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

Abstract

To provide a compound useful for activating a trigger receptor 2 expressed in myeloid cells.SOLUTION: A compound of formula I: (Ring A: fused 6-membered to 6-membered / 5-membered hetero ring. X1, X3, X4:CH, N. X2:CH2, CHF, etc. R1 to R3:H, C1-3 alkyl. R4, R5:C1-6 alkyl, C1 - 6 haloalkyl, etc. n:0, 1. ) The disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for the treatment of, for example, neurodegenerative disorders. In addition, the disclosure provides intermediates useful in the synthesis of compounds of Formula I.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 019,772, filed May 4, 2020, which is incorporated herein by reference in its entirety.

[0002] Submitting a sequence listing as an ASCII text file The contents of the following submission in an ASCII text file are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (Filename: A-2616-WO-PCT_Sequence_Listing_ST25, Creation Date: April 26, 2021, Size: 9,610 bytes).

[0003] 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]

[0004] Microglia are resident innate immune cells in the brain and are important for maintaining homeostasis in the central nervous system. Hickman et al. 2018, Li and Barres 2018. These resident macrophages express a variety of 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 infarctions 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 Microglia interact with neural processes (Paolicelli et al. 2011, Ikegami et al. 2019), neural processes (Paolicelli et al. 2011, Ikegami et al. 2019), and other types of glial cells (Domingues et al. 2016, Liddelow et al. 2017, Shinozaki et al. 2017), playing a role in numerous physiological processes. Capable of rapidly proliferating in response to stimuli, microglia characteristically exhibit myeloid cell functions such as phagocytosis, cytokine / chemokine release, antigen presentation, and migration (Colonna and Butovsky 2017). Microglia's more unique functions include the ability to sever synapses from neurons and directly communicate with highly arborized cellular processes that survey the area surrounding the neuronal cell body (Hong et al. 2016, Sellgren et al. 2019).

[0005] 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 diverse array of cell surface receptors (Hickman et al. 2013). Collectively known as the microglial "sensome," these receptors are involved in transducing 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 of the receptors selectively expressed by brain microglia is the sensome. One of these is TREM2, which consists of a single-pass transmembrane domain, an extracellular stalk region, and an extracellular immunoglobulin variable domain (IgV)-like domain involved in ligand interaction (Kleinberger et al. 2014). Because TREM2 lacks an intracellular signaling mediator domain, biochemical analysis has shown that its interaction with the adaptor proteins DAP10 and DAP12 mediates downstream signaling following ligand recognition (Peng et al. 2010; Jay et al. 2017). In particular, the TREM2 / DAP12 complex acts as a signaling unit that can be characterized as a promoter of the activation of peripheral macrophages and osteoclasts, as well as microglial phenotypes (Otero et al. 2012; Kobayashi et al. 2016; Jaitin et al. 2019). In the CNS, TREM2-mediated signaling has been studied in the context of ligands such as phospholipids, cell debris, apolipoproteins, and myelin. (Wang et al. 2015, Kober and Brett 2017, Shirotani et al. 2019). A central observation in mice lacking functional TREM2 expression or expressing mutant forms of the receptor 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. 2015, Wu et al. 2017).

[0006] 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. 2013, Sims et al. 2017). Genetic variations in other genes selectively expressed by microglia in the CNS, such as CD33, PLCg2, and MS4A4A / 6A, reached genome-wide significance for their association with LOAD risk (Hollingworth et al. 2011, Sims et al. 2017, Deming et al. 2017). al. 2019. Together, these genetic findings are linked with putative biochemical circuits that highlight the importance of microglial innate immune function in LOAD. Furthermore, 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. 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. 2019.

[0007] 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. 2013, Dardiotis et al. 2017). This progressive neurodegenerative disease typically manifests in the third decade and is pathologically characterized by loss of myelin in the brain accompanied by gliosis, unexplained neuroinflammation, and brain atrophy. The presentation of typical neuropsychiatric symptoms often precedes bone abnormalities such as bone cysts and loss of peripheral bone density (Bianchin et al. 2004, Madry et al. 2007, Bianchin et al. 2010). Considering that osteoclasts of the myeloid lineage are also known to express TREM2, PLOSL-associated symptoms such as 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. 2003, Otero et al. 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.

[0008] In addition to 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. 2017, Kang et al. 2018). While it is not possible to reproduce the neurological symptoms of PLOSL, TREM2 KO mice exhibit abnormalities in bone ultrastructure (Otero et al. 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 (Ullich et al. 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, which are characteristic of the microglial response to amyloid pathology (Ulland et al. 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. 2019). Regarding the tau protein pathology observed in LOAD, a familial tauopathy model in mice showed enhanced spread of pathological human tau aggregates from the injection point into the mouse brain in TREM2 KO mice (Leyns et al. 2019). Furthermore, single-cell RNA-Seq 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 critical for a conserved set of phenotypic transformations within the microglial population in response to CNS pathology (Keren-Shaul et al. 2019). et al.2017.

[0009] 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. 2018). Changes in immunohistological markers associated with cerebral amyloid pathology were also accompanied by the presence of attenuated dystrophic neurites when TREM2 was overexpressed (ibid.). Therefore, pharmacological activation of TREM2 is a target for treating or preventing neurological, neurodegenerative, and other diseases. Despite numerous attempts to modify disease progression by targeting the pathological hallmarks of LOAD via anti-amyloid and anti-tau therapeutics, TREM2 activators are needed, 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

[0010] First, 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: Ring A, together with the six-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of the formula X 1 is CH or N, X 2 is CH2, CHF, CF2, O, or NH; X 3 is CH or N, X 4 is CH or N, X 5 is CH or N, X 6is CH or N, R 1 But H or C 1-3 is alkyl, R 2 But H or C 1-3 is alkyl, R 3 But H or C 1-3 is alkyl, R 4 But C 1-6 Alkyl, C 1-6 Haloalkyl, DiC 1-3 Alkylamino, -C(=O)O(C 1-6 alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; (1)C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl is optionally substituted with C=O; (2) The phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally, independently, selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl, and C 3-6 substituted with 1 to 3 substituents selected from heterocycloalkyl; Subsection (2) C 1-6 Alkyl and C 1-6 haloalkyl is optionally substituted with OH; Subsection (2) C 3-6 Heterocycloalkyl optionally contains halogen, C 1-3 Alkyl, and -C(=O)O(C 1-6 substituted with 1 to 3 substituents selected from R 5 But C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkoxy; R 6 is H, halogen, or C 1-3 is alkyl, R 7 is H, halogen, or C 1-3 is alkyl, R 8 But H or C 1-3 is alkyl, R 9 But H or C 1-5 is alkyl, n is 0 or 1, provided that X 1 If is N and n is 0, then X 2 NH or O or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0011] Second, 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.

[0012] Third, 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.

[0013] Fourth, provided herein is a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition as described above, for use in treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke. [Brief explanation of the drawings]

[0014] For the purpose of illustrating the invention, the drawings show embodiments of the disclosed subject matter, but it should be understood that the application is not limited to the precise configurations and embodiments shown in the drawings.

[0015] [Figure 1] 1 is a graph showing the measured concentrations of MCP-1 (CCL2) in the right cortex of mice 24 hours after administration of the compound of Example 192 or antibody 13E7 compared to a control. Error bars are shown as standard error of the mean (SEM). [Figure 2] 1 is a graph showing the measured concentrations of IP-10 (CXCL10) in the right cortex of mice 24 hours after administration of the compound of Example 192 or antibody 13E7 compared to a control. Error bars are shown as SEM. [Figure 3]1 is a graph showing the measured concentrations of IP-10 (CXCL10) in plasma samples taken from mice 24 hours after administration of the compound of Example 192 or antibody 13E7 compared to a control. Error bars are shown as SEM.

[0016] Embodiments of the present disclosure will now be disclosed in detail. While particular embodiments of the present disclosure are disclosed, it should be understood that it is 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 that 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

[0017] Provided herein as embodiment 1 is a compound of formula I [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: Ring A, together with the six-membered ring system to which it is fused, has the formula [ka] forming a bicyclic ring system of the formula X 1 is CH or N, X 2 is CH2, CHF, CF2, O, or NH; X 3 is CH or N, X 4 is CH or N, X 5 is CH or N, X 6 is CH or N, R 1 But H or C 1-3 is alkyl, R 2 But H or C 1-3is alkyl, R 3 But H or C 1-3 is alkyl, R 4 But C 1-6 Alkyl, C 1-6 Haloalkyl, DiC 1-3 Alkylamino, -C(=O)O(C 1-6 alkyl), C 3-6 Cycloalkyl, C 3-6 heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; (1)C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl is optionally substituted with C=O; (2) The phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally, independently, selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, C 2-4 Alkenyl, C 3-6 Cycloalkyl, and C 3-6 substituted with 1 to 3 substituents selected from heterocycloalkyl; Subsection (2) C 1-6 Alkyl and C 1-6 haloalkyl is optionally substituted with OH; Subsection (2) C 3-6 Heterocycloalkyl optionally contains halogen, C 1-3 Alkyl, and -C(=O)O(C 1-6 substituted with 1 to 3 substituents selected from R 5 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkoxy; R 6 is H, halogen, or C 1-3 is alkyl, R 7 is H, halogen, or C 1-3 is alkyl, R 8 But H or C 1-3 is alkyl, R 9 But H or C 1-5 is alkyl, n is 0 or 1, provided that X 1 If is N and n is 0, then X 2 is not NH or O, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0018] Provided herein as embodiment 2 is a compound comprising: 4-(3-fluoro-1-azetidinyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(3,3-difluoro-1-piperidinyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-((cis-3-(trifluoromethyl)cyclobutyl)methoxy)pyrido[2,3-d]pyrimidine, or The compound of embodiment 1 is not 2-methyl-6-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(cis-3-(trifluoromethyl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

[0019] Provided herein as embodiment 3 is a compound of embodiment 1 or embodiment 2, wherein the compound is a compound of formula II, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0020] Provided herein as embodiment 4 is a compound of embodiment 1 or embodiment 2, wherein the compound is a compound of formula IIA, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0021] Provided herein as embodiment 5 is a compound of embodiment 1 or embodiment 2, wherein the compound is a compound of formula IIB, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer: [ka]

[0022] Provided herein as embodiment 6 is a compound of embodiment 1 or embodiment 2, wherein the compound is a compound of formula IIC, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0023] Provided herein as embodiment 7 is a compound according to embodiment 1 or embodiment 2, wherein the compound is a compound of formula IID, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0024] Provided herein as embodiment 8 is a compound according to embodiment 1 or embodiment 2, wherein the compound is a compound of formula IIE, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer: [ka]

[0025] Provided herein as embodiment 9 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis recurrence inhibitor (RAR) to a patient having a pulmonary arthritis recurrence syndrome (RAR) syndrome. X 1is CH; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0026] Provided herein as embodiment 10 is a method for treating a pulmonary arthritis (PTA) comprising: X 1 is N, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0027] Provided herein as embodiment 11 is a method for treating a pulmonary arthritis (PA) comprising: X 2 is CH2, CF2, or O; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0028] Provided herein as embodiment 12 is a method for treating a pulmonary arthritis (PA) comprising: X 2 is O, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0029] Provided herein as embodiment 13 is a method for treating a vascular endothelial cell comprising: X 3 is CH; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0030] Provided herein as embodiment 14 is a method for treating a pulmonary arthritis (PA) comprising: X 3 is N, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0031] Provided herein as embodiment 15 is a method for treating a pulmonary arthritis (PA) comprising: X 4is CH; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0032] Provided herein as embodiment 16 is a method for treating a pulmonary arthritis (PA) comprising: X 4 is N, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0033] Provided herein as embodiment 17 is a method for treating a pulmonary arthritis (PA) comprising: X 5 is CH; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0034] Provided herein as embodiment 18 is a method for treating a pulmonary arthritis (PA) comprising: X 5 is N; or a tautomer thereof. or a pharmaceutically acceptable salt of said compound or said tautomer.

[0035] Provided herein as embodiment 19 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a pulmonary arthritis recurrence inhibitor (RAR) to a patient having a pulmonary arthritis recurrence syndrome (RAR) syndrome. X 6 is CH; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0036] Provided herein as embodiment 20 is a method for treating a pulmonary arthritis (PTA) comprising: X 6 is N, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0037] Provided herein as embodiment 21 is a method for treating a pulmonary arthritis (PA) comprising: R 1is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0038] Provided herein as embodiment 22 is a method for treating a pulmonary arthritis (PA) comprising: R 1 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0039] Provided herein as embodiment 23 is a method for treating a pulmonary arthritis (PA) comprising: R 2 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0040] Provided herein as embodiment 24 is a method for treating a pulmonary arthritis (PA) comprising: R 2 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0041] Provided herein as embodiment 25 is a method for treating a pulmonary arthritis (PA) comprising: R 3 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0042] Provided herein as embodiment 26 is a method for treating a pulmonary arthritis (PA) comprising: R 3 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0043] Provided herein as embodiment 27 is a method for treating a pulmonary arthritis (PA) comprising: R 4 But C 1-6 Alkyl, C3-6 heterocycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, and C 3-6 27. The compound of any one of embodiments 1 to 26, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound or tautomer is substituted with 1 to 3 substituents selected from heterocycloalkyl.

[0044] Provided herein as embodiment 28 is a method for treating a pulmonary arthritis (PA) comprising: R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl and C 3-6 cycloalkyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, according to any one of embodiments 1 to 26, wherein said compound or said tautomer is substituted with one to three substituents selected from:

[0045] Provided herein as embodiment 29 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: R 4 Methyl, tetrahydrofuran-3-yl, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0046] Provided herein as embodiment 30 is a method for treating a pulmonary arthritis (PAS) comprising: R 4 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0047] Provided herein as embodiment 31 is a method for treating a pulmonary arthritis (PA) comprising: R 5 But C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, according to any one of embodiments 1 to 30, further substituted with 1 to 4 substituents selected from alkoxy.

[0048] Provided herein as embodiment 32 is a method for treating a pulmonary arthritis, comprising: R 5 -CH2CH2CF3, optionally 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, substituted aziridin-1-yl, substituted pyrrolidinyl substituted azabicyclo[3.1.0]hexan-3-yl, substituted piperidin-1-yl, or substituted -OCH2-(C 3-4 cycloalkyl), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0049] Provided herein as embodiment 33 is a method for treating a pulmonary arthritis, comprising: R 5 But -CH2CH2CF3, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0050] Provided herein as embodiment 34 is a method for treating a pulmonary arthritis (PA) comprising: R 6 is H, chlorine, or methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. be.

[0051] Provided herein as embodiment 35 is a method for treating a pulmonary arthritis (PA) comprising: R 6 is H, chlorine, or methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0052] Provided herein as embodiment 36 is a method for treating a pulmonary arthritis (PA) comprising: R 6is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0053] Provided herein as embodiment 37 is a method for treating a pulmonary arthritis (PA) comprising: R 7 is H, methyl, or ethyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0054] Provided herein as embodiment 38 is a method for treating a pulmonary arthritis (PA) comprising: R 7 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0055] Provided herein as embodiment 39 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: R 8 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0056] Provided herein as embodiment 40 is a method for treating a pulmonary arthritis (PAS) comprising: R 9 is H, methyl, ethyl, or isopropyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0057] Provided herein as embodiment 41 is a method for treating a pulmonary arthritis (PA) comprising: The compound according to any one of embodiments 1 to 40, wherein n is 0, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0058] Provided herein as embodiment 42 is a method for treating a pulmonary arthritis (PA) comprising: The compound of any one of embodiments 1 to 40, wherein n is 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0059] Provided herein as embodiment 43 is a compound comprising: 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(4-chloro-2-fluorophenyl)-2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-7-methylpteridine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pteridine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-(2-(tetrahydro-3-furanyl)-4-morpholinyl)pteridine, 4-(2,4-difluorophenyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(2,4-difluorophenyl)-7-methylpteridine, 4-(2,4-difluorophenyl)-7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(2-fluoro-4-methylphenyl)-7-methylpteridine, 4-(2-fluoro-4-methylphenyl)-7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-7-methyl-4-(cis-3-(trifluoromethyl)cyclobutyl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-7-methyl-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 7-methyl-2-((2R)-2-(6-methyl-4-pyridazinyl)-4-morpholinyl)-4-(cis-3-(trifluoromethyl)cyclobutyl)pteridine, 7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-4-(cis-3-(trifluoromethyl)cyclobutyl)pteridine, 7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 4-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(3,4,5-trifluorophenyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(6-(trifluoromethyl)-3-pyridinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(6-methyl-3-pyridinyl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(4-chloro-2-fluorophenyl)-2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-6,7-dimethylpteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-(2-(tetrahydro-3-furanyl)-4-morpholinyl)pteridine, 4-((1R,5S)-6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(3-Methoxy-1-azetidinyl)-6,7-dimethyl-2-((2S)-2-( 1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(3-(trifluoromethyl)-1-azetidinyl)pteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(2,4-difluorophenyl)-6,7-dimethylpteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S)-2-((3R)-tetrahydro-3-furanyl)-4-morpholinyl)pteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2R)-2-((3R)-tetrahydro-3-furanyl)-4-morpholinyl)pteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2R)-2-((3S)-tetrahydro-3-furanyl)-4-morpholinyl)pteridine, 4-(2-fluoro-4-methylphenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(2-fluoro-4-methylphenyl)-6,7-dimethylpteridine, 4-(2-fluoro-4-methylphenyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(3,3,3-trifluoropropyl)pteridine, 6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-4-(3,3,3-trifluoropropyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(cis-3-(trifluoromethyl)cyclobutyl)pteridine, 4-(cis-3-(difluoromethyl)cyclobutyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(trans-3-(difluoromethyl)cyclobutyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(6,6-difluorospiro[3.3]heptan-2-yl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(cis-3-(difluoromethyl)cyclobutyl)-6,7-dimethylpteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(trans-3-(difluoromethyl)cyclobutyl)-6,7-dimethylpteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(6,6-difluorospiro[3.3]heptan-2-yl)-6,7 -dimethylpteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-6,7-dimethyl-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 6,7-dimethyl-2-((2S)-2-(6-methyl-4-pyridazinyl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 6,7-dimethyl-2-((2R)-2-(6-methyl-4-pyridazinyl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 4-(cis-3-(difluoromethyl)cyclobutyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridazinyl)-4-morpholinyl)pteridine, 4-(trans-3-(difluoromethyl)cyclobutyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 4-(6,6-difluorospiro[3.3]heptan-2-yl)-6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pteridine, 4-(4-chloro-2-methylphenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(4-fluoro-2-methylphenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(3,4-difluorophenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(2,3,4-trifluorophenyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(2,4,5-trifluorophenyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine, 6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine, 4-(4,4-difluoro-1-piperidinyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(4,4-dimethyl-1-piperidinyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-((3R)-3-fluoro-1-piperidinyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-((3S)-3-fluoro-1-piperidinyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(3,3-Difluoro-1-pyrrolidinyl)-6,7-dimethyl-2-((2S)- 2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(3,3-dimethyl-1-pyrrolidinyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-methylpyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-methylpyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2-methylpyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[3,4-b]pyrazine, 2,3-dimethyl-7((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[3,4-b]pyrazine, 7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethyl-5-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[3,4-b]pyrazine, 2,3-dimethyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-5-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[3,4-b]pyrazine, 4-(4-chloro-2-fluorophenyl)-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-7-methylpyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(6-methyl-4-pyridazinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2R)-2-(6-methyl-4-pyridazinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2R)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-7-methyl-2-((2S)-2-(1-methyl -1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(2,4-difluorophenyl)-7-methylpyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(2-fluoro-4-methylphenyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(2-fluoro-4-methylphenyl)-7-methylpyrido[2,3-d]pyrimidine, 4-(2-fluoro-4-methylphenyl)-7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[2,3-d]pyrimidine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-7-methyl-4-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[2,3-d]pyrimidine, 7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[2,3-d]pyrimidine, 7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidine, 7-methyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S)-2-(6-methyl-4-pyridazinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R)-2-(6-methyl-4-pyridazinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-((3,3-difluorocyclobutyl)methoxy)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(((1R,2R)-2-(trifluoromethyl)cyclopropanol (propyl)methoxy)pyrido[2,3-d]pyrimidine, 4-(((1S)-2,2-dimethylcyclopropyl)methoxy)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[2,3-d]pyrimidine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-6,7-dimethyl-4-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[2,3-d]pyrimidine, 6,7-dimethyl-2-((2S)-2-(6-methyl-4-pyridazinyl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[2,3-d]pyrimidine, 6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pyrido[2,3-d]pyrimidine, 6-chloro-4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-2-methyl-6-((2S)-2-methyl-4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, 4-(4-chloro-2-fluorophenyl)-2-methyl-6-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, 4-(4-chloro-2-fluorophenyl)-6-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, 4-(4-chloro-2-fluorophenyl)-2-ethyl-6-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, 4-(4-chloro-2-fluorophenyl)-6-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-(2-propanyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one, 4-(4-chloro-2-fluorophenyl)-2-((3S)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)-6,7-dimethylpteridine, 4-(4-chloro-2-fluorophenyl)-2-((3R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)-6,7-dimethylpteridine, 4-(4,4-difluoro-1-cyclohexen-1-yl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-((4R)-4-(trifluoromethyl)-1-cyclohexen-1-yl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-((4S)-4-(trifluoromethyl)-1-cyclohexen-1-yl)pteridine, 4-(1-cyclopenten-1-yl)-6,7-dimethyl-2-((2S)-2-(1 -methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-(3-oxetanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[3,4-b]pyrazine, 4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(cis-4-(trifluoromethyl)cyclohexyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(trans-4-(trifluoromethyl)cyclohexyl)pteridine, 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-cyclohexyl-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 6,7-dimethyl-4-(cis-4-methylcyclohexyl)-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 6,7-dimethyl-4-(trans-4-methylcyclohexyl)-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(spiro[2.5]octan-6-yl)pteridine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(4,4-difluorocyclohexyl)-6,7-dimethylpteridine, 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pteridine, 4-cyclopentyl-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(4,4-difluorocyclohexyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(cis-4-(trifluoromethyl)cyclohexyl)pyrido[2,3-d]pyrimidine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-4-(4,4-difluorocyclohexyl)-7-methylpyrido[2,3-d]pyrimidine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-7-methyl-4-(cis-4-(trifluoromethyl)cyclohexyl)pyrido[2,3-d]pyrimidine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-7-methyl-4-(trans-4-(trifluoromethyl)cyclohexyl)pyrido[2,3-d]pyrimidine, 4-(3,3-difluorocyclobutyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 1-(4-chloro-2-fluorophenyl)-6-methyl-3-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)isoquinoline, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-1,6-naphthyridine, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2-methyl-1,6-naphthyridine, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-methyl-1,6-naphthyridine, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)-1,6-naphthyridine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-1,6-naphthyridine, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)quinazoline, 5-(2,4-difluorophenyl)-2-methyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)quinazoline, 4-(4-chloro-2-fluorophenyl)-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-1,8-naphthyridine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-1,8-naphthyridine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-1,8-naphthyridine, 8-(4-chloro-2-fluorophenyl)-2-methyl-6-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-b]pyrazine, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-b]pyrazine, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-b]pyrazine, 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)quinoxaline, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)quinoxaline, 5-(2,4-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)quinoxaline, 4-(trans-4-chlorocyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-7-ethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, 2-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-mol 2,4-difluorophenyl)-6,7-dimethylpyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-7-methylpteridine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2R,4S)-2-(2-methyl-5-pyrimidinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S,4R)-2-(2-methyl-5-pyrimidinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-2-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridine, 4-(4-chloro-2-fluorophenyl)-2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(2-fluoro-4-methylphenyl)-6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(2-fluoro-4-methylphenyl)-6,7-dimethyl-2-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-b]pyrazine, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)pyrido[2,3-b]pyrazine, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-b]pyrazine, 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-b]pyrazine, 8-(2-fluoro-4-methylphenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-b]pyrazine, 8-(2-fluoro-4-methylphenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine, 5-(2,4-difluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine, 5-(2-fluoro-4-methylphenyl)-2,3-dimethyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine, 4-(4-chloro-2-fluorophenyl)-2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-7-methylpyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-2-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(2-fluoro-4-methylphenyl)-6,7-dimethyl-2-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(2-fluoro-4-methylphenyl)-6,7-dimethyl-2-((2R,4S) -2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 6,7-dimethyl-2-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(4-chloro-2-fluorophenyl)-2-((2R,4S)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R,4S)-2-(2-methyl-5-pyrimidinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pteridine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S,4S)-2-(2-methyl 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2R,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pteridine, 6,7-dimethyl-2-((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 6,7-dimethyl-2-((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2R,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-7-methyl-2-((2S,4S)-2-(2- methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(2-fluoro-4-methylphenyl)-6,7-dimethyl-2-((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(2-fluoro-4-methylphenyl)-6,7-dimethyl-2-((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2R,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-((2R,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine, or 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7((2R,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

