absence of microglia. In some embodiments, the method treats or prevents brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS).

[0184] In yet another aspect, the present invention provides a method for treating Nasu-Hakola disease, Alzheimer's disease, frontotemporal dementia, multiple sclerosis, Guillain-Barré syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, traumatic brain injury, spinal cord injury, systemic lupus erythematosus, rheumatoid arthritis, prion disease, stroke, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysostosis, Pyle's disease, autosomal dominant cerebral arteriopathy with subcortical infarction and leukoencephalopathy, autosomal recessive cerebral arteriopathy with subcortical infarction and leukoencephalopathy, cerebral retinal A method of treating or preventing a vascular disease or metachromatic leukodystrophy in a subject in need thereof is provided, wherein any of the aforementioned diseases or disorders is present in a patient exhibiting CSF1R dysfunction or having a genetic mutation affecting the function of CSF1R, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof.

[0185] ABCD1 The ABCD1 gene provides instructions for producing adrenoleukodystrophy protein (ALDP). ABCD1 (ALDP) maps to Xq28. ABCD1 is a member of the ATP-binding cassette (ABC) transporter superfamily. This superfamily contains membrane proteins that transport a wide range of substrates across extracellular and intracellular membranes, including metabolites, lipids, sterols, and drugs. ALDP is located in the membrane of cellular structures called peroxisomes, which are small intracellular sacs that process many types of molecules. ALDP transports a group of lipids called very long-chain fatty acids (VLCFAs) into peroxisomes, where they are degraded. Because ABCD1 is highly expressed in microglia, microglial dysfunction and its close interaction with other cell types may be actively involved in neurodegenerative processes (Gong et al., Annals of Neurology. 2017;82(5):813-827). Severe microglial loss and damage have been shown to be an early feature in patients with cerebral X-linked ALD (cALD) who harbor ABCD1 mutations (Bergner et al., Glia. 2019;67:1196-1209). ABCD1 deficiency also leads to impaired myeloid cell plasticity, reflected by the incomplete establishment of an anti-inflammatory response, and may therefore contribute to the devastating, rapidly progressive demyelination in cerebral adrenoleukodystrophy (Weinhor et al., BRAIN 2018:141;2329-2342). These findings highlight microglia / monocytes / macrophages as important therapeutic targets for preventing or halting myelin destruction in patients with X-linked adrenoleukodystrophy.

[0186] The present invention relates to the unexpected discovery that administration of a TREM2 agonist can rescue microglia loss in cells harboring mutations in the ABCD1 gene. It has previously been shown that the TREM2 agonist antibody 4D9 increases ATP luminescence (a measure of cell number and activity) in a dose-dependent manner when M-CSF levels in the culture medium are reduced to 5 ng / mL (Schlepckow et al., EMBO Mol Med., 2020), and that the TREM2 agonist AL002c increases ATP luminescence when M-CSF is completely removed from the culture medium (Wang et al., J. Exp. Med.; 2020, 217(9):e20200785). This finding suggests that TREM2 agonism can compensate for the lack of ABCD1 function, which leads to sustained microglial activation, proliferation, chemotaxis, and maintenance of an anti-inflammatory environment, as well as reduced astrocyte proliferation caused by reduced ABCD1 and VLCFA accumulation. The present invention relates to the unexpected discovery that activation of TREM2 can rescue microglia in the presence of ABCD1 mutations and increased VLCFAs, and that this effect can also be observed in patients with microglial loss due to ABCD1 mutations, a discovery not previously taught or suggested in the available art.

[0187] In one aspect, the present invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof, for use in treating or preventing a condition associated with dysfunction of ATP-binding cassette transporter 1 (ABCD1).

[0188] In one aspect, the present invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in the treatment or prevention of X-linked adrenoleukodystrophy (x-ALD), globoid cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), vanishing white matter disease (VWM), Alexander disease, Fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[0189] In one aspect, the present invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating or preventing a condition associated with dysfunction of ABCD1.

[0190] In one aspect, the present invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating or preventing X-linked adrenoleukodystrophy (x-ALD), globoid cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), vanishing white matter disease (VWM), Alexander disease, Fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[0191] In yet another aspect, the present invention provides a method of treating or preventing a disease or disorder associated with dysfunction of ABCD1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof. In some embodiments, the patient is selected for treatment based on a diagnosis including the presence of a mutation in the ABCD1 gene that affects the function of ABCD1. In some embodiments, the mutation in the ABCD1 gene is a mutation that causes reduced or abolished ABCD1 activity. In some embodiments, the disease or disorder is caused by a heterozygous ABCD1 mutation. In some embodiments, the disease or disorder is caused by a homozygous ABCD1 mutation. In some embodiments, the disease or disorder is caused by a splice mutation in the ABCD1 gene. In some embodiments, the disease or disorder is caused by a missense mutation in the ABCD1 gene. In some embodiments, the disease or disorder is a disease or disorder resulting from an altered (e.g., increased, decreased, or abolished) activity of ABCD1. In some embodiments, the disease or disorder is a disease or disorder resulting from reduced or absent activity of ABCD1. ABCD1-related activities that are altered in the disease or disorder include, but are not limited to, peroxisomal import of fatty acids and / or fatty acyl-CoA and production of adrenoleukodystrophy protein (ALDP). In some embodiments, the disease or disorder is caused by a loss-of-function mutation in ABCD1. In some embodiments, the loss-of-function mutation results in a complete abolition of ABCD1 function. In some embodiments, the loss-of-function mutation results in a partial loss of ABCD1 function or reduced ABCD1 activity. In some embodiments, the disease or disorder is caused by a homozygous mutation in ABCD1. In some embodiments, the disease or disorder is a neurodegenerative disorder. In some embodiments, the disease or disorder is a neurodegenerative disorder caused by and / or associated with ABCD1 dysfunction. In some embodiments, the disease or disorder is an immune disorder.In some embodiments, the disease or disorder is an immune disorder caused by and / or associated with ABCD1 dysfunction.

[0192] In yet another aspect, the present invention provides a method of treating or preventing X-linked adrenoleukodystrophy (x-ALD), globoid cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), vanishing white matter disease (VWM), Alexander disease, Fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof. In some embodiments, any of the above-mentioned diseases is present in a patient exhibiting ABCD1 dysfunction or having a mutation in a gene affecting ABCD1 function. In some embodiments, the method treats or prevents X-linked adrenoleukodystrophy (x-ALD). In some embodiments, the x-ALD is cerebral x-linked ALD (cALD). In some embodiments, the method treats or prevents Addison's disease in which the patient is known to have a mutation in one or more ABCD1 genes that affects ABCD1 function. In some embodiments, the method treats or prevents Addison's disease in which the patient has a loss-of-function mutation in ABCD1.

[0193] In yet another aspect, the present invention provides a method of treating or preventing Nasu-Hakola disease, Alzheimer's disease, frontotemporal dementia, multiple sclerosis, Guillain-Barré syndrome, amyotrophic lateral sclerosis (ALS), or Parkinson's disease in a subject in need thereof, wherein any of the foregoing diseases or disorders is present in a patient exhibiting ABCD1 dysfunction or having a mutation in a gene affecting ABCD1 function, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.

[0194] Autism spectrum disorder TREM2-deficient mice have been found to exhibit symptoms reminiscent of autism spectrum disorder (ASD) (Filipello et al., Immunity, 2018, 48, 979-991). Microglial depletion of the autophagy gene Aatg7 has also been found to result in synaptic pruning defects, increased dendritic spine density, and abnormal social interactions and repetitive behaviors indicative of ASD (Kim et al., Molecular Psychiatry, 2017, 22, 1576-1584). Further studies have shown that the increased dendritic spine density detected in postmortem ASD brains is likely caused by synaptic pruning defects, leading to reduced circuit connectivity and behavioral impairments, potentially contributing to many neurodevelopmental disorders (Tang et al., Neuron, 2014, 83, 1131-1143). Without intending to be limited to a particular theory, these findings suggest that TREM2 activation can reverse microglial depletion and therefore correct the synaptic pruning defects central to neurodevelopmental disorders such as ASD. The present invention relates to the unexpected discovery that activation of TREM2 using compounds of the present invention can rescue microglia in subjects with ASD. This discovery has not previously been taught or suggested in the available art.

[0195] In another aspect, the present invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in treating autism or an autism spectrum disorder.

[0196] In yet another aspect, the present invention provides a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating autism or an autism spectrum disorder.

[0197] In yet another aspect, the present invention provides a method of treating autism or an autism spectrum disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition thereof. In some embodiments, the method treats autism. In some embodiments, the method treats Asperger's syndrome.

[0198] In some embodiments, the disclosure provides a method of increasing the activity of TREM2, comprising contacting TREM2 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo. In some embodiments, the TREM2 is human TREM2.

[0199] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the present disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease, or condition, being treated."

[0200] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0201] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of a disclosed compound and an additional therapeutic agent or agents acts synergistically.

[0202] Examples of drugs with which the combinations of the present disclosure may be combined include, but are not limited to, treatments for Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0203] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, a combination of the present disclosure may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0204] The amount of additional therapeutic agent present in the compositions of the present disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0205] One or more other therapeutic agents may be administered separately from the compounds or compositions of the present disclosure as part of a multiple dosing regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the present disclosure in a single composition. When administered as a multiple dosing regimen, one or more other therapeutic agents and the compounds or compositions of the present disclosure may be administered simultaneously, sequentially, or within a period of each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours of each other. In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present disclosure are administered partially within a period of more than 24 hours as a multiple dosing regimen.

[0206] In one embodiment, the present disclosure provides a composition comprising a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. The therapeutic agents may be administered together with the provided compound or a pharmaceutically acceptable salt thereof, or may be administered before or after administration of the provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below. In certain embodiments, the provided compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0207] definition The following definitions are provided to aid in understanding the scope of the present disclosure.

[0208] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification or claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0209] As used herein, when any variable occurs more than once in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. When the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0210] As used herein, the following definitions shall apply unless otherwise indicated: For the purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 101 st In addition, the general principles of organic chemistry are identified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2005, and "March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 8 th Ed., Ed.: Smith, MB, John Wiley & Sons, New York: 2019, the entire contents of which are incorporated herein by reference.

[0211] stereoisomer Compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with hindered rotation, and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropoisomers. Accordingly, the scope of the present disclosure should be understood to encompass all possible stereoisomers of the exemplified compounds, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomers pure) and stereoisomeric mixtures (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixtures of any of the foregoing) of any chemical structure (in whole or in part) disclosed herein, unless the stereochemistry is specifically specified.

[0212] If the stereochemistry of a structure or portion of a structure is not indicated, for example, by a bold or dashed line, the structure or portion of a structure should be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is indicated, for example, by a bold or dashed line, the structure or portion of a structure should be interpreted as encompassing only the depicted stereoisomer. For example, (1R)-1-methyl-2-(trifluoromethyl)cyclohexane is meant to encompass (1R,2R)-1-methyl-2-(trifluoromethyl)cyclohexane and (1R,2S)-1-methyl-2-(trifluoromethyl)cyclohexane. Bonds drawn with wavy lines indicate that both stereoisomers are encompassed. This should not be confused with wavy lines drawn perpendicular to the bond indicating the point of attachment of the group to the rest of the molecule.

[0213] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror-image enantiomer of the compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers and diastereomers of the compound. A typical stereoisomerically pure compound will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound.

[0214] The present disclosure also encompasses pharmaceutical compositions comprising stereomerically pure forms and the use of stereomerically pure forms of any compound disclosed herein. Additionally, the present disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compound disclosed herein and the use of such pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods well known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0215] tautomers As those skilled in the art will readily understand, certain compounds disclosed herein can exist in one or more tautomeric forms.Because one chemical structure can only be used to represent one tautomeric form, for convenience, it is understood that reference to a compound of a given structural formula includes other tautomers of this structural formula.Therefore, it should be understood that the scope of the present disclosure encompasses all tautomers of the compounds disclosed herein.

[0216] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, e.g., 2 H and 3 H, isotopes of carbon, e.g. 11 C. 13 C, and 14 C, an isotope of chlorine, e.g. 36 Cl, isotopes of fluorine, e.g. 18 F, an isotope of iodine, e.g. 123 I and 125 I, isotopes of nitrogen, e.g. 13 N and 15 N, isotopes of oxygen, e.g. 15 O. 17 O, and 18 O, isotopes of phosphorus, e.g. 32 P, as well as sulfur isotopes, e.g., 35 Certain isotopically labeled compounds of formula I, for example, compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) is particularly useful for this purpose in view of its ease of incorporation and ease of detection. 2 Substitution with isotopes such as H or D may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some circumstances. 11 C. 18 F, 15 O, and 13Substitution with positron-emitting isotopes, such as N, can be useful, for example, in Positron Emission Topography (PET) studies to examine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques readily known to those of skill in the art, or by processes analogous to those described in the accompanying general synthetic schemes and examples, substituting appropriate isotopically labeled reagents for previously utilized non-labeled reagents.

[0217] solvate As noted above, the compounds disclosed herein, as well as the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharmaceutically acceptable salts of any of the foregoing, can exist in solvated or unsolvated forms.

[0218] The term "solvate," as used herein, refers to a molecular complex comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, in either a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is referred to as a "hydrate."

[0219] Therefore, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein, as well as their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing.

[0220] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0221] Compounds of the present disclosure include those compounds generally described herein, and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 101 stIn addition, the general principles of organic chemistry are identified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2005, and "March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 8 th Ed., Ed.: Smith, MB, John Wiley & Sons, New York: 2019, the entire contents of which are incorporated herein by reference.

[0222] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation but is not aromatic, with a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that has a single point of attachment to the rest of the molecule and that is fully saturated or contains one or more units of unsaturation, but is not aromatic. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0223] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., a carbocyclic or heterocyclic ring system, saturated or having one or more unsaturated units, with one or more atoms common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic rings. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both rings of the bicyclic ring. Such heteroatoms may be present at the ring junction, are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring system, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or an atom or valence bond connecting two bridgeheads, and a "bridgehead" is any skeletal atom of a ring system that is connected to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents described for an aliphatic group. Additionally, or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [ka]

[0224] Exemplary bridged bicycles include: [ka]

[0225] The term "lower alkyl" refers to C 1~4 It refers to a straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0226] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 It refers to a straight or branched chain alkyl group.

[0227] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or an oxygen, sulfur, nitrogen, phosphorus, or silicon atom in a heterocycle).

[0228] The term "unsaturated" as used herein means that a moiety has one or more units of unsaturation.

[0229] As used herein, "divalent C 1~8 (or C 1~6 The term "saturated or unsaturated straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0230] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0231] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0232] The term "halogen" means F, Cl, Br, or I.

[0233] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 4 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[0234] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, groups having 6, 10, or 14 electrons shared in a cyclic array, and groups having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" in the context of "heteroaryl" includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl rings can contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," and any of these terms include optionally substituted rings.The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently can be optionally substituted.

[0235] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. An example is a heterocycle having 0-3 heteroatoms selected from oxygen, sulfur, and nitrogen in a saturated or partially unsaturated ring.

[0236] The heterocycle can be attached to the provided compound at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocycle is fused to one or more alicyclic rings, such as aryl, heteroaryl, or indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic, bridged bicyclic, or spirocyclic. Heterocycles can contain one or more oxo (=O) or thioxo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions can be independently optionally substituted.

