TW202535376A - Heterocyclic pyridinone compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use - Google Patents

Abstract

The present disclosure provides compounds of Formula (I), useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 ("TREM2"). This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a neurodegenerative disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula (I).

Description

Heterocyclic pyridinone compounds as agonists of trigger receptor 2 expressed on bone marrow cells and their methods of use.

This disclosure provides compounds suitable for activating trigger receptor 2 (“TREM2”) expressed on bone marrow cells. This disclosure also provides pharmaceutical compositions comprising such compounds, uses of such compounds, and compositions for treating, for example, neurodegenerative diseases. Furthermore, this disclosure provides intermediates suitable for use with compounds of formula (I).

Microglia are resident innate immune cells in the brain and are crucial for maintaining homeostatic conditions in the central nervous system (Hickman et al., Nat Neurosci 2018; Li and Barres, Nat Rev Immunol. , 2018). These resident macrophages exhibit a variety of receptors that allow them to sense changes in their microenvironment and alter their phenotype to mediate responses to invading pathogens, protein toxicity stress, cellular damage, and other infarcts that may occur in health and disease. (Ibid .) Microglia are commonly found in the brain and spinal cord parenchyma. In addition to other types of glial cells (Domingues et al., Front Cell Dev Biol, 2016; Liddelow et al., Nature, 2017; Shinozaki et al., Cell Rep. , 2017), they also interact with neuronal cell bodies (Cserep et al., Science , 2019) and neuronal processes (Paolicelli et al., Science , 2011; Ikegami et al., Neruopathology , 2019), playing a role in a variety of physiological processes. When rapidly proliferating in response to stimulation, microglia exhibit characteristic bone marrow cell functions, such as phagocytosis, intercytokine/chemotransferase release, antigen presentation, and migration (Colonna and Butovsky, Annu Rev Immunol, 2017). More specific functions of microglia include the ability to prune synapses from neurons and to communicate directly with highly leveled cellular processes in the regions surrounding neuronal cell bodies (Hong et al., Curr Opin Neurobiol, 2016; Sellgren et al., Nat Neurosci, 2019).

Microglial cell plasticity and its various states, as described by single-cell RNA-Seq mapping, are thought to arise from the integration of signaling from arrays of receptors on different cell surfaces (Hickman et al., Nat Neurosci, 2013). These are collectively referred to as microglial cell "sensomes," which are responsible for transducing or activating inhibitory intracellular signaling and include protein families such as sialic acid-binding immunoglobulin-type lectin ("SIGLEC"), toll-like receptors ("TLRs"), Fc receptors, nucleotide-binding oligomer domains ("NODs"), and purine G protein-coupled receptors. (Doens and Fernandez 2014, Madry and Attwell 2015, Hickman and El Khoury 2019). Similar to other cells in the bone marrow lineage, the composition of microglial receptors is dynamically regulated and serves to identify molecular patterns that guide phenotypic responses to stable changes in the central nervous system (“CNS”). Ibid. One of the receptors selectively expressed by brain microglial cells is TREM2, which consists of a single transmembrane domain responsible for ligand interactions, an extracellular stem region, and an extracellular immunoglobulin-variable (“IgV”) domain (Kleinberger et al., Sci Transl Med , 2014). Since TREM2 lacks an intracellular signaling-mediating domain, biochemical analyses have demonstrated that its interaction with the transfer proteins DAP10 and DAP12 mediates downstream signaling after ligand recognition (Peng et al., Sci Signal 2010; Jay et al., Mol Neurodegener, 2017). The TREM2/DAP12 complex particularly functions as a signaling unit, characterized by activation of microglial cell phenotypes excluding peripheral macrophages and osteoclasts (Otero et al., J Immunol, 2012; Kobayashi et al., J Neurosci, 2016; Jaitin et al., Cell , 2019). In the CNS, TREM2 communication has been studied in the context of ligands such as phospholipids, cell debris, lipoproteins, and myelin (Wang et al., Cell, 2015; Kober and Brett, J Mol Biol, 2017; Shirotani et al., Sci Rep , 2019). In mice lacking functional TREM2 expression or mutant forms of expression receptors, the core observation is the passive microglial response to factors such as demyelination of oligodendrocytes, stroke-induced tissue damage in the brain, and damage from in vivo proteotoxic impurities (Cantoni et al., Acta Neuropathol, 2015; Wu et al., Mol Brain, 2017).

In human genome-wide association studies, coding variants at the TREM2 locus have been associated with late-onset Alzheimer's disease ("LOAD"), linking receptor function impairment with increased disease risk (Jonsson et al., N Engl J Med, 2013; Sims et al., Nat Genet, 2017). Genetic variants of other genes selectively expressed by microglia in the CNS, such as CD33, PLCg2, and MS4A4A/6A, have achieved genome-wide significance in association with LOAD risk (Hollingworth et al., Nat Genet 2011; Sims et al., Nat Genet 2017; Deming et al., Sci Transl Med 2019). In summary, these gene findings link together in a putative biochemical circuit, highlighting the importance of microglial cell innate immune function in LOAD. Furthermore, increases or elevations in the soluble form of TREM2 ("sTREM2") in human cerebrospinal fluid (CSF) are associated with disease progression and the occurrence of pathological markers of LOAD, including phosphorylated Tau (Suarez-Calvet et al., Mol Neurodegener 2019). Moreover, natural history and human biological studies indicate that baseline sTREM2 levels in CSF can classify the rate of temporal volume loss and intermittent memory decline in longitudinally monitored populations (Ewers et al., Sci Transl Med 2019).

In addition to human genetic evidence supporting the role of TREM2 in LOAD, loss-of-conjugation mutations in TREM2 are known to be a cause of early-onset dementia syndrome in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) or Nasu-Hacola disease (NHD) (Golde et al., Alzheimers Res Ther 2013; Dardiotis et al., Neurobiol Aging 2017). This progressive neurodegenerative disease typically presents at age 30 and is pathologically characterized by loss of myelin in the brain, accompanied by neurogliomas, undetermined neuroinflammation, and brain atrophy. Typical neuropsychiatric manifestations usually precede bone abnormalities, such as bone cysts and peripheral bone density loss (Bianchin et al., Cell Mol Neurobiol 2004; Madry et al., Clin Orthop Relat Res 2007; Bianchin et al., Nat Rev Neurol 2010). Given that osteoclasts in the bone marrow lineage are also known to express TREM2, PLOSL-related symptoms of wrist and ankle pain, swelling, and fractures indicate that TREM2 can regulate bone stability via a limited signaling pathway of parallel microglial cells in the CNS (Paloneva et al., J Exp Med 2003; Otero et al., J Immunol 2012). The link between TREM2 function and PLOSL illustrates the importance of receptors in the key physiological state of maintaining bone marrow cell function in the human body.

In addition to transgenic mice with LOAD-related TREM2 R47H loss-of-function mutants, efforts have been made to model TREM2 biology in mice to promote the generation of TREM2 knockout ("KO") mice (Ulland et al., Cell, 2017; Kang et al., Hum Mol Genet 2018). Although they cannot reproduce the neurological performance of PLOSL, TREM2 KO mice show skeletal superstructural abnormalities (Otero et al., J Immunol 2012). When TREM2 KO or mutant mice have been crossbred into a background of familial Alzheimer's disease mice (such as 5XFAD amylogenic mutants), a distinct phenotype has been observed (Ulrich et al., Neuron, 2017). In vivo phenotypes of TREM2 loss-of-function in the CNS include increased plaque burden and decreased secretion of microglial cytokines SPP1 and ostipontin, which are characteristic of microglial responses to amyloidosis (Ulland et al., Cell, 2017). Other rodent studies have confirmed that in familial amyloliquefacilitated AD models, TREM2 loss leads to reduced microglial cell aggregation around plaques and a less dense plaque morphology (Parhizkar et al., Nat Neurosci 2019). Regarding Tau protein dysplasia observed in LOAD, a familial tau disease model in mice demonstrated enhanced diffusion of pathological human Tau aggregates from the injection site into the brains of TREM2 KO mice (Leyns et al., Nat Neurosci 2019). Furthermore, single-cell RNA-Seq studies using aged TREM2 KO mice, 5XFAD familial Alzheimer's disease models, and ALS SOD1 mutant mice as a background indicated that TREM2 receptor function is crucial for the conserved aggregation of phenotypic transformation within microglial cell populations responding to CNS lesions (Keren-Shaul et al., Cell 2017).

In rodent models with elevated TREM2 expression, brain amyloid pathology in 5XFAD transgenic mice showed reduced plaque volume and altered morphology (Lee et al., Neuron, 2018). When TREM2 is overexpressed, changes in immunohistochemical markers associated with brain amyloid pathology are accompanied by a reduction in dystrophic neurons. (Ibid.). Therefore, pharmacological activation of TREM2 is a target of interest for the treatment or prevention of neurodegenerative and other diseases. Although many attempts have been made to alter disease progression by targeting pathological markers of LOAD via anti-amyloid and anti-Tau therapies, TREM2 activators are still needed to address genetically related neuroimmunological patterns such as LOAD. These TREM2 activators are suitable for use as therapeutic agents and remain in existence due to the significant and ongoing social burden they pose on diseases such as Alzheimer's.

First, this paper presents a compound of formula (I). (I) or a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer thereof, wherein: ring A, together with its fused 6-membered ring system, forms a bicyclic system selected from one of the following: (Ii) (I-ii) (I-iii) (I-iv); ^V1 and ^V2 are each independently N, ^NR8b, or S, wherein ^V1 and ^V2 are not both S, and the bonds in the rings containing ^V1 and ^V2 are either single or double bonds, depending on the valence of ^V1 and ^V2 ; ^W1 , ^W2 , ^W3 , and ^W4 are each independently C( ^R10 ), N, or ^NR8b , and the bonds connecting ^W3 and ^W4 , and ^W4 and ^{NR8b, are} either single or double bonds, depending on the valence of ^W3 and W4; X is C( ^R11 ) or N; Y is C( ^R12 ) or N; Z is C( ^R18 ) ₂ or O; R ¹ is a cycloalkyl, heterocycloyl, aryl, or heteroaryl group, each of which may be substituted by one or more ^{R13 groups} ; each ^R2 is independently a _C1-6 alkyl, C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, _{heterocycloyl} , halogen, cyano, -O( ^RA ), -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group may be substituted by one or more ^R14 groups; or two ^R2 groups together with the carbon atom to which they are attached form an alkyl group; ^R3 is hydrogen, _C1-6 alkyl, C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 alkyl, C2 ... _1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, -O( ^RA ) or -N( ^RB )( ^RC ), wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogenated, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted with one or more ^R15s as appropriate; ^R4 and ^R5 are each independently hydrogen, _C1-6 alkyl, _C2-6 alkenyl, C2-6 ynyl, _{C1-6 heteroalkyl} , _C1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )(RC ^{) R6} and ^R7 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, _C1-6 heteroalkyl, C1-6 halogenyl, cycloalkyl, heterocycloyl, _aryl , heteroaryl, halogen, cyano, -O( ^RA ) or -N(RB ⁾ (RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, halogenyl, _cycloalkyl , _{heterocycloyl} , aryl, and heteroaryl are substituted with one or more ^R16 as appropriate; ^R8 is hydrogen, _C1-6 alkyl, C1-6 alkyl, C2-6 alkyl, ^C2-6 alkyl, C1-6 alkyl, C1-6 alkyl, C1-6 alkyl, _cycloalkyl , aryl, and heteroaryl ^. _2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, or N(R ^B )(R ^C ), wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl groups are substituted with one or more R ¹⁶ groups as appropriate; R ^8a is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, or heterocycloyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl groups are substituted with _one or more R ¹⁶ groups as appropriate; R ^8b is absent, hydrogen, C1-6 alkyl, _C2-6 alkenyl, _C1-6 alkyl, C2-6 alkyl, C1 ... _2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, or heterocycloyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, or heterocycloyl is substituted by one or more ^R16 groups as appropriate; ^R9a , ^R9b , and ^R9c are, in each case, independently hydrogen, deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, C1-6 heteroalkyl, _C1-6 halogen, or halogen; ^R10 , ^R11 , and ^R12 are, in each case, independently hydrogen, _C1-6 alkyl _{, C2-6} alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl ... _1-6 halogenated, cycloalkyl, heterocyclic, aryl or heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogenated, cycloalkyl, heterocyclic, aryl and heteroaryl are, where applicable, substituted with one or more ^R16 ; each ^R13 is independently deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogenated, cycloalkyl, heterocyclic, halogen, cyano, -O( ^RA ), -C(O)N( ^RB )( ^RC ) or -N( ^RB )(RC ⁾ ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocyclic group is substituted with one or more ^R17 groups as appropriate; each ^R14 , ^R15 , and ^R16 is independently deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocyclic group is substituted with one or more ^{R17 groups} as appropriate; or two ^R14 , two ^R15 , or two R16 groups. ^16, together with the carbon atom to which it is attached, forms a cycloalkyl, heterocycloyl, aryl, or heteroaryl group, wherein each cycloalkyl, heterocycloyl, aryl, and heteroaryl group is, as appropriate, substituted with one or more R ¹⁷ atoms; each R ^A is independently hydrogen, deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, or -N( ^RB )( ^RC ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group is, as appropriate, substituted with one or more R ¹⁷ atoms; each R ^B and R ^C is independently hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C1-6 heteroalkyl, C _1-6 halogenated, cycloalkyl, heterocyclic, or -C(O)-alkyl, wherein each alkyl, alkenyl, heteroalkyl, halogenated, cycloalkyl, and heterocyclic group is, as appropriate, substituted with one or more R ¹⁷ atoms; or ^RB and ^RC together with the nitrogen atom to which they are attached form -N=C( ^RD )( ^RE ) or a heterocyclic group, wherein the heterocyclic group is, as appropriate, substituted with one or more R ^{17 atoms} ; each ^RD and ^RE is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 heteroalkyl, C _1-6 halogenated, cycloalkyl, or heterocyclic, wherein each alkyl, alkenyl, heteroalkyl, halogenated, cycloalkyl, and heterocyclic group is, as appropriate, substituted with one or more R 17 atoms. ¹⁷ substitution; or each R ¹⁷ is deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, halogen or cyano; or two R ¹⁷ form a lateral group; each R ¹⁸ is independently H, C1-6 alkyl or halogen; and n is 0, _1, 2, 3, 4, 5 or 6.

Second, this article provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, and a pharmaceutically acceptable excipient.

Third, this article provides a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, or a pharmaceutical composition described above, for the treatment or prevention of symptoms associated with loss of TREM2 function in humans.

Fourth, this document provides a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer thereof, or a pharmaceutical composition described above, for the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

Examples of embodiments of this disclosure will now be described in detail. Although certain embodiments of this disclosure will be described, it should be understood that this is not intended to limit the embodiments of this disclosure to those described. Rather, reference to embodiments of this disclosure is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the embodiments of this disclosure as defined in the appended claims.

Cross-Reference to Related Applications This application claims the rights of U.S. Provisional Application No. 63/609,327, filed December 12, 2023, and U.S. Provisional Application No. 63/609,320, filed December 12, 2023, under 35 U.S.C. § 119(e), the full text of which is incorporated herein by reference.

This article provides a compound of formula (I). (I) or a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer thereof, wherein: ring A, together with its fused 6-membered ring system, forms a bicyclic system selected from one of the following: (Ii) (I-ii) (I-iii) (I-iv); ^V1 and ^V2 are each independently N, ^NR8b, or S, wherein ^V1 and ^V2 are not both S, and the bonds in the rings containing ^V1 and ^V2 are either single or double bonds, depending on the valence of ^V1 and ^V2 ; ^W1 , ^W2 , ^W3 , and ^W4 are each independently C( ^R10 ), N, or ^NR8b , and the bonds connecting ^W3 and ^W4 , and ^W4 and ^{NR8b, are} either single or double bonds, depending on the valence of ^W3 and W4; X is C( ^R11 ) or N; Y is C( ^R12 ) or N; Z is C( ^R18 ) ₂ or O; R ¹ is a cycloalkyl, heterocycloyl, aryl, or heteroaryl group, each of which may be substituted by one or more ^{R13 groups} ; each ^R2 is independently a _C1-6 alkyl, C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, _{heterocycloyl} , halogen, cyano, -O( ^RA ), -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group may be substituted by one or more ^R14 groups; or two ^R2 groups together with the carbon atom to which they are attached form an alkyl group; ^R3 is hydrogen, _C1-6 alkyl, C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 alkyl, C2 ... _1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, -O( ^RA ) or -N( ^RB )( ^RC ), wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogenated, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted with one or more ^R15s as appropriate; ^R4 and ^R5 are each independently hydrogen, _C1-6 alkyl, _C2-6 alkenyl, C2-6 ynyl, _{C1-6 heteroalkyl} , _C1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )(RC ^{) R6} and ^R7 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, _C1-6 heteroalkyl, C1-6 halogenyl, cycloalkyl, heterocycloyl, _aryl , heteroaryl, halogen, cyano, -O( ^RA ) or -N(RB ⁾ (RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, halogenyl, _cycloalkyl , _{heterocycloyl} , aryl, and heteroaryl are substituted with one or more ^R16 as appropriate; ^R8 is hydrogen, _C1-6 alkyl, C1-6 alkyl, C2-6 alkyl, ^C2-6 alkyl, C1-6 alkyl, C1-6 alkyl, C1-6 alkyl, _cycloalkyl , aryl, and heteroaryl ^. _2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, or N(R ^B )(R ^C ), wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl groups are substituted with one or more R ¹⁶ groups as appropriate; R ^8a is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, or heterocycloyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl groups are substituted with _one or more R ¹⁶ groups as appropriate; R ^8b is absent, hydrogen, C1-6 alkyl, _C2-6 alkenyl, _C1-6 alkyl, C2-6 alkyl, C1 ... _2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, or heterocycloyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, or heterocycloyl is substituted by one or more ^R16 groups as appropriate; ^R9a , ^R9b , and ^R9c are, in each case, independently hydrogen, deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, C1-6 heteroalkyl, _C1-6 halogen, or halogen; ^R10 , ^R11 , and ^R12 are, in each case, independently hydrogen, _C1-6 alkyl _{, C2-6} alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl ... _1-6 halogenated, cycloalkyl, heterocyclic, aryl or heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogenated, cycloalkyl, heterocyclic, aryl and heteroaryl are, where applicable, substituted with one or more ^R16 ; each ^R13 is independently deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogenated, cycloalkyl, heterocyclic, halogen, cyano, -O( ^RA ), -C(O)N( ^RB )( ^RC ) or -N( ^RB )(RC ⁾ ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocyclic group is substituted with one or more ^R17 groups as appropriate; each ^R14 , ^R15 , and ^R16 is independently deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocyclic group is substituted with one or more ^{R17 groups} as appropriate; or two ^R14 , two ^R15 , or two R16 groups. ^16, together with the carbon atom to which it is attached, forms a cycloalkyl, heterocycloyl, aryl, or heteroaryl group, wherein each cycloalkyl, heterocycloyl, aryl, and heteroaryl group is, as appropriate, substituted with one or more R ¹⁷ atoms; each R ^A is independently hydrogen, deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, or -N( ^RB )( ^RC ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group is, as appropriate, substituted with one or more R ¹⁷ atoms; each R ^B and R ^C is independently hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C1-6 heteroalkyl, C _1-6 halogenated, cycloalkyl, heterocyclic, or -C(O)-alkyl, wherein each alkyl, alkenyl, heteroalkyl, halogenated, cycloalkyl, and heterocyclic group is, as appropriate, substituted with one or more R ¹⁷ atoms; or ^RB and ^RC together with the nitrogen atom to which they are attached form -N=C( ^RD )( ^RE ) or a heterocyclic group, wherein the heterocyclic group is, as appropriate, substituted with one or more R ^{17 atoms} ; each ^RD and ^RE is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 heteroalkyl, C _1-6 halogenated, cycloalkyl, or heterocyclic, wherein each alkyl, alkenyl, heteroalkyl, halogenated, cycloalkyl, and heterocyclic group is, as appropriate, substituted with one or more R 17 atoms. ¹⁷ substitution; or each R ¹⁷ is deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, halogen or cyano; or two R ¹⁷ form a lateral group; each R ¹⁸ is independently H, C1-6 alkyl or halogen; and n is 0, _1, 2, 3, 4, 5 or 6.

In some embodiments, the compound of formula (I) is a compound of formula (I'): (I') or a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer thereof, wherein ring A, together with its fused 6-membered ring system, forms a bicyclic system selected from one of the following: (I-i'), (I-ii') or (I-iii'); W is C(R ¹⁰ ) or N; X is C(R ¹¹ ) or N; Y is C(R ¹² ) or N; R ¹ is cycloalkyl, heterocycloyl, aryl, or heteroaryl, each of which may be substituted by one or more R ¹³ ; each R ² is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ynyl, C _1-6 heteroalkyl, C _1-6 halogen, cycloalkyl, heterocycloyl, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group may be substituted by one or more R ¹⁴ ; or two R 13 groups may be substituted by one or more R 14. ^2. R forms an alkyl group together with the carbon atom to which it is attached; ^R3 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, aryl, heteroaryl, or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, heterocycloyl, aryl, and heteroaryl is, as appropriate, substituted by one or more ^R15 groups; ^R4 and ^R5 are each independently hydrogen, _C1-6 alkyl, C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 alkyl, C2 ... _1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogenated, cycloalkyl, heterocyclic, aryl and heteroaryl are, where applicable, substituted with one or more ^{R14 groups} ; ^R6 and ^R7 are each independently hydrogen, _C1-6 alkyl, C2-6 _alkenyl , _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )(RC ⁾ ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, heterocycloyl, aryl, and heteroaryl group is substituted with one or more ^R16 groups as appropriate; ^R8 is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, or N(R ^B )(R ^C ), wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group is substituted with one or more ^R16 groups as appropriate; ^R8a is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, C _1-6 halogenated, cycloalkyl, or heterocyclic, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogenated, cycloalkyl, or heterocyclic group is, where applicable, substituted with one or more ^R16 groups; ^R9a and ^R9b are each independently _C1-6 alkyl, _C2-6 alkenyl, C2-6 ynyl, C1-6 heteroalkyl, _C1-6 halogenated _, or halogen; ^R10 , ^R11 , and ^R12 are each independently hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _{C1-6 heteroalkyl} , _C1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )(RC ⁾ ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, heterocycloyl, aryl, and heteroaryl group is substituted with one or more ^{R16 groups} as appropriate; each ^R13 is independently deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, halogen, _cyano , -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group is substituted with one or more ^{R17 groups} as appropriate; each ^R14 , ^R15 , and ^R16 is independently deuterium, _C1-6 alkyl ... _2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl and heterocyclic group is, as appropriate, substituted with one or more ^{R17 groups} ; each ^RA is independently hydrogen, deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic or -N( ^RB )( ^RC ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl and heterocyclic group is, as appropriate, substituted with one or more ^{R17 groups} ; each ^RB and R ^C is independently hydrogen, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl or -C(O)alkyl, wherein each alkyl, heteroalkyl, halogen, cycloalkyl and heterocycloyl is, as appropriate, substituted with one or more ^R17s ; each ^R17 is deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, halogen or cyano; and n is 0, 1, 2, 3, 4, 5 or 6.

In some implementations, ring A is (I-i'). In some embodiments, W is C(R ¹⁰ ) (e.g., CH).

In some implementations, ring A is (Ii). In some embodiments, ^W1 is C(R ¹⁰ ) (e.g., CH). In some embodiments, ^W2 is C(R ¹⁰ ) (e.g., CH). In some embodiments, ^W3 is C(R ¹⁰ ) (e.g., CH). In some embodiments, ^W1 , ^W2 , and ^W3 are each N.

In some embodiments, ^R1 is a 4-, 5-, or 6-membered cycloalkyl group, each of which is substituted with one or more ^{R13 groups} as appropriate. In some embodiments, ^R1 is selected from cyclopropyl, cyclopentyl, or cyclohexyl groups, each of which is substituted with one or more R13 ^groups as appropriate. In other embodiments, ^R1 is selected from cyclohexyl, 4,4-difluoro-cyclohexyl, 4-fluoro-cyclohexyl, 4-fluoromethyl-cyclohexyl, (spiro)-cyclopropyl-cyclopropyl- _F2 , bicyclo[1.1.1]-trifluoromethyl, bicyclo[1.1.1]-difluoromethyl, bicyclo[1.1.1]-CF-( _CH3 ) ₂ , bicyclo[1.1.1] _-CH2 - _CF3 , bicyclo[1.1.1] _-CH2 - _CHF2 , _bicyclo [1.1.1]-CF2- _CH3 , bicyclo[1.1.1]-chloro, or bicyclo[2.2.1] _-CF2 - _CH3 . In some embodiments, ^R1 is an aryl or heteroaryl group, each of which is substituted with one or more R13 ^groups as appropriate. In some embodiments, ^R1 is a phenyl or thiazolyl group, each of which is substituted with one or more ^{R13 groups} as appropriate. In some embodiments, ^R13 is deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, or halogen.

In some embodiments, ^R1 is chosen from the following:

In some embodiments, ^R1 _{is -CH2CH2CF3 ,} , , , , , , , , , , , , , , , , , , , , , , or .

In some implementations, ^R1 is , , , , , , , , , , , , , , , , or .

In some implementations, ^R1 is , , , or .

In some embodiments, ^R1 is selected from cycloalkyl or heterocyclic groups, each substituted with one or more ^{R13 groups} as appropriate. In some embodiments, ^R1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl or heterocyclic group, each substituted with one or more ^{R13 groups} as appropriate. In some embodiments, ^R1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl group, each substituted with one or more ^{R13 groups} as appropriate. In some embodiments, ^R1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups, each substituted with one or more ^R13 groups as appropriate. In some embodiments, ^R1 is selected from... , , , , , , , , , , , , , , , , , , , and .

In some embodiments, ^R1 is -O( ^RA ), aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each substituted with one or more ^R13 groups, as appropriate. In some embodiments, ^R1 is selected from phenyl, pyridyl, pyrimidinyl, imidazolyl, ... diazole group, iso azole group, Azolyl, isothiazolyl, thiazolyl, pyrazolyl or pyrazolyl The pyrazyl group, each of which is substituted with one or more R13 ^groups as appropriate. In some embodiments, ^R1 is a phenyl or thiazolyl group, each of which is substituted with one or more ^{R13 groups} as appropriate. In some embodiments, ^R1 is selected from... , , , , , and .

In some embodiments, R ¹³ is deuterium, C _1-6 alkyl, C _1-6 heteroalkyl, cycloalkyl, C _1-6 halogen, halogen, cyano or -C(O)N( ^RB )( ^RC ).

In some embodiments, ^R1 is selected from those described in Table A below.

In some embodiments, ^R6 and ^R7 are each independently hydrogen, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, halogen, cyano, or -O( ^RA ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl, and heterocyclic group is, where appropriate, substituted with one or more ^R16 groups. In some embodiments, ^R6 and ^R7 are each independently _C1-6 alkyl (e.g., _CH3 ). In some embodiments, one of ^R6 and ^R7 is independently _C1-6 alkyl (e.g., _CH3 ), and the other of ^R6 and ^R7 is independently -O( ^RA ) (e.g., _CH3 ). In some implementations, one of ^R6 and ^R7 is selected from those described in Table A below.

In some embodiments, ^R6 and ^R7 are each independently hydrogen, _C1-6 alkyl, _C1-6 heteroalkyl, C1-6 halogen, cycloalkyl, heterocycloyl, aryl, heteroaryl, halogen, cyano, or -O( ^RA ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl, heterocycloyl, aryl, and heteroaryl is, as appropriate, substituted with one or more ^R16 _groups . In some embodiments, one of ^R6 and ^R7 is independently _C1-6 alkyl (e.g., _CH3 ), and the other of ^R6 and ^R7 is independently _C1-6 alkyl or -O( ^RA ) (e.g., _OCH3 ). In some embodiments, one of ^R6 and ^R7 is _CH3 , and the other of ^R6 and ^R7 is _OCH3 . In some embodiments, ^R6 and ^R7 are each independently selected from... , , , , , , , , , , , , and .

In some embodiments, X is C(R ¹¹ ) (e.g., CH ₃ ). In some embodiments, X is N. In some embodiments, X is selected from those described in Table A below.

In some embodiments, X is C(R ¹¹ ) (e.g., CH).

In some embodiments, Y is C(R ¹² ). In some embodiments, Y is N. In some embodiments, Y is selected from those described in Table A below.

In some embodiments, ^R12 is hydrogen, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, heteroaryl, halogen, cyano, or -N( ^RB )( ^RC ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl, and heterocyclic group is, as appropriate, substituted with one or more ^R16 groups. In some embodiments, ^R12 is a _C1-6 alkyl group (e.g., _CH3 , _CD3 ) substituted with one or more R16 ^groups . In some embodiments, ^R12 is a _C1-6 halogen (e.g., _{CHF2 , CF3} ). In some embodiments, ^R12 is a cycloalkyl, heterocyclic, or heteroaryl group substituted with one or more ^{R16 groups} , as appropriate. In some embodiments, ^R12 is selected from those depicted in Table A below.

In some embodiments, Z is C(R ¹⁸ ) _2. In some embodiments, R ¹⁸ is hydrogen or halogen. In some embodiments, R ¹⁸ is F. In some embodiments, Z is O.

In some embodiments, ^R2 is independently a _C1-6 alkyl, _{C2-6 alkenyl, C2-6 alkynyl} , _C1-6 heteroalkyl, _C1-6 halogenyl, cycloalkyl, heterocyclic, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cycloalkyl and heterocyclic group is, as appropriate, substituted with one or more ^R14 groups; or two ^R2 groups together with the carbon atom to which they are attached form an oxy-group. In some embodiments, ^R2 is selected from those depicted in Table A below.

In some embodiments, ^R3 is chosen from the following:

In some embodiments, ^R3 is substituted with a _C1-3 alkyl group containing one or more deuterium groups. In some embodiments, ^R3 is substituted with one to three substituents selected from _-CD3 , _-CHD2 and _-CH2D .

In some embodiments, ^R3 is hydrogen, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, aryl, heteroaryl, -O( ^RA ) or -N( ^RB )( ^RC ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cycloalkyl, heterocycloyl, aryl and heteroaryl are substituted with one or more ^R15s as appropriate. In some embodiments, ^R3 is selected from hydrogen, Cl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

In some embodiments, ^R4 and ^R5 are each independently hydrogen or _C1-6 alkyl.

In some embodiments, ^R4 is selected from those described in Table A below.

In some embodiments, ^R4 and ^R5 are each independently hydrogen or _C1-6 alkyl. In some embodiments, one of ^R4 and ^R5 is selected from those described in Table A below.

In some implementations, n is 0 or 1.

In some implementations, n is 0. In some implementations, n is 1.

In some implementations, ring A is (I-ii'). In some embodiments, W is C(R ¹⁰ ) or N, and R ⁸ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _1-6 halogenyl, cycloalkyl, or heterocyclic, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, halogenyl, cycloalkyl, or heterocyclic group is, as appropriate, substituted with one or more R ¹⁶ groups.

In some implementations, ring A is (I-ii). In some embodiments, V1 is S and V2 is N. In some embodiments, V1 is NR 8b and V2 is N. In some embodiments, V1 is N and V2 is NR 8b . In some embodiments, W1 and W2 are each independently N. In some embodiments, R8 is C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 heteroalkyl, C1-6 halogenyl, cycloalkyl , heterocyclic, or -N(RB)( RC ), wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogenyl, cycloalkyl, and heterocyclic groups are, where applicable, substituted with one or more R16 groups . In some embodiments, R8 is -N( RB )( RC ) . In some embodiments, R B and R C  are each independently C 1-6  alkyl. In some embodiments, RB and RC are each independently CH 3 . In some embodiments, R 8b is a C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C1-6 heteroalkyl, C1-6 halogenyl, cycloalkyl , or heterocycloyl group, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, halogenyl, cycloalkyl, or heterocycloyl group is, as appropriate, substituted with one or more R 16  groups. In some embodiments, R 8b  is a C 1-6  alkyl. In some embodiments, R 8b  is CH 3 .

In some implementations, ring A is (I-iii'). In some embodiments, W is C(R ¹⁰ ) or N, and R ^8a is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C 2-6 ynyl, C _1-6 heteroalkyl, C _1-6 halogenyl, _cycloalkyl , or heterocyclic, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogenyl, cycloalkyl, or heterocyclic group is, as appropriate, substituted with one or more R ¹⁶ groups. In some embodiments, each of R ^9a and R ^9b is hydrogen.

In some embodiments, ring A, together with its fused six-member ring system, forms (I-iii). In some embodiments, ^R8a is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogenyl, cycloalkyl, or heterocycloyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogenyl, cycloalkyl, and heterocycloyl groups are, where appropriate, substituted with one or more ^R16 groups. In some embodiments, ^R8a is _C1-6 alkyl. In some embodiments, ^R8a is _CH3 . In some embodiments, each of ^R9a and ^R9b is hydrogen.

In some embodiments, ring A, together with its 6-member ring system, is selected from... , , and .

In some embodiments, the compound of formula (I) is the compound of formula (Ia). (Ia) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, compound (I) is compound (Ib). (Ib) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of such compound, stereoisomer or tautomer, wherein each of X, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R13 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is the compound of formula (Ic). (Ic) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R2 , ^R3 , R4 ^{, R5} , ^R6 , ^R7 , ^R13 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is the compound of formula (Id). (Id) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, compound (I) is compound (Ie). (Ie) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, compound (I) is compound (If). (If) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R2 , ^R13 , n and their subvariables is as defined for formula (I).

In some embodiments, compound (I) is compound (Ig). (Ig) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula ( ^I ).

In some embodiments, compound (I) is compound (Ih). (Ih) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula ( ^I ).

In some embodiments, compound (I) is compound (Ij). (Ij) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula ( ^I ).

In some embodiments, the compound of formula (I) is the compound of formula (Ik). (Ik) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is the compound of formula (IIl). (Il) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (Im). (Im) r is a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined with respect to formula (I).

In some embodiments, compound (I) is compound (In). (In) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R13 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is the compound of formula (Io). (Io) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R13 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (Ip). (Ip) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, compound (I) is compound (Iq). (Iq) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (Ir). (Ir) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R2 , ^R13 , n and their subvariants is as defined for formula (I).

In some embodiments, the compound of formula (I) is the compound of formula (Is). (Is) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, compound (I) is compound (It). (It) or its pharmaceutically acceptable salt, solvent, stereoisomer or tautomer, or pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined with respect to formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (Iu). (Iu) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, compound (I) is compound (Iv). (Iv) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (Iw). (Iw) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (Ix): (Ix), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of such compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R8b , W1, ^W2 , ^W3 , ^W4 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (Iy): (Iy), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , R3, ^R4 , ^{R5 , R8b, W1 , W2 , W3} , ^W4 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (Iz): (Iz), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , R2, ^{R3 , R4} , ^R5 , ^R8b , ^W3 , ^W4 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (I-aa): (I-aa), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , R5 ^{, R8b ,} W1, ^W2 , ^W3 , n and their subvariables are as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (I-bb): (I-bb), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of X, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R8b , ^W3 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (I-cc): (I-cc), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R8b , ^W1 , ^W2 , ^W3 , n and their subvariables are as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (I-dd): (I-dd), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of such compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R8b , ^W1 , ^W2 , ^W4 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (I-ee): (I-ee), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of ^R1 , ^R2 , ^R3 , ^R8b , ^R10 , ^W3 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (I-ff): (I-ff), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of X, Y, Z, ^R1 , ^R2 , ^R3 , ^R8b , ^W3 , ^W4 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is a compound of formula (I-gg): (I-gg), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of rings A, ^W1 , ^W2 , ^R2 , ^R13 , n and their subvariables is as defined for formula (I).

In some embodiments, the compound of formula (I) is the compound provided in Table A.

This document further provides a pharmaceutical composition comprising one or more of the following and a pharmaceutically acceptable excipient: a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer disclosed herein.

In some embodiments, the compound is a compound of any of the foregoing embodiments or a pharmaceutical composition of the foregoing embodiments, used to treat or prevent symptoms associated with loss of TREM2 function in humans.

This article further provides a method for treating or preventing symptoms associated with loss of human TREM2 function in an individual of need, the method comprising administering to the individual a therapeutically effective amount of a compound or pharmaceutical composition according to any of the foregoing embodiments.

In some embodiments, at least one hydrogen atom of the compound is a deuterium atom. In some embodiments, at least one _C1 - _C6 alkyl group of the compound is substituted with at least one deuterium atom. In some embodiments, ^R6 is _-CD3 . In some embodiments, ^R7 is _-CD3 . In some embodiments, both ^R6 and ^R7 are _-CD3 . In some embodiments, ^R6 and ^R7 are each independently selected from H, D, _-CH3 , _-CD3 , _-CHD2 , and _-CH2D . In some embodiments, ^R6 and ^R7 are each independently selected from _-CH3 , _-CD3 , _-CHD2 , and _-CH2D . In some embodiments, ^R2 is deuterium. In some embodiments, the hydrogen atom attached to the same carbon atom as ^R2 is deuterium. In some embodiments, ^R3 is substituted with a _C1-3 alkyl group containing one or more deuterium groups. In some embodiments, ^R3 is substituted with one to three substituents selected from _-CD3 , _-CHD2 and _-CH2D .

The exemplary compounds disclosed herein are described in Table A below. In some embodiments, the compound is a compound described in Table A or a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, its stereoisomer, or tautomer. Table A. Exemplary Compounds Example number Structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355

The foregoing only outlines certain aspects of this disclosure and is not intended or should be construed as limiting this disclosure in any way.

Formulations and routes of administration Although the compounds disclosed herein may be administered alone in the described uses, the compounds are typically administered in the form of an active ingredient in the pharmaceutical composition. Therefore, in one embodiment, a pharmaceutical composition is provided herein comprising the compounds disclosed herein and one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants and the like, and (where appropriate) other active ingredients. See, for example, Remington: The Science and Practice of Pharmacy, Volumes I and II, 22nd ed., edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vols. I–3), edited by Liberman et al., 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), 1st ed., edited by GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the compound disclosed herein.

The compounds disclosed herein can be administered via any suitable route, in the form of a pharmaceutical composition adapted for such route, and at a dose that is expected to be therapeutically effective. The compounds and compositions presented herein can be administered, for example, in the form of unit formulations containing conventionally pharmaceutically acceptable excipients, via oral, mucosal, topical, percutaneous, rectal, pulmonary, non-intestinal, intranasal, intravascular, intravenous, intraarterial, intraperitoneal, intrathecal, subcutaneous, sublingual, intramuscular, intrasternal, vaginal, or infusion techniques.

Pharmaceutical compositions can take the following forms: tablets, chewable tablets, microtablets, capsules, pills, beads, hard capsules, soft capsules, gelatin capsules, granules, powders, lozenges, patches, creams, gels, capsules, microneedle arrays, syrups, flavored syrups, fruit juices, droplets, injectable solutions, emulsions, microemulsions, ointments, aerosols, aqueous suspensions, or oil suspensions. Pharmaceutical compositions are typically manufactured in dosage units containing a specific amount of the active ingredient.

In one embodiment, this disclosure provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, and a pharmaceutically acceptable excipient.

In another embodiment, this disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, or a pharmaceutical composition comprising the compound, salt, solvent, stereoisomer or tautomer, and thus for use as a pharmaceutical preparation.

According to some embodiments, this disclosure provides a composition comprising the compound of this disclosure or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator. The amount of the compound in the composition of this disclosure is such that it can effectively and measurably activate the TREM2 protein or its mutant in a biological sample or patient. In some embodiments, the amount of the compound in the composition of this disclosure is such that it can effectively and measurably activate the TREM2 protein or its mutant in a biological sample or patient. In some embodiments, the composition of this disclosure is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of this disclosure is formulated for oral administration to a patient.

The disclosed composition can be administered orally, non-enterically, by inhalation spray, topically, rectically, nasally, buccally, vaginally, or via an implantable device. As used herein, "non-enterically" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheath, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the disclosed composition can be an aqueous or oil-based suspension. Such suspensions can be formulated using suitable dispersants or humectants and suspending agents according to techniques known in this art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, non-enteric acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable media and solvents, water, Ringer's solutions, and isotonic sodium chloride solutions are acceptable. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media.

For this purpose, any mild, non-volatile oil, including synthetic mono- or diglycerides, may be used. Fatty acids such as oleic acid and their glyceride derivatives are suitable for the preparation of injectable formulations, such as pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylene form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants 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 commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms may also be used for formulation purposes.

The pharmaceutically acceptable combinations disclosed herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also usually added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. Sweeteners, flavorings, or colorants may also be added as needed.

Alternatively, the pharmaceutically acceptable compositions disclosed herein can be administered in the form of rectal suppositories. Such suppositories can be prepared by mixing the medication with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the medication. Such materials include cocoa butter, beeswax, and polyethylene glycol.

The pharmaceutically acceptable compositions disclosed herein can also be administered topically, especially when the therapeutic target includes areas or organs easily accessible by topical application (including diseases of the eyes, skin, or lower intestine). Suitable topical formulations for use in such areas or organs are readily prepared.

For local application in the lower intestine, it can be administered in the form of rectal suppositories (see above) or in the form of a suitable enema preparation. Local percutaneous patches may also be used.

For topical application, the provided pharmaceutically acceptable composition may be formulated as a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds disclosed herein include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide compounds, emulsified wax, and water. Alternatively, the provided pharmaceutically acceptable composition may be formulated as a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, dehydrated sorbitan monostearate, polysorbate 60, cetearyl wax, cetearyl stearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

For ophthalmic use, the pharmaceutically acceptable composition provided may be formulated as a micron-sized suspension, with or without preservatives (such as ammonium chlorobenzyl), in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment (such as paraffin).

The pharmaceutically acceptable compositions disclosed herein may also be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in pharmaceutical formulation and may be prepared as solutions in brine using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons and/or other conventional solubilizers or dispersants.

Ideally, the pharmaceutically acceptable compositions disclosed herein are formulated for oral administration. Such formulations may or may not be administered with food. In some embodiments, the pharmaceutically acceptable compositions disclosed herein are not administered with food. In other embodiments, the pharmaceutically acceptable compositions disclosed herein are administered with food.

The amount of the disclosed compounds, which can be combined with carrier materials to produce a single-dose combination, will vary depending on the host being treated and the specific administration method. Preferably, the provided combinations should be formulated such that a dose of 0.01 to 100 mg/kg body weight/day can be administered to patients receiving such combinations.

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 used, age, weight, general health, sex, diet, time of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the disclosed compound in the composition also depends on the specific compound in the composition.

As described herein (see the section entitled "Definitions"), it should be understood that the compounds described herein include all stereoisomers, tautomers, or pharmaceutically acceptable salts or solvent compounds of any of the foregoing. Therefore, the scope of the methods and uses provided in this disclosure should also be understood to cover methods and uses employing all such forms.

In addition to their application in human treatment, the compounds described herein are applicable to the veterinary treatment of companion animals, rare animals, and livestock, including mammals, rodents, and similar animals. For example, animals including horses, dogs, and cats can be treated with the compounds described herein.

To avoid being bound by any particular theory, it is important to note that TREM2 is involved in several bone marrow cellular processes, including phagocytosis, proliferation, survival, and the regulation of inflammatory interstitial production (Ulrich and Holtzman, 2016). In recent years, TREM2 has been associated with several diseases. For example, mutations in both TREM2 and DAP12 have been linked to the autosomal recessive disorder Nasuk-Hakola disease, characterized by bone cysts, muscle atrophy, and demyelination (Guerreiro et al., 2013). More recently, variants of the TREM2 gene have been associated with an increased risk of Alzheimer's disease (AD) and other forms of dementia, including frontotemporal dementia. Jonsson et al., 2013; Guerreiro, Lohmann et al., 2013; and Jay, Miller et al., 2015. In particular, the R47H variant has been identified in genome-wide studies as associated with an increased risk of late-onset Alzheimer's disease, with an overall regulated 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 1gV-set domain of the TREM2 protein and has been shown to affect lipid binding and apoptotic cells and Aβ uptake (Wang et al., 2015; Yeh et al., 2016), suggesting disease-related loss of function. Furthermore, post-mortem comparisons of the brains of AD patients with and without the R47H mutation strongly supported loss of novel microglial barrier function for the mutant carriers, with R47H carrier microglial cells presumably exhibiting a reduced ability to compress plaques and limit their spread. Yuan et al., 2016. Impairment of microglia has been reported in animal models of prion protein diseases, multiple sclerosis, and stroke, suggesting that TREM2 may play an important role in supporting the response of microglia to lesions or damage to the central nervous system. Ulrich and Holtzman, 2016. Furthermore, TREM2 blockade gene expression has been shown to exacerbate α-syn-induced inflammation in vitro and worsen dopamine-induced neuronal loss in in vivo AAV-SYN (a Parkinson's disease model). This suggests that damaged microglia TREM2 signaling aggravates neurodegeneration by regulating microglia activation. (Guo et al., 2019). Multiple animal models have also shown that doleoid receptor (TLR) signaling is crucial in the pathogenesis of rheumatoid arthritis (RA) via persistent macrophage expression of pro-inflammatory cytokines. The TLR response was inhibited by reducing MAPK (Erk1/2) activation via TREM2/DAP12 signaling, suggesting that TREM2 activation can act as a negative regulator of the TLR-driven pathogenesis of RA. Huang and Pope 2009.

Based on data indicating that insufficient TREM2 activity affects the function of macrophages and microglia, the compounds disclosed herein are specifically used for conditions such as those described above and in the embodiments described below, and more generally for neurodegenerative diseases.

In one embodiment, this disclosure provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment or prevention of symptoms associated with loss of TREM2 function in humans.

In another embodiment, this disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, for the treatment of diseases, conditions, or symptoms. Examples of diseases, conditions, or symptoms include proliferative diseases, cardiovascular diseases, metabolic diseases, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, infectious diseases, and tissue damage.

In some embodiments, proliferative disorders are benign conditions, such as benign tumors. In some embodiments, proliferative disorders are cancers. Cancer can be cancer of any cell or tissue in the body, such as cancer of the brain, eye, thyroid, breast, lung, stomach, kidney, pancreas, bladder, colon, rectum, uterus, ovary, prostate, skin, fibrous tissue, lymphatic system, bone marrow, blood, or immune system. Cancer can include tumors or solid cancers (such as carcinoma) or non-mass cancers. Exemplary cancers include glioblastoma, retinoblastoma, skin cancer, eye cancer, gastrointestinal cancer, breast cancer, lung cancer, ductal carcinoma, lung adenocarcinoma, lymphoma, endometrial cancer, liver cancer, pancreatic cancer, renal cell carcinoma, ovarian cancer, fibrosarcoma, leukemia, myeloma, and polycythemia vera.

In some embodiments, the disease, condition, or symptom is a cardiovascular disease, condition, or symptom. Exemplary cardiovascular diseases, conditions, and symptoms include stroke, coronary artery disease, cardiomyopathy, arrhythmia (e.g., atrial fibrillation), aortic aneurysm, and venous thrombosis.

In some embodiments, the disease, condition, or symptom is a metabolic disease. Exemplary metabolic diseases include diabetes (e.g., type 1 or type 2 diabetes), metabolic disorder-associated steatohepatitis (MASH), nonalcoholic steatohepatitis (NASH), and Gaucher's disease.

In some embodiments, the disease, condition, or symptom is an inflammatory disease. Exemplary inflammatory diseases include arthritis, acute and chronic colitis, ulcerative colitis, inflammatory bowel disease, Behcet's disease, and granulomatous conditions.

In some embodiments, the disease, condition, or symptom is an autoimmune disease. Exemplary autoimmune diseases include diabetes (e.g., type 1 diabetes), lupus, sarcoidosis, and multiple sclerosis.

In some embodiments, the disease, symptom, or condition is a neurological disorder. In some embodiments, the neurological disorder is a neurodegenerative disease. Exemplary neurodegenerative diseases include dementia, Alzheimer's disease, Creutzfeldt-Jakob disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis (ALS), Huntington's disease, taupathy disease, Nasu-Hakola disease, dry age-related macular degeneration (dry AMD), multiple system atrophy (MSA), Shy-Drager syndrome, progressive supranuclear nerve palsy, corticobasal ganglia degeneration, glaucoma, retinitis pigmentosa, and retinopathy. In other embodiments, neurological symptoms include acute trauma, chronic trauma, acute disseminated encephalomyelitis, cognitive deficits and amnesia, essential tremor, central nervous system (CNS) lupus, normobaric hydrocephalus, and epileptic seizures.

In some implementations, the disease, symptom, or illness is an infectious disease. Infectious diseases can be local or systemic. Exemplary infectious diseases include eye infections, malaria, respiratory infections, sepsis, herpes (e.g., CNS herpes), parasitic infections, Trypanosome infections, Cruzi infections, Pseudomonas aeruginosa infections, Leishmania donovani infections, Streptococcus group B infections, Campylobacter jejuni infections, Neisseria meningitidis infections, HIV type I, and Haemophilus influenzae.

In some embodiments, disease, ailment, or condition is tissue damage. Any tissue in the body can be injured. Exemplary injuries include eye injuries (such as anterior chamber hemorrhage), spinal cord injuries, traumatic brain injuries, liver cell damage, and wound repair in diabetes.

In one embodiment, this disclosure provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvent, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent thereof, or a pharmaceutical composition thereof, for the treatment or prevention of a disease, condition or symptom. In another embodiment, this disclosure provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hacola disease, frontotemporal dementia, multiple sclerosis, prion protein disease, or stroke.

In one embodiment, this disclosure provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the preparation of a medicament for the treatment or prevention of symptoms associated with loss of TREM2 function in humans.

In one embodiment, this disclosure provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of an agent for the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hacola disease, frontotemporal dementia, multiple sclerosis, prion protein disease, or stroke.

In another embodiment, this disclosure provides a method for treating or preventing symptoms associated with human TREM2 dysfunction in an individual of need, the method comprising administering to the individual a therapeutically effective amount of a compound of this disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, or a pharmaceutical composition thereof.

In another embodiment, this disclosure provides a method for treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hacola disease, frontotemporal dementia, multiple sclerosis, prion protein disease, or stroke in an individual of need, the method comprising administering to the individual a therapeutically effective amount of a compound of this disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, or a pharmaceutical composition thereof.

CSF1R is primarily used as a cell surface receptor for intercytokine community-stimulating factor 1 (CSF-1) and has recently been identified as a receptor for macrophage community-stimulating factor (M-CSF). It regulates the survival, proliferation, differentiation, and function of monocytes (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 promotes the formation of a homodimer of the receptor and subsequent autophosphorylation of certain tyrosine residues (especially Syk) in the cytoplasmic domain. In the brain, CSF1R is primarily expressed in microglia. Microglial cell depletion and enhanced apoptosis have been observed in CSF1R +/- patients (Oosterhof et al., 2018).

This disclosure relates to the following unexpected finding: administration of TREM2 agonists can rescue microglia from loss in cells with the CSF1R mutation. It has been previously shown that when the M-CSF concentration in the medium is reduced to 5 ng/mL, the TREM2 agonist antibody 4D9 enhances ATP fluorescence (measurement of cell number and activity) in a dose-dependent manner (Schlepckow et al., EMBO Mol Med., 2020) and when M-CSF is completely removed from the medium, the TREM2 agonist AL002c enhances ATP fluorescence (Wang et al., J. Exp. Med.; 2020, 217(9): e20200785). This finding suggests that the activating effect of TREM2 can compensate for the deficiency in CSF1R signaling caused by decreased concentrations of its ligands. In a 5xFAD mouse model of Alzheimer's disease with amyloidosis, doses of CSF1R inhibitors that virtually eliminated microglia in the brains of wild-type animals showed the aggregation of viable microglia around amyloid plaques (Spangenberg et al., Nature Communications 2019). Previously, plaque amyloids have been shown to be ligands of TREM2, and it has been shown that microglia binding to amyloids is TREM2-dependent (Condello et al., Nat Comm., 2015). This disclosure relates to the unexpected finding that TREM2 activation in microglia is rescued in the presence of a CSF1R inhibitor, and that this effect was also observed in patients with microglia loss due to CSF1R mutations. This finding has not been previously taught or suggested in the art.

To date, previous studies have not shown that TREM2 activating action can rescue microglial cell loss in cells (where mutations in the CSF1R kinase domain reduce CSF1R activity) rather than the presence of a CSF1R inhibitor or the lack of a CSF1R ligand. Furthermore, no previous studies have taught or suggested that reversing CSF1R mutation-induced microglial cell loss through TREM2 activating action can be used to treat diseases or conditions caused by and/or related to CSF1R mutations.

Adult-onset leukoencephalopathy with axonospheric structures and pigment glial tissue (ALSP) (formerly known as hereditary diffuse leukoencephalopathy with axonospheric structures (HDLS) or pigmentary orthochromatic leukodystrophy (POLD)) is an autosomal dominant central nervous system disorder characterized by variable behavioral, cognitive, and motor function impairments in affected patients. ALSP is characterized by patchy white matter abnormalities visible on magnetic resonance imaging (MRI). However, clinical symptoms and MRI findings are nonspecific to ALSP and are frequently seen in other neurological conditions, including Nash-Hacola disease (NHD) and Alzheimer's disease (AD), making the diagnosis and treatment of ALSP extremely challenging.

Recent studies have identified ALSP as a Mendelian disorder, in which patients carry a loss-of-binding mutation in the kinase domain of CSF1R, indicating reduced signaling along the macrophage community-stimulating factor (M-CSF)/CSF1R axis (Rademakers et al., Nat Genet 2012; Konno et al., Neurology 2018). In one instance, this disclosure concerns the unexpected finding that activation of the TREM2 pathway can rescue microglial cell loss in CSF1R +/- ALSP patients, prevent microglial cell apoptosis, and thus treat ALSP symptoms.

In one embodiment, this disclosure provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment or prevention of symptoms associated with abnormal function of community-stimulating factor 1 receptor (CSF1R, also known as macrophage community-stimulating factor receptor/M-CSFR or differentiation cluster 115/CD115).

In one embodiment, this disclosure provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, or a pharmaceutical composition thereof, for the treatment or prevention of adult-onset leukoencephalopathy with axonospheric and pigmented glial cells (ALSP), hereditary diffuse leukoencephalopathy with axonospheric cells (HDLS), pigmented normoleukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital microglial cell deficiency, or abnormal neurodegeneration and abnormal osteosclerosis (BANDDOS).

In one embodiment, this disclosure provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the preparation of an agent for the treatment or prevention of symptoms associated with CSF1R dysfunction.

In one embodiment, this disclosure provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, or a pharmaceutical composition thereof, for the preparation of an agent for the treatment or prevention of adult-onset leukoencephalopathy with axonospheric and pigmented glial cells (ALSP), hereditary diffuse leukoencephalopathy with axonospheric cells (HDLS), pigmented normoleukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital microglial cell deficiency, or abnormal neurodegeneration and abnormal osteosclerosis (BANDDOS).

In another embodiment, this disclosure provides a method for treating or preventing a disease or condition associated with CSF1R dysfunction in an individual of need, the method comprising administering to the individual a therapeutically effective amount of a compound of this disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, or a pharmaceutical combination thereof. In some embodiments, individuals are 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 reduces or stops CSF1R activity. In some embodiments, the disease or condition is caused by an incompatible CSF1R mutation. In some embodiments, the disease or condition is caused by an incompatible CSF1R mutation. In some embodiments, the disease or condition is caused by an editing mutation in the csf1r gene. In some embodiments, the disease or condition is caused by a missense mutation in the csf1r gene. In some embodiments, the disease or condition is caused by a mutation in the catalytic kinase domain of CSF1R. In some embodiments, the disease or condition is caused by a mutation in the immunoglobulin domain of CSF1R. In some embodiments, the disease or condition is caused by a mutation in the extracellular domain of CSF1R. In some embodiments, the disease or condition is caused by a change in the activity of CSF1R (e.g., enhancement, reduction, or cessation). In some embodiments, the disease or condition is caused by a reduction or cessation of the activity of CSF1R. Altered CSF1R-related activities in diseases or conditions include, but are not limited to: decreased or absent microglial function; enhanced microglial apoptosis; weakened Src signaling; weakened Syk signaling; reduced microglial proliferation; weakened microglial response to cell debris; reduced phagocytosis; and reduced release of intercytokines in response to stimulation. In some embodiments, the disease or condition is caused by a loss-of-function mutation of CSF1R. In some embodiments, loss-of-function mutations cause complete cessation of CSF1R function. In some embodiments, loss-of-function mutations cause partial loss of CSF1R function or reduced CSF1R activity.

In another embodiment, this disclosure provides a method for treating or preventing adult-onset leukoencephalopathy with axonospheric and pigmented glial cells (ALSP), hereditary diffuse leukoencephalopathy with axonospheric cells (HDLS), pigmented normal leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital microglial cell deficiency or abnormal neurodegeneration and abnormal osteosclerosis (BANDDOS) in individuals of need, the method comprising administering to an individual a therapeutically effective amount of the compound of this disclosure or its tautomer, or a pharmaceutically acceptable salt of the compound or its tautomer, or a pharmaceutical combination thereof. In some embodiments, the method treats or prevents ALSP, which is covered by and replaces the names of both HDLS and POLD. In some embodiments, the disease or condition is a CSF1R isotype-binding mutation. In some embodiments, this method treats or prevents childhood episodic leukoencephalopathy. In some embodiments, this method treats or prevents congenital microglial cell loss. In some embodiments, this method treats or prevents neurodegeneration of the brain and osteosclerosis disorder (BANDDOS).

In another instance, this disclosure provides a treatment or prevention for Nasu-Hacola 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 protein disease, stroke, osteoporosis, osteopenia, osteosclerosis, skeletal dysplasia, osteomalacia, and Pyle's disease. Methods for treating CSF1R disorders, including: CSF1R disease, CSF1R subcortical infarction and leukodystrophy, CSF1R recessive arteriosclerosis, retinal vascular lesions, or metachromatic leukodystrophy, wherein any of the aforementioned diseases or conditions is present in a patient exhibiting CSF1R dysfunction or having a gene mutation affecting CSF1R function, the method comprising administering to an individual a therapeutically effective amount of the disclosed compound or its tautomer, or a pharmaceutically acceptable salt of the compound or its tautomer, or a pharmaceutical composition thereof.

The ABCD1 gene provides an indicator for the production of adrenoleukodystrophy protein (ALDP). ABCD1 (ALDP) corresponds to Xq28. ABCD1 is a member of the ATP-binding cartridge (ABC) transporter superfamily. This superfamily contains membrane proteins that translocate across extracellular and intracellular membranes to various receptors, including metabolites, lipids, sterols, and drugs. ALDP is located in the membrane of a cellular structure called a perosome. Perosomes are small sacs within the cell that process many types of molecules. ALDP allows adipose tissue (called very long-chain fatty acids (VLCFAs)) to enter the peroxisome, where it is broken down. Because ABCD1 is highly expressed in microglia, microglia dysfunction and its close interactions with other cell types may actively participate in neurodegenerative processes (Gong et al., Annals of Neurology. 2017; 82(5):813-827). Severe microglia loss and damage have been shown to be an early feature of patients with cALD (clinical ALD) carrying ABCD1 mutations (Bergner et al., Glia. 2019; 67: (1196-1209). ABCD1 deficiency has also been shown to impair the plasticity of bone marrow lineage cells, reflected in the incomplete establishment of the anti-inflammatory response, and thus may lead to destructive, rapidly progressive demyelination in cerebral adrenoleukodystrophy (Weinhor et al., BRAIN 2018: 141; 2329-2342). These findings highlight microglia/monocytes/macrophages as key therapeutic targets for preventing or halting myelination in patients with X-linked adrenoleukodystrophy.

This disclosure concerns the following unexpected finding: administration of TREM2 agonists can rescue microglial cell loss in cells with the ABCD1 gene mutation. It has been previously shown that when the M-CSF concentration in the medium is reduced to 5 ng/mL, the TREM2 agonist antibody 4D9 enhances ATP fluorescence (measurement of cell number and activity) in a dose-dependent manner (Schlepckow et al., EMBO Mol Med., 2020) and when M-CSF is completely removed from the medium, the TREM2 agonist AL002c enhances ATP fluorescence (Wang et al., J. Exp. Med.; 2020, 217(9): e20200785). This finding indicates that the activating effect of TREM2 can compensate for ABCD1 deficiency, thereby inducing sustained activation, proliferation, and chemotaxis of microglia, maintaining an anti-inflammatory environment, and alleviating astrocytosis caused by ABCD1 deficiency and VLCFA accumulation. This disclosure concerns the unexpected finding that TREM2 activation can rescue microglia in the presence of ABCD1 mutations and increased VLCFA, and this effect can also be observed in patients experiencing microglia loss due to ABCD1 mutations. This finding has not been previously taught or suggested in the art.

To date, no previous studies have shown that TREM2 activating action can rescue microglial cell loss in cells with ABCD1 mutations and increased VLCFA. No previous studies have taught or suggested that reversing microglial cell loss caused by ABCD1 mutations through TREM2 activating action can be used to treat diseases or conditions caused by and/or related to ABCD1 mutations.

In one embodiment, this disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, or a pharmaceutical composition thereof, for the treatment or prevention of symptoms associated with abnormal function of ATP-binding capsule transporter 1 (ABCD1).

In one embodiment, this disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer thereof, or a pharmaceutical composition thereof, for the treatment or prevention of X-linked adrenoleukodystrophy (x-ALD), globular leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), somatic chromosomal arteriosclerosis with subcortical infarction and leukoencephalopathy (CADASIL), ablation leukoencephalopathy (VWM), Alexander's disease. Fragile X-associated tremor syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

In one embodiment, this disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, or a pharmaceutical composition thereof, for the preparation of an agent for the treatment or prevention of symptoms associated with ABCD1 dysfunction.

In one embodiment, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, or a pharmaceutical composition thereof, for the preparation of a compound for the treatment or prevention of X-linked adrenoleukodystrophy (x-ALD), globular leukodystrophy (also known as clavatinib). Drugs for various diseases including metachromatic leukodystrophy (MLD), somatic leukodystrophy with subcortical infarction and leukodystrophy (CADASIL), ablative leukodystrophy (VWM), Alexander's disease, fragile X-linked tremor ataxia syndrome (FXTAS), adult-onset somatic leukodystrophy (ADLD), and X-linked Chuck-Maley-Duss disease (CMTX).

In another embodiment, this disclosure provides a method for treating or preventing diseases or conditions associated with ABCD1 dysfunction in individuals of need, the method comprising administering to the individual a therapeutically effective amount of a compound of this disclosure, a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer of it, or a pharmaceutically acceptable salt and/or solvent of such compound, stereoisomer, or tautomer, or a pharmaceutical combination thereof. In some embodiments, patients are selected for treatment based on a diagnosis including the presence of an ABCD1 gene mutation affecting ABCD1 function. In some embodiments, the ABCD1 gene mutation is a mutation that reduces or stops ABCD1 activity. In some embodiments, the disease or condition is caused by an inversely binding ABCD1 mutation. In some embodiments, the disease or condition is caused by an isotype-binding ABCD1 mutation. In some embodiments, the disease or condition is caused by an editing mutation of the ABCD1 gene. In some embodiments, the disease or condition is caused by a missense mutation of the ABCD1 gene. In some embodiments, the disease or condition is caused by changes in ABCD1 activity (e.g., increase, decrease, or cessation). In some embodiments, the disease or condition is caused by decreased or ceased ABCD1 activity. Changes in ABCD1-related activities in the disease or condition include, but are not limited to, peroxisome introduction of fatty acids and/or fatty acid esters-CoAs and the production of adrenal leukodystrophy protein (ALDP). In some embodiments, the disease or condition is caused by a loss-of-function mutation of ABCD1. In some embodiments, a loss-of-function mutation causes complete cessation of ABCD1 function. In some embodiments, loss-of-function mutations result in partial loss of ABCD1 function or reduced ABCD1 activity. In some embodiments, the disease or condition is caused by isotype-binding mutations of ABCD1. In some embodiments, the disease or condition is a neurodegenerative disease. In some embodiments, the disease or condition is a neurodegenerative disease caused by and/or associated with ABCD1 dysfunction. In some embodiments, the disease or condition is an immune disorder. In some embodiments, the disease or condition is an immune disorder caused by and/or associated with ABCD1 dysfunction.

In another instance, this disclosure provides a treatment or prevention for individuals in need of X-linked adrenoleukodystrophy (x-ALD), globular leukodystrophy (also known as Clapey's disease), metachromatic leukodystrophy (MLD), somatic autosomal dominant arteriosclerosis with subcortical infarction and leukoencephalopathy (CADASIL), ablation leukoencephalopathy (VWM), Alexander's disease, and fragile X-chromosome-associated tremor ataxia syndrome. Methods for treating (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Chuck-Maley-Duss disease (CMTX), comprising administering to an individual a therapeutically effective amount of the disclosed compound, its pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer, or a pharmaceutical combination thereof. In some embodiments, any of the aforementioned diseases is present in patients exhibiting ABCD1 dysfunction or having gene mutations affecting ABCD1 function. In some embodiments, the method treats or prevents X-linked suprenal leukodystrophy (x-ALD). In some embodiments, x-ALD is the brain form of X-linked superior leukodystrophy (cALD). In some embodiments, this method treats or prevents Addison's disease in patients who have been found to have mutations in one or more ABCD1 genes affecting ABCD1 function. In some embodiments, this method treats or prevents Addison's disease in patients who have loss-of-function mutations in ABCD1.

In another embodiment, this disclosure provides a method for treating or preventing Nasu-Hacola disease, Alzheimer's disease, frontotemporal dementia, multiple sclerosis, Guillain-Barré syndrome, amyotrophic lateral sclerosis (ALS), or Parkinson's disease, wherein any of the aforementioned diseases or conditions is present in a patient exhibiting ABCD1 dysfunction or having a gene mutation affecting ABCD1 function, the method comprising administering to an individual a therapeutically effective amount of the compound of this disclosure, its pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof.

Autism spectrum disorder (ASD) has been identified, with TREM2-deficient mice exhibiting symptoms suggestive of ASD (Filipello et al., Immunity, 2018, 48, 979-991). It has also been found that microglia loss of the autophagy Aatg7 gene causes defective synaptic pruning and increased dendritic spine density, and abnormal social interactions and repetitive behaviors are indicative of ASD (Kim et al., Molecular Psychiatry, 2017, 22, 1576-1584). Further studies have shown increased dendritic spine density in post-mortem ASD brains, potentially caused by defective synaptic pruning, which leads to low connectivity and behavioral deficits and is a potential cause of various neurodevelopmental disorders (Tang et al., Neuron, 2014, 83, 1131-1143). Without being limited to any particular theory, these findings suggest that TREM2 activation can reverse microglial cell loss and thus correct defective synaptic pruning in the centers of neurodevelopmental disorders such as ASD. This disclosure relates to the unexpected finding that activation of TREM2 using the compounds disclosed herein can rescue microglial cells in individuals with ASD. This finding has not been previously taught or suggested in the art.

In another embodiment, the present invention provides a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the disclosed compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, or a pharmaceutical composition thereof, for the treatment of autism or pan-autistic disorder.

In another embodiment, the present invention provides a compound disclosed herein, a pharmaceutically acceptable salt thereof, a solvent, a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, or a pharmaceutical composition thereof, for use in the preparation of a medicament for the treatment of autism or pan-autistic disorder.

In another embodiment, the present invention provides a method for treating autism or generalized autism spectrum disorder in an individual in need, the method comprising administering to the individual a therapeutically effective amount of the disclosed compound, its pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof. In some embodiments, the method treats autism. In some embodiments, the method treats Asperger syndrome.

In some embodiments, this disclosure provides a method for increasing the activity of TREM2, the method comprising contacting TREM2 with a compound of the disclosure, a pharmaceutically acceptable salt thereof, a solvent, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof. In some embodiments, the contact occurs in vitro. In some embodiments, the contact occurs in vivo. In some embodiments, TREM2 is human TREM2.

Combination therapy is determined based on the specific symptom or disease to be treated, and additional treatments for the symptom are typically administered in combination with the compounds and combinations disclosed herein. As used herein, additional treatments for a specific disease or symptom are typically referred to as “the disease or symptom to be treated”.

In some embodiments, the provided combination or combination thereof is administered in combination with another treatment.

In some embodiments, this disclosure provides a method for treating the disclosed disease or symptom, the method comprising administering to a patient in need an effective amount of the disclosed compound, its pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer, and simultaneously or sequentially co-administering an effective amount of one or more other therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering an additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the disclosed compound works synergistically with the additional therapeutic agent or reagent.

Examples of reagents that can be combined with the combinations disclosed herein include, but are not limited to, the treatment of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hacola disease, frontotemporal dementia, multiple sclerosis, prion protein disease, or stroke.

As used herein, the terms “combination,” “merging,” and related terms refer to the simultaneous or sequential administration of a treatment agent according to this disclosure. For example, a combination of the treatment agents disclosed herein may be administered simultaneously or sequentially with another treatment agent in a single unit dosage form or together in a single unit dosage form.

The amount of additional therapeutic agent present in the composition disclosed herein will not exceed the amount typically administered in the form of a composition containing the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition disclosed herein will be in the range of approximately 50% to 100% of the amount typically present in a composition containing the reagent as the sole active agent.

One or more additional therapeutic agents may be administered separately from the compounds or compositions disclosed herein as part of a multiple-dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds disclosed herein in a single composition. If administered as a multiple-dose regimen, one or more other therapeutic agents and the compounds or compositions disclosed herein may be administered simultaneously, sequentially, or within a time interval, 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. In some embodiments, one or more other therapeutic agents and the compounds or compositions disclosed herein are administered in a multiple-dose regimen with intervals exceeding 24 hours.

In one embodiment, this disclosure provides a composition comprising the provided compound, a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, and one or more other therapeutic agents. The treatment may be administered with, or together with, the provided compound, its pharmaceutically acceptable salt, solvent, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, its stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, its stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, its stereoisomer or tautomer. Suitable treatments are described in more detail below. In some embodiments, the provided compound, its pharmaceutically acceptable salt, solvent, stereoisomer or tautomer, or pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer 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 prior to the treatment. In other embodiments, the provided compound, its pharmaceutically acceptable salt, solvent, stereoisomer or tautomer, or pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer 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 after the treatment.

Definitions are provided below to help understand the scope of this disclosure.

Unless otherwise indicated, all figures used in this specification or the scope of the patent application to represent the quantities of ingredients, reaction conditions, etc., should be understood to be modified with the term "approximately" in all cases. Therefore, unless indicated to the contrary, the numerical parameters set forth in the following specification and the accompanying scope of the patent application are approximate values, which may vary depending on the standard deviation observed in their individual test measurements.

As used in this article, if any variable appears more than once in a chemical formula, its definition each time it appears is independent of its definition each subsequent appearance. If there is a conflict between the chemical structure and the chemical name, the chemical structure determines the properties of the compound.

As used herein, unless otherwise indicated, the following definitions shall apply. For the 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 Science Books, Sausalito: 2005 and "March's Advanced Organic Chemistry: Reactions Mechanisms and Structure," 8th edition, eds. Smith, M.B., John Wiley & Sons, New York: 2019, the entire contents of which are incorporated herein by reference.

Stereomeric compounds disclosed herein may contain, for example, double bonds, one or more asymmetric carbon atoms and sterically hindered rotation bonds, and therefore may exist as stereomeric compounds, such as double bond isomers (i.e., geometric isomers (E/Z)), mirror isomers, non-mirror isomers and restricted configuration isomers. Therefore, unless stereochemistry is specifically identified, the scope of this disclosure should be understood to cover all possible stereoisomers of the described compounds, including the pure stereoisomers (e.g., geometric purity, mirror isomer purity, non-mirror isomer purity, and restricted configuration purity) and mixtures of stereoisomers (e.g., mixtures of geometric isomers, mirror isomers, non-mirror isomers, and restricted configuration isomers, or mixtures of any of the foregoing) of any chemical structure disclosed herein (all or part of the chemical structure disclosed herein).

If the stereochemical properties of a structure or a portion thereof are not indicated by, for example, bold or dashed lines, then the structure or portion thereof shall be interpreted as covering all its stereoisomers. If the stereochemical properties of a structure or a portion thereof are not indicated by, for example, bold or dashed lines, then the structure or portion thereof shall be interpreted as covering only its specified stereoisomers. For example, (1R)-1-methyl-2-(trifluoromethyl)cyclohexane means covering (1R,2R)-1-methyl-2-(trifluoromethyl)cyclohexane and (1R,2S)-1-methyl-2-(trifluoromethyl)cyclohexane. Keys drawn with wavy lines indicate coverage of two stereoisomers. This should not be confused with the ripples drawn perpendicular to the keys, which indicate the connection points between the groups and the rest of the molecule.

As used herein, the term "stereoisomer" or "stereoisomeric pure" refers to a stereoisomer of a compound (e.g., a geometric isomer, a mirror isomer, a non-mirror isomer, and a restricted configuration isomer) that substantially does not contain any other stereoisomers of that compound. For example, a stereoisomeric pure compound having one antipallic center will substantially not contain any mirror isomers of that compound, and a stereoisomeric pure compound having two antipallic centers will substantially not contain any other mirror isomers or non-mirror isomers of that compound. A typical stereoisomeric pure compound comprises more than about 80% by weight of one stereoisomer of the compound and equal to or less than about 20% by weight of other stereoisomers of the compound; more than about 90% by weight of one stereoisomer of the compound and equal to or less than about 10% by weight of other stereoisomers of the compound; more than about 95% by weight of one stereoisomer of the compound and equal to or less than about 5% by weight of other stereoisomers of the compound; or more than about 97% by weight of one stereoisomer of the compound and equal to or less than about 3% by weight of other stereoisomers of the compound.

This disclosure also covers the use of pharmaceutical compositions comprising the stereoisomer pure form and the stereoisomer pure form of any compound disclosed herein. Furthermore, this disclosure also covers the use of 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 methods disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques such as palmar columns or palmar analytical agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (Eliel ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

As is known to those skilled in the art, some of the compounds disclosed herein can exist in one or more tautomeric forms. Since only one chemical structure can be used to represent one tautomeric form, it should be understood that, for convenience, references to a given structural formula include other tautomeric isomers of that formula. For example, the following describes a tautomeric isomer of compound (I), wherein ring A, together with its fused 6-membered ring system, forms... A dual-ring system, wherein R ^8a is H:

Additionally, a second tautomer of the compound of formula (I) is possible, wherein ^R3 is H:

Therefore, the scope of this disclosure should be understood to cover all tautomerisms of the compounds disclosed herein.

In addition, the scope of this 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 atoms of the same number but different atomic mass or mass number from those of atoms that are normally found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include hydrogen isotopes such as ^2H and ^3H ; carbon isotopes such as ^11C , ^13C and ^14C ; chlorine isotopes such as ^36Cl ; fluorine isotopes such as ^18F ; iodine isotopes such as ^123I and ^125I ; nitrogen isotopes such as ^13N and ^15N ; oxygen isotopes such as ^15O , ^17O and ^18O ; phosphorus isotopes such as ^32P ; and sulfur isotopes such as ^35S . Certain isotopically labeled compounds of formula (I) (e.g., those incorporating radioactive isotopes) are suitable for drug and/or substrate tissue distribution studies. Radioactive isotopes tritium ( ^3H ) and carbon-14 ( ^14C ) are particularly suitable for this purpose due to their ease of incorporation and simple detection. Substitution with isotopes such as deuterium ( ^2H or D) can yield certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and can therefore be advantageous in some cases. Substitution with positron-emitting isotopes (such as ^11C , ^18F , ^15O , and ^13N ) is suitable for positron emission tomography (PET) studies, for example, to examine target occupancy. The isotopically labeled compounds disclosed herein can generally be prepared by means of known techniques known to those skilled in the art, or by means of methods similar to those described in the accompanying general synthetic procedures and examples, using appropriately isotopically labeled reagents instead of previously used unlabeled reagents.

Solvents As discussed above, the compounds disclosed herein, their stereoisomers, tautomers, and isotopically labeled forms, or any of the aforementioned pharmaceutically acceptable salts, may exist in solvent-based or non-solvent-based forms.

As used herein, the term "solvent complex" refers to a molecular complex comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, either chemimetrically or non-chemimetrically. If the solvent is water, the solvent complex is called a "hydrate".

Therefore, the scope of this disclosure should be understood to encompass all solvents containing the compounds disclosed herein and their stereoisomers, tautomers, and isotopically labeled forms or pharmaceutically acceptable salts of any of the foregoing.

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

As used herein, the term "alkyl" means a straight (i.e., unbranched) or branched hydrocarbon chain, substituted or unsubstituted, which is fully saturated or contains one or more unsaturated units that have a single linker to the remainder of the molecule. Unless otherwise stated, an alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 5 alkyl carbon atoms. In other embodiments, the alkyl group contains 1 to 4 alkyl carbon atoms. In still other embodiments, the alkyl group contains 1 to 3 alkyl carbon atoms, and in still other embodiments, the alkyl group contains 1 to 2 alkyl carbon atoms.

