WO2025166215A1

WO2025166215A1 - Triheterocyclic guanidino compounds as prmt5 inhibitors

Info

Publication number: WO2025166215A1
Application number: PCT/US2025/014100
Authority: WO
Inventors: Paul A. Barsanti; Melissa Fleury; Joshua P. G. TAYGERLY
Original assignee: Ideaya Biosciences Inc
Current assignee: Ideaya Biosciences Inc
Priority date: 2024-02-02
Filing date: 2025-01-31
Publication date: 2025-08-07
Anticipated expiration: 2026-08-02

Abstract

Provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. The provided compounds are useful Protein arginine N-methyltransferase 5 (PRMT5) inhibitors. Also, disclosed are pharmaceutical compositions comprising such compounds and methods of making such compounds. Additional utilities and advantages are described herein.

Description

TRIHETEROCYCLIC GUANIDINO COMPOUNDS AS PRMT5 INHIBITORS

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Nos. 63/549,374 filed February 02, 2024; 63/681 ,488 filed August 09, 2024; and 63/738,009 filed December 23, 2024; the contents of each is incorporated by reference in its entirety for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] NOT APPLICABLE

REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK

[0003] NOT APPLICABLE

BACKGROUND

[0004] Cancer is a leading cause of death throughout the world. A limitation of prevailing therapeutic approaches, e.g. chemotherapy and immunotherapy is that their cytotoxic effects are not restricted to cancer cells and adverse side effects can occur within normal tissues. Consequently, novel strategies are needed to better target cancer cells.

[0005] Synthetic lethality arises when a combination of deficiencies in the expression or activity of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The concept of synthetic lethality originates from studies in drosophila model systems in which a combination of mutations in two or more separate genes leads to cell death (in contrast to viability, which occurs when only one of the genes is mutated or deleted). More recently, a multitude of studies have explored maladaptive genetic changes in cancer cells that render them vulnerable to synthetic-lethality approaches. These tumorspecific genetic defects lead to the use of targeted agents that induce the death of tumor cells while sparing normal cells. [0006] Protein arginine N-methyltransferase 5 (PRMT5) is a methyl transferase that uses s- adenosyl methionine (SAM) as a methyl donor. PRMT5 catalyzes symmetrical dimethylarginine in a number of substrates including histone and non-histone proteins. The acti vity of PRMT5 has been associated with development and cancer as well as other biological functions.

[0007] Due to the role of PRMT5 in human diseases such as cancer, several inhibitors of PRMT5 have been developed. A number of these compounds target the SAM-PRMT5 complex either through competitive inhibition with SAM or the protein substrate. A challenge for these inhibitors is that the SAM-PRMT5 complex forms in both normal and cancer cells, making it difficult to selectively inhibit PRMT5 in only cancer cells.

[0008] Chromosome 9p21 encompasses, among others, CDKN2A (cyclin dependent kinase inhibitor 2A), and homozygous deletion of 9p2i genomic locus is implicated in about 15% of all cancers. MTAP is located within the vicinity of the CDKN2A on chromosome 9p21 and is frequently co-deleted with CDKN2A deletion. The MTAP protein (methylthioadenosine phosphorylase) is an enzyme involved in polyamine metabolism, and the deletion of MTAP results in the accumulation of 5’methylihioadenosine (MTA) in the cell.

[0009] Seemingly due to structural similarities between SAM and MIA, PRMT5 is competitively inhibited by MTA. Cells with an MTAP deletion have increased levels of MTA, thereby partially inhibiting PRMT5. A new generation of PRMT5 inhibitors targeting the MTA-PRMT5 complex in MTAP deleted cancers are being developed. These MTA cooperative inhibitors selectively bind to the MTA-PRMT5 complex, effectively inhibiting PRMT5 in MTAP deleted cells, while leaving normal cells relatively unaffected. Inhibition of PRMT5 with MTA cooperative inhibitors leads to ceil death and provides a new synthetic lethality approach for the treatment of MTAP deleted cancers.

[0010] Despite a mechanistic understanding and approach for the treatment of MTAP deleted cancers, there remains a need in the art to develop selective MTA cooperative PRMT5 inhibitors possessing appropriate selectivity and providing suitable therapeutic windows for treatment. The present disclosure addresses these needs and provides related advantages.

SUMMARY

[0011] In one aspect, provided herein is a compound of Formula (I): p or a pharmaceutically acceptable salt thereof. The definitions lor Y¹, X', X², X³, R⁴, n, ring A, ring B, R^s, p, R^b, and q are further described herein.

[0012] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof, and one or more pharmaceutically acceptable excipients.

[0013] In another aspect, provided herein is a method of treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0014] In another aspect, provided herein is a method of treating an MTAP null cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0015] In another aspect, provided herein is a method of treating a cancer in a patient in need thereof, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, reduced function of MTAP protein, or a combination thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0016] In another aspect, provided herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. [0017] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5).

[0018] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an MTAP null cancer.

[0019] lit another aspect, pro vided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof.

[6020] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer.

[0021] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0022] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment of a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5).

[0023] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment of an MTAP null cancer.

[0024] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment of cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof.

[0025] in another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment of cancer.

[0026] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the production of a protein arginine N- methyltransferase 5 (PRMT5) inhibitory effect.

[0027] In another aspect, provided herein is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the production of a protein arginine N- methyltransferase 5 (PRMT5) inhibitory effect.

[0028] In another aspect, provided herein is a method of inhibiting protein arginine N- me thy 1 transferase 5 (PRMT5) in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0029] In another aspect, provided herein is a method of inhibiting cell proliferation in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0030] In some embodiments, the methods, uses, and medicament described herein are for the treatment of human cancers.

[0031] In another aspect, provided are methods of synthesizing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof as defined herein.

[0032] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein. [0033] In another aspect, provided herein are novel intermediates as defined herein which are suitable for use in any one of the synthetic methods as set out herein.

[0034] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] NOT APPLICABLE

DETAILED DESCRIPTION OF THE INVENTION

[0036] Before the present invention is further described, it is to be understood that the invention is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0037] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, patient to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0038] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. GENERAL

[0039] Provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof for inhibition of protein arginine N-methyltransferase 5 (PRMT5), and pharmaceutical compositions comprising the same. Also provided herein are, for example, methods of treating or preventing a disease, disorder or condition, or a symptom thereof, mediated by inhibi tion of PRMT5. Further provided herein are methods treating or preventing a disease, disorder or condition, or a symptom thereof treatable by inhibition of PRMT5.

DEFINITIONS

[0040] Unless otherwise indicated, the following terms are intended to have the meaning set forth below. Other terms are defined elsewhere throughout the specification.

[0041] Unless specifically indicated otherwise, the group “X”""” as used in any one of the structures in Table 1, the Examples, or moieties disclosed herein, refers to methyl (-CH 3) where the wavy line is the point of attachment to the remainder of the molecule.

[0042] As used herein, the singular forms "‘a,” “an,” and “the’’ include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0043] The term "alkyl", by itself or as part of another substituent, refers to, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. Ci-s means one to eight carbons). Alkyl can include any number of carbons, such as Cj-2, C1.3, C_1-,₄ C1.5, C1-6, C1-7, CM, C1.9, Ci-to, C2-3, C_2-4, C2-5, C_2-6, C34, CM, C_3-6, C4-5. C4-6 and C5-6. Examples of alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0044] The term “alkylene” refers to a straight or branched, saturated hydrocarbon radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0045] The term “alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond and having the number of carbon atom indicated (i.e., C_2-6 means to two to six carbons). Alkynyl can include any number of carbons, such as C2, C2-3, C_2-4, C2-5, C_2-6, C2-7, C2-8, C2-9, Cz-to, C3, C3-4, C3-5, C_3-6, C4. C4-5, C4-6, Cs, C5-6, and Ce. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl,

1.3-pentadiynyl, 1,4-pentadiynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl,

1.4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1 ,3,5-hexatriynyl.

[0046] The term "cycloalkyl” refers to a non-aromatic, saturated hydrocarbon ring having the indicated number of ring atoms (e.g., C_3-6 cycloalkyl). For example, “C3-10 cycloalkyl” refers to a cycloalkyl group containing 3 to 10 carbon atoms as ring vertices and the term “C3- 7 cycloalkyl” refers to a cycloalkyl group having 3 to 7 carbon atoms as ring vertices.

Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like,

[0047] The term "halo" or "halogen," by itself or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0048] The term "haloalkyl,” refers to alkyl, as defined above, that is substituted having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl and includes rnonohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" includes trifluoromethyl, 2, 2, 2-tri fluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like,

[0049] The terms "alkoxy," and "haloalkoxy " refer to alkyl and haloalkyl groups respectively, each as defined herein, that is attached to the remainder of the molecule via an oxygen atom, for example -O-alkyl or -O~haloalkyl.

[0050] The term “aryl*’ refers to a monocyclic or bicyclic, hydrocarbon, aromatic radical. An aryl group may contain 6 to 14 carbon atoms. For example, “Ce-so aryl” refers to an aryl moiety having 6 to 10 carbon atoms as ring vertices. Non-limiting examples of aryl groups include phenyl and naphthyl.

[0051] The term "heteroaryl" refers refers to a moiety comprising an aromatic monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benz.imidaz.olyl. benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofury], isoindolyl, indolizinyl, benzotriazinyl , thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzo thiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like.

[0052] The term "5- or 6-membered heieroaryl” refers to a moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and containing one, two, or three heteroatoms independently selected front nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain three heteroatoms. Exemplary groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0053] The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially unsaturated 3 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N, O, and S and the remaining ring atom being carbon. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized and one or two ring carbon atoms of the heterocyclic ring may be replaced by -C=(O) group. However, heterocycloalkyl groups are not aromatic. Non limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolaclam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S -oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, , and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0054] The term "hydroxyalkyl," refers to an alkyl, as defined above, that is substituted with one or two hydroxy. For example, the term “hydroxyCi -4 alkyl” or “Ci -4 hydroxyalky 1” is meant to include hydroxymethyl, 1 -, or 2-hydroxyethyl, 1,2-dihydroxyethyl, hydroxypropyl, and the like.

[0055] The term “optionally substituted” indicates that a group may be unsubstituted or substituted with one or more substituents as defined herein. The term “substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced by one of the defined substituents. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

[0056] The term "oxo" refers to an oxygen atom with a double bond to the point of attachment (O=).

[0057] The term "fused tricyclic moiety" refers to a ring system comprising three fused rings having the number of ring atoms and heteroatoms indicated, wherein each ring in the fused system can be unsaturated, partially unsaturated, or saturated. Therefore, each ring in the fused tricyclic moiety can be aromatic or non aromatic.

[0058] As used herein, a wavy line, that intersects a single, double or triple bond in any chemical structure depicted herein, represent the point attachment of the single, double, or triple bond to the remainder of the molecule. Additionally, a bond extending to the center of a ring (e.g., a phenyl ring) is meant to indicate attachment at any of the available ring vertices. One of skill in the art will understand that multiple substituents shown as being attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible.

[0059] The term “pharmaceutically acceptable” refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0060] As used herein, the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines, such as arginine, betaine, caffeine, choline, -dibenzylethylenediamine, diethyl amine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, liydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine. When compounds of the present disclosure contain relati vely basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydriodic, or phosphorous acids, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic. Also included are salts of amino acids such as arginate, and salts of organic acids like glucuronic or galactunoric acids (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0061] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt, forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[6062] Certain compounds of Formula (I) possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure. When a stereochemical depiction is shown, it is meant to refer to the compound in which one of the isomers is present, and substantially free of the other isomer. “Substantially free of” another isomer indicates at least an 80/20 ratio of the two isomers, more preferably 90/10, or 95/5 or more. In some embodiments, one of the isomers will be present in an amount, of at, least 99% .

[0063] Certain compounds of Formula (I) can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of Formula (I) may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0064] Certain compounds of the present disclosure can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scone of this disclosure.

[0065] Compounds of Formula (I) or a subembodiment thereof may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100%' of the atom in question. Exemplary isotopes that can be incorporated into compounds of the present disclosure, such as a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, “C, ¹³C, ¹⁴C, ^!3N, ¹⁵N, ¹⁵O, ¹⁷O, ⁱ⁸O, ³²P, ³³P, ³⁵S, ^!8F, ³⁶C1, ⁱ²³I, and ‘“'1, respectively. Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of Formula (1) or a subembodiment thereof can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safely, tolerability or efficacy during treatment. Isolopically-Iabeled compounds (e.g., those labeled with ³H and ¹⁴C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ⁵H) and carbon- 14 (i.e., ¹⁴C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo halflife or reduced dosage requirements). In some embodiments, in compounds disclosed herein, including in Table 1 below one or more hydrogen atoms are replaced by ²H or ³H, or one or more carbon atoms are replaced by ¹³C- or ^!4C-enriched carbon. Positron emitting isotopes such as ^!3O, ^1JN, ⁿC, and ^!3F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. All isotopic variations of Formula (I) or a subembodiment thereof, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0066] The terms “patient” or “subject” are used interchangeably to refer to a human or a non-human animal (e.g., a mammal). Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. In one embodiment, the patient or subject is a human.

[6067] “Disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to ha ve a reduced duration or quality of life.

[0068] “In need of treatment” as used herein refers to a judgment made by a physici an or other caregiver that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver’s expertise.

[0069] Ute terms “administration”, “administer” and the like, as they apply to, for example, a subject, cell, tissue, organ, or biological fluid, refer to contact of, for example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, or a diagnostic agent to the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.

[6070] The terms “proliferative disorder,” “proliferative condition,” and “cell proliferation” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, gastric, liver, pancreas, brain, and skin.

[0071] The terms “treat”, “treating”, treatment” and the like refer to a course of action (such as administering an inhibitor of PRMT5 or a pharmaceutical composition comprising the same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a patient, or at least one of the symptoms associated with a disease, disorder, condition afflicting a patient. Thus, treatment includes inhibiting (e.g., arresting the development or further development of the disease, disorder or condition, or clinical symptoms association therewith) an active disease.

[0072] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a PRMT5 inhibitor or a pharmaceutical composition comprising the same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a patient’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a patient predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition, or inhibiting progression thereof to a harmful or otherwise undesired state.

[0073] The terms “inhibiting” and “reducing,” or any variation of these terms in relation of PRMT5, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%;, 55%, 60%, 65%;, 70%, 75%, 80%;, 85%;, 90%, 95%, 99%;, or more, reduction of PRMT5 activity compared to normal.

[0074] The phrase “therapeutically effective amount” as used herein means the amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive effect on any symptom, aspect, or characteristic of a disease, disorder or condition when administered to the patient. It may vary depending on the compound, the disease and its severity and the age and weight of the subject to be treated. The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the patient’s condition, and the like. By way of example, measurement of the serum level of a compound Formula (I) or a pharmaceutically acceptable salt thereof (or. e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically eff ective amount has been used.

[0075] The term “antibody” means an immunoglobulin and is a molecule containing an antigen-binding site immunospecifically binding to an antigen. The class of the antibody of the present disclosure may be any of IgG, IgE, IgM, IgD, IgA, and IgY and is preferably IgG. The subclass of the antibody of the present disclosure may be any of IgGl, JgG2, IgG3, IgG4, Ig Al, and IgA2 and is preferably IgGl or IgG2. The antibody may be derived from any species, and preferred examples of the species can include humans, rats, mice, and rabbits. When the antibody is derived from other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody of the present disclosure may be a polyclonal antibody or a monoclonal antibody. In an embodiment, the antibody is a monoclonal antibody. The antibody of the present disclosure is capable of targeting tumor cells. In an embodiment, the antibody of the present disclosure is conjugated with an antitumor compound having antitumor activity via a linker, the antibody preferably possesses one or more of a property of recognizing a tumor cell, a property of binding to a tumor cell, a property of internalizing in a tumor cell, and a properly of damaging a tumor cell. In an embodiment, the antibody is a monoclonal antibody that is reactive with a target antigen or epitope of an antigen expressed on a cancer or malignant cell. Techniques for preparing monoclonal antibodies against target antigen are known in the art. Non limiting target antigens are B7-H3, B7-H4, Trop-2, PSMA, BCMA, folate receptor, AXL, EGF receptor (ErbBl), ErbB2, ErbB3, EGFRvIlI, FGFR, EpCAM, HER-2, HER-3, tissue factor (TF), CD19, CD22, CD25, ILR2, ANTXR1, ROR1, 5T4, CD.30, CD33, CD79b, CD74, CDI38, CD56, CD70, CD 166, CEACAM5, GPNMB, Claudin-18, folate receptor alpha (FRa), c-Met, Nectin-4, Mesothelin, delta-like ligand 3 (DLL3), PTK7, GPNMB, Ley. CA6, CanAng, Av integrin, SLC44A4, CEACAM5, AGS- 16, Anti-Cripto, Carbonic Anhydrase 9, Mesotheilin, TENB2, 5T4, VEGF, insulin-like growth factor (ILGF), MUC1 and TA-MUC1. COMPOUNDS

[0076] In one aspect, the the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

Y’ is O, NR^y, S, SCO), or S(O)₂;

X’ is C(R¹) or N;

X² is C(R²) or N;

X^J is C( R³) or N;

R^y, R¹, R², and R³ are each independently H, C_1-4 alkyl, halo, or C_1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R⁴ is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, or C_3-6 cycloalkyl; or two R⁴ groups when attached to the same carbon atom combine to form oxo or C_3-6 cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)₂t ring B is C_6-10 aryl or heteroaryl having 5 to 10 ring members with I to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 , 2, or 3 ; q is 0, I, 2, or 3; each R° is independently C_1-6 alkyl. C_1-6 haloalkyl, halo, OH, C_1-6 alkoxy, C_1-6 haloalkoxy, -C(O) C_1-6 alkyl, -C(O)CM haloalkyl, -C(O)OC_1-6 alkyl, or ~C(O)O C_1-6 haloalkyl; each R⁶ is independently C_1-6 alkyl, C_1-6 haloalkyl, halo, OH, C_1-6 alkoxy, C_1-6 haloalkoxy, CN, C_2-6 alkynyl, -O- C_2-6 alkynyl, C_3-6 cycloalkyl, -O-C_3-6 cycloalkyl, ~C(O)C_1-6 alkyl, -C(O)C_1-6 haloalkyl, -C(O)OC_1-6 alkyl, ~C(O)OC_1-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the each of die C_3-6 cycloalkyl, -O-C_3-6 cycloalkyl, and heterocycloalkyl is independently substituted with 0, 1, or 2 R^6a; each R^6a is independently C_1-4 alkyl, halo, C_1-4 haloalkyl, CN, OH, or C_1-4 alkoxy: alternatively, one R⁵ attached to ring A and one R⁶ attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂, wherein ring C is substituted with 0, 1, 2, or 3 R^5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R^3a is independently C_1-4 alkyl, halo, C_1-4 haloalkyl, OH, or C_1-4 alkoxy: alternatively, two R^5a groups attached to the same carbon atom combine to form oxo.

[0077] In some aspects, provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein

Y’ is O, NR^y, S, S(O), or S(O)₃;

X’ is C(R¹) or N;

X² is C(R²) or N;

X³ is C(R³ ) or N;

R^y, R¹, R², and R³ are each independently H, C_1-4 alkyl, halo, or C_1-4 haloalkyl: n is 0, 1, 2, 3, or 4; each R⁴ is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, or C_3-6 cycloalkyl; or two R⁴ groups when attached to the same carbon atom combine to form oxo or C_3-6 cycloalkyl: ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, 0, S, S(O), or S(O)₂; ring B is CMO aryl or heteroaryl having 5 to 10 ring members with I to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 , 2, or 3 ; q is 0, I, 2, or 3; each R³ is independently C_1-6 alkyl. C_1-6 haloalkyl, halo, C_1-6 alkoxy, C_1-6 haloalkoxy, -C(O) C_1-6 alkyl, -C(O)C_1-6 haloalkyl, -C(O)OC_1-6 alkyl, or -C(O)OC_1-6 haloalkyl; each R⁶ is independently C_1-6 alkyl, C_1-6 haloalky], halo, Ci-6 alkoxy, Ci -6 haloalkoxy, CN, -O-C_3-6 cycloalkyl, -C(O)C_1-6 alkyl, ~C(O)Cj-6 haloalkyl, -C(O)OC_1-6 alkyl, - C(O)OCi-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1 , or 2 R^&a;

R^oa is C_1-4 alkyl, halo, or C_1-4 haloalkyl; alternatively, one R⁵ attached to ring A and one R⁶ attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂, wherein ring C is substituted with 0, 1, 2, or 3 R^5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R'³ is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl; alternatively, two R^5a groups attached to the same carbon atom combine to form oxo.

[0078] In some aspects, provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein

R^y, R¹, R², and R³ are each independently H, C_1-4 alkyl, halo, or C_1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R⁴ is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, C_1-6 hydroxy alkyl, or C_3-6 cycloalkyl; or two R⁴ groups when attached to the same carbon atom combine to form oxo or C_3-6 cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(Oh; ring B is CM# aryl or heteroaryl having 5 io 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1 , 2, or 3 ; each R³ is independently Ci-6 alkyl, C_1-6 haloalkyl, halo, C_1-6 alkoxy, C_1-6 haloalkoxy, ~C(O)Ci-6 alkyl, -C(O)Ci-6 haloalkyl, -C(O)OC_1-6 alkyl, or -C(O)OC_1-6 haloalkyl; each R⁶ is independently Ci-6 alkyl, C_1-6 haloalkyl, halo, Ci-6 alkoxy, C_1-6 haloalkoxy, - C(O)Ci-6 alkyl, -C(O)C_1-6 haloalkyl, -CfOlOCvc alkyl, -C(O)OC_1-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1 , or 2 R^ta;

R^oa is C_1-4 alkyl, halo, or C_1-4 haloalkyl; alternatively, one R⁵ attached to ring A and one R⁶ attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, 8, S(O), or S(O)₂, wherein ring C is substituted with 0, 1, 2, or 3 R^5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R^5a is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl; alternatively, two R^5a groups attached to the same carbon atom combine to form oxo.

[0079] In some embodiments of Formula (I), one R⁵ attached to ring A and one R⁶ attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, -S, S(O), or 8(O)₂, wherein ring C is substituted with 0, 1, 2, or 3 R^5a, and ring A, ring B, and ring C form a fused tricyclic moiety.

[0080] In some aspects, provided herein are compounds of Formula (la): or a pharmaceutically acceptable salt thereof, wherein:

R^y, R¹, R², and R³ are each independently II, Cu alkyl, halo, or C_1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R⁴ is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, or C3 6 cycloalkyl; or two R⁴ groups when attached to the same carbon atom combine to form oxo or C_3-6 cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S; ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N. O, or S; ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, or 2; q is 0, 1, or 2; each R³ is independently C_1-6 alkyl, C_1-6 haloalkyl, halo, OH, C_1-,₆ alkoxy. C_1-6 haloalkoxy, -C(O)C_1-6 alkyl, -C(O)Ci-6 haloalkyl, -C(O)OC_1-6 alkyl, or -C(O)OC_1-6 haloalkyl; each R^5a is independently C_1-4 alkyl, halo, C_1-4 haloalkyl, OH, or C_1-4 alkoxy; alternatively, two R^3a groups attached to the same carbon atom combine to form oxo; each R⁶ is independently C_1-6 alkyl. C_1-6 haloalkyl, halo, OH, Cj-6 alkoxy, C>M haloalkoxy, CN, C26 alkynyl, -O-C26 alkynyl, C_3-6 cycloalkyl, -O-C_3-6 cycloalkyl, -C(O)CM alkyl, ~C(O)Ci-₆ haloalkyl, -C(C))OCi 6 alkyl, -C(O)OCi -e haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C_3-6 cycloalkyl, -O-C3 -6 cycloalkyl, and heterocycloalkyl is independently substituted with 0, 1 , or 2 R^6a; and each R⁰³ is independently C_1-4 alkyl, halo, C)-+ haloalkyl, CN, OH, or C_1-4 alkoxy. [GOH 1] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein: each R⁵ is independently C_1-6 alkyl. Ci-6 haloalkyl, halo, Ci-6 alkoxy, Ci-6 haloalkoxy,

-C(O)C1 6 alkyl, -C(O)Ci-₆ haloalkyl, -C(O)OCi -₆ alkyl, or -C(O)OC_1-6 haloalkyl: each R'^a is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl; alternatively, two R^5a groups attached to the same carbon atom combine to form oxo; each R⁶ is independently Ci-6 alkyl, C_1-6 haloalkyl, halo, Ci-6 alkoxy, C_1-6 haloalkoxy, CN, -O-C₃ cycloalkyl, -C(O)Cc₆ alkyl, -C(O)Cw haloalkyl, -C(O)OC_1-6 alkyl, - C(O)OCi-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1 , or 2 R^ba; and each R^6a is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl.

[0082] Unless specifically indicated otherwise, embodiments or subembodiments related to Formula (I) are applicable to any one of Formulae (la), (lai), (Ia2), (lb), (Ibl), (II), (Ila), (Ila- 1 ), and (IIa-2),

[0083] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y^J is O or S.

[0084] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ¥ is S.

[0085] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y^! is O.

[0086] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y ^; is S(O). In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y ¹ is S(O)?.. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y is NR^y.

[0087] In some embdodiments, the compound or a pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein no more than two of X¹, X', and X⁵ are N. In some embdodiments, the compound or a pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein only one of X^s, X². and X³ is N. In some embdodiments, the compound or a pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X² is N: X¹ is C(R¹): and X³ is C(R³). In some embdodiments, the compound or a pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X¹ is C(R^!); X² is C(R²); and X³ is C(R³).

[0088] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X’^: is N.

[ 0089] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X¹ is C(R^;). In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X¹ is C(R^J ) and R¹ is C_1-4 alkyl or halo.

[0099] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X ‘ is CtR¹) and R¹ is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or tri fluoromethyl.

[0091] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X^J is C(R¹) and R¹ is H, methyl, ethyl, fluoro, chloro, or bromo.

[0092] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X^! is C(R^:) and R¹ is H, methyl, fluoro, chloro, or trifluoromethyl.

[0093] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X^; is CH.

[0094] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X² is N.

[0095] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X“ is C(R '). In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X² is C(R²) and R² is Ci 4 alkyl or halo.

[0096] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X² is C(R ') and R² is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or tri fluoromethyl.

[0097] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X² is C(R²) and R² is H, methyl, ethyl, fluoro, chloro, or bromo.

[0098] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X~ is C(R~) and R² is II, methyl, fluoro, chloro, or trifluoromethyl.

[0099] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X² is CH or CF.

[0100] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X² is CH.

[0101] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X² is CF.

[0102] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is N.

[0103] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is C(R³). In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is C(R³) and R³ is C_1-4 alkyl or halo.

[0104] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is C(R⁵) and R³ is II, methyl, ethyl, fluoro, chloro, bromo, fluoromelhyl, difluoromethyl, or trifluoromethyl. [0105] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is C(R³) and R³ is H, methyl, ethyl, fluoro, chloro, or bromo.

[0106] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is C(R³) and R³ is H, methyl, fluoro, chloro, or trifluoromethyl.

[0107] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is CH or CF.

[01 OS] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is CH.

[0109] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X³ is CF.

[0110] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X ¹ is CH; X² is C(R²) or N; and X³ is C(R³).

[0111] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X^: is CH: X² is N; and X³ is CH. X¹ is CH; X² is CH; and X³ is CH or CF, or X¹ is CH; X² is CF; and X³ is CH. In some embodiments, X¹ is CH; X² is N; and X³ is CH. In some embodiments, X¹ is CH; X² is CH; and X³ is CH or CF. In some embodiments, X¹, X², and X³ are each CH. In some embodiments, X¹ is CH; X² is CH; and X³ is CF. In some embodiments, X^! is CH; X² is CF; and X³ is CH.

[0112] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

N; and R² and R³ are each independently H or halo. In some embodiments, X² is N; and R³ is H, X“ is CH; and R³ is II or F, or X² is CF; and R³ is H. In some embodiments, X² is N; and R³ is H. In some embodiments, X- is CH; and R³ is H or F. In some embodiments, X² is CH; and R³ is H. In some embodiments, X^z is CH; and R³ is F. In some embodiments, X² is CF: and R³ is H.

[0113] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁴ is independently Ci-6 alkyl, halo, Ci-e haloalkyl, Ci-e hydroxyalkyl, or C_3-6 cycloalkyl.

[0114] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁴ is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁴ is independently CM alkyl or CM haloalkyl.

[0115] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁴ is independently methyl, ethyl, fluoro, chloro, or bromo. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁴ is independently methyl or -CHF?. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁴ is independently methyl. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁴ is independently -CHF₂.

[0116] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 0, 1, or 2,

[0117] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 0 or 1.

[0118] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 0. [0119] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 1; and R⁴ is methyl.

[0120] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 1 ; and R⁴ is -CHF₂.

[0121] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 2; and each R⁴ is F.

[0122] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 4 to 6 ring members with al least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S.

[0123] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 1 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S.

[0124] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0125] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0126] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0127] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0128] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl.

[0129] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

[0130] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is piperidinyl, substituted with 1 or 2 R⁵.

[0131] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is piperazinyl, substituted with 1 or 2 R³.

[0132] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (1) or a subembodiment, thereof, wherein ring A is morpholinyl, substituted with 1 or 2 R'. [0133] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R⁵. in some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with 0, 1, or 2 R⁵. In some embodiments of Formula (la) or anyone of the embodiments thereof, ring A is piperazinyl substituted with 0, 1, or 2 R⁵. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with 0, 1 , or 2 R \

[0134] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁵ is independently C_1-6 alkyl. Ci-6 haloalkyl, halo, C_1-6 alkoxy, or C>- 6 haloalkoxy,

[0135] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (1) or a subembodiment, thereof, wherein each R⁵ is independently C_1-4 alkyl, Ci .4 haloalkyl, or halo. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁵ is C_1-4 alkyl.

[0136] In some embodiments, the compound or the pharmaceutically acceptable salt, thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁵ is independently C_1-4 alkyl, halo, OH, or C_1-4 alkoxy.

[0137] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment, thereof, wherein each R⁵ is methyl, ethyl, fluoro, chloro, bromo, tluoromethyl, difluoromethyl, or trifluoromethyl.

[0138] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁵ is independently methyl, fluoro, OH, or methoxy.

[6139] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁵ is independently methyl, fluoro, or methoxy. [0140] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁵ is independently methyl or fluoro.

[0141] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁵ is independently methyl or methoxy.

[0142] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^s is methyl .

[0143] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (la): wherein, ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; q is 0, 1, or 2: and ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and the ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂-

[0144] Unless specifically indicated otherwise, embodiments or subembodiments related to

Formula (la) are applicable to any one of Formulae (lai), (Ia2), (II), (Ha), (Ila-1), and (TIa-2).

[0145] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la), or a subembodiment thereof, wherein: ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is independently N or O; ring B is phenyl or heteroaryl having 6 ring members with 1 to 2 nitrogen atom ring vertices; and ring C is C5-6 cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

[0146] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la), or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl. In some embodiments, ring A is piperidinyl, piperazinyl, or morpholinyl.

[hi 47] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein B is phenyl or heteroaryl having 6 ring members with 1 to 2 nitrogen atom ring vertices. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring B is phenyl or pyridyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is phenyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is pyridyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is pyrazinyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is pyrimidinyl. In some embodiments of Formula (la) or anyone of the embodiments thereof, ring B is pyridazinyl.

[0148] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R⁵; and each R⁵ is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R'; and each R³ is independently methyl, fluoro, or methoxy.

[0149] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl substituted with 0 R³. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R⁵; and R³ is methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R³; and R⁵ is methyl, fluoro, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R³; and R³ is methyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R⁵; and R⁵ is fluoro, in some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R⁵; and R⁵ is OH. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R³; and R⁵ is methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R³; and R⁵ is OH.

[0150] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is morpholinyl substituted with 0 R⁵. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with one R⁵; and R⁵ is methyl or fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with one R³; and R⁵ is methyl.

[0151] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl substituted with 2 vicinal R³; and each R⁵ is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R³; one R⁵ is methyl; and the other R⁵ is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R⁵; one R ' is methyl; and the other R⁵ is OH. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R³; one R³ is methyl; and the other R³ is methoxy.

[0152] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subenibodiment thereof, wherein ring A is piperidinyl substituted with 2 geminal R⁵; and each R⁵ is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R³; one R⁵ is methyl; and the other R³ is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R⁵; one R⁵ is methyl; and the other R^s is OH. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R⁵; one R⁵ is methyl; and the other R⁵ is methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R⁵; and each R³ is methyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R⁵; and each R³ is fluoro.

[0153] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperazinyl, substituted with 2 vicinal R³ or 2 geminal R⁵, wherein each R⁵ is any one of embodiments described herein.

[0154] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is morpholinyl substituted with 2 vicinal R⁵ or 2 geminal R³, wherein each R⁵ is any one of embodiments described herein.

[0155] In some embodiments, the compound or die pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (lai): (lai), wherein,

X^a is O. CH z, or CHR³; p is 0 or I ; q is 0, 1 , or 2; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, 0, S, S(O), or S(O)₂. [0156] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C4-7 cycloalkyl substituted with 0, 1, 2, or 3 R'^,a.

[0157] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C4-6 cycloalkyl substituted with 0, 1, 2, or 3 R^5a.

[0158] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C5-6 cycloalkyl substituted with 0, 1 , or 2 R^5a.

[0159] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is Cs cycloalkyl substituted with 0, 1, or 2 R"’'¹.

[11160] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment, thereof, wherein ring C is Cs cycloalkyl substituted with 0, 1, or 2 R^5a.

[0161] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N. O, S, S(O), or S(Oh, wherein ring C is substituted with 0, 1, 2, or 3 R^5a.

[0162] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 4 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)-2, wherein ring C is substituted with 0, I . 2. 01- 3 R".

[0163] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, S(O), or S(O)?, wherein ring C is substituted with 0, 1, 2, or 3 R^5a. [0164] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R^5a.

[0165] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is tire compound of Formula (I) or a subembodiment, thereof, wherein ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroaiom is independently N, O, or S, wherein ring C is substituted with 0, 1, 2, or 3 R^5a.

[0166] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)j, wherein ring C is substituted with 0, 1, 2, or 3 R^Ja.

[0167] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring C is C5-6 cyeloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroaiom is N or O. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is Cs 6 cycloalkyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

[0168] In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is C5 6 cyeloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is Cs-6 cyeloalkyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0169] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydropyranyl substituted with 0, 1 , or 2 R^5a. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydropyranyl substituted with 0 or 1 R^5a. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydropyranyl substituted with 0 R^5a.

[0170] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydrofuranyl substituted with 0 or 1 R^5a. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydrofuranyl substituted with 0 R^5a.

[0171] In some embodiments of Formula ( la) or any one of the embodiments thereof, ring C is tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl, each of which is independently substituted with 0 or 1 R^5a. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is tetrahydrofuranyl substituted with 0 or 1 R^5a. In some embodiments, ring C is tetrahydropyranyl substituted with 0 or I R'^a. In some embodiments, ring C is oxepanyl substituted with 0 or 1 R^5a.

[0172] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ia2) wherein,

X^a is absent, O, CH₂, or CHR⁵;

X^5s is absent, 0, CH₂, or CHR^5a;

X^5b is absent, O, CH₂, or CHR^5a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0173] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2) or a subembodiment thereof, wherein X^5a and X^5b are not each absent or O. [0174] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2) or a subembodiment, thereof, wherein X¹ is C(R‘), X² is C. R' i. and X³ is C(R³).

[0175] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2) or a subembodiment thereof, wherein X¹ is C(R^!), X² is N, and X ³ is C(R³).

[0176] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula ( Ia2 ) or a subembodiment thereof, wherein X^a is O, CH₂, or CHR⁵;

X^5a is O or CH?, or CHR^5a;

X^5b is O or CH₂., or CHR^5a; p is 0, 1 or 2: and q is 0, 1, or 2.

[0177] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2) or a subembodiment thereof, wherein X^5a is O; and X^5b is CH₂.

[0178] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2) or a subembodiment, thereof, wherein X^5a is CH₂.; and X^5b is O.

[0179] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2) or a subembodiment thereof, wherein X^5a is CH?; and X^5b is CH₂..

[0180] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2) or a subembodiment thereof, wherein X^5a is absent; and X^5b is CH₂.

[0181] In some embodiments, the compound or the pharmaceutically acceptable salt, thereof, is the compound of Formula (Ia2) or a subembodiment thereof, wherein X^5a is absent; and X"’^b is O. [0182] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^5a is independently C1.4 alkyl, halo, or Ci 4 haloalkyl.

[0183] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^5a is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0184] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^5a is independently methyl, fluoro, chloro, or trifluoromethyl.

[0185] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein two R ^a groups attached to the same carbon atom combine to form oxo.

[0186] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R° is independently C1-6 alkyl, Ci-6 haloalkyl, halo, Ci-e alkoxy, or Ci-e haloalkoxy.

[0187] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is independently Ci-s alkyl, C1.6 haloalkyl, or halo. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is independently C1-6 haloalkyl, halo, or C1-6 haloalkoxy.

[0188] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^b is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is independently chloro, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, or tri fluoromethyl-O-. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is independently chloro, trifluoromethyl, or difluoromethyl-O- In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is difluoromethyl- O-. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is chloro.

[0189] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is independently bromo or trifl uoromethyl,

[0190] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (lai, or a subembodiment thereof, wherein each R⁶ is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, OH, Ci-6 alkoxy, Ci* haloalkoxy, CN, C_2-6 alkynyl, -O-C_2-6 alkynyl, C_3-6 cycloalkyl, or -O-C_3-6 cycloalkyl, wherein the C_3-6 cycloalkyl and -O-C_3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

[0191] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein each R⁶ is independently chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl.

NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-.

[0192] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R⁶ is Ci* alkyl, C1-6 haloalkyl, halo, OH, C1-6 alkoxy, Ci * haloalkoxy, CN, C_2-6 alkynyl, -O-C_2-6 alkynyl, C_3-6 cycloalkyl, or -O-Cs* cycloalkyl, wherein the C_3-6 cycloalkyl and -O- C3* cycloalkyl are each independently substituted with 0 or 1 CN.

[0193] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (lai, or a subembodiment thereof, wherein q is 1; and R⁶ is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC^C-CHz-O-.

[0194] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1 ; and R'^J is chloro, trifluoromethyl, or difluoromethyl-O-. [0195] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 2; and each R⁶ is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

[0196] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0197] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety [0198] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety any one of formulae:

[0199] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety any one of the formulae according to the Amine intermediates in the Examples, wherein the nitrogen at the ring A is attached to the remainder of the molecule.

[0200] In some embodiments, the compound is represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein:

X^a is O, NH, NR⁵, CH₂, CHR⁵, or C(R⁵)₂; X⁵" is absent, O, CH₂, or CHR'^a;

X^5b is absent, O, CH₂, or CHR^5a, provided that X^5a and X^5b are not each absent or O; and a total number of R⁵ groups is no more than 2; and n, p, q, ring B, Y*, X², R’, R⁴, R⁵, R^5:J, and R⁶ are each defined in Formula (I) or (la), and described in any one of the embodiments thereof,

[0201] Unless specifically indicated otherwise, embodiments or subembodiments related to Formula (II) are applicable to any one of Formulae (Ila), (Ila- 1), and (IIa-2). [0202] In some embodiments of Formula (II), Y¹ is O.

[0203] In some embodiments, the compound is represented by Formula (Ila): wherein: ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl;

X^a is O, NH, NR⁵, CH₂, CHR⁵, or C(R⁵)₂;

X^5a is absent, O, CH₂, or CHR^,a;

X^5b is absent, O, CH₂, or CHR^5a, provided that X^5a and X^5b are not each absent or O; and a total number of R⁵ groups is no more than 2.

[0204] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (II), (Ila), or a subembodiment thereof, wherein ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring B is phenyl. In some embodiments, ring B is pyridyl. In some embodiments, ring B is pyrazinyl. In some embodiments, ring B is pyrimidinyl. In some embodiments, ring B is pyridazinyl.

[0205] In some embodiments, the compound is represented by Formula (Ila- 1 ): wherein:

X^a is O, NH, N(CI-₄ alkyl), CH₂, CHR⁵, or C(R⁵)₂;

X^5a is absent, O, CH₂, or CHR³³; X^5b is absent, O, CH₂, or CHR^5a, provided that X^5a and X^5b are not each absent or O; and a total number of R' groups is no more than 2.

[0206] In some embodiments, the compound is represented by Formula (IIa-2): wherein:

X^a is O, NH, N(CI-₄ alkyl), CH₂, CHR⁵, or C(R⁵)₂;

X^5a is absent, O, CH₂, or CHR^5a;

X^5b is absent, O, CH₂, or CHR^5a, provided that X^5a and X^5b are not each absent or O; and a total number of R³ groups is no more than 2.

[0207] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), a subembodiment thereof, X² is C(R²) or N; and R² and R³ are each independently H or halo.

[0208] In some embodi ments of Formula (II), (Ila ), (lla-1 ), or (IIa-2), or a subembodiment thereof, X² is N and R- is H; X² is CH, and R³ is H or F; or X² is CF and R³ is H.. In some embodiments, X² is N; and R³ is H. In some embodiments, X² is CH; and R³ is II, In some embodiments, X² is CH; and R³ is F. In some embodiments, X* is CF; and R³ is H.

[0209] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), a subembodiment thereof, X² is N and R³ is H; and and X^a is O, CH₂, CHR⁵, or C(.R⁵)₂. In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), a subembodiment thereof, X- is CH; R³ is H or F; and X³ is O, CH₂, CHR⁵, or C(R⁵)₂.

[0210] In some embodiments of Formula (IIa-1 ), a subembodiment thereof, X² is CH; R’ is H or F; and X^a is O, CH. . CHR⁵, or C(R⁵)₂.

[0211] In some embodiments of Formula (Ila- 1 ), a subembodi merit thereof, X² is N. [0212] In some embodiments of Formula (II) or (Ila), or a subembodiment thereof, each R⁴ is independently C_1-4 alkyl or C_1-4 haloalkyl. In some embodiments, each R⁴ is independently methyl or -CHF-. In some embodiments, each R⁴ is methyl.

[0213] In some embodiments of Formula (II) or (Ha), or a subembodiment thereof, n is 0 or 1. In some embodiments of Formula (II) or (Ila), n is 0.

[0214] In some embodiments of Formula (Ila- 1) or ( IIa-2 ), or a subembodiment thereof, R⁴ (when present) is C_1-4 alkyl or C_1-4 haloalkyl. In some embodiments, R⁴ (when present) is methyl or -CHF₂. In some embodiments, R⁴ ( when present) is methyl. In some embodiments, R⁴ (when present) is -CHF?.

[0215] In some embodiments of Formula (Ila- 1 ) or ( 11 a - 2 ) , or a subembodiment thereof, R⁴ is absent.

[0216] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, X^a is O, NH, CH₂, or CHR⁵; X^5a is O, CH₂, or CHR^5a; X^5b is 0, CH₂, or CHR^5a; and p is 0 or 1 .

[021.7] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, X^a is O, NH, or CH₂; X^5a is 0, CH₂, or CHR^5a; X^5b is O, CH₂, or CHR^5a; and p is 0, 1 , or 2.

[0218] In some embodiments of Formula (II), (Ila), (IIa-1 ), or (IIa-2), or a subembodiment thereof. X^s is C(R⁵)₂; X^5a is O, CH₂, or CHR^5a; X^5b is O, CH₂, or CHR^5a; and p is 0.

[0219] In some embodiments of Formula (11), (Ila), (IIa-1 ), or (lia-2), or a subembodiment thereof, X^5a is O and X^5b is CH₂: X^5a is CH₂ and X^5b is O; X^5a is CH₂ and X^5b is CH₂; X^5a is O and X^5b is CH(CH₃); X^5a is CH(CH₃) and X^5b is O; X^5a is CH₂ and X^5b is CH(CH₃); X^5a is CH(CH₃) and X^5b is CH₂; X^5a is absent and X^5b is CH₂; or X^5a is absent and X^5b is O. In some embodiments, X'^,a is O and X^5b is CH₂. In some embodiments, X^ba is CH₂ and X^5b is O. In some embodiments, X^3a is CH₂ and X^5b is CH₂. In some embodiments, X^5a is O and X^5b is CH(CH₃). In some embodiments, X^5a is CH(CH₂,) and X^5b is O. In some embodiments, X^5a is CH₂ and X^5b is CH(CH₃). In some embodiments, X⁵¹' is CH(CH₃) and X^5b is CH₂. In some embodiments, X^5a is absent and X^5b is CH₂. In some embodiments, X^5a is absent and X^5b is O. [0220] In some embodiments of Formula (II), (Ila), (Ila- 1 ), or (IIa-2), or a subembodiment thereof, each R⁵ is independently C_1-4 alkyl, halo, OH, or C_1-4 alkoxy. In some embodiments, each R⁵ is independently methyl, fluoro, OH, or methoxy. In some embodiments, each R⁵ is independently methyl, fluoro, or methoxy.