[0060] Provided herein as embodiment 44 is a compound of embodiment 1, wherein the compound is: [ka] Provided herein as embodiment 45 is a compound of embodiment 1, wherein the compound is: [ka] Provided herein as embodiment 46 is a compound of embodiment 1, wherein the compound is: [ka] Provided herein as embodiment 47 is a compound of embodiment 1, wherein the compound is: [ka] Provided herein as embodiment 48 is a compound of embodiment 1, wherein the compound is: [ka] Provided herein as embodiment 49 is a compound of embodiment 1, wherein the compound is: [ka] Provided herein as embodiment 50 is a compound of embodiment 1, wherein the compound is: [ka] Provided herein as embodiment 51 is a compound of embodiment 1, wherein the compound is: [ka] Provided herein as embodiment 52 is a compound of Formula IIIa [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0061] Provided herein as embodiment 53 is a compound of Formula IIIb [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0062] Provided herein as embodiment 54 is a compound of Formula IIIc [ka] , wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0063] Provided herein as embodiment 55 is a compound of formula IIId: [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0064] Provided herein as embodiment 56 is a compound of Formula IVa [ka] , wherein each variable is as defined above and described individually and in combination in the embodiments herein. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, as described in embodiment 1, 2, or 3, wherein

[0065] Provided herein as embodiment 57 is a compound of Formula IVb [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0066] Provided herein as embodiment 58 is a compound of Formula IVc: [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0067] Provided herein as embodiment 59 is a compound of Formula Va [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0068] Provided herein as embodiment 60 is a compound of Formula Vb [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0069] Provided herein as embodiment 61 is a compound of formula Vc [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0070] Provided herein as embodiment 62 is a compound of Formula VIa [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0071] Provided herein as embodiment 63 is a compound of Formula VIb [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0072] Provided herein as embodiment 64 is a compound of formula Vic [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0073] Provided herein as embodiment 65 is a compound of Formula VII [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0074] Provided herein as embodiment 66 is a compound of Formula VIIIa [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0075] Provided herein as embodiment 67 is a compound of Formula VIIIb [ka] wherein each variable is as defined above and described individually and in combination in the embodiments herein. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, as described in embodiment 1, 2, or 3, wherein

[0076] Provided herein as embodiment 68 is a compound of Formula VIIIc [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0077] Provided herein as embodiment 69 is a compound of Formula IXa [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0078] Provided herein as embodiment 70 is a compound of Formula IXb [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0079] Provided herein as embodiment 71 is a compound of Formula IXc [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0080] Provided herein as embodiment 72 is a compound of formula X [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0081] Provided herein as embodiment 73 is a compound of Formula XI [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0082] Provided herein as embodiment 74 is a compound of Formula XII: [ka] wherein each variable is as defined above and as described in the embodiments herein, alone and in combination, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0083] Provided herein as embodiment 75 is a compound comprising R 2 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0084] Provided herein as embodiment 76 is a compound comprising R 2 is H, or a tautomer thereof, or the compound or tautomer thereof according to any one of embodiments 1 to 74. and pharmaceutically acceptable salts of the isomer.

[0085] Provided herein as embodiment 77 is a compound comprising R 2 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0086] Provided herein as embodiment 78 is a compound comprising R 4is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0087] Provided herein as embodiment 79 is a compound comprising R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl and C 3-6 cycloalkyl. In some embodiments, R is a compound of any one of embodiments 1 to 77, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. 4 are optionally, independently, C 1-6 Alkyl and C 3-6 In some embodiments, R is a 5-membered heteroaryl substituted with 1 to 3 substituents selected from cycloalkyl. 4 are optionally, independently, C 1-6 Alkyl and C 3-6 and 6-membered heteroaryl substituted with 1 to 3 substituents selected from cycloalkyl.

[0088] Provided herein as embodiment 80 is a method for treating a pulmonary arthritis (PA) comprising: R 4 Methyl, tetrahydrofuran-3-yl, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0089] Provided herein as embodiment 81 is a method for treating a pulmonary arthritis (PA) comprising: R 4 Methyl, tetrahydrofuran-3-yl, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0090] Provided herein as embodiment 82 is a method for treating a pulmonary arthritis (PA) comprising: R 4 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0091] Provided herein as embodiment 83 is a method for treating a pulmonary arthritis (PA) comprising: R 4 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0092] Provided herein as embodiment 84 is a method for treating a pulmonary arthritis (PA) comprising: R 4 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0093] Provided herein as embodiment 85 is a method for treating a pulmonary arthritis (PA) comprising: R 4 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0094] Provided herein as embodiment 86 is a method for treating a pulmonary arthritis (PA) comprising: R 4 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0095] Provided herein as embodiment 87 is a method for treating a pulmonary arthritis (PA) comprising: R 5 But C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3Haloalkyl, and C 1-3 87. The compound of any one of embodiments 1-86, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, further substituted with 1 to 4 substituents selected from alkoxy.

[0096] In some embodiments, R 5 is C 1-6 In some embodiments, R 5 are optionally independently halogen, C 1-3 Alkyl, and C 1-3 C substituted with 1 to 4 substituents selected from haloalkyl 3-6 In some embodiments, R 5 are optionally independently halogen, C 1-3 Alkyl, and C 1-3 C substituted with 1 to 4 substituents selected from haloalkyl 5-8 In some embodiments, R 5 are optionally independently halogen, C 1-3 Alkyl, and C 1-3 C substituted with 1 to 4 substituents selected from haloalkyl 5-8 In some embodiments, R 5 are optionally independently halogen, C 1-3 Alkyl, and C 1-3 In some embodiments, R is cyclopent-1-en-1-yl substituted with 1 to 4 substituents selected from haloalkyl. 5 are optionally independently halogen, C 1-3 Alkyl, and C 1-3 In some embodiments, R is cyclohex-1-en-1-yl substituted with 1 to 4 substituents selected from haloalkyl. 5 are optionally independently halogen, C 1-3 Alkyl, and C 1-3 In some embodiments, R is phenyl substituted with 1 to 4 substituents selected from haloalkyl. 5 are optionally independently halogen, C1-3 Alkyl, and C 1-3 In some embodiments, R is a 6-membered heteroaryl substituted with 1 to 4 substituents selected from haloalkyl. 5 are optionally independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 In some embodiments, R is aziridin-1-yl substituted with 1 to 4 substituents selected from alkoxy. 5 are optionally independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 In some embodiments, R is pyrrolidin-1-yl substituted with 1 to 4 substituents selected from alkoxy. 5 are optionally independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 In some embodiments, R is azabicyclo[3.1.0]hexan-3-yl substituted with 1 to 4 substituents selected from alkoxy. 5 are optionally independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 In some embodiments, R is piperidin-1-yl substituted with 1 to 4 substituents selected from alkoxy. 5 are optionally independently halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 -OCH2-(C 3-6 cycloalkyl).

[0097] Provided herein as embodiment 88 is a compound comprising R 5 -CH2CH2CF3, optionally 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, substituted aziridin-1-yl, substituted pyrrolidin-1-yl, substituted azabicyclo[3.1.0]hexan-3-yl, substituted piperidin-1-yl, or substituted -OCH2-(C 3-4 cycloalkyl), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. In some embodiments, R 5 is —CH2CH2CF3. In some embodiments, R 5 is an arbitrary substitution C 3-6 In some embodiments, R 5 is optionally substituted spiro[3.3]heptanyl. In some embodiments, R 5 is optionally substituted spiro[5.2]octanyl. In some embodiments, R 5 is an arbitrary substitution [ka] In some embodiments, R 5 is optionally substituted cyclopent-1-en-1-yl. In some embodiments, R 5 is optionally substituted cyclohex-1-en-1-yl. In some embodiments, R 5 is optionally substituted phenyl. In some embodiments, R 5 is optionally substituted pyridinyl. In some embodiments, R 5 is optionally substituted aziridin-1-yl. In some embodiments, R 5 is optionally substituted pyrrolidin-1-yl. In some embodiments, R 5 is optionally substituted azabicyclo[3.1.0]hexan-3-yl. In some embodiments, R 5 is optionally substituted piperidin-1-yl. In some embodiments, R 5 is an optionally substituted -OCH2-(C 3-4 cycloalkyl).

[0098] Provided herein as embodiment 89 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: R 5 But -CH2CH2CF3, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0099] Provided herein as embodiment 90 is a method for treating a pulmonary arthritis, comprising: R 5 But -CH2CH2CF3, [ka] [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0100] Provided herein as embodiment 91 is a compound comprising R 5 is optionally substituted phenyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0101] Provided herein as embodiment 92 is a method for treating a pulmonary arthritis (PA) comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0102] Provided herein as embodiment 93 is a method for treating a pulmonary arthritis (PA) comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0103] Provided herein as embodiment 94 is a method for treating a pulmonary arthritis (PA) comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0104] Provided herein as embodiment 95 is a method for treating a pulmonary arthritis (PA) comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0105] Provided herein as embodiment 96 is a method for treating a pulmonary arthritis (PA) comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0106] Provided herein as embodiment 97 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0107] Provided herein as embodiment 98 is a compound comprising R 5 But any substitution C 3-6 cycloalkyl, optionally substituted spiro[3.3]heptanyl, optionally substituted spiro[5.2]octanyl, or optionally substituted [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0108] Provided herein as embodiment 99 is a method for treating a pulmonary arthritis (PA) comprising administering to a patient a therapeutically effective amount of a compound comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. In some embodiments, R 5 teeth, [ka] is.

[0109] Provided herein as embodiment 100 is a method for manufacturing a semiconductor device comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0110] Provided herein as embodiment 101 is a method for manufacturing a semiconductor device comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0111] Provided herein as embodiment 102 is a method for manufacturing a semiconductor device comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0112] Provided herein as embodiment 103 is a compound comprising R 5 is optionally substituted cyclopent-1-en-1-yl, or optionally substituted cyclohex-1-en-1-yl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0113] Provided herein as embodiment 104 is a method for manufacturing a semiconductor device comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0114] Provided herein as embodiment 105 is a compound comprising R 5 is optionally substituted pyridinyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0115] Provided herein as embodiment 106 is a method for manufacturing a semiconductor device comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0116] Provided herein as embodiment 107 is a compound comprising R 5 is a substituted aziridin-1-yl, substituted pyrrolidin-1-yl, substituted azabicyclo[3.1.0]hexan-3-yl, or substituted piperidin-1-yl. or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0117] Provided herein as embodiment 108 is a method for manufacturing a semiconductor device comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0118] Provided herein as embodiment 109 is a method for manufacturing a semiconductor device comprising: R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0119] Provided herein as embodiment 110 is a compound comprising R 6is H, chlorine, or methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0120] Provided herein as embodiment 111 is a compound comprising R 6 is H or methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0121] Provided herein as embodiment 112 is a compound comprising R 6 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0122] Provided herein as embodiment 113 is a compound comprising R 6 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0123] Provided herein as embodiment 114 is a compound comprising R 7 is H, methyl, or ethyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0124] Provided herein as embodiment 115 is a compound comprising R 7 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0125] Provided herein as embodiment 116 is a compound comprising R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0126] Provided herein as embodiment 117 is a compound comprising R 7 is ethyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0127] Provided herein as embodiment 118 is a compound comprising R 6 is H or methyl, and R 7 is H or methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0128] Provided herein as embodiment 119 is a compound comprising R 6 is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0129] Provided herein as embodiment 120 is a compound comprising R 6 is H and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0130] Provided herein as embodiment 121 is a compound comprising R 6 is methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0131] Provided herein as embodiment 122 is a compound comprising R 6 is Cl and R 7is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0132] Provided herein as embodiment 123 is a compound comprising R 6 is H and R 7 is ethyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0133] Provided herein as embodiment 124 is a compound comprising R 9 is H, methyl, ethyl, or isopropyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0134] Provided herein as embodiment 125 is a compound comprising R 9 is methyl, ethyl, or isopropyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0135] Provided herein as embodiment 126 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0136] Provided herein as embodiment 127 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0137] Provided herein as embodiment 128 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0138] Provided herein as embodiment 129 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 6is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0139] Provided herein as embodiment 130 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0140] Provided herein as embodiment 131 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0141] Provided herein as embodiment 132 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0142] Provided herein as embodiment 133 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, and R 7 is methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0143] Provided herein as embodiment 134 is a compound comprising R 2 is H or methyl, and R 4 but, [ka] and R 5 but, [ka] and R 9 is methyl, ethyl, or isopropyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0144] Provided herein as embodiment 135 is a compound or tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, according to any one of embodiments 1 to 131, wherein at least one hydrogen atom of the compound is a deuterium atom.

[0145] Provided herein as embodiment 136 is a compound or a tautomer thereof according to any one of embodiments 1 to 131, or a tautomer of the compound or the tautomer, wherein at least one C1-C6 alkyl group of the compound is substituted with at least one deuterium atom. It is a pharmaceutically acceptable salt.

[0146] Provided herein as embodiment 137 is a compound comprising R 6 is -CD3, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0147] Provided herein as embodiment 138 is a compound comprising R 7 is -CD3, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0148] Provided herein as embodiment 139 is a compound comprising R 6 and R 7 and R are both -CD3, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0149] Provided herein as embodiment 140 is a compound of Formula IIIa [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, however, R 4 but [ka] and R 2 If is H, then R 5 but, [ka] Instead, R 4 but [ka] and R 2 If is H, then R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0150] Provided herein as embodiment 141 is a compound of Formula IIIa [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0151] Provided herein as embodiment 142 is a compound of Formula IIIa [ka] During the ceremony, R 2 is methyl, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 Ha further substituted with 1 to 4 substituents selected from alkyl, Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0152] Provided herein as embodiment 143 is a compound of Formula IIIa [ka] During the ceremony, R 2 is H or methyl, R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 but, [ka] and R 6 is H or methyl, R7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0153] Provided herein as embodiment 144 is a compound of Formula IIIb [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, however, R 4 but [ka] If R 5 but, [ka] Instead, R 4 but [ka] and R 2 If is H, then R 5 but, [ka] Instead, R 4 but [ka] If R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0154] Provided herein as embodiment 145 is a compound of Formula IIIb [ka] During the ceremony, R 2 is H or methyl, R 4is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, However, R 4 but [ka] If R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0155] Provided herein as embodiment 146 is a compound of Formula IIIb [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 but, [ka] and R 6is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0156] Provided herein as embodiment 147 is a compound of Formula IIIb [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 but, [ka] or R 2 is methyl, R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0157] Provided herein as embodiment 148 is a compound of Formula Va: [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 But C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, however, R 6 is Me and R 2 If is H, then R 5 but, [ka] Instead, R 2 and R 6 If both are H, then R5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0158] Provided herein as embodiment 149 is a compound of Formula Vb [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 But C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, However, R 2 If is H, then R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0159] Provided herein as embodiment 150 is a compound of Formula Va or Vb [ka] During the ceremony, R 2 is H or methyl, R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0160] Provided herein as embodiment 151 is a compound of Formula Va or Vb [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0161] Provided herein as embodiment 152 is a compound of Formula Va or Vb [ka] During the ceremony, R 2 is methyl, R 4 but, [ka] and R 5 But C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0162] Provided herein as embodiment 153 is a compound of Formula Vb [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R5 but, [ka] and R 6 is H or methyl, R 7 is methyl, However, R 2 If is H, then R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0163] Provided herein as embodiment 154 is a compound of Formula VIIIa [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 But C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 But it is Me, However, R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0164] Provided herein as embodiment 155 is a compound of Formula VIIIa [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 but, [ka] and R 6is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0165] Provided herein as embodiment 156 is a compound of Formula VIIIb [ka] During the ceremony, R 2 is H or methyl, R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 But C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0166] Provided herein as embodiment 157 is a compound of Formula IVb [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 But it is Me, However, R 2 If is H, then R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0167] Provided herein as embodiment 158 ​​is a compound of Formula IIIa [ka] During the ceremony, R 2 is H, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, However, R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0168] Provided herein as embodiment 159 is a compound of Formula IIIa [ka] During the ceremony, R 2 is H, R4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 But -CH2CH2CF3, [ka] and R 6 is H or methyl, R 7 is methyl, However, R 4 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0169] Provided herein as embodiment 160 is a compound of Formula IIIa [ka] During the ceremony, R 2 is H, R 4 but, [ka] and R 5 But -CH2CH2CF3, [ka] and R 6 is H or methyl, R 7is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0170] Provided herein as embodiment 161 is a compound of Formula IIIb [ka] During the ceremony, R 2 is Me and R 4 but, [ka] or R 2 is H and R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, however, R 5 but, [ka] Instead, R 4 but [ka] If R 5 but, [ka] isn't it, R 4 but [ka] If R 5 but, [ka] is not a compound of embodiment 1, 2, or 3, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0171] Provided herein as embodiment 162 is a compound of Formula IIIb [ka] During the ceremony, R 2 is H or methyl, R 4is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, however, R 4 but [ka] If R 5 but, [ka] Instead, R 4 but [ka] If R 5 but, [ka] is not a compound of embodiment 1, 2, or 3, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0172] Provided herein as embodiment 163 is a compound of Formula IIIb [ka] During the ceremony, R 2 is Me and R 4 but, [ka] or R 2 is H and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, however, R 4 but [ka] If R 5 but, [ka] Instead, R 4 but [ka] If R 5 but, [ka] is not a compound of embodiment 1, 2, or 3, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0173] Provided herein as embodiment 164 is a compound of Formula IVa [ka] During the ceremony, R 2is H or methyl, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is Me, Cl, or ethyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0174] Provided herein as embodiment 165 is a compound of Formula IVa [ka] During the ceremony, R 2 is H or methyl, R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 but, [ka] and R 6 is H or methyl, R 7 is Me, Cl, or ethyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0175] Provided herein as embodiment 166 is a compound of Formula IVa [ka] During the ceremony, R 2 is H or methyl, R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, R 7is Me, Cl, or ethyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0176] Provided herein as embodiment 167 is a compound of Formula Va: [ka] During the ceremony, R 2 is H, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, However, R 5 but, [ka] or a tautomer thereof, or the compound according to embodiment 1, 2, or 3, which is not or a pharmaceutically acceptable salt of said tautomer.