[0237] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0238] As described herein, compounds of the present disclosure may contain "substituted" moieties. Generally, the term "substituted" means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted with one or more substituents selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that remains substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0239] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen, -(CH) 0-6 R°, -(CH2) 0-6 OR°, -O(CH2) 0-6 R°, -O-(CH2) 0-6 C(O)OR°, -(CH2) 0-6 CH(OR)2, -(CH2) 0-6 SR, -(CH2) 0-6 Ph, wherein Ph may be substituted with R°, and is —(CH) 0-46 O(CH2) 0-1 Ph (Ph may be substituted with R°), -CH=CHPh, (Ph may be substituted with R°), -(CH2) 0-6 O(CH2) 0-1 -Pyridyl (pyridyl is R°, -NO2, -CN, -N3, -(CH2) 0-6 N(R)2, -(CH2) 0-6 N(R)C(O)R, -N(R)C(S)R, -(CH2) 0-6 N(R)C(O)NR2, -N(R)C(S)NR2, -(CH2) 0-6 N(R)C(O)OR, -N(R)N(R)C(O)R, -N(R)N(R)C(O)NR2, -N(R)N(R)C(O)OR, -(CH2) 0-6C(O)R, -C(S)R, -(CH2) 0-6 C(O)OR, -(CH2) 0-6 C(O)SR, -(CH2) 0-6 C(O)OSiR3, -(CH2) 0-6 OC(O)R, -OC(O)(CH2) 0-6 SR°, -(CH2) 0-6 SC(O)R, -(CH2) 0-6 C(O)NR2, -C(S)NR2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-6 OC(O)NR2, -C(O)N(OR)R, -C(O)C(O)R, -C(O)CH2C(O)R, -C(NOR)R, -(CH2) 0-6 SSR, -(CH2) 0-6 S(O)R, -(CH) 0-6 S(O)2OR, -(CH2) 0-6 OS(O)2R, -S(O)2NR2, -(CH2) 0-6 S(O)R, -N(R)S(O)2NR2, -N(R)S(O)2R, -N(OR)R, -C(NH)NR2, -P(O)2R, -P(O)R2, -P(O)(OR)2, -OP(O)(R)OR, -OP(O)R2, -OP(O)(OR)2, SiR3, -(C 1-4 linear or branched alkylene)ON(R)2, or -(C 1-4 straight or branched chain alkylene)C(O)ON(R)2, where each R may be optionally substituted as defined below and independently represents hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or, notwithstanding the above definitions, two independently occurring R together with their intervening atom(s) form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which may be substituted as defined below.

[0240] R °The above suitable monovalent substituents (or two independently occurring R ° The ring formed by, together with the intervening atoms thereof, is independently selected from halogen, -(CH2) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0-1 or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). Suitable divalent substituents on a saturated carbon atom of R° include ═O and ═S.

[0241] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR * 2, =NNHC(O)R + , =NNHC(O)OR* , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S—, where each independent occurrence of R* is hydrogen, C which may be substituted as defined below 1~6 aliphatic and unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR * 2) 2-3 O-, wherein R * Each independent occurrence of may be substituted as defined below for hydrogen, C 1~6 Selected from aliphatic and unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0242] R * Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0243] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR† 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † wherein each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or, notwithstanding the above definitions, R † two independent occurrences of together with their intervening atoms form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0244] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0245] As used herein, the term "provided compounds" or "compounds of the disclosure" refers to any genus, subgenus, and / or species described herein.

[0246] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of suitable salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0247] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium cations, quaternary ammonium cations, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0248] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E stereoisomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure including the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to this disclosure.

[0249] The terms "patient" and "subject" as used herein refer to mammals, including, but not limited to, humans, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0250] The term "pharmaceutically acceptable carrier, adjuvant, or excipient" refers to a non-toxic carrier, adjuvant, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or excipients that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0251] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory or degradatively active metabolite or residue thereof.

[0252] As used herein, "C 1~3 Alkyl," "C 1~5 alkyl," and "C 1~6 The term "alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. 1~3 Alkyl, C 1~5 Alkyl or C 1~6 Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0253] As used herein, "C 2~4The term "alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon double bond. Alkenyl groups include both straight-chain and branched moieties. 2~4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0254] As used herein, "C 3~6 The term "cycloalkyl" refers to a saturated carbocyclic molecule whose ring structure contains 3 to 6 carbon atoms. 3~5 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0255] As used herein, "di-C" 1~3 The term "alkylamino" refers to -NR * R ** refers to R * and R ** are independently C as defined herein. 1~3 Represents alkyl. DiC 1~3 Representative examples of alkylamino include, but are not limited to, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH2CH2CH3)2, and -N(CH(CH3)2)2.

[0256] As used herein, "C 1~3 Alkoxy" and "C 1~6 The term "alkoxy" refers to the -OR # refers to R # are C as defined herein, respectively. 1~3 Alkyl and C 1~6 Represents an alkyl group. 1~3 Alkoxy or C 1~6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0257] As used herein, the term "5-membered heteroaryl" or "6-membered heteroaryl" refers to a 5- or 6-membered carbocyclic ring having two or three double bonds and containing one ring heteroatom selected from N, S, and O, and optionally one or more additional ring N atoms replacing one or more ring carbon atoms. Representative examples of 5-membered heteroaryls include, but are not limited to, furyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of 6-membered heteroaryls include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl.

[0258] As used herein, "C 3~6 The term "heterocycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic framework has 3 to 6 carbons and one carbon atom is replaced with a heteroatom selected from N, O, and S. 3~6 When the heterocycloalkyl group is a C6 heterocycloalkyl, one or two carbon atoms are independently replaced with a heteroatom selected from N, O, and S. 3~6 Representative examples of heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0259] As used herein, "C 5~8 The term "spiroalkyl" refers to a bicyclic ring system in which the two rings are joined through a single common carbon atom. 5~8 Representative examples of spiroalkyl include, but are not limited to, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, and spiro[2.5]octanyl.

[0260] As used herein, "C 5~8 The term "tricycloalkyl" refers to a tricyclic ring system in which all three cycloalkyl rings share the same two ring atoms. 5~8Representative examples of tricycloalkyl include tricyclo[1.1.1.0 1,3 ]pentanyl, [ka] Tricyclo[2.1.1.0 1,4 ]hexanyl, tricyclo[3.1.1.0 1,5 ]hexanyl, and tricyclo[3.2.1.0 1,5 ]octanyl.

[0261] The term "pharmaceutically acceptable excipient" as used herein refers to a wide variety of ingredients that can be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0262] The term "therapeutically effective amount," as used herein, refers to an amount of a compound disclosed herein that will elicit the biological or medical response in a tissue, system, or subject that is desired by a researcher, veterinarian, physician, or other clinician.

[0263] General synthetic procedure The compounds provided herein can be synthesized according to the procedures described in this section and in the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized by alternative routes utilizing different synthetic strategies, as would be understood by one of ordinary skill in the art. It should be understood that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the disclosure in any way.

[0264] Generally, compounds of Formula I can be synthesized according to the following schemes. Unless otherwise specified, the variables used in the following schemes are those defined in Formula I. All starting materials are commercially available, for example, from Merck Sigma-Aldrich Inc. and Enamine Ltd., or are known in the art and can be synthesized using known procedures with ordinary skill. Starting materials can also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents, for the schemes discussed in this section can be found in the examples provided herein. As used below, Z is a leaving group, including, but not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like. As used below, in certain embodiments, Y is an organometallic coupling reagent group, including, but not limited to, boronic acids and esters, organotin and organozinc reagents.

[0265] [ka]

[0266] As will be appreciated by those of skill in the art, the synthetic schemes and representative examples described above are not intended to comprise a comprehensive list of all the ways in which the compounds described and claimed in this application may be synthesized. Additional methods will be apparent to those of skill in the art. Additionally, the various synthetic steps described above may be performed in alternate routes or orders to arrive at the desired compounds.

[0267] Methods for purifying the compounds described herein are known in the art and include, for example, crystallization, chromatography (eg, liquid and gas phase), extraction, distillation, trituration, and reverse phase HPLC.

[0268] The present disclosure further encompasses "intermediate" compounds, including structures produced from the described synthetic procedures, whether isolated or produced in situ and not isolated, prior to ultimately obtaining the desired compound. These intermediates are included within the scope of the present disclosure. Exemplary embodiments of such intermediate compounds are described in the Examples below. [Example]

[0269] This section provides specific examples of compounds of Formula I and methods for making them.

[0270] [Table 1-1] [Table 1-2]

[0271] General analytical and purification methods This section provides a description of the general analytical and purification methods used to prepare certain compounds provided herein.

[0272] Chromatography: Unless otherwise indicated, the crude product-containing residue was purified by passing the crude material or concentrate over either flash silica (SiO2) or reverse-phase flash silica (C18) pre-packed Biotage brand silica gel columns and eluting the product from the column with a solvent gradient as indicated. For example, a reference to silica gel (0-40% EtOAc / hexanes) means that the product was obtained by eluting the silica-packed column with a solvent gradient of 0% to 40% EtOAc in hexanes.

[0273] Preparative HPLC method: Where so indicated, the compounds described herein were purified by reverse-phase HPLC using a Waters Fractionlynx semi-preparative HPLC-MS system utilizing one of two HPLC columns: (a) a Phenominex Gemini column (5 micron, C18, 150 x 30 mm), or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm).

[0274] A typical flow through the instrument involves eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) over 10 min; conditions can be varied to achieve optimal separation.

[0275] Analytical HPLC method: Where so indicated, the compounds described herein were analyzed using an Agilent 1100 series instrument equipped with a DAD detector.

[0276] Flash Chromatography: Where so indicated, flash chromatography was performed on a Teledyne Isco instrument using prepackaged disposable SiO2 stationary phase columns with an eluent flow rate range of 15-200 mL / min and UV detection (254 and 220 nm).

[0277] Preparative chiral supercritical fluid chromatography (SFC) method: Where so indicated, compounds described herein were purified via chiral SFC using one of two chiral SFC columns: (a) Chiralpak IG 2x25cm, 5μm, or (b) Chiralpak AD-H 2x15cm, 5μm.

[0278] Several CP analytical SFC experiments were performed on an SFC Method Station (Thar, Waters) using the following conditions: column temperature: 40°C, mobile phase: CO2 / methanol (0.2% methanolic ammonia) = flow rate: 4.0 ml / min, back pressure: 120 Bar, detection wavelength: 214 nm.

[0279] Some CP analytical SFC experiments were carried out on an SFC-80 (Thar, Waters) using the following conditions: column temperature: 35°C, mobile phase (example): CO2 / methanol (0.2% methanolic ammonia) = flow rate: 80 g / min, back pressure: 100 bar, detection wavelength: 214 nm.

[0280] Preparative CP method: Acidic reversed-phase MPLC: Instrument type: Revelis™ preparative MPLC; Column: Phenomenex LUNA C18(3) (150x25mm, 10μ); Flow rate: 40 mL / min, Column temperature: room temperature; Eluent A: 0.1% (v / v) formic acid in water, Eluent B: 0.1% (v / v) formic acid in acetonitrile; Use gradient and wavelength as indicated.

[0281] Proton NMR spectrum: Unless otherwise specified, all 1 H NMR spectra were measured on a 300, 400, or 500 MHz Bruker NMR instrument or a 400 MHz Varian NMR instrument. When so characterized, all observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as the reference. All NMR spectra were collected at approximately 25°C.

[0282] Mass spectrum (MS) Unless otherwise stated, all mass spectral data for starting materials, intermediates and / or exemplary compounds is given in [M+H] +The molecular ions are reported as mass / charge (m / z). The reported molecular ions were obtained by electrospray detection (commonly referred to as ESI MS) using a Waters Acquity UPLC / MS system or a Gemini-NX UPLC / MS system. Compounds with isotopic atoms such as bromine are generally reported according to the detected isotopic pattern, as will be understood by those skilled in the art.

[0283] Compound name The compounds disclosed and described herein are named using the IUPAC naming feature in ChemDraw Professional 17.0.

[0284] Specific Examples Provided in this section are procedures for synthesizing specific examples of the compounds provided herein. All starting materials, unless otherwise noted, are either commercially available from Sigma-Aldrich Inc. or known in the art and can be synthesized by utilizing known procedures using ordinary skill.

[0285] Example 1 Synthesis of compounds intermediate 12 and intermediate 14: 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-thiazolo[4,5-d]pyrimidine and 5-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-thiazolo[4,5-d]pyrimidine, respectively [ka]

[0286] Step 1: To a solution of ethyl 4-hydroxy-2-methyl-thiazole-5-carboxylate (1.00 equiv., 4.90 g, 26.2 mmol) in DCM (60 mL) was added TEA (1.50 equiv., 5.4 mL, 39.3 mmol) and trifluoromethanesulfonic anhydride (1.10 equiv., 4.9 mL, 28.8 mmol) at -78 °C, and the mixture was stirred at -78 °C for 4 h. The mixture was concentrated to give the crude product. The crude product was purified by column chromatography on silica gel eluting with EA (0-10%) / PE. Ethyl 2-methyl-4-(trifluoromethylsulfonyloxy)thiazole-5-carboxylate (6.70 g, 21.0 mmol, 80.18% yield) was obtained as a yellow oil. LC-MS: Rt: 0.860 min, m / z: 320.0 [M+H]+, 100% purity at 220 nm.

[0287] Step 2: To a solution of ethyl 2-methyl-4-(trifluoromethylsulfonyloxy)thiazole-5-carboxylate (1.00 equiv., 6.70 g, 21.0 mmol) in 1,4-dioxane (80 mL), benzyl urea (1.10 equiv., 3467 mg, 23.1 mmol), Cs2CO3 (2.00 equiv., 13640 mg, 42.0 mmol), XantPhos (0.0500 equiv., 607 mg, 1.05 mmol), and Pd2(dba)3 (0.0250 equiv., 480 mg, 0.525 mmol) were added, and the mixture was stirred at 60 °C for 12 h. The mixture was poured into water and stirred for 15 min. The mixture was then filtered, the filtrate was collected, and the volume was reduced to approximately one-third in vacuo. The solution was then adjusted to pH 7 with aqueous HCl (1 mol / L). The precipitate was collected by filtration, washed with EtOAc, and finally dried to give the crude product, which was used in the next step without further purification. 6-benzyl-2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione (2.40 g, 7.99 mmol, 38.08% yield) was obtained as a yellow solid. LC-MS: Rt: 0.700 min, m / z: 274.1 [M+H]+; 90% purity at 220 nm.

[0288] Step 3: To a solution of 6-benzyl-2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione (1.00 equiv., 1.40 g, 5.12 mmol) in m-xylene (20 mL), BBr3 (4.00 equiv., 1.9 mL, 20.5 mmol) was added at 25 °C, and the mixture was stirred at 170 °C for 1 h. After cooling to room temperature, the mixture was poured into MeOH (100 mL) at 0 °C. The reaction mixture was filtered, and the filter cake was washed with MeOH and HO and dried in vacuo to give the crude product. The crude product was used in the next step without further purification. 2-Methylthiazolo[4,5-d]pyrimidine-5,7-diol (780 mg, 4.26 mmol, 83.12% yield) was obtained as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=12.27(s,1H),11.32(s,1H),2.74(s,3H)

[0289] Step 4: To a solution of 2-methylthiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 1.00 g, 5.46 mmol) in POCl3 (23.5 equiv., 12 mL, 128 mmol), N,N-dimethylaniline (0.700 equiv., 0.48 mL, 3.82 mmol) was added, and the mixture was stirred at 130 °C for 4 h. The reaction mixture was poured into water (1000 mL). The mixture was stirred at 30 °C for 30 min. The aqueous phase was extracted with DCM (1000 mL × 3), and the combined organic phase was washed with brine (1000 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography using EA (0-25%) / PE. 5,7-Dichloro-2-methyl-thiazolo[4,5-d]pyrimidine (350 mg, 1.59 mmol, 29.13% yield) was obtained as a red solid. 1H NMR (400 MHz, chloroform-d) δ = 2.99 (s, 3H)

[0290] Step 5: To a solution of 5,7-dichloro-2-methylthiazolo[4,5-d]pyrimidine (1.00 equiv., 100 mg, 0.454 mmol), (2,4-difluorophenyl)boronic acid (1.05 equiv., 75 mg, 0.477 mmol), and Pd(dppf)Cl.DCM (0.200 equiv., 74 mg, 0.0909 mmol) in 1,4-dioxane (20 mL) was added a solution of CsCO (1.05 equiv., 155 mg, 0.477 mmol) in water (2.5 mL). The resulting mixture was purged with N for 1 minute and stirred at 40 °C for 0.5 h. The reaction mixture was diluted with EtOAc (20 mL). Brine (10 mL × 2) was added to wash the system, and the organic phase was dried over NaSO and concentrated to dryness to give a residue. The crude product was purified by preparative TLC (DCM). 5-chloro-7-(2,4-difluorophenyl)-2-methyl-thiazolo[4,5-d]pyrimidine (110 mg, 0.358 mmol, 78.88% yield) was obtained as a yellow solid. LC-MS: Rt: 0.808 min, m / z: 298.0 [M+H]+, 97% purity at 220 nm. 1H NMR (400 MHz, chloroform-d) δ = 7.83 (d, J = 6.4 Hz, 1H), 7.10-7.01 (m, 1H), 6.95 (ddd, J = 2.4, 8.5, 10.8 Hz, 1H), 2.90 (s, 3H).