[0221] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, each R⁶ is independently Ci-6 alkyl, C_1-6 haloalkyl, halo, OH, C_1-6 alkoxy. C_1-6 haloalkoxy, CN, C_2-6 alkynyl, -O-C_2-6 alkynyl, C_3-6 cycloalkyl, or -O-C_3-6 cycloalkyl, wherein the C_3-6 cycloalkyl and -O-CM cycloalkyl are each independently substituted with 0 or 1 CN.

[0222] In some embodiments of Formula (II), (Ila), (IIa-1 ), or ( Ila- 2 ), or a subembodiment thereof, each R⁶ is independently chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C~, or HC=C-CH₂-O~.

[6223] In some embodiments of Formula (If), (Ila), (fla-1 ), or (IIa-2), or a subembodiment thereof, q is 1; and R⁶ is C_1-6 alkyl, C_1-6 haloalkyl, halo, OH, C_1-6 alkoxy, C_1-6 haloalkoxy, CN, CM alkynyl, -O-C_2-6 alkynyl, CM cycloalkyl, or -O-C_3-6 cycloalkyl, wherein the C_3-6 cycloalkyl and -O-C_3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

[0224] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, q is 1; and R° is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, tri fluoromethyl, fluoromethyl-0-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C~, or HOC-CH2-O-. In some embodiments, q is 1; and R⁶ is chloro, trifluoromethyl, or difluoromethyl-O-. In some embodiments, q is 2; and each R⁶ is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

[0225] Unless specifically indicated otherwise, amine moieties 1 to 12 below related to Formula (la) are applicable to any one of Formulae (I), (II), (Ila), (IIa-1), and (IIa-2). [0226] In some embodiments of Formula (la), the moiety formula: wherein:

X^a is O, NH, CH₂, or CHR⁵;

X^5a is O, CH₂, or CHR⁵³:

X^5b is O, CH₂, or CHR⁵³; each R^5a i s independen ily C_1-4 alkyl ; each R³ is independently F, OH, C_1-4 alkyl, or C_1-6 alkoxy; and

R⁶ is C_1-4 alkyl, C_1-4 haloalkyl, halo, CN, C_1-4 alkoxy, C_1-4 haloalkoxy, C_2-4 alkynyl, -O-C_2-4 alkynyl, C_3-6 cycloalkyl, or -O- C_3-6 cycloalkyl, wherein the C_3-6 cycloalkyl and -O- C_3-6 cycloalkyl are each independently unsubslituted or substituted with CN, provided that X^5a and X^5b are not each O. [0227] In some embodiments of Formula (II), (Ila), or related Formula (Ila- 1) or (IIa-2), the moiety any one of the above moieties 1 to 12.

[0228] In some embodiments of the above moieties 1 to 12, X" is O, NH, CH₂, CHF, C(CH₃), C(OH), or C(OCH₃); X^5a is O, CH₂, or CH(CH₃); X^5b is O or CH₂; R⁵ is F, CH₃, OH, or OCRs; and R⁶ is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trilluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trilluoromethyl- O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC^C-, or HCsC-CH₂-O~, provided that X^5a and X^5b are not each O. In some embodiments of moieties I to 12, R⁶ is chloro, trifluoromethyl, or difluoromethyl-O- .

[0229] In some embodiments of the above moieties 1 to 12, X^a is O, CH₂, or CHF; X^5a is O, CH2, or CH(CH₃); X^5b is O or CII2; R^b is CH3; and R^b is chloro, trifluoromethyl, or difluoromethyl-O-, provided that X^5aand X^3b are not each O. In some embodiments of moieties 1 to 4, X^a is CH₂; X³³ is CH₂; X^5b is O; and R⁶ is chloro, trifluoromethyl, or difluoromethyl-O- In some embodiments of moieties 1 to 4, X^a is O; X^5a is O; X³⁰ is CH₂; and R^b is chloro, trifl uoromethyl, or difluoromethyl-O-.

[0230] In some embodiments of Formula (la) or any one of related subformulae (II), (Ila),

(IIa-1), and (IIa-2), the moiety any one of the formulae according to Amine intermediates Al , A2, A4 to A6, and A9 to A l 11 in the Examples, wherein the nitrogen at the ring A is attached to the remainder of the molecule. [0231] In some embodiments of Formula (la) or any one of related subformulae (II), (Ila),

(Ila-1), and (IIa-2), wherein the moiety; [0232] In some embodiments of Formula (la) or any one of related subformulae (II), (Ila),

(Ila-1), and (IIa-2), wherein the moiety: [0233] In some embodiments of Formula (la) or any one of related subformulae (II), (Ila), (Ila- 1), and (IIa-2), wherein the moiety:

[0234] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (lb) wherein,

X^a is O, CH₂. or CHR³; ring B is heteroaryl having 9 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; and q is 0, 1, 2, or 3.

[0235] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein p is 1 .

[0236] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein p is 2.

[0237] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein q is 0.

[0238] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein q is 1.

[11239] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein q is 2.

[(1240] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ibl)

[0241] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is independently Cue. alkyl, Ci-6 haloalkyl, halo, Ci-c alkoxy, Ci 6 haloalkoxy, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6a. [0242] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is independently C1.4 alkyl, C1.4 haloalkyl, halo, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6a.

[0243] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^b is independently heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^oa.

[0244] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R⁶ is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 R^6a.

[0245] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^b is piperidinyl substituted with 0, 1, or 2 R?“.

[0246] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^6a is C_1-4 alkyl.

[0247] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^ba is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0248] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R^6a is methyl. [0249] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety [0250] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0251] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0252] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety [0253] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0254] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0255] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0256] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety any one of formulae:

[0257] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0258] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment, thereof, wherein the compound is selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, the present disclosure provides a compound of Examples 1 to 168 in Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is selected from a compound of Examples 1 to 168, or a pharmaceutically acceptable salt thereof. [0260] The present disclosure also includes prodrugs of the compound of Formula (I) or subembodiment thereof. As used herein, the term “prodrug” refers to compounds that readily undergo chemical changes under physiological conditions to provide a pharmacologically acti ve parent compound. The term “prodrug moiety” refers to the chemical moiety of a prodrug that is released under physiological conditions to form the active parent compound. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0261] A number of compounds in T able 1 , below, include one or more stereocenters. When the absolute stereochemistry of a stereocenter is known, the stereocenter in the displayed chemical structure is represented by a w edged solid (S ) and/or dashed ( ■■’■' ) chemical bond(s) at the stereocenter without any markings or with the label of “(R)” or “(S)”. When the absolute stereochemistry of one or more stereocenters in an isolated compound is not known, the following labels are indicated at the stereocenter of the displayed structure: “&” (e.g., “&1”); or “or” (e.g., “orl”, “or2”, or “or3”). Each of these labels is further described below.

[0262] Ute chemical names in the present application are generated from the corresponding structures using software, for example, CHEMDRAW.

[0263] The label in the structures in the present disclosure refers to both chiral centers being present in the mixture. When multiple stereocenters are labelled with “&1” the relative stereochemistry between them is determined. The term “rac” in the chemical names denotes a racemic mixture.

[0264] For example, Al is a racemic mixture of two isomers, wherein the relative stereochemistry between two centers labeled with “&1” is known, as shown below:

[0265] The label “or” in the structures refers to the specific chiral center being a single undefined isomer but absolute stereochemistry was not determined. When multiple stereocenters are labelled with different labels, the relative stereochemistry between them is not determined. For example, in a compound with stereocenters labelled as “orl” and “or2”, the relative stereochemistry between the differently labelled stereocenters is not determined. When multiple stereocenters are labelled with the same label, the relative stereochemistry between the same labelled stereocenters is determined but not the absolute stereochemistry. For example, for all stereocenters labelled “orl”, the relative stereochemistry between those stereocenters labelled “orl” is determined but not the absolute stereochemistry.

[0266] For example, A2 isomer 1 is a single isomer, wherein the relative stereochemistry between two chiral centers labeled with “orl” is known, but the absolute stereochemistry is not yet determined. A2. isomer can be either the S,S-isomer or R.R-isomer. For example, A41 isomer 1 is a single isomer, wherein relative stereochemistry between two chiral centers labeled with the same “orl” is known; relative stereochemistry between chiral centers labeled with “orl” and “or2” is not known; and absolute stereochemistry of all three chiral centers is not yet determined. A41 isomer I can be any one of four isomers, as shown below:

Isomer 1

[11267] The assignment of Isomer 1, Isomer 2, Isomer 3. or Isomer 4 is described in each of respective Examples. Similarly, Isomer 3 refers to a third eluting isomer, and Isomer 4 refers to a fourth eluting isomer during chiral chromatographic separation. Table 1: Exemplary Compounds

[0268] Additional compounds of Formula (I) can be prepared according to die general procedures as described in Examples 1-168 via a coupling reaction of any one of amines intermediates Al to Al l i and any one of carboxylic acid intermediates CAI to CA10, wherein a combination of the amine and carboxylic acid intermediates is not used in Examples 1 to 168.

PHARMACEUTICAL COMPOSITIONS

[0269] The compounds of Formula (I) or pharmaceutically acceptable salts thereof, or subembodiments thereof may be in the form of compositions suitable for administration to a subject. In general, such compositions are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.

[0270] The pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutic agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0271] The pharmaceutical compositions containing the active ingredient (e.g., a compound of Formula (I), a pharmaceutically acceptable salt thereof) may be in a form suitable for oral use (for example as tablets, troches, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, or syrups, solutions, microbeads or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0272] Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. Tablets and/or capsules contain the active ingredient in admixture with non -toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets and/or capsules.

These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[0273] The pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p- hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein.

Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2- elhanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N- Morpholinojethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), and N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0274] After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®')), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.

[0275] Any drug delivery apparatus may be used to deliver the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are known in the art.

[0276] An effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

[0277] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0278] All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein. For example, the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment and/or prevention of all diseases or disorders provided herein. Thus, the compounds and pharmaceutical compositions provided herein are for use as a medicament.

THERAPEUTIC USES AND APPLICATIONS

[0279] Provided herein are compounds that function as inhibitors of protein arginine N- methyl transferase 5 (PRMT5).

[0280] The present disclosure therefore provides a method of inhibiting PRMT5 enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0281] The present disclosure also provides a method of treating a disease or disorder in which PRMT5 activity is implicated in a patient, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer.

[0282] The present disclosure also provides a method of treating a disease or disorder treatable by inhibition of PRMT5 in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer. [0283] The present disclosure also provides a method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0284] The present disclosure also provides a method of treating a cancer deficient in CDKN2A in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0285] The present disclosure also provides a method of treating cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[11286] Ute present disclosure also provides a method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0287] The present disclosure also provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0288] The present disclosure also provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In an embodiment, the proliferative disorder is cancer.

[0289 ] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0290] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In some embodiments, the patient is in recognized need of such treatment.

[0291] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the inhibition of PRMT5 enzyme activity.

[0292] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder in which PRMT5 activity is implicated .

[0293] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder treatable by inhibition of PRMT5.

[0294] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative condition. In some embodiments, the patient is in recognized need of such treatment,

[0295] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer. In some embodiments, the patient is in recognized need of such treatment.

[0296] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of PRMT5 enzyme activity. [0297] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which PRMT5 activity is implicated.

[(1298] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder treatable by inhibition of PRMT5.

[0299] In another aspect, the present disclosure provides a method of treating a cancer in a patient, comprising:

(i) determining if the cancer is MTAP null; and

(ii) if the cancer is MTAP null, administering to the patient a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0300] In some embodiments, the cancers described herein are a solid tumor. In some embodiments, the solid tumor is malignant. In some embodiments, the cancers described herein are a metastatic solid tumor.

[0301] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is neuroblastoma, intestine carcinoma (such as rectum carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer), esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchytn carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors), Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non- small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma or plasmocytoma.

[0302] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is lung cancer, non-small cell lung (NSLC) cancer, bronchioloalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the vagina, carcinoma of the vulva, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenomas, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers.

[0303] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0304] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL) or mantle cell lymphoma (MCI,).

[0305] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is gastric cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is colon cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is liver cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is glioblastoma multiforme (GBM). In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is bladder cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is esophageal cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is breast cancer, in some embodiments, the cancer treated by the methods, uses, or medicaments described herein is NSLCC. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is MCL, In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is DLBCL. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is ALL..

[0306] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma. In some embodiments, the cancer is non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.

[0307] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC: e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL.)), leukemia, head and neck cancer (e.g., head and neck squamous ceil carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma. [0308] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is an MTA-accumu1ating cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is an MTAP ■deficient cancer. In some embodiments, the cancer is treatable by inhibition of PRMT5.

[(1309] Hie disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 by said compounds. The disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 by said compounds. The disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 in MTAP- null cells by said compounds. Further, the present disclosure relates to the use of said compounds for the preparation of a medicament for the treatment and/or prophylaxis of a chromosome 9p21 deletion or MTAP-null associated disease and/or condition through inhibiting PRMT5 in MTAP-null cells by said compounds. In some embodiments the chromosome 9p21 deletion or MTAP-null associated disease or condition is alleviated byinhibition of PRMT5 in MTAP-null cells.

[0310] In some embodiments, provided herein is a method of treating and/or preventing a MTAP-null or chromosome 9p21 deletion associated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0311] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition includes a solid tumor in or arising from a tissue or organ, such as: • bone (e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cell tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma); • lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumors): • esophagus (e.g., Barrett's esophagus, dysplasia and adenocarcinoma); • gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus; * pancreas (e.g., serous neoplasms, including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)- associated serous cystic neoplasm, serous cystadenocarcinoma; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cell cystadenoma, acinar cell cystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid- pseudopapillary neoplasms (SPN), pancreatoblastoma); * gall bladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma); • neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas); * thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, papillary carcinoma, adenocarcinoma); • liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, rhabdoid tumor); ⁹ kidney (e.g., ALK -rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase- deficient renal cell carcinoma, collecting duct carcinoma); • breast (e.g., invasive ductal carcinoma, including without limitation, acinic ceil carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich/clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, niicropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma; • peritoneum (e.g., mesothelioma; primary peritoneal cancer); • female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (E1C), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transi tional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasia), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, endometrial malignant mullerian mixed tumours, gestational trophoblastic tumors (partial hydatiform mole, complete hydatiform mole, invasive hydatiform mole, placental site tumour)), vulva, vagina; • male sex organ tissues, including prostate, testis (e.g., germ cell tumors, spermatocytic seminoma), penis; • bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); • brain, (e.g., gliomas (e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, Non-Hodgkin lymphomas (NHLs), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, pituitary tumors; • eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma); * head and neck (e.g., nasopharyngeal carcinoma. Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal); • thymus (e.g., thymoma); • heart (e.g., cardiac myxoma); • lung (e.g., small cell carcinoma (SCLC). non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma); * lymph (e.g., lymphomas, including Hodgkin’s lymphoma, nonHodgkin’s lymphoma (NHL,), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, Epstein-Ban- virus (EBV)-associated lymphoproliferative diseases, including B cell lymphomas and T cell lymphomas (e.g., Burkitt lymphoma; large B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low grade B cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary' effusion lymphoma; plasniablastic lymphoma; extranodal NK/T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma; follicular T cell lymphoma; systemic T cell lymphoma), lymphangioleiomyomatosis); • central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multifornie) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve glioma, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, Pituitary adenomas, cranial and paraspinal nerve tumors, stellar region tumors); neurofibroma, meningioma, peripheral nerve sheath tumors, peripheral neuroblastic tumours (including without limitation neuroblastoma, ganglioneuroblastoma, ganglioneuroma), trisomy 19 ependymoma); * neuroendocrine tissues (e.g., paraganglionic system including adrenal medulla (pheochromocytomas) and extra-adrenal paraganglia ((extra- adrenal) paragangliomas); • skin (e.g., clear cell hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma. Spitz tumors); and • soft tissues (e.g., aggressive angioroyxoma, alveolar rhabdomyosarcoma, alveolar soft, part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear ceil sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing’s tumors/primilive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoraa, lipoma, chondroid lipoma, liposarcoma / malignant lipomatous tumors, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft parts, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well- differentiated liposarcoma.

[0312] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition is a cancer selected from lung cancer, urothelial cancer, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cell neoplasms, head and neck cancer, bile duct cancer, esophagus cancer, glioblastoma, stomach cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, liver cancer, renal cancer, colorectal cancer, prostate cancer, leukemia, and cervical cancer.

[0313] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition is a cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic, and bladder cancer.

[0314] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is multiple myeloma (MM). In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is breast cancer. The breast cancer can be estrogen receptor negative (ER-) or the breast cancer can be progesterone receptor negative (PR-). In further embodiments, the breast cancer can be HER2 negative. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor negative and HER2 negative, also referred to herein as "triple negative breast cancer". [0315] In further aspects, a breast cancer can be a lobular carcinoma tn situ (LCIS), a ductal carcinoma in situ (DOS), an invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumor, Angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapary carcinoma, mixed carcinoma, or another breast cancer, including but not limited to triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and HER and estrogen and progesterone receptor positive.

[6316] In an embodiment, the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer.

[6317] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is NSCLC (non-small cell lung carcinoma. In one embodiment, the NSCLC can be squamous NSCLC. In another embodiment, it can be adenocarcinoma. [082] In a further aspect, cancer can be glioblastoma (GBM). In a further aspect, cancer can be mesothelioma. In one aspect, cancer can be bladder cancer. In another aspect, cancer can be esophageal cancer. In a further aspect, cancer can be melanoma. In one aspect, cancer can be DLBCL, HNSCC or cholangiocarcinoma.

[6318] In some aspects, one or more compounds described herein are useful for treating any PRMT5- mediated or PRMT5-responsive proliferative cell disorder, for example a cancer that is PRMT5 responsive.

[6319] In one aspect, a cancer that lacks p53 (e.g., a p53 null cancer) is less sensitive to PRMT5 inhibition than a cancer that is p53 positive. Accordingly, a cancer that is PRMT5 responsive can be a p53 positive cancer. The term "p53 positive" refers to a cancer that does not lack p53 expression and/or activity. In some embodiments, one or more compounds described herein are useful for treating a p53 positive cancer. In some aspects, a greater amount of one or more compounds described herein may be required to treat a p53 negative cancer (e.g. , a p53 null cancer) than a p53 positive cancer.

[6320] In some aspects, the disclosure provides a method for identifying subjects having a cancer that is sensitive to treatment with a PRMT5 inhibitor. In some embodiments, the method comprises obtaining a sample from the subject; detecting the presence or absence of p53; and, identifying the subject as having a cancer that is sensitive to treatment with a PRMT5 inhibitor if p53 is present in the sample. Accordingly, in some embodiments, a subject having a p53 positive cancer is identified as a subject for treatment with a PRMT5 inhibitor. In some embodiments, the method further comprises administering to the subject a composition comprising a PRMT5 inhibitor.

[0321] In some embodiments, the disclosure relates to a method for identifying subjects having a cancer that is insensitive (or that has low sensitivity) to treatment with a PRMT5 inhibitor. In some embodiments, the method comprises obtaining a sample from the subject; detecting the presence or absence of p53 ; and, identifying the subject as having a cancer that is not sensitive (for example, a cancer that is less sensitive than a p53 positive cancer) to treatment with a PRMT5 inhibitor if p53 is absent from the sample (e.g., if the cancer is a p53 null cancer). In some embodiments, a p53 negative cancer (e.g., a p53 null cancer) is treated with a PRMT5 inhibitor, but a greater amount of PRMT5 inhibitor may be required to treat the p53 negative cancer than a p53 positive cancer. However, in some embodiments, a subject having a p53 negative cancer (e.g. , a p53 null cancer) is treated with a therapeutic agent that is not a PRMT5 inhibitor.

[0322 ] By "sample" is meant any biological sample derived from the subject, includes but is not limited to, cells, tissues samples, body fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), cancer cells, and cancer tissues. Detection of the presence or absence of p53 in the sample may be achieved by any suitable method for detecting p53 nucleic acid or protein, for example, nucleic acid sequencing (e.g., DNA or RNA sequencing), quantitative PCR, Western blotting, etc., or any combination of thereof.

[0323] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendolheliosarcoma, hemangio sarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g. , cholangiocarcinoma), bladder cancer, brain cancer (e.g., meningioma; glioma, e.g. , astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g. , cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelio sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemonhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g. , adenocarcinoma of the esophagus, Barrett' s adenocarmoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g. , stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g. , fl- cel! AMI.,, T-cell AMI..), chronic myelocytic leukemia (CML) (e g. , B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g. , B-cell CLL, T- cell CLL), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphomas (e.g. , mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., "Waldenstrom’s macro globulinemia"), hairy cell leukemia (HCL), immunoblastic large cell ly mphoma. precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma: and T-cell NHL such as precursor T- lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g.. cutaneous T- cell lymphoma (CTCL) (e.g. , mycosis fungi odes, Sezary syndrome), angioimmunoblastic T- cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis- like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e g„ nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g. , hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g. , systemic mastocytosis), myelodysplasia syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g. , neurofibromatosis (NF) type I or type 2, schwannomatosis), neuroendocrine cancer (e.g., gasiroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g. , cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary' adenocarcinoma, penile cancer (e.g., Paget' s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g. , squamous cell carcinoma (SCO, keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g. , appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant, peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).

[0324] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is spinal cord cancer

COMBINATION THERAPY

[0325] The present disclosure contemplates the use of compounds of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents frequently have different, complementary mechanisms of action. Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby- reducing or eliminating the adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

[0326] As used herein, ‘'combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a “co-formulation”). [0327] In certain embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents. In other embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.

[0328] The present disclosure also contemplates the use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with al least one additional therapeutic agent as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0329] The present disclosure also provides a method of treating a disease or disorder in which PRMT5 activity is implicated in a patient, said method comprising administering to said patient (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer.

[0330] The present disclosure also provides a method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment

[0331] The present disclosure also provides a method of treating a cancer deficient in

CDK.N2A in a patient comprising administering to the patient (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment.

[0332] The present disclosure also provides a method of treating cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combi nation thereof, comprising administering to the patient ia) a therapeutically effective amount of a compound of Formula (1) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment.

[0333] The present disclosure provides methods for treating cancer with (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic or diagnostic agent.

Additional Therapeutic Agents

[0334] The disclosure provides one or more additional therapeutic agents for use with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof and one or more pharmaceutically acceptable excipients. A wide variety of therapeutic agents with anti-cancer activity and methods of making the same are known in the art. Each of these is embraced by this disclosure. In some embodiments, the one or more additional active therapeutic agents are one, two, three, or four additional therapeutic agents. i) Chemotherapeutic Agents

[0335] In an embodiment, the additional therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents include alkylating agent, microtubule inhibitors, antimetabolites, anti-tumor antibiotics, as well as corticosteroids.

[0336] In some embodiments, the chemotherapeutic agent is an alkylating agent. In some embodiments, the alkylating agent is altretamine, bendamustine, busulfan, improsulfan, piposulfan, procarbazine, raechlorethamine, carmustine, lomustine, sernustine chlorambucil, cyclophosphamide, thiotepa, ifosfamide, dacarbazine, temozolomide, or perfosamide. In some embodiments, the alkylating agent is mechloretharnine. In some embodiments, the alkylating agent is perfosamide.

[0337] In an embodiment, the alkylating agent is a platinum- based chemotherapy agent. In some embodiments, the alkylating agent is carboplatin, cisplatin, oxaliplatin, nedaplatin, saraplatin, lobaplatin, or heptaplatin. In some embodiments, the alkylating agent is carboplatin. In some embodiments, the alkylating agent is cisplatin. In some embodiments, the alkylating agent is saraplatin.

[0338] In some embodiments, the chemotherapeutic agent is a microtubule inhibitor. In an embodiment, the microtubule inhibitor is eribulin, ixabepilone, cabazitaxel, entortumab vedotin, trastuzumab emtansine, tirbanibulin. In some embodiments microtuial inhibitors are plant alkaloids. In some embodiments, the plant alkaloid is a taxane (taxol, paclitaxel and docetaxel), a vinca alkaloid (vinblastine, vincristine, vindesine and vinorelbine), colchicine, podophyllotoxin, or abraxane (protein-bound paclitaxel). In some embodiments, the chemotherapeutic agent is paclitaxel.

[0339] In some embodiments, the chemotherapeutic agent is an anti metabolite. In an embodiment, the antimetabolite is 5 -fluorouracil (5-FU), capecitabine, floxuridine, cytarabine, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, cytosine arabinoside, 5 -azacytidine, gemcitabine, clofarabine, mercaptopurine, thioguanine, azathioprine, pentostatin, erythrohydroxynonyladenine, fludarabine, cladribine decitabine, Azacitidine, vidaza, or methotrexate. In an embodiment, the antimetabolite is cladribine. In an embodiment, the antinietabolite is clofarabine. In an embodiment, the antimetabolite is cytarabine. In an embodiment, the antimetabolite is gemcitabine. In an embodiment, the antimetabolite is floxuridine.

[0340] In some embodiments, the chemotherapeutic agent is an antitumor antibiotics. In some embodiments, the antitumor antibiotic is bleomycin, dactinomycin, or mitomycin. In some embodiments, the antitumor antibiotic is daunorubicin, doxorubicin, doxil, epirubicin, idarubicin, mitoxantrone, valrubicin.

[0341] In some embodiments, the chemotherapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is prednisone, methylprednisolone, or dexamethasone.

[0342] Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and eyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and utedopa; ethylenimines and methylamelamines including akretamine, triethylenemelamine, trietylenephosphor amide, triethy lenethiophosphaoramide and trimethy lolomelamime ; nitrogen mustards such as chiorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxO"L-norleucine, doxorubicin, epirubicin, esorabicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti -metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, camiofur, cytarabine, dideoxyuridine, doxifluridine, enoci tabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aidophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2“-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobronian; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g,, paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercapiopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide: mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylomi thine (DMFO); retinoic acid; esperamicins; capeci tabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In a particular embodiment, compounds of the present disclosure are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C. In a particular embodiment, the cytostatic compound is doxorubicin. Chemotherapeutic agents also include anti -hormonal agents that act to regulate or inhibit hormonal action on tumors such as anti- estrogens, including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4 -hydroxy tamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide. enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent. ii) Cell Cycle Checkpoint Inhibitors

[0343] In an embodiment, the additional therapeutic agent is a cell cycle checkpoint inhibitor. In some embodiments, the cell cycle checkpoint inhibitor is KU600I9, AZD0156, Ceralasertib, Camonsertib, VE821 , AZD7762, SRA737, Rabusertib, Prexasertib, SCH900776, or Adavosertib. In some embodiments, the cell cycle checkpoint inhibitor is KU60019. In some embodiments, the cell cycle checkpoint inhibitor is AZD0156. In some embodiments, the cell cycle checkpoint inhibitor is ceralasertib. In some embodiments, the cell cycle checkpoint inhibitor is camonsertib. In some embodiments, the cell cycle checkpoint inhibitor is VE821. In some embodiments, the cell cycle checkpoint inhibitor is AZD7762. In some embodiments, the cell cycle checkpoint inhibitor is SRA737. In some embodiments, the cell cycle checkpoint inhibitor is rabusertib. In some embodiments, the cell cycle checkpoint inhibitor is prexasertib. In some embodiments, the cell cycle checkpoint inhibitor is SCH900776. In some embodiments, the cell cycle checkpoint inhibitor is adavosertib.

Hi) Immune Checkpoint Inhibitors

[6344] In an embodiment, the additional therapeutic agent is an immune check point inhibitor. In some embodiments, the immune checkpoint inhibitor is a PD-1/PD-L1 inhibitor, a LAG-3 inhibitor, a CTLA-4 inhibitor, a BTLA inhibitor, a TIM-3 inhibitor, or a T1GIT inhibitor. [0345] In an embodiment, the PD-1/PD-L1 inhibitor is a PD-1 inhibitor. In an embodiment, the PD-1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, or atezolizumab. In an embodiment, the PD-1 inhibitor is nivolumab. In an embodiment, the PD-1 inhibitor is pembrolizumab. In an embodiment, the PD-1 inhibitor is cemiplimab. In an embodiment, the PD-1 inhibitor is dostarlimab. In an embodiment, the PD-1 inhibitor is zimberelimab. In an embodiment, the PD-I inhibitor is retifanlimab. In an embodiment, the PD-1 inhibitor is atezolizumab.

[0346] In an embodiment PD-l/PD-Ll inhibitor is a PD-L1 inhibitor. In an embodiment, the PD-L1 inhibitor is avelumab, atezolizumab, or durvalumab. In an embodiment, the PD- L1 inhibitor is avelumab. In an embodiment, the PD-L1 inhibitor is atezolizumab. In an embodiment, the PD-L1 inhibitor is durvalumab.

[(1347] In some embodiments, the immune checkpoint inhibitor is a LAG- 3 inhibitor. In some embodiments, the LAG-3 inhibitor is relatlimab.

[6348] In some embodiments, the immune checkpoint inhibitor is a CTL.A-4 inhibitor. In some embodiments, the ipilimumab or tremelimumab

[0349] In some embodiments, the immune checkpoint inhibitor is a BTLA inhibitor.

[0350] In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367 (NCT03099109). In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), orLY3321367 (NCT03099109). In some embodiments, the TIM- 3 inhibitor is sabatolimab. In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is TSR-022 (NCT02817633). In some embodiments, the TIM-3 inhibitor is MBG453 (NCT02608268). In some embodiments, the TIM-3 inhibitor is LY3321367 (NCT03099109).

[6351] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor. In some embodiments, the TIGIT inhibitor is tiragolumab, domvanaiimab, vibostolimab. etigilimab, M6223, or ociperlimab. In some embodiments, the TIGIT inhibitor is tiragolumab. In some embodiments, the TIGIT inhibitor is domvanaiimab. In some embodiments, the TIGIT inhibitor is vibostolimab. In some embodiments, the TIGIT inhibitor is etigilimab. In some embodiments, the TIGIT inhibitor is M6223. In some embodiments, the TIGIT inhibitor is ociperlimab. iv) BCL-2 Inhibitors

[0352] In some embodiments, the additional therapeutic agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoclax, navitoclax, oblimersen, obatoclax mesylate, AT-101 , subatoclax, maritoclax, gossypol, apogossypol, TW-37, UMI-77, or BDA- 366. v; Anti-CD20 therapeutic agent

[0353] In some embodiments, the additional therapeutic agent is an anti-CD20 therapeutic agent. In some embodiments, the anti-CD20 therapeutic agent is rituximab, arzerra, gazyva, ibritumomab tiuxetan, obinutuzumab, ofatumumab, riabni, rituxan, ruxience, truxima, zevalin, or tositumomab. vi) Hormonal Therapeutic Agent

[0354] In some embodiments, the additional therapeutic agent is a hormonal therapeutic agent. In some embodiments, the hormonal therapeutic agent is anastrozole, exemestand, letrozole, zoladex, lupon eligard, tamoxifen, raloxifene, goserelin, leuproreiin, fulvestrant, 4- hydroxy tamoxifen, trioxifene, keoxifene, onapristone, toremifene; flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, or goserelin. vii) PARP Inhibitors

[0355] In some embodiments, the additional therapeutic agent is a PART inhibitor. In some embodiments, the PART inhibitor is niraparib, rucaparib, olaparib, talazoparib, or veliparib. viii) MAT2A Inhibitors [0356] In some embodiments, the additional therapeutic agent is a MAT2A inhibitor. In some embodiments, the MAT2A inhibitor is AG-270, In some embodiments, the MAT2A inhibitor is a compound disclosed in

WO2020/I23395, the contents of which is incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2018/045071 , the contents of which is incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2021/252681,

WO2021/252680, WO2021/252679, WO2021/252678, or WO2023/196985, the contents of which are incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2021/1259815, WO2023/066283,

WO2024/217502, W02020/139991, W02020/139992, WO2018/045071, WO2018/039972,

W02019191470, W02024/002024, or WO2024/217493, the contents of which are incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is ISM3412 or S095035. Tn some embodiments, the MAT2A inhibitor is [0357] In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2022/268180, the contents of which are incorporated herein by reference for all purposes.

[0358] In some embodiments, the MAT2A inhibitor is r pharmaceutically acceptable salt thereof. ix) Radiotherapy

[0359] In some embodiments, the additional therapeutic agent is radiation therapy. x) VEGF Inhibitors

[0360] In some embodiments, the additional therapeutic agent is a VEGF inhibitor. In some embodiments, the VEGF inhibitor is Bevacizumab, aflibercept, ranibizuraab, sorafenib, dasatinib, sunitinib, nilolinib, pazopanib, pegaptanib, axitinib, Jenvatinib, ramucirumab, or regorafenib. xi) Tyrosine Kinase Inhibitors

[0361] In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is afatinib, cetuximab, imatinib, trastuzumab, gefitinib, dacomitinib, osimertinib, neratinib, almonertinib, brigatinib, icotinib, olmutinib, sorafenib, dasatinib, bosutinib, ponatinib, asciminib, sunitinib, erlotinib, nilotinib, lapatinib, tucatinib, pyrotimb, panitumumab, nimotuzumab, necituraumab, mobocertinib, vandetanib, lenvatinib, pazopanib, mubritinib, fostamatinib, calquence, pertuzumab, acalabrutinib, alectinib, cabozantinib, ceritinib, capmatinib, or crizotinib. xii)mTOR Inhibitors

[0362] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is rapamycin, everolimus, sirolimus, terasirolimus, everoiimus, or sirolimus. xiii) AKT Inhibitors

[0363] In some embodiments, the additional therapeutic agent is an ATK inhibitor. In some embodiments, the ATK inhibitor is ipatasertib, mk-2206, perifosine, capivasertib, triciribine, or GSK690693. xiv)CDK Inhibitors

[0364] In some embodiments, the additional therapeutic agent is a CDK inhibitor. In some embodiments, the CDK inhibitor is flavopiridol, roscovitine, RO-3306, dinaciclib, milciclib, palbociclib, ribociclib, abemaciclib, BS-181, DRB, meriolin 3, variolin b, meridianin e, nortopsentins, AZD5438, roniciclib, SNS-032, sorafenib, K03861, THZ531, THZ1, E9, SY- 1365, or seliciclib. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, and abemaciclib.

.n'.) PI3K Inhibitors

[0365] In some embodiments, the additional therapeutic agent is a PI3K inhibitor. In some embodiments, the PI3K inhibitor is idelalisib, alpelisib, leniolisib, duveiisib, or copanlisib. x vi ) J A K Inh i b i to rs

[0366] In some embodiments, the additional therapeutic agent is a JAK inhibitor, hi some embodiments, the JAK inhibitor is tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, filgotinib, or abrocitinib. xvii) Inhibitors of Cereblon (Ubiquitin Ligase)

[0367] In some embodiments, the additional therapeutic agent is a inhibitor of cereblon. In some embodiments, the inhibitor of cereblon is thalidomide, lenalidomide. xviii ) MAPK/ERK Inhibitors

[0368] In some embodiments, the additional therapeutic agent is a MAPK/ERK inhibitor. In some embodiments, the MAPK/ERK inhibitor is vemurafenib, dabrafenib, octreotide, pasireotide, SB590885, GDC0879, LGX818, AZ628, RAF709, binimetinib, L-778, MK2206, pimasertib, rafametinib, salirasib, selumelinib, SML-8-731, tipifarnib, lonafarnib, trametinib, ulixertinib, WX-554, or cobimetinib. xix)Wnt/fi-catenin Inhibitors

[0369] In some embodiments, the additional therapeutic agent is a Wnt/'P-catenin inhibitor. In some embodiments, the Wnt/p-catenin inhibitor is capmatinib, resibufogenin, or isoquercitrin. xd Proteosome Inhibitors

[0370] In some embodiments, the additional therapeutic agent is a proteosome inhibitor. In some embodiments, the proteosome inhibitor bortezoraib, carfilzomib, or ixazomib. xxi)Hi stone Deacetylase Inhibitors

[0371] In some embodiments, the additional therapeutic agent is a histone deacetylase inhibitor. In some embodiments, the histone deacetylase inhibitor vorinostat, romidepsin, panobinostat. or belinostat. xxii) Recombinant IL-2

[0372] In some embodiments, the additional therapeutic agent is a recombinant IL-2. In some embodiments, the recombinant IL-2 is aldesleukin. xxiii) RANKL Inhibitors

[0373] In some embodiments, the additional therapeutic agent is a RANKL inhibitor. In some embodiments, the RANKL inhibitor is Denosumab or AS2676293. xxiv) B4GALNT1 Inhibitors

[0374] In some embodiments, the additional therapeutic agent is a B4GALNT1 inhibitor. Tn some embodiments, the B4GALNT1 inhibitor is Dinutuximab. xvv) SLAMF7 Inhibitors

[0375] In some embodiments, the additional therapeutic agent is a SLAMF7 inhibitor. In some embodiments, the SLAMF7 inhibitor is elotuzumab. xxvi) IDH2/IDH1 Inhibitors [0376] In some embodiments, the additional therapeutic agent is a IDH2/IDH1 inhibitor. In some embodiments, the IDH2/IDH! inhibitor is enasidenib, ivosidenib, AGI-6780, AG- 221, FT-2102, IDH305, GSK 321, or BAY1436032. xxvii) BTK Inhibitors

[0377] In some embodiments, the additional therapeutic agent is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib. xxviii) FLT3 Inhibitors

[(1378] In some embodiments, the additional therapeutic agent is a FLT3 inhibitor. In some embodiments, the FLT3 inhibitor is sunitinib, midostaurin, iestaurtinib, KW-2449, crenolanib, or gilteritinib. xxix) PDGFRa. Inhibitors

[0379] In some embodiments, the additional therapeutic agent is a PDGFRa inhibitor. In some embodiments, the PDGFRa inhibitor is olaratumab, avapritinib, ayvakit, imatinib, ripretinib, or regorafenib.

,.wc) Smoothened (Smo) Inhibitors

[0389] In some embodiments, the additional therapeutic agent is a smoothened inhibitor.

In some embodiments, the smoothened inhibitor is sonidegib, itraconazole, or glasdegib. xxxi) LHRH antagonists or LHRH agonists

[0381] In some embodiments, the additional therapeutic agent is a LHRH antagonist or LHRH agonist. In some embodiments, the LHRH antagonist, or LHRH agonist is goserelin, leuprorelin or buserelin. xxxii) Cell Based Therapy

[0382] In some embodiments, the additional therapeutic agent is a cell based therapy. In some embodiments, the cell based therapy is tumor-infiltrating lymphocyte (TIL) therapy; engineered t cell receptor (TCR) therapy; chimeric antigen receptor (CAR) T cell therapy; Natural Killer (NK) cell therapy ; or sipuleucel-T. xxxiii) 0X40 Inhibitors

[0383] In some embodiments, the additional therapeutic agent is a 0X40 inhibitor. Tn some embodiments, the 0X40 inhibitor is ivuxolimab, cudarolimab, utomilumab, or INBRX- 106. xxxiv) 41BB (CD 137) Inhibitors

[0384] In some embodiments, the additional therapeutic agent is a 41BB (CD 137) inhibitor. In some embodiments, the 41BB (CD1.37) inhibitor is urelumab.

XOT) VISTA Inhibitors

[0385] In some embodiments, the additional therapeutic agent is a VISTA inhibitor. In some embodiments, the VISTA inhibitor is hmbd-002. xxxvi) CD96 Inhibitors

[0386] In some embodiments, the additional therapeutic agent is a CD96 inhibitor, hi some embodiments, the CD96 inhibitor is GSK6097608. xxxvii) TGF/3 Inhibitors

[0387] In some embodiments, the additional therapeutic agent is a TGI inhibitor. In some embodiments, the TGFfi inhibitor is SAR-439459. xxxvii i ) CD 19 Inhibitors

[0388] In some embodiments, the additional therapeutic agent is a CD19 inhibitor. In some embodiments, the CD19 inhibitor is tafasitamab, loncastuximab tesirine, or blinatumomab. xxxix) CD30 Inhibitors

[0389] In some embodiments, the additional therapeutic agent is a CD30 inhibitor. In some embodiments, the CD30 inhibitor is brentuximab, vedotin, SGN-30, or MDX-060. xl) CD38 Inhibitors [0390] In some embodiments, the additional therapeutic agent is a CD38 inhibitor. In some embodiments, the CD38 inhibitor is daratumumab, darzalex, isatuximab, or sarclisa. xli) CD39 Inhibitors

[0391] In some embodiments, the additional therapeutic agent is a CD39 inhibitor. In some embodiments, the CD39 inhibitor is purOOl, ES002023, TTX-030, IPH5201 , or SRF617. xlii) CD52 Inhibitors

[0392] In some embodiments, the additional therapeutic agent is a CD52 inhibitor. In some embodiments, the CD52 inhibitor is alemtuzuraab. xiiii) CD73 Inhibitors

[0393] In some embodiments, the additional therapeutic agent is a CD73 inhibitor. In some embodiments, the CD73 inhibitor is oleclumab, PSB- 12379, OP-5244, AB-680, CD73-IN-3, MethADP triarnmonium, dalutrafusp alfa, BK50164, mupadoiimab, uliledlimab, MRS4620, BMS-986179, NZ.V930, AK 1 19, SYM024, INCA00186, or ORIC-533. xliv) A?AR Inhibitors

[0394] In some embodiments, the additional therapeutic agent is an AjAR inhibitor. Tn some embodiments, the A2AR inhibitor is istradefylline, vipadenant, CVT-6883, enprofylline, ciforadenant, imaradenant, etrumadenant, NIR178, EOS100850, CS3005, PBF- 999, or INCB 106385. xlv)A?BR Inhibitors

[0395] In some embodiments, the additional therapeutic agent is an A2BR inhibitor. In some embodiments, the A2BR inhibitor is pbf-1129, QAF805, LAS 101057 AB928, ISAM140, or TT-4. xlvi) IDO1 & TDO2 Inhibitors

[0396] In some embodiments, the additional therapeutic agent is an IDO1 or a TDO2 inhibitor. In some embodiments, the IDO1 or TDO2 inhibitor is Indoximod, Epacadostat, Navoximod, PF-06840003, BGS-5777, BMS-986205, LW106, IOM2983, RG-70099, LY- 3381916, NLG-802, or LPM-3480226. xlvii) Arginase Inhibitors

[0397] In some embodiments, the additional therapeutic agent is an arginase inhibitor. In some embodiments, the arginase inhibitor is numidargistat, pegzilarginase, or 1NCB001158. xlviii) B7-H3 Inhibitors

[0398] In some embodiments, the additional therapeutic agent is a B7-H3 inhibitor. In some embodiments, the B7-H3 inhibitor is enoblituzumab, I-Omburtamab, DS-7300, or MGC018. xlix) B7-H4 Inhibitors

[0399] In some embodiments, the additional therapeutic agent is a B7-H4 inhibitor. In some embodiments, the B7-H4 inhibitor is ml-1660, FPA150, or AZD8205.

I) i. Signal transduction inhibitor (STI)

[0400] As used herein, the term “signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. Examples of signal transduction inhibitors (STIs) useful in methods described herein include, but are not limited to: (i) bcr/abl kinase inhibitors (e.g,, GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies: (iii) her-2/neu receptor inhibitors (e.g., HERCEPTIN); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositol kinase inhibitors.

H) Spicing inhibitor sulfonamide (SPLAM)

[0401] In some embodiments, the additional therapeutic agent is a Spicing inhibitor sulfonamide (SPLAM).

[0402] In some embodiments, the SPLAM is indisulam or E7820.

Hi ) Additional Therapeutic Agents

[0403] In some embodiments, the additional therapeutic agent is Temozolomide, Pemetrexed, Pegylated liposomal doxorubicin (Doxil), Eribulin (Halaven), Ixabepilone (Ixempra), Protein-bound paclitaxel (Abraxane), Oxaliplatin, Irinotecan, Venatoclax (bc!2 inhibitor), 5-azacytadine, Anti-CD20 therapeutics, such as Rituxan and obinutuzumab, Hormonal agents (anastrozole, exemestand, letrozole, zoladex, lupon eligard), CDK4/6 inhibitors, Palbociclib, Abemaciclib, CPI (Avelumab, Cemiplimab-rwlc, and Bevacizumab).

[0404] In some embodiments, the additional therapeutic agent is a monoclonal antibody against a tumor antigen, a complex of a monoclonal antibody and toxin, a T-cell adjuvant, bone marrow transplant, or antigen presenting cells (e.g., dendritic ceil therapy).

[0405] In some embodiments, the additional therapeutic agent is a an antibody drug conjugate (ADC) comprising one or more antitumor compound conjugated to an antibody via a linker. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody is a monospecific antibody. A number of ADCs comprising antitumor compounds and methods of making the same are known in the art. Each of these is embraced by this disclosure. In an embodiment, the antitumor compound is an additional therapeutic agent disclosed herein. In an embodiment, the antitumor compound is a chemotherapeutic agent disclosed herein.