[0177] Provided herein as embodiment 168 is a compound of Formula Va: [ka] During the ceremony, R 2 is H, R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0178] Provided herein as embodiment 169 is a compound of Formula Va: [ka] During the ceremony, R 2 is H, R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0179] Provided herein as embodiment 170 is a compound of Formula Vb [ka] During the ceremony, R 2 is H, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, However, R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0180] Provided herein as embodiment 171 is a compound of Formula Vb [ka] During the ceremony, R 2 is H, R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, However, R 4 but [ka] If R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0181] Provided herein as embodiment 172 is a compound of Formula Vb [ka] During the ceremony, R 2 is H, R 4 but, [ka] and R 5 but, [ka] and R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, R 7is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0182] Provided herein as embodiment 173 is a compound of Formula VIIIa [ka] During the ceremony, R 2 is H, R 4 but, [ka] and R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3further substituted with 1 to 4 substituents selected from alkoxy; R 6 is H or methyl, R 7 is methyl, However, R 4 but [ka] If R 5 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0183] Provided herein as embodiment 174 is a compound of Formula VIIIa [ka] During the ceremony, R 2 is H, R 4 is a 5-membered heteroaryl or a 6-membered heteroaryl, and the 5-membered heteroaryl or 6-membered heteroaryl group is optionally independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0184] Provided herein as embodiment 175 is a compound of Formula VIIIa [ka] During the ceremony, R 2 is H, R 4 but, [ka] and R 5 but, [ka] and R 6 is H or methyl, R 7 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0185] Provided herein as embodiment 176 is a compound of Formula XII [ka] During the ceremony, R 2 is H, R 4 But C 1-6 alkyl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein the 5-membered heteroaryl or 6-membered heteroaryl groups are optionally independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 cycloalkyl; R 5 But C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, or -OCH2-(C 3-6 cycloalkyl), C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, and 6-membered heteroaryl are optionally, independently, selected from the group consisting of halogen, C 1-3 Alkyl, and C 1-3 further substituted with 1 to 4 substituents selected from haloalkyl; Aziridin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C 3-6 cycloalkyl) are independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 further substituted with 1 to 4 substituents selected from alkoxy; R 9 is methyl, ethyl, or isopropyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0186] Provided herein as embodiment 177 is a compound of Formula XII [ka] During the ceremony, R 2 is H, R 4 But methyl, [ka] and R 5 but, [ka] and R 9 is methyl, ethyl, or isopropyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0187] Exemplary compounds of the invention are set forth below in Table A. In some embodiments, the compound is a compound described in Table A. Provided herein as embodiment 178 is a compound described in Table A, or a pharmaceutically acceptable salt thereof. Table A. Exemplary Compounds [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 Table 1-71 Table 1-72 Table 1-73 Table 1-74 Table 1-75 Table 1-76 Table 1-77 Table 1-78 Table 1-79 Table 1-80 Table 1-81 Table 1-82 Table 1-83 Table 1-84 Table 1-85 Table 1-86 Table 1-87 Table 1-88 Table 1-89

Table 1-90

Table 1-97

Table 1-110

[0188] In some embodiments, the present invention provides a compound shown in Table A, or a pharmaceutically acceptable salt thereof.

[0189] 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.

[0190] Formulation and route of administration In the uses described herein, it may be possible to administer the compounds disclosed herein alone, but typically the administered compounds will be present as the active ingredient of a pharmaceutical composition. Thus, in one embodiment, provided herein are pharmaceutical compositions comprising the compounds disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants, etc., and optionally other active ingredients. For example, Remi ngton: 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.

[0191] The compound(s) disclosed herein can be administered by any suitable route in the form of a pharmaceutical composition adapted for such 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.

[0192] 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.

[0193] Provided herein as embodiment 179 is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 178, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, and a pharmaceutically acceptable excipient.

[0194] Provided herein as embodiment 180 is a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, for use as a medicament.

[0195] 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.

[0196] The compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, Administration may be buccal, vaginal, or via an implanted reservoir. The term "parenteral" as used herein 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 used as solvents or suspending media.

[0197] 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.

[0198] 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, the active ingredient is combined with emulsifying and suspending agents.If necessary, certain sweeteners, flavorings, or colorings can also be added.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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 mineral oil, sorbitan monostearate, poly These include, but are not limited to, sorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0203] For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated into an ointment such as petrolatum.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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 linked to Alzheimer's disease (AD) and frontotemporal glial amyloidosis (FTA). It is associated with an increased risk of other forms of dementia, including idiopathic dementia. 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 supported the loss of novel microbarrier function in mutation carriers, showing that microglia in R47H carriers exhibited 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 CNS 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).

[0211] 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.

[0212] Provided herein as embodiment 181 is a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, for use in treating or preventing a condition associated with loss of function of human TREM2.

[0213] Provided herein as embodiment 182 is a compound or tautomer thereof according to any one of embodiments 1 to 178, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, for use in treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0214] Provided herein as embodiment 183 is the use of a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, in the preparation of a medicament for treating or preventing a condition associated with loss of function of human TREM2.

[0215] Provided herein as embodiment 184 is any of embodiments 1 to 178 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. 179. The use of a compound according to any one of embodiments 178 to 179, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 180.

[0216] Provided herein as embodiment 185 is 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 described in any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 179.

[0217] Provided herein as embodiment 186 is 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 described in any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 179.

[0218] In some embodiments, the condition associated with loss of function of human TREM2 is Parkinson's disease. In some embodiments, the condition associated with loss of function of human TREM2 is rheumatoid arthritis. In some embodiments, the condition associated with loss of function of human TREM2 is Alzheimer's disease. In some embodiments, the condition associated with loss of function of human TREM2 is Nasu-Hakola disease. In some embodiments, the condition associated with loss of function of human TREM2 is frontotemporal dementia. In some embodiments, the condition associated with loss of function of human TREM2 is multiple sclerosis. In some embodiments, the condition associated with loss of function of human TREM2 is a prion disease. In some embodiments, the condition associated with loss of function of human TREM2 is stroke.

[0219] 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 from CSF1R-positive patients have been found to be depleted and exhibit increased apoptosis (Oosterhof et al., 2018).

[0220] The present invention relates to the unexpected discovery that administration of a TREM2 agonist can rescue microglia loss in cells harboring CSF1R mutations. It has previously been shown that the TREM2 agonist antibody 4D9 dose-dependently increases ATP luminescence (a measure of cell number and activity) 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 CSF1R signaling defect caused by reduced concentrations 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 show surviving microglia clustered around amyloid plaques (Spangenberg et al., Nature Communications 2019). Amyloid has previously been shown to be a ligand for TREM2, and microglial engagement with amyloid has been shown to be TREM2 dependent (Condello (Eds. et al., Nat Comm., 2015). The present invention relates to the unexpected discovery that it was activation of TREM2 that rescued microglia in the presence of a CSF1R inhibitor, an effect that is also observed in patients with microglial loss due to CSF1R mutations. This discovery has not been previously taught or suggested in the available art.

[0221] To date, no previous studies have demonstrated that TREM2 agonism can rescue microglial loss in cells where mutations in the CSF1R kinase domain reduce CSF1R activity, rather than the presence of a CSF1R inhibitor or lack of a CSF1R ligand. Furthermore, no previous studies have taught or suggested that reversing microglial loss due to CSF1R mutations via TREM2 agonism could be used to treat diseases or disorders caused by and / or associated with CSF1R mutations.

[0222] Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously recognized as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmented normochromatic leukodystrophy (POLD), is an autosomal dominant central nervous system disorder that manifests as variable behavioral, cognitive, and motor changes in affected individuals. ALSP is characterized by patchy cerebral white matter abnormalities visible by magnetic resonance imaging. However, the clinical symptoms and MRI changes are not unique to ALSP and are shared with other neurological disorders, including Nasu-Hakola disease (NHD) and Alzheimer's disease, making diagnosis and treatment of ALSP extremely challenging.

[0223] 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 signaling levels 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 can rescue microglial loss and prevent microglial apoptosis in CSF1R+ / - ALSP patients, thereby treating the ALSP condition.

[0224] Provided herein as embodiment 187 is a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, for use in treating or preventing 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).

[0225] Provided herein as embodiment 188 is a compound or tautomer thereof according to any one of embodiments 1 to 178, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, for use in 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).

[0226] Provided herein as embodiment 189 is a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutical composition of the compound or the tautomer, in the preparation of a medicament for treating or preventing a condition associated with dysfunction of CSF1R. or the use of a pharmaceutical composition according to embodiment 179.

[0227] Provided herein as embodiment 190 is the use of a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, 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).

[0228] Provided herein as embodiment 191 is a method of treating or preventing a disease or disorder associated with dysfunction of CSF1R in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 179. In some embodiments, the subject is selected for treatment based on a diagnosis including 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 CSF1R activity or abolishes 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 altered (e.g., increased, decreased, or abolished) activity of CSF1R. In some embodiments, the disease or disorder is a disease or disorder resulting from reduced or abolished activity of CSF1R. CSF1R-associated activity that is altered in a disease or disorder includes, but is not limited to, reduced or lost microglial function, increased microglial apoptosis, reduced Src signaling, reduced Syk signaling, reduced microglial proliferation, reduced microglial response to cellular debris, reduced phagocytosis, and reduced 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, hi some embodiments, the loss-of-function mutation results in a partial loss of CSF1R function or a decrease in CSF1R activity.

[0229] Provided herein as embodiment 192 is 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 described in any one of embodiments 1-178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 179. In some embodiments, the method treats or prevents ALSP, which encompasses and supersedes 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 a congenital absence of microglia. In some embodiments, the method treats or prevents brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS).

[0230] Provided herein as embodiment 193 is a method for treating a disease or disorder, wherein any of the diseases or disorders described is present in a patient who exhibits CSF1R dysfunction or has a mutation in a gene affecting the function of CSF1R, including 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, dysplastic syndromes, osteoporosis ... 179. A method of treating or preventing cerebral vasculopathy, Pile's disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, or metachromatic leukodystrophy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 179.

[0231] 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.

[0232] 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 dose-dependently increases ATP luminescence (a measure of cell number and activity) 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 activation of TREM2. This work relates to the unexpected discovery that ABCD1 can rescue microglia in the presence of ABCD1 mutations and increased VLCFA, 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.

[0233] To date, no previous studies have demonstrated that TREM2 agonism can rescue microglial loss in cells with ABCD1 mutations and increased VLCFAs. No previous studies have taught or suggested that reversing microglial loss due to ABCD1 mutations via TREM2 agonism could be used to treat diseases or disorders caused by and / or associated with ABCD1 mutations.

[0234] Provided herein as embodiment 194 is a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, for use in treating or preventing a condition associated with dysfunction of ATP-binding cassette transporter 1 (ABCD1).

[0235] Provided herein as embodiment 195 is a compound or a tautomer thereof according to any one of embodiments 1 to 178, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, for use in 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).

[0236] Provided herein as embodiment 196 is the use of a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, in the preparation of a medicament for treating or preventing a condition associated with dysfunction of ABCD1.

[0237] Provided herein as embodiment 197 is the use of a compound according to any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, 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).

[0238] Provided herein as embodiment 198 is 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 described in any one of embodiments 1-178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 179. 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 ABCD1 activity or abolishes 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 caused by an altered (e.g., increased, decreased, or abolished) activity of ABCD1. In some embodiments, the disease or disorder is caused by a decreased or abolished activity of ABCD1. ABCD1-related activities that are altered in a 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 a decrease in 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 immunological disorder caused by and / or associated with ABCD1 dysfunction.

[0239] Provided herein as embodiment 199 is 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 described in any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 179. In some embodiments, any of the described diseases is present in patients who exhibit ABCD1 dysfunction or who have 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.

[0240] Provided herein as embodiment 200 is 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 described diseases or disorders is present in patients who exhibit ABCD1 dysfunction or who have a mutation in a gene that affects ABCD1 function, the method comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 179.

[0241] Autism spectrum disorder TREM2-deficient mice exhibit symptoms reminiscent of autism spectrum disorder (ASD) It has been found that microglia depletion of the autophagy gene Aatg7 results in synaptic pruning defects, increased dendritic spine density, and abnormal social interactions and repetitive behaviors indicative of ASD (Filipello et al., Immunity, 2018, 48, 979-991). It has also been found that microglia depletion of the autophagy gene Aatg7 results 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 research has shown that 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.

[0242] Provided herein as embodiment 201 is a compound or tautomer thereof according to any one of embodiments 1 to 178, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, for use in treating autism or an autism spectrum disorder.

[0243] Provided herein as embodiment 202 is the use of a compound or tautomer thereof according to any one of embodiments 1 to 178, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 179, in the preparation of a medicament for treating autism or an autism spectrum disorder.

[0244] Provided herein as embodiment 203 is 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 described in any one of embodiments 1-178 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 179. In some embodiments, the method treats autism. In some embodiments, the method treats Asperger's syndrome.

[0245] 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.

[0246] 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."

[0247] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0248] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition, comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need 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 the disclosed compounds and the additional therapeutic agent or agents acts synergistically.

[0249] Examples of drug combinations of the present disclosure may include, but are not limited to, combinations for treating Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0250] As used herein, the terms "combination," "combining," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the 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.

[0251] 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.

[0252] The 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, the 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, the 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, the one or more other therapeutic agents and the compounds or compositions of the present disclosure are administered partially within a 24-hour period as a multiple dosing regimen.

[0253] 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 a provided compound or a pharmaceutically acceptable salt thereof, or may be administered before or after administration of a provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below. In certain embodiments, a 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.

[0254] definition The following definitions are provided to aid in understanding the scope of the present disclosure.

[0255] 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 appended claims are indicative of actual values ​​including the standard deviations found in their respective testing measurements. It is an approximation that may vary depending on the

[0256] 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.

[0257] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 101st Edition. Additionally, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University of California, Davis, CA. 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] The present disclosure provides pharmaceutical compositions, including stereomerically pure forms, and any of the compounds disclosed herein. The present disclosure also encompasses the use of stereomerically pure forms of any compound. 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, e.g., 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, p. 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0262] tautomers As those skilled in the art will readily appreciate, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may 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 that structural formula. For example, the following is an example of a tautomer of a compound of formula I, in which ring A, together with the six-membered ring system to which it is fused, has the formula: [ka] wherein R 9 is H. [ka]

[0263] Therefore, the scope of the present disclosure should be understood to encompass all tautomers of the compounds disclosed herein.

[0264] 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 that 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, e.g., Incorporated compounds are useful for 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 an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0265] 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.

[0266] 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."

[0267] 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.

[0268] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0269] 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 1-6Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0270] As used herein, "C 2-4 The 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.

[0271] 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.

[0272] As used herein, "di-C" 1-3 The term "alkylamino" refers to -NR*R**, where R* and R** are independently C alkylamino groups as defined herein. 1-3 Represents alkyl. C 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.

[0273] 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 1-6Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0274] As used herein, the term "halogen" refers to -F, -CI, -Br, or -I.

[0275] The term "halo," as used herein as a prefix of another term for a chemical group, refers to a modification of a chemical group in which one or more hydrogen atoms are replaced with a halogen, as defined herein. The halogens are independently selected at each occurrence. For example, "C 1-6 The term "haloalkyl" refers to a C 1-6 C refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen. 1-6 Representative examples of haloalkyl include, but are not limited to, -CHF, -CHF, -CF, -CHFCl, -CHCF, -CFHCF, -CFCF, -CH(CF), -CF(CHF), and -CH(CHF)(CF). 1-6 The term "haloalkoxy" refers to, for example, C as defined herein. 1-6 It refers to an alkoxy group in which one or more hydrogen atoms are replaced with halogen. 1-6 Representative examples of haloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCHFCl, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, -OCF(CHF2)2, and -OCH(CH2F)(CF3).

[0276] 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 two 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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 pi 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, including 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, with the radical or point of attachment being 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 may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted.The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently can be optionally substituted.

[0282] As described herein, compounds of the present disclosure may include "substituted" moieties. The term "substituted" means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise specified, 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 compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more purposes disclosed herein.

[0283] As used herein, the term "pharmaceutically acceptable" means generally recognized for use in subjects, particularly humans.

[0284] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like, or (2) salts formed when an acidic proton present in either parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Also, Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also Revised Edition (2011).

[0285] As used herein, the term "pharmaceutically acceptable excipient" 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.

[0286] As used herein, the term "subject" refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0287] As used herein, the term "therapeutically effective amount" 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.

[0288] The present disclosure includes Examples A3 and A4, in which compounds of the invention are tested for TREM2 target binding compared to anti-TREM2 antibodies. Exemplary anti-TREM2 antibodies include those disclosed in PCT Application Publication No. WO2018 / 195506A1, which is incorporated herein by reference in its entirety. In some embodiments, the anti-TREM2 antibody comprises a heavy chain (HC) comprising a variable region (VH) having three complementarity-determining regions (CDRs), referred to herein as VH-CDR1, VH-CDR2, and VH-CDR3, and a variable region (VL) having three complementarity-determining regions (CDRs), referred to herein as VL-CDR1, VL-CDR2, and VL-CDR3. and a light chain (LC) comprising a variable region (VL) having a constant region. In some embodiments, the amino acid sequences of the CDRs of the anti-TREM2 antibody include a VH-CDR1 having the amino acid sequence SYWIG (SEQ ID NO: 1), a VH-CDR2 having the amino acid sequence IIYPGDADARYSPSFQG (SEQ ID NO: 2), a VH-CDR3 having the amino acid sequence RRQGIFGDALDF (SEQ ID NO: 3), a VL-CDR1 having the amino acid sequence RASQSVSSNLA (SEQ ID NO: 4), a VL-CDR2 having the amino acid sequence GASTRAT (SEQ ID NO: 5), and a VL-CDR3 having the amino acid sequence LQDNNFPPT (SEQ ID NO: 6). In some embodiments, the anti-TREM2 antibody comprises a VH chain whose sequence corresponds to SEQ ID NO: 7 and a VL chain whose sequence corresponds to SEQ ID NO: 8. In some embodiments, the anti-TREM2 antibody is antibody Ab-1, comprising a heavy chain amino acid sequence according to SEQ ID NO: 9 and a light chain amino acid sequence according to SEQ ID NO: 10. [Table 2]

[0289] 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 other routes utilizing alternative 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 present disclosure in any way.

[0290] 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 hereinafter, Z is a leaving group, including halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like. As used hereinafter, in certain embodiments, Y is an organometallic coupling reagent group, including, but not limited to, boronic acids and esters, organotin and organozinc reagents. [ka]

[0291] 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. Furthermore, the various synthetic steps described above can be performed in an alternate route or order to give the desired compounds.

[0292] 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.

[0293] 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]

[0294] This section provides specific examples of compounds of Formula I and methods for making them. [Table 3-1] [Table 3-2]

[0295] General analytical and purification methods This section provides a description of the general analytical and purification methods used to prepare certain compounds provided herein.

[0296] Chromatography: Unless otherwise stated, the crude product-containing residue was purified by passing the crude material or concentrate through either flash silica (SiO2) or reverse-phase flash silica (C18) prepacked 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 / hexane) means that the product was obtained by eluting the silica-packed column with a solvent gradient of 0% to 40% EtOAc in hexane. In some experiments, flash chromatography was performed on a Teledyne Isco instrument using a prepacked disposable SiO2 stationary phase column with an eluent flow rate range of 15-200 mL / min and UV detection (254 and 220 nm).

[0297] 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, 150x30mm), or (b) a Waters X-select CSH column (5 micron, C18, 100x30mm).

[0298] A typical flow through the instrument involves eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% MeCN (with 0.1% v / v formic acid) in water over 10 min; conditions can be varied to achieve optimal separation.

[0299] 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.

[0300] A typical flow through the instrument involves a solvent mixture of 30–80% EtOH in supercritical CO2. These include eluting at a flow rate (F) of 30-120 mL / min using a cyclohexane distillation column; conditions can be varied to achieve optimal separation.

[0301] Alternatively, some 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.

[0302] In other runs, several CP prep-SFC experiments were performed 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. Preparative CP method: acidic reversed-phase MPLC: instrument type: Revelis™ preparative MPLC; column: Phenomenex LUNA C18(3) (150x25 mm, 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; gradient and wavelengths as indicated were used.

[0303] 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.

[0304] 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) with the molecular ions being 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.

[0305] Compound name The compounds disclosed and described herein are named using the IUPAC naming functionality provided in Biovia Pipeline Pilot or ChemDraw Professional 17.0.

[0306] 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 using known procedures using ordinary skill.

[0307] Synthesis of Examples Method 1 Example 1: 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine [ka] To a solution of 2-chloro-4-(4-chloro-2-fluorophenyl)-7-methylpteridine (Intermediate 13) (0.0754 g, 0.244 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.063 g, 0.085 mL, 0.488 mmol) in DMSO (0.813 mL) was added (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Enamine, Monmouth Jct., NJ, USA) (0.049 g, 0.293 mmol). The reaction mixture was stirred at 100° C. for 2 hours. After cooling, the mixture was partitioned between DCM and HO. The organic phase was separated and concentrated in vacuo, and the crude material was purified by silica gel chromatography eluting with a gradient of 0–10% MeOH (+1% NH) in DCM to give 4-(4-chloro-2-fluorophenyl)-7-methyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine (0.0694 g, 0.158 mmol, 64.7% yield). 1 H NMR(500MHz,DMSO-d6)δ ppm 8.53(s,1H), 7.74(br d,J=8.2Hz,2H), 7.64(dd,J=9.8,1.8Hz,1H), 7.41-7.54(m,2H), 4.77(br d,J=12.6Hz,1H), 4.64(br d,J=13.6Hz,1H), 4.54(br d,J=8.3Hz,1H), 3.95-4.11(m,1H), 3.82(s,3H), 3.62-3.73(m,1H), 3.20-3.29(m,2H), 2.66(s,3H). m / z(ESI,+ive ion):440.0(M+H) + . [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 [Table 4-23] [Table 4-24]

[0308] Method 2 Example 129: 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-(3-oxetanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[3,4-b]pyrazine [ka] To a 10 mL vial was added 7-chloro-5-(4-chloro-2-fluorophenyl)-2-methylpyrido[3,4-b]pyrazine (Intermediate 32) (0.154 g, 0.5 mmol), (S)-2-(1H-pyrazol-4-yl)morpholine (Enamine, Inc.) (0.128 g, 0.600 mmol), and diisopropylethylamine (0.323 g, 0.437 mL, 2.500 mmol), and DMSO (1.5 mL). The reaction mixture was stirred at 100 °C for 5 h, cooled to room temperature, and then partitioned between EtOAc and HO. The organic phase was dried over NaSO and concentrated in vacuo. The crude intermediate (0.106 g, 0.25 mmol) was dissolved in N,N-dimethylformamide (1 mL), 3-iodooxetane (92 mg, 0.5 mmol) and CsCO (163 mg, 0.50 mmol) were added, and the reaction was stirred at 60 °C for 12 h. The mixture was cooled to room temperature and then partitioned between EtOAc and HO. The organic phase was dried over NaSO and concentrated in vacuo, and the crude product was purified by reverse-phase HPLC to give 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-(3-oxetanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[3,4-b]pyrazine. 1H NMR(600MHz,DMSO-d6)δ ppm 8.49-8.55(m,1H), 7.98(s,1H), 7.62-7.68(m,2H), 7.53-7.58(m,1H), 7.4 2-7.47(m,1H), 7.19-7.24(m,1H), 5.51-5.61(m,1H), 4.87-4.94(m,4H), 4. 58-4.65 (m, 1H), 4.42-4.48 (m, 1H), 4.24-4.29 (m, 1H), 4.01-4.09 (m, 1H), 3.73-3.80 (m, 1H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H), 2.63-2.68 (m, 3H). m / z (ESI, positive ion): 481.0 (M+H) + .