[0291] Step 6: 5-Chloro-7-(2,4-difluorophenyl)-2-methyl-thiazolo[4,5-d]pyrimidine (1.00 equiv., 110 mg, 0.369 mmol) and CPhos (0.100 equiv., 16 mg, 0.0369 mmol) were dissolved in THF (3 mL) (99.5%, Extra Dry over Molecular Weight 800 mg). Palladium(II) acetate (0.0500 equiv., 4.1 mg, 0.0185 mmol) was added to a suspension in a Sieve, Stabilized, Acros, followed by bromo-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl]zinc (1.71 equiv., 2.6 mL, 0.630 mmol), and the mixture was then stirred at 55 °C for 2 h. The mixture was cooled to room temperature and diluted with EtOAc (20 mL), saturated NaHCO (20 mL), and saturated NaHSO (2 mL). The phases were separated and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Silica Flash Purification by column chromatography (eluent: 0-50% ethyl acetate / petroleum ether gradient) afforded 5-[(2R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-thiazolo[4,5-d]pyrimidine (67 mg, 0.148 mmol, 39.98% yield) as a yellow gum. LC-MS: Rt: 0.858 min, m / z: 454.1 [M+H]+, 100% purity at 220 nm.

[0292] Step 7: A mixture of 5-[(2R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-thiazolo[4,5-d]pyrimidine (1.00 equiv., 67 mg, 0.148 mmol) was separated by chiral SFC eluting with CO / 0.1% NH3HO MeOH B% 50% to 50%, DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um). 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-thiazolo[4,5-d]pyrimidine (47 mg, 0.100 mmol, 67.75% yield) was obtained as a white solid, and 5-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-thiazolo[4,5-d]pyrimidine (2.6 mg, 0.00549 mmol, 3.72% yield) was obtained as a white solid.

[0293] Intermediate 79: LC-MS: Rt: 0.857 min, m / z: [M+H]+=454.2, 97.2% purity at 220 nm. 1H NMR (400MHz, chloroform-d) δ=7.86(dt,J=6.5,8.4Hz,1H),7.50(s,2H),7.09(dt,J=1.7,8 .3Hz,1H),7.01(ddd,J=2.4,8.6,10.8Hz,1H),4.54(dd,J=1.7,11.4Hz,1H),4.31-4.19 (m,1H),3.80(dt,J=3.8,11.2Hz,1H),3.55(tt,J=3.7,7.2Hz,1H),3.50-3.37(m,1H),2 .94(s,3H),2.45-2.35(m,1H),2.23-2.10(m,3H),1.12-1.05(m,2H),1.02-0.92(m,2H)

[0294] Intermediate 80: Rt: 0.857 min, m / z: [M+H]+=454.2, 95.8% purity at 220 nm. 1H NMR(400MHz,chloroform-d)δ=8.21-7.72(m,1H),7.49(d,J=7.0Hz,2H),7.17-6.83(m,2H),4.88(d,J=6.0Hz,1H),3. 93(d,J=3.8Hz,2H),3.73-3.50(m,2H),2.97(s,3H),2.74(d,J=13.3Hz,1H),2.49-2.11(m,3H),1.12-0.93(m,4H)

[0295] Example 2 - Synthesis of Compound Intermediate 17: 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-oxazolo[4,5-d]pyrimidine [ka]

[0296] Step 1: A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (2.5 g, 11.71 mmol, 1 equiv) in DMSO (15 mL) was treated with a stream of ammonia gas at 25 °C for 30 min. LCMS showed the reaction was complete, with a major peak having the desired MS (81%, Rt: 0.439 min; [M+H] +The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The organic phase was concentrated in vacuo to give the crude product. The crude was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® Silica Flash Column, eluent: 0-50% ethyl acetate / petroleum ether gradient at 35 mL / min) to give 2,6-dichloro-5-methoxy-pyrimidin-4-amine (1.8 g, 8.88 mmol, 75.80% yield, 95.7% purity) as a white solid, which was confirmed by LCMS and H NMR. EW30176-52-1 (P1): (M+H)+ = 194.0, purity = 95% (220 nm), retention time = 0.366 min. 1 H NMR(400MHz,DMSO-d6)δ=8.28-7.41(m,1H),8.28-7.41(m,1H)

[0297] Step 2: To a mixture of 2,6-dichloro-5-methoxy-pyrimidin-4-amine (1.00 equiv., 600 mg, 3.09 mmol), TEA (3.00 equiv., 1.3 mL, 9.28 mmol), and DMAP (0.10 equiv., 38 mg, 0.309 mmol) in DCM (3 mL) was added di-tert-butyl dicarbonate (2.20 equiv., 1.6 mL, 6.80 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 h. LCMS showed no starting material remained and a new major peak (94%, Rt: 0.952 min; [M+H] + = 238.0 at 220 nm) was found. The mixture was concentrated under vacuum to give the crude product. The crude was purified by flash column chromatography (PE to PE: EtOAc = 5:1, R f =0.4) to give tert-butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)carbamate (1000 mg, 2.51 mmol, 81.12% yield) as a colorless oil, which was purified by LCMS and 1 Confirmed by H NMR. SS-2021-01-65-1(P1):[M+H] + =237.9;Purity=98%(220nm);Retention time=0.760 min1 H NMR (400 MHz, chloroform-d) δ = 3.96-3.86 (m, 3H), 1.50-1.42 (m, 19H).

[0298] Step 3: A 1000 mg reaction mixture was separated into two 500 mg reactions. To a mixture of tert-butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)carbamate (1.00 equiv., 1000 mg, 2.54 mmol) and (2,4-difluorophenyl)boronic acid (0.90 equiv., 360 mg, 2.28 mmol) in 1,4-dioxane (33 mL) and water (6.6 mL) was added CsCO (3.00 equiv., 2473 mg, 7.61 mmol) and Pd(dppf)Cl·DCM (0.10 equiv., 206 mg, 0.25 mmol). The mixture was degassed with N three times and stirred at 55 °C for 12 h. LCMS showed starting material remained and the desired MS was found (39%, Rt: 0.804 min, [M+H]+ = 472.1 (220 nm)). The reactions were combined and the final mixture was concentrated under vacuum to give the crude product. The crude was purified by flash column (PE: EtOAc = 5:1, UV, R f = 0.4) and concentrated in vacuo to give tert-butyl N-tert-butoxycarbonyl-N-[2-chloro-6-(2,4-difluorophenyl)-5-methoxy-pyrimidin-4-yl]carbamate (500 mg, 1.04 mmol, 40.90% yield) as a colorless gum. SS-2021-01-66-1 (P1): [M+H]+ = 472.2; purity = 97% (220 nm); retention time = 0.998 min, H NMR: 1 H NMR (400 MHz, chloroform-d) δ = 7.66-7.57 (m, 1H), 7.10-7.00 (m, 1H), 6.98-6.90 (m, 1H), 3.60 (s, 3H), 1.48-1.45 (m, 20H).

[0299] Step 4: To a mixture of tert-butyl N-tert-butoxycarbonyl-N-[2-chloro-6-(2,4-difluorophenyl)-5-methoxy-pyrimidin-4-yl]carbamate (1.00 equiv., 400 mg, 0.84 mmol) in DCM (12 mL) was added BBr3 (5.00 equiv., 1.3 mL, 4.24 mmol). The mixture was stirred at 25 °C for 12 h. LCMS showed complete consumption of the starting material, with a major peak with the desired MS (98%, Rt: 0.488 min, [M+H]+ = 258.0 at 220 nm). The mixture was added to 100 mL of water and extracted with EtOAc (100 mL x 3). The organic phase was dried over anhydrous NaSO and concentrated in vacuo to give 4-amino-2-chloro-6-(2,4-difluorophenyl)pyrimidin-5-ol (210 mg, 0.81 mmol, 96.16% yield) as a pale yellow solid, which was used crude directly in the next step. SS-2021-01-71-1 (P1): [M+H]=258.0; purity=97% (220 nm); retention time=0.429 min. 1 H NMR (400 MHz, chloroform-d) δ = 7.80-7.64 (m, 1H), 7.14-7.03 (m, 1H), 7.02-6.89 (m, 1H), 5.69 (br s, 2H)

[0300] Step 5: A mixture of 4-amino-2-chloro-6-(2,4-difluorophenyl)pyrimidin-5-ol (1.00 equiv., 210 mg, 0.81 mmol) in 1,1,1-triethoxyethane (34.9 equiv., 5.2 mL, 28.5 mmol) was heated to 80 °C and stirred for 2 h. LCMS showed a major peak with the desired MS (92%, Rt: 0.594 min; [M+H] = 282.0 at 220 nm). The mixture was concentrated in vacuo to give the crude product. The crude was purified by flash column (PE: EtOAc = 3:1, UV) to give 5-chloro-7-(2,4-difluorophenyl)-2-methyl-oxazolo[4,5-d]pyrimidine (180 mg, 0.63 mmol, 78.40% yield) as a pale yellow solid. SS-2021-01-72-1(P1):[M+H]+=281.7;Purity=93%(220nm);Retention time=0.895 min. 1H NMR (400MHz, chloroform-d) δ=8.10-8.00(m,1H),7.16-7.07(m,1H),7.06-6.97(m,1H),2.81(s,3H).

[0301] Step 6: To a solution of 5-chloro-7-(2,4-difluorophenyl)-2-methyl-oxazolo[4,5-d]pyrimidine (1.00 equiv., 150 mg, 0.53 mmol) and C-phos (0.10 equiv., 23 mg, 0.05 mmol) (99.5%, Extra Dry over Molecular Sieve, Stabilized, Acros) in THF (3 mL) was added palladium(II) acetate (0.05 equiv., 6.0 mg, 0.02 mmol), followed by bromo-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]zinc (1.06 equiv., 2.6 mL, 0.5 mmol), and the mixture was stirred at 55 °C for 2 h. LCMS showed the desired MS (56%, Rt: 0.892 min, [M+H]+ = 437.0 at 220 nm). The mixture was cooled to room temperature and diluted with EtOAc (20 mL), saturated NaHCO3 (20 mL), and saturated NaHSO3 (2 mL). The phases were separated and extracted with EtOAc (20 mL × 2). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Silica Flash Column, eluent: 0–50% ethyl acetate / petroleum ether gradient) to give 5-[(2R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-oxazolo[4,5-d]pyrimidine (64 mg, 0.14 mmol, 27.47% yield) as a yellow gum. TH-2021-01-59-1(P1):[M+H] + =437.0;Retention time=0.892 minutes

[0302] Step 7: 5-[(2R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-oxazolo[4,5-d]pyrimidine (1.00 equiv., 62 mg, 0.14 mmol) was separated by SFC (Column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); Conditions: 0.1% NH3HO MEOH) and lyophilized to give the crude product. LCMS indicated 62% was likely ring-opened by-product and 35% was the desired product (35%, Rt: 0.652 min, [M+H] + = 438.1, 220 nm). The crude product was purified by preparative TLC (EtOAc only, R f =0.4) and lyophilized to give 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-2-methyl-oxazolo[4,5-d]pyrimidine (enantiopure, 7.3 mg, room temperature: 2.302 min) as a pale yellow solid. Absolute stereochemistry is arbitrarily assigned. LC-MS Rt: 0.647 min; m / z: 438.1 [M+H] + , 97.3% purity at 220 nm. 1 H NMR (400 MHz, chloroform-d) δ = 8.05 (dt, J = 6.6, 8.4 Hz, 1H), 7.51 (d, J = 4.4 Hz, 2H), 7.11 (dt, J = 1.9, 8.2 Hz, 1H), 7.02 (ddd, J = 2.4, 8.5, 10.5 Hz, 1H), 4.55 (dd, J = 1.7, 11.4 Hz, 1H), 4.30-4 .21(m,1H),3.80(dt,J=3.2,11.5Hz,1H),3.58(tt,J=3.9,7.3Hz,1H),3.50-3.38(m,1H), 2.79(s,3H),2.41-2.33(m,1H),2.23-2.05(m,3H),1.15-1.08(m,2H),1.06-0.97(m,2H).

[0303] Example 3 - Intermediate 26: Synthesis of 4-[5-(4-chloro-2-fluoro-phenyl)-2-methyl-imidazo[1,2-a]pyrimidin-7-yl]-2-(1-cyclopropylpyrazol-4-yl)morpholine [ka]

[0304] Step 1: To a solution of N-(diaminomethylene)acetamide (A 3.28 g, 32.4 mmol, 3.0 equiv.) in MeCN (20 mL) was added 1-chloropropan-2-one (1.0 g, 10.8 mmol, 1.0 equiv.). The mixture was stirred at 82 °C for 24 h. The solvent was evaporated and the residue was purified by column chromatography (DCM / MeOH = 96 / 4) to give the desired product as a white solid (0.23 g, 15%). LCMS (M+H) + =140.20, retention time=0.117 minutes. 1 H NMR(400MHz,DMSO)δ 11.15(s,1H),10.93(s,1H),6.38(s,1H),2.05(s,3H),2.02(s,3H).

[0305] Step 2: To a solution of N-(4-methyl-1H-imidazol-2-yl)acetamide (100 mg, 0.72 mmol, 1.0 equiv) in water (2.5 mL) and methanol (2.5 mL) was added H2SO4 (35 mg, 0.36 mmol, 0.5 equiv). The mixture was stirred at 80 °C for 24 h. The reaction mixture was then basified to pH 10 with 1% KOH / MeOH. The mixture was concentrated under reduced pressure to give the crude product. The product was purified by flash chromatography (MeOH / DCM = 3-8%) to give the desired product as a light oil (59 mg, 80%). LCMS (M+H) + =98.05, retention time=0.143 minutes

[0306] Step 3: To a solution of 4-methyl-1H-imidazol-2-amine (881 mg, 9.07 mmol, 1.0 equiv) and dimethyl malonate (1.43 g, 10.88 mmol, 1.20 equiv) in ethanol (10 mL) was added sodium ethoxide (1.23 g, 18.14 mmol, 2.0 equiv). The resulting mixture was stirred at 80 °C for 12 h. The mixture was acidified with 2 N HCl (6.2 mL) until the pH was approximately 7. The mixture was subjected to lyophilization to give the crude product as a brown solid (1.03 g, 65%). LCMS (M+H) + =166.15, retention time=0.177 minutes

[0307] Step 4: A mixture of 2-methyl-8H-imidazo[1,2-a]pyrimidine-5,7-dione (100 mg, 0.61 mmol, 1.0 equiv) and POCl3 (2 mL) was stirred at 80 °C for 12 h. The reaction was cooled and POCl3 was evaporated. The reaction mixture was quenched with HO (5 mL) and extracted with DCM (10 mL × 5). The organic layers were combined, washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was obtained as a brown solid (106 mg, 55%). LCMS (M+H) + =201.90, retention time=0.619 minutes

[0308] Step 5: To a solution of 5,7-dichloro-2-methyl-imidazo[1,2-a]pyrimidine (130 mg, 0.64 mmol, 1.0 equiv.) and (4-chloro-2-fluoro-phenyl)boronic acid (112 mg, 0.64 mmol, 1.0 equiv.) in toluene (3.0 mL) and water (0.3 mL), KPO (409 mg, 1.93 mmol, 3.0 equiv.) and PdCl(Amphos) (27 mg, 0.039 mmol, 0.06 equiv.) were added. The mixture was stirred at 40 °C for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL × 3). The organic layers were combined, washed with brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using petroleum ether / ethyl acetate (=75 / 25) to give the product as a yellow solid (46 mg, 24%). 1 H NMR(400MHz,CDCl3)δ 7.52(t,J=7.9Hz,1H),7.46 - 7.35(m,2H),7.09(d,J=1.9Hz,1H),6.86(s,1H),2.46(s,3H).

[0309] Step 6: To a solution of 7-chloro-5-(4-chloro-2-fluoro-phenyl)-2-methyl-imidazo[1,2-a]pyrimidine (42 mg, 0.14 mmol, 1.0 equiv.) and 2-(1-cyclopropylpyrazol-4-yl)morpholine (27 mg, 0.14 mmol, 1.0 equiv.) in DMF (1 mL) was added K2CO3 (39 mg, 0.28 mmol, 2.0 equiv.). The resulting mixture was stirred at 110 °C for 12 h. The desired product was obtained as a yellow solid (4.3 mg, 6.3%) by preparative HPLC. LCMS (M+H) + =453.30, retention time=1.606 minutes. HPLC: Purity = 97.97% (254nm), Purity = 95.40% (214nm), Retention time = 2.884 minutes. 1H NMR(400MHz,DMSO)δ 7.88 - 7.79(m,2H),7.74(t,J=7.1Hz,1H),7.63(d,J=8.3Hz,1H),7.48(s,2H),7.32(s,1H),4.79 - 4.58(m,1H),4.53(d,J=9.6Hz,1H),4.49 - 4.14(m,1H),4.07-4.03(m,1H),3.68-3.65(m,2H),3.41 - 3.14(m,2H),2.28(s,3H),0.96-0.94(m,4H).