DOSING

[0406] A compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein may be administered to a subject in an amount that is dependent upon, lor example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered.

[0407] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The “median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated EDso. in other situations the effective amount is less than the calculated EDso, and in still other situations the effective amount is the same as the calculated EDso.

ROUTES OF ADMINISTRATION

[0408] A compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein comprising this compound may be administered to a patient by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).

[0409] Routes or administration include, but are not limited to, oral (e.g., by ingestion): buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., bypessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Some embodiments of the present invention contemplate oral administration.

NON-LIMITING EXEMPLARY EMBODIMENTS

[0410] Ute compounds of the cun-ent application can be further described by the following non-limiting exemplary embodiments: Embodiments 1 to 123 and Embodiments IB to 143B.

[0411] Embodiment 1. A compound of Formula (1): or a pharmaceutically acceptable salt thereof, wherein

Y¹ is O, NR^y, S, S(O), or S(O)₂;

X¹ is C(R‘) or N;

X² is C(R²) or N ; X³ is C( R ³ ) or N;

R^y, R¹, R-, and R^J are each independently H, C_1-4 alkyl, halo, or C_1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R⁴ is independently C_1-6 alkyl, halo, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, or C_3-6 cycloalkyl; or two R⁴ groups when attached to the same carbon atom combine to form oxo or C_3-6 cycloalkyl; ring A is heterocycloalkyl comprising 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)?_; ring B is Ck-io aryl or heteroaryl comprising 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 , 2, or 3; q is 0, 1 , 2, or 3 ; each R is independently C_1-6 alkyl, C_1-6 haloalkyl, halo, C_1-6 alkoxy, C_1-6 haloalkoxy, -C(O)C_1-6 alkyl, -C(O)C_1-6 haloalkyl, -C(O)OC_1-6 alkyl, or ~C(O)OC_1-6 haloalkyl; each R⁶ is independently C_1-6 alkyl. C_1-6 haloalkyl, halo, C_1-6 alkoxy, C_1-6 haloalkoxy, - C(O)C_1-6 alkyl, -C(O)C_1-6 haloalkyl, -C(O)OC_1-6 alkyl, -C(O)OC_1-6 haloalkyl, or heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R⁶“;

R^6a is C_1-4 alkyl, halo, or C_1-4 haloalkyl: alternatively, one R⁵ attached to ring A and one R° attached to ring B combine to form ring C comprising C4-7 cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, 0, S, S(O), or S(O)₂, wherein ring C is substituted with 0, 1, 2, or 3 R^3a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R"'³ is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl; alternatively, two R^5a groups attached to the same carbon atom combine to form oxo.

[0412] Embodiment 2. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein Y’¹ is O or S.

[0413] Embodiment 3. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein Y^; is S. [0414] Embodiment 4. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein Y^! is O.

[9415] Embodiment 5. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 4, wherein X¹ is N.

[9416] Embodiment 6. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 4, wherein X¹ is C(R^]) and R¹ is H, methyl, ethyl, fluoro, chloro, bromo, fluoroinethyl, difluoromethyl, or trifluoromethyl.

[0417] Embodiment 7. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 4, wherein X^s is CiR¹) and R¹ is H, methyl, ethyl, fluoro, chloro, or bromo.

[0418] Embodiment 8. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 4, wherein X’¹ is C(R¹) and R¹ is H, methyl, fluoro, chloro, or trifluoromethyl.

[0419] Embodiment 9. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 4, wherein X¹ is CH.

[0420] Embodiment 10. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 9, wherein X² is N.

[0421] Embodiment 11. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 9, wherein X² is C(R²) and R² is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[9422] Embodiment 12. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 9, wherein X² is C(R²) and R² is H, methyl, ethyl, fluoro, chloro, or bromo.

[0423] Embodiment 13. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 9, wherein X² is C(R²) and R² is H, methyl, fluoro, chloro, or trifluoromethyl.

[0424] Embodiment 14. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 9, wherein X² is CH or CF. [0425] Embodiment 15. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 9, wherein X^z is CH.

[0426] Embodiment 16. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 9, wherein X² is CF.

[11427] Embodiment 17. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 16, wherein X³ is N.

[0428] Embodiment 18. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 16, wherein X³ is C(R³) and R³ is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0429] Embodiment 19. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 16, wherein X³ is C(R³) and R³ is H, methyl, ethyl, fluoro, chloro, or bromo.

[0430] Embodiment 20. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 16, wherein X³ is C(R³) and R³ is H, methyl, fluoro, chloro, or tri fluoromethyl.

[0431] Embodiment 21. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 16, wherein X³ is CH or CF.

[0432] Embodiment 22. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 16, wherein X³ is CH.

[0433] Embodiment 23. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 16, wherein X³ is CF.

[0434] Embodiment 24. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 23, wherein each R⁴ is independently Cj-6 alkyl, halo, Ci-6 haloalkyl, Ci-6 hydroxy alkyl, or Cs s cycloalkyl.

[0435] Embodiment 25. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 23, wherein each R" is independently Cu4 alkyl, halo, or C_1-4 haloalkyl.

[0436] Embodiment 26. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 25, wherein n is 0, 1, or 2. [0437] Embodiment 27. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 25, wherein n is 0 or 1.

[0438] Embodiment 28. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 25, wherein n is 0.

[11439] Embodiment 29. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 25, wherein n is 2 and each R⁴ is independently F.

[0440] Embodiment 30. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 29, wherein ring A is heterocycloalkyl comprising 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0441] Embodiment 31. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 29, wherein ring A is heterocycloalkyl comprising 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 1 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0442] Embodiment 32. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 29, wherein ring A is pynolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl.

[0443] Embodiment 33. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 29, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

[0444] Embodiment 34. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 33, wherein ring A is piperidinyl, substituted with 1 or 2 R⁵.

[0445] Embodiment 35. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 33, wherein ring A is morpholinyl, substituted with 1 or 2 R⁵.

[0446] Embodiment 36. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 35, wherein R is Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or Ci-6 haloalkoxy.

[0447] Embodiment 37. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 35, wherein R⁵ is C_1-4 alkyl, Ci-i haloalkyl, or halo. [0448] Embodiment 38. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 35, wherein R⁵ is methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0449] Embodiment 39. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 35, wherein R⁵ is methyl.

[0450] Embodiment 40. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39, having Formula (la) wherein, ring B is phenyl or heteroaryl comprising 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatoni is independently N, O, or S; p is 0, 1 or 2; q is 0, 1, or 2; and ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and comprises C4-7 cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂.

[0451] Embodiment 41. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39, having Formula (lai) wherein,

X^a is O, CH₂, or CHR⁵; p is 0 or 1 ; q is 0, 1, or 2; and ring C is C4.7 cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂.

[(1452] Embodiment 42. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is C4-7 cycloalkyl substituted with 0, 1, 2, or 3 R^5a.

[0453] Embodiment 43. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is C4-6 cycloalkyl substituted with 0, 1, 2, or 3 R^5a.

[0454] Embodiment. 44. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is C5-6 cycloalkyl substituted with 0, 1, or 2 R^5a.

[0455] Embodiment 45. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is Cs cycloalkyl substituted with 0, 1 , or 2 R^3a.

[0456] Embodiment 46. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is C5 cycloalkyl substituted with 0, 1, or 2 R^3a.

[0457] Embodiment 47. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is heterocycloalkyl comprising 4 to 7 ring members with I to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂, wherein ring C is substituted with 0, 1, 2, or 3 R^5a.

[0458] Embodiment 48. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is heterocycloalkyl comprising 4 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂, wherein ring C is substituted with 0, 1, 2, or 3 R^5a,

[0459] Embodiment 49. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is heterocycloalkyl comprising 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, S(O), or 8(0)₂, wherein ring C is substituted with 0, 1, 2, or 3 R'^a.

[0460] Embodiment 50. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is heterocycloalkyl comprising 5 ring members with I io 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R^3a.

[0461] Embodiment 51. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is heterocycloalkyl comprising 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, 2, or 3 R^5a.

[0462] Embodiment 52. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is heterocycloalkyl comprising 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O') or S(O)₂, wherein ring C is substituted with 0, 1. 2, or 3 R^5a.

[0463] Embodiment 53. The compound or the pharmaceutically acceptable salt thereof of embodiments 40 or 41, wherein ring C is tetrahydropyranyl substituted with 0, 1, or 2 R"¹³.

[0464] Embodiment 54. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39, having Formula (Ia2) wherein,

X³ is absent, O, CH₂. or CUR';

X^5a is absent, O or CH?, or CHR^3a;

X^5b is absent, O or CH₂, or CHR^5a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0465] Embodiment 55. The compound or a pharmaceutically acceptable salt thereof of embodiment 54, wherein p is 0, 1 or 2; and q is 0, 1, or 2.

[0466] Embodiment. 56. The compound or a pharmaceutically acceptable salt thereof of embodiment 54 or 55, wherein X^5a is O, and X^5b is CH2. [0467] Embodiment 57. The compound or a pharmaceutically acceptable salt thereof of embodiment 54 or 55, wherein X^5a is CH₂, and X'^b is O.

[0468] Embodiment 58. The compound or a pharmaceutically acceptable salt thereof of embodiment 54 or 55, wherein X^3a is CH2, and X'^b is CH2.

[0469] Embodiment 59. The compound or a pharmaceutically acceptable salt thereof of embodiment 54, wherein X^5a is absent, and X^5b is CH2.

[0470] Embodiment 60. The compound or a pharmaceutically acceptable salt thereof of embodiment 54, wherein X^5a is absent, and X^5b is O.

[0471] Embodiment 61. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 60, wherein R^5a is C_1-4 alkyl, halo, or C_1-4 haloalkyl. [0472] Embodiment 62. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 60, wherein R is methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0473] Embodiment 63. Hie compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 60, wherein R~^a is methyl, fluoro, chloro, or trifluoromethyl [0474] Embodiment 64. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 60, wherein two R'^a groups attached to the same carbon atom combine to form oxo.

[0475] Embodiment 65. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments I to 64, wherein each R⁶ is independently C_1-6 alkyl, C_1-6 haloalkyl, halo, C_1-6 alkoxy, or C_1-6 haloalkoxy.

[0476] Embodiment 66. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 64, wherein each R⁶ is independently C_1-6 alkyl, C_1-6 haloalkyl, or halo. [0477] Embodiment 67. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 64, wherein each R⁶ is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or triflu oromethyl.

[0478] Embodiment 68. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 64, wherein each R⁶ is independently bromo or trifluoromethyl.

[0479] Embodiment 69. The compound or a pharmaceutically acceptable salt thereof of

[6480] Embodiment 70. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39, having Formula (lb) wherein,

X'^; is O, CH₂. or CHR⁵; ring B is heteroaryl comprising 9 to 10 ring members with 1 to 4 heteroaiom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; and q is 0, 1, 2, or 3.

[0481] Embodiment 71. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 70, wherein p is 1 . [0482] Embodiment 72. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 70, wherein p is 2.

[0483] Embodiment 73. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 72, wherein q is 0.

[11484] Embodiment 74. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 72, wherein q is 1.

[0485] Embodiment 75. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 72, wherein q is 2.

[0486] Embodiment 76. Ute compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39, having Formula (Ibl)

[0487] Embodiment 77. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39 and 70 to 76, wherein each R⁶ is independently Cj .6 alkyl. Cj-6 haloalkyl, halo, C_1-6 alkoxy, Ci-s haloalkoxy, or heterocycloalkyl comprising 4 to 6 ring members with I to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6a.

[0488] Embodiment 78. Hie compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39 and 70 to 76, wherein each R⁶ is independently C_1-4 alkyl, C_1-4 haloalkyl, halo, or heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 beteroatom ring vertices, wherein each heteroatom is independently N, 0, or S, and wherein the heterocycloalkyl is substituted with 0, 1 , or 2 R^Da.

[0489] Embodiment 79. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39 and 70 to 76, wherein each R⁶ is independently heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R'"^J.

[0490] Embodiment 80. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39 and 70 to 76, wherein each R° is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 R^6a.

[0491] Embodiment §1. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39 and 70 to 76, wherein each R⁶ is piperidinyl substituted with 0, 1 , or 2 R^6a.

[0492] Embodiment 82. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39 and 70 to 81, wherein each R^6a is C_1-4 alkyl.

[0493] Embodiment 83. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39 and 70 to 81, wherein each R^ba is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0494] Embodiment 84. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39, and 70 to 81. wherein each R^oa is methyl.

[0495] Embodiment 85. Hie compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 39 and 70 to 84, wherein the moiety has the formula: [0496] Embodiment 86. The compound or a pharmaceutically acceptable salt thereof of any embodiment 1, wherein the compound is selected from Table 1.

[0497] Embodiment 87. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, and a pharmaceutically acceptable excipient.

[0498] Embodiment §8. A method for treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 87.

[0499] Embodiment 89. The method of embodiment 88, wherein the disease is cancer.

[0500] Embodiment 90. A method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 87.

[0501] Embodiment 91. A method for treating a cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, the absence of the MTAP gene, absence of MTAP protein, reduced level of MTAP protein, or reduced function of MTAP protein, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1 io 86, or a pharmaceutical composition of embodiment 87.

[0502] Embodiment 92. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 41.

[0503] Embodiment 93. The method of any one of embodiments 89 to 92, wherein the cancer is an MTAP-deiicient cancer, MTA-accumulating cancer, or a combination thereof.

[0504] Embodiment 94. The method of embodiment 89 or 93, wherein the cancer is deficient in CDKN2A. [0505] Embodiment 95. The method of any one of embodiments 89 to 94, wherein the cancer is a solid tumor.

[0506] Embodiment 96. The method of embodiment 95, wherein the solid tumor is malignant.

[0507] Embodiment 97. The method of any one of embodiments 89 to 96, wherein the patient is in recognized need of such treatment.

[0508] Embodiment 98. The method of any one of embodiments 89 to 97, wherein the cancer is selected from the group consisting of biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0509] Embodiment 99. The method of any one of embodiments 89 to 97, wherein the cancer is selected from the group consisting of leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma.

[0519] Embodiment 100. The method of any one of embodiments 89 to 97, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

[0511] Embodiment 101. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 87, for use in therapy. [0512] Embodiment 102. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 87, for use in the treatment cancer.

[0513] Embodiment 103. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 102, wherein said cancer is an MTAP- deficient cancer, MTA-accumuiating cancer, or a combination thereof.

[0514] Embodiment 104. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 102 or 103, wherein said cancer is deficient in CDKN2A.

[0515] Embodiment 105. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 102 or 104, wherein said cancer is an MTAP null cancer.

[0516] Embodiment 166. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 102 to 104, wherein said cancer is characterized by a reduction or absence of MTAP gene expression, the absence of the MTAP gene, absence of MTAP protein, reduced level of MTAP protein, or reduced function of MTAP protein.

[0517] Embodiment 107. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 102 to 106, wherein said cancer is a solid tumor.

[0518] Embodiment 198. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 107, wherein the solid tumor is malignant.

[0519] Embodiment 109. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 102 to 108, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer {e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarconia, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0520] Embodiment 110. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 102 to 108, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0521] Embodiment 111. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 87, in the manufacture of a medicament for use in therapy.

[0522] Embodiment 112. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 87, in the manufacture of a medicament for use in the treatment of cancer.

[0523] Embodiment 113. The use of embodiment 112, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0524] Embodiment 114. The use of embodiment 112 or 113, wherein said cancer is deficient in CDKN2A.

[0525] Embodiment 115. The use of any one of embodiments 112 to 114, wherein said cancer is an MTAP null cancer.

[0526] Embodiment 116. Ute use of any one of embodiments 112 to 114, wherein said cancer is characterized by a reduction or absence of MTAP gene expression, the absence of the MTAP gene, absence of MTAP protein, reduced level of MTAP protein, or reduced function of MTAP protein.

[0527] Embodiment 117. The use of any one of embodiments 112 to 116, wherein said cancer is a solid tumor. [0528] Embodiment 118. The use of embodiment 117, wherein said solid tumor is malignant.

[0529] Embodiment 119. The use of any one of embodiments 112 to 118, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g.. pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B -cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, chol angiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0530] Embodiment 120. Hie use of any one of embodiments 112 to 118, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0531] Embodiment 121. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 87.

[0532] Embodiment 122. A method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments i to 86, or a pharmaceutical composition of embodiment 87.

[0533] Embodiment 123. A method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired with an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1 to 86, or a pharmaceutical composition of embodiment 87. [0534] Embodiment IB. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein (O), or S(O)₂; are each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R⁴ is independently Civ alkyl, halo, Civ haloalkyl, Ci-6 hydroxyalkyl, or C_3-6 cycloalkyl; or two R⁴ groups when attached to the same carbon atom combine to form oxo or C_3-6 cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, >S, S(O), or S(O)z; ring B is C_6-10 aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 , 2, or 3 ; q is 0, 1 , 2, or 3 ; each R⁵ is independently Civ. alkyl, Civ haloalkyl, halo, Civ alkoxy, C1-6 haloalkoxy, -C(O)C1 6 alkyl, -C(O)Ci-₆ haloalkyl, -C(O)OCi v alkyl, or -C(O)OC_1-6 haloalkyl: each R⁶ is independently Civ alkyl, Civ haloalkyl, halo, Civ alkoxy, Civ haloalkoxy, - C(OjCiv alkyl, -C(O)Civ haloalkyl, -C(O)OCiv alkyl, -C(O)OCiv haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2. R^6a; alternatively each R⁶ is independently Civ alkyl, Civ haloalkyl, halo, Civ alkoxy, Civ haloalkoxy, CN, -O-C?v cycloalkyl, -C(O)Civ alkyl, -C(O)Civ haloalkyl, - C(O)OCj v alkyl, ~C(O)OCiv haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6a;

R^6a is Ci 4 alkyl, halo, or C1.4 haloalkyl; alternatively, one R⁵ attached to ring A and one R⁶ attached to ring B combine to form ring C, wherein ring C is C4-7 cycioalkyl or heterocycloalky! having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N. O, S, S(O), or S(C)b, wherein ring C is substituted with 0, 1, 2, or 3 R^5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R^5a is independently C1-4 alkyl, halo, or C_1-4 haloalkyl; al tentatively, two R'^a groups attached to the same carbon atom combine to form oxo.

[0535] Embodiment 2B. l he compound or a pharmaceutically acceptable salt thereof of embodiment IB, wherein Y¹ is O or S.

[0536] Embodiment 3B. The compound or a pharmaceutically acceptable salt thereof of embodiment IB, wherein Y¹ is S.

[0537] Embodiment 4B. The compound or a pharmaceutically acceptable salt thereof of embodiment IB, wherein Y¹ is O.

[0538] Embodiment SB. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X² is N; X¹ is C(R^!): and X⁵ is C(R³).

[0539] Embodiment 6B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X¹ is C(R^!); X² is C(R~); and X^J is C(R³).

[0540] Embodiment 7B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X¹ is N.

[0541] Embodiment 8B. Ute compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4, wherein no more than two of X¹, X², and X³ are N.

[0542] Embodiment 9B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein only one of X^!, X², and X³ is N.

[0543] Embodiment 10B. Hie compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 6B, wherein X¹ is C(R^!) and R¹ is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difhroromethy!, or trifluoromethyl. [0544] Embodiment 11B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 6B, wherein X¹ is C(R^!) and R¹ is H, methyl, ethyl, fluoro, chloro, or bromo.

[0545] Embodiment 12B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 6B, wherein X¹ is C(R^;) and R¹ is H, methyl, fluoro, chloro, or trifluoromethyl.

[0546] Embodiment 13B, The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 6B, wherein X¹ is CH.

[0547] Embodiment 14B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 5B and 8B to 9B, wherein X² is N.

[0548] Embodiment 15B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 6B to 9B, wherein X² is C(R²) and R² is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[(1549] Embodiment 16B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 6B to 9B, wherein X² is C(R²) and R² is H, methyl, ethyl, fluoro, chloro, or bromo.

[0550] Embodiment 17B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 6B to 9B, wherein X² is C(R²) and R² is H, methyl, fluoro, chloro, or trifluoromethyl.

[0551] Embodiment 18B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 6B to 9B, wherein X² is CH or CF.

[0552] Embodiment 19B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 6B to 9B, wherein X^z is CH.

[0553] Embodiment 20B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 6B to 9B, wherein X² is CF.

[0554] Embodiment 21B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 7B to 20B, wherein X³ is N. [0555] Embodiment 22B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 20B, wherein X³ is C(R³) and R³ is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0556] Embodiment 23B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 20B, wherein X^J is C(R³) and R³ is H, methyl, ethyl, fluoro, chloro, or bromo.

[0557] Embodiment 24B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 20B, wherein X³ is C(R³) and R³ is H, methyl, fluoro, chloro, or trifluoromethyl.

[0558] Embodiment 25B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 20B, wherein X³ is CH or CF.

[0559] Embodiment 26B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 20B, wherein X³ is CH.

[(1560] Embodiment 27B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 20B, wherein X³ is CF.

[0561] Embodiment 28B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R⁴ is independently Ci-6 alkyl, halo, C_1-6 haloalky 1, Cue hydroxyalkyl, or CM cycloalkyl.

[0562] Embodiment. 29B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 28B, wherein each R⁴ is independently C_1-4 alkyl, halo, or Ci 4 haloalkyl.

[(1563] Embodiment 30B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 29B, wherein each R⁴ is independently methyl, ethyl, fluoro, chloro, or bromo.

[0564] Embodiment 31B. Ute compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 30B, wherein each R⁴ is independently methyl.

[0565] Embodiment 32B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, wherein n is 0, 1, or 2. [0566] Embodiment 33B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 32B, wherein n is 0 or 1.

[0567] Embodiment 34B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 33B, wherein n is 0.

[6568] Embodiment 35B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 30B, wherein n is 2; and each R⁴ is F.

[0569] Embodiment 36B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 35B, wherein ring A is heterocycloalkyl having 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0570] Embodiment 37B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 36B, wherein ring A is heterocycloalkyl having 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 1 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0571] Embodiment 38B, The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 35B, wherein ring A is pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or motpholinyl.

[0572] Embodiment 39B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 38B, wherein ring A is piperidinyl, piperazinyl, or motpholinyl.

[6573] Embodiment 46B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 39B, wherein ring A is piperidinyl, substituted with 1 or 2 R'.

[0574] Embodiment 41B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 39B, wherein ring A is morpholinyl, substituted with 1 or 2 R⁵.

[0575] Embodiment 42B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 41B, wherein R⁵ is Civ. alkyl, Coe haloalkyi, halo, Cve alkoxy, or Ci-6 haloalkoxy. [0576] Embodiment 43B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 42B, wherein R^s is C_1-4 alkyl, C_1-4 haloalkyl, or halo.

[0577] Embodiment 44B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 43B, wherein R⁵ is methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difl uorome thy], or trifluoromethyl.

[0578] Embodiment 45B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 44B, wherein R' is methyl.

[0579] Embodiment 46B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B, having Formula (la) wherein, ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; q is 0, 1, or 2; and ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and is Cw cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(Ob.

[0580] Embodiment 47B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B, having Formula (lai) wherein,

X ' is O, CH 2, or CHR⁵; p is 0 or 1 ; q is 0, 1, or 2; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂.

[0581] Embodiment 48B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is C4-7 cycloalkyl substituted with 0, 1 , 2, or 3 R^5a.

[0582] Embodiment 49B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is C4-6 cycloalkyl substituted with 0, 1, 2, or 3 R^5a.

[0583] Embodiment 50B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is C5-6 cycloalkyl substituted with 0, 1, or 2

[0584] Embodiment 51B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is Cr. cycloalkyl substituted with 0, 1, or 2 R^5a.

[0585] Embodiment 52B. Hie compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is C5 cycloalkyl substituted with 0, 1, or 2 R^5a.

[0586] Embodiment 53B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B wherein ring C is heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂, wherein ring C is substituted with 0, 1 , 2, or 3 R^5a.

[0587] Embodiment 54B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is heterocycloalkyl having 4 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)?, wherein ring C is substituted with 0, 1, 2, or 3 R^5a.

[0588] Embodiment 55B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is heterocycloalkyl having 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, S(O ), or 8(0)₂, wherein ring C is substituted with 0, 1, 2, or 3 R^5a. [0589] Embodiment 56B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is heterocycloalkyl having 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1 , or 2 R^5a.

[0590] Embodiment 57B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, 2, or 3 R'^a.

[0591] Embodiment 58B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)₂, wherein ring C is substituted with 0, 1 , 2, or 3 R^5a.

[9592] Embodiment 59B. The compound or a pharmaceutically acceptable salt thereof of embodiments 46B or 47B, wherein ring C is tetrahydropyranyl substituted with 0, I , or 2 R^5a.

[0593] Embodiment 60B The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is tetrahydropyranyl substituted with 0 or 1 R^5s.

[0594] Embodiment 61B. The compound or a pharmaceutically acceptable salt thereof of embodiment 46B or 47B, wherein ring C is unsubstituted tetrahydropyranyl.

[0595] Embodiment 62B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B, having Formula (Ia2) wherein,

X^a is absent, O, CHz, or CHR⁵;

X^5a is absent, O or CH2, or CHR’^5a;

X^5b is absent, O or CH2, or CHR^5a; p is 0, 1 or 2: and q is 0, 1, or 2.

[0596] Embodiment 63B. Hie compound or a pharmaceutically acceptable salt thereof of embodiment 62B, wherein

X^a is O, CH₂, or CHR⁵;

X⁵³ is O or CH ■. or CHR^5a;

X^5b is O or CH₂, or CHR^5a; p is 0, 1, or 2; and q is 0, 1, or 2.

[D597] Embodiment 64B. Hie compound or a pharmaceutically acceptable salt thereof of embodiment 62B or 63B, wherein X^3a is O; and X^5b is CH₂.

[0598] Embodiment 65B. The compound or a pharmaceutically acceptable salt thereof of embodiment 62B or 63B, wherein X^5a is CH₂; and X^5fc is O.

[0599] Embodiment 66B. The compound or a pharmaceutically acceptable salt thereof of embodiment 62B or 63B, wherein X^aa is CH₂.; and X^3b is CH₂.

[0600] Embodiment 67B. The compound or a pharmaceutically acceptable salt thereof of embodiment 62B, wherein X^5a is absent; and X^5b is CH₂.

[0601] Embodiment 68B. Hie compound or a pharmaceutically acceptable salt thereof of embodiment 6215. wherein X^5a is absent: and X^5b is O.

[0602] Embodiment. 69B. Hie compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 63B, wherein each R^5a is independently C_1-4 alkyl, halo, or Ci- 4 haloalkyl.

[0603] Embodiment 70B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 63B, wherein each R^5a is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, diiluoroniethyl, or trifluoromethyl.

[0604] Embodiment 71B. Hie compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 63B. wherein each R^5a is independently methyl, fluoro, chloro, or trifluoromethyl. [0605] Embodiment 72B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 63B, wherein two R^5a groups attached to the same carbon atom combine to form oxo.

[0606] Embodiment 73B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 72B, wherein each R⁶ is independently Ci-6 alkyl, Cue haloalkyl, halo, Cj-6 alkoxy, or Cj-6 haloalkoxy.

[0607] Embodiment 74B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 73B, wherein each R⁶ is independently Ci-6 alkyl, Ci< haloalkyl, or halo.

[0608] Embodiment 75B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, wherein each R⁶ is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifiuoromethyl.

[0609] Embodiment 76B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 75B, wherein each R⁶ is independently bromo or trifiuoromethyl.

[0610] Embodiment 77B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 73B, wherein each R⁶ is independently Ci-o haloalkyl, halo, or Ci -6 haloalkoxy.

[0611] Embodiment 78B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 72B, wherein each R° is independently chloro, fluoromethyl, difluoromethyl, trifiuoromethyl, fluoromethyl-O-, difluoromethyl-O-, or irifluorornethyl-O-.

[0612] Embodiment 79B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 72B and 78B, wherein each R⁶ is independently chloro. trifiuoromethyl, or difluoromethyl-O-.

[0613] Embodiment SOB. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 72B and 78B to 79B, wherein each R⁶ is difluoromethyl-O-.

[0614] Embodiment 81B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 75B and 77B to 79B, wherein each R⁶ is chloro. [0615] Embodiment 82B. The compound or a pharmaceutical] y acceptable salt thereof of any one of embodiments IB to 45 B, wherein the moiety formulae: [0616] Embodiment 83B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B, wherein the moiety formulae: [0617] Embodiment 84B. The compound or a pharmaceutical] y acceptable salt thereof of any one of embodiments IB to 45 B, wherein the moiety formulae:

[0618] Embodiment §5B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B, having Formula (lb) wherein,

X^a is O, CH₂, or CHR⁵; ring B is heteroaryl having 9 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, or 2: and q is 0, 1, 2, or 3.

[0619] Embodiment 86B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 85B, wherein p is 1.

[0620] Embodiment 87B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 85B, wherein p is 2.

[6621] Embodiment 88B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 87B, wherein q is 0.

[0622] Embodiment 89B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 87B, wherein q is 1.

[0623] Embodiment 90B. Hie compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 87B, wherein q is 2. [0624] Embodiment 91B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B. having Formula (Ibl)

[0625] Embodiment 92B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B and 85B to 9 IB. wherein each R⁶ is independently Cj-6 alkyl, Ci-6 haloalkyl, halo, Ci-e alkoxy, Ci-e haloalkoxy, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, 0, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6a.

[0626] Embodiment 93B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B and 85B to 91B, wherein each R° is independently C1-4 alkyl. C_1-4 haloalkyl, halo, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6a.

[06271 Embodiment 94B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B and 85 B to 91B, wherein each R⁶ is independently heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatoni is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R^6a.

[0628] Embodiment 95B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B and 85B to 91B, wherein each R⁶ is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl, each of which is substituted with 0, 1, or 2 R^6a. [0629] Embodiment 96B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B and 85B to 91B, wherein each R^b is piperidinyl substituted with 0, 1, or 2 R'T

[0630] Embodiment 97B. The compound or a pharmaceutically acceptable salt thereof of

5 any one of embodiments IB to 4SB and 85 B to 96B, wherein each R^6a is C_1-4 alkyl.

[0631] Embodiment 9SB. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B and 85B to 96B, wherein each R^oa is independently methyl, ethyl, fluoro, chloro, bromo, tluoromethyl, difluoromethyl, or trifluoromethyl.

[0632] Embodiment 99B. Hie compound or a pharmaceutically acceptable salt thereof of 10 any one of embodiments IB to 45B and 85B to 96B, wherein each R^6a is methyl.

[0633] Embodiment 100B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 45B and 85B to 99B, wherein the moiety is any one of formulae: lb [11634] Embodiment I01B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 100B, wherein the moiety has the formula:

[0635] Embodiment 102B. Hie compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 100B, wherein the moiety formula:

[0636] Embodiment 103B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 100B, wherein the moiety formula: [0637] Embodiment 104B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 100B, wherein the moiety formula: [0638] Embodiment 105B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 100B, wherein the moiety any one of formulae:

[0639] Embodiment I06B. The compound or a pharmaceutically acceptable salt thereof of embodiment IB, wherein the compound is selected from Table 1.

[0640] Embodiment 107B. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, and one or more pharmaceutically acceptable excipient.

[0641] Embodiment 108B, A method for treating a disease treatable by inhibition of protein arginine N-methyl transferase 5 (PRMT5) in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B.

[6642] Embodiment I09B. The method of embodiment 108B, wherein the disease is cancer.

[0643] Embodiment HOB. A method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B.

[0644] Embodiment 111B. A method for treating cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B.

[0645] Embodiment 112B. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B.

[0646] Embodiment 113B. The method of any one of embodiments 109B io 112B, wherein the cancer is a MT A ■ accumulating cancer.

[0647] Embodiment 114B. The method of embodiment 109B or 113B, wherein the cancer is deficient in CDKN2A.

[0648] Embodiment 115B. The method of any one of embodiments 109B to 114B, wherein the cancer is a solid tumor.

[0649] Embodiment 116B. The method of embodiment USB, wherein the solid tumor is malignant.

[0650] Embodiment 117B. The method of any one of embodiments 109B to 116B, wherein the patient is in recognized need of such treatment.

[0651] Embodiment 118B. The method of any one of embodiments 109B to 117B, wherein the cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g.. non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and large intestine, or sarcoma.

[0652] Embodiment 119B. The method of any one of embodiments 109B to 117B, wherein the cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast, cancer, soft tissue sarcoma, nonHodgkin lymphoma, or mesothelioma.

[0653] Embodiment 120B. The method of any one of embodiments 109B to 117B, wherein the cancer is non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.

[0654] Embodiment 121B. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B, for use in therapy.

[0655] Embodiment 122B. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B, for use in the treatment of cancer.

[0656] Embodiment 123B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to embodiment 122B, wherein said cancer is an MTAP null cancer.

[0657] Embodiment 124B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to embodiment 122B, wherein said cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof.

[0658] Embodiment 125B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 122B to 124B, wherein said cancer is MTA-accumulating cancer.

[0659] Embodiment 126B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 122B to 125B, wherein said cancer is deficient in CDKN2A. [0660] Embodiment 127B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 122B to 126B, wherein said cancer is a solid tumor.

[0661] Embodiment 128B. The compound or the pharmaceutically acceptable salt thereof", or the pharmaceutical composition, for use according to embodiment 127B, wherein the solid tumor is malignant.

[0662] Embodiment 129B, The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 122B to 128B, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarconia, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and large intestine, or sarcoma.

[0663] Embodiment 130B, The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 122B to 128B, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[6664] Embodiment 131B. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 166B, or a pharmaceutical composition of embodiment 107B, in the manufacture of a medicament for therapy.

[0665] Embodiment 132B. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B, in the manufacture of a medicament for the treatment of cancer. [0666] Embodiment 133B. The use of embodiment I32B, wherein said cancer is an MTAP null cancer.

[0667] Embodiment 134B. The use of embodiment 132B, wherein said cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MT AP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof.

[0668] Embodiment 135B. The use of any one embodiments 132B to 134B, wherein said cancer is MTA-accumulating cancer.

[6669] Embodiment 136B. The use of any one of embodiments 132B to 135B, wherein said cancer is deficient in CDKN2A.

[0670] Embodiment 137B. The use of any one of embodiments 132B to 136B, wherein said cancer is a solid tumor.

[0671] Embodiment 138B. The use of embodiment 137B, wherein said solid tumor is malignant.

[0672] Embodiment 139B. The use of any one of embodiments 132B to 138B, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and large intestine, or sarcoma*

[0673] Embodiment 140B. Hie use of any one of embodiments 132B to 138B, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma, or mesothelioma.

[0674] Embodiment 141B. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B.

[0675] Embodiment 142B. A method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 B to 106B, or a pharmaceutical composition of embodiment 107B.

[0676] Embodiment 143B. A method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired with an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments IB to 106B, or a pharmaceutical composition of embodiment 107B.

EXAMPLES

[0677] Hie following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of bow to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that die experiments below were performed or that they are all of the experiments that may be performed. It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate data and the like of a nature described therein. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for.

List of Selected Abbreviations:

MeOH - methanol

MeCN - acetonitrile

PdCh(dppf)-DCM adduct - palladium chloride- 1 ,1-ferrocenediy l-bis(diphenylphosphino)- dichloromethane adduct

KriCCh - potassium carbonate APhos Pd G3 - palladium G3-(4-(A(A^r-Dimethylaniino)phenyl)di-/£^,rr-butylphosphine, [4- (Di-tert-butylphosphino)-A',A/’-dimethylani1ine-2-(2'-aminobiphenyl)]pal]adium(II) methanesulfonate dppf Pd G3 - methanesulfonato IJ -ferrocenediyl-bis(diphenylphosphino) (2'-amino-l,l '- biphenyl-2-yl) palladium(II)

DI H2O - deionized water

(4,4'-dtbbpy)NiCh - [4,4'-Bis(l,l-dimethylethy1)-2,2'-bipyridine] nickel (II) dichloride

[Ir(dtbbpy)(ppy)₂]PF6 - [4,4'-5tX1 ,l-diniethyletbyl)-2,2'-bipyridine-A/’l,A1 ']bis[2-(2- pyridinyl-A^phenyl-CJiridium(III) hexailuorophosphate Aminosupersilane - A-(Adamantan- 1 -yl )- 1 , 1 , 1 ,3,3,3-hexamethyl-2-(trirnethylsilyl)trisilan-2- amine

DPPF Pd G3 - Methanesulfonato l,l-ferrocenediyl-bis(diphenylphosphino) (2'-amino-l,l'- bi phenyl -2-yl) pal ladi um(II)

Na2CCh - sodium carbonate AcCN - acetonitrile

TsOH - p-Toluenesulfonic acid z-PrOH - isopropanol

THF - tetrahydrofuran

DMF - A’,A^?-dimethylformamide DCM -dichloromethane

TFA - trifluoroacetic acid

Nall - sodium hydride

TIPSOTf - Triisopropylsilyl trifluoromethanesulfonaie

NH4CI - ammonium chloride EtOAC - ethyl acetate

DBU - l,8-diazabicyclo(5.4.0)undec-7-ene

Synthesis Examples

Carboxylic Acid (CA) intermediate synthesis

Intermediate CAI: 1 :1 mixture of (S)-6-amino-9-fluoro-l ,3,4,1 Ib-tetrahydro-

[l,4]oxazino[4,3-c]quinazoline-10-carboxylic acid and (R)-6-amino-9-fluoro-1 ,3,4,11b- tetrahydro-j 1 ,4]oxazino[4,3-c]quinazoline- 10-carboxylic acid Step 1 : methyl 4-amino-5-bromo-2 -fluorobenzoate

[0678] To a stirred solution of methyl 4-amino-2-fluorobenzoale (200 g, 1.18 mol) in

CHCl?, (2.5 L) was added N-bromosuccinimide (210 g, 1.18 mol) in portions al 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0-30% ethyl acetate in petroleum ether to afford methyl 4- amino-5-bromo-2-fluorobenzoate (256 g, 87%) as a white solid. MS ESI calculated for C₈H₇BrFNO2 [M+H]⁺, 247.96, 249.96; found, 248.00, 250.00.

Step 2: methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-2-fluorobenzoat.e

[0679] A solution of methyl 4-amino-5-bromo-2-fluorobenzoate- (50 g, 201 mmol), BOC2O

(53 g, 241 mmol), TEA (61 g, 605 mmol) and DMAP (246 mg, 2.02 mmol) in DCM ( 100 mL) was stirred at 40 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether, to afford methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-2- fluorobenzoate (35 g, 47%) as a white solid. MS ESI calculated for CisHisBrFNCh [M+H]⁺, 348.02, 350.02; found, 348.05, 350.10.

Step 3: methyl 4-((tert-butoxycarbonyl)amino)-2-fluoro-5-(4,4,5.5-tetamethyl-l ,3,2- dioxaborolan-2-yl)benzoate

[0680] To a stirred mixture of methyl 5-bronio-4-[(tert-butoxycarbonyl)amino]-2- fluorobenzoate (40.0 g, 114.9 mmol) and AcOK (22.6 g, 229.8 mmol) in dioxane (600 mL) was added BPD (43.8 g, 172.3 mmol) and Pd(dppf)Cb (4.20 g, 5.74 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h under nitrogen. The resulting mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 0-25% ethyl acetate in petroleum ether, to afford 32.00 g white solid. The residue was further purified by trituration with petroleum ether to afford methyl 4-((teri-butoxycarbonyl )amino)-2-fluoro-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (30.8 g, 68%) as a white solid. MS ESI calculated for C MfeBFNC )₆ [M+Hff, 396.19; found, 396.10. Step 4: tert-butyl 5-(2-((tert-but0xycarbonyl)arnino)-4-fluoro-5-(methoxycarbonyI)phenyl)-

2 ,3 -dihydro-4H- 1 ,4-oxazine-4-carboxyla te

[0681] To a stirred mixture of methyl 4-[(tert-butoxycarbonyl)amino]-2-fluoro-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (30.8 g, 77.9 mmol) and tert-butyl 5- ((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H- l,4-oxazine-4-carboxylate (40.5 g, 93.5 mmol) in dioxane (600 mL) and H2O (60 mL) were added K2CO3 (32.3 g, 233.8 mmol) and Pd(dppf)C12.CH2CJ2 (6.4 g, 7.8 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 5 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0-15% ethyl acetate in petroleum ether, to afford tert-butyl 5-(2-((tert- butoxycarbonyi)aniino)-4-fluoro-5-(methoxycarbonyl)phenyl)-2,3-dihydro-4H-l,4-oxazine- 4-carboxylate (18.9 g, 54%) as an off-white solid. MS ESI calculated for C22H29FN2O7 [M+H]⁺, 453.20; found, 453.05.

Step 5: 1 :1 mixture of tert-butyl (S)-3-(2-((tert-butoxycaibonyl)atnino)-4-fluoro-5- (methoxycart>onyl)piienyl)morpho1ine-4-carboxylate and tert-butyl (R)-3-(2-((tert- butoxycarbonyl)amino)-4-fluoro-5-(metlwxycarbonyl)phenyl)morpholine-4-carboxyIate

[0682] To a stirred mixture of tert-butyl 5-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)-2,3-dihydro-4H- 1 ,4-oxazine-4-carboxylate ate (18.9 g, 41.9 mmol) in MeOH (300 mL) was added Pd(OH)₂/C (5 g, 20%) and Pd/C (2.5 g, 10%). The resulting mixture was stirred at 50 °C for 16 h under hydrogen atmosphere (20 atm.). The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of tert-butyl (S)-3-(2-(.( tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)morpboline-4-carboxylate and tert-butyl (R)-3-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate (18.17 g, 96%) as a white solid. MS ESI calculated for C22H31FN2O7 [M+H]\ 455.21 ; found, 455.30. Hi NMR (400 MHz, Chloroform- J) 5 9.19 (br, HI), 8.59 (d, .7 - 8.2 Hz, IH), 8.19 (d, J- 14.2 Hz, IH), 5.04 (d, J = 3.9 Hz, IH), 4.34 (d, J = 12.1 Hz, IH), 3.99 (dd, J - 1 1.1, 3.1 Hz, IH), 3.96 - 3.88 (m, 4H), 3.77 - 3.69 (m, IH), 3.65 - 3.56 (m, IH), 3.11 - 3.02 (m, IH), 1.54 (s, 9H), 1.53 (s, 9H).

Step 6: 1 :1 mixture of methyl (S)-4-amino-2-fluoro-5-(morpholin-3-yl)benzoate and methyl

(R)-4-amino-2-fluoro-5-(morpholin-3-yl)benzoate

[0683] To a stirred solution of a 1:1 mixture of tert-butyl (S)-3-(2-((tert- butoxycarbonyl)amino)-4-fluoro-5-(metlioxycarbonyl)phenyI)niorpholine-4-carboxylate and ten-butyl (R)-3-(2-((tert-butoxycarbonyl)amiiio)-4-fluoro-5-

(methoxycarbonyl)phenyl)morpholine-4-carboxylate (8.0 g. 17.6 mmol) in DCM (140 ml..) was added TFA (35 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure. The resulting mixture was dissolved in EtOAc, and basified to pH 8 with saturated NaHCCfi (aq). The organic layer was dried over anhydrous NazSCfo After filtration, the filtrate was concentrated under reduced pressure to afford a 1 :1 mixture of methyl ■ S)-4-amino-2-fluoro- 5-(morpholin-3-yl)benzoate and methyl (R)-4-amino-2-fluoro-5-(morpholin-3-yl)benzoate (4.10 g, crude) as a brown solid. MS ESI calculated for CizHssFNiCh [M+H]⁺, 255.11; found, 255.20.

Step 7: 1 :1 mixture of methyl (S)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[ l,4]oxazino[4,3- c]quinazoline-10-carboxylate and methyl (R)-6-amino-9-l'luoro-l,3,4, 1 Ib-tetrahydro-

[1,4] oxazino [4, 3 - c] quina zoline - 10 - carboxylate

[0684] A 1 :1 mixture of methyl (S)-4-amino-2-fluoro-5-(morpholin-3-yl (benzoate and methyl (R)-4-amino-2-fluoro-5-(morpholm-3-yl)berizoate (4.0 g, crude) and BrCN (1.46 g, 15.8 mmol) in 1,4-dioxane (40 ml.,) was stirred at 80 °C for 16 h. After cooling down, the reaction mixture was filtered, and the filter cake was washed with 1,4-dioxane to afford a 1 : 1 mixture of methyl (S)-6-amino-9-fluoro- l, 3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazoline- 10-carboxylate and methyl (R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- c]quinazoline-10-caiboxy1ate (3.05 g, 71%) as a white solid. MS ESI calculated for C13HUFN3O3 [M+HJ⁺, 280.10; found, 280.15.