[0309] Method 3 Example 130: 4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine [ka]

[0310] Step 1: (S)-4-(4-(4,4-dimethylcyclohex-1-en-1-yl)-6,7-dimethylpteridine-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine. To a 50 mL round-bottom flask were added 2-chloro-4-(4,4-dimethylcyclohex-1-en-1-yl)-6,7-dimethylpteridine (Intermediate 54, 270 mg, 0.892 mmol) and DIEA (0.3 mL, 1.76 mmol) in DMSO (8 mL). Then, (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (164 mg, 0.98 mmol) was added, and the reaction mass was kept stirring at 100° C. for 2 hours. The reaction mixture was quenched with HO (15 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure. The crude material was purified by reverse-phase preparative HPLC using a Revelis C column, CHCN / HO, gradient 0% to 55% over 30 min, to afford (S)-4-(4-(4,4-dimethylcyclohex-1-en-1-yl)-6,7-dimethylpteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl))morpholine (300 mg, 0.692 mmol, 65.5% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d): δ ppm 7.77(s,1H), 7.47(d,J=0.8Hz,1H), 7.40(s,1H), 4.72(d,J=12.9Hz,1H), 4 .61(d,J=13.3Hz,1H), 4.51(dd,J=10.4,2.7Hz,1H), 4.01(d,J=10.5Hz,1H ), 3.84(s,3H), 3.66(td,J=11.5,2.7Hz,1H), 3.19(q,J=14.7,13.6Hz,2H) , 2.59(d,J=11.4Hz,8H), 2.14(dt,J=4.7,2.4Hz,2H), 1.51(t,J=6.5Hz,2H ), 0.98(s,6H).

[0311] Step 2: 4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine and (2S)-4-(4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-7,8-dihydropteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine. To a 100 mL round-bottom flask was added (S)-4-(4-(4,4-dimethylcyclohex-1-en-1-yl)-6,7-dimethylpteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.27 g, 0.623 mmol) in EtOH (20 mL), followed by 10% Pd / C (0.265 g, 2.491 mmol), and the reaction mixture was stirred under a hydrogen gas atmosphere (balloon pressure) at room temperature for 5 h. The mixture was filtered through a Celite bed and concentrated under reduced pressure to give a 1:1 mixture of the desired product and the reduced by-product ((2S)-4-(4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-7,8-dihydropteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine), which was used in the next step without purification.

[0312] Step 3: 4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine. To a 50 mL round-bottom flask was added an approximately 1:1 mixture of 4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine and (2S)-4-(4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-7,8-dihydropteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.23 g, 0.526 mmol) in CHCN (20 mL). Sodium hypochlorite (2.19 mL, 26.3 mmol) was added, and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with HO (30 mL), extracted with EtOAc (2 × 30 mL), and the organic extracts were dried over NaSO. The combined organics were concentrated, and the crude material was purified by reverse-phase preparative HPLC to afford 4-(4,4-dimethylcyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine (0.103 g, 0.236 mmol, 45.0% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.57 (s, 1H), 7.46 (s, 1H), 5.02 (d, J = 13.5 Hz, 1H), 4.85 (d, J = 13.6 Hz, 1H), 4.62 (dd, J = 10.1, 2.8 Hz, 1H), 4.11 (d, J = 11.4 Hz, 1H), 3.93 (s, 3H), 3.76-3.89 (m, 2H), 3.3 5(dd,J=28.4,16.1Hz,2H), 2.68(d,J=15.3Hz,6H), 1.91(q,J=12.8,11.3Hz,2H), 1.76(dd,J=13.8,3.6Hz,2H), 1.48(td,J=13.2,3.9Hz,4H), 1.03(d,J=6.2Hz,6H). m / z(ESI,+ive ion):436.3(M+H) + . [Table 5-1] [Table 5-2] [Table 5-3]

[0313] Method 4 Example 146: 4-(3,3-Difluorocyclobutyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine. [ka]

[0314] Step 1: S)-4-(6,7-dimethyl-4-(5,8-dioxaspiro[3.4]octan-2-yl)pteridine-2-yl)-2-(1-methyl-1H-pyrazol-4-yl))morpholine. To a 20 mL vial was added crude 2-chloro-6,7-dimethyl-4-(5,8-dioxaspiro[3.4]octan-2-yl)pteridine (Intermediate 68, 1.07 g, 3.5 mmol), (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Enamine, Monmouth Jct., NJ, USA) (0.736 g, 4.40 mmol), and DIPEA (1.706 g, 2.306 mL, 13.20 mmol, Sigma) in 5 mL of DMF. The mixture was heated at 90 °C for 12 h. The mixture was diluted with EtOAc (200 mL) and washed twice with brine. The organic layer was dried over MgSO and concentrated. The residue was purified by silica gel chromatography (0% to 100% EtOAc / EtOH = 3 / 1 blend in 10% DCM in heptane) to afford (S)-4-(6,7-dimethyl-4-(5,8-dioxaspiro[3.4]octan-2-yl)pteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (298 mg, 0.681 mmol, 15.48% yield) as a red solid. 1H NMR (chloroform-d, 500MHz) δ 7.58 (s, 1H), 7.47 (s, 1H), 5.0-5.1 (m, 1H), 4.8-4.9 (m, 1H), 4.62 (dd, 1H, J = 2.8, 10.2Hz), 4.4-4.5 (m, 1H), 4.1-4.1 (m, 1H), 4.0-4.1 (m, 2H), 3.9-4.0 (m, 2H). H), 3.9-3.9(m,3H), 3.9-3.9(m,3H), 3.8-3.8(m,1H), 3.3-3.4(m,1H), 3.2-3 .3(m,1H), 2.8-2.9(m,2H), 2.7-2.8(m,3H), 2.7-2.7(m,3H), 2.6-2.7(m,3H)

[0315] Step 2: (S)-3-(6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pteridin-4-yl)cyclobutan-1-one. To a 40 mL vial was added (S)-4-(6,7-dimethyl-4-(5,8-dioxaspiro[3.4]octan-2-yl)pteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (285 mg, 0.651 mmol, 126290-50) and THF (3257 μL). Then, 1.5 mL of 2 N HCl was added. The red suspension was stirred at 65 °C for 5 h. The reaction was quenched with NaHCO (saturated, 4 mL) and concentrated in vacuo. The aqueous layer was extracted with DCM (20 mL × 3) and separated using a phase separator. The solvent was concentrated under vacuum to give a black residue (S)-3-(6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pteridin-4-yl) Cyclobutan-1-one (251 mg, 0.638 mmol, 98% yield) was used directly in the next step without further purification.

[0316] Step 3: 4-(3,3-Difluorocyclobutyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine. To a 40 mL vial containing (S)-3-(6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pteridin-4-yl)cyclobutan-1-one (135 mg, 0.343 mmol), diethylaminosulfur trifluoride, a 1.0 M solution in DCM (7205 μL, 7.21 mmol) was added under N2. The mixture was stirred at room temperature overnight. The reaction was cooled to 0 °C, quenched with NaHCO3, and the aqueous phase was extracted with DCM (20 mL × 3). The DCM extracts were combined, concentrated, and purified by silica gel column (RediSep 4 g, 2% to 100% EA / EtOH in 10% DCM in heptane = 3 / 1) to give 4-(3,3-difluorocyclobutyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine (22.3 mg, 0.054 mmol, 15.6% yield) as a pale red solid. 1 H NMR (chloroform-d, 500 MHz) δ 7.5-7.6 (m, 1H), 7.45 (s, 1H), 5.03 (br d, 1H, J = 12.8 Hz), 4.8-4.9 (m, 1H), 4.61 (dd, 1H, J = 2.8, 10.2 Hz), 4.4-4.6 (m, 1H), 4.13 (br d,1H,J=10.4Hz), 3.93(s,3H), 3.81(dt,1H,J=2.9,11.5Hz), 3.38(ddd,1H,J=3 .5,11.3,13.5Hz), 3.2-3.3(m,1H), 3.0-3.1(m,4H), 2.71(s,3H), 2.65(s,3H). m / z(ESI,+ive ion):416.0(M+H) + .

[0317] Method 5 Example 147: 1-(4-chloro-2-fluorophenyl)-6-methyl-3-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)isoquinoline. [ka] In a 10 mL vial, 3-chloro-1-(4-chloro-2-fluorophenyl)-6-methylisoquinoline (Intermediate 11) (77 mg, 0.250 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii) methanesulfonate (20.91 mg, 0.025 mmol, Combi-Blocks Inc.), 2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl (11.67 mg, 0.025 mmol), 2-(1-methyl-1h-pyrazol-4-yl)morpholine (41.8 mg, 0.042 mL, 0.250 mmol, Enamine), and sodium tert-butoxide (72.1 mg, 0.750 mmol) were added. Toluene (2 mL) was added and the reaction was stirred at 100 °C for 1 h. The reaction mixture was quenched with HO and extracted with EtOAc. The combined organics were dried, concentrated, and purified by reverse phase chromatography to give 1-(4-chloro-2-fluorophenyl)-6-methyl-3- ((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)isoquinoline was obtained. 1 H NMR (500 MHz, chloroform-d) δ ppm 7.55-7.58 (m, 1H), 7.48-7.53 (m, 2H), 7.44-7.48 (m, 2H), 7.29-7.33 (m, 1H), 7.28-7.29 (m, 1H), 7.25-7.28 (m, 1H), 7.07-7.11 (m, 1H), 6.78-6.83 (m, 1H), 4.70-4.7 5(m,1H), 4.30-4.35(m,1H), 4.12-4.17(m,1H), 4.05-4.12(m,1H), 3.93-3.98(m, 1H), 3.90-3.93(m,3H), 3.09-3.17(m,1H), 3.00-3.07(m,1H), 2.47-2.51(m,3H). m / z(ESI,+ive ion):437.0(M+H) + . [Table 6-1] [Table 6-2]

[0318] Method 6 Example 155: 4-(4-chloro-2-fluorophenyl)-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-1,8-naphthyridine. [ka] To a vial containing (S)-4-(4-chloro-1,8-naphthyridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Intermediate 99) (0.1 g, 0.303 mmol), sodium carbonate (0.096 g, 0.910 mmol, JT Baker), (4-chloro-2-fluorophenyl)boronic acid (0.058 g, 0.334 mmol, combi-blocks), and tetrakispalladium triphenylphosphine (0.018 g, 0.015 mmol), 1,4-dioxane (0.809 mL), and HO (0.202 mL) were added. The vial was flushed with N, and the reaction mixture was stirred at 75 °C for 6 h. After cooling, the reaction mixture was reconstituted in DCM / HO, and the organic phase was separated (phase separator) and concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0–10% MeOH (+1% NH) in DCM to give 4-(4-chloro-2-fluorophenyl)-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-1,8-naphthyridine (0.0134 g, 0.032 mmol, 10.43% yield). 1H NMR(500MHz,DMSO-d6)δ ppm 8.76-8.80(m,1H), 7.74-7.77(m,1H), 7.67-7.73(m,2H), 7.55-7.59(m,1H), 7.47-7.53(m,2H), 7.41-7.44(m,1H), 7.21-7.24(m,1H), 4.60-4.67(m,1H), 4.47-4.56(m,2H), 4.01-4.07(m,1H), 3.81-3.83(m,3H), 3.68-3.75(m,1H), 3.14-3.20(m,1H), 3.06-3.12(m,1H). m / z(ESI,+ive ion):424.0(M+H) + . [Table 7-1] [Table 7-2]

[0319] Method 7 Example 165: 4-(trans-4-chlorocyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine [ka] Step 1: (2S)-4-(4-(4-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)-6,7-dimethylpteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine. To a 50 mL round-bottom flask was added 4-(4-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)-2-chloro-6,7-dimethylpteridine (Intermediate 50) (0.35 g, 0.864 mmol), (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Enamine, Monmouth Jct., NJ, USA) (0.159 g, 0.951 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.223 g, 1.728 mmol) in DMSO (20 mL). The reaction was stirred at 100 °C for 2 h (monitored by TLC), then diluted with HO (30 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated to give a yellow oil. The crude material was purified by silica gel chromatography (1% to 3% MeOH in DCM) to afford (2S)-4-(4-(4-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)-6,7-dimethylpteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.3 g, 0.560 mmol, 64.8% yield) as a yellow oil.

[0320] Step 2: (S)-4-(4-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-6,7-dimethylpteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine. To a 10 mL round-bottom flask was added (2S)-4-(4-(4-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)-6,7-dimethylpteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.05 g, 0.093 mmol) in 1-butanol (1.5 mL). The reaction mass was flushed under N for 15 minutes. To this was then added palladium(II) hydroxide (0.013 g, 0.093 mmol), and the reaction was heated to 80° C. The mixture was stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was diluted with HO (3 mL) and extracted with DCM (2 × 5 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give (S)-4-(4-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-6,7-dimethylpteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.030 g, 0.056 mmol, 59.8% yield) as a pale yellow material, which was used in the next step without further purification.

[0321] Step 3: (S)-4-(6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pteridin-4-yl)cyclohexan-1-ol. To a 50 mL round-bottom flask was added (S)-4-(4-(4-((tert-butyldimethylsilyl)-oxy)cyclohexyl)-6,7-dimethylpteridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.28 g, 0.521 mmol) in THF (5 mL). The reaction mixture was cooled to 0 °C, and a solution of HCl in dioxane (1.302 mL, 5.21 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1.5 h (monitored by LCMS). After completion of the reaction, HO (10 mL) was added and extracted with DCM (15 mL × 2). The combined organic layers were dried over copious amounts of NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (4 g) eluting with 100% EtOAc to give (S)-4-(6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pteridin-4-yl)cyclohexan-1-ol (0.15 g, 0.354 mmol, 68.0% yield) as a yellow oil, which was used in the next step without further purification.

[0322] Step 4: 4-(trans-4-chlorocyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine. To a 100 mL round-bottom flask was added (S)-4-(6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pteridin-4-yl)cyclohexan-1-ol (0.150 g, 0.354 mmol) and perchloroethane (1.677 g, 7.08 mmol), followed by tetrabutylammonium iodide (0.654 g, 1.771 mmol) and triphenylphosphine (0.464 g, 1.771 mmol) in 1,2-dichloroethane (20 mL). The reaction was stirred at 60 °C for 5 h (monitored by LCMS). Upon completion, the reaction mixture was cooled to room temperature, poured into H2O, and extracted with DCM (2 x 30 mL). The organic extract was washed with saturated NaCl (50 x mL) and dried over Na2SO4. The solution was concentrated to give the crude material as a yellow oil. The crude material was purified by silica gel chromatography (40% EtOAc in petroleum ether) to give the crude product, which was further purified by preparative HPLC to give 4-(trans-4-chlorocyclohexyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pteridine (0.017 g, 0.038 mmol, 10.86% yield) (7:2 mixture of isomers) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.76(s,1H), 7.47(d,J=3.3Hz,1H), 5.79(s,2H), 4.59-4.80(m,2H), 4.51(dt,J=10.2,2.4Hz,2H), 3.19-3.24(s, 3H), 3.91-4.10(m,2H), 3.78(s,2H), 2.54-2.73(m,6H), 2.15-2.7(m,1H), 2.17-2.38(m,3H), 1.71-1.98(m,3H). m / z(ESI,+ive ion):442.3(M+H) + .

[0323] Method 8 Example 166: 4-(2,4-difluorophenyl)-6,7-dimethyl-2-((2S )-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine, and Example 167: 4-(2,4-difluorophenyl)-7-ethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine [ka] To a 5 mL vial was added (S)-4-amino-6-(2,4-difluorophenyl)-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimidine-5-carbaldehyde (Intermediate 105) (2, 0.164 g, 0.410 mmol, 125891-11-1), methyl ethyl ketone (0.410 mL), and ground KOH (0.023 g, 0.410 mmol). The reaction mixture was stirred overnight at room temperature. HO was added, and the aqueous phase was neutralized with HCl (1N) and extracted with DCM (phase separator). The solvent was concentrated under vacuum, and the crude product was purified by silica gel chromatography (0-10% MeOH (+1% NH) in DCM). 4-(2,4-Difluorophenyl)-6,7-dimethyl-2-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[2,3-d]pyrimidine (0.0502 g, 0.115 mmol, 28.0% yield) was obtained. 1H NMR(500MHz,DMSO-d6)δ ppm 7.75(s,1H), 7.71(dt,J=6.62,8.37Hz,1H), 7.59(br dd,J=0.78,3.11Hz,1H), 7.50(ddd,J=2.59,9.47,10.25Hz,1H), 7.46(s,1H), 7.32(dt,J=2.08,8.43Hz,1H), 4.67-4.83(m,1H), 4.60(br d,J=13.49Hz,1H), 4.52(br dd,J=2.47,10.51Hz,1H), 3.93-4.08(m,1H), 3.82(s,3H), 3.59-3.73(m,1H), 3.11-3.25(m,2H), 2.57(s,3H), 2.30(s,3H). m / z(ESI,+iveイオン):437.0(M+H) + .

[0324] 4-(2,4-ジフルオロフェニル)-7-エチル-2-((2S)-2-(1-メチル-1H-ピラゾール-4-イル)-4-モルホリニル)ピリド[2,3-d]ピリミジン (0.0447g, 0.102mmol, 24.9% yield). 1 H NMR(500MHz,DMSO-d6)δ ppm 7.81(dd,J=8.3,3.2Hz,1H), 7.69-7.78(m,2H), 7.48-7.54(m,1H), 7.46(s,1H) , 7.32(td,J=8.4,2.5Hz,1H), 7.19(d,J=8.4Hz,1H), 4.70-4.84(m,1H), 4.64(br d,J=13.9Hz,1H), 4.52(dd,J=10.3,2.3Hz,1H), 4.01(br d,J=13.0Hz,1H), 3.82(s,3H), 3.60-3.72(m,1H), 3.13-3.27(m,2H), 2.88(q,J=7.6Hz,2H), 1.29(t,J=7.5Hz,3H). m / z(ESI,+iveイオン):437.2(M+H) + . Table 8

[0325] Method 9 Example 170: 4-(4-chloro-2-fluorophenyl)-2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-7-methylpteridine [ka] Step 1: 4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-7-methylpteridine. In a 50 mL round-bottom flask, add 2-chloro-4-(4-chloro-2-fluorophenyl)-7-methyl pteridine in dioxane:HO (9 mL, 5:1 v / v). Pteridine (Intermediate 13) (600 mg, 1.857 mmol) and 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (Intermediate 80) (881 mg, 2.79 mmol) were added, followed by potassium carbonate (513 mg, 3.71 mmol). The reaction was flushed under N for 10 minutes. PdCl(dppf)-DCM adduct (227 mg, 0.279 mmol) was added and the reaction was stirred at 70 °C for 3 hours. The reaction was filtered through Celite, the pad was washed with ethyl acetate (40 mL), and the filtrate was concentrated under reduced pressure to give the crude product. Silica gel chromatography (70% EtOAc in hexanes) followed by trituration with 2 mL of DCM in 50 mL of hexanes afforded 4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-7-methylpteridine (350 mg, 0.734 mmol, 39.5% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.81(s,2H), 7.79(s,1H), 7.42(s,3H), 3.99(s,1H), 2.81(d,J=4.6Hz,3H), 2.69(d,J=4.6Hz,3H)1.01(s,3H), 0.92(t,J=1.0Hz,6H). m / z(ESI,+ive ion):477.1(M+H)+ .

[0326] Step 2: 4-(4-chloro-2-fluorophenyl)-2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-7-methylpteridine. To a round-bottom flask (25 mL) was added 4-(4-chloro-2-fluorophenyl)-2-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-7-methylpteridine (20 mg, 0.043 mmol) and 1,1′-bis(di-i-propylphosphino)ferrocene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (20 mg, 0.043 mmol) in THF (10 mL). The reaction mixture was stirred at 14 psi and monitored by TLC (EtOAc / petroleum ether mixtures). Upon completion of the reaction, the mixture was filtered through Celite and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with 80% EtOAc in hexane to give a mixture of cis and trans isomers of 4-(4-chloro-2-fluorophenyl)-2-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-7-methylpteridine (10 mg, 0.022 mmol, 49.8% yield) as a brown gum. The racemic mixture was purified by chiral SFC (Chiralpak AD-H 2x15 cm, 5 um column, 30% EtOH, F = 120 mL / min) to give the title compound (first eluting peak) 4-(4-chloro-2-fluorophenyl)-2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-7-methylpteridine (6 mg, 0.013 mmol, 14% yield), the absolute stereochemistry arbitrarily assigned and the relative stereochemistry (cis / trans) determined by NMR, as well as the other (impure) isomer. 1H NMR (400MHz, DMSO-d6)δ 9.00(s,1H), 7.78-7.84(m,1H), 7.74(s,1H), 7.70(d,J=9.9Hz,1H), 7.55(d ,J=8.3Hz,1H), 7.40(s,1H), 4.53(d,J=9.9Hz,1H), 4.16-4.08(m,1H), 3.74 -3.62(m,2H), 3.56-3.45(m,1H), 2.82(s,3H), 2.31(d,J=13.2Hz,1H), 2.08 (d,J=13.1Hz,1H), 1.87-1.99(m,2H), 1.06-0.96(m,2H), 0.94-0.83(m,2H). m / z(ESI,+iveイオン):465.2(M+H) + . Table 9-1 Table 9-2 Table 9-3 Table 9-4 Table 9-5 Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10

[0327] Method 10 Example 204: 6,7-dimethyl-2-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine, and Example 205: 6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine [ka] In a 10 mL vial, Xantphos Pd G3 (1.46 mg, 0.023 mmol) and 2-chloro-6,7-dimethyl-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine (Intermediate 59) (89.6 mg, 0.283 mmol) were added. The vial was evacuated and filled with N2 three times. 0.2 mL of THF was added, followed by (2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II) bromide (Intermediate 74, 1476 μL, 0.339 mmol). The mixture was stirred at 50 °C for 5 h, and the suspension became a brown solution. The mixture was concentrated, DCM was added, and the mixture was quenched with HO and 2 N HCl. The aqueous layer was extracted with DCM, and the combined organics were concentrated. Silica gel chromatography (2% to 60% EtOAc / EtOH 3 / 1 blend in 10% DCM in heptane) afforded 6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine (28 mg, 0.063 mmol, 22.17% yield) as a mixture of diastereomers. The mixture was purified by SFC (Chiralpak IG 2x25 cm, 5 μm column, 30% EtOH, F = 80 mL / min) to afford two of the four possible diastereomers: Peak 1: 6,7-dimethyl-2-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl)cyclobutyl)pteridine (3.45 mg, ee>99%). 1 H NMR (chloroform-d, 400 MHz) δ 7.5-7.6 (m, 1H), 7.42 (s, 1H), 4.9-5.0 (m, 2H), 3.9-4.0 (m, 5H), 3.69 (quin, 1H, J = 5.5 Hz), 3.1-3.3 (m, 1H), 2.6-2.8 (m, 1H), 2.4-2.6 (m, 1H), 2.3-2.4 (m, 1H), 2.1-2.3 (m, 1H). m / z (ESI, positive ion): 447.0 (M+H). + Absolute stereochemistry is arbitrarily assigned; relative stereochemistry is determined by NMR.