[0310] Example 4 - Synthesis of Compound Intermediate 22: 7-(4-chloro-2-fluoro-phenyl)-N,N-dimethyl-5-[rac-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine [ka]

[0311] Step 1: To a solution of 5,7-dichloro-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine (1.00 equiv., 200 mg, 0.793 mmol) in THF (10 mL) was added (4-chloro-2-fluorophenyl)boronic acid (1.20 equiv., 166 mg, 0.952 mmol), KPO (aq.) (3.00 equiv., 1.6 mL, 2.38 mmol), and Sphos-Pd-G (0.1000 equiv., 69 mg, 0.0793 mmol). The reaction mixture was purged with nitrogen three times. The reaction mixture was then stirred at 60 °C under a N atmosphere for 16 h. LCMS (5-95 AB / 1.5 min): RT = 1.022 min, 346.0 = [M+H] + , ESI + indicated 45.7% of the desired product. The reaction was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (2:1) (TLC, PE: EtOAc = 1:1, Rf = 0.70) to give 5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine (193 mg, 0.407 mmol, 51.30% yield) as a yellow solid. LCMS: Rt: 0.907 min; [M+H] + =346.0; Purity 73% (220nm).

[0312] Step 2: To a solution of 5-chloro-7-(4-chloro-2-fluoro-phenyl)-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine (1.00 equiv., 270 mg, 0.585 mmol) and (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.00 equiv., 303 mg, 0.585 mmol) in DMF (8 mL) was added DIEA (4.00 equiv., 302 mg, 2.34 mmol). The reaction mixture was then stirred at 50 °C for 12 h. (5-95AB / 1.5 min): RT = 1.106 min, 517.2 = [M+H] + ESI+ showed 38% of the desired product, RT=1.012 min, 505.1=[M+H] +ESI+ showed 30.6% by-products. TLC (PE: EtOAc = 5:1) showed that most of the starting material was consumed (R f =0.50), TLC (PE: EtOAc = 1:2) showed that two new spots were formed (R f =0.55, R f =0.6). The reaction was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography eluting with silica gel. (2S,6R)-4-[7-(4-chloro-2-fluoro-phenyl)-2-methylsulfanyl-thiazolo[4,5-d]pyrimidin-5-yl]-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (208 mg, 0.402 mmol, 68.78% yield) ([petroleum ether] / [ethyl acetate] (1:1)) was obtained as a yellow solid. LCMS: Rt: 1.101 min, [M+H] + = 517.1, 84% purity at 220 nm. 5-Chloro-7-(4-chloro-2-fluoro-phenyl)-2-methylsulfanyl-thiazolo[4,5-d]pyrimidine (37 mg, 0.107 mmol, 18.27% yield) ([petroleum ether] / [ethyl acetate] (9:1)) was recovered as an anhydrous solid. LCMS: Rt: 1.021 min; [M+H]+ = 345.9; purity 98% (220 nm).

[0313] Step 3: To a solution of rac-(2S,6R)-4-[7-(4-chloro-2-fluoro-phenyl)-2-methylsulfanyl-thiazolo[4,5-d]pyrimidin-5-yl]-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.00 equiv., 200 mg, 0.387 mmol) and dimethylamine hydrochloride (6.00 equiv., 189 mg, 2.32 mmol) in DMF (10 mL) was added KCO (8.00 equiv., 428 mg, 3.09 mmol). The reaction mixture was then stirred at 100 °C for 2 h. LCMS (5-95 AB / 1.5 min): RT = 1.039 min, 514.2 = [M+H] +, ESI + indicated 40% of the desired product. The reaction was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: [Phenomenex Synergi C18 150*25mm*10um]; mobile phase: [ACN] and [HO] (conditions: [water (0.225% FA)-ACN], B%: 67%-87%; detector: UV254nm. RT: [10min]) to give the crude product (45mg) as a yellow solid. LCMS (5-95AB / 1.5min): RT=1.027min, 514.2=[M+H]+ showed 68% crude product. The crude product was purified by SFC (column: REGIS(S,S)WHELK-O1 (250mm*25mm, 10um); mobile phase: 0.1% NH in 50%-50% CO 3· Separation with HO MeOH; flow rate: 80 mL / min wavelength: 220 nm afforded 7-(4-chloro-2-fluoro-phenyl)-N,N-dimethyl-5-[rac-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (17 mg, 0.0339 mmol, 8.75% yield) as a white solid.

[0314] Intermediate 92:LCMS:Rt:1.028 min, [M+H] + =514.2, 220nm and 1H NMR(400MHz,chloroform-d)δ ppm 0.97-1.03(m,2H)1.08-1.15(m,2H)1.30(d,J=6.13Hz,3H)2.72(dd,J=12.88,10.88Hz,1H)2.90-3.01(m,1H)3.27(br s,6H)3.57(tt,J=7.13,3.69Hz,1H)3.80(td,J=6.41,3.06Hz,1H)4.58(dd,J=10.76,2.13Hz,1H)4.79(br d,J=13.01Hz,1H)4.90(br d,J=13.13Hz,1H)7.22(br d,J=10.63Hz,1H)7.28(s,1H)7.53(d,J=5.38Hz,2H)7.71(t,J=8.07Hz,1H)and 19 F NMR and HPLC.

[0315] Example 5 - Synthesis of Compound Intermediate 79: 7-(4-chloro-2-fluoro-phenyl)-5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine [ka]

[0316] Step 1: To a solution of 2-chlorothiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 680 mg, 3.34 mmol) and MeNH HCl (2.00 equiv., 545 mg, 6.68 mmol) in DMSO (10 mL) was added DIEA (4.00 equiv., 2.3 mL, 13.4 mmol). The mixture was then stirred at 80 °C for 1 h. Upon completion, a large amount of precipitate formed. The precipitate was collected by filtration. The filter cake was washed with PE (80 mL) and water (40 mL) and then dried under high vacuum. 2-(Dimethylamino)thiazolo[4,5-d]pyrimidine-5,7-diol (640 mg, 3.02 mmol, 90.29% yield) was obtained as a pink solid. The crude product was used in the next step without further purification.

[0317] Step 2: To a suspension of 2-(dimethylamino)thiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 640 mg, 3.02 mmol) in POCl3 (53.2 equiv., 15 mL, 160 mmol), PCl5 (0.271 equiv., 170 mg, 0.816 mmol) was added at 25 °C, followed by stirring at 100 °C for 16 h. LCMS (5-95AB / 1.5 min): RT = 0.787 min, 248.9 = [M+H]+, ESI+ indicated 99.8% of the desired product. The mixture was concentrated under reduced pressure to give a residue. The residue was quenched with saturated aqueous NaHCO3 (80 mL) and then extracted with DCM (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with DCM / EtOAc (10:1) (TLC, DCM:EtOAc = 0:1, Rf = 0.70) to give 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (620 mg, 2.35 mmol, 77.83% yield) as a white solid (P1): [M+H] + = 249.0; purity = 94.3% (220 nm); retention time = 0.633 min;

[0318] Step 3: To a solution of (4-chloro-2-fluoro-phenyl)boronic acid (1.10 equiv., 477 mg, 2.74 mmol) in toluene (10 mL) was added 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 620 mg, 2.49 mmol), PdCl (Amphos) (0.1000 equiv., 176 mg, 0.249 mmol), and KPO (3.00 equiv., 1583 mg, 7.47 mmol). The reaction mixture was purged with nitrogen three times. The reaction mixture was then stirred at 80 °C under a N atmosphere for 16 h. LCMS (5-95 AB / 1.5 min): RT = 0.771 min, 343.0 = [M+H]. +, ESI+ showed 35.8% of the desired product. The reaction was diluted with water (80 mL) and extracted with DCM (80 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using 10% ethyl acetate / DCM to give 5-chloro-7-(4-chloro-2-fluoro-phenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (540 mg, 1.57 mmol, 63.22% yield) as a white solid. (P1): [M+H]+ = 342.9; purity = 33.1% (220 nm); retention time = 0.920 min

[0319] Step 4: To a solution of 5-chloro-7-(4-chloro-2-fluoro-phenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 540 mg, 0.944 mmol), 1-cyclopropyl-4-[(6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (1.10 equiv., 328 mg, 1.04 mmol), and KCO (4.00 equiv., 522 mg, 3.78 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was added Pa(dppf)Cl-DCM (0.150 equiv., 104 mg, 0.142 mmol). The reaction mixture was stirred at 80° C. under N for 2 hours. LCMS (5-95AB / 1.5 min): RT=0.978 min, 497.1=[M+H]+, ESI+ showed 44% of the desired product. The reaction was concentrated under reduced pressure to give a residue. The reaction was diluted with water (100 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with DCM / EtOAc (1:1) (TLC, PE:EtOAc = 0:1, Rf = 0.45) to give 7-(4-chloro-2-fluoro-phenyl)-N,N-dimethyl-5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (340 mg, 0.635 mmol, 67.25% yield) as a yellow oil (P1): [M+H]+ = 497.1; purity = 92.8% (220 nm); retention time = 0.978 min;

[0320] Step 5: To a solution of 7-(4-chloro-2-fluoro-phenyl)-5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 340 mg, 0.684 mmol) in methanol (20 mL) was added PtO (1.00 equiv., 155 mg, 0.684 mmol) under N atmosphere. The mixture was purged with H (15 psi) three times, and then the mixture was stirred under H (15 psi) at 30 °C for 24 h. LCMS (5-95AB / 1.5 min): RT = 0.944 min, 499.1 = [M+H] +, ESI + indicated 43% of the desired product; RT = 0.991 min, 497.1 = [M+H] +, ESI + indicated 40% of the starting material. The reaction mixture was then filtered through a pad of Celite. The filter cake was washed with MeOH (80 mL) and EtOAc (30 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in methanol (30 mL), and PtO2 (1.00 equiv, 155 mg, 0.684 mmol) was added. The mixture was purged with H2 (15 psi) three times and then stirred at 40 °C under an atmosphere of H2 (15 psi) for 48 h. LCMS (5-95AB / 1.5 min): RT = 0.947 min, 499.1 = [M+H] +, ESI + showed 61.1% of the desired product; RT = 0.992 min, 497.1 = [M+H] +, ESI + showed 14.3% of the starting material. The reaction mixture was filtered through a pad of Celite. The filter cake was washed with MeOH (60 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: [Unisil 3-100 C18 Ultra 150*50mm*3um]; mobile phase: [ACN] and [HO] (conditions: [water (0.225% FA)-ACN], B%: 51%-81%; detector: UV 254 nm. RT: [10 min]) to give 7-(4-chloro-2-fluoro-phenyl)-5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (67 mg, 0.134 mmol, 19.52% yield) as a white solid.(P1, single enantiomer of known absolute configuration): [M+H]. + =499.1, purity=100%(220nm); retention time=0.925 min, 1 H NMR(400MHz,chloroform-d)δ ppm 0.92-1.01(m,2H)1.05-1.14(m,2H)2.01-2.22(m,3H)2.33(dt,J=13.17,1.67Hz, 1H)3.32(ddt,J=15.67,7.93,3.79,3.79Hz,7H)3.55(tt,J=7.27,3.73Hz,1H)3.76 (td,J=11.86,2.32Hz,1H)4.19-4.26(m,1H)4.51(dd,J=11.37,1.96Hz,1H)7.25( d,J=1.96Hz,1H)7.32(dd,J=8.38,1.77Hz,1H)7.48(s,2H)7.75(t,J=8.13Hz,1H).

[0321] Example 6 - Synthesis of Compound Intermediate 84: 7-(2,4-difluorophenyl)-N,N-dimethyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine [ka]

[0322] Step 1: 5,7-Dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine To a suspension of 2-(dimethylamino)thiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 1600 mg, 7.54 mmol) in POCl3 (63.8 equiv., 45 mL, 481 mmol), PCl5 (0.437 equiv., 686 mg, 3.29 mmol) was added at 25 °C, followed by stirring at 100 °C for 16 h. LCMS (5-95AB / 1.5 min): RT = 0.593 min, 249.0 = [M+H]+, ESI+ indicated 94.8% of the desired product. The mixture was concentrated under reduced pressure to give a residue. The residue was quenched with saturated aqueous NaHCO3 (120 mL) and then extracted with DCM (300 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.76 g, 7.06 mmol, 93.71% yield) as a brown solid. (P1): [M+H]+ = 249.0; purity = 94.8% (220 nm); retention time = 0.593 min.

[0323] Step 2: 5,7-Dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 100 mg, 0.401 mmol), (2,4-difluorophenyl)boronic acid (1.00 equiv., 63 mg, 0.401 mmol), KPO (3.00 equiv., 256 mg, 1.20 mmol), and PdCl(Amphos) (0.100 equiv., 28 mg, 0.0401 mmol) were charged into a sealed bottle under a N atmosphere, and then toluene (5 mL) and water (0.5000 mL) were added in one portion at 15 °C and the mixture was stirred three times. LCMS (5-95AB / 1.5 min): RT = 0.680 min, 327.0 = [M+H] +, ESI + showed 46.5% of the desired product. The reaction was diluted with water (20 mL) and then extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE: EtOAc = 1:1, Rf = 0.25) to give 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (78 mg, 0.112 mmol, 27.95% yield) as an off-white solid, which was confirmed by LCMS (0-60AB / 1.5 min). RT = 0.891 min, 327.0 = [M+H] + ESI+ showed 49.3% of the desired product. Crude (P1): [M+H]+ = 327.0; Purity = 49.3% (220 nm); Retention time = 0.891 min

[0324] Step 3: To a solution of (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.50 equiv., 91 mg, 0.175 mmol) and 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 78 mg, 0.117 mmol) in DMSO (2 mL) was added DIEA (4.00 equiv., 60 mg, 0.468 mmol) at 25 °C. The reaction mixture was then stirred at 100 °C for 6 h. LCMS (5-95 AB / 1.5 min): RT = 0.768 min, 498.2 = [M+H] + , ESI + indicated 20.7% of the desired product. The reaction mixture was diluted with water (40 mL) and extracted with DCM (40 mL * 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: [Unisil 3-100 C18 Ultra 150*50mm*3 um]; mobile phase: [ACN] and [HO] (conditions: water (0.225% FA)-ACN], B%: 54%-84%; detector: UV) 254 nm. RT: [7 min]) to give 7-(2,4-difluorophenyl)-N,N-dimethyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (28 mg, 0.0559 mmol, 47.77% yield) as a white solid (P1, single enantiomer of known absolute configuration): [M+H]+ = 498.2; purity = 100% (220 nm); retention time = 0.770 min. 1H NMR(400MHz,chloroform-d)δ ppm 0.96-1.04(m,2H)1.08-1.15(m,2H)1.30(d,J=6.24Hz,3H)2.73(dd,J=13.08,10.76Hz,1H)2.96(dd,J=13.08,11.00Hz,1H)3.28(br s,6H)3.57(tt,J=7.27,3.73Hz,1H)3.76-3.85(m,1H)4.58(dd,J=10.94,2.51Hz,1H)4.80(br d,J=13.08Hz,1H)4.91(br d,J=12.84Hz,1H)6.89-6.97(m,1H)6.99-7.05(m,1H)7.53(d,J=4.52Hz,2H)7.71-7.81(m,1H).