Step 8: 1:1 mixture of (S)-6mmino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazoline-10-carboxyhc acid and (R)-6-amino-9-fluoro-l , 3,4,1 1 b-tetrahy droll, 4]oxazino[4,3-c]quinazoline-10-carboxylic acid (CAI)

[0685] To a stirred mixture of a 1: 1 mixture of methyl (S)-6-amino-941uoro-l,3,4,l lb- tetrahydro-[l ,4]oxazino[4,3-c]quinazoline- 10-carboxylate and methyl (R)-6-amino-9-fluoro- 1,3,4, 1 lb-tetahydro-[l,4]oxa?.ino[4,3-clquinazo1ine-10-carboxylate (3.05 g, 10.92 mmol) in THF (40 mL), MeOH (20 mL) and H2O (20 niL) was added LiOH (780 nig, 32.76 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 3 h. The organic solvents were removed under reduced pressure. The mixture was acidified to pH 6 with HC1 (aq.). The resulting mixture was filtered, and the filter cake was washed with H?O to afford a 1: 1 mixture of (S)-6-amino-9-fluoro-l, 3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-cjquinazoline-10- carboxylic acid and (R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- cjquinazoline-10-carboxylic acid (1.80 g, 62%) as a white solid. MS ESI calculated for •C -H -i-N 4) [MW, 266.09; found, 266.20. ^!H NMR (400 MHz, DMSO-tfe) 5 12.63 (br, 1 H), 8.42 (br, 2H), 7.73 (d, ./ - 7.5 Hz, 1 H i. 6.81 (d, J - 1 1 .4 Hz, 1 H), 4.96 - 4.90 (m, 1 H), 4.23 - 4.11 (m, 2H), 3.95 - 3.88 (m, 1H), 3.66 - 3.54 (m, 2H), 3.31 - 3.24 (m, IH).

Intermediates CAI isomer 1 and CAI isomer 2: (R)-6-amino-9-fluoro-lH,3H,4H,l lbH- [l,4]oxazino[4,3-c]quinazoline-10-carboxylic acid, isomer 1 and (S)-6-amino-9-fluoro- 1H,3H,4H,1 lbH-[l,4]oxaz.ino[4,3-c]quinazoiine-10-carboxylic acid, isomer 2 Step I : tert-butyl (R)-3-(2-((tert-buioxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate, isomer 1 and tert-butyl (S)-3-(2-((lert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)inorpholine-4-carboxyIate, isomer 2

[0686] The racemate of tert-butyl 3-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbony])phenyI)morpholine-4-carboxylate (10.00 g, 22.00 mmol) was separated by Prep-Chiral-SFC with the following conditions [Column: (S, S)- Whelk-0 1 Sum Kromasil, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 100 mL/min; Gradient: isocratic 20% B; RTl(min): 5; RT2(min): 7; Sample Solvent: MEOH; Injection Volume: 3.5 mL; Number Of Runs: 70] to afford tert-butyl (R)-3-(2-((tert- butoxycarbonyl)amino)-4-f1uoro-5-(methoxycarbonyl)pheny])morpholine-4-carboxylate, isomer 1 (4.40 g, 44%) as a while solid with the first peak on Chiral SFC and tert-butyl (S)-3- (2-((tert-butoxycarbonyl)amino)-4-fluoro-5-(metboxycarbonyl)phenyl)morpholine-4- carboxylate, isomer 2 (5.10 g, 51%) as a white solid with the second peak on Chiral SFC. MS ESI calculated for C22H31FN2O7 [M+H] L 455.21: found, 455.15.

Step 2: methyl (R)-4-amino-2-fluoro-5-(morpholin-3-y1)benzoate, isomer 1 isomer 1

[0687] To a stirred mixture of tert-butyl (R)-3-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate, isomer 1 (4.40 g, 9.68 mmol) in DCM (40 mL) was added TF.A (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure. The resulting mixture was dissolved in EtOAc, and basified to pH 8 with saturated NaHCOj (aq.). The organic layer was dried over anhydrous NajSO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (R)-3-(2-((tert- butoxycarbonyl)aniino)-4-fluoro-5-(methoxycarbonyl)phenyl)moipholine-4-carboxylate, isomer 1 (3.20 g, crude) as a brown solid. MS ESI calculated for CnHjiFNzCh [M+H] ⁺, 255.11; found, 255.10.

Step 3: methyl (R)-6-amino-9-f1uoro-l ,3,4,1 1b-tetrahydro-[l ,4]oxazino[4,3-c]quinazoline-

10-carboxylate, isomer 1 isomer 1

[0688] A mixture of methyl (R)-4-amino-2-fluoro-5-(moTpholin-3-yl)benzoate, isomer 1 (3.20 g, crude) and BrCN (1 .33 g, 12.59 mmol) in 1 ,4-dioxane (35 mL) was stirred at 80 °C for 16 h. After cooling down, the reaction mixture was filtered, and the filter cake was collected and washed with 1 ,4-dioxane to affordmethyl (R)-6-amino-9-fluoro-l,3,4,l 1b- tetrahydro-[l,4]oxazino[4,3-c]quinazoline-10-carboxylate, isomer 1 (2.57 g, 73%) as a white solid. MS ESI calculated for C13H14FN3O3 [M+H]\ 280.10; found, 280.10.

Step 4: (R)-6-amino-9-fluoro-l ,3,4, 1 lb-tetrahydro-[l ,4]oxaztno[4,3-c]quinazoline-10- carboxylic acid, isomer 1 (CAI isomer 1 )

CA1 isomer 1

[0689] To a stirred mixture of methyl (R)-6 -aniino-9-fluoro-l,3,4,l lb-tetrahydro-

[l,4]oxazino[4,3-c]qumazoline- 10-carboxylate, isomer 1 (2.57 g, 9.20 mmol) in MeOH (10 mL), THE (20 mL) and H2O (10 ml..) was added LiOH (660 mg, 27.6 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 2 h. The reaction solution was concentrated under reduced pressure. The mixture was acidified to pH 6 with HC1 (2 N). The resulting mixture was filtered, and the filter cake was collected and washed with H2O to afford (R)-6-amino-9-fluoro- 1 ,3,4, 1 lb-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazoline- 10- carboxylic acid, isomer 1 (1.66 g, 68%) as a white solid. MS ESI calculated for C12H12FN3O3 [M+H]⁺, 266.09; found, 266.00. ^!H NMR (300 MHz, DMSO-cA) 5 12.38 (br, 1 H), 7.38 (d, J = 8.1 Hz, 1H), 6.58 (br, 2H), 6.29 (d, J = 13.3 Hz, 1H), 4.63 - 4.57 (m, IH), 3.94 (dd, J = 1 1.0, 3.3 Hz, 1H), 3.86 - 3.75 (m, 2H), 3.57 - 3.40 (m, 2H), 3.15 - 3.04 (m, IH).

Step 5: methyl (S)-4-amiao-2-fluoro-5-(morpholin-3-yi)benzoate, isomer 2 isomer 2

[0690] To a stirred mixture of tert-butyl (S)-3-(2-(.(tert-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate, isomer 2 (5.10 g, 11.22 mmol) in DCM (40 niL) was added TEA (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure. The resulting mixture was dissolved in EtOAc, and basified to pH 8 with saturated NaHCO?

(aq.). The organic layer was dried over anhydrous NajSCh. After filtration, the filtrate was concentrated under reduced pressure to afford methyl (S)-4-amino-2-fluoro-5-(morpholin-3- yl)benzoate, isomer 2 (2.90 g, crude) as a brown solid. MS ESI calculated for C12H15FN2O3 [M+Hf , 255.11 ; found, 255.15.

Step 6: methyl (S)-6-amino-9-fluoro-l, 3,4,1 lb-tetrahydro-| l,4]oxazino|4,3-c{quinazoline- 10- carboxylate, isomer 2

[0691] A mixture of methyl (S)-4-amino-2-fluoro-5-(morpho1in-3-yl)benzoate, isomer 2 (2.90 g, crude) and BrCN (1.21 g, 11.41 mmol) in 1,4-dioxane (35 mL) was stirred at 80 °C for 16 h. After cooling down, the reaction mixture was filtered, and the filter cake was washed with 1,4-dioxane to afford methyl (S)-6-amino-9-fluoro-l,3,4,l Ib-tetrahydro- [l,4]oxazino[4,3-c]quinazoline-10-carboxylate, isomer 2 (2.74 g, 86%) as a white solid. MS ESI calculated for C13H14FN3O3 [M+H]⁺, 280.10; found, 280.15.

Step 7: (S)-6-amino-9-fluoro-l ,3,4,1 lb-teirahydro-[l ,4]oxazino[4,3-c]quinazoline-10- carboxylic acid, isomer 2 (CAI isomer 2)

[0692] To a stirred mixture of methyl (S)-6-amino-9-f]uoro-l,3,4, 1 Ib-tetrabydro- [l,4]oxazino|4,3-c]qumazoline- 10-carboxylate, isomer 2 (2.74 g, 9.81 mmol) in MeOH (10 rot), THF (20 mLj and H?O (10 ml..) was added LiOH (700 mg, 29.43 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 2 h. The reaction solution was concentrated under reduced pressure. The mixture was acidified to pH 6 with HC1 (2 AQ. The resulting mixture was filtered, and the filter cake was collected and washed with H2O to afford (S)-6-amino-9-lluoro- 1,3.4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazoline-10- carboxylic acid, isomer 2 (1.69 g, 65%) as a white solid. MS ESI calculated for C12H12FN3O3 [M+H]⁺, 266.09; found, 266.00. TI NMR (300 MHz, DMSO-Je) 3 12.38 (br, 1H), 7.38 (d, J = 8.1 Hz, 1H), 6.58 (br, 2H), 6.29 (d, 13.3 Hz, 1H), 4.63 - 4.57 (m, 1H), 3.94 (dd, J =

1 1.0, 3.3 Hz, 1H), 3.86 - 3.75 (m, 2H), 3.57 - 3.40 (m, 2H), 3.15 - 3.04 (m, 1H).

[0693] The absolute stereochemistry of CAI isomer 2 was determined by single crystal X- ray crystallography. The absolute stereochemistry of CAI isomer 2 was further confirmed by crystallography based on the co-crystal structure of selected compounds disclosed herein with PRMT5 enzyme, where the compounds were prepared using CAI isomer 2. As such, CAI isomer 2 has the S-configuration represented by:

CA1 isomer 2

[0694] Accordingly, the CAI isomer 1 has the R-configuration represented by: Intermediate CA2: 1 :1 mixture of (S)-6-amino-8-fluoro-l ,3,4,1 lb-tetrahydro-

[1 ,4]oxazino[4,3-c]quinazoline- 10-carboxylic acid and (R)-6-amino-8-fluoro- 1 ,3,4,11b- tetrahydro-f 1 ,4]oxazino[4,3-c]quinazoline- 10-carboxylic acid

Step 1: methyl 4-amino-3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate)

[0695] To a stirred solution of methyl 4-amino-3-bromo-5-fluorobenzoate (50.00 g, 201.6 mmol) in dioxane (500 mL) were sequentially added BPD (76.8 g, 302.4 mmol), AcOK (59.4 g, 604.7 mmol) and Pd(dppf)Ch (14.75 g, 20.15 mmol). The resulting solution was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction was quenched with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCU The residue was purified by trituration with ethyl ether. The precipitated solids were collected by filtration and washed with petroleum ether to afford methyl 4-amino-3-fluoro-5-(4,4,5,5-tetraroethyl-l,3,2-dioxaborolan-2-yl)benzoate (23.93 g, 24%) as a grey solid. MS ESI calculated for C14H19BFNO4 [M+H]⁺, 296.14; found, 296.00.

Step 2: tert-butyl 3-[2-amino-3-fluoro-5-(methoxycarbonyl)pheiiyl]-5,6-dihydro-oxazine-4- carboxylate

[0696] To a solution of methyl 4-amino-3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (5.39 g, 18.28 mmol) in MeCN (100 mL) and H2O (25 mL) were sequentially added tert-butyl 3-[(diphenoxyphosphoryl)oxy]-5,6-dihydro-oxazine-4- carboxylate (8.72 g, 20.1 1 mmol), K3PO4 (11.7 g, 54.9 mmol) and Pd[(t-Bu)?P]2 (0.93 g, 1.82 mmol). The resulting mixture was stirred at 65 °C for 16 h under nitrogen atmosphere. The mixture was quenched with water. The aqueous layer was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford tert-butyl 3-[2-amino-3-fluoro-5-(methoxycarbonyI)phenyl]-5,6- dihydro-oxazine-4-carboxylate (2.70 g 33%) as a yellow solid. MS ESI calculated for C17H21FN2O5 [M-100+HJL 353.14; found, 353.25.

Step 3: methyl 4-amino-3-(5,6-dihydro-2H-l ,4-oxazin-3-yl)-5-fluorobenzoate

[0697] A solution of tert-butyl 3-[2-amino-3-fluoro-5-(methoxycarbonyl)phenyl]-5,6- dihydro-oxazine-4-carboxylate (1.45 g, 4.11 mmol) in DCM (10 mL) and TEA (5 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford methyl 4-amino-3-(5,6-dihydro-2H-l,4-oxazin-3-yI)-5-fluorobenzoate (2.55 g, crude) as a brown oil. MS ESI calculated for C12H15FN2O2 [M+H]⁺, 253.09; found, 253.10.

Step 4: 1: 1 mixture of methyl (S)-4-amino-3-iluoro-5-(morpholin-3-yl)benzoate and methyl (R)-4-amino-3-fhioro-5-(morpholin-3-yl)benzoate

[0698] To a stirred solution of methyl 4-amino-3-(5,6-dihydro-2H-l ,4-oxazin-3-yl)-5- fluorobenzoate (2.55 g, 10.109 mmol) in DCM <25 mL) was added NaBH(AcO)s (4.29 g, 20.3 rnmol) at 0 °C. The resulting mixture was stirred at 40 °C for 4 h. The mixtitre was quenched with water. The aqueous layer was extracted with CH2O2. The combined organic layers were washed with brine, dried over anhydrous Na2SCU The residue was purified by silica gel column chromatography with 0-100%' EtOAc in petroleum ether to afford a 1:1 mixture of methyl (S)-4-amino-3-nuoro-5-(morpbolin-3-yl)benzoate and methyl (R)-4- amino-3-fluoro-5-(morpholin-3-yl)benzoaie (210 mg g, 6%) as a brown solid. MS ESI calculated for C12H15FN2O3 [M+H]’, 255.1 1 ; found, 255.10.

Step 5: 1: 1 mixture of methyl (S)-6-amino-8-fluoro-l,3,4.11b-tetrahydro-[l,4]oxazino[4,3- c]quinazoline-10-carboxy]ate and methyl (R)-6-amino-8-fluoro- 1,3,4, 1 Ib-tetrahydro-

[ 1 ,4]oxazino[4,3-c]quinazoline- 1 ()-carboxylate

[0699] To a stirred solution of a 1:1 mixture of methyl (S)-4-amino-3-fluoro-5-(morpholin- 3-yl)benzoate and methyl (R)-4-amino-3-fluoro-5-(morpholin-3-yl)benzoate (600 mg, 2.36 mmol) in dioxane (6 mL) was added BrCN (249 mg, 2.36 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The precipitated solids were collected byfiltration and washed with EtOAc to afford a 1: 1 mixture of methyl (S)-6-aniino-8 -fluoro- 1, 3, 4, l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazoline- 10-carboxylate and methyl (R)-6-amino- 8-fluoro- 1,3,4, 1 1 b-tetrahy dro- [ 1 ,4]oxazino[4,3-c]quinazoline- 10-carboxyl ate (626 mg, 90%) as a white solid. MS ESI calculated for C13H14FN3O3 [M+Hf , 280.10; found, 280.20. ^!H NMR (400 MHz, DMSO-d₆) 8 8.05 (br, 2H), 7.79 - 7.75 (m, 2H), 5.07 (dd, .7 = 10.4, 3.2 Hz, 1 H), 4.24 (dd, 11.2. 3.2 Hz, 1H), 4.07 (d, J= 13.2 H, HI), 3.97 (dd, J = 12.0, 3.2 Hz, IH),

3.85 (s, 3H), 3.69 - 3.59 (m, 2H), 3.41 - 3.31 (m, 1 H).

Step 6: 1: 1 mixture of (S)-6-amino-8-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3 c]quinazoline-10-carboxylic acid and (R)-6-amino-8-fluoro-l,3,4,l lb-tetrahydro- [l,4]oxazino[4,3-c]quinazoline-10-carboxylic acid (CA2)

[0700] To a stirred solution of a 1: 1 mixture of methyl (S)-6-amino-8-fluoro- 1.3,4, 11b- tetrahydro-[l ,4]oxazino[4,3-c]quinazoline- 10-carboxylate and methyl (R)-6-amino-8-fluoro- 1, 3, 4, llb-tetrahydro-[l,4]oxazino[4,3-c]quinazoline- 10-carboxylate (630 mg, 2.25 mmol) in THF (4 mL) and H2O (1 mL) was added LiOH (108 trig, 4.51 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 16 h. The mixture was acidified to pH 5 with HC1 (2 M). The precipitated solids were collected by filtration and dried under vacuum to afford a 1: 1 mixture of (S)-6-amino-8-fluoro-l,3,4, J lb-tetrahydro-[l,4]oxazino[4,3- c]quinazoline-10-carboxylic acid and (R)-6-amino-8-fluoro-l, 3,4,1 Ib-tetrahydro- [l,4]oxazino[4,3-c]quinazoline-10-carboxylic acid (325 mg, 46%) as a white solid. MS ESI calculated for CMHnFNsCh [M+H]⁺, 266.09; found, 266.20. 'H NMR (400 MHz, DMS0-d₆) 5 7.37 (dd, J = 11.6, 2.0 Hz, 1H), 7.32 (s, 1H), 6.70 (s, 2H), 4.68 (dd, .7 = 10.4, 3.2 Hz, 1H), 3.96 (dd, J = 11.2, 3.2 Hz, 1H), 3.87 - 3.77 (m, 2H), 3.58 - 3.43 (m, 2H), 3.16 - 3.04 (m, 1H).

Intermediate CA3: 1:1 mixture of (S)-6-amino-l,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3- c]quinazoline-40-carboxylic acid and (R)-6-amino-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazoline- 10-carboxylic acid

Step 1 : tert-butyl 5-((diphenylphosphoryl)oxy)-2,3-dihydro-4H- 1 ,4-oxazine-4-carboxylate Boc

[0701] To a stirred solution of tert-butyl 3-oxomorpholine-4-carboxylate (50 g, 248 mmol) in THF (500 mL) was added LiHMDS (273 mL, 273 mmol) dropwise at -30 °C under nitrogen atmosphere. The mixture was stirred at -30 °C for 1 h. To the above mixture was added diphenyl phosphorochloridate (70 g. 261 mmol) dropwise at -30 °C. The resulting mixture was allowed to warm slowly to 25 °C and stirred for 6 h under nitrogen. Ute reaction mixture was quenched by the addition of sat. NH4C1 (aq.) (100 mL) at 25 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaHCO3 (aq., sat.) and brine, dried over anhydrous Na-TSCE. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-30% ethyl acetate in petroleum ether to afford tert-butyl 5- ((diphenylphosphoryl)oxy)-2,3-dihydro-4H-l,4-oxazine-4-carboxylale (69 g, 58.3%) as a colorless oil.

Step 2: methyl 4-amino-3-(4,4,5,5-tetrametbyl-1 ,3,2-dioxaborolan-2-yl)benzoate

[0702] To a stirred mixture of methyl 4-amino-3-bromobenzoate (5.00 g, 21 .7 mmol) and bis(pinacolato)diboron (8.28 g, 32.6 mmol) in 1,4-dioxane (100 ml) were added AcOK (4.27 g, 43.5 mmol) and Pd(dppf)Clj.CH2C12 (1.77 g, 2.17 mmol). The resulting mixture was stirred at. 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0- 100% ethyl acetate in petroleum ether to afford methyl 4-amino-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (6.00 g, 65%) as an orange solid. MS (ESI) calculated for (C14H20BNO4) [M+Hj\ 278.15; found, 278.20.

Step 3: methyl 4-ainino-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzoate

[0703] To a stirred mixture of methyl 4-amino-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan- 2-yl)benzoate (5.90 g, 21.3 mmol) and tert-butyl 3-[(dipbenyJphosphoroso)oxy]-5,6-dihydro- oxazine-4-carboxylate (7.12 g, 17.7 mmol) in MeCN (60 mL) and H2O (15 ml..) were added Pd[(t-Bu)3P]2 (0.91 g, 1.77 mmol) and K3PO4 (11.30 g, 53.2 mmol), lire resulting mixture was stirred at 65 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SOa- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford tert-butyl 3-[2-amino-5-(methoxycarbonyl)phenyl]-5,6-dihydro-oxazine-4- carboxylate (650 mg, 10%) as a off-white solid. MS (ESI) calculated for (C17H22N2O5) [M+H]⁺, 335.15: found, 279.05.

Step 4: 1 : 1 mixture of tert-butyl (S)-3-(2-ammo-5-(rnethoxycarbonyl)phenyl)morpholine-4 carboxylate and tert-butyl (R)-3-(2-amino-5-(methoxycarbonyl)phenyl)morpholine-4- carboxylate

[0704] To a stirred mixture of tert-butyl 3-[2-amino-5-(methoxycarbonyl)phenyl]-5,6- dihydro-oxazine-4- carboxylate (650 mg, 1.94 mmol) in MeOH (5 mL) were added Pd/C (47.6 mg, 10%) and PdfOHWC (240 mg, 20%). The resulting mixture was stirred at 25 °C for 16 h under hydrogen atmosphere (1 atm). The resulting mixture was filtered, the filter cake was washed with CH2CI2. The filtrate was collected and concentrated under reduced pressure to afford a 1: 1 mixture of tert-butyl (S)-3-(2-amino-5- (methoxycart>onyl)phenyl)morpholine-4-carboxylate and tert-butyl (R)-3-(2-amino-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate (680 mg, crude) as a colorless oil. MS (ESI) calculated for (C17H24N2O5) [M+Hf, 337.17; found, 281.05.

Step 5: 1: 1 mixture of methyl (S)-4-amino-3-(morpholin-3-yl)benzoate and methyl (R)-4- amino-3-(morpholin-3-yl)benzoate

[0705] To a stirred solution of a 1: 1 mixture of tert-butyl (S)-3-(2-amino-5- (methoxycarbonyl)phenyl)moipholine-4-carboxylate and tert-butyl (R)-3-(2-amino-5- (methoxycart>onyl)phenyl)moipho1ine-4-carboxylate (680 mg, crude) in DCM (6 mL) was added TFA (2 mL) dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 16 h. The resulting mixture was basified to pH 8 with saturated NaHCCh (aq.). The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure to afford a 1: 1 mixture of methyl (S)-4-amino-3-(morpholin-3-yl)benzoate and methyl (R)-4-amino-3-(morpholin-3-y1)benzoate (400 mg, 84%) as a brown solid. MS (ESI) calculated for (CizHieNzCh) [M+H]⁺, 237.12; found, 237.20.

Step 6: 1:1 mixture of methyl (S)-6-amino-1 ,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazoline-10-carboxylate and methyl (R)-6-amino-l ,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3- c]quinazoline- 10-caiboxylate

[0706] To a stirred solution of a 1:1 mixture of methyl (S)-4-amino-3-(morpholin-3- yl)benzoate and methyl (R)-4-amino-3-(morpholin-3-yl)benzoate (400 mg, 1.69 mmol) in 1,4-dioxane (10 mL) was added BrCN (179 mg, 1.69 mmol). The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: [column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 40 min: detector, UV 254 nm] to afford a 1: 1 mixture of methyl (S)-6-arnino-l,3,4,l lb- tetraliydro-[l,4]oxazino[4,3-c]quinazoline-10-carboxylate and methyl (R)-6-amino- 1,3,4,11b- teirahydro-[l,4]oxazino[4,3-c]quinazoline-10-carboxylate (300 mg, 68%) as an off white solid. MS (ESI) calculated for (CM-I15N3O3) [M+H]⁺, 262.1 1 ; found, 262.05.

Step 7: 1 : 1 mixture of (S)-6-amino-l, 3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolme-l0- carboxylic acid and (R)-6-amino-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazoline-10- carboxylic acid (CA3)

[0707] To a stirred solution of a 1 : 1 mixture of methyl (S)-6-amino-l.3,4,1 1 b-tetrahydro-

[1.4]oxazino[4,3-c]quinazoline-10-carboxylate and methyl (R)-6- amino- 1,3, 4,1 lb-tetrahydro-

[1.4]oxazino[4,3-c]qumazoline- 10-carboxylate (250 mg, 0.96 mmol) in THE (2 mL) and IhO

(2 mL) was added LiOH (46 mg, 1 .91 mmol) slowly at 25 °C. The resulting mixture was stirred for at 25 °C 16 h. The resulting mixture was concentrated under reduced pressure to afford a 1: 1 mixture of (S)-6-amino-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazoline-10- carboxylic acid and (R)-6-amino- 1,3,4, rib-ietrahydro-[l,4]oxazino[4,3-c]quinazoline- 10- carboxylic acid (500 mg, crude) as a brown oil. MS (ESI) calculated for (C12H13N3O3) [M+H]⁺, 248.10: found, 248.25. ^!H NMR (400 MHz, DMSO-rfe) 6 7.57 (dd, 8.1, 1.8 Hz, 1 H), 7.42 (s, 1H), 6.50 (d, 8.0 Hz, 1H), 4.48 (dd, J ~ 10.0, 3.2 Hz, 1H), 3.95 (dd, 11.2,

3.2 Hz, 1H), 3.84 - 3.73 (m, 2H), 3.55 - 3.38 (m, 2H), 3.09 - 2.97 (m, 1H). Intermediate CA4 (Method 1): (R)-6-amino- 1,3,4, 1 1b- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid

Step-1: methyl 5-amino-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2.-yl)pyridine-2- carboxylate

[0708] A mixture of methyl 5-aminopyridine-2-cart>oxylate (25.00 g, 164.31 mmol) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (31.54 g, 246.46 mmol) in anhydrous THF (200 ml) was stirred at 50 °C for 1 h under nitrogen atmosphere. The reaction mixture was cooled to 25 °C and then added to a mixture of Bis(pinacolato)diboron (20.86 g, 82.15 mmol), dtbppy (1.32 g, 4.93 mmol) and [Ir(CC)D)(OMe)]2 (1.63 g, 2.47 mmol) in anhydrous THF (200 raL) at 25 °C under nitrogen atmosphere. The mixture was stirred at 80 °C for 16 h. The organic solvent was removed under vacuum. The residue was triturated with n-heptane and tert-Butyl methyl ether (1/1) to afford methyl 5-amino-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine-2-carboxylate (62.4 g, crude) as a brown solid. MS (ESI) calculated for (C13H19BN2O4) [M+H]⁺, 279.14; found, 279.15. ^!H NMR (400 MHz, Chloroform-^ 5 8.30 (s, 1H). 8.11 (s, 1H), 5.26 (br, 2H), 3.94 (s, 3H), 1.37 (s, 12H).

Step-2: tert-butyl 3-[5-amino-2-(methoxycarbonyl)pyridin-4-yI]-5,6-dihydTO-oxazine-4- carboxylate

[0709] A mixture of methyl 5 -amino-4- (4,4,5,5-tetraniethyl- l,3,2-dioxaboroIan-2- yl)pyridine-2-carboxylate (48.50 g, 174.39 mmol), tert-butyl 3-[(diphenoxyphosphoryl)oxy]- 5,6-dihydro-oxazine-4-carboxylate (37.79 g, 87.19 mmol), Pd(dppt)C12 (6.38 g, 8.72 mmol) and K2CO3 (24.10 g, 174.39 mmol) in dioxane (1000 mL) and H2O (200 mL) was stirred at 90 °C for 2 h under nitrogen atmosphere, lire reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-100% ethyl acetate in petroleum ether to afford tertbutyl 3-L5-amino-2-(methoxycarbonyDpyridin-4-yl]-5,6-dihydro-oxazine-4-carboxylate (19.3 g, 33%) as a brown solid. MS (ESI) calculated for (C16H21N3O5) [M+H]⁺, 336.15; found, 336.10.

Step-3: 1:1 mixture of tert-butyl (3R)-3-|5-amino-2-(methoxycarbonyl)pyridin-4- yl]morpholine-4-carboxylate and tert -butyl (3S)-3-[5-amino-2-(methoxycarbonyl)pyridin-4- yl]morpholine-4-carboxylate

[0710] To a solution of tert-butyl 3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]-5,6- dihydro-oxazine-4-carboxylate (20.00 g, 59.64 mmol) in MeOH (600 mL) was placed in an autoclave, then Pd/C ( 10% active on carbon) (3.17 g) and Palladium hydroxide (20% active on carbon, nominally 50% water) (4.19 g) were added to above mixture. The mixture was stirred at 50 °C for 16 h under hydrogen atmosphere (30 atm.). The resulting mixture was filtered, the filler cake was washed wdth methanol. The filtrate was collected and concentrated under reduced pressure to afford a 1 :1 mixture of tert-butyl (3R)-3-[5-amino-2- (niethoxycarbonyl)pyridin-4-yi]morpholine-4-carboxylate and tert-butyl (3S)-3-(5-amino-2- (methoxycarbonyl)pyridin-4-yl]morpholine-4-carboxylate (18.2 g, crude) as a yellow solid. MS (ESI) calculated for (C ? I L X ;O o [M+H]⁺, 338.16; found, 338.25.

Step-4: tert-butyl (3S)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]morpholine-4- carboxylate tert-butyl (3R)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]morpholine-4 -carboxylate .0.

[0711] The racemic compound of tert-butyl 3-[5-amino-2-(methoxycarbonyl)pyridin-4- yl]morpholine-4-carboxylaie (19.00 g) was separated by prep-chiral SFC with the following conditions: [Column: CHIRAL. ART CelluIose-SZ, 5*25 cm, 5 gm; Mobile Phase A: CO2, Mobile Phase B: MeOH: Flow rate: 200 niL/min: Gradient: isocratic 60% B; Wave Length: 220 nm; RTl(min): 4.2: RT2(min): 7.9: Sample Solvent: MeOH] to afford tert -butyl (3S)-3- [5-amino-2-(methoxycarbonyl)pyridin-4-yl]morpholine-4-carboxylate (9.5 g, 50%) as a brown solid with the first peak on Chiral SFC and tert-butyl (3R)-3-[5-amino-2- (methoxycarbonyl)pyridin-4-yl]niorpholine-4-carboxylate (8.7 g, 45%) as a brown solid with the second peak on Chiral SFC. MS (ESI) calculated for (C16H23N3O5) [M+H]⁺, 338.16; found, 338.15.

Step-5 : methyl 5-amino-4-[ (3R)-morphoiin-3-yl |pyridine-2-carboxylate (6 )

[0712] To a stirred solution of tert-butyl (3R)-3-[5-amino-2-(methoxycarbonyl)pyridin-4- ylJmorpholine-4-cafboxylate (8.50 g, 25.14 mmol) in DCM (75 ml) was added trifluoroacetic acid (25 mL) at. 25 °C. The resulting solution was stirred at 25 °C for 2 h. The solvents were removed under vacuum to afford methyl 5-amino-4-[(3R)-morpholin-3- ylJpyridine-2-carboxylate (17.8 g, crude) as a brown oil. MS (ESI) calculated for (C] iHi 5N3O3) [M+H]⁺, 238.11; found, 238.05.

Step-6: methyl (R)-6-amino-l,3,4 ,1 lb-tetrahydropyrido[3‘,4’:4,5]pyrimido[6,l- c] [ 1, 4]ox azine- 10-carboxylate

[0713] To a stirred solution of methyl 5-amino-4-[(3R)-morpholin-3-yl]pyridine-2- carboxylate ( 17.8 g, crude from previous batch) in isopropanol (400 mL) was added carbononitridic bromide (7.95 g, 75.02 mmol) at 25 °C. The resulting solution was stirred at 80 °C for 16 h. The precipitated solid was collected by filtration and washed with isopropanol to afford methyl (R)-6-amino-l, 3,4,1 lb-tetrahydropyrido[3', 4’:4, 5]pyrimido[6,l- clfl,4]oxazine-10-carboxylate (5.4 g, 26%) as a white solid. MS (ESI) calculated for (C12H14N4O3) [M+H]⁺, 263.11; found, 263.10.

Step-7: (R)-6-amino-l,3,4,l lb-tetahydropyrido[3*,4':4,5]pyrimido[6,l-c][l,4]oxazine-10- carboxylic acid (CA4)

[0714] To a stirred mixture of methyl (R)-6-amino- 1,3,4,11b- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxyjate (5.40 g, 20.59 mmol) in THF (40 niL) and H2O (20 niL) was added LiOH (1.48 g, 61.77 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The organic solvent was removed under vacuum. The aqueous layer was acidified with TIG (6 N) to pH -6. The suspension was filtered through paper. The filter cake was collected and dried under vacuum to afford (R)-6- amino-l,3,4,llb-tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazine-10-caiboxylic acid (5.00 g, 90%) as a white solid. MS (ESI) calculated for (CiiHnNrCh) [M+H]⁺, 249.09; found, 249.10. ^!H NMR (400 MHz, DMSO-de) 57.86 (s, 1 H), 7.54 (s, 1 H), 6.78 (s, 2H), 4.69 (dd, J = 10.0, 3.2 Hz, 1H), 4.10 (dd, J = 11.2, 3.2 Hz, 1H), 3.91 - 3.80 (m, 1H), 3.79 - 3.72 (m, 1 H), 3.56 - 3.42 (m, 2H), 3.1 1 - 3.00 (m, 1 H).

[0715] The absolute stereochemistry of CA4 was determined by crystallography based on the single-crystal X-ray structure of compound 22 that was prepared using intermediate CA4.

Intermediate CA4 (Method 2): (R)-6-amino- l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid Step-1: (R)-N-[( lE)-2-[(tert-buiyldimeihylsilyl)oxy]ethylidene]-2-metbylpropane-2- sulfinamide

[0716] To a stirred solution of 2-[(tert-butyldimethylsily1)oxy]acetaldehyde (50.00 g, 286.84 mmol) in DCM (500 mL) were added (R)-2-methylpropane-2-sulfinamide (supplier: Dalian BBChem Co., Ltd. CAS# 196929-78-9) (38.24 g, 315.52 mmol) and CuSCL (114.45 g, 717.09 mmol) at 20 °C. The resulting solution was stirred at 20 °C for 16 h. The suspension was filtered through celite. The filtrate was collected and concentrated under vacuum. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford (R)-N-[(lE)-2-[(tert-butyldimethylsilyl)oxy]ethylidene]-2- methylpropane-2-sulfinamide (62.00 g, 77%) as a colorless oil. MS ESI calculated for C12H27NO2SS1 [M+H?, 278.15; found, 278.15.

Step-2: tert-butyl (4-((R)-2-((tert-butyldimethylsilyl)oxy)-l-(((R)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate tert-butyl (4-((S)-2-((tert-bulyldimeihylsilyl)oxy)-l-(((R)-tert-butylsulfinyl)am!no)ethyl)-6- chloropyridin-3-yl)carbamate

[0717] To a stirred solution of tert-butyl N-(6-chloropyridin-3-yl)carbamate (20.00 g, 87.46 mmol) and N,N,N',N‘-Tetramethylethylenedian)ine (30.49 g, 262.37 mmol) in Diethyl ether (400 mL) was added butyllithium (1.6 M in n-hexane) (164 mL, 262.40 mmol) dropwise at - 78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h under nitrogen atmosphere. Then a solution of (R)-N-[(lE)-2-[(tert- butyldimethylsilyl)oxy]ethylidene]-2-methvlpropane-2-sulfinamide (48.54 g, 174.92 mmol) in Diethyl ether (50 mL) was added dropwise at -78 °C. The resulting mixture was warmed at room temperature with stirring for 16 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-30% ethyl acetate in petroleum ether to afford tert.-butyl (4-((R)-2-((tert-butyldimethylsilyl)oxy)-l- (((R)-tert-butylsuliinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate (24.7 g, 55%) as a yellow oil and tert-butyl (4-((S)-2-((tert-butyldimethylsilyl)oxy)-l-(((R)-tert- butylsulfinyljamino)ethyl)-6-chloropyridin-3-yJ)carbamate (8.80 g, 19%) as a yellow oil. MS ESI calculated for C22H4oClN304SSi [M+H]⁺, 506.22; found, 506.25.

[11718] tert-butyl (4-((R)-2-((tert-butyldimethylsilyl)oxy)-l-(((R)-teit- buiy]sulfiny])amino)ethyl)-6-chloropyridin-3-yl)carbamate : MS ESI calculated for C22H40CIN3O4SS! [M+H]⁺, 506.22; found, 506.25. ^;H NMR (400 MHz, DMSO-rf₆) 5 8.85 (s, 1H), 8.43 (s, IH), 7.54 (s, 1H), 5.29 (d, J = 6.4 Hz, 1H), 4.71 (q, J = 6.0 Hz, 1H), 3.87 - 3.77 (in, 2H), 1.46 (s, 9H), 1.12 (s, 9H), 0.82 (s, 911), -0.02 (s, 3H), -0.03 (s, 3H).

[0719] tert-butyl (4-((S)-2-((tert-butykiimethylsilyl)oxy)-l -(((R)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate: MS ESI calculated for C22H4oClN₃04SSi [M+H]⁺, 506.22; found, 506.25. ^!H NMR (400 MHz, DMSO-A) 5 8.83 (s, 1H), 8.40 (s, 1H), 7.61 (s, 1H), 5.86 (d, J = 8.2 Hz, 1 H), 4.74 - 4.57 (m, 1H), 3.80 - 3.67 (m, 2H), 1.46 (s, 9H), 1.13 (s, 9H), 0.81 (s, 9H), -0.04 (s, 3H), -0.06 (s, 3H).

Step-3: (2R)-2-amino-2-(5-amino-2-chloropyridin-4-yl)ethanol hydrochloride

[0720] A mixture of tert-butyl (4-((R)-2-((tert-butyldimethylsilyl)oxy)-l-(((R)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate (12.10 g, 23.94 mmol) and HC1 (4M in dioxane) (15 mL) was stirred at 25 °C for 1 h. The organic solvent was removed under vacuum. The residue was triturated with EtcO to afford (2R)-2-amino-2-(5-amino-2- chloropyridin-4-yl)ethanol hydrochloride (6.00 g, crude) as a yellow solid. MS ESI calculated for C7H10CIN3O [M+H]⁺, 188.05; found, 188.10.

Step-4: N-[(lR)-l-(5-amino-2-chloropyridin-4-yl)-2-hydroxyethyl]-2-chloroacetamide

[0721] To a stirred solution of (2R)-2-amino-2-(5-amino-2-chloropyridin-4-yl)ethanol hydrochloride (6.00 g, 26.78 mmol) in DCM (400 mL) was added EtjN (6.47 g, 63.95 mmol) at 0 °C. Then chloroacetyl chloride (2.89 g, 25.58 mmol) was added slowly to the above mixture at 0 °C. The resulting solution was stirred at 25 °C for 16 b. The organic solvent was removed under vacuum. The residue was purified by flash column chromatography with 0- 15% methanol in dichloromethane to afford N-[(lR)-l-(5-amino-2-chloropyridin-4-yl)-2- hydroxyethyl]-2-chIoroacetamide (5.40 g, 85% over two steps) as a yellow solid. MS ESI calculated for C9H11CI2N3O2 [M+H]⁺, 264.02; found, 264.10.

Step-5 : (5R)-5-(5-amino--2-chloropyridin-4-yl)morpholin "3-oiie

[0722] To a stirred solution of N-[(lR)-l-(5-amino-2-chloropyridin-4-yl)-2-hydroxyethylJ- 2-chloroacetamide (5.40 g, 20.44 mmol) in isopropanol (48 mL) and THF (12 mL) was added t-BuOK (9.18 g, 81.76 mmol) in potions at 0 °C. The resulting solution was stirred at 20 °C for 16 h. The reaction was quenched by the addition of NHsCl (sat.). The resulting mixture was extracted with EtOAc The combined organic layers were washed with brine, dried over anhydrous Na2SO4- After filtration, the filtrate was concentrated under reduced pressure to afford (5R)-5-(5-amino-2-chloropyridin-4-yl)morpholin-3-one (1.80 g, 20%) as a yellow solid. MS ESI calculated for C9H10CIN3O2 [M+l]⁺, 228.04; found, 228.15.

Step-6: 6-chloro-4-[(3R)-morpholin-3-yl]pyridin-3-amine

[0723] To a stirred mixture of (5R)-5-(5-amino-2--chloropyridm-4-yl)morpholin-3-oiie

(1.46 g, 6.41 mmol) and boron triiluoride diethyl etherate (2.73 g, 19.24 mmol) in THF (20 ml.,) was added NaBILs (73 mg, 19.24 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 40 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by water at room temperature. The mixture was acidified to pH 2 with HC1 (4 M). The aqueous layer was extracted with EtOAc. The aqueous layer was collected and basified to pH 9 with Nap-COs (sat.). The nixture was extracted with EtOAc. The organic layers were dried over anhydrous Na^SOr. After filtration, the filtrate was concentrated under reduced pressure to afford 6- chloro-4-[(3R)-tnorpholin-3-yl]pyridin-3-amine (320 mg, crude) as a yellow solid, which was used in next step without further purification. MS ESI calculated for C9H12CIN3O [M+l]⁺, 214.06; found, 214.25.

Step-7 : (RM 0-chloro- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-6- amine

[0724] A mixture of 6-chloro-4-[(3R)-morpholin-3-yl]pyridin-3-amine (320 mg, 1.50 mmol) and carbononitridic bromide (159 nig, 1.50 mmol) in 1,4-dioxane (5 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The mixture was cooled down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with DCM. The precipitated solids were collected by filtration and dried under vacuum to afford (R)-10-chloro-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-6-amine (290 mg, 81 %) as a yellow solid. MS ESI calculated for C10H11CIN4O |M+H]⁺, 239.06: found, 239.15.

Step-8: (R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l ,4]oxazine-10- carbonitrile

[0725] To a stirred mixture of (R)-10-chioro-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-6-amine (530 mg, 2.22 mmol) and Zinc cyanide (391 mg, 3.33 mmol) in NMP (7 mL) were added RuPhos Pd G3 (185 mg. 0.22mmol) and XantPhos (128 mg, 0.22 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 1 h under nitrogen atmosphere. The reaction mixture was applied to a 40 g Cl 8 column and purified by Combi Flash (Biotage Isolera Prime), eluted with 5~70% acetonitrile in water (10 mM NH4HCO3) to afford (R)-6-amino-l,3,4,l lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-e][l ,4]oxazine-10- carbonitrile (230 mg, 45%) as a light yellow solid. MS ESI calculated for C; iHnNsO |M+H]⁺, 230.09; found, 230.25. ^!H NMR (400 MHz, DMSO-tfc) 6 7.86 (s, 1H), 7.53 ( s, IH), 6.77 (s, 2H), 4.69 (dd, J = 10.4, 3.2 Hz, IH), 4.21 - 3.98 (m, IH), 3.92 - 3.73 (m, 2H), 3.58 - 3.43 (m, 2H), 3.12 - 3.00 (m, IH).

Step -9 : (R)-6-amino- 1 ,3 ,4.1 Ib-tetrahydropyridoj 3 ',4’:4,5 ]pyrimido| 6, 1 -c |[ 1 ,4 [oxazine- 10- carboxylic acid (CA4)

CA4

[0726] A mixture of (R)-6-amino- 1,3, 4,1 lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l- c][l,4]oxazine-10-carbonitrile (230 mg, 1.00 mmol) and HO (cone., 3 mL) was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure to afford (R)-6- amino- 1 ,3,4, 11 b-tetrahydropyrido[3’,4’:4,5]pyrimido[6,l-c][l,4]oxazine-l0-carboxylic acid (CA4) (250 nig, crude) as a yellow solid. MS ESI calculated for C11H12CIN4O3 [M+H]⁺, 249.09; found, 249.10. ^!H NMR (300 MHz, DMSO-db) 3 11.83 (s, IH), 8.48 (s, 2H), 8.33 (s, I H), 7.96 (s, IH), 5.04 (dd, 7 = 10.5, 3.6 Hz, IH), 4.28 (dd, 7 = 1 1.1, 3.3 Hz, IH), 4.14 (d, .J = 13.5 Hz, IH), 3.97 - 3.92 (m, IH), 3.78 - 3.54 (m, 2H), 3.43 - 3.13 (m, IH).

[0727] The absolute stereochemistry of CA4 synthesized by method 2 was determined by comparing to the CA4 synthesized by method 1 using chiral HPLC peak retention.