As used herein, the terms "cycloalkyl" or "carbocyclic" refer to a substituted or unsubstituted hydrocarbon ring that is fully saturated or contains one or more unsaturated units, but is not an aromatic ring and has a single bond site to the remainder of the molecule. In some embodiments, "cycloalkyl" refers to a monocyclic or bicyclic, bridged bicyclic or spirocyclic _C3-12 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not an aromatic ring and has a single bond site to the remainder of the molecule. Suitable cycloalkyl groups include, but are not limited to, straight-chain or branched-chain, substituted or unsubstituted alkyl, alkenyl, ynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term "bicyclic" or "bicyclic system" refers to any bicyclic system that is saturated or contains one or more unsaturated units, i.e., a carbon ring or heterocyclic system having one or more common atoms between the two rings of the system. Therefore, the term includes any permissible ring fusion, such as contiguous fusion or spirocyclic. As used herein, the term "hybrid bicyclic" is a subset of "bicyclic" that requires one or more heteroatoms to be present in one or both rings of the bicyclic system. Such heteroatoms may be present at ring junctions and, where applicable, may be substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfonates and urethanes), phosphorus (including oxidized forms, such as phosphonates and phosphates), boron, etc. In some embodiments, the bicyclic group has 7 to 12 ring members and 0 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic system, i.e., a carbon ring or heterocycle, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched atom or an atom or valence bond connecting two bridgeheads, wherein a "bridgehead" is any skeletal atom of a ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups are well known in the art and include those listed below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise stated, a bridged bicyclic group may be substituted with one or more substituents as described for alkyl groups. Alternatively, any substituted nitrogen group in the bridging bicyclic group may be substituted, as appropriate. Exemplary bicyclic groups include:

An exemplary bridge-connected double ring includes:

The term "lower alkyl" refers to _C1-4 straight-chain or branched alkyl groups. Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term "lower halogenated alkyl" refers to a _C1-4 straight-chain or branched alkyl group in which one or more halogen atoms are substituted.

The term " _C1-6 halogenated" refers to a _C1-6 straight-chain or branched-chain alkyl group that has been substituted with one or more halogen atoms.

The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any quaternary ammonium form of basic nitrogen; or oxygen, sulfur, nitrogen, phosphorus or silicon atom in a heterocycle).

As used in this article, the term "unsaturated" refers to a portion having one or more unsaturated units.

As used herein, the term "divalent _C1-8 (or _C1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain" refers to a straight or branched divalent alkyl chain, alkenyl chain, or alkyne chain as defined herein.

The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is polymethylene, i.e., -( _CH₂ ) _n- , where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is polymethylene in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted alkyl groups.

The term "alkenyl" refers to a divalent alkenyl group. A substituted alkenyl chain is a polymethylene chain containing at least one double bond, wherein one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted alkyl groups.

As used herein, the terms "heterocyclic," "heterocyclic group," "heterocyclic radical," and "heterocyclic" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion (which may be saturated or partially unsaturated) having one or more (preferably 1 to 4) heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring (having 0 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen).

The heterocycle may be attached to the provided compound at any heteroatom or carbon atom that produces a stable structure, and any ring atom may be substituted, if applicable. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrophenylthiopyrrolidyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, etc. Azoxyl, piper Basic, Second Alkyl, di alkyl, diazonyl, oxynitropyronyl, sulfonylpyronyl Phinyl and quinuclidinyl. The terms "heterocycle,""heterocyclyl,""heterocyclylring,""heterocyclicgroup,""heterocyclicmoiety," and "heterocyclic radical" are used interchangeably herein and also include groups fused with one or more aryl, heteroaryl, or cycloalkyl rings, such as dihydroindolyl, 3H- indolyl, chromyl, phenidyl, or tetrahydroquinolinyl. Heterocyclic groups can be monocyclic or bicyclic, bridged bicyclic, or spirocyclic. Heterocyclic compounds may include one or more oxygen (=O) or thio (=S) substituents. The term "heterocyclic alkyl" refers to an alkyl group substituted by a heterocyclic group, wherein the alkyl and heterocyclic portions are substituted independently, as appropriate.

As used herein, the term "partially unsaturated" refers to a ring portion comprising at least one double- or triple-bonded element. The term "partially unsaturated" is intended to encompass rings with multiple unsaturated sites, but not necessarily aryl or heteroaryl portions as defined herein.

As used herein, the terms " _C1-3 alkyl", " _C1-5 alkyl" and " _C1-6 alkyl" refer to straight-chain or branched hydrocarbons containing 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. Representative examples of _C1-3 alkyl, _C1-5 alkyl, or _C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, isobutyl, tert-butyl, pentyl, and hexyl.

As used herein, the term " _C2-4 alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms, having at least one carbon-carbon double bond. Alkenyl groups include both linear and branched moieties. Representative examples of _C2-4 alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

As used herein, the term " _C3-6 cycloalkyl" refers to a saturated carbon ring molecule in which the cyclic framework has 3 to 6 carbon atoms. Representative examples of _C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term " _diC1-3 alkylamino" refers to -NR*R**, where R* and R** independently represent _C1-3 alkyl as defined herein. Representative examples of _diC1-3 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 .

As used herein, the terms " _C1-3 alkoxy" and " _C1-6 alkoxy" refer to -OR ^# , where R ^# indicates _{C1-3 alkyl and C1-6 alkyl as defined herein, respectively. Representative examples of C1-3 alkoxy or C1-6} alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

As used in this article, the term "halogen" refers to -F, -CI, -Br, or -I.

As used herein, the term "halogen" as a prefix to another term for a chemical group refers to a modification of the chemical group in which one or more hydrogen atoms are substituted with a halogen as defined herein. The halogen is chosen independently in each occurrence. For example, the term " _C1-6 halogenated" refers to a _C1-6 alkyl group as defined herein in which one or more hydrogen atoms are substituted with a halogen. Representative examples of _C1-6 halogenated groups include, but are not limited to, _-CH2F , _-CHF2 , _-CF3 , _-CHFCl , _-CH2CF3 , _-CFHCF3 , _-CF2CF3 , -CH( _CF3 ) ₂ , -CF( _CHF2 ) ₂ , _and -CH( _CH2F )( _CF3 ). Furthermore, the term " _C1-6 halogenated alkoxy" refers, for example, to a _C1-6 alkoxy group as defined herein, in which one or more hydrogen atoms are substituted with halogens. Representative examples of _C1-6 halogenated alkoxy groups include, but are not limited to, _-OCH₂F , _-OCHF₂ , _-OCF₃ , _-OCHFCl , _-OCH₂CF₃ , _-OCFHCF₃ , _-OCF₂CF₃ , -OCH( _{CF₃ ) ₂} , -OCF( _CHF₂ ) _₂ , and -OCH( _CH₂F )( _CF₃ ).

As used herein, the terms "5-membered heteroaryl" or "6-membered heteroaryl" refer to a 5- or 6-membered carbon ring having two or three double bonds, containing one cyclic heteroatom selected from N, S, and O, and, where appropriate, one or two further cyclic N atoms replacing one or more cyclic carbon atoms. Representative examples of 5-membered heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrazolyl, and isozylated groups. azole group, isothiazol group, diazole group and Azolium group. Representative examples of the six heteroaryl groups include, but are not limited to, pyridinium, pyrimidinium, and pyridyl groups. Jijida base.

As used herein, the term "C _3-6 heterocycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic framework has 3 to 6 carbon atoms, one of which is substituted with a heteroatom selected from N, O, and S. If the C _3-6 heterocycloalkyl is a C ₆ heterocycloalkyl, then one or two carbon atoms are substituted with a heteroatom selected independently from N, O, and S. Representative examples of C _3-6 heterocycloalkyl include, but are not limited to, aziridine, aziridine, oxo-aziridine, pyrrolidyl, and piperazine. base, linyl and thio phyll group.

As used herein, the term "C _5-8 spiroalkyl" refers to a bicyclic system in which two rings are linked by a single common carbon atom. Representative examples of C _5-8 spiroalkyl include, but are not limited to, spiro[2.2]pentyl, spiro[3.2]hexyl, spiro[3.3]heptyl, spiro[3.4]octyl and spiro[2.5]octyl.

As used herein, the term "C _5-8 tricycloalkyl" refers to a tricyclic system in which all three cycloalkyl rings share the same two ring atoms. Representative examples of C _5-8 tricycloalkyl include, but are not limited to, tricyclo[1.1.1.0 ^1,3 ]pentyl, Tricyclo[2.1.1.0 ^1,4 ]hexyl, tricyclo[3.1.1.0 ^1,5 ]hexyl and tricyclo[3.2.1.0 ^1,5 ]octyl.

The term "aryl," used alone or as a larger part of "aranyl," "aranalkoxy," or "aranoxyalkyl," refers to a monocyclic or bicyclic system having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains three to seven ring members. The term "aryl" is used interchangeably with the term "aromatic ring." In some embodiments of this disclosure, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracene, and similar groups, which may carry one or more substituents. As used herein, the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindyl, phenoxydimethylimino, naphthylimino, phenidyl, or tetrahydronaphthyl and their analogues.

The terms "heteroaryl" and "heteroaryl-" used alone or as part of a larger portion of, for example, "heteroarylalkyl" or "heteroarylalkoxy" refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; sharing 6, 10, or 14 π electrons in the ring array; and having one to five heteroatoms in addition to carbon atoms. In the context of "heteroaryl," the term "heteroatom" specifically includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternary ammonium form of basic nitrogen. Heteroaryl includes, but is not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. azole group, iso azole group, Diazole, thiazolyl, isothiazolyl, thiadiazole, pyridyl, tadazole pyrimidinyl, pyrimidinyl Indole alkyl, purine group, Pyridyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups in which a heteroaryl ring is fused with one or more aryl, cycloalkyl, or heterocyclic rings, wherein the linking group or linking point is on the heteroaryl ring. Non-limiting examples include indolyl, isoyindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, phyllyl, alkyl, quinazolinyl, quin linyl, 4H -quin carbazolyl, acridine, phenazine Base, Phytothia Base, coffee yl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4- -3(4H)-ketone. The heteroaryl group can be monocyclic or bicyclic. The heteroaryl ring may include one or more lateral oxygen (=O) or thionyl (=S) substituents. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring,""heteroarylgroup," or "heteroaryl group," any of which includes, where appropriate, a substituted ring. The term "heteroarylalkyl" refers to a heteroaryl-substituted alkyl group, wherein the alkyl and heteroaryl portions are independently substituted, where appropriate.

As described herein, the compounds disclosed herein may contain a "substituted" moiety. Generally, the term "substituted" means that one or more hydrogen atoms in the specified moiety are replaced by suitable substituents. Unless otherwise indicated, a "substituted" group may have suitable substituents at one or more substituted positions of that group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this disclosure are preferably combinations that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means that the compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and (in some embodiments) recovered, purified, and used for one or more of the purposes disclosed herein.

As used in this article, "medically acceptable" means that it is generally considered to be suitable for individuals, especially humans.

As used herein, "pharmacologically acceptable salt" means 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 from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed from organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentadienoic 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-hydroxyl) (1) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid and the like; or (2) a salt formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion); or a salt formed by coordination with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methyl-reduced glucosamine, dicyclohexylamine and the like. Other examples of such salts can be found in Berge et al., J. Pharm. Sci . 66(1):1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2nd revised edition (2011).

As used herein, the term "pharmaceutically acceptable excipient" refers to a broad range of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, mordants, anti-adhesion agents, lubricants, disintegrants, flavoring agents, coatings, adhesives, sweeteners, lubricants, adsorbents, preservatives, and the like.

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

As used herein, the term "therapeutic effective amount" refers to the amount of the compound disclosed herein that will elicit a biological or medical response in a tissue, system, or individual being sought by an investigator, veterinarian, physician, or other clinician.

General Synthetic Procedures The compounds provided herein can be synthesized according to the procedures described in this and the following sections. The synthetic methods described herein are merely illustrative, and the compounds disclosed herein can also be synthesized via alternative routes utilizing alternative synthetic strategies, as will be understood by those skilled 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 this disclosure in any way. As will be understood by those skilled in the art, the above synthetic procedures and representative examples are not intended to constitute a comprehensive list of all means by which the compounds described and claimed in this application can be synthesized. Other methods will be readily apparent to those skilled in the art. Furthermore, the multiple synthetic steps described above can be performed alternately or sequentially to obtain the desired compounds.

Purification methods for the compounds described herein are known in the art and include, for example, crystallization, chromatography (e.g., liquid and gas phases), extraction, distillation, grinding, and reversed-phase HPLC.

This disclosure further covers "intermediate" compounds, including structures generated from the described synthetic procedure prior to obtaining the final desired compound, whether isolated, generated in situ, or not isolated. Such intermediates are included within the scope of this disclosure. Exemplary examples of such intermediate compounds are described in the examples below.

Examples This section provides specific examples of compounds of formula (I) and methods of their preparation.

Abbreviation List AcOH Acetic acid Amphos Di-tert-butyl(4-dimethylaminophenyl)phosphine aq or aq. Aqueous solution/water-based bipy 2,2'-Bipyridine Bn benzyl CAN ammonium nitrate CDI 1,1'-Carbonyldiimidazole COD 1,5-Cyclooctadiene C-Phos or CPhos 2-Dicyclohexylphosphino-2′,6′-bis( N,N -dimethylamino)biphenyl CuTc Copper thiophene-2-carboxylate (I) DAST trifluoride (diethylamino) sulfur dba Diphenylmethylene acetone DCE 1,2-Dichloroethane DCM dichloromethane dF(CF ₃ )ppy 3,5-Difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C DIBAL-H diisobutylaluminum hydrogenide DMAP 4-Dimethylaminopyridine DMEDA N,N'-Dimethylethylenediamine DMF N,N-Dimethylformamide DMSO Secondary Asia dppb 1,4-bis(biphenylphosphine)butane Dppf, DPPF, or dppf 1,1'-bis(biphenylphosphine)ferrocene dtbpf 1,1'-Bis(di-tert-butylphosphino)ferrocene dtbbpy 4,4'-Bis(tert-butyl)-2,2'-bipyridine eq or eq. or equiv. Equivalent ESI or ES Electro-spray ionization Et Ethyl EtOAc or EA Ethyl acetate g gram Grubbs II (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium h or hr hour HATU Nitrogen hexafluorophosphate benzotriazole tetramethylureon HFIP 1,1,1,3,3,3-Hexafluoroprop-2-ol HMDS Hexamethyldisilylamine Hoveyda-Grubbs II (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(neoisopropoxyphenylmethylene)ruthenium HPLC High-pressure liquid chromatography iPr Isopropyl iPr ₂ Net, DIEA or DIPEA N-Ethyldiisopropylamine (Hunig's base) LC MS, LCMS, LC-MS or LC/MS Liquid chromatography-mass spectrometry analysis m/z Mass divided by charge m-CPBA 3-Chloroperbenzoic acid Me methyl MeCN, ACN, or CH ₃ CN Acetonitrile MeOH methanol mg mg min minute mL milliliters MS Mass spectrometry analysis MsOH mesylate MTBE Methyl tributyl ether n-BuLi n-Butyl Lithium NMP N-methylpyrrolidone NMR Nuclear magnetic resonance Ns (4-Nitrophenyl)sulfonyl OTf or TfO Trifluoromethanesulfonate PE petroleum ether Ph Phenyl phen 1,10-Phenyline Piv or PivO Pteropenic or pteropenic ester (salt) PyBroP Tripyridine hexafluorophosphate RT or rt or rt room temperature RuPhos Pd G3 Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) sat. Saturation SFC Supercritical fluid chromatography tBu or ^t Bu Grade III Butyl TEA or Et ₃ N Triethylamine TES N-[tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TMP 2,2,6,6-Tetramethylpiperidine TMS Trimethylsilyl TsO or TsOH Toluenesulfonate (salt) or toluenesulfonic acid Xantphos Pd G3 Methanesulfonic acid [(4,5-bis(biphenylphosphino)-9,9-dimethyldibenzopiperan)-2-(2'-amino-1,1'-biphenyl)]palladium(II) Xphos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl PE petroleum ether

General Analytical and Purification Methods: This section describes general analytical and purification methods used to prepare the specific compounds described herein.

Chromatography: Unless otherwise indicated, residues containing crude products are purified by passing the crude material or concentrate through a Biotage brand silicone column pre-packed with rapid silica ( _SiO2 ) or reverse rapid silica (C18) and by dissolution of the product from the column using the indicated solvent gradient. For example, the description of silicone (0 to 40% EtOAc/hexane) means that the product is obtained by dissolution from a silica-packed column using a solvent gradient of 0% to 40% EtOAc/hexane.

Preparation-type HPLC or reversed-phase rapid chromatography purification: If specified, the compounds described herein were purified by reversed-phase HPLC using a Waters Fractionlynx semi-preparative HPLC-MS system employing one of the following two HPLC columns: (a) a Phenominex Gemini column (5 μm, C18, 150 x 30 mm) or (b) a Waters X-Select CSH column (5 μm, C18, 100 x 30 mm).

Typical operation of the instrument includes: dissolution at 45 mL/min and a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v formic acid)/water (0.1% formic acid) for 10 minutes; conditions can be varied to achieve optimal separation.

Preparative HPLC or reversed-phase rapid purification should be performed under one of the following conditions:

Condition 1: Column: Phenomenex luna C18 250×50 mm×10 μm; Mobile phase A: [ _H₂O ] (condition: [water 0.225% _NH₃ · _H₂O (FA))]); Mobile phase B: Acetonitrile (ACN); Gradient a: 65% B to 90% B;

Condition 2: Column: Phenomenex luna C18 250×50 mm×10 μm; Mobile phase A: [ _H₂O ] (condition: [water (0.225% FA)]); Mobile phase B: ACN; Gradient a: 65% B to 90% B;

Condition 3: Column: Phenomenex luna C18 150×25 mm×10 μm; Mobile phase A: [ _H₂O ] (condition: [water (0.225% FA]); Mobile phase B: ACN; Gradient a: 55% B to 85% B; Gradient b: 48% B to 78% B; Gradient c: 50% to 80%;

Condition 4: Column: YMC-Actus Triart C18 150×30 mm×7 μm; Mobile phase A: [ _H₂O ] (condition: [water (0.05% FA)]); Mobile phase B: ACN;

Condition 5: Column: Welch Xtimate C18 150×25 mm×5 μm; Mobile phase A: [ _H₂O ] (condition: [water (0.225% FA)]); Mobile phase B: ACN; Gradient a: 30% B to 60% B, 40 min; Gradient b: 55% B to 74% B, 40 min; Gradient c: 50% B to 80% B, 40 min; Gradient d: 35% B to 65% B, 40 min; Gradient e: 40% B to 70% B, 35 min; Gradient f: 35% B to 75% B, 40 min; Gradient g: 45% B to 75% B, 12 min; Mobile phase A: [ _H₂O (0.1% FA)];

Condition 6: Column: DAICEL CHIRALCEL OJ (250 mm × 50 mm, 10 μm); Mobile phase A: 0.1% _NH3 · _H2O /ethanol (EtOH); Flow rate (150 mL/min); Gradient a: 0% B, 8.5 min;

Condition 7: Column: Phenomenex luna C18 150×25 mm×10 μm; Mobile phase A: [ _H₂O ] (condition: [water (0.1% FA)]); Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient a: 38% B to 68% B, 10 min; Gradient b: 35% B to 65% B, 10 min; Gradient c: 48% B to 78% B, 7 min; Gradient d: 50% B to 80% B, 7 min;

Condition 8: Column: Phenomenex luna C18 150×40 mm×15 μm; Mobile phase A: [ _H₂O ] (condition: [water (0.1% FA)]); Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient a: 25% B to 55% B;

Condition 9: Column: 12 g C18 column; Mobile phase A: [ _H₂O ] (condition: [water (0.1% FA)]); Mobile phase B: ACN; Gradient a: 10% B to 90% B; Gradient b: 30% B to 95% B; Gradient c: 15% B to 100% B; Gradient d: 30% B to 80% B;

Condition 10: Column: Gemini 5 µm NX-C18 110 Å, 100 × 30 mm column; Mobile phase A: [ _H₂O ] (condition: [water (10 mM _{NH₄HCO₂ )} ]); Mobile phase B: ACN; Gradient a: 40% B to 100% B; Gradient b: 60% B to 100% B; Gradient c: 35% B to 50% B; Gradient d: 45% B to 65% B; Gradient e: 30% B to 100% B; Gradient f: 55% B to 100% B;

Condition 11: Column: 12 g C18 column; Mobile phase A: [ _H₂O ] (condition: [water (10 mM ammonium bicarbonate)]); Mobile phase B: ACN; Gradient a: 15% B to 80% B;

Condition 12: Column: 6 g Biotage reversed phase; Mobile phase A: [ _H₂O ] (condition: [water (0.1% FA)]); Mobile phase B: ACN; Gradient a: 5% B to 95% B;

Condition 13: Column: 18 g Biotage reversed phase; Mobile phase A: [ _H₂O ] (condition: [water (0.1% FA)]); Mobile phase B: ACN; Gradient a: 15% B to 85% B;

Condition 14: Column: Gemini 5 µm NX-C18 110 Å, 100 × 30 mm column; Mobile phase A: [ _H₂O ] (condition: [water (0.1% FA)]); Mobile phase B: MeOH; Gradient a: 25% B to 45% B; Gradient b: 60% B to 80% B; Gradient c: 50% B to 70% B;

Condition 15: Column: Gemini 5 µm NX-C18 110 Å, 100 × 30 mm column; Mobile phase A: [ _H₂O ] (condition: [water (10 mM ammonium bicarbonate)]); Mobile phase B: MeOH; Gradient a: 45% B to 55% B;

Condition 16: Column: Gemini 5 µm NX-C18 110 Å, 100 × 30 mm column; Mobile phase A: [ _H₂O ] (condition: [water (10 mM _{NH₄HCO₂ )} ]); Mobile phase B: MeOH; Gradient a: 50% B to 70% B; Gradient b: 45% B to 100% B; Gradient c: 55% B to 75% B;

Condition 17: Column: Gemini 5 µm NX-C18 110 Å, 100 × 30 mm column; Mobile phase A: [ _H₂O ] (condition: [water (0.1% FA)]); Mobile phase B: MeCN; Gradient a: 10% B to 95% B;

Condition 18: Column: Boston Green ODS, 150 × 30 mm × 5 µm; Mobile phase A: [ _H₂O ] (condition: [water (0.225% FA)]); Mobile phase B: MeCN; Gradient a: 45% B to 75% B; Gradient b: 38% B to 68% B; Gradient c: 48% B to 78% B;

Condition 19: Column: Phenomenex luna C18 250×70 mm×10 μm; Mobile phase A: [ _H₂O ] (condition: [water (0.225% FA)]); Mobile phase B: ACN; Gradient a: 30% B to 60% B;

Preparative normal phase liquid chromatography (Prep-NPLC): Condition 1: Column: Welch Ultimate XB- _NH2 250×50×10 µm, hexane-EtOH;

Analytical HPLC method: If specified, the compounds described herein were analyzed using an Aglilent 1100 series instrument with a DAD detector.

Rapid chromatography: If specified, rapid chromatography is performed on a Teledyne Isco instrument using a pre-packed disposable _SiO2 static column with a solvent flow rate ranging from 15 to 200 mL/min and UV detection (254 and 220 nm).

Preparative palmar supercritical fluid chromatography (SFC) method: If specified, the compounds described herein were purified by palmar SFC using one of the following two palmar SFC columns: (a) Chiralpak IG 2x25 cm, 5 µm or (b) Chiralpak AD-H 2x15 cm, 5 μm.

Some CP-analytical SFC experiments are run on the SFC Method Station (Thar, Waters) under the following conditions: column temperature: 40°C, mobile phase: _CO2 /methanol (0.2% methanol ammonia) = flow rate: 4.0 mL/min, back pressure: 120 bar, detection wavelength: 214 nm.

Some CP-analytical SFC experiments are run on an SFC-80 (Thar, Waters) under the following conditions: column temperature: 35°C, mobile phase (example): _CO2 /methanol (0.2% methanol ammonia) = flow rate: 80 g/min, back pressure: 100 bar, detection wavelength: 214 nm.

Preparative CP method: Acidic reversed-phase MPLC: Instrument type: Reveleris™ preparative MPLC; Column: Phenomenex LUNA C18(3) (150x25 mm, 10 μm); Flow rate: 40 mL/min; Column temperature: room temperature; Solvent A: 0.1% (v/v) formic acid/water, Solvent B: 0.1% (v/v) formic acid/acetonitrile; Specified gradient and wavelength used.

Condition 1: Column: Chiralcel OJ-3, 50×4.6mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: Methanol (MeOH) (0.05% diethanolamine (DEA)); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 5% B to 40% B; Gradient a-1: 5% B to 40% B, Mobile phase B: EtOH (0.05% DEA); Gradient a-2: 5% B to 40% B, Mobile phase B: Isopropanol (iPOH) (0.05% DEA);

Condition 2: Column: Chiralpak AD-3, 50×4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: MeOH (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 40% B;

Condition 3: Column: DAIICEL Chiralpak IG, 250 mm × 50 mm, 10 μm; Mobile phase A: _CO2 ; Mobile phase B: EtOH/ACN; Flow rate: 100 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 75% B, 8.1 min; Gradient b: 75% B, 7.5 min;

Condition 4: Column: Chiralpak AD-3, 50 × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: EtOH (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 5% B to 40% B; b: 40% B;

Condition 5: Column: Chiralpak IG-3, 50 × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: EtOH (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 40% B; Gradient a-1: 40% B, Mobile phase B: MeOH (0.05% DEA); Gradient a-2: 40% B, Mobile phase B: iPOH + ACN (0.05% DEA); Gradient b: 60% B, Mobile phase B: iPOH + ACN (0.05% DEA); Gradient c: 50% B;

Condition 6: Column: DAICL Chiralpak AD, 250 mm × 30 mm, 10 μm; Mobile phase A: _CO2 ; Mobile phase B: EtOH (0.1% _NH3 · _H2O ); Flow rate: 150 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 23% B, 5.3 min; Gradient b: 25% B, 2.5 min; Gradient c: 3.9 min; Gradient d: 5.0 min; Gradient e: 34% B, 6.5 min; Gradient f: 4.4 min; Mobile phase B: ACN/(+) i-PrOH (0.1% _NH3 · _H2O ), Flow rate: 120 mL/min;

Condition 7: Column: DAIICEL Chiralpak AD, 250 mm × 50 mm, 10 μm; Mobile phase A: _CO2 ; Mobile phase B: i-PrOH (0.1% _NH3 · _H2O ); Flow rate: 150 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 35% B, 5 min;

Condition 8: Column: DAIICEL Chiralpak IH, 250 mm × 50 mm, 10 μm; Mobile phase A: _CO2 ; Mobile phase B: EtOH (0.1% _NH3 · _H2O ); Flow rate: 150 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 27% B, 5.5 min;

Condition 9: Column: DAICL Chiralpak OD-3, 50 mm × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: MeOH (0.5% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 5% B to 40% B;

Condition 10: Column: DAIICEL Chiralpak AD (250 mm × 30 mm, 10 μm); Mobile phase A: MeOH (0.1% _NH3 · _H2O ); Flow rate (100 mL/min); Gradient a: 0% B, 8.2 min;

Condition 11: Column: Chiralpak IG-3, 250 mm × 30 mm, 10 μm; Mobile phase A: _CO₂ ; Mobile phase B: MeOH (0.1% _NH₃ · _H₂O ); Flow rate: 150 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 35% B; Gradient b: 56% B, mobile phase B: EtOH; Gradient c: 40% B, flow rate: 120 mL/min; Gradient d: 40% B, mobile phase B: MeOH; Gradient e: 35% B, mobile phase B: iPrOH (0.1% _NH₃ · _H₂O )

Condition 12: Column: Chiralcel OJ, 250 mm × 30 mm, 10 μm; Mobile phase A: _CO2 ; Mobile phase B: MeOH (0.1% NH3 _{· H2O} ); Flow rate: 120 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 30% B;

Condition 13: Column: Chiralpak AD-3, 50×4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: IPA+ACN (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 40% B;

Condition 14: Column: DAICL Chiralpak IE-3, 50 mm × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: IPA + ACN (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 40% B;

Condition 15: Column: DAICL CHIRALPAK IF, 50 mm × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: EtOH (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 40% B;

Condition 16: Column: DAIICEL Chiralpak IG-3, 50 mm × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: IPA + ACN (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 60% B;

Condition 17: Column: Chiralcel OD-3, 50 mm × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: IPA (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 5% B to 40% B;

Condition 18: Column: DAIICEL Chiralpak IG-3, 50 mm × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: IPA (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 60% B;

Condition 19: Column: Chiralpak AD-3, 50 × 4.6 mm, 3 μm; Mobile phase A: _CO2 ; Mobile phase B: IPA (0.05% DEA); Flow rate: 3 mL/min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 5% B to 40% B;

Condition 20: Column: DAIICEL Chiralcel OD, 250×30 mm, 10 μm; Mobile phase A: _CO2 ; Mobile phase B: EtOH (0.1% _NH3H2O ); Flow rate: 150 mL _/ min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 30% B;

Condition 21: Column: Phenomenex-Cellulose-2, 250×30 mm, 10 μm; Mobile phase A: _CO2 ; Mobile phase B: EtOH (0.1% _NH3H2O ); Flow rate: 150 mL _/ min; Column temperature: 35℃; Back pressure: 100 bar; Gradient a: 45% B;

Proton NMR spectroscopy: Unless otherwise indicated, all ^1H NMR spectra were collected on a Bruker NMR instrument at 300, 400, or 500 MHz or a Varian NMR instrument at 400 MHz. For qualitative analysis, all observed protons were reported as parts per million (ppm) low-field from tetramethylsilane (TMS) using the internal solvent peak as a reference. All NMR spectra were collected at approximately 25 °C.

Mass Spectrometry (MS) Unless otherwise indicated, all mass spectrometric data for starting materials, intermediates, and/or exemplary compounds are reported as mass/charge (m/z) of ions in the [M+H] ⁺ molecular state. The reported molecular ions are obtained using an electrospray detection method (commonly referred to as ESI MS) on a Waters Acquity UPLC/MS system or a Gemini-NX UPLC/MS system. Compounds with isotopic atoms (such as bromine and its analogues) are generally reported based on the detected isotopic pattern, as understood by those skilled in the art.

Compound Names The compounds disclosed and described in this article have been named using the IUPAC naming function of ChemDraw Professional 17.0.

Specific Examples This section provides procedures for specific examples of synthesizing the compounds presented herein. Unless otherwise indicated, all starting materials are commercially available from, for example, Sigma-Aldrich, or are known in this art and can be synthesized using known procedures employing common techniques.

Example A1 : Synthetic intermediate method Int 1. Intermediate Int-A1 5-acetyl-1-methyl-pyridin-2-one

5-Bromo-1-methylpyridin-2-one (1 equivalent, 6.9 g, 36.7 mmol) was reacted with 1,4-dimethylpyridinium chloride. Pd(dppf) _Cl₂ (0.1 equivalent, 2.7 g, 3.67 mmol), CuI (0.2 equivalent, 1.4 g, 7.34 mmol), and tributyl(1-ethoxyvinyl)stanzane (1.1 equivalent, 14 mL, 40.4 mmol) were added to a solution of alkane (130 mL), and the reaction mixture was stirred at 80 °C for 12 hours under nitrogen. LCMS showed 32% of the desired mass. A saturated aqueous solution of KF (aq.) (20 mL) was added, and the mixture was stirred at 25 °C for 1 hour. The resulting mixture was extracted with ethyl acetate (EtOAc) (3 × 100 mL), and the combined organic layer was washed with a saturated aqueous solution of NaCl (50 mL ₎ , dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude residue. The residue was purified by preparative HPLC (condition 1, gradient a) and freeze-dried to give 5-acetyl-1-methyl-pyridin-2-one (Int-A1 , 3 g, 18.9 mmol, 51% yield) as a solid. LCMS : [M+H] ^⁺ = 152.0; purity = 95% (220 nm); retention time = 0.179 min.

Method Int 2. Intermediate Int-A2: 5-(2-bromoacetylated)-1-methylpyridin-2-one

At 0 °C, Br₂ (1 equivalent , 700 mg, 4.6 mmol)/AcOH containing 33% HBr in acetic acid (AcOH) (29 equivalents, 10.9 g, 136 mmol) was slowly added dropwise to a solution of 5-acetyl- _1- methyl-pyridin-2-one (Int-A1, 1 equivalent, 700 mg, 4.6 mmol)/AcOH containing 33% HBr (7.4 equivalents, 2.7 g, 34 mmol), followed by stirring at 25 °C for 2 hours. LC-MS showed 51% of the desired product. The reaction mixture was extracted with EtOAc (3 × 100 mL). The combined organic layer was dried _{with Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by silicone column chromatography (100% EtOAc) (TLC, 100% EtOAc, _Rf = 0.50) to obtain a solid 5-(2-bromoacetylated)-1-methylpyridin-2-one (Int-A2 , 1.7 g, 6.9 mmol, 99% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.25 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 2.6, 9.6 Hz, 1H), 6.59 (d, J = 9.6 Hz, 1H), 4.20 (s, 2H), 3.65 (s, 3H).

Method Int 3. Intermediate Int-A3: N-[(2R)-2-hydroxypropyl]-N-[2-(1-methyl-6-epoxy-3-pyridyl)-2-epoxy-ethyl]-4-nitro-benzenesulfonamide

To a solution of 5-(2-bromoacetyl)-1-methylpyridin-2-one (Int-A2 , 1 equivalent, 700 mg, 3 mmol) and N-[(2R)-2-hydroxypropyl]-4-nitrobenzenesulfonamide (1 equivalent, 792 mg, 3 mmol) in acetone (15 mL), _K₂CO₃ (3 equivalent, 1262 mg, 9 mmol) and _KI (1.1 equivalent, 556 mg, 3.3 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 hours. LCMS showed 73% of the desired product. The reaction mixture was filtered through a diatomaceous earth mat. The filter cake was washed with EtOAc (3 × 5 mL) and then extracted with EtOAc (3 × 50 mL). The combined organic layer was dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by silica gel column chromatography (10% dichloromethane (DCM)/MeOH) to obtain N-[(2R)-2-hydroxypropyl]-N-[2-(1-methyl-6-sideoxy-3-pyridyl)-2-sideoxy-ethyl]-4-nitro-benzenesulfonamide (Int-A3 , 400 mg, 0.87 mmol, 29% yield) as a solid. LCMS : [M+H] ^⁺ = 410.0; purity = 89% (220 nm); retention time = 0.485 min.

Method Int 4. Intermediate Int-A4: 1-Methyl-5-[(2S,6R)-6-methyl-4-(4-nitrophenyl)sulfonyl- [Lin-2-yl]pyridin-2-one

TES (10 equivalents, 1.4 mL, 9.8 mmol) was added to a solution of N-[(2R)-2-hydroxypropyl]-N-[2-(1-methyl-6-sideoxy-3-pyridyl)-2-sideoxy-ethyl]-4-nitro-benzenesulfonamide (Int-A3 , 1 equivalent, 400 mg, 0.98 mmol) in DCM (4 mL), followed by the slow addition of TMSOTf (10 equivalents, 1.8 mL, 9.8 mmol) at 0 °C, and the reaction mixture was stirred at 25 °C for 12 hours. LCMS showed 61% of the desired product. The reaction mixture was poured into 10 mL of saturated 50% NaOH aqueous solution until pH=14, and then stirred at 60 °C for 2 hours. The mixture was completely dissolved, extracted with DCM (3 × 20 mL), and _the combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain 1-methyl-5-[(2S,6R)-6-methyl-4-(4-nitrophenyl)sulfonyl- [Lin-2-yl]pyridin-2-one (Int-A4 , 400 mg, 0.81 mmol, 83% yield). LCMS : [M+H]+ = 393.9; purity = 82% (220 nm); retention time = 0.847 min.

Method Int 5. Intermediate Int-A5: 1-Methyl-5-[(2S,6R)-6-methyl] [Lin-2-yl]pyridin-2-one

Under a _nitrogen atmosphere, at 0–5°C, 1-methyl-5-[(2S,6R)-6-methyl-4-(4-nitrophenyl)sulfonyl- [Lin-2-yl]pyridin-2-one (Int-A4, 1 equivalent, 350 mg, 0.71 mmol) was added dropwise to a solution of dodecane-1-thiol (2.5 equivalent, 13 mg, 0.063 mmol) in THF (15 mL). The reaction mixture was stirred at 0–5 °C for 0.5 h under _N2 atmosphere, followed by the addition of sodium methoxide (3 equivalent, 115 mg, 2.14 mmol) to the solution at 0–5 °C. The resulting mixture was stirred at 0–5 °C for 1 h under _N2 protection. LCMS showed 21% of the desired product. The reaction mixture was poured into 10 mL of saturated 50% NaOH aqueous solution until pH=14, followed by stirring at 25 °C for 1 h. The mixture was completely dissolved and extracted with DCM (3 × 20 mL). The combined organic layer was then dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain 1-methyl-5-[(2S,6R)-6-methyl] in solid form. [Lin-2-yl]pyridin-2-one (Int-A5 , 70 mg, 0.27 mmol, 38% yield). LCMS : [M+H] ⁺ = 209.5; purity = 100% (220 nm); retention time = 0.123 min.

Method Int 6. Intermediate Int-A6: 2-chloro-6,7-dimethyl-4-methylthio-pteridine

At -10°C, NaSMe (1.2 equivalent, 551 mg, 7.9 mmol) (dissolved in water (5 mL)) was added dropwise to a solution of 2,4-dichloro-6,7-dimethyl-pteridine (1 equivalent, 1.5 g, 6.6 mmol) in THF (15 mL), and the reaction mixture was stirred at 25°C for 14 hours. LCMS showed 76% of the desired product. The reaction mixture was poured into _H₂O (50 mL) and then extracted with EtOAc (3 × 80 mL). _The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silicone column chromatography (25% EtOAc/petroleum ether (PE), _Rf = 0.3) to give 2-chloro-6,7-dimethyl-4-methylthio-pteridine (Int-A6 , 800 mg, 3.3 mmol, 51% yield) as a solid. LCMS : retention time = 0.504 min, [M+H] ⁺ = 240.8 ESI+.

Method Int 7. Intermediate Int-A7: 5-[(2S,6R)-4-(6,7-dimethyl-4-methylthio-pteridin-2-yl)-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one

At 100 °C, 2-chloro-6,7-dimethyl-4-methylthio-pteridine (Int-A6 , 1 equivalent, 35 mg, 0.15 mmol) and 1-methyl-5-[(2S, 6R)-6-methyl [Lin-2-yl]pyridin-2-one (1.2 equivalents, 36 mg, 0.17 mmol) was added to a solution of DMSO (1 mL) with DIPEA (5 equivalents, 94 mg, 0.73 mmol) for 2 h. LCMS showed 88% of the desired product. The reaction mixture was combined with another batch for further purification. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by HPLC (50% [water (0.1% FA)-ACN], 5 min) to obtain an oily substance, 5-[(2S,6R)-4-(6,7-dimethyl-4-methylthio-pteridin-2-yl)-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Int-A7 , 86 mg, 0.21 mmol, 141% yield). LCMS : retention time = 0.487 min, [M+H] ⁺ = 413.0, ESI+, 98% purity (220 nm).

Method Int 8. Intermediate Int-A8: Bromo-[2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc

Synthesis was performed at a scale of 2.4 g, but two 1.2 g batches were run in parallel. The 1.2 g program is shown below:

Add 1,2-dibromoethane (0.05 equivalents, 0.019 mL, 0.22 mmol) to a solution of zinc (3 equivalents, 865 mg, 13 mmol) suspended in LiCl (0.5 M in THF) (1 equivalent, 9.0 mL, 4.4 mmol), and stir the suspension at 55 °C for 20 min. Then, cool the resulting mixture, introduce TMSCl (0.05 equivalents, 0.028 mL, 0.22 mmol), and stir the mixture again for 20 min. Cool the resulting mixture, then introduce 1 mL of THF containing iodine (0.02 equivalents, 22 mg, 0.09 mmol), and stir the reaction mixture at 55 °C for another 20 min. Next, 9 mL of THF containing 5-(4-bromotetrahydropiperan-2-yl)-1-methylpyridin-2-one (1 equivalent, 1.2 g, 4.4 mmol) was added to a warm suspension of activated zinc, and the reaction solution was stirred at 55°C for 12 hours. The reaction mixture was then transferred via syringe and used directly in the next step.

Method Int 9. Intermediate Int-A10: Chloro-[2,3-difluoro-4-(trifluoromethyl)phenyl]zinc,

Under _N2 conditions at 25°C, i-PrMgCl·LiCl (1.1 equivalent, 1.1 mL, 1.48 mmol) was slowly added to a solution of 1-bromo-2,3-difluoro-4-(trifluoromethyl)benzene (1 equivalent, 350 mg, 1.34 mmol) in THF (4 mL), and the mixture was stirred at 25°C for 1 h. The solution changed color. The mixture was cooled to -60°C, and then _ZnCl2 (1.1 equivalent, 3.0 mL, 1.48 mmol) was added to the mixture and stirred at 25°C for 1 h. The solution changed color, and the mixture (Int-A10) was used directly for the next step.

Method Int 10. Intermediate Int-A11: 2-chloro-4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridine

Chloro-[2,3-difluoro-4-(trifluoromethyl)phenyl]zinc (Int-A10, ₁ equivalent, 378 mg, 1.34 mmol) was added to a solution of 2,4-dichloro-6,7-dimethyl-pteridine (0.814 equivalent, 250 mg, 1.09 mmol) and Pd(Amphos) _2Cl2 (0.0326 equivalent, 31 mg, 0.0437 mmol) in THF (3 mL), and the reaction mixture was stirred at 25 °C for 2 h. LCMS showed that the starting materials were exhausted and the main peak indicated the desired mass. Water (10 mL) was added to the reaction mixture and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with 10 mL of saturated brine solution, separated, dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by preparative HPLC (FA) to give 2-chloro-4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridine (Int-A11 , 180 mg, 0.480 mmol, 36% yield) as a solid. LCMS : [M+H] ^⁺ = 375.2, purity = 77%.

Following a similar method, the following intermediate was obtained. Structure Starting materials Characteristics Int-B18 The crude product was purified by silicone column chromatography (0-33% EtOAc/PE) to give solid 2-chloro-7-methyl-4-[3-(trifluoromethyl)-1-biscyclic[1.1.1]pentyl]pyrido[2,3-d]pyrimidine (Int-B18, 250 mg, 0.797 mmol, 56% yield). LCMS : [M+H] ⁺ = 314.2; purity = 91% (220 nm); retention time = 0.542 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 2.83 (s, 3H), 2.66 (s, 6H).

Method Int 11. Intermediate Int-A12: 2-bromo-5-nitro-6-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidin-4-amine

A solution of 2-bromo-5-nitropyrimidine-4-amine (1 equivalent, 500 mg, 2.28 mmol) in MeCN (1 mL) and water (0.5 mL) was supplemented with ( _NH₄ ) _₂S₂O₈ (3 equivalents, 1.56 g, 6.85 mmol), _AgNO₃ (1.3 equivalents, 501 _mg , 2.97 mmol), and 3-(trifluoromethyl)bicyclo[ _1.1.1 ]pentane-1-carboxylic acid (1.2 equivalents, 493 mg, 2.74 mmol), and the reaction mixture was stirred at 80 °C for 2 h. LC-MS showed complete exhaustion of the starting material and detection of the desired mass (63%). The mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with a saline solution (3 × 40 mL), dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (0% to 25% EtOAc/PE) (TLC, 25% EtOAC/PE, desired product _Rf = 0.5) to give solid 2-bromo-5-nitro-6-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimidin-4-amine (Int-A12 , 500 mg, 1.42 mmol, 62% yield). LCMS : [M+H] ⁺ = 353.0; purity = 98% (220 nm); retention time = 0.586 min. ^1H NMR (400 MHz, _CDCl3 ) δ 7.01 - 6.14 (m, 2H), 2.44 (s, 6H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C46 Modification : After vigorous stirring at 80°C for 5 min, ammonium persulfate (3.3 equivalents) was added. The reaction mixture was extracted three times with DCM, and the crude product was purified by normal phase chromatography (0-4% MeOH/DCM) to give solid methyl 3-(6-amino-2-chloro-5-nitro-pyrimidin-4-yl)bicyclic [1.1.1]pentane-1-carboxylate (Int-C46, 1.06 g, 3.55 mmol, 41% yield). ESI-MS : [M+H] ⁺ = 299.1. ^1H NMR (CD ₃ OD, 400 MHz) δ 3.66 (s, 3H), 2.37 (s, 6H).

Method Int 12. Intermediate Int-A13: 2-bromo-6-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidin-4,5-diamine

Fe (powder, 5 equivalents, 427 mg, 7.65 mmol) and NH₄Cl (6 equivalents, 491 mg, 9.18 mmol) were added to a solution of 2-bromo-5-nitro-6-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidin- _4- amine (Int-A12, 1 equivalent, 540 mg, 1.53 mmol) in EtOH (10 mL) and water (2 mL), and the reaction mixture was stirred at 60 °C for 12 hours. LCMS showed the desired product (85%). The reaction mixture was filtered and concentrated under reduced pressure to give 2-bromo-6-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimidine-4,5-diamine (Int-A13 , 495 mg, 1.53 mmol, 100% yield) as a solid. LCMS : [M+H] ⁺ = 325.1; purity = 90% (220 nm); retention time = 0.484 min.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-D29 Int-D28 Modified : The reactants were stirred at 80 °C for 3 h to obtain ethyl 3-amino-1,6-dimethyl-2-sideoxy-pyridine-4-carboxylate as a solid (Int-D29, 9.00 g, 42.8 mmol, 93% yield). LCMS : [M+H] ⁺ = 211.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 6.66 (br s, 2H), 6.31 (d, J = 0.9 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.46 (s, 3H), 2.25 (d, J = 0.7 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H).

Method Int 13. Intermediate Int-A14: 2-bromo-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridine

Add _CaSO₄ (5.2 equivalents, 1085 mg, 7.97 mmol) to a mixture of 2-bromo-6-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimidine-4,5-diamine (Int-A13, 1 equivalent, 495 mg, 1.53 mmol) suspended in DCE (10 mL), followed by the addition of diacetyl (1.05 equivalents, 0.14 mL, 1.61 mmol). Stir the mixture at 85 °C for 20 h. LCMS showed the formation of the desired product (82%). Combine the reaction mixture with a second batch and filter. Concentrate the filtrate and wash the filter cake with DCM (20 mL). The crude material was purified by rapid chromatography (0-67% EtOAc/PE) to give 2-bromo-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridine (Int-A14 , 520 mg, 1.39 mmol, 91% yield) as a solid. LCMS : [M+H] ⁺ = 373.2; purity = 82% (220 nm); retention time = 0.612 min. ^¹H NMR (400 MHz, DMSO - _d6 ) δ 2.76 (d, J = 2.1 Hz, 6H), 2.64 (s, 6H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-A15 The residue was purified by silicone column chromatography (0-80% EtOAc/PE) (TLC: EtOAc, _Rf = 0.6) to give 2-bromo-4-[3-(difluoromethyl)-1-biscyclic[1.1.1]pentyl]-6,7-dimethyl-pteridine (Int-A15, 500 mg, 1.41 mmol, 72% yield) as a solid. LCMS : retention time = 0.570 min, [M+H] ⁺ = 357.0, ESI ⁺ . ^1H NMR (400 MHz, _CDCl3 ) δ 2.58 (s, 6H), 2.80 (d, J = 15.0 Hz, 6H), 5.67 - 6.09 (m, 1H). Modification: The final step was performed at 25°C for 2 hours. The crude product was purified by silicone column chromatography (0-50% EtOAc/PE) (TLC, 50% EtOAc/petroleum ether, desired product _Rf = 0.5) to give 2-bromo-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridine (Int-A50 , 600 mg, 1.67 mmol, 60% yield) as a solid. LCMS : [M+H] ⁺ = 359.0; purity = 97% (220 nm); retention time = 0.584 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 2.89 (s, 3H), 2.68 (s, 6H). Modification: The reaction was carried out at 20°C for 12 hours. The residue was purified by silicone column chromatography (0-100% EtOAc/PE) (TLC, 25% EtOAc/PE, new product _Rf = 0.6) to give solid 6,8-dichloro-2,3-dimethyl-pyridano[2,3-b]pyridine. (Int-B21 , 2.2 g, 9.65 mmol, 101% yield). LCMS : retention time = 0.496 min; [M+H] ⁺ = 227.9. ^1H NMR (400 MHz, _CDCl3 ) δ 7.73 (s, 1H), 2.83 (s, 6H). Modification: The reaction was carried out at 80℃ for 16 hours, followed by cooling, filtration through diatomaceous earth, and depressurization concentration to obtain solid 2-chloro-6,7-bis(methyl- _d3 )-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridine (Int-C13, 298 mg, 0.89 µmol, 99%). ESI-MS : [M+H] ⁺ = 279.1. ^1H NMR ( _CDCl3 , 400 MHz): δ 2.67 (s, 6H). ^19F NMR ( _CDCl3 , 376 MHz): δ -73.1 (s, 3F).

Method Int 14. Intermediate Int-A16: 2-Benzoxy-5-[(2R,4S,6R)-4-bromo-6-methyl-tetrahydropiperan-2-yl]pyridine

Under a _nitrogen atmosphere at -20°C, HBr (in AcOH) (3 equivalents, 25 mL, 141 mmol) was added dropwise to a mixture of 6-benzyloxypyridine-3-carboxaldehyde (1 equivalent, 10 g, 46.9 mmol) and (2R)-pent-4-en-2-ol (1 equivalent, 4.8 mL, 46.9 mmol) in DCM (250 mL). The mixture was then stirred at -20°C for 4 h under a _nitrogen atmosphere. LCMS showed the desired product (48%). The reaction mixture was slowly poured into _NaHCO3 (aq.) to adjust the pH to ≥7, extracted with EtOAc (300 mL × 2), and washed with 200 mL of saturated brine. The combined organic layer was dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by preparative HPLC (0.5% FA conditions) and freeze-dried to obtain an oily 2-benzyloxy-5-[(2R,4S,6R)-4-bromo-6-methyl-tetrahydropiperan-2-yl]pyridine (Int-A16 , 5.4 g, 14.9 mmol, 32% yield). LCMS : [M+H+2] ^⁺ = 364.0, purity = 100% (220 nm), retention time = 0.656 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.29 (dd, J=6.17, 2.6 Hz, 3H), 1.76 - 1.90 (m, 1H), 1.95 - 2.11 (m, 2H), 2.12 - 2.22 (m, 1H), 2.27 - 2.47 (m, 1H), 3.59 - 3.71 (m, 1H), 4.17 - 4.41 (m, 2H), 4.77 - 4.99 (m, 1H), 5.38 (s, 2H), 6.81 (dd, J=8.5, 3.6 Hz, 1H), 7.28 - 7.42 (m, 3H), 7.43 - 7.51 (m, 2H), 7.63 (dd, J=8.6, 1.9 Hz, 1H), 8.14 (dd, J=13.75, 1.9 Hz, 1H).

Method Int 15. Intermediate Int-A17: Bromo-[(2R,4S,6R)-2-methyl-6-(6-phenoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc

Synthesized in 2 g batches, but in parallel 5 batches of 400 mg each.

Zinc (5.54 equivalents, 2.0 g, 30.6 mmol) was suspended in LiCl (0.5 M in THF) (1 equivalent, 20 mL, 5.52 mmol), and 1,2-dibromoethane (0.05 equivalents, 0.024 mL, 0.28 mmol) was added. The suspension was stirred at 55 °C for 20 min, cooled, and then TMSCl (0.05 equivalents, mg, 0.276 mmol) was introduced. The mixture was stirred at 55 °C for another 20 min. The mixture was cooled, and then 1 mL of THF containing iodine (0.02 equivalent, 28 mg, 0.11 mmol) was introduced. The reaction mixture was then stirred at 55 °C for 20 min. 20 mL of THF containing 2-benzyloxy-5-[(2R,4S,6R)-4-bromo-6-methyl-tetrahydropiperan-2-yl]pyridine (Int-A16 , 1 equivalent, 200 mg, 0.55 mmol) was added to the warm suspension of activated zinc. The reaction mixture was stirred at 55 °C for 12 h, and the mixture was used directly in the next step.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-F15 Int-F14 The procedure yields a mixture of bromo-[2-(1-cyclobutyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc (Int-F15), which is used directly in the next synthetic step.

Method Int 16. Intermediate Int-A18: 2-[(2R,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-tetrahydropiperan-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridine

_THF (0.3 mL) was added as a solvent to a mixture of 2-bromo-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridine (Int-A14 , 1 equivalent, 100 mg, 0.268 mmol), C-Phos (0.2 equivalent, 23 mg, 0.0536 mmol) and Pd(OAc) ₂ (0.1 equivalent, 6.0 mg, 0.0268 mmol) purged three times with N2. Next, bromo-[(2R,4S,6R)-2-methyl-6-(6-phenoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc (Int-A17 , 1.2 equivalents, 5.0 mL, 0.322 mmol) was added, and the mixture was stirred at 55 °C for 2 h. Trace amounts of the desired product were observed by LCMS. The reaction mixture (combined with 5 other batches) was quenched with 100 mL of _H₂O , extracted with EtOAc (100 mL × 3), and the organic matter was washed with 50 mL of saturated brine _solution . The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude residue. The crude material was purified by silicone column chromatography (0-50% PE/EtOAc) (TLC, 33% EtOAc/PE, desired product _Rf = 0.6) to give an oily 2-[(2R,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-tetrahydropiperan-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-1-biscyclic[1.1.1]-pentyl]pteridine (Int-A18 , 700 mg, 1.11 mmol, 413% yield). LCMS : [M+H] ⁺ = 576.3, purity = 91% (220 nm), retention time = 0.729 min.

Method Int 17. Intermediate Int-A20: 2-chloro-4-(4,4-difluorocyclohexyl-1-en-1-yl)-6,7-dimethylpteridine

A mixture of 2,4-dichloro-6,7-dimethyl-pteridine (1 equivalent, 1600 mg, 6.99 mmol), 2-(4,4-difluorocyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentane (1 equivalent, 1705 mg, 6.99 mmol), _K₃PO₄ (3 equivalent, 4448 mg, 21.0 mmol), and Pd(Amphos) _₂Cl₂ (0.1 _equivalent , 495 mg, _0.699 mmol) in toluene (50 mL) and water (5 mL) was degassed and purged three times with _N₂ . The mixture was then stirred at 30 °C for 1 h under _N₂ atmosphere. The reaction mixture was separately dissolved between EtOAc (2 × 100 mL) and water (80 mL) and extracted. _The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silicone column chromatography (0-100% EtOAc/PE) (TLC, 25% EtOAc/PE, desired product _Rf = 0.5) to give an oily 2-chloro-4-(4,4-difluorocyclohex-1-en-1-yl)-6,7-dimethylpteridine (Int-A20 , 1050 mg, 3.38 mmol, 48% yield). LCMS : [M+H] ⁺ = 311.1; Purity = 89% (220 nm); Retention time = 0.549 min. ^1H NMR (400 MHz, _CDCl3 ) δ 7.44 - 7.39 (m, 1H), 3.15 - 3.08 (m, 2H), 3.00 - 2.89 (m, 2H), 2.84 - 2.81 (m, 3H), 2.79 (s, 3H), 2.31 - 2.19 (m, 2H).

Method Int 18. Intermediate Int-A21: 2-chloro-4-(4,4-difluorocyclohexyl)-6,7-dimethyl-5,6,7,8-tetrahydropteridine

Under a _nitrogen atmosphere, PtO₂ (1 equivalent, 767 mg, 3.38 mmol) was added to a solution of 2-chloro-4-(4,4-difluorocyclohexen-1-yl)-6,7- _dimethyl -pteridine (Int-A20 , 1 equivalent, 1050 mg, 3.38 mmol) in MeOH (20 mL). The suspension was degassed and purged three times with _H₂ . The mixture was stirred in _H₂ (15 psi) at 30 °C for 12 h. LCMS showed 39% of the desired product. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. Under a _nitrogen atmosphere, _PtO₂ (1 equivalent, 767 mg, 3.38 mmol) was added to MeOH (20 mL) containing the residue. The suspension was degassed and purged three times with _H₂ . The mixture was stirred at 25°C for 12 h with _H₂ (15 psi). LCMS showed 59% of the desired product. The reaction mixture was filtered and concentrated under reduced pressure to give 1.0 g of crude product (Int-A21 ) .

Method Int 19. Intermediate Int-A22: 2-chloro-4-(4,4-difluorocyclohexyl)-6,7-dimethylpteridine

_MnO₂ (10 equivalents, 2.74 g, 31.6 mmol) was added to a mixture of 2-chloro-4-(4,4-difluorocyclohexyl)-6,7-dimethyl-5,6,7,8-tetrahydropteridine (Int-A21 , 1 equivalent, 1.0 g, 3.16 mmol) in a DCE (50 mL), followed by stirring at 40 °C for 12 h. LCMS showed a peak with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue (approximately 900 mg). _MnO₂ (10 equivalents, 2.74 g, 31.6 mmol) was added to a DCE (50 mL) containing the residue, followed by stirring at 40 °C for 12 h. LCMS showed 73% of the desired product. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue (approximately 660 mg). The crude product was purified by silicone column chromatography (0-100% EtOAc/PE) (TLC, 25% EtOAc/PE, desired product _Rf = 0.4) to give 300 mg (54% purity) and 2-chloro-4-(4,4-difluorocyclohexyl)-6,7-dimethylpteridine (Int-A22 , 250 mg, 0.799 mmol, 25% yield) as a solid. LCMS : [M+H] ⁺ = 313.2; purity = 96% (220 nm); retention time = 0.553 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.20 - 4.09 (m, 1H), 2.84 (s, 3H), 2.80 (s, 3H), 2.37 - 2.26 (m, 2H), 2.25 - 2.12 (m, 2H), 2.09 - 1.93 (m, 4H).

Method Int 20. Intermediate Int-A24: 3-(1-hydroxy-1-methyl-ethyl)bicyclo[1.1.1]pentane-1-carboxylic acid

At 0 °C, methylmagnesium bromide (4 equivalents, 39 mL, 118 mmol) was added to a solution of 3-methoxycarbonylbis([1.1.1]pentane-1-carboxylic acid) (1 equivalent, 5.0 g, 29.4 mmol) in THF (100 mL), and the solution was stirred at 0 °C for 2 h. TLC showed complete exhaustion of the starting material and two new spots were observed. Water (10 mL) was added to the solution, and extraction was performed with EtOAc (10 mL × 3). The organic phase was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid column chromatography (100% EtOAc/PE, _Rf = 0.3) and concentrated under reduced pressure to obtain two batches of product. Batch 1: 3-(1-hydroxy-1-methyl-ethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in solid form (Int-A24 , 2.0 g, 12.3 mmol, 42% yield); and Batch 2: 3-(1-hydroxy-1-methyl-ethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in solid form (Int-A24 , 2.1 g, 12.3 mmol, 40% yield).

(Batch 1): ^1H NMR (400 MHz, CDCl ₃ ) δ 1.99 (s, 6H), 1.19 - 1.17 (m, 6H).

(Batch 2): ^1H NMR (400 MHz, CDCl ₃ ) δ 1.99 - 1.97 (m, 3H), 1.94 - 1.89 (m, 3H), 1.22 - 1.15 (m, 6H).

Method Int 21. Intermediate Int-A25: 3-(1-hydroxy-1-methyl-ethyl)-N-methoxy-N-methyl-bicyclo[1.1.1]pentane-1-methylamine

A solution of 3-(1-hydroxy-1-methyl-ethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Int-A24 , 1 equivalent, 2.0 g, 11.8 mmol) in DCM (40 mL) was purged under _N2 and stirred at 20 °C. HATU (1.5 equivalent, 6702 mg, 17.6 mmol) was added to the solution, and the mixture was stirred at 20 °C for 1 h under _N2 . N,N-diisopropylethylamine (2 equivalent, 4.1 mL, 23.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.2 equivalent, 1375 mg, 14.1 mmol) were added, and the reaction mixture was stirred at 20 °C for another 12 h. LCMS showed complete exhaustion of the starting material and detected a peak with the desired mass. The reactant was combined with a second batch. The final mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid column chromatography (67% EtOAc/PE, _Rf = 0.3) to give 3-(1-hydroxy-1-methyl-ethyl)-N-methoxy-N-methyl-bicyclo[1.1.1]pentane-1-methylamine (Int-A25 , 2.10 g, 7.68 mmol, 65% yield) as a solid. LCMS : [M+H] ⁺ = 214.0; purity = 79% (UV 220 nm); residence time = 0.384 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.67 (s, 3H), 3.18 (s, 3H), 2.80 - 2.79 (m, 1H), 2.03 - 1.98 (m, 6H), 1.18 (s, 6H).

Method Int 22. Intermediate Int-A26: Methyl-3-(1-fluoro-1-methyl-ethyl)bicyclo[1.1.1]pentane-1-carboxylate

A mixture of methyl 3-(1-hydroxy-1-methyl-ethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A25 , 1 equivalent, 170 mg, 0.923 mmol) in DCM (4 mL) was cooled to -78 °C. Then, DAST (3 equivalents, 0.26 mL, 2.77 mmol) was slowly added at -78 °C. The mixture was heated to 20 °C and stirred for 12 h. LCMS showed complete exhaustion of the starting material and a peak of the desired mass was detected. The mixture was cooled to -78 °C, and water was slowly added. Then, 20 mL of water was added to the solution, and extraction was performed using EtOAc (20 mL × 3). Silicone was added to the combined organic layer and concentrated under a reduction process to obtain a crude substance. The crude substance was purified by a rapid column chromatography (17% EtOAc/PE, _Rf = 0.3) to obtain a liquid methyl-3-(1-fluoro-1-methyl-ethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A26 , 50 mg, 0.268 mmol, 29% yield). LCMS : [M+H] ⁺ = 216.2; purity = 86% (UV 220 nm); residence time = 0.453 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.67 (s, 3H), 3.19 (s, 3H), 2.06 (s, 6H), 1.36 - 1.32 (m, 3H), 1.31 - 1.26 (m, 3H).

Method Int 23. Intermediate Int-A27: (3-chloro-5,6-dimethyl-pyridine) -2-yl)-[3-(1-fluoro-1-methyl-ethyl)-1-biscyclic[1.1.1]pentyl] methyl ketone

Add 5-chloro-2,3-dimethylpyridine to a solution of 3-(1-fluoro-1-methyl-ethyl)-N-methoxy-N-methyl-bis(1.1.1)pentane-1-methylamine (Int-A26, 1 equivalent, 200 mg, 0.93 mmol) in THF (6 mL). (1.5 equivalent, 199 mg, 1.39 mmol). The flask was capped and purged under _N2 . The solution was cooled to -20°C. TMPMgCl·LiCl (1.5 equivalent, 1.4 mL, 1.39 mmol) was added dropwise over 2 min, and the reaction mixture was stirred at -20°C for 1 h. LCMS showed 58% of the starting material (SM ₁ ) and 14% of SM ₂ remaining, and the desired MS peak was detected. At 0°C, TMPMgCl·LiCl (0.75 equivalent, 0.70 mL, 0.697 mmol) was added, and the mixture was stirred at 0°C for 1 h. LCMS showed 56% of SM ₁ remaining, and the desired mass peak was detected. The reaction mixture was diluted with 5 mL of water and extracted with solvent EtOAc (10 mL × 3). The combined organic layer was dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by reversed-phase chromatography (40% [water (FA)-ACN]) to obtain a solid (3-chloro-5,6-dimethyl-pyridine) -2-yl)-[3-(1-fluoro-1-methyl-ethyl)-1-biscyclic[1.1.1]pentyl]methyl ketone (Int-A27 , 140 mg, 0.406 mmol, 44% yield). LCMS : [M+H] ⁺ = 279.2; purity = 86% (220 nm); retention time = 0.590 min. ^¹H NMR (400 MHz, _CDCl₃ ) δ 2.64 - 2.50 (m, 6H), 2.22 - 2.13 (m, 6H), 1.37 - 1.32 (m, 3H), 1.31 - 1.28 (m, 3H).

Method Int 24. Intermediate Int-A28: Methyl-3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate

A mixture of 3-methoxycarbonylbis(1.1.1)pentane-1-carboxylic acid (1 equivalent, 20 g, 118 mmol) in THF (800 mL) was cooled to 0 °C. At 0 °C, _BH₃ - _Me₂S (1.2 equivalent, 14 mL, 141 mmol) was slowly added. The mixture was then stirred at 20 °C for 12 h. New spots were observed by TLC. MeOH was slowly added until gas was produced. The mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by rapid column chromatography (50% EtOAc/PE; molybdenum phosphate; _Rf = 0.3) to give an oily methyl-3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A28 , 18.3 g, 117 mmol, 99.7% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 3.68 (s, 3H), 3.64 (s, 2H), 2.00 (s, 6H).

Method Int 25. Intermediate Int-A29: Methyl 3-methacrylbicyclo[1.1.1]pentane-1-carboxylate

A mixture of oxalool (1.3 equivalents, 7.1 mL, 83.2 mmol) in DCM (160 mL) was cooled to -65°C. Then, at a temperature below -60°C, 26 mL of DCM containing DMSO (2.6 equivalents, 13.01 g, 166 mmol) was slowly added. The mixture was stirred at -65°C for 0.5 h. Next, 180 mL of DCM containing methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A28, 1 equivalent, 10 g, 64.0 mmol) was slowly added. The mixture was stirred at -65°C for 0.5 h. At -65°C, 50 mL of TEA was added to the mixture. The mixture was then heated to 20°C and filtered. The filter cake was washed with 200 mL of EtOAc, and the filtrate was concentrated under reduced pressure to obtain crude material. The crude material was purified by rapid column chromatography (25% EtOAc/PE; (2,4-dinitrophenyl)hydrazine, _Rf = 0.2) to give an oily methyl 3-methacrylbicyclo[1.1.1]pentane-1-carboxylate (Int-A29 , 8.6 g, 55.8 mmol, 87% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 9.60 (s, 1H), 3.70 (s, 3H), 2.32 (s, 6H).

Method Int 26. Intermediate Int-A30: Methyl-3-(2,2-difluorovinyl)bicyclo[1.1.1]pentane-1-carboxylate

At 20 °C, PPh ₃ (3 equivalents, 26 g, 97.3 mmol) and sodium dichlorofluoroacetate (3 equivalents, 14.8 g, 97.3 mmol) were added to a mixture of methyl 3-methoxybicyclo[1.1.1]pentane - 1-carboxylate (Int-A29, 1 equivalent, 5 g, 32.4 mmol) in DMF (100 mL), and the mixture was degassed three times with _N2 . The mixture was stirred at 100 °C for 1 h. TLC showed complete exhaustion of the starting material. New spots were detected by TLC. The mixture was added to water (100 mL) and extracted with EtOAc (100 mL × 3). Silicone was added to the combined organic layer, and the mixture was concentrated under reduced pressure to obtain a crude substance. The crude substance was purified by silicone column chromatography (25% EtOAc/PE, _Rf = 0.2) to obtain an oily methyl-3-(2,2-difluorovinyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A30 , 1.4 g, 7.44 mmol, 23% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 4.34–4.22 (m, 1H), 3.67 (s, 3H), 2.17 (s, 6H).

Method Int 27. Intermediate Int-A31: Methyl-3-(2,2-difluoroethyl)bicyclo[1.1.1]pentane-1-carboxylate

Under _N2 at 20°C, palladium/carbon (1 equivalent, 396 mg, 3.72 mmol) was added to a mixture of methyl 3-(2,2-difluorovinyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A30 , 1 equivalent, 700 mg, 3.72 mmol) in MeOH (16 mL). The mixture was degassed three times with _H2 and stirred for 2 h at 20°C under _H2 (15 psi) atmosphere. TLC showed complete exhaustion of the starting material and detection of new spots. The mixture was degassed three times with _N2 . The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give an oily methyl-3-(2,2-difluoroethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A31 , 560 mg, 2.94 mmol, 79% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 5.80 (tt, J = 4.5, 56.2 Hz, 1H), 3.67 (s, 3H), 2.11–1.99 (m, 8H).

Method Int 28. Intermediate Int-A32: 3-(2,2-difluoroethyl)bicyclo[1.1.1]pentane-1-carboxylic acid

At 25 °C, LiOH (2 equivalents, 141 mg, 5.89 mmol) was added to a mixture of methyl 3-(2,2-difluoroethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A31 , 1 equivalent, 560 mg, 2.94 mmol) in THF (8.4 mL) and water (2.8 mL). The mixture was stirred at 25 °C for 1 h. TLC showed complete exhaustion of the starting material and detection of new spots. Water (20 mL) was added to the mixture and it was extracted with EtOAc (20 mL × 3). _The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give 3-(2,2-difluoroethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Int-A32 , 600 mg, 3.41 mmol, 116% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 5.91–5.56 (m, 1H), 2.02 (s, 6H), 2.00–1.93 (m, 2H).

Method Int 29. Intermediate Int-A33: 3-(2,2-difluoroethyl)-N-methoxy-N-methyl-bicyclo[1.1.1]pentane-1-methylamine

CDI (1.3 equivalents, 790 mg, 4.87 mmol) and N,N-diisopropylethylamine (1.3 equivalents, 0.85 mL, 4.87 mmol) were added to a solution of 3-(2,2-difluoroethyl)bicyclo[1.1.1]pentane - 1-carboxylic acid (Int-A32, 1 equivalent, 660 mg, 3.75 mmol) in DCM (30 mL). The mixture was stirred at 25 °C for 0.5 h. At 25 °C, N,N-diisopropylethylamine (1.5 equivalents, 0.98 mL, 5.62 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.3 equivalents, 475 mg, 4.87 mmol) were added to the mixture. The mixture was stirred at 25 °C for 12 h. LCMS showed complete exhaustion of the starting material and detection of a main peak with the desired mass. Water (50 mL) was added to the mixture and extracted with EtOAc (50 mL × 3). The combined organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reversed-phase chromatography (60% [water (FA)-ACN]) to remove ACN from the solution, and the remainder was extracted with EtOAc (3 × 50 mL). The combined organic phase was concentrated under reduced pressure to obtain an oily 3-(2,2-difluoroethyl)-N-methoxy-N-methyl-bicyclo[1.1.1]pentane-1-methylamine (Int-A33 , 600 mg, 2.74 mmol, 73% yield). LCMS : [M+H] ⁺ = 220.2; purity = 82% (UV 220 nm); retention time = 0.456 min. ^1H NMR (400 MHz, _CDCl3 ) δ 5.81 (tt, J = 4.6, 56.3 Hz, 1H), 3.67 (s, 3H), 3.18 (s, 3H), 2.13 - 2.10 (m, 6H), 2.10 - 2.00 (m, 2H).

Following a similar method, the following intermediate was obtained. Structure Starting materials Characteristics Int-E4 Modified: The reaction begins with 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid to give N -methoxy- N -methyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Int-E4, 3.09 g, 13.8 mmol, 92% yield) as an oil, which slowly crystallizes into a solid. ^¹H NMR ( _CDCl₃ , 400 MHz): δ 3.68 (3H, s), 3.19 (3H, s), 2.29 (6H, s). ^¹⁹F NMR ( _CDCl₃ , 376 MHz): δ -73.2 (3F, s). LCMS : [M+H] ^⁺ = 224.2.

Method Int 30. Intermediate Int-A34: (3-chloro-5,6-dimethyl-pyridine) -2-yl)-[3-(2,2-difluoroethyl)-1-bis(1.1.1)pentyl]methyl ketone

3-(2,2-difluoroethyl)-N-methoxy-N-methyl-bis(1.1.1)pentane-1-methamide (Int-A33 , 1 equivalent, 300 mg, 1.4 mmol) and 5-chloro-2,3-dimethyl-pyridine were added. A mixture of (1.5 equivalents, 0.25 mL, 2.1 mmol) in THF (4.5 mL) was degassed three times with _N₂ . The mixture was cooled to -20 °C, and TMPMgCl·LiCl (2.2 equivalents, 3.0 mL, 3 mmol) was added dropwise at -20 °C. The mixture was stirred at -20 °C for 2 h. LCMS showed 38% of the starting material remaining and a peak with the desired mass was detected. The mixture was stirred at -20 °C for another 1 h. LCMS showed complete depletion of the starting material and a peak with the desired mass was detected. The mixture was added to water (10 mL) and extracted with EtOAc (10 mL × 3) and concentrated under reduced pressure to obtain the crude material. The crude product was purified by reversed-phase rapid chromatography (0.1% FA conditions). The desired solvent was concentrated to remove _CH3CN , and the pH was adjusted to approximately _9–10 using _{solid Na2CO3} , followed by extraction with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure to obtain a solid (3-chloro-5,6-dimethyl-pyridine) -2-yl)-[3-(2,2-difluoroethyl)-1-bis(1.1.1)pentyl]methyl ketone (Int-A34 , 190 mg, 0.632 mmol, 46% yield). LCMS : [M+H] ⁺ = 301.1; purity = 55% (UV 220 nm); retention time = 0.581 min. ^1H NMR (400 MHz, CDCl3 ₎ δ 6.00 - 5.64 (m, 1H), 2.58 (s, 3H), 2.56 (s, 3H), 2.23 (s, 6H), 2.08 (dt, J = 4.6, 17.6 Hz, 2H).

Method Int 31. Intermediate Int-A35: prop-1-ynylcyclopropane

THF (400 mL) and ethynylcyclopropane (1 equivalent, 20 g, 303 mmol) were added to a dry three-necked reaction flask. The mixture was degassed three times with _N₂ and cooled to -65 °C. After stirring the mixture at -78 °C for 1 hour, n-BuLi (1.6 equivalent, 194 mL, 484 mmol) was slowly added to the mixture below -60 °C. Then, MeI (3 equivalent, 57 mL, 908 mmol) was slowly added below -60 °C, and the reaction mixture was stirred at -60 °C for 1 hour and then heated to 20 °C for 1 hour. The reaction mixture was poured into a saturated _NH₄Cl aqueous solution (200 mL) and then extracted with DCM (3 × 200 mL). _The combined organic layer was dried over _Na₂SO₄ and filtered. Then, most of the solvent was evaporated (< 25°C, 25 mmHg) to obtain a crude product, prop-1-ynylcyclopropane (Int-A35 , 53 g, 185 mmol, 61% yield), in liquid form. The crude product was used in the next step without further purification.

Method Int 32. Intermediate Int-A36: 1-Cyclopropylpropane-1,2-dione

_NaIO₄ (2.2 equivalents, 29362 mg, 137 mmol) (dissolved in water (100 mL)) was added to a solution of prop-1-ynylcyclopropane (Int-A35 , 1 equivalent, 20.0 g, 62.4 mmol) in carbon tetrachloride (100 mL) and MeCN (100 mL). Then, _RuO₂ · _H₂O (0.022 equivalents, 207 mg, 1.37 mmol) was added (Note: a large amount of green precipitate formed after the addition of _RuO₂ · _H₂O ). The reaction mixture was then vigorously stirred in air for 2 h. TLC showed the formation of a new spot with fluorescence at 254 nm. The reaction mixture was filtered through a diatomaceous earth mat. The filter cake was washed with DCM (100 mL). The filtrate was diluted with water (100 mL) and then extracted with DCM (3 × 50 mL). The combined organic layer was washed with brine and dried _{over Na₂SO₄} . The organic layer was then combined with another batch and purified by distillation. A crude product (9 g) in an oily state was obtained (760 mmHg, bp > 90 °C). It was then further purified by reduced pressure distillation. Pure 1-cyclopropylpropane-1,2-dione (Int-A36 , 1650 mg, 14.7 mmol, 24% yield) in an oily state was obtained (20 mmHg, bp = 56 ~ 60 °C). ¹ H NMR : (400 MHz, CDCl ₃ , 299 K) δ 2.70 (tt, J = 4.9, 7.6 Hz, 1H), 2.29 (s, 3H), 1.10 - 1.00 (m, 4H).

Method Int 33. Intermediate Int-A37: 2-bromo-6-cyclopropyl-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine; Intermediate Int-A38: 2-bromo-7-cyclopropyl-6-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine

A mixture of 2-bromo-6-[3-(trifluoromethyl)-1-biscyclic[1.1.1]pentyl]pyrimidine-4,5-diamine (1 equivalent, 500 mg, 1.32 mmol), 1-cyclopropylpropane-1,2-dione (Int-A36 , 1.6 equivalent, 295 mg, 2.10 mmol), and _CaSO4 (6 equivalent, 1074 mg, 7.89 mmol) in a DCE (10 mL) was stirred at 60 °C for 12 h. LCMS showed 39% and 49% of the products. The reaction mixture was combined with another batch for further processing. The combined reaction mixture was filtered through a diatomaceous earth mat. The filter cake was washed with EtOAc (20 mL). The filtrate was evaporated under reduced pressure to obtain the residue (700 mg). The residue was purified by silicone column chromatography (12% EtOAc/petroleum ether, TLC, 25% EtOAc/PE, _Rf = 0.7) (50 mL/min) to give crystalline 2-bromo-6-cyclopropyl-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine (Int-A37 , 325 mg, 0.81 mmol, 62% yield) and solid 2-bromo-7-cyclopropyl-6-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine (Int-A38 , 280 mg, 0.70 mmol, 53% yield) (17% EtOAc/petroleum ether, TLC, 25%). EtOAc/PE, _Rf = 0.65).

Int-A37: LCMS : [M+H] ⁺ = 401.0; Purity = 99.5% (220 nm); Retention time = 0.644 min. ^1H NMR (400 MHz, _CDCl3 , 301 K) δ 2.91 (s, 3H), 2.66 (s, 6H), 2.36 (tt, J = 4.6, 7.9 Hz, 1H), 1.56 - 1.50 (m, 2H), 1.35 - 1.29 (m, 2H).

Int-A38 : LCMS : [M+H] ⁺ = 401.0; Purity = 100% (220 nm); Retention time = 0.625 min. ^1H NMR (400 MHz, _CDCl3 , 301 K) δ 2.96 (s, 3H), 2.62 (s, 6H), 2.44 - 2.35 (m, 1H), 1.36 - 1.24 (m, 4H).