[0325] Example 7 - Compound Intermediate 89: Synthesis of Compound 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine [ka]

[0326] Step 1: 5,7-Dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 400 mg, 1.61 mmol), (2,4-difluorophenyl)boronic acid (1.00 equiv., 254 mg, 1.61 mmol), KPO (3.00 equiv., 1022 mg, 4.82 mmol), and PdCl (Amphos) (0.100 equiv., 114 mg, 0.161 mmol) were charged to a sealed bottle under a N atmosphere, and then toluene (10 mL) and water (1 mL) were added in one portion at 15 °C, and the mixture was stirred at 15 °C. LCMS (5-95 AB / 1.5 min): RT = 0.687 min, 327.0 = [M+H] +, ESI+ showed 52.1% of the desired product. The reaction was diluted with water (50 mL) and then extracted with DCM (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (1:1) (TLC, PE:EtOAc = 1:2, Rf = 0.45) to give the crude product 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethylthiazolo[4,5-d]pyrimidin-2-amine (280 mg, 0.360 mmol, 22.42% yield) as a white solid. (P1): [M+H] + =327.0;Purity=41%(220nm);Retention time=0.683 minutes

[0327] Step 2: To a solution of 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 150 mg, 0.193 mmol), Pd(dppf)Cl·DCM (0.150 equiv., 21 mg, 0.0289 mmol), and KCO (3.50 equiv., 93 mg, 0.675 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl·DCM (0.150 equiv., 21 mg, 0.0289 mmol). The reaction mixture was stirred at 80 °C under a N atmosphere for 3 h. LCMS (5-95AB / 1.5 min): RT = 0.743 min, 481.1 = [M+H]+, ESI+ indicated 38% of the desired product. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (40 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (1:1) (TLC, PE:EtOAc = 0:1, Rf = 0.2) to give 7-(2,4-difluorophenyl)-N,N-dimethyl-5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (100 mg, 0.179 mmol, 92.82% yield) as a yellow gum. (P1):[M+H]+=481.1;Purity=86%(220nm);Retention time=0.739min

[0328] Step 3: To a solution of 5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 100 mg, 0.179 mmol) in ethanol (20 mL) was added PtO (1.00 equiv., 41 mg, 0.179 mmol) under N. The mixture was purged with H (15 psi) three times and then stirred under H (15 psi) at 30 °C for 24 h. LCMS (5-95AB / 1.5 min): RT=0.704 min, 483.1=[M+H]+, ESI+ showed 10% of the desired product, RT=0.737 min, 481.1=[M+H] +, ESI+ indicated 62.2% starting material. The reaction was then purged with H2 (15 psi) three times and stirred at 40 °C for 48 h. LCMS (5-95AB / 1.0 min): RT = 0.591 min, 483.1 = [M+H]+, ESI+ indicated 24.7% desired product; RT = 0.637 min, 481.1 = [M+H]+, ESI+ indicated 15.1% starting material. The reaction mixture was then filtered through a pad of diatomaceous earth. The filter cake was washed with EtOH (40 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in methanol (20 mL) and PtO2 (1.00 equiv, 41 mg, 0.179 mmol) was added. The mixture was then purged with H2 (15 psi) three times, and the mixture was then stirred at 30 °C under an atmosphere of H2 (15 psi) for 24 h. LCMS (5-95AB / 1.0 min): RT = 0.587 min, 483.1 = [M+H] +, ESI + showed 50.9% of the desired product; RT = 0.633 min, 481.1 = [M+H] +, ESI + showed 19.4% of the starting material. The reaction mixture was then filtered through a pad of diatomaceous earth. The filter cake was washed with MeOH (40 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: [Unisil 3-100 C18 Ultra 150*50mm*3um]; mobile phase: [ACN] and [HO] (conditions: [water (0.225% FA)-ACN], B%: 47%-77%; detector: UV 254nm. RT: [7min]) to give 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (15mg, 0.0306mmol, 17.09% yield) as a white solid. (P1, single enantiomer of known absolute configuration): [M+H] + =483.2, purity = 98.6% (220nm), retention time = 0.721 min. 1H NMR (400 MHz, chloroform-d) δ ppm 0.94-1.03 (m, 2H) 1.04-1.13 (m, 2H) 2.03-2.22 (m, 3H) 2.33 (br d,J=13.20Hz,1H)3.08-3.51(m,7H)3.55(tt,J=7.23,3.71Hz,1H)3.76(td,J=11.83,2.38Hz,1H)4.19-4.26(m,1H)4.51(dd,J=1 1.31,1.77Hz,1H)6.97(ddd,J=10.70,8.62,2.45Hz,1H)7.06(td,J=8.16,2.14Hz,1H)7.49(s,2H)7.80(td,J=8.44,6.48Hz,1H).

[0329] Example 8 - Synthesis of Compound Intermediate 94: 7-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine [ka]

[0330] Step 1: A solution of 2-aminothiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 2000 mg, 10.9 mmol) and NaNO (8.00 equiv., 5.99 g, 86.9 mmol) in 10% aqueous NaOH (1.00 equiv., 20 mL, 10.9 mmol) was added slowly to a stirred solution of concentrated HCl (1.00 equiv., 64 mL, 10.9 mmol) and water (16 mL) at 80 °C. The reaction mixture was then stirred at 70 °C for 35 min. The mixture was then stirred at 60 °C for an additional 30 min. The reaction mixture was then cooled in ice, and the precipitate was collected, washed with water, and dried under reduced pressure to give 2-chlorothiazolo[4,5-d]pyrimidine-5,7-diol (1.71 g, 8.40 mmol, 77.34% yield) as an orange solid, which was 1 Confirmed by 1 H NMR. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.54(s,1H)12.52(s,1H).

[0331] Step 2: To a solution of 2-chlorothiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 1500 mg, 7.37 mmol) and 1-(4-methoxyphenyl)-N-methyl-methanamine (2.00 equiv., 2228 mg, 14.7 mmol) in DMSO (15 mL) was added DIEA (4.00 equiv., 5.1 mL, 29.5 mmol). The reaction mixture was then stirred at 80 °C for 12 h. LCMS (5-95 AB / 1.5 min): RT = 0.777 min, 319.0 = [M+H] + , ESI + indicated 97.3% of the desired product. The reaction was diluted with water (10 mL). During this time, a red precipitate formed. It was collected by filtration, washed with PE (30 mL × 3), and dried under high vacuum. The crude product, 2-[(4-methoxyphenyl)methyl-methyl-amino]thiazolo[4,5-d]pyrimidine-5,7-diol (2.62 g, 8.23 ​​mmol, 111.71% yield), was obtained as a red solid, which was confirmed by LCMS (5-95AB / 1.5 min): RT = 0.583 min, [M+H] + 319.1; ESI + showed 99.2% of the desired product. The crude was used in the next step without further purification. (P1): [M+H] + = 319.1; purity = 99.2% (220 nm); retention time = 0.583 min

[0332] Step 3: To a suspension of 2-[(4-methoxyphenyl)methyl-methyl-amino]thiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 2.62 g, 8.23 ​​mmol) in POCl (52.0 equiv., 40 mL, 428 mmol), PCl (0.500 equiv., 857 mg, 4.11 mmol) was added at 25 °C, followed by stirring at 100 °C for 16 h. The reaction was concentrated under reduced pressure to give a residue. The residue was quenched with saturated aqueous NaHCO (120 mL) and then extracted with DCM (300 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (3:2) (TLC, PE: EtOAc = 1: 1, Rf = 0.65) to give 5,7-dichloro-N-[(4-methoxyphenyl)methyl]-N-methyl-thiazolo[4,5-d]pyrimidin-2-amine (460 mg, 1.29 mmol, 15.73% yield) as a yellow gum. 5,7-Dichloro-N-methyl-thiazolo[4,5-d]pyrimidin-2-amine (1000 mg, 4.25 mmol, 51.69% yield) was purified by flash chromatography on silica gel eluting with PE / EtOAc (1: 1) (TLC, PE: EtOAc = 1: 1, Rf = 0.35) as an off-white solid. (P1): [M+H] + =243.9;Purity=42%(220nm);Retention time=0.753min

[0333] Step 4: To a solution of 5,7-dichloro-N-methyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 950 mg, 4.04 mmol) and TEA (4.00 equiv., 2.2 mL, 16.2 mmol) in THF (15 mL) was added AcCl (1.50 equiv., 0.43 mL, 6.06 mmol) at 30 °C. The reaction was then stirred at 30 °C for 2 h. LCMS (5-95 AB / 1.5 min): RT = 0.826 min, 276.9 [M+H] + , ESI + indicated 86.5% of the desired product. The reaction mixture was adjusted to pH = 6-7 with saturated aqueous NaHCO3, diluted with water (50 mL), and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product N-(5,7-dichlorothiazolo[4,5-d]pyrimidin-2-yl)-N-methyl-acetamide (1.15 g, 3.59 mmol, 88.83% yield) as a yellow solid. The crude was used in the next step without further purification. (P1): [M+H] + =276.9;Purity=86.5%(220nm);Retention time=0.826min

[0334] Step 5: N-(5,7-Dichlorothiazolo[4,5-d]pyrimidin-2-yl)-N-methyl-acetamide (1.00 equiv., 1150 mg, 3.53 mmol), (4-chloro-2-fluoro-phenyl)boronic acid (0.900 equiv., 554 mg, 3.17 mmol), KPO (3.00 equiv., 2243 mg, 10.6 mmol), and PdCl (Amphos) (0.100 equiv., 250 mg, 0.353 mmol) were charged to a sealed bottle under N atmosphere and then purged three times with toluene (15 mL) and water (1.5 mL) at 15 °C. LCMS (5-95AB / 1.5 min): RT = 0.784 min, 371.0 = [M+H] +,ESI+ showed 44.4% of the desired product. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (80 mL) and then extracted with DCM (80 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with DCM / EtOAc (5:1) (TLC, DCM:EtOAc = 10:1, Rf = 0.60) to give N-[7-(4-chloro-2-fluoro-phenyl)-5-fluoro-thiazolo[4,5-d]pyrimidin-2-yl]-N-methyl-acetamide (790 mg, 1.74 mmol, 49.24% yield) as a yellow solid. (P1): [M+H]+ = 370.9; purity = 78% (220 nm); retention time = 0.942 min

[0335] Step 6: To a solution of (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.04 equiv., 1115 mg, 2.15 mmol), N-[5-chloro-7-(4-chloro-2-fluoro-phenyl)thiazolo[4,5-d]pyrimidin-2-yl]-N-methyl-acetamide (1.00 equiv., 770 mg, 2.07 mmol), and (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (0.326 equiv., 140 mg, 0.675 mmol) in DMSO (15 mL) was added DIEA (5.00 equiv., 1340 mg, 10.4 mmol) at 25° C. The reaction mixture was then stirred at 100° C. for 16 h. (5-95AB / 1.5 min): RT = 0.958 min, 500.1 = [M+H]+, ESI+ indicated 56.7% of the desired product. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (1:4) (TLC, PE: EtOAc = 0:1, Rf = 0.55) to give 7-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (650 mg, 1.26 mmol, 60.79% yield) as a yellow solid. (P1, single enantiomer of known absolute configuration): [M+H] + =500.1, purity=97.0%(220nm); retention time=0.955 min, 1H NMR(400MHz,chloroform-d)δ ppm 0.97-1.06(m,2H)1.06-1.15(m,2H)1.30(d,J=6.25Hz,3H)2.73(dd,J=13.26,10.63Hz,1H)2.96(dd,J=13.20,1 0.94Hz,1H)3.17(s,3H)3.57(tt,J=7.30,3.71Hz,1H)3.75-3.87(m,1H)4.58(dd,J=10.88,2.63Hz,1H)4.78(br d,J=12.88Hz,1H)4.89(br d,J=12.88Hz,1H)5.99-6.49(m,1H)7.20-7.25(m,1H)7.27-7.31(m,1H)7.53(d,J=3.50Hz,2H)7.71(t,J=8.13Hz,1H).

[0336] Example 9 - Synthesis of Compound Intermediate 99: N-[7-(4-chloro-2-fluoro-phenyl)-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-yl]-N-methyl-acetamide [ka]

[0337] Step 1: To a solution of 7-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 80 mg, 0.160 mmol) and TEA (4.00 equiv., 0.089 mL, 0.640 mmol) in THF (1.5 mL) was added AcCl (2.50 equiv., 0.028 mL, 0.400 mmol) at 30 °C. The reaction was then stirred at 30 °C for 5 h. LCMS (5-95 AB / 1.5 min): RT = 1.029 min, 542.1 = [M+H] + , ESI + indicated 89.7% of the desired product. The combined reaction mixture was adjusted to pH=7-8 with saturated aqueous NaHCO3. The reaction was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: [Unisil 3-100 C18 Ultra 150*50mm*3um]; mobile phase: [ACN] and [HO] (conditions: [water (0.225% FA)-ACN], B%: 60%-90%; detector: UV 254nm. RT: [7min]) to give N-[7-(4-chloro-2-fluoro-phenyl)-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-yl]-N-methyl-acetamide (49mg, 0.0896mmol, 55.98% yield) as a yellow solid. (P1, single enantiomer of known absolute configuration): [M+H] + =542.2, purity=100%(220nm); retention time=1.011 min, 1H NMR(400MHz,chloroform-d)δ ppm 0.98-1.04(m,2H)1.09-1.15(m,2H)1.32(d,J=6.24Hz,3H)2.49(s,3H)2.78(dd,J=13.14,10.70Hz,1H)3.01(dd,J=13 .20,10.88Hz,1H)3.58(tt,J=7.29,3.71Hz,1H)3.78-3.85(m,1H)3.86(s,3H)4.60(dd,J=10.88,2.57Hz,1H)4.82(br d,J=13.08Hz,1H)4.94(br d,J=12.35Hz,1H)7.24-7.27(m,1H)7.29-7.32(m,1H)7.54(d,J=3.79Hz,2H)7.73(t,J=8.01Hz,1H).

[0338] Example 10 - Synthesis of compounds Intermediate 104 and Intermediate 308: 2-[[7-(4-chloro-2-fluoro-phenyl)-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-yl]-methyl-amino]ethanol and 2-((Z)-7-(4-chloro-2-fluorophenyl)-5-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2-(methylimino)thiazolo[4,5-d]pyrimidin-3(2H)-yl)ethan-1-ol [ka]

[0339] Step 1: To a mixture of 7-(4-chloro-2-fluorophenyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 90 mg, 0.180 mmol) and KCO (4.00 equiv., 100 mg, 0.720 mmol) in DMF (2 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (2.00 equiv., 0.078 mL, 0.360 mmol) at 25 °C. The reaction mixture was then stirred at 80 °C for 5 h. TLC (PE:EtOAc = 2:1) showed that the starting material was consumed (Rf = 0.60) and a new spot was formed (Rf = 0.35). The reaction mixture was adjusted to pH 2-3 with 1M aqueous HCl and stirred at 30 °C for 30 min. LCMS (5-95AB / 1.5 min): RT = 0.953 min, 544.2 = [M+H] +, ESI + indicated 79.8% of the desired product; RT = 0.860 min, 544.2 = [M+H] +, ESI + indicated 18.4% of the isomer. The reaction was diluted with water (15 mL) and then extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: [Phenomenex luna C18 250*50mm*10um]; mobile phase: [ACN] and [HO] (conditions: [water (0.225% FA)-ACN], B%: 53%-83%; detector: UV 254nm. RT: [7min]) to give 2-[[7-(4-chloro-2-fluoro-phenyl)-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-yl]-methyl-amino]ethanol (40mg, 0.0736mmol, 40.87% yield) as a white solid. (P1, single enantiomer of known absolute configuration): [M+H] + =544.1, purity=99.2%(220nm); retention time=0.958 min, 1H NMR(400MHz,chloroform-d)δ ppm 0.97-1.03(m,2H)1.07-1.14(m,2H)1.30(d,J=6.24Hz,3H)2.72(dd,J=13.14,10.58Hz,1H)2.95(dd,J=13.20,11.00Hz,1H)3.28(br s,3H)3.57(tt,J=7.27,3.73Hz,1H)3.72-4.00(m,5H)4.57(dd,J=10.94,2.63Hz,1H)4.76(br d,J=13.08Hz,1H)4.87(br d,J=13.20Hz,1H)7.20-7.26(m,1H)7.29(d,J=1.96Hz,1H)7.53(d,J=3.91Hz,2H)7.70(t,J=8.07Hz,1H).

[0340] Another peak (RT=0.860 min) was obtained as a white solid, which HPLC showed was impure. This was then purified by preparative TLC (PE: EtOAc=0:1, Rf=0.25) to give the isomer 2-[(2E)-7-(4-chloro-2-fluoro-phenyl)-2-methylimino-5-[rac-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-3-yl]ethanol (1.7 mg, 0.00312 mmol, 1.74% yield) as a white solid. LCMS and HPLC showed 100% purity of the isomer, 1 1 H NMR showed unacceptable purity. Note 2: The absolute configuration of the isomers was confirmed by 2D NMR.