Intermediate CAS: (4S,1 lbS)-6-amino-4- methyl- 1,3, 4, l ib- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid .0. ; and

Intermediate CA6: (4S.1 lbR)-6-amino-4-methyl- 1,3,4, 1 lb- tetrahydropyrido[3^,,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid

Step-1: tert-bulyl (3S)-3-methyl-5-oxoniorpholine-4-carboxylate

Boc

[0728] To a mixture of (5S)-5-methylmorpholin-3-one (supplier: Shanghai Balmxy Pharmaceutic Co., Ltd. CAS# 119844-66-5) (10.03 g, 87.11 mmol) and DMAP (1.06 g, 8.71 mmol) in THF (100 mL) was added di-ten-butyl dicarbonate (28.52 g, 130.67 mmol) at room temperature. The mixture was stirred at 40 °C for 2 h. The solvents were removed under vacuum. The resulting residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford tert-butyl (3S)-3-methyl-5-oxomorpholine-4- carboxylate (17.31 g, 88%) as a colorless oil. MS ESI calculated for C10H17NO4 [M+H]⁺, 216.12; found, 216.15. ^!H NMR (400 MHz, Chloroform-d) 8 4.35 - 4.15 (m, 3H), 3.86 - 3.76 (in, 2H), 1.57 (s, 9H), 1.41 (d, J - 6.6 Hz, 3H).

Step-2: tert-butyl (5S)-3-[(diphenoxypbosphoryl)oxy]-5-methyl-5,6-dihydro-oxazine-4- carboxylate

[0729] To a mixture of tert-butyl (3S)-3-naethyl-5-oxomorpholine-4-carboxylate (17.30 g, 80.37 mmol) in THF ( 170 mL) was added LiHMDS (83 ml, 83.00 mmol, I M in THF) dropwise at -30 °C under nitrogen atmosphere. After stirring at -30 °C for 1 h, a solution of diphenyl chlorophosphonale (22.45 g, 83.58 mmol) in THF (20 mL) was added to the above mixture dropwise at -30 *C under nitrogen atmosphere. The mixture was allowed to warm to room temperature for 1 h with stirring. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with 0-40% ethyl acetate in petroleum ether to afford tert-butyl (5S)-3-[(diphenoxyphosphoryl)oxy]-5-methyl-5,6- dihydro-oxazine-4-carboxylate (29.90 g, 83%) as a yellow solid. MS ESI calculated for C22H-.6NO7P [M+H]⁺, 448.14; found, 448.10. *H NMR (400 MHz, DMSO-Jg) 6 7.49 - 7.37 (m, 4H), 7.30 - 7.22 (m, 6H), 6.49 (d, J = 4.0 Hz, 1H), 4.49 - 4.43 (m, 1H), 4.01 (dd, J = 11.2, 1.2 Hz, 1H), 3.61 (dd, J= 1 1.2, 2.8 Hz., 1H), 1.37 (s, 9H), 1.09 (d, .J = 6.8 Hz, 3H).

Step-3: tert-butyl (5S)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]-5-methyl-5,6-dihydro- oxazine-4 -carboxylate

[0730] To a stirred solution of tert-butyl (5S)-3-[(diphenoxyphosphoryl)oxy]-5 -methyl-5,6- dihydro-oxazine-4-carboxylate (30.50 g, 67.05 mmol) and methyl 5-amino-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (from CA4) (27.97 g, 100.57 mmol) in 1,4-dioxane (300 mL) and H2O (30 mL) were added K2CO3 <18.53 g, 134.10 mmol) and Pd(dppt)C12-CH2C12 (5.48 g, 6.70 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 40-70% EtOAc in petroleum ether to afford tert-butyl (5S)-3-[5-amino-2- (methoxycarbonyl)pyridin-4-y]]-5-methyl-5,6-dihydro-oxaznie-4-carboxylale (11.50 g, 49%) as a yellow solid. MS ESI calculated for C17H23N3O5 [M+H]⁺, 350.16; found, 350.05. ’H NMR (400 MHz, DMSO-de) 8 8.01 (s, 1H), 7.50 (s, 1H), 6.36 (s, 1H), 5.70 (s, 2H), 4.60 - 4.51 (m, 1H), 4.14 (dd, .7 = 10.8, 1.2 Hz, 1 H), 3.90 (dd, J = 10.8, 2.8 Hz, 1H), 3.77 (s, 3H), 1.24 (d, 7 = 6.8 Hz, 3H), 1.05 (s, 9H).

Step-4: methyl 5-amino-4-[(3R,5S)-5-methyImorpholin-3-yl]pyridine-2-carboxylate and methyl 5-amino-4-[(3S,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate

[0731] To a solution of tert-butyl (5S)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]-5- methyl-5,6-dihydro-oxazine-4-carboxylate (3.80 g, 10.87 mmol) in methanol (80 mL) were added Pd/C ( 1.85 g, 0.87 mmol, 5% active on carbon) and Pd(OH)₂/C (1.62 g, 0.76 mmol, 5% active on carbon). The mixture was stirred at 60 °C for 16 b under hydrogen atmosphere (50 atm). The mixture was filtered through a Celite pad. The filtrate was collected and concentrated under vacuum. Hie resulting residue was purified by normal phase flash column chromatography eluted with 0-5% methanol in dichloromethane to afford methyl 5-amino-4- [(3R,5S)-5-methylrnorpho]in-3-yl]pyridme-2-carboxylate (1.20 g, 31%) as a yellow solid with the first eluting peak and methyl 5-amino-4-[(3S,5S)-5-metbylmorphoHn-3-yl]pyridine- 2 -carboxylate (2.20 g, 57%) as a white solid with the second eluting peak.

[0732] Methyl 5-amino-4-[(3R,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate: MS

ESI calculated for CnlfeNrOs [M+H]⁺, 352.18; found, 352.15. 'H NMR (400 MHz, DMSO- db) 5 8.18 (s, 1H), 8.02 (s, 1H), 6.31 (s, 2H), 4.99 - 4.83 (m, 1H), 4.26 - 4.20 (m, 1H), 4, 15 ■■■ 4.06 (m, 1H), 3.78 (s, 3H), 3.77 - 3.64 (m, 3H), 1.38 (s, 9H), 1.06 (d, J = 7.2 Hz, 3H).

[0733] Methyl 5-amino-4-[(3S,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate: MS ESI calculated for C17H25N3O5 [M+H]⁺, 352.18; found, 352.20. *H NMR (400 MHz, DMSO- db) 8 7.97 (s, 1H), 7.68 (s, 1H), 6.12 (s, 2H), 4.68 (dd, J = 9.2, 4.6 Hz, 1H), 4.10 - 3.98 (m, 1H), 3.80 (dd, J = 11.6, 3.4 Hz, 1H), 3.77 (s, 3H), 3.75 - 3.66 (m, 2H), 3.20 (dd, J = 11.6, 9.2 Hz, 1 H), 1.24 (d, 7 = 6.6 Hz, 3H), 1.10 (s, 9H).

Step-5a: methyl 5-amino-4-[(3S,5S)-5-methyimorpholin-3-yi]pyridine-2-carboxylate

[0734] To a mixture of tert-butyl (3S,5S)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-y1]-5- methylmorpholine-4-carboxylate (2.20 g, 6.26 mmol) in DCM (25 mL) was added TFA (7 mL). The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum. The residue was basified with NaHCOs (sat.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford methyl 5-amino-4-[(3S,5S)-5- methylmorpholin-3-yl]pyridine-2-carboxylate (1.51 g, crude) as a yellow solid. MS ESI calculated for C12H17N3O3 [MW, 252.13; found, 252.15. ^!H NMR (400 MHz, Methanol- d₄) 8 8.11 (s, IH), 8.01 (s, 1H), 4.17 (dd. 7 = 5.6, 3.6 Hz, IH), 3.95 (dd, 7 = 11.8, 5.6 Hz, 1H), 3.90 (s, 3H), 3.86 - 3.80 (m, 2H), 3.41 (dd, J = 11.2, 6.0 Hz, IH), 2.98 - 2.93 (m, IH), 1.16 (d, 7= 6.6 Hz, 3H).

Step-6a: methyl (4S, 1 lbS)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate

[0735] To a mixture of methyl 5-amino-4-[(3S,5S)-5-methylmorpholin-3-yl]pyridine-2- carboxylate (1.51 g, crude from previous step) in isopropanol (20 niL) was added carbononitridic bromide (757 mg, 7.21 mmol). The mixture was stirred at 80 °C for 16 h. The suspended solids were collected by filtration and dried under vacuum to afford methyl (4S, 1 lbS)-6-amino-4-methyl-l,3,4,1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- cj[l,4]oxazine-10-carboxylate (1.35 g, crude) as a white solid. MS ESI calculated for Ci3H!6N4O3 [M+H]⁺, 272.12; found, 272.10. (400 MHz, Methanol-A) 8 8.31 (s, IH), 7.99 (s, IH), 5.37 - 5.33 (rm IH), 4.49 (dd, 7 = 1 1.4, 3.6 Hz, IH), 4.20 - 4.09 (ra, IH), 3.98 (s, 3H), 3.93 - 3.81 (m, 2H), 3.78 - 3.67 (m, IH), 1.55 (d, J = 6.9 Hz, 3H).

Step-7a: (4S.l lbS)-6-amino-4-methyl-l,3,4.11b-teirahydropyrido[3’,4':4,5]pyrimido[6,l- c][l ,4]oxazine-10-carboxylic acid (CAS)

[0736] To a mixture of methyl (4S, 1 lbS)-6-amino-4-methyl-l ,3,4, l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate (1.35 g, 4.89 mmol) in THF (15 mL) and H2O (15 mL) was added LiOH (234 mg, 9.76 mmol). The mixture was stirred at 50 °C for 1 b. The organic solvent was removed under vacuum. The remaining aqueous layer was neutralized with HC1 (aq., 2N) to pH -7. The suspended solids were collected by filtration and dried under vacuum to afford (4S,11bS)-6-amino-4-methyl-

1 ,3.4,1 lb-tetrahydropyrido[3',4’:4,5]pyriinido[6,l-cl[l,4]oxazine-10-carboxylic acid (CAS) (1.10 g, 60% over 3 steps) as a yellow solid. MS ESI calculated for C12H14N4O3 [M+H]⁺, 263.1 1; found, 263.10. ^rH NMR (400 MHz, DMSO-</₆) 8 8.18 (s, 1H), 8.02 (br, 2H), 7.82 (s, IH), 5.19 (dd, 7 = 10.4, 3.6 Hz, IH), 4.38 (dd, .J = 11.2, 3.6 Hz, IH), 4.18 - 4.13 (m, IH), 3.77 - 3.74 (m, 2H), 3.57 (t, 7 = 10.8 Hz, IH), 1.37 (d, 7 = 6.6 Hz, 3H).

[0737] The absolute stereochemistry of CAS was determined by crystallography based on the co-crystal structure of selected compounds disclosed herein with PRMT5 enzyme, where the compounds were prepared using intermediate CA5.

Step-5b: methyl 5-amino-4-[(3R,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate

[0738] To a mixture of tert-butyl (3R,5S)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]-5- methylmorpholine-4-carboxylate (1.20 g, 3.41 mmol) in DCM (12 mL) was added TEA (4 ml). The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum. The residue was basified with NaHCOj (sat.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford methyl 5-amino-4-[(3R,5S)-5- methylmorpholin-3-yl]pyridine-2-carboxylate (700 mg, crude) as a yellow solid. MS ESI calculated for C12H17N3O3 [M+Hf, 252.13; found, 252.15. ^;H NMR (400 MHz, Methanol- cU) 3 7.99 (s, IH), 7.98 (s, IH), 4.11 (dd, J = 10.4, 3.2 Hz, IH), 3.90 (s, 3H), 3.79 (dd, 7 = 1 1.0, 3.2 Hz, 2H), 3.43 (t, 7 = 10.6 Hz, IH), 3.19 (t, 7 = 10.6 Hz, IH), 3.10 - 3.03 (m, IH), 1.07 (d, 7 = 6.4 Hz, 3H).

Step-6b: methyl (4S,llbR)-6-amino-4-niethyl- 1,3,4, lib- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate

[0739] To a mixture of methyl 5-amino-4-[(3R,5S)-5-methylmorpholin-3-yl]pyridine-2- carboxylate (700 mg, 2.78 mmol) in isopropanol (10 mL) was added carbononitridic bromide (351 mg, 3.31 mmol). The mixture was stirred at 80 ^C’C for 16 h. The suspension was filtered. The filter cake was collected and dried under vacuum to afford methyl (4S,1 lbR)-6-amino-4- methyl-1.3,4,llb-tetraliydropyrido[3'_>4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate (620 mg, crude) as a yellow solid. MS ESI calculated for C13H16N4O3 [M-i-Hp, 272.12; found, 272.10. ¹H NMR (400 MHz, Methanol -d₄) 8 8.39 (s, 1H), 7.96 (s, 1H), 5.59 - 5.43 (m, 1H), 4.77 (dd, 10.8, 4.2 Hz, 1H), 4.44 (dd, 12.4, 3.2 Hz, 1H), 4.26 (t, J = 11.0 Hz, 1H), 4.16 - 4.14 (in, 1H), 3.98 (s, 3H), 3.77 (dd, J = 12.4, 3.0 Hz, 1 Hi. 1.49 (d, J = 6.4 Hz, 3H).

Step-7b: (4S,1 lbR)-6-amino-4-methyl-l,3,4,l lb-tetrahydropyrido[3^!,4':4,5]pyrimido[6,l- c] [l,4]ox azine- 10-carboxy lie acid (CA6)

[0740] To a mixture of methyl (4S,llbR)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-cafboxylate (620 nig, 2.24 mmol) in THF (5 niL) and H2O (5 niL) was added LiOH (107 mg, 4.46 mmol). The mixture was stirred at 50 °C for 1 h. The organic solvent was removed under vacuum. The remained aqueous layer was neutralized with HC1 (aq., 2N) to pH ~7. The suspended solids were collected by filtration and dried under vacuum to afford (4S,l lbR)-6-amino-4-methyl- 1 ,3,4,1 lb-tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid (CA6) (580 mg, 65% over 3 steps) as a yellow solid. MS ESI calculated for C12HMN4O3 [M+H]⁺, 263.11; found, 263.10. ^!H NMR (400 MHz, DMSCfofo) 87.95 is, 1H), 7.55 (s, 1H), 6.76 (br, 2H), 4.76 - 4.73 (m, 1H), 4.50 (dd, J = 10.8, 4.2 Hz, 1H), 4.09 (dd, 11.8, 3.8 Hz, 1H), 3.95 (t, J- 10.6 Hz, 1H), 3.81 - 3.78 (m, 1H), 3.47 - 3.42 (m, 1H), 1.18 (d, J = 6.0 Hz, 3H).

Intermediate CA7 (Method 1): (S)-6-amino- 1,3,4, 1 1b- tetrahydropyrido[3',4':4,5]pyrimido[6, 1-c] [ 1 ,4]oxazine- 10-carboxylic acid

Step - 1 :

[0741] To a stirred mixture of tert-butyl (S)-3-(5-amino-2-(methoxycarbonyl)pyridin-4- yl)morpholme-4-carboxylate (80.00 g, 237.12 mmol) in DCM (240 mL) was added trifluoroacetic acid (210 mL) at room temperature. Ihe resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford methyl (S)-5-amino-4-(morpho1in-3-yl)picolinate (160 g, crude) as a yellow oil. MS ESI calculated for C12H16N2O3 [M+H]⁺, 238.11; found, 238.20.

Step-2:

[0742] To a stirred mixture of methyl (S)-5-amino-4-(morpholin-3-yl)picolinate (55.80 g, 235.18 mmol) in isopropanol (800 mL) was added Cyanogen bromide (26.16 g, 246.94 mmol). The resulting mixture was stirred at 80 °C for 16 hours. The precipitated solids were collected by filtration and washed with isopropanol (500 mL), the solids were dried under vacuum to afford methyl (S)-6-ammo-l ,3,4,11b-t.etrahydropyrido[3',4':4,5]pyrimido[6,l- cj[l,4]oxazine-10-carboxylate (16.7 g, 27% yield) as a white solid. MS ESI calculated for C12H14N4O3 [M+H]⁺, 263.11 ; found. 263.10.

Step-3:

[0743] To a stirred mixture of methyl (S)-6-amino-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate (30.00 g, 114.38 mmol) in THF (30 mL) and H2O (15 mL) was added LiOH (8.22 g, 343.16 mmol) at 25 °C.

The resulting mixture was stirred at the room temperature for 1 hour. The organic solvent was removed under vacuum. The aqueous layer was acidified with HC1 (6 M) to pH -6. The suspended solids were collected by filtration, then wash by water. The filter cake was dried under vacuum to afford (S)-6-amino-l,3,4,l lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l- c][l,4]oxazine-10-carboxy1ic acid (CA7) (13.3 g, 46% yield) as a white solid. MS ESI calculated for CnHisNrCh [M+H]⁺, 249.09; found, 249.20. ^!H NMR (300 MHz, DMSO-de) 6 11.67 (s, 1H), 8.40 (s, 2H), 8.34 (s, 1H), 7.96 (s, 1H), 5.04 (dd, J - 10.5, 3.3 Hz, 1H), 4.35 - 4.13 (m, 2H), 3.95 (dd, J - 12,0, 3.0 Hz, 1H), .3.73 - 3.59 (m, 2H), 3.38 - 3.21 (m, 1H).

Intermediate CA7 (Method 2): (S)-6-amino- 1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid

CA7

Step-1:

[0744] To a stirred solution of 2-((tert-butyldimethylsilyl)oxy (acetaldehyde (50.00 g, 286.84 mmol) in DCM (500 mL) were added (S)-2-methylpropane-2-sulfinamide (38.24 g, 315.52 mmol) (supplier: Accel a ChemBio Co., Ltd. CAS# 343338-28-3) and CuSCU (114.45 g, 717.09 mmol) at 20 °C. The resulting solution was stirred at 20 °C for 16 h. The suspension was filtered through celite. The filtrate was collected and concentrated under vacuum. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford (S,E)-N-(2-((tert-butyldimethylsi1yl)oxy)ethylidene)-2- methylpropane-2-sulfinamide (62 g, 77%) as a colorless oil. MS ESI calculated for Ci2H27NO₂SSi [M+H]⁺, 278.15; found, 278.15.

Step-2:

[0745] To a stirred solution of tert-butyl N-(6-chloropyridin-3-yl)carbamate (20.00 g, 87.46 mmol) and TMEDA (30.49 g, 262.37 mmol) in Et2O (400 ml) was added n-BuLi (1.6 M in n-hexane) (105 mL, 168.00 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h. A solution of (S,E)-N-(2-((tert- butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (48.54 g, 174.92 mmol) in THE (50 mL) was added dropwise to above mixture at -78 °C. The resulting mixture was allowed to warm at room temperature with stirring for additional 16 h. The reaction was quenched with NH4CI (sat.) at 0 °C. The resulting mixture was extracted with EtOAc. Hie combined organic layers were washed with brine, dried over anhydrous NajSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified byflash column chromatography with 0-30% ethyl acetate in petroleum ether within 30 min to afford tert-butyl (4- ((S )-2-((tert-butyldimethylsilyl)oxy)- 1 -(((S)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate (18.6 g, 42%) as an orange oil and tert-butyl (4-((R)-2-((tert-butyIdimetbylsilyl)oxy)-l-(((S)-tert-butylsulfinyl)amino)ethyl)-6- chloropyridin-3-yl)carbamate (13.1 g, 25(E) as an orange oil.

[0746] tert-butyl (4-((S)-2-( (tert-butyldimethyIsilyl)oxy)-l-(((S)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate: MS ESI calculated tor C22H40CIN3O4SS1 [M+H]⁺, 506.22; found, 506.15. ^!H NMR (400 MHz, DMSO-ds) 5 8.85 (s, 1H), 8.43 (s, 1H), 7.55 (s, 1H). 5.29 (d, ./ = 6.4 Hz, 1H), 4.71 (q, ./ = 6.0 Hz, 1H), 3.87 - 3.76 (m, 2H), 1 .46 (s, 9H), 1.12 (s, 9H), 0.82 (s, 9H), -0.02 (s, 6H).

[0747] tert-butyl (4-((R)-2-((tert-butyldirnethylsilyl)oxy)-l-(((S)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yr)carbamate: MS ESI calculated for

C22H₄oClN₃04SSi [M +11]⁺, 506.22; found, 506.20. ^!H NMR (400 MHz, DMSO-tfc) 5 8.84 (s, 1 H), 8.39 (s, 1H), 7.61 (s, 1H), 5.86 (d, J- 8.4 Hz, 1H), 4.75 - 4.62 (m, 1H), 3.79 - 3.64 (m, 2H), 1.46 (s, 9H), 1.13 (s, 9H), 0.81 (s, 9H), -0.04 (s, 3H), -0.06 (s, 3H).

[0748] A solution of tert-butyl (4-((S)-2-((tert-butyldimethylsi1yl)oxy)-l-(((S)-tert- butylsulfinyl)amino)ethy])-6-chloropyridin-3-yl)carbamate (15.00 g, 29.63 mmol) and HCI (4.0 M in 1,4-dioxane) (150 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with EbO (50 mL). The precipitated solids were collected by filtration and washed with EbO to afford (S)-2-amino-2-(5-amino-2-chloropyridin-4-yl)ethan-l-ol hydrochloride (9.4 g, crude) as a brown solid. MS ESI calculated for C7H10CIN3O [M+H]⁺, 188.05: found, 188.15.

Step-4:

[0749] To a stirred solution of (S)-2-amino-2-(5-amino-2-chloropyridin-4-yl)ethan-l-ol hydrochloride (6.90 g, 36.78 mmol) and EtsN (7.44 g, 73.55 mmol) in DCM (280 mL) was added a solution of 2-chloroacetyl chloride (3.74 g, 33.10 mmol) in DCM (140 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0- 18% methanol (0.1% NH3 in MeOH) in dichloromethane to afford (S)-N-(l-(5-amino-2- chloropyridin-4-yl)-2-hydroxyethyl)-2-chloroacetamide (3.2 g, 32%) as a brown semi-solid. MS ESI calculated for C9HHCI2N3O2 [M+H]⁺, 264.02; found, 264.00.

Step-5:

[0750] To a stirred solution of (S)-N-( l-(5-amino-2-chloropyridin-4-yl)-2-hydroxyethyl)-2- chloroacetamide (7.30 g, 27.64 mmol) in THF (30 niL) and isopropanol (120 niL) was added t-BuOK (12.41 g, 1 10.56 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCV After filtration, the filtrate was concentrated under reduced pressure to afford (S)-5-(5-amino-2-chloropyridin-4-yl)morpholin-3-one (1.30 g, crude) as a brown oil. MS ESI calculated for C9H10CIN3O2 [M+H]*, 228.05; found, 228.10.

Step-6:

[0751] To a stirred solution of (S)-5-(5-amino-2-chloropyridin-4-yl)morpholin-3-one (1.30 g, 5.71 mmol) in THF ( 15 ml..) were added boron trifluoride diethyl etherate (2.43 g, 17.13 mmol) and NaBH.j (648 mg, 17. 13 mmol) at 0 °C. The resulting mixture was stirred at 40 °C for 16 h. The reaction was quenched with water at 0 °C. The mixture acidified by HC1 (4 M) to pH 2~4. The resulting mixture was extracted with EtOAc. The aqueous layer was collected and basified to pH 9~10 with NaHCCh (sat.), then the mixture was extracted with EtOAc.

The combined organic layers were washed with brine, dried over anhydrous NajSCU After filtration, the filtrate was concentrated under reduced pressure to afford (S)-6-chloro-4- (morpholin-3-yl)pyridin-3-amine (450 mg, crude) as a yellow solid. MS ESI calculated for C9H12CIN3O [M+H]⁺, 214.07; found, 214.15.

Step-7 : [0752] To a stirred solution of (S)-6-chloro-4-(morpholin-3-yl)pyridin-3-ainine (490 mg, 2.29 mmol) in 1,4-dioxane (5 mL) was added cyanic bromide (242 mg, 2.29 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was trituration with DCM to afford (S)-lO-chloro- l,3,4,l lb-letrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazin-6-amine (470 mg, crude) as a yellow solid. MS ESI calculated for CioH; sONlsQ [M+H]⁺, 239.06; found, 239.10.

Step-8:

[0753] To a stirred solution of (S)-lO-chloro-l ,3,4,11b- tetrahydropyrido[3',4':4,5]pyriniido|6,l-c][l,4]oxazin-6-amine (500 mg, 2.10 mmol) and Zinc cyanide (369 mg, 3.14 mmol) in N-methyl-2-pyrrolidone (5 mL) were added RuPhos Pd G3 (175 mg, 0.21 mmol) and XantPhos (121mg, 0.21 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 1 h under nitrogen atmosphere. The resulting mixture was filtered. The filtrate was applied to a 120 g C18 column and purified by Combi Flash (Biotage Isolera Prime), eluted with 5-20% acetonitrile in water (10 mM NH4HCO3) to afford (S)-6-amino- l,3,4,t lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonitrile (160 mg, 33%) as a yellow solid. MS ESI calculated for CuHnNsO [M+Hf, 230.10; found, 230.20. 'H NMR (300 MHz, DMSO-fifc) 6 7.87 (s, 1H), 7.53 (s, 1H), 6.78 (s, 2H), 4.69 (dd, J = 10.5, 3.3 Hz, 1H), 4.10 (dd, 7 = 11.1, 3.3 Hz, 1H), 3.90 - 3.69 (m, 2H), 3.59 - 3.40 (m. 2H), 3.19 - 2.99 (rn, 1H).

Step-9:

[0754] A solution of (S)-6-ammo- 1,3,4, 1 lb-tetrahydropyrido[3‘, 4’:4, 5]pyrimido[6,l- c][l ,4]oxa7me-10-carbonilrile (100 mg, 0.44 mmol) and HCI (cone.) (1.5 mL) was stirred at 80 °C for 1 h. The resulting mixture was concentrated under vacuum to afford (S)-6-amino- 1 ,3,4,1 lb-teiTahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid (CA7) (128 mg, crude) as a brown solid. MS ESI calculated for CHH12N4O3 [M+H]⁺, 249.09; found, 249.20. 11 NMR (300 MHz, DMSO-c/₆) 8 12.05 (s, IH), 8.60 (s, 2H), 8.30 (s, 1H), 7.95 (s, IH), 5.05 (dd, J = 10.5, 3.3 Hz, IH), 4.35 - 4.13 (m, 2H), 3.93 (dd, /= 12.0, 3.0 Hz, 1H), 3.73 - 3.50 (m, 2H), 3.38 - 3.21 (m, IH).

Intermediate CAS: (4R, 1 lbS)-6-amino-4-methyl- 1,3,4, 1 lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid

CA8

Step-1 : Boc

[0755] To a mixture of (R)-5-methylmorpholin-3-one (supplier: Shanghai Balmxy. Pharmaceutic Co. Ltd. CAS# 119844-67-6) (10.00 g, 86.85 mmol) and DMAP (1.06 g, 8.68 mmol) in THE ( 100 mL) was added di-tert-butyl dicarbonate (28.43 g, 130.28 mmol) slowly. The mixture was stirred at 40 °C for 2 h. The solvents were removed under vacuum. The resulting residue was purified by flash column chromatography using a 120 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford tert-butyl (R)-3-niethyl- 5-oxomorpholine-4-carboxylate (17.90 g, 95%) as a colorless oil. MS ESI calculated for C10H17NO4 [M+Hf, 216.12; found, 216.15. ^!H NMR (400 MHz, DMSO) 6 4.28 - 3.99 (m, 3H), 3.91 - 3.69 (m, 2H), 1.47 (s, 9H), 1.27 (d, 6.6 Hz, 3H). [0756] To a mixture of tert-butyl (R)-3-methyl-5-oxomorpho1ine-4-carboxylate ( 17.30 g, 80.37 mmol) in THF (180 mL) was added LiHMDS (2M in THF) (50 ml.., 100.00 mmol) dropwise at -30 °C under nitrogen atmosphere. After stirring at -30 °C for 1 h, a solution of diphenyl chlorophosphonate (27.1 1 g, 100.90 mmol) in THF (50 mL) was added to the above mixture at -30 °C. The mixture was allowed to warm to room temperature for 1 h with stirring. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by normal phase flash column chromatography with 0-40% ethyl acetate in petroleum ether to afford tert-butyl (R)- 5-((diphenoxyphosphoryl)oxy)-3-methyl-2,3-dihydro-4H- l,4-oxazine-4-carboxylate (26.10 g, 69%) as a yellow solid. MS ESI calculated tor C22H26NQ7P [M+H]*, 448. 14; found, 448. 10. ^!H NMR (400 MHz, DMSO) 8 7.48 - 7.35 (m, 4H), 7.34 - 7. 17 (m, 6H), 6.48 (d. J = 4.0 Hz, 1H), 4.51 - 4.39 (m, 1H), 4.03 - 3.99 (m, 1H), 3.60 (dd, J - 11.2, 2.8 Hz, 1H), 1.37 (s, 9H), 1.08 (d, J - 6.8 Hz, 3H).

Step-3:

[0757] To a stirred solution of tert-butyl (R)-5-((diphenoxyphosphoryl)oxy)-3-methyl-2,3- dihydro-4H-l,4-oxazine-4-carboxylate (26.10 g, 58.39 mmol) and methyl 5-amino-4- (4,4,5,5-tetramethyl-l,3,2-dioxaboroian-2-yl)pyridine-2-carboxylate (from CA4) (24.35 g, 87.58 mmol) in 1 ,4-dioxane (300 mL) and H2O (30 mL) were added K2CO3 (18.53 g, 134.10 mmol) and Pd(dppf)C12-CH2Ch (5.48 g, 6.70 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 40-70% EtOAc in petroleum ether to afford tert-butyl (R)-5-(5-amino-2- (methoxycarbonyl)pyridin-4-yl)-3-methyl-2,3-dihydro-4H-l,4-oxazine-4-carboxylate (8.5 g, 41%) as a yellow solid. MS ESI calculated for C17H23N3O5 [M+H]⁺, 350.16; found, 350.05.

Step-4:

[0758] To a solution of tert-butyl tert-butyl (R)-5-(5-amino-2-(methoxycarbonyl)pyridjn-4- yl)-3-methyl-2,3-dihydro-4H-l,4-oxazine-4-carboxylate (8.5 g, 24.32 mmol) in methanol (150 mL) were added Pd/C (5.18 g, 2.43 mmol, 5% active on carbon) and PdfOHWC (6.83 g, 2.43 mmol, 5% active on carbon). The mixture was stirred at 50 °C for 72 h under hydrogen atmosphere (50 atm.). The mixture was filtered through a Celite pad. The filtrate was collected and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography eluted with 0-5% methanol in dichloromethane to afford tert-butyl (3S,5R)-3-(5-amino-2-(metlioxycarbonyl)pyridin-4-yl)-5-methylmorpholine-4- carboxylate (1.8 g, 21 %) as a white solid as first eluting peak and tert-butyl (3R,5R)-3-[5- amino-2-(methoxycarbonyl)pyridin-4-yl]-5-methyImorpholine-4-carboxyiate (4.28 g, 50%) as a white solid as the second eluting peak.

[0759] Ten-butyl (3S,5R)-3-(5-amino-2-(methoxycarbonyl)pyridin-4-yl)-5- methyImorpholine-4-carboxylate: MS ESI calculated for C17H25N3O5 [M+H]⁺, 352.18; found, 352.20. ^SH NMR (400 MHz, DMSO) 5 8.18 (s, IH), 8.02 (s, IH), 6.32 (s, 2H), 4.90 (d, J = 4.4 Hz, 1H), 4.27 - 4.19 (m, ITT), 4.20 - 4.06 (m, IH), 3.79 - 3.76 (m, 3H). 3.76 - 3.62 (m, 2H), 3.18 - 3.16 (m, IH), 1.38 (s, 9H), 1.05 (d, J = 1.8 Hz, 3H). Absolute stereochemistry was determined by NOESY.

[0760] Ten-butyl (3R,5R)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]-5- methylmoTpholine-4-carboxylate: MS ESI calculated for C17H25N3O5 [M+H]⁺, 352.18; found, 352.20. ^;H NMR (400 MHz, DMSO) 6 7.97 (s, IH), 7.68 (s, IH), 6.12 (s, 2H), 4.71 ■■■ 4.65 (m, IH), 4.14 - 3.98 (m, 2H), 3.83 - 3.65 (m, 5H), 3.19 - 3.16 (m, IH), 1.24 (d, J = 6.6 Hz, 3H), 1.10 (s, 9H). Absolute stereochemistry was determined by NOESY.

Step-5 :

[0761] To a mixture of tert-butyl (3S,5R)-3-(5-amino-2-(methoxycarbonyi)pyridin-4-yl)-5- methylmorpholiiie-4-carboxylate (1.8 g, 5.12 mmol) in DCM (18 mL) was added trifluoroacetic acid (6 mL). The mixture was stirred at room temperature for 3 h. The solvents were removed under vacuum. The residue was basified with NaHCCh (sat.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford methyl 5-amino- 4-((3S,5R)-5-meihylmoTpho]in-3-y])picolinate (1.7 g, crude) as a yellow solid. MS ESI calculated for C12H17N3O3 [M+H]⁺, 252.13; found, 252.15.

Step-6:

[0762] To a mixture of methyl 5-amino-4-((3S,5R)-5-meihylmorpho1in-3-y1)picolinate (1.7 g, 6.76 mmol) in isopropanol (20 mL) was added carbononitridic bromide (0.86 g, 8. 11 mmol). The mixture was stirred at 80 °C for 16 h. The suspension was filtered. The filter cake was collected and dried under vacuum to afford methyl methyl (4R.1 lbS)-6-anuno-4-methyl- 1,3,4, 1 lb-tetrahydropyrido[3‘,4':4,5]pyriniido[6,l-c][l,4]oxazine-10-carboxylate (700 mg, crude) as a yellow solid. MS ESI calculated for C13H16N4O3 [M+HJ⁺. 277.12; found, 272.15.

Step-7:

CA8

[0763] To a mixture of methyl methyl (4R,1 lbS)-6-amino-4-methyl-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,i-c][l,4]oxazine-10-carboxylate (700 mg, 2.53 mmol) in THF (7 ml.,) and H2O (3 ml) was added LiOH (140 mg, 5.84 mmol). The mixture was stirred at room temperature for 2 h. The organic solvents were removed under vacuum. The remained aqueous layer was neutralized with HC1 (aq., 2N) to pH -7. The suspended solids were collected by filtration and dried under vacuum to afford (4R,l lbS)-6-amino-4-methyl- l,3,4,llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine- 10-carboxyiic acid (CA8) (560 nig, 42% over 3 steps) as a yellow solid. MS ESI calculated for CnHi^Ch [M+H]⁺.

263.1 1 ; found, 263.05. T-I NMR (400 MHz, DMSO-d₆) 8 7.95 (s, 1H), 7.55 (s, 1H), 6.76 (br. 2H), 4.76 - 4.73 (m, 1H), 4.50 (dd, ./ = 10.8, 4.2 Hz, 1H), 4.09 (dd, 7 = 11.8, 3.8 Hz, 1H), 3.95 (t, ./ = 10.6 Hz, 1H), 3.81 - 3.78 (m, 1H), 3.47 - 3.42 (m, 1H), 1.18 (d, J - 6.0 Hz, 3H).

Intermediate CA9: (4R,1 lbR)-6-amino-4-methyl-l,3,4>Hb- tetrahydropyrido[3',4':4,5]pyriniido[6,Tc][T,4]oxazine-10-carboxylic acid

CAS

Step- 1 :

[0764] To a mixture of (3R,5R)-3-[5-amino-2-(rnethoxycarbonyl)pyridin-4-yl]-5- methylmorphoIine-4-carboxylate (4.28 g, 12.19 mmol) in DCM (45 ml.,) was added TFA (10 mL). The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum. The residue was basified with NaHCCh (sat.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford methyl 5-amino-4-((3R,5R)-5- methylmorpholin-3-yl)picolinate (4.60 g, crude) as a yellow solid. MS ESI calculated for Cr 41. -VO; [M+H]⁺, 252.13: found. 252.15.

Step-2: [0765] To a mixture of methyl 5-amino-4-((3R,5R)-5-methylmorpholin-3-yl)picolinate (4.44 g, 17.66 mmol) in isopropanol (40 mL) was added carbononitridic bromide (2.25 g, 21.20 mmol). The mixture was stirred at 80 °C for 16 h. The suspended solids were collected by filtration and dried under vacuum to afford methyl (4R,llbR)-6-amino-4-methyl- l,3,4,i lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate (3.17 g, crude) as a white solid. MS ESI calculated for C13H16N4O3 [M+H]⁺, 277.12; found, 277.15.

Step-3 :

CA9

[0766] To a mixture of methyl (4R,llbR)-6-amino-4-meihyl-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate (3.17 g, 11.47 mmol) in THE (30 mL) and H2O (15 mL) was added LiOH (0.82 g, 34.41 mmol). The mixture was stirred at. 50 °C for 2 h. The organic solvent, was removed under vacuum. The remaining aqueous layer was neutralized with HC1 (aq., 2N) to pH ~7. The suspended solids were collected by filtration and dried under vacuum to afford (4R,1 lbR)-6-amino-4-methyl-

1 ,3,4,1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,1 -c][l,4]oxazine-10-carboxylic acid (CA9) (1.9 g, 58% over 3 steps) as a yellow solid. MS ESI calculated for C12H14N4O3 [M+H]*, 263.11; found, 263.05. ^!H NMR (400 MHz, DMSO-ds) 6 8.18 is, 1H), 8.02 (br, 2H), 7.82 (s, 1 H), 5.19 (dd, 10.4, 3.6 Hz, 1H), 4.38 (dd, J - 1 1.2, 3.6 Hz, 1H), 4.18 - 4.13 (m, 1H), 3.77 - 3.74 (m, 2H), 3.57 (t, J = 10.8 Hz, 1H), 1.37 (d, J = 6.6 Hz, 3H).

Intermediate CA10: 1: 1 mixture of (4S,llbR)-6-ammo-4-(difluoromethyl)-l,3,4,l lb- tetrahydropyrido[3^l,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid and (4R,1 1 bS)-6- amino-4-(difluoromethyl)-l,3,4,llb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazine- 10-carboxylic acid Step-1:

[f)767] To a stirred solution of DMSO (226. 19 g, 2.89 mol) in DCM (1.0 L) was added a solution of oxalyl chloride (183.72 g, 1.45 mol) in DCM (500 ml) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture w'as stirred at -78 °C for 30 minutes, then a solution of 1:1 mixture of (R)-(4-benzylmorpholin-3-yl)methanol and (S)-(4- benzylmorpholin-3-yl)methanol (100.01 g, 0.48 mol) in DCM (500 ml) was added dropwise over 30 minutes at -78 °C. The resulting mixture was stirred at -78 °C for additional 30 minutes. Then EtsN (585.91 g, 5.79 mol) was added dropwise to the mixture over 20 minutes at -78 °C. The resulting mixture was stirred at -78 °C for additional 1 h. Then the mixture was warmed to room temperature for 16 h with stirring. Tire reaction mixture was quenched by NaHCOi (sat.) and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography eluted with 0-50% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (S)-4- benzyImorpholine-3-carbaldehyde and (R)-4-benzylmorpholine-3-carbaldehyde (38.90 g, 39%) as a yellow oil. MS ESI calculated for C12H15NO2 [M+H]⁺, 206. 11 ; found, 206. 15.

[0768] To a stirred solution of 1 : 1 mixture of (S)-4-benzylmorpholine-3-carbaldehyde and (R)-4-benzylmorpholine-3-carbaldehyde (38.01 g, 185.18 mmol) in DCM (600 ml.,) was added Diethylaminosulfur trifluoride (44.77 g, 277.77 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched carefully by NaHCOr (sat.) and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography using a 330 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford a 1:1 mixture of (S)-4-benzyl-3- (difluoromethyl)morpholine and (R)-4-benzyl-3-(difluoromethyl)morphoIine (17.80 g, 42%) as a yellow oil. MS ESI calculated for C12H15F2NO [M+H]⁺, 228.11; found, 228.15.

[0769] To a solution of 1: 1 mixture of (S)-4-benzyl-3-(difluoromethyl)morpho1ine and (R)- 4-benzyl-3-(difluoromethyl)morpholine (14.6 g, 64,24 mmol) in methanol ( 150 mL) was added BOC2O (16.83 g, 77.09 mmol). Then Pd/C (5% active on carbon) (20 g, 187.93 mmol) was added at room temperature. Ute mixture was placed under hydrogen atmosphere with a balloon (1 aim.). The reaction mixture was degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The mixture was filtered through a Celite pad. The filtrate was collected and concentrated under vacuum to afford to afford a 1 :1 mixture of tert-butyl (S)-3-(difluoromethyl)niorpholine-4-carboxylate and tert-butyl (R)-3- (diiluoromethyl)morpholine-4-carboxylate (17.0 g, crude) as a yellow oil. MS ESI calculated for CioH -FsNO-i [M+H]⁺, 238.12; found, 228.25.

[0779] To a solution of a 1 : 1 mixture of tert-butyl (S)-3-(dilluoromethyl)morpholine-4- carboxylate and tert-butyl (R)-3-(difluoromethyl)morpholine-4-carboxylate (17.80 g, 75.02 mmol) in THE (170 mL) were added trichlororuthenium hydrate (3.38 g, 15.00 mmol) and H?O (170 mL). Then NaICU (48.30 g, 225.83 mmol) was added in portions. The resulting mixture was stirred at room temperature for 16 h. The suspension was filtered. The filtrate was collected and concentrated under vacuum. The residue wras purified by normal phase flash column chromatography using a 330 g silica gel column eluted with 0 - 60% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl (R)-3-(difluorontethyl)-5- oxomorpholine-4-carboxylate and tert-butyl (S)-3-(difluoromethyl)-5-oxomorpholine-4- carboxylate (6.8 g, 36%) as a colorless oil. MS ESI calculated for C10H15F2NO4 [M+H]⁺, 252.10; found, 252.15. Step-5:

[0771] To a stirred solution of 1: 1 mixture of tert-butyl (R)-3-(difluoromethyl)-5- oxomorpholine-4-carboxylate and tert-butyl (S)-3-(difluoromethyl)-5-oxomorpholine-4- carboxylate (6.80 g, 27.06 mmol) in THF (70 rnL) was added LiHMDS(1.0 M in THF) (32.5 mb, 32.50 mmol) dropwise at -30 °C under nitrogen atmosphere. After stirring at -30 °C for 1 h, diphenyl chlorophosphonate (48 mL, 48.00 mmol) was added dropwise at -30 °C. The resulting mixture was stirred at -30 °C for additional 1 h, then the mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 120 g silica gel column eluted with 0 - 40% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl (S)-3- (difiuoromethyl)-5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1.4-oxazine-4-carboxylate and tert-butyl (R)-3-(difluoromethyl)-5-((diphenoxyphospboryl)oxy)-2,3-dibydro-4H-l,4- oxazine-4-carboxylate (5.90 g, 45%) as a yellow oil. MS ESI calculated for C22H24F2NO7P [ M+f 1 | ⁺, 484.13; found, 484.10.

Step-6:

[0772] To a mixture of a 1 : 1 mixture of tert-butyl (S)-3-(difluoromethyl)-5- ((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-l,4-oxazine-4-carboxylate and tert-butyl (R)-3- (difluoromethyl)-5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-l,4-oxazine-4-carboxylate (5.90 g, 12.20 mmol), Pd(dppf)C12-CH2Ch (1.00 g, 1.22 mmol) and K2CO3 (3.37 g, 24.41 mmol) in Dioxane (60 mL) was added H2O (6 rnL). The resulting mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography using a 120 g silica gel column eluted with 0 - 80% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl (S)- 5-(5-amino-2-(methoxycarbonyl)pyridin-4-yl)-3-(difluoromethyl)-23-dihydro-4H-l ,4- oxazine-4-carboxylate and tert-butyl (R)-5-(5-amino-2-(methoxyearbonyl)pyridin-4-yl)-3- (difluoromethyl)-2,3-dihydro-4H-l,4-oxazine-4-carboxylate (4.10 g, 87%) as a yellow solid. MS ESI calculated for C17H21F2N3O5 [M+H]⁺, 386.14; found, 386. 15.

Step-7 :

[0773] To a solution of 1: 1 mixture of tert-butyl (S)-5-(5-amino-2-

(methoxycart>onyl)pyridin-4-yl)-3-(dilluorometbyl)-2,3-dihydro-4H-l,4-oxazine-4- carboxylate and tert-butyl (R)-5-(5-amino-2-(methoxycarbonyl)pyridin-4-y1)-3- (difluoromethyl)-2,3-dihydro-4H-l,4-oxazine-4-carboxylate (4.00 g, 10.38 mmol) in methanol (120 mL) was added Pd/C (10% active on carbon) (3.98 g, 3.73 mmol) and Palladium hydroxide (5% active on carbon) (4.08 g, 1.45 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 16 h under hydrogen atmosphere (30 atm.). The mixture was filtered through a Celite pad. The filtrate was collected and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 120 g silica gel column eluted with 0 - 60% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl (3R,5S)-3-(5-amino-2-(methoxycarbony1)pyridin-4-yr)-5- (difluoromethyl)morpholine-4-carboxylate and tert-butyl (3S,5R)-3-(5-amino-2- (methoxycarbonyl)pyridin-4-yl)-5-(diiluoromethyl)morpholme-4-carboxylate (2.70 g, 67%) as a white solid. MS ESI calculated for C17H23F2N3O5 [M+H]⁺, 388.16; found, 388.20. Trans relative stereochemistry was determined by NOESY.