Method Int 34. Intermediate Int-A39: Methyl-(Z)-3-(2-fluorovinyl)bicyclo[1.1.1]pentane-1-carboxylate

A mixture of fluoromethyl (triphenyl)phosphonium tetrafluoroborate (1.5 equivalents, 7.44 g, 19.5 mmol) in THF (75 mL) was degassed three times with _N₂ and cooled to -20 °C. Then, NaHMDS (1.5 equivalents, 19 mL, 19.5 mmol) was added dropwise. The mixture was stirred at -20 °C for 15 min. At -20 °C, THF (5 mL) containing methyl 3-methacrylbicyclo[1.1.1]pentane-1-carboxylate (1 equivalent, 2.0 g, 13.0 mmol) was added. The mixture was then stirred at 20 °C for 1 h. LCMS showed exhaustion of the reactants, but the desired mass was not detected, and the product was predominantly triphenylphosphine oxide. TLC showed a new spot detected. The mixture was diluted with 100 mL of water, extracted with EtOAc (3 × 100 mL), and concentrated under reduced pressure to obtain a crude substance. The crude substance was purified by silicone column chromatography (9% EtOAc/PE, KMnO ₄ , R _f = 0.6) to obtain a liquid methyl-(Z)-3-(2-fluorovinyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A39 , 500 mg, 2.23 mmol, 17% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.61 - 6.30 (m, 1H), 5.52 - 4.70 (m, 1H), 3.68 (s, 3H), 2.28 - 2.21 (m, 2H), 2.12 - 2.05 (m, 4H).

Method Int 35. Intermediate Int-A40: Methyl-3-(2-fluoroethyl)bicyclo[1.1.1]pentane-1-carboxylate

Under _N2 at 20°C, palladium/carbon (1 equivalent, 313 mg, 2.94 mmol) was added to a mixture of methyl 3-[(Z)-2-fluorovinyl]biscyclic[1.1.1]pentane-1-carboxylate (Int-A39 , 1 equivalent, 500 mg, 2.94 mmol) in MeOH (10 mL). The mixture was degassed three times with _H2 and stirred for 2 h at 20°C under _H2 (15 psi) atmosphere. TLC showed complete exhaustion of the starting material. The mixture was then degassed three times with _N2 . The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a liquid methyl-3-(2-fluoroethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A40 , 350 mg, 2.03 mmol, 69% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 4.59–4.37 (m, 2H), 3.67 (s, 3H), 2.05–2.00 (m, 6H), 1.90–1.85 (m, 2H).

Method Int 36. Intermediate Int-A41: 3-(2-fluoroethyl)bicyclo[1.1.1]pentane-1-carboxylic acid

At 20 °C, LiOH (2 equivalents, 98 mg, 4.07 mmol) was added to a mixture of methyl 3-(2-fluoroethyl)bicyclo[1.1.1]pentane-1-carboxylate (Int-A40 , 1 equivalent, 350 mg, 2.03 mmol) in THF (6 mL) and water (2 mL). The mixture was stirred at 20 °C for 12 h. TLC showed complete exhaustion of the starting material and the appearance of a new spot. The reaction mixture was aliquoted between EtOAc (30 mL) and water (30 mL). 1 M HCl (1 mL) was added to the combined aqueous layer to adjust the pH to < 7, and the mixture was aliquoted between EtOAc (2 × 40 mL) and water (30 mL) and extracted. _The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain an oily 3-(2-fluoroethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Int-A41 , 270 mg, 1.71 mmol, 84% yield). ^¹H NMR (400 MHz, _CDCl₃ ) δ 4.58–4.38 (m, 2H), 2.04 (s, 6H), 1.93–1.90 (m, 2H).

Following a similar method, the following intermediate was obtained. Structure Starting materials Characteristics Int-C30 Int-D29 Modified: The reaction was carried out in a THF/MeOH/ _H₂O solvent mixture (1:1:1 volume ratio) to give 3-amino-1,6-dimethyl-2-sideoxy-pyridine-4-carboxylic acid as a solid (7.50 g, 41.2 mmol, 96% yield). LCMS : [M+H] ^⁺ = 183.0. ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 6.30 (br s, ¹H), 3.45 (br s, ³H), 2.23 (br s, ³H).

Method Int 37. Intermediate Int-A42: 3-(2-fluoroethyl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-methylamine

CDI (1.3 equivalents, 320 mg, 1.97 mmol) and N,N-diisopropylethylamine (1.3 equivalents, 0.34 mL, 1.97 mmol) were added to a solution of 3-(2-fluoroethyl)bicyclo[1.1.1]pentane - 1-carboxylic acid (Int-A41, 1 equivalent, 240 mg, 1.52 mmol) in DCM (5 mL), and the mixture was stirred at 25 °C for 0.5 h. At 25 °C, N,N-diisopropylethylamine (1.5 equivalents, 0.40 mL, 2.28 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.3 equivalents, 192 mg, 1.97 mmol) were added to the mixture. The mixture was stirred at 25 °C for 12 h. LCMS showed 57% of the desired product. The reaction mixture was separately dissolved between EtOAc (2 × 50 mL) and water (80 mL) and extracted. _The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a residue. The crude residue was purified by reversed-phase HPLC (0.1% FA conditions) to obtain an oily 3-(2-fluoroethyl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-methylamine (Int-A42 , 150 mg, 0.745 mmol, 49% yield). LCMS : [M+H] ^⁺ = 202.2; purity = 100% (220 nm); retention time = 0.443 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.59 - 4.39 (m, 2H), 3.67 (s, 3H), 3.22 - 3.15 (m, 3H), 2.08 - 2.04 (m, 6H), 1.95 - 1.83 (m, 2H).

Following a similar method, the following intermediate was obtained. Structure Starting materials Characteristics Int-D39 Modified: The reaction was carried out using 4,4-difluorocyanohexanecarboxylic acid, 1.05 equivalents of N,O-dimethylhydroxylamine hydrochloride, and 1.2 equivalents each of CDI and DIPEA. The crude material was purified by passing it through a silicone column (PE/EtOAc = 3:1, (PMA, 300 °C, 10 s, _Rf = 0.6)) to obtain an oily 4,4-difluoro-N-methoxy-N-methyl-cyclohexanemethylamine (Int-D39, 4.00 g, 19.3 mmol, 79% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.69 - 1.90 (m, 6H) 2.12 - 2.26 (m, 2H) 2.66 - 2.81 (m, 1H) 3.19 (s, 3H) 3.72 (s, 3H).

Method Int 38. Intermediate Int-A43: (3-chloro-5,6-dimethylpyridine) -2-yl)(3-(2-fluoroethyl)biscyclic[1.1.1]pent-1-yl)methyl ketone

3-(2-fluoroethyl)-N-methoxy-N-methyl-bis(1.1.1)pentane-1-methamide (Int-A42 , 1 equivalent, 120 mg, 0.596 mmol) and 5-chloro-2,3-dimethyl-pyridine were added. The mixture (1.5 equivalents, 0.11 mL, 0.894 mmol) in THF (3 mL) was degassed with _N2 (×3). The mixture was cooled to -20 °C, and TMPMgCl·LiCl (1.3 equivalents, 0.78 mL, 0.775 mmol) was added dropwise at -20 °C, with the mixture stirred at -20 °C for 1 h. LCMS showed that most of the starting material remained. TMPMgCl•LiCl (1.2 equivalents, 0.72 mL, 0.716 mmol) was added at -20 °C, with the mixture stirred at -20 °C for 1 h. LCMS showed 29% of the desired product. TLC showed that the starting material was completely consumed and a new spot was observed. _The reaction mixture was added to _NH₄Cl (aq, 10 mL), separately dissolved between EtOAc (2 × 40 mL) and water (40 mL), and extracted. The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silicone column chromatography (0–30% EtOAc/PE) (TLC, 25% EtOAc/PE, desired product _Rf = 0.6) to obtain a solid (3-chloro-5,6-dimethylpyridine) -2-yl)(3-(2-fluoroethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-A43 , 90 mg, 0.318 mmol, 53% yield). LCMS : [M+H] ⁺ = 285.0; purity = 86% (220 nm); retention time = 0.573 min. ^1H NMR (400 MHz, _CDCl3 ) δ 4.59 - 4.43 (m, 2H), 2.57 (d, J = 5.9 Hz, 6H), 2.20 - 2.16 (m, 6H), 1.97 - 1.86 (m, 2H).

Following a similar method, the following intermediate was obtained. Structure Starting materials Characteristics Int-C20 Modification: The reaction was carried out at -15°C with anhydrous DME containing N-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-methylamine for 2 h. The crude mixture was purified by silica gel fast column chromatography using a 2%–10% EtOAc/hexane dissolution gradient to obtain (3-chloro-5-methylpyridine) as a solid. -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-C20, 40% yield). ESI-MS : [M+H] ⁺ = 289.0; [M+Na] ⁺ = 316.1. ^¹H NMR (CDCl₃, 400 MHz): δ 8.41 (¹H, s), 2.64 (³H, s) _, 2.44 (⁶H, s). ^¹⁹F NMR ( _CDCl₃ , 376 MHz): δ -73.4 (³F, s). Int-C30 Modification: The reaction was carried out at -15°C with anhydrous DME containing N-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-methaneamine for 2 h. The crude mixture was purified by silica gel fast column chromatography with a dissolution gradient of 2%-10% EtOAc/hexane to obtain (3-chloro-6-methyl-pyridine) as a crystalline solid. -2-yl)-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]methyl ketone (Int-C30, 2.57 g, 7.79 mmol, 78% yield). ESI-MS : [M+H] ⁺ = 291.2. ^¹H NMR : ( _CDCl₃ , 400 MHz): δ 8.37 (¹H, s), 2.61 (³H, s), 2.44 (⁶H, s). Int-D40 Int-D39 Modification: The reaction was carried out using Int-D39 and 1.5 equivalents of 5-chloro-2,3-dimethyl-pyridine and TMPMgCl•LiCl. The crude material was then purified by reversed-phase HPLC (FA conditions) to obtain solid (3-chloro-5,6-dimethyl-pyridine) -2-yl)-(4,4-difluorocyclohexyl)methyl ketone (Int-D40, 4000 mg, 13.9 mmol, 72% yield). LCMS : [M+H] ⁺ = 289.0. ^1H NMR (400 MHz, _CDCl3 ) δ 1.80 - 2.02 (m, 6H) 2.12 - 2.25 (m, 2H) 2.59 (d, J=7.3 Hz, 6H) 3.63 (br dd, J=5.9, 3.4 Hz, 1H). Int-F1 Modification : At -45°C (dry ice/acetonitrile bath), use 2,3-dimethyl-5-chloropyridine. The mixture was reacted with N-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-methylamine for 1 h. The crude residue was purified by rapid chromatography (220 g _SiO2 column, 2-15% EtOAc/hexane dissolution gradient) to obtain (3-chloro-5,6-dimethyl-pyridine) as a solid. -2-yl)-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]methyl ketone (Int-F1, 9.6 g, 18.3 mmol, 94% yield). ^¹H NMR ( _CDCl₃ , 400 MHz): δ 2.59 (3H, s), 2.58 (3H, s), 2.43 (6H, s). ^¹⁹F NMR ( _CDCl₃ , 376 MHz): δ -733 (3F, s).

Method Int 39. Intermediate Int-A44: 1-Cyclopropyl-6-sideoxy-1,6-dihydropyridine-3-carboxaldehyde

Cyclopropylboronic acid (1.5 equivalent, 2.09 g, 24.4 mmol), Cu(OAc) _₂ (1.5 equivalent, 4.43 g, 24.4 mmol), _Na₂CO₃ (3 equivalent, 5.17 g, 48.7 mmol), and bipyridine (1 equivalent, 2.54 g, 16.2 mmol) were added to a mixture of 6-sidekto _- 1H-pyridine-3-carboxaldehyde (1 equivalent, 4.43 g, 24.4 mmol), _Na₂CO₃ (3 equivalent, 5.17 g, 48.7 mmol), and stirred at 70 °C for 12 h under O₂ atmosphere. LC-MS showed 62% of the desired product. The reaction mixture was adjusted to pH = 7 with 1 M HCl (200 mL) and fractionally dissolved in DCM (2 × 150 mL). _The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a residue. The crude residue was purified by silicone column chromatography (0-100% petroleum ether/EtOAc) (TLC, 50% petroleum ether/EtOAc, desired product _Rf = 0.3) to give 1-cyclopropyl-6-sideoxy-1,6-dihydropyridine-3-carboxaldehyde (Int-A44 , 1.37 g, 8.4 mmol, 52% yield) as a solid. LCMS : [M+H] ^⁺ = 164.1; purity = 95% (220 nm); retention time = 0.315 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.61 (s, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 2.3, 9.4 Hz, 1H), 6.58 (d, J = 9.5 Hz, 1H), 3.48 - 3.36 (m, 1H), 1.30 - 1.16 (m, 2H), 1.00 - 0.88 (m, 2H).

Method Int 40. Intermediate Int-A45: 5-(4-bromotetrahydro-2H-piperan-2-yl)-1-cyclopropylpyridine-2(1H)-one

Under a _nitrogen atmosphere at 0°C, 1-cyclopropyl-6-sideoxy-pyridine-3-carboxaldehyde (Int-A44 , 1 equivalent, 1.5 g, 9.19 mmol) and 3-buten-1-ol (1 equivalent, 0.79 mL, 9.19 mmol) in a DCM (20 mL) mixture was added dropwise with AcOH (3 equivalents, 4.9 mL, 27.6 mmol) containing HBr, followed by stirring at 25°C for 12 h under a _nitrogen atmosphere. LCMS showed 68% of the desired product. The reaction mixture was adjusted to pH 7 with _NaHCO3 (200 mL) and partially dissolved in EtOAc (2 × 200 mL). _The combined organic layers were dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a residue. The crude residue was purified by silicone column chromatography (0-100% petroleum ether/EtOAc) (TLC, 100% EtOAc, desired product _Rf = 0.2) to obtain an oily 5-(4-bromotetrahydro-2H-piperan-2-yl)-1-cyclopropylpyridine-2(1H)-one (Int-A45 , 2.0 g, 6.71 mmol, 73% yield). LCMS : [M+H] ^⁺ = 300.1; purity = 89% (220 nm); retention time = 0.457 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 - 7.27 (m, 2H), 6.55 (d, J = 9.6 Hz, 1H), 4.82 - 4.59 (m, 0.5H), 4.20 - 4.03 (m, 2H), 3.60 - 3.49 (m, 0.5H), 3.36 - 3.25 (m, 1H), 2.17 (br dd, J = 4.8, 6.9 Hz, 2H), 2.05 (s, 3H), 1.14 (br d, J = 6.6 Hz, 2H), 0.91 - 0.84 (m, 2H).

Method Int 41. Intermediate Int-A46: 1-Isopropyl-6-sideoxy-pyridine-3-carboxaldehyde

2-Iodopropane (1.1 equivalent, 7.1 mL, 71.5 mmol) was slowly added to a solution of 6-sidekto-1H-pyridine-3- _{carboxaldehyde} (1 equivalent, 8.0 g, 65.0 mmol) and _Cs₂CO₃ (2 equivalents, 42.3 g, 130 mmol) in DMF (300 mL). The mixture was stirred at 25 °C for 4 hours. TLC showed complete consumption of the starting materials and the formation of two spots. The reaction mixture was filtered, and the filter cake was washed with EtOAc (2 × 50 mL). The filtrate was concentrated and extracted with EtOAc (3 × 500 mL). _The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silicone column chromatography (0-100% EtOAc/PE) (TLC, 100% EtOAc, desired product _Rf = 0.40) to give a solid product, 1-isopropyl-6-sideoxy-pyridine-3-carboxaldehyde (Int-A46 , 3.6 g, 20.5 mmol, 32% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.65 (d, J = 0.6 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 2.4, 9.4 Hz, 1H), 6.61 (d, J = 9.4 Hz, 1H), 5.26 (td, J = 6.8, 13.7 Hz, 1H), 1.44 (d, J = 6.9 Hz, 6H).

Following a similar method, the following intermediate was obtained. Structure Starting materials Characteristics Int-F13 Modified: The reaction was carried out at 90 °C with two equivalents of cyclobutane and Cs₂CO₃ for 12 h. The crude residue was purified by rapid chromatography (330 g _SiO₂ column, 0-58% ethyl acetate/petroleum ether gradient) to give 1-cyclobutyl-6-sideoxy-pyridine-3-carboxaldehyde as a solid (5.70 g, 32.2 mmol, 40% yield). LCMS : [M+H] ^⁺ = 178.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.88 - 1.98 (m, 2 H) 2.26 (qd, J=9.68, 2.69 Hz, 2 H) 2.53 - 2.62 (m, 2 H) 5.02 - 5.12 (m, 1 H) 6.57 (d, J=9.38 Hz, 1 H) 7.79 (dd, J=9.44, 2.31 Hz, 1 H) 8.03 (d, J=2.25 Hz, 1 H) 9.66 (s, 1 H).

Method Int 42. Intermediate Int-A47: 5-(4-bromotetrahydropiperan-2-yl)-1-isopropyl-pyridin-2-one

Under a nitrogen atmosphere at 0 °C, 1-isopropyl-6-sideoxy-pyridine-3-carboxaldehyde (Int-A46 , 1 equivalent, 3.5 g, 21.2 mmol) and 3-buten-1-ol (5 equivalent, 9.1 mL, 106 mmol) in DCM (120 mL) were added dropwise with AcOH containing HBr (5 equivalent, 6.3 mL, 106 mmol), and the mixture was stirred at 25 °C for 16 hours. LCMS showed the desired product (44%). The reaction mixture was adjusted to pH = 7 with an aqueous solution of _NaHCO3 . The reaction mixture was extracted with DCM (3 × 200 mL), and _the combined organic layer was dried over _Na2SO4 , filtered, and concentrated under reduced pressure to obtain the residue. The reactants were purified and concentrated by reversed-phase chromatography (65-90% [water (FA)-MeCN]) to give an oily 5-(4-bromotetrahydropiperan-2-yl)-1-isopropyl-pyridin-2-one (Int-A47 , 2.8 g, 8.4 mmol, 40% yield). LCMS : [M+H] ⁺ = 302.1; purity = 90% (220 nm); retention time = 0.596 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.36 - 7.31 (m, 1H), 7.31 - 7.27 (m, 1H), 6.60 (d, J = 9.3 Hz, 1H), 5.27 (spt, J = 6.8 Hz, 1H), 4.35 - 4.04 (m, 3H), 3.65 - 3.46 (m, 1H), 2.43 (td, J = 2.1, 12.9 Hz, 1H), 2.30 - 1.93 (m, 4H), 1.36 (dd, J = 2.6, 6.9 Hz, 6H).

Following a similar method, the following intermediate was obtained. Structure Starting materials Characteristics Int-A48 Modification: The first reaction was performed using the left-side intermediate in an ACN. The residue was purified by silicone column chromatography (0-50% EtOAc/petroleum ether) (TLC, 50% EtOAc/PE, desired product _Rf = 0.4) to give 1.3 g of crude product. The crude product was purified by preparative HPLC (condition 8, gradient a) and lyophilized to give an oily 5-(4-bromotetrahydropiperan-2-yl)-1-(2,2-difluoroethyl)pyridin-2-one (Int-A48 , 1.0 g, 2.79 mmol, 62% yield). LCMS : [M+H] ⁺ = 323.9; Purity = 97% (220 nm); Retention time = 0.475 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (dd, J = 2.3, 9.5 Hz, 1H), 7.28 (s, 1H), 6.64 (d, J = 9.4 Hz, 1H), 6.30 - 5.93 (m, 1H), 4.24 (br d, J = 4.4 Hz, 3H), 4.15 - 4.05 (m, 2H), 3.55 (dt, J = 1.8, 12.1 Hz, 1H), 2.43 (td, J = 1.9, 12.9 Hz, 1H), 2.29 - 2.21 (m, 1H), 2.18 - 2.07 (m, 1H), 2.05 - 1.91 (m, 1H). Int-F14 Int-F13 Modified : The reaction was carried out with 1.2 equivalents of 3-buten-1-ol and 3 equivalents of HBr (in AcOH) for 12 h. The crude residue was purified by rapid chromatography (120 g _SiO2 column, 0-65% EtOAc/PE) and then by preparative HPLC (condition 19, gradient a) to give a gel-like 5-(4-bromotetrahydropiperan-2-yl)-1-cyclobutyl-pyridin-2-one (Int-F14, 5.70 g, 18.3 mmol, 69% yield). LCMS : [M+H] ⁺ = 313.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.81 - 1.91 (m, 2 H) 1.93 - 2.32 (m, 7 H) 2.39 - 2.55 (m, 3 H) 3.56 (td, J=12.13, 2.13 Hz, 1 H) 4.00 (br dd, J=11.94, 4.82 Hz, 1 H) 4.08 - 4.17 (m, 2 H) 4.23 (tt, J=11.87, 4.46 Hz, 1 H) 4.65 - 4.84 (m, 1 H) 5.06 - 5.18 (m, 1 H) 6.53 (d, J=9.38 Hz, 1 H) 7.27 - 7.31 (m, 1 H) 7.41 - 7.46 (m, 1 H).

Method Int 43. Intermediate Int-A23: (2R,4S)-N-[3-[3-(1,1-difluoroethyl)bicyclo[1.1.1]pentane-1-carbonyl]-5,6-dimethyl-pyridine [-2-yl]-2-(1-methyl-6-epoxy-3-pyridyl)tetrahydropiperan-4-methylamine

Add (3-chloro-5,6-dimethyl-pyridine) to a glass vial equipped with a Teflon-coated magnetic stirring rod. -2-yl)-[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentyl]methyl ketone (1.2 equivalent, 305 mg, 1.02 mmol), (2R,4S)-2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-methylamine (1 equivalent, 200 mg, 0.846 mmol), _Cs₂CO₃ (1 equivalent, 276 _mg , 0.846 mmol) and anhydrous 1,4-di( ... and Alkane (10 mL). Cap the vial and degas with Ar for 5 min. Add XantPhos Pd G ₃ (0.1 equivalent, 80 mg, 0.085 mmol), and stir the reaction mixture at 100°C for 2 hours under N _2. LCMS showed complete exhaustion of the starting material and detection of the desired mass. Filter the reaction mixture and concentrate under reduced pressure to obtain the residue. The residue was purified by silicone column chromatography (25% EtOAc/PE, followed by 17% MeOH/EtOAc) (TLC, 5% MeOH/DCM, _Rf = 0.4) to obtain an oily substance (2R,4S)-N-[3-[3-(1,1-difluoroethyl)bicyclo[1.1.1]pentane-1-carbonyl]-5,6-dimethyl-pyridine [-2-yl]-2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-methamide (Int-A23 , 350 mg, 0.699 mmol, 83% yield). LCMS : [M+H] ⁺ = 501.2; purity = 98% (220 nm); retention time = 0.520 min. ¹ HNMR (400 MHz, CDCl ₃ ) δ 1.61 (t, J=18.2 Hz, 3H) 1.76 - 1.86 (m, 1H) 1.93 - 2.03 (m, 2H) 2.11 - 2.19 (m, 1H) 2.40 (s, 6H) 2.54 - 2.64 (m, 6H) 2.86 - 2.99 (m, 1H) 3.55 (s, 3H) 3.60 - 3.71 (m, 1H) 4.14 - 4.29 (m, 2H) 6.58 (d, J=10.1 Hz, 1H) 7.32 - 7.38 (m, 2H) 11.17 (s, 1H).

Method Int 44. Intermediate Int-A49: Methyl (1-methylcyclopropyl) methanesulfonate

At 0 °C, methanesulfonic anhydride (1.5 equivalent, 607 mg, 3.48 mmol) was added to a solution of (1-methylcyclopropyl)methanol (1 equivalent, 0.14 mL, 2.32 mmol) and TEA (3 equivalent, 0.97 mL, 6.97 mmol) in DCM (6 mL), and the mixture was then stirred at 0 °C for 2 h. The reaction solution was extracted with _EtOAc (2 × 10 mL), followed by washing with 10 mL of saturated brine. The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give a liquid form of (1-methylcyclopropyl)methanesulfonic acid (Int-A49 , 150 mg, 0.913 mmol, 39% yield), which was used directly.

Method Int 45. Intermediate Int-B1: 5-[4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one

A solution of 2-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridine (1 equivalent, 800 mg, 2.33 mmol), Pd(OAc) _₂ (0.1 equivalent, 53 mg, 0.233 mmol), and C-Phos (0.2 equivalent, 204 mg, 0.467 mmol) in THF (3 mL) was purged three times with _N₂ . Then, bromo-[2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc ( Int-A8, 1.2 equivalent, 946 mg, 2.80 mmol) was added, and the reaction solution was stirred at 55 °C for 2 hours. LCMS showed ~40% detection of the desired product. The mixture was quenched with _H₂O (200 mL), extracted with DCM (3 × 150 mL), and _the combined organic layer was dried with anhydrous _Na₂SO₄ , filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by silicone column chromatography (0-100% EtOAc/PE, followed by 0-50% MeOH/EtOAc) (TLC, 100% EtOAc, desired product _Rf = 0.1) to give 5-[4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Int-B1 , 500 mg, 1 mmol, 43% yield) as a solid. LCMS : [M+H]+ = 500.1; purity = 92% (UV 220 nm); retention time = 0.526 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 - 8.83 (m, 1H), 7.92 - 7.81 (m, 1H), 7.65 (br d, J = 7.9 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.43 - 7.39 (m, 2H), 7.36 - 7.29 (m, 1H), 6.63 - 6.54 (m, 1H), 4.39 - 4.28 (m, 2H), 3.82 (dt, J = 2.8, 11.7 Hz, 1H), 3.65 - 3.59 (m, 1H), 3.58 - 3.52 (m, 4H), 2.96 - 2.90 (m, 3H), 2.28 - 2.12 (m, 3H).

Method Int 46. Intermediate Int-B2: Methyl-3-[[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-carbonyl]amino]-6-methoxy-5-methyl-pyridyl 2-carboxylate

At 20 °C, (2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-methylamine (1 equivalent, 2.8 g, 8.96 mmol) was reacted with 1,4-dioxane to form 4-dioxane. 3-Chloro-6-methoxy-5-methyl-pyridine was added to the mixture in alkyl (45 mL). Methyl 2-carboxylate (1.2 equivalents, 2.33 g, 10.8 mmol), _Cs₂CO₃ (2 equivalents, 5.84 g, 17.9 mmol), and XantPhos Pd G₃ (0.1 equivalents, 0.85 _g , 0.896 mmol). The mixture was degassed three times with _N₂ . The mixture was stirred at 105 °C for 4 h. LCMS showed complete exhaustion of the starting material and detection of the desired mass. The solution (combined with another batch) was extracted with EtOAc (3 × 50 mL), and the organic matter was washed with 100 mL of saturated brine _solution . The combined organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude residue. The crude material was purified by silicone column chromatography (67% EtOAc/PE, _Rf = 0.5) to obtain a solid methyl-3-[[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-carbonyl]amino]-6-methoxy-5-methyl-pyridyl 2-Carbamate (Int-B2 , 3.3 g, 5.76 mmol, 64% yield). LCMS : [M+H] ⁺ = 493.2; purity = 87% (220 nm); retention time = 0.551 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.86 - 2.06 (m, 3H), 2.12 - 2.22 (m, 1H), 2.57 (s, 3H), 2.83 - 3.00 (m, 1H), 3.64 - 3.78 (m, 1H), 4.00 (d, J = 9.4 Hz, 6H), 4.23 - 4.31 (m, 1H), 4.40 (dd, J=11.4, 2.0 Hz, 1H), 5.39 (s, 2H), 6.82 (d, J = 8.5 Hz, 1H), 7.29 - 7.41 (m, 3H), 7.42 - 7.50 (m, 2H), 7.66 (dd, J = 8.57, 2.4 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 10.35 (s, 1H).

Method Int 47. Intermediate Int-B3: 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-6-methoxy-7-methyl-3H-pteridin-4-one

To 3-[[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-carbonyl]amino]-6-methoxy-5-methyl-pyridyl Methyl 2-carboxylate (Int-B2 , 1 equivalent, 2.35 g, 4.77 mmol) was added to a solution of 1-butanol (25 mL) with ammonium acetate (20 equivalents, 7.36 g, 95.4 mmol). The reaction mixture was then stirred in a sealed tube at 130 °C for 12 h. LCMS showed complete exhaustion of the starting material and detection of the desired mass. The reaction mixture was filtered, concentrated under reduced pressure, and milled with MTBE (50 mL) to give 2-[(2R,4S)-2-(6-benzoxy-3-pyridyl)tetrahydropiperan-4-yl]-6-methoxy-7-methyl-3H-pteridin-4-one (Int-B3 , 2.2 g, 4.79 mmol, 100% yield) as a solid. LCMS : [M+H] ⁺ = 460.2; Purity = 96% (220 nm); Retention time = 0.513 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.07 - 10.71 (m, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.69 (dd, J = 2.4, 8.6 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.41 - 7.30 (m, 3H), 6.80 (d, J = 8.6 Hz, 1H), 5.38 (s, 2H), 4.56 - 4.47 (m, 1H), 4.33 (br dd, J = 3.2, 11.7 Hz, 1H), 4.18 (s, 3H), 3.86 - 3.73 (m, 1H), 3.26 - 3.10 (m, 1H), 2.68 (s, 3H), 2.33 - 2.01 (m, 4H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-D42 Int-D41 Modified : The reaction was carried out at 115 °C for 1 h to give 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-4-(4,4-difluorocyclohexyl)-6,7-dimethyl-pteridine (Int-D42, 2800 mg, 4.93 mmol, 93% yield) in solid form. LCMS : [M+H] ⁺ = 546.3. Int-E9 Int-E8 Modification : The reaction was carried out at 115 °C for 1 h to give 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-7-methyl-6-(trifluoromethyl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidine (Int-E9, 30 mg, 0.05 mmol, 99% yield) in solid form. Int-E23 Int-E22 Modification : The reaction was carried out at 115 °C for 1 h to give 2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-piperan-4-yl)-6-fluoro-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidine (Int-E23, 196 mg, 0.35 mmol, 96% yield). Int-E30 Int-E29 The procedure yields 2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-piperan-4-yl)-6-bromo-7-methyl-4-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidine (Int-E30). Int-E39 Int-E38 The crude mixture was purified by rapid column chromatography (80 g, _SiO2 column, 20-60% EtOAc/hexane dissolution gradient) to give foamy 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-6-bromo-4-cyclohexyl-7-methyl-pyrido[2,3-d]pyrimidine (Int-E39, 780 mg, 1.36 mmol, 63% yield). Int-F9 Int-F8 The crude material was purified by normal phase chromatography (0-80% EtOAc/hexane) to give 2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-piperan-4-yl)-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridine (Int-F9, 2.4 g, 99% yield) in solid form. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.17 (1H, d, J = 2.4 Hz), 7.68 (1H, dd, J = 8.6, 2.4 Hz), 7.41 - 7.44 (2H, m), 7.33 - 7.37 (2H, m), 6.79 (1H, d, J = 8.6 Hz), 4.52 (1H, dd, J = 11.4, 2.1 Hz), 4.28 - 4.32 (1H, m), 3.78 - 3.85 (1H, m), 3.45 - 3.50 (1H, m), 2.79 (3H, s), 2.75 (3H, s), 2.63 (6H, s), 2.30 (1H, dd, J = 13.4, 3.0 Hz), 2.12 - 2.16 (2H, m), 2.06 - 2.09 (1H, m). ESI-MS : [M+H] ⁺ = 562.4.

Method Int 48. Intermediate Int-B4: 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridine

A solution of 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-6-methoxy-7-methyl-3H-pteridin-4-one (Int-B3 , 1 equivalent, 1.9 g, 4.13 mmol), TEA (3 equivalent, 1.7 mL, 12.4 mmol), and PyBroP (2 equivalent, 3.86 g, 8.3 mmol) in THF (40 mL) was stirred at 40 °C for 16 h. LCMS showed that the starting material was completely consumed and the desired mass (82%) was detected. Next, [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (1.35 equivalents, 1.16 g, _5.58 mmol), (dtbpf) _PdCl₂ (0.1 equivalents, 269 mg, 0.413 mmol), _K₂CO₃ (3 equivalents, 1.7 g, 12.4 mmol), and water (4 mL) were added to the mixture, and the mixture was stirred at 60 °C for 1 h under _N₂ . LCMS showed that the starting material was completely consumed and the desired mass (69%) was detected. The reactants were filtered and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative TLC (PE: EtOAc = 1:1, _Rf = 0.4) to give 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridine (Int-B4 , 1.9 g, 3.04 mmol, 74% yield) as a solid. LCMS : [M+H] ⁺ = 606.2; purity = 97% (220 nm); retention time = 0.691 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 2.3 Hz, 1H), 7.87 (t, J = 7.3 Hz, 1H), 7.71 (dd, J = 2.3, 8.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 9.8 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.34 - 7.29 (m, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.39 (s, 2H), 4.61 - 4.50 (m, 1H), 4.34 (br dd, J = 3.0, 10.3 Hz, 1H), 4.01 (s, 3H), 3.85 (dt, J = 3.6, 11.2 Hz, 1H), 3.66 - 3.52 (m, 1H), 2.77 (s, 3H), 2.38 (br d, J = 13.5 Hz, 1H), 2.30 - 2.09 (m, 3H).

Method Int 49. Intermediate Int-B5: 5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one

TFA (9.0 mL) was added to a solution of 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridine (Int-B4 , 1 equivalent, 1.80 g, 2.97 mmol) in DCM (9 mL), and the mixture was then stirred at 60 °C for 8 h. LCMS showed complete exhaustion of the starting material and detection of the desired mass (76%). The reaction solution was added dropwise to _NaHCO3 (aq) to adjust the pH to ≥7. The reaction solution was then extracted with EtOAc (3 × 20 mL) and washed with 60 mL of saturated salt solution. The combined organic layer was dried _with anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain coarse residue. The crude substance was used without purification and was used as batch 1: 5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one in solid form (Int-B5 batch 1, 200 mg, 0.358 mmol, 12% yield); and as batch 2: 5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one in solid form (Int-B5 batch 2, 270 mg, 0.277 mmol, 12% yield). mmol, 9% yield); and as batch 3: 5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one in solid form (Int-B5 batch 3, 900 mg, 1.59 mmol, 53% yield).

Int-B5 batch 1 : LCMS : [M+H] ⁺ = 516.2; Purity = 92% (220 nm); Retention time = 0.536 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (t, J = 7.3 Hz, 1H), 7.66 - 7.47 (m, 3H), 7.38 (br s, 1H), 6.67 - 6.53 (m, 1H), 4.67 - 4.48 (m, 2H), 4.07 - 3.97 (m, 3H), 3.86 - 3.70 (m, 1H), 3.60 - 3.44 (m, 1H), 2.77 (s, 3H), 2.36 (br d, J = 12.1 Hz, 1H), 2.27 - 2.01 (m, 4H).

Int-B5 batch 2 : LCMS : [M+H] ⁺ = 516.2; Purity = 53% (220 nm); Retention time = 0.539 min.

Int-B5 batch 3 : LCMS : [M+H] ⁺ = 516.2; Purity = 91% (220 nm); Retention time = 0.527 min.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C10 Int-C1 (2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl-4-(4-nitrophenyl)sulfonyl- A porphyrin (Int-C1, 1 equivalent, 2.0 g, 4.3 mmol) was added to a mixture of TFA (21 mL) and DCM (21 mL), and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by rapid chromatography (80 g _SiO2 column) using a dissolution gradient of 0-4% MeOH/DCM to obtain a solid 5-((2S,6R)-6-methyl-4-((4-nitrophenyl)sulfonyl) (Lin-2-yl)pyridin-2(1H)-one (Int-C10, 1.57 g, 4.14 mmol, 97%). ESI-MS : [M+H] ⁺ = 381.2. Int-C16 Int-C15 Modification : The reaction was carried out in a sealed MW vial at 80°C for 3 h. The reaction mixture was evaporated to dryness and purified by normal-phase rapid chromatography (24 g _SiO2 column) using a dissolution gradient of 0-10% MeOH to give solid 5-[(2S,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]-6-methyl- [Lin-2-yl]-1H-pyridin-2-one (Int-C16, 64 mg, 0.13 mmol, 58% yield). Int-D25 Int-D24 Modification : The reaction was carried out at 80℃ for 12 h to obtain 4-[2-fluoro-4-(trifluoromethyl)phenyl]-2-[(2R,6S)-2-methyl-6-(6-sideoxy-1H-pyridin-3-yl) in solid form. [Prin-4-yl]-7H-pyrimidino[4,5-d]tadalafil] -8-one (Int-D25, 90 mg, 0.179 mmol, 62% yield). LCMS : [M+H] ⁺ = 503.1. Int-D35 Int-D34 Modification : Int-D34 was treated with a 2:1 mixture of DCE and TFA at 50 °C for 12 h to obtain 4-(2,4-difluorophenyl)-6,7-dimethyl-2-[(2R,6S)-2-methyl-6-(6-sideoxy-1H-pyridin-3-yl)] in solid form. [Lin-4-yl]pyrido[3,4-d]pyrimidin-8-one (230 mg, 0.480 mmol, 109% yield). LCMS : [M+H] ⁺ = 480.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.68 - 7.62 (m, 1H), 7.55 - 7.40 (m, 4H), 7.33 - 7.27 (m, 1H), 6.34 (d, J = 9.3 Hz, 1H), 6.00 (d, J = 2.6 Hz, 1H), 4.62 (br t, J = 12.4 Hz, 2H), 4.40 (dd, J = 2.3, 10.6 Hz, 1H), 3.78 - 3.69 (m, 1H), 3.49 (s, 3H), 2.97 - 2.86 (m, 1H), 2.77 - 2.64 (m, 1H), 2.31 (s, 3H), 1.22 (br d, J = 5.7 Hz, 3H). Int-D38 Int-D37 Modification : Int-D37 was treated with a 2:1 mixture of DCE and TFA at 50°C for 12 h to obtain a solid crude substance, 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-2-[(2R,6S)-2-methyl-6-(6-sideoxy-1H-pyridin-3-yl)]. [Lin-4-yl]pyrido[3,4-d]pyrimidin-8-one (Int-D38, 200 mg, 0.378 mmol, 156% yield). LCMS : [M+H] ⁺ = 530.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 - 11.49 (m, 1H), 7.93 (br d, J = 9.5 Hz, 1H), 7.89 - 7.75 (m, 2H), 7.55 - 7.49 (m, 1H), 7.47 - 7.40 (m, 2H), 7.35 - 7.27 (m, 2H), 7.26 - 7.15 (m, 1H), 6.35 (br d, J = 9.4 Hz, 1H), 6.03 (br s, 1H), 4.72 - 4.53 (m, 2H), 4.49 (d, J = 5.4 Hz, 1H), 4.41 (br d, J = 10.8 Hz, 1H), 3.80 - 3.68 (m, 1H), 3.53 - 3.48 (m, 3H), 2.31 (s, 3H), 1.23 (br d, J = 5.1 Hz, 4H). Int-E10 Int-E9 Modified : The reaction was carried out at 80 °C for 1 h and purified by normal-phase rapid column chromatography (4 g _SiO2 column) (0-10% MeOH/DCM) to give solid 5-[( 2R , 4S )-4-[7-methyl-6-(trifluoromethyl)-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl] -1H -pyridin-2-one (Int-E10, 20 mg, 0.04 mmol, 78% yield). ESI-MS : [M+H] ⁺ = 525.2. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.91 (s, 1H), 7.68 (dd, J = 9.4, 2.5 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 6.53 (d, J = 9.6 Hz, 1H), 4.44 (dd, J = 11.3, 1.7 Hz, 1H), 4.26-4.22 (m, 1H), 3.84-3.77 (m, 1H), 3.53-3.45 (m, 1H), 2.89 (s, 3H), 2.68 (s, 6H), 2.27 (d, J = 13.3 Hz, 1H), 2.10-2.04 (m, 2H), 1.95 (dd, J = 24.8, 11.8 Hz, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD): δ -63.7 (s, 3F), -74.6 (s, 3F). Int-E14 Int-E13 Modification : The reaction was carried out at 80°C for 5 h, and the crude material was purified by rapid chromatography (12 g Isco RediSep® column, using a gradient dissolution of 0-10% MeOH/DCM) to obtain solid 5-((2S,6R)-4-(4-(3,3-difluorocyclobutoxy)-6,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)-6-methyl (Lin-2-yl)pyridin-2(1H)-one (Int-E14, 47.9 mg, 0.11 mmol, 88%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 11.7 (br s, 1H), 8.21 (s, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 6.69 (d, J = 9.3 Hz, 1H), 5.32 (br s, 1H), 5.29 (s, 1H), 4.75 (br s, 1H), 4.59 (br s, 1H), 4.34 (d, J = 10.6 Hz, 1H), 3.70 (br s, 1H), 3.19 (br s, 2H), 2.97-2.83 (m, 2H), 2.79 (s, 3H), 2.41 (s, 3H), 1.30 (d, J = 6.1 Hz, 3H), 1.25 (s, 1H). ESI-MS : [M+H] ⁺ = 458.4. Int-E24 Int-E23 Modification : The reaction was carried out at 75°C in DCE solvent with 100 equivalents of TFA for 2 h. The crude product was purified by chromatography (40 g SiO ₂ ) using a 0-15% DCM/MeOH gradient to give foamy 5-[(2R,4S)-4-[6-fluoro-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Int-E24, 167 mg, 0.35 mmol, 99% yield). Int-E31 Int-E30 The procedure yields 5-((2R,4S)-4-(6-bromo-7-methyl-4-(3-(trifluoromethyl)bis(1.1.1)pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Int-E31). Int-E34 Int-E33 Modification : The reaction was carried out at 75 °C in DCE solvent with 100 equivalents of TFA for 2 h. The crude mixture was purified by normal phase chromatography (0-50% MeOH/DCM dissolution gradient) to give solid 7-methyl-2-((2R,4S)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidin-6-carboxylonitrile (Int-E34, 55 mg, 73% yield). ESI-MS : [M+H] ⁺ = 482.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.81-8.84 (1H, m), 7.77 (1H, d, J = 9.0 Hz), 7.61 (1H, s), 7.38 (1H, s), 6.78 (1H, d, J = 9.3 Hz), 4.43 (1H, d, J = 11.1 Hz), 4.30 (1H, d, J = 11.3 Hz), 3.79 (1H, t, J = 12.1 Hz), 3.49 (1H, br s), 3.00 (3H, s), 2.65 (6H, s), 2.33 (1H, d, J = 13.8 Hz), 2.06-2.13 (2H, m), 1.99 (1H, t, J = 12.7 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.2 (3F, s). Int-E41 Int-E40 Modification : The reaction was carried out at 75 °C in DCE solvent with 100 equivalents of TFA for 2 h. The crude mixture was purified by normal phase chromatography (0-15% MeOH/DCM dissolution gradient) to give solid 4-cyclohexyl-7-methyl-2-[(2R,4S)-2-(6-sideoxy-1H-pyridin-3-yl)tetrahydropiperan-4-yl]pyrido[2,3-d]pyrimidin-6-carboxynitrile (Int-E41, 220 mg, 0.51 mmol, 74% yield).

Method Int 50. Intermediate Int-B6: 5-methyl-6-sideoxy-1H-pyridine-3-carboxaldehyde

A mixture of 5-bromo-3-methyl-1H-pyridin-2-one (1 equivalent, 23 g, 122 mmol) in THF (1150 mL) was degassed three times with _N₂ . The mixture was cooled to -78 °C and stirred for 20 min. At -78 °C, n-butyllithium (3 equivalents, 147 mL, 367 mmol) was added to the mixture. The mixture was stirred at -78 °C for 3 h. At -78 °C, N,N-dimethylformamide (24 equivalents, 227 mL, 2936 mmol) was added. The mixture was stirred at -70 °C for 1 h. TLC showed complete exhaustion of the starting material and detection of a new point ( _Rf = 0.2). At -70 °C, water (200 mL) was slowly added to the mixture. The mixture was heated to 25°C and saturated sodium chloride solution (100 mL) was added. The mixture was extracted with EtOAc (1 L × 5) and DCM (1 L × 10). Silicone was added to the organic layer and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silicone column chromatography (50% EtOAc/PE, 2,4-dinitrophenylhydrazine, _Rf = 0.1) to give solid 5-methyl-6-sideoxy-1H-pyridine-3-carboxaldehyde (Int-B6 batch 1, 8.4 g, 61.3 mmol, 50% yield) and solid 5-methyl-6-sideoxy-1H-pyridine-3-carboxaldehyde (Int-B6 batch 2, 3.4 g, 24.8 mmol, 20% yield).

Int-B6 batch 1 : LCMS : [M+H] ⁺ = 138.0; purity = 95% (UV 220 nm); residence time = 0.393 min. ^1H NMR (400 MHz, _CDCl3 ) δ 9.64 (s, 1H), 7.91 - 7.77 (m, 2H), 2.20 (s, 3H).

Int-B6 batch 2 : LCMS : [M+H] ⁺ = 137.9; purity = 64% (UV 220 nm); residence time = 0.282 min. ^1H NMR (400 MHz, _CDCl3 ) δ 9.62 (s, 1H), 8.01 (s, 2H), 7.91 - 7.84 (m, 1H), 7.83 - 7.73 (m, 1H), 2.95 (s, 5H), 2.88 (s, 5H), 2.18 (s, 3H).

Method Int 51. Intermediate Int-B7: 6-Benzoxy-5-methyl-pyridine-3-carboxaldehyde

At 20 °C, brominated benzyl (1.1 equivalent, 9.5 mL, 27.3 mmol) and Ag₂CO₃ (1.3 equivalent, 8887 mg, 32.2 mmol) were added to a mixture of 5-methyl-6-sideoxy- _1H -pyridine- ₃ -carboxaldehyde (Int-B6, 1 equivalent, 3400 mg, 24.8 mmol) in MeCN (68 mL). The mixture was stirred at 20 °C for 12 h. LCMS showed complete exhaustion of the starting material and a peak of the desired mass was detected. The mixture was combined with another batch. The mixture was filtered and washed with EtOAc (500 mL). Silicone was added to the filtrate and concentrated under reduced pressure to obtain a crude product. The crude material was purified by silicone column chromatography (PE:EtOAc = 10:1; UV, _Rf = 0.6) to obtain an oily 6-benzoxy-5-methyl-pyridine-3-carboxaldehyde (Int-B7 , 12200 mg, 53.7 mmol, 217% yield). LCMS : [M+H] ⁺ = 228.1; purity = 98% (UV 220 nm); retention time = 0.573 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 1.0, 2.1 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.43 - 7.31 (m, 3H), 5.52 (s, 2H), 2.29 (s, 3H).

Method Int 52. Intermediate Int-B8: (2R)-2-(6-benzoxy-5-methyl-3-pyridyl)-2,3-dihydropiperan-4-one

Solution A: At 25°C, (R)-(+)-5,5,6,6,7,7,8,8-octahydro-1,1-binaphthol (0.2 equivalent, 2591 mg, 8.80 mmol) was added to a mixture of Ti(OiPr) _₄ (0.4 equivalent, 5003 mg, 17.6 mmol) and toluene (30 mL). The mixture was stirred at 25°C for 1 h. The mixture was then concentrated under reduced pressure at 50°C to obtain a solid. The solid was dissolved in toluene (30 mL). At 25 °C, trans-1-methoxy-3-(trimethylsiloxy)-1,3-butadiene (4 equivalents, 34 mL, 176 mmol) and _H₂O (0.1 equivalents, 0.079 mL, 4.4 mmol) were added to a mixture of 6-benzyloxy-5-methylpyridin-3-carboxaldehyde (1 equivalent, 10.0 g, 44 mmol) in toluene (90 mL). The mixture was degassed with _N₂ (×3) and solution A was added at 25 °C. The mixture was stirred at 30 °C for 12 h. LC-MS showed complete exhaustion of the starting material and detection of the desired MS peak. 200 mL of water was added to the mixture, and the mixture was extracted with EtOAc (200 mL × 6). Silicone was added to the organic layer, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silicone column chromatography (25% EtOAc/PE, _Rf = 0.3) to give an oily (2R)-2-(6-benzoxy-5-methyl-3-pyridyl)-2,3-dihydropiperan-4-one (Int-B8 , 3.2 g, 10.1 mmol, 23% yield). LCMS : [M+H] ⁺ = 296.3; purity = 93% (UV 220 nm); retention time = 0.579 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, J = 1.7 Hz, 1H), 7.52 - 7.43 (m, 4H), 7.38 (t, J = 7.4 Hz, 2H), 7.33 (br d, J = 7.2 Hz, 1H), 5.53 (d, J = 6.1 Hz, 1H), 5.43 (s, 2H), 5.37 (dd, J = 3.2, 14.5 Hz, 1H), 3.26 (s, 1H), 2.94 (dd, J = 14.5, 16.7 Hz, 1H), 2.62 (dd, J = 3.2, 16.6 Hz, 1H), 2.27 (s, 3H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-F4 The reaction was carried out with 6-benzyloxypyridin-3-carboxaldehyde to give (R)-2-(6-(benzyloxy)pyridin-3-yl)-2,3-dihydro-4H-piperan-4-one in solid form (Int-F4, 80% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.19 (1H, d, J = 2.5 Hz), 7.64 (1H, dd, J = 8.6, 2.6 Hz), 7.42 - 7.45 (3H, m), 7.29 - 7.39 (3H, m), 6.86 (1H, d, J = 8.6 Hz), 5.52 (1H, dd, J = 6.0, 1.3 Hz), 5.36 - 5.40 (3H, m), 2.91 (1H, dd, J = 16.8, 14.4 Hz), 2.62 (1H, ddd, J = 16.8, 3.4, 1.3 Hz). ESI-MS : [M+H] ⁺ = 282.2.

Method Int 53. Intermediate Int-B9: (2R)-2-(6-benzyloxy-5-methyl-3-pyridyl)tetrahydropiperan-4-one

Under _N2 at 25 °C, TEA (1 equivalent, 2.2 mL, 5.08 mmol) and palladium/carbon (1 equivalent, 540 mg, 5.08 mmol) were added to a mixture of (2R)-2-(6-benzyloxy-5-methyl-3-pyridyl)-2,3-dihydropiperan-4-one (1 equivalent, 1.5 g, 5.08 mmol) in EtOH (21.5 mL). The mixture was degassed three times with _H2 and cooled to 0 °C. The mixture was stirred at 0 °C for 30 min under _H2 (15 psi) atmosphere. LCMS showed complete exhaustion of the starting material and detected the desired MS peak. The mixture was filtered and washed with EtOH (50 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified and concentrated by reverse-phase scalding (0.1% FA conditions) to remove _CH3CN , followed by pH adjustment to approximately 9–10 using _{solid Na2CO3} , and then extraction with EtOAc (3 × 40 mL). The combined organic layers were dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under reduced pressure to give an oily (2R)-2-(6-benzyloxy-5-methyl-3-pyridyl)tetrahydropiperan-4-one (Int-B9 , 440 mg, 1.48 mmol, 29% yield). LCMS : [M+H] ⁺ = 298.3; Purity = 100% (UV 220 nm); Retention time = 0.580 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 - 7.94 (m, 1H), 7.50 - 7.43 (m, 3H), 7.41 - 7.28 (m, 3H), 5.44 - 5.39 (m, 2H), 4.60 (dd, J = 3.4, 10.7 Hz, 1H), 4.45 - 4.37 (m, 1H), 3.84 (dt, J = 2.9, 12.0 Hz, 1H), 2.79 - 2.57 (m, 3H), 2.49 - 2.39 (m, 1H), 2.26 (s, 3H).

Method Int 54. Intermediate Int-B10: (5R)-5-(6-benzoxy-5-methyl-3-pyridyl)-1,6-dioxane[2.5]octane-2-carboxylonitrile

At 25°C, _BnEt3 NCl (0.05 equivalent, 50 mg, 0.219 mmol) was added to a mixture of KOH (3 equivalents, 734 mg, 13.1 mmol) in _H2O (9.33 equivalents, 0.73 mL, 40.8 mmol) and THF (26 mL). The mixture was cooled to 0°C. At 0°C, THF (8.5 mL) containing (2R)-2-(6-benzyloxy-5-methyl-3-pyridyl)tetrahydropiperan-4-one (Int-B9 , 1 equivalent, 1300 mg, 4.37 mmol) and _ClCH2CN (1.3 equivalents, 429 mg, 5.68 mmol) was added to the mixture. The mixture was stirred at 0°C for 2 h. LCMS showed 12% of the starting material remaining and detected a main peak of the desired mass. The mixture was stirred at 0°C for another 12 h. LCMS showed 7% of the starting material remaining and detected a main peak of the desired mass. The mixture was stirred at 0°C for another 2 h. LCMS showed 2% of the starting material remaining and detected a main peak of the desired MS mass. The reactants were diluted with water (50 mL) and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain an oily crude product (5R)-5-(6-benzoxy-5-methyl-3-pyridyl)-1,6-dioxane[2.5]octane-2-carboxylonitrile (Int-B10, 1500 mg, 4.46 mmol, 102% yield). The crude product was used in the next step without further purification. LCMS : [M+H] ^⁺ = 337.3; purity = 86% (UV 220 nm); retention time = 0.612 min.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-F6 Int-F5 The procedure yielded (5R)-5-(6-(benzyloxy)pyridin-3-yl)-1,6-dioxane[2.5]octane-2-carboxylonitrile (Int-F6). ESI-MS : [M+H] ⁺ = 323.2.

Method Int 55. Intermediate Int-B11: (2R,4S)-2-(6-benzyloxy-5-methyl-3-pyridyl)tetrahydropiperan-4-carboxylic acid

A mixture of LiBr (1.5 equivalent, 581 mg, 6.69 mmol), _NaHCO3 (1 equivalent, 375 mg, 4.46 mmol), and _H2O (1.25 equivalent, 0.10 mL, 5.57 mmol) in DMF (7.5 mL) and MeCN (7.5 mL) was stirred at 25 °C for 15 min. At 25 °C, DMF (7.5 mL) and MeCN (7.5 mL) containing (5R)-5-(6-benzyloxy-5-methyl-3-pyridyl)-1,6-dioxane[2.5]octane-2-carboxylonitrile (Int-B10, 1 equivalent, 1500 mg, 4.46 mmol) were added to the mixture. The mixture was stirred at 100 °C for 12 h. LCMS showed complete exhaustion of the starting material and detection of a peak with the desired mass. The reaction solution was cooled to room temperature and alkalized _{with Na₂CO₃} (aq.) to adjust the pH to ~13, followed by extraction with EtOAc (3 × 100 mL). The aqueous layer was then adjusted to pH 2-3 with 1 M HCl aqueous solution and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give an oily product of (2R,4S)-2-(6-benzoxy-5-methyl-3-pyridyl)tetrahydropiperan-4-carboxylic acid (Int-B11, 2.1 _g , 6.41 mmol, 144% yield). The crude product was used in the next step without further purification. LCMS : [M+H] ⁺ = 328.1.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-F7 Int-F6 Modification : The reaction was carried out by replacing _NaHCO3 with 1.5 equivalents _{of Li2CO3} and incubating overnight at 90°C to give (2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-piperan-4-carboxylic acid (Int-F7, 4.1 g, 78% yield, in two steps). ¹ H NMR (CD ₃ OD, 400 MHz): δ 8.11 (1H, s), 7.69 (1H, d, J = 8.5 Hz), 7.42 (2H, d, J = 7.3 Hz), 7.34 (2H, t, J = 7.2 Hz), 7.29 (1H, d, J = 7.3 Hz), 6.83 (1H, d, J = 8.6 Hz), 5.32 (2H, s), 4.38 (1H, d, J = 11.5 Hz), 4.13 (1H, d, J = 11.5 Hz), 3.64 (1H, t, J = 12.0 Hz), 2.73 (1H, t, J = 11.9 Hz), 2.08 (1H, d, J = 13.4 Hz), 1.90 (1H, d, J = 13.4 Hz), 1.75 (1H, t, J = 13.0 Hz), 1.63 (1H, q, J = 12.4 Hz). ESI-MS : [M+H] ⁺ = 314.2.

Method Int 56. Intermediate Int-B12: (4S)-2-(6-benzyloxy-5-methyl-3-pyridyl)tetrahydropiperan-4-methamide

At -15 °C, isobutyl ionomer (1.2 equivalents, 1.1 mL, 8.04 mmol) was added dropwise to a solution of (4S)-2-(6-benzyloxy-5-methyl-3-pyridyl)tetrahydropiperan-4-carboxylic acid (Int-B11, 1 equivalent, 2194 mg, 6.70 mmol) and TEA (2 equivalents, 1.9 mL, 13.4 mmol) in THF (21 mL), and the mixture was stirred for 30 min. Then, _NH₃ · _H₂O (50 equivalents, 13 mL, 335 mmol) was added to the mixture, and the mixture was stirred at -15 °C for 1 h. LC-MS showed complete exhaustion of the starting material and detection of the desired MS peak. The reaction solution was poured into water (50 mL) and then extracted with EtOAc (3 × 50 mL), and the organic matter was washed with 20 mL of saturated brine solution. _The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product (50% EtOAc/PE, 20 mL) (×3) was ground to give (4S)-2-(6-benzyloxy-5-methyl-3-pyridyl)tetrahydropiperan-4-methylamine (Int-B12, 1.0 g, 3.06 mmol, 46% yield) as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 2.1 Hz, 1H), 7.52 - 7.44 (m, 3H), 7.42 - 7.31 (m, 3H), 5.43 (s, 2H), 4.33 (dd, J = 2.0, 11.4 Hz, 1H), 4.28 - 4.21 (m, 1H), 3.66 (br dd, J = 11.5, 14.8 Hz, 1H), 2.61 (br s, 1H), 2.26 (s, 3H), 2.04 (td, J = 1.9, 11.1 Hz, 1H), 1.96 - 1.76 (m, 3H).

Method Int 57. Intermediate Int-B30: (2R,4S)-2-(6-benzyloxy-3-pyridyl)-N-[5-methoxy-6-methyl-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]pyridine -2-yl]tetrahydropiperan-4-methylamine

(3-chloro-6-methoxy-5-methyl-pyridine) -2-yl)-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]methyl ketone (1 equivalent, 380 mg, 1.18 mmol), (2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-methylamine (1 equivalent, 370 mg, 1.18 mmol), _Cs₂CO₃ (2 equivalent, 772 mg, 2.37 mmol) and XantPhos Pd G3 (0.1 equivalent, 112 mg, 0.118 mmol) in 1,4 _- di The mixture in alkyl (6.3 mL) was degassed three times with _N2 . The mixture was stirred at 100 °C for 2 h. LCMS showed no residue of starting material and detected a main peak of the desired mass. The reactant was combined with another batch, and the final mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid column chromatography (100% EtOAc to 9% MeOH/DCM, _Rf = 0.1) to obtain (2R,4S)-2-(6-benzyloxy-3-pyridyl)-N-[5-methoxy-6-methyl-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]pyridyl [-2-yl]tetrahydropiperan-4-methamide (Int-B30, 350 mg, 0.587 mmol, 50% yield). LCMS : [M+H] ⁺ = 597.2; purity = 100% (UV 220 nm); retention time = 0.658 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.97 (s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 2.4, 8.6 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.40 - 7.33 (m, 2H), 7.33 - 7.28 (m, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.38 (s, 2H), 4.47 - 4.22 (m, 2H), 4.01 (s, 2H), 2.58 (s, 2H), 2.52 (s, 4H), 2.14 (br s, 1H), 2.03 - 1.96 (m, 2H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-D17 Int-D16 Modification : The reaction was carried out at 85 °C with Int-D16 and 0.8 equivalents of (2R,4S)-2-(1-(dimethylamino)-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-carboxamide for 30 min. The crude material was purified by rapid chromatography (24 g Isco RediSep column, using a gradient dissolution of 1-10% MeOH/DCM). The selected dissolution fraction was evaporated to give the desired product (2R,4S)-N-(5-(difluoromethyl)-6-methyl-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridine -2-yl)-2-(1-(dimethylamino)-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-methamide (Int-D17, 17 mg, 0.03 mmol, 11% yield). ESI-MS : [M+H] ⁺ = 570.3. Int-D41 Int-D40 Next, the crude material was purified using a silicone column (PE/EtOAc = 1:1, _Rf = 0.5) to obtain a solid (2R,4S)-2-(6-benzyloxy-3-pyridyl)-N-[3-(4,4-difluorocyclohexanecarbonyl)-5,6-dimethyl-pyridyl] [-2-yl]tetrahydropiperan-4-methamide (Int-D41, 3000 mg, 4.93 mmol, 95% yield). LCMS : [M+H] ⁺ = 565.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.79 - 2.03 (m, 9H) 2.12 - 2.28 (m, 3H) 2.52 - 2.73 (m, 6H) 2.93 - 3.07 (m, 1H) 3.62 - 3.79 (m, 1H) 3.99 - 4.09 (m, 1H) 4.24 - 4.33 (m, 1H) 4.41 (dd, J=11.3, 1.8 Hz, 1H) 5.38 (s, 2H) 6.82 (d, J=8.6 Hz, 1H) 7.28 - 7.41 (m, 3H) 7.46 (d, J=7.2 Hz, 2H) 7.66 (dd, J=8.6, 2.4 Hz, 1H) 8.16 (d, J=2.2 Hz, 1H) 11.28 (s, 1H). Int-D45 Int-D44 Purification by rapid column chromatography using _SiO2 with a solvent gradient of 10-45% acetone/hexane yielded a foamy methyl(2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)-N-(2-methyl-3-sideoxy-5-(3-(trifluoromethyl)bis(1.1.1)pentane-1-carbonyl)-2,3-dihydropyridine. (Int-D45, 97 mg, 0.17 mmol, 8% yield) Tetrahydro-2H-piperan-4-methamide (EI-D45, 97 mg, 0.17 mmol, 8% yield). ESI-MS : [M+H] ⁺ = 583.3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.76 (s, 1H), 8.14 (d, J = 2.3 Hz, 1H), 7.66-7.63 (m, 2H), 7.44 (d, J = 6.9 Hz, 2H), 7.38-7.29 (m, 3H), 6.82 (d, J = 8.5 Hz, 1H), 5.39 (s, 2H), 4.38-4.35 (m, 1H), 4.26-4.22 (m, 1H), 3.83 (s, 3H), 3.68-3.62 (m, 1H), 2.83-2.77 (m, 1H), 2.29 (s, 6H), 2.03 (d, J = 13.5 Hz, 1H), 1.92-1.86 (m, 2H), 1.77 (dd, J = 24.8, 12.0 Hz, 1H). Int-D46 Modification : At 85℃, use (3-chloro-5,6-dimethyl-pyridine) (2-yl)-[cubic-1-yl]methyl ketone (1 equivalent) and (2R,4S)-2-(1-(dimethylamino)-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-methylamine (1.5 equivalent) were reacted for 2.5 h. The crude material was purified by silica gel rapid column chromatography using a 5-45% acetone/hexane dissolution gradient to give (2R,4S)-N-(3-(cubic-1-carbonyl)-5,6-dimethylpyridin-3-yl)methyl ketone as a solid. -2-yl)-2-(1-(dimethylamino)-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-methamide (Int-D46, 62 mg, 0.123 mmol, 41% yield). ESI-MS : [M+H] ⁺ = 472.4. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.70 (d, J = 9.1 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.37 (dd, J = 9.4, 2.5 Hz, 1H), 6.34 (d, J = 9.4 Hz, 1H), 4.29-4.26 (m, 3H), 4.16 (d, J = 10.1 Hz, 1H), 4.03-3.94 (m, 5H), 3.52-3.46 (m, 1H), 3.29 (s, 3H), 2.87 (d, J = 13.5 Hz, 6H), 2.43 (s, 3H), 1.88 (d, J = 13.0 Hz, 1H), 1.74 (d, J = 12.6 Hz, 1H), 1.63-1.47 (m, 2H). Int-D47 The crude material was purified by rapid silica gel column chromatography using a 10-60% acetone/hexane dissolution gradient to obtain a solid (2R,4S)-N-(5,6-dimethyl-3-(4-(trifluoromethyl)cubicane-1-carbonyl)pyridine. (-2-yl)-2-(1-methyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-methamide (Int-D47, 136 mg, 0.25 mmol, 63% yield). ESI-MS : [M+H] ⁺ = 541.4. ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.22 (s, 1H), 7.33 (dd, J = 7.0, 2.6 Hz, 2H), 6.56 (q, J = 3.4 Hz, 1H), 4.40 (t, J = 4.8 Hz, 3H), 4.27 (t, J = 4.6 Hz, 3H), 4.24-4.16 (m, 2H), 3.64 (td, J = 11.5, 3.4 Hz, 1H), 3.53 (s, 3H), 2.92 (t, J = 11.7 Hz, 1H), 2.62 (t, J = 3.5 Hz, 3H), 2.50 (s, 3H), 2.14 (d, J = 15.8 Hz, 1H), 2.00-1.92 (m, 2H), 1.80 (dd, J = 24.8, 12.0 Hz, 1H).

Method Int 58. Intermediate Int-B13: 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-biscyclic[1.1.1]-pentyl]pteridine

To (2R,4S)-2-(6-benzyloxy-3-pyridyl)-N-[5-methoxy-6-methyl-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]pyr [-2-yl]tetrahydropiperan-4-methylamide (Int-B30 , 1 equivalent, 300 mg, 0.503 mmol) was added to a solution of 1-butanol (15 mL) with ammonium acetate (20 equivalents, 775 mg, 10.1 mmol), and the mixture was stirred at 115 °C for 2 h. LCMS showed complete exhaustion of the starting material and detection of a main peak with the desired mass. The mixture was combined with another batch, added to water (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic phase was concentrated under reduced pressure to obtain 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridine (Int-B13, 360 mg, 0.623 mmol, 124% yield) in solid form, which was used directly in the next step. LCMS : [M+H] ⁺ = 578.3; purity = 83% (UV 220 nm); residence time = 0.694 min.

Method Int 59. Intermediates Int-B14: (5-(4-bromotetrahydropiperan-2-yl)-2-chloropyrimidine); Int-B15: 2-bromo-5-(4-bromotetrahydropiperan-2-yl)pyrimidine

Under a _nitrogen atmosphere at 0°C, AcOH containing HBr (3 equivalents, 7.5 mL, 42.1 mmol) was added dropwise to a mixture of 2-chloropyrimidine-5-carboxaldehyde (1 equivalent, 2.0 g, 14.0 mmol) and 3-buten-1-ol (1.2 equivalents, 1.4 mL, 16.8 mmol) in DCM (80 mL). The reaction mixture was then stirred at 0°C for 2 h under a _nitrogen atmosphere. LCMS showed 76% of the desired product and byproducts. The reaction mixture was poured into a saturated aqueous solution of _NaHCO3 (100 mL ₎ and then extracted with DCM (100 mL × 3). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give a residue (4 g). The residue was purified by silicone column chromatography (25% EtOAc/petroleum ether, _Rf = 0.5) to give a mixture of 5-(4-bromotetrahydropiperan-2-yl)-2-chloropyrimidine (Int-B14) and 2-bromo-5-(4-bromotetrahydropiperan-2-yl)pyrimidine (Int-B15) (3.36 g) as an inseparable oil, which was used in the next step without further purification.

Intermediate Int-B16 : 2- Benzoxy -5-(4- bromotetrahydropiperan -2- yl ) pyrimidine

Under a _nitrogen atmosphere, (5-(4-bromotetrahydropiperan-2-yl)-2-chloropyrimidine) (int-B14) and 2-bromo-5-(4-bromotetrahydropiperan-2-yl)pyrimidine (Int-B15) (1 equivalent, 2400 mg, 5.66 mmol) and phenylmethanol (1.3 equivalent, 0.77 mL, 7.36 mmol) were reacted in a 1,4-dichlorodichloropyrimidine solution. _Pd₂ (dba) _₃ (0.1 equivalent, 519 mg, _0.566 mmol), XantPhos (0.2 equivalent, 656 mg, 1.13 mmol), and _Cs₂CO₃ (2.5 equivalent, 4614 mg, 14.2 mmol) were added to a mixture of alkanes (25 mL). The reaction mixture was then purged three times with nitrogen and stirred at 100 °C for 8 hours under nitrogen. LC-MS showed 46% of the desired product. The reaction mixture was diluted with water (100 mL) and then extracted with EtOAc (3 × 150 mL ₎ . The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silicone column chromatography (20% EtOAc/petroleum ether) (TLC, 9% EtOAc/PE, _Rf = 0.60) to give 2-benzyloxy-5-(4-bromotetrahydropiperan-2-yl)pyrimidine (Int-B16, 1.36 g, 3.89 mmol, 69% yield) as a solid. LCMS : [M+H] ⁺ = 351.0; purity = 100% (220 nm); retention time = 0.572 min. ¹ H NMR (400 MHz, CDCl ₃ , 301 K) δ ]ppm] 8.50 (s, 2H), 7.48 (d, J = 7.1 Hz, 2H), 7.41 - 7.29 (m, 3H), 5.46 (s, 2H), 4.34 (dd, J = 2.0, 11.4 Hz, 1H), 4.26 (tt, J = 4.5, 11.9 Hz, 1H), 4.15 (ddd, J = 1.6, 4.9, 12.0 Hz, 1H), 3.60 (dt, J = 2.3, 12.1 Hz, 1H), 2.47 (tdd, J = 2.0, 4.2, 12.9 Hz, 1H), 2.32 - 2.25 (m, 1H), 2.18 (dt, J = 4.8, 12.4 Hz, 1H), 2.13 - 2.01 (m, 1H).

Method Int 60. Intermediate Int-B17: 4-Methylbenzenesulfonic acid [6-methoxy-7-methyl-2-[(2R)-2-(1-methyl-6-epoxy-3-pyridyl)-tetrahydropiperan-4-yl]pteridin-4-yl ester]

A solution of 6-methoxy-7-methyl-2-[(2R,4S)-2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]-3H-pteridin-4-one (1 equivalent, 30 mg, 0.0782 mmol) and _K₂CO₃ ( ₅ equivalent, 54 mg, 0.391 mmol) in MeCN (1 mL) was added to the mixture at 0 °C, followed by stirring at 25 °C for 3 h. LC-MS showed that the starting material was largely consumed and a new main peak appeared as desired. The solution was extracted with EtOAc (2 × 5 mL) and washed with saturated brine (5 mL). The combined organic layer was dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain the residue 4-methylbenzenesulfonic acid [6-methoxy-7-methyl-2-[(2R)-2-(1-methyl-6-sideoxy-3-pyridyl)-tetrahydropiperan-4-yl]pteridin-4-yl ester] (Int-B17, 30 mg, 0.056 mmol, 71% yield), which was used directly in the next step. LCMS : [M+H] ^⁺ = 538.1, purity = 45%, uv = 220 nm, retention time = 0.560 min.

Method Int 61. Intermediate Int-B19: 5-[(2R,4S)-4-(4-bromo-6-methoxy-7-methyl-pteridin-2-yl)tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one

LiBr (3.5 equivalents, 187 mg, 2.15 mmol) was added to a solution of 4-methylbenzenesulfonic acid [6-methoxy-7-methyl-2-[(2R,4S)-2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]pteridin-4-yl ester] (Int-B17, 1 equivalent, 330 mg, 0.614 mmol) in THF (6 mL). The resulting mixture was stirred at 60 °C for 16 h under N2 _. LCMS showed that the starting material was not completely consumed and the desired mass (72%) was detected. The reactants were extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (30 mL ₎ , dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (8% MeOH/EtOAc, desired product _Rf = 0.5) to give an oily 5-[(2R,4S)-4-(4-bromo-6-methoxy-7-methyl-pteridin-2-yl)tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Int-B19, 170 mg, 0.373 mmol, 61% yield). LCMS : [M+H] ⁺ = 448.1; Purity = 98% (220 nm); Retention time = 0.493 min.

Method Int 62. Intermediate Int-B20: Bromo-[2-(1-cyclopropyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc

Zinc (3.04 equivalents, 200 mg, 3.06 mmol) was suspended in LiCl (0.5 M in THF) (1 equivalent, 2.0 mL, 1 mmol), and 1,2-dibromoethane (0.05 equivalents, 0.004 mL, 0.05 mmol) was added. The suspension was stirred at 55 °C for 20 min, cooled, and then TMSCl (0.05 equivalents, 0.006 mL, 0.05 mmol) was introduced. The mixture was then stirred at 55 °C for another 20 min. After cooling, 0.1 mL of THF containing iodine (0.02 equivalents, 5.1 mg, 0.0201 mmol) was introduced, and the reaction mixture was stirred at 55°C for another 20 min. 4-Bromo-1,1-difluorocyclohexane (1 equivalent, 200 mg, 1 mmol) was added to the warm suspension of activated zinc. The reaction mixture was stirred at 55°C for 12 h. The solution was used directly in the next step.

Method Int 63. Intermediate Int-B22: 5-[4-(8-chloro-2,3-dimethyl-pyrido[2,3-b]pyridine] -6-yl)tetrahydropiperan-2-yl]-1-methylpyridin-2-one

Under a _nitrogen atmosphere, 6,8-dichloro-2,3-dimethyl-pyrido[2,3-b]pyridine was... (1 equivalent, 130 mg, 0.57 mmol) and Pd(Amphos) _₂Cl₂ (0.05 equivalent, 20 mg _, 0.0285 mmol) and THF (1 mL) were placed in a sealed bottle and purged three times with _N₂ . At 25°C, bromo-[2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc (1.2 equivalent, 231 mg, 0.684 mmol) was added dropwise to the reaction solution, followed by heating to 45°C and stirring for 1 hour. LCMS showed ~35% detection of the desired product. The mixture was combined with two other batches and quenched with 100 mL of _H₂O . Extraction was performed using DCM (3 × 100 mL). _The combined organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to give a crude product (450 mg). The crude product was purified by silicone column chromatography (0–100% EtOAc/petroleum ether and 100–70% EtOAc/MeOH) (TLC, 25% MeOH/EtOAc, desired product: _Rf = 0.6) to give a solid 5-[4-(8-chloro-2,3-dimethyl-pyridano[2,3-b]pyridine]pyridine. [-6-yl)tetrahydropiperan-2-yl]-1-methylpyridin-2-one (Int-B22, 250 mg, 0.650 mmol, 56% yield). LCMS : [M+H] ⁺ = 385.2; purity = 96% (UV 220 nm); retention time = 0.451 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 - 7.61 (m, 1H), 7.47 - 7.32 (m, 2H), 6.63 - 6.50 (m, 1H), 4.36 - 4.21 (m, 1H), 4.01 - 3.86 (m, 1H), 3.76 (dt, J = 2.3, 11.8 Hz, 1H), 3.54 (s, 3H), 3.30 (tdd, J = 3.9, 8.0, 11.9 Hz, 1H), 2.88 - 2.76 (m, 6H), 2.34 - 2.13 (m, 2H), 2.11 - 2.05 (m, 1H), 2.03 - 1.97 (m, 1H).

Method Int 64. Intermediate Int-C12: 1-Cyclopropyl-5-((2S,6R)-6-methyl (Lin-2-yl)pyridin-2(1H)-one

Under argon atmosphere and at 50°C, thiophenol (3 equivalents, 36 µL, 0.36 mmol) was added dropwise to 1-cyclopropyl-5-[(2S,6R)-6-methyl-4-(4-nitrophenyl)sulfonyl- [Lin-2-yl]pyridin-2-one 4 (Int-C11, 1 equivalent, 50.0 mg, 0.12 mmol) and potassium carbonate (5 equivalent, 82.3 mg, 0.60 mmol) were suspended in MeCN (1.0 mL). The resulting mixture was stirred at 50 °C for 18 h, then cooled to room temperature and filtered through a diatomaceous earth mat. The filtrate was concentrated to dryness, and the residue was diluted with DCM (100 mL) and extracted with 3M HCl (aq) (3 × 20 mL). The combined aqueous layers were alkalized with 1M NaOH (aq) until pH = 12 and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried _over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure. The crude material was purified by rapid chromatography (12 g _SiO₂ column) using a dissolution gradient of 0-10% MeOH/DCM to obtain an oily 1-cyclopropyl-5-[(2S,6R)-6-methyl [Lin-2-yl]pyridin-2-one (Int-C12, 20 mg, 0.08 mmol, 72% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.29 (d, J = 6.9 Hz, 2H), 6.52 (d, J = 10.0 Hz, 1H), 4.29 (d, J = 10.2 Hz, 1H), 3.74 (s, 1H), 3.26-3.32 (m, 1H), 2.95 (br s, 2H), 2.58 (br d, J = 58.5 Hz, 3H), 1.19 (d, J = 6.2 Hz, 3H), 1.11-1.14 (m, 2H), 0.85-0.87 (m, 2H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C1 (2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl-4-(4-nitrophenyl)sulfonyl- phyto Modification : The crude reaction product was purified by normal-phase rapid column chromatography (25 g SiO2 column) using a dissolution gradient of 1-10% MeOH/DCM to obtain (2S,6R)-2-(6-(benzyloxy)pyridin-3-yl)-6-methyl as a turbid oil. Phosphate (Int-C1, 79%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.15 (1H, d, J = 2.3 Hz), 7.63 (1H, dd, J = 8.5, 2.4 Hz), 7.45 (2H, d, J = 7.5 Hz), 7.29-7.39 (3H, m), 6.80 (1H, d, J = 8.5 Hz), 5.38 (2H, s), 4.50 (1H, dd, J = 10.5, 2.3 Hz), 3.75-3.79 (1H, m), 2.97 (2H, dd, J = 25.2, 12.3 Hz), 2.71 (1H, t, J = 11.4 Hz), 2.56 (1H, t, J = 11.3 Hz), 2.10-2.14 (1H, m), 1.21 (3H, d, J = 6.2 Hz).

