RELATED APPLICATIONS

This application claims priority to U.S. provisional application no. 63/221,825, filed on July 14, 2021, the entire teachings of which are incorporated herein by reference.

FIELD

This application is directed to MAP4K1 inhibitors and methods for their use, such as to control the activity of MAP4K1 in a subject.

BACKGROUND

MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1), was originally cloned from hematopoietic progenitor cells (Hu, M.C., et al., Genes Dev, 1996. 10(18): p. 2251-64). MAP4K1 is of particular interest as a target, because it is predominantly expressed in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Hu, M.C., et al, Genes Dev, 1996. 10(18): p. 2251-64; Kiefer, F., et al, EMBO J, 1996. 15(24): p. 7013-25). MAP4K1 kinase activity has been shown to be induced upon activation of T cell receptors (TCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B cell receptors (BCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), transforming growth factor receptor (TGF- R) (Wang, W., et al, J Biol Chem, 1997. 272(36): p. 22771-5; Zhou, G., et al, J Biol Chem, 1999. 274(19): p. 13133-8), or G _s -coupled PGE2 receptors (EP2 and EP4) (Ikegami, R, et al, J Immunol, 2001. 166(7): p. 4689-96). As such, MAP4K1 regulates diverse functions of various immune cells.

MAP4K1 is important in regulating the functions of various immune cells and it has been implicated in autoimmune diseases and anti-tumor immunity (Shui, J.W., et al, Nat Immunol, 2007. 8(1): p. 84-91; Wang, X., et al, J Biol Chem, 2012. 287(14): p. 11037-48). Those observations suggested that attenuation of MAP4K1 activity may contribute to autoimmunity in patients. Furthermore, MAP4K1 may also control anti-tumor immunity via T cell-dependent mechanisms. In the PGE2-producing Lewis lung carcinoma tumor model, the tumors developed more slowly in MAP4K1 knockout mice as compared to wild-type mice (see US 2007/0087988). In addition, it was shown that adoptive transfer of MAP4K1 deficient T cells was more effective in controlling tumor growth and metastasis than wildtype T cells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p. 419-29). Similarly, bone marrow derived dendritic cells (BMDCs) from MAP4K1 knockout mice were more efficient to mount a T cell response to eradicate Lewis lung carcinoma as compared to wild-type BMDCs (Alzabin, S., et al., J Immunol, 2009.182(10): p.6187-94). Data obtained from MAP4K1 kinase dead mice demonstrated that MAP4K1 kinase activity is critical in conferring suppressive functions of MAP4K1 in a wide range of immune cells including CD4+, CD8+, DC, NK to T regulatory cells (Tregs) and inactivation of kinase domain was sufficient to elict robust anti-tumor immune responses. Liu et al., PLoS ONE 14(3):e0212670 https://doi.org/10.1371/journal.pone.0212670. Moreover, loss of MAP4K1 kinase function suppresses tumor growth in preclinical tumor models and therapeutic co-blockade of MAP4K1 kinase and PD-L1 enhances anti-tumor responses. Hernandez S. et al., Cell Reports 201825: p.80-94. Recently presented results show tumor growth inhibition in a CT-26 syngeneic mouse model using a small molecule MAP4K1 inhibitor (Seungmook, L., Cancer research.AACR Journal, 2019, Abstract 4150). These data have validated MAP4K1 as a novel drug target for enhancing antitumor immunity. Accordingly, there is a need for new compounds that modulate MAP4K1 activity for the treatment of MAP4K1-dependent diseases or disorders such as cancer, viral infection, and other diseases and disorders. Of particular importance is the need for new compounds that selectively modulate MAP4K1 activity. SUMMARY Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions which inhibit MAP4K1, thereby enhancing an immune response in a subject. For example, the IC50 values for inhibition of MAP4K1 provided in Table 3 demonstrate that these compounds are potent inhibitors of MAP4K1. Also disclosed are methods of using the compounds and compositions described herein for treating cancer and viral infection.

A first embodiment of the disclosure is a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, wherein: T is selected from and 4-5 membered heterocycle containing wherein said heterocycle is optionally substituted with 1-2 R ⁶ ; Z is absent, O or NH; Ring A is C _4-6 cycloalkyl or 4-6 membered heterocycle containing nitrogen, wherein said cycloalkyl or heterocycle is optionally substituted with 1-2 R ⁶ ; L ¹ is selected from bond and C1-C3 alkylene, wherein said alkylene is optionally substituted with 1-2 R ¹¹ ; L ² is selected from bond and C ₁ -C ₃ alkylene; B is O or NH; Q is N or CH; x is 0, 1, or 2; n is 0, 1, 2, 3, or 4; R ¹ and R ² are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, and 4 to 6-membered heterocycle, wherein said alkyl is optionally substituted with 1-2 R ³ ; each R ³ is independently selected from halogen, hydroxyl and OR ⁴ ; each R ⁴ is independently selected from C1-3 alkyl, CF3, CH2F, and CHF2; each R ⁵ is independently selected from C1-2 alkyl, CF3, CH2F, and CHF2, or two R ⁵ attached to the same carbon atom taken together with the carbon atom to which they attach form C _3-5 cycloalkyl; or two R ⁵ attached to two adjacent carbon atoms taken together with the two adjacent carbon atoms to which they attach form C4-6 cycloalkyl; each R ⁶ is independently selected from CH3, methoxy, CF3, CH2F, and CHF2; R ⁷ is selected from C _1-3 alkyl, C _3-6 cycloalkyl, OC _1-4 alkyl, NR ⁹ R ¹⁰ , and 3-5 membered heterocycle containing nitrogen or oxygen, wherein said alkyl, cycloalkyl, or heterocycle is optionally substituted with 1-3 R ⁸ ; each R ⁸ is independently selected from halogen, C1-3 alkyl, hydroxyl and OC1-3 alkyl, wherein said alkyl is optionally substituted with 1-3 R ¹² ; R ⁹ is selected from C1-2 alkyl; R ¹⁰ is selected from C1-2 alkyl; each R ¹¹ is independently selected from halogen, methoxy, C _1-2 alkyl, CH ₂ F, CHF ₂ and CF3, or two R ¹¹ taken together with the two adjacent carbon atoms to which they attach form cyclopropyl; and each R ¹² is halogen. Another embodiment of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof. Another embodiment of the disclosure is a method of inhibiting MAP4K1 in a subject in need thereof, comprising contacting MAP4K1 with an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof. Another embodiment of the disclosure is a method of treating a MAP4K1-dependent disorder or disease (e.g., treating a cancer) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s). Another embodiment of the disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s), for the preparation of a medicament for treating a MAP4K1-dependent disorder or disease (e.g., treating a cancer) in a subject in need thereof. Another embodiment of the disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(s), for use in treating a MAP4K1-dependent disorder or disease (e.g., treating a cancer) in a subject in need thereof. DETAILED DESCRIPTION The disclosed compounds or pharmaceutically acceptable salts thereof are MAP4K1 inhibitors, which can be used for treating a MAP4K1-dependent disorder or disease. Such diseases or disorders include cancer and viral infection. Compound Embodiments Example embodiments include: First embodiment: a compound represented by Formula I: I, or a pharmaceutically acceptable salt thereof. The variables in Formula I are described in the summary above.

Second embodiment: a compound represented by Formula II: or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables in Formula II are as defined in the first embodiment. Third embodiment: a compound represented by Formula III: III, or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables in Formula III are as defined in the first embodiment. Fourth embodiment: a compound is represented by Formula IV:

IV, or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables in Formula IV are as defined in the first embodiment. Fifth embodiment: a compound represented by Formula V: V, or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables in Formula V are as defined in the first embodiment. Sixth embodiment: a compound represented by Formula VI: VI, or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables in Formula VI are as defined in the first embodiment. Seventh embodiment: a compound represented by Formula VII: VII, or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables in Formula VII are as defined in the first embodiment. Eighth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein L ¹ is bond; T is ; and L ² is a bond or methylene, wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first embodiment. Ninth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from azetidinylene, cyclobutylene, cyclopentylene and pyrrolidinylene, and said azetidinylene, cyclobutylene, cyclopentylene and pyrrolidinylene is optionally substituted with 1-2 R ⁶ , wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first and/or eighth embodiments. Tenth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclobutylene optionally substituted with 1-2 R ⁶ , and the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first and/or eighth embodiments. Eleventh embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein L ¹ is C1-C3 alkylene optionally substituted with 1-2 R ¹¹ ; and T is , wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first embodiment. Twelfth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein wherein L ¹ is propylene optionally substituted with 1-2 R ¹¹ , and the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first and/or eleventh embodiments. Thirteenth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein L ¹ is selected from Formula L-1, L-2, L-3, L-4, L-5, L-6 and L-7: L-1 , L-2 , L-3 , L-4 , 5 , 6 a d 7 , wherein represents a bond to B, and ― represents a bond to T, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eleventh and/or twelfth embodiments. Fourteenth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein Z is O, and the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eleventh, twelfth and/or thirteenth embodiments. Fifteenth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein Z is NH, and the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eleventh, twelfth and/or thirteenth embodiments. Sixteenth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein Z is absent, and the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eleventh, twelfth and/or thirteenth embodiments. Seventeenth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein T is 4-5 membered heterocycle containing sulfone, and said heterocycle is optionally substituted with 1-2 R ⁶ ; and L ¹ is selected from bond, methylene and ethylene, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first embodiment. Eighteenth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein T is 4-membered heterocycle containing sulfone, wherein said heterocycle is optionally substituted with 1-2 R ⁶ , and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first and/or seventeenth embodiments. Nineteenth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently selected from hydrogen, C1-6 alkyl, and C3-6 cycloalkyl, wherein said alkyl is optionally substituted with OR ³ ; each R ³ is independently selected from halogen, hydroxyl and OR ⁴ ; and each R ⁴ is independently selected from C1-3 alkyl, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth and/or eighteenth embodiments. Twentieth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently selected from hydrogen, CH3, CH2CH3, CH2CH2CH3, CH2-OCH3 and cyclopropyl, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth and/or eighteenth embodiments. In alternative embodiments, for a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof: R ¹ and R ² are each CH ₃ ; or R ¹ is hydrogen and R ² is CH ₂ CH ₃ ; or R ¹ is CH3 and R ² is CH2CH3; or R ¹ is CH3 and R ² is CH2-OCH3; or R ¹ is hydrogen and R ² is CH2CH2CH3; or R ¹ is CH3 and R ² is CH2CH2CH3; or R ¹ is hydrogen and R ² is cyclopropyl; or R ¹ is CH ₃ and R ² is cyclopropyl, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth and/or eighteenth embodiments. Twentyfirst embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is CH ₃ , or two R ⁵ attached to the same carbon atom taken together with the carbon atom to which they attach form cyclopropyl; and n is 1, 2, 3 or 4, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth and/or twentieth embodiments. In alternative embodiments: for a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof: n is 0; or n is 1 and R ⁵ is CH ₃ ; or n is 2 and each R ⁵ is CH ₃ ; or n is 3 and each R ⁵ is CH ₃ ; or n is 3, two R ⁵ attached to the same carbon atom taken together with the carbon atom to which they attach form cyclopropyl, and one R ⁵ is CH3; or n is 4, two R ⁵ attached to the same carbon atom taken together with the carbon atom to which they attach form cyclopropyl, and two R ⁵ are CH3, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth and/or twentieth embodiments. Twentysecond embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein each R ⁶ is CH3, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, seventeenth, eighteenth, nineteenth, twentieth and/or twentyfirst embodiments. Twentythird embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from C _1-3 alkyl, CH2F, CHF2, CF3, C3-6 cycloalkyl and NR ⁹ R ¹⁰ ; R ⁹ is selected from C1-2 alkyl; and R ¹⁰ is selected from C1-2 alkyl, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, nineteenth, twentieth, twentyfirst and/or twentysecond embodiments. Twentyfourth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from CH ₃ , CF ₃ , CH2CH3, CH(CH3)2, cyclopropyl and N(CH3)2, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, nineteenth, twentieth, twentyfirst and/or twentysecond embodiments. Twentyfifth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein each R ¹¹ is independently selected from CH3, CF3 and CH2CH3, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twentyfirst, twentysecond, twentythird and/or twentyfourth embodiments. Twentysixth embodiment: a compound represented by Formulae I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof, wherein each R ¹¹ is CH3, and wherein the definitions for the other variables in Formulae I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twentyfirst, twentysecond, twentythird and/or twentyfourth embodiments. In alternative embodiments, for a compound represented by Formulae I, II or V, or a pharmaceutically acceptable salt thereof, B is NH, and wherein the definitions for the other variables in Formulae I, II and V are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteen, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twentyfirst, twentysecond, twentythird, twentyfourth, twentyfifth and/or twentysixth embodiments. The disclosure also includes the compounds depicted in Table 1 and prepared in the Exemplification, in both the neutral form and pharmaceutically acceptable salts thereof. The synthetic protocol used to prepare compounds in Table 1 is listed in the last column of Table 1 and full details for each synthetic protocol are described in Schemes 1 and 2 and in the General Synthetic Methods and Intermediates section. Table 1

5

526 526

25 26

34 35

36 37

40 41 554 554

556 556

554

554

568

568

568

Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein (including compounds 1-192 disclosed in Table 1 and the Exemplification) as well as the corresponding charge neutral form e.g., free base. Another embodiment of the disclosure is a compound disclosed herein, including a compound of Formulae I, II, III, IV, V, VI or VII, or a compound in Table 1 or in the Exemplification, or a pharmaceutically acceptable salt of any of the foregoing, in which one or more hydrogen atoms is replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of compounds with deuterium enrichment at the site of enrichment with the number of compounds having hydrogen or deuterium at the site of enrichment. Definitions As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of the present teachings with basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy”, “hydroxyalkyl” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms (C1-6 alkyl), (i.e., 1, 2, 3, 4, 5 or 6) alternatively, 1 to 3 carbon atoms (C1-3 alkyl) (i.e., 1, 2 or 3). “C ₁ – ₆ alkyl” is means a radical having 1 to 6 carbon atoms in a linear or branched arrangement, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like. The term “alkylene” means a bivalent alkyl group, for example C1-C6 alkyl is a group ‒(CH ₂ )n‒ where n is 1 to 6, C ₁ -C ₃ alkyl is a group ‒(CH ₂ )n‒ where n is 1 to 3, unless otherwise specified. “Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl has 3 to 8 ring carbon atoms (C ₃ - ₈ cycloalkyl) (i.e., 3, 4, 5, 6, 7, or 8), alternatively, 3 to 6 ring carbon atoms (C3-6 cycloalkyl) (i.e., 3, 4, 5, or 6), alternatively, 3 to 5 carbon atoms (C3-5 cycloalkyl) (i.e., 3, 4, or 5). “C3-6 Cycloalkyl” means a radical having from 3 to 6 carbon atoms arranged in a monocyclic ring. A C ₃ - ₆ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A C3-5 cycloalkyl includes cyclopropyl, cyclobutyl, and cyclopentyl. The term “halogen” or “halo” means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I). The term “heterocycle” refers to a monocyclic non-aromatic ring radical containing unless otherwise specified, 3 to 8 ring atoms (i.e., “3, 4, 5, 6, 7, or 8 membered”) selected from carbon atom and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO); oxygen; and sulfur, including sulfoxide and sulfone. For example, 4-6 membered heterocycle containing nitrogen refers to a monocyclic non-aromatic ring radical containing 2-5 carbon atoms and 1 or 2 nitrogen atoms; 4-6 membered heterocycle containing oxygen atoms refers to a monocyclic non-aromatic ring radical containing 2-5 carbon atoms and 1 or 2 oxygen. Representative heterocycles include azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. The term “hydroxyl” or “hydroxy” refers to the group OH. The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated). If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. If a group is described as optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl optionally substituted with up to 3 non- hydrogen substituents, then any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the cycloalkyl has substitutable positions. The term “sulfone” refers to the group –S(O) ₂ –. Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other. When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “ ” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (except when the designation “rac” or “racemate accompanies the structure or name, as explained in the following two paragraphs). “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture. When the stereochemical configuration at a chiral center in a compound is depicted by chemical name (e.g., where the configuration is indicated in the name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds) and the designation “rac” or “racemate” accompanies the structure or is designated in the chemical name, a racemic mixture is intended. When two or more stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two or more stereoisomers is intended, but not both. The enrichment of one stereoisomer relative to the other is as indicated above. When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center. A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods. “Peak 1” or “first eluting isomer” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation/purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2” or “second eluting isomer”. When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers. When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers. Use Embodiments Compounds of the disclosure are MAP4K1 inhibitors. The use of the word “inhibitor” means that a compound or a pharmaceutically acceptable salt thereof inhibits activity of MAP4K1. By “inhibit” herein is meant to decrease the activity of the target enzyme as compared to the activity of that enzyme in the absence of the inhibitor. In some alternatives, the term “inhibit” means a decrease in MAP4K1 activity of at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, at least 80%, at least 90% or at least 95%. In other alternatives, inhibit means a decrease in MAP4K1 activity of 5% to 25%, 25% to 50%, 50 to 70%, 75 to 100%. In some embodiments, inhibit means a decrease in MAP4K1 activity about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of techniques that would be recognizable by one of skill in the art, including in vitro kinase assays. Compounds of the disclosure are selective MAP4K1 inhibitors. As used herein, a “selective MAP4K1 inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof, which has the ability to selectively inhibit MAP4K1 kinase over other targets. More specifically, a selective MAP4K1 inhibitor has the ability to selectively inhibit MAP4K1 over another kinases. A selective MAP4K1 inhibitor has the ability to selectively reduce target signaling activity relative to off-target signaling activity, via direct or indirect interaction with the target. The ability to selectively target MAP4K1 with a compound or pharmaceutically acceptable salt therof provides advantages in terms of improved potency on the desired target, less off-target activity and an increased probability of clinical success in comparison with a non-selective compound or salt. A MAP4K1 inhibitor that selectively inhibits MAP4K1 may have an activity that is at least 2-fold relative to another kinase (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200-fold. In some alternatives, a selective MAP4K1 inhibitor exhibits at least 15-fold selectivity over another kinase, e.g., LCK and MAP4K family members (MAP4K4 (HGK) and MAP4K3 (GLK)). In some alternatives, the selective MAP4K1 inhibitors are selective over EGFR and L858R/T790M EGFR. In some alternatives, the selective MAP4K1 inhibitors of the disclosure are selective over BTK. In some alternatives, the selective MAP4K1 inhibitors of the disclosure are selective over JNK. The disclosure provides methods of modulating (e.g., inhibiting) MAP4K1 activity in a subject in need thereof, said method comprising administering to the subject a compound provided herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to enhance, stimulate and/or increase immunity in subjects in need thereof, e.g., in cancer patients or patients with viral infection. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof reduce, inhibit, or otherwise diminish phsophorylation of SLP76. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to enhance at least one of activation, priming, migration, proliferation, survival and cytolytic activity of T cells relative to prior to administration. In certain aspects, T cell activation is characterized by enhanced levels of IL- 2, IFN-gamma, or granzyme B production by T cells relative to prior to administration of the compound or pharmaceutically acceptable salt thereof. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for therapeutic administration to induce a change in cell cycle or cell viability. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for improving function of T effector cells. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for inhibiting the suppressive effects of T regulatory cells or improving the T cell response to immune suppressive factors including adenosine and PGE2. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for increasing the frequency of CD8+ tumor infiltrating lymphocytes (TILS). In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for enhancing CD3+/Treg ratios. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for enhancing cytokines. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for enhanacing cytokines with no impact on IL-6. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, indirectly inhibit the growth of cancer cells. In some instances, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are useful for priming of the immune response (i.e., vaccines) to tumors or viruses for booting or generating anti-viral/anti-tumor immunity. In one instance, the compounds of the disclosure, or pharmaceutically acceptable salts thereof, are used for enhancing or boosting response to a vaccine (such as a cancer vaccine or a personalized cancer vaccine (PCV)) or a CAR-T cell therapy. Methods of treating a MAP4K1-dependent disease or disorder can include administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. For example, the MAP4K1- dependent disease or disorder is a cancer. The term “cancer” encompasses all forms of cancer including, but not limited to, all forms of carcinomas, melanomas, blastomas, sarcomas, lymphomas, and leukemias. In some embodiments, cancer includes metastatic forms. Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure or pharmaceutically acceptable salts thereof. For the uses described herein, any of the compounds of the disclosure, or pharmaceutically acceptable salts thereof, may be used alone or in combination with other therapeutic agents. In some embodiments, the treatment results in a sustained response in the subject after cessation of the treatment. “Sustained response” refers to the sustained effect on reducing tumor growth after cessation of a treatment. For example, the tumor size may remain the same or smaller as compared to the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least the same as the treatment duration, at least 1.5X, 2.0X, 2.5X, or 3.0X length of the treatment duration. The treatment methods disclosed herein may result in a partial or complete response. As used herein,“complete response” or“CR” refers to disappearance of all target lesions; “partial response” or“PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD; and“stable disease” or“SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started. As used herein, “overall response rate” (ORR) refers to the sum of complete response (CR) rate and partial response (PR) rate. The treatment methods disclosed herein can lead to an increase in progression free survival and overall survival of the subject administered the selective MAP4K1 inhibitor. As used herein, “progression free survival” (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time subjects have experienced a complete response or a partial response, as well as the amount of time subjects have experienced stable disease. As used herein,“overall survival” (OS) refers to the percentage of subjects in a group who are likely to be alive after a particular duration of time. In some embodiments, cancers treatable with compounds of the disclosure or pharmaceutically acceptable salts thereof, include colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, bladder cancer, stomach cancer, liver cancer, gastric cancer, cancer of the head and neck, lymphoma, leukemia, urothelial carcinoma, merkel cell carcinoma, gastroesophageal junction carcinoma, esophageal squamous cell carcinoma, skin squamous cell carcinoma and melanoma. In some embodiments, the cancer is gastroesophageal cancer (GEC). In some embodiments, cancers treatable with compounds of the disclosure or pharmaceutically acceptable salts thereof include colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, bladder cancer, stomach cancer, liver cancer, cancer of the head and neck, lymphoma, leukemia, and melanoma. In some embodiments, cancers that are treatable using the compounds of the disclosure or pharmaceutically acceptable salts thereof include, but are not limited to, solid tumors, including prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, brain cancer, and bladder cancer and hematological cancer, including lymphoma, leukemia (chronic and acute forms) such as acute lymphotic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphotic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin’s lymphoma (NHL), including relapsed or refractory NHL and recurrent follicular, Hodgkin’s lymphoma and multiple myeloma, and myeloproliferative diseases. In some embodiments, diseases and disorders that are treatable using the compounds of the disclosure or pharmaceutically acceptable salts thereof include, but are not limited to hematological cancer, sarcomas, respiratory cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer. Exemplary hematological cancer includes, for example, lymphomas and leukemias such as ALL, AML, acute promyelocyte leukemia (APL), CLL, CML, DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (NHL), including Primary mediastinal B-cell lymphoma (PMBCL), relapsed or refractory NHL, recurrent follicular, and primary CNS lymphoma, Hodgkin’s lymphoma, myeloproliferative diseases, including, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma, and Burkitt's lymphoma. Exemplary sarcoma includes, for example, chondrosarcoma, Ewing's sarcoma, Kaposi’s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, sarcoma of the soft tissue, and teratoma. Exemplary respiratory tract cancer includes, for example, lung cancer such as non- small cell lung cancer (NSCLC), small cell lung cancer, epidermoid cancer, bronchogenic carcinoma, including squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, and pleuropulmonary blastoma. Exemplary gastrointestinal cancer includes, for example, cancers of the esophagus, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; stomach, including carcinoma, lymphoma, and leiomyosarcoma; pancreas, including ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; small instestine, including adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; large intestine, including adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma; colon; and gall bladder, including adenocarcinoma; and intestinal type and diffuse type gastric adenocarcinoma, rectum carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer (CRC). Exemplary genitourinary tract cancer includes, for example, cancers of the kidney, including adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma, urothelial carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellinio duct carcinoma, clear-cell sarcoma of the kidney, and mesoblastic nephroma; adrenal gland; renal pelvis; bladder, including transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma; urethra, including squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; prostate, including adenocarcinoma, sarcoma, and carcinoma; testis, including seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma; penis; and pancreas. Exemplary liver cancer includes, for example, hepatoma, including hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, biliary tract cancer, and hemangioma. Exemplary bone cancer includes, for example, osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, including reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, including osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors Exemplary nervous system cancer includes, for example, cancer of the skull, including osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; meninges including, meningioma, meningiosarcoma, and gliomatosis; brain, including astrocytoma, meduoblastoma, glioma, ependymoma, germinoma (pinealoma), neuroectodermal tumor, glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, brain stem and hypopthamic glioma; and spinal cord, including neurofibroma, meningioma, glioma, and sarcoma; as well as neuroblastoma and Lhermitte- Duclos disease. Exemplary gynecological cancer includes, for example, cancer of the uterus, including endometrial carcinoma; cervix, including cervical carcinoma, pre-tumor cervical dysplasia, squamouse cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, glassy cell carcinoma and villoglandular adenocarcinoma; ovaries, including ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, endometroid tumor, high-grade serous carcinoma(HGSC) or high-grade serous ovarian cancer (HGSOC)), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma, and arrhenoblastoma; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; vagina, including clear cell carcinoma, squamous cell carcinoma, and botryoid sarcoma (embryonal rhabdomyosarcoma); labia; and fallopian tubes. Exemplary skin cancer includes, for example, melanoma, sebaceous gland carcinoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. Examples of breast cancer include, for example, ER+/HER2- breast cancer, triple- negative breast cancer (TNBC), invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Exemplary head and neck cancer includes, for example, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, throat cancer, including oropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancer, salivary gland cancer, mouth cancer, eye cancer, acoustic neuroma, pituitary adenoma, hypopharngx, and thyroid (medullary and papillary) and parathyroid cancer. Other cancers include, for example, sweat gland cancer, spinal axis tumor, chest cancer, sickle cell anemia, and environmentally induced cancers including those induced by asbestos. In some embodiments, compounds of the disclosure or pharmaceutically acceptable salts thereof are for the treatment of advanced melanoma, advanced NSCLC, or head and neck squamous cell cancer, including advanced head and neck squamous cell cancer, including where the subject was refractory to, or had a partial response to, immune checkpoint inhibitor therapy. In some instances, the MAP4K1-dependent disease or disorder is a viral infection, such as infection caused by hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, and human immunodeficiency virus (HIV). Combination Therapies Compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered as the sole pharmaceutical agent or in combination with one or more other anti- cancer agents for the treatment of cancer, where the combination causes no unacceptable adverse effects. In some embodiments, the other anti-cancer agents are immune-oncology agent, anticancer agents that are enzyme/protein/receptor inhibitors, radiation or chemotherapy. Compounds of the disclosure or pharmaceutically acceptable salts thereof can be co- formulated with an immuno-oncology agent. Immuno-oncology agents include, for example, a small molecule drug, antibody, antibody drug conjugate, or other biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In another aspect, the antibody is a bispecific antibody. In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators, in some instances immune checkpoint inhibitors). Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co- inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2,TNFRl, Lymphotoxin α/ΤΝΡβ, TNFR2, TNF a, LT R, Lymphotoxin a 1β2, FAS, FASL, RELT, DR6, TROY, NGFR. In one aspect, T cell responses can be stimulated by a combination of a compound of the disclosure or a pharmaceutically acceptable salt thereof and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H. In one aspect, compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered in combination with at least one other immune checkpoint inhibitor. In other aspects, compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered for the treatment of immune checkpoint inhibitor-resistant NSCLC, including where the subject is refractory to, or had a partial response to, platinium and/or paclitaxel and/or docetaxel therapy. Optionally, compounds of the diclosure or pharmaceutically acceptable salts thereof can be administered in combination with at least one other anti-cancer agent, such as paclitaxel, docetaxel or platinum anticancer therapy. In some aspects, compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered post-platinium therapy as second or third line treatment. Compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered for the treatment of first line NSCLC expressing high PD-L1 (≥50% Tumor Proportion Score (TPS)), wild- type EGFR, or wild-type ALK. Other agents that can be combined with compounds of the disclosure or pharmaceutically acceptable salts thereof for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of the disclosure or pharmaceutically acceptable salts thereof can be combined with antagonists of KIR, such as lirilumab. Yet other agents for combination therapies with the MAP4K1 inhibitors disclosed herein include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 or FPA-008. In another aspect, compounds of the disclosure or pharmaceutically acceptable salts thereof can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-Ll/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti- CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites. In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP- 514; WO2012/145493). The immuno-oncology agent may also include pidilizumab (CT- 011), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224. In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, atezolizumab, (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174). In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO09/44273). In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (W012/32433). In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WOl 1/028683). In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indoximod, or NLG-919 (WO09/73620, WO09/1156652, WOl1/56652, W012/142237). In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879). In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab. In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab. In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WOl 1/109400). The compounds of the disclosure or pharmaceutically acceptable salts thereof can be used in combination with anticancer agents that are enzyme/protein/receptor inhibitors, exhibiting different preferences in the targets which they modulate the activities of, to treat such conditions. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment. The compounds of the disclosure or pharmaceutically acceptable salts thereof can be used in combination with one or more other enzyme/protein/receptor inhibitors for the treatment of cancer. For example, the compounds of the disclosure or pharmaceutically acceptable salts thereof can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Aktl, Akt2, Akt3, TGF-βΡν, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFotR, PDGFpR, CSFIR, KIT, FLK-II, KDR/FLK-1, KRAS, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In some embodiments, the compounds of the disclosure or pharmaceutically acceptable salts thereof can be combined with one or more of the following inhibitors for the treatment of cancer. Non-limiting examples of inhibitors that can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof for treatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., fisogatinib, AZD4547, BAY 1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS- 120, J J-42756493, Debiol347, INCB54828, INCB62079, and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib (INCB39110)), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g., GSK2979552, INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selective inhibitor (e.g., eganelisib) or a dual PI3K-delta/gamma selective inhibitor (e.g, duvelisib), a CSF1R inhibitor (e.g., PLX3397 and LY3022855), a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesis inhibitor (e.g, bevacizumab), an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors e.g., OTX015, CPI-0610, INCB54329, and INCB57643), and an adenosine receptor antagonist or combinations thereof. Inhibitors of HDAC e.g., panobinostat and vorinostat can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of c-Met e.g., onartumzumab, tivantnib, and capmatinib (INC-280) be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of BTK such as ibrutinib can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of mTOR e.g., rapamycin, sirolimus, temsirolimus, and everolimus can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of Raf, e.g., vemurafenib and dabrafenib can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of MEK e.g., trametinib, selumetinib and GDC-0973 can be combined with the compounds of the disclosure or pharmaceutically acceptable salts thereof. Inhibitors of KIT e.g., avapritinib, BLU-263, imatinib, sunitinib, regorafenib, ripritinib (DCC2618), PLX9486, PLX3397, crenolanib, CDX-0158, and CDX-0159. Inhibitors of RET e.g., pralsetinib, selperctinib, alectinib, levatinib, cabozantinib, BOS172738 (DS-5010), SL-1001, TPX-0046, sitravatinib (MGCD516), and RXDX-105. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), Pim kinases (e.g., LGH447, INCB053914, and SGI-1776), and KRAS (e.g. sotorasib) can also be combined with compounds of the disclosure or pharmaceutically acceptable salts thereof. Compounds of the disclosure or pharmaceutically acceptable salts thereof can be used in combination with one or more agents for the treatment of cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include bendamustine, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cyclophosphamide , ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone. The compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carmustine, cediranib, cetuximab, chlorambucil, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, cisplatin, carboplatin, oxaliplatin, ponatinib, prednisone, procarbazine, quinacrine, rasburicase, regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate. Other anti-cancer agent(s) include antibody therapeutics e.g., trastuzumab. Compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered as the sole pharmaceutical agent or in combination with one or more anti-viral agents for the treatment of chronic viral infections, where the combination causes no unacceptable adverse effects. Chronic viral infections include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). Parasitic infections (e.g. , malaria) may also be treated by the above methods wherein compounds known to treat the parasitic conditions are optionally added in place of the antiviral agents. Suitable antiviral agents contemplated for use in combination with the compound of the disclosure or a pharmaceutically acceptable salt thereof can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs. Examples of suitable NRTIs include e.g., zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emitricitabine [(-)- FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2',3'-dicleoxy-5-fluoro- cytidene); DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721 ; AG-1549; MKC-442 (l-(ethoxy-methyl)-5-(l- methylethyl)-6-(phenylmethyl)-(2,4(lH,3H)-pyrirnidinedione); and (+)-calanolide A (NSC- 675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607. When more than one pharmaceutical agent is administered to a subject, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents). For examples, when administered together with an additional anti-cancer or antiviral agent, the disclosed compounds or pharmaceutically acceptable salts thereof can be administered simultaneously in the same pharmaceutical formulation or simultaneously in separate pharmaceutical formulations. Alternatively, when administered together with an additional anti-cancer or antiviral agent, the disclosed compounds or pharmaceutically acceptable salts thereof can be administered at separate times, depending the dosing requirements of the additional anti-cancer or antiviral agent. Pharmaceutical compositions are disclosed that include one or more compounds provided herein (such as the compound of Formulas I, II, III, IV, V, VI or VII), and typically at least one additional substance, such as an excipient, a known therapeutic other than those of the disclosure, and combinations thereof. In some embodiments, the disclosed compounds or pharmaceutically acceptable salts thereof can be used in combination with other agents known to have beneficial activity targeting diseases or disorders listed above. For example, disclosed compounds or pharmaceutically acceptable salts thereof can be administered alone or in combination with one or more anti-cancer or antiviral agent. The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. A “subject” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., when administered in combination with an anti-cancer or antiviral agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003). The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day; and in another alternatively from 10 mg to 1 gram per day). The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years. The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In preferred embodiments, the pharmaceutical composition is formulated for intravenous administration. “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds. General Synthetic Methods and Intermediates The synthetic protocol used to prepare the compounds in Table 1 is listed in the last column of Table 1 and full details for each synthetic protocol are described in Schemes 1 and 2 (below) in the General Synthetic Methods and Intermediates section. Scheme 1 shows a synthetic protocol for the preparation of compounds of formula iv The azide-substituted chloro heterocyclic intermediates i can be coupled to the substituted anilines ii under Pd-catalyzed coupling conditions to give iii. The azide intermediate iii can be reduced under catalytic hydrogenation conditions with a catalyst such as Pd/C or PtO2 to give the amine compounds iv which are examples of MAP4K1 inhibitors described herein. Scheme 2 Scheme 2 shows a synthetic protocol for the preparation of compounds of formula iv The sulfinamide-substituted chloro heterocyclic intermediates i can be coupled to the substituted anilines ii under Pd-catalyzed coupling conditions to give iii. The sulfinamide group of intermediate iii can converted to an amine under acidic conditions such as HCl to give amine compounds iv which are examples of MAP4K1 inhibitors described herein. The following examples are intended to be illustrative and are not meant in any way to be limiting. EXEMPLIFICATION Abbreviations ACN acetonitrile (“MeCN”) AcOH acetic acid ATP adenosine triphosphate BrettPhos Dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphe nyl]-2- yl)phosphine t-BuOK potassium tert-butoxide C Celsius DBU diazabicyclo[5.4.0]undec-7-ene DCE dichloroethane DCM dichloromethane DIAD disopropyl azodicarboxylate DIBAL diisobutylaluminium hydride DIPEA diisopropylethylamine DMBNH2 2,4-dimethoxybenzylamine DMF dimethyl formamide DMSO dimethyl sulfoxide DTT dithiothreitol eq equivalents EA ethyl acetate EDTA ethylenediaminetetracetic acid Et2O diethyl ether EtSH ethanethiol FA formic acid h hours HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC high performance liquid chromatography IBX 2-iodoxybenzoic acid IC50 inhibitory concentration 50% IPA isopropanol KF potassium fluoride KOAc potassium acetate LiHMDS lithium bis(trimethylsilyl)amide MeMgBr methyl magnesium bromide min minutes MTBE methyl tert-butyl ether MeOH methanol MsCl methanesulfonyl chloride NBS N-bromosuccinimide NMO N-methylmorpholine N-oxide NMP N-methyl-2-pyrrolidone Oxone potassium peroxymonosulfate PE petroleum ether PrMgBr isopropyl magnesium bromide SFC supercritical fluid chromatography TEA trimethylamine THF tetrahydrofuran TFA trifluoroacetic acid TfOH trifluoromethanesulfonic acid TMEDA tetramethylethylenediamine TMSN3 azidotrimethylsilane Methods for preparing compounds of the disclosure can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of compounds of the disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety. Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., ¹ H or ¹³ C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Analytical instruments and methods for compound characterization: LC-MS: Unless otherwise indicated, all liquid chromatography-mass spectrometry (LC-MS) data (sample analyzed for purity and identity) were obtained with an Agilent model-1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES-API ionization fitted with an Agilent Poroshel 120 (EC-C18, 2.7 um particle size, 3.0 x 50mm dimensions) reverse-phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.1% FA in water and 0.1% FA in acetonitrile. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 4 minutes was utilized. The flow rate was constant at 1mL/min. Prep LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP® Preparative system fitted with a Luna 5u C18(2) 100A, AXIA packed, 250 x 21.2 mm reverse-phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.1% FA in water and 0.1% FA in ACN. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 25 minutes was utilized. The flow rate was constant at 20 mL/min. Reactions carried out in a microwave were done so in a Biotage Initiator microwave unit. Silica gel chromatography: Silica gel chromatography was performed on either a Teledyne Isco CombiFlash® Rf unit or a Biotage® Isolera Four unit. Proton NMR: Unless otherwise indicated, all ¹ H NMR spectra were obtained with a Varian 400MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds with a 1 second delay; 16 to 64 scans). Where characterized, all protons were reported in DMSO- d6 solvent as parts-per million (ppm) with respect to residual DMSO (2.50 ppm). One of ordinary skill in the art will recognize that modifications of the gradient, column length, and flow rate are possible and that some conditions may be more suitable for compound characterization than others, depending on the chemical species being analyzed.