Step-8:

[0774] To a solution of 1: 1 mixture of tert-butyl (3R,5S)-3-(5-amino-2-

(methoxycarbonyl)pyridin-4-yl)-5-(difluoromethyl)morpholine-4-carboxylate and tert-butyl (3S,5R)-3-(5-amino-2-(methoxycarbonyl)pyridin-4-yl)-5-(ditluororaethyl)moroholine-4- carboxylate (2.7 g, 6.97 mmol) in DCM (30 mL) was added tri fluoroacetic acid (6 mL). The resulting mixture was stirred at room temperature for 3 h under air atmosphere. The solvents were removed under vacuum to afford a 1 : 1 mixture of methyl 5-amino-4-((3R,5S)-5- (difluoromethyl)morpholin-3-yl)picolinate and methyl 5-amino-4-((3S,5R)-5- (difluoromethyl)morpholin-3-yl)picolinate (4.80 g, crude) as a yellow oil, which was used in the next step without further purification. MS ESI calculated for C12H15F2N3O3 [M+H]\ 288. 1 1 ; found, 288. 10.

Step-9:

[0775] To a solution of 1:1 mixture of methyl 5-amino-4-((3R,5S)-5-

(difluoromethyl)morpholin-3-yl)picolinate and methyl 5-amino-4-((3S,5R)-5-

(difluoromethyl)morpholin-3-yl)picolmate (4.01 g, 6.98 mmol) in MeCN (40 mL) and H2O

(8 mL) was added carbononitridic bromide (2.21 g, 20.87 mmol). The mixture was stirred at

80 °C for 16 h. The mixture was concentrated under vacuum. The residue was purified by reverse phase flash column chromatography with a 120 g Cl 8 column eluted with 5 - 40% acetonitrile in water to afford a 1 :1 mixture of methyl (4S,HbR)-6-amino-4- (difluoromethyl)-l,3,4,l lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l ,4]oxazine-10- carboxylate and methyl (4R,llbS)-6-amino-4-(difluoromethyl)-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate (700 mg, 32%) as a yellow solid. MS ESI calculated for C13H14F2N4O3 [M+H]⁺, 313.10: found, 313.05.

Step- 10:

CAio

[0776] A 1 :1 mixture of methyl (4S,1 lbR)-6-amino-4-(difluoromethyl)-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylate and methyl (4R,l lbS)-6-amino-4-(difluoromethyl)-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- c][l ,4]oxazine-10-carboxylate (100 mg, 0.32 mmol) and HO (aq., 2N) (2 mL) was stirred at 60 °C for 16 h. The solvents were removed under vacuum to afford a 1 : 1 mixture of

(4S, 1 lbR)-6-amino-4-(difluoromethyl) ■ 1 ,3,4, 1 lb-tetrahydropyridoj3',4':4,5]pyrimido[6, 1- c][l,4]oxazine-10-carboxylic acid and (4R,l lbS)-6-amino-4-(difluoromethyl)-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid (CAIO) (110 mg, crude) as a yellow solid, which was used in the next step without further purification. MS ESI calculated for C12H12F2N4O3 [M+H]⁺, 299.09; found, 299.15. ^rH NMR (400 MHz, DMSO) 5

11.92 (s, 1H), 8.64 (s, 2H), 8.34 (s, 1H), 7.93 (s, 1H), 6.78 - 6.50 (m, 1H), 5.42 (dd. J = 10.6,

3.6 Hz, 1H), 4.62 - 4.50 (m, 1 H), 4.43 (dd, 7 - 11 .2, 3.6 Hz, 1 H), 4.12 (d, J = 12.8 Hz, 1H), 3.98 - 3.92 (m, 1H), 3.86 - 3.74 (m, 1H).

Acid chloride (AC) intermediate synthesis

Intermediate ACl: 6-amino-9-fluoro- 1 ,3,4, 11 b-tetrahydro -| 1 ,4 |oxazino|4,3-c]quinazoline-

10-carbonyl chloride [9777] A mixture of 6-amino-9-fluoro- 1 H,3H,4H, 1 IbH- [ 1 ,4]oxazino[4,3-c]quinazoline- 10- carboxylic acid (500 mg, 1.88 mmol) and HC1 (gas) (4M in 1,4-dioxane) (7 mL) was stirred at 25 °C for 30 minutes. The resulting mixture was concentrated under reduced pressure. Hie residue was dissolved in SOCh (7 mL). The resulting mixture was stirred at 60 °C for 1.5 h. The mixture was cooled. The precipitated solids were collected by filtration and washed with DCM to afford 6-amino-9-fluoro-lH,3H,4H,llbH-[l,4]oxazino[4,3- cjquinazoline-10-carbonyl chloride hydrochloride (280 mg, 52%) as a brown solid.

Intermediate AC1 isomer 1: (R)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3- c]quinazoline-10-carbonyl chloride, isomer 1

AC1 isomer 1

[0778] A mixture of CAI, isomer 1 (930 mg, 3.49 mmol) and HC1 (4M in dioxane) (10 mL) was stirred at room temperature for 1 h, The mixture was concentrated under vacuum. Then SOCh (10 mL) was added to the residue. The mixture was stirred at 50 °C for 3 h. The mixture was concentrated under vacuum to afford (R)-6-amino-9-fluoro- 1,3, 4,11b- tetrahydro-[l,4]oxazino[4,3-c]quinazoline-10-carbonyl chloride, isomer 1 (1.15 g, crude) as a white solid that is used directly in subsequent reactions.

Intermediate AC1 isomer 2: (S)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3- c]quinazoline-10-carbonyl chloride, isomer 2

[0779] A mixture of CAI, isomer 2 (960 mg, 3.60 mmol) and HCl (4M in dioxane) (10 mL) was stirred at room temperature for 1 h, The mixture was concentrated under vacuum. Then SOCh (10 mL) was added to the residue. The mixture was stirred at 50 °C for 3 h. The mixture was concentrated under vacuum to afford (S)-6-amino-9-lluoro-l ,3,4,Ilb-ietrahydro- [l ,4]oxazino[4,3-c]quinazoline-10-carbonyl chloride, isomer 2 (930 mg, crude) as a white solid that is used directly in subsequent reactions.

[0780] The absolute stereochemistry of AC1 isomer 2 was determined based on its precursor acid ( i.e., CAI isomer 2). The absolute stereochemistry of AC1 isomer 2 was further confirmed by crystallography based on the co-crystal structure of selected compounds disclosed herein with PRMT5 enzyme, where the compounds were prepared using AC1 isomer 2. As such, AC1 isomer 2 has the S- configuration represented by:

AC1 isomer 2

[0781] Accordingly, AC1 isomer 1 has the R-configuration represented by:

AC1 isomer 1

Intermediate AC4: (R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1- c] [ 1 ,4]ox azine- 10-carbonyl chloride

AC4

[0782] A mixture of CA4 (10 g, 40.28 mmol) and hydrogen chloride (4.0 M in 1,4- dioxane) (50 mL) was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure. The residue was suspended in DCM (50 mL) and DMF (1 mL), then oxalic dichloride (10.23 g, 80.56 mmol) was added dropwise to above mixture at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The solvents were removed under vacuum to afford (R)-6-amino-l,3,4_sllb-tetrahydropyrido[3',4':4,5]pyriniido[6,l- c] [l,4]ox azine- 10-carbonyl chloride (13.5 g, crude) as a light yellow solid that is used directly in subsequent reactions.

[0783] The absolute stereochemistry of AC4 was assigned as the same absolute stereochemistry of precursor CA4.

Intermediate ACS: (4S,l lbS)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4';4,5]pyrirnido[6,l-c][l,4]oxazine-10-carbonyl chloride

AC5

[0784] A mixture of CAS (50 mg, 0. 19 mmol) and HO (4M in 1 ,4-dioxane) (0.5 mL) was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure. The residue was suspended in DCM (1 mL) and DMF (0.02 mL), then oxalic dichloride (96.7 mg, 0.76 mmol) was added at 0 °C. The resulting solution was stirred at 25 °C for 1 h. 'The solvents were removed under vacuum to afford (48,1 lbS)-6-amino-4-methyl- 1,3,4, llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl chloride (50 mg) as a yellow solid that is used directly in subsequent reactions.

[0785] The absolute stereochemistry of AC5 was determined by crystallography based on the co-crysial structure of selected compounds disclosed herein with PRMT5 enzyme, where the compounds were prepared using intermediate AC5.

Intermediate AC6: (S)-6-amino- 1 ,3,4, 1 1 b-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 - c] [ 1 ,4]ox azine- 10- carbonyl chloride

[0786] A solution of (S)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4’:4,5]pyrimido[6, 1- c] [ 1 ,4]oxazine-10-carboxylic acid (2.00 g, 8.05 mmol) and hydrogen chloride (4.0 M in ethyl acetate) (20 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. Then the residue was supended in DCM (80 mL), DMF (0.12 g, 1 .61 mmol) was added to the mixture. This was followed by the addition of Oxalyl chloride (3.58 g, 28.20 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to afford (S)-6-amino- l,3,4,l lb-letrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl chloride (AC6) (2 g) as a yellow solid that is used directly in subsequent reactions.

Intermediate AC7 : (4S , 1 lbR)-6-amino-4-methyl- 1,3,4.11b- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][1 ,4]oxazine-l0-carbonyl chloride

AC7

[0787] A mixture of (4S.llbR)-6-ammo-4-methyl-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carboxylic acid (100 mg, 0.43 mmol) in HC1 in l,4-dioxane(4.0 M) (2 mL) was stirred at room temperature for L0 min. The solvents were removed under vacuum. The resultant solid was suspended in DCM (2 mL), then oxalic dichloride (227 mg, 1.78 mmol) was added dropwise at 0 °C, then DMF (one drop) was added. The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum to afford (4S, 1 lbR)-6-amino-4-methyl-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l -c][l,4]oxazine-l 0-carbonyl chloride (AC7) (110 mg, crude) as a yellow solid, which was used in the next step without further purification.

Intermediate ACS: (4R, 1 lbS)-6-amino-4-methyl- 1 ,3 ,4, 11b- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl chloride

[0788] A mixture of (4R,llbS)-6-amino-4-methyl"l,3,4,llb- tetahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-caiboxylic acid (117 rag, 0.44 mmol) and HC1 in 1 ,4-dioxane(4.0 M) (2 mL) was stirred at room temperature for 10 min. The solvents were removed under vacuum. Then the residue was supended in DCM (2 ml). Then oxalic dichloride (227 mg, 1.78 mmol) was added dropwise at 0 °C, then DMF (one drop) was added. The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum to afford (4R,l1bS)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-cafbonyl chloride (AC8) (110 mg) as a yellow solid, which was used in the next step without further purification.

Intermediate AC9: (4R, 1 IbR) -6-amino~4-niethyl- 1,3,4,11 b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl chloride

CAS ACS

[8789] A mixture of (4R,l lbR)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l ,4]oxazine- 10-carboxylic acid (100 rag, 0.43 mmol) and HC1 in 1 ,4-dioxane(4.0 M) (2 mL) was stirred at room temperature for 10 min. The solvents were removed under vacuum. Then the residue was supended in DCM (2 mL). Then oxalic dichloride (227 mg, 1.78 mmol) was added dropwise at 0 °C, followed by the addition of DMF (one drop). The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum to afford (4R,llbR)-6-amino-4-methyl-l,3, 4,11b- teirahydropyrido[3',4‘:4,5]pyrimido[6,l-c][l,4]oxazine-10-caTbonyl chloride (AC9) (1 10 mg, crude) as a yellow solid, which was used in the next step without further purification. i

97^

Intermediate Al: 1 :1 mixture of (4aR,10bR)-8-methoxy-2,3,4.4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine and (4aS, 10bS)-8-methoxy-2,3,4,4a,6, 1 Ob-hexahydro- 1H- isochromeno[4,3-b]pyridine Step 1: methyl 5 -nietlioxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yi)benzoate

[$79I)J To a stirred solution of methyl 2-bromo-5 -methoxybenzoate (7.50 g, 30.60 mmol) in anhydrous 1,4-dioxane (50 mL) were added Pd(dppf)Ch (0.45 g, 0.61 mmol), AcOK (9.01 g, 91.80 mmol) and BPD (9.33 g, 36.72 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 12. h under hydrogen. After completion of reaction, the reaction mixture was quenched by addition of water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography with 5% to 35% EtOAc in petroleum ether to afford methyl 5-methoxy-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (6.1 g, 68%) as a yellow solid. MS (ESI) calculated for (C d f - BOO: fol+H i ' . 293.15; found, 293.10.

Step 2; methyl 5-methoxy-2-[3-(methoxymethoxy)pyridin-2-yl]benzoate

[0791] To a stirred mixture of methyl 5-methoxy-2-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)benzoate (7.8 g, 26.70 mmol) and 2-bromo-3-(methoxyraethoxy)pyridine (6.98 g, 32.04 mmol) in 1 ,4-dioxane (100 mL) and water (4 mL) were added K2CO3 (15.06 g, 108.93 mmol), Pd(OAc>2 (599 mg, 2.67 mmol) and triphenylphosphine (3.00 g, 11.48 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight under nitrogen. The solvents were removed under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford methyl 5-methoxy-2-[3-(melhoxymethoxy)pyridin-2-yl]benzoate (6.00 g, 74%) as a colorless oil. MS (ESI) calculated for (C16H17NO5) [M+H|⁺, 304.1 1 ; found, 304.05.

Step 3 : 8- methoxy -6H-isochromeno[4,3-bjpyridin-6-one

[0792] To a solution of methyl 5-methoxy-2-[3"(methoxymethoxy)pyridin-2- yl]benzoate (6.00 g, 19.78 mmol) in DCM (60 mL) was added TEA (20 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to afford 8-methoxy-6H- lsochromeno[4,3-b]pyridin-6-one (4 g, crude) as a yellow solid. MS (ESI) calculated for (C13H9NO3) [M+H]⁺, 228.06: found. 228.00.

Step 4: 8-met.hoxy-6H-isochromeno[4,3-b]pyridine

[0793] To a stirred solution of 8-methoxyisocliromeno[4,3-b]pyridin-6-one (8.00 g, 35.20 mmol) in anhydrous E12O (80 mL) was added borane ammonia complex (2.17 g, 70.41 mmol) and TiCh (83 mg, 0.44 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After completion of reaction, the reaction mixture was quenched by addition of Na/CCh (sat.) and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by flash column chromatography with 5% to 55% EtOAc in petroleum ether to afford 8-methoxy -6H- isochromeno[4,3-b]pyridine (1.1 g, 14%). MS (ESI) calculated for (CJ3H11NO2) [M+H]⁺, 214.08; found, 214.15.

Step 5: 1: 1 mixture of (4aR,10bR)-8-methoxy-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine and (4aS J0bS)-8-methoxy-2,3,4,4a,6, 1 Ob-hexahydro- 1H- isochromeno [4 , 3 -bjpyridi n e

[9794] To a solution of 8-methoxy-6H-isochromeno[4,3-b]pyridine (800 mg, 3.75 mmol) in MeOH (7 mL) was added HC1 (1.8 mL. cone.) at 25 °C. The reaction mixture was degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at 25 °C for 2 h under hydrogen with a balloon (1 atm.). The mixture was filtered. The filtrate was basified with NaiCOj (sat.) to pH 10. The mixture was extracted with EtOAc. The combined organic layers were dried anhydrous sodium sulfate, filtered and concentrated under vacuum to afford a 1:1 mixture of (4aR,10bR)-8-methoxy-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine and (4aS,l()bS)-8-methoxy-2,3,4,4a,6, l0b-hexahydro-lH-isochromeno[4,3-b]pyridine (478 mg,

49%) as an off-white solid. MS ESI calculated for (C13H17NO2) fM+Hl⁺, 220.13; found, 220.20.

Intermediate A2: 1:1 mixture of (4aR,10bR)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro- lH-isochromeno[4,3-b]pyridine and (4aS,10bS)-8-(trifluoronielhyl)-2,3,4,4a,6,10b“ hexahydro- lH-isochromeno[4,3-b]pyri dine

Step 1 : methyl 2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate [0795] To a stirred mixture of methyl 2-bromo-5-(trifluorometliyl)benzoate (50.2 g, 177 mmol) and BPD (49.5 g. 195 mmol) in dioxane (500 mL) were added AcOK (34.8 g, 355 mmol) and Pd(dppf)C12-CH2C12 (14.45 g, 17.73 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 85 °C for 16 h under nitrogen atmosphere.

The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford methyl 2-(4,4,5,5-tetramethyI-1.3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate (49.2 g, 84%) as a light yellow solid. MS ESI calculated for CisHjgBFaOr [M+H]⁺, 331.13; found, 331.05.

Step 2: 2-bromo-3-(methoxymethoxy)pyridine

[0796] To a stirred solution of 2-bromopyridin-3-ol (50 g, 287 mmol) and K2CO3 (79.4 g, 574 mmol) in MeCN (500 mL) was added bromoC .methoxylmethane (39.5 g, 316 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was filtered.

The filtrate was concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) with a 330 g silica gel column eluted with 0-34% ethyl acetate in petroleum ether to afford 2-bromo-3-(methoxymethoxy)pyridine (38.5 g, 60%) as a white solid. MS ESI calculated for C₇H₈BrNO₂ [M+H]⁺, 217.97, 219.97; found, 217.80, 219.80.

S tep 3 : methyl 2- [3 -(methoxymethoxy )pyridin-2-yl] - 5 - (trifluoromethyl (benzoate

[0797] To a stirred solution of methyl 2-(4,4,5,5-tetramethyi-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)benzoate (20.1 g, 60.88 mmol) and 2-bromo-3-(melhoxymethoxy)pyridine ( 13.2.8 g, 60.88 mmol) in dioxane (200 mL) were added K2CO3 (16.83 g, 121.77 mmol) and Pd(dppf)Cl₂-CH₂Cl₂ (4.96 g, 6.089 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0-25% ethyl acetate in petroleum ether to afford methyl 2-[3-(methoxymethoxy)pyridin-2-yl]-5- (trifluorotnethyl)benzoate (18.7 g, 89%) as a yellow oil. MS ESI calculated for C1&H14F3NO4 [M+Hp , 342.09; found, 342.30.

Step 4: 8-(trifluoromethyl)isochromeno[4,3-b]pyridin-6"One

[0798] To a stirred solution of methyl 2-[3-(methoxymethoxy)pyridin-2-yl]-5- (trifluoromethyl)benzoate (18.7 g, 54.8 mmol) in DCM (180 mL) was added TFA (60 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was concentrated under vacuum. The residue was diluted by water and extracted with CH2CI2. The combined organic layers were washed with NaHCOs (sat.), dried over anhydrous NajSOa. After filtration, the filtrate was concentrated under reduced pressure to afford 8-(trifluoromethyl)isochromeno[4,3-b]pyridin-6-one (8.6 g, 58%) as a yellow solid. MS ESI calculated for C13H6F3NO2 [M+H]+, 266.04; found, 266.00.

Step 5: Synthesis of 8-(trilluoromethyl)-6H-isochromeno[4,3-b]pyridine

[0799] To a stirred solution of 8-(trifluoromethyl)isochromeno[4,3-bjpyridin-6-one (8.6 g, 32.4 mmol) and NH3-BH3 (2.00 g, 64.9 mmol) in Et?O (100 mL) was added TiCL (12.3 g, 64.9 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of water/ice at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCfo After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography with a 120 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether within 50 min to afford 8-(trilTuoromethyl)-6H-isochromeno[4,3- blpyridine (3.8 g, 46%) as a white solid. MS ESI calculated for C13H8F3NO [M+Hf , 252.06; found, 251.95. Step 6: 1 :1 mixture of (4aR, 10bR)-8-(trifluoromethyl)-2,3,4,4a,6,l Ob-hex ahydro-lH- isochromeno[4,3-b]pyridine and (4aS,10bS)-8-(trifluoromethyi)-2,3,4,4a,6,10b-hexahydro- lH-isochromeno[4,3-b]pyridine (A2)

[0800] To a stirred solution of 8-(trifluoromethyl)-6H-isocliromeno[4,3-bjpyridme (3.8 g, 15.12 mmol) in AcOH (30 mL) was added P1O2 (0.34 g, 1.51 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight under hydrogen atmosphere. Tire resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue -was dissolved in ethyl acetate and basified with NaHCCh (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCfo After filtration, the filtrate was concentrated under reduced pressure to afford a 1:1 mixture of (4aR, 10bR)-8-(trifluorornethyl)-2,3,4,4a,6,l()b-hexahydro- lH-isochromeno[4,3-b]pyridine and (4aS, 10bS)-8-(trifluoromethyl)-2, 3,4, 4a, 6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine (3 g, 70%) as a light grey solid. MS ESI calculated for CuHuFsNO [M+H]⁺, 258.10: found, 258.05. ‘H NMR (300 MHz, DMSO-tfe) 57.59 - 7.48 (m. 2H). 7.44 (d, J = 1 .8 Hz, 1H), 4.98 - 4.67 (m, 2H), 3.64 - 3.53 (m, 2H), 2.93 - 2.82 (m, 1H), 2.70 - 2.61 (m, 1H), 2.03 - 1.91 (m, 1H), 1.83 - 1.67 (m, 1H), 1.65 - 1.52 (m, 1H), 1.40 - 1.28 (m, 1H).

Intermediate A2 isomer 1: rel-(4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro- lH-isocliromeno[4,3-b]pyridine, isomer 1 (A2, isomer T):

A2, isomer Intermediate A2, isomer 2: rel-(4aR,10bR)-8-(trifluoromethy])-2,3,4,4a,6,10b-hexahydro- lH-isochromeno[4,3-b]pyridine, isomer 2 (A2, isomer 2):

A2, isomer 2

[0801] A 1:1 mixture of (4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine and (4aR,10bR)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro- lH-isochromeno[4,3-b]pyridine (980 mg) was purified by Prep-chiral SFC with the following conditions [Column: Column: CHiRALPAK 1G, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NHs-.MeOH): Flow rate: 80 mL/min: Gradient: isocratic 15% B; RTl(min): 4; RT2(min): 7: Sample Solvent: MeOH; Injection Volume: 1.5 ml;

Number Of Runs: 20] to afford rel-(4aS,10bS)-8-(trifluoroniethyl)-2,3,4,4a,6,10b-hexahydro- lH-isochromeno[4,3-b]pyridine, isomer 1 (A2, isomer 1) (205 mg, 22%) as a yellow oil MS ESI calculated for C13IT4F3NO [M+H]⁺, 258.10; found, 258.05. ^:H NMR (400 MHz, DMSO- <%,) 6 7,57 - 7.49 (m, 2H), 7.46 (s, 1H), 4.92 (d, 7 = 15.6 Hz, 1H), 4.72 (d, 7 = 15.6 Hz, 1H), 3.61 - 3.60 (m, 1H), 3.57 - 3.56 (in, 1H), 2.90 - 2.85 (m, 1H), 2.72 - 2.59 (m, 1H), 1.99 - 1.93 (m, 1H), 1.79 - 1.72 (m, 1H), 1.61 - 1.51 (m. I H), 1.36 - 1.30 (rn, 1H). Absolute stereochemistry was not determined.

[0802] The chiral resolution also afforded rel-(4aR,10bR)-8-(trifluoromethyl)- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine, isomer 2 (A2, isomer 2) (305 mg, 33%) as a yellow oil. MS ESI calculated for CisHiaFsNO [M+H]⁺, 258.10; found, 258.05. ^SH NMR (400 MHz, DMSO-h₆j 6 7.57 - 7.49 (m, 2H), 7.46 (s, 1 H), 4.92 (d, 7 = 15.6 Hz, 1H), 4.72 (d, 7 = 15.6 Hz, 1H), 3.61 - 3.60 (m, 1H). 3.57 - 3.56 (m, 1H), 2.90 - 2.85 (m, 1H), 2.72 - 2.59 (m, 1H), 1.99 - 1.93 (m, 1H), 1.79 - 1.72 (rn, 1H), 1.61 - 1.51 (m, 1H), 1.36 - 1.30 (m, 1H). Absolute stereochemistry was not determined.

Intermediate A3: b-((2R,5S)-5-methylpiperidin-2-yl)-2-(l-niethylpiperidin-4- yl)benzo[d]thi azole

Step 1 : (5 S )-5-methyl-2-(trifiuoromethanesulfonyioxy) -5 ,6-dihydro-4H -pyridine - 1 - carboxylate

[0803] To a stirred solution of tert-butyl (5S) -5- methyl-2 -oxopiperidine- 1- carboxylate (Supplier: Shanghai Tianze biological medicine Co., LTD cas# 572246-00-4) (3.00 g, 14.06 mmol) in THF (40 mL) was added KHMDS (56.28 mL, 28.14 mmol, 0.5M in toluene) dropwise at -78 °C under nitrogen atmosphere. After stirring at -78 °C for 2 h, a solution of 1,1,1 -trifluoro-N -phenyl-N-trifluoromethanesulfonylmethanesulfonamide (7.54 g, 21.09 mmol) in THF (10 mL) was added dropwise to above mixture at -78 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction was quenched by the addition of NH4CI (sat.) at 25 °C. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous NaiSCU- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% EtOAc in PE to afford tert-butyl (5S)-5-methyl-2-(trifluoromethanesulfonyloxy)-5,6- dihydro-4H-pyridine-l -carboxylate (3.76 g, 74%) as a colorless oil. MS ESI calculated for CicH.sFsNOsS [M+HT, 346.09; found, 346.10. ^?H NMR (400 MHz, DMSO-rL) 5 (ppm) 5.51 (t, 7 = 3.8 Hz, 1H), 3.67 (dd, 7 = 12.8, 3.0 Hz, 1H), 3.06 (dd, 7 = 12.8, 8.4 Hz, 1H), 2.46 - 2.31 (m, 1H), 1.93 - 1.75 (m, 2H), 1.43 (s, 9H), 0.92 id, 7 = 6.4 Hz, 3H).

Step 2: 5-chloro-2-(1 -methylpiperidin-4-yl)benzo[d]thiazole [0804] A mixture of PPA (28.82 g, 250.58 mmol) and P2O5 (35.57 g, 250.58 mmol) was stirred at. room temperature for 10 minutes. Then 2-amino-4-chlorobenzenethiol (10.00 g, 62.64 mmol) and l-methylpiperidine-4- carboxylic acid (10.76 g, 75.17 mmol) were added to the mixture at room temperature. The resulting mixture was stirred at 1 10 °C overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with a mixture of water and DCM. The mixture was basified with NaOH (aq.) to pH 10. The resulting mixture was extracted with CH2CI2. The organic layers were dried over anhydrous NaoSOr- After filtration, the fillrate was concentrated under reduced pressure to afford 5-chloro-2-(l-methylpiperidin-4-yl)-l,3-benzotbiazole (8.86 g, 50%) as a light brown solid. MS ESI calculated for C13H15CIN2S [M+H]⁺, 267.06; found, 267.00.

Step 3: 2-( 1 -methylpiperidin-4-yl)-5-(4,4,5,5-teiramethyl- 1 ,3,2-dioxaborolan-2- yl)benzo[d]thiazole

[0805] To a stirred mixture of 5-chloro-2-(l-methylpiperidin-4-yl)- 1,3-benzothiazole (8.86 g, 33.21 mmol) in dioxane (88 mL) were added BPD (9.28 g, 36.53 mmol), AcOK (6.52 g, 66.42 mmol), XPhos (3. 17 g, 6.64 mmol) and Pdj(dba)3 (1 .52 g, 1.66 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 4 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with 1 ,4-dioxane. The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with MTBE (140 mL). The product was precipitated by the addition of HC1 (4 M in 1 ,4- dioxane, 20 mL). The precipitated solids were collected by filtration and washed with MTBE to afford 2-( 1 -methylpiperi din-4-yl )-5-(4,4.5 ,5-tetramethyl- 1,3 ,2-dioxaboroJ an-2-yl )- 1 ,3- benzothiazole (15.01 g, 80%) as a brown solid. MS ESI calculated for C19H27BN2O2S [M+H]⁺, 359.18; found, 359.30

Step 4: tert-butyl (S)-3-methyl-6-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)-3,4- dihy dropyridine- 1 (2H)-carboxylale

[0806] To a stirred mixture of 2-(l-methylpiperidin-4-yl)-5-(4,4,5,5-tetamethyl- 1,3,2- dioxaborolan-2-yl)-l,3-benzothiazole (3.42 g, 9.55 mmol) in dioxane (1 10 mL) and H2O (22 mL) were added K2CO3 (3.96 g, 28.66 mmol), tert-butyl (5S)-5-methyl-2- (trifluoromethanesulfonyloxy)-5,6-dihydro-4H-pyridine-l-carboxyiate (3.30 g, 9.55 mmol) and Pd(dppf)C12 (0.70 g, 0.95 mmol). The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue -was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford tert-butyl (5S)-5- methyl-2-[2-(l-methylpiperidin-4-yl)-l,3-benzothiazol-5-yl]-5,6-dihydro-4H-pyridine-l- carboxylate (4.6 g) as a brown oil. MS ESI calculated for C24H33N3O2S [M+H]⁺, 428.23; found, 428.38.

Step 5: (S)’5’(5~methyk3.4,5,6"tetrahydrGpyridin"2"yl)--2--(l -methylpiperidin-4- yl)benzo[d]thiazole

[0807] To a solution of tert-butyl (5S)-5-methyl-2-[2-(l-methylpiperidin-4-yl)-l,3- benzothiazol-5-yl]-5,6-dihydro-4H-pyridine-1 -carboxylate (2.35 g, 5.49 mmol) DCM (20 mL) was added TEA (5 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford 5-[(5S)-5-methyl-3,4,5,6- tetrahydropyridin-2-yl]-2-( l-methylpiperidin-4-yl)- L3-benzothlazole (5.6 g, crude) as a brown oil. MS ESI calculated for C19H25N3S [M+H]L 328.18; found, 328.40

Step 6: 5-((2R_>5S)-5-methylpiperidin-2-yl)-2-(l-methylpiperidin-4-yl)benzo[d]thiazole (A3)

[0808] To a stirred solution of 5-[(5S)-5-methyl-l,4,5.6-tetrahydropyridin-2-yl]-2-(l- methylpiperidin-4-yl)-l,3-benzothiazole (3.52 g, 10.74 mmol) in MeOH (35 mL) was added NaBHLt (2.85 g, 75.23 mmol) in portions at -20 °C. The resulting mixture was stirred for 3 h at -20 °C. The reaction was quenched by the addition of water. The mixture was basified with NaHCOj (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous NasSOj. After filtration, the filtrate was concentrated under reduced pressure to afford 5-[(2R,5S)-5-methylpiperidin-2-yl]-2-(l - methylpiperidin-4-yl)- 1,3- benzothiazole (4.6 g, 97%) as a brown solid. MS ESI calculated for Ci9H₂7N₃S [M+H]⁺, 330. 19; found, 330.25. ^SH NMR (400 MHz, DMSO-ds) 8 (ppm) 8.25 (d, 7 - 1 .6 Hz, 1H), 8.14 (d, .J ” 8.4 Hz, 1 H), 7.69 (dd, 8.4, 1.6 Hz, 1H), 4.30 (dd, 12.0, 3.2 Hz, 1H), 3.43 - 3.35 (m, 2H), 3.29 - 3.18 (m, 1H), 3.11 - 2.94 (m, 2H), 2.74 ■■■■ 2.71 (m, 1H), 2.68 (s, 3H), 2.32 - 2.28 (m, 2H), 2.23 - 2.15 (m, 2H), 2.08 (s, 3H), 2.06 - 1.82 (m. 2H), 1 .42 - 1.32 (m, 1H), 0.96 (d, 7 - 6.6 Hz, 3H).

Intermediate A4: 1: 1 mixture of (4aR,10bR)-8-(trifluoromethyl)-l, 2,3, 4a, 5,10b- hexahydrochromeno[3,4-b] [ 1 ,4]oxazine and (4aS , 10bS)-8-(tri fluoromethyl)- 1 ,2,3 ,4a, 5, 10b- hexahydrochromeno[3,4-b][l,4]oxazine Step 1 : 1 : 1 mixture of (S)-3-bromo-7-(irifluoromethyl)chroman-4-one and (R)-3-bromo-7- (trifluoromethyl)chioman-4-one and (R)-3-bromo-7-(trifluoromethyl)chroman-4-one and (R)- 3-bromo-7-(trifluoromethyl)chroman-4-one

[0809] To a stirred mixture of 7-(trifluoromethyl) -2,3-dihydro-l-benzopyran-4-one (10.11 g, 46.8 mmol) in Et2O (150 mL) was added Bra (2.40 mL, 46.8 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was poured into NaSzCh (sat.) and stirred for 5 minutes. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with an 80 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (S)-3-bromo-7-(trifluoromethyl)chroman-4-one and (R)-3-bromo-7- (trifluoromethyl)chroman-4-one (11 .80 g, 76%) as a while solid. MS ESI calculated for CJ LBrKO. |M+Hf, 294.95, 296.95; found, 294.85, 296.85.

Step 2: 1: 1 mixture of (3S,4R)-3-bromo- /-(trifluoromethyl)chroman-4-ol and (3R,4S)-3- bromo-7 -(trill uoromethy 1 )chroman-4-ol

[0819] To a solution of a 1 : 1 mixture of (S)-3-bromo-7-(tritluoromethyl)chroman-4-one and (R)-3-bronio-7-(trifluoroniethyl)chroman-4-one (8.7 g, 29.48 mmol) in EtOH (88 mL) was added NaBHr (0.56 g, 14.74 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na-rSOr. After filtration, the filtrate was concentrated under reduced pressure to afford a 1:1 mixture of (3S,4R)-3-bromo-7- (trifluoromethyl)chioman-4-ol and (3R,4S)-3-bromo-7-(trifluoromethyl)chroman-4-ol (8.0 g, 90%) as a white solid. MS ESI calculated for CioHgBrFrCh [M+H]⁴, 296.97, 298.97: found, 296.90, 298.90.

Step 3: 1: 1 mixture of (3R,4R)-4-amino-7-(trifluoromethyl)chroman-3-ol and (3S,4S)-4- amino-7 -(trifluoromethyl)chroman -3 -ol

[0811] To a solution of a 1 : 1 mixture of (3S,4R)-3-bromo-7-(trifluoromethyl)chroman-4-ol and (3R,4S)-3-bromo-7-(trifiuoromethyl)chroman-4-ol (10 g, 33.66 mmol) and MeCN (4.15 g, 100.98 mmol) in DCE (50 mL) was added cone. H2SO4 (6.60 g, 67.32 mmol) at 25 °C. Hie mixture was stirred at 25 °C for 3 h. Then water (66.60 ml..) was added to the mixture at 25 °C. The mixture was stirred at 60 °C for 14 h. The mixture was cooled to room temperature and extracted with DCM. The aqueous phase was collected and basified by NaOH (aq., 25%) to pH 12. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure to afford a 1: 1 mixture of (3R,4R)-4-amino-7- (tritluororaethyl)chroman-3-ol and (3S,4S)-4-amino-7 -(trifluoromethyl)chroman-3-ol (2.5 g, 31%) as an off-white solid. MS ESI calculated for C10H10F3NO2 [M+H] ¹’, 234.07; found, 233.95.

Step 4: 1: 1 mixture of (4aR,10bR)-8-(.trifluoromethyl)-I,4a,5.10b-tetrahydrochromeno[3,4- b][l,4]oxazin-2(3H)-one and (4aS,10bS)-8-(trifJuoromethyl)-l,4a,5,10b- tetrahydrochromeno [ 3 ,4-b] [ 1 ,4 j oxazin- 2( 3H) ■ one [0812] To a solution of a 1 : 1 mixture of (3R,4R)-4-amino-7-(trif]uoromeliiyI)chroman-3-ol and (3S,4S)-4-amino-7-(trifluoromethyl)chroman-3-ol (2.00 g, 8.57 mmol) and CS2CO3 (5.59 g, 17.15 mmol) in MeCN (20 mL) was added 2-chloroacetyl chloride (0.97 g. 8.57 mmol) dropwise at 25 °C. The mixture was stirred at 25 °C for 1 h. Then the mixture was heated at 50° C and stirred for 12 h. The resulting mixture -was filtered, the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography 10 - 50% MeCN in water (0.1% TFA) to afford a 1 :1 mixture of (4aR,10bR)-8-(trifluoromethyl)-l,4a,5,10b-tetrahydrochromeno[3,4- b] [1 ,4]oxazin-2(3H)-one and (4aS , 10bS)-8-(trifluoromethyl)- 1 ,4a, 5 , 10b- tetrahydrochromeno[3,4-bJ[l,4]oxazin-2(3H)-one (760 mg, 32%) as a white solid. MS ESI calculated for C^HwFiNCh [M+H]⁺. 274.06; found, 274.00.

Step 5: 1: 1 mixture of (4aR,10bR)-8-(trifluoromethyl)-l ,2,3,4a,5,10b- hexahydrochromeno[3,4-b][l ,4]oxazine and (4aS,10bS)-8-(trifluoroniethyl)- 1 , 2, 3 ,4a, 5,10b- hexahydrochromeno[3,4-b][l,4]oxazine

[0813] A mixture of NaBI-ff (221 mg, 5.85 mmol) and BFs-EtcO (1.03 g, 7.32 mmol) in THF (4 mL) was stirred at 0 °C for 1 h, then a solution of a 1 : 1 mixture of (4aR,10bR)-8- (trifluoromethyl)-l,4a,5,10b-tetahydrochromeno[3,4-b][l,4]oxazin-2(3H)-one and

(4aS , 1 ObS )- 8- (trifl uoromethy 1 )- 1 ,4a, 5.10b-tetrahydrochromeno[3 ,4-b] [ 1 ,4]oxazin-2(3 H)-one (400 mg, 1.46 mmol) in THF (2mL) was added, and the mixture was stirred at. 10 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash column chromatography with 5-30% MeCN in water to afford a 1 :1 mixture of (4aR,10bR)-8-(trif]uoromeihyl)-l,2,3,4a,5, 10b-hexahydrocbromeno[3,4- b][l,4]oxazine and (4aS,10bS)-8-(trifluoromethyl)-l,2,3,4a,5,10b-hexahydrochromeno[3,4- b][l,4]oxazine (300 mg, 79%) as a grey solid. MS ESI calculated for C12H12F3NO2 [M+H]⁺, 260.08; found, 260.00. ^SH NMR (400 MHz, DMSO-tfc) 8 (ppm) 7.87 (d, J = 8.2 Hz, 1H), 7.39 (dd, 8.2, 1.8 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 5.10 - 4.90 (m, 1 H), 4.47 - 4.17 (m, 3H), 4.05 - 3.81 (m, 2H), 3.15 - 3.09 (m, 1H), 2.81 - 2.73 (m, 1H).

Intermediate A4 isomer 1: rel-(4aR,10bR)-8-(trifluoromethyl)- 1 ,2,3, 4a, 5,10b- hexahydrochromeno[3,4-b][l ,4]oxazine isomer 1 isomer 1

Intermediate A4 isomer 2: rel-(4aR,l0bR)-8-(irifluoromethyl)-1 ,2,3,4a,5,l0b- hexahydrochromeno[3,4-b][l,4]oxazine isomer 2 [0814] The intermediate A4 (300 mg) was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IE. 2*25 cm, 5 jun; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH), Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 5% B to 5% B in 20 min; Wave Length: 220/254 nm; RTl(min): 12.21 ; RT2(min): 15.03; Sample Solvent: EtOH: DCM-1: 1-HPLC; Injection Volume: 0.3 mL; Number Of Runs: 19] to afford rel-(4aR,10bR)-8-(trifluoromethyl)-l, 2,3, 4a, 5,10b- hexahydrochromeno[3,4-b][l,4]oxazine isomer I (A4 isomer 1) (64 mg, 21%) as a white solid with retention time at 12.21 minute. MS ESI calculated for C12H12F3NO2 [M+H]⁺, 260.08; found, 260.00. ^!H NMR (400 MHz, DMSO-cfc) 3 (ppm) 7.87 (d, J = 8.2 Hz, 1H), 7.39 (dd, J= 8.2, 1.8 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 5.10 - 4.90 (m, 1H), 4.47 - 4.17 (m, 3H), 4.05 - 3.81 (m, 21 h. 3.15 - 3.09 (m, 1H), 2.81 - 2.73 (m, 1H).

[0815] The separation also affords rel-(4aR. 10bR)-8-(trilluoromethyl)-L 2,3, 4a, 5.10b- hexahydrochromeno[3,4-b][l ,4]oxazine isomer 2 (A4 isomer 2) (140 mg, 46% yield) as a white solid with retention time at 15.03 minute. MS ESI calculated for C12H12F3NO2 [M+H]⁺, 260.08; found, 260.00. TI NMR (400 MHz, DMSO-rfe) 6 (ppm) 7.87 (d, J= 8.2 Hz, 1H), 7.39 (dd, J = 8.2, 1.8 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 5.10 - 4.90 (m, 1H), 4.47 - 4.17 (m, 3H), 4.05 - 3.81 (m, 2H), 3.15 - 3.09 (m, 1H), 2.81 - 2.73 (m. 1H).

Infermediate A5: 1:1 mixture of (4aR,10bS)-8-bromo-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine and (4aS,10bR)-8-bromo-l,3,4,4a,5,10b-hexahydro-2H- chromeno [4,3 -bjpyridine

Step 1 : methyl 2-(4-bromo-2-methoxyphenyl)pyridine-3-caiboxylate [0816] To a stirred solution of methyl 2-chloropyridine-3-carboxy1ate (7.43 g, 43.32 mmol) and K2CO3 (8.98 g, 64.98 mmol) in DMF (60 mL) and H2O (6 mL) were added Pd(PPhs)4 (2.50 g, 2.17 mmol) and 4-bromo-2-methoxyphenylboronic acid (5 g, 21.66 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 120 g silica gel column eluted with 0-40% ethyl acetate in petroleum ether within 35 min to afford methyl 2-(4-bromo-2- methoxyphenyl)pyridine-3-carboxylate (4.6 g, 65%) as a yellow solid. MS (ESI) calc’d for (CirHicBrNCh) [M+H]*, 322.00, 324.00; found, 321.95, 323.95.

Step 2: 8-bromochroraeno[4,3-b]pyridin-5-one

[0817] To a stirred solution of methyl 2-(4-bromo-2-methoxyphenyl)pyridine-3- carboxylate (4.60 g, 14.28 mmol) in DCM (80 mL) was added BBrs (71.39 mL, 71.40 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with VVater/Ice and neutralized to pH -7 with saturated NaHCOs (aq.j. The resulting mixture was extracted with CH2Q2. The combined organic layers were washed with brine, dried over anhydrous NazSOa- After filtration, the filtrate was concentrated under reduced pressure to afford 8-bromochromeno[4,3"b]pyridin-5-one (3.8 g, crude) as a yellow solid. MS (ESI) calc’d for (CnHeBrNCh) [M+H]⁺, 275.96, 277.96; found, 275.95, 277.95.

Step 3 : 8-bromo-5H-chromeno[4,3-b]pyridine

[0818] To a stirred solution of 8-bromochromeno[4,3-b]pyridin-5-one (3.8 g, 13.76 mmol) and NH3.BH3 (L70 g, 55.06 mmol) in Et?O (50 mL) was added TiCL (7.65 mL, 55.06 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. Ute reaction mixture was quenched by the addition of ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 80 g silica gel column eluted with 0-80% ethyl acetate in petroleum ether within 35 min to afford 8-bromo-5H-chromeno[4,3-b]pyridine (865 mg, 22%) as a yellow solid. MS (ESI) calc'd for (CuHgBrNO) [M+H]⁺. 261.98, 263.98; found, 261.85, 263.85.