[0328] Peak 2: 6,7-dimethyl-2-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-(trans-3-(trifluoromethyl))cyclobutyl)pteridine (9.83 mg, ee >99%) 1 H NMR (chloroform-d, 400 MHz) δ 7.54 (s, 1H), 7.44 (s, 1H), 4.91 (quin, 1H, J = 8.1 Hz), 4.60 (dd, 1H, J = 1.8, 11.4 Hz), 4.3-4.3 (m, 1H), 3.8-3.9 (m, 4H), 3.4-3.6 (m, 1H), 3.1-3.3 (m, 1H), 2.82 (s, 3H), 2.6-2.8 (m, 7H), 2.45 (br d, 1H, J = 13.4 Hz), 2.1-2.3 (m, 3H). m / z (ESI, positive ion): 447.0 (M+H). + Absolute stereochemistry is arbitrarily assigned; relative stereochemistry is determined by NMR. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6]

[0329] Example 231: (S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridin-2-yl)morpholine [ka] Into a 1-dram vial was weighed 2-chloro-7-methyl-4-(3-trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine (43.4 mg, 0.138 mmol, Intermediate 108) and (S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine (32.0 mg, 0.165 mmol, Intermediate 109). The vial was equipped with a stir bar, and acetonitrile (690 μL) was added, followed by N,N-diisopropylethylamine (53.5 mg, 72.3 μL, 0.414 mmol, Sigma-Aldrich). The mixture was continued to stir at 24 °C and monitored over time by LCMS. After sufficient conversion was observed, the reaction was terminated and the crude product was isolated and purified as described in Method 1 to give (S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridin-2-yl)morpholine (22.5 mg, 0.0478 mmol, 35% yield). 1 H NMR (600 MHz, DMSO-d6) δ ppm 8.53-8.56(m,1H), 7.84(s,1H), 7.47(s,1H), 4.76(br d,J=12.53Hz,1H), 4.62(br s,1H), 4.49(dd,J=10.35,2.72Hz,1H), 3.98-4.05(m,1H), 3.68-3.73(m,1H), 3.60-3.68( m,1H), 3.14-3.25(m,1H), 2.63(s,3H), 2.57(s,6H), 1.19-1.32(m,1H), 0.93-1.05(m,5H). m / z(ESI,+ive ion):472.0(M+H) + .

[0330] Example 232: (S)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridin-2-yl)-2-(2-methylpyridin-4-yl)morpholine [ka]

[0331] In one dram vial, add 2-chloro-7-methyl-4-(3-trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine (43.4 mg, 0.138 mmol). (I, Intermediate 108) and (S)-2-(2-methylpyridin-4-yl)morpholine (29.5 mg, 0.165 mmol, Syngene) were weighed. A stir bar was attached to the vial, and acetonitrile (690 μL) was added, followed by N,N-diisopropylethylamine (53.5 mg, 72.3 μL, 0.414 mmol, Sigma-Aldrich). The mixture was left stirring at 24 °C and monitored over time by LCMS. After sufficient conversion was observed, the reaction was terminated and the crude product was isolated and purified as described in Method 1 to give (S)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridin-2-yl)-2-(2-methylpyridin-4-yl)morpholine (11.7 mg, 0.0256 mmol, 18.5% yield). 1H NMR(600MHz,DMSO-d6)δ ppm 8.56(s,1H), 8.43-8.51(m,1H), 7.35(s,1H), 7.25-7.32(m,1H), 4.87(br d,J=11.63Hz,1H), 4.61(br dd,=10.44,2.45Hz,1H),4.15(br dd,J=11.90,2.27Hz,1H), 3.68-3.77(m,1H), 2.98-3.10(m,1H), 2.64(s,3 H), 2.58(s,5H), 2.52-2.53(m,1H), 2.43-2.49(m,1H), 0.97-1.07(m,1H). m / z(ESI,+ive ion):457.0(M+H) + .

[0332] Method 37 Example 309: 6,7-dimethyl-2-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pteridine [ka]

[0333] A flame-dried microwave vial under argon was charged with 2-chloro-6,7-dimethyl-4-(6-(trifluoromethyl)pyridin-3-yl)pteridine (105 mg, 308 μmol), CPhos (25.8 mg, 59.0 μmol), and THF (2.70 mL). The reaction mixture was degassed with argon for 5 minutes, then ((2S,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II) bromide (1.54 mL, 384 μmol) was added dropwise. The reaction vial was sealed and immersed in an oil bath preheated to 60° C. The reaction was stirred at 60° C. overnight. When the conversion was complete as judged by LCMS, the reaction mixture was cooled to room temperature, diluted with EtOAc (5 mL), and passed through a silica pad (1 cm). The silica was rinsed with EtOAc (10 mL) followed by 10% MeOH in CHCl. ​​The volatiles were removed in vacuo and the crude material was purified by flash chromatography (24 g Isco RediSep column, gradient from 50% EtOAc in CHCl to 100% EtOAc, followed by 5 CV of 10% MeOH in CHCl). Evaporation of selected fractions afforded the desired 6,7-dimethyl-2-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pteridine (57.2 mg, 39%). LCMS: m / z (ESI) [M+H] + 481.20, t R =1.302 minutes . 1 H NMR outer diameter (DMSO-d6,400MHz):δ H1.77(1H,q,J=12.2Hz), 2.06-1.93(1H,m), 2.16(1H,d,J=13.1Hz), 2.44(3H,s), 2 .73(3H,s), 2.78(3H,s), 3.59(1H,t,J=11.6Hz), 3.80(1H,t,J=11.8Hz), 4.25(1H ,dd,J=11.3,4.2Hz), 4.62(1H,d,J=11.2Hz), 7.19(1H,d,J=5.3Hz), 7.27(1H,s), 8.15(1H,d,J=8.3Hz), 8.37(1H,d,J=5.3Hz), 8.90(1H,d,J=8.2Hz), 9.59(1H,s).

[0334] Method 38 Example 394: 4-(4-chloro-2,3-difluorophenyl)-7-methyl-2-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pteridine [ka]

[0335] Into a flame-dried 50 mL microwave vial, 2-chloro-4-(4-chloro-2,3-difluorophenyl)-7-methyl-pteridine (100 mg, 0.306 mmol), palladium acetate (6.9 mg, 0.0306 mmol), C-Phos (0.200 equiv., 27 mg, 0.0611 mmol), and THF (3.5 mL) were added. The reaction mixture was degassed under N for 5 minutes, and bromo-[2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]zinc bromide solution (0.17 M in THF) (1.8 mL, 0.3057 mmol) was added dropwise over 30 minutes. The mixture was stirred at 22 °C for 2 hours. The reaction was quenched by adding saturated NaHCO (20 mL), and the reaction mixture was extracted with DCM (50 mL). The aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were dried over NaSO and the solvent was removed in vacuo. The crude material was purified by flash chromatography (40 g Isco RediSep column) using EtOAc and hexanes (0-100%) followed by MeOH and DCM (0-10%) to give a solid (100 mg), which was purified by preparative HPLC (Gemini 5 μm NX-C18 column) using MeOH and aqueous 10 mM ammonium formate. Further purification on a 110Å, 100x30mm column gave 4-(4-chloro-2,3-difluoro-phenyl)-7-methyl-2-[rac-(2R,4S)-2-(2-methyl- 4-(4-chloro-2,3-difluoro-phenyl)-7-methyl-2-[rac-(2R,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pteridine was obtained as a mixture of cis diastereomers (32.3 mg, 22%), and 4-(4-chloro-2,3-difluoro-phenyl)-7-methyl-2-[rac-(2R,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pteridine was obtained as a mixture of trans diastereomers (2.8 mg, 2%). Cis isomer: ESI-MS (m / z+): 468.20 [M+H] + , LC-RT: 1.307 minutes. 1H NMR (400 MHz, CD2Cl2) δ 8.81(s,1H), 8.41(s,1H), 7.50-7.45(m,1H), 7.43-7.37(m,1H), 7.23(s ,1H), 7.13(d,J=4.6Hz,1H), 4.55(d,J=11.5Hz,1H), 4.34(dd,J=10.6,3 .8Hz,1H), 3.84(td,J=11.7,3.2Hz,1H), 3.66-3.57(m,1H), 2.86(s,3H) , 2.51(s,3H), 2.47-2.40(m,1H), 2.25-2.13(m,2H), 2.01-1.90(m,1H). 19 F NMR (376 MHz, CD2Cl2) δ ppm -133.01(s), -138.66(s). Trans isomer: 1 H NMR (400 MHz, CD2Cl2) δ ppm 8.85(s,1H), 8.42(d,J=5.5Hz,1H), 7.56-7.51(m,1H), 7.46-7.38(m,1H), 7.21(s,1H), 7.12(d,J=4.7Hz,1H), 4.78(dd,J=9.6,2.4Hz,1H), 4.0 4-3.97(m,1H), 3.90(td,J=11.3,2.5Hz,1H), 3.76-3.71(m,1H), 2.89( s,3H), 2.52(s,3H), 2.52(s,2H), 2.30-2.24(m,1H), 2.22-2.16(m,1H).

[0336] Method 39 Example 392: 7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[3,4-b]pyrazine [ka] Step 1: To a solution of 7-chloro-2,3-dimethyl-5-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-b]pyrazine (490 mg, 1.50 mmol, Intermediate 114) and 1-cyclopropyl-4-[(6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (520 mg, 1.64 mmol) in 1,4-dioxane (10 mL), cesium carbonate (1461 mg, 4.49 mmol), water (1 mL), and Pd(dppf)Cl (109 mg, 0.150 mmol) was added. was added. The mixture was then stirred at 90 °C overnight. Upon completion, the mixture was cooled to room temperature and diluted with EtOAc. The organic layer was then washed with water, then brine, dried over MgSO4, filtered through a plug of silica, and concentrated in vacuo. The residue was then purified by flash chromatography using a DCM / EtOAc gradient (20% to 100%) to afford the desired material (560 mg, 75%) as a pale yellow foam. 1 H NMR (400MHz, chloroform-d): δ ppm 7.69(1H,s), 7.53(1H,s), 7.50(1H,s), 7.18(1H,s), 5.42(1H,d,J=2.9Hz), 4.09-4.16(1H,m), 3.93(1H,m), 3 .54-3.60(1H,m), 2.74(4H,s), 2.73(3H,s), 2.67(1H,m), 2.62(6H,s), 1.10-1.13(2H,m), 0.97-1.03(2H,m).

[0337] Step 2: To a flask under argon containing 2,3-dimethyl-7-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-b]pyrazine (1.00 equiv., 254 mg, 0.528 mmol) in ethanol (8 mL) was added PtO (0.710 equiv., 85 mg, 0.374 mmol). The system was purged with hydrogen and stirred under 1 atmosphere of H overnight. The reaction was monitored by LCMS and NMR. 1Upon completion as judged by H NMR, the mixture was diluted with EtOAc, filtered through Celite and evaporated. The crude material was used in the next step without further purification.

[0338] Step 3: To an argon-atmosphere flask containing 2,3-dimethyl-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-5-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (1.00 equiv., 254 mg, 0.521 mmol) in DCE (5 mL) was added MnO (20.1 equiv., 900 mg, 10.5 mmol). The reaction was then stirred at 50 °C overnight. Upon completion, the mixture was cooled to room temperature, diluted with EtOAc, filtered through a silica plug, and the solvent was evaporated in vacuo. The residue was purified by column chromatography using a 35% to 100% DCM / EtOAc gradient to afford the desired material as an 11:1 diastereomeric mixture. Further purification by reverse phase chromatography using a Gemini® 5um NX-C18 110Å, 100x30mm column and a 55% to 75% methanol / water (10mm ammonium formate) gradient gave, after lyophilization, the desired material (113mg, 45%) as a white solid. 1H NMR (400MHz, chloroform-d): δ ppm 7.54(1H,s), 7.48(2H,s), 4.55(1H,d,J=11.2Hz), 4.25(1H,d,J=11.4Hz), 3.84-3.78(1H,m), 3.59-3.53(1H,m), 3.22(1 H,m), 2.74(3H,s), 2.73(3H,s), 2.61(6H,s), 2.30(1H,d,J=13.1Hz), 2.02-1.95(3H,m), 1.10(2H,m), 1.04-0.97(2H,m). LCMS:m / z(ESI)[M+H] + 484.2

[0339] method 40 Example 346: 4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,6-naphthyridin-7-yl)-2-(2-methylpyridin-4-yl)morpholine [ka] Step 1: A 50 mL microwave vial was charged with (2,4-difluorophenyl)boronic acid (556 mg, 3.52 mmol), 5,7-dichloro-2,3-dimethyl-1,6-naphthyridine (800 mg, 3.52 mmol), cesium carbonate (3.44 g, 10.6 mmol), 1,4-dioxane (16 mL), and water (4.8 mL). The reaction mixture was degassed with nitrogen for 10 minutes. Pd(dppf)Cl2·CHCl2 (144 mg, 0.176 mmol) was added, and the mixture was heated at 40 °C for 1 hour. The mixture was cooled to room temperature and diluted with DCM (50 mL) and water (10 mL). The aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were washed with brine (10 mL), dried (NaSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g SilicaSep cartridge) using EtOAc and hexanes (30-40%) to give 7-chloro-5-(2,4-difluorophenyl)-2,3-dimethyl-1,6-naphthyridine (660 mg, 2.17 mmol, 62%) as a solid. ESI-MS (m / z+): 305.1 [M+H] + , LC-RT: 2.09 minutes. 1 H NMR (400MHz, CDCl3) δ ppm 7.92(s,1H), 7.70(d,J=2.7Hz,1H), 7.62-7.53(m,1H), 7.13-7.05(m,1H), 7.04-6.95(m,1H), 2.73(s,3H), 2.43(s,3H). 19 F NMR (376MHz, CDCl3) δ ppm -107.43(s), -109.37(s).

[0340] Step 2: A mixture of 7-chloro-5-(2,4-difluorophenyl)-2,3-dimethyl-1,6-naphthyridine (50 mg, 0.164 mmol), 2-(2-methyl-4-pyridyl)morpholin-4-ium chloride (36 mg, 0.169 mmol), sodium tert-butoxide (63 mg, 0.658 mmol), and Pd(amphos)Cl (12 mg, 0.0164 mmol) in a 10 mL microwave vial was subjected to three vacuum / nitrogen-fill cycles. 1,4-Dioxane (2.5 mL) was added, and the mixture was stirred at 80 °C for 5 h. The mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (SilicaSep® 24 g cartridge) using MeOH and dichloromethane (20-30%) to give an oil, which was further purified by reverse-phase chromatography on an ACCQ preparative HPLC (Gemini 150x30 mm C18 column) using acetonitrile and water (80-90%) to give 4-[5-(2,4-difluorophenyl)-2,3-dimethyl-1,6-naphthyridin-7-yl]-2-(2-methyl-4-pyridyl)morpholine (19 mg, 0.0410 mmol, 25%) as a yellow solid. ESI-MS (m / z+):447.20[M+H]+, LC-RT:2.313 minutes. 1 H NMR(400MHz,CD2Cl2)δ ppm 8.45(d,J=5.2Hz,1H), 7.57-7.49(m,2H), 7.25(s,1H), 7.18(d,J=5.1Hz,1H), 7.12-6.98(m,3H), 4.64(dd,J=10.4,2.5Hz,1H), 4.46(d,J=1 2.4Hz,1H), 4.25-4.16(m,2H), 3.95-3.86(m,1H), 3.19-3.09(m,1H), 2.85(dd,J=12.7,10.6Hz,1H), 2.62(s,3H), 2.54(s,3H), 2.32(s,3H). 19F NMR (376MHz, CD2Cl2) δ ppm -109.71(s), -110.69(s).

[0341] Method 41 Examples 389 and 390: 4-(4-chloro-3,5-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pteridine and 4-(4-chloro-3,5-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pteridine [ka] Step 1: A 100 mL round-bottom flask was charged with 2,4-dichloro-6,7-dimethyl-pteridine (3.00 g, 13.1 mmol) and THF (40 mL). The solution was cooled to -10 °C, and a suspension of NaSMe (1.01 g, 14.4 mmol) in water (5 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 17 h. The mixture was diluted with DCM (50 mL) and water (10 mL). The aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The crude residue was purified by silica gel chromatography (80 g SilicaSep column) using EtOAc and hexanes (50-60%) to give 2-chloro-6,7-dimethyl-4-methylsulfonyl pteridine. Sulfanyl-pteridine (1.92 g, 7.98 mmol, 61%) was obtained as a pale yellow solid. ESI-MS (m / z+): 241.0 [M+H] + , LC-RT:2.907 minutes. 1 H NMR (400MHz, CDCl3) δ ppm 2.79(s,3H), 2.76(s,3H), 2.70(s,3H).

[0342] Step 2: A 50 mL microwave vial was charged with a solution of 2-chloro-6,7-dimethyl-4-methylsulfanyl-pteridine (600 mg, 2.49 mmol), Pd(dba) (36 mg, 0.0626 mmol), and tri(2-furyl)phosphine (30 mg, 0.129 mmol) in THF (12 mL) and subjected to three vacuum / nitrogen fill cycles. Bromo-[2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]zinc bromide solution (0.16 M in THF, 23 mL, 3.74 mmol) was then added dropwise at 25 °C, and the mixture was stirred for 44 h. The mixture was diluted with DCM (100 mL) and saturated NaHCO (20 mL). The aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (SilicaSep 40 g cartridge) using EtOAc and hexanes (0-100%), followed by MeOH and DCM (5-15%) to give an oil, which was further purified by reverse-phase chromatography (30 g C-18 cartridge) using acetonitrile and 0.1% aqueous formic acid to give 6,7-dimethyl-2-[2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]-4-methylsulfanyl-pteridine (255 mg, 0.655 mmol, 26%) as a solid. ESI-MS (m / z+): 382.10 [M+H] + , LC-RT:2.136 minutes. 1 H NMR(400MHz,CD2Cl2)δ ppm 8.41(d,J=4.9Hz,1H), 7.23(s,1H), 7.14(d,J=4.8Hz,1H), 4.56-4.49(m,1H), 4.37-4.28(m,1H), 3.85-3.77(m,1H), 3.48- 3.38(m,1H), 2.74(s,3H), 2.72(s,3H), 2.66(s,3H), 2.52(s,3H), 2.43-2.36(m,1H), 2.17-2.09(m,2H), 1.95-1.84(m,1H).

[0343] Step 3: In a flame-dried 50 mL microwave vial, 6,7-dimethyl-2-[2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]-4-methylsulfanyl-pteridine (122 mg, 0.320 mmol), Pd(OAc) (1.8 mg, 0.0080 mmol), SPhos (6.6 mg, 0.016 mmol), and THF (1 mL) were added. The reaction mixture was degassed under N for 5 minutes, and chloro-(4-chloro-2,3-difluorophenyl)zinc chloride solution (0.089 M in THF) (5.3 mL, 0.4797 mmol) was added dropwise over 30 minutes at 25 °C. The mixture was stirred at 25 °C for 2 hours. The reaction was quenched by adding saturated NaHCO (20 mL), and the reaction mixture was extracted with DCM (50 mL). The aqueous layer was extracted with (2 x 50 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. The crude material was purified by flash chromatography (40 g Isco RediSep® column) using EtOAc and hexanes (0-100%) followed by MeOH and DCM (10-20%) to give a solid (34 mg) which was purified by preparative HPLC (Gemini® 5 μm NX-C18 column) using MeOH and aqueous ammonium bicarbonate. Further purification on a column (110 Å, 100x30 mm) gave a mixture of cis isomers 4-(4-chloro-3,5-difluoro-phenyl)-6,7-dimethyl-2-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pteridine (14 mg, 0.0277 mmol, 9%) as one peak and a mixture of trans isomers 4-(4-chloro-3,5-difluoro-phenyl)-6,7-dimethyl-2-[rac-(2R,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pteridine (4.5 mg, 0.00907 mmol, 3%) as another peak. Cis isomer: ESI-MS (m / z+): 482.2 [M+H] + , LC-RT: 1.598 minutes. 1H NMR(400MHz,CD2Cl2)δ ppm 8.41(s,2H), 8.39(s,1H), 7.23(s,1H), 7.14(d,J=4.0Hz,1H), 4.56(dd,J=11.3,1.1Hz,1H), 4.39-4.32(m,1H), 3.90-3.79( m,1H), 3.64-3.51(m,1H), 2.81(s,3H), 2.79(s,3H), 2.52(s,3H), 2.48-2.40(m,1H), 2.24-2.13(m,2H), 2.01-1.88(m,1H). 19 F NMR (376MHz, CD2Cl2) δ ppm -113.77(s), -113.80(s). Trans isomer:ESI-MS(m / z+):482.2[M+H] + , LC-RT: 1.560 min. 1 H NMR(400MHz,CD2Cl2)δ ppm 8.42(d,J=5.0Hz,1H), 8.35(d,J=8.2Hz,2H), 7.23(s,1H), 7.14(d,J=4.9Hz,1H), 4.69-4.57(m,2H), 4.40-4.33(m,1H), 3.99-3 .89(m,1H), 2.83(s,3H), 2.82(s,3H), 2.52(s,3H), 2.34-2.24(m,1H), 2.23-2.16(m,1H), 2.12-2.01(m,1H), 2.01-1.93(m,1H). 19 F NMR (376MHz, CD2Cl2) δ ppm -113.54(s), -113.56(s).