[0341] Example 11 - Synthesis of Compound Intermediate 109: 7-(4-chloro-2-fluoro-phenyl)-N-(cyclopropylmethyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine [ka]

[0342] Step 1: To a mixture of 7-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 90 mg, 0.180 mmol) and K2CO3 (4.00 equiv., 100 mg, 0.720 mmol) in DMF (1.5 mL) was added bromomethylcyclopropane (4.00 equiv., 97 mg, 0.720 mmol) at 25 °C. The reaction mixture was then stirred at 80 °C for 16 h. LCMS (5-95AB / 1.5 min): RT = 1.092 min, 554.1 = [M+H] + , ESI+ showed 53.1% of the desired product, RT=0.925 min, 554.1=[M+H] + , ESI+ showed 18.0% of isomers, RT=0.974 min, 500.1=[M+H] + ESI+ showed 25.5% of the starting material. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column, [Waters Xbridge 150*25mm*5um]; mobile phase: [ACN] and [H2O] (conditions: [water (NH4HCO3)-ACN], B%: 69%-99%; detector, UV 254nm. RT: [8min]) to give 7-(4-chloro-2-fluoro-phenyl)-N-(cyclopropylmethyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (34mg, 0.0613mmol, 34.08% yield) as a white solid (P1, single enantiomer of known absolute configuration): [M+H] + =554.1, purity=100%(220nm); retention time=1.084 min, 1H NMR(400MHz,chloroform-d)δ ppm 0.33(q,J=4.93Hz,2H)0.55-0.65(m,2H)0.97-1.03(m,2H)1.07-1.16(m,3H)1.30(d,J=6.24Hz,3H)2.66-2.79(m,1H)2.95 (dd,J=13.20,10.88Hz,1H)3.09-3.71(m,6H)3.80(ddd,J=10.45,6.30,2.57Hz,1H)4.58(dd,J=10.88,2.69Hz,1H)4.79(br d,J=12.96Hz,1H)4.90(br d,J=12.72Hz,1H)7.22(dd,J=10.21,1.90Hz,1H)7.26(d,J=2.32Hz,1H)7.53(d,J=5.14Hz,2H)7.70(t,J=8.07Hz,1H).

[0343] The starting material, 7-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (20 mg, 0.0404 mmol, 22.44% yield), was recycled as a white solid and confirmed by LCMS (5-95 AB / 1.5 min). RT = 1.012 min, 500.2 = [M+H]+, ESI+ indicated 100% starting material. Note: The absolute configuration of the isomers was confirmed by 2D NMR. This product should have the same regioselectivity for the final step.

[0344] Example 12 - Compound: Synthesis of 7-(4-chloro-2-fluoro-phenyl)-N-(2-fluoroethyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (Intermediate 114) and (E)-7-(4-chloro-2-fluoro-phenyl)-3-(2-fluoroethyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-imine (Intermediate 159) [ka]

[0345] Step 1: To a mixture of 7-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 90 mg, 0.180 mmol) and KCO (4.00 equiv., 100 mg, 0.720 mmol) in DMF (1.5 mL) was added 1-bromo-2-fluoroethane (2.50 equiv., 0.034 mL, 0.450 mmol) at 25° C. The reaction mixture was then stirred at 80° C. for 6 h. LCMS (5-95AB / 1.5 min): RT = 1.023 min, 546.1 = [M+H] +, ESI + showed 69.4% of the desired product, RT = 0.901 min, 546.1 = [M+H] +, ESI + showed 22.7% of the isomer. The combined reactions were filtered. The filtrate was purified by preparative HPLC (column, [Waters Xbridge 150*25mm*5um]; mobile phase: [ACN] and [HO] (conditions: [water (NHHCO)-ACN], B%: 60%-90%; detector, UV 254nm. RT: [8min]) to give 7-(4-chloro-2-fluoro-phenyl)-N-(2-fluoroethyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (38mg, 0.0683mmol, yield 37.93%) as a white solid.

[0346] (P1, single enantiomer of known absolute configuration): [M+H] + =546.1, purity=98.8%(220nm); retention time=1.026 minutes, 1H NMR(400MHz,chloroform-d)δ ppm 0.97-1.06(m,2H)1.06-1.14(m,2H)1.30(d,J=6.24Hz,3H)2.73(dd,J=13.20,10.64Hz,1H)2.96(dd,J=13.20,10.88Hz,1H)3.29(br s,3H)3.57(tt,J=7.31,3.82Hz,1H)3.76-3.86(m,1H)3.92-4.18(m,2H)4.5 8(dd,J=10.82,2.63Hz,1H)4.68(t,J=4.46Hz,1H)4.74-4.83(m,2H)4.89(br d,J=13.08Hz,1H)7.23(dd,J=10.21,1.90Hz,1H)7.29(br d,J=1.71Hz,1H)7.53(d,J=4.03Hz,2H)7.71(t,J=8.07Hz,1H).

[0347] (E)-7-(4-chloro-2-fluoro-phenyl)-3-(2-fluoroethyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-imine (5.6 mg, 0.00993 mmol, 5.51% yield) was obtained as a white solid (P2, single enantiomer of known absolute configuration): [M+H]+ = 546.1; purity = 96.45% (220 nm); retention time = 0.905 min; 1 H NMR(400MHz,chloroform-d)δ ppm 0.98-1.05(m,2H)1.13(br d,J=2.50Hz,2H)1.31(br d,J=6.00Hz,3H)2.67-2.77(m,1H)2.95(br t,J=12.01Hz,1H)3.09(s,3H)3.54-3.63(m,1H)3.73-3.84(m,1H)4.30-4.43(m,2H)4.56(br d,J=11.01Hz,1H)4.64(br d,J=13.01Hz,1H)4.67-4.77(m,2H)4.81(br t,J=5.00Hz,1H)7.22(br d,J=10.51Hz,1H)7.25-7.27(m,1H)7.54(s,2H)7.61(t,J=8.00Hz,1H).

[0348] Example 13 - Compound synthesis: Synthesis of compounds 7-(4-chloro-2-fluoro-phenyl)-N-ethyl-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (Intermediate 119) and (E)-7-(4-chloro-2-fluoro-phenyl)-3-ethyl-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-imine (Intermediate 154) [ka]

[0349] Step 1: To a mixture of 7-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 90 mg, 0.180 mmol) and KCO (4.00 equiv., 100 mg, 0.720 mmol) in DMF (1.5 mL) was added EtI (2.50 equiv., 0.036 mL, 0.450 mmol) at 25° C. The reaction mixture was then stirred at 80° C. for 24 h. LCMS (5-95AB / 1.5 min): RT = 1.041 min, 528.1 = [M+H] +, ESI + showed 33% desired product; RT = 0.966 min, 500.1 = [M+H] +, ESI + showed 33% starting material; RT = 0.890 min, 528.1 = [M+H] +, ESI + showed 27.2% isomer. Iodomethane (3.00 equiv, 0.044 mL, 0.540 mmol) was then added and the reaction was stirred at 80 °C for 24 h. LCMS (5-95AB / 1.5 min): RT=1.036 min, 528.1=[M+H]+, ESI+ showed 38% desired product, RT=0.961 min, 500.1=[M+H]+, ESI+ showed 16.8% starting material, RT=0.885 min, 528.1=[M+H]+, ESI+ showed 36% isomer. The reaction was filtered. The filtrate was purified by preparative HPLC (column, [Waters Xbridge 150*25mm*5um]; mobile phase: [ACN] and [HO] (conditions: [water (NHHCO)-ACN], B%: 62%-92%; detector, UV 254nm. RT: [8min]) to give 7-(4-chloro-2-fluoro-phenyl)-N-ethyl-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (25mg, 0.0481mmol, 26.72% yield) as a white solid. (P1, single enantiomer of known absolute configuration): [M+H] + =528.1, purity = 100% (220nm), retention time = 1.037 minutes. 1H NMR(400MHz,chloroform-d)δ ppm 0.98-1.03(m,2H)1.08-1.14(m,2H)1.26-1.31(m,6H)2.72(dd,J=13.14,10.70Hz,1H)2.96(dd,J =13.14,10.94Hz,1H)3.08-3.40(m,3H)3.44-3.94(m,4H)4.58(dd,J=10.88,2.57Hz,1H)4.79(br d,J=13.20Hz,1H)4.90(br d,J=13.08Hz,1H)7.22(dd,J=10.15,1.83Hz,1H)7.28(d,J=1.83Hz,1H)7.53(d,J=4.77Hz,2H)7.70(t,J=8.07Hz,1H).

[0350] (E)-7-(4-chloro-2-fluoro-phenyl)-3-ethyl-N-methyl-5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]thiazolo[4,5-d]pyrimidin-2-imine (13 mg, 0.0242 mmol, 13.47% yield) was obtained as a white solid (P2, single enantiomer of known absolute configuration): [M+H] + =528.1, purity = 100% (220nm), retention time = 0.886 min. 1 H NMR(400MHz,chloroform-d)δ ppm 0.98-1.05(m,2H)1.09-1.17(m,2H)1.29-1.34(m,6H)2.71(dd,J=13.14,10.70Hz,1H)2.95(d d,J=13.20,11.00Hz,1H)3.10(s,3H)3.58(tt,J=7.29,3.77Hz,1H)3.74-3.85(m,1H)4.09(br d,J=7.09Hz,2H)4.57(dd,J=10.82,2.51Hz,1H)4.65(br d,J=12.96Hz,1H)4.76(br d,J=13.45Hz,1H)7.22(dd,J=10.15,1.83Hz,1H)7.26(d,J=1.96Hz,1H)7.54(s,2H)7.62(t,J=8.07Hz,1H).

[0351] Example 14Synthesis of the compounds: (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(2,4-difluorophenyl)-2-isopropyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-6-methylmorpholine (Intermediate 129) and 2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(2,4-difluorophenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-6-methylmorpholine (Intermediate 139) [ka]

[0352] Step 1: To a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1.0 equiv., 2.0 g, 10.6 mmol) and (1S)-(+)-10-camphorsulfonic acid (0.1 equiv., 246 mg, 1.1 mmol) in DCM (105 mL) was added 3,4-dihydro-2H-pyran (1.1 equiv., 1.1 mL, 11.6 mmol) at 0° C., and the resulting solution was stirred at room temperature overnight. When the reaction was judged complete by TLC analysis, the reaction mixture was washed with saturated Na2CO3 (aq), water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine 2 (1.67 g, 6.11 mmol, 57%). 1 H NMR (400 MHz, CDCl): δ H 8.25(s,1H),6.04-6.00(d,1H),4.18-4.13(m,1H),3.85-3.80(t,1H),2.60-2.58( m,1H),2.17-2.15(m,1H),1.99-1.96(d,1H),1.84-1.82(t,2H),1.77-1.76(d,1H).

[0353] Step 2: A 100 mL round-bottom flask flame-dried under argon was charged with Pd(amphos)Cl (0.05 equiv., 110 mg, 0.16 mmol), 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.0 equiv., 850 mg, 3.1 mmol), and THF (35 mL). Bromo-(2,4-difluorophenyl)zinc (1.0 equiv., 24 mL, 3.1 mmol) was added dropwise over 30 min, and the reaction mixture was stirred at room temperature for an additional 1.5 h. At this time, the reaction mixture was filtered through a pad of Celite, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (Biotage® Sfar column 50 g, using a gradient from 100% hexanes to 30% EtOAc). Evaporation of selected fractions afforded the desired (4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine 4 (180 mg, 0.51 mmol, 16%). 1 H NMR (DMSO-d6, 400 MHz): δ H 8.46(1H,d,J=4.2Hz),8.03(1H,td,J=8.6,6.5Hz),7.57(1H,ddd,J=11.2,9.3,2.5Hz),7.36(1H,td,J=8.5,2. 5Hz),5.97(1H,dd,J=10.2,2.5Hz),3.95(1H,d,J=11.5Hz),3.71-3.77(1H,m),2.38-2.44(1H,m),2.02(1H,br s),1.93(1H,dd,J=13.1,3.6Hz),1.78(1H,br s),1.58(2H,s).

[0354] Step 3: DIPEA (3.0 equiv., 0.27 mL, 1.5 mmol) was added to a solution of 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.00 equiv., 180 mg, 0.513 mmol) in DMSO (2.5 mL), and the resulting solution was heated to 100° C. for 30 min. The reaction mixture was cooled to room temperature, and the reaction mixture was directly purified by C18 chromatography (Biotage® 24 g column, using a gradient of 5% CHCN / water (0.1% FA) to 85% CHCN / water (0.1% FA)). Evaporation of selected fractions afforded the desired (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(2,4-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-6-methylmorpholine 6 (240 mg, 0.46 mmol, 89%). ESI-MS (m / z): 522.3 [M+H], LC-RT: 1.86 min.

[0355] Step 4: HCl (20.0 equiv., 2.3 mL, 9.20 mmol) was added to a solution of rac-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-4-[4-(2,4-difluorophenyl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-d]pyrimidin-6-yl]-6-methyl-morpholine (1.00 equiv., 240 mg, 0.460 mmol) in DCM (2 mL) / 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. At this time, the reaction mixture was diluted with EtOAc (20 mL), washed with saturated Na2CO3 (aq.), water, brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude material was purified by C18 chromatography (Biotage column 24 g, gradient 5% CHCN / water (0.1% FA) to 85% CHCN / water (0.1% FA)). Evaporation of selected fractions afforded the desired product (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-6-methylmorpholine 7 (140 mg, 0.32 mmol, 70%). ESI-MS (m / z): 438.3 [M+1], LC-RT: 1.52 min.

[0356] Step 5: To a solution of (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(2,4-difluorophenyl)-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)-6-methylmorpholine (1.0 equiv., 80 mg, 0.18 mmol) in THF (230 μL) was added NaHMDS (1.5 equiv., 0.27 mL, 0.27 mmol) at 0° C., followed by 2-iodopropane (3.0 equiv., 0.06 mL, 0.55 mmol), and the mixture was stirred at 160° C. under controlled microwave irradiation for 1 h when the reaction was determined to be complete by LCMS (1 h). The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The crude material was purified by C18 chromatography (Biotage® C18 column 40 g using a gradient of 30% ACN / water (0.1% FA) to 85% ACN / water (0.1% FA)). Evaporation of selected fractions afforded the desired products (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(2,4-difluorophenyl)-2-isopropyl-2H-pyrazolo[3,4-d]pyrimidin-6-yl)-6-methylmorpholine (57 mg, 0.12 mmol, 65%) and 2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(2,4-difluorophenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-6-methylmorpholine (14 mg, 0.03 mmol, 14%).

[0357] Intermediate 129: 1 H NMR (CHCl3-d, 400 MHz): δ H7.93(1H, td, J = 8.5, 6.5 Hz), 7.86(1H, d, J = 4.6 Hz), 7.51(2H, d, J = 4.0 Hz), 7.03(1H, td, J = 8.3, 2.4 Hz), 6.95(1H, ddd, J = 10.9, 8.7, 2.5 Hz), 5.00(1H, dd, J = 13.3, 2.3 Hz), 4.87(1H, dd, J = 13.2, .............

[0358] Intermediate 139: 1 1H NMR (DMSO-d6, 400 MHz): δ H ... 7.91 - 7.95(2H, m), 7.82(1H, s), 7.43 - 7.49(2H, m), 7.27(1H, td, J = 8.5, 2.4 Hz), 4.92 - 4.99(1H, m), 4.67 - 4.75(2H, m), 4.49(1H, dd, J = 10.9, 2.6 Hz), 3.65 - 3.73(2H, m), 3.00(1H, dd, J = 13.2, 11.0 Hz), 2.70(1H, dd, J = 13.2, 10.6 Hz), 1.41(6H, d, J = 6.7 Hz), 1.18(3H, d, J = 6.2 Hz), 0.97 - 1.02(2H, m), 0.87 - 0.94(2H, m). 19 19F NMR (DMSO-d6 ,376MHz):δ δF -106.4, -109.6.

[0359] ... Example 15Synthesis of the compounds: 5-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Intermediate 135) and 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Intermediate 134) [ka]

[0360] Step 1: To a solution of 2-chlorothiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 680 mg, 3.34 mmol) and dimethylamine hydrochloride (2.00 equiv., 545 mg, 6.68 mmol) in DMSO (10 mL) was added DIEA (4.00 equiv., 2.3 mL, 13.4 mmol). The mixture was stirred at 80 °C for 1 h. Upon completion, a large amount of precipitate formed. The precipitate was collected by filtration. The filter cake was washed with PE (80 mL) and water (40 mL) and then dried under high vacuum to give 2-(dimethylamino)thiazolo[4,5-d]pyrimidine-5,7-diol (720 mg, 3.39 mmol, 69.08% yield) as a pink solid. The crude material was used in the next step without further purification.