Step 4: 1 : 1 mixture of (4aR,10bS)-8-bromo-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3- bjpyridine and (4aS,10bR)-8-bromo-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine

[0819] To a solution of 8-bromo-5H-chromeno[4,3-b]pyridine (270 mg, 1.03 mmol) in propan-2-ol (4 mL) and AcOH (4 mb) was added Pt/C (58 mg, 0.30 mmol) at 20 °C under nitrogen. The mixture was placed under hydrogen atmosphere with a balloon (1 atm.). The reaction mixture degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at 20 °C for 16 h under hydrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in DMF (1.5 mb.) and was purified by reverse phase flash chromatography on 48 g Cl 8 column with 5-80% acetonitrile in water ( 10 mM NH4HCO3) within 35 min to afford a 1 : 1 mixture of (4aR, 10bS)-8-bromo- 1 ,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine and (4aS,10bR)-8-bromo- l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine (50 mg, 16%) as a colorless oil. MS (ESI) calc’d for (Ci₂H_!4BrNO) [M+Hf, 268.03, 270.03; found. 268.15, 270.15. ^!H NMR (400 MHz, DMSO-tfe) 6 7.28 (d, J - 8.2 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.92 (dd, 7 - 9.4, 2.0 Hz, 1H), 4.29 (dd, J = 10.6, 7.8 Hz, 1H), 4.14 - 4.04 (m, 1H), 3.89 - 3.72 (m, 1H), 2.70 - 2.54 (m, 3H), 1.99 - 1.95 (m, 1H), 1.72 - 1.55 (m, 2H), 1.49 - 1.17 (m, 2H). Intermediate A6, isomer 1: rel-(2R,4aS,l0bR)-2-meliiyl-8-(trifluoromeihyl)-l,.3,4,4a,5,10b- hexahydro-2H-chromeno[4,3-b]pyridine, isomer 1

A6, isomer 1 . _and

Intermediate A6, isomer 2: rel-(2S,4aR,10bS)-2-naethyl-8-(trifluorometliyl)-l,3,4,4a,5,10b- hexahydro-2H-chromeno[4,3-b]pyridine, isomer 2

A6, isomer 2

Step 1 : methyl 2-[2-methoxy-4-(trifluoroniethyl)phenylJ-6-methylpyridine-3-carboxylate

[0820] To a stirred solution of 2-methoxy-4-(trifiuoromethyl)phenylboronic acid ( 10 g, 45.5 mmol) in dioxane (100 mL) and H2O (10 mL) was added methyl 2-chloro-6- methylpyridine-3 -carboxylate (8.44 g, 45.5 mmol), Pd(dppf)C12CH2C12 (3.70 g, 4.55 mmol) and K2CO3 ( 12.57 g, 90.9 mmol). The resulting solution was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford methyl 2-[2-methoxy-4-(trifhjoromethyI)phenyIj-6miethylpyridine-3 -carboxyiate (13.5 g, 88%) as an off-white solid. MS ESI calculated for (C16H14F3NO3) [M+H]⁺, 326.09; found, 326.10. 'H N MR (400 MHz, DMSO-Js) 8 8.08 (d, 8.0 Hz, 1H), 7.62 (dd, 7.6, 1.2 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.31 (d, J= 1.6 Hz, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 2.57 (s,

3H). Step 2: 2-methyl-8-(trifluoromethyl)chromeno[4,3-b]pyridin-5-one

[0821] Into a 1000 mL 3-necked round-bottom flask were added methyl 2-[2-niethoxy-4- (trifIuoromethyl)phenyl]-6-niethylpyridine-3-carboxylate (13.50 g, 41.50 mmol) and DCM (135 mL) at room temperature. To the above mixture was added BBr, (62.38 g, 249.01 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h under nitrogen atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with CH2CI2. The combined organic layers were dried over anhydrous NazSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether to afford 2-methyl-8-(trinuoromelhyl)chromeno[4,3-b]pyridin-5-one (9.5 g, 78%) as a white solid. MS ESI calculated for (CiJHfeFsNO?) [M+H]⁺, 280.05; found, 280.15. ^!H NMR (400 MHz, Chloroform -d) 8 8.83 - 8.63 (m, 1H), 8.52 (d, J - 8.0 Hz, 1 H), 7.70 - 7.56 (m, 2H), 7.46 (d, J - 8.4 Hz, 1H), 2.81 (s, 3H).

Step 3: 2-metliyI-8-(trifluoromethyl)-5H-chromeno[4,3-b]pyridine

[0822] Into a 1000 mL vial were added 2-methyl-8-(trilluoromethyl)cbromeno[4,3- b]pyridin-5-one (20 g, 71.62 mmol), NH3.BH3 (4.42 g, 143.25 mmol) and EtjO (200 mL) at room temperature. To the above mixture was added T1CI4 (1 moi/L in DCM) (143 mL, 143.26 mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 2 days at room temperature. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford 2-methyl-8-(trifluoromethyl)-5H-chronieno[4,3-b]pyridine (9.8 g, 46%) as a white solid. MS ESI calculated for (C14H10F3NO) [M+HJL 266.07; found, 266. 10. ‘H NMR (400 MHz, DMSO-O 5 8.28 (d, J= 8.0 Hz, IH), 7.61 (d, J = 7.6 Hz, IH), 7.42 (dd, .7 - 8.0, 1.8 Hz, 1H), 7.35 - 7.21 (m, 2H), 5.35 (s, 2H), 2.54 (s, 3H).

Step 4: 1: 1 mixture of rel-(2R,4aS,10bR)-2-methyl-8-(triftaoromethyl)4,3,4,4a,5,10b- hexahydro-2H-chromeno[4,3-b]pyridine, isomer 1 and rel-(2S,4aR,10bS)-2-methyl-8- (trifluoroTnethy1)-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine, isomer 2

A6, isomer 1 A6, isomer 2

[0823] To a solution of 2-methyl-8-(tif]uoromeihyl)-5H-chromeno[4,3-b]pyridine (5.0 g, 18.85 mmol) in AcOH (30 mL) and 2-propanol (30 mL) was added Pt/C (1 10 mg, 0.56 mmol) at 20 °C under nitrogen atmosphere. The reaction mixture was degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at 20 ^GC for 16 h under hydrogen with a balloon (1 atm.). The suspension was filtered. The filtrate was collected and concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Tsolera Prime) using a 120 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether within 25 min to afford a 1: 1 mixture of rel-(2R,4aS,10bR)-2-metliyl-8-(trifluoromethyl)-l,3.4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine, isomer 1 and rel-(2S,4aR,10bS)-2-methyl-8-(trifluoromethyl)- 1 ,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine, isomer 2 (900 mg, 14%) as a yellow oil. MS (ESI) cak’d for (CuHssFsNO) [M+H]⁺, 272.12; found, 272.15. ^!H NMR (400 MHz, DMSO-rfc) 87.44 (d, .J - 8.0 Hz. IH), 7.18 - 7.1 1 (ra, IH), 7.05 (d, / - 1.6 Hz, 1H), 4.58 - 4.45 (m, 1H), 4.04 - 3.94 (m, IH), 3.73 (d, J = 3.2 Hz, IH), 2.83 - 2.66 (m, 1H), 2.10 - 2.08 (m, IH), 2.04 - 1.93 (m, IH), 1.83 - 1.69 (m, 2H), 1.42 - 1.38 (m, IH). 1.38 - 1.34 (m, IH), 1 .00 (d, J - 6.0 Hz, 3H).

Step 5: rel-(2R,4aS,10bR)-2-methyl-8-(trifluoron)ethyl)-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine, isomer 1 (A6 isomer 1):

AS, isomer rel-(2S,4aR.10bS)-2-methyl"8-(trifluoromethyl)-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3- bjpyridine, isomer 2 (A6 isomer 2):

A6, isomer 2

[0824] A 1:1 mixture of rel-(2R,4aS,10bR)-2-methyl-8-(trifluoromethyl)-l,3,4,4a,5,10b- hexahydro-2H-chromeno[4,3-b]pyridine, isomer 1 and rel-(2S,4aR,10bS)-2-methyl-8- (trifluoromethyl)-l ,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-bjpyridine, isomer 2 (900 mg, 3.31 mmol) was separated by prep-chiral SFC with the following conditions: [Column: CHIRALPAK IG, 5*25 cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NHs-MeOH); Flow rate: 100 mL/min; Gradient: isocratic 20% B; RT1 (min): 6.6; RT2 (min): 7.7: Sample Solvent: MeOH; Injection Volume: 1 rnL; Number Of Runs: 38] to afford rel-(2R,4aS,10bR)-2-methyl-8-(trifluoromethyl)-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine, isomer 1 (A6 isomer 1) (185 mg, 20%) as a light yellow oil with retention time at 6.6 minute. The chiral separation also afford rel-(2S,4aR,10bS)-2-rnethyl-8- (trifluoromethyl)-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine, isomer 2 (A6 isomer 2) (165 mg, 17%) as a light yellow oil with retention time at 7.7 minute.

[0825] rel-(2R,4aS,10bR)-2-methyl-8-(trifluoromethyl)-l ,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine, isomer 1 (A6 isomer 1): MS ESI calculated for (C14H16F3NO) [M+H]⁺, 272.12; found, 272.15. ^;H NMR (400 MHz, DMSO-cfe) 87.44 (d, 8.0 Hz, 1H),

7.15 (dd, J = 8.0, 2.0 Hz, 1H), 7.05 (d. J = 1.6 Hz, 1H), 4.58 - 4.41 (m. 1H), 4.09 - 3.95 (m.

1H), 3.73 (d, 3.2 Hz, 1H), 2.80 - 2.63 (m, 1H), 2.14 - 2.06 (m, 1H), 2.04 - 1.95 (m, 1H),

1.82 - 1.69 (m, 2H), 1.42 - 1.38 (m, 1H), 1.38 - 1.33 (m, 1H), 0.99 (d, 6.0 Hz, 3H).

Absolute stereochemistry was not determined. [0826] rel-(2S,4aR,10bS)-2-methyl-8-(trifluoromethyl)-l ,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine, isomer 2 (A6 isomer 2): MS ESI calculated for (CMH^FSNO) [M+HF, 272.12; found, 272. 15. ^!H NMR (400 MHz, DMSO-cfc) 8 7.44 (d, J = 8.0 Hz, 1H), 7.16 (dd, /= 8.0, 2.0 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 4.61 - 4.41 (m, 1H), 4.05 - 3.96 (m, 1H), 3.74 (d, J - 3.2 Hz, 1 H ), 2.83 - 2.64 (m, 1H), 2.16 - 2.05 (m, 1H), 2.05 - 1 .92 (m, 1H), 1.82 - 1.68 (m, 2H), 1.42 - 1.38 (m, 1H), 1.38 - 1.33 (m, 1H), 1.00 (d, 7 = 6.0 Hz, 3H).

Absolute stereochemistry was not determined.

Intermediate A7: 5-[(2R,5S)-5-methylpiperidin-2-yl]-l,3-benzothiazole

Step 1 : 5-(4,4,5 ,5-tetramelhyl- 1,3 ,2 -dioxaborolan-2 -yl)- 1 ,3 ■■benzothiazole

[0827] To a stirred solution of 5-bromo- 1 ,3-benzothiazole (20 g, 93.42 mmol) in dioxane (200 mL) were added bis(pinacolato)diboron (35.59 g, 140.14 mmol), PdldppfjCF. (6.84 g, 9.34 mmol) and AcOK (18.34 g, 186.85 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether to afford 5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l ,3-benzothiazole (21 g, 86%) as a white solid MS ESI calculated for Ci ₃H [M+HF, 262. 10; found, 262.05.

Step 2: tert-butyl (5S)-2-(l,3-benzothiazol-5-yl)-5-methyl-5,6-dihydro-4H-pyridine- 1- carboxylate

[0828] To a stirred solution of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3- benzothiazole (365 mg, 1.40 mmol) and tert-butyl (5S)-5-methyl-2- (trifluoromethanesulfonyloxy)-5,6-dihydro-4H-pyridine-1 -carboxylate (Supplier: Shanghai Tianze biological medicine Co., LTD cas# 572246-00-4) (483 mg, 1.40 mmol) in dioxane (3 mL) and H2O (3 mL) was added K2CO3 ( 387 mg, 2.80 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford tert-butyl (5S)-2-(l,3-benzothiazol-5-yl)-5-methyl-5,6-dihydro-4H-pyridine-l- carboxylate (240 mg, 30%) as a white solid. MS ESI calculated for C18H22N2O2S [M+H]⁺, 331.14; found, 331.05.

Step 3: 5-[(2R,5S)-5-methylpiperidin-2-yl]-l,3-benzothiazo1e (A'7)

[0829] A solution of tert-butyl (5S)-2-(l,3-benzothiazol-5-yl)-5-methyl-5,6-dihj'dro-4H- pyridine-1 -carboxylate (240 mg, 0.73 mmol) and TFA (0.6 ml.,) in DCM (2.4 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in MeOH (5 mL). and NaBKU (82 mg, 2.18 mmol) was added in portions at -20 °C under nitrogen atmosphere. The resulting mixture was stirred at -20 °C for 4 h under nitrogen atmosphere. The reaction was quenched with water and basified to pH 8 with saturated NaHCOj (aq .). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NacSCri- After filtration, the filtrate was concentrated under reduced pressure to give 5-[(2R,5S)-5- methylpiperidin-2-yl]-l,3-benzothiazole (152 mg, 90%) as a light green oil. MS ESI calculated for C13H16N2S [M+H]⁺, 233.10; found, 233.05. ^rH NMR (400 MHz, DMSO-Je) 8 9.39 (s, 1H), 8.15 - 8.10 (m, 2H), 7.53 (dd, .Z - 8.2, 1.7 Hz, 1H), 3.87 (dd, 1 1.5, 2.6 Hz, 1H), 3.16 - 3.10 (m, 1H), 2.45 (t, 11.5 Hz, 1H), 1.90 - 1.80 (m, 2H), 1.76 - 1.53 (m, 2H),

1.29 - 1.20 (ni, 1H), 0.90 (d, J = 6.6 Hz. 3H).

Intermediate A8: 1:1 mixture of 5-((2R,5S)-5-methylpiperidin-2-yl)-2-((S)-l- methylpiperidin-3-yl)benzo[d]thiazole and 5-((2R,5S)-5"methylpiperidin-2-yl)--2--((R)- l- methylpiperidin-3-yl)benzo[d]ihiazole

Step 1: 1: 1 mixture of (S)-5-chloro-2-(l-methylpiperidin-3-yl)benzo[dJthiazole and (R)-5- chloro-2-( 1 -meihy Ipiperi din-3 -yl)benzo [d] thiazole

[0830] A solution of PPA (25.3 g, 219 mmol) and P2O5 (31.2 g, 219 mmol) was stirred at room temperature for 10 minutes under nitrogen atmosphere. Then 2-amino-4- chlorobenzenethiol (8.77 g, 54.9 mmol) and rac-l-methylpiperidine-3-carboxylic acid (9.44 g, 65.4 mmol) was added to above mixture in one portion at room temperature. The resulting mixture was stirred at 1 10 °C for 16 h. The resulting mixture was quenched with water. The mixture made basic with NaOH (10% aq.) to pH 10. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with a 120 g silica gel column eluted with 0- 4% MeOH in DCM to afford a 1:1 mixture of (S)-5-chloro-2-(l-methylpiperidin-3- yl)benzo[d]thiazole and (R)-5-chloro-2-(l -methylpiperidin-3-y1)benzo[d]fliiazole (4.2 g, 28%) as a yellow oil. MS ESI calculated for C13H15CIN2S [M+H]⁺, 267.06; found, 267.00.

Step 2: 1: 1 mixture of (S)-2-(l-methylpiperidin-3-yl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzo[djthiazole and (R)-2-( l-methylpiperidin-3-yl)-5-(4, 4,5,5- tetramethyl- 1, 3, 2-dioxaborolan-2-yl)benzo[d]thiazole

[0831] To a stirred solution of a 1: 1 mixture of (S)-5-chloro-2-(l-methylpiperidin-3- yl)benzo[d]thiazole and (R)-5-chloro-2-(l •methylpiperidin-3-yl)benzo[djthiazole (2.00 g, 7.49 mmol), AcOK (1.47 g, 14.99 mmol) and BPD (2.09 g, 8.24 mmol) in dioxane (20 ml) were added Pd2(dba)s (343 mg, 0.37 mmol) and XPhos (714 mg, 1.49 mmol) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with 1,4-dioxane. The filtrate was concentrated under reduced pressure. Then HCI (4M in dioxane) was added to the residue and stirred for 15 minutes. The precipitated solids were collected by filtration and dried under vacuum to afford a 1: 1 mixture of (S)-2-(l-methylpiperidin-3-yl)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d]thiazole and (R)-2-(l -methylpiperidin-3-yl)-5- (4,4,5,5-tetraroethyl-l,3,2-dioxaborolan-2-y1)benzo[dlthiazole as HCI salts (3.4 g, crude) as a yellow solid. MS ESI calculated for C19H27BN2O2S [M+H]⁺, 359.19; found, 359.10.

Step 3: 1: 1 mixture of tert-butyl (S)-3-methyl-6-(2-((S)“l-methylpiperidin-3- yl)benzo[d]thiazo1-5-yl)-3,4-dihydropyridine- 1 (2H)-carboxylate and tert-butyl (S)-3-methyl-

6-(2-((R)-l-methyJpiperidin-3-yl)benzo[d]thiazol-5-yl)-3,4-dibydropyridine-l(2H)- carboxylate

[0832] To a stirred solution of a 1 : 1 mixture of (S)-2-(l -methylpiperidin-3-yl)-5-(4, 4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzo[d]tbiazole and (R)-2-( 1 -methylpiperidin-3-yl)-5- (4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzo|d]thiazole (259 nig, 0.72 mmol) and tertbutyl (5S)-5-methyl-2-(trifluoromethanesulfbnyloxy)-5,6-dihydro-4H-pyridine-l-cait>oxylate (28 mg, 0.08 mmol) in dioxane (2.5 mL)/water (0.5 mL) were added K2CO3 (200 mg, 1.44 mmol) and Pd(dppf)Cl? (52 mg, 0.07 mmol) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. The resulting mixture was quenched with water. The resulting mixture was extracted with EtO.Ac. The combined organic layers were washed with brine, dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with a 25 g silica gel column eluted with 0-10% MeOH in DCM to afford a 1:1 mixture of tert-butyl (S)-3-methyl-6-(2-((S)-l-methylpiperidin-3- yl)benzo[d]thiazoi-5-yl) -3,4-dihydropyridine- l(2H)-carboxylate and tert -butyl (S)-3-methyl- 6-(2-((R)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)-3,4-dihydropyridine-l(2H)- carboxylate (130 mg, 36%) as a brown oil. MS ESI calculated for C24H33N3O2S [M+H]⁺, 428.23; found, 428.20.

Step 4: 1: 1 mixture of 5-((2R,5S)-5-metliylpiperidin-2-yl)-2-((S)-l-methylpiperidin-3- yl)benzo[d]thiazole and 5-((2R,5S)-5-meihy]piperidin-2-yl)-2-((R)-l-metbylpiperidin-3- y l)ben zo [d j thiazole ( A 8 ) [0833] To a solution of tert-butyl (5S)-5-methyl-2-[2-(l-methylpiperidin-3-y1)-l,3- benzothiazol-5-yl]-5,6-dihydro-4H-pyridine-l-carboxylate (1.00 g, 2.34 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in MeOH (9 mL) and cooled to -20 °C, NaBIL (519 mg, 13.74 mmol) was added in portions. After stirring at -20 °C for 1 h, the reaction was quenched with water. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous NasSOi. Alter filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of 5-((2R,5S)-5- methylpiperidin-2-yl)-2-((S)-l-metbylpiperidin-3-yl)benzo[d]thiazole and 5-((2R,5S)-5- methylpiperidin-2-yl)-2-((R)-l-methylpiperidin-3-yl)benzo[d]thiazole (900 mg, 77%) as a brown oil. MS ESI calculated for C19H27N3S [M+H]⁺, 310.19; found, 310.10. ^!H NMR (400 MHz. DMSO-(fc) 8 (ppm) 8.02 - 7.90 (m, 2H), 7.45 (dd, J = 8.4, 1 .6 Hz, 1H), 3.78 (dd, J = 11.4, 2.4 Hz, 1H), 3.35 - 3.31 (m, 1H), 3.17 ■■• 2.95 (m, 2H), 2.67 - 2.65 (m, 1H), 2.42 (t, J = 1 1.4 Hz, III), 2.29 - 2.25 (m, 1H). 2.23 (s, 3H), 2. 10 - 2.01 (m, 2H ), 1.88 - 1.46 (m, 9H), 0.88 (d, J = 6.6 Hz, 3H).

Intermediate A9: 1 :1 mixture of (3R,4aS,10bR)-3-methyl-8-(trifluoromethylj- l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine and (3S,4aR, 10bS)-3-methyl-8-

(trifluoromethyl)- 1 ,3 ,4,4 a, 5 , 10b-hexahydro-2H-chromeno[4,3-b]pyridine

Step 1 : methyl 2-chloro-5-methylpyridine-3 -carboxylate

[0834] To a stirred solution of 2-chloro-5-methylpyridine-3-carboxylic acid (19.12 g,

111.44 mmol) and Mel (47.45 g, 334.31 mmol) in DMF (200 mL) was added K2CO3 (46.20 g, 334.31 mmol) at 25 °C. The resulting mixture was stirred at 60 °C for 16 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ?SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford methyl 2- chloro-5-methylpyridine-3-carboxylate (14.60 g, 70%) as a yellow solid. MS ESI calculated for CsHsCINCh [M+H]⁺, 186.02; found, 186.10.

Step 2: methyl 2-[2-methoxy-4-(trifluoromethyl)phenyl]-5-metliylpyridine-3-carboxylate

[0835] A degassed mixture of methyl 2-chloro-5-methylpyridine-3-carboxylate (10. 1 g, 53.9 mmol), 2-methoxy-4-(trilluoromethyi)phenylboronic acid (14.2 g, 64.7 mmol), Pd(dppf)C12-CH₂Ci2 (4.39 g, 5.39 mmol) and K2CO3 (14.8 g, 107 mmol) in 1, 4-dioxane (100 mL) and H?O (10 niL) was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by Combi Flash with a 120 g silica gel column eluted with 0—50% ethyl acetate in petroleum ether to afford methyl 2-[2-methoxy-4-(trifluoromeihyl)pheny1]-5-methylpyridme-3-carboxylate (14.71 g, 83%) as a yellow solid. MS ESI calculated for C16H14F3NO3 |M+H|⁺, 326.09; found, 326.15.

Step 3: 3-methyl-8-(trifluoromethyl)chromeno[4,3-b]pyridin-5-one

[0836] To a solution of methyl 2-[2-methoxy-4-(trifluoromethyl)phenyl] ■■ 5 methylpyridine 3-carboxylate (14.7 g, 45.2 mmol) in DCM (150 mL) was added BBn (158 mL, 158 mmol) (1 M in DCM) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with DCM. Tire combined organic lavers were washed with brine, dried over anhydrous NasSO^i. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford 3-methyl-8-(trifluoromethyl)chromeno[4.3-b]pyridin-5-one (9.55 g, 75%) as a yellow solid. MS ESI calculated for CMHSFSNOS [M+H]⁺, 280.05; found, 280.00.

Step 4: 3-methyl-8-(trifluoromethyl)-5H-chromeno[4,3-b]pyridine

[0837] To a stirred solution of 3-methyl-8-(trifluoromethyl)chromeno[4,3-b]pyridin-5-one (8.55 g, 30.6 mmol) and NH3-BH3 (1-89 g, 61.22 mmol) in Et?,0 (160 mL) was added TiCfi (6.7 mL, 61.2 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by the addition of ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with a 120 g silica gel column eluted with 0- 30% ethyl acetate in dichloromethane within 35 min to afford 3-methyl-8-(trifluoromethyl)- 5H-chromeno[4,3-b]pyridine (4.1 g, 38%) as a yellow solid. MS ESI calculated for C14H10F3NO [M+H]⁺, 266.07; found, 266.15.

Step 5: 1: 1 mixture of (3R,4aS,10bR)-3-methyl-8-(trifiuoromethyl)-l,3,4,4a,5,10b- hexahydro-2H-chromeno[4,3-b]pyridine and (3S,4aR,10bS)-3-methyl-8-(trifluoromethyl)- l,3,4,4a,5,10b-hexahydro-2H-chronieno[4,3-b]pyridine

[0838] A solution of 3-methyl-8-(trifluoromethyl)-5H-chromeno[4,3-b]pyridine (5.00 g,

18.9 mmol) in 2-Propanol ( 100 mL) was placed in an autoclave, then Rh/C (3 .01 g, 5% active on carbon) was added to above mixture. The mixture was stirred at 50 °C for 16 h under hydrogen atmosphere (50 atm.). The suspension was filtered. The filtrate was collected and concentrated under vacuum. The resulting residue was purified by Combi Flash with a 120 g C18 column eluted with 5-100% acetonitrile in water (20 mM NH4HCO3) to afford a 1: 1 mixture of (3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine and (3S, 4aR, 10bS)-3-methyl-8-(trifluoromethyl)- 1 ,3,4 ,4a, 5,10b- hexahydro-2H-chromeno[4,3-b]pyridine (1.80 g, 36%) as a yellow solid. MS ESI calculated [M+Hf, 272.12; found, 272.15. ^SH NMR (400 MHz, DMSO-afe) 8 7.76 (d, ./ = 8.0 Hz, 1H), 7.22 (dd, 7 = 8.2, 2.0 Hz, HI), 7.02 (d, .J = 1.8 Hz, 1 H), 4.24 (dd, J = 11.2, 2.2 Hz, 1H), 4.18 (d, 7 = 5.4 Hz, 1H), 4.08 (dd, 7 = 11.2, 2.2 Hz, 1H), 2.60 - 2.53 (m, 1H), 2.10 - 1.98 (m, 1H), 1.78 - 1.69 (m, 1H), 1.69 - 1.62 (m, 1H), 1.61 - 1.49 (m, 1H), 0.95 - 0.93 (m, 1H), 0.69 (d, 7 - 6.4 Hz. 3H ).

Intermediate A10: 1 :1 mixture of (4aS,9bS)-7-(trifluoromethy1)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine and (4aR,9bR)-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine

Step 1: 2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(methoxymethoxy)pyridine

[0839] To a stirred solution of 2-fluoro-4-(trifluoromethyl)phenylboronic acid (5.00 g, 24.0 mmol) and 2-bromo-3-(methoxymetboxy)pyridine (5.24 g, 24.0 mmol) in 1 ,4-dioxane (40 mL) and H2O (4 ml) were added PPha (3.15 g, 12.0 mmol), K2CO3 (6.65 g, 48.1 mmol) and Pd(OAc)c (0.54 g, 2.40 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting residue was dissolved in DCM and purified by Combi Flash (Biotage Isolera Prime) using a 120 g silica gel column that was eluted with 0- 50% ethyl acetate in petroleum ether within 35 min to afford 2-[2-fluoro-4- (trifluoromethyl)phenyl]-3-(methoxymethoxy)pyridine (3.70 g, 45%) as a yellow oil. MS (ESI) calculated for (C14HHF4NO2) [M+H]⁺, 302.07; found, 302.15.

Step 2: Synthesis of 2-[2-fluoro-4-(trifluorometliyl)phenyI]pyridin-3-ol

[0840] To a stirred solution of 2-[2-fluoro-4-(trifluoromeihyl)phenyl]-3- (methoxymethoxyjpyridine (4.01 g, 13.3 mmol) in DCM (40 mL) was added TFA (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum to afford 2-[2-fluoro-4- (trifluoromethyl)phenyl]pyridin-3-ol (7.20 g, crude) as a yellow oil. MS (ESI) calculated for (C12H7F4NO) [M+H]\ 258.05; found, 257.95.

Step 3 : 7 -(trifluoromethyl)benzofuro[3,2-b]pyridine

[0841] To a stirred solution of 2-[2-fluoro-4-(trifluoromethyl)phenyl]pyridin-3-ol (7.20 g, 28.0 mmol) in DMF (40 mL) was added K2CO3 (11.61 g, 84.0 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 16 h under nitrogen atmosphere. The resulting mixture was cooled down to room temperature. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCU After filtration, the filtrate was concentrated under vacuum to afford 7-(trifluoromethyJ)benzofuro[3,2-b]pyridine (6.10 g, 84%) as a brown solid. MS (ESI) calculated for (CirHeFiNO) [M+H]\ 238.04; found, 238.15. Step 4: 1 :1 mixture of (4aS,9bS)-7-(trifluoromethyl)- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine and (4aR,9bR)-7-(lrifluoromethyl)-l,2_!3>4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine

[0842] To a solution of 7-(trifluoromediyl)benzofuro[3,2-b]pyridine(3.00 g, 12.6 mmol) in i-PrOH (150 mL) was added Pd(OH)₂./C ( 100 mg) under nitrogen. The mixture was stirred at 50 °C for 16 h under hydrogen atmosphere (50 atm.). The resulting mixture was filtered, the filter cake was washed with i-PrOH (150 mL). The filtrate was collected and concentrated under vacuum. The resulting residue was dissolved in DMF (2 mL) which was applied to a 120 g C18 column and purified by Combi Flash (Biotage Tsolera Prime), eluted with 5-50% acetonitrile in water (10 mM NH4HCO3) within 30 min to afford a 1:1 mixture of (4aS,9bS)- 7-(trifluoromethyI)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine and (4aR,9bR)-7- ( trifluoromethyl)- 1,2, 3, 4, 4a, 9b-hexahydrobenzofuro[3,2-b]pyridine (240 mg, 7%) as a white solid. MS ESI calculated for (C12H12F3NO) [M+H]⁴, 244.09; found, 244.20. ^!H NMR (400 MHz, DMSO-tfc) 6 7.48 (d, 7= 7.6 Hz, 1H), 7.22 (d, 7.6 Hz, 1H), 7.13 (s, 1H), 4.54 (q. J

= 4.8 Hz, HI), 4.29 (d, 7 = 6.0 Hz, 1 H), 2.66 - 2.56 (m, 2H), 2.33 (br, 1H), 2.06 - 1.86 (m, 2H), 1.52 - 1.35 (m, 2H).

Intermediate A10 isomer 1: rel-(4aS,9bS)-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1

Intermediate A10 isomer 2: rel-(4aS,9bS)-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2

AiC isomer 2

[0843] Intermediate A10 (200 nig) was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK. IF, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M Nl L-.VleOl 1)--HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 2% B to 2% B in 15 min; Wave Length: 220/254 nm; RTl(min): 5.55; RT2(min): 6.24; Sample Solvent: EtOH: Hex-1: 1-HPLC; Injection Volume: 0.55 mb; Number Of Runs: 8] to afford rel-(4aS,9bS)-7-(irifluoromethyl)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 1 (A10 isomer I) (22.6 mg) as a white solid with the first peak on chiral-HPLC. MS ESI calculated for (C12H12F3NO) [M+H]⁺, 244.09; found, 244.20. 'H NMR (400 MHz, DMSO- d₆) 8 7.47 (d, J - 7.6 Hz, 1H), 7.22 (d, J - 7.6 Hz, 1H), 7.13 (s, 1H), 4.54 (q, J - 4.8 Hz, 1H), 4.29 (d, 7 = 6.0 Hz, 1H), 2.66 - 2.56 (m, 2H), 2.33 (s, 1H), 2.06 - 1.87 (m, 2H), 1.51 - 1.35 (m, 2H). Absolute stereochemistry was not determined.

[0844] The chiral resolution also afforded rel-(4aS,9bS)-7-(trifluoromethyl)- 1, 2.3,4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2 (A10 isomer 2) (19.7 mg) as a white solid with the second peak on chiral-HPLC. MS ESI calculated for (CJZH^NO) [M+H]⁺, 244.09; found, 244.20. 'H NMR (400 MHz, DMSO-tfc) 5 7.47 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1 H), 7.13 (s, 1H), 4.54 (q, 7 - 4.8 Hz, 1H), 4.29 (d, 7 - 6.0 Hz, 1H), 2.66 - 2.56 (m, 2H), 2.33 (s, 1 H), 2.06 - 1 .87 (m, 2H), 1 .51 - 1 .35 (m, 2H). Absolute stereochemistry' was not. determined.

Intermediate All: 1 : 1 mixture of (4aS,9bS)-7-(difluoromethoxy)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine and (4aR,9bR)-7-(difluoromethoxy)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine

Step 1: Synthesis of l-bromo-4-(difluoromethoxy)-2-fluorobenzene

[0845] To a stirred solution of 4-bromo-3-fluorophenol (10 g, 52.36 mmol) in MeCN (500 mL) was added a solution of KOH (2.9.37 g, 523.56 mmol) in H2O (120 niL) at room temperature. To the above mixture was added diethyl bromodifluoromethylphosphonate (55.92 g, 209.42 mmol) at room temperature. The resulting mixture was stirred at 30 °C for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 120 g silica gel column eluted with 0-10% ethyl acetate in petroleurn ether within 35 min to afford l-bromo-4-(difluoromethoxy)-2- fluorobenzene (9.3 g, 72%) as a colorless oil. ^SH NMR (400 MHz, DMSO-tfc) 8 7.83 - 7.69 (m, 1H), 7.54 - 7.11 (m, 2H), 7.06 - 7.02 (m, IH). Step 2: 2-[4-(difluoromethoxy)-2-fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

[0846] To a stirred solution of l-bromo-4-(difluoromethoxy)-2-fluorobenzene (9.30 g, 38.59 mmol) and BPD (9.80 g, 38.59 mmol) in 1,4-dioxane (100 mL) were added AcOK (11.36 g, 1 15.75 mmol) and Pd(dppp)Ch (2.28 g, 3.86 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 330 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether within 35 min to afford 2-[4-(difluoromethoxy)-2- fluorophenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (8 g, 71%) as a yellow solid. ‘H NMR (400 MHz, DMSO-Jc,) 8 7.73 - 7.65 (m, 1H), 7.54 - 7.15 (m, H i ). 7.07 - 7.02 (m, 2H), 1.44 - 1.18 (m, 12H).

Step 3 : 2- [4- (difluoromethoxy )-2-fluorophenyl] -3-(methoxymethoxy)pyridine

[0847] To a stirred solution of 2-[4-(difluoromethoxy)-2-fluorophenyl]-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (8 g, 27.78 mmol) and 2-bromo-3-(methoxymethoxy)pyridine (6.06 g, 27.78 mmol) in 1,4-dioxane (30 mL.) and HzO (6 mL) were added NajCCh (5.89 g, 55.54 mmol) and Pd(PPh3)4 (3.21 g, 2.78 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched by the addition of -water and extracted with ethyl acetate. The combined organic layers were w'ashed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by nonrial phase flash chromatography using a 120 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether within 40 min to afford 2-[4-(difluorometboxy)-2-fluoropheny1]-3- (rnethoxymethoxy)pyridine (7.3 g, 86%) as a yellow oil. MS ESI calc’d for C14H12F3NO3 [M+H]⁺, 300.08; found, 300.10.

Step 4: Synthesis of 2-[4-(dinuoromethoxy)-2-fluorophenyl]pyridin-3-ol

[0848] A solution of 2-[4-(difluoromethoxy)-2-fluorophenyl]-3-(rneihoxymethoxy)pyridine (7.30 g, 24.39 mmol) and TFA (35 mL) in DCM ('70 mL) was stirred al room temperature for 16 h. The resulting mixture wxis concentrated under reduced pressure to afford 2- [4- (difluoromethoxy )-2-fluorophenyl]pyridin-3-ol (11 g, crude) as a brown oil. MS ESI calc’d 256.05; found, 256.05.

Step 5 : 7-(difluoromethoxy)benzofuro[3,2-b]pyridine

[0849] To a stirred solution of 2-[4-(difluoromethoxy)-2-fluorophenyl]pyridin-3-ol (11 g, 43.1 mmol) in DMF (150 mL) was added K2CO3 (29.8 g, 215.52 mmol) at room temperature.

The resulting mixture was stirred at 120 °C for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 7-(difluoromelhoxy)benzofuro[3,2-b]pyridine (5.3 g, crude) as a yellow solid. MS ESI calc’d for (C12H7F2NO2) [M+H]\ 236.04; found, 235.95.

Step 6: 1:1 mixture of (4aS,9bS)-7-(difluoromethoxy)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine and (4aR,9bR)-7-(difluoromethoxy )- 1 ,2,3.4,4a,9l>hexahydrobenzofuro[3,2- bjpyridine

[0§50] To a stirred solution of 7-(difluoromethoxy)benzofuro[3,2-bjpyridme (5 g, 21.3 mmol) and tris(2,3,4,5,6-pentafluorophenyl)borane (1.09 g, 2.13 mmol) in Toluene (50 ml..) were added 4,4,5,5-tetramethyl-1.3,2-dioxaborolane (13.60 g, 106.30 mmol) and N- phenylaniline (14.4 g, 85.0 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 16 h. The mixture was acidified to pH - 10 with saturated NaHCOa (aq.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCb After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash chromatography using a 120 g silica gel column eluted with 0-15% methanol in dichloromethane within 30 min to afford a 1 :1 mixture of (4aS,9bS)-7-(difluoromethoxy)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b|pyridine and (4aR, 9bR)-7 -(difluoromethoxy)- 1,2, 3, 4,4a, 9b- hexahydrobenzofuro[3,2-b]pyridine (4.5 g, 70%) as a yellow' oil. MS ESI calculated for C12HI3F2NO2 [M+H]⁺, 242.09; found, 242.15. (400 MHz, DMSO-b) 87.41 - 6.95 (m, 2H), 6.66 (d, J = 6.8 Hz, 2H), 4.50 - 4.45 (m, 1H), 4.19 (d, J = 5.8 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.65 - 2.54 (m, 1H), 2.00 - 1.89 (m, 2H), 1.53 - 1.33 (m, 2H).

Intermediate All isomer 1: rel-(4aR,9bR)-7-(difluoromethoxy)-1 , 2,3,4, 4a ,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 isomer 1 _and

Intermediate All isomer 2: rel-(4aR,9bR)-7-(difluoromethoxy)-l,2,3,4,4a,9b- hexahydrobeiizofuro[3,2-b]pyridine isomer 2

Isomer 2

[0851] Intermediate Al l (9.3 g) was separated by prep-ANAL- SFC with the following conditions: [Column: CHIRALPAK. IH 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.1 % 7M NH?-MeOH); Flow rate: 100 mL/min; Gradient: isocratic 10% B;

RTl(min): 4.8; RT2(min): 7; Sample Solvent: MEOH] to afford rel-(4aR,9bR)-7- (difluoromethoxy)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-bjpyridine isomer 1 (All isomer

1) (2.0 g, 21% yield) as a brown oil with retention time at 4.8 minute and rel-(4aR,9bR)-7- (difluoromethoxy)-l,2,3,4,4a,9b-hexahydrobenzofuro|3,2-b]pyridine isomer 2 (Al 1 isomer

2) (2.55 g, 27% yield) as a brown oil with the second peak on ANAL-SFC with retention time at 7 minute.

[9852] re1-(4aR,9bR)-7-(difluoromethoxy)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine isomer 1 (Al 1 isomer 1): MS ESI calculated for C12H13F2NO2 [M+H]\ 242.09; found, 242.15. ^]H NMR (400 MHz, DMSO-tfc) 8 7.41 - 6.95 (m, 2H), 6.66 (d, 7 = 6.8 Hz, 2H), 4.50 - 4.45 (m, 1H), 4.19 (d, 7= 5.8 Hz, 1H), 2.68 - 2.59 (m, HI), 2.65 - 2.54 (m, 1H), 2.00 - 1.89 (m, 2H), 1.53 - 1.33 (m, 2H). Absolute stereochemistry was not determined.

[0853] rel-(4aR,9bR)-7-(difluoromethoxy)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine isomer 2 (Al 1 isomer 2); MS ESI calculated for C12H13F2NO2 [M+H]*, 242.09; found, 242.15. (400 MHz, DMSO-tfc) 6 7.41 - 6.95 (m, 2H), 6.66 (d, 7 - 6.8 Hz, 2H), 4.50 - 4.45 (m, 1H), 4.19 (d, 7 = 5.8 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.65 - 2.54 (m, 1H), 2.00 - 1.89 (m, 2H), 1.53 - 1.33 (ni, 2H). Absolute stereochemistry was not determined.

Intermediate A12: 1: 1 mixture of (4aR,9bR)-7-(difluoromethoxy)-2,3,4,4a,5,9b-hexahydro- lH-indeno[l,2-b]pyridine and (4aS,9b,S)-7-(difluoromethoxy)-2,3,4,4a,5,9b-hexahydro-lH- indeno [ 1 ,2 -b] pyridine

Step 1 : (2-(4-(difluoromethoxy)phenyl)pyridin-3-yl)niethanol

[0854] To a stirred solution of 4-(difluoromethoxy)phenylboronic acid (3.00 g, 15.96 mmol) and (2-chloropyridin-3-yl)methanol (2.75 g, 19.15 mmol) in dioxane (30 mL) were added NaiCOa (5.08 g, 47.88 mmol) and Pd(PPhs)4 (1.84 g. 1.59 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 b under nitrogen atmosphere. The residue was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether within 30 min to afford (2-(4-(difluoromethoxy)phenyl)pyridin-3-yl)methanol (3.5 g, 86%) as a yellow oil. MS ESI calculated for C_!3HI 1F2NO2 [M+H]⁺, 252.08; found, 252.10.

Step 2: 3-(chloromethyl)-2-[4-(difiuoromethoxy)phenyl]pyridine

[0855] A solution of {2-[4-(difluoromethoxy)phenyl]pyridin-3-yl [methanol (3.50 g. 13.93 mmol) and SOCh (2.49 g, 20.89 mmol) in DCM (35 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford 3- (cblorornethyl)-2-[4-(difluoromethoxy)phenyl]pyridir)e (4.0 g, crude) as a yellow solid. MS ESI calculated for C13H10CIF2NO [M+HJ⁺, 270.04, 272.04; found, 270.05, 272.05.

Step 3 : 7-(difluoromethoxy)-5H-indeno[ 1 ,2-b [pyridine

[0856] To a stirred solution of 3-(chloromethyl)-2-[4-(difluoromethoxy)phenyl]pyridine (4.00 g, 14.83 mmol) and Na2CCh (6.29 g, 59.32 mmol) in DME (40 mL) were added Pd(OAc)?. (0.33 g, 1.48 mmol) and P(m-Tolh (0.90 g, 2.96 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 2 h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether within 30 min to afford 7-(difluoromethoxy)-5H-indeno[l,2-b]pyridine (2.7 g, 77%) as a light brown solid. MS ESI calculated for C13H9F2NO [M+H]⁺, 234.07; found, 234.10.

Step 4: 1 : 1 mixture of (4aR,9bR)-7-(difluoromethoxy)-2,3,4,4a,5,9b-hexahydro-lH- indeno[ l,2-b|pyridine and (4aS,9bS)-7-(difluoromethoxy)-2,3,4,4a.5,9b-hexahydro-lH- indeno[l ,2-b]pyridine

[0857] To a stirred solution of 7-(difluoromethoxy)-5H-indeno[l,2-b]pyridine (2.20 g, 9.43 mmol) and tris(2,3,4,5,6-pentafluorophenyl)borane (0.48 g, 0.94 mmol) in Toluene (44 mL) were added N-phenylaniline (6.38 g, 37.73 mmol) and 4,4,5,5-tetramethyl-l,3,2- dioxaborolane (6.03 g, 47.16 mmol) at room temperature. The resulting mixture was stirred at 110°C for 16 h. The resulting mixture was concentrated under vacuum. The resulting residue was dissolved in MeCN which was applied to a 80 g Cl 8 column and purified by Combi Flash, eluted with 5-50% acetonitrile in water (10 mM NH4HCO3) within 30 min to afford a 1:1 mixture of (4aR,9bR)-7-(difluoromethoxy)-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2- bjpyridine and (4aS,9bS)-7-(difluoromethoxy)-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2- bjpyridine (1.3 g, 54%) as a brown oil. MS ESI calculated for CBHUFINO [M+H?, 240.11; found, 240.10. 'H NMR (400 MHz, DMSO-d₆) 57.40 - 7.27 (m, 1H), 7. 18 - 6.92 (m, 3H), 4.15 (d, J = 5.6 Hz, 1 H), 2.86 - 2.73 (m, 1H). 2.68 - 2.55 (m, 2H), 2.49 - 2.40 (m. 1 H), 2.39 - 2.23 (m, 1H), 1.76 - 1.58 (m, 1H), 1.51 - 1.31 (tn, 2H), 1.31 - 1.15 (m, 1H).

Intermediate A 13: 1: 1 mixture of (4aS,9aR)-7-(difluoromethoxy)-2,3,4,4a,9,9a- hexahydroindeno[2,l-b][l,4]oxazine and (4aR,9aS)-7-(difluoromethoxy)-2,3,4,4a,9,9a- hexahydroindeno[2, l-b][ 1 ,4]oxaz.ine

Step 1 : 5-(difluoromethoxy)-2,3-dihydroinden- 1-one

[0858] To a stirred solution of 5 -hydroxy-2,3 -dihydroinden-1 -one (25.00 g, 168.73 mmol) and KOH (56.80 g, 1012.41 mmol) in DCM (250 mLywater (150 mL) was added (bromodifluoromethyl)trimethylsilane (68.54 g, 337.47 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether to afford 5-(difluoromeihoxy)-2,3-dihydroinden- 1-one) as a yellow oil.