Synthesis of Intermediates Intermediates 1 and 2: (7S,8R)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one (Intermediate 1) and (7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H- each of which is represented by the structures shown below: (Precursor I of Intermediate 1) each of which is represented by the structures shown below: each of which is represented by the structures shown below: Step 1: Methyl (E)-2-(but-2-en-2-yl)-6-methoxynicotinate K3PO4 (120 g, 565 mmol, 3.00 eq) and Pd(dppf)Cl2-CH2Cl2 (7.70 g, 9.42 mmol, 0.05 eq) were added to a solution of methyl 2-chloro-6-methoxynicotinate (38.0 g, 188 mmol, 1.00 eq) and (Z)-2-(but-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan e (44.6 g, 245 mmol, 1.30 eq) in THF (320 mL) and H2O (80.0 mL). The reaction mixture was stirred under N2 at 70 °C for 2 h. The reaction mixture was diluted with water (300 mL) and extracted with EA (250 mL x 3). The organic layers were combined and dried over sodium sulfate, then filtered and concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (ACN-H2O gradient with 0.1% TFA additive). The product-containing fractions were adjusted to pH = 8–9 with solid sodium carbonate and the mixture was extracted with EA (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to give the title compound (37.0 g, 167 mmol, 88.7% yield) as a yellow oil. Step 2: 2-Methoxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5 -one A solution of methyl (E)-2-(but-2-en-2-yl)-6-methoxynicotinate (37.0 g, 167 mmol, 1.00 eq) in TfOH (171 g, 1.15 mol, 101 mL, 6.85 eq) was stirred at 80 °C for 0.5 h. The mixture was then cooled to ambient temperature, poured into saturated aqueous NaHCO3 solution (1000 mL) and extracted with EA (300 mL x 5). The organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash-column chromatography on silica gel (gradient elution, 1% to 25% EA-PE) to give the title compound (30.0 g, 144 mmol, 86.6% yield) as a yellow oil. Steps 3: 2-Hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5 -one A mixture of 2-methoxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5 -one (30.0 g, 144 mmol, 1.00 eq) and pyridine-hydrochloride (41.8 g, 361 mmol, 2.50 eq) was stirred at 150 °C for 0.5 h. The reaction mixture was purified directly by flash-column chromatography on silica gel (gradient elution, 2% to 10% MeOH-DCM) to give the title compound (26.0 g, 134 mmol, 92.9% yield) as a yellow solid. Step 4: rac-(7S,8S)-2-Hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3 -b]pyridin-5- one and rac-(7S,8R)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3 -b]pyridin-5-one DBU (60.8 mL, 403 mmol, 3.00 eq) was added to a solution of 2-hydroxy-7,8- dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (26.0 g, 134 mmol, 1.00 eq) in toluene (290 mL). The reaction mixture was stirred at 100 °C for 12 h, then was cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash-column chromatography on silica gel (gradient elution, 1% to 10% MeOH-DCM) to afford the title compounds as a mixture of isomers that were used in the next step without further purification. Step 5: rac-(7S,8S)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5- one and rac-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one A mixture of rac-(7S,8S)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3 - b]pyridin-5-one and rac-(7S,8R)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3 - b]pyridin-5-one (26.0 g, 134 mmol, 1 equiv) in POCl3 (150 mL, 1.61 mol, 11.9 equiv) was stirred at 100 °C for 1 h. The reaction mixture was then cooled to ambient temperature and poured into saturated aqueous NaHCO ₃ solution (2 L) at 0-10 °C. The quenched mixture was extracted with EA (300 mL x 3) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The cis-and trans- racemic isomers were separated by prep-HPLC (column: Phenomenex Luna C18250*50mm*10 um; mobile phase: [water(0.1%TFA)-ACN];B%: 35% ACN-55% CAN over 20min). rac-(7S,8S)-2- Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-on e was the first compound to elute and was obtained as a white solid. MS (ES+) C ₁₀ H ₁₀ ClNO ₂ requires: 211, found: 212[M+H] ⁺ . ¹ H NMR: 400 MHz, CDCl3 δ 8.29 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 4.83 (dq, J = 3.2, 6.6 Hz, 1H), 3.09 (dq, J = 3.2, 7.2 Hz, 1H), 1.49 (d, J = 6.5 Hz, 3H), 1.30 (d, J = 7.2 Hz, 3H). rac-(7S,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one was the second compound to elute and was obtained as a white solid. MS (ES+) C10H10ClNO2 requires: 211, found: 212[M+H] ⁺ . ¹ H NMR: 400 MHz, CDCl3 δ 8.28 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 4.58 - 4.43 (m, 1H), 3.05 (quin, J = 7.2 Hz, 1H), 1.56 - 1.40 (m, 6H). Step 6: (7S,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]py ridin-5-one and (7R,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]py ridin-5-one rac-(7S,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one was separated by SFC (column: DAICEL CHIRALPAK AD (250mm x 50mm,10um); mobile phase: MeOH in CO2) to give the first eluting isomer (peak 1) as a white solid and second eluting isomer (peak 2) as a white solid. Step 7: (7S,8R)-2-((2,4-Dimethoxybenzyl)amino)-7,8-dimethyl-7,8-dihy dro-5H- pyrano[4,3-b]pyridin-5-one DIPEA (7.48 g, 57.8 mmol, 10.1 mL, 2.50 eq) and DMBNH2 (5.03 g, 30.1 mmol, 4.53 mL, 1.30 eq) were added to a solution of (7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro- 5H-pyrano[4,3-b]pyridin-5-one (1 ^st eluting isomer (peak 1) from Step 6 above) (4.90 g, 23.1 mmol, 1.00 eq) in NMP (50.0 mL). The reaction mixture was stirred at 100 °C for 1 h, then was poured into water (500 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (7.93 g, crude) as a yellow oil that was used directly in the next step. MS (ES+) C ₁₉ H ₁₁ N ₂ O ₄ requires: 342, found: 343[M+H] ⁺ . Step 8: (7S,8R)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyr idin-5-one A solution of (7S,8R)-2-((2,4-Dimethoxybenzyl)amino)-7,8-dimethyl-7,8-dihy dro- 5H-pyrano[4,3-b]pyridin-5-one (7.93 g, 23.1 mmol, 1.00 eq) in HCl/dioxane (4.00 M, 50.0 mL, 8.64 eq) was stirred at 70 °C for 1 h. The reaction mixture was then concentrated and partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and was extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated. The residue was triturated in MTBE (50 mL) for 10 mins and filtered to get a yellow solid. The yellow solid was dried under vacuum to give the title compound, Intermediate 1(3.23 g, 16.4 mmol, 71.2% yield, 98.1% purity). MS (ES+) C ₁₀ H ₁₂ N ₂ O ₂ requires: 192, found: 193[M+H] ⁺ . ¹ H NMR: 400 MHz, DMSO-d6 δ 7.77 (d, J = 8.6 Hz, 1H), 6.97 (s, 2H), 6.40 (d, J = 8.6 Hz, 1H), 4.43 - 4.21 (m, 1H), 2.88 - 2.65 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H). The absolute stereochemistry of the title compound was determined by X-ray crystal structure of a final compound prepared from this intermediate. Steps 9 and 10: (7R,8S)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one The title compound (Intermediate 2) was prepared separately from (7R,8S)-2-chloro- 7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (the second eluting isomer (peak 2) of Step 6) using the same two-step procedure as described in Steps 7 and 8 for Intermediate 2. MS (ES+) C ₁₀ H ₁₂ N ₂ O ₂ requires: 192, found: 193[M+H] ⁺ . ¹ H NMR: 400 MHz, DMSO-d ₆ δ 7.77 (d, J = 8.6 Hz, 1H), 6.97 (s, 2H), 6.40 (d, J = 8.6 Hz, 1H), 4.43 - 4.21 (m, 1H), 2.88 - 2.65 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H). Intermediates 3 and 4: (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one and (S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyri din-5-one each of which is represented by the structure shown below: each of which is represented by the structure shown below: Steps 1-5: rac 2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5 H- pyrano[4,3-b]pyridin-5-one The title compound was prepared from methyl 2-chloro-6-methoxynicotinate and 4,4,5,5-tetramethyl-2-(3-methylbut-2-en-2-yl)-1,3,2-dioxabor olane using similar procedures as described above in Steps 1-3, 5, and 7 for Intermediate 1. Step 6: (R)-2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihyd ro-5H- pyrano[4,3-b]pyridin-5-one and (S)-2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8- dihydro-5H-pyrano[4,3-b]pyridin-5-one Rac 2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5 H-pyrano[4,3- b]pyridin-5-one was separated by SFC (column: DAICEL CHIRALPAK AS-H (250mm*30mm,5um); mobile phase: [0.1% NH ₄ OH MeOH in CO ₂ ]) to give (R)-2-((2,4- dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano [4,3-b]pyridin-5-one (1 ^st eluting isomer (Precursor to Intermediate 3), 0.55 g, 79% yield) and (S)-2-((2,4- dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano [4,3-b]pyridin-5-one (2 ^nd eluting isomer (Precursor to Intermediate 4), 0.55 g, 79% yield). Each intermediate was isolated as a yellow oil. Step 7 and 8: (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyri din-5- one and (S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyri din-5-one The title compounds (Intermediates 3 and 4) were prepared separately from the 1 ^st and 2 ^nd eluting isomers, i.e., (R)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihyd ro- 5H-pyrano[4,3-b]pyridin-5-one and (S)-2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl- 7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one, using the same procedure as described in Step 8 of Intermediate 1. Intermediate 3, (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one, was obtained as a yellow solid. MS (ES+) C11H14N2O2 requires: 206, found: 207[M+H] ⁺ . ¹ H-NMR (400 MHz, CD3OD): δ ppm 7.89 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 2.85-2.80 (m, 1H), 1.41 (s, 6H), 1.27 (d, J = 7.2 Hz, 3H). Intermediate 4, (S)-2- Amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5- one, was obtained as a yellow solid. MS (ES+) C11H14N2O2 requires: 206, found: 207[M+H] ⁺ . ¹ H-NMR (400 MHz, CD ₃ OD): δ ppm 7.89 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 2.85-2.80 (m, 1H), 1.41 (s, 6H), 1.27 (d, J = 7.2 Hz, 3H). The absolute stereochemistry of the title compound was determined by X-ray crystal structure of a final compound prepared from this intermediate. Intermediate 5: 2-Amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-o ne Step 1: 7,7-Dimethyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-on e A mixture of 2,2-dimethyltetrahydro-4H-pyran-4-one (500 g, 3.90 mol, 1.00 eq) and pyrrolidine (391 mL, 4.68 mol, 1.20 eq) in toluene (4.00 L) was heated at 145 °C with a Dean-Stark trap for 2 h. The water layer (~16 mL) was removed from the Dean-Stark trap and the reaction mixture was cooled to 15 °C. After cooling, prop-2-ynamide (539 g, 7.80 mol, 2.00 eq) was added and the reaction mixture was heated to 150 °C. The reaction mixture was heated at 150 °C for 10 h, then was cooled to ambient temperature. The cooled reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash-column chromatography on silica gel (10% methanol-dichloromethane) to give the title compound (560 g, 62% yield) as a yellow solid. Step 2: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine A solution of 7,7-dimethyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-on e (500 g, 2.23 mol, 1 eq) in POCl ₃ (350 mL, 3.77 mol, 9.64 eq) was heated to 100 °C for 6 h. The reaction mixture then cooled to ambient temperature and concentrated under vacuum. The residue was poured over ice-water (1.00 L). The mixture was extracted with EA (750 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (363 g, 82.2% yield) as a brown oil. Step 3: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5- one A solution of NaIO4 (487 g, 2.28 mol, 3.00 eq) in water (1.20 L) as added to a mixture of 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (150 g, 759 mmol, 1.00 eq) in MeCN (50.0 mL) and CCl4 (2.70 L). The mixture was cooled to 0 °C, and then RuCl3 (11.0 g, 53.1 mmol, 0.07 eq) was added. The reaction mixture was stirred at 0 °C for 0.5 h, then was warmed to 20 °C for 11.5 h. Saturated aqueous sodium sulfite solution (1.00 L) was added, and the mixture was filtered. The filtrate was extracted with EA (500 mL x 3), and the organic layers were combined. The combined organic layer was washed with brine (1.00 L), dried over Na2SO4, filtered and concentrated to give the title compound (132 g, 624 mmol, 82.1% yield) as a yellow solid. Step 4: 2-((2,4-Dimethoxybenzyl)amino)-7,7-dimethyl-7,8-dihydro-5H-p yrano[4,3- b]pyridin-5-one (2,4-Dimethoxyphenyl) methanamine (160 g, 957 mmol, 1.50 eq) was added to a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5- one (135 g, 638 mmol, 1.00 eq) and DIPEA (222 mL, 1.28 mol, 2.00 eq) in NMP (1.08 L) at ambient temperature. The reaction mixture was heated to 140 °C for 2 h, and then was cooled to ambient temperature. The reaction mixture was then partitioned between water (700 mL) and EA. The layers were separated, and the aqueous layer was further extracted with EA (500 mL x 3). The organic layers were combined and washed with brine (400 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a yellow solid (160 g). The crude product was used for next step directly. Step 5: 2-Amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-o ne HCl (4.0 M in dioxane, 1.20 L, 11.0 equiv) was added to : 2-((2,4- dimethoxybenzyl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4, 3-b]pyridin-5-one (150 g, 438 mmol, 1.00 eq) at 20 °C. The reaction mixture was heated to 60 °C for 2 h, then was cooled to ambient temperature and concentrated under vacuum. The residue was poured into saturated NaHCO3 aqueous solution (1.00 L) and extracted with EA (500 mL x 4). The combined organic layer was washed with brine (500 x 2), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in EA (300 mL) and petroleum ether (150 mL) was added drop wise to get yellow slurry. The solids were filtered and collected to give the title compound (52.0 g, 60.9% yield) as a yellow solid. MS (ES+) C ₁₀ H ₁₂ N ₂ O ₂ requires: 192, found: 193[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.4 Hz, 1H), 6.98 (s, 2H), 6.39 (d, J = 8.8 Hz, 1H), 2.89 (s, 2H), 1.37 (s, 6H). Intermediate 6: 2-Amino-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one Step 1: Methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate Pd(dppf)Cl ₂ (544 mg, 744 umol, 0.500 equiv) and cesium fluoride (4.52 g, 29.8 mmol, 2.00 equiv) were added to a mixture of methyl 2-chloro-6-methoxynicotinate (3.00 g, 14.9 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.75 g, 22.3 mmol) in MeCN (50 mL). The mixture was stirred at 70 °C for 2 h under nitrogen atmosphere, then was cooled to ambient temperature. The reaction mixture was then poured onto water (200 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash-column chromatography on silica gel (gradient elution, 1% to 2% EA-petroleum ether) to give the title compound (3.0 g, crude) as a colorless oil. Step 2: 2-Methoxy-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one A solution of Methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate (3.00 g, 14.5 mmol) in TfOH (17.0 g, 113 mmol, 10 mL) was stirred at 25 °C for 12 h. The reaction mixture was then poured over water (50 mL) and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7. The mixture was extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash-column chromatography on silica gel (gradient elution, 10% to 33% EA-petroleum ether) to give the title compound (2.3 g, 82% yield) as a yellow solid. Steps 3-6: 2-Amino-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one The title compound was prepared from 2-Methoxy-7,7-dimethylfuro[3,4-b]pyridin- 5(7H)-one using the four-step procedure described in Steps 3, 5, 7 and 8 for Intermediate 1. MS (ES+) C9H10N2O2 requires: 178, found: 179[M+H] ⁺ . Intermediate 7: 2-Amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one Step 1: 2-Amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound was prepared from tetrahydro-4H-pyran-4-one using the same five-step procedure described in Steps 1-5 for Intermediate 5. MS (ES+) C ₈ H ₈ N ₂ O ₂ requires: 164, found: 165[M+H] ⁺ . NMR, 400 MHz, DMSO-d6, δ = 7.77 (d, J = 8.8 Hz, 1H), 7.01 (s, 2H), 6.41 (d, J = 8.8 Hz, 1H), 4.44 - 4.41 (m, 2H), 2.88 – 2.85 (m, 2H). Intermediate 8: 2-Amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one Step 1: 2-Methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one BH ₃ -Me ₂ S (10 M, 5.31 mL, 53.1 mmol, 1.10 equiv) was added dropwise to a solution of methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate (10.0 g, 48.3 mmol, 1.00 eq) in THF (100 mL) at 0 °C. The mixture was warmed to 20 °C and stirred at that temperature for 2 h. The reaction mixture was then cooled to 0 °C and NaHCO ₃ (20.3 g, 241 mmol, 5.00 eq) in water (35.0 mL) and H2O2 (30% in water, 69.6 mL, 724 mmol, 15.0 eq) were added dropwise. The reaction mixture was stirred at 20 °C for 30 min and at 30 - 45 °C for 12 h. The reaction mixture was then poured into saturated aqueous Na ₂ SO ₃ solution (200 mL) and extracted with EA (50.0 mL x 3). The organic layers were combined and washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash-column chromatography on silica gel (gradient elution, 5% to 15% EA-petroleum ether) to give the title compound (15.0 g, 77.6 mmol, 80.4% yield) as yellow solid. Steps 2-5: -Amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound was prepared from 2-methoxy-8-methyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one using the four-step procedure described in Steps 3, 5, 7 and 8 for Intermediate 1. MS (ES+) C9H10N2O2 requires: 178, found: 179[M+H] ⁺ . ¹ H NMR: 400 MHz, DMSO-d6 δ 7.76 (d, J = 8.6 Hz, 1H), 7.01 (s, 2H), 6.40 (d, J = 8.6 Hz, 1H), 4.44 (dd, J = 11.2 Hz, 4.4 Hz, 1H), 4.12 (dd, J = 11.0 Hz, 6.8 Hz, 1H), 2.93 (td, J = 7.0 Hz, 4.4 Hz, 1H), 1.20 (d, J = 7.0 Hz, 3H). Intermediate 9: 2'-Amino-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridi n]-5'- one Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate LiHMDS (1 M, 388 mL) was added to a solution of 3-bromo-6-chloro-2- methylpyridine (20.0 g, 96.9 mmol) in THF (300 mL) at 25 °C under nitrogen. After 2.5 h, dimethyl carbonate (14.0 g, 155 mmol) was added to the mixture and stirred at 25 °C for 13.5 h. The reaction mixture was then was added to saturated aqueous NH4Cl (1000 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash- column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to give the title compound (18.0 g, 70% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl3): δ ppm 7.81 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.039s, 2H), 3.74 (s, 3H). Step 2: Methyl 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate Tetrabutylammonium bromide (2.44 g, 7.56 mmol) and NaOH (50 mL, 50 wt% in water) were added to a solution of 1,2-dibromoethane (10.7 g, 56.7 mmol) and methyl 2-(3- bromo-6-chloropyridin-2-yl)acetate (10.0 g, 37.8 mmol) in toluene (50 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, then was diluted with water (300 mL) and extracted with EA (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash- column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to give the title compound (6.10 g, 56% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl3): δ ppm 7.81 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.66 (s, 3H), 1.81-1.75 (m, 2H), 1.46- 1.41 (m, 2H). Step 3: (1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)methanol Diisobutylaluminium hydride (1 M, 56 mL) was added to a solution of methyl 1-(3- bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate (5.40 g, 18.6 mmol) in DCM (80 mL) at –78 °C under nitrogen. The reaction mixture was stirred at –78 °C for 0.5 h, then was quenched by addition of aqueous saturated NH4Cl solution (50 mL), diluted with water (200 mL) and extracted with EA (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude title compound (5.00 g, crude) as a yellow solid which was used in the next step without further purification. Step 4: Methyl 5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine ]-2'- carboxylate Triethylamine (2.31 g, 22.9 mmol) and Pd(dppf)Cl2 (557 mg, 762 μmol) were added to a solution of (1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)methanol in MeOH (25 mL) and DMF (25 mL) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with carbon monoxide several times. The mixture was stirred under carbon monoxide (50 psi) at 80 °C for 16 h. The reaction mixture was then concentrated to remove methanol, diluted with water (100 mL) and extracted with EA (60 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The title compound (1.8 g, crude) was obtained as a yellow solid and used in the next step without further purification. MS (ES+) C ₁₀ H ₁₀ N ₂ O ₂ requires: 233, found: 234[M+H] ⁺ . Step 5: 5'-Oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine ]-2'-carboxylic acid Lithium hydroxide (555 mg, 23.2 mmol) was added to a solution of methyl 5'-oxo- 5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-ca rboxylate (1.80 g, 7.72 mmol) in methanol (30 mL) and water (10 mL). The reaction mixture was stirred at 25 °C for 0.5 h, then was concentrated to remove the methanol. The mixture was diluted with water (60 mL) and extracted with EA (50 mL × 3). The aqueous layer was acidified by addition aqueous hydrochloric acid solution (6 M, 5 mL), then the mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.20 g, 71% yield) as a brown solid that was used without further purification. Step 6: tert-Butyl (5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin ]-2'- yl)carbamate Triethylamine (831 mg, 8.21 mmol) and diphenyl phosphoryl azide (2.26 g, 8.21 mmol) were added to a solution of 5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3- b]pyridine]-2'-carboxylic acid (1.20 g, 5.47 mmol) in tert-butanol (20 mL). The reaction mixture was stirred at 100 °C for 1 h, then was cooled to ambient temperature, diluted with water (60 mL), and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash-column chromatography on silica gel (gradient elution, 0% to 50% EA- petroleum ether) to give the title compound (330 mg, 19% yield) as a yellow solid and 2'- amino-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]- 5'-one (420 mg, 28% yield) as a yellow oil. Step 7: 2'-Amino-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridi n]-5'-one HCl in dioxane (4.0 M, 0.5 mL) was added to a solution of tert-butyl (5'-oxo-5'H,7'H- spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamat e (100 mg, 344 μmol) in dioxane (1.5 mL) at 25 °C. The reaction mixture was stirred for 10 min, then was concentrated. DCM (2 mL) and TFA (1 mL, 13.5 mmol) were added to the residue, and the reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was then concentrated and EA (5 mL) was added to the residue. The mixture was neutralized by addition of saturated aqueous NaHCO3 (20 mL) and extracted with EA (15 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under to give the title compound (60.0 mg, 92% yield) as a yellow oil that was used in the next step without further purification. MS (ES+) C12H11NO4 requires: 190, found: 191[M+H] ⁺ . Intermediates 10 and 11: (R)-2-Amino-8-methyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one and (S)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-o ne each of which is represented by one of the structures shown below: . which is represented by one of the structures shown below: . which is represented by one of the structures shown below: . Step 1: (R)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5- one and (S)-2- chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one rac-2-Chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5- one (title compound from Step 3 of Intermediate 8, 700 mg, 3.54 mmol) was separated by SFC (Daicel Chiralpak IG, MeOH gradient in CO2 with 0.1% NH4OH) to give two peaks separately. The first eluting isomer (330 mg, 47% yield) and second eluting isomer (330 mg, 47% yield) were obtained as yellow solids. Steps 2 and 3: One of (R or S)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one The title compound (Intermediate 10) was prepared from one of (R or S)-2-chloro-8- methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (first eluting isomer from step 1) using the same two-step procedure as described in Steps 4 and 5 for Intermediate 5. MS (ES+) C9H10N2O2 requires: 178, found: 179[M+H] ⁺ . Steps 3 and 4: The remaining one of (R or S)-2-amino-8-methyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one The title compound (Intermediate 11) was prepared from the remaining one of (R or S)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-o ne (second eluting isomer from step 1) using the same two-step procedure as described in Steps 4 and 5 for Intermediate 2. MS (ES+) C ₉ H ₁₀ N ₂ O ₂ requires: 178, found: 179[M+H] ⁺ . Intermediates 12 and 13: (R)-2'-Amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'- pyrano[4,3-b]pyridin]-5'-one and (S)-2'-Amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'- pyrano[4,3-b]pyridin]-5'-one each of which is represented by one of the structures shown below: which is represented by one of the structures shown below: Step 1: 1-(3-Bromo-6-chloropyridin-2-yl)cyclopropane-1-carbaldehyde IBX (6.50 g, 10.7 mmol, 46% purity) was added to a solution of (1-(3-bromo-6- chloropyridin-2-yl)cyclopropyl)methanol (2.65 g, 10.1 mmol) in EA (80 mL). The reaction mixture was stirred at 80 °C for 1 h, then additional IBX (2.00 g, 3.29 mmol, 46% purity) was added. The reaction mixture was stirred at 80 °C for 0.5 h, then was filtered and concentrated to give the title compound (2.60 g, crude) as a yellow solid that was used without further purification. MS (ES+) C9H7BrClNO requires: 261, found: 262 [M+H] ⁺ . Step 2: 1-(1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)ethan-1-ol Methylmagnesium bromide (3 M, 17 mL) was added to a solution of 1-(3-bromo-6- chloropyridin-2-yl)cyclopropane-1-carbaldehyde (2.60 g, 9.98 mmol) in THF (80 mL) at 0 °C. The reaction mixture was stirred for 10 min, then was quenched by addition of aqueous saturated NH4Cl solution (80 mL), diluted with water (40 mL) and extracted with EA (80 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.70 g, crude) as a yellow oil that was used without further purification. MS (ES+) C10H11N2O2 requires: 277, found: 278 [M+H] ⁺ . Steps 3-5: tert-Butyl (7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3 - b]pyridin]-2'-yl)carbamate The title compound was prepared from 1-(1-(3-bromo-6-chloropyridin-2- yl)cyclopropyl)ethan-1-ol using a similar procedure as described in Steps 4-6 for Intermediate 9 above. NMR (400 MHz, CDCl3): δ ppm 8.29 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 4.63-4.53 (m, 1H), 1.61 (s, 3H), 1.53 (s, 9H), 1.38-1.35 (m,1 H), 1.09-1.00 (m, 2H). Step 6: tert-Butyl (R)-(7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano [4,3- b]pyridin]-2'-yl)carbamate and tert-butyl (S)-(7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane- 1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamate tert-Butyl (7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3 -b]pyridin]- 2'-yl)carbamate (400 mg) was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm × 50 mm, 10 um), EtOH gradient in CO ₂ with 0.1% NH ₄ OH) to give two separate peaks. The first eluting isomer (100 mg, 24% yield) and second eluting isomer (140 mg, 34% yield) were obtained as yellow solids. Step 7: One of (R or S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'- pyrano[4,3-b]pyridin]-5'-one TFA (2.31 g, 20.3 mmol) was added to a solution of one of tert-butyl (R or S)-(7'- methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]p yridin]-2'-yl)carbamate (first eluting isomer from Step 6, 100 mg) in DCM (6 mL). The reaction mixture was stirred at 25 °C for 30 min, then was quenched with saturated aqueous NaHCO3 solution (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (Intermediate 12, 70 mg, crude) as a yellow oil that was used without further purification. MS (ES+) C ₁₁ H ₁₂ N ₂ O ₂ requires: 204, found: 205[M+H] ⁺ . Step 8: The remaining one of (R or S)-2'-amino-7'-methyl-5'H,7'H- spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one The title compound (Intermediate 13) was prepared from one of tert-butyl (R or S)- (7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3 -b]pyridin]-2'-yl)carbamate (second eluting isomer from Step 6) using the same procedure as described in Step 7 for Intermediate 12. MS (ES+) C11H12N2O2 requires: 204, found: 205[M+H] ⁺ .