Method Int 66. Intermediate Int-C3: 5-((2S,6R)-2-(6-(benzyloxy)pyridin-3-yl)-6-methyl(N- (Linyl)-7-(2,4-difluorophenyl)-N,N-dimethylthiazo[4,5-d]pyrimidin-2-amine

(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- A solution of 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazo[4,5-d]pyrimidin-2-amine (Int-C2, 1.2 equivalents, 159 mg, 0.485 mmol) in DMSO (2 mL) was mixed with DIPEA (3 equivalents, 0.21 mL, 1.21 mmol), and the mixture was then stirred at 135 °C for 4 h. 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazo[4,5-d]pyrimidin-2-amine (Int-C2, 0.5 equivalents, 66 mg, 0.202 mmol) was added to the mixture again, and the mixture was then stirred at 135 °C for another 12 h. The reaction solution was extracted with ethyl acetate (10 mL × 2) and washed with 10 mL of saturated saline solution. The organic matter was then separated and dried ( _{Na₂SO₄ )} , followed by concentration to dryness. The residue was then purified using a silicone column (50% EtOAc/PE, _Rf = 0.5) to obtain a gel-like 5-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- [Lin-4-yl]-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazo[4,5-d]pyrimidine-2-amine (Int-C3, 100 mg, 0.174 mmol, 43% yield). LCMS : [M+H] ⁺ = 575.2; purity = 77.8%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.3 (d, J=6.1 Hz, 3H) 2.76 (d, J=13.3, 10.7 Hz, 1H) 2.90 (dd, J=13.1, 11.3 Hz, 1H) 3.20 - 3.37 (m, 6H) 3.78 - 3.92 (m, 1H) 4.59 (dd, J=10.6, 2.6 Hz, 1H) 4.80 - 4.95 (m, 2H) 5.40 (s, 2H) 6.83 (d, J=8.7 Hz, 1H) 6.90 - 6.97 (m, 1H) 6.98 - 7.05 (m, 1H) 7.32 - 7.41 (m, 3H) 7.44 - 7.49 (m, 2H) 7.70 - 7.81 (m, 2H) 8.24 (d, J=2.3 Hz, 1H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C15 Int-C1 Modification : Using anhydrous THF as solvent, at 65°C, (2S,6R)-2-(2-benzyloxy-1,2-dihydropyridin-5-yl)-6-methyl- Starting with porphyrin (Int-C1) and 2-chloro-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine, the reaction was carried out in a MW vial for 3 h. The resulting crude product was purified by normal-phase rapid column chromatography (12 g _SiO2 column) using a 0-10% EtOAc/DCM dissolution gradient to give solid (2S,6R)-2-(6-benzyloxy-3-pyridyl)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine-2-yl]-6-methyl- Phosphorus (Int-C15, 123 mg, 0.21 mmol, 58% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.26 (1H, s), 7.74 (1H, d, J = 8.5 Hz), 7.28-7.46 (5H, m), 6.86 (1H, d, J = 8.5 Hz), 5.43 (2H, s), 4.94-5.05 (1H, m), 4.57-4.60 (1H, m), 3.81-3.89 (1H, m), 2.93-3.01 (1H, m), 2.78-2.85 (2H, m), 2.69 (3H, s), 2.64 (3H, s), 2.58 (6H, s), 1.35 (3H, d, J = 6.0 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). Int-C18 Int-C17 Int-C14 Modification : The reaction was carried out at 70°C in THF for 45 min. The crude reaction mixture was purified by rapid chromatography (Isco RediSep® column, 4 g, using a gradient of 0% to 2% MeOH/DCM). The selected solvent was evaporated to give 5-[(2S,6R)-6-methyl-4-[7-methyl-6-(oxacyclobut-3-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl] as a solid. [Lin-2-yl]-1H-pyridin-2-one (Int-C18, 63% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.64-7.69 (m, 2H), 6.73-6.76 (m, 1H), 5.09 (d, J = 7.73Hz, 4H), 4.93-5.00 (m, 1H), 4.60-4.68 (m, 1H), 4.43-4.47 (m, 1H), 3.79-3.87 (m, 1H), 2.98 (s, 1H), 2.84-2.92 (m, 1H), 2.75-2.82 (m, 1H), 2.66-2.71 (m, 1H), 2.61 (s, 6H), 2.54 (s, 3H), 1.32-1.37 (m, 3H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.0 (s, 3F). ESI-MS : [M+H] ⁺ = 529.3. Int-C47 Int-C46 Int-C1 Modification : Int-C1 (1 equivalent), Int-C46 (1.2 equivalents), and DIPEA (3 equivalents) were reacted in THF solvent at 70°C for 1 h, followed by depressurization concentration. The residue was purified by normal-phase chromatography (0-40% EtOAc/hexane) to obtain 3-[6-amino-2-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-] as a solid. Methyl 1-pentane-1-carboxylate [1.1.1]-lin-4-yl]-5-nitro-pyrimidin-4-yl]bicyclo[1.1.1]-carboxylate (Int-C47, 464 mg, 0.85 mmol, 86% yield). ESI-MS : [M+H] ⁺ = 547.3. Int-D34 Int-C1 Int-D33 Modification : The reaction was carried out at 100°C for 1 h, and then poured into water. The precipitate was collected by filtration to obtain 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- [Lin-4-yl]-4-(2,4-difluorophenyl)-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one (Int-D34, 600 mg, 0.927 mmol, 99% yield). LCMS : [M+H] ⁺ = 570.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 2.3, 8.6 Hz, 1H), 7.53 - 7.44 (m, 3H), 7.41 - 7.29 (m, 4H), 7.06 (dt, J = 2.0, 8.3 Hz, 1H), 7.02 - 6.95 (m, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.00 (d, J = 3.1 Hz, 1H), 5.40 (s, 2H), 5.00 - 4.83 (m, 2H), 4.59 (dd, J = 2.4, 10.8 Hz, 1H), 3.91 - 3.82 (m, 1H), 3.62 (s, 3H), 2.97 (dd, J = 10.9, 13.1 Hz, 1H), 2.83 (dd, J = 10.8, 13.3 Hz, 1H), 2.34 (s, 3H), 1.35 (d, J = 6.2 Hz, 3H). Int-D37 Int-C1 Int-D36 Modification : The reaction was carried out at 100°C for 1 h, and then poured into water. The precipitate was collected by filtration to obtain 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- [Lin-4-yl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one (Int-D37, 200 mg, 0.323 mmol, 60% yield). LCMS : [M+H] ⁺ = 620.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.28 - 8.20 (m, 1H), 7.98 - 7.76 (m, 4H), 7.51 - 7.29 (m, 6H), 6.91 (d, J = 8.5 Hz, 1H), 6.04 (d, J = 2.5 Hz, 1H), 5.37 (s, 2H), 4.77 - 4.60 (m, 3H), 3.56 - 3.48 (m, 3H), 3.04 - 2.95 (m, 2H), 2.82 - 2.71 (m, 1H), 2.32 (s, 3H), 1.29 - 1.24 (m, 3H). Int-E13 Int-E12 Int-C1 Modification : The reaction was carried out at 70°C in THF solvent for 90 min, and purified by rapid chromatography (12 g Isco RediSep® column, using a gradient of 0-50% EtOAc/hexane). Evaporation of the selected solvent yielded (2S,6R)-2-(6-(benzyloxy)pyridin-3-yl)-4-(4-(3,3-difluorocyclobutoxy)-6,7-dimethylpyridano[2,3-d]pyrimidin-2-yl) as a solid (Int-E13, 66 mg, 0.12 mmol, 72%). ^¹H NMR ( _CDCl₃ , 400 MHz): δ 8.22 (d, J = 2.3 Hz, 1H), 7.91 (s, 1H), 7.71 (dd, J = 8.6, 2.4 Hz, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.36–7.40 (m, 2H), 7.30–7.34 (m, 1H). 6.84 (d, J = 8.5Hz, 1H), 5.40 (s, 2H), 4.54 (dd, J = 10.8, 2.6Hz, 1H), 3.79-3.84 (m, 1H), 3.10-3.21 (m, 2H), 2.89-2.96 (m, 1H), 2.76-2.84 (m, 1H), 2.64 (s, 3H), 2.36 (s, 3H), 1.33 (d, J = 6.2 Hz, 3H). ESI-MS : [M+H] ⁺ = 548.3.

Method Int 67. Intermediate Int-C4: 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1-(methyleneamino)pyridin-2-one

To 1-amino-5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]pyridin-2-one (Example 174, 1 equivalent, 100 mg, 0.200 mmol) and formaldehyde (2 equivalents, 0.030 mL, 0.400 mmol) were added to a solution of _MgSO₄ (10 equivalents, 240 mg, 2.00 mmol) in THF (5 mL), followed by the addition of AcOH (0.25 equivalents, 6.9 mg, 0.050 mmol). The mixture was stirred at 30 °C for 2 h, and then added to _an aqueous solution of NaHCO₃ (10 mL), and extracted with DCM (10 mL × 2). The organic matter was washed with 10 mL of saturated saline solution, separated, dried ( _Na₂SO₄ ), and concentrated to give 5-[(2S, _6R )-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1-(methyleneamino)pyridin-2-one (Int-C4, 60 mg, 0.117 mmol, 59% yield) was used directly in the next step. LCMS : [M+H] ⁺ = 512.1; purity = 51% (UV 220 nm); retention time = 0.569 min.

Method Int 68. Intermediate Int-C5: ((biphenylphospho)oxy)(methyl)aminocarbamate tributyl ester

Add N-hydroxy-N-methylcarbamate tributyl ester (1.1 equivalent, 0.68 g, 4.63 mmol) and DCM (9 mL) to a flame-dried round-bottom flask under _N2 atmosphere. Cool the mixture to -10°C and add triethylamine (1.25 equivalent, 0.73 mL, 5.27 mmol) dropwise over 10 min. Under _N2 atmosphere, add diphenylphosphine chloride (1 equivalent, 1.00 g, 4.23 mmol) and DCM (6 mL) to a separate flask. After 30 min, add this solution dropwise to the hydroxylamine solution to maintain the internal temperature of the reaction solution below 0°C. After 1 h, heat the mixture to above 10°C and add citric acid aqueous solution (5% by weight, 2.5 mL) over 5 min. The phases were separated, and the organic layer was concentrated under reduced pressure until the product began to precipitate. Heptane (30 mL) was added to the resulting slurry, and the solvent was removed under reduced pressure. The desired product, N-biphenylphosphoxy-N-methyl-aminocarbamate tributyl ester (Int-C5, 1.1 g, 3.2 mmol, 75% yield), was given as a solid. ^¹H NMR (400 MHz, _CDCl₃ ): δ 8.01 – 7.90 (4H, m), 7.57 – 7.50 (2H, m), 7.48 – 7.40 (4H, m), 1.39 (9H, s).

Method Int 69. Intermediate Int-C6: N -Biphenylphosphoxymethylamine

Under a _nitrogen atmosphere, tributyl N-biphenylphospho-N-methylcarbamate (Int-C5, 1 equivalent, 1.50 g, 4.32 mmol) was added to a round-bottom flask and dissolved in DCM (80 mL). The solution was cooled to 0°C with stirring, and trifluoromethanesulfonic acid (2.5 equivalent, 0.95 mL, 10.8 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 30 min. The reaction mixture was diluted with DCM and washed with saturated _NaHCO3 (aq) solution (50 mL) and water. The organic phase was dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to give N-biphenylphosphoxymethylamine (Int-C6, 0.75 g, 3.01 mmol, 70% yield) as a solid. ^¹H NMR (400 MHz, _CDCl₃ ): δ 7.91 – 7.79 (4H, m), 7.57 – 7.50 (2H, m), 7.49 – 7.37 (4H, m), 2.89 (3H, s).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C9 Int-C8 In a similar manner, Int-C8 (240 mg, 0.664 mmol) was treated with trifluoromethanesulfonic acid to obtain N-biphenylphosphoxyethylamine in solid form (Int-C9, 156 mg, 0.60 mmol, 90% yield).

Method Int 70. Intermediate Int-C7: 2-chloro-6-(difluoromethyl)-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine

Zinc difluoromethane sulfate (3 equivalents, 1.40 g, 4.77 mmol) was added to a solution of 2-chloro-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine (1 equivalent, 500 mg, 1.59 mmol) and TFA (2 equivalents, 243 µL, 3.18 mmol) in a 1:1 mixture of DMSO (30 mL) and DCM (30 mL). Then, under vigorous stirring, a solution of tertiary butyl hydroperoxide (70 wt% in _H₂O , 5 equivalents, 1.1 mL, 7.94 mmol) and ferric(III) acetoacetone (0.1 equivalent, 56 mg, 0.159 mmol) were added. The reaction mixture was stirred at room temperature until complete conversion was observed by LC-MS. The reaction mixture was separately dissolved between DCM (10 mL) and saturated _NaHCO3 (aq) (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layer was dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (40 g _SiO2 column) using a dissolution gradient of 0-100% EtOAc/hexane to obtain a solid (2-chloro-6-(difluoromethyl)-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine (Int-C7, 204 mg, 0.425 mmol, 27% yield). ^¹H NMR ( _CDCl₃ , 400 MHz): δ 6.83 (¹H, t, J = 53.8 Hz), 3.03 (³H, s), 2.68 (⁶H, s). ^¹⁹F NMR ( _CDCl₃ , 376 MHz): δ -73.1 (³F, s), -115.8 (²F, s). (d, J = 54.0 Hz).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-D16 Int-C20 Modification : The crude material was purified by rapid chromatography (Isco RediSep® column 40 g, using a gradient of 20-60% EtOAc/hexane). Evaporation of the selected solvent yielded a solid (3-chloro-6-(difluoromethyl)-5-methylpyridine) -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-D16, 162 mg, 0.48 mmol, 28% yield). ESI-MS : [M+H] ⁺ = 338.9. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.36 (t, J = 52.9 Hz, 1H), 2.45 (s, 3H). ^19F NMR (376 MHz, DMSO- _d6 ) δ -71.5 (s, 3F), -118.2 (dd, J = 53.1, 1.6 Hz, 2F).

Method Int 71. Intermediate Int-C8: N-biphenylphosphoxy-N-ethylcarbamate tributyl ester

Tributyl N-biphenylphosphocarboxylate (1 equivalent, 0.95 g, 2.84 mmol) and anhydrous THF (15 mL) were added to a 50 mL round-bottom flask under _N2 atmosphere. The reaction mixture was cooled to -78 °C, and NaHMDS (1.0 M in THF, 1.5 equivalent, 4.3 mL, 4.25 mmol) was added dropwise while stirring at -78 °C for 30 min. After 30 min, a solution of iodoethane (1.7 equivalent, 0.39 mL, 4.82 mmol) in anhydrous THF (4.5 mL) was added dropwise to the reaction mixture. The reaction mixture was slowly heated to room temperature and stirred for 24 h. The reactants were quenched with saturated _NH₄Cl (aq.) (10 mL) and extracted with EtOAc (3 × 40 mL). The combined organic phases were washed with brine, dried _over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure. The crude material was purified by rapid normal-phase chromatography (40 g _SiO₂ column) using a 5-60% EtOAc/hexane dissolution gradient to give an oily tributyl N-biphenylphosphoxy-N-ethylcarbamate (Int-C8, 0.28 g, 0.78 mmol, 27% yield).

Method Int 72. Intermediate Int-C11: 1-Cyclopropyl-5-((2S,6R)-6-methyl-4-((4-nitrophenyl)sulfonyl) (Lin-2-yl)pyridin-2(1H)-one

Add potassium carbonate (2 equivalents, 364 mg, 2.64 mmol), 1,10-phenanthroline (0.13 equivalents, 29.7 mg, 0.17 mmol), and 5-[(2S,6R)-6-methyl-4-(4-nitrophenyl)sulfonyl- The reaction mixture contained 1,3-(Int-C9, 1 equivalent, 500 mg, 1.32 mmol), Cu(OAc) _₂ (0.25 equivalent, 59.8 mg, 0.33 mmol), potassium cyclopropyltrifluoroborate (3 equivalent, 585 mg, 3.95 mmol), DCE (5 mL), and water (1.7 mL). _O₂ gas was bubbled into the reaction mixture for 5 min, and the mixture was stirred overnight at 70 °C under an oxygen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by rapid chromatography (24 g _SiO2 column) using a dissolution gradient of 60-100% EtOAc/hexane to obtain a solid 1-cyclopropyl-5-((2S,6R)-6-methyl-4-((4-nitrophenyl)sulfonyl) (Lin-2-yl)pyridin-2(1H)-one (Int-C11, 377 mg, 0.90 mmol, 68% yield). ESI-MS : [M+H] ⁺ = 420.2. ¹ H NMR (CDCl ₃ , 400 MHz): _δ 8.42-8.39 (m, 2H), 7.95-7.92 (m, 2H), 7.31 (d, J = 2.5 Hz, 1H), 7.23-7.25 (m, 1H), 6.61 (d, J = 9.4 Hz, 1H), 4.40-4.43 (m, 1H), 3.83-3.89 (m, 1H), 3.69-3.75 (m, 2H), 3.34-3.26 (m, 1H), 2.18-2.07 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H), 1.11-1.17 (m, 2H), 0.83-0.87 (m, 2H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C35 Following the procedure described above, (R)-5-(4-(4-amino-5-nitro-6-(3-(trifluoromethyl)bis(1.1.1)pentan-1-yl)pyrimidin-2-yl)-5,6-dihydro-2H-piperan-2-yl)pyridin-2(1H)-one was N-alkylated, and by using 20-60% Purification by rapid silica gel column chromatography over a solubility gradient of EtOAc/hexane yielded (R)-5-(4-(4-amino-5-nitro-6-(3-(trifluoromethyl)bis(1.1.1)pentyl-1-yl)pyrimidin-2-yl)-5,6-dihydro-2H-piperan-2-yl)-1-cyclopropylpyridine-2(1H)-one (Int-C35, 313 mg, 0.64 mmol, 82% yield). ESI-MS : [M+H] ⁺ = 490.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.31 (2H, m), 7.18 (1H, s), 6.71 (1H, br s), 6.54 (1H, d, J = 9.3 Hz), 5.08 (1H, s), 4.10 (1H, dt, J = 11.4, 4.1 Hz), 3.75-3.81 (1H, m), 3.30 (1H, s), 2.63 (2H, s), 2.39 (6H, s), 1.11 (2H, d, J = 6.6 Hz), 0.85 (2H, s).

Method Int 73. Intermediate Int-C14: 2-chloro-7-methyl-6-(oxacyclobut-3-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine

At room temperature, after 2 min, hydrogen peroxide (30 wt% in water, 3 equivalents, 974 µL, 9.53 mmol) was added dropwise to a stirred solution of 2-chloro-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine (1 equivalent, 1.0 g, 3.2 mmol), concentrated sulfuric acid (2 equivalents, 339 µL, 6.4 mmol), 3-iodocyclobutane (2 equivalents, 559 µL, 6.4 mmol), and ferric sulfate(II) heptahydrate (0.3 equivalents, 267 mg, 0.95 mmol) in DMSO (20 mL). After 1–2 min, another portion of ferric sulfate(II) heptahydrate (0.3 equivalents, 267 mg, 0.95 mmol) was added, and the mixture was stirred at room temperature for 60 min. The mixture was poured into a mixture of saturated _NaHCO3 (aq.) (10 mL) and EtOAc (15 mL). The aqueous and organic layers were separated, and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic extract was washed with brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The resulting oil was purified by rapid normal-phase chromatography (40 g SiO2 column) using a dissolution gradient of 1-100% EtOAc/hexane to give solid 2-chloro-7-methyl-6-(oxacyclobut-3-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine (Int-C14, 270 mg, 0.73 mmol, 23% yield). ESI-MS : [M+H] ⁺ = 371.3.

Method Int 74. Intermediate Int-C17: 5-((2S,6R)-6-methyl (Lin-2-yl)pyridin-2(1H)-one

Add (2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl- to a flame-dried round-bottom flask equipped with a Teflon-coated magnetic stirring rod. Phosphorus (Int-C1, 1 equivalent, 200 mg, 0.7 mmol) and MeOH (13 mL) were added. The reaction mixture was purged three times under vacuum/nitrogen circulation, _and 10 wt% Pd/C (0.27 equivalent, 20.0 mg, 0.19 mmol) was added. The reaction vial was circulated three times under vacuum with _H2 (g) balloons and stirred for 30 min at 1 atm of _H2 (g). The reaction mixture was then filtered through a diatomaceous earth mat, washed with DCM, and concentrated under reduced pressure to obtain an oily 5-((2S,6R)-6-methyl (Lin-2-yl)pyridin-2(1H)-one (Int-C17, 124 mg, 0.64 mmol, 91% yield). ¹ H NMR (CD ₃ OD, 400 MHz): δ 7.61 (dd, J = 9.40, 2.6 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 9.4 Hz, 1H), 4.33-4.36 (m, 1H), 3.73 (dd, J = 10.4, 6.1 Hz, 1H), 3.34 (s, 1H), 2.95 (d, J = 12.8 Hz, 1H), 2.88 (d, J = 12.6 Hz, 1H), 2.56 (dd, J = 12.7, 10.7 Hz, 1H), 2.44 (dd, J = 12.7, 10.5 Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C24 Int-C23 Modification : The reaction mixture was stirred for 30 min under a hydrogen atmosphere, then purged with argon and filtered through diatomaceous earth, and washed with a 4:1 solution of DCM/MeOH. The filtrate was concentrated under vacuum to obtain a foamy (2R,4S)-N-(6-methyl-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridine (-2-yl)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-methamide (Int-C24, 0.97 g, 1.91 mmol, 95% yield), used without further purification. ESI-MS : [M+H] ⁺ = 477.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 11.22 (1H, s), 8.23 (1H, s), 7.59 (1H, dd, J = 9.4, 2.5 Hz), 7.48 (1H, d, J = 2.4 Hz), 6.67 (1H, d, J = 9.4 Hz), 4.24 (2H, d, J = 11.6 Hz), 3.61-3.68 (1H, m), 2.94-3.00 (1H, m), 2.64 (3H, s), 2.51 (6H, s), 2.13 (1H, d, J = 13.3 Hz), 1.93-1.99 (2H, m), 1.80 (1H, dd, J = 24.5, 12.2 Hz). Int-C34 Int-C33 Modification : The reaction mixture was stirred for 30 min under a hydrogen atmosphere, then purged with argon and filtered through diatomaceous earth, and washed with a 4:1 solution of DCM/MeOH. The filtrate was concentrated under vacuum to obtain a foamy (2R,4S)-N-(5-methyl-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridine (-2-yl)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-methamide (Int-C34, 1.31 g, 2.48 mmol, 93% yield), used without further purification. ESI-MS : [M+H] ⁺ = 477.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 11.08 (1H, s), 8.51 (1H, s), 7.63 (1H, dd, J = 9.4, 2.5 Hz), 7.55 (1H, d, J = 2.4 Hz), 6.71 (1H, d, J = 9.4 Hz), 4.22-4.27 (2H, m), 3.66 (1H, dd, J = 13.3, 10.3 Hz), 2.84-2.92 (1H, m), 2.59 (3H, s), 2.53 (6H, s), 2.14 (1H, d, J = 13.5 Hz), 1.92-2.01 (2H, m), 1.80 (1H, (dd, J = 24.5, 12.2 Hz). Int-C42 Int-C41 Modified : The reaction was carried out with 0.1 equivalents of EtOH containing Pd/C (10 wt%) for 1 h to give a gel-like methyl (2R,4S)-2-(1-hydroxy-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-carboxylate (Int-C42, 303 mg, 1.2 mmol, 99% yield). ESI-MS : [M+H] ⁺ = 254.2. Int-D2 Int-D1 Modified : The reaction was carried out with 0.03 equivalents of EtOH containing Pd/C (10 wt%) for 16 h to give solid (2R,4S)-2-(6-sideoxy-1H-pyridin-3-yl)tetrahydropiperan-4-carboxylate (Int-D2, 6.6 g, 27.9 mmol, 97% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 12.00 (br s, 1H), 7.48 (dd, J = 9.5, 2.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 9.4 Hz, 1H), 4.18-4.12 (m, 2H), 3.70 (s, 3H), 3.57 (td, J=12.0, 2.2 Hz, 1H), 2.68 (tt, J=12.2, 3.9 Hz, 1H), 2.06 (d, J=13.5 Hz, 1H), 1.90 (dd, J = 13.5, 1.8 Hz, 1H), 1.77 (ddd, J = 25.5, 12.5, 4.5 Hz, 1H), 1.64 (q, J = 12.4 Hz, 1H). ESI-MS : [M+H] ⁺ = 238.2. Int-E11 Int-E8 Modification : The reaction was carried out in a 1:1 EtOH/EtOAc solvent to give solid ( 2R , 4S ) -N- (6-methyl-5-(trifluoromethyl)-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridin-2-yl)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro- 2H -piperan-4-carboxamide (Int-E11, 0.45 g, 0.84 mmol, 99% yield), which was used without further purification. ESI-MS : [M+H] ⁺ = 546.3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.03 (s, 1H), 8.39 (s, 1H), 7.61 (dd, J = 9.4, 2.3 Hz, 1H), 7.51 (s, 1H), 6.69 (d, J = 9.4 Hz, 1H), 4.26-4.21 (m, 2H), 3.65 (td, J = 11.6, 3.3 Hz, 1H), 3.13-3.07 (m, 1H), 2.72-2.69 (m, 3H), 2.49 (s, 6H), 2.28-2.41 (0H), 2.11 (d, J = 14.1 Hz, 1H), 1.98-1.87 (m, 2H), 1.78 (dd, J = 24.8, 11.9 Hz, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -61.8 (s, 3F), -73.2 (s, 3F).

Method Int 75. Intermediate Int-C19: (2S,6R)-2-(6-(benzyloxy)pyridin-3-yl)-4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine -7-yl)-6-methyl phyto

7-chloro-5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine in a 10 mL microwave-safe vial (1 equivalent, 100 mg, 0.33 mmol), (2S,6R)-2-(6-(benzyloxy)pyridin-3-yl)-6-methyl A mixture of porphyrin (Int-C1, 1.1 equivalent, 102 mg _, 0.360 mmol), sodium tributoxide (4 equivalent, 126 mg, 1.31 mmol), and Pd(Amphos) _₂Cl₂ (0.1 equivalent, 23 mg, 0.03 mmol) underwent three vacuum/nitrogen-filled cycles. 1,4-dioxane was added. 5.0 mL of hexane was added, and the mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature, filtered through a diatomaceous earth mat, washed with 10 mL of EtOAc, and concentrated under reduced pressure. The crude material was purified by rapid chromatography (Isco Redisep 4 g column, using a gradient from 100% hexane to 100% EtOAc) to give (2S,6R)-2-(6-(benzyloxy)pyridin-3-yl)-4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine -7-yl)-6-methyl Phosphorus (Int-C19, 76 mg, 0.137 mmol, 42% yield). ESI-MS : [M+H] ⁺ = 554.3.

Method Int 76. Intermediate Int-C21: (3-((2,4-dimethoxybenzyl)amino)-5-methylpyridine -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl) methyl ketone

To (3-chloro-5-methylpyridine) -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-C20, 1 equivalent, 1.26 g, 4.33 mmol) was added to a stirred solution in anhydrous THF (40 mL) with potassium carbonate (2 equivalents, 1.2 g, 8.6 mmol) and (2,4-dimethoxyphenyl)methylamine (2.1 equivalents, 1.4 mL, 9.1 mmol). The reaction flask was fitted with a reflux condenser and stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (150 mL). The resulting suspension was washed with saturated ammonium chloride (aq) and brine. The organic layer was dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure onto diatomaceous earth (15 g). The crude mixture was purified by rapid silica gel column chromatography using a dissolution gradient of 2%–10% EtOAc/hexane to obtain a solid (3-((2,4-dimethoxybenzyl)amino)-5-methylpyridine. -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-C21, 1.52 g, 3.6 mmol, 83% yield). ESI-MS : [M+H] ⁺ = 422.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.99 (1H, t, J = 5.7 Hz), 7.68 (1H, s), 7.24-7.26 (1H, m), 6.47 (1H, d, J = 2.4 Hz), 6.41 (1H, dd, J = 8.3, 2.4 Hz), 4.69 (2H, d, J = 5.0 Hz), 3.87 (3H, s), 3.79 (3H, s), 2.46 (3H, s), 2.43 (6H, s).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C31 Int-C30 The procedure yields (3-((2,4-dimethoxybenzyl)amino)-6-methylpyridine in solid form. -2-yl)(3-(trifluoromethyl)-bis(1.1.1)pent-1-yl)methyl ketone (Int-C31, 3.16 g, 7.50 mmol, 86% yield). ESI-MS : [M+H] ⁺ = 422.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.83 (1H, t, J = 5.7 Hz), 8.13 (1H, s), 6.47 (1H, d, J = 2.4 Hz), 6.40 (1H, dd, J = 8.3, 2.4 Hz), 4.66 (2H, d, J = 5.1 Hz), 3.86 (3H, s), 3.78 (3H, s), 2.45 (6H, s), 2.41 (3H, s). Int-F2 Int-F1 The procedure yields 3-((3,4-dimethylbenzyl)amino)-5,6-dimethylpyridine in solid form. -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-F2, 9.9 g, 22.8 mmol, 77% yield). ^¹H NMR ( _CDCl₃ , 400 MHz): δ 8.75 (¹H, s), 7.21 (¹H, d, J = 8.3 Hz), 6.45 (¹H, d, J = 2.4 Hz), 6.39 (¹H, dd, J = 8.2, 2.4 Hz), 4.64 (2H, d, J = 5.9 Hz), 3.85 (3H, s), 3.77 (3H, s), 2.43 (3H, s), 2.42 (6H, s), 2.37 (3H, s).

Method Int 77. Intermediate Int-C22: (3-amino-5-methylpyridine) -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl) methyl ketone

(3-((2,4-dimethoxybenzyl)amino)-5-methylpyridine -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-C21, 1 equivalent, 1.51 g, 3.58 mmol) and anisole (1 equivalent, 0.39 mL, 3.58 mmol) were added to a stirred solution in anhydrous DCM (50 mL) with TFA (9.11 equivalents, 2.5 mL, 32.6 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum and diluted with EtOAc (150 mL). The resulting solution was washed with saturated _NaHCO3 (aq) and brine. The organic layer was dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under vacuum onto diatomaceous earth (20 g). The crude mixture was purified by rapid silica gel column chromatography using a solubility gradient of 10%-25% EtOAc/hexane to obtain a solid (3-amino-5-methylpyridine) -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-C22, 0.93 g, 3.44 mmol, 96% yield). ESI-MS : [M+H] ⁺ = 272.2. ^1H NMR (400 MHz, _CDCl3 ): δ 7.84 (1H, s), 2.47 (6H, s), 2.44 (3H, s).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C32 Int-C31 The procedure yields (3-amino-6-methylpyridine) as a crystalline solid. -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-C32, 1.81 g, 6.68 mmol, 89% yield). ESI-MS : [M+H] ⁺ = 272.2. ^1H NMR (400 MHz, _CDCl3 ): δ 8.09 (1H, s), 2.48 (6H, s), 2.45 (3H, s). Int-F3 Int-F2 The procedure yields (3-amino-5,6-dimethyl-pyridine) in solid form. -2-yl)-[3-(trifluoromethyl)-1-biscyclic[1.1.1]pentyl]methyl ketone (Int-F3, 6.0 g, 21.0 mmol, 92% yield). ^¹H NMR ( _CDCl₃ , 400 MHz): δ 2.47 (6H, s), 2.43 (3H, s), 2.42 (3H, s).

Method Int 78. Intermediate Int-C23: ( 2R , 4S )-2-(6-(benzyloxy)pyridin-3-yl) -N- (6-methyl-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridine -2-yl)tetrahydro- 2H -piperan-4-methylamine

DMF (0.05 mL) and oxaloyl chloride (1.2 equivalents, 0.36 mL, 4.09 mmol) were added to a stirred solution of (2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-carboxylic acid (Int-F7, 1.05 equivalents, 1.12 g, 3.58 mmol) in anhydrous DCM (40 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h and concentrated to a solid under vacuum. Freshly prepared anhydrous DCM (20 mL) was added, and the resulting solution was stirred at 0 °C under argon. At 0 °C, (3-amino-5-methylpyridyl) -2-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Int-C22, 1 equivalent, 0.93 g, 3.4 mmol) and pyridine (3 equivalent, 0.83 mL, 10.2 mmol) in anhydrous DCM (20 mL) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum and diluted with EtOAc (150 mL). The resulting solution was washed with saturated ammonium chloride (aq ₎ , saturated _NaHCO3 (aq) and brine. The organic layer was dried over anhydrous _Na2SO4 , filtered, and concentrated under vacuum onto diatomaceous earth (20 g). The crude mixture was purified by rapid silica gel column chromatography using a 10%–35% acetone/hexane dissolution gradient to obtain a foamy (2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)-N-(6-methyl-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridine -2-yl)tetrahydro-2H-piperan-4-methamide (Int-C22, 1.54 g, 2.72 mmol, 63% yield). ESI-MS : [M+H] ⁺ = 567.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 11.21 (1H, s), 8.23 (1H, s), 8.15 (1H, d, J = 2.4 Hz), 7.65 (1H, dd, J = 8.6, 2.4 Hz), 7.45 (2H, d, J = 7.5 Hz), 7.31-7.39 (3H, m), 6.81 (1H, d, J = 8.6 Hz), 5.38 (2H, s), 4.40 (1H, dd, J = 11.4, 2.0 Hz), 4.27 (1H, dt, J = 11.5, 3.0 Hz), 3.67-3.73 (1H, m), 2.95-3.04 (1H, m), 2.65 (3H, s), 2.51 (6H, s), 2.16 (1H, d, J = 12.2 Hz), 1.98-2.03 (2H, m), 1.90 (1H, dd, J = 24.6, 12.2 Hz).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C33 Int-C32 The procedure yields a foam-like (2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)-N-(5-methyl-3-(3-(trifluoromethyl)-bis(1.1.1)pentane-1-carbonyl)pyridine -2-yl)tetrahydro-2H-piperan-4-methamide (Int-C33, 1.54 g, 2.72 mmol, 63% yield). ESI-MS : [M+H] ⁺ = 567.4. ¹ H NMR (400 MHz, CDCl ₃ ): δ 11.05 (1H, s), 8.49 (1H, s), 8.16 (1H, d, J = 2.4 Hz), 7.66 (1H, dd, J = 8.6, 2.4 Hz), 7.45 (2H, d, J = 7.5 Hz), 7.29-7.39 (3H, m), 6.81 (1H, d, J = 8.6 Hz), 5.38 (2H, s), 4.40 (1H, d, J = 11.3 Hz), 4.27 (1H, dt, J = 11.5, 3.0 Hz), 3.67-3.73 (1H, m), 2.88-2.94 (1H, m), 2.59 (3H, s), 2.53 (6H, s), 2.13-2.18 (1H, m), 1.98-2.03 (2H, m), 1.89 (1H, dd, J = 24.6, 12.2 Hz). Int-C45 Int-C44 Int-F3 Modification : Int-C44 and Int-F3 were reacted for 72 h in the presence of 1.1 equivalents of oxalichlor. The crude reaction mixture was diluted with EtOAc and washed with 5% citric acid (aq.) and brine. The crude mixture was purified by rapid column chromatography (12 g _SiO2 column) using a dissolution gradient of 0-10% MeOH/DCM to give a solid (2R,4S)-N-[5,6-dimethyl-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]pyridine [-2-yl]-2-(1-methoxy-6-sideoxy-3-pyridyl)tetrahydropiperan-4-methamide (Int-C45, 48 mg, 0.09 mmol, 46% yield). ESI-MS : [M+H] ⁺ = 521.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 11.10 (s, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 9.6, 2.5 Hz, 1H), 6.68 (d, J = 9.6 Hz, 1H), 4.26-4.19 (m, 2H), 4.08 (s, 3H), 3.65 (td, J = 11.4, 3.6 Hz, 1H), 2.93-2.93 (m, 1H), 2.62 (s, 3H), 2.56 (s, 3H), 2.52 (s, 6H), 2.18-2.14 (m, 1H), 1.99-1.93 (m, 2H), 1.80 (dd, J = 25.0, 11.8 Hz, 1H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (s, 3F). Int-D8 Int-D7 Int-F3 Modification : Int-D7 (1 equivalent) and Int-F3 (1.1 equivalent) were reacted for 16 h in the presence of 1.02 equivalents of oxalic acid. The reaction mixture was concentrated under reduced pressure and then purified by rapid column chromatography (12 g _SiO2 column) using a dissolution gradient of 10-50% EtOAc:EtOH (1:1)/hexane to obtain (2R,4S)-N-[5,6-dimethyl-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]pyridine as a solid. [-2-yl]-2-(6-sideoxy-1-pyrrolidin-1-yl-3-pyridyl)tetrahydropiperan-4-methamide (Int-D8, 95 mg, 0.17 mmol, 27% yield). ESI-MS : [M+H] ⁺ = 560.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 11.08 (s, 1H), 7.58 (s, 1H), 7.35 (dd, J = 9.4, 2.5 Hz, 1H), 6.58 (d, J = 9.4 Hz, 1H), 4.25-4.20 (m, 1H), 4.17 (d, J = 11.2 Hz, 1H), 3.74 (d, J = 6.2 Hz, 1H), 3.65 (dd, J = 14.9, 11.7 Hz, 1H), 3.42 (t, J = 6.3 Hz, 4H), 2.93 (d, J = 29.5 Hz, 1H), 2.62 (s, 3H), 2.56 (s, 3H), 2.52 (s, 6H), 2.13 (d, J = 13.5 Hz, 1H), 1.99-1.84 (m, 6H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (s, 3F). Int-D11 Int-D10 Int-F3 Modification : Int-D10 (1 equivalent) and Int-F3 (1.1 equivalent) were reacted for 16 h in the presence of 1.1 equivalent of oxalic acid. The reaction mixture was concentrated under reduced pressure and then purified by rapid column chromatography (12 g _SiO2 column) using a dissolution gradient of 0-5% MeOH/DCM to obtain (2R,4S)-2-[1-(2,5-dihydropyrrolidinyl)-6-sideoxy-3-pyridinyl]-N-[5,6-dimethyl-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]pyridinyl [-2-yl]tetrahydropiperan-4-methamide (Int-D11, 20.0 mg, 0.034 mmol, 16% yield). Int-F8 Int-F3 The crude mixture was purified by normal-phase chromatography (20-80% EtOAc/hexane) to obtain (2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)-N-(5,6-dimethyl-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridine as a solid. -2-yl)tetrahydro-2H-piperan-4-methamide (Int-F8, 560 mg, 43% yield). ¹ H NMR (CD ₃ OD, 400 MHz): δ 8.13 (1H, d, J = 2.5 Hz), 7.72 (1H, dd, J = 8.6, 2.5 Hz), 7.42 (2H, d, J = 7.6 Hz), 7.31 (3H, d, J = 10.4 Hz), 6.84 (1H, d, J = 8.6 Hz), 5.33 (2H, s), 5.28 (1H, d, J = 5.3 Hz), 4.45 (1H, d, J = 11.2 Hz), 4.17 - 4.21 (1H, m), 3.68 - 3.74 (1H, m), 2.99 (1H, d, J = 13.4 Hz), 2.70 (1H, t, J = 5.8 Hz), 2.55 (6H, d, J = 1.9 Hz), 2.47 (6H, s), 1.89 (2H, s). ESI-MS : [M+H] ⁺ = 581.3.

Method Int 79. Intermediate Int-C25: Tributyl 3-(6-benzyloxy-3-pyridyl)-4-side-oxy-piperidine-1-carboxylic acid

1-Boc-4-piperidinone (1.5 equivalents, 0.96 g, 4.82 mmol) and 2-benzyloxy-5-iodopyridine 1 (1 equivalent, 1.0 g, 3.21 mmol) were added to THF (32 mL) containing sodium tributoxide (3 equivalents, 0.93 g, 9.64 mmol). The mixture was purged with argon, followed by the addition of XPos (10 mol%, 153 mg, 0.32 mmol) and d(OAc) ₂ (5 mol%, 36 mg, 0.16 mmol). The resulting mixture was stirred overnight at 50 °C, quenched with water, and extracted three times with DCM. The combined organic layers were washed with brine, dried over _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain an oily tributyl 3-(6-benzyloxy-3-pyridyl)-4-sideoxy-piperidine-1-carboxylic acid (Int-C25, 780 mg, 2.04 mmol, 63% yield). ESI-MS : [M+H] ^⁺ = 383.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.92 (1H, d, J = 2.4 Hz), 7.38 (2H, d, J = 7.5 Hz), 7.22-7.35 (4H, m), 6.73 (1H, d, J = 8.6 Hz), 5.31 (2H, s), 4.19 (1H, br s), 3.58-3.62 (1H, m), 3.28-3.35 (1H, m), 2.32-2.56 (2H, m), 1.44 (9H, s), 1.41 (2H, s).

Method Int 80. Intermediate Int-C26: Tributyl 3-(6-benzoxy-3-pyridyl)-4,4-difluoro-piperidine-1-carboxylic acid

At -78 °C, DAST (5 equivalents, 0.29 mL, 2.22 mmol) was added dropwise to a stirred solution of 3-(6-benzoxy-3-pyridyl)-4-difluoro-piperidine-1-carboxylic acid tributyl ester (Int-C25, 1 equivalent, 170 mg, 0.44 mmol) in DCM (5 mL). The resulting mixture was heated to room temperature overnight. The crude material was concentrated under reduced pressure and purified by normal phase chromatography (0% to 30% EtOAc/hexane) to give an oily form of 3-(6-benzoxy-3-pyridyl)-4,4-difluoro-piperidine-1-carboxylic acid tributyl ester (Int-C26, 70 mg, 0.17 mmol, 39% yield). ESI-MS : [M+H] ⁺ = 405.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.10 (1H, d, J = 2.3 Hz), 7.55 (1H, d, J = 8.7 Hz), 7.46 (2H, d, J = 7.5 Hz), 7.38 (2H, t, J = 7.4 Hz), 7.32 (1H, d, J = 7.1 Hz), 6.80 (1H, d, J = 8.6 Hz), 5.37-5.38 (2H, m), 4.22 (2H, br s), 2.96-3.21 (3H, m), 2.14 (1H, t, J = 9.9 Hz), 1.92-2.01 (1H, m), 1.47 (9H, s).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-F11 Int-F10 The procedure yields methyl 4-(1,1-difluoroethyl)bicyclo[2.2.1]heptane-1-carboxylate (Int-F11).

Method Int 81. Intermediate Int-C27: 5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one

At room temperature, TFA (90 equivalents, 1.2 mL, 15.6 mmol) was added to a solution of tributyl 3-(6-benzoxy-3-pyridinyl)-4,4-difluoro-piperidin-1-carboxylic acid (Int-C26, 1 equivalent, 70 mg, 0.17 mmol) in DCM (1.7 mL). The resulting mixture was stirred in a microwave-safe vial at 80 °C for 30 min. The reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The residue was co-evaporated three times with DCM to obtain a crude, oily substance, 5-(4,4-difluoropiperidin-3-yl)pyridin-2(1H)-one (Int-C27, 37 mg, 0.17 mmol, 99% yield). The crude mixture was used in the next step without further purification.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C48 Int-C47 Modification : The reaction was carried out at 80℃ for 1 h to give 3-[6-amino-2-[(2R,6S)-2-methyl-6-(6-sideoxy-1H-pyridin-3-yl)] Methyl 1-pentane-1-carboxylate [1.1.1]-5-nitro-pyrimidin-4-yl]bicyclo[1.1.1] (Int-C48, 438 mg, 0.96 mmol, 99% yield). ESI-MS : [M+H] ⁺ = 457.3.

Method Int 82. Intermediate Int-C28: 5-(4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridano[3,4-b]pyridine -7-yl)-5,6-dihydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one

Add 1-methyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-3,6-dihydro-2H-piperan-6-yl]pyridin-2-one (1.15 equivalents, 170 mg, 0.37 mmol) and 7-chloro-5-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[3,4-b]pyridinium to a glass vial equipped with a Teflon-coated magnetic stir bar. (1 equivalent, 100 mg, 0.33 mmol), Pd(dppf) _Cl₂ ·DCM (0.15 equivalent, 40 mg, 0.49 mmol), 1,4-didi Alkane (3.3 mL) and 1.0 M _Na₂CO₃ (aq.) (3 equivalents, 0.50 mL, 0.99 mmol). The vial was sealed, purged under argon, and stirred at 90 °C for 2.5 _h . The reaction mixture was then cooled to room temperature, filtered through a diatomaceous earth mat, and washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by rapid chromatography (12 g Isco RediSep® column, using a dissolution gradient of 0.5% to 2% MeOH/DCM) to give solid 5-(4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine -7-yl)-5,6-dihydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Int-C28, 59 mg, 0.13 mmol, 87% yield). ESI-MS : [M+H] ⁺ = 461.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.84 (s, 1H), 7.67 (q, J = 7.6 Hz, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.35 (s, 1H), 7.00-7.05 (m, 2H), 6.95, (t, J = 9.5 Hz, 1H), 6.59 (d, J = 9.0 Hz, 1H), 5.17 (s, 1H), 4.19 (d, J = 11.0 Hz, 1H), 3.90-4.03 (m, 2H), 3.53 (s, 3H), 2.76 (s, 3H), 2.68 (s, 3H), 1.84 (br s, 1H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C40 Int-C39 Edited : In 4:1 The reaction was carried out in a mixed solvent of alkane/ _H₂O using 2 equivalents _{of K₂CO₃} (solid) as the base reagent. The reaction mixture was heated to 105 °C for 16 h. The crude material was purified by silica gel rapid column chromatography with a solubility gradient of 40-100% acetone/hexane to give an oily 5-(4-(8-(dimethylamino)-7-methyl-6-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)-7H-purin-2-yl)-5,6-dihydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Int-C40, 195 mg, 0.39 mmol, 99% yield). ESI-MS : [M+H] ⁺ = 501.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.44 (1H, s), 7.42 (1H, s), 6.59 (1H, d, J = 9.4 Hz), 5.16 (1H, s), 4.06-4.10 (1H, m), 3.84-3.88 (1H, m), 3.75 (3H, s), 3.55 (3H, s), 3.21 (7H, s), 2.83 (2H, s), 2.63 (1H, s), 2.54 (6H, s). Int-D15 Int-D14 Modification : The reaction was carried out using Int-D14 and 2-benzoxy-5-[rac-(6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-3,6-dihydro-2H-piperan-6-yl]pyridine ( _1.3 equivalents), with _Cs₂CO₃ (solid) as the base. The crude reaction product was purified by rapid chromatography (12 g _SiO2 column) using a dissolution gradient of 20–80% EtOAc/hexane to give solid 2,3-dimethyl-6-[rac-(6R)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-piperan-4-yl]-8-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrimidino[5,4-d]pyrimidin-4-one (Int-D15, 73 mg, 0.13 mmol, 87% yield). ESI-MS : [M+H] ⁺ = 576.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.21 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.6, 2.4 Hz, 1H), 7.47-7.44 (m, 2H), 7.39-7.35 (m, 3H), 7.33-7.29 (m, 1H), 6.81 (d, J = 8.7 Hz, 1H), 5.38 (d, J = 3.9 Hz, 3H), 4.18 (ddd, J = 11.3, 4.7, 3.9 Hz, 1H), 3.93-3.87 (m, 1H), 3.65 (s, 3H), 2.99-2.85 (m, 2H), 2.65 (s, 3H), 2.56 (s, 6H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.0 (s, 3F). Int-E4 Int-E3 Edited: In 7:12 The reaction was carried out in alkane/ _H₂O for 1.5 h, and purified by rapid chromatography (0-3% MeOH/DCM) using an Isco RediSep® column (4 g) to give an oily 5-[4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]-3,6-dihydro-2H-piperan-6-yl]-1-methyl-pyridin-2-one (Int-E3, 39 mg, 81.2 μmol, 59% yield). ESI-MS : [M+H] ^⁺ = 483.4. Int-E15 The residue was purified by column chromatography using a 0-50% EtOAc/DCM gradient (220 g SiO ₂ ) to obtain 4-amino-2-chloro-6-(2,4-difluorophenyl)pyrimidine-5-carboxaldehyde (Int-E15, 2.75 g, 10.2 mmol, 39%). Int-E16 Int-E15 The residue was purified on a 120 g silicon dioxide column using a 0-20% MeOH/DCM gradient to give solid (R)-4-amino-6-(2,4-difluorophenyl)-2-(6-(6-sideoxy-1,6-dihydropyridin-3-yl)-3,6-dihydro-2H-piperan-4-yl)pyrimidine-5-carboxaldehyde (Int-E16, 480 mg, 1.17 mmol, 57%). ESI-MS : [M+H] ⁺ = 411.2. Int-E44 Int-E43 Modified : Use 2 _equivalents of _K₂CO₃ in a 10:1 ratio. The reaction of alkane/ _H₂O was carried out at 100 °C for 12 h, followed by purification by rapid column chromatography (first 0-100% EtOAc/PE, then 0-50% MeOH/MeOH) to give an oily 5-[4-[4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-pteridin-2-yl]-3,6-dihydro-2H-piperan-6-yl]-1-methyl-pyridin-2-one (Int-E44, 124 mg, 0.259 mmol, 84% yield). ESI-MS : [M+H] ^⁺ = 478.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 2.4, 9.4 Hz, 1H), 7.37 - 7.33 (m, 2H), 7.32 - 7.27 (m, 1H), 6.61 (d, J = 9.4 Hz, 1H), 5.22 (br d, J = 2.5 Hz, 1H), 4.20 (td, J = 4.5, 11.3 Hz, 1H), 3.95 - 3.90 (m, 1H), 3.55 (s, 3H), 3.00 (br d, J = 2.3 Hz, 2H), 2.85 (s, 3H), 2.74 (s, 3H). ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -108.44 (s, 1F).

Method Int 83. Intermediate Int-C29: 5-(4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,2,3,4-tetrahydropyridino[3,4-b]pyridine -7-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one

Under an argon atmosphere, (R)-5-(4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine was added to a flame-dried microwave-safe vial equipped with a Teflon-coated magnetic stirring rod. -7-yl)-5,6-dihydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Int-C28, 1 equivalent, 103 mg, 0.22 mmol) and Pd/C (10 wt%, moistened with ~55% water) (0.4 equivalent, 10 mg, 0.94 mmol). MeOH (1.6 mL) was added, and three vacuum/hydrogen cycles were performed. An _H₂ balloon was fitted to the vessel, and the reaction mixture was stirred at 1 atm under _H₂ for 6 h. The reaction mixture was then purged under argon, filtered through a diatomaceous earth plug, and washed with a 9:1 EtOAc:MeOH mixture (100 mL). The filtrate was reduced-pressure concentrated, and the crude mixture was purified by rapid column chromatography (4 g _SiO2 column, liquid loading) using a dissolution gradient of 5% to 10% MeOH/DCM to obtain 5-(4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,2,3,4-tetrahydropyridino[3,4-b]pyridine as a solid. -7-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Int-C29, 40 mg, 0.87 mmol, 39% yield). ESI-MS : [M+H] ⁺ = 463.3.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-D6 Int-D5 Modified : The reaction was carried out with 0.03 equivalents of Pd/C (10 wt%, unwetted) and EtOH solvent for 1 h to give solid (2R,4S)-2-(6-sideoxy-1-pyrrolidin-1-yl-3-pyridinyl)tetrahydropiperan-4-carboxylate (Int-D6, 240 mg, 0.78 mmol, 96% yield). ESI-MS : [M+H] ⁺ = 307.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.53 (d, J = 2.5 Hz, 1H), 7.31 (dd, J = 9.4, 2.5 Hz, 1H), 6.55 (d, J = 9.4 Hz, 1H), 4.18-4.14 (m, 1H), 4.09 (dd, J = 11.5, 1.9 Hz, 1H), 3.71 (s, 3H), 3.57 (td, J = 12.1, 2.4 Hz, 1H), 3.41 (t, J = 6.5 Hz, 4H), 2.67 (tt, J = 12.3, 3.9 Hz, 1H), 2.08 (dt, J = 13.2, 1.8 Hz, 1H), 2.00-1.64 (m, 7H).

Method Int 84. Intermediate Int-C36: 1-Cyclopropyl-5-((2R,4S)-4-(4,5-diamino-6-(3-(trifluoromethyl)bis(1.1.1)pent-1-yl)pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one

Under argon atmosphere and at room temperature, Pd/C (10 wt%) (0.15 equivalents, 98 mg, 92.0 µmol) was added to a stirred solution of (R)-5-(4-(4-amino-5-nitro-6-(3-(trifluoromethyl)bis(1.1.1)pentyl[1.1.1]pentyl-1-yl)pyrimidin-2-yl)-5,6-dihydro-2H-piperan-2-yl)-1-cyclopropylpyridine-2(1H)-one (Int-C35, 1 equivalent, 300 mg, 0.61 mmol) in EtOAc (7.0 mL) and EtOH (5.0 mL). A hydrogen-filled balloon was connected to the reaction flask and stirred for 3 days. Next, the reaction mixture was purged with argon, filtered through a short diatomaceous earth bed, and rinsed with MeOH (10 mL). The filtrate was reduced-pressure concentrated and first subjected to rapid silica gel column chromatography using a dissolution gradient of 1–8% MeOH/DCM, followed by purification by two rounds of preparative HPLC: (condition 14, gradient a) and then (condition 15, gradient a), to give 1-cyclopropyl-5-((2R,4S)-4-(4,5-diamino-6-(3-(trifluoromethyl)bis(1.1.1)pentan-1-yl)pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Int-C36, 72 mg, 0.16 mmol, 25% yield). ESI-MS : [M+H] ⁺ = 462.3. ¹ H NMR (CD ₃ OD, 400 MHz): δ 7.53-7.56 (2H, m), 6.51 (1H, d, J = 9.1 Hz), 4.30 (1H, d, J = 11.3 Hz), 4.15 (1H, dd, J = 11.4, 4.3 Hz), 3.68 (1H, dd, J = 12.7, 11.0 Hz), 2.90-2.96 (1H, m), 2.43 (6H, s), 1.88-1.96 (2H, m), 1.76-1.84 (2H, m), 1.11 (2H, d, J = 7.3 Hz), 0.89 (2H, s).

Method Int 85. Intermediate Int-C37: 2-chloro-6-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidin-4,5-diamine

Iron (2.5 equivalents, 0.42 g, 7.5 mmol) was added to a stirred solution of 2-chloro-5-nitro-6-(3-(trifluoromethyl)biscyclo[1.1.1]pentan-1-yl)pyrimidin-4-amine (1 equivalent, 0.93 g, 3.0 mmol) in acetic acid (8.0 mL). The reaction mixture was stirred at room temperature for 16 h, then filtered through a diatomaceous earth bed and washed with toluene (50 mL). The filtrate was concentrated under reduced pressure and reduced in EtOAc (50 mL) and _H₂O (50 mL). The pH of the aqueous layer was adjusted to pH = 8 using saturated _NaHCO3 (aq), and the two-phase system was filtered through diatomaceous earth and washed with EtOAc (50 mL) and _H2O (50 mL). The aqueous layer was separated and extracted three times with EtOAc (50 mL). The combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure to give solid 2-chloro-6-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimidine-4,5-diamine (Int-C37, 0.83 g, 2.98 mmol, 99% yield). ESI-MS : [M+H] ⁺ = 279.2. ¹ H NMR (400 MHz, CDCl ₃ ): δ 2.44 (6H, s).

Method Int 86. Intermediate Int-C38: 2-chloro-N- ⁵ -methyl-6-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidin-4,5-diamine

Iodomethane (1.3 equivalents, 0.13 mL, 2.02 mmol) was added to a stirred solution of 2-chloro-6-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)pyrimidine-4,5-diamine (Int-C37, 1 equivalent, 433 mg, 1.55 mmol) and potassium carbonate (1.2 equivalents, 258 mg, 1.86 mmol) in anhydrous DMF (4 mL). The reaction mixture was stirred at 80 °C for 36 h, then cooled to room temperature and diluted with EtOAc (100 mL). The resulting solution was washed with 50% saturated _NaHCO3 (aq) and then washed three times with brine. _The organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure. The crude mixture was purified by rapid silica gel column chromatography with a dissolution gradient of 10–50% EtOAc/hexane to give solid 2-chloro-N- ^5- methyl-6-(3-(trifluoromethyl)biscyclic[1.1.1]pentan-1-yl)pyrimidine-4,5-diamine (Int-C38, 130 mg, 0.44 mmol, 29% yield). ESI-MS : [M+H] ^⁺ = 293.1. ^¹H NMR (400 MHz, _CDCl₃ ): δ 2.59 (3H, s), 2.43 (6H, s).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C43 Int-C42 Modified : The reaction was carried out at room temperature with 2 equivalents of MeI and _K₂CO₃ for 2 h. The resulting residue was purified by rapid chromatography (6 g _SiO₂ column) using a dissolution gradient of 0-10% MeOH/ _DCM to give an oily (2R,4S)-2-(1-methoxy-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-carboxylate (Int-C43, 20 mg, 0.075 mmol, 26% yield). ESI-MS : [M+H] ^⁺ = 268.2 (obs). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.53 (d, J = 2.3 Hz, 1H), 7.28 (dd, J = 9.4, 2.5 Hz, 1H), 6.64 (d, J = 9.4 Hz, 1H), 4.17-4.09 (m, 2H), 4.04 (s, 3H), 3.68 (s, 3H), 3.55 (td, J = 12.1, 2.4 Hz, 1H), 2.65 (tt, J = 12.4, 3.8 Hz, 1H), 2.11-2.05 (m, 1H), 1.89 (ddd, J = 13.6, 3.9, 2.1 Hz, 1H), 1.74 (ddd, J = 25.4, 12.9, 4.8 Hz, 1H), 1.60 (q, J = 12.5 Hz, 1H). Int-D13 Int-D12 Modification : _{The reaction was carried out at 55 °C in MeCN solvent with 1.67 equivalents of MeI and 2.5 equivalents of K₂CO₃ for} 16 h, followed by filtration through diatomaceous earth and depressurization concentration. The crude material was purified by rapid chromatography (80 g _SiO₂ column) using a dissolution gradient of 10-70% EtOAc:EtOH (3:1)/hexane to obtain 6-chloro-2,3-dimethyl-pyrimidino[5,4-d]pyrimidin-4-one (Int-D13, 1.37 g, 6.5 mmol, 83% yield) as powder. ¹ H NMR (CDCl ₃ , 400 MHz): δ 9.12 (s, 1H), 3.69 (s, 3H), 2.68 (s, 3H). ESI-MS : [M+H] ⁺ = 211.1. Int-D28 Int-D27 Modified : The reaction was carried out at 50 °C with 3 equivalents of MeI and 2 _equivalents of _K₂CO₃ for 2 h. The crude material was purified by column chromatography (gradient dissolution of hexane/EtOAc = 5:1 to 0:1) to give ethyl 1,6-dimethyl-3-nitro-2-sideoxy-pyridine-4-carboxylate as a solid (Int-D28, 11.00 g, 45.8 mmol, 83% yield). LCMS : [M+H] ^⁺ = 241.1. ¹ H NMR (400 MHz, CD ₃ OD) δ 6.62 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.66 (s, 3H), 2.56 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H)

Method Int 87. Intermediate Int-C39: 2-chloro-N,N,7-trimethyl-6-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)-7H-purine-8-amine

Add dichloromethylene(dimethyl)ammonium chloride (1.2 equivalents, 87 mg, 0.533 mmol) and DIPEA (3 equivalents, 0.23 mL, 1.33 mmol) to a stirred solution of 2-chloro-N- ⁵ -methyl-6-(3-(trifluoromethyl)biscyclo[1.1.1]pent-1-yl)pyrimidin-4,5-diamine (Int-C38, 1 equivalent, 130 mg, 0.44 mmol) in anhydrous DCE (4.0 mL) at room temperature. The reaction mixture was heated to 85 °C for 2 h, then cooled to room temperature and diluted with EtOAc. The resulting solution was washed with saturated ammonium chloride (aq) followed by brine. _The organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure. The crude mixture was purified by rapid silica gel column chromatography using a 40–100% EtOAc/hexane dissolution gradient to give solid 2-chloro-N,N,7-trimethyl-6-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)-7H-purin-8-amine (Int-C39, 140 mg, 0.41 mmol, 91% yield). ESI-MS : [M+H] ^⁺ = 346.1. ¹ H NMR (CDCl ₃ , 400 MHz): δ 3.71 (3H, s), 3.19 (6H, s), 2.51 (6H, s).

Method Int 88. Intermediate Int-C41: ( 2R , 4S )-2-(6-benzyloxy-1-oxono-pyridin-1-cation-3-yl)tetrahydropiperan-4-carboxylic acid methyl ester

(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-carboxylate (1 equivalent, 1.0 g, 3.1 mmol) and anhydrous DCM (20 mL) were added to a flame-dried 100 mL round-bottom flask equipped with a Teflon-coated magnetic stir bar. Then, mCPBA (2.5 equivalent, 1.6 g, 7.6 mmol) was added at 0 °C under argon atmosphere, and the reaction mixture was stirred at room temperature for 16 h. _CaCO₃ (4 equivalent, 1.23 g, 12.3 mmol) was added to the suspension, and the reaction mixture was stirred for 10 min, then filtered through a sintered funnel and rinsed with DCM. The resulting residue was purified by rapid chromatography (120 g _SiO2 column, using a dissolution gradient of 0.5–10% MeOH/DCM, solid-supported) to give solid (2R,4S)-2-(6-benzyloxy-1-oxono-pyridin-1-cation-3-yl)tetrahydropiperan-4-carboxylate (Int-C41, 412 mg, 1.2 mmol, 39% yield). ESI-MS : [M+H] ⁺ = 344.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.31 (d, J = 2.1 Hz, 1H), 7.45-7.33 (m, 5H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 5.43 (s, 2H), 4.25 (dd, J = 11.5, 1.9 Hz, 1H), 4.18 (ddd, J = 11.7, 4.6, 1.3 Hz, 1H), 3.67-3.70 (3H), 3.57 (td, J = 12.1, 2.2 Hz, 1H), 2.69 (tt, J = 12.3, 3.8 Hz, 1H), 2.12-2.06 (m, 1H), 1.91 (dd, J = 13.5, 1.8 Hz, 1H), 1.76 (ddd, J = 25.9, 12.5, 4.6 Hz, 1H), 1.60 (q, J = 12.4 Hz, 1H).

Method Int 89. Intermediate Int-C44: (2R,4S)-2-(1-methoxy-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-carboxylic acid

A 1:1 mixture (2 mL) of (2R,4S)-2-(1-methoxy-6-epoxy-3-pyridyl)tetrahydropiperan-4-carboxylate (Int-C43, 1 equivalent, 48 mg, 0.18 mmol) and THF/MeOH was placed in a vial equipped with a Teflon-coated stirring rod. LiOH (2.5 equivalent, 11 mg, 0.45 mmol) was added, followed by water (0.2 mL), and the reaction mixture was stirred at room temperature for 16 h. After cooling to 0 °C, 1 N HCl (aq.) was added until pH = 4 was obtained. Next, the organic phase was extracted with EtOAc (3 × 10 mL), combined, washed with brine (30 mL ₎ , dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to give (2R,4S)-2-(1-methoxy-6-sideoxy-3-pyridyl)tetrahydropiperan-4-carboxylic acid (Int-C44, 28 mg, 0.11 mmol, 61% yield) as a solid. ESI-MS : [M+H] ⁺ 254.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.58 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 9.4, 2.5 Hz, 1H), 6.73 (d, J = 9.4 Hz, 1H), 4.20-4.14 (m, 2H), 4.07 (s, 3H), 3.59 (td, J = 12.0, 2.0 Hz, 1H), 2.74-2.68 (m, 1H), 2.14 (d, J = 13.0 Hz, 1H), 1.97-1.94 (m, 1H), 1.78 (dd, J = 13.0, 4.6 Hz, 1H), 1.63 (q, J = 12.3 Hz, 1H).

Method Int 90. Intermediate Int-C49: 3-[6-amino-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] [Lin-4-yl]-5-nitro-pyrimidin-4-yl]bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester

3-[6-amino-2-[(2R,6S)-2-methyl-6-(6-sideoxy-1H-pyridin-3-yl)] A mixture of methyl 1-pentane-1-carboxylate [1.1.1]-5-nitro-pyrimidin-4-yl]bicyclo[1.1.1]-1-pentane (Int-C48, 1 equivalent, 438 mg, 0.96 mmol), methyl iodomethane (2 equivalents, 0.12 mL, 1.92 mmol), and cesium carbonate (3 equivalents, 938 mg, 2.88 mmol) was stirred in THF (10 mL) at 50 °C for 2 h. The reaction mixture was quenched with water and extracted three times with DCM. The combined organic layers were washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure to give 3-[6-amino-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl] Methyl 1-pentane-1-carboxylate [1.1.1]-lin-4-yl]-5-nitro-pyrimidin-4-yl]bicyclo[1.1.1]-carboxylate (Int-C49, 451 mg, 0.96 mmol, 99% yield), used without further purification. ESI-MS : [M+H] ⁺ = 471.4.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-E19 Int-E18 The crude material was purified by rapid chromatography using a 0-20% MeOH/DCM dissolution gradient to give solid methyl 4-(2,4-difluorophenyl)-7-methyl-2-((2R,4S)-2-(1-methyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)pyrido[2,3-d]pyrimidin-6-carboxylate (Int-E19, 35 mg, 0.07 mmol, 50% yield). ESI-MS : [M+H] ⁺ = 507.3. Int-E32 Int-E31 The crude reaction mixture was purified by rapid column chromatography (40 g _SiO2 column) using a dissolution gradient of 1–10% MeOH/DCM to give a foamy 5-[(2R,4S)-4-[6-bromo-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]-1-methylpyridin-2-one (Int-E32, 164 mg, 0.30 mmol, 78% yield). ESI-MS : [M+H] ⁺ = 549.1.

Method Int 91. Intermediate Int-C50: 3-[6-amino-2-[( 2R , 6S )-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] [1.1.1]pentane-1-methylamine

3-[6-amino-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] Methyl 1-pentane-1-carboxylate [1.1.1]-5-nitro-pyrimidin-4-yl]bicyclo[1.1.1]pentane-1-carboxylate (Int-C49, 1 equivalent, 465 mg, 0.99 mmol) was stirred for 2 days in a solution of 7.0 M ammonia (28 equivalents, 4.0 mL, 27.7 mmol) in methanol. The reaction mixture was concentrated under reduced pressure to give 3-[6-amino-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] [1.1.1]pentane-1-methamide (Int-C50, 445 mg, 0.98 mmol, 99% yield), used without further purification. ESI-MS : [M+H] ⁺ = 456.3.

Method Int 92. Intermediate Int-C51: 3-[6-amino-2-[( 2R , 6S )-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] [1.1.1]pentane-1-methylamine

3-[6-amino-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] A mixture of lin-4-yl]-5-nitro-pyrimidin-4-yl]bicyclo[1.1.1]pentane-1-carbamate (Int-C50, 1 equivalent, 445 mg, 0.98 mmol), ammonium formate (8 equivalent, 493 mg, 7.82 mmol), and zinc (8 equivalent, 511 mg, 7.82 mmol) was stirred at 0°C for 1 hour. The reaction mixture was filtered through a diatomaceous earth mat and concentrated under reduced pressure to give 3-[5,6-diamino-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] [Lin-4-yl]pyrimidin-4-yl]bicyclo[1.1.1]pentane-1-methamide (Int-C51, 415 mg, 0.98 mmol, 99% yield), used without further purification. ESI-MS : [M+H] ⁺ = 426.4.

Method Int 93. Intermediate Int-D1: (2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-carboxylic acid methyl ester

A solution of (2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-carboxylic acid (1 equivalent, 4.0 g, 12.8 mmol), MeOH (2 equivalents, 1.0 mL, 25.5 mmol), and DMAP (0.2 equivalents, 312 mg, 2.6 mmol) in DCM (35 mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with 25 mL of 10% citric acid (aq.) and then extracted with DCM (3 × 50 mL). The combined organic phases were washed with water and brine, dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to give methyl (2R,4S)-2-(6-benzoxy-3-pyridyl)tetrahydropiperan-4-carboxylate as a solid (Int-D1, 4.1 g, 12.4 mmol, 96% yield). ESI-MS : 328.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.11 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 8.6, 2.4 Hz, 1H), 7.44 (d, J = 7.1 Hz, 2H), 7.37-7.27 (m, 3H), 6.78 (d, J = 8.5 Hz, 1H), 5.36 (s, 2H), 4.31 (dd, J = 11.4, 2.1 Hz, 1H), 4.18 (ddd, J = 11.6, 4.5, 1.5 Hz, 1H), 4.11 (q, J = 7.2 Hz, 1H), 3.69 (s, 3H), 3.60 (td, J = 12.0, 2.5 Hz, 1H), 2.70 (qd, J = 8.1, 4.0 Hz, 1H), 2.10-2.05 (m, 1H), 1.92-1.67 (m, 3H), 1.25 (t, J = 7.1 Hz, 1H).

Method Int 94. Intermediate Int-D2: (2R,4S)-2-(1-amino-6-sideoxy-3-pyridyl)tetrahydropiperan-4-carboxylic acid methyl ester

(2R,4S)-2-(6-sideoxy-1H-pyridin-3-yl)tetrahydropiperan-4-carboxylate (Int-D2, 1 equivalent, 6.6 g, 27.9 mmol) was added to a 250 mL round-bottom flask equipped with a Teflon-coated stirring rod, and then cooled to 0°C. DMF (139 mL) was added, followed by cesium carbonate (3 equivalents, 27.3 g, 83.7 mmol) and o-biphenylphosphohydroxyamine (2 equivalents, 13.0 g, 55.8 mmol). The reaction mixture was stirred at room temperature under argon for 16 h, concentrated under reduced pressure, restored in DCM, filtered through a diatomaceous earth mat, and washed with 350 mL of DCM. The filtrate was concentrated under reduced pressure to approximately 40 mL. Saturated _NaHCO3 (aq.) (50 mL) was added, the layers were separated, and the aqueous phase was extracted with DCM (5 × 130 mL). The organic phases were combined, washed with brine (70 mL), dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to give solid (2R,4S)-2-(1-amino-6-sideoxy-3-pyridyl)tetrahydropiperan-4-carboxylate (Int-D3, 6.6 g, 24.7 mmol, 88% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.61 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 9.4, 2.5 Hz, 1H), 6.61 (d, J = 9.4 Hz, 1H), 5.15 (s, 2H), 4.18-4.09 (m, 2H), 3.70 (s, 3H), 3.57 (td, J = 12.1, 2.2 Hz, 1H), 2.67 (tt, J = 12.2, 3.8 Hz, 1H), 2.07 (dt, J = 13.3, 1.8 Hz, 1H), 1.92-1.88 (m, 1H), 1.76 (ddd, J = 25.8, 12.5, 4.6 Hz, 1H), 1.64 (dd, J = 25.2, 12.1 Hz, 1H). ESI-MS : [M+H] ⁺ = 253.2.

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-D43 Example 224 The procedure yielded a gel-like 1-amino-5-[(2R,4S)-4-[4-(4,4-difluorocyclohexyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Int-D43, 500 mg, 1.06 mmol, 97% yield). LCMS : [M+H] ⁺ = 471.2.

Method Int 95. Intermediate Int-D4: (2R,4S)-2-[1-(diallylamino)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-carboxylic acid methyl ester

To a reaction vial, add methyl (2R,4S)-2-(1-amino-6-sideoxy-3-pyridyl)tetrahydropiperan-4-carboxylate (Int-D3, 1 equivalent, 2.8 g, 11.1 mmol), MeCN (40 mL), and allyl bromide (3 equivalents, 2.9 mL, 33.4 mmol). Seal the vial, purge with argon, and heat at 90°C for 18 h. Add another portion of allyl bromide (2 equivalents, 2.0 mL, 23.0 mmol), and stir the vial at 90°C for another 5 h. Filter the reaction mixture through a diatomaceous earth mat, wash with MeCN, and concentrate the filtrate under reduced pressure. The resulting solid was purified by rapid chromatography (120 g _SiO2 column) using a dissolution gradient of 25–80% EtOAc/hexane to give (2R,4S)-2-[1-(diallylamino)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-carboxylate (Int-D4, 1.98 g, 5.9 mmol, 53% yield) as a solid. ESI-MS : [M+H] ⁺ = 333.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.27 (d, J = 2.5 Hz, 1H), 6.48-6.46 (m, 1H), 5.77 (dd, J = 17.0, 10.2 Hz, 2H), 5.18 (dd, J = 17.2, 1.4 Hz, 2H), 5.05 (d, J = 9.8 Hz, 2H), 4.16-4.10 (m, 3H), 4.04 (dd, J = 11.4, 1.8 Hz, 1H), 3.77-3.73 (m, 2H), 3.70 (s, 3H), 3.55 (td, J = 12.0, 2.3 Hz, 1H), 2.65 (tt, J = 12.3, 3.9 Hz, 1H), 2.01 (dt, J = 13.3, 1.7 Hz, 1H), 1.87-1.77 (m, 2H), 1.62 (t, J = 12.5 Hz, 1H).

Method Int 96. Intermediate Int-D5: ( 2R , 4S )-2-[1-(2,5-dihydropyrrolo-1-yl)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-carboxylic acid methyl ester

At 40 °C, the second-generation Hoveyda-Grubbs catalyst (0.02 equivalents, 15 mg, 0.0235 mmol) was added to a stirred solution of (2R,4S)-2-[1-(diallylamino)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-carboxylate (Int-D4, 1 equivalent, 665 mg, 2.0 mmol) in DCM (20 mL), and the resulting green reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was then treated with 150 mg of silicone, stirred at room temperature for 30 min, filtered through a diatomaceous earth mat, and washed with DCM. The filtrate was concentrated under reduced pressure onto diatomaceous earth (9 g) and purified by rapid column chromatography (80 g _SiO2 column) using a dissolution gradient of 1–10% MeOH/DCM to give solid (2R,4S)-2-[1-(2,5-dihydropyrrolo-1-yl)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-carboxylate (Int-D5, 483 mg, 1.6 mmol, 79% yield). ESI-MS : [M+H] ⁺ = 305.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.53 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 9.5, 2.6 Hz, 1H), 6.58 (d, J = 9.6 Hz, 1H), 5.82 (s, 2H), 4.18 (s, 4H), 4.09 (dd, J = 11.5, 2.4 Hz, 1H), 3.74 (d, J = 6.6 Hz, 1H), 3.70 (s, 3H), 3.60-3.54 (m, 1H), 2.71-2.63 (m, 1H), 2.04-2.12 (1H), 1.88-1.67 (m, 3H).

Method Int 97. Intermediate Int-D7: (2R,4S)-2-(6-side-oxy-1-pyrrolidin-1-yl-3-pyridinyl)tetrahydropiperan-4-carboxylic acid

A solution of lithium hydroxide (2.1 equivalents, 40 mg, 1.7 mmol) in water (0.5 mL) was added to a solution of (2R,4S)-2-(6-sideoxy-1-pyrrolidin-1-yl-3-pyridinyl)tetrahydropiperan-4-carboxylate (Int-D6, 1 equivalent, 240 mg, 0.78 mmol) in MeOH (2 mL). The reaction mixture was stirred at 55 °C for 16 h, then dissolved in water, acidified with 1N HCl (aq.) until pH=2, and extracted four times with EtOAc. The combined organic phases were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under reduced pressure to give (2R,4S)-2-(6-sideoxy-1-pyrrolidin-1-yl-3-pyridinyl)tetrahydropiperan-4-carboxylic acid (Int-D6, 186 mg, 0.64 mmol, 81% yield) as a solid. ESI-MS : [M+H] ^⁺ = 293.3. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.83-12.36 (1H), 7.53 (d, J = 2.5 Hz, 1H), 7.39 (dd, J = 9.4, 2.5 Hz, 1H), 6.37 (d, J = 9.4 Hz, 1H), 4.11 (d, J = 9.8 Hz, 1H), 3.96 (dd, J = 11.0, 3.9 Hz, 1H), 3.47-3.42 (m, 1H), 3.26 (d, J = 8.2 Hz, -3H), 2.64-2.55 (m, 1H), 1.95-1.73 (m, 5H), 1.51-1.37 (m, 2H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-C43 Int-C42 Modified : The reaction was carried out with 5 equivalents of LiOH at 40 °C for 1 h to give (2R,4S)-2-[1-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-6-sideoxy-3-pyridinyl]tetrahydropiperan-4-carboxylic acid in solid form (Int-C43, 44 mg, 0.13 mmol, 99% yield). ESI-MS : [M+H] ⁺ = 341.2.

Method Int 98. Intermediate Int-D9: (2R,4S)-2-[1-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-carboxylic acid methyl ester

Under a nitrogen atmosphere, sodium iodide (0.4 equivalents, 39 mg, 0.26 mmol) was added to a solution of (2R,4S)-2-[1-(2,5-dihydropyrrolo-1-yl)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-carboxylate (Int-D5, 1 equivalent, 200 mg, 0.66 mmol) in anhydrous THF (5 mL). The reaction mixture was refluxed and allowed to stand for 24 h, followed by the addition of five parts of trimethyl(trifluoromethyl)silane (3.5 equivalents, 340 µL, 2.3 mmol). The reaction mixture was concentrated under reduced pressure and purified by rapid chromatography (24 g _SiO2 column) using a dissolution gradient of 10-60% EtOAc:EtOH (3:1)/hexane to give solid (2R,4S)-2-[1-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-6-sideoxy-3-pyridinyl]tetrahydropiperan-4-carboxylate (Int-D9, 105 mg, 0.15 mmol, 22% yield). ESI-MS : [M+H] ⁺ = 355.3.