[0344] method 42 Example 341: 2-(1-cyclopropylpyrazol-4-yl)-4-[5-(2,4-difluorophenyl)-2-methyl-pyrido[3,4-b]pyrazin-7-yl]morpholine [ka] To a mixture of 7-chloro-5-(2,4-difluorophenyl)-2-methyl-pyrido[3,4-b]pyrazine (90 mg, 0.309 mmol), 2-(1-cyclopropylpyrazol-4-yl)morpholin-4-ium chloride (85 mg, 0.370 mmol), and sodium tert-butoxide (26 mg, 0.269 mmol) in toluene (2.5 mL) was added XPhos Pd G4 (19 mg, 0.022 mmol). The mixture was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature, and water was added. The solid was filtered through Celite and rinsed with EtOAc. The product was extracted from the filtrate with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 20-100% EtOAc in hexanes to afford the title compound 2-(1-cyclopropylpyrazol-4-yl)-4-[5-(2,4-difluorophenyl)-2-methyl-pyrido[3,4-b]pyrazin-7-yl]morpholine (65 mg, 0.138 mmol, 45% yield) as an orange solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.51(s,1H), 7.85(s,1H), 7.66(td,J=8.4,6.6Hz,1H), 7.48(s,1H), 7.36(td,J=9.8,2.5Hz,1H), 7.23(td,J=8.6,2.6Hz,1 H), 7.18(s,1H), 4.56(dd,J=10.4,2.7Hz,1H), 4.41(d,J=13.2Hz,1H), 4.29-4.19(m,1H), 4.09-3.86(m,1H), 3.89-3.52(m ,2H), 3.21-2.84(m,2H), 2.64(s,3H), 1.11-0.98(m,2H), 0.98-0.89(m,2H). LC / MS(ESI + ) m / z = 449.2 [M+H] +

[0345] method 44 Example 402: 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[2,3-b]pyrazine [ka] Step 1: To a solution of 6,8-dichloro-2,3-dimethylpyrido[2,3-b]pyrazine (1 g, 4.4 mmol) in dioxane (20 mL) and HO (4 mL) was added 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (1.4 g, 4.4 mmol) and KCO (1.8 g, 13 mmol), and the reaction mixture was purged with nitrogen. Pd(dppf)Cl·DCM (0.29 g, 0.36 mmol) was then added, and the reaction mixture was heated at 80 °C for 5 h. The reaction mixture was then cooled to room temperature and monitored by LCMS. After completion, the aqueous layer was extracted with ethyl acetate (3 x 200 ml), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue. The residue was purified by column chromatography on silica gel (PE:EA = 1:1) to give 8-chloro-6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethylpyrido[2,3-b]pyrazine (1.3 g, 76%) as a purple solid. LCMS: (M+H) + =382.0;

[0346] Step 2: A 250 mL round-bottom flask was charged with 4-chloro-2-fluoro-1-iodobenzene (2.2 g, 8.6 mmol) in THF (40 mL). The mixture was cooled to −40° C., and iPrMgCl (4.7 mL, 9.5 mmol) (2 M solution in THF) was added dropwise and stirred at −40° C. for 30 minutes. The reaction mixture was then cooled to −78° C. ZnCl (4.3 mL, 8.6 mmol) (2 M solution in THF) was then added dropwise, and the reaction mixture was allowed to warm to room temperature. 40 mL of THF was added and stirred for 10 minutes to give (4-chloro-2-fluorophenyl)zinc(II) iodide, which was used directly in the next reaction.

[0347] In a 250 mL three-necked round-bottom flask purged and maintained with N2, 8-chloro-6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethylpyrido[2,3-b]pyrazoline was added in THF (10 mL). The reaction mixture was stirred, and (4-chloro-2-fluorophenyl)zinc(II) iodide (2.2 g, 8.6 mmol) was added. The reaction mixture was stirred at room temperature for 40 minutes and monitored by LCMS. After completion, the reaction mixture was quenched with H2O (200 ml). The aqueous layer was extracted with EA (3 x 200 ml), and the combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give the crude residue. The residue was purified by column chromatography on silica gel (PE:EA=1:1) to give 8-(4-chloro-2-fluorophenyl)-6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethylpyrido[2,3-b]pyrazine (900 mg, 64%) as a white solid. LCMS: (M+H) + =476.0.

[0348] Step 3: To a solution of 8-(4-chloro-2-fluorophenyl)-6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethylpyrido[2,3-b]pyrazine (400 mg, 0.84 mmol) in THF (8 mL) was added Rh(cod)dppf.BF (122 mg, 0.17 mmol) and the reaction mixture was purged with hydrogen at room temperature for 3 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was evaporated under reduced pressure to give the crude residue. The residue was purified by silica gel chromatography (PE:EA=1:2) to give 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[2,3-b]pyrazine (123 mg, 31%) as a white solid. LCMS: (M+H) + =478.0. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] Table 11-11 Table 11-12 Table 11-13 Table 11-14 Table 11-15 Table 11-16 Table 11-17 Table 11-18 Table 11-19 Table 11-20 Table 11-21 Table 11-22 Table 11-23 Table 11-24 Table 11-25 Table 11-26 Table 11-27 Table 12-1 Table 12-2 Table 12-3 Table 12-4 Table 12-5 Table 12-6 Table 12-7 Table 12-8 Table 12-9 Table 12-10 Table 12-11 Table 12-12 Table 12-13 Table 12-14 Table 12-15 Table 13-1 Table 13-2 Table 13-3 Table 13-4 Table 13-5 Table 13-6 Table 13-7 Table 13-8 Table 13-9 Table 13-10 Table 13-11 Table 13-12 Table 13-13 Table 13-14 Table 13-15 Table 13-16 Table 13-17 Table 13-18 Table 13-19 Table 13-20 Table 13-21 Table 13-22 Table 13-23 Table 13-24 Table 13-25 Table 13-26 Table 13-27 Table 13-28 Table 13-29 Table 14-1 Table 14-2 Table 14-3 Table 14-4 Table 14-5 Table 14-6 [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10] [Table 14-11] [Table 14-12] [Table 14-13] [Table 14-14] [Table 14-15]

[0349] Synthesis of intermediates Method 11 Intermediate 1: 5,7-dichloro-2,3-dimethylpyrido[3,4-b]pyrazine [ka] A 500 mL round-bottom flask was charged with 3,4-diamino-2,6-dichloropyridine (27 g, 152 mmol) and 2,3-butanedione (15.99 mL, 182 mmol). EtOH (152 mL) was added to the flask, and the mixture was heated to 70 °C. After 5 h, the mixture was filtered through a fritted funnel, and the eluent was concentrated under reduced pressure to approximately 75 mL. HO (150 mL) was added to the solution, and the resulting solid was filtered. The combined solid from both filtrates was washed three times with HO and dried on the filter under air to give 5,7-dichloro-2,3-dimethylpyrido[3,4-b]pyrazine as a light brown solid (34.5 g, 152 mmol). LC / MS (ESI + ) m / z=228.0[M+H] + 1 H NMR (500 MHz, chloroform-d) δ ppm 7.82 (s, 1H), 2.83 (s, 3H), 2.80 (s, 3H).

[0350] Method 12 Intermediate 2: 6,8-Dichloro-2,3-dimethylpyrido[2,3-b]pyrazine [ka] 4,6-Dichloropyridine-2,3-diamine (30 g, 169 mmol) and butane-2,3-dione (16.12 mL, 185 mmol) were combined in a 1 L round-bottom flask. EtOH (600 mL) was added and the mixture was heated to 80° C. for 5 h. After cooling, the solvent was removed under reduced pressure. The resulting solid was triturated with diethyl ether and filtered to give 6,8-dichloro-2,3-dimethylpyrido[2,3-b]pyrazine as a light brown solid (36.5 g, 160 mmol). LC / MS (ESI + ) m / z=228.0[M+H] + 1 H NMR (400MHz, DMSO-d6): δ ppm 8.21 (s, 1H), 2.76 (s, 6H)

[0351] Method 13 Intermediate 3: 2,4-Dichloro-6,7-dimethylpteridine [ka] In a 100 mL round-bottom flask, 2,6-dichloropyrimidine-4,5-diamine (5 g, 27.9 mmol) and butane-2,3-dione (2.91 mL, 33.5 mmol) were combined in EtOH (27.9 mL), and the mixture was stirred at 30° C. for 18 h. After cooling, the solvent was removed under reduced pressure. The resulting solid was triturated with diethyl ether and filtered to give 2,4-dichloro-6,7-dimethylpteridine (6.02 g, 26.3 mmol) as a light brown solid. LC / MS (ESI + ) m / z = 229.0 [M+H] + 1 H NMR (500 MHz, chloroform-d) δ ppm 2.88 (s, 3H), 2.87 (s, 3H).

[0352] Method 14 Intermediate 4: 5,7-Dichloro-2-methylpyrido[3,4-b]pyrazine [ka] The reaction was set up in two batches using 20 g and 25 g of 2,6-dichloropyridine-3,4-diamine (45 g, 252 mmol total). To a 50 mL round-bottom flask was added 2,6-dichloropyridine-3,4-diamine (25 g, 140 mmol) and 2-oxopropanal (30.4 g, 169 mmol) in EtOH (250 mL). The reaction mixture was heated at 85 °C for 2 hours. The reaction flask was cooled to room temperature. The mixture was diluted with HO, and the resulting solid was filtered and washed with HO. The solid material was dissolved in DCM, dried over NaSO, filtered, and concentrated under reduced pressure to give the crude reaction product. This crude material was combined with 2,6-dichloropyridine-3,4-diamine from the second batch, and both were adsorbed onto a plug of silica gel and purified by chromatography on a silica gel column eluted with a gradient of 100% DCM to give 5,7-dichloro-2-methylpyrido[3,4-b]pyrazine (25.57 g, 119 mmol) as an off-white solid and 7.8 g of two A mixture of isomers was obtained. Major isomer: + ) m / z=213.9[M+H] + 1 H NMR (400MHz, DMSO-d6): δ ppm 9.06 (s, 1H), 8.11 (s, 1H), 2.79 (s, 3H). Minority isomers: LC / MS (ESI + ) m / z=214.0[M+H] + 1 H NMR (400MHz, DMSO-d6): δ ppm 9.16 (s, 1H), 8.20 (s, 1H), 2.79 (s, 3H).

[0353] Method 15 Intermediate 5: 5,7-dichloro-2,3-dimethyl-1,8-naphthyridine and Intermediate 6: 2,4-Dichloro-7-ethyl-1,8-naphthyridine [ka] A screw-cap vial was charged with 2-amino-4,6-dichloronicotinaldehyde (0.5 g, 2.62 mmol) and methyl ethyl ketone (2.62 mL). To this solution was added KOH (0.147 g, 2.62 mmol). The reaction was stirred overnight at room temperature. H2O was added, and the aqueous phase was neutralized to pH 7 using 1N aqueous HCl. The aqueous phase was extracted with DCM. The organic phase was separated using a phase separator and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-10% MeOH in DCM (+1% NH3)) to give 5,7-dichloro-2,3-dimethyl-1,8-naphthyridine (0.284 g, 1.25 mmol, 47.7%). LC / MS (ESI + ) m / z = 227.0 [M+H] + and 2,4-dichloro-7-ethyl-1,8-naphthyridine (0.18 g, 0.79 mmol) LC / MS (ESI + ) m / z = 227.0 [M+H] + .

[0354] Method 16 Intermediate 7: 5,7-Dichloro-2-methyl-1,6-naphthyridine [ka] To a 50 mL vial was added 4-amino-2,6-dichloronicotinaldehyde (1.91 g, 10 mmol, JW Pharmlab) and KOH (0.84 g, 15.0 mmol) in acetone (10 mL). The reaction was stirred at room temperature for 30 minutes, and a precipitate formed. The reaction mixture was diluted with EtOAc, dried, and concentrated. The crude material was purified by chromatography (0 to 30% EtOAc in DCM) to give 1.65 g (71%) of 5,7-dichloro-2-methyl-1,6-naphthyridine as an off-white solid.

[0355] Method 17 Intermediate 8: 2,4-Dichloro-7-methyl-1,8-naphthyridine [ka] To a 50 mL vial was added 2-amino-4,6-dichloronicotinaldehyde (0.3507 g, 1.836 mmol) and acetone (1.836 mL). To this solution was added KOH (0.155 g, 2.75 mmol). The reaction was stirred at room temperature for 30 minutes. H2O was added and the aqueous phase was extracted with DCM. The organic phase was separated using a phase separator and concentrated under reduced pressure to give 2,4-dichloro-7-methyl-1,8-naphthyridine (0.317 g, 1.49 mmol). LC / MS (ESI + ) m / z=213.0[M+H] +

[0356] Method 18 Intermediate 9: 7-chloro-5-(4-chloro-2-fluorophenyl)-2-methyl-1,6-naphthyridine [ka] 5,7-Dichloro-2-methyl-1,6-naphthyridine (Intermediate 7, 0.852 g, 4 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (0.146 g, 0.200 mmol), (4-chloro-2-fluorophenyl)-boranediol (0.697 g, 4.00 mmol), and CsCO (3.91 g, 12.00 mmol) were combined in a 50 mL vial. The vial was evacuated and backfilled with N, and 1,4-dioxane (10 mL) and HO (3 mL) were added. The reaction was stirred at 60 °C for 30 min, cooled to room temperature, and partitioned between DCM and HO. The mixture was passed through a phase separation cartridge, concentrated, and purified by silica gel chromatography (0-50% EtOAc in heptane) to give 7-chloro-5-(4-chloro-2-fluorophenyl)-2-methyl-1,6-naphthyridine (710 mg, 2.3 mmol, 58%). [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 15-7] [Table 15-8]

[0357] Method 19 Intermediate 59: 2-chloro-6,7-dimethyl-4-((trans)-3-(trifluoromethyl)cyclobutyl)pteridine and Intermediate 60: 2-chloro-6,7-dimethyl-4-((cis)-3-(trifluoromethylcyclobutyl)pteridine [ka] Step 1: (3-(trifluoromethyl)cyclobutyl)zinc(II) chloride. Magnesium (0.190 g, 7.82 mmol) was washed with iodine crystals and suspended in dry THF (3 mL) under N2. 1-Bromo-3-(trifluoromethyl)cyclobutane (1.25 g, 6.16 mmol) was added, and the mixture was stirred at room temperature. The mixture was stirred at ambient temperature for approximately 60 minutes, resulting in a milky white suspension. A solution of zinc chloride in 2-MeTHF (2.92 mL, 5.54 mmol) was added dropwise, and the mixture was stirred for 30 minutes. A white precipitate formed. The mixture was centrifuged for 10 minutes, and the resulting dark yellow supernatant solution was used without further manipulation.

[0358] Step 2: 2-Chloro-6,7-dimethyl-4-(3-(trifluoromethyl)cyclobutyl)pteridine. To a 40 mL vial, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (0.354 g, 0.500 mmol) and 2,4-dichloro-6,7-dimethylpteridine (Intermediate 3) (1.145 g, 5.00 mmol, Syngene) were added under N2, and 2.0 mL of THF was added at room temperature, followed by ((1R,3R)-3-(trifluoromethyl)cyclobutyl)zinc(II) bromide in THF (1.0 equiv.). The solution turned purple and was stirred at 45 °C for 40 min. The reaction was concentrated, diluted with DCM (20 mL), quenched with HO (10 mL) and HCl (2 N, 3 mL), and extracted with DCM. The DCM extracts were combined. The residue was purified by silica gel chromatography (0% to 40% EtOAc / EtOH in 10% DCM in heptane) to give 2-chloro-6,7-dimethyl-4-(3-(trifluoromethyl)cyclobutyl)pteridine (1.51 g, 4.77 mmol, 95% yield) as a yellow solid (cis / trans isomers in approximately 2.5 / 1 ratio). The compound was repurified by silica gel chromatography (0% to 80% EtOAc in 10% DCM in heptane). Peak 1: 2-chloro-6,7-dimethyl-4-(trans-3-(trifluoromethyl)cyclobutyl)-pteridine (0.864 g, 2.73 mmol, 54.6% yield) was obtained as a yellow solid. 1 H NMR (500 MHz, chloroform-d) δ ppm 4.89-4.98 (m, 1H), 3.08-3.29 (m, 1H), 2.66-2.88 (m, 10H), 19 F NMR (chloroform-d, 471 MHz) δ ppm -74.03 (s); m / z (ESI, +ve ion): 317.0 (M+H) + Peak 2: 2-chloro-6,7-dimethyl-4-(cis-3-(trifluoromethyl)cyclobutyl)pteridine was obtained as a yellow solid in 19% yield. 1H NMR (500 MHz, chloroform-d) δ ppm 4.56-4.68 (m, 1H), 3.10-3.17 (m, 1H), 2.63-2.78 (m, 10H), 19 F NMR (chloroform-d, 471 MHz) δ ppm -73.38 (s); m / z (ESI, +ve ion): 317.0 (M+H) + [Table 16-1] [Table 16-2] [Table 16-3]

[0359] method 20 Intermediate 71: 2-chloro-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine [ka] Step 1: (3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-yl) (I)zinc(II) chloride. To an oven-dried 40 mL vial was added magnesium (122 mg, 5.04 mmol) and small pieces of I2 (approximately 5 mg). The vial was evacuated and backfilled with N2 three times, and 1.0 mL of THF was added. The vial was sonicated for 1 minute and stirred at room temperature for 5 minutes. The mixture became a dark red / purple suspension. 1-Iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (1200 mg, 4.58 mmol) in 1 mL of THF was then added dropwise at room temperature. The purple I2 color immediately disappeared, but no further exotherm was observed. The vial was sealed and heated to 74 °C. The mixture immediately became clear and gradually became cloudy again. The mixture was heated for an additional 30 minutes until minimal Mg remained. An aliquot of the mixture was taken and subjected to H and F NMR analysis, which showed >90% conversion relative to the Grignard reagent [product: 19F NMR (chloroform-d, 471 MHz) δ -73.99 (s, 1F); substrate: 19 F NMR (chloroform-d, 471 MHz) δ -71.81 (s, 1F)]. The reaction mixture was cooled to room temperature. A solution of zinc chloride in 2-MeTHF (2290 μL, 4.58 mmol) was added dropwise in an ice-HO bath. The mixture was warmed to room temperature and stirred for 30 min. A white precipitate formed, and the mixture was allowed to stand overnight. The clear supernatant solution was used without further manipulation. Titration with I confirmed organozinc formation (12.3 mg of I, 0.115 mL of a 0.42 M solution in THF). Approximately 6.5 mL could be removed (2.7 mmol, 59% yield).

[0360] Step 2: 2-chloro-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine. To a 40 mL vial was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloro-palladium(II) (49.6 mg, 0.070 mmol) and 2,4-dichloro-6,7-dimethylpteridine (Intermediate 3) (160 mg, 0.700 mmol, Syngene). The vial was evacuated and backfilled with N2 three times. 0.5 mL of THF was added at room temperature, followed by (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) chloride (1.0 equiv.). The solution gradually turned purple and was stirred at 45 °C. After 40 min, the reaction reached approximately 90% conversion. After 2 h, no change was observed. The reaction was concentrated, diluted with DCM (8 mL), quenched with HO (4 mL) and HCl (2N, 0.4 mL), and extracted with DCM (10 mL × 3). The DCM extract was separated on a phase separator, concentrated, and purified by column chromatography (RediSep 12 g, 0% to 40% EA / EtOH = 3 / 1 blend in 10% DCM in heptane) to give 2-chloro-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine (174 mg, 0.529 mmol, 76% yield) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 2.82 (m, 6H), 2.69 (s, 6H). 19 F NMR (471 MHz, chloroform-d) δ ppm -73.11 (s). m / z (ESI, +ve ion): 329.0 (M+H) + . [Table 17]

[0361] Intermediate 108: 2-chloro-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridine [ka] Intermediate 108 was prepared essentially as described in Method 20. To a 40 mL vial were added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloro-palladium(II) (99 mg, 0.140 mmol) and 2,4-dichloro-7-dimethylpteridine (300 mg, 1.395 mmol, Wu Xi). The vial was evacuated and backfilled with N2 three times. 3.5 mL of THF was added at room temperature, followed by (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) chloride (3671 μL, 1.395 mmol, 1.0 equiv., see Method 20, Step 1). The solution gradually turned purple and was stirred at 45 °C overnight. The reaction was quenched with NH4Cl and EtOAc and extracted into EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the crude product. The crude material was purified by column chromatography to give the desired product. m / z (ESI, +ve ion): 315.0 (M+H). + .

[0362] Method 21 Intermediate 73: 4,4-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine [ka] Step 1: Tert-butyl 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate. To a 100 mL round-bottom flask was added tert-butyl 3-(1-methyl-1H-pyrazol-4-yl)-4-oxopiperidine-1-carboxylate (1 g, 1.647 mmol) and DAST (2.2 mL, 16.47 mmol) in DCM (40 mL) at 0 °C. The reaction mixture was warmed to room temperature, stirred for 48 hours, quenched with 10% sodium bicarbonate (50 mL), and extracted with DCM (30 mL). The organic extract was dried over Na SO . The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude material was purified by silica gel chromatography eluting with 50% EtOAc in hexanes to afford tert-butyl 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (500 mg, 1.1 mmol, 64.5% yield) as a yellow oil.

[0363] Step 2: 4,4-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine hydrochloride. To a 10 mL round-bottom flask was added tert-butyl 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (60 mg, 0.199 mmol) in DCM (4 mL). The mixture was cooled to 0 °C, and HCl in dioxane (0.5 mL, 2.000 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 h, and then concentrated in vacuo to give the crude product, which was washed with diethyl ether to give 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine hydrochloride (25 mg, 0.124 mmol, 62.4% yield) as a white solid (hygroscopic). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.36(d,J=25.1Hz,2H), 7.73(s,1H), 7.41(s,1H), 3.82(s,4H), 3.57(s,2H), 3.18(d,J=5.1Hz,1H), 2.39(d,J=11.9Hz,2H).