Intermediate 14: 2-Amino-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-o ne Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)-2-methylpropanoate Sodium hydride (2.91 g, 72.8 mmol, 60% purity) was added to a solution of methyl 2- (3-bromo-6-chloropyridin-2-yl)acetate (5.50 g, 20.8 mmol) in THF (20 mL) at 0 °C. The reaction mixture was stirred for 15 minutes at 0 °C, then iodomethane (7.38 g, 51.9 mmol) was added. The reaction mixture was warmed to 25 °C and stirred for 45 min, then was quenched with water (30 mL) and extracted with EA (30 mL× 2). The combined organic layers were concentrated to give a residue. The residue was purified by flash-column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to give the title compound (5.5 g, 90% yield) as a yellow oil. ¹ H NMR (400 MHz, CD ₃ OD): δ ppm 7.97 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 3.95 (s, 2H), 1.50 (s, 6H) Steps 2-6: 2-Amino-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-o ne The title compound was prepared using similar procedures as described in Steps 3-6 of Intermediate 9 and Step 7 of Intermediate 12. MS (ES+) C ₁₀ H ₁₂ N ₂ O ₂ requires: 192, found: 193 [M+H] ⁺ . ¹ H NMR (400 MHz, 6d-DMSO): δ ppm 7.77 (d, J = 8.8 Hz, 1H), 7.01 (s, 2H), 6.40 (d, J = 8.8 Hz, 1H), 4.15 (s, 2H), 1.21 (s, 6H). Intermediate 15: 2'-Amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'- pyrano[4,3-b]pyridin]-5'-one Step 1: 2-(1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)propan-2-ol To a solution of methyl 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate (1.3 g, 4.47 mmol) in THF (10 mL) was added MeMgBr (3 M, 14.9 mL) at 25 ⁰C. The reaction mixture was stirred at 25 ⁰C for 10 min, then was poured into water (20 mL) and extracted with EA (50 mL × 3). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA =1/0 to 50/1) to give the title compound (500 mg, 38% yield) as colorless oil. Steps 2-5: 2'-Amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyra no[4,3- b]pyridin]-5'-one The title compound was prepared from 2-(1-(3-Bromo-6-chloropyridin-2- yl)cyclopropyl)propan-2-ol using a similar procedure as described in Steps 4-6 for Intermediate 9 and Step 7 of Intermediate 12 above. ¹ H NMR (400 MHz, CDCl3): δ ppm 8.05 (d, J = 8.4 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 4.85 (s, 2H), 1.42-1.32 (m, 8H), 1.06-1.03 (m, 2H). Intermediate 16: 4-Bromo-1,6-dichloro-2,7-naphthyridine Step 1: 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one NBS (70.9 g, 398 mmol, 1.20 eq) was added to a solution of 6-chloro-2,7- naphthyridin-1(2H)-one (60.0 g, 332 mmol, 1.00 eq) in DMF (600 mL). The reaction mixture was stirred at 20 °C for 2 h, then was poured into water (1 L) and filtered. The filter cake was dried under vacuum to give 4-bromo-6-chloro-2,7-naphthyridin-1(2H)-one (90.8 g, crude) as a brown solid. MS (ES+) C ₈ H ₄ BrClN ₂ O requires: 260, found: 261[M+H] ⁺ . Step 2: 4-Bromo-1,6-dichloro-2,7-naphthyridine 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one (70.8 g, 272 mmol, 1.00 eq) was added in portions to POCl3 (484 g, 3.16 mol, 293 mL, 11.5 eq) at 25 °C. The reaction mixture was then stirred at 110 °C for 3 h. The reaction mixture was then concentrated under vacuum, and the residue was adjusted to pH = 8 with saturated aqueous Na2CO3 at 25 °C. The mixture was extracted with DCM (500 mL × 3), washed with brine (500 mL), dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the title compound (75.0 g, 269 mmol, 98.9% yield) as a yellow solid.. MS (ES+) C8H3BrCl2N2 requires: 278, found: 279[M+H] ⁺ . Intermediate 17: 4-(2-Azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine Step 1: 4-Bromo-6-chloro-1-methoxy-2,7-naphthyridine A suspension of 4-bromo-1,6-dichloro-2,7-naphthyridine (75.0 g, 269 mmol, 1.00 eq), K ₂ CO ₃ (111 g, 809 mmol, 3.00 eq) in MeOH (3 L) was stirred at 25 °C for 16 h. The reaction mixture was then concentrated under vacuum, and the residue was dissolved in H2O (300 mL) and extracted with DCM (100 mL x 2). The combined organic layers were concentrated under vacuum to give a residue. The residue was triturated in PE/EA (40 mL 20:1) and filtered. The filter cake was dried under vacuum to give the title compound (47.0 g, 171 mmol, 63.6% yield) as a yellow solid. Step 2: 6-Chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine A solution of 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine (47.0 g, 171 mmol, 1.00 eq), tributyl(1-ethoxyvinyl)stannane (74.4 g, 206 mmol, 69.6 mL, 1.20 eq) and Pd(PPh3)4 (19.8 g, 17.1 mmol, 0.10 eq) in toluene (500 mL) was stirred at 80 °C for 16 h under N ₂ . The reaction mixture was then cooled to 20 °C and poured into saturated aqueous KF solution (500 mL) and stirred for 1 h. The aqueous mixture was extracted with EA (300 mL x 3), and the organic layers were combined. The combined organic layer was concentrated under vacuum to give the title compound (64.0 g, crude) as a yellow oil. MS (ES+) C ₁₃ H ₁₃ ClN ₂ O ₂ requires: 264, found: 265[M+H] ⁺ . Step 3: 1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one Aqueous HCl (1.50 M, 20.1 mL, 0.10 eq) was added to a solution of 6-chloro-4-(1- ethoxyvinyl)-1-methoxy-2,7-naphthyridine (80.0 g, 302 mmol, 1.00 eq) in THF (480 mL) and H2O (80 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then poured into saturated aqueous NaHCO3 solution (500 mL) and extracted with EA (300 mL x 2). The organic layers were combined and concentrated under vacuum. The residue was purified by flash-column chromatography on silica gel (gradient elution, 5% to 50% EA- PE) to give the title compound (28.0 g, 118 mmol, 39.1% yield) as a white solid. MS (ES+) C ₁₁ H ₉ ClN ₂ O ₂ requires: 236, found: 237[M+H] ⁺ . Step 4: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol MeMgBr (3.0 M in diethyl ether, 118 mL, 3.00 eq) was added to a solution of 1-(6- chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (28.0 g, 118 mmol, 1.00 eq) in THF (300 mL) at 0~10 °C. The mixture was stirred at 0~10 °C for 2 h, and then was poured into saturated aqueous NH4Cl solution (300 mL) and extracted with EA (200 mL x 2). The organic layers were combined and concentrated under vacuum to give the title compound (33 g, crude) as a yellow oil. MS (ES+) C ₁₂ H ₁₃ ClN ₂ O ₂ requires: 252, found: 253[M+H] ⁺ . Step 5: 4-(2-Azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine TMSN3 (14.4 g, 125 mmol, 16.5 mL, 2.50 eq) was added to a solution of 2-(6-chloro- 1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol (28.0 g, 50.3 mmol, 45.4% purity, 1.00 eq) and BF3.Et2O (15.5 g, 50.3 mmol, 13.5 mL, 46.0% purity, 1.00 eq) in DCM (280 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h, then was partitioned between saturated aqueous NaHCO ₃ solution (350 mL) and DCM (200 mL). The layers were separated, and the aqueous layer was further extracted with DCM (200 mL). The organic layers were combined and washed with brine (200 mL), dried over sodium sulfate, filtered, and then concentrated. The residue was purified by flash-column chromatography on silica gel (gradient elution, 2% to 50% EA-PE) to give the title compound (20.0 g, 65.% yield, 91% purity) as an off-white solid. MS (ES+) C12H12ClN5O requires: 277, found: 278[M+H] ⁺ . Step 6: 4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol Aqueous HCl (2 M, 163 mL, 5.00 eq) was added to a solution of 4-(2-azidopropan-2- yl)-6-chloro-1-methoxy-2,7-naphthyridine (20.0 g, 65.5 mmol, 91% purity, 1.00 eq) in THF (200 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h, then was poured into saturated aqueous NaHCO ₃ (1.00 L) and extracted with EA (500 mL * 2). The organic layers were combined and washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (19.0 g, 96% yield, 88% purity) as a yellow solid. MS (ES+) C11H10ClN5O requires: 263, found: 264[M+H] ⁺ . Step 7: 4-(2-Azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine POCl3 (2.54 g, 16.5 mmol, 1.54 mL, 4.37 eq) and Et3N (1.01 g, 9.99 mmol, 1.39 mL, 2.63 eq) were added to a mixture of 4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol 7 (1.00 g, 3.79 mmol, 1.00 eq) in ACN (20.0 mL). The reaction mixture was then heated to 100 °C for 20 h. The reaction mixture was then concentrated, and the residue was diluted with EA. The diluted residue was quenched with water, and the mixture was adjusted to pH = 8 with aqueous sodium carbonate. The mixture was then extracted with EA, and the organic layer was washed with brine. The washed organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash-column chromatography on silica gel (gradient elution, 0% to 5% EA-PE) to give the title compound (14.2 g, 84% yield) as a light yellow solid. MS (ES+) C ₁₁ H ₉ Cl ₂ N ₂ requires: 281, found: 282[M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d6): δ ppm 9.57 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 1.83 (s, 6H). Intermediate 18: (S)-4-(2-Azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7- naphthyridine Step 1: 6-Chloro-1-methoxy-4-(prop-1-en-2-yl)-2,7-naphthyridine To a solution of 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine (Title compound from Step 1 of Intermediate 17, 12.4 g, 45.3 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2- yl)-1,3,2-dioxaborolane (7.62 g, 45.3 mmol) in dioxane (500 mL) and water (50 mL) was added Pd(dppf)Cl ₂ (3.32 g, 4.53 mmol), K ₂ CO ₃ (12.5 g, 90.6 mmol). The mixture was stirred at 80 °C for 2 hours under nitrogen atmosphere, then the reaction mixture was diluted with water (200 mL) and extracted with EA (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash-column chromatography on silica gel (PE/EA = 100/1 to 10/1) to give the title compound (7.00 g, 65% yield) as a white solid. Step 2: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propane-1,2-diol OsO4 (1.02 g, 4.01 mmol) was added to a mixture of 6-chloro-1-methoxy-4-(prop-1- en-2-yl)-2,7-naphthyridine (9.4 g, 40.0 mmol) and NMO (9.38 g, 80.1 mmol) in acetone (160 mL) and H2O (40 mL). The reaction mixture was stirred at 25 °C for 12 h, then was quenched saturated aqueous KF solution (150 mL) and filtered. The solution was extracted with EA (2 x 300 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (9.3 g, 86% yield) as yellow oil which was used in the next step without further purification. Step 3: 6-Chloro-4-(1,2-dimethoxypropan-2-yl)-1-methoxy-2,7-naphthyr idine NaH (4.85 g, 121 mmol, 60% purity) was added to a solution of 2-(6-chloro-1- methoxy-2,7-naphthyridin-4-yl)propane-1,2-diol (9.3 g, 34.6 mmol) in THF (150 mL). The reaction mixture was stirred at 25 °C for 0.5 h, then MeI (12.3 g, 86.5 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 h, and then stirred at 40 °C for 2 h. The reaction mixture was then added into a stirring solution of the saturated aqueous NH4Cl (50 mL) and extracted with EA (300 mL). The organic layer was washed with saturated aqueous NH4Cl (100 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (10 g, 85% yield) as a yellow oil which was used in the next step without further purification. Step 4: 4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naph thyridine BF ₃ .Et ₂ O (8.80 g, 62.0 mmol) was added to a mixture of 6-chloro-4-(1,2- dimethoxypropan-2-yl)-1-methoxy-2,7-naphthyridine (9.2 g, 31.0 mmol), TMSN3 (17.9 g, 155 mmol) in DCE (150 mL) at 25 °C. The reaction mixture heated to 60 °C for 6 h under N ₂ . The reaction mixture was then added into a stirring solution of aqueous saturated NaHCO ₃ (300 mL) and extracted with EA (300 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash-column chromatography on silica gel (20% EA-PE) to give the title compound (8 g, 73% yield) as a colorless oil. Step 4: (R)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7- naphthyridine and (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7- naphthyridine The title compounds were prepared by chiral SFC separation of 4-(2-azido-1- methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (column: Daicel ChiralPak IG (250 * 30 mm, 10 um); mobile phase: [15% (IPA with 0.1% NH ₄ OH)] to give the title two isomers. The first eluting isomer was (R)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1- methoxy-2,7-naphthyridine and the second eluting isomer was (S)-4-(2-azido-1- methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine. The absolute stereochemistry of the title compounds was determined by X-ray crystal structure of a final compound prepared from the second eluting isomer. Step 5: (S)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-2,7-naphthyrid in-1-ol Aqueous HCl (6 M, 5.41 mL) was added to a solution of (S)-4-(2-azido-1- methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (3 g, 9.75 mmol) in THF (240 mL). The mixture was stirred at 25 °C for 12 h, then was adjusted to pH ~8 with addition of solid NaHCO3. The mixture was extracted with EA (2 X 150 mL) and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (2.7 g, 83% yield, 88% purity) as a white solid which was used in the next step without further purification. Step 6: (S)-4-(2-Azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphth yridine POCl3 (3.34 g, 21.8 mmol) was added to a mixture of (S)-4-(2-azido-1- methoxypropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol (1.28 g, 4.36 mmol) and TEA (1.16 g, 11.5 mmol) in ACN (20 mL). The mixture was heated to 100 °C for 12 h. The reaction mixture was then added to saturated aqueous NH4Cl (50 mL) and extracted with EA (100 mL x 3). The organic layers were combined and dried over Na ₂ SO ₄ , filtered, and concentrated to give a residue. The residue was purified by flash-column chromatography on silica gel (25% EA-PE) to give the title compound (1.2 g, 88% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 9.61 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 3.98 (d, J = 9.6Hz, 1H), 3.78 (d, J = 9.6Hz, 1H), 3.41 (s, 3H), 1.80 (s, 3H). Intermediate 19: (R)-4-(2-Azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine Step 1: 6-Chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine A suspension of 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine (220 g, 804 mmol, 1.00 eq), tributyl(1-ethoxyvinyl)stannane (264 g, 731 mmol, 246 mL, 0.90 eq), Pd(PPh ₃ ) ₄ (46.4 g, 40.2 mmol, 0.05 eq) in toluene (2.20 L) was stirred at 100 °C under N2 for 36 h. The mixture was cooled to 25 °C and more tributyl(1-ethoxyvinyl)stannane (0.35 eq) was added to above solution under N ₂ . The mixture was stirred at 100 °C for 12 h. The mixture was cooled to 25 °C and poured into saturated aqueous KF solution (2.00 L). The mixture was filtered through a pad of celite and the filtrate was extracted with EA (1.00 L x 2). The combined organic layer was concentrated, and the residue was purified by column chromatography (SiO ₂ , PE/EA = 20/1~10/1) to give the title compound (157 g, 668 mmol, 83.1% yield) as a white solid. Step 2: 1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one To a solution of 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine (157 g, 593 mmol, 1.00 eq) in THF (942 mL) and H2O (157 mL) was added HCl (1.50 M, 39.5 mL, 0.10 eq), then the suspension was stirred 25 °C for 1 h. The mixture was poured into saturated aqueous NaHCO ₃ solution (1.50 L) and extracted with EA (1.50 L x 2). The combined organic layer was concentrated to give a residue. The residue was slurried in PE/EA =10:1 (550 mL) at 20-25 °C for 10 mins, then the suspension was filtered, and the filter cake dried to give the title compound (114 g) as a white solid. MS (ES+) C11H9ClN2O2 requires: 236, found: 237[M+H] ⁺ . Step 3: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)butan-2-ol A solution of 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (114 g, 481 mmol, 1.00 eq) in THF (2.28 L) was added to a mixture of EtMgBr (3.00 M, 481 mL, 3.00 eq) at 0~10 °C. The reaction mixture was stirred at 0~10 °C for 0.5 h, then was poured into saturated aqueous NH4Cl solution (1.50 L) and extracted with EA (1.00 L*2). The combined organic layer was washed with brine (1.00 L), dried over with Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EA = 5/1 to 2/1) to give the title compound (100 g) as a yellow oil. MS (ES+) C13H15ClN2O2 requires: 266, found: 267[M+H] ⁺ . Step 4: 4-(2-Azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine To a solution of 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)butan-2-ol (100 g, 374 mmol, 1.00 eq) and BF3•Et2O (49.2 mL, 187 mmol, 47.0% purity, 0.50 eq) in DCM (1.00 L) was added TMSN ₃ (123 mL, 937 mmol, 2.50 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hrs. The reaction mixture was then added slowly to saturated aqueous NaHCO3 solution (1.00 L) and extracted with DCM (200 mL x 2). The organic layer was washed with brine (1.00 L), dried over with Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EA = 100/1~5/1) to give a solid. The solid was slurried in PE/EA = 8/1 (90.0 mL) at 25 °C for 10 min, then was filtered and the filter cake was dried to give the title compound (46.0 g, 155 mmol, 41.5% yield) as a white solid. MS (ES+) C ₁₃ H ₁₄ ClN ₅ O requires: 291, found: 292[M+H] ⁺ . Step 5: (R)-4-(2-Azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridi ne 4-(2-Azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (46.0 g, 157 mmol, 98.7% purity, 1.00 eq) was separated by SFC (column: Daicel ChiralPak IG (250*30mm, 10um) ; mobile phase: [0.1%NH3H2O MEOH] ; B%: 20% - 20%). The second eluting peak was concentrated to give the title compound (21.5 g, 46.7% yield) as a white solid. The absolute stereochemistry of the title compound was determined by X-ray crystal structure of a final compound prepared from this Intermediate 19. MS (ES+) C13H14ClN5O requires: 291, found: 292[M+H] ⁺ . Step 6: (R)-4-(2-Azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-ol To a solution of (R)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridi ne (21.5 g, 72.7 mmol, 1.00 eq) in THF (215 mL) was added HCl (3.00 M, 122 mL, 5.07 eq) at 25 °C, then the suspension was stirred at 25 °C for 12 h, followed by stirring at 30 °C for 12 h. The reaction mixture poured into saturated aqueous NaHCO ₃ (500 mL) and extracted with EA (150 mL x 2), washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was slurried in PE (100 mL) at 25 °C for 10 mins, then was filtered and the filter cake was dried to give the title compound (18.5 g) as a white solid. MS (ES+) C12H12ClN5O requires: 277, found: 278[M+H] ⁺ . Step 7: (R)-4-(2-Azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine Three reactions below were carried out in parallel and combined for purification. To a solution of (R)-4-(2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-ol (6.16 g, 22.1 mmol, 1.00 eq) in MeCN (190 mL) was added POCl3 (10.3 mL, 110 mmol, 5.00 eq) and Et3N (8.03 mL, 57.6 mmol, 2.60 eq). The reaction mixture was stirred at 120 °C for 64 h, then was concentrated to give a residue. The residue was diluted with EA (500 mL), then was quenched with water (500 mL) at 20 ~ 30 °C and stirred at 30 °C for 30 min. The mixture was adjusted pH = 8 with addition of saturated aqueous Na2CO3 solution at 25 °C, then was extracted with EA (500 mL x 2). The combined organic layer was washed with brine (500 mL), dried over with Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EA = 1/0 ~ 8/1) to give the title compound (18.0 g, 88.4% yield) as a light yellow solid. MS (ES+) C ₁₂ H ₁₁ Cl ₂ N ₅ requires: 295, found: 296[M+H] ⁺ . ¹ H NMR (400 MHz, CDCl3): δ 9.62 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 2.03 - 2.16 (m, 2H), 1.61-1.89 (m, 3H), 0.85 – 0.89 (m, 3H). Intermediate 20: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1-(methylsulfonyl)azetid in-3- yl)oxy)-2,7-naphthyridine Step 1: tert-Butyl 3-((4-bromo-6-chloro-2,7-naphthyridin-1-yl)oxy)azetidine-1- carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.06 g, 11.9 mmol) in THF (84 mL) was added NaH (518 mg, 13.0 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 20 °C for 0.5 h, then 4-bromo-1,6-dichloro-2,7-naphthyridine (3 g, 10.8 mmol) was added and the obtained mixture was stirred at 20 °C for 0.5 h. The reaction mixture was then quenched by addition water 80 mL slowly at 0 °C, then extracted with EA (100 mL x 3). The combined organic layers were dried over by anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA =1/0 to 10/1) to give the title compound (4.00 g, 88% yield) as a white solid. MS (ES+) C16H17BrClN3O3 requires: 415, found: 416[M+H] ⁺ . Step 2: tert-Butyl 3-((6-chloro-4-(1-ethoxyvinyl)-2,7-naphthyridin-1- yl)oxy)azetidine-1-carboxylate To a solution of tert-butyl 3-((4-bromo-6-chloro-2,7-naphthyridin-1-yl)oxy)azetidine- 1-carboxylate (4.00 g, 9.65 mmol) in toluene (100 mL) was added Pd(PPh ₃ ) ₄ (1.11 g, 965 umol) and tributyl(1-ethoxyvinyl)stannane (3.48 g, 9.65 mmol, 3.26 mL). The reaction mixture was stirred at 80 °C for 16 h under nitrogen, then saturated aqueous potassium fluoride solution was added. The mixture was stirred for 4 h, then was extracted with EA (100 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1/0 to 10/1) to give the title compound (3.40 g, 43% yield) as a white solid. Step 3: tert-Butyl 3-((4-acetyl-6-chloro-2,7-naphthyridin-1-yl)oxy)azetidine-1- carboxylate To a solution of tert-butyl 3-((6-chloro-4-(1-ethoxyvinyl)-2,7-naphthyridin-1- yl)oxy)azetidine-1-carboxylate (3.40 g, 4.19 mmol) in THF (68 mL) and H ₂ O (8 mL) was added HCl (2 M, 2.09 mL). The mixture was stirred at 20 °C for 0.5 h, then was diluted with water (20 mL) and the pH of the mixture was adjusted to 8-9 by addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with DCM (20 mL x 3), the combined organic layers were washed with water (30 mL x 3), dried over by anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=10/0 to 1/1) to give the title compound (1.4 g, 83% yield) as a white solid. Step 4: tert-Butyl 3-((6-chloro-4-(2-hydroxypropan-2-yl)-2,7-naphthyridin-1- yl)oxy)azetidine-1-carboxylate To a solution of tert-butyl 3-((4-acetyl-6-chloro-2,7-naphthyridin-1-yl)oxy)azetidine- 1-carboxylate (1.4 g, 3.71 mmol, 1 eq) in THF (30 mL) was added methyl magnesium bromide (3 M, 6.18 mL, 5 eq). The reaction mixture was stirred at 20 °C for 1 h, then was poured into saturated aqueous ammonium chloride solution (30 mL), diluted with water (20 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 10/0 to 1/1) to give the title compound (1.2 g, 76% yield) as a white solid. Step 5: 2-(1-(Azetidin-3-yloxy)-6-chloro-2,7-naphthyridin-4-yl)propa n-2-ol tert-Butyl 3-((6-chloro-4-(2-hydroxypropan-2-yl)-2,7-naphthyridin-1- yl)oxy)azetidine-1-carboxylate (1.10 g, 2.79 mmol) was added to a solution of HCl in dioxane (4 M, 11 mL). The reaction mixture was stirred at 20 °C for 0.5 h, then was concentrated to give a residue. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with DCM (20 mL x 3). The combined organic layers were washed with water (30 mL x 3), dried over by anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by pre-HPLC (column: Waters Xbridge BEH C18250*50mm*10um; mobile phase: [water (0.05% ammonia hydroxide v/v)- ACN]; B%: 12%-42%, 20min). to give the title compound (300 mg, 32% yield) as a white solid. Step 6: 2-(6-Chloro-1-((1-(methylsulfonyl)azetidin-3-yl)oxy)-2,7-nap hthyridin-4- yl)propan-2-ol To a solution of 2-(1-(azetidin-3-yloxy)-6-chloro-2,7-naphthyridin-4-yl)propa n-2-ol (50 mg, 170 umol) and triethylamine (51.7 mg, 511 umol, 71.1 uL) in DCM (5 mL) was added MsCl (21.5 mg, 187 umol, 14.5 uL). The reaction mixture was stirred at 25 °C for 2 h, then was quenched by addition of water (20 mL). The mixture was extracted with EA (20 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (PE/EA = 0:1) to give the title compound (40 mg, 61% yield) as a white solid. Step 7: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1-(methylsulfonyl)azetid in-3-yl)oxy)- 2,7-naphthyridine To a solution of 2-(6-chloro-1-((1-(methylsulfonyl)azetidin-3-yl)oxy)-2,7- naphthyridin-4-yl)propan-2-ol (150 mg, 403 umol) in DCM (5 mL) was added TMSN3 (265 uL, 2.02 mmol) and InBr3 (172 mg). The mixture was stirred at 20 °C for 1 h, then water (20 mL) was added and the pH was adjusted to 8-9 by addition of saturated sodium bicarbonate solution. The mixture was extracted with DCM (20 mL x 3) and the combined organic layers were washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1/1 to 0/1) to give the title compound (120 mg, 75% yield) as a white solid. MS (ES+) C15H17ClN6O3S requires: 396, found: 397[M+H] ⁺ . Intermediate 21: 3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)thietane 1,1-dioxide Step 1: 4-(2-Azidopropan-2-yl)-6-chloro-1-(thietan-3-yloxy)-2,7-naph thyridine To a solution of thietan-3-ol (17.6 mg, 195 umol) in THF (1 mL) was added NaH (10.6 mg, 266 umol, 60% purity). The mixture was stirred for 10 min, then 4-(2-azidopropan- 2-yl)-1,6-dichloro-2,7-naphthyridine (Intermediate 17, 50 mg, 177 umol) was added and the mixture was stirred at 20 °C for 50 min. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (2 mL) and extracted with EA (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (59 mg, 99 % yield) as a white solid. Step 2: 3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)ox y)thietane 1,1- dioxide To a solution 4-(2-azidopropan-2-yl)-6-chloro-1-(thietan-3-yloxy)-2,7-naph thyridine (59.0 mg, 176 umol) in THF (0.9 mL) and water (0.3 mL) was added Oxone (216mg, 351 umol). The mixture was stirred at 20 °C for 1 h, then was quenched by addition of saturated aqueous sodium sulfite (10 mL) and extracted with EA (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (60 mg, 93% yield) as a white solid. ¹ H-NMR (400 MHz, CDCl3): δ ppm 9.47 (s, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 5.72 (tt, J = 4.0, 7.8 Hz, 1H), 4.81 - 4.70 (m, 2H), 4.45 (dd, J = 3.8, 15.6 Hz, 2H), 1.82 (s, 6H). Intermediate 22: 4-(2-Azidopropan-2-yl)-6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: 4-(2-Azidopropan-2-yl)-6-chloro-1-(cis-3-(methylsulfonyl)cyc lobutoxy)-2,7- naphthyridine To a solution of cis-3-(methylsulfonyl)cyclobutan-1-ol (5.70 g, 37.9 mmol) in THF (260 mL) was added NaH (1.97 g, 49.3mmol, 60% purity) at 0 °C. The mixture was stirred for 0.5 h, then 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (10.7 g, 37.9 mmol) was added and the reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched by addition of water (200 mL) and extracted with EA (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (16 g, crude) as a white solid that was used in the next step without further purification. MS (ES+) C16H18ClN5O3S requires: 395, found: 396[M+H] ⁺ . Intermediate 23: 4-(2-Azidopropan-2-yl)-6-chloro-1-(3-(methylsulfonyl)propoxy )- 2,7-naphthyridine Step 1: 4-(2-Azidopropan-2-yl)-6-chloro-1-(3-(methylsulfonyl)propoxy )-2,7- naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and 3-(methylsulfonyl)propan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C ₁₅ H ₁₈ ClN ₅ O ₃ S requires: 383, found: 384[M+H] ⁺ . Intermediate 24: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1s,3S)-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7- naphthyridine (Intermediate 19) and cis-3-(methylsulfonyl)cyclobutan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C17H20ClN5O3S requires: 409, found: 410[M+H] ⁺ . Intermediate 25: 3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)ox y)-3- methylthietane 1,1-dioxide Steps 1-2: 3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)ox y)-3- methylthietane 1,1-dioxide The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and 3-methylthietan-3-ol using a similar procedure as described in Steps 1-2 of Intermediate 21. MS (ES+) C ₁₅ H ₁₆ ClN ₅ O ₃ S requires: 381, found: 382[M+H] ⁺ . Intermediate 26: 3-(((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)methyl)thietane 1,1-dioxide Step 1: 3-(((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)methyl)thietane 1,1-dioxide The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and 3-(hydroxymethyl)thietane 1,1-dioxide using a similar procedure as described above for Intermediate 22. MS (ES+) C15H16ClN5O3S requires: 381, found: 382[M+H] ⁺ . Intermediate 27: 4-(2-Azidopropan-2-yl)-6-chloro-1-(trans-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: 4-(2-Azidopropan-2-yl)-6-chloro-1-(trans-3-(methylsulfonyl)c yclobutoxy)- 2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and trans-3-(methylsulfonyl)cyclobutan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C16H18ClN5O3S requires: 395, found: 396[M+H] ⁺ . Intermediates 28 and 29: (R)-4-(2-Azidopropan-2-yl)-6-chloro-1-((4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and (S)-4-(2-azidopropan-2-yl)-6-chloro- 1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine

each of which is represented by one of the structures shown below: Step 1: 4-(Methylsulfonyl)butan-2-one To the solution of 4-(methylthio)butan-2-one (2.00 g, 16.9 mmol) in THF (100 mL) and water (20 mL) was added Oxone® (10.4 g, 16.9 mmol). The reaction mixture was stirred for 2 h at 25 °C, then was quenched with water (30 mL) and adjusted to pH=8 by addition of saturated aqueous sodium carbonate solution (20mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with a saturated solution of sodium thiosulfate (30 mL) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 3:1 to 0:1) to give the title compound (0.80 g, 31% yield) as white solid. Step 2: 4-(Methylsulfonyl)butan-2-ol To a solution of 4-(methylsulfonyl)butan-2-one (400 mg, 2.66 mmol) in methanol (10 mL) was added NaBH ₄ (202 mg,5.33 mmol) in portions. The mixture was stirred for 0.5 h at 25°C, then was poured into water (40 mL) and extracted with EA (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 0:1) to give the title compound (300 mg, 74% yield) as yellow gum. Step 3: 4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan- 2-yl)oxy)-2,7- naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and 4-(methylsulfonyl)butan-2-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C16H20ClN5O3S requires: 397, found: 398[M+H] ⁺ . Step 4: (R)-4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)bu tan-2-yl)oxy)- 2,7-naphthyridine and (S)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)bu tan-2- yl)oxy)-2,7-naphthyridine 4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan- 2-yl)oxy)-2,7- naphthyridine (330 mg, 829 umol) was separated by chiral SFC (column: Daicel Chiralpak AD (250mm*30mm,10um); mobile phase:[0.1%NH3H2O IPA]; B%: 30%-30%) to give one of (R or S)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)but an-2-yl)oxy)-2,7- naphthyridine (130 mg, 45% yield, yellow oil, Intermediate 28) as the first eluting isomer and the other one of (R or S)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)but an-2- yl)oxy)-2,7-naphthyridine (130 mg , 39% yield, yellow oil, Intermediate 29) as the second eluting isomer. Intermediate 28: MS (ES+) C ₁₆ H ₂₀ ClN ₅ O ₃ S requires: 397, found: 398[M+H] ⁺ . Intermediate 29: MS (ES+) C16H20ClN5O3S requires: 397, found: 398[M+H] ⁺ . Step 1: Methyl (R)-3-((tert-butyldimethylsilyl)oxy)butanoate To a mixture of methyl (R)-3-hydroxybutanoate (50 g, 423 mmol, 48.5 mL), imidazole (43.2 g, 635 mmol) and DMAP (25.9 g, 212 mmol) in DMF (1000 mL) was added TBSCl (67.0 g, 444 mmol) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then warmed to 25 °C and stirred for another 12 h. The reaction mixture was then diluted with H ₂ O (300 mL) and EA (500 mL). The organic layer was washed with saturated aqueous NH ₄ Cl (3 x 300 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue. The residue was purified by column chromatography (PE/EA = 50/1) to give the title compound (91 g, 93% yield) as a colorless oil. Step 2: (R)-3-((tert-Butyldimethylsilyl)oxy)butan-1-ol A mixture of methyl (R)-3-((tert-butyldimethylsilyl)oxy)butanoate (45.5 g, 196 mmol) in THF (500 mL) was cooled to -70 °C, then DIBAL (1 M in toluene, 450 mL) was added dropwise. The resulting mixture was stirred for 30 min at -70 °C, then allowed to warm to 25 °C and stirred for another 2 h. The reaction mixture was added into a stirring solution of NaOH (58.7 g, 1.47 mol) in H2O (300 mL), and filtered to remove the solids. The filtrate was washed with brine (3 x 300 mL), saturated aqueous Na ₂ SO ₃ (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (40 g, crude) as a colorless oil, which was used directly for next step without further purification. Step 3: (R)-3-((tert-Butyldimethylsilyl)oxy)butyl methanesulfonate To a mixture of (R)-3-((tert-butyldimethylsilyl)oxy)butan-1-ol (80 g, 391 mmol) and TEA (70.5 g, 697 mmol) in DCM (500 mL) was added MsCl (61.0 g, 532 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then was diluted with H ₂ O (100 mL). The organic layer was washed with the saturated aqueous NH ₄ Cl (3 x 300 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (110 g, crude) as colorless oil. Step 4: (R)-tert-Butyldimethyl((4-(methylthio)butan-2-yl)oxy)silane A mixture of sodium thiomethoxide (54.6 g, 779 mmol), (R)-3-((tert- butyldimethylsilyl)oxy)butyl methanesulfonate (110 g, 389 mmol) in DMF (500 mL) was stirred at 25 °C for 2 h. The reaction mixture then was diluted with EA (500 mL), the organic layer was washed with brine (3 x 300 mL), and concentrated to give the title compound (82.6 g, 90% yield) as a colorless oil, which was used directly for next step without further purification. Step 5: (R)-tert-Butyldimethyl((4-(methylsulfonyl)butan-2-yl)oxy)sil ane To a mixture of (R)-tert-butyldimethyl((4-(methylthio)butan-2-yl)oxy)silane (77.6 g, 331 mmol) and NaHCO ₃ (222 g, 2.65 mol) in THF (1000 mL) and H ₂ O (200 mL) was added Oxone® (509 g, 827 mmol) by portions. The mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered, the organic layer of the filtrate was washed with the saturated aqueous Na ₂ SO ₃ (3 X 300 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give 81 g of the crude product, which contained 60% of the corresponding sulfoxide. Half of the crude product (42 g) and NaHCO3 (113 g, 1.34 mol) were re-dissolved in THF (1000 mL) and H2O (500 mL), and then Oxone (206 g, 335 mmol) was added by portions. The mixture was stirred at 25 °C for 2 h, then was filtered. The organic layer of the filtrate was washed with the saturated aqueous Na2SO3 (500 mL), dried over Na2SO4, filtered and concentrated in vacuo to give title compound (44.6 g, 99.8% yield) as a colorless oil, which was used directly in the next step without further purification. Step 6: (R)-4-(Methylsulfonyl)butan-2-ol (R)-tert-Butyldimethyl((4-(methylsulfonyl)butan-2-yl)oxy)sil ane (44.6 g, 167 mmol) was added to HCl/MeOH (4 M, 178 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h, then was filtered and concentrated to give a residue. The residue was purified by column chromatography (PE/EA = 5/1, and then MeOH) to give the title compound (18.7 g, 73% yield) as a yellow semisolid. ¹ H NMR (400 MHz, CD3Cl): δ ppm 4.08 -3.95 (m, 1H), 3.25- 3.10 (m, 2H), 2.94 (s, 3H), 2.30 (br s, 1H), 2.06-1.87 (m, 2H), 1.27 (d, J=6.0 Hz, 3H). Intermediate 31: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine Step 1: To a mixture of (R)-4-(methylsulfonyl)butan-2-ol (15.37 g, 101 mmol) in THF (300 mL) was added NaH (7.14 g, 179 mmol, 60% purity) at 25°C. The mixture was stirred for 1 h, then (R)-4-(2-Azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine (23 g, 77.7 mmol) in THF (150 mL) was added. The reaction mixture was stirred at 25 °C for 1.5 h, then was poured into saturated aqueous NH4Cl solution (500 mL). The mixture was extracted with EA (500 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (31 g, 93% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl3): δ ppm 9.41 (s, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 5.71-5.64 (m, 1H), 3.26-3.16 (m, 2H), 2.95 (s, 3H), 2.40- 2.36 (m, 2H), 2.10-2.05 (m, 1H), 1.97-1.80 (m, 4H), 1.52 (d, J = 6.0 Hz, 3H), 0.90-0.85 (m, 3H). Intermediate 32: 4-(2-Azidopropan-2-yl)-6-chloro-1-(cis-3- (cyclopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: trans-3-(Benzyloxy)cyclobutyl methanesulfonate To a solution of trans-3-(benzyloxy)cyclobutan-1-ol (1.9 g, 10.7 mmol) and NEt ₃ (3.24 g, 32.0 mmol) in DCM (38 mL) was added MsCl (2.44 g, 21.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then was diluted with water (40 mL) and extracted with DCM (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (2.9 g, crude) as yellow oil that was used in the next step without further purification. Step 2: S-trans-3-(Benzyloxy)cyclobutyl) ethanethioate A solution of trans-3-(benzyloxy)cyclobutyl methanesulfonate (1.5 g, 5.85 mmol) and potassium ethanethioate (802 mg, 7.02 mmol) in DMSO (12 mL) was stirred at 50 °C for 12 h. The reaction mixture was diluted with water (40 mL) and extracted with PE (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (890 mg, 64% yield) as a white oil that was used in the next step without further purification. MS (ES+) C13H16O2S requires: 236, found: 237[M+H] ⁺ . Step 3: cis-3-(Benzyloxy)cyclobutane-1-thiol To a solution of S-trans-3-(benzyloxy)cyclobutyl) ethanethioate (840 mg, 3.55 mmol) in methanol (20 mL) was added K2CO3 (1.47 g, 10.7 mmol). The reaction mixture was stirred at 70 °C for 1 h, then NaOH (284 mg, 7.11 mmol) was added and the mixture was stirred at 70 °C for an additional 2 h. The reaction mixture was diluted with water (40 mL) and was extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 1/0 to 10/1) to give the title compound (500 mg, 72% yield) as a white oil. Step 4: cis-3-(Benzyloxy)cyclobutyl)(cyclopropyl)sulfane To a solution of cis-3-(benzyloxy)cyclobutane-1-thiol (250 mg, 1.29 mmol) in DMSO (6 mL) was added potassium tert-butoxide (173 mg, 1.54 mmol) and bromocyclopropane (202 mg, 1.67 mmol, 134 uL). The reaction mixture was at 80 °C for 2 h, then was diluted with water (15 mL) and extracted with EA (15 mL × 4). The combined organic layers were washed with brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1/0 to 10/1) to give the title compound (120 mg, 40% yield) as a yellow oil. MS (ES+) C ₁₄ H ₁₈ OS requires: 234, found: 235[M+H] ⁺ . Step 5: ((cis-3-(Cyclopropylsulfonyl)cyclobutoxy)methyl)benzene To a solution of cis-3-(benzyloxy)cyclobutyl)(cyclopropyl)sulfane (120 mg, 512 umol) in THF (9 mL) and water (3 mL) was added Oxone® (629 mg, 1.02 mmol). The reaction mixture was stirred at 25 °C for 1 h, then was quenched by addition of saturated aqueous sodium sulfite (40 mL). The reaction mixture was diluted with water (20 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to the title compound (120 mg, 88% yield) as a white oil that was used in the next step without further purification. Step 6: cis-3-(Cyclopropylsulfonyl)cyclobutan-1-ol To a solution of ((cis-3-(cyclopropylsulfonyl)cyclobutoxy)methyl)benzene (100 mg, 375 umol) in DCM (4 mL) was added a solution of BCl3 (1 M, 2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then was quenched by addition of methanol (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1/0 to 0/1) to give the title compound (65 mg, 98% yield) as a white oil. MS (ES+) C7H12O3S requires: 176, found: 177[M+H] ⁺ . Step 7: 4-(2-Azidopropan-2-yl)-6-chloro-1-(cis-3-(cyclopropylsulfony l)cyclobutoxy)- 2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and cis-3-(cyclopropylsulfonyl)cyclobutan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C18H20ClN5O3S requires: 421, found: 422[M+H] ⁺ . Intermediate 33: 5-Bromo-3-chloroisoquinolin-8-ol Step 1: (E)-2-(Hydroxyimino)-7-methoxy-2,3-dihydro-1H-inden-1-one t-BuONO (67.9 g, 659 mmol, 78.4 mL, 1.10 eq) was added to a solution of 7- methoxy-2,3-dihydro-1H-inden-1-one (99.0 g, 599 mmol, 1.00 eq) in THF (500 mL) at -10-0 °C, followed by dropwise addition of HCl (4 M in MeOH, 15.0 mL, 0.10 eq) to the mixture at -10-0 °C. The reaction mixture was stirred at 0 °C for 2 h, then was concentrated to give a residue. The residue was slurried in PE/EA = 20:1 (200 mL) and filtered to give the title compound (107 g, 87% yield) as yellow solid. MS (ES+) C10H9NO3 requires: 191, found: 192[M+H] ⁺ . Step 2: 1,3-Dichloro-8-methoxyisoquinoline To a solution of (E)-2-(hydroxyimino)-7-methoxy-2,3-dihydro-1H-inden-1-one (107 g, 522 mmol, 1.00 eq) in dioxane (500 mL) was added POCl ₃ (126 g, 827 mmol, 76.9 mL, 1.59 eq) and HCl (4 M in dioxane, 1.31 mL, 0.01 eq) at 0-10 °C. The reaction mixture was stirred at 70 °C for 12 h, then was cooled to 25 °C and quenched with water (2.00 L). The quenched mixture was extracted with DCM (500 mL x 4) and the organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 20/1 to 10/1) to give the title compound (48.8 g, 40.9% yield) as light yellow solid. MS (ES+) C ₁₀ H ₇ Cl ₂ NO requires: 227, found: 228[M+H] ⁺ . Step 3: 3-Chloro-8-methoxyisoquinoline To a solution of 1,3-dichloro-8-methoxyisoquinoline (48.8 g, 213 mmol, 1.00 eq) in THF (250 mL) was added TMEDA (37.3 g, 320 mmol, 48.4 mL, 1.50 eq) and Pd(dppf)Cl ₂ (1.57 g, 2.14 mmol, 0.01 eq) at 25 °C. Then NaBH4 (17.2 g, 456 mmol, 2.13 eq) was slowly added to the reaction mixture and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into 1N HCl (1.00 L), extracted with EA (200 mL x 3). The combined organic layers were filtered through Celite® and the filtrate was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 20/1 to 5/1) to give the title compound (26.7 g, 64.3% yield) as a light yellow solid. MS (ES+) C ₁₀ H ₈ ClNO requires: 193, found: 194[M+H] ⁺ . Step 4: 5-Bromo-3-chloro-8-methoxyisoquinoline To a solution of 3-chloro-8-methoxyisoquinoline (26.7 g, 137 mmol, 1.00 eq) in MeCN (300 mL) was added NBS (29.3 g, 165 mmol, 1.20 eq) at 25 °C. The reaction mixture was stirred at 70 °C for 1 h, then was cooled to 25 °C. The mixture was filtered, and the filter cake was washed with MeCN (100 mL). The filter cake was collected and dried under vacuum. The filtrate was purified by column chromatography (SiO2, PE/EA = 1:0 to 1:1, Rf = 0.45) to give the title compound (26.17 g, 69.6% yield) as an off-white solid. MS (ES+) C ₁₀ H ₇ BrClNO requires: 273, found: 274[M+H] ⁺ . Step 5: 5-Bromo-3-chloroisoquinolin-8-ol To a solution of 5-bromo-3-chloro-8-methoxyisoquinoline (3.00 g, 11.01 mmol) in DCM (50 mL) was added BBr3 (13.8 g, 55.0 mmol) in one portion. The reaction mixture was stirred at 50 °C for 12 h, then was quenched with MeOH (15 mL) and concentrated to give a residue. The residue was purified by column chromatography (PE/EA = 10:1 to 1:1) to give the title compound (2.5 g, 88% yield) as a yellow solid. ¹ H NMR (400 MHz, 6d-DMSO): δ ppm 11.3 (s, 1H), 9.21 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 8.85 (d, J = 8.4 Hz, 1H). Intermediate 34: 5-(2-Azidopropan-2-yl)-3-chloro-8-((4-(methylsulfonyl)butan- 2- yl)oxy)isoquinoline Step 1: 4-(Methylsulfonyl)butan-2-yl methanesulfonate To a solution of 4-(methylsulfonyl)butan-2-ol (50 mg, 328 umol) in DCM (5 mL) was added TEA (99.7 mg, 985 umol) and MsCl (753mg, 657 umol). The reaction mixture was stirred at 25 °C for 2 h, then was poured into water (20 mL) and extracted with DCM (20 mL × 3). The organic layer was washed with water (20 mL × 3) and concentrated to give the title compound (60.0 mg, 79% yield) as a yellow solid that was used in the next step without further purification. Step 2: 5-Bromo-3-chloro-8-((4-(methylsulfonyl)butan-2-yl)oxy)isoqui noline To a solution of compound 4-(methylsulfonyl)butan-2-yl methanesulfonate (400 mg, 1.55 mmol) in DMF (3 mL) was added K2CO3 (642mg, 4.64 mmol) in one portion at 25 °C, then 5-bromo-3-chloroisoquinolin-8-ol (Intermediate 33)(756 mg, 3.28 mmol) was added to the reaction mixture. The reaction mixture was stirred at 45°C for 12 h, then was poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL × 3) and concentrated to give a residue. The residue was purified by prep-TLC (PE/EA = 1:1) to give the title compound (600 mg, 1.53 mmol, 99% yield) as a yellow solid. Steps 3-6: 5-(2-Azidopropan-2-yl)-3-chloro-8-((4-(methylsulfonyl)butan- 2- yl)oxy)isoquinoline The title compound was prepared using a similar four-step procedure as described in Steps 2-5 of Intermediate 17. Intermediate 35: 5-(2-Azidopropan-2-yl)-3-chloro-8-(cis-3- (methylsulfonyl)cyclobutoxy)isoquinoline Step 1: cis-3-(Benzyloxy)cyclobutyl methanesulfonate To a solution of 3-benzyloxycyclobutanol (2.5 g, 14.0 mmol) and TEA (4.26 g, 42.1 mmol) in DCM (25 mL) was added MsCl (2.41 g, 21.0 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h, then was poured into water (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (3.5 g, 97% yield) as a yellow solid. Step 2: 8-(trans-3-(Benzyloxy)cyclobutoxy)-5-bromo-3-chloroisoquinol ine To a solution of 5-bromo-3-chloro-isoquinolin-8-ol (Intermediate 33)(2.3 g, 8.90 mmol) and cis-3-(benzyloxy)cyclobutyl methanesulfonate (3.5 g, 13.7 mmol) in DMF (20 mL) was added K2CO3 (2.46 g, 17.8 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 6 h, then was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (80 mL x 3),dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE/EA = 40/1 to 6/1) to give the title compound (2.7 g, 72% yield) as a white solid. ¹ H-NMR (400 MHz, CDCl3): δ ppm 9.40 (s, 1H), 7.97 (s, 1H), 7.83 - 7.79 (m, 1H), 7.41 - 7.28 (m, 5H), 6.55 (d, J = 8.4 Hz, 1H), 5.10 - 5.01 (m, 1H), 4.53 - 4.47 (m, 2H), 4.46 - 4.38 (m, 1H), 3.00 - 2.32 (m, 4H). Step 3: trans-3-((5-Bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutan-1- ol To a solution of 8-(trans-3-(benzyloxy)cyclobutoxy)-5-bromo-3-chloroisoquinol ine (2.0 g, 4.78 mmol) in the DCM (30 mL) was added BCl3 (1 M, 14.3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with EA (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.55 g, 99% yield) as a white solid. Step 4: trans-3-((5-Bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutyl methanesulfonate To a solution of trans-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutan-1- ol (1.55 g, 4.72 mmol) in the DCM (30 mL) was added TEA (1.43 g, 14.2 mmol) and MsCl (810 mg, 7.08 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then was poured into water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.9 g, 99% yield) as a white solid. Step 5: S-(cis-3-((5-Bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutyl) ethanethioate To a solution of trans-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutyl methanesulfonate (1.9 g, 4.67 mmol) in the DMSO (30 mL) was added potassium ethanethioate (1.60 g, 14.0 mmol). The mixture was stirred at 100 °C for 2 h, then was poured into water (150 mL) and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography SiO2 (PE/EA =50:1 to 20:1) to give the title compound (1.8 g, 99% yield) as a yellow solid. Step 6: cis-3-((5-Bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutane-1-t hiol To a solution of S-(cis-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutyl) ethanethioate (1.80 g, 4.65 mmol) in the THF (20 mL), MeOH (10 mL) and water (10 mL) was added NaOH (931 mg, 23.3 mmol). The reaction mixture was stirred at 20 °C for 2 h, then was adjusted to pH = 5-6 by addition of aqueous HCl (1 M). Then mixture was diluted with EA (100 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.5 g, 93% yield) as a yellow solid. Step 7: 5-Bromo-3-chloro-8-(cis-3-(methylthio)cyclobutoxy)isoquinoli ne To a solution of cis-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutane-1-t hiol (400 mg, 1.16 mmol) in THF (8 mL) was added NaH (69.6 mg, 1.74 mmol, 60% purity) and methyl iodide (494 mg, 3.48 mmol). The reaction mixture was stirred at 20 °C for 1 h, then was quenched with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography SiO2 (PE/EA =50:1 to 20:1) to give the title compound (400 mg, 96% yield) as a white solid. Step 8: 5-Bromo-3-chloro-8-(cis-3-(methylsulfonyl)cyclobutoxy)isoqui noline To a solution of 5-bromo-3-chloro-8-(cis-3-(methylthio)cyclobutoxy)isoquinoli ne (200 mg, 558 umol) in THF (3 mL) and water (1 mL) was added Oxone® (686 mg, 1.12 mmol). The reaction mixture was stirred at 20 °C for 1 h, then was quenched by addition of saturated aqueous sodium sulfite (5 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (210 mg, 96% yield) as a white solid. Steps 9-12: 5-(2-Azidopropan-2-yl)-3-chloro-8-(cis-3- (methylsulfonyl)cyclobutoxy)isoquinoline The title compound was prepared using a similar four-step procedure as described in Steps 2-5 of Intermediate 17. Intermediate 36: 4-(2-Azidopropan-2-yl)-6-chloro-N-(cis-3- (methylsulfonyl)cyclobutyl)-2,7-naphthyridin-1-amine Step 1: 4-(2-Azidopropan-2-yl)-6-chloro-N-(cis-3-(methylsulfonyl)cyc lobutyl)-2,7- naphthyridin-1-amine To a solution of 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (100 mg, 354 umol) in NMP (2 mL) was added DIEA (68.7 mg, 532umol, 92.6 uL) and cis-3- (methylsulfonyl)cyclobutan-1-amine (79.3 mg, 532 umol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h, then was diluted with water (20 mL) and extracted with EA (30 mL × 4). The combined organic layers were washed with brine (30 mL ×3), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep- TLC (PE/EA =1:1) to give the title compound (100 mg, 58% yield) as a yellow oil. MS (ES+) C ₁₆ H ₁₉ ClN ₆ O ₂ S requires: 394, found: 395[M+H] ⁺ . Intermediate 37: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2- methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine

Step 1: ((Prop-1-en-1-yloxy)methyl)benzene To a solution of ((allyloxy)methyl)benzene (1 g, 6.75 mmol) in DMSO (10 mL) was added t-BuOK (1.14 g, 10.1 mmol), then the mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl solution (300 mL) and extracted with EA (500 mL). The organic layer was washed with brine (3 x 300 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (823 mg, 82% yield) as a yellow oil, which was used to next step without further purification. Steps 2 and 3: (1R,2S,3S and 1S,2R,3R)-3-(Benzyloxy)-2-methylcyclobutan-1-ol To a mixture of ((prop-1-en-1-yloxy)methyl)benzene (2 g, 13.5 mmol) and copper/zinc (16.0 g, 124 mmol) in Et2O (40 mL) was added 2,2,2-trichloroacetyl chloride (4.91 g, 27.0 mmol) drop-wise at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h, then was added into a mixture solution of saturated aqueous NH ₄ Cl (40 mL) and MeOH (50 mL). The resulting mixture was stirred at 50 °C for 10 min, then filtered and concentrated to remove residual MeOH. The mixture was extracted with EA (100 mL) and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 50/1 to 30/1) to give a mixture of (2S,3S and 2R,3R)- 3-(benzyloxy)-2-methylcyclobutan-1-one and (2S,3R and 2R,3S)-3-(benzyloxy)-2- methylcyclobutan-1-one (660 mg, 26%yield) as a colorless oil. The mixture of diastereomers (460 mg, 2.42 mmol) was dissolved in THF (10 mL) and NaBH ₄ (183 mg, 4.84 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h, then was diluted with H2O (20 mL) and extracted with EA (50 mL). The organic layer was dried in vacuo to give the title compound (450 mg, 97% yield, not a pure diastereomer) as a colorless oil, which was used to next step without further purification. Step 4: (1R,2R,3S and 1S,2S,3R)-3-(Benzyloxy)-2-methylcyclobutyl methanesulfonate To a mixture of (1R,2S,3S and 1S,2R,3R)-3-(benzyloxy)-2-methylcyclobutan-1-ol (450 mg, 2.34 mmol) and TEA (474 mg, 4.68 mmol) in DCM (10 mL) was added MsCl (402 mg, 3.51 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, then was diluted with EA (50 mL) and washed with the saturated aqueous NH ₄ Cl solution (3 X 50 mL). The organic layer was concentrated to give the title compound (600 mg, crude) as a colorless oil, which was used to next step without further purification. Step 5: ((1S,2R,3S and 1R,2S,3R)-3-(Benzyloxy)-2-methylcyclobutyl)(methyl)sulfane A mixture of sodium methanethiolate (259 mg, 3.70 mmol) and (1R,2R,3S and 1S,2S,3R)-3-(benzyloxy)-2-methylcyclobutyl methanesulfonate (500 mg, 1.85 mmol) in DMF (10 mL) was stirred at 25 °C for 2 h. The reaction mixture was then diluted with EA (100 mL), washed with brine (3 x 100 mL), and the organic layer was concentrated to give title compound (420 mg, crude) as a yellow oil, which was used to next step without further purification. Step 6: (1S,2R,3S and 1R,2S,3R)-2-Methyl-3-(methylthio)cyclobutan-1-ol To a solution of ((1S,2R,3S and 1R,2S,3R)-3-(benzyloxy)-2- methylcyclobutyl)(methyl)sulfane (420 mg, 1.89 mmol) in DCM (5 mL) was added BCl3 (2.37 g, 20.2 mmol). The reaction mixture was stirred at 25 °C for 2 h, then methanol was added, and the mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 5/1 and then MeOH) to give the title compound (180 mg, 72% yield) as a yellow oil. Step 7: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2-methyl-3- (methylthio)cyclobutoxy)-2,7-naphthyridine To a solution of (1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methylthio)cyclobutan-1-ol (180 mg, 1.36 mmol) in THF (10 mL) was added NaH (136 mg, 3.40 mmol, 60% purity) and the mixture was stirred at 25 °C for 0.5 h, then 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine (384 mg, 1.36 mmol) in THF (10 mL) was added. The mixture was stirred at 25 °C for 1 h, then was quenched with water (20 mL) and extracted with EA (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE/EA = 20/1 to 5/1) and then further purified by Prep-HPLC (column: Phenomenex Luna C18150 * 25 mm * 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 70%-100%, 10 min) to give the title compound (130 mg, 48% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl3): δ ppm 9.44 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 5.34-5.25 (m, 1H), 3.59-3.53 (m, 1H), 3.05-3.00 (m, 1H), 2.55-2.50 (m, 2H), 2.11 (s, 3H), 1.79 (s, 6H), 1.34 (d, J=7.2 Hz, 3H). Step 8: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2-methyl-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine To a mixture of 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2- methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyridine (130 mg, 344.01 umol), NaHCO3 (231 mg, 2.75 mmol, 107 uL) in THF (10 mL) and H2O (4 mL) was added Oxone (529 mg, 860 umol). The reaction mixture was stirred at 25 °C for 1.5 h, then was diluted with EA (50 mL) and H2O (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (120 mg, 85% yield) as a colorless oil. MS (ES+) C17H20ClN5O3S requires: 409, found: 410[M+H] ⁺ . Intermediate 38: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1S,2R,3R and 1R,2S,3S)-2- methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: (1S,2R,3S and 1R,2S,3R)-3-(Benzyloxy)-2-methylcyclobutyl 4-nitrobenzoate To a solution of (1R,2S,3S and 1S,2R,3R)-3-(benzyloxy)-2-methylcyclobutan-1-ol (1.4 g, 7.28 mmol), 4-nitrobenzoic acid (2.43 g, 14.6 mmol) and PPh ₃ (5.73 g, 21.9 mmol) in THF (30 mL) was added DIAD (4.42 g, 21.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, then was diluted with saturated aqueous NH4Cl solution (50 mL) and extracted with EA (150 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 20/1) to give the title compound (2 g, 80 % yield) as a colorless oil. Step 2: (1S,2S,3S)-3-(Benzyloxy)-2-methylcyclobutan-1-ol and (1R,2R,3R)-3- (benzyloxy)-2-methylcyclobutan-1-ol To a solution of (1S,2R,3S and 1R,2S,3R)-3-(benzyloxy)-2-methylcyclobutyl 4- nitrobenzoate (2.0 g, 5.86 mmol) in THF (15 mL) and H2O (5 mL) was added LiOH•H2O (2.46 g, 58.6 mmol) at 25 °C. The reaction mixture was stirred at 25°C for 1 h, and then stirred at 60 °C for 1 h. The reaction mixture was then diluted with aqueous NaHCO3 solution (50 mL) and EA (100 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (3 x 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (1.02 g, 90% yield) as a colorless oil. Steps 3-7: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1S,2R,3R and 1R,2S,3S)-2-methyl-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (1S,2S,3S)-3-(benzyloxy)-2- methylcyclobutan-1-ol and (1R,2R,3R)-3-(benzyloxy)-2-methylcyclobutan-1-ol using similar procedures as described in Steps 4-8 for Intermediate 37. During Step 6, the penultimate intermediate was purified by prep-HPLC (column: Phenomenex Luna C18150 * 40 mm * 15 um; mobile phase: [water (0.225% FA)-ACN]; B%: 78%-88%, 10 min) to remove a minor stereoisomer. MS (ES+) C17H20ClN5O3S requires: 409, found: 410[M+H] ⁺ . Intermediates 39 and 40: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl- 3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-(2-azidopropan-2-yl)-6-chloro-1-(( 1R,2S,3S)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphth yridine each of which is represented by one of the structures shown below: Step 1: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-(2-azidopropan-2-yl)-6-chloro-1-(( 1R,2S,3S)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphth yridine rac-4-(2-Azidopropan-2-yl)-6-chloro-1-((1S,2R,3R and 1R,2S,3S)-2-methyl-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine (190 mg, 464 umol) was separated by Chiral-SFC (column: Daicel ChiralPak IG (250 * 30 mm, 10 um); mobile phase: [0.1%NH3H2O MEOH]; B%: 40%-40%) to give to peaks. The first peak (Intermediate 39 (50 mg, 26% yield) was isolated as a white solid and the second peak (Intermediate 40, 57 mg, 30% yield) was isolated as a white solid. Intermediate 39: MS (ES+) C17H20ClN5O3S requires: 409, found: 410[M+H] ⁺ . Intermediate 40: MS (ES+) C ₁₇ H ₂₀ ClN ₅ O ₃ S requires: 409, found: 410[M+H] ⁺ . Intermediates 41 and 42: cis-4-(2-Azidopropan-2-yl)-6-chloro-1-((-3- (methylsulfonyl)cyclopentyl)oxy)-2,7-naphthyridine and trans-4-(2-azidopropan-2-yl)-6- chloro-1-((-3-(methylsulfonyl)cyclopentyl)oxy)-2,7-naphthyri dine

Step 1: 3-(Methylthio)cyclopentan-1-one To a solution of cyclopent-2-en-1-one (10.0 g, 122 mmol) in ACN (100 mL) was added AcOH (8.05 g, 134 mmol) in one portion at 0 °C, then sodium methanethiolate (17.7 g, 253 mmol) in water (50 mL) was added to the solution dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 1.5 h, then was poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE/EA = 10:1-1:1) to give the title compound (15.0 g, 95% yield) as a yellow oil. Step 2: 3-(Methylthio)cyclopentan-1-ol To a solution of 3-(methylthio)cyclopentan-1-one (2.00 g, 15.4 mmol) in MeOH (20 mL) was added NaBH4 (1.16 g, 30.7 mmol) in portions. The reaction mixture was stirred at 25 °C for 2 h, then was poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE : EA = 10:1-1:1) and concentrated in vacuo to give the title compound (1.50 g, 74% yield) as a yellow oil. Steps 3 and 4: cis-4-(2-Azidopropan-2-yl)-6-chloro-1-((-3- (methylsulfonyl)cyclopentyl)oxy)-2,7-naphthyridine and trans-4-(2-azidopropan-2-yl)-6- chloro-1-((-3-(methylsulfonyl)cyclopentyl)oxy)-2,7-naphthyri dine The title compounds were prepared from 3-(methylthio)cyclopentan-1-ol and 4-(2- azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described in Steps 1 and 2 of Intermediate 21. The cis and trans isomers were separated by prep-TLC (PE/EA = 1:1) to give Intermediate 42 (racemic trans isomer, 100 mg, 16% yield) and Intermediate 41 (racemic cis isomer, 100 mg, 16% yield) Intermediate 41: MS (ES+) C17H20ClN5O3S requires: 409, found: 410[M+H] ⁺ . Intermediate 42: NMR (400 MHz, CDCl3): δ ppm 9.36 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 5.80 – 5.75 (m, 1H), 3.75 – 3.70 (m, 1H), 3.48 (s, 2H), 2.93 (s, 3H), 2.57-2.48 (m, 2H), 2.30- 2.25 (m, 3H), 2.23-2.20 (m, 1H), 1.80(s, 6H). MS (ES+) C17H20ClN5O3S requires: 409, found: 410[M+H] ⁺ . Intermediate 43: 3-(((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)methyl)tetrahydrothiophene 1,1-dioxide Step 1: 3-(((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)methyl)tetrahydrothiophene 1,1-dioxide The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and 3-(hydroxymethyl)tetrahydrothiophene 1,1-dioxide using a similar procedure as described above for Intermediate 22. MS (ES+) C ₁₆ H ₁₈ ClN ₅ O ₃ S requires: 395, found: 396[M+H] ⁺ . Intermediate 44: 4-(2-Azidopropan-2-yl)-6-chloro-1-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: (cis-3-(Benzyloxy)cyclobutyl)(ethyl)sulfane To a solution of trans-3-(benzyloxy)cyclobutyl methanesulfonate (0.5 g, 1.95 mmol) in DMF (2 mL) was added sodium ethanethiolate (328 mg, 3.90 mmol). The reaction mixture was stirred at 100 °C for 0.5 h, then was diluted with water (100 mL) and extracted with EA (100 mL × 3 ). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel chromatography (PE/EA = 1: 0 to 20: 1) to give the title compound (160 mg, 37% yield) as colorless oil. Steps 2-4: 4-(2-Azidopropan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cycl obutoxy)-2,7- naphthyridine The title compound was prepared using a similar procedure as described in Steps 5-7 of Intermediate 32. Intermediate 45: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)c yclobutoxy)-2,7- naphthyridine The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7- naphthyridine and cis-3-(ethylsulfonyl)cyclobutan-1-ol (described in the preparation of Intermediate 44) using a similar procedure as described in Step 1 of Intermediate 22. MS (ES+) C18H22ClN5O3S requires: 423, found: 424[M+H] ⁺ . Intermediate 46: (S)-N-(1-(6-Chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7- naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

Step 1: 4-Bromo-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-na phthyridine The title compound was prepared from 4-bromo-1,6-dichloro-2,7-naphthyridine and cis-3-(ethylsulfonyl)cyclobutan-1-ol (described in the preparation of Intermediate 44) using a similar procedure as described in Step 1 of Intermediate 22. Step 2: 6-Chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-4-vinyl-2,7-na phthyridine A mixture of compound 4-bromo-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7- naphthyridine (1.35 g, 3.33 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (563.75 mg, 3.66 mmol, 620.87 uL, 1.1 eq) , Pd(dppf)Cl ₂ (243.49 mg, 332.76 umol, 0.1 eq), and K2CO3 (919.82 mg, 6.66 mmol, 2 eq) in H2O (2 mL) and dioxane (10 mL) was degassed and purged with N23 times, and then the mixture was stirred at 80 °C for 2 h. The reaction mixture was then diluted with H ₂ O (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 10/1 to 1/1) to give the title compound (700 mg, 60% yield) as a yellow oil. Step 3: 6-Chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyrid ine-4- carbaldehyde Ozone was bubbled into a solution of 6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)- 4-vinyl-2,7-naphthyridine (700 mg, 1.98 mmol) in DCM (30 mL) for 10 min at -78 °C. The reaction mixture was then flushed with nitrogen and quenched with Me2S (1.02 mL, 13.89 mmol, 7 eq). The reaction mixture was allowed to warm to 25 °C and stirred for 50 min, then was concentrated. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 1:1) to give the title compound (500 mg, 71% yield) as a yellow solid. MS (ES+) C15H15ClN2O4S requires: 354, found: 355[M+H] ⁺ . Step 4: (S)-N-((E)-(6-Chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2, 7-naphthyridin- 4-yl)methylene)-2-methylpropane-2-sulfinamide To a solution of 6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyrid ine-4- carbaldehyde (0.85 g, 2.40 mmol, 1 eq) and (S)-2-methylpropane-2-sulfinamide (435.53 mg, 3.59 mmol, 1.5 eq) in THF (10 mL) was added Ti(Oi-Pr) ₄ (2.04 g, 7.19 mmol, 2.12 mL, 3 eq). The mixture was stirred at 60 °C for 2 h, then was quenched by addition of H2O (50 mL) at 25 °C, diluted with EA (50 mL), and filtered. The filtrate was extracted with EA (80 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 0/1 to 1/1) to give the title compound (1 g, 91% yield) as a yellow solid. Step 4: (S)-N-(1-(6-Chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7- naphthyridin-4- yl)propyl)-2-methylpropane-2-sulfinamide To a solution of compound (S)-N-((E)-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)- 2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinami de (300 mg, 655 umol, 1 eq) in THF (10 mL) was added EtMgBr (3 M, 655 uL, 3 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 15 min, then was quenched by addition of aqueous ammonium chloride solution (45 mL) and extracted with EA (45 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (400 mg, crude) as a yellow oil that was used in the next step without further purification. MS (ES+) C21H30ClN3O4S2 requires: 487, found: 488[M+H] ⁺ . Intermediate 47: 4-(2-Azidopropan-2-yl)-6-chloro-1-(3- ((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine

Step 1: (3-(Benzyloxy)cyclobutyl)methanol To a solution of methyl 3-(benzyloxy)cyclobutane-1-carboxylate (2 g, 9.08 mmol) in THF (60 mL) was added LiAlH4 (689 mg, 18.16 mmol) at 0 °C. The reaction mixture was stirred at 0~25 °C for 1 h, then was quenched by addition of water (6 mL) and aqueous NaOH solution (20 mL, 15% MW) at 0 °C. The reaction mixture was then extracted with EA (40 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (1.8 g, crude) as a colorless oil that was used directly in the next step. MS (ES+) C ₁₂ H ₁₆ O ₂ requires: 192, found: 193[M+H] ⁺ . Step 2: (3-(Benzyloxy)cyclobutyl)methyl methanesulfonate The title compound was prepared from (3-(benzyloxy)cyclobutyl)methanol using a procedure similar to that described in Step 3 of Intermediate 30. Step 3: ((3-(Benzyloxy)cyclobutyl)methyl)(methyl)sulfane To a solution of (3-(benzyloxy)cyclobutyl)methyl methanesulfonate (1.5 g, 5.55 mmol) in DMF (10 mL) was added MeSNa (1.82 g, 11.1 mmol). The reaction mixture was stirred at 100 °C for 1 h, then was diluted with water (40 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 1/0 to 10/1) to give the title compound (2 g) as a colorless oil. MS (ES+) C ₁₃ H ₁₈ OS requires: 222, found: 223[M+H] ⁺ . Steps 4-6: 4-(2-Azidopropan-2-yl)-6-chloro-1-(3- ((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared using a similar procedure as described in Steps 5-7 of Intermediate 32. MS (ES+) C17H20ClN5O3S requires: 409, found: 410[M+H] ⁺ . Intermediates 48 and 49: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(cis-3- ((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6- chloro-1-(trans-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-n aphthyridine Step 1: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(cis-3- ((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6- chloro-1-(trans-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-n aphthyridine The title compounds were prepared from 3-((methylsulfonyl)methyl)cyclobutan-1-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described in Step 1 of Intermediate 31. The mixture of diastereomers was separated by SFC (column: Daicel ChiralPak IG (250×30mm, 10μm); mobile phase: [0.1%NH3H2O ETOH]; B%: 60%-60%) to give Intermediate 48 (cis isomer, 220 mg, 63% yield) as a colorless oil and Intermediate 49 (trans isomer 90 mg, 26% yield) obtained as a colorless oil. Intermediate 48: MS (ES+) C ₁₈ H ₂₂ ClN ₅ O ₃ S requires: 423, found: 424[M+H] ⁺ . Intermediate 49: MS (ES+) C18H22ClN5O3S requires: 423, found: 424[M+H] ⁺ . Intermediates 50 and 51: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3- ((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine and 4-((S)-2-azido-1- methoxypropan-2-yl)-6-chloro-1-(trans-3-((methylsulfonyl)met hyl)cyclobutoxy)-2,7- naphthyridine Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3- ((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine and 4-((S)-2-azido-1- methoxypropan-2-yl)-6-chloro-1-(trans-3-((methylsulfonyl)met hyl)cyclobutoxy)-2,7- naphthyridine The title compounds were prepared from 3-((methylsulfonyl)methyl)cyclobutan-1-ol and (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphth yridine (Intermediate 18) using a similar procedure as described in Step 1 of Intermediate 31. The mixture of diastereomers was separated by SFC (column: Daicel ChiralPak IG (250*30mm, 10um);mobile phase: [0.1%NH3H2O MeOH];B%: 70%-70%) to give Intermediate 50 (cis isomer, 360 mg, 20% yield) as a yellow oil and Intermediate 51 (trans isomer, 120 mg, 6.50% yield) as a yellow oil. Intermediate 50: MS (ES+) C18H22ClN5O4S requires: 439, found: 440[M+H] ⁺ . Intermediate 51: MS (ES+) C ₁₈ H ₂₂ ClN ₅ O ₄ S requires: 439, found: 440[M+H] ⁺ . Intermediate 52: 4-(2-Azidopropan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine Step 1: (2R,4R)-4-((tert-Butyldimethylsilyl)oxy)pentan-2-ol To a solution of (2R,4R)-pentane-2,4-diol (3.80 g, 36.5 mmol) in THF (120 mL) was added NaH (1.75 g, 43.8 mmol, 60% purity) at 0 °C. The reaction mixture was stirred for 30 min, then tert-butyldimethylsilyl chloride (6.05 g, 40.1 mmol) was added and the reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was then added to water (200 mL) and extracted with EA (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 5:1) to give the title compound (7.80 g, 98% yield) as a colorless oil. Step 2: (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)pentan-2-yl 4-nitrobenzoate To a solution of (2R,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-ol (1.00 g, 4.58 mmol), compound 4-nitrobenzoic acid (1.53 g, 9.16 mmol), and triphenylphosphine (3.60 g, 13.7 mmol) in THF (34 mL) was added DIAD (2.78 g, 13.74 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then was stirred at 25 °C for 15.5 h, diluted with water (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 10:1) to give the title compound (1.50 g, 78% yield) as a yellow oil. Step 3: (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)pentan-2-ol To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-yl 4-nitrobenzoate (1.50 g, 4.08 mmol) in THF (12 mL) and water (4 mL) was added LiOH•H ₂ O (977 mg, 40.8 mmol). The reaction mixture was stirred at 60 °C for 1 h, then was diluted with water (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (890 mg, 100% yield) as a yellow oil that was used in the next step without further purification. Step 4: (2S,4R)-4-((tert-Butyldimethylsilyl)oxy)pentan-2-yl methanesulfonate To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-ol (890 mg, 4.07 mmol) in DCM (15 mL) was added TEA (1.24 g, 12.2 mmol) and MsCl (934 mg, 8.15 mmol) at 0 °C. The reaction mixture was stirred for 1 h, then was diluted with water (100 mL) and extracted with DCM (80 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.20 g, 99% yield) as a yellow oil that was used in the next step without further purification. Step 5: tert-Butyldimethyl(((2R,4R)-4-(methylthio)pentan-2-yl)oxy)si lane To a solution of compound (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-yl methanesulfonate (1.20 g, 4.05 mmol) in DMF (30 mL) was added sodium methanethiolate (709 mg, 10.1 mmol). The reaction mixture was stirred at 25 °C for 0.5 h, then was diluted with water (80 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.00 g, 99% yield) as a yellow oil that was used in the next step without further purification. Step 6: tert-Butyldimethyl(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)ox y)silane To a solution of tert-butyldimethyl(((2R,4R)-4-(methylthio)pentan-2-yl)oxy)si lane (1.00 g, 4.02 mmol) in THF (14 mL) and water (7 mL) was added Oxone® (4.95 g, 8.05 mmol). The reaction mixture was stirred at 25 °C for 0.5 h, then was quenched by addition of saturated aqueous sodium sulfite solution (30 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.10 g, 97% yield) as a yellow oil that was used without further purification. Step 7: (2R,4R)-4-(Methylsulfonyl)pentan-2-ol To a solution of tert-butyldimethyl(((2R,4R)-4-(methylsulfonyl)pentan-2- yl)oxy)silane (1.10 g, 3.92 mmol) in THF (8 mL) was added aqueous HCl (6 M, 2 mL). The reaction mixture was stirred at 25 °C for 0.5 h, then was diluted with water (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 0:1) to give the title compound (230 mg, 35% yield) as a yellow oil. Step 8: 4-(2-Azidopropan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfony l)pentan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from (2R,4R)-4-(methylsulfonyl)pentan-2-ol and 4- (2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described in Step 1 of Intermediate 22. MS (ES+) C ₁₇ H ₂₂ ClN ₅ O ₃ S requires: 411, found: 412[M+H] ⁺ . Intermediate 53: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine Step 1: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulf onyl)pentan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from (2R,4R)-4-(methylsulfonyl)pentan-2-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described in Step 1 of Intermediate 22. MS (ES+) C18H24ClN5O3S requires: 425, found: 426[M+H] ⁺ . Intermediate 54: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((S)-4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine Step 1: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((S)-4-(methylsulfonyl )butan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-(methylsulfonyl)butan-2-ol and (R)-4-(2- azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described in Step 1 of Intermediate 22. The resulting mixture of diastereomers was separated by SFC (column: Daicel Chiralpak AD-H (250mm*30mm, 5um); mobile phase: [0.1%NH3H2O IPA];B%: 35%-35%).to give the title compound as the first eluting isomer. The stereochemistry of was determined by chiral SFC analysis of this mixture and Intermediate 31, which was prepared from an enantiomerically pure starting material. Intermediate 55: (R)-4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)bu tan- 2-yl)oxy)-2,7-naphthyridine Step 1: (R)-4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)bu tan-2-yl)oxy)- 2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and (R)-4-(methylsulfonyl)butan-2-ol using a similar procedure as described in Step 1 of Intermediate 22. MS (ES+) C16H20ClN5O3S requires: 397, found: 398[M+H] ⁺ . Intermediates 56 and 57: 4-((R)-1-Azido-1-cyclopropylethyl)-6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-((S)-1-azido-1-cyclopropylethyl)-6- chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridi ne each of which is represented by one of the structures shown below: Step 1: 1-(6-Chloro-1-hydroxy-2,7-naphthyridin-4-yl)ethan-1-one To a solution of 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (Title compound from Step 3 of Intermediate 17, 3.00 g, 12.7 mmol) in THF (30 mL) was added aqueous HCl (6 M, 20 mL). The reaction mixture was stirred at 25 °C for 16 h, then was diluted with water (80 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.80 g, crude) which was used in the next step without any further purification. Step 2: 1-(1,6-Dichloro-2,7-naphthyridin-4-yl)ethan-1-one 1-(6-Chloro-1-hydroxy-2,7-naphthyridin-4-yl)ethan-1-one (1.00 g, 4.49 mmol) was added to POCl ₃ (10 mL) and the reaction mixture was stirred at 100 °C for 2 h, then was cooled to room temperature and poured slowly into saturated aqueous sodium bicarbonate solution (500 mL). The mixture was extracted with EA (200 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 3:1) to give the title compound (660 mg, 58% yield) as a white solid. Step 3: 1-Cyclopropyl-1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1- ol To a solution of 1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1-one (600 mg, 2.49 mmol) in MTBE (200 mL) was added cyclopropylmagnesium bromide (0.5 M, 15 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 40 min, then was diluted with water (80 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 3:1) to give the title compound (550 mg, 78% yield) as a yellow solid. Step 4: 1-(6-Chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphth yridin-4-yl)-1- cyclopropylethan-1-ol To a solution of cis-3-(methylsulfonyl)cyclobutan-1-ol (167 mg, 1.11 mmol) in THF (20 mL) was added NaH (85.0 mg, 2.12 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, then 1-cyclopropyl-1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1- ol (300 mg, 1.06 mmol) was added and the mixture was stirred at 25 °C for 45 min. The reaction mixture was then diluted with water (50 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (390 mg, crude) as a yellow oil that was used in the next step without further purification. Step 5: 4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine To a solution of 1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphth yridin- 4-yl)-1-cyclopropylethan-1-ol (390 mg, 983 μmol) in 1,2-DCE (10 mL) was added TMSN ₃ (340 mg, 2.95 mmol) and BF3.Et2O (279 mg, 1.97 mmol). The reaction mixture was stirred at 25 °C for 1 h, then was diluted with water (80 mL) and extracted with DCE (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 0:1) to give the title compound (240 mg, 58% yield) as a yellow oil. Step 6: 4-((R)-1-Azido-1-cyclopropylethyl)-6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-((S)-1-azido-1-cyclopropylethyl)-6- chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridi ne 4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulf onyl)cyclobutoxy)-2,7- naphthyridine (240 mg, 569 μmol) was separated by SFC (column: Daicel Chiralpak AY-H (250 mm × 30 mm, 10 um); mobile phase: [0.1% NH3H2O IPA]; B%: 40%-40%) to give one of 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methyl sulfonyl)cyclobutoxy)-2,7- naphthyridine or 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine as the first eluting isomer (Intermediate 56, 110 mg, 45% yield) as a yellow oil and the other one of 4-((R)-1-azido-1-cyclopropylethyl)- 6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyri dine or 4-((S)-1-azido-1- cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobut oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 57, 110 mg, 45% yield) as a yellow oil. Intermediate 56: MS (ES+) C ₁₈ H ₂₀ ClN ₅ O ₃ S requires: 421, found: 422[M+H] ⁺ . Intermediate 57: MS (ES+) C ₁₈ H ₂₀ ClN ₅ O ₃ S requires: 421, found: 422[M+H] ⁺ . Intermediate 58: (S)-N-((6-Chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7- naphthyridin-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sul finamide