Method Int 99. Intermediate Int-D12: 6-chloro-2-methyl- 1H -pyrimidino[5,4- d ]pyrimidin-4-one hydrochloride

Add ethyl 5-amino-2-chloro-pyrimidin-4-carboxylate (1 equivalent, 2.0 g, 9.9 mmol) to a vial in HCl (in 1,4-diethylcarboxylate). A solution was prepared in 4 M alkane (6.1 equivalents, 15 mL, 60.0 mmol) and in MeCN (6 equivalents, 3.1 mL, 59.4 mmol). The reaction mixture was sealed, stirred at 80 °C for 4 h, cooled to room temperature, and filtered. The solid was washed with MeCN and dried under high vacuum to give a solid hydrochloride of 6-chloro-2-methyl-1H-pyrimidino[5,4-d]pyrimidin-4-one (Int-D12, 2.35 g, 10.1 mmol, 100% yield). ESI-MS : [M+H] ⁺ = 197.0.

Method Int 100. Intermediate Int-D14: 6-chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrimidino[5,4-d]pyrimidin-4-one

Ir[dF( _CF3 )ppy] ₂ (dtbbpy) _PF6 (0.005 equivalent, 28 mg, 0.026 mmol), ammonium persulfate (2 equivalent, 2.32 g, 10.2 mmol), 6-chloro-2,3-dimethyl-pyrimidino[5,4-d]pyrimidin-4-one (Int-D13, 1 equivalent, 1.07 g, 5.1 mmol), and 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (5 equivalent, 4.58 g, 25.4 mmol) were added to a reaction vial equipped with a Teflon-coated magnetic stir bar. The vial was sealed, purged three times with argon, and anhydrous DMSO (28 mL) was added. The reactants were placed in a Penn PhD photoreactor M2 and irradiated at 450 nm for 2 h. The reaction mixture was then diluted with DCM, washed with saturated _NaHCO3 (aq.), and the aqueous phase was extracted twice with DCM. The combined organic phase was washed with brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid chromatography (40 g _SiO2 column) using a dissolution gradient of 2-65% EtOAc:EtOH (3:1)/hexane to give 6-chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-biscyclic[1.1.1]pentyl]pyrimidino[5,4-d]pyrimidin-4-one (Int-D14, 373 mg, 1

Method Int 101. Intermediate Int-D18: 2,4,6-trichloro-5-(1,3-dioxanecyclopentan-2-yl)pyrimidine

TsOH (0.2 equivalent, 4.07 g, 23.6 mmol) was added to a solution of 2,4,6-trichloropyrimidin-5-carboxaldehyde (1 equivalent, 25.0 g, 118 mmol) and ethane-1,2-diol (3 equivalents, 20 mL, 355 mmol) in toluene (250 mL). The mixture was stirred at 120 °C for 12 h, concentrated under reduced pressure, and purified by a silicone column (PE/EtOAc = 5:1, _Rf = 0.4) to give an oily 2,4,6-trichloro-5-(1,3-dioxanecyclopentan-2-yl)pyrimidine (19.00 g, 74.4 mmol, 63% yield). LCMS : [M+H] ⁺ = 254.9.

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.04-4.16 (m, 2H) 4.27-4.36 (m, 2H) 6.32 (s, 1H).

Method Int 102. Intermediate Int-D-19: 2,4-Dichloro-5-(1,3-dioxanecyclopentan-2-yl)-6-(1-ethoxyvinyl)pyrimidine

Tributyl(1-ethoxyvinyl)sinane (1 equivalent, 25 mL, 74.4 mmol) and Pd(PPh3)2Cl2 (0.1 equivalent, 5220 mg, 7.44 mmol) were added to a mixture of 2,4,6-trichloro-5-(1,3-dioxanecyclopentan- ₂ -yl)pyrimidine ( _Int -D18, 1 equivalent, 19.0 g, 74.4 mmol) in _DMF (200 mL). The reaction flask was degassed and refilled with _N2 , and this process was repeated three times. The mixture was stirred at 80 °C for 2 h. The mixture was cooled to 25 °C, added to saturated KF (aq., 800 mL), and stirred at 25 °C for 2 h. The mixture was extracted with ethyl acetate (500 mL × 3), washed with saturated brine (500 mL), and dried ( _Na₂SO₄ ), then concentrated to dryness. The residue was purified by passing it through a silicone column (PE/EtOAc = 5:1, _Rf = 0.4) to give _an oily 2,4-dichloro-5-(1,3-dioxanecyclopentan-2-yl)-6-(1-ethoxyvinyl)pyrimidine (Int-D19, 16.0 g, 45.4 mmol, 61% yield). LCMS : [M+H]⁺ = 291.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38 (t, J=7.0 Hz, 3H) 3.88 - 3.98 (m, 2H) 3.99 - 4.08 (m, 2H) 4.24 - 4.33 (m, 2H) 4.59 (d, J=3.1 Hz, 1H) 4.67 - 4.70 (m, 1H) 6.11 (s, 1H).

Method Int 103. Intermediate Int-D20: Ethyl 2,6-dichloro-5-(1,3-dioxanepentan-2-yl)pyrimidine-4-carboxylate

Add 2,4-dichloro-5-(1,3-dioxacyclopentan-2-yl)-6-(1-ethoxyvinyl)pyrimidine (Int-D19, 1 equivalent, 13.0 g, 36.9 mmol) to a solution of sodium periodate (2 equivalents, 15.78 g, 73.8 mmol) in water (75 mL) A solution was prepared in alkyl (150 mL). Potassium permanganate (0.4 equivalent, 2.33 g, 14.8 mmol) was then slowly added to the mixture at 40–50 °C. The mixture was stirred at 25 °C for 2 hours, then added to water (500 mL) and extracted with EtOAc (300 mL × 3). The organic phase was concentrated under vacuum to obtain a crude product. The crude product was purified by a silicone column (PE/EtOAc = 5:1, _Rf = 0.4) to give an oily ethyl 2,6-dichloro-5-(1,3-dioxanecyclopentan-2-yl)pyrimidine-4-carboxylate (Int-D20, 6.00 g, 20.5 mmol, 56% yield). LCMS : [M+H] ⁺ = 292.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38 - 1.43 (m, 3H) 4.00 - 4.07 (m, 4H) 4.41 (q, J=7.2 Hz, 2H) 6.16 (s, 1H).

Method Int 104. Intermediate Int-D21: Ethyl 2-chloro-5-(1,3-dioxanecyclopentan-2-yl)-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-4-carboxylate

Under N2 _conditions , ethyl 2,6-dichloro-5-(1,3-dioxanepentan-2-yl)pyrimidin-4-carboxylate (Int-D20, 1 equivalent, 700 mg, 2.39 mmol) and [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (0.95 equivalent, 472 mg, 2.27 mmol) were reacted in a 1,4-dichloro-5-(1,3-dioxanepentan-2-yl)pyrimidin-4-carboxylate solution. _K₃PO₄ (2 _equivalents , 1013 mg, 4.78 mmol) and Pd(dppf) _Cl₂ ·DCM (0.1 equivalents, 175 mg, 0.239 mmol) were added to a solution of alkane (7 mL) and water (0.70 mL). The mixture was stirred at 60 °C for 2 hours, added to water (60 mL), and then extracted with ethyl acetate (30 mL × 3). The organic phase was washed with a saturated brine solution (30 mL). The organic matter was then separated and dried ( _{Na₂SO₄ )} , and then concentrated to dryness. The crude material was then purified by preparative HPLC (~60% ACN/0.1% FA (aq.)) to give ethyl 2-chloro-5-(1,3-dioxanecyclopentan-2-yl)-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidine-4-carboxylate as a solid (620 mg, 1.47 mmol, 62% yield). LCMS : [M+H] ⁺ = 420.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.44 (t, J=7.2 Hz, 3H) 3.79 - 3.90 (m, 4H) 4.47 (q, J=7.1 Hz, 2H) 5.97 (s, 1H) 7.47 (d, J=9.4 Hz, 1H) 7.53 - 7.59 (m, 1H) 7.63 - 7.70 (m, 1H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-D33 Int-D32 Modified : The reaction was carried out at 40 °C with (2,4-difluorophenyl)boric acid for 1 h. The crude reaction product was purified by column chromatography (gradient dissolution of hexane/EtOAc = 1:1 to 0:1) to give solid 2-chloro-4-(2,4-difluorophenyl)-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one (Int-D33, 330 mg, 1.03 mmol, 83% yield). LCMS : [M+H] ⁺ = 322.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (q, J = 7.8 Hz, 1H), 7.61 - 7.51 (m, 1H), 7.36 (br t, J = 7.9 Hz, 1H), 6.27 (br s, 1H), 3.56 (s, 3H), 2.43 (s, 3H) Int-D36 Int-D32 Modified : The reaction was carried out at 40 °C with [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid for 1 h. The crude reaction product was purified by column chromatography (gradient dissolution of hexane/EtOAc = 1:0 to 0:1) to give 2-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one (Int-D36, 650 mg, 1.75 mmol, 66% yield) as a solid. LCMS : [M+H] ⁺ = 372.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (d, J = 9.9 Hz, 1H), 7.91 - 7.82 (m, 2H), 6.30 (d, J = 2.1 Hz, 1H), 3.56 (s, 3H), 2.43 (s, 3H). Int-E45 Modification : The reaction was carried out using 2 _equivalents of K₂CO₃ instead of _K₃PO₄ , and purified by reversed-phase HPLC to give a solid 6-chloro-4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Int-E45, 383 mg, 1.11 mmol, 48% yield). ESI-MS : [M+H] ^⁺ = 345.0. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.83 (br s, 2H), 7.63–7.46 (m, 2H), 4.57–4.37 (m, 2H), 3.23 (s, 3H).

Method Int 105. Intermediate Int-D22: 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- [Lin-4-yl]-5-(1,3-dioxanecyclopentan-2-yl)-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-carboxylic acid ethyl ester

Ethyl 2-chloro-5-(1,3-dioxacyclopentan-2-yl)-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-carboxylate (Int-D21, 1 equivalent, 250 mg, 0.594 mmol) and (2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl- Phospholine (1.1 equivalent, 186 mg, 0.654 mmol) in 1,4-dioxanone _K₃PO₄ (2 equivalents, 252 mg, 1.19 mmol) was added to a solution of alkane (5 _mL ), and the mixture was stirred at 100 °C for 1 hour. The reaction solution was added to water (30 mL), and then extracted with ethyl acetate (10 mL × 2). The organic matter was washed with 10 mL of saturated saline solution, separated, dried _{over Na₂SO₄} , and concentrated under reduced pressure to dryness. The crude material was then purified by passing it through a silicone column (PE/EtOAc = 3:1, _Rf = 0.6) to give 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- Ethyl pyrimidin-4-carboxylate [-4-yl]-5-(1,3-dioxanecyclopentan-2-yl)-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-carboxylate (Int-D22, 360 mg, 0.538 mmol, 91% yield). LCMS [M+H] ⁺ = 669.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.31 (br d, J=6.1 Hz, 3H) 1.42 (t, J=7.1 Hz, 3H) 2.70 - 2.81 (m, 1H) 2.90 (br t, J=12.2 Hz, 1H) 3.82 (s, 4H) 4.42 (q, J=7.1 Hz, 2H) 4.53 (br d, J=9.5 Hz, 1H) 4.66 - 4.83 (m, 2H) 5.39 (s, 2H) 5.68 (s, 1H) 6.82 (d, J=8.6 Hz, 1H) 7.29 - 7.34 (m, 1H) 7.35 - 7.47 (m, 5H) 7.48 - 7.53 (m, 1H) 7.55 - 7.61 (m, 1H) 7.66 - 7.73 (m, 1H) 8.20 (s, 1H).

Method Int 106. Intermediate Int-D23: 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- [Lin-4-yl]-6-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methoxypyrimidin-4-carboxylic acid ethyl ester

To 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- Ethyl 2-[(2S,6R)-5-(1,3-dioxanepentan-2-yl)-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-carboxylate (Int-D22, 1 equivalent, 360 mg, 0.538 mmol) was added to a solution in acetone (6 mL) with TsOH (0.2 equivalent, 19 mg, 0.108 mmol), and the mixture was stirred at 60 °C for 1 h. The reaction solution was concentrated under vacuum to obtain a solid 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- Ethyl lin-4-yl]-6-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methoxy-pyrimidin-4-carboxylate (Int-D23, 330 mg, 0.528 mmol, 98% yield). LCMS : [M+H] ⁺ = 625.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.35 (br dd, J=11.9, 6.2 Hz, 3H) 1.40 - 1.48 (m, 3H) 2.81 - 3.04 (m, 2H) 3.83 (br dd, J=6.6, 3.5 Hz, 1H) 4.46 - 4.65 (m, 3H) 4.80 - 5.08 (m, 2H) 5.45 (br d, J=7.9 Hz, 2H) 6.91 - 6.98 (m, 1H) 7.34 - 7.52 (m, 6H) 7.57 - 7.71 (m, 2H) 7.85 (d, J=8.3 Hz, 1H) 8.38 (br d, J=4.9 Hz, 1H) 9.69 (d, J=3.8 Hz, 1H).

Method Int 107. Intermediate Int-D24: 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- [Lin-4-yl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7H-pyrimidino[4,5-d]tadalafil] -8-keto

To 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- Ethyl lin-4-yl]-6-[2-fluoro-4-(trifluoromethyl)phenyl]-5-methylpyrimidin-4-carboxylate (Int-D23, 1 equivalent, 330 mg, 0.528 mmol) in 1,4-di _N₂H₄ · _H₂O (2 equivalents, 56 _mg , 1.06 mmol) was added to the mixture in alkane (6 mL), and the mixture was stirred at 90 °C for 2 hours. The reaction solution was added to water (20 mL) and extracted with EtOAc (20 mL × ₃ ). The organic matter was washed with 20 mL of saturated saline solution. The organic matter was then separated and dried ( _Na₂SO₄ ), and then concentrated to dryness. The crude material was purified by passing it through a silicone column (PE/EtOAc = 3/1, _Rf = 0.5) to give 2-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- [Lin-4-yl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7H-pyrimidino[4,5-d]tadalafil] -8-one (Int-D24, 220 mg, 0.371 mmol, 70% yield). LCMS : [M+H] ⁺ = 593.4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.32 - 1.42 (m, 3H) 2.79 - 3.19 (m, 2H) 3.77 - 3.94 (m, 1H) 4.53 - 4.65 (m, 1H) 4.81 - 4.98 (m, 1H) 5.06 - 5.21 (m, 1H) 5.29 - 5.52 (m, 2H) 6.84 (d, J=8.5 Hz, 1H) 7.31 - 7.50 (m, 5H) 7.53 - 7.75 (m, 4H) 7.78 (d, J=3.5 Hz, 1H) 8.16 - 8.37 (m, 1H) 9.97 - 10.21 (m, 1H).

Method Int 108. Intermediate Int-D26: 2-Nitroacetamide

In a sealed tube, a mixture of ethyl 2-nitroacetyl (1 equivalent, 15.00 g, 113 mmol) and _NH₃ • _H₂O (5.32 equivalents, 50 mL, 600 mmol) was stirred at 80 °C for 12 h. The mixture was cooled to 20 °C, poured into water (100 mL), and concentrated to half the initial volume. The mixture was treated with HCl (1 N, 20 mL) to adjust the pH to 1–2, and extracted with EtOAc (300 mL × 6 ₎ . The organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to give 2-nitroacetylamine as a solid (10.00 g, 96.1 mmol, 85% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (br s, 1H), 7.63 (br s, 1H), 5.28 (s, 2H).

Method Int 109. Intermediate Int-D27: 6-Methyl-3-nitro-2-sideoxy-1H-pyridine-4-methylethyl ester

Piperidinium acetate (1 equivalent, 20.00 g, 192 mmol) was added to a mixture of 2-nitroacetamide (1 equivalent, 20.00 g, 192 mmol) and ethyl 2,4-dioxyvalerate (1.1 equivalent, 33.44 g, 211 mmol) in water (300 mL). The mixture was stirred at 40 °C for 12 h, extracted with EtOAc (500 mL × 4), and concentrated under vacuum to obtain a residue. The residue was wet-milled in EtOAc (20 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (hexane/EtOAc gradient dissolution = 1:1 to 0:1) to give ethyl 6-methyl-3-nitro-2-sideoxy-1H-pyridine-4-carboxylate as a solid (Int-D27, 8.00 g, 35.4 mmol, 18% yield). LCMS : [M+H] ⁺ = 227.1. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 13.45 - 12.81 (m, 1H), 6.41 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).

Method Int 110. Intermediate Int-D28: 2,4-Dihydroxy-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one

AcOH (1.5 equivalents, 2470 mg, 41.2 mmol) was added to a suspension of 3-amino-1,6-dimethyl-2-sideoxy-pyridine-4-carboxylic acid (Int-D30, 1 equivalent, 5000 mg, 27.4 mmol) in water (100 mL), and the mixture was stirred at 40 °C for 15 min. Water (30 mL) containing potassium cyanate (2.5 equivalents, 5566 mg, 68.6 mmol) was added dropwise. The mixture was stirred at 40 °C for 1 h and then cooled to 0 °C. NaOH (10 equivalents, 10978 mg, 274 mmol) was added, and the mixture was stirred for 2 h before being heated to 40 °C. Water (50 mL) was added to the mixture, and the pH was adjusted to 7 by adding HCl (aq.). The resulting slurry was filtered, and the filter cake was washed with water (10 mL × 3). The combined filtrates were then concentrated to give 2,4-dihydroxy-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one as a solid (5200 mg, 25.1 mmol, 91% yield). LCMS : [M+H] ⁺ = 208.0. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ = 11.92 - 10.20 (m, 2H), 6.47 (br s, 1H), 3.51 (br s, 3H), 2.37 (br s, 3H).

Method Int 111. Intermediate Int-D32: 2,4-dichloro-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one

Under _N2 at 0°C, DIPEA ( ₁ equivalent, 624 mg, 4.83 mmol) was added to a solution of 2,4-dihydroxy-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one (Int-D31, 1 equivalent, 1000 mg, 4.83 mmol) in POCl3 (24.7 equivalent, 10 mL, 119 mmol). The mixture was stirred under _N2 at 100°C for 1 h and then concentrated under reduced pressure to obtain a residue. EtOAc (20 mL) was added, and the mixture was slowly added to _NaHCO3 (aq., 150 mL) at below 40°C and filtered to obtain a crude starting material (0.7 g). The filtrate was extracted with EtOAc (100 mL × 2). The organic layer was washed with brine (50 mL) and evaporated to give 2,4-dichloro-6,7-dimethyl-pyrido[3,4-d]pyrimidin-8-one as a solid (350 mg, 1.43 mmol, 29.71% yield). LCMS : [M+H] ⁺ = 244.0. ^1H NMR (400 MHz, _CDCl3 ) δ 6.59 (d, J = 0.8 Hz, 1H), 3.68 (s, 3H), 2.53 (d, J = 0.6 Hz, 3H).

Method Int 112. Intermediate Int-D44: 4-chloro-2-methyl-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl) -3(2H)-keto

4-chloro-5-iodo-2-methyl-2-dichloro-5-iodo ... -3-one (1 equivalent, 1.53 g, 5.65 mmol) and N-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-methylamine (Int-E4, 1 equivalent, 2.67 g, 10.0 mmol) were added dropwise to a stirred solution of anhydrous THF (15 mL) with a mixture of isopropyl magnesium chloride and lithium chloride (1.3 equivalent, 13 mL, 13.0 mmol). The reaction mixture was stirred at -5 °C for 1 h, then quenched with saturated _NH4Cl (aq) (2 mL) and heated to room temperature. The reaction mixture was diluted with EtOAc and washed with 5% citric acid (aq) and brine. The organic layer was dried _with anhydrous _Na₂SO₄ , filtered, and concentrated under vacuum. Purification was then achieved by rapid column chromatography using a 5-25% EtOAc/hexane dissolution gradient with _SiO₂ to obtain a solid 4-chloro-2-methyl-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)- -3(2H)-one (Int-D44, 915 mg, 2.98 mmol, 53% yield). ^¹H NMR (400 MHz, _CDCl₃ ): δ 7.51 (s, 1H), 3.86 (s, 3H), 2.37 (s, 6H).

Method Int 113. Intermediate Int-E1: ([4-amino-2-chloro-6-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrimidin-5-yl]methanol

Dibaal-H (25% in toluene) (4 equivalents, 10 mL, 17.8 mmol) was slowly added to a stirred solution of ethyl 4-amino-2-chloro-6-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrimidine-5-carboxylate (1 equivalent, 1.49 g, 4.44 mmol) in THF (14.9 mL) at 0 °C, and the reaction mixture was stirred in an ice bath for 1 h. A saturated aqueous solution of Rochelle salt (50 mL) was added, and the mixture was stirred at room temperature for 1 h. The resulting solution was extracted with EtOAc (3 × 50 mL), washed with brine, dried over _MgSO₄ , and filtered. The filtrate was reduced in pressure and concentrated, and purified by rapid chromatography (Isco RediSep® column 40 g) (5-100% EtOAc/hexane) to give a solid ([4-amino-2-chloro-6-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrimidin-5-yl]methanol (Int-E1, 480 mg, 1.63 mmol, 55% yield). ESI-MS : [M+H] ⁺ = 292.0. ^1H NMR ( _CDCl3 , 400 MHz): δ 5.77 (2H, s), 4.79 (2H, d, = 5.0 Hz), 2.41 (6H, s). ^19F NMR ( _CDCl3 , 376 MHz) MHz): δ -73.2 (3F, s).

Method Int 114. Intermediate Int-E2: 4-amino-2-chloro-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidine-5-carboxaldehyde

Add [4-amino-2-chloro-6-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrimidin-5-yl]methanol (Int-E1, 1 equivalent, 806 mg, 2.74 mmol) and manganese oxide (IV) (20 equivalents, 4.77 g, 54.9 mmol) to a round-bottom flask equipped with a Teflon-coated magnetic stir bar. Seal the flask, purge under argon, and add anhydrous DCM (21.6 mL). Stir the reaction mixture overnight at room temperature. The reaction mixture was filtered through a diatomaceous earth mat, washed with DCM (30 mL), and concentrated under reduced pressure to give 4-amino-2-chloro-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidine-5-carboxaldehyde as a solid (Int-E2, 800 mg, 2.74 mmol, 99% yield). ESI-MS : [M+H] ⁺ = 292.1.

Method Int 115. Intermediate Int-E3: 2-chloro-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidine

_TiCl₄ (1.1 equivalent, 0.10 mL, 0.90 mmol) was added to a stirred solution of butan-2-one (1 equivalent, 77.0 μL, 0.86 mmol) in anhydrous DCM (3 mL) at -78 °C. The reaction mixture was heated to 0 °C and stirred for 30 min. Then, the solution was cooled to -78 °C, and DIPEA (2.1 equivalent, 0.31 mL, 1.77 mmol) was added dropwise, while the mixture was stirred at 0 °C for 30 min. The mixture was cooled to -30°C, and a solution of 4-amino-2-chloro-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidine-5-carboxaldehyde (Int-E2, 1.2 equivalents, 300 mg, 1.03 mmol) was added dropwise to anhydrous DCM (15 mL), and the mixture was stirred at 0°C for 1 h. Saturated _NH4Cl (aq.) (10 mL) was added, and the resulting mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (Isco RediSep® column 25 g) (0-30% EtOAc/hexane) to give solid 2-chloro-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidine (Int-E3, 54 mg, 0.16 mmol, 16% yield). ESI-MS : [M+H] ⁺ = 328.1. ^1H NMR (400 MHz, _CDCl3 ): δ 8.19 (s, 1H); 2.74 (s, 3H); 2.64 (s, 6H); 2.51 (s, 3H).

Method Int 116. Intermediate Int-E5: 2,2-Dimethyl-N-[6-methyl-5-(trifluoromethyl)-2-pyridyl]propionic acid

Add 6-methyl-5-(trifluoromethyl)pyridin-2-amine (1 equivalent, 2.5 g, 14.2 mmol) and DMAP (0.1 equivalent, 0.17 g, 1.42 mmol) to a flame-dried round-bottom flask equipped with a Teflon-coated magnetic stir bar. Cap the flask and place it under a _nitrogen atmosphere, then add anhydrous DCM (20 mL) and NEt ₃ (1.5 equivalent, 3.0 mL, 21.3 mmol). Cool the reaction mixture to 0°C in an ice bath, add pentylenetetrazol (1.2 equivalent, 2.1 mL, 17.0 mmol), and heat the mixture to room temperature while stirring overnight. _The reaction mixture was diluted with DCM (50 mL), washed with saturated _NH₄Cl (aq.), and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by normal-phase rapid column chromatography (80 g _SiO₂ column) (1-30% EtOAc/hexane) to give solid 2,2-dimethyl-N-[6-methyl-5-(trifluoromethyl)-2-pyridyl]propane (Int-E5, 3.62 g, 13.9 mmol, 98% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.13 (1H, d, J = 8.7 Hz), 8.08 (1H, s), 7.85 (1H, d, J = 8.7 Hz), 2.56 (3H, s), 1.32 (9H, s). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -61.3 (3F, s).

Method Int 117. Intermediate Int-E6: 2,2-Dimethyl-N-[6-methyl-5-(trifluoromethyl)-3-[3-(trifluoromethyl)-bicyclo[1.1.1]pentane-1-carbonyl]-2-pyridyl]acrylamide

Add 2,2-dimethyl-N-[6-methyl-5-(trifluoromethyl)-2-pyridyl]acrylamide (Int-E5, 1.1 equivalents, 1.74 g, 6.7 mmol) and anhydrous THF (20 mL) to a flame-dried round-bottom flask equipped with a magnetic stir bar. Seal the flask, purge under argon, and cool to -78°C with stirring. Add ^tBuLi (1.7 M in pentane) dropwise (2.2 equivalents, 7.9 mL, 13.4 mmol). After 15 min, heat the flask to 0°C and stir for 1 h. The flask was recooled to -78°C, and a solution of N-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-methylamine (Int-E4, 1 equivalent, 1.36 g, 6.09 mmol) in anhydrous THF (10 mL) was added. The resulting mixture was stirred at -78°C, gradually heated to room temperature, and cooled to 0°C after 18 h, and quenched with saturated _NH₄Cl (aq.). The mixture was diluted with EtOAc and washed with saturated _NH₄Cl (aq.) and brine. The organic layer was dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated under vacuum onto diatomaceous earth (15 g). The crude material was purified by normal-phase rapid column chromatography (200 g _SiO2 column) (5-20% EtOAc/hexane) to give solid 2,2-dimethyl-N-[6-methyl-5-(trifluoromethyl)-3-[3-(trifluoromethyl)-bicyclo[1.1.1]pentane-1-carbonyl]-2-pyridyl]acrylamide (Int-E6, 757 mg, 1.79 mmol, 29% yield).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-E20 Int-E4 The crude reaction mixture was purified by rapid column chromatography (120 g SiO ₂ column) using a 10-50% EtOAc/hexane dissolution gradient to give N-[5-fluoro-6-methyl-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]-2-pyridyl]-2,2-dimethyl-propionic acid (Int-E20, 0.91 g, 2.44 mmol, 51% yield) as a solid. Int-E26 Int-E4 Int-E25 The crude material was purified by normal-phase chromatography (10-80% EtOAc/hexane) to give N-(6-methyl-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridin-2-yl)pentylamine (Int-E26, 400 mg, 56% yield) as a solid. ESI-MS : [M+H] ⁺ = 355.2. ^1H NMR ( _CDCl3 , 400 MHz): δ 10.92 (1H, s), 8.08 (1H, d, J = 8.0 Hz), 6.93 (1H, d, J = 8.0 Hz), 2.60 (3H, s), 2.47 (6H, s), 1.34 (9H, s). Int-E35 Int-E25 The crude reaction mixture was purified by rapid column chromatography (120 g _SiO2 column, 5-60% EtOAc/hexane dissolution gradient) to give N-[3-(cyclohexanecarbonyl)-6-methyl-2-pyridyl]-2,2-dimethylpropionic acid (2.3 g, 7.6 mmol, 38% yield) as a solid.

Method Int 118. Intermediate Int-E7: [2-amino-6-methyl-5-(trifluoromethyl)-3-pyridyl]-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl] ketone

2,2-Dimethyl-N-[6-methyl-5-(trifluoromethyl)-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]-2-pyridyl]propionic acid (Int-E6, 1 equivalent, 123 mg, 0.29 mmol), water (3 mL), and 6N HCl (aq.) (21 equivalent, 1.0 mL, 6.0 mmol) were added to a reaction vial equipped with a Teflon-coated magnetic stir bar, and the reaction mixture was stirred at 105 °C for 18 h. The resulting heterogeneous mixture was cooled in an ice bath, and 1N NaOH solution (aq.) was added dropwise until pH = 10 was obtained. The suspension was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under reduced pressure to give solid [2-amino-6-methyl-5-(trifluoromethyl)-3-pyridyl]-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl] methyl ketone (Int-E7, 72 mg, 0.21 mmol, 73% yield). ^¹H NMR ( _CHCl₃ , 400 MHz): δ 8.32 (s, 1H), 2.55 (s, 3H), 2.46 (s, 6H).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-E21 Int-E20 The procedure yielded (2-amino-5-fluoro-6-methyl-3-pyridyl)-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl) methyl ketone in solid form (Int-E21, 704 mg, 2.44 mmol, 99% yield). Int-E27 Int-E26 The procedure yielded 2-amino-6-methylpyridin-3-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl) methyl ketone in solid form (Int-E27, 142 mg, 90% yield). ESI-MS : [M+H] ⁺ = 272.1. ^¹H NMR ( _CDCl₃ , 400 MHz): δ 8.01 (¹H, d, J = 8.0 Hz), 6.49 (¹H, d, J = 8.0 Hz), 2.45 (6H, s), 2.41 (3H, s). Int-E36 Int-E35 The crude reaction mixture was filtered through a silicon dioxide plug to obtain (2-amino-6-methyl-3-pyridyl)-cyclohexyl-methyl ketone (Int-E36, 1.6 g, 7.3 mmol, 96% yield), which was used directly in the next step.

Method Int 119. Intermediate Int-E8: (2R,4S)-2-(6-benzyloxy-3-pyridyl)-N-[6-methyl-5-(trifluoromethyl)-3-[3-(trifluoromethyl)bicyclo[1.1.1]-pentane-1-carbonyl]-2-pyridyl]tetrahydropiperan-4-methylamine

Under an Ar atmosphere, (2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-carbochloro (1.4 equivalents, 100 mg, 0.3 mmol) and anhydrous DCM (1 mL) were added to a flame-dried flask, and the resulting solution was stirred at 0 °C. Next, a solution of [2-amino-6-methyl-5-(trifluoromethyl)-3-pyridyl]-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl] ketone (Int-E7, 1 equivalent, 72 mg, 0.213 mmol) and pyridine (3.45 equivalents, 0.06 mL, 0.74 mmol) in anhydrous DCM (1 mL) was added dropwise, and the resulting mixture was stirred overnight under Ar atmosphere at 50 °C. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc (50 mL). The _resulting solution was washed with 5% citric acid (aq.) and brine. The organic layer was collected, dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by normal-phase rapid column chromatography (12 g SiO ₂ column) (10-60% EtOAc/hexane) to give solid (2R,4S)-2-(6-benzyloxy-3-pyridyl)-N-[6-methyl-5-(trifluoromethyl)-3-[3-(trifluoromethyl)bicyclo[1.1.1]-pentane-1-carbonyl]-2-pyridyl]tetrahydropiperan-4-carboxylamine (Int-E8, 30 mg, 0.05 mmol, 22% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.98 (1H, s), 8.40 (1H, s), 8.14 (1H, s), 7.65 (1H, dd, J = 8.5, 2.5 Hz), 7.29-7.44 (5H, m), 6.81 (1H, d, J = 8.5 Hz), 5.38 (2H, s), 4.39 (1H, d, J = 11.3 Hz), 4.27 (1H, d, J = 11.6 Hz), 3.66-3.71 (1H, m), 3.12-3.14 (1H, m), 2.73 (3H, s), 2.49 (6H, s), 2.14 (1H, d, J = 12.9 Hz), 1.82-1.97 (3H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -61.8 (3F, s), -73.2 (3F, s).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-E22 Int-E21 The crude mixture was purified by rapid column chromatography (40 g SiO ₂ column) using a dissolution gradient of 50-100% EtOAc/hexane to give solid (2R,4S)-2-(6-benzyloxy-3-pyridyl)-N-[5-fluoro-6-methyl-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]-2-pyridyl]tetrahydropiperan-4-carboxylamine (Int-E22, 213 mg, 0.365 mmol, 64% yield). Int-E29 Int-E28 The crude material was purified by normal-phase chromatography (50-80% EtOAc/hexane dissolution gradient) to give (2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)-N-(5-bromo-6-methyl-3-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)pyridin-2-yl)tetrahydro-2H-piperan-4-carboxylamine (Int-E29, 860 mg, 55% yield) as a solid. ESI-MS : [M+H] ⁺ = 644.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.59 (1H, s), 8.23 (1H, s), 8.13 (1H, d, J = 2.3 Hz), 7.64 (1H, dd, J = 8.6, 2.4 Hz), 7.45 (2H, d, J = 7.5 Hz), 7.37 (2H, t, J = 7.4 Hz), 7.29-7.33 (1H, m), 6.81 (1H, d, J = 8.6 Hz), 5.37 (2H, s), 4.38 (1H, d, J = 11.2 Hz), 4.24-4.28 (1H, m), 3.64-3.71 (1H, m), 2.96-3.04 (1H, m), 2.69 (3H, s), 2.48 (6H, s), 2.11-2.15 (1H, m), 1.93-2.02 (2H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.2 (3F, s). Int-E38 Int-E37 Modification : 4 equivalents of DIPEA were used instead of pyridine. The crude reaction mixture was purified by rapid column chromatography (120 g _SiO2 column, 0-35% EtOAc/DCM dissolution gradient) to give (2R,4S)-2-(6-benzyloxy-3-pyridyl)-N-[5-bromo-3-(cyclohexanecarbonyl)-6-methyl-2-pyridyl]tetrahydropiperan-4-carboxamide (1.3 g, 2.2 mmol, 69% yield) as a solid.

Method Int 120. Intermediate Int-E12: 2-chloro-4-(3,3-difluorocyclobutoxy)-6,7-dimethylpyrido[2,3-d]pyrimidine

At -10 °C, lithium bis(trimethylsilyl)amine (1 equivalent, 0.88 mL, 0.88 mmol) was added to a stirred solution of 3,3-difluorocyclobutanol (1 equivalent, 0.1 mL, 0.88 mmol) in anhydrous THF (17.5 mL), and stirred at the same temperature for 30 min. The resulting solution was then added dropwise to a solution of 2,4-dichloro-6,7-dimethylpyridino[2,3-d]pyrimidine (1 equivalent, 200 mg, 0.88 mmol) in anhydrous THF (1 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under reduced pressure. The crude material was purified by rapid chromatography (Isco RediSep® column 12g, using a gradient of 0% to 60% EtOAc/hexane). The selected solvent was evaporated to give solid 2-chloro-4-(3,3-difluorocyclobutoxy)-6,7-dimethylpyridino[2,3-d]pyrimidine (Int-E12, 198 mg, 0.66 mmol, 75%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.12 (s, 1H), 5.49-5.38 (m, 1H), 3.22-3.31 (m, 1H), 2.83-2.95 (m, 1H), 2.74 (s, 3H), 2.48 (s, 3H). ESI-MS : [M+H] ⁺ = 366.0.

Method Int 121. Intermediate Int-E17: 4-amino-6-(2,4-difluorophenyl)-2-((2R,4S)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)pyrimidine-5-carboxaldehyde

Platinum dioxide (0.6 eq, 159 mg, 0.70 mmol) was added to a solution of (R)-4-amino-6-(2,4-difluorophenyl)-2-(6-(6-sideoxy-1,6-dihydropyridin-3-yl)-3,6-dihydro-2H-piperan-4-yl)pyrimidine-5-carboxaldehyde (Int-E16, 1 equivalent, 480 mg, 1.17 mmol) in ethanol (10 mL). The mixture was purged with hydrogen and stirred at 25 °C for 4 h under a hydrogen bulb. The reaction mixture was then purged with nitrogen, diluted with DCM, filtered through diatomaceous earth, and evaporated under vacuum. The residue was diluted in DCM (10 mL) and manganese dioxide (10 eq, 2.7 g, 11.7 mmol) was added. The resulting mixture was stirred overnight at room temperature, then filtered through diatomaceous earth and evaporated. The residue was purified by column chromatography (80 g, SiO ₂ ) using a 0-20% MeOH/DCM gradient to give foamy 4-amino-6-(2,4-difluorophenyl)-2-((2R,4S)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)pyrimidine-5-carboxaldehyde (Int-E17, 240 mg, 0.58 mmol, 50%).

Method Int 122. Intermediate Int-E18: methyl 4-(2,4-difluorophenyl)-7-methyl-2-((2R,4S)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)pyrido[2,3-d]pyrimidine-6-carboxylate

Add methyl 3-sideoxybutyrate 7 (2 equivalents, 59 mg, 0.51 mmol) to a solution in methanol (1 mL). Phosphorus (1 equivalent, 22 µL, 0.26 mmol). The mixture was stirred for 30 min and then added to a solution of 4-amino-6-(2,4-difluorophenyl)-2-[(2R,4S)-2-(6-sideoxy-1H-pyridin-3-yl)tetrahydropiperan-4-yl]pyrimidine-5-carboxaldehyde (Int-E17, 1 eq, ₁₀₅ mg, 0.26 mmol) in methanol (1 mL). The solution was stirred overnight at 90 °C in a sealed container. The mixture was cooled, diluted with AcOEt, washed with AcOH aqueous solution (10%) and brine, dried over _Na₂SO₄ , filtered and evaporated. The residue was purified on a 40 g silica column using a 0-20% MeOH/DCM dissolution gradient to obtain a foamy methyl 4-(2,4-difluorophenyl)-7-methyl-2-((2R,4S)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)pyrido[2,3-d]pyrimidine-6-carboxylate (Int-E18, 68 mg, 0.14 mmol, 54%).

Method Int 123. Intermediate Int-E25: N-(6-methylpyridin-2-yl)pentylamine

Add 6-methylpyridin-2-amine (1 equivalent, 30.0 g, 277 mmol), DCM (60 mL), and triethylamine (1.5 equivalent, 58 mL, 416 mmol) to a flame-dried round-bottom flask equipped with a Teflon-coated magnetic stir bar under a nitrogen atmosphere. Cool the flask and add pentylenetetrazol (1.2 equivalent, 41 mL, 333 mmol) dropwise over 4 minutes. Stir the mixture for 3 h. Wash the reaction mixture with water (300 mL) and extract with EtOAc (3 × 500 mL). Combine the organic layers, wash with brine, filter, and concentrate under reduced pressure. The crude material was purified by rapid chromatography (0-50% EtOAc/hexane dissolution gradient) to obtain N-(6-methylpyridin-2-yl)pentafenamide (Int-E25, 50.0 g, 94% yield) in solid form. ESI-MS : [M+H] ⁺ = 193.2. ^¹H NMR ( _CDCl₃ , 400 MHz): δ 8.03 (¹H, d, J = 8.3 Hz), 7.89 (¹H, s), 7.56 (¹H, t, J = 7.9 Hz), 6.86 (¹H, d, J = 7.5 Hz), 2.43 (³H, s), 1.31 (⁹H, s).

Method Int 124. Intermediate Int-E28: (2-amino-5-bromo-6-methylpyridin-3-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl) methyl ketone

(2-amino-6-methyl-3-pyridyl)-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]methyl ketone (Int-E27, 1 equivalent, 203 mg, 0.75 mmol) and acetic acid (2 mL) were added to a glass vial equipped with a Teflon-coated magnetic stirring rod. Bromine (1.1 equivalent, 43 μL, 0.83 mmol) was added at room temperature while stirring. After 10 min, the reaction mixture was diluted with _H₂O (2 mL) and alkalized to pH 10 with 1 M NaOH (aq). The precipitate was collected by vacuum filtration, washed with _H₂O , and dried under reduced pressure. The crude material was purified by normal-phase chromatography (5% to 20% EtOAc/hexane) to give solid (2-amino-5-bromo-6-methylpyridin-3-yl)(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl) methyl ketone (Int-E28, 217 mg, 83% yield). ESI-MS : [M+H] ⁺ = 351.3. ^¹H NMR ( _CDCl₃ , 400 MHz): δH 8.15 (¹H, s), 2.52 (³H, s), 2.46 (⁶H, s).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-E37 Int-E36 The product was purified by rapid column chromatography (120 g _SiO2 column, 5-20% EtOAc/hexane dissolution gradient) to give (2-amino-5-bromo-6-methyl-3-pyridyl)-cyclohexyl-methyl ketone (Int-E37, 1.9 g, 6.4 mmol, 87% yield).

Method Int 125. Intermediate Int-E33: 2-(( 2R , 4S )-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-piperan-4-yl)-7-methyl-4-(3-(trifluoromethyl)biscyclic[1.1.1]pentan-1-yl)pyrido[2,3- d ]pyrimidin-6-carboxynitrile

2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-6-bromo-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidine (Int-E30, 1 equivalent, 100 mg, 0.16 mmol), zinc cyanide (2 equivalents, 38 mg, 0.32 mmol), and Pd( _PPh3 ) ₄ (0.10 equivalents, 18 mg, 0.02 mmol) were stirred in NMP (1.5 mL) at 110 °C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure. The crude material was purified by normal-phase chromatography (50-100% EtOAc/ _hexane dissolution gradient) to give solid 2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-piperan-4-yl)-7-methyl-4-(3-(trifluoromethyl)bis(1.1.1)pentan-1-yl)pyrido[2,3-d]pyrimidin-6-carboxylonitrile (Int-E33, 80 mg, 87% yield). ESI-MS : [M+H] ^⁺ = 572.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.80 (1H, s), 8.15 (1H, s), 7.66 (1H, dd, J = 8.5, 2.4 Hz), 7.42 (2H, d, J = 7.5 Hz), 7.33 (2H, t, J = 7.4 Hz), 6.78 (1H, d, J = 8.5 Hz), 5.35 (2H, s), 4.51 (1H, d, J = 11.2 Hz), 4.30 (1H, d, J = 11.4 Hz), 3.75-3.85 (1H, m), 3.46-3.53 (1H, m), 2.99 (3H, s), 2.64 (6H, s), 2.29 (1H, d, J = 13.2 Hz), 2.12-2.17 (2H, m), 2.07 (1H, t, J = 12.2 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s).

Following a similar procedure, the following intermediate was obtained. Structure Starting materials Characteristics Int-E40 Int-E39 The crude mixture was purified by rapid column chromatography using a 50-100% EtOAc/hexane dissolution gradient to give solid 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-4-cyclohexyl-7-methyl-pyrido[2,3-d]pyrimidin-6-carboxynitrile (Int-E40, 390 mg, 0.75 mmol, 86% yield).

Method Int 126. Intermediate Int-E42: Trifluoromethanesulfonic acid [6-(1-methyl-6-sideoxy-3-pyridyl)-3,6-dihydro-2H-piperan-4-yl ester]

3-Butyn-1-ol (1 equivalent, 1.9 mL, 25.5 mmol) was added to DCM (40 mL) containing 1-methyl-6-sideoxy-pyridine-3-carboxaldehyde (1 equivalent, 3500 mg, 25.5 mmol), and the mixture was stirred at -15 °C for 30 min under nitrogen. TfOH (3 equivalents, 6.8 mL, 76.6 mmol) was added dropwise at -15 to -5 °C under nitrogen, and the mixture was stirred at -10 to 0 °C for 1 h, followed by stirring at 10 to 20 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine (50 mL), dried over _Na₂SO₄ , purified by reversed-phase rapid chromatography, and freeze-dried to give an oily trifluoromethanesulfonic acid [6-(1-methyl- ₆ -sideoxy-3-pyridinyl)-3,6-dihydro-2H-piperan-4-yl ester] (Int-E42, 2.40 g, 7.07 mmol, 28% yield). ESI-MS : [M+H] ^⁺ = 340.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (dd, J = 2.6, 9.3 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 6.64 (d, J = 9.4 Hz, 1H), 5.86 - 5.81 (m, 1H), 5.07 (q, J = 2.6 Hz, 1H), 4.06 (ddd, J = 3.9, 5.4, 11.6 Hz, 1H), 3.84 - 3.80 (m, 1H), 3.56 (s, 3H), 2.70 - 2.63 (m, 1H), 2.47 - 2.36 (m, 1H).

Method Int 127. Intermediate Int-E43: 1-Methyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-3,6-dihydro-2H-piperan-6-yl]pyridin-2-one

Trifluoromethanesulfonic acid [6-(1-methyl-6-sideoxy-3-pyridyl)-3,6-dihydro-2H-piperan-4-yl ester] (Int-E42, 1 equivalent, 1.40 g, 4.13 mmol) was reacted with di... Bis(pinnatrol)diboron (1.5 eq, 1572 mg, 6.19 mmol) and potassium acetate (4 eq, 1620 mg, 16.5 mmol) were added to a solution of alkane (14 mL), and the mixture was then stirred at 25 °C for 30 min under a _nitrogen atmosphere. Pd(dppf) _Cl₂ (0.0300 eq, 91 mg, 0.124 mmol) was added, and the mixture was heated at 80 °C for 4 h under a _nitrogen atmosphere. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (20 mL), dried over _Na₂SO₄ , purified by reversed-phase rapid chromatography, and freeze-dried to give an oily 1-methyl- _5- [4-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-3,6-dihydro-2H-piperan-6-yl]pyridin-2-one (Int-E43, 240 mg, 0.757 mmol, 18% yield). ESI-MS : [M+H] ^⁺ = 318.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J = 1.0 Hz, 1H), 7.38 (br d, J = 9.3 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H), 6.62 (br d, J = 9.4 Hz, 1H), 6.45 (s, 1H), 4.94 (br d, J = 1.8 Hz, 1H), 4.00 - 3.92 (m, 1H), 3.77 - 3.69 (m, 1H), 3.56 (s, 3H), 2.41 - 2.33 (m, 1H), 1.29 (s, 12H).

Method Int 128. Intermediate Int-F5: (R)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-4H-piperan-4-one

2-(6-Benzoxy-3-pyridinyl)-2,3-dihydropiperan-4-one (Int-F4, 1 equivalent, 0.90 g, 3.20 mmol) was placed in a vial containing EtOAc (20 mL, 0.16 M), and the solution was purged with argon. Palladium/alumina (0.03 equivalent, 0.20 g, 0.096 mmol) was then added. The reaction mixture was purged three times with hydrogen, and the mixture was stirred overnight at room temperature with _H₂ (g) at 1 atm. The mixture was filtered through a diatomaceous earth mat and concentrated under vacuum. Remethylation procedure: The reaction residue was diluted in toluene (20 mL, 0.16 M), and brominated benzyl (1.2 equivalents, 0.66 g, 3.84 mmol) and silver carbonate (1.5 equivalents, 1.32 g, 4.80 mmol) were added. The resulting mixture was stirred at 100 °C for 1 h, filtered through a diatomaceous earth mat, and concentrated under vacuum. The crude material was purified by normal-phase chromatography (0-20% EtOAc/DCM) to give (R)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-4H-piperan-4-one (Int-F5, 460 mg, 51% yield, in two steps) as a solid. ^¹H NMR ( _CDCl₃ , 400 MHz): δ 8.15 (¹H, d, J = 2.4 Hz), 7.64 (¹H, dd, J = 8.6, 2.4 Hz), 7.45 (2H, d, J = 7.5 Hz), 7.37 (2H, t, J = 7.3 Hz), 7.32 (¹H, d, J = 7.0 Hz), 6.84 (¹H, d, J = 2.4 Hz). 8.6 Hz), 5.39 (2H, s), 4.63 (1H, dd, J = 9.0, 5.2 Hz), 4.42 (1H, dd, J = 11.5, 7.4 Hz), 3.84 (1H, td, J = 11.9, 2.8 Hz), 2.67 - 2.76 (1H, m), 2.64 (1H, d, J = 4.3 Hz), 2.44 (1H, d, J = 14.7 Hz). ESI-MS : [M+H] ⁺ = 284.3.

Method Int 129. Intermediate Int-F10: methyl 4-acetylbiricyclo[2.2.1]heptane-1-carboxylate

Excess thionyl chloride was reacted with 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid at 80 °C for 5 h, followed by separation to obtain the intermediate thionyl chloride. The thionyl chloride was dissolved in THF, cooled to -78 °C, and treated with CuI (1.2 equivalents) and MeLi (2.4 equivalents). After two hours, the reactants were heated to room temperature to obtain methyl 4-acetylated bicyclo[2.2.1]heptane-1-carboxylic acid (Int-F10).

Method Int 130. Intermediate Int-F12: 4-(1,1-difluoroethyl)-N-methoxy-N-methylbicyclo[2.2.1]heptane-1-methylamine

4-(1,1-difluoroethyl)bicyclo[2.2.1]heptane-1-carboxylate methyl ester (Int-F11, 1 equivalent), iPrMgCl (2M solution in THF, 2.4 equivalent), and N,O-dimethylhydroxylamine hydrochloride (1.2 equivalent) were reacted in THF at -15°C for 15 min to give 4-(1,1-difluoroethyl)-N-methoxy-N-methylbicyclo[2.2.1]heptane-1-carboxylamine (Int-F12). Example A2 : Synthesis of an exemplary compound

Method 1: Synthesis of Examples 7, 16 and 62. Example 7 : 5-[(2S,6R)-4-[4-[2- fluoro - 4-( trifluoromethyl ) phenyl ]-6,7 - dimethyl - pteridin -2 -yl ]-6- methyl- [Lin -2- yl ]-1 - methylpyridin - 2- one

To 2-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridine (1 equivalent, 50 mg, 0.14 mmol) and 1-methyl-5-[(2S,6R)-6-methyl [Lin-2-yl]pyridin-2-one (Int-A5, 2 equivalents, 58 mg, 0.28 mmol) was added to a solution of DMSO (0.5 mL) with DIPEA (5 equivalents, 0.12 mL, 0.7 mmol), and the reaction mixture was stirred at 100 °C for 1 h. LCMS showed 87% of the desired product. The reaction mixture was poured into water ( ₁₀ mL) and then extracted with EtOAc (3 × 20 mL). The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (condition 2, gradient a) to obtain 5-[(2S,6R)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridin-2-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Example 7, 40 mg, 0.075 mmol, 53% yield). LCMS : [M+H] ⁺ = 529.2; purity = 99% (220 nm); retention time = 0.953 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (br t, J = 7.2 Hz, 1H), 7.60 (br d, J = 7.9 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.43 (s, 2H), 6.61 (d, J = 9.4 Hz, 1H), 5.24 - 4.88 (m, 2H), 4.47 - 4.36 (m, 1H), 3.93 - 3.76 (m, 1H), 3.58 (s, 3H), 2.97 - 2.81 (m, 2H), 2.73 (s, 3H), 2.60 (s, 3H), 1.36 (s, 1H), 1.39 - 1.31 (m, 1H).

Following a similar procedure, the following compounds were obtained. Structure Starting materials Characteristics Example 16 The residue was purified by preparative TLC (50% EtOAc/petroleum ether (PE), _Rf = 0.1) to obtain a crude product. The crude product was further purified by preparative HPLC (0.5% FA) and extracted with EtOAc (3 × 20 mL). The combined organic layer was dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure to obtain a residue. The residue was further purified by preparative HPLC (condition 3) and freeze-dried to obtain a final residue. The residue was purified again by preparative TLC (100% EtOAc) to obtain 5-[(2S,6R)-4-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Example 16, 5.5 mg, 0.011 mmol, 7% yield). LCMS : [M+H] ⁺ = 479.2; purity = 98% (220 nm); retention time = 0.531 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (q, J = 7.5 Hz, 1H), 7.50 - 7.38 (m, 2H), 7.09 - 7.02 (m, 1H), 6.99 (dt, J = 2.4, 9.4 Hz, 1H), 6.61 (d, J = 9.3 Hz, 1H), 5.15 - 4.91 (m, 2H), 4.45 - 4.33 (m, 1H), 3.90 - 3.79 (m, 1H), 3.58 (s, 3H), 2.93 (dd, J = 10.9, 13.3 Hz, 1H), 2.83 (dd, J = 10.8, 13.3 Hz, 1H), 2.73 (s, 3H), 2.60 (s, 3H), 1.38 - 1.32 (m, 3H). Example 62 Modification : The reaction was carried out at 110°C with DIPEA for 2 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (condition 4) and freeze-dried to give 5-[(2S,6R)-4-[6,7-dimethyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Example 62, 3.7 mg, 0.007 mmol, 14% yield). LCMS : [M+H] ⁺ = 501.4, purity = 100% (220 nm); retention time = 0.608 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 - 7.40 (m, 2H), 6.62 (br d, J = 9.5 Hz, 1H), 5.10 - 4.89 (m, 2H), 4.37 (dd, J = 2.4, 10.7 Hz, 1H), 3.87 - 3.75 (m, 1H), 3.59 (s, 3H), 2.88 (dd, J = 10.9, 13.3 Hz, 1H), 2.78 (dd, J = 10.8, 13.4 Hz, 1H), 2.69 (s, 3H), 2.65 (s, 3H), 2.59 (s, 6H), 1.35 (d, J = 6.1 Hz, 3H). ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -73.05 (s, 1F). Example 189 Int-C27 Modification : The reaction was carried out at 90 °C in DMSO for 1 h. The crude mixture was purified by normal-phase chromatography (50% to 100% EtOAc/hexane, followed by 0% to 2% MeOH/DCM) to give 5-[1-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]-4,4-difluoro-3-piperidinyl]-1H-pyridin-2-one as a solid (Example 189, 50 mg, 0.10 mmol, 55% yield). ESI-MS : [M+H] ⁺ = 485.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.67 (1H, q, J = 7.5 Hz), 7.44 (1H, d, J = 9.5 Hz), 7.34 (1H, s), 6.99 (1H, t, J = 7.8 Hz), 6.92 (1H, t, J = 9.4 Hz), 6.53 (1H, d, J = 9.3 Hz), 5.15 (2H, br s), 3.30-3.40 (2H, m), 2.97 (1H, br s), 2.67 (3H, s), 2.55 (3H, s), 2.23 (1H, br s), 1.98-2.06 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -96.0 (1F, d, J = 248.6 Hz), -106.6 (2F, s), -113.7 (1F, d, J = 237.8 Hz)

Method 2: Synthesis of Examples 23 and 21. Example 23: 5-[(2S,6R)-4-[6,7-dimethyl-4-[2-(trifluoromethyl)thiazo-5-yl]pterin-2-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one

5-[(2S,6R)-4-(6,7-dimethyl-4-methylthio-pteridin-2-yl)-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Int-A7 , 1 equivalent, 55 mg, 0.09 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxoborocyclopentan-2-yl)-2-(trifluoromethyl)thiazole (3 equivalent, 78 mg, 0.28 mmol), CuTc (2.2 equivalent, 39 mg, 0.21 mmol), and Pd(dppf) _Cl₂ ·DCM (0.3 equivalent, 20 mg, 0.028 mmol) in anhydrous DMF (2 mL) were purged with argon for 3 min and the suspension was irradiated with argon (365 nm) for 8 h. LCMS showed 20% of the desired product. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). _The combined organic layers were washed with brine, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (condition 3, gradient a) to obtain a solid 5-[(2S,6R)-4-[6,7-dimethyl-4-[2-(trifluoromethyl)thiazolyl-5-yl]pteridin-2-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Example 23, 4.7 mg, 0.009 mmol, 10% yield). LCMS : [M+H] ⁺ = 518.4; purity = 100% (220 nm); retention time = 0.591 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.29 (br d, J =5.0 Hz, 3H), 2.78 (br d, J =3.0 Hz, 6H), 2.85 - 2.94 (m, 1H), 2.95 - 3.05 (m, 1H), 3.63 (s, 3H), 3.82 - 3.91 (m, 1H), 4.40 - 4.48 (m, 1H), 4.84 - 5.19 (m, 2H), 6.59 - 6.75 (m, 1H), 7.44 - 7.56 (m, 2H), 9.36 (s, 1H),

Following a similar procedure, the following compounds were obtained. Structure intermediate Characteristics Example 21 The residue was purified by preparative HPLC (condition 3, gradient b) to obtain 5-[(2S,6R)-4-[4-(2-cyclopropylthiazolyl-5-yl)-6,7-dimethyl-pteridin-2-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Example 21, 14 mg, 0.026 mmol, 43% yield). LCMS : [M+H] ⁺ = 490.1; purity = 92% (220 nm); retention time = 0.546 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.26 (br d, J =5.4 Hz, 4H), 1.37 (br d, J =5.9 Hz, 3H), 2.37 - 2.50 (m, 1H), 2.72 (d, J =5.1 Hz, 6H), 2.83 (br dd, J =13.1, 11.2 Hz, 1H), 2.88 - 2.97 (m, 1H), 3.60 (s, 3H), 3.78 - 3.88 (m, 1H), 4.35 - 4.44 (m, 1H), 4.86 - 5.13 (m, 2H), 6.64 (br d, J =8.3 Hz, 1H), 7.40 - 7.51 (m, 2H), 9.19 (s, 1H).

Method 3: Synthetic Examples 1-6, 11-15, 18-20, 25-26, 31-32, 64-65, 67-79, 123-125 and 155-160 Example 3: 5-(4-(4-(2,4-difluorophenyl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one

To _a suspension of C-phos (0.1 equivalent, 85 mg, 0.196 mmol), Pd(OAc) _₂ (0.05 equivalent, 22 mg, 0.098 mmol), and 2-chloro-4-(2,4-difluorophenyl)-6,7-dimethyl-pteridine (1 equivalent, 600 mg, 1.96 mmol) in THF (6 mL), bromo-[2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc (Int-A8, 1.2 equivalent, 792 mg, 2.4 mmol) was added. The resulting mixture was stirred at 55 °C for 2 hours. LC-MS showed exhaustion of the reaction mixture, and the product was obtained at 33% of the desired mass. The reaction mixture was poured into _H₂O (12 mL), extracted with EtOAc (15 mL × 3), dried _{over Na₂SO₄} , filtered and concentrated under reduced pressure to obtain a crude substance. The crude substance was then purified by silicone column chromatography (9% MeOH/EtOAc, _Rf = 0.3) and concentrated under reduced pressure to obtain 400 mg of 5-(4-(4-(2,4-difluorophenyl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 3). The product was further purified by preparative HPLC (FA) and freeze-dried to give 1-methyl-5-[rac-(2R,4R)-4-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (100 mg, 0.216 mmol, 11% yield) and 1-methyl-5-[rac-(2R,4S)-4-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (140 mg, 0.302 mmol, 15% yield) in solid form.

LCMS (1-Methyl-5-[rac-(2R,4R)-4-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one): [M+H]+ = 464.3; Purity = 99% (220 nm); Retention time = 0.491 min

LCMS (1-methyl-5-[rac-(2R,4S)-4-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one): [M+H]+ = 464.3; purity = 99% (220 nm); retention time = 0.498 min

Examples 1 and 2

The racemic compound was purified by SFC (condition 1, gradient a) and preparative TLC (9% MeOH/DCM, _Rf = 0.4) to give 1-methyl-5-[(2R,4S)-4-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 1, 20 mg, 0.04 mmol, 38% yield) and 5-[(2S,4R)-4-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one as a solid (Example 2, 8.7 mg, 0.02 mmol, 17% yield).

Example 1 : LCMS : [M+H] ⁺ = 464.1; Purity = 94% (220 nm); Retention time = 0.501 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 - 7.71 (m, 1H), 7.45 - 7.34 (m, 2H), 7.13 - 6.97 (m, 2H), 6.56 (br d, J = 10.0 Hz, 1H), 4.38 - 4.25 (m, 2H), 3.80 (dt, J = 3.1, 11.4 Hz, 1H), 3.64 - 3.47 (m, 4H), 2.84 (s, 3H), 2.73 (s, 3H), 2.45 - 2.31 (m, 1H), 2.24 - 2.05 (m, 3H).

Example 2 : LCMS : [M+H] ⁺ = 464.1; Purity = 98% (220 nm); Retention time = 0.500 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 - 7.70 (m, 1H), 7.47 - 7.37 (m, 2H), 7.09 (br t, J = 8.2 Hz, 1H), 7.04 - 6.96 (m, 1H), 6.58 (d, J = 9.5 Hz, 1H), 4.41 - 4.26 (m, 2H), 3.86 - 3.74 (m, 1H), 3.55 (s, 3H), 2.85 (s, 3H), 2.73 (s, 3H), 2.38 (br d, J = 13.3 Hz, 1H), 2.23 - 2.07 (m, 3H).

Following a similar procedure, the following compounds were obtained. Structure Starting materials Characteristics Example 6 continues with SFC : Example 4 Example 5 The solid was purified by preparative HPLC (FA) and lyophilized to give ~140 mg of racemic product Example 6. It was then purified by SFC and lyophilized to give 1-methyl-5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoro-methyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 4, 33 mg, 0.06 mmol, 4% yield) and 1-methyl-5-[(2S,4R)-4-[4-[2-fluoro-4-(trifluoro-methyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 5, 56 mg, 0.11 mmol, 6% yield). Example 4 : LCMS : [M+H] ⁺ = 514.3; Purity = 98% (220 nm); Retention time = 0.535 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (t, J = 7.1 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.57 - 7.51 (m, 1H), 7.43 - 7.37 (m, 2H), 6.60 - 6.53 (m, 1H), 4.41 - 4.25 (m, 2H), 3.81 (dt, J = 3.5, 11.5 Hz, 1H), 3.56 (s, 4H), 2.87 (s, 3H), 2.74 (s, 3H), 2.43 - 2.36 (m, 1H), 2.28 - 2.04 (m, 3H). Example 5 : LCMS : [M+H] ⁺ = 514.3; Purity = 98% (220 nm); Retention time = 0.535 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (t, J = 7.3 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.44 - 7.37 (m, 2H), 6.60 - 6.54 (m, 1H), 4.39 - 4.28 (m, 2H), 3.81 (dt, J = 3.1, 11.5 Hz, 1H), 3.62 - 3.53 (m, 4H), 2.87 (s, 3H), 2.74 (s, 3H), 2.39 (br d, J = 13.4 Hz, 1H), 2.29 - 2.07 (m, 3H). Example 20 continues with SFC : Example 18 Example 19 The crude material (Example 20) was purified by silicone tube column chromatography (33% EtOAc/PE, _Rf = 0.3) to remove color, and then purified by preparative HPLC (FA) and freeze-dried to obtain 90 mg of racemic product. 90 mg of the racemic product was combined with another batch and purified by SFC (condition 2, gradient a) to give solid 5-[(2R,4S)-4-[4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 18, 7.2 mg, 0.014 mmol, 2.5% yield) and solid 5-[(2S,4R)-4-[4-[2,3-difluoro-4-(trifluoro-methyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 19, 8.3 mg, 0.016 mmol, 3% yield). Example 18 : LCMS : Retention time = 0.632 min; [M+H] ⁺ = 532.4, Purity = 100%, (220 nm), Retention time = 0.559 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.04 - 2.12 (m, 1H), 2.14 - 2.25 (m, 1H), 2.21 (br d, J=3.5 Hz, 1H), 2.33 - 2.43 (m, 1H), 2.76 (s, 3H), 2.87 (s, 3H), 3.52 - 3.60 (m, 1H), 3.56 (s, 2H), 3.81 (td, J=11.60, 2.9 Hz, 1H), 4.26 - 4.39 (m, 2H), 6.55 - 6.61 (m, 1H), 7.37 - 7.44 (m, 2H), 7.59 (t, J=2.9 Hz, 2H). Example 19 : LCMS : Retention time = 1.253 min; [M+H] ⁺ = 532.4, purity = 100%, (220 nm), retention time = 0.552 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.04 - 2.25 (m, 3H), 2.32 - 2.44 (m, 1H), 2.76 (s, 3H), 2.87 (s, 3H), 3.52 - 3.64 (m, 4H), 3.73 - 3.88 (m, 1H), 4.25 - 4.41 (m, 2H), 6.58 (br d, J=10.1 Hz, 1H), 7.36 - 7.45 (m, 2H), 7.54 - 7.64 (m, 2H). Example 27 continues with SFC : Example 25 Example 26 The residue was purified by silicone column chromatography (100% to 66% EtOAc/MeOH) (TLC: 9% MeOH/DCM, _Rf = 0.5) to give 270 mg of crude product. The crude product was then purified by preparative TLC (6% MeOH/DCM; desired product _Rf = 0.3) to give 30 mg of the desired product (86% purity, as verified by LCMS). 30 mg of the desired product was purified by reversed-phase chromatography (40-60% [(0.1% FA) _H₂O -MeCN) and freeze-dried to give 5-(4-(6,7-dimethyl-4-(3-(trifluoromethyl)-bis(1.1.1)pentan-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one as a solid (Example 27, 15 mg, 0.031 mmol, 6% yield). LCMS : [M+H] ^⁺ = 486.4; purity = 97% (220 nm); retention time = 0.563 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 - 7.34 (m, 2H), 6.70 - 6.58 (m, 1H), 4.61 - 4.25 (m, 2H), 3.88 - 3.76 (m, 1H), 3.57 (s, 3H), 3.51 - 3.40 (m, 1H), 2.84 - 2.78 (m, 6H), 2.68 - 2.63 (m, 6H), 2.32 (br d, J = 13.3 Hz, 1H), 2.20 - 2.06 (m, 2H), 2.05 - 2.01 (m, 1H). Example 27 ( 1 equivalent, 13 mg, 0.027 mmol) was purified by preparative SFC to give 10 mg of cis product (86% purity) and 3 mg of trans product (60% purity). The 10 mg cis product was purified by preparative TLC (6% MeOH/DCM, _Rf = 0.6) and freeze-dried to give cis-5-(4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]-pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one as a solid (Example 27a, 4.4 mg, 0.008 mmol, 31% yield). LCMS : [M+H] ⁺ = 486.4; Purity = 92% (220 nm); Retention time = 0.558 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 - 7.34 (m, 2H), 6.59 (d, J = 10.3 Hz, 1H), 4.42 - 4.23 (m, 2H), 3.80 (dt, J = 3.3, 11.5 Hz, 1H), 3.56 (s, 3H), 3.46 (tt, J = 4.3, 11.6 Hz, 1H), 2.80 (d, J = 14.4 Hz, 6H), 2.65 (s, 6H), 2.32 (br d, J = 13.1 Hz, 1H), 2.20 - 2.09 (m, 2H), 2.07 - 2.01 (m, 1H). Cis-5-[4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]-tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 27a, 1 equivalent, 140 mg, 0.29 mmol) was separated by a preparative SFC (condition 1, gradient a-1) to obtain solid 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]-tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 25, 28 mg, 0.055 mmol). mmol, 19% yield) and 5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one in solid form (Example 26, 38 mg, 0.072 mmol, 25% yield). Example 25 : LCMS : [M+H] ⁺ = 486.2; purity = 96% (220 nm); retention time = 0.561 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 - 7.36 (m, 2H), 6.57 (d, J = 10.0 Hz, 1H), 4.38 - 4.24 (m, 2H), 3.79 (dt, J = 2.8, 11.4 Hz, 1H), 3.55 (s, 3H), 3.50 - 3.40 (m, 1H), 2.80 (d, J = 14.4 Hz, 6H), 2.65 (s, 6H), 2.31 (br d, J = 13.3 Hz, 1H), 2.19 - 1.97 (m, 3H). Example 26 : LCMS : [M+H] ⁺ = 486.2; Purity = 92% (220 nm); Retention time = 0.563 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 - 7.36 (m, 2H), 6.58 (br d, J = 10.0 Hz, 1H), 4.39 - 4.24 (m, 2H), 3.80 (dt, J = 3.1, 11.4 Hz, 1H), 3.56 (s, 3H), 3.49 (br s, 1H), 2.80 (d, J = 14.4 Hz, 6H), 2.65 (s, 6H), 2.32 (br d, J = 13.0 Hz, 1H), 2.18 - 1.96 (m, 3H). Example 33 Example 31 Example 32 The residue was purified by rapid silica gel chromatography (0-30% EtOAc/MeOH) to obtain a crude product, which was then purified by preparative TLC (5% MeOH/DCM, _Rf = 0.3) to give a solid 5-[4-[4-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (cis-Example 33, 100 mg, 0.214 mmol, 76% yield). LCMS : retention time = 0.537 min, 468.2 = [M+H] ⁺ , ESI ⁺ . 5-[4-[4-[3-(difluoromethyl)-1-bicyclo[1.1.1]-pentyl]-6,7-dimethyl-pteridin-2-yl]-tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 33, 1 equivalent, 100 mg, 0.214 mmol) was purified by SFC (condition 4, gradient a) to give solid 5-[(2R,4S)-4-[4-[3-(difluoromethyl)-1-bicyclo[1.1.1]-pentyl]-6,7-dimethyl-pteridin-2-yl]-tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 31, 24 mg, 0.050 mmol, 23% yield). The crude product was purified by a second SFC (condition 5, gradient a) to give 5-[(2S,4R)-4-[4-[3-(difluoromethyl)-1-bicyclo[1.1.1]-pentyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one as a solid (Example 32, 9.5 mg, 0.02 mmol, 9% yield). Example 31 : LCMS : [M+H] ⁺ = 468.2; purity = 95% (220 nm); retention time = 0.530 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.98 - 2.08 (m, 1H), 2.09 - 2.19 (m, 2H), 2.32 (br d, J=13.4 Hz, 1H), 2.55 (s, 6H), 2.79 (d, J=14.3 Hz, 6H), 3.39 - 3.50 (m, 1H), 3.56 (s, 3H), 3.80 (td, J=11.4, 3.6 Hz, 1H), 4.23 - 4.38 (m, 2H), 5.65 - 6.05 (m, 1H), 6.53 - 6.60 (m, 1H), 7.36 - 7.44 (m, 2H). Example 32 : LCMS : [M+H] ⁺ = 468.2; Purity = 97% (220 nm); Retention time = 0.530 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.96 - 2.17 (m, 3H), 2.32 (br d, J=13.1 Hz, 1H), 2.55 (s, 6H), 2.79 (d, J=14.1 Hz, 6H), 3.39 - 3.50 (m, 1H), 3.56 (s, 3H), 3.80 (td, J=11.5, 3.3 Hz, 1H), 4.25 - 4.37 (m, 2H), 5.70 - 6.02 (m, 1H), 6.54 - 6.61 (m, 1H), 7.37 - 7.44 (m, 2H). Example 157 continues with SFC : Example 155 Example 156 First purification: The crude product 5-[4-[7-cyclopropyl-6-methyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)-pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-methylpyridin-2-one (Example 157, 1 equivalent, 1.0 g, 1.95 mmol) was purified for the first time by reversed-phase HPLC (35-45% [water (0.05% FA)-ACN], 5 min) to obtain an oily crude product (130 mg). Second purification: The crude product (130 mg) was purified by SFC (condition 6, gradient a) to obtain crude product A and crude product B. Third purification: Crude substance A was further purified by preparative HPLC (condition 5, gradient a) to obtain 1-methyl-5-[(2S,4R)-4-[7-cyclopropyl-6-methyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 156, 4.4 mg, 0.008 mmol, 0.43% yield). LCMS : [M+H] ⁺ = 512.2; purity = 99% (220 nm); retention time = 0.598 min. ¹ H NMR (400 MHz, CDCl ₃ , 301 K) δ 7.45 - 7.37 (m, 2H), 6.59 (d, J = 10.1 Hz, 1H), 4.38 - 4.25 (m, 2H), 3.80 (dt, J = 3.4, 11.4 Hz, 1H), 3.57 (s, 3H), 3.50 - 3.40 (m, 1H), 2.97 (s, 3H), 2.61 (s, 6H), 2.43 - 2.35 (m, 1H), 2.31 (br d, J = 13.1 Hz, 1H), 2.18 - 2.08 (m, 2H), 2.07 - 1.97 (m, 1H), 1.31 - 1.24 (m, 4H). Crude substance B was further purified by preparative HPLC (condition 5, gradient b) to give 1-methyl-5-[(2R,4S)-4-[7-cyclopropyl-6-methyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 155, 18 mg, 0.034 mmol, 2% yield). LCMS : [M+H] ⁺ = 512.3; purity = 97% (220 nm); retention time = 0.595 min. ¹ H NMR (400 MHz, CDCl ₃ , 301 K) δ 7.42 - 7.38 (m, 2H), 6.59 - 6.55 (m, 1H), 4.35 - 4.25 (m, 2H), 3.79 (dt, J = 3.4, 11.4 Hz, 1H), 3.55 (s, 3H), 3.48 - 3.39 (m, 1H), 2.96 (s, 3H), 2.60 (s, 6H), 2.42 - 2.34 (m, 1H), 2.30 (br d, J = 13.3 Hz, 1H), 2.15 - 1.96 (m, 3H), 1.30 - 1.24 (m, 4H). Example 160 followed by SFC : Example 158 Example 159 First purification: The crude material 5-[4-[6-cyclopropyl-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 160, 1 equivalent, 1.0 g, 1.95 mmol) was purified by reversed-phase HPLC (85-90% [water (0.05% FA)-ACN], 5 min) to give an oily crude product (120 mg). Second purification: The crude product (120 mg) was purified by SFC (condition 7, gradient a) to give crude product A (48 mg) and crude product B (52 mg). Third purification: Crude substance A was further purified by SFC (condition 8, gradient a) to obtain crude substance 1 and crude substance 2. Crude substance B was further purified by SFC (condition 6, gradient b) to obtain crude substance 3 and crude substance 4. Fourth purification: Crude substance 1 was further purified by preparative HPLC (condition 5, gradient c) to obtain 1-methyl-5-[(2S,4R)-4-[6-cyclopropyl-7-methyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one in solid form (Example 159, 3.3 mg, 0.006 mmol, 0.3% yield). The crude material 2 was further purified by preparative HPLC (condition 5, gradient c) to obtain 1-methyl-5-[(2R,4S)-4-[6-cyclopropyl-7-methyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 158, 4.4 mg, 0.009 mmol, 0.4% yield). Crude material 3 was further purified by preparative HPLC (condition 5, gradient c) to obtain 1-methyl-5-[(2S,4R)-4-[6-cyclopropyl-7-methyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 159, 13 mg, 0.025 mmol, 1.3% yield). LCMS : [M+H] ⁺ = 512.2; purity = 99% (220 nm); retention time = 0.614 min. ¹ H NMR (400 MHz, CDCl ₃ , 301 K) δ 7.41 - 7.36 (m, 2H), 6.60 - 6.55 (m, 1H), 4.34 - 4.24 (m, 2H), 3.77 (dt, J = 2.4, 11.9 Hz, 1H), 3.55 (s, 3H), 3.45 (tt, J = 3.7, 11.9 Hz, 1H), 2.90 (s, 3H), 2.64 (s, 6H), 2.39 - 2.31 (m, 1H), 2.27 - 2.20 (m, 1H), 2.19 - 2.10 (m, 1H), 2.09 - 1.93 (m, 2H), 1.53 - 1.48 (m, 2H), 1.30 - 1.24 (m, 2H), and ee = 100%. Crude material 4 was further purified by preparative HPLC (condition 5, gradient c) to give 1-methyl-5-[(2R,4S)-4-[6-cyclopropyl-7-methyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 158, 14 mg, 0.0267 mmol, 1.5% yield). LCMS : [M+H] ⁺ = 512.2; purity = 99.6% (220 nm); retention time = 0.607 min. ¹ H NMR (400 MHz, CDCl ₃ , 301 K) δ 7.41 - 7.35 (m, 2H), 6.60 - 6.55 (m, 1H), 4.35 - 4.24 (m, 2H), 3.77 (dt, J = 2.3, 12.0 Hz, 1H), 3.55 (s, 3H), 3.45 (tt, J = 3.7, 11.9 Hz, 1H), 2.90 (s, 3H), 2.64 (s, 6H), 2.38 - 2.31 (m, 1H), 2.27 - 2.20 (m, 1H), 2.15 (dt, J = 4.5, 12.5 Hz, 1H), 2.09 - 1.94 (m, 2H), 1.53 - 1.47 (m, 2H), 1.30 - 1.24 (m, 2H). ee = 100%. Example 159 : LCMS : (M+H) ⁺ = 512.2; purity = 98% (220 nm); retention time = 0.610 min. ¹ H NMR (400 MHz, CDCl ₃ , 301 K) δ 7.41 - 7.36 (m, 2H), 6.60 - 6.55 (m, 1H), 4.34 - 4.25 (m, 2H), 3.77 (dt, J = 2.3, 12.0 Hz, 1H), 3.55 (s, 3H), 3.45 (tt, J = 3.9, 12.0 Hz, 1H), 2.91 (s, 3H), 2.64 (s, 6H), 2.39 - 2.31 (m, 1H), 2.26 - 2.20 (m, 1H), 2.19 - 2.11 (m, 1H), 2.08 - 1.94 (m, 2H), 1.52 - 1.48 (m, 2H), 1.28 - 1.26 (m, 2H), and ee. 100%. Example 158 : LCMS : (M+H) ⁺ = 512.2; purity = 99% (220 nm); residence time = 0.608 min. ¹ H NMR (400 MHz, CDCl ₃ , 301 K) δ 7.43 - 7.37 (m, 2H), 6.63 - 6.56 (m, 1H), 4.35 - 4.27 (m, 2H), 3.78 (dt, J = 2.3, 12.0 Hz, 1H), 3.57 (s, 3H), 3.47 (tt, J = 3.6, 11.9 Hz, 1H), 2.92 (s, 3H), 2.65 (s, 6H), 2.40 - 2.33 (m, 1H), 2.28 - 2.21 (m, 1H), 2.20 - 2.12 (m, 1H), 2.10 - 1.95 (m, 2H), 1.54 - 1.49 (m, 2H), 1.31 - 1.26 (m, 2H), and ee = 100%. Example 125 continues with SFC : Example 123 Example 124 Example 343 The crude product was purified by silicone column chromatography (0-100% petroleum ether/EtOAc, and 100-50% EtOAc/MeOH) (TLC, 9% MeOH/DCM, desired product _Rf = 0.4) to give 1-methyl-5-(4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]-pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 125, 1 equivalent, 150 mg, 0.32 mmol). Then, SFC was applied : the crude product was purified by SFC (condition 5, gradient a-1) to give crude product A (20 mg) and crude product B (10 mg). 10 mg of crude substance B was lyophilized to give 1-methyl-5-((2R,4S)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one as a solid (Example 123, 7.6 mg, 0.013 mmol, 4% yield). LCMS : [M+H] ⁺ = 472.2; purity = 80% (220 nm); retention time = 0.549 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.83 - 8.79 (m, 1H), 7.44 - 7.37 (m, 2H), 6.61 - 6.54 (m, 1H), 4.37 - 4.25 (m, 2H), 3.87 (s, 1H), 3.56 (s, 3H), 3.53 - 3.44 (m, 1H), 2.87 (s, 3H), 2.66 (s, 6H), 2.33 (br d, J = 13.0 Hz, 1H), 2.18 - 2.01 (m, 3H). 20 mg of crude substance A was purified by SFC (condition 9, gradient a) to give 1-methyl-5-[(2R,4R)-4-[7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 343, 3.0 mg, 0.006 mmol, 2% yield) and 1-methyl-5-((2S,4R)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one in solid form (Example 124, 4.7 mg, 0.008 mmol, 3% yield). LCMS : [M+H] ⁺ = 472.2; Purity = 80% (220 nm); Retention time = 0.545 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 7.43 - 7.38 (m, 2H), 6.60 - 6.56 (m, 1H), 4.37 - 4.26 (m, 2H), 3.85 - 3.76 (m, 1H), 3.56 (s, 3H), 3.53 - 3.43 (m, 1H), 2.87 (s, 3H), 2.69 - 2.63 (m, 6H), 2.37 - 2.28 (m, 1H), 2.22 - 2.02 (m, 3H). Example 15 continues with SFC : Example 11 Example 12 Example 13 Example 14 The crude material (Example 15) was purified by silicone column chromatography (9% MeOH/EtOAc, _Rf = 0.3) and concentrated under reduced pressure to give 400 mg of product. This product was then purified by preparative HPLC (condition 6, gradient a) and freeze-dried to give a solid 1-methyl-5-[rac-(2R,4S)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 15a, 150 mg, 0.31 mg). mmol, 17% yield) and 1-methyl-5-[rac-(2R,4R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]tetrahydropiperan-2-yl]pyridin-2-one in solid form (Example 15b , 110 mg, 0.23 mmol, 12% yield). Example 15a : LCMS : [M+H] ⁺ = 484.3; purity = 100% (220 nm); retention time = 0.486 min. Example 15b : LCMS : [M+H] ⁺ = 484.3; purity = 100% (220 nm); retention time = 0.492 min. Next , SFC was used to purify 1-methyl-5-[rac-(2R,4S)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)-thiazo[4,5-d]pyrimidin-5-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 15a, 150 mg) to give crude product A (60 mg) and crude product B (60 mg). Crude substance A was separated by SFC (condition 10, gradient a) and freeze-dried to obtain solid 5-[(2R,4S)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 13, 54 mg, 0.11 mmol, 90% yield). LCMS : [M+H]+ = 484.2, purity = 100% (220 nm); retention time = 0.480 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (dt, J = 6.6, 8.4 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.06 (dt, J = 2.4, 8.3 Hz, 1H), 6.98 (ddd, J = 2.5, 8.7, 10.7 Hz, 1H), 6.56 (d, J = 9.1 Hz, 1H), 4.32 - 4.23 (m, 2H), 3.75 (dt, J = 3.1, 11.5 Hz, 1H), 3.55 (s, 3H), 3.33 (ddd, J = 3.9, 7.8, 15.4 Hz, 6H), 2.31 - 2.23 (m, 1H), 2.21 - 1.98 (m, 4H). Crude substance B was separated by SFC (condition 10, gradient a) and freeze-dried to give solid 5-[(2S,4R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 14, 46 mg, 0.09 mmol, 75% yield). LCMS : [M+H] ⁺ = 484.2, purity = 99% (220 nm); retention time = 0.482 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (dt, J = 6.5, 8.4 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.06 (dt, J = 2.1, 8.1 Hz, 1H), 6.98 (ddd, J = 2.4, 8.6, 10.7 Hz, 1H), 6.56 (d, J = 9.1 Hz, 1H), 4.28 (dt, J = 2.3, 10.7 Hz, 2H), 3.75 (dt, J = 3.0, 11.6 Hz, 1H), 3.55 (s, 3H), 3.42 - 3.24 (m, 6H), 2.30 - 2.22 (m, 1H), 2.21 - 1.98 (m, 4H). 1-Methyl-5-[rac-(2R,4R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 15b , 110 mg) was separated by SFC (condition 10, gradient a) and freeze-dried to give solid 5-[(2S,4S)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 11, 46 mg, 0.09 mg). mmol, 45% yield) and 5-[(2R,4R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one in solid form (Example 12, 42 mg, 0.07 mmol, 37% yield). Example 11 : LCMS : [M+H] ⁺ = 484.2, purity = 90% (220 nm); retention time = 0.494 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (dt, J = 6.4, 8.5 Hz, 1H), 7.40 (dd, J = 2.4, 9.3 Hz, 1H), 7.37 (s, 1H), 7.08 (dt, J = 2.3, 8.2 Hz, 1H), 7.01 (ddd, J = 2.4, 8.6, 10.7 Hz, 1H), 6.58 (d, J = 9.4 Hz, 1H), 4.63 (dd, J = 2.3, 9.9 Hz, 1H), 3.97 - 3.86 (m, 2H), 3.63 - 3.57 (m, 1H), 3.55 (s, 3H), 3.36 (br d, J = 12.3 Hz, 6H), 2.72 (br d, J = 13.5 Hz, 1H), 2.52 (br dd, J = 1.8, 13.7 Hz, 1H), 2.19 - 2.11 (m, 1H), 2.11 - 2.01 (m, 1H). Example 12 : LCMS : [M+H] ⁺ = 484.2, purity = 98% (220 nm); residence time = 0.494 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (dt, J = 6.4, 8.5 Hz, 1H), 7.41 (dd, J = 2.4, 9.3 Hz, 1H), 7.37 (s, 1H), 7.08 (dt, J = 2.1, 8.1 Hz, 1H), 7.01 (ddd, J = 2.4, 8.6, 10.7 Hz, 1H), 6.58 (d, J = 9.4 Hz, 1H), 4.63 (dd, J = 2.3, 10.0 Hz, 1H), 3.97 - 3.87 (m, 2H), 3.59 (br s, 1H), 3.56 (s, 3H), 3.36 (br d, J = 12.4 Hz, 6H), 2.72 (br d, J = 13.4 Hz, 1H), 2.52 (br dd, J = 1.8, 13.7 Hz, 1H), 2.20 - 2.11 (m, 1H), 2.10 - 2.01 (m, 1H).