[0361] Step 2: To a suspension of 2-(dimethylamino)thiazolo[4,5-d]pyrimidine-5,7-diol (1.00 equiv., 720 mg, 3.39 mmol) in POCl3 (53.2 equiv., 17 mL, 180 mmol) was added PCl5 (0.271 equiv., 191 mg, 0.918 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h. LCMS showed 99.8% of the desired product (99.8%, Rt = 0.768 min; [M+H]+ = 249.1 (220 nm)). The mixture was concentrated under reduced pressure to give a residue. The residue was quenched with saturated aqueous NaHCO3 (80 mL) and then extracted with DCM (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with DCM / EtOAc (10:1) (TLC, DCM / EtOAc = 0:1 / V:V, Rf = 0.7) to give 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (730 mg, 2.76 mmol, 81.45% yield) as a white solid, the structure of which was confirmed by LCMS: [M+H]+ = 249.1; purity = 94.6% (220 nm); retention time = 0.766 min.

[0362] Step 3: 2-[2-Fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 equiv., 871 mg, 3.00 mmol), 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 680 mg, 2.73 mmol), KPO (3.00 equiv., 1738 mg, 8.19 mmol) and Pd(Amphos)Cl (0.130 eq., 251 mg, 0.355 mmol) were placed in a sealed bottle under N atmosphere and purged three times with N. Then, 1,4-dioxane (15 mL) and water (1.5 mL) were added in one portion at 15 °C and the mixture was stirred at 60 °C for 24 h. LCMS revealed 47.4% of the desired product (47.4%, Rt = 0.906 min, [M+H] + = 377.1 (220 nm)). The mixture was quenched with HO (50 mL) and extracted with EA (100 mL * 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE:EA = 0:1 to 1:0, PE:EA = 1:1, desired product Rf = 0.3) to give 5-chloro-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (600 mg, 1.59 mmol, 58.34% yield) as a white solid, the structure of which was confirmed by LCMS. (P1):[M+H]+=377.0;Purity=98%(220nm);Retention time=0.906 min

[0363] Step 4: To a solution of 5-chloro-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 550 mg, 1.46 mmol), 1-cyclopropyl-4-[(6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (1.10 equiv., 508 mg, 1.61 mmol), and KCO (4.00 equiv., 807 mg, 5.84 mmol) in 1,4-dioxane (22 mL) and water (2.2 mL) was added Pd(dppf)Cl-DCM (0.150 equiv., 179 mg, 0.219 mmol) under a N atmosphere. The reaction mixture was purged with N2 three times and stirred under N2 atmosphere at 80 °C for 2 h. LCMS showed 64% of the desired product (64%, Rt = 0.997 min, [M+H]+ = 531.2). The mixture was quenched with 100 mL of H2O and extracted with EA (200 mL * 3), and the combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE:EA = 1:0 to 0:1, PE:EA = 0:1, desired product Rf = 0.3) to give 5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (450 mg, 0.848 mmol, 58.10% yield) as a white solid. The structure was confirmed by LCMS, H NMR, and F NMR. [M+H] = 531.3; purity = 100% (220 nm); retention time = 0.998 min. 1H NMR(400MHz,DMSO-d6)δ=8.03(t,J=7.8Hz,1H),7.97(d,J=11.2Hz,1H),7.85-7.78(m,2H),7.48-7.44(m,1H),7.28(br d,J=1.2Hz,1H),4.61(dd,J=3.4,9.9Hz,1H),4.46(br d,J=2.0Hz,2H),3.69(tt,J=3.9,7.4Hz,1H),3.30(s,6H),3.00(br d,J=16.9Hz,1H),2.66-2.60(m,1H),1.06-0.97(m,2H),0.96-0.88(m,2H)

[0364] Step 5: To a solution of 5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 430 mg, 0.810 mmol) in methanol (10 mL) was added PtO (1.16 equiv., 100 mg, 0.943 mmol) under N.sub.2 atmosphere. The mixture was purged with H.sub.2 (15 psi) three times and then stirred under H.sub.2 (15 psi) atmosphere at 30.degree. C. for 12 h. LCMS showed 52% of the desired product (52%, Rt = 0.923 min, [M+H] = 533.1 (220 nm)) and 44% of the starting material remained. The reaction mixture was stirred at 30° C. for an additional 24 h. LCMS indicated that 20% of the starting material remained and 70% of the desired product was detected (70%, Rt=0.923 min, [M+H]+=533.1 (220 nm)). The mixture was filtered and concentrated. The residue was dissolved in methanol (20 mL), and PtO2 (0.544 equiv., 100 mg, 0.441 mmol) was added to the reaction mixture, which was then purged with H2 three times. The mixture was stirred under an H2 atmosphere (15 psi) at 30° C. for an additional 12 h. LCMS indicated that ∼15% of the starting material remained and ∼76% of the desired product was detected (76%, Rt=0.923 min, [M+H]+=533.1 (220 nm)). The mixture was filtered, the filter cake was washed with MeOH (20 mL*3), and the combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (DCE:MeOH=10:1, desired product R f=0.5) to obtain a residue. The residue was purified by preparative HPLC (Phenomenex luna C18 150*25mm*10um, water (FA)-ACN) and freeze-dried to obtain 5-[(2R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (100mg, 0.188mmol, yield 23.17%) as a white solid, and then the residue was purified by SFC (column: Chiralpak AD-3 Purification by column chromatography (50 × 4.6 mm ID, 3 μm, mobile phase: CO phase A, IPA phase B (0.05% DEA), gradient elution: 5% to 40% IPA in CO (0.05% DEA), flow rate: 3 mL / min, detector: PDA, column temperature: 35°C, back pressure: 100 Bar) afforded 5-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine intermediate 153 (P1, 18 mg, 0.0329 mmol, 17.51% yield) as a white solid. Intermediate 152 (P2, 63 mg, 0.118 mmol, 62.75% yield) was obtained as a white solid, confirmed by LCMS, HPLC, H NMR, F NMR, SFC, and 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine. This was confirmed by LCMS, HPLC, H NMR, F NMR, SFC.

[0365] Intermediate 135: (P1, single enantiomer of known absolute configuration), LCMS: (M+H)+ = 533.2, purity = 98.6% (220 nm), retention time = 0.908 min. 1H NMR(400MHz,chloroform-d)δ ppm 0.93-1.02(m,2H)1.06-1.14(m,2H)2.06-2.17(m,1H)2.25(ddd,J=13.29,8.10,4.75Hz,1H)2.33-2.45(m,1H)2.64-2.76(m,1H)3.34(br d,J=2.25Hz,6H)3.49-3.62(m,2H)3.83-3.98(m,2H)4.89(dd,J=7.82,3.19Hz,1H)7.43-7.54(m,3H)7.60(br d,J=7.88Hz,1H)7.94(t,J=7.44Hz,1H).

[0366] Intermediate 134: (P2, single enantiomer of known absolute configuration), LCMS: (M+H)+ = 533.2, purity = 100% (220 nm), retention time = 0.907 min. 1 H NMR(400MHz,chloroform-d)δ ppm 0.93-1.02(m,2H)1.04-1.12(m,2H)2.04-2.22(m,3H)2.33(br d,J=13.13Hz,1H)3.33(ddd,J=11.76,8.00,3.88Hz,7H)3.55(tt,J=7.25,3.69Hz,1H)3.76(td,J=11.82,2.25Hz,1H)4.23(br dd,J=11.44,2.81Hz,1H)4.51(dd,J=11.32,1.69Hz,1H)7.45-7.54(m,3H)7.59(br d,J=8.13Hz,1H)7.93(t,J=7.44Hz,1H).

[0367] Example 16 Synthesis of the compounds: (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(6-(2,4-difluorophenyl)-7-methyl-7H-purin-2-yl)-6-methylmorpholine (Intermediate 124) and (2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2,4-difluorophenyl)-N,N,7-trimethyl-7H-purin-8-amine (Intermediate 144) [ka]

[0368] Step 1: MeMgCl (3.0 M in THF) (1.1 equiv., 3.9 mL, 11.6 mmol) was added dropwise to a solution of 2,6-dichloro-9H-purine (1.0 equiv., 2.0 g, 10.6 mmol) in THF (40 mL) at room temperature. The reaction mixture was stirred for 30 minutes, and MeI (3.0 equiv., 2.0 mL, 31.7 mmol) was added in one portion. The reaction was stirred at 50°C for 16 hours. When the reaction was judged complete by LCMS, the solution was cooled to room temperature, and MeOH (2 mL) was added to neutralize the unreacted base. The solvent was removed under reduced pressure, and the residue was directly purified by flash chromatography (Biotage® Sfar 100 g column, using a gradient of 2% MeOH / DCM to 10% MeOH / DCM). Evaporation of selected fractions gave the desired 2,6-dichloro-7-methyl-purine 2 (1.20 g, 5.9 mmol, 56%). 1 H NMR (CHCl3-d, 400 MHz): δ H 8.19 (1H,s), 4.16 (3H,s). Note: Other regioisomers are observed at 8.08 ppm and 3.9 ppm (approximately 4%).

[0369] Step 2: A flame-dried round-bottom flask under argon was charged with 2,6-dichloro-7-methyl-purine (1.0 equiv., 1.45 g, 7.1 mmol), Pd(amPhos)Cl (0.05 equiv., 253 mg, 0.36 mmol), and THF (70 mL). The solution was cooled to -10 °C, and a THF solution of chloro-(2,4-difluorophenyl)zinc (1.05 equiv., 30 mL, 7.5 mmol) was added dropwise. The reaction was stirred at 0 °C for 2 h. When the reaction was judged complete by LCMS, the reaction mixture was filtered over a pad of Celite, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (Biotage Sfar® 100 g column, using a gradient of 100% CHCl to 100% EtOAc). Evaporation of selected fractions gave the desired 2-chloro-6-(2,4-difluorophenyl)-7-methyl-7H-purine 4 (1.08 g, 3.8 mmol, 54%). 1 H NMR (CHCl3-d, 400 MHz): δ H 7.65(1H,td,J=8.4,6.1Hz),7.13(1H,td,J=8.3,2.4Hz),6.99-7.04(1H,m),4.20(1H,s),3.79(3H,s).

[0370] Step 3: To a solution of 2-chloro-6-(2,4-difluorophenyl)-7-methyl-7H-purine (1.0 equiv., 0.5 g, 1.8 mmol) in THF (15 mL) was added DIPEA (5.0 equiv., 1.6 mL, 8.9 mmol), followed by (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.0 equiv., 0.37 g, 1.8 mmol). The mixture was then stirred at 70 °C for 16 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with saturated NH4Cl (sat.), brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (Biotage Sfar® column 50 g, using a gradient from 100% DCM to 100% EtOAc). Evaporation of selected fractions afforded the desired (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(6-(2,4-difluorophenyl)-7-methyl-7H-purin-2-yl)-6-methylmorpholine intermediate 124 (110 mg, 0.24 mmol, 13%). 1 H NMR (CHCl3-d, 400 MHz): δ H 7.90(1H,s),7.55(1H,td,J=8.4,6.3Hz),7.51(2H,d,J=3.1Hz),7.06(1H,td,J=8.3 ,2.5Hz),6.96(1H,ddd,J=9.8,8.7,2.5Hz),4.83-4.87(1H,m),4.71-4.75(1H,m),4. 57(1H,dd,J=10.9,2.7Hz),3.75-3.82(1H,m),3.51-3.56(4H,m),2.93(1H,dd,J=13. 2,10.9Hz),2.70(1H,dd,J=13.2,10.6Hz),1.28(3H,d,J=6.2Hz),0.94-1.01(2H,m). 19 F NMR (CHCl3-d, 376 MHz): δF -110.3, -106.6. ESI-MS (m / z+): 452.3 [M+1]+, LC-RT: 1.36 min. Note: 10% of the other regioisomer is observed in 1H NMR.

[0371] Step 4: (2S,6R)-2-(1-Cyclopropylpyrazol-4-yl)-4-[6-(2,4-difluorophenyl)-7-methyl-purin-2-yl]-6-methyl-morpholine (1.0 equiv., 121 mg, 0.27 mmol) was dissolved in anhydrous THF (2.5 mL) and cooled to -78 °C. TMPMgCl·LiCl (1 M in THF) (1.05 equiv., 281 μL, 0.281 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 2 h. A solution of NBS (3.0 equiv., 143 mg, 0.8 mmol) in THF (1 mL) was added to the reaction mixture at -78 °C. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (Biotage Sfar® column 50 g, using a gradient of 100% hexane to 10% EtOAc / hexane) to give (2S,6R)-4-(8-chloro-6-(2,4-difluorophenyl)-7-methyl-7H-purin-2-yl)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine 6 (110 mg, 0.23 mmol, 85% yield). ESI-MS (m / z+): 486.3 [M+H]+, LC-RT: 1.55 min. No NMR data available.

[0372] Step 5: A flame-dried microwave vial under N2 was charged with (2S,6R)-4-(8-chloro-6-(2,4-difluorophenyl)-7-methyl-7H-purin-2-yl)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (1.0 equiv., 40 mg, 0.08 mmol), dimethylamine (1.1 equiv., 4.6 μL, 0.1 mmol), DIPEA (3.0 equiv., 43 μL, 0.3 mmol), and DMSO (1.0 mL), and the reaction mixture was heated to 115 °C for 2 h. The reaction mixture was cooled to room temperature and loaded directly onto a Biotage 12 g C18 column. The desired product was eluted using a gradient of 30% CH3CN / water (0.1% FA) to 95% CH3CN / water (0.1% FA). The desired fractions were lyophilized to give (2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2,4-difluorophenyl)-N,N,7-trimethyl-7H-purin-8-amine (20 mg, 0.04 mmol, 49%) as a white solid. 1 H NMR (DMSO-d6, 400MHz): δ H 7.80(1H,s),7.70-7.76(1H,m),7.40-7.44(2H,m),7.26(1H,td,J=8.5,2.5Hz),4.51-4.56(2H,m),4.45-4.49(2H,m),3.65-3.71(2H,m) ,3.13(4H,s),3.07(7H,s),2.80(2H,t,J=11.9Hz),2.55(1H,d,J=11.7Hz),1.18(4H,d,J=6.2Hz),1.00-1.03(3H,m),0.92-0.95(2H,m). 19 F NMR (DMSO-d6, 376 MHz): δ F -110.7,-108.3. ESI-MS(m / z+):495.3 [M+1]+,LC-RT:1.27 min.

[0373] Intermediate 191 and Intermediate 283 are synthesized according to the procedure of Intermediate 144 using the following starting materials. [Table 2] [Table 3]

[0374] Example 17 - Synthesis of Compound Intermediate 149: 7-[2-fluoro-4-(trifluoromethyl)phenyl]-5-[(2S,6R)-2-[1-(methoxymethyl)pyrazol-4-yl]-6-methyl-morpholin-4-yl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine [ka]

[0375] Step 1: To a solution of (2R,6S)-2-methyl-4-(p-tolylsulfonyl)-6-(1H-pyrazol-4-yl)morpholine (1.00 equiv., 800 mg, 2.49 mmol) and K2CO3 (2.00 equiv., 688 mg, 4.98 mmol) in DMF (10 mL) was added bromo(methoxy)methane (1.70 equiv., 0.35 mL, 4.23 mmol). The mixture was stirred at 25 °C for 2 h. LCMS (5-95 AB / 1.5 min): RT = 0.820 min, 366.1 = [M+H]+, ESI+ showed 85% of the desired product. The mixture was quenched with 20 mL of saturated NaHCO3 solution and extracted with EA (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate = 100:1 → 1:1, PE:EA = 1:1, target Rf = 0.4) to give (2S,6R)-2-[1-(methoxymethyl)pyrazol-4-yl]-6-methyl-4-(p-tolylsulfonyl)morpholine (600 mg, 1.64 mmol, 65.96% yield) as a colorless oil, the structure of which was confirmed by LCMS and H NMR. (P1): (M+H) + =366.2, purity=99.3%(220nm), retention time=0.824 min. 1H NMR (400MHz, chloroform-d) δ=7.64(d,J=8.3Hz,2H),7.51(d,J=8.1Hz,2H),7.3 6(d,J=8.0Hz,2H),5.34(s,2H),4.75-4.57(m,1H),3.91-3.82(m,1H),3.76( td,J=2.1,11.4Hz,1H),3.64(td,J=2.1,11.3Hz,1H),3.33(s,3H),2.46(s,3 H),2.29-2.19(m,1H),2.09-2.06(m,1H),2.03(s,1H),1.21(d,J=6.4Hz,3H)

[0376] Step 2: To a solution of (2S,6R)-2-[1-(methoxymethyl)pyrazol-4-yl]-6-methyl-4-(p-tolylsulfonyl)morpholine (1.00 equiv., 600 mg, 1.64 mmol) in methanol (30 mL), Mg(powder) (15.2 equiv., 600 mg, 25.0 mmol) and Mg(chips) (15.2 equiv., 600 mg, 25.0 mmol) were added at 25 °C, and the mixture was stirred at 80 °C for 16 h. LCMS showed that 32% of the starting material remained and one new peak was detected (no desired mass signal). Mg(chips) (15.2 equiv., 600 mg, 25.0 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C for an additional 16 h. LCMS showed that the starting material was completely consumed and one new peak was detected (no desired mass signal). The reaction mixture was filtered, and the filter cake was washed with MeOH (20 mL × 3). The combined organic layers were concentrated under reduced pressure to give crude (2S,6R)-2-[1-(methoxymethyl)pyrazol-4-yl]-6-methyl-morpholine (840 mg, 3.98 mmol, yield 242.18%) as a white solid, which was used directly in the next step.