Steps 1-4: (S)-N-((E)-(6-Chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2 ,7- naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide The title compound was prepared from 4-bromo-1,6-dichloro-2,7-naphthyridine and cis-3-(methylsulfonyl)cyclobutan-1-ol using a similar procedure as described in Steps 1-4 of Intermediate 46. Step 5: (S)-N-((6-Chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-n aphthyridin-4- yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2 ,7- naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (500 mg, 1.13 mmol) in MTBE (60 mL) was added cyclopropylmagnesium bromide (0.5 M, 10.0 mL). The reaction mixture was stirred at 60 °C 0.5 h, then was quenched by addition of saturated aqueous NH ₄ Cl solution (20 mL). The mixture was diluted with water (20 mL) and extracted with EA (40mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE/EA 1:0 to 0:1) to give the title compound (100 mg, 16% yield) as a yellow oil. MS (ES+) C ₂₁ H ₂₈ ClN ₃ O ₄ S ₂ requires: 485, found: 486[M+H] ⁺ . Intermediate 59: 5-(2-Azidopropan-2-yl)-3-chloro-8-(cis-3- (ethylsulfonyl)cyclobutoxy)isoquinoline

Steps 1-6: 5-(2-Azidopropan-2-yl)-3-chloro-8-(cis-3- (ethylsulfonyl)cyclobutoxy)isoquinoline The title compound was prepared from cis-3-((5-bromo-3-chloroisoquinolin-8- yl)oxy)cyclobutane-1-thiol (Intermediate 35, step 6) and ethyl iodide using a procedure similar to that described in Steps 7-12 for Intermediate 35. MS (ES+) C ₁₈ H ₂₁ ClN ₄ O ₃ S requires: 408, found: 409[M+H] ⁺ . Intermediate 60: 4-(2-Azidopropan-2-yl)-6-chloro-N-(cis-3- (ethylsulfonyl)cyclobutyl)-2,7-naphthyridin-1-amine Step 1: trans-3-((tert-Butoxycarbonyl)amino)cyclobutyl methanesulfonate To a solution of tert-butyl (trans-3-hydroxycyclobutyl)carbamate (2.00 g, 10.7 mmol) in DCM (20 mL) was added TEA (4.46 mL, 32.1 mmol) and MsCl (2.45 g, 21.4 mmol) in one portion at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then was poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (2.83 g, crude) as a yellow oil that was used directly in the next step. Step 2: tert-Butyl (cis-3-(ethylthio)cyclobutyl)carbamate To a solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (2.83 g, 10.7 mmol) in DMF (20 mL) was added sodium ethanethiolate (1.80 g, 21.3 mmol). The reaction mixture was stirred at 100 °C for 1 h, then was poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.40 g, 57% yield) as a yellow solid. Step 3: tert-Butyl (cis-3-(ethylsulfonyl)cyclobutyl)carbamate To a solution of tert-butyl (cis-3-(ethylthio)cyclobutyl)carbamate (700 mg, 3.03 mmol) in THF (10 mL) and water (5 mL) was added Oxone® (1.86 g, 3.03 mmol). The reaction mixture was stirred at 25 °C for 1 h, then was poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 10:1-1:1) to give the title compound (200 mg, 25% yield) as a yellow solid. Step 4: cis-3-(Ethylsulfonyl)cyclobutan-1-amine To a solution of tert-butyl (cis-3-(ethylsulfonyl)cyclobutyl)carbamate (150 mg, 570 umol) in dioxane (2 mL) was added HCl (4 M solution in dioxane, 427 uL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then was concentrated to give the title compound (90 mg, crude) as a yellow oil that was used in the next step without further purification. Step 5: 4-(2-Azidopropan-2-yl)-6-chloro-N-(cis-3-(ethylsulfonyl)cycl obutyl)-2,7- naphthyridin-1-amine To a solution of cis-3-(ethylsulfonyl)cyclobutan-1-amine (90.0 mg, 551 umol) and 4- (2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (156 mg, 551 umol) in NMP (1 mL) was added DIPEA (214 mg, 1.65 mmol). The reaction mixture was stirred at 25 °C for 2 h, then was poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 10:1-1:1) to give the title compound (150 mg, 67% yield) as a yellow oil. MS (ES+) C17H21ClN6O2S requires: 409, found: 410[M+H] ⁺ . Intermediates 61 and 62: (S)-N-((S)-1-(6-Chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2- methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy) -2,7-naphthyridin-4- yl)butyl)-2-methylpropane-2-sulfinamide each of which is represented by one of the structures shown below: Step 1: (S)-N-((S)-1-(6-Chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy) -2,7- naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2- methylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2 ,7- naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (Title compound from Step 4 of Intermediate 58, 200 mg, 450 umol) in toluene (10 mL) was added n-PrMgBr (2 M, 1.13 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min, then was quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 × 25mm × 10 μm; mobile phase: [water (0.225%FA)-ACN]; B%: 40%-70%) to give one of (S)-N-((S)-1-(6-chloro-1- (cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)bu tyl)-2-methylpropane-2- sulfinamide or (S)-N-((R)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy) -2,7- naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide as the first eluting isomer (Intermediate 61, 25 mg, 5.5% yield) as a white solid and the other one of (S)-N-((S)-1-(6- chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridi n-4-yl)butyl)-2-methylpropane- 2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy) -2,7- naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide as the second eluting isomer (Intermediate 62, 30 mg, 6.7% yield) as a white solid. Intermediate 61: MS (ES+) C21H30ClN3O4S2 requires: 487, found: 488[M+H] ⁺ . Intermediate 62: MS (ES+) C ₂₁ H ₃₀ ClN ₃ O ₄ S ₂ requires: 487, found: 488[M+H] ⁺ . Intermediates 63 and 64: trans-3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7- naphthyridin-1-yl)oxy)-N,N-dimethylcyclobutane-1-sulfonamide and cis-3-((4-(2- Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-N,N-di methylcyclobutane-1- sulfonamide Step 1: S-(3-(benzyloxy)cyclobutyl) ethanethioate The solution of compound 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (1.00 g, 3.01 mmol) in ACN (1 mL) and DMF (4 mL) was added potassium ethanethioate (2.63 g, 23.0 mmol). The reaction mixture was stirred at 60 °C for 1 h, then was poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over sodium sulfate, filtered and concentrated to give the title compound (400 mg, 56% yield) as a yellow solid. Steps 2 and 3: trans-3-(Benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide and cis- 3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide To a solution of S-(3-(benzyloxy)cyclobutyl) ethanethioate (400 mg, 1.69 mmol) in ACN (20 mL) and concentrated HCl (845 mg, 8.46 mmol) was added NCS (1.02 g, 7.62 mmol) at 0 °C. The reaction mixture was stirred at 25°C for 3 h, then was poured into water (10 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over sodium sulfate, filtered and concentrated. The organic phase was concentrated in vacuo to give a residue. Then dimethylamine (2 M, 3.39 mL) was added to the residue, and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was then was poured into water (10 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3 ), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10um;mobile phase: [water(0.225%FA)-ACN];B%: 11%-41%) to give trans-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 44% yield) as a yellow solid, and cis-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 44% yield) as a yellow solid.. trans-3-(Benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide: ¹ H NMR (400 MHz, CDCl3): δ ppm7.37-7.28 (m, 5H), 4.37 (s, 2H), 4.00-3.94 (m, 1H), 3.32-3.25 (m, 1H), 2.88 (s, 6H), 2.58-2.51 (m, 4H). cis-3-(Benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide: ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm7.30-7.22 (m, 5H), 4.35 (s, 2H), 4.50-4.40 (m, 1H), 3.75-3.65 (m, 1H), 2.40-2.30 (m, 4H), 1.49 (s, 6H). Step 4: trans-3-Hydroxy-N,N-dimethylcyclobutane-1-sulfonamide To a solution of trans-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 743 umol in methanol (10 mL) was added Pd/C (5 mg, 74.25 umol). The reaction mixture was stirred under hydrogen (15 Psi) at 25 °C for 12 h, then was filtered and concentrated to give the title compound (120 mg, 90% yield) as a yellow solid. Step 5: trans-3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1 -yl)oxy)-N,N- dimethylcyclobutane-1-sulfonamide (Intermediate 63) The title compound was prepared from trans-3-hydroxy-N,N-dimethylcyclobutane-1- sulfonamide and 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described in Step 1 of Intermediate 22. Step 6: cis-3-Hydroxy-N,N-dimethylcyclobutane-1-sulfonamide The title compound was prepared from cis-3-(benzyloxy)-N,N-dimethylcyclobutane- 1-sulfonamide using a similar procedure as described in Step 4 above for the trans isomer. Step 7: cis-3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-y l)oxy)-N,N- dimethylcyclobutane-1-sulfonamide (Intermediate 64) The title compound was prepared from cis-3-hydroxy-N,N-dimethylcyclobutane-1- sulfonamide and 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described in Step 1 of Intermediate 22. Intermediate 65: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((1-(methylsulfonyl)pen tan- 3-yl)oxy)-2,7-naphthyridine Step 1: 1-(Methylthio)pentan-3-one To a solution of pent-1-en-3-one (1 g, 11.9 mmol) in ACN (10 mL) and water (10 mL) was added AcOH (785 mg, 13.1 mmol) and sodium methanethiolate (1.25 g, 17.8 mmol). The reaction mixture was stirred at 60 °C for 1 h, then was diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (PE / EA = 1: 0 to 50: 1) to give the title compound (1.10 g, 70% yield) as yellow oil. Step 2: 1-(Methylsulfonyl)pentan-3-one To a solution of 1-(methylthio)pentan-3-one (1.1 g, 8.32 mmol) in THF (40 mL) and water (20 mL) was added Oxone® (6.14 g, 9.98 mmol). The reaction mixture was stirred at 25 °C for 2 h, then was diluted with water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with saturated aqueous sodium sulfite solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.30 g, 95% yield) as a white solid that was used in the next step without further purification. Step 3: 1-(Methylsulfonyl)pentan-3-ol To a solution of 1-(methylsulfonyl)pentan-3-one (2.60 g, 1.30 mmol) in MeOH (50 mL) was slowly added NaBH ₄ (449 mg, 11.9 mmol). The reaction mixture was stirred at 25 °C for 10 min, then was diluted with water (100 mL) and concentrated to remove the MeOH. The mixture was then extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (650 mg, 50% yield) as a yellow solid that was used in the next step without further purification. Step 4: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((1-(methylsulfonyl)pen tan-3-yl)oxy)- 2,7-naphthyridine The title compound was prepared from 1-(methylsulfonyl)pentan-3-ol and (R)-4-(2- azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described in Step 1 of Intermediate 22. MS (ES+) C ₁₈ H ₂₄ ClN ₅ O ₃ S requires: 425, found: 426[M+H] ⁺ . Intermediates 66 and 67: 4-((R)-2-Azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-2-azidopentan-2-yl)-6-chloro- 1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyri dine each of which is represented by one of the structures shown below: Steps 1-3: 4-(2-Azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfony l)pentan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from 1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1- one (Title compound from Steps 2 of Intermediate 56) and n-PrMgBr using a similar procedure as described in Steps 3-5 of Intermediates 56 and 57. Step 4: 4-((R)-2-Azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsul fonyl)pentan- 2-yl)oxy)-2,7-naphthyridine and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine 4-(2-Azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfony l)pentan-2-yl)oxy)- 2,7-naphthyridine (300 mg, 682 μmol) was separated by SFC (column: Daicel Chiralpak IC (250mm*30mm, 10um); mobile phase: [0.1%NH3H2O IPA]; B%: 60%-60%) to give one of 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsul fonyl)pentan-2-yl)oxy)-2,7- naphthyridine or 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsul fonyl)pentan-2-yl)oxy)- 2,7-naphthyridine as the first eluting isomer (Intermediate 66, 135 mg, 44% yield) as a yellow solid and the other one of 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-2-azidopentan-2-yl)-6-chloro- 1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyri dine as the second eluting isomer (Intermediate 67, 120 mg, 40% yield) as a yellow solid. Intermediate 66: MS (ES+) C ₁₉ H ₂₆ ClN ₅ O ₃ S requires: 439, found: 440[M+H] ⁺ . Intermediate 67: MS (ES+) C19H26ClN5O3S requires: 439, found: 440[M+H] ⁺ . Intermediates 68 and 69: 4-((R)-2-Azidopentan-2-yl)-6-chloro-1-(((R)-4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-2-azidopentan-2-yl)-6-chloro- 1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine each of which is represented by one of the structures shown below: Steps 1-2: 4-(2-Azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)bu tan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from 2-(1,6-dichloro-2,7-naphthyridin-4-yl)pentan- 2-ol (Title compound from Step 1 of Intermediate 66) and (R)-4-(methylsulfonyl)butan-2-ol using a similar procedure as described in Steps 4-5 of Intermediates 56 and 57. Step 3: 4-((R)-2-Azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfony l)butan-2- yl)oxy)-2,7-naphthyridine and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine 4-(2-Azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)bu tan-2-yl)oxy)-2,7- naphthyridine (350 mg, 822μmol) was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O IPA];B%: 70%-70%) to give one of 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfony l)butan-2-yl)oxy)-2,7- naphthyridine or 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfony l)butan-2- yl)oxy)-2,7-naphthyridine as the first eluting isomer (Intermediate 68, 185 mg, 52% yield) as a colorless oil and the other one of 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-2-azidopentan-2-yl)-6-chloro-1- (((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 69, 190 mg, 54% yield) as a colorless oil. Intermediate 68: MS (ES+) C ₁₈ H ₂₄ ClN ₅ O ₃ S requires: 425, found: 426[M+H] ⁺ . Intermediate 69: MS (ES+) C18H24ClN5O3S requires: 425, found: 426[M+H] ⁺ . Intermediate 70: 4-(2-Azidopropan-2-yl)-6-chloro-1-(((2R,4R)-4- (ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine Step 1: tert-Butyl(((2R,4R)-4-(ethylthio)pentan-2-yl)oxy)dimethylsil ane To a solution of EtSH (1.94 g, 31.2 mmol) in DMSO (40 mL) was added NaOH (1.08 g, 27.0 mmol) at 25 °C. The suspension was stirred for 0.5 h at 25 °C, then (2S,4R)-4-((tert- butyldimethylsilyl)oxy)pentan-2-yl methanesulfonate (4 g, 13.5 mmol) in DMSO (10 mL) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 3.5 h, then was diluted with water (40mL) and extracted with EA (60mL × 4). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (3.6 g, crude) as a white oil that was used in the next step directly. Steps 2-4: 4-(2-Azidopropan-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl )pentan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from tert-butyl(((2R,4R)-4-(ethylthio)pentan-2- yl)oxy)dimethylsilane using a similar procedure as described in Steps 6 and 7 of Intermediate 52 and Step 1 of Intermediate 22. MS (ES+) C ₁₈ H ₂₄ ClN ₅ O ₃ S requires: 425, found: 426[M+H] ⁺ . Intermediate 71: 4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)butan-2 - yl)oxy)-2,7-naphthyridine Steps 1-4: 4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)butan-2 -yl)oxy)-2,7- naphthyridine The title compound was prepared from sodium ethanethiolate and but-3-en-2-one using a similar procedure as described in Steps 1-3 of Intermediate 65 and Step 1 of Intermediate 22. MS (ES+) C ₁₇ H ₂₂ ClN ₅ O ₃ S requires: 411, found: 412[M+H] ⁺ . Intermediates 72 and 73: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4- (ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1- (((S)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine each of which is represented by one of the structures shown below: Step 1: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)buta n-2-yl)oxy)-2,7- naphthyridine The title compound was prepared from (R)-4-(2-Azidobutan-2-yl)-1,6-dichloro-2,7- naphthyridine and 4-(ethylsulfonyl)butan-2-ol using a similar procedure as described in Step 1 of Intermediate 22. Step 2: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4-(ethylsulfonyl) butan-2-yl)oxy)- 2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-(ethylsulfonyl) butan-2- yl)oxy)-2,7-naphthyridine 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)buta n-2-yl)oxy)-2,7- naphthyridine (370 mg, 869 μmol) was separated by SFC (column: Daicel Chiralpak IG (250mm*30mm, 10um); mobile phase: [0.1%NH ₃ H ₂ O IPA]; B%: 70%-70%) to give one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(ethylsulfonyl) butan-2-yl)oxy)-2,7- naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-(ethylsulfonyl) butan-2- yl)oxy)-2,7-naphthyridine as the first eluting isomer (Intermediate 72, 140 mg, 38% yield) as colorless oil and the other one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4- (ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1- (((S)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 73, 135 mg, 36% yield) as colorless oil. Intermediate 72: MS (ES+) C18H24ClN5O3S requires: 425, found: 426[M+H] ⁺ . Intermediate 73: MS (ES+) C18H24ClN5O3S requires: 425, found: 426[M+H] ⁺ . Intermediate 74: (S)-N-((6-Chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7- naphthyridin-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sul finamide Step 1: (S)-N-((6-Chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-na phthyridin-4- yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2, 7- naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 655 umol) in toluene (30 mL) was added cyclopropylmagnesium bromide (0.5 M, 6.55 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h, then was quenched by addition of saturated aqueous ammonium chloride (20 mL). The mixture was diluted with water (10 mL) and extracted with EA (40mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE/EA 1:0 to 0:1) to give the title compound (70 mg, 20% yield) as a yellow oil. MS (ES+) C22H30ClN3O4S2 requires: 499, found: 500[M+H] ⁺ . Intermediate 75: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4- (cyclopropylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine Step 1: S-(3-Oxobutyl) ethanethioate To a solution of pyridine (11.3 g, 143 mmol) and AcOH (6.51 g, 108 mmol) in DCM (120 mL) was added but-3-en-2-one (5.00 g, 71.3 mmol) and potassium ethanethioate (12.3 g, 108 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, then the reaction mixture was diluted with DCM (80 mL). The organic layer was washed with aqueous hydrochloric acid (1 M, 200 mL), saturated aqueous sodium bicarbonate solution (250 mL × 3), and brine (300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 3:1) to give the title compound (5.40 g, 52% yield) as a yellow oil. Step 2: 4-Mercaptobutan-2-ol To a solution of S-(3-oxobutyl) ethanethioate (3.00 g, 20.52 mmol) in THF (60 mL) and MeOH (6 mL) was added NaBH4 (1.16 g, 30.8 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h, then was diluted with H2O (100 mL) and extracted with EA (80 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 3:1) to give the title compound (2.00 g, 92% yield) as a yellow oil. Step 3: 4-(Cyclopropylthio)butan-2-ol To a solution of 4-mercaptobutan-2-ol (200 mg, 1.88 mmol) and bromocyclopropane (453 mg, 3.74 mmol) in DMSO (2 mL) was added potassium tert-butoxide (254 mg, 2.26 mmol). The reaction mixture was stirred at 80 °C for 1 h, then was diluted with water (50 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 3:1) to give the title compound (150 mg, 54% yield) as a colorless oil. Step 4: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-(cyclopropylthio)bu tan-2-yl)oxy)- 2,7-naphthyridine To a solution of 4-(cyclopropylthio)butan-2-ol (30.0 mg, 205 μmol) in THF (10 mL) was added NaH (10.0 mg, 250 μmol, 60% purity) at 25 °C. After 0.5 h, (R)-4-(2-azidobutan- 2-yl)-1,6-dichloro-2,7-naphthyridine (40.0 mg, 135 μmol) was added and the reaction mixture was stirred at 25 °C for 15.5. DMF (0.05 mL) was then added, and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 3:1) to give the title compound (40.0 mg, 62% yield) as a yellow oil. Step 5: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-(cyclopropylsulfony l)butan-2- yl)oxy)-2,7-naphthyridine To a solution of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-(cyclopropylthio)bu tan-2- yl)oxy)-2,7-naphthyridine (70.0 mg, 172 μmol) in THF (10 mL) and H2O (5 mL) was added Oxone® (212 mg, 345 μmol). The reaction mixture was stirred at 15 °C for 1 h, then was quenched by addition of saturated aqueous sodium sulfite solution (100 mL) and stirred at 25 °C for 10 min. The quenched reaction mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EA = 1:0 to 1:1) to give the title compound (70.0 mg, 91% yield) as a yellow oil. MS (ES+) C ₁₉ H ₂₄ ClN ₅ O ₃ S requires: 437, found: 438[M+H] ⁺ . Intermediates 76 and 77: 4-((R)-1-Azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)- 4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-1-azido-1- cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pen tan-2-yl)oxy)-2,7- naphthyridine and

each of which is represented by one of the structures shown below: Steps 1-2: 4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 1-cyclopropyl-1-(1,6-dichloro-2,7- naphthyridin-4-yl)ethan-1-ol (Title compound from Step 3 of Intermediate 56) and (2R,4R)- 4-(methylsulfonyl) pentan-2-ol (Step 7, Intermediate 52) using a similar procedure as described in Steps 4 and 5 of Intermediates 56 and 57. MS (ES+) C ₁₉ H ₂₄ ClN ₅ O ₃ S requires: 437, found: 438[M+H] ⁺ . Step 3: 4-((R)-1-Azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-1-azido-1-cyclopropylethyl)- 6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7- naphthyridine 4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methy lsulfonyl)pentan-2- yl)oxy)-2,7-naphthyridine (360 mg, 822 μmol) was separated by SFC (column: Daicel Chiralpak IG (250 mm × 30 mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O MeOH]; B%: 60%- 60%) to give one of 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-1-azido-1-cyclopropylethyl)-6- chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-na phthyridine as the first eluting isomer (Intermediate 76, (120 mg, 32% yield) as a yellow oil and the other one of 4-((R)-1- azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulf onyl)pentan-2-yl)oxy)-2,7- naphthyridine or 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 77, 170 mg, 44% yield) as a yellow oil. Intermediate 76: MS (ES+) C19H24ClN5O3S requires: 437, found: 438[M+H] ⁺ . Intermediate 77: MS (ES+) C19H24ClN5O3S requires: 437, found: 438[M+H] ⁺ . Intermediates 78 and 79: 4-((R)-Azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-azido(cyclopropyl)methyl)-6- chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-na phthyridine each of which is represented by one of the structures shown below: Step 1: 4-Bromo-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)o xy)-2,7- naphthyridine The title compound was prepared from 4-bromo-1,6-dichloro-2,7-naphthyridine and (2R,4R)-4-(methylsulfonyl)pentan-2-olusing a similar procedure as described in Step 1of Intermediate 22. Step 2: 6-Chloro-4-(2-methylprop-1-en-1-yl)-1-(((2R,4R)-4-(methylsul fonyl)pentan- 2-yl)oxy)-2,7-naphthyridine A mixture of 4-bromo-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)o xy)-2,7- naphthyridine (890 mg, 2.18 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)- 1,3,2-dioxaborolane (397.44 mg, 2.18 mmol, 1 eq), Pd(dppf)Cl2 (159.73 mg, 218.29 umol, 0.1 eq) and K2CO3 (603.40 mg, 4.37 mmol, 2 eq) in H2O (2 mL) and dioxane (10 mL) was degassed and purged with N ₂ 3 times, and then the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with H2O (80 mL) and extracted with EA (100 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA = 10/1 to 3/1) to give the title compound (620 mg, 74.18% yield) as a yellow oil. Step 3: 6-Chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7- naphthyridine- 4-carbaldehyde Ozone was bubbled into a solution of 6-chloro-4-(2-methylprop-1-en-1-yl)-1- (((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridi ne (520 mg, 1.36 mmol, 1 eq) in DCM (60 mL) and MeOH (6 mL) at -78 °C for 10 minutes. The reaction mixture was then flushed with nitrogen and Me ₂ S (590.63 mg, 9.51 mmol, 698.14 uL, 7 eq) was added to the mixture. The reaction mixture was allowed to warm to 25 °C and stirred for 50 min, then was concentrated to give the title compound (580 mg, crude) as a yellow oil that was used in the next step without further purification. Step 4: (6-Chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7 -naphthyridin- 4-yl)(cyclopropyl)methanol To a solution of 6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7- naphthyridine- 4-carbaldehyde (530 mg, 1.49 mmol, 1 eq) in THF (10 mL) was added cyclopropylmagnesium bromide (0.5 M, 5.94 mL, 2 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min, then was quenched by addition of aqueous ammonium chloride solution (20 mL) at 25 °C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (580 mg, crude) as a yellow solid that was used in the next step without further purification. MS (ES+) C ₁₈ H ₂₃ ClN ₂ O ₄ S requires: 398, found: 399[M+H] ⁺ . Step 5: 4-(Azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine To a solution of (6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7 - naphthyridin-4-yl)(cyclopropyl)methanol (530 mg, 1.33 mmol, 1 eq) in DCE (10 mL) was added TMSN3 (765.36 mg, 6.64 mmol, 873.70 uL, 5 eq) and BF3.Et2O (377.15 mg, 2.66 mmol, 327.96 uL, 2 eq). The mixture was stirred at 25 °C for 10 min, then was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA =10/1 to 1/1) and prep-HPLC (column: Phenomenex Luna C18150*40mm* 15um; mobile phase: [water(0.1%TFA)-ACN];B%: 44%-74%,11min) to give the title compound (120 mg, 21% yield) as a light yellow solid. MS (ES+) C18H22ClN5O3S requires: 423, found: 424M+H] ⁺ . Step 6: 4-((R)-Azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-azido(cyclopropyl)methyl)-6- chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-na phthyridine 4-(Azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methyls ulfonyl)pentan-2- yl)oxy)-2,7-naphthyridine (120 mg, 283 umol, 1 eq) was separated by SFC (column: Daicel ChiralPak IG (250*30mm, 10um);mobile phase: [0.1%NH3H2O MeOH];B%: 70%-70%) to give one of 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-azido(cyclopropyl)methyl)-6- chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-na phthyridine as the first eluting isomer (Intermediate 78, 40 mg, 33% yield) as a white solid and the other one of 4-((R)- azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulf onyl)pentan-2-yl)oxy)-2,7- naphthyridine or 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 79, 35 mg, 29% yield) as a white solid Intermediate 78: MS (ES+) C ₁₈ H ₂₂ ClN ₅ O ₃ S requires: 423, found: 424[M+H] ⁺ . Intermediate 79: MS (ES+) C18H22ClN5O3S requires: 423, found: 424[M+H] ⁺ . Intermediate 80: 4-(2-Azidopropan-2-yl)-6-chloro-1-(3- ((ethylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine

Step 1: ((3-(Benzyloxy)cyclobutyl)methyl)(ethyl)sulfane To a solution of (3-(benzyloxy)cyclobutyl)methyl methanesulfonate (2.4 g, 8.88 mmol, 1 eq) in DMF (30 mL) was added NaSEt (1.49 g, 17.76 mmol, 2 eq). The reaction mixture was stirred at 100 °C for 1 h, then was quenched by addition of saturated aqueous sodium hypochlorite solution (30 mL) at 25 °C. The mixture was extracted with EA (50 mL x 3) and the combined organic layers were washed with brine (50 mL * 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.6 g, crude) as a colorless oil that was used in the next step without further purification. Steps 2-4: 4-(2-Azidopropan-2-yl)-6-chloro-1-(3- ((ethylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared using a similar procedure as described in Steps 5-7 of Intermediate 32. MS (ES+) C ₁₈ H ₂₂ ClN ₅ O ₃ S requires: 423, found: 424[M+H] ⁺ . Intermediates 81 and 82: (S)-N-((S)-1-(6-Chloro-1-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-m ethylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)- 2,7-naphthyridin-4- yl)butyl)-2-methylpropane-2-sulfinamide each of which is represented by the structures shown below: Step 1: (S)-N-((S)-1-(6-Chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)- 2,7- naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-m ethylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2, 7- naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 655 umol) in toluene (20 mL) was added PrMgBr (2 M, 1.64 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h, then saturated aqueous ammonium chloride (20 mL) was added. The mixture was diluted with water (10 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875×30mm×3μm; mobile phase: [water (0.225%FA)-ACN]; B%: 48%-58%) to give one of (S)-N-((S)-1-(6- chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin -4-yl)butyl)-2-methylpropane-2- sulfinamide or (S)-N-((R)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)- 2,7-naphthyridin- 4-yl)butyl)-2-methylpropane-2-sulfinamide as the first eluting isomer (Intermediate 81, 50 mg, 15% yield) and the other one of (S)-N-((S)-1-(6-chloro-1-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-m ethylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)- 2,7-naphthyridin-4-yl)butyl)-2- methylpropane-2-sulfinamide as the second eluting isomer (Intermediate 82, 40 mg, 12% yield) as a white solid. Intermediate 81: MS (ES+) C ₂₂ H ₃₂ ClN ₃ O ₄ S ₂ requires: 501, found: 502[M+H] ⁺ . Intermediate 82: MS (ES+) C22H32ClN3O4S2 requires: 501, found: 502[M+H] ⁺ . Intermediate 83: 4-(2-Azidopropan-2-yl)-6-chloro-1-(cis-3- (isopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine

Step 1: (cis-3-(Benzyloxy)cyclobutyl)(isopropyl)sulfane To a solution of propane-2-thiol (579 mg, 7.61 mmol) in DMF (30 mL) was added t- BuOK (1.14 g, 10.1 mmol) at -10 °C. The reaction mixture was stirred at -10 °C for 0.5 h, then trans-3-(benzyloxy)cyclobutyl methanesulfonate (1.3 g, 5.07 mmol) in DMF (3 mL) was added. The reaction mixture was stirred at -10~0 °C for 3 h, then was diluted with saturated aqueous NH4Cl (300 mL) and extracted with EA (200 mL). The organic layer was washed with brine (3 x 50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150 * 40 mm * 15um; mobile phase: [water (0.225% FA)-ACN]; B%: 65%-72%, 10 min) to give the title compound (311 mg, 26% yield) as colorless oil. Steps 2-4: 4-(2-Azidopropan-2-yl)-6-chloro-1-(cis-3- (isopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared using a similar procedure as described in Steps 5-7 of Intermediate 32. Intermediate 84: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6- dichloro-2,7-naphthyridine and cis-3-(ethylsulfonyl)cyclobutan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C18H22ClN5O4S requires: 439, found: 440[M+H] ⁺ . Intermediate 85: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6- dichloro-2,7-naphthyridine and cis-3-(methylsulfonyl)cyclobutan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C ₁₇ H ₂₀ ClN ₅ O ₄ S requires: 425, found: 426[M+H] ⁺ . Intermediate 86: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4- (ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine Step 2: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfo nyl)pentan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7- naphthyridine and (2R,4R)-4-(ethylsulfonyl)pentan-2-ol (Step 7, Intermediate 52) using a similar procedure as described in Step 1 of Intermediate 22. MS (ES+) C ₁₉ H ₂₆ ClN ₅ O ₃ S requires: 439, found: 440[M+H] ⁺ . Intermediate 87: 4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)-3- methylbutan-2-yl)oxy)-2,7-naphthyridine Steps 1-4: 4-(2-Azidopropan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)-3-meth ylbutan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from sodium ethanethiolate and but-3-en-2-one using a similar procedure as described in Steps 1-3 of Intermediate 65 and Step 1 of Intermediate 22. MS (ES+) C ₁₈ H ₂₄ ClN ₅ O ₃ S requires: 425, found: 426[M+H] ⁺ . Intermediate 88: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine

Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6- dichloro-2,7-naphthyridine and (2R,4R)-4-(methylsulfonyl)pentan-2-ol using a similar procedure as described in Step 1 of Intermediate 22. MS (ES+) C18H24ClN5O4S requires: 441, found: 442[M+H] ⁺ . Intermediates 89 and 90: 4-((R)-Azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-azido(cyclopropyl)methyl)-6- chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-nap hthyridine

each of which is represented by the structures shown below: Steps 1-5: 4-(Azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared using a similar procedure as described in Steps 1-5 of Intermediates 78 and 79. Step 6: 4-((R)-Azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-azido(cyclopropyl)methyl)-6- chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-nap hthyridine 4-(Azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsu lfonyl)pentan-2- yl)oxy)-2,7-naphthyridine (150 mg) was separated by SFC (Daicel Chiralpak AD- H(250mm*30mm,5um);mobile phase: [0.1%NH3H2O IPA];B%: 30%-30%) to give one of 4- ((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethyl sulfonyl)pentan-2-yl)oxy)-2,7- naphthyridine or 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4- (ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine as the first eluting isomer (Intermediate 89, 70 mg) as a white solid and the other one of 4-((R)-azido(cyclopropyl)methyl)-6-chloro- 1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyrid ine or 4-((S)- azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfo nyl)pentan-2-yl)oxy)-2,7- naphthyridine as the second eluting isomer (Intermediate 90, 70 mg) as a white solid. Intermediate 91: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3- (cyclopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3- (cyclopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6- dichloro-2,7-naphthyridine and cis-3-(cyclopropylsulfonyl)cyclobutan-1-ol using a similar procedure as described in Step 1 of Intermediate 22. MS (ES+) C ₁₉ H ₂₂ ClN ₅ O ₄ S requires: 451, found: 452[M+H] ⁺ . Intermediate 92: 2-(2-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)propyl)tetrahydrothiophene 1,1-dioxide Step 1: 2-(2-Hydroxyethyl)tetrahydrothiophene 1,1-dioxide To a solution of 2-(tetrahydrothiophen-2-yl)ethan-1-ol (1 g, 7.56 mmol) in THF (18 mL) and water (6 mL) was added Oxone® (9.30 g, 15.1 mmol). The reaction mixture was stirred at 25 °C for 1 h, then was quenched by addition of saturated aqueous sodium sulfite (20 mL). The mixture was diluted with water (20 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (750 mg, crude) as a colorless solid. MS (ES+) C ₆ H ₁₂ O ₃ S requires: 164, found: 165[M+H] ⁺ . Step 2: 2-(1,1-Dioxidotetrahydrothiophen-2-yl)acetaldehyde To a solution of DMSO (1.43 g, 18.3 mmol, 1.43 mL) in DCM (30 mL) was added oxalyl chloride (1.74 g, 13.7 mmol, 1.20 mL) at -78 °C. The reaction mixture was stirred at - 78 °C for 20 min, then 2-(2-hydroxyethyl)tetrahydrothiophene 1,1-dioxide (750 mg, 4.57 mmol) in DCM (10 mL). The reaction mixture was stirred at -78 °C for another 20 min, then TEA (2.77 g, 27.4 mmol) in DCM (10 mL) was added dropwise to the reaction mixture as the temperature was kept below -60 °C. After the addition, the mixture was stirred at -78 °C for 20 min, then was diluted with water (40 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.1 g, crude) was obtained as a colorless oil that was used in the next step without purification. Step 3: 2-(2-Hydroxypropyl)tetrahydrothiophene 1,1-dioxide To a solution of 2-(1,1-dioxidotetrahydrothiophen-2-yl)acetaldehyde (1 g, 6.16 mmol) in THF (30 mL) was added MeMgBr (3 M, 6.16 mL) at 0 °C, then the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water (40 mL) and extracted with EA (40 mL × 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1/0 to 0/1) to give the title compound (270 mg, 25% yield) as a yellow oil. MS (ES+) C7H14O3S requires: 178, found: 179[M+H] ⁺ . Step 4: 2-(2-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)propyl)tetrahydrothiophene 1,1-dioxide The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and 2-(2-hydroxypropyl)tetrahydrothiophene 1,1-dioxide using a similar procedure as described above for Intermediate 22. MS (ES+) C ₁₈ H ₂₂ ClN ₅ O ₃ S requires: 423, found: 424[M+H] ⁺ . Intermediates 93 and 94: (7R,8R)-2-Amino-7,8-dimethyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one and (7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one each of which is represented by one of the structures shown below: which is represented by one of the structures shown below: . which is represented by one of the structures shown below: . Step 1: (7R,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]py ridin-5-one and (7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]py ridin-5-one rac-(7R,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one (reported in Step 5 of Intermediates 1 and 2) (6.0 g, 28.3 mmol) was separated by SFC (Daicel Chiralpak AD, MeOH gradient in CO2 with 0.1% NH4OH) to give two peaks separately. The first eluting isomer (3 g, 50% yield) and second eluting isomer (2.8 g, 46% yield) were obtained as yellow solids. Steps 2 and 3: One of (7R,8R)- or (7S,8S)-2-Amino-7,8-dimethyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one The title compound (Intermediate 93) was prepared from one of (7R,8R)- or (7S,8S)- 2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5- one (first eluting isomer from step 1) using the same two-step procedure as described in Steps 7 and 8 for Intermediate 1. ¹ H-NMR (400 MHz, 6d-DMSO): δ ppm 7.76 (d, J = 8.8 Hz, 1H), 7.02 (s, 2H), 6.41 (d, J = 8.8 Hz, 1H), 4.70 (d, J = 3.2, 6.4 Hz, 1H), 2.77-2.66 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H). MS (ES+) C10H12N2O2 requires: 192, found: 193[M+H] ⁺ . Steps 4 and 5: The remaining one of (7R,8R)- or (7S,8S)-2-Amino-7,8-dimethyl-7,8- dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound (Intermediate 94) was prepared from the remaining one of (7R,8R)- or (7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]py ridin-5-one (second eluting isomer from step 1) using the same two-step procedure as described in Steps 7 and 8 for Intermediate 1. MS (ES+) C ₁₀ H ₁₂ N ₂ O ₂ requires: 192, found: 193[M+H] ⁺ . Intermediates 95 and 96: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2- methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6- chloro-1-((1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy) -2,7-naphthyridine each of which is represented by one of the structures below: Step 1: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3- (methylthio)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1- ((1R,2S,3S)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyr idine The title compounds were prepared from rac-(1S,2R,3R)-2-methyl-3- (methylthio)cyclobutan-1-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described above for Intermediate 22. The title compounds were not separated and carried into the next step. MS (ES+) C ₁₈ H ₂₂ ClN ₅ OS requires: 391, found: 392[M+H] ⁺ . Step 2: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1- ((1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naph thyridine To a mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3- (methylthio)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1- ((1R,2S,3S)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyr idine (730 mg, 1.86 mmol), NaHCO3 (1.25 g, 14.9 mmol) in THF (20 mL) and H2O (4 mL) was added Oxone® (2.86 g, 4.66 mmol). The reaction mixture was stirred at 25 °C for 2 h, then was filtered, diluted with water (20 mL) and extracted with EA (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was re-dissolved into a mixture solution of THF (20 mL) and H2O (4 mL), and NaHCO3 (1.25 g, 14.9 mmol) and Oxone (2.86 g, 4.66 mmol) were added. The mixture was stirred at 25 °C for 1 h, then was filtered, diluted with H ₂ O (20 mL) and extracted with EA (50 mL). The organic layer was dried to give a mixture of the title compounds (780 mg, 96% yield) as a colorless semisolid. The mixture was separated by chiral SFC (column: Daicel Chiralpak AD-H (250 mm *30 mm, 5um); mobile phase: [0.1%NH ₃ H ₂ O IPA]; B%: 30%-30%) to give one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1- ((1S,2R,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naph thyridine or 4-((R)-2- azidobutan-2-yl)-6-chloro-1-((1R,2S,3R)-2-methyl-3-(methylsu lfonyl)cyclobutoxy)-2,7- naphthyridine (first eluting isomer, Intermediate 95, 240 mg, 31% yield) as a colorless semisolid and the other one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1- ((1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naph thyridine (second eluting isomer, Intermediate 96, 260 mg, 33% yield) as a colorless semisolid. Intermediate 95: MS (ES+) C ₁₈ H ₂₂ ClN ₅ O ₃ S requires: 423, found: 424[M+H] ⁺ . Intermediate 96: MS (ES+) C18H22ClN5O3S requires: 423, found: 424[M+H] ⁺ . Intermediates 97 and 98: (R)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3- b]pyridin-5-one and (S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyri din-5-one Steps 1-5: (rac)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]py ridin-5- one The title compound was prepared from 2-(3-bromo-6-chloropyridin-2-yl)-2- methylpropan-1-ol using a similar procedure as described in Steps 1-5 of Intermediate 12. C ₁₁ H ₁₄ N ₂ O ₂ requires: 206, found: 207 [M+H] ⁺ . Step 6: (R)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyri din-5-one and (S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyri din-5-one (rac)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]py ridin-5-one (120 mg) was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm × 50 mm, 10 um), MeOH gradient in CO2 with 0.1% NH4OH) to give two peaks separately. The first eluting isomer, one of (R or S)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyrid in-5-one (Intermediate 97, 60 mg, 50% yield) and second eluting isomer, one of (R or S)-2-Amino- 7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 98, 60 mg, 50% yield) were obtained as yellow solids. Intermediate 99: (S)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(3- (methylsulfonyl)propoxy)-2,7-naphthyridine Step 1: (S)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(3- (methylsulfonyl)propoxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6- dichloro-2,7-naphthyridine and 3-(methylsulfonyl)propan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C ₁₆ H ₂₀ ClN ₅ O ₄ S requires: 413, found: 414[M+H] ⁺ . Intermediate 100: (R)-4-(2-Azidobutan-2-yl)-6-chloro-1-(3- (methylsulfonyl)propoxy)-2,7-naphthyridine Step 1: (R)-4-(2-Azidobutan-2-yl)-6-chloro-1-(3-(methylsulfonyl)prop oxy)-2,7- naphthyridine The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7- naphthyridine and 3-(methylsulfonyl)propan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C ₁₆ H ₂₀ ClN ₅ O ₃ S requires: 397, found: 398[M+H] ⁺ . Intermediates 101 and 102: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4-((R)- methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1- (((R)-4-((S)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridin e Step 1: (R)-4-(Methylthio)butan-2-ol The title compound was prepared from (R)-tert-butyldimethyl((4-(methylthio)butan- 2-yl)oxy)silane using a similar procedure as described above in Step 5 of Intermediate 30. Step 2: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4-(methylthio)but an-2-yl)oxy)- 2,7-naphthyridine The title compound was prepared from (R)-4-(methylthio)butan-2-ol and (R)-4-(2- azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described above for Intermediate 22. MS (ES+) C ₁₇ H ₂₂ ClN ₅ OS requires: 379, found: 380[M+H] ⁺ . Step 3: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((2R)-4-(methylsulfiny l)butan-2- yl)oxy)-2,7-naphthyridine To a solution of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(methylthio)but an-2- yl)oxy)-2,7-naphthyridine (280 mg, 643 umol, 87.2% purity) in DCM (8 mL) was added m- CPBA (196 mg, 964 umol, 85% purity) at 25 °C. The mixture was stirred at 25 °C for 1 h, then was diluted with DCM (15 mL), washed with water (20 mL x 2), filtered, and concentrated to give a residue. The residue was purified by prep-TLC (PE/EA =1/2) to give the title compound (220 mg, 86% yield) as a white solid. MS (ES+) C17H22ClN5O2S requires: 395, found: 396[M+H] ⁺ . Step 4: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4-((R)-methylsulf inyl)butan-2- yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((S)- methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((2R)-4-(methylsulfiny l)butan-2-yl)oxy)-2,7- naphthyridine (220 mg) was separated by SFC (column: Daicel Chiralpak AD (250 mm * 30 mm, 10 um); mobile phase: [0.1%NH ₃ H ₂ O-MeOH]; B%: 60%-60%) to give two peaks separately. The first eluting isomer, one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((R)- methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1- (((R)-4-((S)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridin e (Intermediate 101, 95 mg, 42% yield) and second eluting isomer, one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4- ((R)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro- 1-(((R)-4-((S)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyrid ine (Intermediate 102, 101 mg, 45% yield) were obtained as colorless oils. MS (ES+) C ₁₇ H ₂₂ ClN ₅ O ₂ S requires: 395, found: 396[M+H] ⁺ . Intermediates 103 and 104: (S)-(3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7- naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ ⁶ -sulfanone and (R)-(3-((4-(2-azidopropan-2- yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl )-λ ⁶ -sulfanone Step 1: 4-(2-Azidopropan-2-yl)-6-chloro-1-(3-(methylthio)propoxy)-2, 7- naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro- 2,7-naphthyridine and 3-(methylthio)propan-1-ol using a similar procedure as described above for Intermediate 22. MS (ES+) C15H18ClN5OS requires: 351, found: 352[M+H] ⁺ . Step 2: (3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)propyl)(imino)(methyl)-λ ⁶ -sulfanone 4-(2-Azidopropan-2-yl)-6-chloro-1-(3-(methylthio)propoxy)-2, 7-naphthyridine (320 mg, 909 umol) was dissolved in MeOH (10 mL), and then NH ₄ HCO ₃ (108 mg, 1.36 mmol) and PhI(OAc) ₂ (586 mg, 1.82 mmol) were added. The reaction mixture was stirred at 25 °C for 16 h, then was diluted with saturated aqueous NH4Cl solution (50 mL) and extracted with EA (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (PE:EA = 0:1) to give the title compound (283 mg, 73% yield) as a yellow solid. MS (ES+) C15H19ClN6O2S requires: 382, found: 383[M+H] ⁺ . LCMS data: M+1 (382.9); MW (382.1). Step 3: (S)-(3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)propyl)(imino)(methyl)-λ ⁶ -sulfanone and (R)-(3-((4-(2-azidopropan-2-yl)-6-chloro- 2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ ⁶ -sulfanone (3-((4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)propyl)(imino)(methyl)-λ ⁶ -sulfanone (283 mg) was separated by SFC ((column: Daicel Chiralpak AY-H (250 mm x 30 mm,10 um); mobile phase: [0.1%NH ₃ H ₂ O EtOH]; B%: 50%-50%) to give two peaks separately. The first eluting isomer, one of (S)-(3-((4-(2- azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl) (imino)(methyl)-λ ⁶ -sulfanone or (R)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)propyl)(imino)(methyl)-λ ⁶ -sulfanone (Intermediate 103, 129 mg, 41% yield) and second eluting isomer, one of (S)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1- yl)oxy)propyl)(imino)(methyl)-λ ⁶ -sulfanone or (R)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7- naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ ⁶ -sulfanone (Intermediate 104, 114 mg, 39% yield) were obtained as yellow solids. MS (ES+) C ₁₅ H ₁₉ ClN ₆ O ₂ S requires: 382, found: 383[M+H] ⁺ . Intermediates 105 and 106: (S)-4-(2-Azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro- 4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and (R)-4-(2-azidopropan-2-yl)-6- chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy) -2,7-naphthyridine