Following a similar method, the following compounds were obtained. Structure Intermediate materials used Characteristics Example 67 continues with SFC : Example 64 Example 65 Example 66 The crude product was purified by silicone column chromatography (0-100% PE/EtOAc and 0-50% EtOAc/MeOH) to obtain a crude residue, which was then purified by reversed-phase HPLC (0.1% FA conditions) to obtain an oily 1-cyclopropyl-5-(4-(4-(2-fluoro-4-(trifluoromethyl)-phenyl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 67, 60 mg, 0.11 mmol, 16% yield). Next , SFC was used to purify 1-cyclopropyl-5-[4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 67) by SFC (condition 16, gradient a) to give 1-cyclopropyl-5-[(2R,4R)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 66, 49 mg, 0.087 mg). 1-Cyclopropyl-5-[(2S,4R)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 65, 95 mg, 0.176 mmol, 16% yield) was obtained as a pink solid, and 1-Cyclopropyl-5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 64, 51 mg, 0.0944 mmol, 8% yield) was obtained as a solid. Example 66 : SFC (condition 17, gradient a): This shows that Example 66 is a ~1:1 mixture of two trans isomers. LCMS : [M+H] ⁺ = 540.4; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (t, J = 7.3 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.44 - 7.35 (m, 2H), 6.61 - 6.50 (m, 1H), 4.37 - 4.24 (m, 2H), 3.86 - 3.75 (m, 1H), 3.57 (ddd, J = 3.7, 11.9, 15.8 Hz, 1H), 3.36 - 3.27 (m, 1H), 2.86 (s, 3H), 2.76 - 2.71 (m, 3H), 2.36 (br d, J = 13.3 Hz, 1H), 2.26 - 2.17 (m, 2H), 2.16 - 2.03 (m, 1H), 1.18 - 1.08 (m, 2H), 0.96 - 0.84 (m, 2H). Example 65 : LCMS : [M+H] ⁺ = 540.2; Purity = 97% (220 nm); Retention time = 0.561 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (t, J = 7.3 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.54 (br d, J = 9.5 Hz, 1H), 7.42 - 7.37 (m, 2H), 6.58 (d, J = 10.1 Hz, 1H), 4.32 (br t, J = 9.3 Hz, 2H), 3.84 - 3.76 (m, 1H), 3.62 - 3.52 (m, 1H), 3.37 - 3.29 (m, 1H), 2.86 (s, 3H), 2.74 (s, 3H), 2.40 - 2.33 (m, 1H), 2.25 - 2.17 (m, 2H), 2.15 - 2.04 (m, 1H), 1.17 - 1.11 (m, 2H), 0.91 - 0.88 (m, 2H). Example 64 : LCMS : [M+H] ⁺ = 540.2; Purity = 97% (220 nm); Retention time = 0.558 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 - 7.82 (m, 1H), 7.66 - 7.60 (m, 1H), 7.56 - 7.51 (m, 1H), 7.38 (br s, 2H), 6.56 (br d, J = 10.0 Hz, 1H), 4.36 - 4.26 (m, 2H), 3.84 - 3.74 (m, 1H), 3.62 - 3.51 (m, 1H), 3.37 - 3.28 (m, 1H), 2.86 (s, 3H), 2.74 (s, 3H), 2.40 - 2.32 (m, 1H), 2.24 - 2.17 (m, 2H), 2.05 (s, 1H), 1.14 (br d, J = 7.3 Hz, 2H), 0.89 (br d, J = 3.0 Hz, 2H). Example 76 continues with SFC : Example 74 Example 75 The residue was purified by silicone column chromatography (0-100% MeOH/EtOAc) (TLC, 9% MeOH/DCM, _Rf = 0.6), and further purified by preparative TLC (9% MeOH/DCM, _Rf = 0.6) to obtain 150 mg for SFC separation. Example 76 : LCMS : [M+H] ⁺ = 512.3; purity = 84% (220 nm); retention time = 0.587 min. Next , SFC was used to separate Example 76 (150 mg, 84% purity) by SFC (condition 5, gradient c) to obtain 1-cyclopropyl-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 74, 19 mg, 0.037 mg) in solid form. mmol, 13% yield) and 1-cyclopropyl-5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)-pentyl]-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one in solid form (Example 75, 14 mg, 0.027 mmol, 9% yield). Example 74 : LCMS : [M+H] ⁺ = 512.3; purity = 98% (220 nm); retention time = 0.580 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 - 7.32 (m, 2H), 6.57 - 6.50 (m, 1H), 4.35 - 4.22 (m, 2H), 3.86 - 3.64 (m, 2H), 3.49 - 3.38 (m, 1H), 3.35 - 3.27 (m, 1H), 2.78 (d, J = 13.8 Hz, 6H), 2.64 (s, 6H), 2.28 (br d, J = 13.3 Hz, 1H), 2.16 - 2.08 (m, 2H), 2.06 - 1.95 (m, 1H), 1.19 - 1.06 (m, 2H), 0.88 (br d, J = 4.1 Hz, 2H). Example 75 : LCMS : [M+H] ⁺ = 512.3; purity = 99.3% (220 nm); residence time = 0.585 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 - 7.34 (m, 2H), 6.56 - 6.50 (m, 1H), 4.35 - 4.23 (m, 2H), 3.78 (ddd, J = 4.6, 6.7, 15.0 Hz, 1H), 3.50 - 3.36 (m, 1H), 3.35 - 3.27 (m, 1H), 2.79 (d, J = 13.9 Hz, 6H), 2.64 (s, 6H), 2.28 (br d, J = 13.4 Hz, 1H), 2.17 - 2.09 (m, 2H), 2.02 - 1.99 (m, 1H), 1.17 - 1.08 (m, 2H), 0.91 - 0.86 (m, 2H). Example 70 continues with SFC : Example 68 Example 69 The residue was purified by silicone column chromatography (0-100% MeOH/EtOAc) (TLC, 6% MeOH/DCM, _Rf = 0.60) to obtain a solid. The product was purified twice by preparative TLC (6% MeOH/DCM, _Rf = 0.55) to remove the color and obtain the desired product 5-[4-[4-[2-fluoro-4-(trifluoro-methyl)phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-isopropyl-pyridin-2-one (Example 70, 70 mg, 0.106 mmol, 12% yield). LCMS : [M+H] ⁺ = 542.1; purity = 84% (220 nm); retention time = 0.576 min. Then, SFC : The residue (Example 70) was separated by SFC (condition 1, gradient a) to obtain 1-isopropyl-5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)-phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 68, 12 mg, 0.0218 mmol, 26% yield). Example 68 : LCMS : [M+H] ⁺ = 542.2; purity = 95% (220 nm); retention time = 0.580 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (t, J = 7.2 Hz, 1H), 7.63 (br d, J = 7.9 Hz, 1H), 7.53 (d, J = 9.4 Hz, 1H), 7.40 (br d, J = 3.6 Hz, 2H), 6.64 - 6.45 (m, 1H), 5.49 - 5.13 (m, 1H), 4.53 - 4.19 (m, 2H), 3.92 - 3.72 (m, 1H), 3.65 - 3.51 (m, 1H), 2.86 (s, 3H), 2.74 (s, 3H), 2.46 - 2.30 (m, 1H), 2.27 - 2.16 (m, 2H), 2.14 - 1.99 (m, 1H), 1.37 (br d, J = 5.3 Hz, 6H). Another fraction (20 mg, 88% purity) was further separated by SFC (condition 1, gradient a) to give solid 1-isopropyl-5-[(2S,4R)-4-[4-[2-fluoro-4-(trifluoromethyl)-phenyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 69, 6.7 mg, 0.012 mmol, 15% yield). Example 69 : LCMS : [M+H] ⁺ = 542.2; purity = 97% (220 nm); retention time = 0.579 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (t, J = 7.3 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 9.4 Hz, 1H), 7.45 - 7.30 (m, 2H), 6.66 - 6.50 (m, 1H), 5.40 - 5.21 (m, 1H), 4.53 - 4.21 (m, 2H), 3.85 - 3.71 (m, 1H), 3.63 - 3.52 (m, 1H), 2.86 (s, 3H), 2.74 (s, 3H), 2.37 (br d, J = 13.3 Hz, 1H), 2.28 - 2.19 (m, 2H), 2.16 - 2.02 (m, 1H), 1.37 (br d, J = 5.4 Hz, 6H). Example 79 continues with SFC : Example 77 Example 78 The combined organic layer was dried _with anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude residue (Example 79). Next, SFC was performed : the crude material (Example 79) was purified by silicone column chromatography (9% MeOH/EtOAc, _Rf = 0.3) to obtain 80 mg of solid product. Next, 80 mg of the product was separated and freeze-dried using SFC (condition 6, gradient c) to give crude product A and solid 1-isopropyl-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 77, 18 mg, 0.032 mmol, 14% yield). Example 77 : LCMS : [M+H] ⁺ = 514.2; purity = 95% (UV 220 nm); retention time = 0.601 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 - 7.32 (m, 2H), 6.56 (d, J = 9.3 Hz, 1H), 5.38 - 5.19 (m, 1H), 4.39 - 4.25 (m, 2H), 3.84 - 3.73 (m, 1H), 3.55 - 3.37 (m, 1H), 2.81 (s, 3H), 2.77 (s, 3H), 2.68 - 2.62 (m, 6H), 2.34 - 2.24 (m, 1H), 2.18 - 2.08 (m, 2H), 2.06 - 1.96 (m, 1H), 1.38 - 1.34 (m, 6H). SFC : 100% ee. Crude substance A (40 mg) was further separated by SFC (condition 6, gradient d) and freeze-dried to obtain crude substances B and C. Crude substance C (18 mg) was purified by preparative TLC (9% MeOH/DCM, _Rf = 0.3) (×3) and concentrated under reduced pressure to give 1-isopropyl-5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one in solid form (Example 78, 3.6 mg, 0.006 mmol, 3% yield). Example 78 : LCMS : [M+H] ⁺ = 514.3; Purity = 92% (UV 220 nm); Retention time = 0.608 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 - 7.33 (m, 2H), 6.56 (d, J = 9.1 Hz, 1H), 5.33 - 5.21 (m, 1H), 4.33 (br dd, J = 2.1, 13.3 Hz, 2H), 3.86 - 3.72 (m, 1H), 3.53 - 3.39 (m, 1H), 2.80 (s, 3H), 2.78 - 2.74 (m, 3H), 2.64 (s, 6H), 2.33 - 2.26 (m, 1H), 2.22 - 2.10 (m, 2H), 2.02 - 2.00 (m, 1H), 1.36 (dd, J = 1.2, 6.8 Hz, 6H). SFC : 100%ee. Example 73 continues with SFC : Example 71 Example 72 The crude substance 1-(2,2-difluoroethyl)-5-[4-[6,7-dimethyl-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 73, 144 mg, 0.268 mmol, 100% yield) was obtained in solid form. Next, SFC : 1-(2,2-difluoroethyl)-5-[4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 73, 1 equivalent, 400 mg, 0.747 mmol) was purified by preparative TLC (100% EtOAc, desired product _Rf = 0.4) to give crude product (130 mg). The crude product was purified by SFC (condition 11, gradient c) and freeze-dried to give solid 1-(2,2-difluoroethyl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 71, 27 mg, 0.045 mmol, 6% yield) and solid 1-(2,2-difluoroethyl)-5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoro-methyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 72, 27 mg, 0.045 mmol, 6% yield). mg, 0.047 mmol, 6% yield). Example 71 : LCMS : [M+H] ⁺ = 536.0; purity = 93% (220 nm); retention time = 0.608 min. HPLC : retention time = 2.020 min, 89% purity, at 220 nm. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (dd, J = 2.4, 9.4 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 9.5 Hz, 1H), 6.31 - 5.94 (m, 1H), 4.36 - 4.18 (m, 4H), 3.78 (dt, J = 3.3, 11.5 Hz, 1H), 3.51 - 3.40 (m, 1H), 2.79 (d, J = 14.1 Hz, 6H), 2.64 (s, 6H), 2.32 (br d, J = 13.6 Hz, 1H), 2.20 - 2.08 (m, 2H), 2.07 - 1.94 (m, 1H). Example 72 : LCMS : [M+H] ⁺ = 536.0; purity = 94% (220 nm); retention time = 0.606 min. HPLC : retention time = 2.019 min, 92% purity, at 220 nm. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (dd, J = 2.4, 9.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 9.5 Hz, 1H), 6.29 - 5.96 (m, 1H), 4.36 - 4.17 (m, 4H), 3.78 (dt, J = 3.3, 11.6 Hz, 1H), 3.51 - 3.39 (m, 1H), 2.79 (d, J = 14.3 Hz, 6H), 2.64 (s, 6H), 2.32 (br dd, J = 1.5, 13.1 Hz, 1H), 2.21 - 2.09 (m, 2H), 2.07 - 1.93 (m, 1H). Example 319 continues with SFC : Example 320 Example 321 Int-B18 The crude residue (150 mg) was purified by silicone column chromatography (0-100% EtOAc/PE, and EtOAc/MeOH) (TLC, 25% MeOH/EtOAc, _Rf = 0.4) to obtain 71 mg of crude product as a solid (Example 319). The crude product was further purified by SFC (condition 11, gradient a) to obtain crude substance A (20 mg, 78% purity) and crude substance B (20 mg, 81% purity). Crude substance A (20 mg) was purified by SFC (condition 11, gradient b) followed by preparative HPLC (condition 7, gradient a) to give 1-methyl-5-[(2R,4S)-4-[7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)-pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 320, 4.2 mg, 0.01 mmol, 3% yield). LCMS : [M+H] ⁺ = 471.0; retention time = 0.516 min. HPLC : retention time = 1.495 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 8.5 Hz, 1H), 7.46-7.35 (m, 3H), 6.57 (d, J = 10.3 Hz, 1H), 4.38-4.24 (m, 2H), 3.79 (dt, J = 3.7, 11.2 Hz, 1H), 3.55 (s, 3H), 3.48-3.36 (m, 1H), 2.83 (s, 3H), 2.63 (s, 6H), 2.31 (br d, J = 13.3 Hz, 1H), 2.18-2.08 (m, 2H), 2.03 (br d, J = 13.0 Hz, 1H). Crude substance B (20 mg) was purified by HPLC (condition 7, gradient a) to give 1-methyl-5-[(2S,4R)-4-[7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)-pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 321, 5.8 mg, 0.012 mmol, 4% yield). LCMS : [M+H] ⁺ = 471.2; retention time = 0.509 min. HPLC : retention time = 1.491 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 8.5 Hz, 1H), 7.47-7.34 (m, 3H), 6.57 (d, J = 10.1 Hz, 1H), 4.37-4.21 (m, 2H), 3.86-3.72 (m, 1H), 3.55 (s, 3H), 3.48-3.37 (m, 1H), 2.83 (s, 3H), 2.63 (s, 6H), 2.31 (br d, J = 13.1 Hz, 1H), 2.18-1.98 (m, 3H). Example 344 continues with SFC : Example 94 Example 95 Int-F15 The procedure yields 1-cyclobutyl-5-(4-(6,7-dimethyl-4-(3-(trifluoromethyl)bis(1.1.1)pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 344). It is further purified by SFC (condition 20, gradient a) to obtain a concentrated mixture A in solid form. Mixture A was further purified by SFC (condition 21, gradient a) to two absolute configuration products, yielding solid 1-cyclobutyl-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 94, 28 mg, 0.0525 mmol, 6% yield) and 1-cyclobutyl-5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 95, 27 mg, 0.0495 mmol ... (mmol, 5% yield). Example 94: LCMS : [M+H] ⁺ = 526.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.82 - 1.90 (m, 2 H) 1.99 - 2.08 (m, 1 H) 2.12 - 2.19 (m, 2 H) 2.20 - 2.34 (m, 3 H) 2.46 - 2.54 (m, 2 H) 2.65 (s, 6 H) 2.78 (s, 3 H) 2.82 (s, 3 H) 3.42 - 3.52 (m, 1 H) 3.76 - 3.85 (m, 1 H) 4.28 - 4.38 (m, 2 H) 5.10 - 5.20 (m, 1 H) 6.53 (d, J=9.4 Hz, 1 H) 7.37 (dd, J=9.4, 2.50 Hz, 1 H) 7.51 (d, J=2.4 Hz, 1 H). Example 95: LCMS : [M+H] ⁺ = 526.4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.74 - 1.82 (m, 2 H) 1.91 - 2.00 (m, 1 H) 2.05 - 2.11 (m, 2 H) 2.13 - 2.25 (m, 3 H) 2.38 - 2.46 (m, 2 H) 2.58 (s, 6 H) 2.72 (d, J=14.0 Hz, 6 H) 3.32 - 3.45 (m, 1 H) 3.69 - 3.78 (m, 1 H) 4.19 - 4.32 (m, 2 H) 5.01 - 5.12 (m, 1 H) 6.45 (d, J=9.3 Hz, 1 H) 7.29 (dd, J=9.4, 2.5 Hz, 1 H) 7.43 (d, J=2.4 Hz, 1 H).

Method 4: Synthetic Examples 56, 57, 59, 161-163 Example 59: 5-[(2R,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]-6-methyl-tetrahydropiperan-2-yl]pyridin-2-ol

TFA (1 equivalent, 10 mL, 1.22 mmol) was added to a solution of 2-[(2R,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-tetrahydropiperan-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine (Int-A18 , 1 equivalent, 700 mg, 1.22 mmol) in DCM (10 mL), and the mixture was stirred at 40 °C for 2 h. LCMS showed the desired product (95%). The mixture was quenched with 100 mL of saturated _NaHCO3 solution, extracted with EtOAc (50 mL × 3 ₎ , and the combined organic layer was dried with anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to obtain crude residue. The residue was purified by silicone column chromatography (0-100% EtOAc/PE, followed by 0-50% MeOH/EtOAc) (TLC, 9% MeOH/DCM, desired product _Rf = 0.4) to give 5-[(2R,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]-6-methyl-tetrahydropiperan-2-yl]pyridin-2-ol as a solid (Example 59, 500 mg, 1.03 mmol, 85% yield). LCMS : [M+H] ⁺ = 486.1, purity = 96% (220 nm), retention time = 0.572 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.21 - 11.51 (m, 1H), 7.60 (dd, J = 2.3, 9.4 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 6.61 (br d, J = 9.4 Hz, 1H), 4.41 (br d, J = 10.5 Hz, 1H), 3.90 - 3.77 (m, 1H), 3.53 - 3.41 (m, 1H), 2.79 (d, J = 13.1 Hz, 5H), 2.65 (s, 6H), 2.31 - 2.11 (m, 2H), 1.32 (d, J = 6.1 Hz, 3H).

Example 57: 2-[(2R,6R)-2-(6-methoxy-3-pyridyl)-6-methyl-tetrahydropiperan-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine

CH3I (4 equivalents, 257 mg, 1.81 mmol) was added to a solution of 5-[rac-(2R,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl] _-6 -methyl-tetrahydropiperan-2-yl]-1H-pyridin- ₂ -one (Example 59, 1 equivalent, 220 mg, 0.453 mmol) and _Cs2CO3 (4 equivalents, 591 mg, 1.81 mmol) in MeCN (3 mL). The solution was stirred at 30 °C for 2 hours. LCMS showed two peaks (3%; 65%) of the desired product. The mixture was quenched with 50 mL of _H₂O , extracted with EtOAc (50 mL × 3 ₎ , and the combined organic layer was dried with anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silicone column chromatography (0-100% EtOAc/PE, followed by 0-50% MeOH/EtOAc) to give solid 2-[(2R,6R)-2-(6-methoxy-3-pyridyl)-6-methyl-tetrahydropiperan-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine (Example 57, 4.9 mg, 0.009 mmol, 2% yield) (TLC, 67% EtOAc/PE, _Rf = 0.3); and the solid byproduct 5-[(2R,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]-6-methyl-tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (200 mg, 0.400 mmol, 88% yield) (TLC, 67% EtOAc/PE, _Rf = 0.1). Example 57 : LCMS : [M+H] ⁺ = 500.2, purity = 94% (220 nm), retention time = 0.654 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 2.4, 8.6 Hz, 1H), 6.78 - 6.69 (m, 1H), 4.59 (dd, J = 1.8, 11.4 Hz, 1H), 3.88 (ddd, J = 1.8, 6.1, 11.1 Hz, 1H), 3.52 (tt, J = 3.8, 12.1 Hz, 1H), 2.79 (d, J = 14.3 Hz, 6H), 2.65 (s, 6H), 2.28 (td, J = 1.7, 13.1 Hz, 1H), 2.23 - 2.16 (m, 1H), 2.05 - 1.97 (m, 1H), 1.90 - 1.79 (m, 1H), 1.35 (d, J = 6.1 Hz, 3H). SFC displays ee ~67%.

Example 56: 5-[(2R,4S,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]-6-methyl-tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one

The residue (Example 57) was purified by SFC (condition 4, gradient b) and freeze-dried to give solid 5-[(2R,4S,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]-6-methyl-tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 56, 118 mg, 0.232 mmol, 58% yield). LCMS : [M+H] ⁺ = 500.2, purity = 99% (220 nm), retention time = 0.591 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 - 7.37 (m, 2H), 6.57 (d, J = 9.5 Hz, 1H), 4.39 (dd, J = 1.6, 11.4 Hz, 1H), 3.93 - 3.78 (m, 1H), 3.58 - 3.53 (m, 3H), 3.47 (tt, J = 3.7, 12.1 Hz, 1H), 2.80 (d, J = 14.5 Hz, 6H), 2.65 (s, 6H), 2.32 - 2.25 (m, 1H), 2.20 (td, J = 1.7, 13.3 Hz, 1H), 1.94 (q, J = 12.1 (Hz, 1H), 1.83 - 1.71 (m, 1H), 1.34 (d, J = 6.3 Hz, 3H). SFC displays ee ~100%.

Following a similar method, the following compounds were obtained. Structure Starting materials Characteristics Example 161 Example 162 Example 163 The residue was purified by reversed-phase HPLC (60-65% [water (0.1% _NH3 · _H2O )-ACN], flow rate: 60 mL/min) to obtain a racemic compound (85 mg) in the form of a gel. The racemic compound (85 mg) was then purified by SFC (condition 6, gradient e) to obtain three impure mirror isomers (crude substance A (15 mg), crude substance B (22 mg), and crude substance C (19 mg)). Crude substance A (15 mg) was further purified by preparative HPLC (condition 5, gradient d) to give 1-methyl-5-[(2S,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyrimidin-2-one as a solid (Example 163, 3.1 mg, 0.006 mmol, 1% yield). LCMS : [M+H] ⁺ = 487.1; Purity = 94% (220 nm); Retention time = 0.537 min; ^¹H NMR (400 MHz, _CDCl₃ , 301 K) δ 8.62 (d, J = 3.1 Hz, 1H), 7.72 (d, J = 3.1 Hz, 1H), 4.67 (dd, J = 2.0, 10.5 Hz, 1H), 4.02 - 3.93 (m, 1H), 3.83 (dt, J = 2.3, 11.8 Hz, 1H), 3.73 - 3.65 (m, 1H), 3.59 (s, 3H), 2.84 - 2.77 (m, 7H), 2.66 (s, 6H), 2.58 (br d, J = 13.9 Hz, 1H), 2.27 - 2.15 (m, 1H), 2.07 (ddd, J = 5.3, 10.7, 13.6 Hz, 1H); ee = 81%. Crude substance B (22 mg) was further purified by preparative HPLC (condition 5, gradient e) to give 1-methyl-5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyrimidin-2-one as a solid (Example 162, 2.8 mg, 0.0056 mmol, 1% yield). LCMS : [M+H] ⁺ = 487.1; Purity = 97% (220 nm); Retention time = 0.530 min; ^¹H NMR (400 MHz, _CDCl₃ , 301 K) δ 8.63 (d, J = 3.3 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 4.43 (dd, J = 1.6, 11.5 Hz, 1H), 4.29 (br dd, J = 3.4, 11.3 Hz, 1H), 3.81 (dt, J = 2.4, 12.0 Hz, 1H), 3.59 (s, 3H), 3.47 (tt, J = 3.7, 11.9 Hz, 1H), 2.80 (d, J = 14.0 Hz, 6H), 2.65 (s, 6H), 2.37 (br d, J = 13.4 Hz, 1H), 2.22 - 2.15 (m, 1H), 1.98 (s, 2H); ee = 84%. The crude material C (19 mg) was further purified by preparative HPLC (condition 5, gradient f) to give 1-methyl-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]-pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyrimidin-2-one as a solid (Example 161, 3.9 mg, 0.008 mmol, 2% yield). LCMS : [M+H] ⁺ = 487.2; Purity = 98% (220 nm); Retention time = 0.530 min; ^1H NMR (400 MHz, _CDCl3 , 298 K) δ (ppm) = 8.63 (br d, J = 2.1 Hz, 1H), 7.78 (br d, J = 2.6 Hz, 1H), 4.43 (br d, J = 11.3 Hz, 1H), 4.29 (br dd, J = 3.8, 11.4 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.59 (s, 3H), 3.53 - 3.42 (m, 1H), 2.82 (s, 3H), 2.78 (s, 3H), 2.65 (s, 6H), 2.37 (br d, J = 13.3 Hz, 1H), 2.22 - 2.14 (m, 1H), 2.12 - 1.98 (m, 2H); ee= 88%.

Method 5: Synthesis Examples 102, 134, 142 Example 102 : 1 -Cyclopropyl -5-[(2R,4S,6R)-4-[6,7 -Dimethyl -4-[3-( trifluoromethyl )-1- bis (1.1.1) pentyl ] pteridin -2 -yl ]-6- methyl - tetrahydropiperan -2- yl ] pyridin -2 -one

Add Na₂CO₃ (3 equivalents, 151 mg, 1.42 mmol), Cu(OAc)₂ (1.5 equivalents, 129 mg, 0.711 mmol), and bipyridine (1 equivalent, 74 mg, 0.474 mmol) to a mixture of 5-[(2R,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]-6-methyl-tetrahydropiperan-2-yl]-1H-pyridin-2-one (Example ₅₉ , 1 equivalent, 230 mg, 0.474 mmol), cyclopropylboronic acid (2 equivalents, 81 mg, 0.947 mmol) in a DCE (12 mL) to a mixture of _Na₂CO₃ (3 equivalents, 151 mg, 1.42 mmol), Cu(OAc) _₂ (1.5 equivalents, 129 mg, 0.711 mmol), and bipyridine (1 equivalent, 74 mg, 0.474 mmol), and then stir the mixture at 70 °C for 0.5 h under _O₂ (15 psi). LCMS showed complete exhaustion of the starting material and detection of the desired mass. The reaction mixture was poured into _H₂O (20 mL) and extracted with DCM (20 mL × 3). _The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. The reaction mixture was purified by reversed-phase chromatography (40–60% (water (FA)-MeCN)). After reversed-phase purification, the solution was concentrated and evaporated to remove the organic solvent. The residual aqueous solution was freeze-dried to obtain a solid 1-cyclopropyl-5-((2R,6R)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)-1-bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)-6-methyltetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (150 mg), which was purified by SFC (condition 4, gradient b) to obtain a solid 1-cyclopropyl-5-[(2R,4S,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]-6-methyl-tetrahydropiperan-2-yl]pyridin-2-one (Example 102, 74). mg, 0.137 mmol, 29% yield). LCMS : [M+H] ⁺ = 526.2; purity = 98% (UV 220 nm); residence time = 0.608 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.81 - 0.94 (m, 2H), 1.04 - 1.20 (m, 2H), 1.34 (d, J=6.1 Hz, 3H), 1.70 - 1.86 (m, 1H), 1.90 - 2.02 (m, 1H), 2.12 - 2.30 (m, 2H), 2.65 (s, 6H), 2.80 (d, J=14.4 Hz, 6H), 3.26 - 3.35 (m, 1H), 3.40 - 3.50 (m, 1H), 3.84 (ddd, J=11.1, 6.1, 1.9 Hz, 1H), 4.37 (dd, J=11.4, 1.8 Hz, 1H), 6.55 (d, J=9.3 Hz, 1H), 7.36 - 7.43 (m, 2H).

Following a similar method, the following compounds were obtained. Compound number Starting materials Characteristics Example 134 Next, the crude material was purified by preparative HPLC (30-70% [water (FA)-ACN], 10 min) and freeze-dried to give 1-cyclopropyl-5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 134, 40 mg, 0.07 mmol, 27% yield). LCMS : [M+H] ⁺ = 556.3; purity = 100% (220 nm); retention time = 0.567 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (t, J = 7.3 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 9.6 Hz, 1H), 7.41 - 7.35 (m, 2H), 6.59 - 6.51 (m, 1H), 4.38 - 4.24 (m, 2H), 4.01 (s, 3H), 3.86 - 3.72 (m, 1H), 3.60 - 3.46 (m, 1H), 3.38 - 3.26 (m, 1H), 2.77 (s, 3H), 2.34 (br d, J = 13.4 Hz, 1H), 2.24 - 2.15 (m, 2H), 2.13 - 2.00 (m, 1H), 1.18 - 1.06 (m, 2H), 0.94 - 0.82 (m, 2H). SFCee : 100%. Example 142 Example 143 Modification: The crude material was purified by reversed-phase HPLC (0-100% [(0.05% FA) water/ACN]) and freeze-dried to give 1-cyclopropyl-5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 142, 28 mg, 0.0511 mmol, 34% yield). LCMS : [M+H] ⁺ = 528.3; purity = 97% (UV 220 nm); retention time = 0.610 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 - 7.33 (m, 2H), 6.54 (d, J = 10.1 Hz, 1H), 4.38 - 4.22 (m, 2H), 4.14 (s, 3H), 3.85 - 3.71 (m, 1H), 3.48 - 3.36 (m, 1H), 3.36 - 3.27 (m, 1H), 2.73 (s, 3H), 2.63 (s, 6H), 2.31 - 2.23 (m, 1H), 2.17 - 2.07 (m, 2H), 2.05 - 1.93 (m, 1H), 1.17 - 1.09 (m, 2H), 0.95 - 0.84 (m, 2H). SFC : 98% purity. Example 225 Example 224 Modification: The crude material was processed for 1 h. The crude material was purified by preparative HPLC (condition 18, gradient c) and freeze-dried to give 1-cyclopropyl-5-[(2R,4S)-4-[4-(4,4-difluorocyclohexyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 225, a single mirror isomer of known absolute configuration, 79 mg, 0.159 mmol, 48% yield). LCMS : [M+H] ⁺ = 496.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.86 - 0.94 (m, 2H) 1.10 - 1.18 (m, 2H) 1.94 - 2.20 (m, 9H) 2.24 - 2.37 (m, 3H) 2.80 (d, J=15.0 Hz, 6H) 3.27 - 3.37 (m, 1H) 3.40 - 3.52 (m, 1H) 3.79 (td, J=11.3, 3.7 Hz, 1H) 4.17 (br t, J=11.8 Hz, 1H) 4.25 - 4.37 (m, 2H) 6.52 - 6.60 (m, 1H) 7.38 (dq, J=4.9, 2.4 Hz, 2H). ee ~92%

Method 6: Synthesis of Examples 28-30 Example 30 : 5-(4-(4-(4,4 -difluorocyclohexyl )-6,7 -dimethylpteridin- 2 -yl ) tetrahydro -2H- piperan -2- yl )-1 -methylpyridin -2(1H) -one

A solution of 2-chloro-4-(4,4-difluorocyclohexyl)-6,7-dimethylpteridine (Int-A22 , 1 equivalent, 10 mg, 0.027 mmol), Pd(OAc) ₂ (0.1 equivalent, 0.60 mg, 0.003 mmol) and C-Phos (0.2 equivalent, 2.3 mg, 0.005 mmol) in THF (1 mL) was purged three times with _N2 . Then, bromide (2-(1-methyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)zinc(II) (Int-A8 , 1.2 equivalent, 12 mg, 0.032 mmol) was added, and the reaction solution was stirred at 55 °C for 2 h. LCMS showed that ~32% of the desired product was detected. The mixture was quenched with 150 mL _H₂O , extracted with DCM (100 mL × 3), and the combined organic layer was dried _with anhydrous _Na₂SO₄ , filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by silicone column chromatography (0-100% EtOAc/PE, followed by 0-50% MeOH/EtOAc) (TLC, 5% MeOH/DCM, desired product _Rf = 0.3) to give 5-(4-(4-(4,4-difluorocyclohexyl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one as a solid (Example 30, 150 mg, 0.291 mmol, 61% yield). LCMS : [M+H] ⁺ = 470.1.

Separation Examples 28-29

5-[4-[4-(4,4-difluorocyclohexyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 30, 1 equivalent, 150 mg, 0.319 mmol) was purified by SFC (condition 4, gradient b) to give 25 mg of crude substance A and 70 mg of crude substance B.

25 mg of crude substance A was lyophilized to give 5-((2R,4S)-4-(4-(4,4-difluorocyclohexyl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one as a solid (Example 28, 21 mg, 0.043 mmol, 13% yield). LCMS : [M+H] ⁺ = 470.3; purity = 98% (220 nm); retention time = 0.526 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 - 7.37 (m, 2H), 6.58 (d, J = 10.1 Hz, 1H), 4.37 - 4.25 (m, 2H), 4.23 - 4.13 (m, 1H), 3.80 (dt, J = 2.9, 11.8 Hz, 1H), 3.56 (s, 3H), 3.45 (tt, J = 4.0, 11.8 Hz, 1H), 2.81 (d, J = 15.5 Hz, 6H), 2.38 - 2.18 (m, 4H), 2.15 - 1.96 (m, 8H).

5-[4-[4-(4,4-difluorocyclohexyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (crude substance B, 1 equivalent, 70 mg, 0.149 mmol) was purified by SFC (conditional gradient a) to give solid 5-((2S,4R)-4-(4-(4,4-difluorocyclohexyl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 29, 16 mg, 0.0314 mmol, 21% yield). LCMS : [M+H] ⁺ = 470.3; Purity = 90% (220 nm); Retention time = 0.529 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 - 7.37 (m, 2H), 6.61 - 6.54 (m, 1H), 4.38 - 4.26 (m, 2H), 4.22 - 4.13 (m, 1H), 3.80 (dt, J = 2.8, 11.7 Hz, 1H), 3.56 (s, 3H), 3.45 (tt, J = 4.1, 11.6 Hz, 1H), 2.83 (s, 3H), 2.79 (s, 3H), 2.36 - 2.19 (m, 4H), 2.17 - 1.99 (m, 8H).

Following a similar method, the following compounds were obtained: Structure Starting materials Characteristics Example 166 continues with SFC : Example 165 Example 342 Int-E45 The crude material was purified by preparative TLC (EtOAc/MeOH = 10:1) to give an oily 4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methyl-6-(2-(1-methyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Example 166, 30 mg, 0.0598 mmol, 21% yield). ESI-MS: [M+H] ⁺ = 502.2. Next, Example 166 was purified by SFC (condition 18, gradient a) to give peak 1 at 15 mg and peak 2 at 10 mg. Peak 1 was purified by SFC (condition 19, gradient a) to give 4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methyl-6-((2S,4R)-2-(1-methyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one as a solid (Example 342, 5.9 mg, 0.0116 mmol, 19% yield). LCMS : [M+H] ⁺ = 502.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 - 7.69 (m, 2H), 7.64 - 7.56 (m, 1H), 7.54 - 7.47 (m, 1H), 7.40 - 7.33 (m, 2H), 6.60 - 6.55 (m, 1H), 4.45 (s, 2H), 4.35 - 4.26 (m, 2H), 3.85 - 3.71 (m, 1H), 3.58 - 3.51 (m, 3H), 3.36 - 3.27 (m, 1H), 3.24 (s, 3H), 2.21 (br d, J = 13.3 Hz, 1H), 2.07 - 2.00 (m, 2H), 1.91 - 1.82 (m, 1H). The peak was lyophilized at 10 mg to give solid 4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methyl-6-((2R,4S)-2-(1-methyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Example 165, 5.1 mg, 0.0010 mmol, 17% yield). LCMS : [M+H] ⁺ = 502.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 - 7.78 (m, 1H), 7.72 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.40 - 7.32 (m, 2H), 6.60 - 6.54 (m, 1H), 4.49 - 4.41 (m, 2H), 4.37 - 4.23 (m, 2H), 3.83 - 3.73 (m, 1H), 3.61 - 3.46 (m, 3H), 3.36 - 3.27 (m, 1H), 3.27 - 3.18 (m, 3H), 2.25 - 2.16 (m, 1H), 2.09 - 1.99 (m, 2H), 1.91 - 1.79 (m, 1H).

Method 7: Synthesis of Examples 38, 40, 42, 43, 44, 46, 48, 50 and 52. Example 38: 5-[(2R,4S)-4-[4-[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one

To (2R,4S)-N-[3-[3-(1,1-difluoroethyl)bicyclo[1.1.1]pentane-1-carbonyl]-5,6-dimethyl-pyridine [-2-yl]-2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-carboxamide (Int-A23 , 1 equivalent, 350 mg, 0.699 mmol) was added to a solution of 1-butanol (15 mL) with ammonium acetate (20 equivalents, 1078 mg, 14.0 mmol). The reaction mixture was then stirred at 115 °C for 2 hours. LCMS showed complete exhaustion of the starting material and detection of the desired mass. The reaction mixture was diluted with 10 mL of water and extracted with EtOAc (20 mL × 2 ₎ . The combined organic layer was dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude residue. The residue was purified by silicone column chromatography (0-100% EtOAc/PE) (TLC, 5% MeOH/DCM, _Rf = 0.4) to give a crude product (200 mg). The crude product was purified by SFC (condition 13, gradient a) to give solid 5-[(2R,4S)-4-[4-[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 38, 114 mg, 0.237 mmol, 34% yield). LCMS : [M+H] ⁺ = 482.1; Purity = 99% (220 nm); Retention time = 0.553 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.66 - 1.71 (m, 3H), 1.97 - 2.08 (m, 1H), 2.08 - 2.21 (m, 2H), 2.32 (br d, J=13.1 Hz, 1H), 2.53 (s, 6H), 2.79 (d, J=13.6 Hz, 6H), 3.40 - 3.50 (m, 1H), 3.56 (s, 3H), 3.80 (td, J=11.4, 3.3 Hz, 1H), 4.25 - 4.37 (m, 2H), 6.59 (dd, J=8.5, 1.5 Hz, 1H), 7.37 - 7.46 (m, 2H).

Following a similar procedure, the following compounds were obtained. Structure intermediate Characteristics Example 52 Int-A27 The crude material was purified by reversed-phase chromatography (40% [water(FA)-ACN]) and freeze-dried to give 5-[(2R,4S)-4-[4-[3-(1-fluoro-1-methyl-ethyl)-1-bicyclo[1.1.1]pentyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one as a solid (Example 52, 6.0 mg, 0.012 mmol, 12% yield). LCMS : [M+H] ⁺ = 478.3; purity = 96% (UV 220 nm); retention time = 0.573 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 - 7.36 (m, 2H), 6.60 - 6.53 (m, 1H), 4.35 - 4.24 (m, 2H), 3.85 - 3.69 (m, 1H), 3.55 (s, 3H), 3.49 - 3.39 (m, 1H), 2.79 (s, 3H), 2.76 (s, 3H), 2.42 - 2.39 (m, 6H), 2.33 (br d, J = 1.0 Hz, 1H), 2.12 (br s, 2H), 2.05 - 2.00 (m, 1H), 1.45 - 1.42 (m, 3H), 1.39 - 1.37 (m, 3H). SFC: 95.7%ee. Example 40 The residue was purified by rapid column chromatography (100% EtOAc, _Rf = 0.3) and concentrated under reduced pressure to give solid 5-[(2R,4S)-4-[4-(3-chloro-1-bicyclo[1.1.1]-pentyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (160 mg, 0.342 mmol, 90% yield). The 160 mg product was separated by SFC (condition 6, gradient f) and freeze-dried, yielding two peaks (peak 1 and peak 2). Peak 2: 5-[(2R,4S)-4-[4-(3-chloro-1-bicyclo[1.1.1]pentyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one in solid form (Example 40, 82 mg, 0.178 mmol, 50% yield). LCMS : [M+H] ⁺ = 452.2; purity = 99% (UV 220 nm); retention time = 0.563 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 - 7.36 (m, 2H), 6.59 - 6.52 (m, 1H), 4.41 - 4.17 (m, 2H), 3.78 (dt, J = 3.6, 11.4 Hz, 1H), 3.54 (s, 3H), 3.43 (br t, J = 4.2 Hz, 1H), 2.85 - 2.78 (m, 9H), 2.78 - 2.74 (m, 3H), 2.30 (br dd, J = 1.9, 13.3 Hz, 1H), 2.18 - 2.07 (m, 2H), 2.06 - 1.96 (m, 1H). SFC : 98.7% ee. Example 46 Int-A34 The crude material was purified by reverse-phase rapid purification (0.1% FA) to give 5-[(2R,4S)-4-[4-[3-(2,2-difluoroethyl)-1-bicyclo[1.1.1]pentyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one as a solid (Example 46, 14 mg, 0.029 mmol, 72% yield). LCMS : [M+H] ⁺ = 482.2; purity = 99% (UV 220 nm); retention time = 0.541 min. SFC : 99% purity. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 1H), 7.42 - 7.37 (m, 1H), 6.56 (d, J = 9.6 Hz, 1H), 5.91 (tt, J = 4.6, 56.4 Hz, 1H), 4.35 - 4.24 (m, 2H), 3.78 (dt, J = 3.7, 11.4 Hz, 1H), 3.55 (s, 3H), 3.48 - 3.37 (m, 1H), 2.77 (d, J = 12.6 Hz, 6H), 2.46 (s, 6H), 2.34 - 2.26 (m, 1H), 2.09 (br d, J = 4.4 Hz, 4H), 2.08 - 1.96 (m, 1H). Example 50 The crude product was purified by reversed-phase HPLC (40-60% [(0.05% FA) _H₂O -ACN] and freeze-dried to obtain crude product A 5-[(2R,4S)-4-[4-[4-(fluoromethyl)cyclohexyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (14 mg, 0.03 mmol, 11% yield) and crude product B 5-[(2R,4S)-4-[4-[4-(fluoromethyl)cyclohexyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (32 mg, 0.07 mmol, 11% yield) in solid form. Pure 5-[(2R,4S)-4-[4-[4-[4-(fluoromethyl)-cyclohexyl]-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methylpyridin-2-one (Example 50, 9.1 mg, 0.019 mmol, 7% yield) in solid form. LCMS : [M+H] ⁺ = 466.2, purity = 97% (220 nm); retention time = 0.548 min. ^¹H NMR (400 MHz, _CDCl₃ ) δ 7.44 - 7.37 (m, 2H), 6.61 - 6.55 (m, 1H), 4.41 (d, J = 5.8 Hz, 1H), 4.36 - 4.27 (m, 3H), 4.14 - 4.04 (m, 1H), 3.80 (dt, J = 3.3, 11.7 Hz, 1H), 3.57 - 3.54 (m, 3H), 3.50 - 3.41 (m, 1H), 2.80 (d, J = 13.4 Hz, 6H), 2.38 - 2.31 (m, 1H), 2.21 - 2.09 (m, 2H), 2.05 - 1.94 (m, 5H), 1.92 - 1.81 (m, 3H), 1.44 - 1.30 (m, 2H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -223.02 (s, 1F). Example 44 continues with SFC : Example 42 Example 43 Example 44 : The residue was purified by preparative TLC (6% MeOH/DCM, TLC, desired product _Rf = 0.5) to obtain a crude product, which was further purified by SFC (condition 1, gradient a-1) and then freeze-dried to obtain a crude product. SFC showed ee ~30%. The crude product was purified again by SFC (condition 4, gradient b) (×2) and then freeze-dried to obtain 5-((2R,4S)-4-(4-(4-fluorocyclohexyl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 44). SFC showed ee ~99%. Next, SFC : Example 44 (1.14 equivalents, 80 mg, 0.177 mmol) was purified by preparative HPLC (condition 7, gradient b) to give 5-((2R,4S)-4-(4-((1S,4R)-4-fluorocyclohexyl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one as a solid (Example 43, 19 mg, 0.042 mmol, 27% yield). Example 43 : LCMS : [M+H] ⁺ = 452.3; purity = 100%; retention time = 0.510 min. HPLC : retention time = 1.346 min, 99.8% purity, at 220 nm. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 - 7.36 (m, 2H), 6.57 (d, J = 10.3 Hz, 1H), 5.08 - 4.88 (m, 1H), 4.30 (br s, 2H), 4.18 - 4.06 (m, 1H), 3.78 (dt, J = 2.9, 11.6 Hz, 1H), 3.55 (s, 3H), 3.50 - 3.38 (m, 1H), 2.78 (d, J = 13.9 Hz, 6H), 2.33 (br d, J = 13.3 Hz, 1H), 2.27 - 2.07 (m, 6H), 2.06 - 1.94 (m, 1H), 1.90 - 1.82 (m, 1H), 1.78 (br d, J = 10.1 Hz, 3H). 5-((2R,4S)-4-(4-(((1r,4S)-4-fluorocyclohexyl)-6,7-dimethyl-pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (1 equivalent, 70 mg, 0.155 mmol) was purified by preparative HPLC (condition 7, gradient a) to give 5-((2R,4S)-4-(4-(((1r,4S)-4-fluorocyclohexyl)-6,7-dimethyl-pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one as a solid (Example 42, 12 mg, 0.0264 mmol, 17% yield). Example 42 : LCMS : [M+H] ⁺ = 452.3; purity = 100% (UV 220 nm); retention time = 0.510 min. HPLC : retention time = 1.368 min, 99.5% purity, at 220 nm. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 - 7.36 (m, 2H), 6.57 (d, J = 10.3 Hz, 1H), 4.79 - 4.55 (m, 1H), 4.30 (s, 2H), 4.14 - 4.02 (m, 1H), 3.78 (dt, J = 2.8, 11.7 Hz, 1H), 3.55 (s, 3H), 3.48 - 3.36 (m, 1H), 2.79 (d, J = 11.5 Hz, 6H), 2.29 (br s, 3H), 2.13 (br d, J = 3.3 Hz, 2H), 2.08 - 1.97 (m, 3H), 1.88 (br d, J = 12.4 Hz, 2H), 1.83 - 1.76 (m, 2H). Example 48 Int-A43 The crude product was purified by preparative TLC (DCM/MeOH = 10:1, _Rf = 0.4) and freeze-dried to give a solid 5-((2R,4S)-4-(4-(3-(2-fluoroethyl)bicyclo[1.1.1]pent-1-yl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 48, 42 mg, 0.0897 mmol, 62% yield). LCMS : [M+H] ⁺ = 464.4; purity = 98% (220 nm); retention time = 0.540 min. SFC showed ee = 89%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 - 7.36 (m, 2H), 6.61 - 6.53 (m, 1H), 4.68 - 4.51 (m, 2H), 4.36 - 4.24 (m, 2H), 3.83 - 3.74 (m, 1H), 3.55 (s, 3H), 3.49 - 3.38 (m, 1H), 2.78 (d, J = 11.6 Hz, 6H), 2.40 (s, 6H), 2.31 (br dd, J = 1.7, 13.2 Hz, 1H), 2.19 - 2.10 (m, 2H), 2.10 - 2.04 (m, 2H), 2.04 - 1.96 (m, 2H). Example 187 Int-C24 The crude mixture was purified by rapid silica gel column chromatography with a dissolution gradient of 1%–7% MeOH/DCM to give a foamy 5-((2R,4S)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 187) (898 mg, 1.91 mmol, 94% yield). ESI-MS : [M+H] ⁺ = 458.4. ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 11.49 (1H, s), 9.00 (1H, s), 7.49 (1H, dd, J = 9.5, 2.6 Hz), 7.32 (1H, d, J = 2.5 Hz), 6.31 (1H, d, J = 9.4 Hz), 4.37 (1H, dd, J = 11.2, 2.0 Hz), 4.14 (1H, dd, J = 11.3, 4.2 Hz), 3.70 (1H, t, J = 11.7 Hz), 3.37-3.45 (1H, m), 2.78 (3H, s), 2.62 (6H, s), 2.17 (1H, d, J = 12.8 Hz), 2.03 (1H, d, J = 13.2 Hz), 1.90 (1H, qd, J = 12.5, 4.6 Hz), 1.79 (1H, dd, J = 24.2, 12.0 Hz). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz): δ -71.5 (3F, s). Example 197 Int-C34 Modification : The crude mixture was purified by rapid silica gel column chromatography with a dissolution gradient of 1%–7% MeOH/DCM to give a foamy 5-((2R,4S)-4-(6-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 197) (1.03 g, 2.03 mmol, 83% yield). ESI-MS : [M+H] ⁺ = 458.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 9.01 (1H, s), 7.83 (1H, d, J = 9.2 Hz), 7.74 (1H, s), 6.87 (1H, d, J = 9.3 Hz), 4.47 (1H, d, J = 11.3 Hz), 4.29-4.33 (1H, m), 3.77-3.84 (1H, m), 3.47-3.53 (1H, m), 2.82 (3H, s), 2.66 (6H, s), 2.35 (1H, d, J = 14.1 Hz), 2.09-2.18 (3H, m), 1.94-2.03 (1H, m). ¹⁹ F NMR (CDCl3, 376 MHz): δ -73.1 (3F, s). Example 203 Int-C45 Modification : The crude reaction mixture was first purified by rapid normal-phase chromatography using a dissolution gradient of 0-10% MeOH/DCM, and then second purified by preparative HPLC (condition 16, gradient b) to give 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-methoxypyridin-2-one as a solid (Example 203, 21 mg, 0.036 mmol, 38% yield). ESI-MS : [M+H] ⁺ = 502.4. ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 7.89 (d, J = 2.5 Hz, 1H), 7.47 (dd, J = 9.5, 2.4 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 4.36 (dd, J = 11.0, 0.9 Hz, 1H), 4.12 (dd, J = 11.2, 3.4 Hz, 1H), 3.90 (s, 3H), 3.71-3.65 (m, 1H), 3.40-3.35 (m, 1H), 2.70 (s, 6H), 2.59 (s, 6H), 2.20-2.17 (m, 1H), 2.01-1.98 (m, 1H), 1.93-1.82 (m, 1H), 1.76 (q, J = 12.1 Hz, 1H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz): δ -71.3 (s, 3F). Example 209 Int-D8 Modification : The reaction was carried out in ethanol (0.6 mL/mmol _NH₄OAc ) at 80 °C for 4 h. The crude reaction product was purified by normal-phase rapid chromatography using a dissolution gradient of 10–50% EtOAc:EtOH (3:1)/hexane to give solid 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-pyrrolidin-1-yl-pyridin-2-one (Example 209, 53 mg, 0.098 mmol, 57% yield). ESI-MS : [M+H] ^⁺ = 541.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ δ 7.59 (d, J = 2.5 Hz, 1H), 7.39 (dd, J = 9.5, 2.6 Hz, 1H), 6.55 (d, J = 9.4 Hz, 1H), 4.31-4.25 (m, 2H), 3.82-3.75 (m, 1H), 3.48-3.39 (m, 5H), 2.81 (s, 3H), 2.77 (s, 3H), 2.65 (s, 6H), 2.32-2.29 (m, 1H), 2.17-2.01 (m, 3H), 1.98-1.93 (m, 4H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -72.9 (s, 3F). Example 215 Int-D11 Modification : The crude material was purified by preparative HPLC (condition 10, gradient d) to give 1-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 215, 4.8 mg, 8.2 µmol, 25% yield). ESI-MS : [M+H] ⁺ = 589.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.51 (d, J = 2.5 Hz, 1H), 7.41 (dd, J = 9.5, 2.6 Hz, 1H), 6.55 (d, J = 9.4 Hz, 1H), 4.31-4.26 (m, 2H), 4.11-4.09 (m, 2H), 3.78 (td, J = 11.7, 2.7 Hz, 1H), 3.49 (d, J = 8.5 Hz, 2H), 3.46-3.39 (m, 1H), 2.81 (s, 3H), 2.77 (s, 3H), 2.64 (s, 6H), 2.32-2.27 (m, 3H), 2.18-1.99 (m, 3H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.0 (s, 3F), -127.7 (dt, J = 158.3, 13.0 Hz, 1F), -151.1 (d, J = 159.8 Hz, 1F). Example 220 Int-D17 Modification : The reaction was carried out at 115 °C for 10 min. The crude material was purified by preparative HPLC (condition 19, gradient a) to obtain the desired product 5-((2R,4R)-4-(6-(difluoromethyl)-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(dimethylamino)pyridin-2(1H)-one (Example 220, 3.0 mg, 5.45 µmol, 18% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.54-7.52 (m, 1H), 7.44-7.39 (m, 1H), 6.35 (d, J = 9.4 Hz, 1H), 4.35 (d, J = 10.1 Hz, 1H), 4.12 (dd, J = 11.3, 3.3 Hz, 1H), 3.68 (t, J = 10.9 Hz, 1H), 3.44-3.38 (m, 1H), 2.89 (s, 6H), 2.84 (d, J = 10.3 Hz, 3H), 2.63-2.61 (m, 7H), 2.29 (t, J = 1.8 Hz, 1H), 2.18 (d, J = 12.6 Hz, 1H), 2.04-2.00 (m, 1H), 1.88 (dd, J = 12.9, 4.2 Hz, 1H), 1.76 (dd, J = 24.6, 11.8 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -71.3 (s, 3F), -119.0 (m, 2F). ESI-MS : [M+H] ⁺ = 551.4. Example 231 Int-D46 Modification : The reaction was carried out in EtOH at 60 °C for 36 h. The crude material was purified by rapid column chromatography with a dissolution gradient of 1–8% MeOH/DCM using _SiO2 to give solid 5-((2R,4S)-4-(4-(cubican-1-yl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(dimethylamino)pyridin-2(1H)-one (Example 231, 45 mg, 0.086 mmol, 74% yield). ESI-MS : [M+H] ⁺ = 483.5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.53 (d, J = 2.5 Hz, 1H), 7.42 (dd, J = 9.4, 2.5 Hz, 1H), 6.33 (d, J = 9.4 Hz, 1H), 4.47-4.44 (m, 3H), 4.32 (d, J = 10.1 Hz, 1H), 4.15-4.06 (m, 5H), 3.68-3.62 (m, 1H), 3.33 (dt, J = 12.0, 3.7 Hz, 1H), 2.89 (s, 6H), 2.70 (s, 3H), 2.66 (s, 3H), 2.17 (d, J = 13.0 Hz, 1H), 2.00 (d, J = 11.7 Hz, 1H), 1.92-1.82 (m, 1H), 1.75 (dd, J = 24.6, 12.0 Hz, 1H). Example 233 Int-D47 Modification : The reaction was carried out in EtOH at 60 °C for 36 h. The crude material was purified by rapid column chromatography with a dissolution gradient of 1–8% MeOH/DCM using _SiO₂ to give solid 5-((2R,4S)-4-(6,7-dimethyl-4-(4-(trifluoromethyl)cubican-1-yl)pterin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 233, 28 mg, 0.051 mmol, 65% yield). ESI-MS : [M+H] ^⁺ = 522.3. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.66 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 9.1, 2.5 Hz, 1H), 6.32 (d, J = 9.4 Hz, 1H), 4.48 (t, J = 4.9 Hz, 3H), 4.36 (t, J = 4.7 Hz, 3H), 4.31 (d, J = 10.1 Hz, 1H), 4.11 (dd, J = 11.2, 3.4 Hz, 1H), 3.70-3.65 (m, 1H), 3.44-3.33 (m, 4H), 2.70 (s, 3H), 2.68 (s, 3H), 2.18 (d, J = 13.0 Hz, 1H), 2.01 (d, J = 11.4 Hz, 1H), 1.93-1.74 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ): δ -75.7 (s, 3F). Example 330 Int-E11 The crude mixture was purified by expedited silica gel column chromatography (2-10% MeOH/DCM) to give a foamy 5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 330). ESI-MS : [M+H] ⁺ = 525.2. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.91 (s, 1H), 7.68 (dd, J = 9.4, 2.5 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 6.53 (d, J = 9.6 Hz, 1H), 4.44 (dd, J = 11.3, 1.7 Hz, 1H), 4.26-4.22 (m, 1H), 3.84-3.77 (m, 1H), 3.53-3.45 (m, 1H), 2.89 (s, 3H), 2.68 (s, 6H), 2.27 (d, J = 13.3 Hz, 1H), 2.10-2.04 (m, 2H), 1.95 (dd, J = 24.8, 11.8 Hz, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD): δ -63.7 (s, 3F), -74.6 (s, 3F).

Method 8: Synthetic Examples 88, 98, and 100. Example 88: 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]-1-[1,2,2,2-tetradeuter-1-(trideutermethyl)ethyl]pyridin-2-one

Cs₂CO₃ (3 equivalents, 415 mg, 1.27 mmol) was added to a solution of 2-bromo-1,1,1,2,3,3,3-heptadeuterium-propane (1.5 equivalents, 83 mg, 0.636 mmol) and 5-[(2R,4S)-4-[6,7-dimethyl- _4- [ _3- (trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Example 34, 1 equivalent, 200 mg, 0.424 mmol) in MeCN (2 mL). The mixture was stirred at 40 °C for 12 hours. LCMS showed 50% of the raw material remaining and detected two peaks (22% and 28%) of the desired mass. The solution was heated to 60°C and stirred at 60°C for 2 hours. LCMS showed two peaks (33% and 54%) with the desired mass (33%). The reaction mixture was filtered through a diatomaceous earth mat. The filter cake was washed with DCM (2 × 10 mL). The combined organic layers were concentrated under reduced pressure to obtain the residue. The residue was purified and concentrated by reversed-phase chromatography (60-75% [water (FA)-MeCN]), and the residual aqueous solution was freeze-dried to obtain a solid 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-[1,2,2,2-tetradeuter-1-(trideutermethyl)ethyl]pyridin-2-one (Example 88, 42 mg, 0.0814 mg). (mmol, 19% yield) and 6,7-dimethyl-2-[(2R,4S)-2-[6-[1,2,2,2-tetradeuter-1-(trideutermethyl)ethoxy]-3-pyridyl]tetrahydropiperan-4-yl]-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine (byproduct, 42 mg, 0.0797 mmol, 19% yield).

Example 88 : LCMS : [M+H] ⁺ = 521.2; Purity = 100% (220 nm); Retention time = 0.538 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (brd, J = 1.9 Hz, 1H), 7.35 (d,J= 2.4 Hz, 1H), 6.56 (d, J= 9.1 Hz, 1H), 4.40 - 4.23 (m, 2H), 3.87 - 3.72 (m, 1H), 3.54 - 3.38 (m, 1H), 2.79 (d, J= 13.8 Hz, 6H), 2.65 (s, 6H), 2.30 (brd, J = 13.4 Hz, 1H), 2.20 - 2.10 (m, 2H), 2.07 - 1.95 (m, 1H).

Byproducts : LCMS : [M+H] ⁺ = 521.2; purity = 99% (220 nm); residence time = 0.636 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 2.4, 8.5 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 4.56 - 4.45 (m, 1H), 4.31 (br dd, J = 3.1, 10.4 Hz, 1H), 3.83 (dt, J = 3.6, 11.3 Hz, 1H), 3.56 - 3.38 (m, 1H), 2.79 (d, J = 14.3 Hz, 6H), 2.64 (s, 6H), 2.31 (br d, J = 13.4 Hz, 1H), 2.24 - 2.13 (m, 2H), 2.12 - 2.03 (m, 1H).

Following a similar method, the following compounds were obtained. Structure SM Characteristics Example 36 CD ₃ I ESI-MS : [M+H]+ = 489.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.38-7.41 (2H, m), 6.56 (1H, d, J = 9.1 Hz), 4.30 (2H, t, J = 12.6 Hz), 3.75-3.82 (1H, m), 3.41-3.49 (1H, m), 2.81 (3H, s), 2.77 (3H, s), 2.64 (6H, s), 2.31 (1H, d, J = 13.4 Hz), 1.98-2.15 (3H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). Example 98 Modification: The reaction was carried out at 40°C for 2 hours. The residue was purified by preparative TLC (100% EtOAc, desired product _Rf = 0.35) to give 1-[[5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-2-sideoxy-1-pyridinyl]methyl]cyclopropanecarboxylate (Example 98 , 33 mg, 0.057 mg) as a solid. mmol, 29% yield) and 1-[[5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-2-pyridinyl]-oxymethyl]cyclopropane-formonitrile (byproduct, 7.7 mg, 0.014 mmol, 7% yield). Example 98 : LMCS : [M+H] ⁺ = 551.3; purity = 95% (220 nm); retention time = 0.581 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 2.4, 9.4 Hz, 1H), 6.59 (d, J = 9.4 Hz, 1H), 4.37 (br d, J = 10.1 Hz, 1H), 4.33 - 4.25 (m, 1H), 4.08 (d, J = 1.3 Hz, 2H), 3.80 (dt, J = 4.1, 11.1 Hz, 1H), 3.51 - 3.38 (m, 1H), 2.79 (d, J = 14.1 Hz, 6H), 2.65 (s, 6H), 2.34 (br d, J = 13.1 Hz, 1H), 2.19 - 2.08 (m, 2H), 2.07 - 1.98 (m, 1H), 1.46 - 1.36 (m, 2H), 1.35 - 1.28 (m, 2H). Byproducts : LCMS : [M+H] ⁺ = 551.3; purity = 96% (220 nm); retention time = 0.633 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 2.3, 8.6 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 4.60 - 4.46 (m, 1H), 4.35 - 4.29 (m, 3H), 3.90 - 3.76 (m, 1H), 3.59 - 3.40 (m, 1H), 2.79 (d, J = 14.3 Hz, 6H), 2.65 (s, 6H), 2.32 (br d, J = 13.1 Hz, 1H), 2.22 - 2.12 (m, 2H), 2.11 - 2.00 (m, 1H), 1.38 - 1.33 (m, 2H), 1.16 - 1.11 (m, 2H). Example 100 Int-A49 Modification: The reaction was carried out at 60°C for 12 hours. The crude material was then purified by preparative HPLC (FA) and freeze-dried to obtain a solid 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]-1-[(1-methylcyclopropyl)methyl]pyridin-2-one (Example 100, 26 mg, 0.0467 mg). mmol, 11% yield) and 6,7-dimethyl-2-[(2R,4S)-2-[6-[(1-methylcyclopropyl)methoxy]-3-pyridyl]-tetrahydropiperan-4-yl]-4-[3-(trifluoro-methyl)-1-bis(1.1.1)pentyl]pteridine (byproduct, 5.2 mg, 0.01 mmol, 2% yield). Example 100 : LCMS : [M+H] ⁺ = 540.3, purity = 97% (220 nm). Retention time = 0.621 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.37 - 0.45 (m, 2H), 0.62 - 0.71 (m, 2H), 1.06 (s, 3H), 1.91 - 2.08 (m, 1H), 2.11 - 2.21 (m, 2H), 2.31 (br d, J=13.1 Hz, 1H), 2.66 (s, 6H), 2.80 (d, J=14.0 Hz, 6H), 3.41 - 3.53 (m, 1H), 3.74 - 3.85 (m, 1H), 3.89 (s, 2H), 4.19 - 4.47 (m, 2H), 6.53 - 6.63 (m, 1H), 7.36 - 7.44 (m, 2H). Byproduct : LCMS : [M+H] ⁺ = 540.2, purity = 100% (220 nm). Retention time = 0.693 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.36 - 0.43 (m, 2H), 0.51 - 0.60 (m, 2H), 1.22 (s, 3H), 2.04 - 2.23 (m, 3H), 2.26 - 2.37 (m, 1H), 2.65 (s, 6H), 2.79 (d, J=14.5 Hz, 6H), 3.44 - 3.57 (m, 1H), 3.83 (td, J=11.4, 3.8 Hz, 1H), 4.08 (s, 2H), 4.25 - 4.40 (m, 1H), 4.52 (dd, J=11.5, 2.0 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 7.68 (dd, J=8.6, 2.4 Hz, 1H), 8.13 (d, J=2.4 Hz, 1H).

Method 9: Synthetic Examples 104-105, 109-110, 114, 116 and 153 Example 104: 5-((2R)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(5-methylthiophene-3-yl)pyridin-2(1H)-one

Add 4-bromo-2-methylthiophene (1.5 equivalents, 0.061 mL, 0.477 mmol), Na₂CO₃ (2 equivalents, 88 mg, 0.636 mmol), DMEDA (0.4 equivalents, 11 mg, 0.127 mmol), and CuI (0.2 equivalents, 12 mg, 0.0636 mmol) to a solution of 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl) _{pterin -2} -yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 34, 1 equivalent, 150 mg, 0.318 mmol) in DMF (5 mL), and stir the mixture at 110 °C for 2 h under a _N₂ atmosphere. LCMS showed complete exhaustion of the starting material and detection of the desired mass (63%). The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 40 mL). The combined organic layer was washed with brine (50 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue _. The residue was purified by preparative TLC (100% EtOAc; desired product _Rf = 0.6) and freeze-dried to give 5-((2R)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(5-methylthiophen-3-yl)pyridin-2(1H)-one as a solid (Example 104, 86 mg, 0.142 mmol, 45% yield). LCMS : [M+H] ⁺ = 568.1; purity = 94% (220 nm); retention time = 0.634 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 - 7.41 (m, 2H), 7.15 (d, J = 1.5 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.67 - 6.60 (m, 1H), 4.39 - 4.24 (m, 2H), 3.80 (dt, J = 3.4, 11.5 Hz, 1H), 3.53 - 3.39 (m, 1H), 2.81 (s, 3H), 2.78 (s, 3H), 2.65 (s, 6H), 2.51 (d, J = 0.9 Hz, 3H), 2.33 (br dd, J = 1.8, 13.1 Hz, 1H), 2.19 - 1.99 (m, 3H). 83%ee.

Example 105: 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(5-methylthiophen-3-yl)pyridin-2(1H)-one

5-((2R)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(5-methylthiophen-3-yl)pyridin-2(1H)-one (Example 104, 1 equivalent, 83 mg, 0.146 mmol) was purified by SFC (condition 3, gradient a) to give 60 mg of the desired product, which showed 95% purity according to LCMS. The product was freeze-dried to give 50 mg of the desired product, which showed 80% purity according to LCMS. 50 mg of the desired product was purified by reversed-phase chromatography (40-60% [water (FA)-ACN], 10 min) and freeze-dried to give 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(5-methylthiophene-3-yl)pyridin-2(1H)-one as a solid (Example 105, 32 mg, 0.052 mmol). LCMS : [M+H] ⁺ = 568.1; purity = 93% (220 nm); retention time = 0.636 min; 97% ee. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 - 7.40 (m, 2H), 7.14 (d, J = 1.4 Hz, 1H), 6.92 (s, 1H), 6.71 - 6.54 (m, 1H), 4.40 - 4.25 (m, 2H), 3.79 (dt, J = 3.4, 11.4 Hz, 1H), 3.53 - 3.39 (m, 1H), 2.79 (d, J = 13.6 Hz, 6H), 2.65 (s, 6H), 2.50 (s, 3H), 2.33 (br d, J = 13.1 Hz, 1H), 2.18 - 1.98 (m, 3H).

Following a similar method, the following compounds were obtained. Example number Structure Starting materials Characteristics 109, 110 Example 109 continues with SFC : Example 110 The crude residue was purified by silicone column chromatography (0-80% EtOAc/PE, 30 mL/min) and freeze-dried to give a solid 5-((2R)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(thiazo-4-yl)pyridin-2(1H)-one (Example 109, 28 mg, 0.049 mmol, 23% yield). LCMS (mixture of non-mirror isomers) : [M+H] ⁺ = 555.2; purity = 97% (220 nm); retention time = 0.377 min; 89% ee. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J = 2.4 Hz, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 2.5, 9.4 Hz, 1H), 6.70 (d, J = 9.5 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.35 - 4.28 (m, 1H), 3.88 - 3.74 (m, 1H), 3.48 (br dd, J = 3.2, 6.9 Hz, 1H), 2.82 (s, 3H), 2.78 (s, 3H), 2.66 (s, 6H), 2.36 (br d, J = 13.3 Hz, 1H), 2.20 - 2.05 (m, 3H). Then SFC : 5-((2R)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(thiazolyl-4-yl)pyridin-2(1H)-one (Example 109, 1 equivalent, 20 mg, 0.036 mmol) was subjected to SFC. Purification and freeze-drying under (condition 3, gradient b) yielded 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(thiazolyl-4-yl)pyridin-2(1H)-one as a solid (Example 110 , 10 mg, 0.018 mmol). LCMS : [M+H] ⁺ = 555.2; purity = 96% (220 nm); retention time = 0.601 min; 100% ee. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J = 2.3 Hz, 1H), 8.50 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 2.4, 9.4 Hz, 1H), 6.70 (d, J = 9.5 Hz, 1H), 4.42 (br d, J = 11.4 Hz, 1H), 4.31 (br dd, J = 3.0, 11.0 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.59 - 3.41 (m, 1H), 2.80 (d, J = 14.3 Hz, 6H), 2.65 (s, 6H), 2.36 (br d, J = 13.5 Hz, 1H), 2.18 - 2.02 (m, 3H). 114 Example 114 Modification: The reaction was carried out at 100 °C for 1.5 hours. The residue was purified by reverse-phase chromatography (45-75% [water (0.1% FA)-ACN], 12 min) and freeze-dried to give solid 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoro-methyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(2-methyl-thiazolyl-4-yl)pyridin-2(1H)-one (Example 114, 2.5 mg, 0.004 mmol, 5% yield). LCMS : [M+H] ⁺ = 569.3; Purity = 98% (220 nm); Retention time = 0.622 min. 92% ee. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.48 (dd, J = 2.5, 9.5 Hz, 1H), 6.67 (d, J = 9.4 Hz, 1H), 4.42 (dd, J = 1.6, 11.3 Hz, 1H), 4.35 - 4.26 (m, 1H), 3.86 - 3.75 (m, 1H), 3.53 - 3.42 (m, 1H), 2.82 (s, 3H), 2.78 (s, 3H), 2.74 (s, 3H), 2.66 (s, 6H), 2.34 (br d, J = 13.5 Hz, 1H), 2.19 - 2.05 (m, 3H). 116 Example 116 Modification: The reaction was carried out at 100°C. The crude product was purified by preparative HPLC (condition 5, gradient g) and combined with another batch. The combined phase was freeze-dried to give a solid 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)-bis(1.1.1)pent-1-yl)pterin-2-yl)tetrahydro-2H-piperan-2-yl)-1-( (Azol-5-yl)pyridin-2(1H)-one (Example 116, 1.6 mg, 0.003 mmol, 3% yield). LCMS : [M+H] ⁺ = 539.2; purity = 97% (220 nm); retention time = 0.571 min; 91.7% ee. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (s, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.46 (dd, J = 2.3, 9.4 Hz, 1H), 6.67 (d, J = 9.5 Hz, 1H), 4.40 (br d, J = 10.9 Hz, 1H), 4.36 - 4.27 (m, 1H), 3.82 (dt, J = 2.8, 11.6 Hz, 1H), 3.55 - 3.38 (m, 1H), 2.80 (d, J = 14.0 Hz, 6H), 2.65 (s, 6H), 2.37 (br d, J = 13.9 Hz, 1H), 2.21 - 2.08 (m, 2H), 2.07 - 2.01 (m, 1H).