[0377] Step 3: To a solution of 5-chloro-7-[2-fluoro-4-(trifluoromethyl)phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.00 equiv., 100 mg, 0.265 mmol) and (2S,6R)-2-[1-(methoxymethyl)pyrazol-4-yl]-6-methyl-morpholine (2.50 equiv., 140 mg, 0.664 mmol) in DMSO (2 mL) was added DIEA (5.00 equiv., 0.54 mL, 3.26 mmol), and the mixture was stirred at 100° C. for 1.5 h. LCMS (5-95AB / 1.5 min): RT = 0.830 min, 552.1 = [M+H] + , ESI + indicated complete consumption of starting material and the desired mass was detected. The reaction mixture was diluted with 5 mL of water and extracted with EA (10 mL × 3). The combined organic layers were dried over [Na2SO4], filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EA) (TLC: EA, Rf = 0.4) to give the crude product. The residue was purified by preparative HPLC (Phenomenex C18 75*30mm*3um, water (FA)-ACN) to give 7-[2-fluoro-4-(trifluoromethyl)phenyl]-5-[(2S,6R)-2-[1-(methoxymethyl)pyrazol-4-yl]-6-methyl-morpholin-4-yl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (103 mg, 0.186 mmol, 70.03% yield) as an off-white solid, which was confirmed by LCMS, HPLC, H NMR, F NMR, and SFC.

[0378] Intermediate 149 (P1, single enantiomer of known absolute configuration), LCMS: (M+H)+ = 552.0; purity = 100% (220 nm); retention time = 1.013 min. 1H NMR(400MHz,chloroform-d)δ ppm 1.31(d,J=6.25Hz,3H)2.75(dd,J=13.26,10.76Hz,1H)2.98(dd,J=13.20, 10.94Hz,1H)3.15-3.42(m,9H)3.77-3.87(m,1H)4.58-4.67(m,1H)4.80(br d,J=13.13Hz,1H)4.90-4.99(m,1H)5.37(s,2H)7.47(d,J=10.26Hz,1H)7.56(d,J=7.75Hz,1H)7.64(s,2H)7.89(t,J=7.50Hz,1H).

[0379] Example 18 - Synthesis of Compound Intermediate 179: N-(4-chloro-2-fluoro-phenyl)-2-[[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]oxymethyl]-6-methyl-5-propyl-pyridin-3-amine [ka]

[0380] Step 1: A mixture of 5-bromo-6-methylpyridin-3-amine (8.90 g, 59.2 mmol, 1.0 equiv.), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.9 g, 71.1 mmol, 1.2 equiv.), Pd(PPh3)4 (1.37 g, 1.18 mmol, 0.02 equiv.), and Cs2CO3 (57.8 g, 177.7 mmol, 3.0 equiv.) was prepared in a round-bottom flask under nitrogen. 1,4-Dioxane (150 mL) was then added, and the suspension was stirred at 100 °C for 8 h. LCMS indicated complete consumption of the starting material and 80% of the desired compound. The reaction mixture was cooled to room temperature, filtered through a plug of silica gel, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO 2 , EtOAc / Et 3 N=5:1) to give the product 5-allyl-6-methylpyridin-3-amine (6.43 g, 30.0 mmol, 50% yield) as a yellow solid. 1H NMR(400MHz,DMSO)δ 7.67(d,J=2.4Hz,1H),6.68(d,J=2.4Hz,1H),5.94-5.83(m,1H),5.07-5.00(m,4H),3.21(d,J=6.8Hz,2H),2.24(s,3H).

[0381] Step 2: To a solution of 5-allyl-6-methylpyridin-3-amine (6.43 g, 43.4 mmol, 1.0 equiv) in MeOH (30 mL) was added 10% Pd / C (1.84 g, 1.74 mmol, 0.04 equiv). The mixture was stirred under H2 at room temperature for 4 h. LCMS showed that the starting material was consumed and the desired compound was detected. The suspension was filtered through a plug of silica gel and concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0382] Step 3: To a solution of 6-methyl-5-propyl-pyridin-3-amine (6.0 g, 39.9 mmol, 1.0 equiv.) and CuBr (11.6 g, 51.9 mmol, 1.3 equiv.) in 45% HBr (50 mL), a solution of NaNO (4.7 g, 67.9 mmol, 1.7 equiv.) in water (20 mL) was added dropwise under nitrogen at 0 °C. The mixture was stirred at 0 °C for an additional 2 h. LCMS indicated that the starting material had been consumed and the desired compound had been detected. The resulting solution was adjusted to pH 7–8 with aqueous NaOH and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2, petroleum ether / ethyl acetate=5:1) to give the product 5-bromo-2-methyl-3-propyl-pyridine (5.16 g, 60.3 mmol, 60% yield) as a yellow solid. 1 H NMR(400MHz,DMSO)δ 8.39(s,1H),7.77(d,J=2.0Hz,1H),2.56(t,J=7.6Hz,2H),2.42(s,3H),1.60-1.51(m,2H),1.08(s,1H),0.93(t,J=7.4Hz,3H).

[0383] Step 4: To a solution of 5-bromo-2-methyl-3-propyl-pyridine (5.0 g, 23.4 mmol, 1.0 equiv.) in DCM (30 mL) was added m-CPBA (6.04 g, 35.0 mmol, 1.5 equiv.) under nitrogen. The mixture was stirred at room temperature for 3 h. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was washed with aqueous NaSO, extracted with ethyl acetate (20 mL × 3), and washed with water. The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1:1) to give 5-bromo-2-methyl-3-propyl-pyridine 1-oxide (5.0 g, 21.7 mmol, 93% yield) as a yellow oil. LC-MS Rt: 0.907 min; m / z: 229.9 [M+H] + , 87% purity at 254 nm.

[0384] Step 5: A mixture of 5-bromo-2-methyl-3-propyl-pyridine-1-oxide (4.4 g, 19.1 mmol, 1.0 equiv) and MeSO (12.0 g, 95.3 mmol, 5.0 equiv) was stirred at 100 °C for 2 h. The mixture was then cooled to room temperature, and a solution of NaCN (3.73 g, 76.2 mmol, 4.0 equiv) in water (30 mL) was added. The mixture was stirred at room temperature for 12 h. LCMS showed that the starting material was consumed and the desired product was detected. The reaction mixture was washed with aqueous NaSO, washed with water, and extracted with EtOAc. The organic phase was dried over NaSO and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether / ethyl acetate=10:1) to give the product 3-bromo-6-methyl-5-propyl-pyridine-2-carbonitrile as a yellow crystalline solid (1.30 g, 5.44 mmol, 29% yield). 1 H NMR(400MHz,DMSO)δ 8.11(s,1H),3.44(s,3H),2.65(t,J=7.8Hz,2H),1.63-1.54(m,2H),0.94(t,J=7.4Hz,3H).

[0385] Step 6: To a solution of 3-bromo-6-methyl-5-propyl-pyridine-2-carbonitrile (1.65 g, 6.90 mmol, 1.0 equiv) in MeOH (35 mL) was added H2SO4 (5 mL) at room temperature. The solution was then stirred at 100 °C for 12 h. LCMS indicated that the starting material had been consumed and the desired product had been detected. The solution was cooled to room temperature and made basic with aqueous NaOH to adjust the pH to approximately 7. The solution...

Claims

1. Compounds of Formula I 【Chemistry 1】 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, wherein: R １ is optionally substituted C １～６ aliphatic group, C １～６ Haloalkyl, optionally substituted OCH ２ - (C ３～６ cycloalkyl), optionally substituted O-phenyl, or a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 5-12 membered saturated or partially unsaturated bridged carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6-12 membered saturated or partially unsaturated bridged heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a cyclic group selected from a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted; X １ But, CR １３ , CH, or N; X ２ But, CR １４ , CH, or N; Ring A, together with the six-membered ring system to which it is fused, forms a bicyclic system of the formula 【Chemistry 2】 and Y, when required by the bicyclic ring system formed by ring A, is C or N; X ３ But, CHR ３ , or NR ４ and X ４ But, CHR ３ , N.R. ４ , O, or S; Z １ Each of them is independently CR ２ or N, Z ２ But, CR ３ or N, Z １１ But, CHR ３ , C(R ３ ) ２ , or NR ４ and Z １２ But, CHR ２ , C(R ２ ) ２ , N.R. ４ , or C(=N-R ４ ) and R ２ and R ３ each independently represents hydrogen, optionally substituted C １～６ Aliphatic groups, halogens, -OR, -CN, -NR ２ , -C(=O)R, -NR-C(O)-R, -C(=O)OR, -C(=O)NR ２ , -SO ２ R, -SO ２ N.R. ２ , C １～６ Haloalkyl, C １～６ haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or Or R ２ and R ３ together with their intervening atoms form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; R ４ is hydrogen, optionally substituted C １～６ an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocycle, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R ３ and R ４ together with their intervening atoms form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; Ring B is 【Chemistry 3】 and L is a bond or an optionally substituted linear or branched C １～６ is alkylene, X ５ is CH, N, or CR ５ and X ６ is CH, N, or CR ６ and However, X ５ Or X ６ is N, then the other is not N; R ５ and R ６ each independently represents hydrogen, optionally substituted C １～６ Aliphatic group, -OR, -CN, -NR ２ , -C(=O)R, -C(=O)OR, -C(=O)NR ２ , -SO ２ R, -SO ２ N.R. ２ , halogen, C １～６ Haloalkyl, C １～６ haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or Or R ５ and R ６ together with their intervening atoms form a cyclic group selected from a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7- to 12-membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8- to 10-membered bicyclic aromatic carbocycle, a 3- to 8-membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5- to 6-membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8- to 10-membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; X ７ is N, CH, or CR ７ and X ８ But, O, NR ８ , C(R ８ ) ２ , CHR ８ , S.O. ２ or C=O, X ９ But, O, NR ９ , C(R ９ ) ２ , CHR ９ , S.O. ２ or C=O, X １０ But, O, NR １０ , C(R １０ ) ２ , CHR １０ , S.O. ２ or C=O, X １１ But, O, NR １１ , C(R １１ ) ２ , CHR １１ , S.O. ２ or C=O, X １２ is a direct bond, O, NR １２ , C(R １２ ) ２ , CHR １２ , -CH ２ CH ２ --, --OCH ２ -, SO ２ or C=O, R ７ is an optionally substituted aliphatic group, a halogen, -OR, -CN, -NR ２ , -C(=O)R, -C(=O)OR, -C(=O)NR ２ , -SO ２ R, -SO ２ N.R. ２ , C １～６ Haloalkyl, or C １～６ is haloalkoxy; R ８ , R ９ , R １０ , R １１ , and R １２ each independently represents hydrogen, optionally substituted C １～６ Aliphatic group, -OR, -CN, -NR ２ , -C(=O)R, -C(=O)OR, -C(=O)NR ２ , -SO ２ R, -SO ２ N.R. ２ , C １～６ Haloalkyl, C １～６ haloalkoxy, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocycle, phenyl, an 8-10 membered bicyclic aromatic carbocycle, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group is optionally substituted or Or R ７ , R ８ , R ９ , R １０ , R １１ , and R １２ any two of, together with their intervening atoms, form a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocycle (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic aromatic heterocycle (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic aromatic heterocycle (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which cyclic group is optionally substituted; R １３ and R １４ each independently represents hydrogen, optionally substituted C １～６ Aliphatic groups, halogens, -OR, -CN, -NR ２ , -C(=O)R, -C(=O)OR, -C(=O)NR ２ , -SO ２ R, -SO ２ N.R. ２ , C １～６ Haloalkyl, or C １～６ is haloalkoxy; R １６ is optionally substituted C １～６ Aliphatic groups, halogens, -OR, -CN, -NR ２ , -C(=O)R, -C(=O)OR, -C(=O)NR ２ , -SO ２ R, -SO ２ N.R. ２ , C １～６ Haloalkyl, or C １～６ is haloalkoxy; m is 0, 1, or 2; Each R is independently hydrogen, optionally substituted C １～６ an aliphatic group, an optionally substituted phenyl, an optionally substituted 3- to 7-membered saturated or partially unsaturated carbocycle, an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Compounds in which two R groups on the same nitrogen, together with their intervening atoms, form an optionally substituted 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. R １ is optionally substituted C ３～６ cycloalkyl, optionally substituted spiro[3.3]heptanyl, optionally substituted spiro[5.2]octanyl, optionally substituted 【Chemistry 4】 optionally substituted cyclopent-1-en-1-yl, optionally substituted cyclohex-1-en-1-yl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted aziridin-1-yl, optionally substituted pyrrolidin-1-yl, optionally substituted azabicyclo[3.1.0]hexan-3-yl, optionally substituted piperidin-1-yl, or optionally substituted —OCH ２ - (C ３～４ cycloalkyl).

3. R １ The compound of claim 1 , wherein is optionally substituted phenyl.

4. R １ but, (A)-CH ２ CH ２ CF ３ 、 【Chemistry 5】 or (B) a substituent selected from the following: 【Chemistry 6】 The compound according to claim 1,

5. Ring A, together with the six-membered ring system to which it is fused, has the formula: 【Chemistry 7】 5. The compound according to claim 1 , wherein the compound forms a bicyclic ring of the formula:

6. X １ The compound according to any one of claims 1 to 5, wherein is CH or N.

7. X ２ The compound according to any one of claims 1 to 6, wherein is CH or N.

8. X ３ But, N.R. ４ The compound according to any one of claims 1 to 7,

9. X ４ But, N.R. ４ The compound according to any one of claims 1 to 8,

10. Ring B is 【Chemistry 8】 The compound according to any one of claims 1 to 9,

11. The compound of any one of claims 1 to 10, wherein L is a bond.

12. Ring B is 【Chemistry 9】 The compound according to any one of claims 1 to 11,

13. Ring B is 【Chemistry 10】 The compound according to any one of claims 1 to 9,

14. Ring B is 【Chemistry 11】 The compound according to any one of claims 1 to 9, selected from:

15. Ring B is 【Chemistry 12】 The compound according to any one of claims 1 to 9,

16. R ９ but, 【Chemistry 13】 The compound according to any one of claims 1 to 9, 13 and 14, selected from:

17. R ９ but, 【Chemistry 14】 The compound according to any one of claims 1 to 9, 13 and 14,

18. 18. The compound of any one of claims 1 to 17, wherein the compound is a compound of formula IIa, IIb, IIc, IIIa, IIIb, IIIc, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIIIa, VIIIb, or VIIIc.

19. A compound of Table A or Table A2, or a pharma- ceutically acceptable salt thereof.

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, and a pharma- ceutically acceptable excipient.

21. A compound or a tautomer thereof according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 20, for use as a medicament.

22. A compound according to any one of claims 1 to 19 or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 20, for use in the treatment or prevention of a condition associated with loss of function of human TREM2.

23. 21. The compound or tautomer thereof according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to claim 20, for use in the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

24. Use of a compound or a tautomer thereof according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for treating or preventing a condition associated with loss of function of human TREM2.

25. 21. Use of a compound or a tautomer thereof according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to claim 20, in the preparation of a medicament for treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

26. 20. A method of treating or preventing a condition associated with loss of function of human TREM2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer.

27. 20. A method of treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a tautomer thereof, or a pharmacologic acceptable salt of said compound or said tautomer.

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