[0364] Method 22 Intermediate 74: (2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II) bromide [ka] Step 1: 4-(4-Bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole. A 100 mL flask was charged with 1-methyl-1H-pyrazole-4-carbaldehyde (1.03 g, 9.35 mmol), 3-buten-1-ol (0.708 g, 0.842 mL, 9.82 mmol), and DCM (18.7 mL). To the flask was added a portion of hydrogen bromide-acetic acid (6.88 g, 5.08 mL, 28.1 mmol). After 1 h, the crude reaction was carefully quenched with saturated NaHCO3 solution and washed with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting crude material was purified by silica gel chromatography eluting with 0% to 40% EtOAc / EtOH (3:1) in heptane to give 4-(4-bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (1.31 g, 5.33 mmol, 57% yield) as a pale yellow oil as a ca. 3:1 mixture of cis / trans diastereomers. A second silica gel column afforded the pure cis (0.85 g) and trans (0.27 g) isomers. If necessary, the major (cis) diastereomer can be separated by SFC (Chiralpak AY-H 2x25 cm, 5 μm column, mobile phase = 10% EtOH, F = 60 mL / min).

[0365] Major diastereomer (cis isomer): 1H NMR (500 MHz, chloroform-d) δ ppm 7.46 (s, 1H), 7.36 (s, 1H), 4.36 (dd, J = 11.3, 2.1 Hz, 1H), 4.25 (tt, J = 11.9, 4.5 Hz, 1H), 4.08 (ddd, J = 12.0, 4.8, 1.8 Hz, 1H), 3.89 (s, 3H), 3.58 (td, J = 12.1, 2.3 Hz, 1H), 2.52 (ddt, J = 12.9, 4.3, 2.1, 2.1 Hz, 1H), 2.12-2.26 (m, 3H). m / z (ESI, +ve ion): 245.0 [M+H] + .

[0366] Minor diastereomers (trans isomers): 1 H NMR (500 MHz, chloroform-d) δ ppm 7.46 (s, 1H), 7.35 (s, 1H), 4.93 (dd, J = 10.0, 2.9 Hz, 1H), 4.79 (quin, J = 3.1 Hz, 1H), 4.12 (td, J = 11.6, 2.1 Hz, 1H), 3.92-3.99 (m, 1H), 3.89 (s, 3H), 2.16-2.29 (m, 3H), 1.93-2.02 (m, 1H). m / z (ESI, +ve ion): 245.0 [M+H] + .

[0367] Step 2: (2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II) bromide. Zn (0.320 g, 4.90 mmol) was added to an oven-dried 50 mL flask, which was then evacuated and filled with N2 three times, and the flask was capped with a rubber septum. A thermocouple probe was then inserted and anhydrous THCM was added. A 0.5 M solution of lithium chloride in F (3.26 mL, 1.632 mmol) was added. 1,2-Dibromoethane (0.015 g, 7.03 μL, 0.082 mmol) was then added, and the mixture was heated to an internal temperature of 50°C and held for 20 minutes. The flask was removed from the heating block and allowed to cool to room temperature. Chlorotrimethylsilane (8.86 mg, 10.36 μL, 0.082 mmol) was added, and the mixture was heated to an internal temperature of 50°C and held at that temperature for 20 minutes. The flask was removed from the heating block and allowed to cool to room temperature. Diiodine (8.28 mg, 0.033 mmol) was added as a 0.1 mL solution in THF, and the mixture was heated to an internal temperature of 50°C and held at that temperature for 20 minutes. While hot, 4-bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (3:1 cis / trans mixture, 0.4 g, 1.632 mmol) was added as a THF solution (1.5 mL), and the resulting mixture was stirred overnight at 50° C. The reaction solution was cooled to room temperature, at which point zinc powder precipitated, giving a yellow solution of (2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II) bromide. [Table 18]

[0368] Method 23 Intermediate 79: 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole [ka] Step 1: A 20 mL scintillation vial was charged with 1-methyl-1H-pyrazole-4-carbaldehyde (200 mg, 1.816 mmol) and purged with N. (2-hydroxyethyl)acetylene (191 mg, 206 μL, 2.72 mmol) and DCM (3.6 mL) were then added. Trifluoromethanesulfonic acid (327 mg, 194 μL, 2.180 mmol) was slowly added to the vial at 0 °C. After 5 min, the reaction was allowed to warm to room temperature. After 5 h, additional trifluoromethanesulfonic acid (327 mg, 194 μL, 2.180 mmol) was added. After an additional 18 h, the crude reaction was carefully quenched with saturated NaHCO solution and washed with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with 0% to 70% EtOAc in heptane to afford 6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (227 mg, 0.727 mmol, 40% yield) as a pale yellow oil. m / z (ESI, +ve ion): 313.0 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ ppm 7.49 (s, 1H), 7.37 (s, 1H), 5.96 (dt, J = 2.6, 1.4 Hz, 1H), 5.34 (q, J = 2.6 Hz, 1H), 3.98-4.04 (m, 1H), 3.92 (s, 3H), 3.85 (ddd, J = 11.5, 6.4, 5.2 Hz, 1H), 2.45-2.60 (m, 2H).

[0369] Step 2: 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole. A 20 mL scintillation vial was loaded with 6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (227 mg, 0.727 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with DCM (59.4 mg, 0.073 mmol), bis(pinacolato)diboron (277 mg, 1.09 mmol), and potassium acetate (285 mg, 2.91 mmol). The flask was purged with N2 and 1,4-dioxane (2.9 mL) was added. The reaction was heated to 90 °C for 2 h, and the reaction was cooled to room temperature. The reaction mixture was diluted with EtOAc and filtered through a plug of silica gel. The crude material was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to afford 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (87 mg, 0.30 mmol, 41% yield) as a red oil. m / z (ESI, +ve ion): 291.2 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ ppm 7.48 (s, 1H), 7.36 (s, 1H), 6.61 (q, J = 1.9 Hz, 1H), 5.20 (q, J = 2.6 Hz, 1H), 3.89-3.93 (m, 1H), 3.89 (s, 3H), 3.71-3.78 (m, 1H), 2.28-2.39(m,1H), 2.17-2.27(m,1H), 1.30(s,12H). [Table 19]

[0370] Method 24 Intermediate 83: 2-chloro-4-(3-methoxyazetidin-1-yl)-6,7-dimethylpteridine [ka] To a 10 mL vial containing 3-methoxyazetidine (0.026 g, 0.3 mmol) in DMF (1 mL) was added 2,4-dichloro-6,7-dimethylpteridine (Intermediate 3) (0.069 g, 0.3 mmol) and diisopropylethylamine (0.209 mL, 1.200 mmol). The mixture was heated at 95° C. for 7 h and then cooled to room temperature. Conversion to the desired product (LCMS analysis) was high, and the mixture was used without purification. [Table 20-1] [Table 20-2]

[0371] Method 25 Intermediate 93: 2-chloro-4-((3,3-difluorocyclobutyl)methoxy)-6,7-dimethylpyrido[2,3-d]pyrimidine [ka] To a 10 mL vial was added 2,4-dichloro-6,7-dimethylpyrido[2,3-d]pyrimidine (49.8 mg, 0.218 mmol) and (3,3-difluorocyclobutyl)methanol (32.0 mg, 0.262 mmol) in tetrahydrofuran (1091 μL). The mixture was cooled to 0 °C, and potassium t-butoxide (262 μL, 0.262 mmol) solution was added. After stirring for 1 h, the solution was quenched with HO (10 mL), extracted with EtOAc, and the organic layer was dried over NaSO and concentrated in vacuo. The crude product, 2-chloro-4-((3,3-difluorocyclobutyl)methoxy)-6,7-dimethylpyrido[2,3-d]pyrimidine, was used in the subsequent step without further purification. [Table 21]

[0372] Method 26 Intermediate 97: (S)-4-(4-chloro-6,7-dimethyl-1,8-naphthyridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine [ka] To a solution of 5,7-dichloro-2,3-dimethyl-1,8-naphthyridine (Intermediate 5, 0.234 g, 1.030 mmol) and DIEA (0.266 g, 0.359 mL, 2.061 mmol) in DMSO (3.4 mL) was added (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Enamine, Monmouth Jct., NJ, USA) (0.207 g, 1.237 mmol). The reaction mixture was stirred at 100 °C for 7 h. After cooling, the mixture was diluted with HO and extracted with DCM. The organic phase was separated, concentrated in vacuo, and purified by silica gel chromatography (0-10% MeOH (+1% NH) in DCM) to give the title compound (S)-4-(4-chloro-6,7-dimethyl-1,8-naphthyridin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.121 g, 0.339 mmol, 33.0%) m / z (ESI, positive ion): 358.0 (M+H). + , and the regioisomeric by-product (S)-4-(2-chloro-6,7-dimethyl-1,8-naphthyridin-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.0183 g, 0.051 mmol, 4.9% yield) ) was obtained. [Table 22]

[0373] Method 27 Intermediate 103: (S)-4-(8-chloro-2,3-dimethylquinoxalin-6-yl)-2-(2-methylpyridin-4-yl)morpholine [ka] To a 25-mL reaction vial was added 7-bromo-5-chloro-2,3-dimethylquinoxaline (0.200 g, 0.737 mmol) and (S)-2-(2-methylpyridin-4-yl)morpholine (0.131 g, 0.737 mmol) in toluene (8 mL), followed by sodium tert-butoxide (0.106 g, 1.105 mmol). The reaction mixture was degassed with nitrogen for 5 minutes, and then RuPhos-Pd-G (0.062 g, 0.074 mmol) and RuPhos (0.034 g, 0.074 mmol) were added. The reaction mixture was then heated at 80 °C for 2 hours. The reaction mixture was diluted with HO (7 mL) and extracted with EtOAc (2 × 10 mL). The organic extract was dried over NaSO and concentrated to give the crude material. Purification by silica gel chromatography (30% to 100% EtOAc in hexanes) gave (S)-4-(8-chloro-2,3-dimethylquinoxalin-6-yl)-2-(2-methylpyridin-4-yl)morpholine (0.170 g, 0.4 The compound (61 mmol, 62.6% yield) was obtained as an orange solid. m / z (ESI, positive ion): 351.0 (M+H). + . [Table 23]

[0374] Method 28 Intermediate 105: (S)-4-amino-6-(2,4-difluorophenyl)-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimidine-5-carbaldehyde [ka] Step 1: 4-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-5-carbaldehyde. In a 100 mL round-bottom flask, add dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II) (0.150 g, 0.198 mmol), (4-chloro-2-fluorophenyl)boronic acid (1.73 g, 9.90 mmol), 4-amino-2,6-dichloropyrimidine-5-carbaldehyde (1.9 g, 9.90 mmol), followed by 2-methyltetrahydrofuran (24. 7 mL) and potassium phosphate (5.57 mL, 22.27 mmol) were added. The vial was flushed under nitrogen (3 times) and the reaction was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature, water was added, and the precipitate was filtered and washed several times with water and diethyl ether. The crude 4-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-5-carbaldehyde (1.3 g, 4.54 mmol, 45.9% yield) was used directly in the next step without further purification. m / z (ESI, positive ion): 270.1 (M+H) + .

[0375] Step 2: (S)-4-Amino-6-(2,4-difluorophenyl)-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimidine-5-carbaldehyde. To a solution of 4-amino-2-chloro-6-(2,4-difluorophenyl)pyrimidine-5-carbaldehyde (0.2 g, 0.742 mmol) and DIEA (0.192 g, 0.258 mL, 1.48 mmol) in DMSO (2.47 mL) was added (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Enamine, Monmouth Jct., NJ, USA) (0.149 g, 0.890 mmol). The reaction mixture was stirred at 80 °C for 1 h, cooled to room temperature, and water was added. The precipitate was filtered and washed several times with water, followed by a small amount of diethyl ether. The resulting solid was dried under vacuum. The crude (S)-4-amino-6-(2,4-difluorophenyl)-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimidine-5-carbaldehyde (0.177 g, 0.441 mmol, 59.5% yield) was used without further purification. m / z (ESI, positive ion): 401.0 (M+H). + . [Table 24]

[0376] Method 29 Intermediate 117: 2,4-Dichloro-7-methylpteridine [ka] To a suspension of 2,6-dichloropyrimidine-4,5-diamine (5.00 g, 27.9 mmol) in DCE (250 mL) was added calcium sulfate (10.0 g, 73.5 mmol), followed by the dropwise addition of 2-oxopropane (40% in water, 5.0 mL, 32.1 mmol). The reaction was stirred overnight at 25° C., then filtered through a plug of Celite and evaporated under reduced pressure to give the desired material as a pale yellow solid (5.3 g, 88%). MS (m / z+): 215.0 [M+1] + , 1H NMR (400 MHz, chloroform-d): 8.93 (1H, s), 2.91 (3H, s). [Table 25]

[0377] method 30 Intermediate 119: 4-((2R,4S)-4-Bromotetrahydro-2H-pyran-2-yl)-1-cyclopropyl-1H-pyrazole [ka] Step 1: Ethyl 1-benzyl-1H-pyrazole-4-carboxylate. To a solution of ethyl 1H-pyrazole-4-carboxylate (11.0 g, 78.5 mmol) in DMF (105 mL) was added cesium carbonate (51.2 g, 157 mmol), followed by benzyl bromide (9.3 mL, 78.4 mmol). The reaction was stirred at room temperature for 3 days. Water was added, and the product was extracted with EtOAc. The combined organic layers were washed several times with HO and then brine, dried over NaSO, filtered, and concentrated in vacuo to afford ethyl 1-benzyl-1H-pyrazole-4-carboxylate as a colorless syrup (16.7 g, 75.3 mmol, 96% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 7.94(s,1H), 7.85(s,1H), 7.43-7.30(m,3H), 7.26-7.22(m,2H), 5.30(s,2H), 4.27(q,J=7.1Hz,2H), 1.32(t,J=7.1Hz,3H). LC / MS(ESI + ) m / z=231.1[M+H] + .

[0378] Step 2: (1-benzyl-1H-pyrazol-4-yl)methanol. To a solution of ethyl 1-benzyl-1H-pyrazole-4-carboxylate (6.37 g, 27.7 mmol) in THF (69 mL) at 0 °C was slowly added lithium aluminum hydride (2 M in THF, 28 mL, 56.0 mmol). The solution was warmed to room temperature and stirred for 1 h. The reaction was cooled to 0 °C and water (2.2 mL) was added dropwise, followed by 1 M NaOH (6.0 mL) and water (2.2 mL). The solid was filtered through Celite and the filter cake was rinsed with EtOAc. The filtrate was concentrated in vacuo to give (1-benzyl-1 H-pyrazol-4-yl)methanol (4.43 g, 22.8 mmol, 85% yield) was obtained as a colorless syrup. 1 H NMR (400MHz, chloroform-d) δ ppm 7.54(s,1H), 7.41-7.28(m,4H), 7.25-7.19(m,2H), 5.28(s,2H), 4.57(s,2H). LC / MS(ESI + ) m / z = 189.1 [M+H] + .

[0379] Step 3: 1-Benzyl-1H-pyrazole-4-carbaldehyde. To a solution of (1-benzyl-1H-pyrazol-4-yl)methanol (4.43 g, 22.8 mmol) in DCM (40 mL) was added activated manganese(IV) oxide (20.7 g, 235 mmol) in portions. The mixture was stirred at room temperature overnight. The solid was filtered through Celite and rinsed with DCM. The filtrate was concentrated in vacuo, and the crude material was purified by silica gel chromatography eluting with 0–40% EtOAc in hexanes to give 1-benzyl-1H-pyrazole-4-carbaldehyde-1 (3.41 g, 18.3 mmol, 76% yield) as a colorless syrup. 1 H NMR (400 MHz, chloroform-d) δ ppm 9.84 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.44-7.32 (m, 3H), 7.31-7.21 (m, 2H), 5.34 (s, 2H). LC / MS (ESI + ) m / z = 187.1 [M+H] + .

[0380] Step 4: 1-benzyl-4-(4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole. To a solution of 1-benzyl-1H-pyrazole-4-carbaldehyde (3.05 g, 16.4 mmol) and 3-buten-1-ol (1.5 mL, 17.0 mmol) in DCM (41 mL) at 0 °C was added dropwise 33% hydrobromic acid in acetic acid (8.1 mL, 49.1 mmol). The solution was allowed to warm slowly to room temperature overnight. The solution was then cooled to 0 °C and slowly quenched with saturated NaHCO3 solution. The product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-35% EtOAc in hexanes to give 1-benzyl-4-(4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole (4.13 g, 12.9 mmol, 75% yield) as a 1:1 mixture of cis / trans diastereomers (reported as a 1:1 mixture of cis and trans diastereomers). 1 H NMR) 1 H NMR(400MHz,chloroform-d)δ ppm 7.50(s,2H), 7.39-7.27(m,8H), 7.24-7.19(m,4H), 5.26(s,4H), 4.90(dd,J=9.8,3.1Hz,1 H), 4.76(t,J=3.4Hz,1H), 4.33(dd,J=11.4,2.0Hz,1H), 4.21(tt,J=11.8,4.5Hz,1H), 4.13 -4.01(m,2H), 3.92(dd,J=12.3,4.7Hz,1H), 3.54(td,J=12.1,2.3Hz,1H), 2.48(dt,J=14. 0,2.8Hz,1H), 2.25-2.18(m,2H), 2.18-2.12(m,3H), 2.11-2.03(m,1H), 1.99-1.87(m,1H). LC / MS(ESI + ) m / z=320.9[M+H] + .

[0381] Step 5: 1-benzyl-4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole. The racemic product was purified by chiral SFC on a ChiralART Cel-SB column, 5-60% MeOH in aqueous NH4OH to give 1-benzyl-4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.50 (s, 1H), 7.44-7.28 (m, 4H), 7.22 (d, J = 7.1 Hz, 2H), 5.26 (s, 2H), 4.33 (dd, J = 11.4, 2.2 Hz, 1H), 4.26-4.13 (m, 1H), 4.12-3.95 (m, 1H), 3.54 (tt, J = 12.1, 2.2 Hz, 1H), 2.48 (ddd, J = 13.1, 4.5, 2.2 Hz, 1H), 2.27-2.18 (m, 1H), 2.11 (qd, J =11.9,5.1Hz,2H). LC / MS(ESI+)m / z=321.0[M+H] + .

[0382] Step 6: 4-((2R,4S)-4-Bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole. A solution of 1-benzyl-4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole (400 mg, 1.25 mmol) in EtOH (6.5 mL) and acetic acid (2.2 mL) was purged with argon via balloon and outlet for 10 minutes. Palladium hydroxide on carbon (70 mg, 0.25 mmol) was quickly added, and the solution was purged with argon via balloon and outlet for an additional 10 minutes. The argon balloon was replaced with a hydrogen balloon, and the reaction was stirred at room temperature overnight. The catalyst was removed by filtration over Celite and washed several times with ethanol. The filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 30-100% EtOAc in hexanes to give 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole (160 mg, 0.692 mmol, 56% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 12.70(s,1H), 7.68(s,1H), 7.44(s,1H), 4.50(td,J=12.0,5.9Hz,1H), 4.37(dd,J=11.1,2.1Hz,1H), 3.91(dd,J=1 1.8,4.8Hz,1H), 3.51(td,J=12.0,2.1Hz,1H), 2.43(dt,J=13.0,2.6Hz,1H), 2.26-2.12(m,1H), 2.07-1.87(m,2H). LC / MS(ESI+)m / z=230.0[M+H] + .

[0383] Step 7: 4-((2R,4S)-4-Bromotetrahydro-2H-pyran-2-yl)-1-cyclopropyl-1H-pyrazole. To a solution of 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole (150 mg, 0.649 mmol) and cyclopropylboronic acid (112 mg, 1.30 mmol) in dichloroethane (4.3 mL) at 70 °C was added a portion of a mixture of copper(II) acetate (119 mg, 0.649 mmol) and 2,2'-dipyridyl (101 mg, 0.649 mmol). The mixture was stirred overnight at 70 °C under an oxygen atmosphere. The mixture was cooled to room temperature, and saturated NaHCO was added. The product was extracted with DCM, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 10–60% EtOAc in hexanes to give 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1-cyclopropyl-1H-pyrazole (160 mg, 0.561 mmol, 86% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ ppm 7.73(s,1H), 7.36(s,1H), 4.49(tt,J=11.9,4.4Hz,1H), 4.32(dd,J=11.2,2. 0Hz,1H), 3.90(ddd,J=11.8,5.0,1.8Hz,1H), 3.65(tt,J=7.4,3.9Hz,1H), 3.4 9(td,J=12.0,2.1Hz,1H), 2.41(ddt,J=12.6,4.3,2.1Hz,1H), 2.17(ddd,J=12 .7,4.5,2.2Hz,1H), 2.05-1.86(m,2H), 1.05-0.95(m,2H), 0.95-0.87(m,2H). LC / MS(ESI+)m / z=270.8[M+H] + .