Following a similar method, the following compounds were obtained. Example number Structure Starting materials Characteristics 153 Example 153 Example 143 Modification: The reaction was carried out at 80°C for 2.5 hours. The residue was purified by reverse-phase chromatography (45-75% [water (0.1% FA)-ACN], 12 min) and freeze-dried to give solid 5-((2R,4S)-4-(6-methoxy-7-methyl-4-(3-(trifluoromethyl)-bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(2-methylthiazolyl-4-yl)pyridin-2(1H)-one (Example 153, 1.9 mg, 0.003 mmol, 4% yield). LCMS : [M+H] ⁺ = 585.3; Purity = 96% (220 nm); Retention time = 0.627 min. 92% ee. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.57 - 7.41 (m, 1H), 6.67 (d, J = 9.5 Hz, 1H), 4.41 (dd, J = 1.6, 11.3 Hz, 1H), 4.35 - 4.26 (m, 1H), 4.15 (s, 3H), 3.86 - 3.75 (m, 1H), 3.45 (ddd, J = 3.8, 11.8, 15.6 Hz, 1H), 2.74 (d, J = 3.0 Hz, 6H), 2.64 (s, 6H), 2.32 (br d, J = 13.4 Hz, 1H), 2.19 - 2.05 (m, 3H).

Method 10: Synthesis of Examples 120 and 121 Example 120: 1-(1-bicyclo[1.1.1]pentyl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one; Example 121: 1-(1-bicyclo[1.1.1]pentyl)-5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one

The residue (500 mg) was purified by silicone column chromatography (0-100% EtOAc/petroleum ether and EtOAc/MeOH) (TLC, 25% MeOH/EtOAc, desired product _Rf = 0.3) to give 1-(1-bicyclo[1.1.1]pentyl)-5-[4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 122, 120 mg, 0.22 mmol, 85% purity). Next, it was purified by silicone column chromatography (0-100% EtOAc/PE, followed by 0-50% MeOH/EtOAc) (TLC, 9% MeOH/DCM, _Rf = 0.3) to obtain the residue (~98% purity, 35 mg). The residue was purified by SFC (condition 5, gradient a-2) to obtain crude substance A (~10 mg, ~85% purity) and crude substance B (~20 mg, ~50% purity).

The crude substance A was purified again by preparative HPLC (condition 5) and freeze-dried to obtain 1-(1-bicyclo[1.1.1]pentyl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 120, 2.0 mg, 0.003 mmol, 1.5% yield).

The crude substance B was purified by SFC (condition 4, gradient a), concentrated by depressurization, and further purified by preparative HPLC (condition 5) and freeze-dried to obtain 1-(1-bicyclo[1.1.1]pentyl)-5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 121, 1.3 mg, 0.0024 mmol, 1% yield).

Example 120 : LCMS : [M+H] ⁺ = 538.3; Purity = 100% (220 nm); Retention time = 0.625 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (dd, J = 2.5, 9.4 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 9.4 Hz, 1H), 4.36 - 4.24 (m, 2H), 3.85 - 3.74 (m, 1H), 3.39 (s, 1H), 2.80 (d, J = 14.1 Hz, 6H), 2.66 - 2.63 (m, 7H), 2.38 (s, 6H), 2.28 (br d, J = 13.1 Hz, 1H), 2.19 - 2.10 (m, 2H), 2.07 - 1.97 (m, 2H). ee ~ 92%.

Example 121 : LCMS : [M+H] ⁺ = 538.3; Purity = 100% (220 nm); Retention time = 0.626 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (dd, J = 2.5, 9.4 Hz, 1H), 7.26 (br s, 1H), 6.47 (d, J = 9.4 Hz, 1H), 4.35 - 4.26 (m, 2H), 3.85 - 3.73 (m, 1H), 3.52 - 3.40 (m, 1H), 2.80 (d, J = 14.1 Hz, 6H), 2.66 - 2.64 (m, 6H), 2.39 (s, 6H), 2.31 - 2.24 (m, 1H), 2.17 - 2.11 (m, 2H), 2.08 - 1.97 (m, 1H). ee : 92.5%.

Method 11: Synthetic Examples 126-128 Example 128: 5-[4-[6-(difluoromethyl)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one

Under vigorous stirring, tributyl hydroperoxide (5 equivalents, 129 mg, 1 mmol) was added to a solution of 5-[4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Int-B1 , 1 equivalent, 100 mg, 0.2 mmol) and zinc difluoromethane sulfate (2.7 equivalents, 159 mg, 0.54 mmol) in DMSO (5 mL), and _N2 was bubbled through for 30 seconds. The reaction mixture was stirred at 20°C for 2 hours. Next, zinc difluoromethane sulfate (2.7 equivalents, 159 mg, 0.54 mmol) was added to the reaction mixture, and the mixture was then stirred at 20°C for 12 hours. LCMS showed ~19% of the starting material remaining and ~21% of the desired product detected. The mixture (combined with three other batches) was quenched with 200 mL of _H₂O , extracted with DCM (3 × 150 mL), and _the combined organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude residue. The residue was purified by silicone column chromatography (0-100% EtOAc/PE, followed by 0-50% MeOH/EtOAc) (TLC, 9% MeOH/DCM, desired product _Rf = 0.6) to obtain the crude product. The crude product was further purified by preparative TLC (9% MeOH/DCM, desired product _Rf = 0.6) to give 5-[4-[6-(difluoromethyl)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one as a solid (Example 128, 30 mg, 0.055 mmol, 27% yield). LCMS : [M+H] ⁺ = 500.1; Purity = 94% (UV 220 nm); Retention time = 0.565 min. Separation Example 126: 5-[(2R,4S)-4-[6-(difluoromethyl)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one; Example 127: 5-[(2S,4R)-4-[6-(difluoromethyl)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one

The crude material (Example 128) was separated by SFC (condition 14, gradient a) to obtain solid 5-[(2R,4S)-4-[6-(difluoromethyl)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 126, 6.3 mg, 0.011 mmol, 13% yield) and solid 5-[(2S,4R)-4-[6-(difluoromethyl)-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 127, 7.6 mg, 0.0138 mmol, 17% yield).

Example 126 : LCMS : [M+H] ⁺ = 550.3; Purity = 94% (UV 220 nm); Retention time = 0.557 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 - 7.83 (m, 1H), 7.72 - 7.62 (m, 1H), 7.60 - 7.53 (m, 1H), 7.44 - 7.37 (m, 2H), 6.89 - 6.55 (m, 2H), 4.40 - 4.28 (m, 2H), 3.82 (dt, J = 2.8, 11.8 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.56 (s, 3H), 3.14 - 3.03 (m, 3H), 2.47 - 2.36 (m, 1H), 2.26 - 2.02 (m, 3H).

Example 127 : LCMS : [M+H] ⁺ = 550.3; Purity = 100% (UV 220 nm); Retention time = 0.557 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 - 7.83 (m, 1H), 7.87 (t, J = 7.3 Hz, 1H), 7.66 (br d, J = 7.9 Hz, 1H), 7.56 (br d, J = 9.3 Hz, 1H), 7.45 - 7.35 (m, 2H), 6.88 (s, 1H), 6.74 (s, 1H), 6.68 - 6.46 (m, 1H), 4.40 - 4.30 (m, 2H), 3.82 (dt, J = 2.8, 11.7 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.56 (s, 3H), 3.08 (s, 3H), 2.43 - 2.38 (m, 1H), 2.24 - 2.13 (m, 3H).

Method 12: Synthetic Examples 129-130: Example 129: 1-Methyl-5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one Example 130: 1-Methyl-5-[(2S,4R)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one

At 0 °C, CAN (1.5 equivalent, 494 mg, 0.901 mmol) was added in portions to a solution of 5-[4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Int-B1 , 1 equivalent, 300 mg, 0.601 mmol) in _MeOH (10 mL), and the mixture was stirred at 0 °C for 20 min. LC-MS showed that most of the starting material was consumed, and the main peak indicated the desired mass. The reaction mixture was poured into _Na₂SO₃ (aq. 20 mL) and extracted with EtOAc (15 mL × 3). Organic matter was washed with 20 mL of saturated salt solution. _The combined organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by preparative NPLC (condition 1) to obtain 100 mg of the desired product. The 100 mg product was then combined with 47 mg from another batch and separated by SFC (condition 15, gradient a) to obtain 30 mg of crude product A and a solid 1-methyl-5-[(2S,4R)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 130, 32 mg, 0.0600 mmol, 10% yield). LCMS : Retention time = 1.391 min. MS [M+H] ⁺ = 530.3, purity = 100%, uv = 220 nm, retention time = 0.567 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.05 - 2.23 (m, 3H) 2.37 (br d, J=13.1 Hz, 1H), 2.78 (s, 3H), 3.52 - 3.57 (m, 4H), 3.77 - 3.85 (m, 1H) 4.01 (s, 3H) 4.21 - 4.45 (m, 2H) 6.51 - 6.64 (m, 1H), 7.36 - 7.44 (m, 2H) 7.52 (br d, J=9.8 Hz, 1H) 7.63 (d, J=8.1 Hz, 1H), 7.87 (t, J=7.2 Hz, 1H).

Crude substance A (30 mg) was purified by preparative TLC (9% MeOH/EtOAc, _Rf = 0.5) to obtain approximately 20 mg of oil, which was then separated by SFC (condition 1, gradient a-1) to give a solid 1-methyl-5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 129, 9.0 mg, 0.017 mmol, 3% yield). LCMS : [M+H] ⁺ = 530.2, purity = 100% (220 nm), retention time = 0.568 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.04 - 2.24 (m, 2H), 2.23 - 2.24 (m, 1H), 2.37 (br d, J =13.4 Hz, 1H), 2.77 (s, 3H), 3.49 - 3.58 (m, 4H), 3.75 - 3.86 (m, 1H), 4.01 (s, 3H), 4.24 - 4.40 (m, 2H), 6.52 - 6.62 (m, 1H), 7.37 - 7.43 (m, 2H), 7.52 (d, J =9.6 Hz, 1H), 7.62 (d, J =7.8 Hz, 1H), 7.86 (t, J =7.3 Hz, 1H).

Method 13: Synthetic Examples 140, 145, 147 and 149: Example 140 : 5-[(2R,4S)-4-[6- methoxy -7- methyl -4-[3-( trifluoromethyl )-1- bicyclo [1.1.1] pentyl ] pteridin -2- yl ] tetrahydropiperan -2- yl ]-1- methylpyridin - 2 - one

MeI (5 equivalents, 0.026 mL, 0.410 mmol) was added to a mixture of 5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[ _3- (trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Example 143, 1 equivalent, 40 mg, 0.0821 mmol) and _Cs₂CO₃ (2 equivalents, 53 mg, 0.164 mmol) in MeCN (2 mL), and the reaction mixture was stirred at 40 °C for 0.5 h. LCMS showed a main peak of the desired mass. The mixture was combined with another batch, and the final mixture was added to 20 mL of water and extracted with EtOAc (3 × 20 mL). The organic phase was concentrated under reduced pressure to obtain a crude residue, which was purified twice by reversed-phase HPLC (100-0% [(0.05% FA) water:ACN]) and then freeze-dried to obtain a solid 5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 140, 24 mg, 0.0452 mmol, 55% yield). LCMS : [M+H] ⁺ = 502.2; purity = 93% (UV 220 nm); retention time = 0.577 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 - 7.36 (m, 2H), 6.68 - 6.53 (m, 1H), 4.43 - 4.25 (m, 2H), 4.16 (s, 3H), 3.80 (br d, J = 3.6 Hz, 1H), 3.57 (s, 3H), 3.50 - 3.37 (m, 1H), 2.75 (s, 3H), 2.65 (s, 6H), 2.30 (br s, 1H), 2.20 - 2.08 (m, 2H), 2.08 - 1.97 (m, 1H). SFC : 95% purity.

Following a similar method, the following compounds were obtained. Structure Starting materials Characteristics Example 145 Modification: The reaction was carried out at 25°C for 1 hour. The crude material was purified by reversed-phase HPLC (100-0% [(0.05% FA) water:ACN]) and freeze-dried to give 2-[5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-2-sideoxy-1-pyridinyl]acetonitrile (Example 145, 4.3 mg, 0.008 mmol, 37% yield). LCMS : [M+H] ⁺ = 527.2; purity = 94% (UV 220 nm); retention time = 0.568 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (qd, J = 2.5, 5.1 Hz, 2H), 6.68 - 6.57 (m, 1H), 4.84 (s, 2H), 4.41 - 4.24 (m, 2H), 4.14 (s, 3H), 3.78 (dt, J = 3.0, 11.6 Hz, 1H), 3.48 - 3.35 (m, 1H), 2.73 (s, 3H), 2.63 (s, 6H), 2.38 - 2.29 (m, 1H), 2.19 - 2.06 (m, 2H), 2.02 - 1.91 (m, 1H). SFC: 88% purity. Example 147 CD ₃ I Modification: The reaction was carried out at 25°C for 12 hours. The crude product was purified by reversed-phase chromatography (30-70% [water (FA)-ACN], 10 min) and freeze-dried to give solid 5-((2R,4S)-4-(6-methoxy-7-methyl-4-(3-(trifluoromethyl)-bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(methyl-d3)pyridin-2(1H)-one (Example 147, 40 mg, 0.078 mmol, 38% yield). LCMS : [M+H] ⁺ = 505.3; purity = 99%; retention time = 0.580 min; 100% ee. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 - 7.36 (m, 2H), 6.57 (dd, J = 0.8, 8.9 Hz, 1H), 4.36 - 4.24 (m, 2H), 4.15 (s, 3H), 3.79 (dt, J = 3.6, 11.4 Hz, 1H), 3.50 - 3.36 (m, 1H), 2.74 (s, 3H), 2.64 (s, 6H), 2.30 (br dd, J = 1.9, 13.4 Hz, 1H), 2.18 - 2.07 (m, 2H), 2.07 - 1.95 (m, 1H).

Following a similar method, the following compounds were obtained. Example number Structure Starting materials Characteristics 149 Example 149 CD ₃ I Example 151 Modification: The reaction was carried out at 25°C for 2 hours. The crude material was purified by reversed-phase HPLC (100-0% [(0.05% FA) water:ACN]) and freeze-dried to give 5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-3-methyl-1-(trideutermethyl)-pyridin-2-one as a solid (Example 149, 21 mg, 0.037 mmol, 27% yield). LCMS : [M+H] ⁺ = 519.2; purity = 91% (UV 220 nm); retention time = 0.600 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34 - 7.30 (m, 1H), 7.26 (br s, 1H), 4.35 - 4.24 (m, 2H), 4.19 - 4.10 (m, 3H), 3.86 - 3.74 (m, 1H), 3.49 - 3.37 (m, 1H), 2.78 - 2.71 (m, 3H), 2.67 - 2.59 (m, 6H), 2.32 - 2.25 (m, 1H), 2.19 - 2.15 (m, 3H), 2.15 - 2.00 (m, 3H). SFC : 93% purity.

Method 14: Synthetic Example 132 Example 132: 5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-(trideutermethyl)pyridin-2-one

Trideuterium (iodide)methane (5 equivalents, 235 mg, 1.62 mmol) was added to a mixture of 5-[(2R,4S)-4-[ _4- [2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Int-B5 , 1 equivalent, 180 mg, 0.324 mmol) and _Cs₂CO₃ (2 equivalents, 211 mg, 0.647 mmol) in MeCN (4 mL). The mixture was stirred at 30 °C for 2 h. LCMS showed exhaustion of the starting material and detection of 88% of the desired mass. The reactants were filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (30–70% [water (FA)-ACN], 10 min) and freeze-dried to give solid 5-[(2R,4S)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-(trideutermethyl)pyridin-2-one (Example 132, 84 mg, 0.152 mmol, 47% yield). LCMS : [M+H] ⁺ = 533.2; purity = 97%; retention time = 0.553 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (t, J = 7.3 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 9.5 Hz, 1H), 7.43 - 7.36 (m, 2H), 6.61 - 6.53 (m, 1H), 4.40 - 4.25 (m, 2H), 4.01 (s, 3H), 3.80 (dt, J = 3.9, 11.2 Hz, 1H), 3.61 - 3.46 (m, 1H), 2.78 (s, 3H), 2.37 (br d, J = 13.3 Hz, 1H), 2.25 - 2.14 (m, 2H), 2.12 - 2.02 (m, 1H). SFC residence time = 1.145 min, ee: 100%.

Method 15: Synthesizing Examples 143 and 151: Example 143: 5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]-pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one

A mixture of 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropiperan-4-yl]-6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine (Int-B13, 1 equivalent, 180 mg, 0.312 mmol) in DCM (3.6 mL) and TFA (3.6 mL) was stirred at 20 °C for 3 h. LC-MS showed the desired MS peak. Saturated _NaHCO3 (aq) was added to the mixture to pH = 7-8, and extraction was performed with EtOAc (50 mL × 3). The organic phase was concentrated under reduced pressure to obtain 5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]-pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Example 143, 100 mg, 0.205 mmol, 66% yield) in solid form, which can be used directly in the next step. LCMS : [M+H] ⁺ = 488.2; purity = 77% (UV 220 nm); retention time = 0.552 min.

Following a similar method, the following compounds were obtained. Structure Starting materials Characteristics Example 151 Int-B12 _The mixture was saturated with _Na₂CO₃ (aq) to pH 7–8 and extracted with EtOAc (20 mL × 3) to give 5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-3-methyl-1H-pyridin-2-one (Example 151, 80 mg, 0.136 mmol, 100% yield) as a solid (crude material). The crude material was used directly in the next step. LCMS : [M+H] ^⁺ = 502.3; purity = 85% (UV 220 nm); retention time = 0.591 min. Example 186 Int-C19 The reaction was carried out at 80°C for 3 h in 4 mL vials sealed with red screw caps equipped with pressure-reducing diaphragms. The crude product was first purified by rapid chromatography (Isco RediSep® column 12 g, using a gradient from 100% hexane to 100% EtOAc), followed by further purification by reversed-phase rapid chromatography (condition 12, gradient a) to give 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine -7-yl)-6-methyl (Lin-2-yl)pyridin-2(1H)-one (Example 186, 4.0 mg, 8.63 µmol, 5% yield). ¹ H NMR (CD ₃ OD, 400 MHz): δ 7.74 (1H, dd, J = 9.4, 2.5 Hz), 7.59-7.63 (1H, m), 7.53 (1H, d, J = 2.4 Hz), 7.03-7.11 (2H, m), 7.01 (1H, s), 6.57 (1H, d, J = 9.4 Hz), 4.56 (1H, d, J = 10.7 Hz), 4.47 (1H, d, J = 12.9 Hz), 4.34 (1H, d, J = 12.7 Hz), 3.91 (1H, s), 2.82 (1H, t, J = 11.7 Hz), 2.68-2.74 (4H, m), 2.57 (3H, s), 1.33 (3H, d, J = 6.2 Hz). ¹⁹ F NMR (CD ₃ OD, 376 MHz): δ -111.5 (1F, dd, 9.4, 17.2 Hz), -110.2 (1F, m). ESI-MS : [M+H] ⁺ = 464.4. Example 192 (2S,6R)-2-(6-(benzooxy)pyridin-3-yl)-4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,6- (P-7-yl)-6-methyl phyto Use the procedure in Example 186 to obtain 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,6- (P-7-yl)-6-methyl (Lin-2-yl)pyridin-2(1H)-one (Example 192). ¹ H NMR (CD ₃ OD, 400 MHz): δ 7.74 (1H, dd, J = 9.4, 2.5 Hz), 7.51-7.60 (3H, m), 7.15 (2H, t, J = 8.7 Hz), 7.00 (1H, s), 6.57 (1H, d, J = 9.4 Hz), 4.56 (1H, d, J = 10.6 Hz), 4.42 (1H, d, J = 12.8 Hz), 4.30 (1H, d, J = 12.6 Hz), 3.91 (1H, s), 2.79 (1H, t, J = 11.7 Hz), 2.70 (1H, d, J = 11.7 Hz), 2.64 (3H, s), 2.35 (3H, s), 1.33 (3H, d, J = 6.2 Hz). ¹⁹ F NMR (CD ₃ OD, 376 MHz): δ -110.6 (1F, m), -112.2 (1F, m). ESI-MS : [M+H] ⁺ = 463.4. Example 224 Int-D42 Modification : The reaction was carried out at 55°C for 12 h using 1 equivalent of Int-D42, 4 equivalents of TFA, and DCE solvent. The crude material was first purified by a silicone column (EtOAc/MeOH = 1:1, _Rf = 0.4), followed by purification by preparative HPLC (condition 18, gradient b) and freeze-drying to obtain a solid 5-[(2R,4S)-4-[4-(4,4-difluorocyclohexyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Example 224, a single mirror isomer with known absolute configuration). LCMS : [M+H] ⁺ = 456.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.95 - 2.20 (m, 9H) 2.26 - 2.37 (m, 3H) 2.80 (d, J=15.1 Hz, 6H) 3.36 - 3.54 (m, 1H) 3.72 - 3.85 (m, 1H) 4.16 (br t, J=11.7 Hz, 1H) 4.29 (br dd, J=10.5, 2.8 Hz, 1H) 4.35 (br d, J=10.4 Hz, 1H) 6.59 (d, J=9.4 Hz, 1H) 7.41 (d, J=1.9 Hz, 1H) 7.58 (dd, J=9.4, 2.3 Hz, 1H) 11.46 - 12.70 (m, 1H). Example 34 Int-F9 Modification : The reaction was carried out at reflux temperature for 1.5 h and purified by reversed-phase chromatography (35-85% / water (0.1% formic acid)) to give 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 34, 1.05 g, 69% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.56 (1H, dd, J = 9.4, 2.5 Hz), 7.41 (1H, d, J = 2.4 Hz), 6.56 (1H, d, J = 9.4 Hz), 4.32 (1H, d, J = 11.3 Hz), 4.24 (1H, d, J = 11.5 Hz), 3.71 - 3.77 (1H, m), 3.39 - 3.45 (1H, m), 2.77 (3H, s), 2.73 (3H, s), 2.61 (6H, s), 2.25 (1H, d, J = 13.3 Hz), 2.06 - 2.11 (2H, m), 1.97 (1H, q, J = 12.3 Hz). ESI-MS : [M+H] ⁺ = 472.3.

Method 16: Synthetic Example 136 Example 136: 5-[(2R)-4-(4-cyclohexyl-6-methoxy-7-methyl-pteridin-2-yl)tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one

Under _{N2 conditions} , bromo(cyclohexyl)zinc (3 equivalents, 0.33 mL, 0.167 mmol) was added to a solution of 4-methylbenzenesulfonic acid [6-methoxy-7-methyl-2-[(2R)-2-(1-methyl-6 _- sideoxy-3-pyridyl)tetrahydropiperan-4-yl]pteridin-4-yl ester] (Int-B17, 1 equivalent, 30 mg, 0.056 mmol) and Pd(Amphos) _2Cl2 (0.1 equivalent, 4.0 mg, 0.006 mmol) in THF (1 mL). The mixture was then stirred at 45 °C for 1 h. LC-MS showed complete exhaustion of the starting materials and the desired peak was observed. The reaction solution was extracted with EtOAc (5 mL × 2), and the organic layer was washed with saturated brine (5 mL). Next, the combined organic layer was dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain a crude residue. The residue was purified by preparative TLC (9% MeOH/EtOAc, _Rf = 0.4) (×2) to give 15 mg of product. The product was then purified by preparative HPLC (FA) and freeze-dried to give 5-[(2R)-4-(4-cyclohexyl-6-methoxy-7-methyl-pteridin-2-yl)tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 136, 2.3 mg, 0.005 mmol, 9% yield). LCMS : [M+H] ⁺ = 450.3, purity = 97%, uv = 220 nm, residence time = 0.608 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.39 (br t, J =12.5 Hz, 1H), 1.45 - 1.58 (m, 2H), 1.81 (br s, 2H), 1.92 (br d, J =10.4 Hz, 4H), 2.09 - 2.17 (m, 2H), 2.32 (br d, J =13.0 Hz, 1H), 2.72 (s, 3H), 3.33 - 3.48 (m, 1H), 3.56 (s, 3H), 3.70 - 3.90 (m, 2H), 4.15 (s, 3H), 4.25 - 4.38 (m, 2H), 6.58 (d, J =9.2 Hz, 1H), 7.38 - 7.45 (m, 2H).

Method 17: Synthesis Example 138 Example 138: 5-[(2R,4S)-4-[4-(4,4-difluorocyclohexyl)-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one

A mixture of 2-bromo-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridine (Int-B19, 1 equivalent, 10 mg, 0.027 mmol), Pd(OAc) _₂ (0.1 equivalent, 0.60 mg, 0.003 mmol) and C-Phos (0.2 equivalent, 2.3 mg, 0.005 mmol) was purged three times with _N₂ . Then, THF (0.5 mL) was added, followed by a solution of bromo-[2-(1-cyclopropyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]zinc (Int-B20, 1.2 equivalent, 12 mg, 0.032 mmol). The mixture was stirred at 55 °C for 2 h. LCMS detected ~32% of the desired product. The mixture _was quenched with _H₂O (50 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to give the crude product. The mixture was purified by preparative HPLC (FA) to give the crude product (17 mg). The crude product was purified by preparative TLC (8% MeOH/EtOAc, _Rf = 0.4) and freeze-dried to give 5-[(2R,4S)-4-[4-(4,4-difluorocyclohexyl)-6-methoxy-7-methyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one as a solid (Example 138, 4.3 mg, 0.008 mmol). LCMS : [M+H] ⁺ = 486.3; purity = 94% (220 nm); retention time = 0.547 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 - 7.37 (m, 2H), 6.61 - 6.55 (m, 1H), 4.38 - 4.24 (m, 2H), 4.15 (s, 3H), 3.97 - 3.73 (m, 2H), 3.56 (s, 3H), 3.49 - 3.34 (m, 1H), 2.74 (s, 3H), 2.36 - 2.27 (m, 3H), 2.26 - 2.17 (m, 2H), 2.13 (br dd, J = 4.0, 11.1 Hz, 2H), 2.09 - 1.97 (m, 5H).

Method 18: Synthetic Examples 167-171 Example 171: 5-(4-(2,3-dimethyl-8-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-b]pyridine -6-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one

5-[4-(8-chloro-2,3-dimethyl-pyrido[2,3- _b ]pyridine] A mixture of [-6-yl)tetrahydropiperan-2-yl]-1-methylpyridin-2-one (Int-B22, 1 equivalent, 150 mg, 0.39 mmol), Pd(Amphos) _2Cl2 (0.05 equivalent, 14 mg, 0.0195 mmol), and THF ( ₁ mL) was purged three times with _N2 . Then, at 25 °C, chloro-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]zinc (1.2 equivalent, 110 mg, 0.47 mmol) was added dropwise to the reaction solution, followed by heating to 45 °C and stirring for 1 hour. LCMS showed ~61% detection of the desired product. The mixture was combined with another batch, then quenched with _H₂O (100 mL), extracted with DCM (3 × 100 mL), and _the combined organic layer was dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to give a crude product (200 mg). The crude product was purified by silicone column chromatography (0-100% EtOAc/petroleum ether, followed by 0-30% MeOH/EtOAc) (TLC, 25% MeOH/EtOAc, desired product _Rf = 0.4) to give a crude substance (Example 171, 100 mg).

Separation Examples 167-170

The crude material (Example 171) was purified by preparative HPLC (condition 7, gradient c) to obtain crude material A (40 mg) and crude material B (30 mg, 85% purity).

Crude material A (40 mg) was purified by SFC (condition 11, gradient d) and freeze-dried to obtain solid 1-methyl-5-[(2R,4S)-4-[2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[2,3-b]pyridyl -6-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 167, 9.3 mg, 0.0188 mmol, 6% yield) and 1-methyl-5-[(2S,4R)-4-[2,3-dimethyl-8-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-b]pyridyl [-6-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 168, 7.1 mg, 0.015 mmol, 5% yield).

Crude substance B (30 mg, 85% purity) was purified by preparative HPLC (condition 7, gradient d) to obtain crude substance B (17 mg, 95% purity), which was then purified by SFC (condition 11, gradient e) and freeze-dried to obtain a solid 1-methyl-5-[(2R,4R)-4-[2,3-dimethyl-8-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-b]pyridyl -6-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 169, 5.9 mg, 0.012 mmol, 4% yield) and 1-methyl-5-[(2S,4S)-4-[2,3-dimethyl-8-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-b]pyridyl [-6-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 170, 8.6 mg, 0.0162 mmol, 5% yield).

Example 167 : LCMS : [M+H] ⁺ = 485.1; purity = 100% (UV 220 nm); retention time = 0.568 min. HPLC : retention time = 1.731 min, 98% purity, at 220 nm. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39 - 7.35 (m, 2H), 7.22 (s, 1H), 6.56 (d, J = 10.1 Hz, 1H), 4.29 (br s, 2H), 3.77 (br t, J = 11.1 Hz, 1H), 3.54 (s, 3H), 3.35 - 3.22 (m, 1H), 2.76 (d, J = 11.3 Hz, 6H), 2.58 (s, 6H), 2.22 - 1.94 (m, 4H).

Example 168 : LCMS : [M+H] ⁺ = 485.0; purity = 100% (UV 220 nm); retention time = 0.568 min. HPLC : retention time = 1.725 min, 99% purity, at 220 nm. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 2H), 7.22 (s, 1H), 6.56 (d, J = 10.1 Hz, 1H), 4.35 - 4.23 (m, 2H), 3.77 (dt, J = 2.1, 11.9 Hz, 1H), 3.54 (s, 3H), 3.36 - 3.23 (m, 1H), 2.76 (d, J = 11.4 Hz, 6H), 2.58 (s, 6H), 2.20 - 1.94 (m, 4H).

Example 169 : LCMS : [M+H] ⁺ = 485.2; purity = 95% (UV 220 nm); retention time = 0.581 min. HPLC : retention time = 1.623 min, 96% purity, at 220 nm. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (br d, J = 9.3 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.27 (s, 1H), 6.59 (d, J = 9.4 Hz, 1H), 4.78 (dd, J = 2.8, 9.0 Hz, 1H), 3.92 (s, 2H), 3.57 - 3.51 (m, 4H), 2.78 (d, J = 13.3 Hz, 6H), 2.58 (s, 6H), 2.56 - 2.50 (m, 1H), 2.30 - 2.12 (m, 3H).

Example 170 : LCMS : [M+H] ⁺ = 485.1; purity = 99% (UV 220 nm); retention time = 0.580 min. HPLC : retention time = 1.625 min, 91% purity, at 220 nm. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (dd, J = 2.4, 9.3 Hz, 1H), 7.39 (br s, 1H), 7.28 (s, 1H), 6.60 (d, J = 9.4 Hz, 1H), 4.79 (dd, J = 2.9, 8.6 Hz, 1H), 4.03 - 3.86 (m, 2H), 3.56 (s, 4H), 2.80 (s, 3H), 2.77 (s, 3H), 2.59 (s, 6H), 2.28 - 2.13 (m, 4H).

Method 19. Synthetic Example 173 Example 173: 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1H-pyridin-2-one

To 5-[(2S,6R)-2-(6-benzoxy-3-pyridyl)-6-methyl- A solution of lin-4-yl]-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazo[4,5-d]pyrimidine-2-amine (Int-C3, 1 equivalent, 90 mg, 0.157 mmol) in 1,1,1,3,3,3-hexafluoroprop-2-ol (1.0 mL) was mixed with MsOH (0.10 mL), and the mixture was stirred at 20 °C for 12 h, followed by stirring at 25 °C for another 12 h. The reaction solution was added to an aqueous solution of _NaHCO3 (10 mL), extracted with DCM (10 mL × ₂ ), and washed with a saturated salt solution. The organic matter was separated, dried ( _Na2SO4 ), and concentrated to obtain a residue. One-third of the residue was purified by preparative TLC (DCM/MeOH = 20/1, _Rf = 0.4) and freeze-dried to obtain solid 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1H-pyridin-2-one (Example 173). LCMS : [M+H] ⁺ = 485.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.31 (d, J=6.3 Hz, 3H) 2.65 - 2.85 (m, 2H) 3.09 - 3.43 (m, 6H) 3.72 - 3.87 (m, 1H) 4.40 (dd, J=10.6, 2.4 Hz, 1H) 4.78 - 4.95 (m, 2H) 6.61 (d, J=9.4 Hz, 1H) 6.95 (ddd, J=10.7, 8.7, 2.5 Hz, 1H) 7.00 - 7.08 (m, 1H) 7.45 (d, J=2.3 Hz, 1H) 7.57 (dd, J=9.5, 2.5 Hz, 1H) 7.75 (td, J=8.5, 6.6 Hz, 1H).

Method 20. Synthetic Example 174. Example 174: 1-amino-5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]pyridin-2-one

At 0 °C, 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- O-biphenylphosphohydroxyamine (2 equivalents, 29 mg, 0.124 mmol) was added to a mixture of lin-2-yl]-1H-pyridin-2-one (Example 173, 1 equivalent, 30 _mg , 0.0619 mmol) and _Cs₂CO₃ (3.5 equivalents, 71 mg, 0.217 mmol) in DMF (1 mL). The mixture was then stirred at 20 °C for 45 min. The reaction solution was extracted with DCM (10 mL × 2) and washed with 20 _mL of saturated brine. The organic matter was separated and dried ( _Na₂SO₄ ), then concentrated to dryness. Next, the residue was purified by preparative TLC (DCM/MeOH = 10/1, _Rf = 0.6) and freeze-dried to obtain a solid 1-amino-5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]pyridin-2-one (Example 174). LCMS : [M+H] ⁺ = 500.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.31 (d, J=6.3 Hz, 3H) 2.66 - 2.85 (m, 2H) 3.77 - 3.86 (m, 1H) 4.40 (dd, J=10.7, 2.6 Hz, 1H) 4.79 - 4.94 (m, 2H) 6.66 (d, J=9.3 Hz, 1H) 6.95 (ddd, J=10.7, 8.7, 2.4 Hz, 1H) 7.00 - 7.06 (m, 1H) 7.5 (dd, J=9.3, 2.4 Hz, 1H) 7.72 - 7.79 (m, 2H).

Following a similar method, the following compounds were obtained. Structure Starting materials Characteristics Example 177 Example 34 Modification: The reaction was carried out in a flame-dried microwave-safe vial containing 200 mg of starting material under argon atmosphere. The crude material was purified by rapid chromatography (12 g silicone column) using a dissolution gradient of 0–10% MeOH/DCM to give solid 1-amino-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 177, 149 mg, 0.306 mmol, 72% yield). ESI-MS : [M+H] ⁺ = 487.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.70 (1H, d, J = 2.4 Hz), 7.45 (1H, dd, J = 9.4, 2.5 Hz), 6.69 (1H, d, J = 9.5 Hz), 4.34 (1H, d, J = 11.4 Hz), 4.26-4.30 (1H, m), 3.74-3.81 (1H, m), 3.46-3.54 (1H, m), 2.80 (3H, s), 2.77 (3H, s), 2.65 (6H, s), 2.29-2.32 (1H, m), 2.08-2.15 (2H, m), 1.96-2.05 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). Example 184 Int-C16 Modification: At 40℃, using 5-[(2S,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]-6-methyl- The reaction was carried out with lin-2-yl]-1H-pyridin-2-one (Int-C16) for 3 h. The orange residue was first purified by rapid chromatography (6 g C18 column) using a dissolution gradient of 10-90% ACN/0.1% FA (aq.), and then purified by preparative HPLC (condition 10, gradient a) to give a solid 1-amino-5-[(2S,6R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]-6-methyl- [Lin-2-yl]pyridin-2-one (Example 184, 1.6 mg, 320 µmol, 2% yield). ESI-MS : [M+H] ⁺ = 502.4. ¹ H NMR : (CD ₃ OD, 400 MHz): δ 7.89 (1H, s), 7.63 (1H, d, J = 9.1 Hz), 6.64 (1H, d, J = 9.2 Hz), 4.94 (2H, dd, J = 30.1, 13.3 Hz), 4.46 (1H, dd, J = 10.7, 2.6 Hz), 3.80 (1H, ddd, J = 10.6, 6.2, 2.7 Hz), 2.92 (1H, dd, J = 13.3, 10.8 Hz), 2.81 (1H, dd, J = 13.3, 10.7 Hz), 2.67 (3H, s), 2.65 (3H, s), 2.59 (6H, s), 1.32 (3H, d, J = 6.2 Hz). ¹⁹ F NMR (CD ₃ OD, 376 MHz): δ -74.8 (3F, s). Example 185 Int-C18 Modification : The reaction was initiated at 0°C in an ice-water bath and slowly heated to room temperature over 3.5 h with stirring. The crude material was purified by rapid chromatography (12 g Isco RediSep column using a gradient of 0 to 2% MeOH/DCM) to obtain a solid 1-amino-5-[(2S,6R)-6-methyl-4-[7-methyl-6-(oxacyclobut-3-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl] [Lin-2-yl]pyridin-2-one (Example 185, 55% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.76 (s, 1H), 7.46 (d, J = 9.0 Hz, 1H), 6.67-6.69 (m, 1H), 5.08 (t, J = 7.6 Hz, 4H), 4.99-5.04 (m, 1H), 4.92-5.00 (m, 1H), 4.60-4.68 (m, 1H), 4.39 (dd, J = 10.7, 2.6 Hz, 1H), 3.75-3.84 (m, 1H), 2.77-2.95 (m, 3H), 2.62 (s, 6H), 2.55 (s, 2H), 1.34 (d, J = 6.1 Hz, 3H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -72.9 (s, 3F). ESI-MS : [M+H] ⁺ = 544.3. Example 193 Example 192 Modification: 25 mg of starting material Example 192 and each reagent were added to a flame-dried microwave-safe vial, cooled to 0°C, and then 1.1 mL of DMF was added with stirring. The reaction was heated to room temperature and maintained for 1 h. The crude material was purified by reversed-phase chromatography (condition 13, gradient a) to obtain 1-amino-5-[(2S,6R)-4-[5-(2,4-difluorophenyl)-2,3-dimethyl-1,6-]in solid form. [Pyridine-7-yl]-6-methyl- [Lin-2-yl]pyridin-2-one (Example 193, 12.2 mg, 25.5 µmol, 47% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76 (s, 1H), 7.46 (d, J = 9.0 Hz, 1H), 6.67-6.69 (m, 1H), 5.08 (t, J = 7.6 Hz, 5H), 4.99-5.04 (m, 1H), 4.92-5.00 (m, 1H), 4.60-4.68 (m, 1H), 4.39 (dd, J = 10.7, 2.6 Hz, 1H), 3.75-3.84 (m, 1H), 2.77-2.95 (m, 3H), 2.62 (s, 6H), 2.55 (s, 2H), 1.34 (d, J = 6.1 Hz, 3H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -109.6 (s, 2F). ESI-MS : [M+H] ⁺ = 533.3. Example 218 Example 216 Modification : The reaction was carried out using 3 _equivalents of _Cs₂CO₃ . The crude residue was purified by rapid chromatography (4 g _SiO₂ ) using a dissolution gradient of 0–10% MeOH/DCM to give solid 2,3-dimethyl-6-[rac-(2R,4S)-2-(1-amino-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[5,4-d]pyrimidin-4-one (Example 218, 3.2 mg, 6.4 µmol, 34% yield). ESI-MS : [M+H] ^⁺ = 503.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.67 (d, J = 2.5 Hz, 1H), 7.41 (dd, J = 9.4, 2.5 Hz, 1H), 6.64 (d, J = 9.4 Hz, 1H), 4.31-4.24 (m, 2H), 3.74 (td, J = 11.9, 2.3 Hz, 1H), 3.66 (s, 3H), 3.47 (tt, J = 11.9, 3.8 Hz, 1H), 2.65 (s, 3H), 2.57 (s, 6H), 2.21-2.18 (m, 1H), 2.13-2.05 (m, 1H), 2.01 (d, J = 13.5 Hz, 1H), 1.93 (dd, J = 24.8, 11.8 Hz, 1H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.0 (s, 3F). Example 229 Example 227 The crude mixture was purified by rapid silica gel column chromatography with a dissolution gradient of 1-10% MeOH/DCM to obtain a solid 2-((2R,4S)-2-(1-amino-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimido[4,5-d]pyridoxane. -8(7H)-ketone (Example 229, 12 mg, 0.024 mmol, 76% yield). ESI-MS : [M+H] ⁺ = 489.3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.44 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.39 (dd, J = 9.3, 2.6 Hz, 1H), 6.62 (d, J = 9.4 Hz, 1H), 5.17 (s, 2H), 4.31-4.24 (m, 2H), 3.89 (s, 3H), 3.74 (td, J = 11.8, 2.5 Hz, 1H), 3.58-3.53 (m, 1H), 2.61 (s, 6H), 2.21 (d, J = 13.0 Hz, 1H), 2.12-2.00 (m, 2H), 1.92 (dd, J = 24.6, 12.0 Hz, 1H), 1.24 (s, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -73.0 (s, 3F). Example 332 Example 330 The crude mixture was purified by expedited silica gel column chromatography (1-7% MeOH/DCM) to give 1-amino-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one as a solid (Example 332, 67 mg, 0.12 mmol, 71% yield). ESI-MS : [M+H] ⁺ = 540.3. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.84 (s, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.40 (dd, J = 9.1, 2.5 Hz, 1H), 6.41 (d, J = 9.4 Hz, 1H), 6.12 (s, 2H), 4.38 (d, J = 9.8 Hz, 1H), 4.12 (dd, J = 11.3, 3.5 Hz, 1H), 3.72-3.66 (m, 1H), 3.39 (tt, J = 11.8, 3.6 Hz, 1H), 2.81 (s, 3H), 2.65 (s, 6H), 2.18 (d, J = 13.0 Hz, 1H), 2.04-2.00 (m, 1H), 1.92-1.72 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ): δ -60.8 (s, 3F), -71.2 (s, 3F).

Method 21: Synthetic Example 175 Example 175: 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1-(methylamino)pyridin-2-one

To 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1-(methyleneamino)pyridin-2-one (Int-C4, 1 equivalent, 60 mg, 0.117 mmol) was added to a solution in THF (2 mL) and AcOH (2 equivalent, 32 mg, 0.235 mmol) was added to adjust the pH to ~4. _NaBH3CN (2.5 equivalent, 18 mg, 0.293 mmol) was added at 0 °C, and the mixture was then stirred at 20 °C for 1 h. The reaction solution was added to an aqueous solution of _NH4Cl (10 mL) and then extracted with DCM (15 mL × ₃ ). The organic matter was washed with 10 mL of saturated salt solution, separated, and dried ( _Na2SO4 ), then concentrated to dryness. Next, the crude material was purified by preparative HPLC (condition 3, gradient c) and freeze-dried to obtain 25 mg of residue, which was then purified by preparative TLC (DCM/MeOH=7/1, _Rf =0.4) to obtain 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1-(methylamino)pyridin-2-one (Example 175, 2.2 mg, 0.00396 mmol, 3% yield). LCMS : [M+H] ⁺ = 514.1; purity = 88.5% (UV 220 nm); retention time = 0.611 min. ¹ H NMR (400 MHz, CD ₃ OD) δ 1.31 (br s, 3H) 1.56 - 1.66 (m, 1H) 1.93 - 2.09 (m, 1H) 2.66 - 2.91 (m, 5H) 3.28 (br s, 6H) 3.81 (ddd, J=10.6, 6.4, 2.8 Hz, 1H) 4.47 (dd, J=10.7, 2.4 Hz, 1H) 4.74 (br d, J=12.4 Hz, 1H) 6.7 (d, J=9.4 Hz, 1H) 7.09 - 7.19 (m, 2H) 7.64 (dd, J=9.3, 2.4 Hz, 1H) 7.75 - 7.89 (m, 2H).

Method 22: Synthetic Example 176 Example 176: 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one

To 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1H-pyridin-2-one (Example 173, 1 equivalent, 20 mg, 0.0413 mmol) _{and K₂CO₃} (2 equivalents, 11 mg, 0.0826 mmol) were added to a solution of DMF (0.50 mL) with MeI (1.5 equivalents, 8.8 mg, 0.0619 mmol), and the mixture was then stirred at 20 °C for 12 h. The reaction solution was added to an aqueous solution of _NH₄Cl (5 mL), extracted with ethyl acetate (5 mL × 3), and washed with 10 mL of saturated salt solution. The organic matter was then separated and concentrated to dryness. Next, the residue was purified by preparative HPLC (condition 3) and freeze-dried to obtain 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazo[4,5-d]pyrimidin-5-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Example 176, 7.2 mg, 0.0142 mmol, 34% yield). LCMS : [M+H] ⁺ = 499.3; purity = 100% (UV 220 nm); retention time = 0.548 min. ¹ H NMR (400 MHz, CDCl ₃ δ 1.32 (d, J=6.1 Hz, 3H) 2.65 - 2.87 (m, 2H) 3.12 - 3.47 (m, 6H) 3.57 (s, 3H) 3.81 (ddd, J=10.5, 6.3, 2.6 Hz, 1H) 4.38 (dd, J=10.7, 2.6 Hz, 1H) 4.73 - 4.97 (m, 2H) 6.59 (d, J=9.3 Hz, 1H) 6.91 - 7.06 (m, 2H) 7.39 - 7.47 (m, 2H) 7.75 (td, J=8.4, 6.5 Hz, 1H).

Following a similar method, the following compounds were obtained. Structure Starting materials Characteristics Example 221 Int-D25 Modification : The reaction was carried out at 50 °C for 2 h using 3 equivalents _{of K₂CO₃} and 5 equivalents of MeI. The crude material was purified by preparative HPLC (condition 18, gradient a) and freeze-dried to obtain 4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] as a solid. [Lin-4-yl]pyrimidino[4,5-d]tadalafil] -8-one (Example 221, 37 mg, 0.0676 mmol, 85% yield, a single mirror isomer with known absolute configuration). LCMS : [M+H] ⁺ = 531.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.36 (br d, J=14.3 Hz, 3H) 2.80 - 3.04 (m, 2H) 3.53 - 3.63 (m, 3H) 3.78 - 3.90 (m, 4H) 4.38 (br s, 1H) 4.80 - 4.95 (m, 1H) 5.08 - 5.25 (m, 1H) 6.63 (br s, 1H) 7.34 - 7.52 (m, 2H) 7.57 (br d, J=9.3 Hz, 1H) 7.63 - 7.79 (m, 3H). Example 222 Int-D35 Modification : The reaction was carried out at 50 °C for 18 h using 3 equivalents _{of K₂CO₃} and 10 equivalents of MeI. The crude material was purified by preparative HPLC (column: C18 150×40 mm×15 µm; mobile phase A: water (0.3% FA); mobile phase B: ACN) to obtain 4-(2,4-difluorophenyl)-6,7-dimethyl-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] as a solid. Formate of lin-4-yl]pyrido[3,4-d]pyrimidin-8-one (Example 222, 28.2 mg, 0.0516 mmol, 31% yield, a single mirror isomer with known absolute configuration). LCMS : [M+H] ⁺ = 494.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (d, J = 1.5 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.55 - 7.44 (m, 2H), 7.30 (dt, J = 2.3, 8.4 Hz, 1H), 6.40 (d, J = 9.3 Hz, 1H), 6.00 (d, J = 2.4 Hz, 1H), 4.72 - 4.53 (m, 2H), 4.38 (dd, J = 2.2, 10.8 Hz, 1H), 3.80 - 3.70 (m, 1H), 3.50 (s, 3H), 3.43 (s, 3H), 2.95 (dd, J = 11.1, 13.0 Hz, 1H), 2.73 (dd, J = 10.8, 13.1 Hz, 1H), 2.31 (s, 3H), 1.23 (br d, J = 6.0 Hz, 3H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -107.35, -110.12. Example 223 Int-D38 Modification : The reaction was carried out at 50 °C for 18 h using 3 equivalents _{of K₂CO₃} and 10 equivalents of MeI. The crude material was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 µm; mobile phase A: water (0.1% FA); mobile phase B: ACN) to obtain 4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] as a solid. [Lin-4-yl]pyrido[3,4-d]pyrimidin-8-one (Example 223, 85 mg, 0.154 mmol, 54% yield, as a single mirror isomer with a known absolute configuration). LCMS : [M+H]+ = 544.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.94 (d, J = 9.8 Hz, 1H), 7.86 - 7.73 (m, 3H), 7.51 (dd, J = 2.4, 9.3 Hz, 1H), 6.40 (d, J = 9.3 Hz, 1H), 6.03 (d, J = 2.1 Hz, 1H), 4.64 (br dd, J = 6.9, 8.7 Hz, 2H), 4.39 (dd, J = 2.5, 10.8 Hz, 1H), 3.85 - 3.71 (m, 1H), 3.54 - 3.48 (m, 3H), 3.46 - 3.39 (m, 3H), 3.02 - 2.91 (m, 1H), 2.79 - 2.65 (m, 1H), 2.32 (s, 3H), 1.24 (br d, J = 6.0 Hz, 3H). ee : ~100%.

Method 23: Synthetic Example 178 Example 178: 1-(dimethylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one

Under argon atmosphere at -15°C, NaOtBu (2.0 M in THF, 2 equivalents, 514 µL, 1.03 mmol) was added dropwise to a solution of 1-amino-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 177, 1 equivalent, 250 mg, 0.51 mmol) in MeCN (5 mL). MeI (1.0 M in MeCN, 1.56 equivalents, 50 µL, 0.800 mmol) was added, and the reaction mixture was stirred for 20 min under argon atmosphere at -15°C. The reaction mixture was then heated to 0°C, and water was added. The aqueous phase was extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine, dried over anhydrous _{Na₂SO₄ ,} filtered, and concentrated under reduced pressure. The resulting oil was first purified by reversed-phase rapid column chromatography (condition 9, gradient a) and then second purified by preparative HPLC (condition 10, gradient a) to give 1-(dimethylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a powder (Example 178, 31 mg, 0.061 mmol, 12% yield). ESI-MS : [M+H] ⁺ = 515.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.52 (1H, d, J = 2.4 Hz), 7.37 (1H, dd, J = 9.4, 2.5 Hz), 6.56 (1H, d, J = 9.4 Hz), 4.26-4.31 (2H, m), 3.79 (1H, ddd, J = 11.7, 11.2, 3.2 Hz), 3.40-3.47 (1H, m), 3.03 (6H, s), 2.81 (3H, s), 2.77 (3H, s), 2.65 (6H, s), 2.29-2.33 (1H, m), 2.01-2.16 (3H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s).

Method 24: Synthetic Example 179 Example 179: 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-(methylamino)pyridin-2-one

Add 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Example 34, 1 equivalent, 100 mg, 0.21 mmol), cesium carbonate (4 equivalent, 276 mg, 0.85 mmol), N-biphenylphosphoxymethylamine (Int-C6, 4 equivalent, 210 mg, 0.85 mmol), and DMF (2 mL) to a flame-dried MW vial. Seal the vial and stir the reaction mixture at 65°C for 2 h. Cool the reaction mixture to 0°C and add water. Extract the formed aqueous suspension with EtOAc (4 × 20 mL). The combined organic phase was washed with water and brine. The organic layer was dried with anhydrous _{Na₂SO₄ ,} filtered, and evaporated under reduced pressure. The crude material was first purified by rapid chromatography (12 g _SiO2 column) using a dissolution gradient of 0-10% MeOH/DCM, and then second purified by reversed-phase rapid chromatography (condition 11, gradient a) to give solid 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-(methylamino)pyridin-2-one (Example 179, 5.0 mg, 10.0 µmol, 5% yield). ESI-MS : [M+H] ⁺ = 501.3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65 (1H, d, J = 2.4 Hz), 7.45 (1H, dd, J = 9.3, 2.5 Hz), 6.72 (1H, d, J = 9.4 Hz), 4.34-4.37 (1H, m), 4.26-4.31 (1H, m), 3.76-3.83 (1H, m), 3.46-3.53 (1H, m), 2.81 (6H, m), 2.77 (3H, s), 2.66 (6H, s), 2.31-2.35 (1H, m), 2.12-2.16 (2H, m), 1.98-2.07 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s).

Following a similar method, the following compounds were obtained. Structure Starting materials Characteristics Example 181 Int-C8 Modification: The reaction was carried out using 2 equivalents of Int-C8 and 3.5 _equivalents of _Cs₂CO₃ . The crude organic extract was first purified by normal-phase rapid column chromatography (12 g _SiO₂ column) with a dissolution gradient of 0–6% MeOH (1% _NH₄OH (aq.))/DCM, and second purified by preparative HPLC (condition 10, gradient b) to give a solid 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-(ethylamino)pyridin-2-one (Example 181). ESI-MS : [M+H] ^⁺ = 515.4. ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 7.69 (1H, d, J = 2.4 Hz), 7.47 (1H, dd, J = 9.3, 2.5 Hz), 6.52 (1H, t, J = 6.1 Hz), 6.46 (1H, d, J = 9.3 Hz), 4.36-4.39 (1H, m), 4.12-4.16 (1H, m), 3.65-3.72 (1H, m), 3.27-3.27 (1H, m), 2.95 (2H, p, J = 6.8 Hz), 2.72 (6H, s), 2.61 (6H, s), 2.15-2.20 (1H, m), 1.98-2.03 (1H, m), 1.90 (1H, td, J = 12.6, 4.6 Hz), 1.77 (1H, q, J = 12.2 Hz), 0.99 (3H, t, J = 7.2 Hz). ¹⁹ F NMR (DMSO- d ₆ , 376 MHz): δ -71.4 (3H, s).

Method 25: Synthetic Example 180 Example 180: 5-[(2S,6R)-4-[6-(difluoromethyl)-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one

A vial containing 2-chloro-6-(difluoromethyl)-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridine (Int-C7, 1 equivalent, 70 mg, 0.146 mmol) and 1-methyl-5-[(2S,6R)-6-methyl] [Lin-2-yl]pyridin-2-one (3) (1.05 equivalents, 32 mg, 0.153 mmol) in anhydrous THF (1 mL). Huenig's base (3 equivalents, 76 µL, 0.438 mmol) was added, and the reaction mixture was stirred at 65 °C for 2 h. After 2 h, the reaction mixture was cooled, quenched with water (20 mL), and diluted in EtOAc (25 mL). The aqueous phase was extracted with EtOAc (3 × 25 mL). The combined organic phase was washed with brine, dried _over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid column chromatography (12 g _SiO2 column) using a dissolution gradient of 0-10% MeOH/DCM to obtain solid 5-[(2S,6R)-4-[6-(difluoromethyl)-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]-6-methyl- [Lin-2-yl]-1-methylpyridin-2-one (Example 180, 59 mg, 0.11 mmol, 76% yield). ESI-MS : [M+H] ⁺ : 537.4. ^¹H NMR ( _CDCl₃ , 400 MHz): δ 7.44 (2H, m), 6.72 (1H, t, J = 54.1 Hz), 6.69 (1H, m), 5.02 (2H, m), 4.38 (1H, d, J = 10.5 Hz), 3.80 (1H, m), 3.60 (3H, s), 2.83–2.87 (5H, m), 2.59 (6H, s), 1.36 (3H, s). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s), -114.3 (2F, d).

Following a similar method, the following compounds were obtained. Structure Starting materials Characteristics Example 182 Int-C13 Int-C12 Modification: The reaction was carried out at 70°C for 1 h. The crude residue was purified by rapid chromatography (12 g _SiO2 column) using a dissolution gradient of 50-100% EtOAc/hexane to obtain solid 5-[(2S,6R)-4-[6,7-bis(methyl _- d3 )-4-[3-(trifluoromethyl)-1-bis(1.1.1)pent-1-yl]pteridin-2-yl]-6-methyl- [Lin-2-yl]-1-cyclopropylpyridine-2(1H)-one (Example 182, 28 mg, 53 µmol, 62% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.40 (s, 2H), 6.60 (dt, J = 9.5, 1.6 Hz, 1H), 4.90-5.00 (m, 2H), 4.32-4.36 (m, 1H), 3.75-3.81 (m, 1H), 3.31-3.37 (m, 1H), 2.84-2.91 (m, 1H), 2.74-2.80 (m, 1H), 2.59 (s, 6H), 1.32-1.34 (m, 3H), 1.13-1.18 (m, H), 0.86-0.92 (m, 2H). ^{1 9} F NMR (CDCl ₃ , 376 MHz): δ -73.1 (s, 3F). ESI-M : [M+H] ⁺ = 533.3. Example 183 Int-C14 Int-C12 Modification: The crude residue was first purified by normal-phase rapid chromatography (12 g _SiO2 column) using a dissolution gradient of 0-10% MeOH/DCM, and then purified a second time by reverse-phase rapid column chromatography (condition 8, gradient a) to obtain 1-cyclopropyl-5-((2S,6R)-6-methyl-4-(7-methyl-6-(oxacyclobut-3-yl)-4-(3-(trifluoromethyl)bis(1.1.1)pent-1-yl)pterin-2-yl) in solid form. (Lin-2-yl)pyridin-2(1H)-one (Example 183, 41 mg, 0.072 mmol, 23% yield). ESI-MS : [M+H] ⁺ = 569.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.42-7.43 (1H, m), 6.65 (1H, d, J = 9.4 Hz), 5.11 (2H, s), 5.09 (2H, s), 4.91-5.04 (2H, m), 4.64 (1H, p, J = 7.7 Hz), 4.36 (1H, dd, J = 10.8, 2.6 Hz), 3.77-3.82 (1H, m), 3.33-3.37 (1H, m), 2.92 (1H, dd, J = 13.3, 10.8 Hz), 2.81 (1H, dd, J = 13.4, 10.6 Hz), 2.62 (6H, s), 2.55 (3H, s), 1.34 (3H, d, J = 6.2 Hz), 1.17 (2H, d, J = 7.2 Hz), 0.91 (2H, d, J = 5.0 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.0 (3F, s). Example 195 Int-C14 This method yields 5-[( 2S , 6R )-6-methyl-4-[7-methyl-6-(oxocyclobut-3-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl] in solid form. [Lin-2-yl]-1H-pyridin-2-one (Example 195, 13 mg, 0.024 mmol, 21% yield). ESI-MS : [M+H] ⁺ = 529.3. ¹ H NMR (DMSO- d ₆ , 400 MHz): δ 11.61 (1H, s), 7.52 (1H, dd, J = 9.5, 2.6 Hz), 7.41 (1H, d, J = 2.5 Hz), 6.35 (1H, d, J = 9.4 Hz), 4.95 (2H, dd, J = 8.4, 5.5 Hz), 4.90 (2H, t, J = 6.2 Hz), 4.66-4.74 (2H, m), 4.36-4.39 (1H, m), 3.67-3.73 (1H, m), 3.29-3.29 (1H, m), 2.92-3.01 (1H, m), 2.72-2.80 (1H, m), 2.58 (6H, s), 2.45 (3H, s), 1.22 (3H, d, J = 6.3 Hz). ¹⁹ F NMR (DMSO- d ₆ , 376 MHz): δ -71.4 (3F, s).

Method 26: Synthetic Example 190 Example 190: 5-[1-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]-4,4-difluoro-3-piperidinyl]-1-methyl-pyridin-2-one

_Cs₂CO₃ (3 equivalents, 61 mg, 0.19 mmol) was added to _a solution of 5-[1-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]-4,4-difluoro-3-piperidinyl]-1H-pyridin-2-one (compound 189, 1 equivalent, 30 mg, 0.062 mmol) and iodomethane (2 equivalents, 7.7 µL, 0.12 mmol) in THF (2.0 mL). The mixture was stirred at 50 °C for 2 hours, followed by washing with water and extraction three times with DCM. The combined organic layer was washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure. The crude material was purified by reversed-phase chromatography (40% to 80% MeCN/water (containing 0.5% formic acid)) to give 5-[1-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]-4,4-difluoro-3-piperidinyl]-1-methyl-pyridin-2-one as a solid (compound 190, 14 mg, 0.028 mmol, 45% yield). ESI-MS : [M+H] ⁺ = 499.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.70 (1H, q, J = 7.6 Hz), 7.35 (1H, d, J = 9.5 Hz), 7.26 (1H, s), 7.04 (1H, t, J = 8.2 Hz), 6.97 (1H, t, J = 9.6 Hz), 6.57 (1H, d, J = 9.4 Hz), 5.19 (2H, br s), 3.55 (3H, s), 3.40 (2H, q, J = 12.5 Hz), 2.93 (1H, br d, J = 27.7 Hz), 2.71 (3H, s), 2.60 (3H, s), 2.28 (1H, br s), 1.99-2.15 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -95.9 (1F, d, J = 247.7 Hz), -106.5 (1F, s), -106.7 (1F, s), -113.7 (1F, d, J = 246.7 Hz).

Following a similar procedure, the following compounds were obtained. Structure intermediate Characteristics Example 198 Example 197 N-methylation of compound 197 was performed using 3 equivalents of iodomethane and 2 _equivalents of _K₂CO₃ . The crude mixture was purified by rapid silica gel column chromatography with a solubility gradient of 30%–65% acetone/hexane to give a foamy 1-methyl-5-((2R,4S)-4-(6-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 198, 0.86 g, 1.83 mmol, 96% yield). ESI-MS : [M+H] ^⁺ = 472.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 9.01 (1H, s), 7.40-7.43 (2H, m), 6.61 (1H, d, J = 9.7 Hz), 4.27-4.34 (2H, m), 3.76-3.83 (1H, m), 3.56 (3H, s), 3.44-3.52 (1H, m), 2.82 (3H, s), 2.66 (6H, s), 2.31 (1H, d, J = 13.2 Hz), 2.10-2.18 (2H, m), 1.96-2.05 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). Example 217 Example 216 Modification : The reaction was carried out at 45°C for 1 h with 3 equivalents of _Cs₂CO₃ . The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by rapid chromatography (4 g _SiO₂ ) using a dissolution gradient of 0-50% EtOAc:EtOH (3: ₁ )/hexane to give solid 2,3-dimethyl-6-[rac-(2R,4S)-2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[5,4-d]pyrimidin-4-one (Example 217, 3.0 mg, 6.0 µmol, 32% yield). ESI-MS : [M+H] ⁺ = 502.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.38-7.36 (m, 2H), 6.58-6.55 (m, 1H), 4.30-4.24 (m, 2H), 3.75 (td, J = 11.9, 2.4 Hz, 1H), 3.66 (s, 3H), 3.55 (s, 3H), 3.48 (tt, J = 12.0, 3.9 Hz, 1H), 2.66 (s, 3H), 2.58 (s, 6H), 2.20 (d, J = 13.3 Hz, 1H), 2.17-2.06 (m, 1H), 2.01 (d, J = 13.3 Hz, 1H), 1.91 (dd, J = 24.7, 11.9 Hz, 1H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.0 (s, 3F). Example 228 Example 227 The crude mixture was purified by rapid silica gel column chromatography with a dissolution gradient of 1-10% MeOH/DCM to obtain a solid 7-methyl-2-((2R,4S)-2-(1-methyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidino[4,5-d]pyridyl -8(7H)-ketone (Example 228, 14 mg, 0.027 mmol, 86% yield). ESI-MS : [M+H] ⁺ = 488.3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.43 (s, 1H), 7.35-7.33 (m, 2H), 6.56 (dd, J = 6.9, 3.4 Hz, 1H), 4.29-4.24 (m, 2H), 3.90 (s, 3H), 3.74 (td, J = 11.9, 2.4 Hz, 1H), 3.58-3.51 (m, 4H), 2.61 (s, 6H), 2.21 (d, J = 13.3 Hz, 1H), 2.13-2.00 (m, 2H), 1.90 (dd, J = 24.7, 11.9 Hz, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ -d): δ -73.0 (s, 3F). Example 326 Int-E10 Modified : The reaction was carried out at room temperature for 1 h, and purified by normal-phase rapid column chromatography (4 g _SiO2 column) (0-10% MeOH/DCM), followed by purification by reverse-phase rapid column chromatography (10-90% MeCN/0.1% formic acid (aq.)) to give 1-methyl-5-[(2R,4S)-4-[7-methyl-6-(trifluoromethyl)-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 326, 6.0 mg, 0.011 mmol, 29% yield). ESI-MS : [M+H] ⁺ = 539.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.78 (1H, s), 7.41 (2H, d, J = 4.6 Hz), 6.61-6.66 (1H, m), 4.28-4.36 (2H, m), 3.75-3.82 (1H, m), 3.57 (3H, s), 3.44-3.52 (1H, m), 2.96 (3H, s), 2.66 (6H, s), 2.29-2.35 (1H, m), 2.02-2.20 (3H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -62.6 (3F, s), -73.1 (3F, s). Example 334 Example 330 Modification : The reaction was carried out with 2 equivalents of Cs₂CO₃ and 3 equivalents of _CD₃I for more than 2.5 h. The crude mixture was purified by _SiO₂ column chromatography (20-50% acetone/hexane) to give 1-(methyl- _d₃ )-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one as a solid (Example 334, 56 mg, 0.101 mmol, 81% yield). ESI-MS : [M+H] ^⁺ = 542.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.76 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 9.8 Hz, 1H), 4.37 (d, J = 11.0 Hz, 1H), 4.31-4.28 (m, 1H), 3.79 (td, J = 11.5, 3.1 Hz, 1H), 3.50-3.45 (m, 1H), 2.95 (s, 3H), 2.64 (s, 6H), 2.32 (d, J = 13.0 Hz, 1H), 2.17-1.97 (m, 4H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -62.5 (s, 3F), -73.0 (s, 3F). Example 340 Int-E14 Modification : The reaction was carried out using 1.05 equivalents of MeI, and the crude material was purified by rapid chromatography (4 g Isco RediSep® column, using a gradient dissolution of 0-10% MeOH/DCM) to obtain 5-((2S,6R)-4(4-(3,3-difluorocyclobutoxy)-6,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)-6-methyl as a solid. (Lin-2-yl)-1-methylpyridin-2(1H)-one (Example 340, 14 mg, 29.7 μmol, 54%). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.91 (s, 1H), 7.40-7.43 (m, 2H), 6.60-6.62 (d, J = 10.1Hz, 1H), 5.29 (s, 3H), 4.31-4.34 (m, 1H), 3.72-3.80 (m, 1H), 3.57 (s, 3H), 3.11-3.21 (m, 2H), 2.95-2.79 (m, 3H), 2.78-2.69 (dd, J = 12.2, 10.1Hz, 1H), 2.64 (s, 3H), 2.36 (s, 3H), 1.32 (d, J = 6.2 Hz, 3H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -84.6 (s, 1F), -96.7 (s, 1F). ESI-MS : [M+H] ⁺ = 472.4. Example 301 CD ₃ I Int-E24 Modification : The reaction was carried out overnight at room temperature with 1.5 equivalents of _CD3I . The residue was purified by chromatography (4 g _SiO2 ) using a 0-15% DCM/MeOH dissolution gradient to give solid 5-((2R,4S)-4-(6-fluoro-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(methyl- _d3 )pyridin-2(1H)-one (Example 301, 16 mg, 0.03 mmol, 44% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.03 (1H, d, J = 8.5 Hz), 7.37-7.40 (2H, m), 6.54-6.57 (1H, m), 4.24-4.31 (2H, m), 3.73-3.80 (1H, m), 3.40- 3.46 (1H, m), 2.79 (3H, d, J = 2.9 Hz), 2.61 (7H, s), 2.29 (1H, d, J = 13.4 Hz), 1.96-2.14 (4H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.2 (3F, s), -120.2 (1F, s). ESI-MS : [M+H] ⁺ = 492.3. Example 307 Int-E24 Modification : The reaction was carried out overnight at room temperature with 1.5 equivalents of MeI to give 5-((2R,4S)-4-(6-fluoro-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 307). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.03 (1H, d, J = 8.5 Hz), 7.37-7.39 (2H, m), 6.56 (1H, d, J = 9.9 Hz), 4.29 (2H, t, J = 13.1 Hz), 3.77 (1H, t, J = 11.5 Hz), 3.54 (3H, s), 3.42 (1H, br s), 2.79 (3H, d, J = 2.8 Hz), 2.61 (6H, s), 2.29 (1H, d, J = 13.4 Hz), 2.12 (2H, s), 1.95-2.04 (2H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.2 (3F, s), -120.2 (1F, s). ESI-MS : [M+H] ⁺ = 489.3. Example 303 CD ₃ I Int-E31 Modification : The reaction was carried out at 60 °C for 1 h with 3 equivalents of _CD3I . The crude material was purified by rapid chromatography (0-10% MeOH/DCM dissolution gradient) to give solid 5-((2R,4S)-4-(6-bromo-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(methyl- _d3 )pyridin-2(1H)-one (Example 303, 365 mg, 78% yield). ESI-MS : [M+H] ⁺ = 552.1. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.62 (1H, s), 7.36-7.38 (2H, m), 6.55 (1H, d, J = 9.5 Hz), 4.29 (2H, t, J = 12.4 Hz), 3.73-3.80 (1H, m), 3.37-3.45 (1H, m), 2.92 (3H, s), 2.62 (6H, s), 2.27-2.31 (1H, m), 2.06-2.12 (2H, m), 1.95-2.04 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1. Example 25 Example 34 Modification : The reaction was carried out with 3 _equivalents of _Cs₂CO₃ and purified by reversed-phase rapid chromatography using 30-85% MeCN/water (0.1% formic acid) to give solid 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 25, 522 mg, 85% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.37 - 7.40 (2H, m), 6.54 - 6.57 (1H, m), 4.23 - 4.31 (2H, m), 3.76 (1H, td, J = 11.5, 3.3 Hz), 3.53 (3H, s), 3.38 - 3.46 (1H, m), 2.78 (3H, s), 2.74 (3H, s), 2.61 (6H, s), 2.28 (1H, d, J = 13.3 Hz), 2.05 - 2.13 (2H, m), 1.94 - 2.03 (1H, m). ESI-MS : [M+H] ⁺ = 486.4. Example 80 Iodoethane Example 34 Modification : The reaction was carried out with 3 _equivalents of _Cs₂CO₃ to give 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-ethylpyridin-2-one (Example 80). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.39-7.36 (2H, m), 6.56-6.54 (1H, m), 4.34-4.28 (2H, m), 4.01-3.96 (2H, m), 3.82-3.76 (1H, m), 3.48-3.42 (1H, m), 2.81 (3H, s), 2.77 (3H, s), 2.65 (6H, s), 2.31 (1H, d, J = 13.3 Hz), 2.14-2.11 (2H, m), 2.03 (1H, q, J = 12.3 Hz), 1.36 (3H, t, J = 7.2 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). ESI-MS : [M+H] ⁺ = 500.4. Example 82 1-Bromo-2-methoxyethane Example 34 Modification : The reaction was carried out with 3 _equivalents of _Cs₂CO₃ to give 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]-1-(2-methoxyethyl)pyridin-2-one (Example 82). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.44-7.39 (2H, m), 6.56 (1H, d, J = 9.3 Hz), 4.33-4.4.27 (2H, m), 4.10 (2H, t, J = 5.1 Hz), 3.81-3.75 (1H, m), 3.67 (2H, t, J = 5.1 Hz), 3.48-3.41 (1H, m), 3.32 (3H, s), 2.81 (3H, s), 2.77 (3H, s), 2.65 (6H, s), 2.29 (1H, d, J = 13.4 Hz), 2.15-2.11 (2H, m), 2.07-1.98 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). ESI-MS : [M+H] ⁺ = 530.4. Example 84 2-Bromoethanol Example 34 Modification : The reaction was carried out with 3 _equivalents of _Cs₂CO₃ to give 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pterin-2-yl]tetrahydropiperan-2-yl]-1-(2-hydroxyethyl)pyridin-2-one (Example 84). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.45 (1H, dd, J = 9.4, 2.4 Hz), 7.42-7.38 (1H, m), 6.61 (1H, d, J = 9.3 Hz), 4.34-4.25 (2H, m), 4.15 (2H, t, J = 4.7 Hz), 3.97-3.95 (2H, m), 3.82-3.75 (1H, m), 3.46-3.39 (2H, m), 2.81 (3H, s), 2.77 (3H, s), 2.65 (6H, s), 2.34-2.30 (1H, m), 2.15-2.08 (2H, m), 2.05-1.96 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). ESI-MS : [M+H] ⁺ = 516.3. Example 86 2-Bromoacetonitrile Example 34 Modification : The reaction was carried out with 3 _equivalents of _Cs₂CO₃ to give 2-[5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-2-sideoxy-1-pyridinyl]acetonitrile (Example 86). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.46-7.43 (2H, m), 6.63-6.60 (1H, m), 4.84 (2H, s), 4.35-4.26 (2H, m), 3.81-3.75 (1H, m), 3.48-3.40 (1H, m), 2.81 (3H, s), 2.77 (3H, s), 2.64-2.63 (6H, m), 2.34 (1H, d, J = 13.4 Hz), 2.19-2.07 (2H, m), 1.98 (1H, q, J = 12.4 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). ESI-MS : [M+H] ⁺ = 511.3. Example 96 3-Iodotetrahydrofuran Example 34 Modification : The reaction was carried out with 3 _equivalents of _Cs₂CO₃ to give 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Example 96). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.50 (1H, s), 7.40 (1H, dt, J = 9.4, 3.0 Hz), 6.55 (1H, d, J = 9.5 Hz), 5.68-5.63 (1H, m), 4.32-4.25 (2H, m), 4.21-4.13 (1H, m), 4.01 (1H, t, J = 8.9 Hz), 3.93-3.88 (1H, m), 3.84-3.73 (2H, m), 3.46-3.39 (1H, m), 2.80 (3H, s), 2.76 (3H, s), 2.64-2.62 (6H, m), 2.60-2.52 (1H, m), 2.29-2.24 (1H, m), 2.16-2.10 (2H, m), 2.01-1.92 (2H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). ESI-MS : [M+H] ⁺ = 542.4. Example 107 3-Iodooxyhexacyclobutane Example 34 Modification : The reaction was carried out with 3 _equivalents of _Cs₂CO₃ to give 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-(oxacyclobut-3-yl)pyridin-2-one (Example 107). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.65 (1H, d, J = 2.4 Hz), 7.40 (1H, dd, J = 9.4, 2.5 Hz), 6.52 (1H, d, J = 9.4 Hz), 5.80 (1H, p, J = 6.9 Hz), 5.08 (2H, td, J = 7.4, 1.8 Hz), 4.78 (2H, td, J = 6.8, 2.8 Hz), 4.37 (1H, d, J = 11.3 Hz), 4.27-4.31 (1H, m), 3.75-3.82 (1H, m), 3.41-3.49 (1H, m), 2.79 (3H, s), 2.76 (3H, s), 2.63 (6H, s), 2.32 (1H, d, J = 13.4 Hz), 2.09-2.15 (2H, m), 1.97-2.07 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). ESI-MS : [M+H] ⁺ = 528.3. Example 54 Starting with the following building block: 5-chloro-2,3-dimethyl-pyridine And 3-(2,2,2-trifluoroethyl)bicyclo[1.1.1]pentane-1-carboxylic acid, using the same synthetic route as in Example 80, yielded 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(2,2,2-trifluoroethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydro-2H-piperan-2-yl]-1-methyl-pyridin-2(1H)-one (Example 54). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.39-7.42 (2H, m), 6.58 (1H, dd, J = 8.8, 1.4 Hz), 4.25-4.32 (2H, m), 3.74-3.81 (1H, m), 3.55 (3H, s), 3.39-3.47 (1H, m), 2.79 (3H, s), 2.76 (3H, s), 2.50 (6H, s), 2.45 (2H, q, J = 11.1 Hz), 2.28-2.32 (1H, m), 2.11-2.15 (2H, m), 1.98-2.10 (2H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -64.2 (3F, t, J = 11 Hz). ESI-MS : [M+H] ⁺ = 500.4 Example 60 Int-F12 Starting with the following building block: 5-chloro-2,3-dimethyl-pyridine And Int-F12, using the same synthetic route as in Example 80, yielded 5-((2R,4S)-4-(4-(4-(1,1-difluoroethyl)bicyclo[2.2.1]hept-1-yl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 60). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.37-7.40 (2H, m), 6.54-6.57 (1H, m), 4.30 (1H, d, J = 11.8 Hz), 4.24-4.27 (1H, m), 3.71-3.80 (1H, m), 3.54 (3H, s), 3.36-3.44 (1H, m), 2.78 (3H, s), 2.74 (3H, s), 2.44 (2H, t, J = 9.8 Hz), 2.32 (1H, d, J = 13.6 Hz), 2.26 (2H, s), 2.02-2.15 (7H, m), 1.93-1.99 (2H, m), 1.64-1.67 (3H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -96.4 (2F, s). ESI-MS : [M+H] ⁺ = 510.4. Example 92 Starting with the following building block: 5-chloro-2,3-dimethyl-pyridine And 4,4-difluorospiro[2.2]pentane-1-carboxylic acid, using the same synthetic route as in Example 80, yielded 5-((2R,4S)-4-(4-(4,4-difluorospiro[2.2]pent-1-yl)-6,7-dimethylpteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(methyl-d3)pyridin-2(1H)-one (Example 92). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.36-7.39 (2H, m), 6.57 (1H, d, J = 9.5 Hz), 4.24-4.31 (2H, m), 4.16 (1H, t, J = 6.6 Hz), 3.73-3.80 (1H, m), 3.34-3.41 (1H, m), 2.81 (3H, s), 2.78 (3H, s), 2.29 (1H, t, J = 12.4 Hz), 1.88-2.13 (6H, m), 1.52 (1H, t, J = 9.2 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -133.22 (1F, dd, J = 152.0, 8.9 Hz), -134.21 (1F, dt, J = 152.2, 8.5 Hz). ESI-MS : [M+H] ⁺ = 457.4.