Step 1: 1,1,1-Trifluoro-4-(methylthio)butan-2-ol To a solution of 3-(methylthio)propanal (2 g, 19.2 mmol) and TMSCF3 (13.7 g, 96.0 mmol) in THF (40 mL) was added Cs ₂ CO ₃ (6.26 g, 19.2 mmol) at 0 °C, then the mixture was stirred at 25 °C for 16 h. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash-column chromatography (PE/EA=5/1) to give WH105714-2 (1.4 g) as a colorless oil. Step 2: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methy lthio)butan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7- naphthyridine and 1,1,1-Trifluoro-4-(methylthio)butan-2-ol using a similar procedure as described above for Intermediate 22, except that the reaction mixture was stirred for 16 h. MS (ES+) C16H17ClF3N5OS requires: 419, found: 420[M+H] ⁺ . Step 3: 4-(2-Azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methy lsulfonyl)butan- 2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1- trifluoro-4-(methylthio)butan-2-yl)oxy)-2,7-naphthyridine using a similar procedure as described in Step 5 of Intermediate 30. MS (ES+) C ₁₆ H ₁₇ ClF ₃ N ₅ O ₃ S requires: 451, found: 452[M+H] ⁺ . Step 4: (S)-4-(2-Azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and (R)-4-(2-azidopropan-2-yl)-6-chloro- 1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-na phthyridine 4-(2-Azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methy lsulfonyl)butan-2- yl)oxy)-2,7-naphthyridine (100 mg) was separated by SFC (column: Daicel Chiralpak IG (250 mm x 30 mm, 10 um); mobile phase: [0.1%NH3H2O ETOH]; B%: 35%-35%) to give two peaks separately. The first eluting isomer, one of (S)-4-(2-azidopropan-2-yl)-6-chloro-1- ((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naph thyridine or (R)-4-(2- azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulf onyl)butan-2-yl)oxy)-2,7- naphthyridine (Intermediate 105, 35 mg, 35% yield) and second eluting isomer, one of (S)-4- (2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methyls ulfonyl)butan-2-yl)oxy)-2,7- naphthyridine and (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (Intermediate 106, 36 mg, 35% yield) were obtained as colorless oils. MS (ES+) C16H17ClF3N5O3S requires: 451, found: 452[M+H] ⁺ . Intermediates 107 and 108: (S)-((2R,4R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro- 2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-su lfanone and (R)-((2R,4R)-4-((4- ((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)p entan-2-yl)(imino)(methyl)- λ6-sulfanone Step 1: (2R,4R)-4-(Methylthio)pentan-2-ol A solution of t-butyldimethyl(((2R,4R)-4-(methylthio)pentan-2-yl)oxy)silan e (8.8 g, 35.4 mmol) in HCl/MeOH (4 M, 100 mL) was stirred at 25 °C for 1 h. The reaction mixture was then concentrated to give a residue. The residue was purified by flash-column chromatography (gradient elution, 5-100% EA/PE) to give the title compound (3.04 g, 64% yield) as a slightly yellow oil. Step 2: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylthio )pentan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from (2R,4R)-4-(methylthio)pentan-2-ol and (R)-4- (2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described above for Intermediate 22. MS (ES+) C ₁₈ H ₂₄ ClN ₅ OS requires: 393, found: 394[M+H] ⁺ . Step 3: ((2R,4R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1- yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-sulfanone To a mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylthio)pentan-2-yl)oxy)-2,7-naphthyridine (600 mg, 1.52 mmol) and NH ₄ HCO ₃ (421 mg, 5.33 mmol) in MeOH (20 mL) was added PhI(OAc) ₂ (1.96 g, 6.09 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, then was diluted with saturated aqueous NH4Cl solution (30 mL) and extracted with EA (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40 mm x 15um; mobile phase: [water (FA)-ACN]; B%: 42%-72%, 10 min) to give the title compound (360 mg, 47% yield, 84.3% purity) as a slight yellow semisolid. MS (ES+) C ₁₈ H ₂₅ ClN ₆ O ₂ S requires: 424, found: 425[M+H] ⁺ . Step 4: (S)-((2R,4R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naph thyridin-1- yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((2R,4R)-4-((4-((R)-2-Azidobutan- 2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino) (methyl)-λ6-sulfanone ((2R,4R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)pentan-2- yl)(imino)(methyl)-λ6-sulfanone (700 mg) was separated by SFC (column: Daicel Chiralcel OJ-H (250mm x 30 mm, 5um); mobile phase: [0.1%NH3H2O-IPA]; B%: 20%-20%) to give two peaks separately. The first eluting isomer, one of (S)-((2R,4R)-4-((4-((R)-2-azidobutan-2- yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(m ethyl)-λ6-sulfanone or (R)- ((2R,4R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)pentan-2- yl)(imino)(methyl)-λ6-sulfanone (Intermediate 107, 276 mg, 38% yield) and second eluting isomer, one of (S)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naph thyridin-1- yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((2R,4R)-4-((4-((R)-2-Azidobutan-2- yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(m ethyl)-λ6-sulfanone (Intermediate 108, 453 mg, 64% yield) were obtained as white semisolids. MS (ES+) C ₁₈ H ₂₅ ClN ₆ O ₂ S requires: 424, found: 425[M+H] ⁺ . Intermediates 109 and 110: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro- 1-(((S)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naph thyridine Step 1: 4-Methyl-4-(methylthio)pentan-2-ol To a mixture of 4-methyl-4-(methylthio)pentan-2-one (1 g, 6.84 mmol) in THF (10 mL) and MeOH (1 mL) was added NaBH4 (517 mg, 13.7 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, then was quenched with H2O (30 mL) and extracted with EA (100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound (970 mg, 96% yield, crude) as a colorless oil Step 2: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylthi o)pentan-2- yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-methyl-4-(methylthio)pentan-2-ol and (R)-4- (2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a similar procedure as described above for Intermediate 22. MS (ES+) C19H26ClN5OS requires: 407, found: 408[M+H] ⁺ . Step 3: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylsul fonyl)pentan- 2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4- methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine using a similar procedure as described in Step 5 of Intermediate 30. MS (ES+) C ₁₉ H ₂₆ ClN ₅ O ₃ S requires: 439, found: 440[M+H] ⁺ . Step 4: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro- 1-(((S)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naph thyridine 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylsul fonyl)pentan-2- yl)oxy)-2,7-naphthyridine (215 mg) was separated by SFC (column: Daicel Chiralpak IG (250 mm x 50 mm, 10um); mobile phase: [0.1%NH3H2O MEOH]; B%: 40%-40%) to give two peaks separately. The first eluting isomer, one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1- (((R)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphth yridine or 4-((R)-2- azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylsulfonyl )pentan-2-yl)oxy)-2,7- naphthyridine (Intermediate 109, 100 mg, 47% yield) and second eluting isomer, one of 4- ((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methyls ulfonyl)pentan-2-yl)oxy)-2,7- naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (Intermediate 110, 100 mg, 46% yield) were obtained as white solids. MS (ES+) C ₁₉ H ₂₆ ClN ₅ O ₃ S requires: 439, found: 440[M+H] ⁺ . Intermediates 111, 112, 113, and 114: (S)-((R)-4-((4-((R)-2-Azidobutan-2-yl)-6- chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino )(methyl)-λ6-sulfanone and (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)-2-methylpentan- 2-yl)(imino)(methyl)-λ6-sulfanone and (S)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7- naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-� �6-sulfanone and ( )-4- ((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)o xy)-2-methylpentan-2- yl)(imino)(methyl)-λ6-sulfanone each of which is represented by one of the structures below: which is represented by one of the structures below: SFC separation P _{recursor II of Intermediates 111 and 112} ^{Intermediate 111} and Intermediate 112 (1st eluting isomer) (2nd eluting isomer) Each of which is represented by one of the four structures below: which is represented by one of the structures below: Each of which is represented by one of the four structures below: Step 1: 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methy lthio)pentan-2- yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4- (methylthio)pentan-2-yl)oxy)-2,7-naphthyridine 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylthi o)pentan-2-yl)oxy)-2,7- naphthyridine (500 mg) was separated by SFC (column: Daicel Chiralpak IG (250mm x 30mm, 10 um); mobile phase: [0.1%NH3H2O MeOH]; B%: 15%-15%) to give two peaks separately. The first eluting isomer, one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4- methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6- chloro-1-(((S)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-n aphthyridine (Precursor I to Intermediates 111 and 112, 200 mg, 40% yield) and second eluting isomer, one of 4-((R)-2- azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylthio)pen tan-2-yl)oxy)-2,7- naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methy lthio)pentan- 2-yl)oxy)-2,7-naphthyridine (Precursor I to Intermediates 113 and 114, 200 mg, 40% yield) were obtained as colorless oils. MS (ES+) C ₁₉ H ₂₆ ClN ₅ OS requires: 407, found: 408[M+H] ⁺ . Step 2: ((R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyridin -1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or ((S)-4-((4-((R)-2-azidobutan-2-yl)-6- chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino )(methyl)-λ6-sulfanone The title compound (Precursor II to Intermediates 111 and 112) was prepared from 4- ((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylt hio)pentan-2-yl)oxy)-2,7- naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methy lthio)pentan- 2-yl)oxy)-2,7-naphthyridine (Precursor 1 to Intermediates 111 and 112, 1 ^st eluting isomer from above) using a procedure similar to that described in Step 3 of Intermediate 107. MS (ES+) C ₁₉ H ₂₇ ClN ₆ O ₂ S requires: 438, found: 439[M+H] ⁺ . Step 3: (S)-((R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)- 2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((R)-4-((4-((R)-2-azidobutan-2- yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl) (imino)(methyl)-λ6-sulfanone and (S)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)- 6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imi no)(methyl)-λ6-sulfanone ((R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyridin -1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or ((S)-4-((4-((R)-2-azidobutan-2-yl)-6- chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino )(methyl)-λ6-sulfanone (Precursor II to Intermediates 111 and 112, 120 mg) was separated by SFC (column: Daicel Chiralpak IG (250mm x 30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O IPA];B%: 55%-55%) to give two peaks separately. The first eluting isomer, one of (S)-((R)-4-((4-((R)-2-azidobutan- 2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-y l)(imino)(methyl)-λ6- sulfanone or (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (S)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6- chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino )(methyl)-λ6-sulfanone or (R)- ((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin -1-yl)oxy)-2-methylpentan-2- yl)(imino)(methyl)-λ6-sulfanone (Intermediate 111, 31 mg, 24% yield) and second eluting isomer, one of (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6- chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino )(methyl)-λ6-sulfanone or (S)- ((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin -1-yl)oxy)-2-methylpentan-2- yl)(imino)(methyl)-λ6-sulfanone or (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7- naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-� �6-sulfanone (Intermediate 112, 75 mg, 59% yield) were obtained as white solids. MS (ES+) C19H27ClN6O2S requires: 438, found: 439[M+H] ⁺ . Step 4: ((R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyridin -1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or ((S)-4-((4-((R)-2-azidobutan-2-yl)-6- chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino )(methyl)-λ6-sulfanone The title compound (Precursor II to Intermediates 113 and 114) was prepared from 4- ((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylt hio)pentan-2-yl)oxy)-2,7- naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methy lthio)pentan- 2-yl)oxy)-2,7-naphthyridine (Precursor 1 to Intermediates 113 and 114, 2 ^nd eluting isomer from above) using a procedure similar to that described in Step 3 of Intermediate 107. MS (ES+) C ₁₉ H ₂₇ ClN ₆ O ₂ S requires: 438, found: 439[M+H] ⁺ . Step 5: (S)-((R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)- 2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((R)-4-((4-((R)-2-azidobutan-2- yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl) (imino)(methyl)-λ6-sulfanone and (S)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)- 6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imi no)(methyl)-λ6-sulfanone ((R)-4-((4-((R)-2-Azidobutan-2-yl)-6-chloro-2,7-naphthyridin -1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or ((S)-4-((4-((R)-2-azidobutan-2-yl)-6- chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino )(methyl)-λ6-sulfanone (Precursor II to Intermediates 113 and 114, 120 mg) was separated by SFC (column: Daicel Chiralpak AD-H (250mm x 30mm,5um); mobile phase: [0.1%NH3H2O EtOH];B%: 20%- 20%) to give two peaks separately. The first eluting isomer, one of (S)-((R)-4-((4-((R)-2- azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methy lpentan-2-yl)(imino)(methyl)- λ6-sulfanone or (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)- 2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (S)-((S)-4-((4-((R)-2-azidobutan-2-yl)- 6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imi no)(methyl)-λ6-sulfanone or (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)-2-methylpentan- 2-yl)(imino)(methyl)-λ6-sulfanone (Intermediate 113, 31 mg, 25% yield) and second eluting isomer, one of (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyr idin-1-yl)oxy)-2- methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6- chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino )(methyl)-λ6-sulfanone or (S)- ((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin -1-yl)oxy)-2-methylpentan-2- yl)(imino)(methyl)-λ6-sulfanone or (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7- naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-� �6-sulfanone (Intermediate 114, 60 mg, 5947% yield) were obtained as white solids. MS (ES+) C19H27ClN6O2S requires: 438, found: 439[M+H] ⁺ . Intermediates 115 and 116: (S)-N-((S)-1-(6-Chloro-1-((cis)-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2 -methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutox y)-2,7-naphthyridin-4- yl)propyl)-2-methylpropane-2-sulfinamide each of which is represented by one of the structures shown below: Step 1: (S)-N-((S)-1-(6-Chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy) -2,7- naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2- methylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2 ,7- naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (500 mg, 1.13 mmol) in THF (20 mL) was added EtMgBr (3 M, 1.13 mL) at 0 °C. The cooling bath was removed, and the reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was then quenched by addition of saturated aqueous NH ₄ Cl solution (40mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150×40mm× 15um; mobile phase: [water (0.1%TFA)-ACN]; B%: 36%-46%, 10min) to give one of (S)-N-((S)-1-(6-chloro-1-((cis)-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2 -methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutox y)-2,7-naphthyridin-4- yl)propyl)-2-methylpropane-2-sulfinamide as the first eluting isomer (Intermediate 115, 100 mg, 16% yield) as a white solid and the other one of (S)-N-((S)-1-(6-chloro-1-((cis)-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2 -methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutox y)-2,7-naphthyridin-4- yl)propyl)-2-methylpropane-2-sulfinamide as the second eluting isomer (Intermediate 116, 100 mg, 17% yield, the second fraction) as a white solid. Intermediate 115: MS (ES+) C ₂₀ H ₂₈ ClN ₃ O ₄ S ₂ requires: 44., found: 474[M+H] ⁺ . Intermediate 116: MS (ES+) C20H28ClN3O4S2 requires: 44., found: 474[M+H] ⁺ . Representative Methods to Synthesize Compounds in Table 1 Example 1a: Synthetic Method 1 (7S,8R)-2-((5-(2-Aminopropan-2-yl)-8-((cis)-3-(ethylsulfonyl )cyclobutoxy)-2,7- naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[ 4,3-b]pyridin-5-one (Compound 39) Step 1: (7S,8R)-2-((5-((R)-2-Azidobutan-2-yl)-8-(cis-3-(ethylsulfony l)cyclobutoxy)- 2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyr ano[4,3-b]pyridin-5-one A mixture of 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cycl obutoxy)- 2,7-naphthyridine (Intermediate 44, 60 mg, 146 μmol), (7S,8R)-2-amino-7,8-dimethyl-7,8- dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 1, 31.0 mg, 161 μmol), BrettPhos G4 precatalyst (6.74 mg, 7.32 μmol), BrettPhos (3.93 mg, 7.32 μmol) and KOAc (35.9 mg, 366 μmol) in dioxane (2 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 100 °C for 4 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by prep-TLC (PE/EA = 0:1) to give the title compound (40.0 mg, 49% yield) as a white solid. Step 2: (7S,8R)-2-((5-(2-Aminopropan-2-yl)-8-((cis)-3-(ethylsulfonyl )cyclobutoxy)- 2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyr ano[4,3-b]pyridin-5-one To a solution of (7S,8R)-2-((5-((R)-2-azidobutan-2-yl)-8-(cis-3- (ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8 -dimethyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one (40.0 mg, 70.7 μmol) in EA (30 mL) was added platinum dioxide (12.1 mg, 53.1 μmol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25 °C for 16 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (10mM NH ₄ HCO ₃ )-ACN]; B%: 22%-52%) to give the title compound (11.7 mg, 31% yield) as a yellow solid. MS (ES+) C27H33N5O5S requires: 539, found: 540[M+H] ⁺ . NMR (400 MHz, CD3OD): δ ppm 10.70 (s, 1H), 9.42 (s, 1H), 9.32 (s, 1H), 8.14 (s, 1H), 8.08 (d, J = 8.63 Hz, 1H) 7.37 (d, J = 8.8 Hz, 1H), 5.42-5.30 (m, 1H), 4.67-4.49 (m, 1H), 3.99-3.77 (m, 1H), 3.10-3.04 (m, 2H), 3.02-2.95 (m, 1H), 2.89-2.82 (m, 2H), 2.57-2.53 (m, 1H), 1.65 (d, J = 2.4 Hz, 6H), 1.44 (d, J = 7.2 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.4 Hz, 3H). Example 1b: Synthetic Method 1 (R)-2-((5-(2-Aminopropan-2-yl)-8-(cis-3-(methylsulfonyl)cycl obutoxy)-2,7- naphthyridin-3-yl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyra no[4,3-b]pyridin-5-one (Compound 42)

Step 1: (R)-2-((5-(2-Azidopropan-2-yl)-8-(cis-3-(methylsulfonyl)cycl obutoxy)-2,7- naphthyridin-3-yl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyra no[4,3-b]pyridin-5-one A mixture of 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(methylsulfonyl)cyc lobutoxy)- 2,7-naphthyridine (Intermediate 22, 400 mg, 1.01 mmol), (R)-2-amino-7,7,8-trimethyl-7,8- dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 3, 229 mg, 1.11 mmol), BrettPhos G4 precatalyst (93.0 mg, 101 umol), BrettPhos (108 mg, 202 umol) and KOAc (298 mg, 3.03 mmol) in dioxane (8 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 100 °C for 1 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by flash-column chromatography on silica gel (0 to 60% EA/PE) to give the title compound (370 mg, 61% yield) as a yellow solid. Step 2: (R)-2-((5-(2-Aminopropan-2-yl)-8-(cis-3-(methylsulfonyl)cycl obutoxy)-2,7- naphthyridin-3-yl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyra no[4,3-b]pyridin-5-one To a solution of (R)-2-((5-(2-Azidopropan-2-yl)-8-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7, 7,8-trimethyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one (370 mg, 654 umol) in EA (12 mL) was added platinum dioxide (44.6 mg, 196 umol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25 °C for 2 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150×40mm× 15μm; mobile phase: [water (0.225%FA)-ACN]; B%: 10%-40%) to give the title compound (279 mg, 79% yield) as an off-white solid. MS (ES+) C27H33N5O5S requires: 539, found: 540[M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD):δ ppm 9.39 (s, 1 H), 9.21 (s, 1 H), 8.54 (s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 8.07-8.03 (m, 1 H), 7.25 (d, J = 8.8 Hz, 1 H), 5.51-5.36 (m, 1 H), 3.92-3.75 (m, 1 H), 3.05-2.95 (m, 3 H), 2.93 (s, 3 H), 2.76-2.63 (m, 2 H), 1.94 (d, J = 11.2 Hz, 6 H), 1.53 (s, 3 H), 1.45 (s, 3 H), 1.40 (d, J = 7.2 Hz, 3 H). Example 1c: Synthetic Method 1 (7S,8R)-2-((5-((R)-2-Aminobutan-2-yl)-8-(((R)-4-(methylsulfo nyl)butan-2-yl)oxy)- 2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyr ano[4,3-b]pyridin-5-one (Compound 52) Step 1: (7S,8R)-2-((5-((R)-2-Azidobutan-2-yl)-8-(((R)-4-(methylsulfo nyl)butan-2- yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydr o-5H-pyrano[4,3-b]pyridin-5- one A mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl )butan-2- yl)oxy)-2,7-naphthyridine (Intermediate 31, 130 mg, 316 μmol), (7S,8R)-2-amino-7,8- dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 1, 60.7 mg, 316 μmol), BrettPhos G4 precatalyst (29.1 mg, 31.6 umol), BrettPhos (16.9 mg, 31.6 μmol) and KOAc (77.4 mg, 789 μmol) in dioxane (3 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 100 °C for 1 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by prep-TLC (PE/EA = 1: 2) to give the title compound (130 mg, 73% yield) as a yellow solid. Step 2: (7S,8R)-2-((5-((R)-2-Aminobutan-2-yl)-8-(((R)-4-(methylsulfo nyl)butan-2- yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydr o-5H-pyrano[4,3-b]pyridin-5- one To a solution of (7S,8R)-2-((5-((R)-2-azidobutan-2-yl)-8-(((R)-4- (methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino) -7,8-dimethyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one (130 mg, 229 μmol) in EA (10 mL) was added platinum dioxide (39.2 mg, 172 μmol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25 °C for 16 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (PE/EA = 1:0 to 0:1, followed by EA/MeOH = 1:0 to 10:1) to give the title compound (59.0 mg, 46% yield) as a yellow solid. MS (ES+) C27H35N5O5S requires: 541, found: 542[M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.14 (s, 1H), 8.20-8.11 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 5.71-5.53 (m, 1H), 4.73-4.63 (m, 1H), 3.42-3.32 (m, 2H), 3.07-2.97 (m, 4H), 2.50-2.39 (m, 1H), 2.37-2.29 (m, 2H), 2.24- 2.11 (m, 1H), 1.78 (s, 3H), 1.54-1.48 (m, 6H), 1.46 (d, J = 6.8 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H). Example 1d: Synthetic Method 1 (7S,8R)-2-((5-((R)-2-Aminobutan-2-yl)-8-(((2R,4R)-4-(ethylsu lfonyl)pentan-2- yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydr o-5H-pyrano[4,3-b]pyridin-5- one (Compound 127) Step 1: (7S,8R)-2-((5-((R)-2-Azidobutan-2-yl)-8-(((2R,4R)-4-(ethylsu lfonyl)pentan-2- yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydr o-5H-pyrano[4,3-b]pyridin-5- one A mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfo nyl)pentan- 2-yl)oxy)-2,7-naphthyridine (Intermediate 86, 85 mg, 193 umol), (7S,8R)-2-amino-7,8- dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 1, 37.1 mg, 193 umol), BrettPhos G4 precatalyst (17.8 mg, 19.3 umol), BrettPhos (20.7 mg, 38.6 umol) and KOAc (56.9 mg, 579 umol) in dioxane (3 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 100 °C for 1 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by flash-column chromatography on silica gel (0 to 60% EA/PE) to give the title compound (120 mg, 54% yield) as a white solid. Step 2: (7S,8R)-2-((5-((R)-2-Aminobutan-2-yl)-8-(((2R,4R)-4-(ethylsu lfonyl)pentan- 2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihy dro-5H-pyrano[4,3-b]pyridin- 5-one To a solution of (7S,8R)-2-((5-((R)-2-Azidobutan-2-yl)-8-(((2R,4R)-4- (ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino) -7,8-dimethyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one (120 mg, 201 umol) in EA (16 mL) was added platinum dioxide ((13.7 mg, 60.4 umol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25 °C for 2 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by prep-TLC (EA/MeOH = 1:1) to give the title compound (31.2 mg, 27% yield) as a white solid. MS (ES+) C ₂₉ H ₃₉ N ₅ O ₅ S requires: 569, found: 570[M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD): δ ppm 9.36 (s, 1 H), 9.15 (s, 1 H), 8.28-8.00 (m, 2 H), 7.29 (d, J = 8.8 Hz, 1 H), 5.80-5.61 (m, 1 H), 4.73-4.56 (m, 1 H), 3.45-3.35 (m, 1 H), 3.14-3.06 (m, 2 H), 3.06-2.98 (m, 1 H), 2.49-2.30 (m, 2 H), 2.23-2.03 (m, 2 H), 1.73 (s, 3 H), 1.51-1.43 (m, 12 H), 1.34-1.27 (m, 3 H), 0.78-0.68 (m, 3 H). Example 1e: Synthetic Method 1 2'-((5-((R)-2-Aminobutan-2-yl)-8-(((2R,4R)-4-(methylsulfonyl )pentan-2-yl)oxy)-2,7- naphthyridin-3-yl)amino)-7',7'-dimethyl-5'H,7'H-spiro[cyclop ropane-1,8'-pyrano[4,3- b]pyridin]-5'-one (Compound 136)

Step 1: 2'-((5-((R)-2-Azidobutan-2-yl)-8-(((2R,4R)-4-(methylsulfonyl )pentan-2- yl)oxy)-2,7-naphthyridin-3-yl)amino)-7',7'-dimethyl-5'H,7'H- spiro[cyclopropane-1,8'- pyrano[4,3-b]pyridin]-5'-one A mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (Intermediate 53, 70.0 mg, 164 μmol), 2'-amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyra no[4,3-b]pyridin]-5'-one (Intermediate 15, 36.0 mg, 164 μmol), BrettPhos G4 precatalyst (8.00 mg, 8.22 μmol), BrettPhos (9.00 mg, 16.4 μmol) and KOAc (48.0 mg, 493 μmol) in dioxane (2 mL) was degassed and purged with nitrogen 3 times, then the mixture was stirred at 100 °C for 3 h. The reaction mixture was then filtered and concentrated to give a residue. The residue (90.0 mg, 90% yield, yellow oil) was used in the next step without further purification. Step 2: 2'-((5-((R)-2-Aminobutan-2-yl)-8-(((2R,4R)-4-(methylsulfonyl )pentan-2- yl)oxy)-2,7-naphthyridin-3-yl)amino)-7',7'-dimethyl-5'H,7'H- spiro[cyclopropane-1,8'- pyrano[4,3-b]pyridin]-5'-one To a solution of 2'-((5-((R)-2-Azidobutan-2-yl)-8-(((2R,4R)-4- (methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino )-7',7'-dimethyl-5'H,7'H- spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one (90.0 mg, 148 μmol) in EA (10 mL) was added platinum dioxide (13.0 mg, 55.3 μmol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25 °C for 16 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by prep-TLC (EA/MeOH = 10:1) to give the title compound (30.2 mg, 33% yield) as a yellow solid. MS (ES+) C ₃₀ H ₃₉ N ₅ O ₅ S requires: 581, found: 582[M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD): δ ppm 9.41 (s, 1H), 8.33 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 5.75-5.65 (m, 1H), 3.40-3.33 (m, 1H), 2.93 (s, 3H), 2.45-2.30 (m, 2H), 2.18-2.08 (m, 2H), 1.76 (s, 3H), 1.559-1.53 (m, 2H), 1.52- 1.47 (m, 6H), 1.42 (s, 6H), 1.31-1.27 (m, 2H), 0.76 (d, J = 7.2 Hz, 3H). Example 2: Synthetic Method 2 (R)-2-((5-((S or R)-Amino(cyclopropyl)methyl)-8-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7, 7,8-trimethyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one (Compound 62) Step 1: (S)-N-((R or S)-Cyclopropyl(1-(cis-3-(methylsulfonyl)cyclobutoxy)-6-(((R) - 7,7,8-trimethyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2- yl)amino)-2,7-naphthyridin-4- yl)methyl)-2-methylpropane-2-sulfinamide A mixture of (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyri din-5- one (Intermediate 3, 44.6 mg, 216 umol), (S)-N-((6-chloro-1-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)(cyclopro pyl)methyl)-2-methylpropane- 2-sulfinamide (Intermediate 58, 100 mg, 206 umol), BrettPhos (22.1 mg, 41.2 umol), BrettPhos G4 precatalyst (18.9 mg, 20.6 umol), and KOAc (60.6 mg, 617 umol) in dioxane (3 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 100 °C for 1 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by prep-TLC (PE/EA = 0:1) to give the title compound (one of two isomers, stereochemistry at the cyclopropyl position undetermined) as the second eluting isomer (20 mg, 15% yield, white solid). MS (ES+) C ₃₂ H ₄₁ N ₅ O ₆ S ₂ requires: 655, found: 656[M+H] ⁺ . Step 2: (R)-2-((5-((S or R)-Amino(cyclopropyl)methyl)-8-(cis-3- (methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7, 7,8-trimethyl-7,8-dihydro-5H- pyrano[4,3-b]pyridin-5-one To a solution of (S)-N-((R or S)-cyclopropyl(1-(cis-3-(methylsulfonyl)cyclobutoxy)-6- (((R)-7,7,8-trimethyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyri din-2-yl)amino)-2,7- naphthyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide (20 mg, 30.5 umol) in dioxane (2 mL) was added 4 M HCl in dioxane (1 mL). The reaction mixture was stirred at 25 °C for 5 min, then was concentrated to give a residue was purified by prep-HPLC (column: Waters Xbridge 150×25mm× 5μm; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 25%-55%, 10min) to give the title compound (16 mg, 93% yield) as a yellow solid. MS (ES+) C28H33N5O5S requires: 551, found: 552[M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD): δ ppm 9.39-9.23 (m, 1H), 8.97-8.83 (m, 1H), 8.20 (s, 1 H), 8.15-8.07 (m, 1H), 7.19 ( d, J = 8.8 Hz, 1H), 5.61-5.27 (m, 2H), 3.83 (d, J = 6.4 Hz, 2H), 3.67-3.56 (m, 1H), 3.22-3.11 (m, 1H), 2.93 (s, 4H), 2.68 (d, J = 5.2 Hz, 2H), 1.54-1.43 (m, 9H), 0.73-0.34 (m, 4H). Example 3: Inhibition of MAP4K1 Biochemical Enzymatic Activity MAP4K1 (HPK1) and relevant off-target enzymatic activity was monitored using the Perkin Elmer electrophoretic mobility shift technology platform – the EZReader 2. Fluorescent labeled substrate peptide was incubated in the presence of kinase and ATP, and in the presence of dosed compound, such that each dose of compound resulted in a reflective proportion of the peptide to be phosphorylated. Within the linear, steady-state phase of the kinase enzymatic reaction, the mixed pool of phosphorylated (product) and non- phosphorylated (substrate) peptides was passed through the microfluidic system of the PerkinElmer EZ Reader 2, under an applied electric potential difference. The presence of the phosphate group on the product peptide provided a difference in mass and charge between that of the substrate peptide, resulting in a separation of the substrate and product pools in the sample (Perrin et al. 2010). As the product and substrate peptide mixture passes the lasers within the instrument, these pools are detected (λex = 488 nm, λem = 568 nm) and resolved as separate peaks. The ratio between these peaks reflects the activity of the compound at that concentration, in that well, under those conditions. Enzyme Activity Inhibition Assay Protocol: Inhibitors were dissolved in 100% DMSO at a stock concentration of 10 mM. A 100X, 10-point, 4-fold serial dilution of each inhibitor was created in 100% DMSO either manually or on a Hamilton STAR liquid handler, starting at a relevant concentration, usually 1 mM. A volume of 0.130 µL of each concentration was transferred to the relevant wells of a 384-well plate (Greiner 781 201) in duplicate using a TTPLabtech Mosquito nano-litre dispenser. Using a Multidrop Combi, the remaining constituents of the kinase reaction were added to the 130 nL of dosed compound as follows (see table below for final reaction details): Enzyme activity assays at the ^APP KM for ATP or 1 mM ATP: In each well of a 384- well plate, 0.1 - 15 nM of untreated enzyme was incubated in a total of 13 µL of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl ₂ , 1mM DTT) with 1.5 µM fluorescent peptid and 20 - 1000 µM ATP, at 25 ^o C, for 60 - 180 minutes in the presence or absence of a dosed concentration series of compound (1% DMSO final concentration). The kinase reactions were stopped by the addition of 70 µl of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)). The plates were read on a Caliper EZReader 2 as described above. Table 2 Kinase Reaction Conditions S6K2tide; Carna Biosciences (5-FAM-Proprietary Sequence-CONH2) FL4tide; Perkin Elmer (5-FAM-EGIYGVLFKKK (SEQ ID NO: 1)-CONH2) FL25tide; Perkin Elmer (5-FAM-VDGKEIYNTIRRK (SEQ ID NO: 2)-CONH2) PKAtide; Anaspec Peptide Co.(5-FAM-GRTGRRNSI (SEQ ID NO: 3)-CONH ₂ ) Perrin D, Frémaux C, Shutes A. Capillary microfluidic electrophoretic mobility shift assays: application to enzymatic assays in drug discovery. Expert Opin Drug Discov.2010, 5(1):51-63. The results obtained in these experiments for compounds prepared according to the examples are summarized in Table 3 below. Table 3

Example 4: T Cell Enhancement of Cytokines Isolation and Expansion of T cells from whole blood T cells are isolated from whole blood of healthy donors by immunomagnetic negative selection following manufacture’s protocol (StemCell Technologies, human T cell isolation kit). Purity of isolated cells is assessed by flow cytometry and yields 95-98% CD3 ⁺ T cells. For expansion of T cells, 1x10 ⁶ cells/well are plated in serum free cell expansion media (ThermoFisher) containing 30U of recombinant human IL2 (R&D) and stimulated with 25ul of CD3/CD28 beads (Invitrogen) in 24 well plates for 3-4 days. T cells are then expanded in 175cm flasks and maintained at a cell density of 1 to 2.5x10 ⁶ cells/ml days by addition of 2/3 of fresh media every 2-3 days. After 10-14 days, cells are frozen in BamBanker freezing media (Thermo) and stored in liquid nitrogen. Phenotypic analysis of expanded T cells by flow cytometry, routinely shows 60% cells are CD8 ⁺ T cells upon freezing. Cytokine Measurement For IL2 measurement, expanded CD3 ⁺ T cells are dispensed at 100K cells/well (cultured in X-VIVO 10 Serum-free media) and are stimulated with plate-bound anti-CD3 and soluble anti-CD28 in the presence of vehicle or compound of the disclosure at various concentrations for 24h. As outlined in the manufacturer’s protocol (Cisbio), 16 µL of conditioned media is transferred to a white 384-well low volume plate. Following a 24h incubation with the anti-IL2 antibodies, the homogenous time resolved fluorescence (HTRF) is measured. Example 5: Inhibition of Anti-Tumor Activity in a Syngeneic Mouse Model Generation of the MCA205 Syngeneic xenograft anti-tumor efficacy study Six to eight-week-old female, C57BL/6 mice (Jackson Labs, Bar Harbor, ME) are implanted subcutaneously on the left flank with 1 x 10 ⁶ MCA205 cells / mouse. After tumors reach an average volume of 50 mm ³ , mice are randomized into treatment groups, 10 mice per group, with tumors in the size range of 30-70 mm ³ . Compounds of the disclosure 10-30 mg/kg, anti-mouse PD-L1 mAb (B7 H1, clone # 10F.9G2 Bio-X-cell, Lebanon, NH) and vehicle either alone or in different combinations are administered to tumor bearing mice. Reduction in tumor volume is measured [mm ³ ] over time. Equivalents In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described and claimed herein. Such equivalents are intended to be encompassed by the following claims.