[0384] Method 31 Intermediate 120: 4-((2R,4S,6R)-4-bromo-6-methyltetrahydro-2H-pyran-2-yl)-1-cyclopropyl-1H-pyrazole [ka] To iron(III) bromide (3.20 g, 10.8 mmol) in a flame-dried 40 mL pressure vial equipped with a stir bar under argon was added a solution of 1-cyclopropylpyrazole-4-carbaldehyde (1.23 g, 9.03 mmol) and (2R)-pent-4-en-2-ol (778 mg, 9.03 mmol) in DCM (17 mL) at 0 °C under N. The reaction mixture was warmed to room temperature and stirred overnight. Water (20 mL) was added and the mixture was stirred for 30 min. The product was extracted with DCM, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-30% EtOAc in hexanes followed by reverse-phase chromatography eluting with 5-95% MeCN in HO to give 4-[(2R,4S,6R)-4-bromo-6-methyl-tetrahydropyran-2-yl]-1-cyclopropyl-pyrazole (612 mg, 2.10 mmol, 23% yield) as a colorless syrup. 1H NMR(400MHz,chloroform-d)δ ppm 7.66-7.34(m,2H), 4.36(dd,J=11.4,2.0Hz,1H), 4.22(tt,J=12.1,4.5Hz,1H), 3.6 0(ddd,J=11.0,6.2,1.9Hz,1H), 3.54(tt,J=7.3,3.9Hz,1H), 2.45(ddt,J=13.0,4. 4,2.0Hz,1H), 2.28(ddt,J=12.9,4.1,2.0Hz,1H), 2.06(q,J=12.0Hz,1H), 1.78(td ,J=12.5,11.0Hz,1H), 1.25(d,J=6.2Hz,3H), 1.13-1.05(m,2H), 1.04-0.94(m,2H). LC / MS(ESI + ) m / z=285.0[M+H] +

[0385] Method 32 Intermediate 121: 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole [ka] To a solution of 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole (25 mg, 0.108 mmol) in DMF (2.2 mL) was added cesium carbonate (88 mg, 0.270 mmol), followed by methyl iodide (0.0081 mL, 0.130 mmol). The reaction was stirred at room temperature overnight. Water was added and the product was extracted with EtOAc. The combined organic layers were washed several times with HO, then brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0-5% MeOH in DCM to give 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (18 mg, 0.0734 mmol, 68% yield) as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ ppm 7.64(s,1H), 7.36(s,1H), 4.50(tt,J=12.0,4.6Hz,1H), 4.33(d,J=11.3Hz,1H), 3.90(dd,J=11.8,4.8Hz,1H),3. 78(s,3H), 3.50(td,J=11.8,2.0Hz,1H), 2.41(d,J=12.5Hz,1H), 2.17(dd,J=9.9,6.4Hz,1H), 2.04-1.85(m,2H). LC / MS(ESI + ) m / z = 245.0 [M+H] + The absolute configuration of the starting material, 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-1H-pyrazole, was elucidated by X-ray crystallography.

[0386] Method 33 Intermediate 122: 2-(2-methylpyridin-4-yl)morpholine [ka] Step 1: 4-(1-ethoxyvinyl)-2-methylpyridine. A 250 mL pressure vessel was charged with 4-bromo-2-methylpyridine (6.90 mL, 58.1 mmol), 1-ethoxyvinyltributyltin (21.6 mL, 63.9 mmol, 1.1 equiv.), and toluene (100 mL) and purged with N gas at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (2.04 g, 2.91 mmol, 5 mol%) was added under an N atmosphere, and the reaction mixture was purged with N gas at room temperature for 5 minutes. The reaction vessel was sealed and stirred at 110 °C for 16 hours. When the reaction was judged complete by LCMS, the reaction mixture was cooled to room temperature and diluted with KF (3.72 g, 1.1 equiv.), Na-CO (6.78 g, 1.1 equiv.), and silica (30 g) were added. The reaction mixture was stirred for 10 min and filtered through a pad of Celite. The Celite bed was washed with hexane (50 mL) and the combined filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel eluting with 0-5% EtOAc in hexane to give 4-(1-ethoxyvinyl )-2-Methylpyridine was obtained as a colorless oil (7.46 g, 79%). 1 H NMR (400 MHz, DMSO-d): δ H 8.41(d,J=5.2Hz,1H), 7.35(s,1H), 8.41(d,J=4.7Hz,1H), 5.01(s,1H), 4.46(s,1H), 3.91(q,J=6.9Hz,2H), 2.47(s,3H), 1.35(t,J=6.9Hz,3H). ESI-MS(m / z+):164.2[M+H] + , LC-RT: 0.505 min.

[0387] Step 2: 1-(2-methylpyridin-4-yl)ethan-1-one. A suspension of 5-(1-ethoxyvinyl)-2-methylpyridine (7.46 g, 45.7 mmol) in 3 M HCl (30.5 mL, 91.4 mmol, 2 equiv.) was stirred at room temperature for 30 minutes. When the reaction was judged complete by LCMS, the reaction mixture was diluted with water (60 mL), basified to pH 11 with 5 M NaOH, and extracted with EtOAc (3 × 60 mL). The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure to provide 1-(2-methylpyridin-4-yl)ethan-1-one as a colorless oil (5.35 g, 82%). 1 H NMR (400MHz, DMSO-d): δ H 8.65(d,J=5.0Hz,1H), 7.69(s,1H), 7.60(d,J=4.2Hz,1H), 2.49(s,3H), 2.57(s,3H). ESI-MS(m / z+):136.10[M+H] + , LC-RT: 0.202 minutes.

[0388] Step 3: 2-Bromo-1-(2-methylpyridin-4-yl)ethan-1-one. A 100 mL round-bottom flask was charged with 1-(2-methylpyridin-4-yl)ethan-1-one (5.00 g, 37.0 mmol) and HBr (33% in AcOH, 21 mL). The reaction mixture was cooled to 0 °C using an ice / water bath, and a solution of bromine (1.9 mL, 37.0 mmol, 1.0 equiv) in HBr (33% in AcOH, 7 mL) was added dropwise. The reaction mixture was stirred at 40 °C for 1 h and then at 80 °C for an additional 1 h. When the reaction was judged complete by LCMS, the reaction mixture was cooled to room temperature, poured into EtO (100 mL), and stirred at room temperature for 30 min. The precipitate was filtered, washed with EtO (50 mL), and dried under reduced pressure to give 2-bromo-1-(2-methylpyridin-4-yl)ethan-1-one (HBr salt) as a yellow solid (10.7 g, 96%). ESI-MS (m / z+): 274.0 [M+H] + , LC-RT: 1.459 minutes.

[0389] Step 4: 2-(benzyl(2-hydroxyethyl)amino)-1-(2-methylpyridin-4-yl)ethan-1-one. To a solution of 2-bromo-1-(2-methylpyridin-4-yl)ethan-1-one acetate (10.7 g, 39.0 mmol) in THF (182 mL) at 0 °C, N-benzylethanolamine (5.54 mL, 39.0 mmol, 1.0 equiv.) was slowly added, followed by DIPEA (13.6 mL, 78.1 mmol). The reaction was allowed to warm gradually to room temperature overnight, after which a precipitate formed. The solvent was removed in vacuo. Water was then added to the reaction mixture, and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over NaSO, filtered, and concentrated in vacuo to give 2-(benzyl(2-hydroxyethyl)amino)-1-(2-methylpyridin-4-yl)ethan-1-one (11.1 g, 100%) as a yellow solid. ESI-MS (m / z+): 285.10 [M+H] + , LC-RT:0.642 min.

[0390] Step 5: 2-(benzyl(2-hydroxyethyl)amino)-1-(2-methylpyridin-4-yl)ethan-1-one. A 500 mL round-bottom flask was charged with 2-(benzyl(2-hydroxyethyl)amino)-1-(2-methylpyridin-4-yl)ethan-1-one (11.10 g, 39.0 mmol, 1 equiv) in methanol (390 mL) and cooled to 0 °C. Sodium borohydride (2.95 g, 78.1 mmol, 2.0 equiv) was added in portions, and the reaction was then allowed to warm gradually to room temperature over 12 h. When the reaction was judged complete by LCMS, the solution was cooled to 0 °C and water (250 mL) was added. The product was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the pure product 2-(benzyl(2-hydroxyethyl)amino)-1-(2-methylpyridin-4-yl)ethan-1-ol (8.45 g, 29.5 mmol, 75.6%) as a clear oil. ESI-MS (m / z+): 287.20 [M+H] + , LC-RT: 0.215 min.

[0391] Step 6: 2-(2-Methylpyridin-4-yl)morpholine hydrochloride. A flame-dried 50 mL round-bottom flask under nitrogen was charged with 4-benzyl-2-(2-methyl-4-pyridyl)morpholine (1.00 equiv., 1.35 g, 5.03 mmol), Pd / C (0.252 equiv., 135 mg, 1.27 mmol), and HCl (4 M in dioxane, 1.00 equiv., 5.03 mmol). The reaction vial was purged with N2, and then H2 was bubbled through the reaction mixture for 2 minutes. The needle was removed from the solution, and the reaction was stirred under a positive pressure (balloon) of H2 at room temperature overnight. Complete conversion was observed by TLC and LCMS. The reaction mixture was filtered through a pad of Celite and the solvent was removed in vacuo to give the desired 2-(2-methyl-4-pyridyl)morpholine hydrochloride (1.01 g, 4.70 mmol, 93.51%): ESI-MS (m / z+): 179.1 [M+H]+, LC-RT: 0.240 min. 1 H NMR (DMSO-d6, 400 MHz): δ H8.53(1H,d,J=5.4Hz), 7.45(1H,s), 7.36(1H,d,J=5.3Hz), 4.94(1H,d,J=11.0Hz), 4.13(1H,d,J=12.7Hz), 4 .00(1H,t,J=12.3Hz), 3.52(1H,d,J=12.7Hz), 3.06(1H,t,J=12.4Hz), 2.90(1H,t,J=11.9Hz), 2.54(3H,s).

[0392] Method 34 Intermediate 123: 2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine [ka] Step 1: 1-(1H-pyrazol-4-yl)ethane- in DMF (100 mL) To a stirred solution of 1-pyrazol-4-yl (10 g, 0.1 mol) and CsCO (48.3 g, 0.15 mol) was added dropwise (bromomethyl)benzene (20.3 g, 0.12 mol) at room temperature under N. The reaction was stirred at 80 °C for 1 h. The mixture was poured into water (500 mL) and extracted with EA (100 mL × 3). The organic phase was washed with brine (100 mL × 2), dried over NaSO, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE:EA = 5:1) to give 1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (16.0 g) as a pale yellow solid. LCMS: (M+H) + =201.1; Purity = 97.36% (UV254nm); Retention time = 1.542 minutes.

[0393] Step 2: To a solution of 1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (3.9 g, 19.47 mmol) in 1,4-dioxane (40 mL) was added CuBr (7.23 g, 32.37 mmol) at room temperature. After the addition, the reaction mixture was stirred at 85 °C for 7 h. The reaction mixture was poured into water (160 mL) and extracted with EA (80 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column (PE / EA, 1:10 to 1:5) to give 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one (2.9 g, 10.39 mmol) as a white solid. LCMS: (M+H) + =280;Holding time=1.75 minutes

[0394] Step 3: To a solution of compound 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one (2.9 g, 10.39 mmol) in THF (20 mL) at room temperature, 1-(benzylamino)propan-2-ol (1.89 g, 11.44 mmol) was added slowly under N2. The reaction mixture was stirred at 35 °C for 3 h to give a yellow solution. Water (20 mL) was added dropwise to quench the reaction. The reaction mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The combined crude material was absorbed onto a plug of silica gel and purified by chromatography on a silica gel column eluted with PE / EA (1:10 to 1:2) to give the compound 2-(benzyl(2-hydroxypropyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (2.81 g, 7.73 mmol). LCMS: (M+H) + =364;Retention time=1.34 minutes

[0395] Step 4: To a solution of compound 2-(benzyl(2-hydroxypropyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (2.8 g, 7.70 mmol) in methanol (28 mL) at 0 °C, sodium tetrahydroborate (0.58 g, 15.40 mmol) was added portionwise. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 2 h. Ice-cold water (20 mL) was added dropwise to quench the reaction. The reaction mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 1-(benzyl(2-(1-benzyl-1H-pyrazol-4-yl)-2-hydroxyethyl)amino)propan-2-ol (2.8 g, 7.66 mmol) as a yellow liquid compound, which was used directly in the next step without further purification. LCMS: (M+H) + =366;Retention time=1.42 minutes

[0396] Step 5: To a solution of compound 1-(benzyl(2-(1-benzyl-1H-pyrazol-4-yl)-2-hydroxyethyl)amino)propan-2-ol (2.8 g, 7.66 mmol) in 1,4-dioxane (15 mL) at room temperature, 6 M HCl (15 ml) was added slowly. The reaction mixture was stirred at 110 °C for 4 h. 15% KOH was added dropwise to quench the reaction and adjust the pH to 8-9. The reaction mixture was extracted with EA (100 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)-6-methylmorpholine ( 2.39 g, 6.88 mmol) was obtained as a yellow liquid compound, which was used directly in the next step without further purification. LCMS: (M+H) + =348;Holding time=1.40 minutes

[0397] Step 6: To a solution of 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)-6-methylmorpholine (2.39 g, 6.88 mmol) in methanol (12 mL) and 2.4 mL of HCl (6 M), Pd(OH)2 / C (0.48 g) was added and the reaction mixture was stirred at 30 °C for 16 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and the residue was adjusted to pH 9-10 with aqueous Na2CO3. The aqueous phase was used directly in the next step. LCMS: (M+H) + =168;Retention time=0.37 minutes

[0398] Step 7: To a solution of Step 6 in water / 1,4-dioxane (10 mL / 10 mL) was added Na2CO3 (0.88 g, 8.30 mml) and BoC2O (1.58 g, 7.24 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (20 mL) and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give crude tert-butyl 2-methyl-6-(1H-pyrazol-4-yl)morpholine-4-carboxylate. The crude product was used directly in the next step. LCMS: (M+H) + =268;Retention time=1.57 minutes

[0399] Step 8: To a solution of tert-butyl 2-methyl-6-(1H-pyrazol-4-yl)morpholine-4-carboxylate (1.77 g, 6.62 mmol) in DMF (35 mL) was added cyclopropylboronic acid (1.71 g, 19.9 mmol), Cu(OAc) (1.32 g, 7.27 mmol), NaCO (1.40 g, 13.2 mmol), and 2,2'-dipyridyl (1.14 g, 7.30 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 10 h. The mixture was poured into water (100 mL) and extracted with EA (60 mL × 3). The organic phase was washed with brine (60 mL × 2), dried over NaSO, and filtered. The filtrate was concentrated in vacuo and the crude product was purified by silica gel column (PE / EA, 1:10 to 1:5) to give tert-butyl 2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine-4-carboxylate (1.6 g, 5.20 mmol) as a yellow liquid. LCMS: (M+H)+ = 308; retention time = 1.51 min.

[0400] Step 9: To a solution of tert-butyl 2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine-4-carboxylate (1.6 g, 5.20 mmol) in dichloromethane (10 mL), TFA (3 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The filtrate was concentrated in vacuo to give 2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (1.02 g, 4.93 mmol) as a yellow liquid. LCMS: (M+H)+ = 208; retention time = 1.14 min.

[0401] Method 35 Intermediate 124: 2-chloro-4-(4-chloro-2,3-difluoro-phenyl)-6,7-dimethyl-pteridine [ka] To a 20 mL microwave vial was added 2,4-dichloro-6,7-dimethyl-pteridine (500 mg, 2.18 mmol), (4-chloro-2,3-difluoro-phenyl)boronic acid (420 mg, 2.18 mmol), sodium carbonate (694 mg, 6.55 mmol), 1,4-dioxane (10 mL), and water (3 mL). The reaction mixture was degassed with nitrogen for 10 minutes. Pd(PPh3)4 (126 mg, 0.109 mmol) was added, and the reaction mixture was heated at 40 °C for 3.5 hours. The mixture was cooled to room temperature and diluted with DCM (50 mL) and water (10 mL). The aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40 g SilicaSep column) using EtOAc and hexanes (50-60%) to give 2-chloro-4-(4-chloro-2,3-difluoro-phenyl)-6,7-dimethyl-pteridine (176 mg, 0.516 mmol, 24%) as a brown solid. ESI-MS (m / z+): 342.0 [M+H] + , LC-RT:3.579 minutes. 1 H NMR (400MHz, CDCl3) δ ppm 7.53-7.46(m,1H), 7.43-7.35(m,1H), 2.86(s,3H), 2.75(s,3H). 19 F NMR (376MHz, CDCl3) δ ppm -130.92(s), -137.18(s). [Table 26]

[0402] method 36 Intermediate 126: 2-chloro-6,7-dimethyl-4-(6-(trifluoromethyl)pyridin-3-yl)pteridine [ka] To a 20 mL sealed tube were added 2,4-dichloro-6,7-dimethylpteridine (2 equiv., 1.2 g, 5.24 mmol) and 2-trifluoromethyl-pyridine-5-boronic acid (1 equiv., 500 mg, 2.62 mmol), 1,4-dioxane (24.0 mL), and water (4.0 mL). Potassium carbonate (6 equiv., 2.18 g, 15.8 mmol) was added, and the reaction mixture was degassed with nitrogen for 10 minutes. RuPhos Pd G3 (0.1 equiv., 200 mg, 283 μmol) was added, and the reaction mixture was heated at 50 °C for 1 hour. The mixture was cooled to room temperature, diluted with water (50.0 mL), and extracted with EtOAc (3 × 100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (120 g cartridge) using hexanes and EtOAc (50-60%) to afford 2-chloro-6,7-dimethyl-4-(6-(trifluoromethyl)pyridin-3-yl)pteridine as a brown solid (867 mg, 65%). 1 H NMR (400MHz, CDCl3) δ ppm 9.88(s,1H), 8.94(d,J=8.3Hz,1H), 7.91(d,J=8.2Hz,1H), 2.89(s,3H), 2.83(s,3H). 19 F NMR (376 MHz, chloroform-d) δ ppm -68.2 (s). m / z (ESI+): 340.0 [M+H] + .

[0403] method 43 Intermediate 109: (S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine [ka] Step 1: To a 3 L round-bottom flask was added 1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (70.0 g, 350 mmol) in dichloromethane (2000 mL), and ethanol (550 mL) and pyridinium tribromide (117 g, 367 mmol) were added in portions at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with 1 N sodium sulfate solution (1.5 L) and extracted with CHCl (2 x 1500 mL), and the organic extract was dried over NaSO. The solution was filtered and concentrated in vacuo to give the crude product as an off-white solid. This crude product was used directly in the next step. 1 H NMR (400MHz, DMSO-d6): δ ppm 8.65 (s, 1H), 8.05 (s, 1H), 7.28-7.38 (m, 5H), 5.39 (s, 2H), 4.60 (s, 2H). [ka]

[0404] Step 2: To a 3 L round-bottom flask was added 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one (203.0 g, 727 mmol) in tetrahydrofuran (2000 mL). The reaction mixture was cooled to 0 °C, and then 2-(benzylamino)ethan-1-ol (176 g, 1164 mmol) was added. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 5 hours. The reaction mixture was diluted with water (1500 mL), extracted with EtOAc (2 × 1500 mL), and the organic extract was dried over Na SO . The solution was filtered and concentrated in vacuo to give crude 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (240 g, 687 mmol, 94% yield) as a pale yellow oil. This crude product was used directly in the next step. 1H NMR(400MHz,DMSO-d6):δ ppm 8.57(s,1H), 7.97(s,1H), 7.20-7.31(m,10H), 5.36(s,2H), 4.44(t,J=5. 2Hz,1H), 3.68(d,J=3.1Hz,2H), 3.46-3.50(m,4H), 2.60(t,J=6.2Hz,2H). [ka]

[0405] Step 3: To a 3 L round-bottom flask was added 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (240.0 g, 687 mmol) in methanol (2500 mL) and the reaction mixture was cooled to 0 °C. Sodium borohydride (52.0 g, 1374 mmol) was added in portions and the reaction mixture was stirred at 0 °C, then warmed to room temperature and stirred for 3 h. The solvent was evaporated under reduced pressure and the crude material was diluted with water (700 mL) and extracted with CHCl (2 × 500 mL), and the organic extract was dried over NaSO. The solution was filtered and concentrated in vacuo to give crude (2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-ol (236 g, 672 mmol, 98% yield) as a pale colorless oil. The crude product was used directly in the next step. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.62(s,1H), 7.19-7.35(m,11H), 5.26(s,2H), 4.82(d,J=3.8Hz,1H), 4.61-4.64(m ,1H), 4.37(t,J=5.4Hz,1H), 3.68(d,J=3.5Hz,2H), 3.40-3.46(m,2H), 2.64(m,4H). [ka]

[0406] Step 4: To a 3 L round-bottom flask was added 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-ol (236.0 g, 672 mmol) in 6 N HCl (2000 mL, 1.20E+04 mmol) at room temperature, and the reaction mixture was heated at 110° C. for 3 hours and then cooled to room temperature. The solvent was evaporated under reduced pressure to give the crude material. The crude material was dissolved in water (300 mL), basified to pH 9 with 10% sodium bicarbonate solution, extracted with ethyl acetate (2×800 mL), and the organic extract was dried over NaSO. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a pre-packed silica gel column (330 g) eluting with a gradient of 5% to 80% EtOAc in hexanes to give 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine (152 g, 456 mmol, 67.9% yield) as a light brown oil. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.74(s,1H), 7.19-7.39(m,11H), 5.25(s,2H), 4.43-4.46(dd,J=11.1,2.3Hz,1H), 3.78-3.81(dd,J=11 .7,2.4Hz,1H), 3.49-3.61(m,3H), 2.79(dd,J=12.2,2.4Hz,1H), 2.57-2.65(m,1H), 2.05-2.17(m,2H). [ka]

[0407] Step 5: Chiral Separation. The enantiomers were separated via supercritical fluid chromatography. (S)-4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine was collected as the first eluting product. [ka]

[0408] Step 6: To a 50 mL round-bottom flask was added (S)-4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine (70 g, 210 mmol) in ethanol (7 mL) and HCl (12.76 mL, 420 mmol), and 10% palladium hydroxide on carbon (36.9 g, 52.5 mmol) was added, and the reaction mixture was stirred under 5 kg of hydrogen gas. The mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated to give (S)-2-(1H-pyrazol-4-yl)morpholine dihydrochloride (40 g, 177 mmol, 84% yield). 1 H NMR(400MHz,DMSO-d6):δ ppm 9.86(s,1H), 9.70(s,1H), 7.68(d,J=2.8Hz,2H), 4.81(dt,J=11.2,2.7Hz,1H), 4.00(dd,J=12.6,4.0Hz,1H) , 3.91(tt,J=12.4,2.7Hz,1H), 3.34(d,J=12.6Hz,1H), 3.20(d,J=12.6Hz,1H), 3.03(dq,J=22.6,11.3Hz,2H) [ka]

[0409] Step 7: To a 1 L round-bottom flask was added (S)-2-(1H-pyrazol-4-yl)morpholine dihydrochloride (40.0 g, 177 mmol) in dichloromethane (800 mL), fo...

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[Claim 1] An invention as described in the specification or drawings.

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