Method 27: Synthetic Example 191 Example 191: 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine -7-yl)-6-methyl (-2-yl)-1-methylpyridin-2(1H)-one

From 1-methyl-5-((2S,6R)-6-methyl (Lin-2-yl)pyridin-2(1H)-one and 7-chloro-5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine The coupling procedure, similar to Method 5 of WO 2022/236272, was used to obtain 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine. -7-yl)-6-methyl (Lin-2-yl)-1-methylpyridin-2(1H)-one (Example 191). ¹ H NMR (CD ₃ OD, 400 MHz): δ 7.77 (1H, d, J = 2.4 Hz), 7.68 (1H, dd, J = 9.3, 2.5 Hz), 7.61 (1H, s), 7.53-7.59 (1H, m), 7.16 (2H, t, J = 8.7 Hz), 7.00 (1H, s), 6.57 (1H, d, J = 9.3 Hz), 4.52-4.55 (1H, m), 4.43 (1H, d, J = 12.8 Hz), 4.29 (1H, d, J = 12.6 Hz), 3.90-3.92 (1H, m), 3.59 (3H, s), 2.80 (1H, t, J = 11.7 Hz), 2.64-2.71 (4H, m), 2.35 (3H, s), 1.33 (3H, d, J = 6.2 Hz). ¹⁹ F NMR (CD ₃ OD, 376 MHz): δ -110.68 (1F, m), -112.2 (1F, m). ESI-MS : [M+H] ⁺ = 478.4.

Method 28: Synthetic Example 196 Example 196: 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,6- (P-7-yl)-6-methyl (-2-yl)-1-methylpyridin-2(1H)-one

From 1-methyl-5-((2S,6R)-6-methyl (Lin-2-yl)pyridin-2(1H)-one and 7-chloro-5-(2,4-difluorophenyl)-2,3-dimethyl-1,6- Pyridine, using a coupling procedure similar to Method 4 of WO 2022/236272 to obtain 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,6- (P-7-yl)-6-methyl (Lin-2-yl)-1-methylpyridin-2(1H)-one (Example 196). ESI-MS : [M+H] ⁺ = 477.4. ¹ H NMR (CD ₃ OD, 400 MHz): δ 7.77 (1H, s), 7.68 (1H, dd, J = 9.3, 2.4 Hz), 7.62 (1H, q, J = 7.6 Hz), 7.02-7.10 (2H, m), 7.01 (1H, s), 6.57 (1H, d, J = 9.3 Hz), 4.54 (1H, d, J = 10.8 Hz), 4.47 (1H, d, J = 13.0 Hz), 4.34 (1H, d, J = 12.7 Hz), 3.91 (1H, s), 3.59 (3H, s), 2.83 (1H, t, J = 11.7 Hz), 2.67-2.74 (4H, m), 2.57 (3H, s), 1.33 (3H, d, J = 6.2 Hz). ¹⁹ F NMR (CD ₃ OD, 376 MHz): δ -110.2 (1F, m), -111.5 (1F, m).

Method 29: Synthesis Example 194 Example 194: 5-(4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine -7-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one

Add 5-(4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,2,3,4-tetrahydropyridinium[3,4-b]pyridine to a glass vial dried in a flame under argon atmosphere with a Teflon-coated magnetic stirring rod. -7-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Int-C28, 1 equivalent, 40 mg, 0.09 mmol), _MnO2 (20 equivalent, 149 mg, 1.72 mmol) and anhydrous DCE (0.8 mL). The vials were sealed and purged under argon, and the reaction mixture was stirred overnight at 50°C. The reaction solution was then filtered through a diatomaceous earth mat and washed with 9:1 DCM:MeOH (100 mL). The filtrate was concentrated under reduced pressure, and the crude mixture was first purified by rapid column chromatography (4 g _SiO2 column, using a dissolution gradient of 35% to 100% EtOAc/DCM) on an ISCO CombiFlash system, followed by purification by preparative HPLC (condition 10, gradient c) to obtain 5-(4-(5-(2,4-difluorophenyl)-2,3-dimethylpyridino[3,4-b]pyridine as a solid. -7-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 194, 3 mg, 6.5 µmol, 8% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.70 (s, 1H), 7.61-7.67 (m, 1H), 7.37-7.40 (m, 2H), 7.05 (td, J = 8.31, 2.42Hz, 1H), 6.96 (td, J = 9.43, 2.5 Hz, 1H), 6.59 (d, J = 9.2 Hz 1H), 4.28-4.35 (m, 2H), 3.80 (td, J = 11.7, 2.8 Hz, 1H), 3.55 (s, 3H), 3.32-3.38 (m, 1H), 2.76 (s, 3H), 2.68 (s, 3H), 2.30-2.34 (m, 1H), 2.00-2.13 (m, 2H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -107.9 (s, 1F), -108.9 (s, 1F). ESI-MS : [M+H] ⁺ = 463.4.

Method 31: Synthesis Example 201 Example 201: ₅ -(( 2R , 4S )-4-(6,7-bis(methyl- d3 )-4-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)pterin-2-yl)tetrahydro- 2H -piperan-2-yl)-1-cyclopropylpyridin-2( 1H )-one

1-Cyclopropyl-5-((2R,4S)-4-(4,5-diamino-6-(3-(trifluoromethyl)bis(1.1.1)pentan-1-yl)pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Int-C36, 1 equivalent, 72 mg, 0.16 mmol) was dissolved in _CD3 OD and concentrated under reduced pressure. This initial process was repeated three times. Anhydrous DCE (2.0 mL), anhydrous _CaSO₄ (10 equivalents, 212 mg, 1.6 mmol), and 1,1,1,4,4,4-hexadeuterated-2,3-dione (1.5 equivalents, 0.022 mL, 0.234 mmol) were added, and the reaction vessel was sealed and stirred at 75 °C for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure onto diatomaceous earth (4.0 g). The crude mixture was purified by rapid silica gel column chromatography using a dissolution gradient of 1–10% MeOH/DCM to give solid 5-((2R,4S)-4-(6,7-bis(methyl-d3)-4-(3-(trifluoromethyl)biscyclo[1.1.1]pent-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)-1-cyclopropylpyridin-2(1H)-one (Example 201, 73 mg, 0.14 mmol, 89% yield). ESI-MS : [M+H] ⁺ = 518.4. ¹ H NMR (CD ₃ OD, 400 MHz): δ 7.59-7.62 (2H, m), 6.53 (1H, d, J = 9.1 Hz), 4.43 (1H, d, J = 11.3 Hz), 4.25 (1H, dt, J = 11.5, 3.1 Hz), 3.78-3.84 (1H, m), 3.42-3.49 (1H, m), 3.32-3.35 (1H, m), 2.66 (6H, s), 2.24 (1H, d, J = 13.1 Hz), 2.05-2.09 (2H, m), 1.96 (1H, dd, J = 24.4, 12.3 Hz), 1.10-1.15 (2H, m), 0.90-0.94 (2H, m). ¹⁹ F NMR (CD ₃ OD, 376 MHz): δ -74.8 (3F, s).

Following a similar procedure, the following compounds were obtained. Structure intermediate Characteristics Example 204 Int-C51 Modification : Int-C51 was reacted with 2,3-butanedione at 80°C for 16 h. The crude material was first purified by normal-phase chromatography (50-100% EtOAc/hexane), and then purified by reverse-phase chromatography (15-85% ACN/water (containing 0.1% FA)) to obtain 3-[6,7-dimethyl-2-[( 2R , 6S )-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] as a solid. [Lin-4-yl]pteridin-4-yl]bicyclo[1.1.1]pentane-1-methamide (Example 204, 14 mg, 0.029 mmol, 13% yield). ESI-MS : [M+H] ⁺ = 476.4. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.40 (s, 2H), 6.59 (d, J = 9.6 Hz, 1H), 5.63 (d, J = 12.1 Hz, 2H), 4.97 (d, J = 46.0 Hz, 2H), 4.35 (dd, J = 10.7, 2.3 Hz, 1H), 3.80 (s, 1H), 3.56 (s, 3H), 2.80 (ddd, J = 37.8, 13.2, 10.9 Hz, 2H), 2.66 (s, 3H), 2.64 (s, 6H), 2.61 (s, 3H), 1.32 (d, J = 6.2 Hz, 3H).

Method 32: Synthesis Example 202 Example 202: 5-((2R,4S)-4-(8-(dimethylamino)-7-methyl-6-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)-7H-purin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one

Add [Rh(dppb)(COD)]BF4 (0.24 equivalents, 65 mg, 0.09 mmol) to a stirred solution of (5-(4-(8-(dimethylamino)-7-methyl-6-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)-7H-purin-2-yl)-5,6-dihydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Int-C40, 1 equivalent, 190 mg, 0.39 mmol) in anhydrous _THF (4.0 mL) (0.24 equivalents, 65 mg, 0.09 mmol). Stir the resulting solution at room temperature under _H2 atmosphere for 16 h. Purge the reaction mixture under argon and concentrate under reduced pressure to diatomaceous earth (5.0 mL). g). The crude mixture was purified by silica gel rapid column chromatography using a dissolution gradient of 40-100% acetone/hexane, followed by purification by preparative HPLC (condition 16, gradient) to give a solid 5-((2R,4S)-4-(8-(dimethylamino)-7-methyl-6-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)-7H-purin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 202). ESI-MS : [M+H] ⁺ = 503.4. ^1H NMR ( _CDCl3 , 400 MHz): δ 7.35-7.39 (2H, m), 6.55 (1H, d, J = 9.2 Hz), 4.28 (1H, d, J = 11.4 Hz), 4.22 (1H, d, J = 11.5 Hz), 3.71 (3H, s), 3.53 (3H, s), 3.17 (6H, s), 2.51 (6H, s), 2.21 (1H, d, J = 13.2 Hz), 2.01-2.05 (2H, m), 1.92 (1H, dd, J = 24.5, 12.2 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -72.9 (3F, s).

Following a similar procedure, the following compounds were obtained. Structure intermediate Characteristics Example 211 Example 206 Modification : The reaction was carried out at 55 °C for 16 h, concentrated under reduced pressure, and purified by rapid chromatography (4 g SiO ₂ ) using a dissolution gradient of 0-45% EtOAc:EtOH (3:1)/hexane to give solid 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-(dipropylamino)pyridin-2-one (Example 211, 1.0 mg, 17.5 µmol, 6% yield). ESI-MS : [M+H] ⁺ = 571.4. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.59-7.55 (m, 2H), 6.51 (d, J = 9.1 Hz, 1H), 4.42-4.39 (m, 1H), 4.25-4.22 (m, 1H), 3.83-3.76 (m, 1H), 3.49-3.42 (m, 3H), 2.97-2.90 (m, 2H), 2.78-2.76 (m, 6H), 2.64 (s, 6H), 2.22 (d, J = 13.0 Hz, 1H), 2.07-2.02 (m, 2H), 1.93 (dd, J = 24.7, 11.9 Hz, 1H), 1.39-1.26 (m, 4H), 0.90 (td, J = 7.4, 4.2 Hz, 6H). ¹⁹ F NMR (376 MHz, CD ₃ OD): δ -74.7 (s, 3F). Example 212 Example 207 The crude reaction mixture was purified by rapid chromatography (4 g _SiO₂ ) using a dissolution gradient of 0–100% EtOAc:EtOH (3:1)/hexane to give solid 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1-(propylamino)pyridin-2-one (Example 212, 7.0 mg, 13 µmol, 12% yield). ESI-MS : [M+H] ^⁺ = 529.4. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.79 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 9.4, 2.5 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 4.46 (d, J = 9.6 Hz, 1H), 4.28-4.24 (m, 1H), 3.86-3.80 (m, 1H), 3.52-3.44 (m, 1H), 3.00 (t, J = 7.2 Hz, 2H), 2.80 (s, 3H), 2.74-2.80 (3H), 2.67 (s, 6H), 2.28 (d, J = 13.5 Hz, 1H), 2.11-2.06 (m, 2H), 1.97 (dd, J = 24.8, 12.0 Hz, 1H), 1.56 (td, J = 14.7, 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). ¹⁹ F NMR (376 MHz, CD ₃ OD): δ -74.7 (s, 3F). Example 325 Int-A70 The crude material was purified by rapid chromatography (Isco RediSep® column 4 g) (1.5–3% MeOH/DCM), followed by preparative HPLC (condition 10, gradient f) to give a solid 5-(4-(6,7-dimethyl-4-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 325, 3.2 mg, 6.6 μmol, 8% yield). ESI-MS : [M+H] ⁺ = 485.3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.18 (s, 1H), 7.38-7.40 (m, 2H), 6.57 (d, J = 10.0 Hz, 1H), 4.29 (t, J = 13.5 Hz, 2H), 3.78 (dd, J = 13.8, 9.9 Hz, 1H), 3.55 (s, 3H), 3.41 (br s, 1H), 2.76 (s, 3H), 2.62 (s, 6H), 2.51 (s, 3H), 2.30 (d, J = 13.4 Hz, 1H), 2.01-2.17 (m, 3H). Example 10 Example 9 Int-E44 Modification : The reaction was carried out at 50 °C for 2 h and purified by preparative TLC (DCM/MeOH 10:1), followed by preparative HPLC, to give solid 5-[4-[4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (Example 10, 1.2 mg, 0.0022 mmol, 1% yield) and solid 1-methyl-5-[rac-(2R,4R)-4-[4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 9, 0.70 mg, 0.0013 mmol, 1% yield). Example 10: LCMS : cis mixture with ~4% trans mixture; [M+H] ⁺ = 480.2. ¹ H NMR (400 MHz, CDCl ³ ) δ 7.72 (t, J = 7.8 Hz, 1H), 7.45 - 7.30 (m, 4H), 6.59 (d, J = 9.4 Hz, 1H), 4.59 (br d, J = 9.8 Hz, 1H), 4.03 - 3.96 (m, 1H), 3.95 - 3.87 (m, 1H), 3.78 (br s, 1H), 3.56 (s, 3H), 2.87 (s, 3H), 2.82 (br d, J = 6.5 Hz, 1H), 2.76 (s, 3H), 2.63 (br d, J = 13.6 Hz, 1H), 2.31 - 2.20 (m, 1H), 2.19 - 2.09 (m, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -108.88 (s, 1F). Example 9: LCMS : [M+H] ⁺ = 480.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (t, J = 7.8 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.36 (br d, J = 8.3 Hz, 1H), 7.30 (d, J = 9.5 Hz, 1H), 6.60 (br d, J = 8.2 Hz, 1H), 4.40 - 4.26 (m, 2H), 3.81 (dt, J = 3.1, 11.3 Hz, 1H), 3.57 (s, 4H), 2.85 (s, 3H), 2.74 (s, 3H), 2.38 (br d, J = 13.4 Hz, 1H), 2.27 - 2.15 (m, 2H), 2.14 - 2.02 (m, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -108.49 (s, 1F).

Method 33: Synthesis Example 205 Example 205: 3-[6,7-dimethyl-2-[( 2R , 6S )-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] [Lin-4-yl]Pteridin-4-yl]Bicyclo[1.1.1]pentane-1-carboxylonitrile

TFAA (1 equivalent, 0.015 mL, 0.11 mmol) was added dropwise to 3-[6,7-dimethyl-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] [Lin-4-yl]pteridin-4-yl]bicyclo[1.1.1]pentane-1-methylamine (Example 204, 1 equivalent, 50 mg, 0.11 mmol) and pyridine (2 equivalents, 0.017 mL, 0.21 mmol) were added to a solution of DCM (1 mL), and the resulting mixture was stirred at room temperature for 1 hour. Another equivalent of TFAA (1 equivalent, 0.015 mL, 0.11 mmol) was added, and the reaction mixture was stirred for another 1 hour. The reaction mixture was depressurized and concentrated, and purified by normal-phase chromatography (50-100% EtOAc/hexane) to obtain 3-[6,7-dimethyl-2-[(2R,6S)-2-methyl-6-(1-methyl-6-sideoxy-3-pyridyl)] as a solid. [Lin-4-yl]pteridin-4-yl]bicyclo[1.1.1]pentane-1-carboxylonitrile (Example 205, 28 mg, 0.06 mmol, 58% yield). ESI-MS : [M+H] ⁺ = 458.4. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.40 (d, J = 6.9 Hz, 2H), 6.58 (d, J = 9.8 Hz, 1H), 4.91 (d, J = 29.7 Hz, 2H), 4.33 (dd, J = 10.7, 2.5 Hz, 1H), 3.79-3.74 (m, 1H), 3.54 (s, 3H), 2.87-2.82 (m, 7H), 2.74 (dd, J = 13.5, 10.7 Hz, 1H), 2.65 (s, 3H), 2.61 (s, 3H), 1.31 (d, J = 5.9 Hz, 3H).

Method 34: Synthesis of Examples 206 and 207. Example 206: 1-(diallylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one; and Example 207: 1-(allylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one.

Under an argon atmosphere, 1-amino-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 177 , 1 equivalent, 395 mg, 0.81 mmol), potassium carbonate (2.5 equivalent, 281 mg, 2.0 mmol) , MeCN (3.5 mL), and allyl bromide (2.2 equivalent, 155 µL, 1.79 mmol) were added to a 20 mL microwave-safe vial. The vial was sealed and stirred at 90 °C for 24 h. The reaction mixture was cooled to room temperature and filtered through a sintered funnel. The filtrate was concentrated under reduced pressure and purified by rapid chromatography (24 g _SiO2 column) using a dissolution gradient of 10-100% EtOAc:EtOH (3:1)/hexane to give two main products: 1-(diallylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 206, 214 mg, 0.37 mg). mmol, 46% yield) and 1-(allylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 207, 60 mg, 0.11 mmol, 14% yield).

Example 206 : ESI-MS : [M+H] ⁺ = 567.4. ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 7.43-7.40 (m, 2H), 6.34 (d, J = 9.8 Hz, 1H), 5.80 (s, 2H), 5.11 (d, J = 16.5 Hz, 2H), 5.04 (d, J = 9.4 Hz, 2H), 4.33 (d, J = 9.8 Hz, 1H), 4.16-4.07 (m, 3H), 3.72-3.66 (m, 3H), 3.42-3.35 (m, 1H), 2.74 (d, J = 2.1 Hz, 6H), 2.63 (s, 6H), 2.15-2.12 (m, 1H), 2.04-2.00 (m, 1H), 1.89 (ddd, J = 25.4, 12.4, 4.5 Hz, 1H), 1.72 (q, J = 12.1 Hz, 1H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz): δ -71.3 (s, 3F).

Example 207 : ESI-MS : [M+H]+ = 527.4. ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 7.64 (d, J = 2.5 Hz, 1H), 7.43 (dd, J = 9.4, 2.5 Hz, 1H), 6.74 (t, J = 5.3 Hz, 1H), 6.43 (d, J = 9.1 Hz, 1H), 5.87-5.77 (m, 1H), 5.08-5.06 (m, 1H), 5.03 (s, 1H), 4.35 (d, J = 9.8 Hz, 1H), 4.11 (dd, J = 11.2, 3.7 Hz, 1H), 3.67 (dd, J = 11.8, 9.7 Hz, 1H), 3.57-3.53 (m, 2H), 3.35 (tt, J = 11.9, 3.7 Hz, 1H), 2.70 (d, J = 1.4 Hz, 6H), 2.59 (s, 6H), 2.14 (d, J = 12.3 Hz, 1H), 1.99 (d, J = 14.0 Hz, 1H), 1.92-1.84 (m, 1H), 1.73 (dd, J = 24.6, 11.8 Hz, 1H). ¹⁹ F NMR (DMSO-d ₆ , 376 MHz): δ -71.3 (s, 3F).

Following a similar procedure, the following compounds were obtained. Structure intermediate Characteristics Example 214 Example 177 Modification : The reaction was carried out with 2,2-difluoroethyl trifluoromethanesulfonic acid for 16 h, and the crude material was purified by rapid chromatography (Isco RediSep® column 12 g, using a gradient of 0-100% AcOEt:EtOH (3:1)/hexane). The material was further purified by reversed-phase rapid chromatography (Biotage column 6 g) using a gradient dissolution of 5-95% _CH3CN /water (0.1% HCOOH). Evaporation of the selected solvent yielded 1-((2,2-difluoroethyl)amino)-5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 214, 6.0 mg, 0.01 mmol, 9% yield). ESI-MS : [M+H] ⁺ = 551.3. ¹ H NMR (400 MHz, CD ₃ CN) δ 7.58 (d, J = 2.5 Hz, 1H), 7.46 (dd, J = 9.5, 2.6 Hz, 1H), 6.46 (d, J = 9.4 Hz, 1H), 6.19 (t, J = 5.7 Hz, 1H), 5.99 (tt, J = 55.5, 4.1 Hz, 1H), 4.34 (dd, J = 11.4, 1.8 Hz, 1H), 4.19-4.15 (m, 1H), 3.73 (td, J = 11.8, 2.7 Hz, 1H), 3.40-3.30 (m, 3H), 2.70 (d, J = 3.0 Hz, 6H), 2.61 (s, 6H). Note: Some tetrahydropiperanone protons are masked by the solvent peak. ¹⁹ F NMR (376 MHz, CD ₃ CN) δ -73.6 (s, 3F), -122.9 (dt, J = 55.5, 15.6 Hz, 2F). Example 226 Int-D43 Modification: The reaction was carried out at 50 °C for 12 h in DMF solvent with 3 equivalents _{of K₂CO₃} and 5 equivalents of MeI. The crude material was then purified by preparative HPLC (condition 18, gradient c) and freeze-dried to give solid 5-[(2R,4S)-4-[4-(4,4-difluorocyclohexyl)-6,7-dimethyl-pteridin-2-yl]tetrahydropiperan-2-yl]-1-(dimethylamino)pyridin-2-one (Example 226, 61 mg of a single mirror isomer of known absolute configuration, 0.113 mmol, 21% yield). LCMS : [M+H] ^⁺ = 499.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.18 (br s, 10H) 2.30 - 2.35 (m, 2H) 2.78 (s, 3H) 2.82 (s, 3H) 3.03 (s, 6H) 3.44 (tt, J=11.8, 3.9 Hz, 1H) 3.74 - 3.86 (m, 1H) 4.12 - 4.22 (m, 1H) 4.26 - 4.36 (m, 2H) 6.54 (d, J=9.4 Hz, 1H) 7.38 (dd, J=9.35, 2.5 Hz, 1H) 7.52 (d, J=2.5 Hz, 1H). Example 232 Example 229 Modification : The reaction was carried out for 4 days at 80°C using 2.2 equivalents _{of K₂CO₃ and} 4 equivalents of MeI in MeCN solvent. The crude material was then purified by silica gel rapid column chromatography with a solubility gradient of 0-10% MeOH/DCM to obtain a solid 2-((2R,4S)-2-(1-(dimethylamino)-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimido[4,5-d]pyridyl ... -8(7H)-ketone (Example 232, 7 mg, 0.012 mmol, 57% yield). ESI-MS : [M+H] ⁺ 517.3. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.69 (s, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.40 (dd, J = 9.4, 2.5 Hz, 1H), 6.34 (d, J = 9.4 Hz, 1H), 4.33 (d, J = 11.0 Hz, 1H), 4.10 (dd, J = 10.9, 3.5 Hz, 1H), 3.72 (s, 3H), 3.68-3.63 (m, 1H), 3.40-3.35 (m, 1H), 2.89 (s, 6H), 2.61 (s, 6H), 2.11 (d, J = 12.8 Hz, 1H), 1.96-1.86 (m, 2H), 1.71 (d, J = 12.3 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ): δ -71.2 (s, 3F).

Method 35: Synthetic Example 208 Example 208: 5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(propyl-2-ylemamino)pyridin-2(1H)-one

Add silicone (50 mg) to a stirred solution of 1-amino-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bis(1.1.1)pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 332, 1 equivalent, 15 mg, 0.026 mmol) in anhydrous acetone (1.0 mL). The resulting solution was stirred at room temperature for 2 h, filtered, and concentrated under reduced pressure to give solid 5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(propyl-2-ylamino)pyridin-2(1H)-one (Example 208, 14 mg, 0.022 mmol, 85% yield). ESI-MS : [M+H] ⁺ = 580.3. ¹ H NMR (CD ₃ OD, 400 MHz): _δ 8.91 (s, 1H), 7.63 (dd, J = 9.4, 2.5 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 4.47 (d, J = 9.8 Hz, 1H), 4.26-4.22 (m, 1H), 3.81 (td, J = 11.3, 3.7 Hz, 1H), 3.53-3.45 (m, 1H), 2.89 (d, J = 1.1 Hz, 3H), 2.68 (s, 6H), 2.31 (d, J = 13.3 Hz, 1H), 2.25 (s, 3H), 2.13-1.92 (m, 3H), 1.81 (d, J = 4.1 Hz, 3H). ¹⁹ F NMR (CD ₃ OD, 376 MHz): δ -63.7 (s, 3F), -74.6 (s, 3F).

Method 36: Synthesis Example 210 Example 210: 1-(2,5-dihydropyrrole-1-yl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one

Under argon atmosphere, DCM (1 mL) was added to a round-bottom flask containing 1-(diallylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 206, 1 equivalent, 14 mg, 0.02 mmol) and second-generation Grubbs catalyst (0.2 equivalent, 4.0 mg, 4.7 µmol). The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure, and then purified directly by rapid chromatography (12 g _SiO2 column) using a dissolution gradient of 0-100% EtOAc/EtOH (3:1)/hexane to give a solid 1-(2,5-dihydropyrrolo-1-yl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 210, 4.0 mg, 7.4 µmol, 32% yield). ESI-MS : [M+H] ⁺ = 539.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.61 (d, J = 2.3 Hz, 1H), 7.41 (dd, J = 9.4, 2.7 Hz, 1H), 6.59 (d, J = 9.4 Hz, 1H), 5.83 (s, 2H), 4.33-4.26 (m, 2H), 4.20 (s, 4H), 3.79 (td, J = 11.5, 3.1 Hz, 1H), 3.45 (t, J = 4.0 Hz, 1H), 2.81 (s, 3H), 2.77 (s, 3H), 2.65 (s, 6H), 2.31 (d, J = 13.5 Hz, 1H), 2.15-2.02 (m, 3H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.0 (s, 3F).

Method 37: Synthetic Example 213 Example 213: N-[5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-2-sideoxy-1-pyridyl]prop-2-enylamine

To a reaction vial equipped with a Teflon-coated stirring rod, add 1-amino-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 177, 1 equivalent, 50 mg, 0.1 mmol), DIPEA (2 equivalents, 36 µL, 0.21 mmol), and THF (1 mL). Seal the vial and stir at 80°C for 2 h. Heat the reaction mixture to 80°C for 16 h. Cool the reaction mixture to room temperature, add water, and extract the aqueous phase three times with EtOAc. The organic phases are combined, dried with anhydrous _{Na₂SO₄ ,} filtered, and evaporated under reduced pressure. The residue was first purified by normal-phase rapid chromatography (12 g SiO ₂ ) using a dissolution gradient of 0-100% EtOAc:EtOH (3:1)/hexane, and secondly purified by reverse-phase rapid chromatography (6 g C18) using a dissolution gradient of 20-80% CH ₃ CN/0.1% formic acid (aq.) to give N-[5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-2-sideoxy-1-pyridinyl]prop-2-enylamine (Example 213, 2.5 mg, 4.6 µmol, 4% yield). ESI-MS : [M+H] ⁺ = 541.3. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.49-8.59 (0H), 7.77 (s, 0H), 7.64 (d, J = 9.6 Hz, 1H), 7.53 (s, 1H), 6.63 (d, J = 9.4 Hz, 1H), 6.57 (d, J = 9.4 Hz, 0H), 6.39 (d, J = 5.7 Hz, 2H), 5.84 (t, J = 6.1 Hz, 1H), 4.42 (d, J = 11.2 Hz, 1H), 4.23 (d, J = 11.2 Hz, 1H), 3.81 (d, J = 11.9 Hz, 1H), 3.46 (s, 1H), 2.77 (d, J = 3.0 Hz, 7H), 2.64 (s, 6H), 2.28 (d, J = 13.0 Hz, 1H), 2.07-1.94 (m, 3H). ¹⁹ F NMR (376 MHz, CD ₃ OD): δ -74.7 (s, 3F).

Method 38: Synthetic Example 216 Example 216: 2,3-Dimethyl-6-[rac-(2R,4S)-2-(6-sideoxy-1H-pyridin-3-yl)tetrahydropiperan-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[5,4-d]pyrimidin-4-one

Pd/C (10 wt%, 0.1 equivalent, 13 mg, 0.013 mmol) was added to a 100 mL round-bottom flask equipped with a Teflon-coated stirring rod and purged three times with argon. A solution of 6-[6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-piperan-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrimidino[5,4-d]pyrimidin-4-one (Int-D15, 1 equivalent, 73 mg, 0.13 mmol) in EtOH (1.3 mL) was added. The reaction vials were purged three times with _H₂ (g) and vacuum, equipped with _H₂ balloons (1 atm), and stirred at room temperature for 72 h. The reaction mixture was purged with argon, filtered through a diatomaceous earth mat, rinsed with DCM, and concentrated under reduced pressure. The residue was purified by preparative HPLC (condition 10, gradient e) to give 2,3-dimethyl-6-[rac-(2R,4S)-2-(6-sideoxy-1H-pyridin-3-yl)tetrahydropiperan-4-yl]-8-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrimidino[5,4-d]pyrimidin-4-one as a solid (Example 216, 19 mg, 0.04 mmol, 30% yield). ESI-MS : [M+H] ⁺ = 488.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.53 (dd, J = 9.1, 2.5 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 6.58 (d, J = 9.4 Hz, 1H), 4.29 (dd, J = 11.3, 1.5 Hz, 1H), 4.25 (ddd, J = 11.8, 4.5, 1.3 Hz, 1H), 3.74 (td, J = 12.0, 2.3 Hz, 1H), 3.66 (s, 3H), 3.47 (tt, J = 11.9, 3.8 Hz, 1H), 2.65 (s, 3H), 2.57 (s, 6H), 2.19-1.87 (m, 4H). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.6 (3F).

Method 39: Synthetic Example 227 Example 227: 7-Methyl-2-((2R,4S)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidino[4,5-d]tadalafil -8(7H)-ketone:

At room temperature, methyl(2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)-N-(2-methyl-3-sideoxy-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)-2,3-dihydropyridine Ammonium acetate (10 equivalents, 126 mg, 1.63 mmol) was added to a stirred solution of 4-yl)tetrahydro-2H-piperan-4-methylamide (Int-D45, 1 equivalent, 93 mg, 0.16 mmol) in EtOH (50 mL). The resulting solution was stirred at 60 °C for 6 h. The reaction mixture was cooled to room temperature, degassed with Ar, and then packed with 10 wt% Pd/C (0.1 equivalents, 17 mg, 0.02 mmol). The reaction mixture was stirred at room temperature under _H2 atmosphere for 4 h. The reaction mixture was degassed with Ar, filtered through a short diatomaceous earth mat, and washed with EtOH. The filtrate was vacuum concentrated and purified by rapid column chromatography with a dissolution gradient of 1-8% MeOH/DCM using _SiO2 to obtain a solid 7-methyl-2-((2R,4S)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-4-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)pyrimidino[4,5-d]pyrimido ... -8(7H)-ketone (Example 227, 57 mg, 0.12 mmol, 57% yield). ESI-MS : [M+H] ⁺ = 474.3. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.45 (s, 1H), 8.69 (s, 1H), 7.44 (dd, J = 9.4, 2.5 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 6.27 (d, J = 9.4 Hz, 1H), 4.32 (d, J = 9.8 Hz, 1H), 4.10 (dd, J = 11.2, 3.4 Hz, 1H), 3.71 (s, 3H), 3.65 (td, J = 11.7, 2.3 Hz, 1H), 3.37 (qd, J = 7.9, 3.9 Hz, 1H), 2.62 (s, 6H), 2.08 (d, J = 13.0 Hz, 1H), 1.95-1.83 (m, 2H), 1.75-1.66 (m, J = 9.1 Hz, 1H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ): δ -71.2 (s, 3F).

Method 40: Synthesis Example 230 Example 230: 2-((2R,4S)-2-(1-cyclopropyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidino[4,5-d]tadalafil -8(7H)-keto

7-Methyl-2-((2R,4S)-2-(6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-4-(3-(trifluoromethyl)biscyclic[1.1.1]pent-1-yl)pyrimidino[4,5-d]ta -8(7H)-one (Example 227, 1 equivalent, 12 mg, _0.025 mmol), cyclopropyl(trifluoro)potassium borohydride (3 equivalents, 11 mg, 0.076 mmol), _K₂CO₃ (2 equivalents, 7 mg, 0.051 mmol), and 1,10-phenanthroline (0.5 equivalents, 2.3 mg, 0.013 mmol) were reacted in a stirred solution of toluene (1.0 mL) and _H₂O (0.5 mL) with Cu(OAc) _₂ (1 equivalent, 4.6 mg, 0.025 mmol). The resulting mixture was purged with oxygen for 5 min, capped, and stirred at 70 °C for 72 h. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried with anhydrous _Na₂SO₄ , filtered, and concentrated under vacuum. The crude mixture was purified by silica gel rapid column chromatography with a dissolution gradient of 1-10% MeOH/DCM to obtain _a solid 2-((2R,4S)-2-(1-cyclopropyl-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrimidino[4,5-d]pyridyl ... -8(7H)-ketone (Example 230, 5 mg, 9 µmol, 37% yield). ESI-MS : [M+H] ⁺ = 514.3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.43 (s, 1H), 7.35-7.31 (m, 2H), 6.56-6.52 (m, 1H), 4.28-4.25 (m, 2H), 3.89 (s, 3H), 3.73 (td, J = 11.9, 2.3 Hz, 1H), 3.55 (tt, J = 11.9, 3.7 Hz, 1H), 3.33-3.27 (m, 1H), 2.60 (s, 6H), 2.18 (d, J = 12.8 Hz, 1H), 2.14-2.06 (m, 1H), 2.03-2.00 (m, 1H), 1.89 (dd, J = 24.7, 11.9 Hz, 1H), 1.14-1.07 (m, 2H), 0.89-0.84 (m, 2H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ -73.0 (d, J = 5.8 Hz, 3F).

Following a similar procedure, the following compounds were obtained. Structure intermediate Characteristics Example 328 Example 330 The crude material was purified by rapid chromatography (20-50% acetone/hexane gradient dissolution) to give 1-cyclopropyl-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)biscyclo[1.1.1]-pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one as a solid (Example 328, 18 mg, 0.032 mmol, 21% yield). ESI-MS : [M+H] ⁺ = 565.3. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.91 (s, 1H), 7.62-7.58 (m, 2H), 6.52 (d, J = 9.1 Hz, 1H), 4.43 (dd, J = 11.3, 1.7 Hz, 1H), 4.26-4.22 (m, 1H), 3.84-3.77 (m, 1H), 3.52-3.44 (m, 1H), 3.35-3.30 (m, 1H), 2.90 (d, J = 1.1 Hz, 3H), 2.68 (s, 7H), 2.25 (d, J = 13.0 Hz, 1H), 2.10-2.04 (m, 2H), 1.96 (dd, J = 24.7, 11.9 Hz, 1H), 1.14-1.09 (m, 2H), 0.92-0.88 (m, 2H). ¹⁹ F NMR (376 MHz, CD ₃ OD): _δ -63.7 (s, 3F), -74.6 (d, J = 10.0 Hz, 3F).

Method 41: Synthesis of Examples 336 and 338. Example 336: 1-(dimethylamino)-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one; and Example 338: 1-(methylamino)-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one

Sodium cyanoboronide (2 equivalents, 5.8 mg, 0.09 mmol) was added to a stirred solution of 1-amino-5-[(2R,4S)-4-[7-methyl-6-(trifluoromethyl)-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]pyridin-2(1H)-one (Example 332, 1 equivalent, 25 mg, 0.046 mmol), paraformaldehyde (5 equivalents, 0.017 mL, 0.23 mmol), and acetic acid (1.5 equivalents, 40 µL, 0.007 mmol) in MeCN (1.0 mL) at room temperature. The reaction mixture was stirred at this temperature for 2 days. The reaction mixture was diluted with EtOAc, and the resulting solution was washed with saturated _NaHCO3 (aq) and brine. _The organic layer was dried over anhydrous _Na2SO4 , filtered, and concentrated under vacuum. The crude mixture was purified by silica gel rapid column chromatography (20-50% acetone/hexane) to give a solid 1-(dimethylamino)-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2- 1-(methylamino)-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 338).

Example 336: ESI-MS : [M+H] ⁺ 568.3. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.91 (s, 1H), 8.50 (s, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.57 (dd, J = 9.4, 2.5 Hz, 1H), 6.52 (d, J = 9.1 Hz, 1H), 4.42 (dd, J = 11.3, 1.7 Hz, 1H), 4.26-4.22 (m, 1H), 3.84-3.77 (m, 1H), 3.49-3.46 (m, 1H), 2.95 (s, 6H), 2.90 (d, J = 1.1 Hz, 3H), 2.68 (d, J = 5.9 Hz, 6H), 2.27 (d, J = 13.3 Hz, 1H), 2.10-2.04 (m, 2H), 1.96 (dd, J = 24.8, 11.8 Hz, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD): δ -63.7 (s, 3F), -74.6 (s, 3F).

Example 338: ESI-MS : 554.3. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.91 (s, 1H), 8.50 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.61-7.58 (m, 1H), 6.60 (d, J = 9.4 Hz, 1H), 4.45 (dd, J = 11.4, 1.8 Hz, 1H), 4.27-4.23 (m, 1H), 3.85-3.78 (m, 1H), 3.52-3.45 (m, 1H), 2.90 (d, J = 1.1 Hz, 3H), 2.77 (s, 3H), 2.68 (d, J = 6.6 Hz, 6H), 2.29 (d, J = 13.3 Hz, 1H), 2.10-2.05 (m, 2H), 1.96 (dd, J = 24.8, 11.8 Hz, 1H). ^{1 9} F NMR (376 MHz, CD ₃ OD): δ -63.7 (s, 3F), -74.6 (s, 3F).

Method 42: Synthesis of Examples 311 and 322. Example 311: 5-((2R,4S)-4-(6-chloro-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(methyl- _d3 )pyridin-2(1H)-one; and Example 322: 1-(methyl- _d3 )-5-((2R,4S)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one.

To a flame-dried microwave-safe vial, add 5-[(2R,4S)-4-[6-bromo-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]-1-(trideuteryl)pyridin-2-one (Example 303, 1 equivalent, 60 mg, 0.11 mmol), _Cu₂O (0.2 equivalent, 3.1 mg, 0.022 mmol), _Me₄NCl (4 equivalent, 48 mg, 0.43 mmol), and ethanol (2.2 mL). Stir the mixture at 120 °C for 16 h. Add saturated _NaHCO₃ (20 mL) and extract the reaction mixture with EtOAc (2 × 20 mL). The combined organic layer was washed with brine (10 mL), dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (30-100% EtOAc/hexane, followed by 0-20% MeOH/DCM). The material was further purified by preparative HPLC (condition 14, gradient b) to obtain the desired products 5-((2R,4S)-4-(6-chloro-7-methyl-4-(3-(trifluoromethyl)bis(1.1.1)pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(methyl- _d3 )pyridin-2(1H)-one (Example 311, 9.5 mg, 17% yield) and 1-(methyl- _d3) pyridin-2(1H)-one in solid form. )-5-((2R,4S)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]-pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 322, 5.5 mg, 11% yield).

Example 311: ESI-MS : [M+H] ⁺ = 508.3. ^1H NMR ( _CDCl3 , 400 MHz): δ 8.42 (1H, s), 7.36-7.39 (2H, m), 6.53-6.56 (1H, m), 4.24-4.31 (2H, m), 3.73-3.80 (1H, m), 3.38-3.46 (1H, m), 2.88 (3H, s), 2.62 (6H, s), 2.26-2.31 (1H, m), 2.06-2.14 (2H, m), 1.95-2.04 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s).

Example 322: ESI-MS : [M+H] ⁺ = 473.51. ^1H NMR ( _CDCl3 , 400 MHz): δ 8.43 (1H, d, J = 8.5 Hz), 7.37-7.41 (3H, m), 6.55 (1H, d, J = 9.4 Hz), 4.25-4.32 (2H, m), 3.74-3.81 (1H, m), 3.38-3.46 (1H, m), 2.82 (3H, s), 2.61 (6H, s), 2.29-2.33 (1H, m), 2.06-2.13 (2H, m), 1.98-2.04 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.2 (3F, s).

Method 43: Synthetic Example 295 Example 295: 5-((2R,4S)-4-(6-chloro-7-methyl-4-(3-(trifluoromethyl)bis(1.1.1)pent-1-yl)pyrido[2,3-d]pyrimidine-2-

Sodium hydroxide (1.2 eq, 3.3 mg, 0.083 mmol) was added to a solution of methyl 4-(2,4-difluorophenyl)-7-methyl-2-[(2R,4S)-2-(1-methyl-6-sideoxy-3-pyridyl)tetrahydropiperan-4-yl]pyrido[2,3-d]pyrimidin-6-carboxylate (Int-E19, 1 equivalent, 35 mg, 0.07 mmol) and N'-hydroxyacetamidine (1.2 equivalent, 6.1 mg, 0.083 mmol) in THF (1 mL). The resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched by adding a solution of NH4Cl (10 mL) and EtOAc (10 mL). The organic phase was washed with brine, filtered, and concentrated under reduced pressure. The crude material was purified by rapid chromatography using a 0-20% MeOH/DCM dissolution gradient, followed by reversed-phase chromatography using a 25-85% MeCN/water (containing 0.1% formic acid) gradient to obtain 5-((2R,4S)-4-(4-(2,4-difluorophenyl)-7-methyl-6-(3-methyl-1,2,4-) (diazol-5-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-methylpyridin-2(1H)-one (Example 295, 9 mg, 0.017 mmol, 25%) ^¹H NMR ( _CDCl₃ , 400 MHz): δ 8.79 (1H, d, J = 4.0 Hz), 7.69 (1H, td, J = 8.3, 6.2 Hz), 7.36–7.39 (2H, m), 7.17 (1H, td, J = 8.2, 2.4 Hz), 7.06–7.11 (1H, m), 6.54–6.57 (1H, m), 4.27–4.34 (2H, m), 3.75–3.82 (1H, m), 3.54 (3H, s), 3.20 (3H, s), 2.51 (3H, s), 2.34-2.39 (1H, m), 2.08-2.24 (3H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -104.2 (1F, s), -108.8 (1F, s). ESI-MS : [M+H] ⁺ = 531.3.

Method 44: Synthetic Example 309 Example 309: 1-(difluoromethyl)-5-((2R,4S)-4-(6-fluoro-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one

Under argon atmosphere, 5-[(2R,4S)-4-[6-fluoro-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Int-E24, 1 equivalent, 45 mg, 0.1 mmol) and sodium tributoxide (2.2 equivalent, 1.1 mmol, 106 mg) were added to a dried vial. MeCN (0.4 mL) was added at room temperature under argon atmosphere, and the solution was stirred at -15°C ( _NH₄Cl /ice bath) for 10 min. 50 µL of MeCN containing TMSCF _2Br (1.2 eq, 18 µL, 0.1 mmol) was added dropwise, and the solution was stirred at -15 °C for 1 h. Subsequently, the reaction mixture was heated to room temperature, diluted with brine (15 mL), and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated under reduced pressure. The crude material was purified by reversed-phase rapid chromatography (condition 9, gradient b) to give 1-(difluoromethyl)-5-((2R,4S)-4-(6-fluoro-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)pyridin-2(1H)-one (Example 309, 7.0 mg, 0.01 mmol, 14% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.04 (1H, d, J = 8.5 Hz), 7.69 (1H, t, J = 60.3 Hz), 7.44-7.49 (2H, m), 6.54-6.56 (1H, m), 4.28-4.35 (2H, m), 3.75-3.82 (1H, m), 3.40-3.48 (1H, m), 2.81 (4H, d, J = 2.9 Hz), 2.63 (7H, s), 2.33 (1H, d, J = 13.3 Hz), 2.10-2.18 (2H, m), 1.94-2.03 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.2 (3F, s), -103.5 (2F, d, J = 60.3 Hz), -120.16-120.23 (1F, m). ESI-MS : [M+H] ⁺ = 525.3.

Following a similar procedure, the following compounds were obtained. Structure intermediate Characteristics Example 313 Int-E31 The crude material was purified by normal-phase chromatography (50-100% EtOAc/hexane dissolution gradient) to give solid 5-[(2R,4S)-4-[6-bromo-7-methyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]-1-(difluoromethyl)pyridin-2-one (Example 313, 41 mg, 19% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.62 (1H, s), 7.75 (1H, d, J = 60.3 Hz), 7.42-7.51 (3H, m), 6.54 (1H, d, J = 9.6 Hz), 4.26-4.34 (2H, m), 3.73-3.80 (1H, m), 3.38-3.46 (1H, m), 2.92 (3H, s), 2.62 (6H, s), 2.28-2.33 (1H, m), 2.08-2.16 (2H,m), 1.99 (1H, q, J = 12.3 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1, -103.5, -103.6. ESI-MS : [M+H] ⁺ = 587.2. Example 315 Int-E34 The crude material was purified by normal-phase chromatography (50-100% EtOAc/hexane dissolution gradient) followed by preparative HPLC (condition 16, gradient c) to give 2-[(2R,4S)-2-[1-(difluoromethyl)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-yl]-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-6-carboxynitrile (Example 315, 3.5 mg, 13% yield). ESI-MS : [M+H] ⁺ = 532.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.82 (1H, s), 7.69 (1H, t, J = 60.3 Hz), 7.51 (1H, d, J = 2.3 Hz), 7.46 (1H, dd, J = 9.6, 2.5 Hz), 6.56 (1H, d, J = 9.6 Hz), 4.28-4.35 (2H, m), 3.79 (1H, td, J = 11.6, 3.2 Hz), 3.44-3.51 (1H, m), 3.02-3.02 (3H, m), 2.67 (6H, s), 2.33 (1H, d, J = 13.6 Hz), 2.08-2.15 (2H, m), 1.94-2.03 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s), -103.4 (2F, q, J = 60.5 Hz). Example 317 Int-E41 The residue was purified by rapid chromatography using a 50-100% EtOAc/DCM gradient to give solid 4-cyclohexyl-2-[(2R,4S)-2-[1-(difluoromethyl)-6-sideoxy-3-pyridyl]tetrahydropiperan-4-yl]-7-methylpyrido[2,3-d]pyrimidin-6-carboxynitrile (Example 317, 25 mg, 0.052 mmol, 34% yield). ESI-MS : [M+H] ⁺ = 480.4. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.76 (1H, s), 7.67 (1H, t, J = 60.3 Hz), 7.50 (1H, s), 7.45 (1H, dd, J = 9.6, 2.4 Hz), 6.54 (1H, d, J = 9.6 Hz), 4.27-4.34 (2H, m), 3.78 (1H, td, J = 11.6, 3.0 Hz), 3.38-3.48 (2H, m), 2.99 (3H, s), 2.60 (1H, s), 2.33 (1H, d, J = 13.4 Hz), 2.05-2.18 (2H, m), 1.76-2.00 (8H, m), 1.35-1.53 (4H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -103.5 (1F, s), -103.6 (1F, s). Example 90 Example 34 Modification : The reaction was carried out in diglyme solvent and purified by rapid chromatography (24 g _SiO2 column, 10-50% acetone/hexane dissolution gradient). Further purification by reversed-phase rapid chromatography (condition 9, gradient b) yielded (1-(difluoromethyl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one as a solid (Example 90, 7.5 mg, 0.01 mmol, 7% yield). ^¹H NMR ( _CDCl₃ , 400 MHz): δ 7.38–7.75 (3H, m), 6.54 (1H, d, J = 9.6 Hz), 4.26–4.34 (2H, m), 3.74–3.81 (1H, m), 3.40–3.47 (1H, m). 2.80 (3H, s), 2.76 (3H, s), 2.63 (6H, s), 2.30-2.34 (1H, m), 2.07-2.14 (2H, m), 2.01 (1H, t, J = 12.4 Hz). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.2 (3F, s), -103.5 (2F, d, J = 60.3 Hz). ESI-MS : [M+H] ⁺ = 522.3.

Method 45: Synthesis Example 305 Example 305: 7-Methyl-2-((2R,4S)-2-(1-(methyl- _d3 )-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidin-6-carboxynitrile

5-((2R,4S)-4-(6-bromo-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-piperan-2-yl)-1-(methyl- _d3 )pyridin-2(1H)-one (Example 303, 1 equivalent, 60 mg, 0.11 mmol), Zn(CN) ₂ (2 equivalents, 26 mg, 0.22 mmol), and Pd( _PPh3 ) ₄ (0.1 equivalents, 13 mg) were stirred in NMP (1.5 mL) at 110 °C for 6 h. The reaction mixture was washed with water and extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine, dried with _Na₂SO₄ , filtered, and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (0-100% EtOAc/ _hexane dissolution gradient, followed by 0-20% MeOH/DCM dissolution gradient). The material was further purified by preparative HPLC (condition 14, gradient c) to give 7-methyl-2-((2R,4S)-2-(1-(methyl- _d3 )-6-sideoxy-1,6-dihydropyridin-3-yl)tetrahydro-2H-piperan-4-yl)-4-(3-(trifluoromethyl)biscyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidin-6-carboxylonitrile as a solid (Example 305, 22 mg, 41% yield). ESI-MS : [M+H] ⁺ = 482.3. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.81 (1H, s), 7.37 (2H, dd, J = 7.1, 2.8 Hz), 6.54-6.57 (1H, m), 4.26-4.32 (2H, m), 3.73-3.80 (1H, m), 3.46 (1H, dd, J = 12.1, 10.1 Hz), 3.01 (3H, s), 2.65 (6H, s), 2.29 (1H, d, J = 13.3 Hz), 2.07-2.13 (2H, m), 1.93-2.02 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.2 (3F, s).

Method 46: Synthetic Example 297 Example 297: 1-Methyl-5-[(2R,4S)-4-[7-Methyl-6-(4-methyl) azol-2-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one

Add 5-[(2R,4S)-4-[6-bromo-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]-1-methylpyridin-2-one (1 equivalent, 45 mg, 0.08 mmol) and tributyl-(4-methyl)pyridin-2-one to a flame-dried round-bottom flask equipped with a Teflon-coated magnetic stirring rod. (2-azolyl)stanne (4 equivalents, 122 mg, 0.33 mmol) and Pd( _PPh3 ) ₄ (0.1 equivalents, 9.5 mg, 10 mol%). The vials were sealed and purged under argon. Anhydrous toluene (1 mL) was added. The resulting solution was degassed with argon for 2 min, and then heated to 95 °C with stirring. After 18 h at 95 °C, the reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL). The resulting solution was washed with saturated _NH4Cl (aq ₎ and brine. The organic layer was collected, dried over _Na2SO4 , filtered, and concentrated under vacuum. The crude mixture was purified by reversed-phase rapid column chromatography (condition 9, gradient c) to obtain 1-methyl-5-[(2R,4S)-4-[7-methyl-6-(4-methyl)] as a powder. (Azol-2-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 297, 32 mg, 0.06 mmol, 69% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 9.06 (1H, s), 7.59 (1H, d, J = 1.5 Hz), 7.37-7.40 (2H, m), 6.57 (1H, d, J = 10.1 Hz), 4.27-4.34 (2H, m), 3.75-3.82 (1H, m), 3.55 (3H, s), 3.42-3.49 (1H, m), 3.17 (3H, s), 2.68 (6H, s), 2.30-2.33 (4H, m), 2.11-2.16 (2H, m), 1.99-2.08 (1H,m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.0 (3F, s). ESI-MS : [M+H] ⁺ = 552.3.

Method 47: Synthetic Example 299 Example 299: 1-Methyl-5-[(2R,4S)-4-[7-Methyl-6-(3-Methyl-1,2,4-] (diazol-5-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one

Add N'-hydroxyacetamidine (3 equivalents, 18 mg, 0.25 mmol), 5-[(2R,4S)-4-[6-bromo-7-methyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]-1-methyl-pyridin-2-one (1 equivalent, 45 mg, 0.0819 mmol), Pd( _PPh3 ) _2Cl2 (0.05 equivalents, 2.9 mg), and anhydrous _toluene (0.8 mL) to a flame-dried microwave-safe vial equipped with a Teflon-coated magnetic stir bar. Seal the vial and purge under argon. Triethylamine (2 equivalents, 23 µL, 0.16 mmol) was added, and the reaction flask was purged with CO (balloon). The flask was heated to 95°C overnight at 1 atm CO with stirring. After 16 h, additional N'-hydroxyacetamidine (3 equivalents, 18 mg, 0.25 mmol), Pd( _PPh3 ) _2Cl2 (0.05 equivalents, 2.9 mg) _, and triethylamine (2 equivalents, 23 µL, 0.16 mmol) were added. The reaction mixture was stirred at 95°C with CO (balloon) for 2 days. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated _NH4Cl (aq) and brine, dried over _{Na2SO4 ,} filtered, and concentrated under vacuum. The product was purified by reversed-phase chromatography (condition 9, gradient d) to obtain 1-methyl-5-[(2R,4S)-4-[7-methyl-6-(3-methyl-1,2,4-)] as a solid. (diazol-5-yl)-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 299, 14 mg, 0.02 mmol, 29% yield). ¹ H NMR (CDCl ₃ , 400 MHz): δ 9.24 (1H, d, J = 2.6 Hz), 7.38-7.40 (2H, m), 6.57 (1H, dd, J = 9.4, 3.0 Hz), 4.28-4.34 (2H, m), 3.80 (1H, t, J = 11.0 Hz), 3.55 (3H, d, J = 2.6 Hz), 3.43-3.48 (1H, m), 3.19 (3H, d, J = 2.6 Hz), 2.69 (6H, d, J = 2.7 Hz), 2.56 (3H, d, J = 2.7 Hz), 2.32 (1H, d, J = 13.3 Hz), 2.13-2.16 (2H, m), 1.98-2.07 (1H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). ESI-MS : [M+H] ⁺ = 553.3.

Method 48: Synthetic Example 118 Example 118: 1-(1-deuteriumcyclopropyl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pterin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one

Add bipyridyl (2.0 equivalent, 46 mg, 0.30 mmol) to a microwave vial equipped with a Teflon-coated magnetic stir bar, and then flame-dry the vial under vacuum. 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]-1H-pyridin-2-one (Example 34, 1 equivalent, 70 mg, 0.15 mmol), (1-deuteriumcyclopropyl)boronic acid (2 equivalent, 26 mg, 0.30 mmol), triethylamine (2.0 equivalent, 41 µL, 0.30 mmol) and Cu(OAc) ₂ (2.0 equivalent, 54 mg, 0.30 mmol) were added to a reaction vial, which was then purged under argon. Add DCE (1.5 mL), then degas the reaction mixture and heat it under argon with stirring to 70 °C for 18 h. Cool the reaction mixture to room temperature and dilute with EtOAc. Wash the resulting suspension with saturated _NH₄Cl (aq. ₎ and brine. Collect the organic layer, dry it with _Na₂SO₄ , filter it, and concentrate it under vacuum. The crude reaction mixture was purified by rapid chromatography (12 g _SiO2 column, 10-50% acetone/hexane) to give 11.5 mg of 1-(1-deuteriumcyclopropyl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bis(1.1.1)pentyl]pteridin-2-yl]tetrahydropiperan-2-yl]pyridin-2-one (Example 118). ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.35-7.37 (2H, m), 6.53 (1H, d, J = 9.7 Hz), 4.28 (2H, t, J = 9.8 Hz), 3.74-3.80 (1H, m), 3.39-3.47 (1H, m), 2.79 (3H, s), 2.76 (3H, s), 2.63 (7H, s), 2.25-2.29 (1H, m), 2.09-2.14 (2H, m), 1.95-2.04 (1H, m), 1.11 (3H, s), 0.86-0.87 (3H, m). ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ -73.1 (3F, s). ESI-MS : [M+H] ⁺ = 513.3.

Example A3 : In vivo analysis of cellular phosphorylation using spleen tyrosine kinase ( " Syk " ) data. In vivo measurement of trigger receptor 2 activity expressed on bone marrow cells. The efficacy of TREM2 agonists was measured using HEK cell lines expressing human TREM2 and DAP12 (HEK293T-hTREM2 cells). The binding of small molecules to TREM2 and activation of TREM2 enhance Syk phosphorylation. Syk phosphorylation levels were measured using the commercially available AlphaLisa reagent kit. To perform the analysis, HEK-hTREM2 cells were plated at a density of 14,000 cells/well in 25 μL of complete growth medium in 384-well culture dishes and incubated at 37°C and 5% _CO2 for 20–24 hours.

Prior to analysis, the test compound was diluted in analytical buffer in 384-well culture dishes and equilibrated for 30 minutes. The growth medium was removed from the cell culture dish by turning the dish over on dotted paper, and 25 μL of analytical buffer containing the test compound was added to the cells. The cells were incubated at room temperature for 45 minutes. After 45 minutes, the analytical buffer was removed, and 10 μL of dissolving buffer was added. The culture dishes were shaken at 350 RPM at room temperature for 20 minutes. After complete dissolution, AlphaLisa reagent was added to the solution, and fluorescence intensity was measured using a Perkin Elmer Envision disc reader. The intensity was used to generate a standard curve and to calculate the activation percentage. The Prism v9 software log (activator) was used to perform curve fitting with a variable slope (four parameters) of the comparison response, and EC50 was calculated based on the curve fitting.

The results presented in Table B were generated using the in vitro analysis described above. This analysis can be used to test any of the compounds described herein to evaluate and characterize the ability of the compounds to act as TREM2 agonists.

Compounds designated "A" exhibit an _EC50 of ≤ 100 nM. Compounds designated "B" exhibit an _EC50 of > 100 nM and ≤ 500 nM. Compounds designated "C" exhibit an _EC50 of > 500 nM. Table B. hTREM2 _EC50 data (HEK293 cells) Example number hTREM2 EC50 nM 1 A 2 C 4 A 5 A 7 A 9 A 11 B 12 B 13 B 14 A 15 A 16 A 18 B 19 A twenty one A twenty three A 25 A 26 A 27 A 28 A 29 B 31 A 32 B 34 A 36 A 38 A 40 A 42 A 43 A 46 A 48 A 50 A 52 A 54 A 56 A 60 A 62 A 64 A 65 A 66 A 68 A 69 A 71 A 72 A 74 A 75 A 77 A 78 A 80 A 82 A 84 A 86 A 88 A 90 A 92 C 94 A 96 A 98 A 100 A 102 A 104 A 105 A 107 A 109 A 110 A 112 A 114 A 116 A 118 A 120 A 121 A 123 A 124 B 126 B 127 A 129 A 130 A 131 A 132 A 134 A 136 A 138 A 140 A 142 A 145 A 147 A 149 A 153 A 155 A 156 A 158 A 159 A 161 A 162 A 163 A 165 B 167 A 168 A 169 A 170 B 173 A 174 A 175 A 176 A 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 B 186 B 187 B 188 C 189 A 190 A 191 A 192 B 193 A 194 B 195 A 196 A 197 B 198 B 201 A 202 B 203 A 204 C 205 A 206 A 207 A 208 A 209 A 210 A 211 A 212 A 213 A 214 A 215 A 216 B 217 A 218 B 219 A 220 A 324 A 326 A 328 A 330 A 332 A 334 A 336 A 338 A 348 C 349 C 350 A 352 C 353 A 354 A 355 A

All references cited in this document (e.g., scientific publications or patent application publications) are incorporated herein by full reference for all purposes, as if each reference were specifically and individually instructed to be incorporated herein by full reference for all purposes.

Claims (94)

One compound of formula (I): (I) or a pharmaceutically acceptable salt, solvent, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer, or tautomer thereof, wherein: ring A, together with its fused 6-membered ring system, forms a bicyclic system selected from one of the following: (Ii) (I-ii) (I-iii) (I-iv); ^V1 and ^V2 are each independently N, ^NR8b, or S, wherein ^V1 and ^V2 are not both S, and the bonds in the rings containing ^V1 and ^V2 are either single or double bonds, depending on the valence of ^V1 and ^V2 ; ^W1 , ^W2 , ^W3 , and ^W4 are each independently C( ^R10 ), N, or ^NR8b , and the bonds connecting ^W3 and ^W4 , and ^W4 and ^{NR8b, are} either single or double bonds, depending on the valence of ^W3 and W4; X is C( ^R11 ) or N; Y is C( ^R12 ) or N; Z is C( ^R18 ) ₂ or O; R ¹ is a cycloalkyl, heterocycloyl, aryl, or heteroaryl group, each of which may be substituted by one or more ^{R13 groups} ; each ^R2 is independently a _C1-6 alkyl, C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, _{heterocycloyl} , halogen, cyano, -O( ^RA ), -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group may be substituted by one or more ^R14 groups; or two ^R2 groups together with the carbon atom to which they are attached form an alkyl group; ^R3 is hydrogen, _C1-6 alkyl, C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 alkyl, C2 ... _1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, -O( ^RA ) or -N( ^RB )( ^RC ), wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogenated, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted with one or more ^R15s as appropriate; ^R4 and ^R5 are each independently hydrogen, _C1-6 alkyl, _C2-6 alkenyl, C2-6 ynyl, _{C1-6 heteroalkyl} , _C1-6 halogenated, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )(RC ^{) R6} and ^R7 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, _C1-6 heteroalkyl, C1-6 halogenyl, cycloalkyl, heterocycloyl, _aryl , heteroaryl, halogen, cyano, -O( ^RA ) or -N(RB ⁾ (RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, halogenyl, _cycloalkyl , _{heterocycloyl} , aryl, and heteroaryl are substituted with one or more ^R16 as appropriate; ^R8 is hydrogen, _C1-6 alkyl, C1-6 alkyl, C2-6 alkyl, ^C2-6 alkyl, C1-6 alkyl, C1-6 alkyl, C1-6 alkyl, _cycloalkyl , aryl, and heteroaryl ^. _2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, or N(R ^B )(R ^C ), wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl groups are substituted with one or more R ¹⁶ groups as appropriate; R ^8a is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, or heterocycloyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl groups are substituted with _one or more R ¹⁶ groups as appropriate; R ^8b is absent, hydrogen, C1-6 alkyl, _C2-6 alkenyl, _C1-6 alkyl, C2-6 alkyl, C1 ... _2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, or heterocycloyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, or heterocycloyl is substituted by one or more ^R16 groups as appropriate; ^R9a , ^R9b , and ^R9c are, in each case, independently hydrogen, deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, C1-6 heteroalkyl, _C1-6 halogen, or halogen; ^R10 , ^R11 , and ^R12 are, in each case, independently hydrogen, _C1-6 alkyl _{, C2-6} alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl ... _1-6 halogenated, cycloalkyl, heterocyclic, aryl or heteroaryl, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogenated, cycloalkyl, heterocyclic, aryl and heteroaryl are, where applicable, substituted with one or more ^R16 ; each ^R13 is independently deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogenated, cycloalkyl, heterocyclic, halogen, cyano, -O( ^RA ), -C(O)N( ^RB )( ^RC ) or -N( ^RB )(RC ⁾ ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocyclic group is substituted with one or more ^R17 groups as appropriate; each ^R14 , ^R15 , and ^R16 is independently deuterium, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, halogen, cyano, -O( ^RA ) or -N( ^RB )( ^RC ), wherein each alkyl, alkenyl, ynyl, heteroalkyl, halogen, cycloalkyl, and heterocyclic group is substituted with one or more ^{R17 groups} as appropriate; or two ^R14 , two ^R15 , or two R16 groups. ^16, together with the carbon atom to which it is attached, forms a cycloalkyl, heterocycloyl, aryl, or heteroaryl group, wherein each cycloalkyl, heterocycloyl, aryl, and heteroaryl group is, as appropriate, substituted with one or more R ¹⁷ atoms; each R ^A is independently hydrogen, deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocycloyl, or -N( ^RB )( ^RC ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl, and heterocycloyl group is, as appropriate, substituted with one or more R ¹⁷ atoms; each R ^B and R ^C is independently hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C1-6 heteroalkyl, C _1-6 halogenated, cycloalkyl, heterocyclic, or -C(O)-alkyl, wherein each alkyl, alkenyl, heteroalkyl, halogenated, cycloalkyl, and heterocyclic group is, as appropriate, substituted with one or more R ¹⁷ atoms; or ^RB and ^RC together with the nitrogen atom to which they are attached form -N=C( ^RD )( ^RE ) or a heterocyclic group, wherein the heterocyclic group is, as appropriate, substituted with one or more R ^{17 atoms} ; each ^RD and ^RE is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 heteroalkyl, C _1-6 halogenated, cycloalkyl, or heterocyclic, wherein each alkyl, alkenyl, heteroalkyl, halogenated, cycloalkyl, and heterocyclic group is, as appropriate, substituted with one or more R 17 atoms. ¹⁷ substitution; or each R ¹⁷ is deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, halogen or cyano; or two R ¹⁷ form a lateral group; each R ¹⁸ is independently H, C1-6 alkyl or halogen; and n is 0, _1, 2, 3, 4, 5 or 6. For example, in the compound of claim 1, ring A is (Ii). Compounds as described in any of the preceding claims, wherein ^W1 is C( ^R10 ) (e.g., CH). Compounds as described in any of the preceding claims, wherein ^W2 is C( ^R10 ) (e.g., CH). Compounds as described in any of the aforementioned claims, wherein ^W3 is C( ^R10 ) (e.g., CH). The compound in claim 2, wherein ^W1 , ^W2 and ^W3 are each N. Compounds as claimed in any of the preceding claims, wherein ^R1 is selected from cycloalkyl or heterocyclic groups, each of which is substituted by one or more ^R13 as appropriate. Compounds as claimed in any of the preceding claims, wherein ^R1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl or heterocyclic group, each of which is, as appropriate, substituted by one or more ^R13 groups. Compounds as claimed in any of the preceding claims, wherein ^R1 is a 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl group, each of which is substituted by one or more ^{R13 groups} as appropriate. For example, in the compound of claim 8, ^R1 is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is, as appropriate, substituted by one or more ^R13 . Compounds as described in any of the aforementioned claims, wherein ^R1 is selected from , , , , , , , , , , , , , , , , , , , and . Compounds of any of claims 1 to 6, wherein ^R1 is -O( ^RA ), aryl or heteroaryl, wherein the aryl and heteroaryl groups are each substituted by one or more ^R13 groups as appropriate. For example, in the compound of claim 11, ^R1 is selected from phenyl, pyridyl, pyrimidinyl, imidazole, ... diazole group, iso azole group, Azolyl, isothiazolyl, thiazolyl, pyrazolyl or pyrazolyl The base (pyrazyl) is substituted by one or more ^R13s , depending on the situation. The compound of claim 13, wherein ^R1 is a phenyl or thiazolyl group, each of which is substituted by one or more R13 ^groups as appropriate. Compounds as described in any of the aforementioned claims, wherein ^R1 is selected from , , , , , and . Compounds as claimed in any of the preceding claims, wherein R ¹³ is deuterium, _C1-6 alkyl, _C1-6 heteroalkyl, cycloalkyl, _C1-6 halogen, halogen, cyano or -C(O)N( ^RB )( ^RC ). For any of the claims 1 to 15, wherein ^R6 and ^R7 are each independently hydrogen, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, aryl, heteroaryl, halogen, cyano or -O( ^RA ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl, heterocyclic, aryl and heteroaryl is, as appropriate, substituted by one or more ^R16 . The compound of any one of claims 1 to 17, wherein ^R6 and ^R7 are each independently _C1-6 alkyl (e.g., _CH3 ). The compound of any one of claims 1 to 17, wherein one of ^R6 and ^R7 is independently a _C1-6 alkyl (e.g., _CH3 ) and the other of ^R6 and ^R7 is independently a _C1-6 alkyl or -O( ^RA ) (e.g., _OCH3 ). The compound in claim 19, wherein one of ^R6 and ^R7 is _CH3 , and the other of ^R6 and ^R7 is _OCH3 . The compound as described in any of the aforementioned claims, wherein ^R6 and ^R7 are each independently selected from... , , , , , , , , , , , , and . Compounds of any of claims 1 to 21, wherein X is C(R ¹¹ ) (e.g., CH). The compound in claim 22, wherein X is CH. The compound of any one of claims 1 to 21, where X is N. Compounds of any of claims 1 to 24, wherein Y is C(R ¹² ). The compound of claim 25, wherein R ¹² is hydrogen, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, heteroaryl, halogen, cyano or -N( ^RB )( ^RC ), wherein each alkyl, heteroalkyl, halogen, cycloalkyl and heterocyclic group is substituted by one or more R ¹⁶ as appropriate. Compounds as described in any of the preceding claims, wherein ^R12 is, where appropriate, a _C1-6 alkyl group substituted with one or more R16 ^{alkyl groups} (e.g., _CH3 , _CD3 ). Compounds as described in any of the preceding claims, wherein ^R12 is a _C1-6 halogenated alkyl group (e.g., _CHF2 , _CF3 ). Compounds as claimed in any of the preceding claims, wherein R ¹² is, where appropriate, a cycloalkyl, heterocyclic, or heteroaryl group substituted with one or more R ^{16 groups} . The compound of any one of claims 1 to 29, where Y is N. The compound of any one of claims 1 to 29, wherein Z is C(R ¹⁸ ) ₂ . Compounds as described in any of the preceding claims, wherein R ¹⁸ is hydrogen or halogen. Compounds as described in any of the aforementioned claims, wherein R ¹⁸ is F. The compound of any one of the claims 1 to 30, where Z is O. Compounds as claimed in any of the preceding claims, wherein ^R3 is hydrogen, _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 halogen, cycloalkyl, heterocyclic, aryl, heteroaryl, -O( ^RA ) or -N( ^RB )( ^RC ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, halogen, cycloalkyl, heterocyclic, aryl and heteroaryl are, as appropriate, substituted by one or more ^R15 . Compounds as described in any of the aforementioned claims, wherein ^R3 is selected from hydrogen, Cl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . Compounds as claimed in any of the preceding claims, wherein ^R4 and ^R5 are each independently hydrogen or _C1-6 alkyl. Compounds as described in any of the aforementioned requests, where n is 0 or 1. Compounds as described in any of the aforementioned requests, where n is 0. Compounds as described in any of the aforementioned requests, where n is 1. For example, in the compound of claim 1, ring A is (I-ii). The compound in claim 41, wherein ^V1 is S and ^V2 is N. The compound in claim 41, wherein ^V1 is NR ^8b and ^V2 is N. The compound of claim 41, wherein ^V1 is N and ^V2 is NR ^8b . The compound of claim 41, wherein ^W1 and ^W2 are each independently N. For example, in the compound of claim 41, ^R8 is _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 heteroalkyl, _C1-6 halogenyl, cycloalkyl, heterocyclic or -N( ^RB )( ^RC ), wherein the alkyl, alkenyl, alkynyl, heteroalkyl, halogenyl, cycloalkyl and heterocyclic are substituted by one or more ^R16 as appropriate. The compound of any one of claims 41 to 46, wherein ^R8 is -N( ^RB )( ^RC ). The compound of claim 47, wherein ^RB and ^RC are each independently _C1-6 alkyl. The compound in claim 47, wherein ^RB and ^RC are each independently _CH3 . The compound as claimed in any of the preceding claims, wherein R ^8b is a _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 heteroalkyl, _C1-6 halogenyl, cycloalkyl, or heterocyclic group, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, halogenyl, cycloalkyl, or heterocyclic group is, as appropriate, substituted with one or more R ¹⁶ groups. Compounds as described in any of the preceding claims, wherein R ^8b is a _C1-6 alkyl group. Compounds as described in any of the aforementioned claims, wherein R ^8b is CH ₃ . The compound of claim 1, wherein ring A is formed together with its fused 6-membered ring system. (I-iii). The compound of claim 53, wherein R ^8a is hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 heteroalkyl, _C1-6 halogenyl, cycloalkyl, or heterocyclic, wherein the alkyl, alkenyl, ynyl, heteroalkyl, halogenyl, cycloalkyl, and heterocyclic are, as appropriate, substituted by one or more R ¹⁶ . The compound of claim 53, wherein R ^8a is a _C1-6 alkyl group. The compound in claim 53, wherein R ^8a is CH ₃ . For example, in the compound of claim 53, each of R ^9a and R ^9b is hydrogen. The compound as described in any of the preceding claims, wherein ring A and its fused 6-membered ring system are selected from... , , and . The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Ia): (Ia) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Ib): (Ib) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of such compound, stereoisomer or tautomer, wherein each of X, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R13 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Ic): (Ic) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R2 , ^R3 , R4 ^{, R5} , ^R6 , ^R7 , ^R13 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Id): (Id) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Ie): (Ie) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (If): (If) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula ( ^I ). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Ig): (Ig) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula ( ^I ). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Ih): (Ih) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula ( ^I ). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Ij): (Ij) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula ( ^I ). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Ik): (Ik) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Il): (Il) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of X, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula ( ^I ). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Im). (Im) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (In). (In) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer thereof, wherein each of ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R13 , n and their subvariables is as defined for formula (I). A compound as described in any of the preceding claims, wherein the compound of formula (I) is a compound of formula (Io). (Io) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R13 , n and their subvariables is as defined for formula (I). Compounds as described in any of the preceding claims, wherein the compound of formula (I) is a compound of formula (Ip). (Ip) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). Compounds as described in any of the preceding claims, wherein compound (I) is a compound of formula (Iq). (Iq) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). Compounds as described in any of the preceding claims, wherein the compound of formula (I) is a compound of formula (Ir). (Ir) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R2 , ^R13 , n and their subvariants is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Is). (Is) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (It). (It) or its pharmaceutically acceptable salt, solvent, stereoisomer or tautomer, or pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined with respect to formula (I). Compounds as described in any of the preceding claims, wherein the compound of formula (I) is a compound of formula (Iu). (Iu) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Iv). (Iv) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Iw). (Iw) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of ^R1 , ^{R2 ,} R3, ^R4 , ^R5 , ^R6 , ^R7 , n and their subvariables is as defined for formula (I). Compounds as described in any of the preceding claims, wherein compound (I) is a compound of formula (Ix): (Ix), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , R2, ^R3 , ^R4 , ^R5 , ^R8b , ^W1 , ^W2 , ^W3 , ^W4 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Iy): (Iy), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , R2, ^R3 , ^R4 , ^R5 , ^R8b , ^W1 , ^W2 , ^W3 , ^W4 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (Iz): (Iz), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , R2, ^R3 , ^R4 , ^R5 , ^R8b , ^W1 , ^W2 , ^W3 , ^W4 , n and their subvariables is as defined for formula (I). Compounds as claimed in any of the preceding claims, wherein compound (I) is a compound of formula (I-aa): (I-aa), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R8b , ^{W1, W2 , W3} , ^W4 , n and their subvariables is as defined for formula (I). Compounds as described in any of the preceding claims, wherein the compound of formula (I) is a compound of formula (I-bb): (I-bb), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of such compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R8b , ^{W1, W2 , W3} , ^W4 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (I-cc): (I-cc), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R8b , ^{W1, W2 , W3} , ^W4 , n and their subvariables is as defined for formula (I). The compound of any of the aforementioned claims, wherein the compound of formula (I) is a compound of formula (I-dd): (I-dd), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R8b , ^{W1, W2 , W3} , ^W4 , n and their subvariables is as defined with respect to formula (I). Compounds as claimed in any of the preceding claims, wherein the compound of formula (I) is a compound of formula (I-ee): (I-ee), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt and/or solvent of such compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R8b , W1, ^W2 , ^W3 , ^W4 , n and their subvariables is as defined with respect to formula (I). Compounds as described in any of the preceding claims, wherein compound (I) is a compound of formula (I-ff): (I-ff), or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, or a pharmaceutically acceptable salt and/or solvent of the compound, stereoisomer or tautomer, wherein each of X, Y, Z, ^R1 , ^R2 , R3, ^R4 , ^R5 , ^R8b , ^{W1, W2 , W3} , ^W4 , n and their subvariables is as defined for formula (I). Compounds as described in any of the preceding claims, wherein the compound of formula (I) is a compound of formula (I-gg). (I-gg) or a pharmaceutically acceptable salt, solvent, stereoisomer or tautomer of the compound, stereoisomer or tautomer, wherein each of A, ^W1 , W2, ^R2 , ^R13 , n and their ^subvariables is as defined for formula (I). The compound requested is any one of items 1 to 90, wherein the compound is one of the compounds provided in Table A. A pharmaceutical composition comprising a compound as described in any of claims 1 to 91 or a pharmaceutically acceptable excipient. The compound of any one of claims 1 to 91 or the pharmaceutical composition of claim 92 is used for the treatment or prevention of symptoms associated with loss of TREM2 function in humans. A method for treating or preventing symptoms associated with loss of TREM2 function in an individual of need, the method comprising administering to the individual a therapeutically effective amount of a compound as described in any one of claims 1 to 91 or a pharmaceutical composition as described in claim 92.