MS ESI calculated for C 10H .%•()• 1 M+H] \ 199.05; found, 199.10.

Step 2: 1: 1 mixture of (S)-2-bromo-5-(difluoromethoxy)-2,3-dihydroinden- 1-one and (R)-2- bromo-5-(difluoromethoxy)-2,3-dihydroinden-l -one

[0859] To a mixture of 5-(difluoromethoxy)-2,3-dihydroinden- 1-one (2.00 g, 10.09 mmol) in EtOAc (20 mL) was added CuBrc (4.51 g, 20.18 mmol). The mixture was stirred at 80 °C for 16 b. The reaction mixture was filtered. The filtrate was collected and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with 0-40% ethyl acetate in petroleum ether to afford a 1:1 mixture of (S)-2-bromo-5- (difhjoromethoxy)-2,3-dihydroinden-l-one and (R)-2-bromo-5-(difluoromethoxy)-2,3- dihydroinden-l-one ( 1.80 g, 63%) as a yellow' oil. MS ESI calculated for CioHrBrFrCL [M+H]⁺, 276.96, 278.96; found, 276.90, 278.90.

Step 3: 1 :1 mixture of (1 S,2R)-2-bromo-5-(difluoromethoxy)-2,3-dihydro- lH-inden-l-ol and

(lR,2S)-2-bromo-5-(difluoroniethoxy)-2,3-dihydro-lH-inden-l-ol

[0860] To a stirred solution of a 1:1 mixture of (S)-2-bromo-5-(difluoromethoxy)-2,3- dihydroinden-l-one and (R)-2-bromo-5-(difluoroniethoxy)-2,3-dihydroinden- l -one (1.80 g, 6.49 mmol) in EtOH (20 mL) was added NaBEU (0.12 g, 3.24 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for I h. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a 1 :1 mixture of (l S,2R)-2-bromo-5-(difluoroniethoxy)- 2 ,3 -dihydro- 1 H-inden- 1 -ol and ( 1 R ,2S)-2-bromo-5-(difl uoromethoxy )-2,3 -dihydro- 1 H- inden-l-ol (1.80 g, 86%) as a yellow solid. MS ESI calculated for CioHyBrFjO? [M+H] ⁺, 278.98, 280.98; found, 278.95, 280.95.

Step 4: 1 : 1 mixture of (1 S,2R)-1 -amino-5-(difluoromethoxy)-2,3-dihydro-lH-inden-2-ol and

(1R,2S)- 1 -amino-5-(difluoromethoxy )-2,3-dihydro- lH-inden-2-ol

[0861 ] To a stirred solution of a 1 : 1 mixture of (1 S,2R)-2-bromo-5-(dilluoromethoxy)-2.3- dihydro-^H-inden-l-ol and (lR,2S)-2-bromo-5-(difluoromethoxy)-2,3-dihydro-1 H-inden- 1 - ol (11.12 g, 39.84 mmol) and MeCN (4.91 g, 119.53 mmol) in DCE (120 mL) was added H2SO4 (5.86 g, 59.8 mmol) dropwise at room temperature. Hie resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was separated. The aqueous solution was basified with NaOH (sat.) to pH -12 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a 1 : 1 mixture of (1S,2R)-l-amino-5-(difluoromethoxy)-2,3-dihydro-lH- inden-2-ol and (lR,2S)-l-amino-5-(difluoromethoxy)-2,3-dihydro-lH-inden-2-ol (3.60 g, 29%) as a yellow solid. MS ESI calculated for C10H11F2NO2 [M+HJ*. 216.08; found, 216.10.

Step 5: 1: 1 mixture of (4aS,9aR)-7-(difluoromethoxy)-4,4a,9,9a-tetrahydroindeno[2,l- b][l,4]oxazin-3(2H)-one and (4aR,9aS)-7-(difluoromethoxy)-4,4a,9,9a-tetrahydroindeno[2,1 - b] [ 1 ,4]oxazin-3(2H)-one

[0862] To a stirred suspension of a 1 :1 mixture of (lS,2R)-l-amino-5-(difluoromethoxy)- 2,3-dihydro- lH-inden-2-ol and ( 1R,2S)- 1 -amino- 5 -(difluoromethoxy) -2,3-dihydro- lH-inden- 2- (3.40 g, 15.79 mmol) and CS2CO3 (10.30 g, 31.59 mmol) in MeCN (35 mL) was added 2- chloroacetyl chloride (1 .82 g, 16.1 1 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature tor 1 h. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in THF (35 mL) and cooled to 0 °C, then NaH (0.75 g, 18.75 mmol, 60% in mineral oil) was added in portions with stirring. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a 1:1 mixture of (4aS,9aR)-7-(difluoromethoxy)- 4,4a,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-3(2H)-one and (4aR,9aS)-7-(difluoromethoxy)- 4,4a,9,9a-tetrahydroindeno[2,l-bj[l,4Joxazin-3(2H)-one (4.10 g, 86%) as a yellow solid. MS ESI calculated for CnHnFzNCh [M+H]⁺, 256.07; found, 256.15.

Step 6: 1: 1 mixture of (4aS,9aR)-7-(difluoromethoxy)-2,3,4,4a,9.9a-hexahydroindeno[2, l - b][l,4]oxazine and (4aR,9aS)-7 -(difluoromethoxy )-2, 3, 4, 4a, 9, 9a-hexahydroindeno[2,lb][l,4]oxazine

[0863] To a stirred mixture of NaBHt (1.78 g, 47.13 mmol) in THF (40 mL) was added BFi-EtiO (6.69 g, 47.13 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 1 h. Then a 1:1 mixture of (4aS,9aR)-7-(difluoromethoxy)-4,4a,9,9a- tetrahydroindeno[2, 1 -b] [ 1 ,4]oxazin-3(2H)-one and ((4aR,9aS)-7-(difluoromethoxy)- 4,4a,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-3(2H)-one (4.01 g, 15.71 mmol) was added at 0 °C. The resulting mixture was stirred at 25 °C. The reaction mixture was quenched by acetone at 0 °C. The suspension was filtered. The filtrate was collected and concentrated under vacuum. The residue was purified by reverse phase flash column chromatography with 5-50% acetonitrile in water (0.1% TEA) to afford a 1:1 mixture of (4aS,9aR)-7- (difhtoromethoxy)-2,3,4,4a,9,9a-hexahydroindeno[2, l-b][l ,4]oxazine and (4aR,9aS)-7- (difluoromethoxy)-2,3,4,4a,9,9a-hexahydroindeno[2,1 -b][l ,4]oxazine (760 mg, 16%) as a yellow oil. MS ESI calculated for C^HuFiNCh [M+H]⁺, 242.09; found, 242.15. Intermediate A14, isomerl: reI-(2R,4aS,10bS)-2-methyJ-8-(trifluoroniethyl)-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine, isomer 1:

A14, isomerl . j Intermediate A14, isomerl: rel-(2S,4aR,10bR)-2-methyl-8-(trifluoromethyl)-

2, 3, 4.4a, 6, lOb-hexahydro- LH-isochromeno[4,3-b]pyridine, isomer 2:

A14. isomer2

Step ! : methyl 2-bromo-5-(tafluoromethyl)benzoate [0864] To a stirred solution of 2-bromo-5-(trifluoromethyl)benzoic acid (100.00 g, 371.72 mmol) and K2CO3 (102.75 g, 743.44 mmol) in DMF (1000 mL) was added Mel (58.04 g, 408.89 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 4 h under nitrogen atmosphere. The reaction was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na -SO:. After filtration, the filtrate was concentrated to afford methyl 2-bromo-5-(trifluoromethyl)benzoate (98.40 g, 92%) as a light yellow solid. MS ESI calculated for CgHsBrFsOr [M+H]⁺, 282.95, 284.04; found, 283.05, 285.00.

Step 2: methyl 2-(4,4,5,5-tetramethy1-l,3.2-dioxaborolan-2-yl)-5-(trifluoromethy1)benzoate

[0865] To a stirred solution of methyl 2-bromo-5-(trifluoromethyl)benzoate (98.40 g, 347.64 mmol) and BPD (97.11 g, 382.41 mmol) in dioxane (980 mL) were added Pd(dppf)Ch (25.44 g, 34.76 mmol) and KOAc (102.36 g, 1042.94 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 85 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-20% ethyl acetate in petroleum ether to afford methyl 2-(4,4,5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate (91.00 g. 79%) as a light yellow solid. MS ESI calculated for CisHisBFsCE [M+H]⁺, 331.13; found, 331.15.

Step 3 : methyl 2-(3-fluoro-6-methylpyridin-2-y1)-5-(trifluoroTnethy1)benzoate

[0866] To a stirred mixture of methyl 2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yi)-5- (trifluoromethyl)benzoate (91.00 g, 275.66 mmol) in 1,4-dioxane (910 mL) and water (91 mL) were added 2-bromo-3-fluoro-6-methylpyridine (52.38 g, 275.66 mmol), K2CO3 (113.82 g, 826.98 mmol) and Pd(dppf)Ch (20.17 g, 27.56 mmol). The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with water.

The resulting mixture was extracted with EtOAc. Ute combined organic layers were washed with water, dried over anhydrous NaeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-20% ethyl acetate in petroleum ether to afford methyl 2-(3-fluorO"6-methylpyridin"2-yl)-5- (trifluoromethyl (benzoate (62.40 g, 52%) as a light yellow oil. MS ESI calculated for C 15H 0F4NO2 [M+HK, 314.07; found, 314.00.

Step 4: [2-(3-fluoro-6-methylpyridin-2-yl)-5-(trifluoromethyl)phenyl]methanol

[0867] To a stirred mixture of Lithium aluminum hydriden (15.12 g, 398.40 mmol) in THF (500 mL) was added a solution of methyl 2-(3-fluoro-6-methylpyridin-2-yl)-5- (trifluoromethyl)benzoate (62.40 g, 199.20 mmol) in THE (150 mL.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of water (15 mL) and NaOH (aq., 10%) ( 15 mL) at 0 °C. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous NazSO?,. After filtration, the filtrate was concentrated under reduced pressure to afford [2-(3-fluoro-6-methylpyridin-2-yl)-5-(trifiuoromethyl)phenyl]niethanol (54 g, 47%) as a light yellow solid. MS ESI calculated for C14H11F4NO [M+H]⁺, 286.08; found, 286.15.

Step 5: 2-methyl-8-(trifluoromethy])-6H-isochronieno[4,3-b]pyridine

[0868] To a stirred solution of [2-(3-fluoro-6-methylpyridin-2-yl)-5- (trifluoromethyl)phenyl]methanol (54.00 g, 189,31 mmol) in DMF (540 mL) was added t- BuOK (42.49 g, 378.62 mmol) in portions at 0 °C. The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOn After filtration, the filtrate was concentrated under reduced pressure to afford 2- methyl-8-(trifluorornethyl)-6H-isochromeno[4,3-b]pyridine (45.7 g, crude) as a brown solid, which was used directly in next reactions. MS ESI calculated for C14H10F3NO [M+H]⁺,

266.07; found, 266.10.

Step 6: 1: 1 mixture of (2R,4aS,10bS)-2-methyl-8-(trifluoromethyI)-2,3,4,4a,6,10b- bexahydro- lH-isochromeno[4,3-b]pyridine and (2S,4aR,10bR)-2-methy]-8-(trifluoromethyl)-

2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4_>3-b]pyridine (A14)

[0869] To a stirred solution of 2-methyl-8-(trifluoroniethyl)-6H-isochromeno[4,3- b]pyridine (45.00 g, 169.81 mmol) in AcOH (450 mL) was added PtCh (9.00 g, 39.34 mmol) at room temperature. The mixture was hydrogenated at room temperature for 16 b under hydrogen atmosphere. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was dissolved in water and neutralized to pH 7 - 8 with NaHCO? (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaaSCU The residue was purified by silica gel column chromatography, eluted with 0 - 20% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (2R,4aS,10bS)-2-methyl-8-(trifluorometliyl)- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine and (2S,4aR,10bR)-2-methyl-8- (trifluoromediyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3"blpyridine (12,7 g, 27%) as a light brown solid. The methyl group has the syn position with the tricyclic by NOE. MS ESI calculated for CI₄H_{; 6}F₃NO [M+H]⁺, 272. 12; found, 272.10. NMR (400 MHz, CD₃OD) 5 7.62 - 7.49 (m, 2H), 7.42 (s, 1H), 5.01 (d, 15.6 Hz, 1H), 4.84 (d, J= 15.6 Hz,

1H). 3.72 - 3.71 (m, IH), 3.70 - 3.67 (m, HI). 2.93 - 2.85 (m, IH), 2.18 - 2.07 (m, IH), 1.93 - 1.84 (m, IH), 1.59 - 1.49 (m, IH). 1.49 - 1.43 (m, 1H),1 . 13 (d, .7- 6.4 Hz, 3H).

Step 7: rel-(2R,4aS,10bS)-2-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- isocliromeno[4,3-b]pyridine, isomer 1 (A14, isomer 1):

A14, isomer! . _anj rel-(2R,4aS,10bS)-2-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine, isomer 2 (A14, isomer 2):

A14. ssomar2

[0870] A 1 : 1 mixture of (2R,4aS,10bS)-2-methyl-8-(trifluoromethyl)-2,.3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine and (2S,4aR,10bR)-2-metbyl-8-(trifluoromethyl)- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine (7.4 g) was separated by prep- chiral SFC with the following conditions: [Column: CHIRALPAK IG, 3*25 cm, 5 pm; Mobile Phase A: CO₂, Mobile Phase B: MEOH (0.1% 2M NH3-MEOH); Flow rate: 80 mL/niin: Gradient: isocratic 10% B; RTl(min): 5; RT2(min): 6.5; Sample Solvent: MEOH; Injection Volume: i mL: Number Of Runs: 100] to afford re1-(2R,4aS,10bS)-2-methyl-8- (trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-l H-isochromeno[4,3-b]pyridine, isomer 1 (A 14, isomer 1) (2.85 g, 42%) as a brown oil with the first peak on chiral SFC. MS (ESI) calculated for (C14H16F3NO) [M+H]⁺, 272.12: found, 272.15. ^!H NMR (400 MHz, CD3OD) 6 7.61 -

7.49 (m. 2H), 7.42 (s. 1H), 5.01 (d, .J = 15.6 Hz, 1 H), 4.84 (d, .7 - 15.6 Hz, 1H), 3.76 - 3.65 (m, 2H), 2.92 - 2.84 (m, 1H), 2.15 - 2.09 (m, 1H), 1 .93 - 1.84 (m, 1H), 1.56 - 1.49 (m, 1 H),

1.49 - 1.39 (ni, 1H), 1.13 (d, J ~ 6.4 Hz, 3H). Absolute stereochemistry was not determined.

[0871] The chiral separation also afford rel-(2R,4aS,10bS)-2-methyl-8-(trifluorometiiyl)- 2,3,4,4a,6,10b-hexabydro-lH-isochromeno[4,3-b]pyridine, isomer 2 (A14, isomer 2) (3.3 g, 49%) as a brown oil with the second peak on chiral SFC. MS (ESI) calculated for (C14H16F3NO) [M+H]⁺, 272.12; found, 272.15. ^SH NMR (400 MHz, CD3OD) 5 7.61 - 7.49 (m, 2H), 7.42 (s, 1 H), 5.01 (d, 15.6 Hz, 1H), 4.84 (d, J - 15.6 Hz, 1H), 3.75 - 3.66 (m,

2H), 2.92 - 2.84 (m, 1H), 2.14 - 2.09 (m, 1H), 1.93 ~ 1.84 (m, 1H), 1.58 - 1.49 (m, 1H), 1.49 - 1.40 (m, 1H), 1.13 (d, J ~ 6.4 Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A15, isomer 1: (3R,4aR,9aS)-7-(difluoromethoxy)-3-methyl-2,3,4,4a,9,9a- hexahydroindeno[2,1 -b] [ 1 ,4]oxazine hydrochloride (A15, isomer 1 ):

At 5, isomer 1 ; and

Intermediate A 15, isomer 2: (3R,4aS,9aR)-7-(difluoromethoxy)-3-methy]-2,3,4,4a,9,9a- hexahydroindeno[2,l -b] [1 ,4]oxazine hydrochloride (A15, isomer 2):

A15, isomer 2

Step- 1 : 5-(difluoromethoxy)-2,3-dihydroinden- 1 -one

[0872] To a stirred solution of 5 -hydroxy-2,3 -dihydroinden-1- one (55.00 g, 371.21 mmol) in DCM (550 ml) was added a solution of KOH (124.96 g, 2227.30 mmol) and H2O (456 mb) at 0 °C under nitrogen atmosphere. Then (bromodifluoromethyl)trimethylsilane (150.79 g, 742.43 mmol) was added to the above mixture dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The reaction mixture was quenched by the addition of Water/Ice at room temperature. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NaeSCb. After filtration, the filtrate was concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 330 g silica gel column eluted with 0 ~ 30% ethyl acetate in petroleum ether to afford 5-(difluoromethoxy)-2,3-dihydroinden-l-one (52.00 g, 77%) as a light yellow solid. MS ESI calculated for C10H8F2O2 [M+H]⁺, 199.05; found, 199.05. Step-2: 1:1 mixture of (S)-2-bromo-5-(difluoromethoxy)-2,3-dihydro-lH-inden-l -one and (R)-2-bromo-5-(difluoromethoxy)-2,3-dihydro- 1 H-inden- 1 -one

[0873] To a stirred solution of 5-(difluoromethoxy)-2,3-dihydroinden-l -one (52.00 g, 262.40 mmol) in EtOAc (520 niL) was added CuBr? (117.22 g, 524.80 mmol). The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) which applied to 330 g silica gel column eluted with 0-17% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (S)-2-bromo-5-(difluoromethoxy)-2,3-dihydro-lH- inden- 1-one and (R)-2-brorno-5-(diiluoromethoxy)-2,3-dihydro-lH-inden- 1-one (62 g, 85%) as a yellow oil. MS ESI calculated for CjoHrBrFjO? [M+H]⁺, 276.96, 278.96; found, 276.95, 278.95.

Step-3: 1: 1 mixture of (lR,2S)-2-bromo-5-(diiluoromethoxy)-2,3-dihydro-lH-inden-l-ol and (lS,2R)-2-bromo-5-(dinuoromethoxy)-2,3-dihydro-lH-inden-l-ol

[0874] To a stirred solution of a 1:1 mixture of (S)-2-bromo-5-(diHuoromethoxy)-2,3- dihydro- lH-inden-1-one and (R)-2-bromo-5-(difluoromethoxy)-2,3-dihydro-lH-inden-l-one (60.00 g, 216.55 mmol) in EtOH (600 mL) was added NaBH.t (4.10 g. 108.27 mmol) at 0 °C. Hie resulting mixture was stirred at room temperature for 1 b. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to affort a 1: 1 mixture of ( lR,2S)-2-bromo-5-(diiluoromethoxy)-2,3-dihydro-lH- inden-l-ol and (lS,2R)-2-bromo-5-(difluoromethoxy)-2,3-dihydro-lH-inden-1 -ol (62.00 g. crude) as a light yellow solid. MS ESI calculated for CioHgBrF^Oi [M+H]⁺, 278.98, 280.98; found, 261.00, 263.00.

Step-4: 1:1 mixture of (lS,2R)-l-amino-5-(difluoromethoxy)-2,3-dihydro-lH-inden-2-ol and

(lR,2S)-l-amino-5-(difluoromethoxy)-2,3-dihydro-lH-inden-2-ol

[0875] To a stirred solution of a 1: 1 mixture of (lS,2R)-2-bromo-5-(difluoromethoxy)-2,3- dihydro- IH-inden- l-ol and (lR,2S)-2-bromo-5-(difluororaethoxy)-2,3-dihydro-lH-inden-l- ol (62.00 g, 222.15 mmol) in acetonitrile (620 mL) was added H2SO4 (43,57 g, 444.31 mmol) dropwise at room temperature. The resulting mixture was stirred at 60 °C for 1 h. To the above mixture was added H2O (620 mL) at 60 °C. The resulting mixture was stirred at 80 °C for 16 h. The layers was separeated and the aqueous solution was basified with NaOH to pH ~ 8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a 1: 1 mixture of (1 S,2R)-l-amino-5-(difluoromethoxy)-2,3-dihydro- 1 H-inden-2-ol and ( 1R,2S)- 1- amino-5-(difluoromethoxy)-2,3-dihydro-lH-inden-2-ol (27 g, 58% over two steps) as a light yellow solid. MS ESI calculated for C10HHF2NO2 [M+H]⁺, 216.08; found, 216.00.

Step-5: 1 : 1 mixture of tert-butyl N-[(lS,2R)-5-(difluoromethoxy)-2-hydroxy-2,3-dihydro-lH- inden-l-yl]carbamate and tert-butyl N-[(1R,2S)-5-(difluoromethoxy)-2-hydroxy-2,3-dihydro-

IH-inden- l-yl]carbamate

[0876] To a stirred solution of a 1:1 mixture of (lS,2R)-l-amino-5-(difluoromethoxy)-2,3- dihydro-lH-inden-2-ol and (lR,2S)-l-amino-5-(difluoromethoxy)-2,3-dihydro-lH-inden-2-ol (60.00 g, 278.81 mmol) in methanol (600 mL) was added EtjN (56.43 g, 557.62 mmol) and di-tert-butyl dicarbonate (73.02 g, 334.57 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford a 1 :1 mixture of tertbutyl N-[(lS,2R)-5-(difluoromethoxy)-2-hydroxy-2,3-dihydro-IH-inden-l-yl]carbamate and tert-butyl N-[(lR,2S)-5-(difluoromethoxy)-2-hydroxy-2,3-dihydro-lH-inden-l-y1]cart>ainate (88.00 g. crude) as brown solid. MS ESI calculated for CisHisFsNOa [M+H]⁺, 316.13; found, 316.20.

Step-6: 1:1 mixture of tert-butyl N-[(lS,2R)-5-(dif]uoromethoxy)-2-[(2S)-2- hydroxypropoxy]-2,3-dihydro-!H-inden-l-yl]carbamate and tert-butyl N-[(lR,2S)-5-

(difluoromethoxy)-2-[(2S)-2-hydroxypropoxy]-2,3-dihydro-lH-inden-l-yl]carbamate

[0877] To a stirred solution of a 1: 1 mixture of tert-butyl N-| (lS,2R)-5-(difluoromethoxy)- 2-hydroxy-2,3-dihydro-lH-inden-l-yl]cafbamate and tert-butyl N-[(lR,2S)-5-

(difluoromethoxy)-2-hydroxy-2,3-dihydro-lH-inden-l -yl]carbamale (40.00 g, 126.85 mmol) and NaOH (35.52 g, 887.99 mmol) in DCM (100 mL) was added (4S)-4-methyl-l ,3,2-/..-6- dioxathiolane-2, 2-dione (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30- 1 ) (22.78 g, 164.91 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved in H2O. The aqueous solution was neutralized with aq. HC1 to pH 7~8. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 2-methoxy-2-methylpropane (1914 mL)/H20 (66 mL). To the above solution was added a solution of TsOH ( 14.11 g, 81.94 mmol) in dioxane (540 mL) at room temperature. 'The resulting mixture was stirred at 40 °C overnight. The reaction was quenched with aq. NaHCOs at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NacSCri- After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash chromatography using a 330 g silica gel column eluted with 0-40% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl N-[(lS,2R)-5- (difluoromethoxy)-2-[(2S)-2-hydroxypropoxy]-2,3-dihydro-lH-inden-l-yl]cafbamate and tert-butyl N-[(lR,2S)-5-(difluoromethoxy)-2-[(2S)-2-hydroxypropoxy]-2,3-dihydro-lH- inden-l-yl]carbamate (36 g, 70% over two steps) as a brown oil. MS ESI calculated for C1SH25F2NO5 [M+H]*, 316.13; found, 316.20.

Step-7: 1:1 mixture of tert-butyl (3R,4aS,9aR)-7-(difluoromethoxy)-3-methyl-2,3,9,9a- tetrahydroindeno[2,l-b][ l,4]oxazine-4(4aH)-carboxylate and tert-butyl (3R,4aR,9aS)-7- (difluoromethoxy)-3-methyl-2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazine-4(4aH)- carboxylate

[0878] To a stirred solution of a 1 : 1 mixture of tert-butyl N-[(lS,2R)-5-(difluoromethoxy)- 2-[(2S)-2-hydroxypropoxy]-2,3-dihydro-lH-inden-l-yl]carbamate and tert-butyl N-[(1 R,2S)- 5-(difluoromethoxy)-2-[(2S)-2-hydroxypropoxy] -2,3-dihydro-lH-inden-l-yl]carbamate (36 g, 96.41 mmol) in toluene (360 mL) was added 2-(tributyl-/.⁵-phosphaneylidene)acetonitrile (46.54 g, 192.82 mmol) (CAS No. 157141-27-0) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 330 g silica gel column eluted with 0—15% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl (3R,4aS,9aR)-7-(.difluoromethoxy)-3-methyl-2,3,9,9a-tetrahydroindeno[2,l-b][l,4joxazine- 4(4aH)-carboxylate and tert-butyl (3R,4aR,9aS)-7-(difluoromethoxy)-3-methyl-2,3,9,9a- tetrahydroindeno[2,l-b][l,4]oxazine-4(4aH)-carboxylate (27.00 g, 78%) as a yellow' oil. MS ESI calculated for C18H23F2NO4 [M+H ]’, 356.16; found, 356.00.

Step-8: (3R,4aR,9aS)-7-(difluoromethoxy)-3-methyl-2,3,4,4a.9,9a-hexahydroindeno[2,l- b][l ,4]oxazine hydrochloride (A 15, isomer I):

Al 5, isomer

(3R,4aS,9aR)-7-(difluorome±oxy)-3-methy1-2,3,4,4a,9_!9a-hexahydroindeno[2,l- b][l,4]oxazine hydrochloride (A 15, isomer 2):

A15, isomer 2

[0879] To a solution of a 1 : 1 mixture of tert-butyl (3R,4aS,9aR)-7-(difluoromethoxy)-3- methyl-2,3,9,9a-tetrahydroindeno[2,l -b][l,4]oxazine-4(4aH)-carboxylate and tert-butyl (3R,4aR,9aS)-7-(difluoromethoxy)-3-methyl-2,3,9,9a-tetrahydroindeno[2,l -b][l,4]oxazine- 4(4aH)-carboxylate (37.00 g, 104.11 mmol) in EtOAc (400 mL) was added hydrogen chloride (4.0 M in ethyl acetate) (370 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated tinder vacuum. The residue was purified by trituration with EtOAc to afford (3R,4aS,9aR)-7-(difluoromethoxy)-3-methyl- 2,3,4,4a,9,9a-hexahydroindeno[2,l-b][l,4]oxazine hydrochloride (A15, isomer 2) (10.8 g, 35%) as a white solid. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for (C13H16FONO2CI) [M+H]⁺, 256.11; found, 256.20. ^!H NMR (400 MHz, DMSO-rfc) 5 10.91 (br, 1H), 8.86 (br, 1H), 7.68 (d, J - 8.4 Hz, 1H), 7.46 - 7.09 (m, 3H), 4.65 - 4.58 (m, 2H), 3.86 - 3.82 (m, 1H), 3.59 - 3.54 (m, 1 H), 3.37 - 3.35 (m, 1H), 3.29 - 3.23 (m, III), 3.09 - 3.04 (m, 1H), 1.20 (d, 6.4 Hz, 3H).

The ethyl acetate filtrate from above was concentrated under vacuum. The residue was triturated with MTBE to afford (3R,4aR,9aS)-7-(difluoromethoxy)-3-methyl-2,3,4,4a,9,9a- hexahydroindeno[2,l-b][l,4]oxazine hydrochloride (A15, isomer 1) (14.8 g, 48%) as a white solid. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for (C13H16F2NO2CI) i M O h . 256.11; found, 256.20. Tl NMR (300 MHz, DMSO-tfe) 5 10.56 (br, 2H), 8.02 (d, J - 8.4 Hz, 1 H), 7.51 - 6.98 (m, 3H), 4.85 - 4.84 (m, 1 H), 4.54 - 4.52 (m, 1 H), 3.73 - 3.68 (m, 1H), 3.54 - 3.50 (m, 1H), 3.15 - 3.08 (m, 2H), 2.88 - 2.82 (m, 1H), 1.25 (d, J = 6.3 Hz, 3H).

Intermediate A16: (3R,4aS,9aR)-7-chloro-3-methyl-2,3,4,4a,9,9a-hexaliydroindeno[2,l- b] [ 1 ,4]oxazine (A16)

A16

Step-l : 1 : 1 mixture of (S)-2-brorao-5-chloro-2,3-dihydroinden-l -one and (R)-2-bromo-5- chloro -2,3- dihydroinden- 1 -one

[0880] To a stirred mixture of 5-chloro-2,3-dihydroinden- 1-one (50.00 g, 300. 12 mmol) in EtzO (500 mL) was added Brz (47.90 g, 300.120 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by water and extracted with ethyl acetate. Use combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with 0-30% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (S)-2-bromo-5-chloro- 2,3-dihydroinden-l -one and (R)-2-bromo-5-chloro-2,3-dihydroinden-l-one (68.00 g, 90%) as a yellow solid. MS (ESI) calculated for (CyHeBrClO) [M+H]⁺, 244.93, 246.93; found, 244.95, 246.95.

Step-2: 1: 1 mixture of (lR,2S)-2-bromo-5-chloro-2,3-dihydro-lH-inden-l-ol and (lS,2R)-2- bromo-5-chloro-2,3-dihydro- 1 H-inden- 1 -ol

[0881] To a stirred solution of a 1:1 mixture of (S)-2-bromo-5-chloro-2,3-dibydroinden-l- one and (R)~2-bromo-5-chloro-2,3-dihydroinden-l-one (68.00 g, 276.98 mmol) in methanol (600 mL) was added NaBHU (20.90 g, 553.972 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 3 h. The reaction was quenched with water/ice at 0 °C. lire resulting mixture was extracted with DCM three times. The combined organic layers were washed with water, dried over anhydrous NLoSCL. After filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of (l R.2S)-2-bromo- 5-chloro-2,3-dihydro- 1 H-inden- 1 -ol and ( 1 S ,2R )-2-bromo-5-chloro-2,3-dihydro- IH-inden- 1 - ol (65.00 g, 99%) as an off-white- solid. MS (ESI) calculated for (CgHsBrClO) [M+H]⁺, 246.94, 248.94; found, 244.90, 246.90. 'H NMR (400 MHz, DMSO-cfe) 5 7.38 - 7.26 (m, 3H), 5.93 (d, J = 6.0 Hz, 1H), 4.99 - 4.84 (m, 2H), 3.45 (dd, J = 17.2, 5.2 Hz, 1H), 3.19 (dd, J = 17.2, 2.6 Hz, 1 H).

Step-3: 1:1 mixture of (lS,2R)-l-amino-5-chloro-2,3-dihydro-lH-inden-2-ol and (1R,2S)-1- araino-5-cbloro-2,3-dihydro-lH-inden-2-ol

[1)882] To a stirred solution of a 1 : 1 mixture of (1R,2S)-2-bromo-5-chloro-2,3-dihydro-lH- inden-l-ol and (lS,2R)-2-bromo-5-chloro-2,3-dihydro- IH-inden- l-ol (96.40 g, 389.46 mmol) and MeCN (31.90 g, 778.92 mmol) in DCE (900 mL) was added H2SO4 (cone.) (57.29 g, 584.195 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 3 h. Then H2O (600 mL) was added to the above mixture at room temperature. The resulting mixture was stirred at 60 °C overnight. The resulting mixture was diluted by water (-600 mL) and extracted with DCM. Then the aqueous layer was collected and basified with NaOH (25% aqueous solution) to pH 12. The precipitated solids were collected by filtration and dried over vacuum to afford a 1 : 1 mixture of ( 1S,2R)- 1 -amino-5- chJoro-2,3-dihydro-1 H-inden-2-oJ and (1R,2S)- l-amino-5-cbloro-2,3-dihydro- lH-inden-2-ol (50.40 g, 90%) as an off-white solid. MS ESI calculated for C14H10F3N [M+H]⁺, 183.05; found, 184.00.

Step-4: 1:1 mixture of tert-butyl ((lS,2R)-5-chloro-2-hydroxy-2,3-dihydro-lH-mden-l- yllcarbaniate and tert-butyl ((lR,2S)-5-chloro-2-hydroxy-2,3-dihydro-lH-inden-l- yljcarbamate

To a stirred solution of a 1: 1 mixture of (lS,2R)-l-amino-5-chloro-2,3-dihydro-lH- inden-2-ol and (lR,2S)-i-amino-5-chloro-2,3-dihydro-lH-inden-2-ol (34.00 g, 185.14 mmol) in methanol (340 mL) was added di-tert-butyl dicarbonate (32.30 g, 148.1 1 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl ((lS,2R)-5-chloro-2-hydroxy-2,3-dihydro-lH-inden-l-y1)carbamate and tertbutyl ((lR,2S)-5-chloro-2-hydroxy-2,3-dihydro-lH-inden-l-yl)carbamate (36.00 g, 68%) as an off-white solid. MS (ESI) calculated for (CMHISCINOJ) [M+H]⁺, 284.10; found, 284.25.

Step-5: 1 :1 mixture of (S)-l-(((lS,2R)-l-amino-5-chloro-2,3-dihydro-lH-inden-2- yl)oxy)propan-2-ol and (S)-l-(((lR,2S)-l-amino-5-chloro-2,3-dihydro-lH-inden-2- yl)oxy)propan-2-ol

[0883] To a stirred mixture of a 1:1 mixture of tert-butyl ((!S,2R)-5-chloro-2-hydroxy-2,3- dihydro-lH-inden-l-yl)carbamate and tert-butyl ((1R,2S)-5-chIoro-2-hydroxy-2,3-dihydro- lH-inden-l-yl)carbamate (44.80 g, 157.88 mmol) in DCM (450 mL) were added tetrabutylazanium hydrogen sulfate (10.72 g, 31.57 mmol) and NaOH (44.20 g, 1105.19 mmol) at room temperature. This was followed by the addition of (4S)-4-methyl- l,3,2-X-6- dioxathiolane-2, 2-dione (supplier: Suzhou spark Biotechnology Co., Lid. CAS# 174953-30- 1 ) (28.35 g, 205.25 mmol) in dropwise at room temperature. The resulting mixture was warmed at room temperature for 1 h with stirring. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (450 tnL), and then H2SO4 (cone.) (309.68 g, 3157.70 mmol) was added slowly at 0 °C. The resulting mixture was stirred at 70 °C overnight. The mixture was basified with NaOH (aq.) to pH 8. The resulting mixture was extracted with DCM. Ute combined organic layers were washed with water, dried over anhydrous NaaSCU- After filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of (S)-l-(((lS,2R)-l-amino-5-chloro-2,3-dihydro-lH-inden- 2-yl)oxy)propan-2-ol and (S)-l-(((lR,2S)-l-amino-5-chloro-2,3-dihydro-lH-inden-2- yljoxy )propan-2-ol (35,40 g, 93%) as a brown oil. MS (ESI) calculated for (C12H16CINO2) [ M+l I r , 242.09; found, 242.25.

Step-6: 1 :1 mixture of tert-butyl ((lS,2R)-5-chloro-2-((S)-2-hydroxypropoxy)-2,3-dihydro- IH-inden- 1-yl (carbamate and tert-butyl (( 1R,2S) -5-chloro-2-((S)-2-hydroxypropoxy) -2,3- dihydro- IH-inden- 1 -yDcarbamate

[0884] To a stirred solution of a 1 : 1 mixture of (S)-l -(((lS,2R)-l-amino-5-chloro-2,3- dihydro- lH-inden-2-yl)oxy)propan-2-ol and (S)- 1 -((( 1R,2S)- l -amino-5-chloro-2,3-dihydro- lH-inden-2-yl)oxy)propan-2-ol (60.00 g, 248.22 mmol) and di -tert -butyl dicarbonate (65.00 g, 297.86 mmol) in methanol (600 ml,.) was added EtsN (75.30 g, 744.66 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. Tire mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl ((lS,2R)-5-chloro-2-((S)-2-hydroxypropoxy)-2,3-dihydro-lH-inden-l- yllcarbamate and tert-butyl ((lR,2S)-5-chloro-2-((S)-2-hydroxypropoxy)-2,3-dihydro-lH- inden- 1-yl (carbamate (67.50 g, 79%) as a yellow solid. MS (ESI) calculated for (CJ7H24CINO4) [M+H]⁺, 342.14, 344.14; found, 342.25, 344.25. ^!H NMR (400 MHz, DMSO-tfc) 67.38 - 7.11 (m, 3H), 6.88 - 6.97 (m, 1H), 4.95 - 4.99 (m, 1 H), 4.66 and 4.56 (d, J = 4.2 Hz, 1H), 4.26 - 4.10 (m, 1H), 3.62 - 3.73 (m, 1H), 3.40 - 3.11 (m, 2H), 2.96 - 2.98 (m, 2H), 1.45 (s, 9H), 1.00 (d, J = 6.3, Hz, 3H).

Step-7: tert-butyl (3R,4aS,9aR)-/-chloro-3-methyl-2,3,9,9a-tetahydroiadeno[2,l- b][l,4]oxaz!iie-4(4aH)-carboxylate tert-butyl (3R,4aR,9aS)-7-chloro-3-methyl-2, 3,9, 9a-tetrahydroindeno[2,l-bHT, 4 [oxazine- 4(4aH)-carboxylate

[0885] To a stirred solution of a 1:1 mixture of tert-butyl ((lS,2R)-5-chloro-2-((S)-2- hydroxypropoxy)-2,3-dihydro-lH-inden-l-yl)carbamate and tert-butyl ((lR,2S)-5-chloro-2- ((S)-2-hydroxypropoxy)-2,3-dihydro-lH-inden-l-yl)carbamate (47.40 g, 138.66 mmol) in anhydrous toluene (500 mL) was added 2-(tributy1-X⁵-phosphaneylidene)acetonitri1e (66.94 g, 277.33 mmol) (CAS No. 157141-27-0) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 1 10 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford a mixture of tert-butyl (3R,4aS,9aR)-7-chloro-3-methy1-2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazine- 4(4aH)- carboxylate and tert -butyl (3R,4aR,9aS)-7-chloro-3-methyl-2,3,9,9a- tetrahydroindeno[2,l-b][l,4]oxazine-4(4aH)-cai'boxylate (40.20 g) as a yellow oil.

[(1886] About 60 g of the mixture was separated by Prep-Chiral SFC with following condition [Column: CHIRALPAK IG, 7*25cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: IPA (0.1% 7M NHs-MeOH); Flow rate: 200 mL/min; Gradient: isocratic 20% B; Wave Length: 220 nm; RTl(min): 7.97; RT2(min): 10.25; Injection Volume: 2 mL; Number Of Runs: 165] to afford tert-butyl (3R,4aS,9aR)-7-chloro-3-methyl-2,3,9,9a- tetrahydroiiideno[2,l-b][l,4]oxazine-4(4aH)-carboxylate (20.60 g) as yellow oil with the first peak on chiral SFC. Absolute stereochemistry was confirmed by NOE. MS (ESI) calculated for (C17H22CINO3) [ M+H ]’, 324.13; found, 324.05. ^]H NMR (400 MHz, DMSO-E.i 8 7.30 (s, 1H), 7.30 - 7.23 (m, 1H), 7.18 - 6.96 (m. 1H), 5.08 - 5.04 (m, 1H), 4.24 (t, 7 = 4.4 Hz, 1H), 3.94 - 3.90 (m, 1H), 3.59 - 3.52 (m, 2H), 3. 13 (dd, J = 16.8, 4.6 Hz, 1 H), 2.85 (d. J = 16.8 Hz, 1 H), 1.64 - 1.36 (m, 9H), 0.0.81 - 0.76 (m, 3H).

[0887] The chiral resolution also afford tert-butyl (3R,4aR,9aS)-7-chloro-3-meihy1- 2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazine-4(4aH)-carboxylate (21.60 g) as yellow oil with the second peak on chiral SFC. Absolute stereochemistry was confirmed by NOE. MS (ESI) calculated for (CnH^ClNOs) [M+H]\ 324.13; found, 324.05. ^;H NMR (400 MHz, DMSO- de) 8 7.36 (d, 7 = 2.0 Hz, 1H), 7.29 (dd, 7 = 8.0, 2.0 Hz, 1 H), 7.06 (dd, J = 8.0, 1.2 Hz, 1H), 5.18 (d, 7= 4.6 Hz, 1H), 4.62 (t, J = 4.4 Hz, 1H), 3.58 - 3.44 (m, 1H), 3.39 (dd, 7 = 11.8, 3.0 Hz, 1H), 3.29 (dd, 7 = 11.8, 5.0 Hz, 1H). 3.09 (dd, 7 = 16.6, 4.2 Hz, 1 H), 2.84 (d. 7 = 16.6 Hz, 1H), 1.49 (s, 9H), 1.28 (d, 7 = 6.4 Hz, 3H).

Step-8: (3R,4aS,9aR)-7-chloro-3-methyl-2,3,4,4a,9,9a-hexahydroindeno[2,l-b][l,4]oxazine (A 16)

A16

[0888] To a stirred solution of tert-butyl (3R,4aS,9aR)-7-chloro-3-methyl-

2H,3H,4aH,9H,9aH-indeno[2,l-b][l,4]oxazine-4-carboxylate (10.00 g, 30.88 mmol) in DCM (100 mL) was added Zinc bromide (13.91 g, 61.76 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filter cake was washed with DCM. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford (3R,4aS,9aR)-7- chloro-3-methyl-2,3,4,4a,9,9a-hexahydroindeno[2,l-b][l,4joxazine (A 16) (5.00 g, 72%) as a yellow solid. MS (ESI) calculated for (C12H14CINO) [M+H]*, 224.08; found. 224.10. ^!H NMR (300 MHz, DMSO-tA) 5 7.43 - 7.33 (m, 2H), 7.27 (dd, 7 = 8.0, 2.0 Hz, 1 H), 4.33 - 4.26 (m, 1H), 4.13 (d, 7= 5.2 Hz, 1H), 3.60 (dd, 7 = 11.2, 3.2 Hz, 1H), 3.33 (dd, J = 11.2, 8.0 Hz, 1 H), 3.20 (dd, ./ = 15.8, 7.0 Hz, 1H), 3.01 - 2.78 (m, 2H), 0.91 (d, ./ = 6.4 Hz, 3H). Intermediate A17, isomer 1: (2R,4aS,10bR)-8-chloro-2-methyl- lH,2H,3H,4aH,5H,6H,10bH-[l,4]oxazino[3,2-f]quinoline, isomer 1:

A17, isomer intermediate A17, isomer 2: (2R,4aR,10bS)-8-chloro-2-methyl- lH,2H,3H,4aH,5H,6H,10bH-[l,4]oxazino[3,2-f]quinoiine, isomer 2:

At 7, isomer 2

Step 1: 1: 1 mixture of (S)-2-chloro-5,6,7,8-tetrahydroquinolin-5-ol and (R)-2-chloro-5, 6,7,8- tetrahydroqu inolin- 5 -ol

[0889] To a stirred solution of 2-chloro-7,8-dihydro-6H-quinolin-5-one (12.00 g, 66.07 mmol) in MeOH (120 mL) was added NaBHa (5.00 g, 132. 14 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4. After filtration, the filtrate v/as concentrated under reduced pressure to afford a 1: 1 mixture of (S)-2-chioro-5,6,7,8-tetrahydroquinolin-5-ol and (R)-2-chloro-5, 6,7,8- tetrahydroquinolin-5-ol (12.00 g, 89%) as a yellow oil. MS ESI calculated for C9H10CINO [M+H]⁺, 184.05; found, 184.00.

Step 2: 2-chloro-7,8-dihydroquinoline

[0890] A solution of 2-chloro-5,6,7,8-tetrahydroquinolin-5-ol ( i 1 .00 g, 59.90 mmol) and

PPA (50 mL) was stirred at 120 °C for 2 h. The reaction mixture was cooled at room temperature and quenched by water. The mixture was basified to pH 8 with NaOH. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-chloro-7,8-dihydroquinoline (8.6 g, 86%) as a y ellow oil. MS

ESI calculated for CyHsCIN [M+H]⁺, 166.03; found, 166.05.

Step 3: 1: 1 mixture of (5S,6S)-5-amino-2-chloro-5,6,7.8-tetrahydroquinolin-6-ol and (5R,6R)-5-amino-2-chloro-5,6,7,8-tetrahydroquinolin-6-ol

[0891] To a stirred solution of 2-chloro-7,8-dihydroquinoline (8.60 g, 51 .92 mmol) in THF (10 mL) was added NBS (9.24 g, 51.92 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The residue was dissolved in water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCk. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of MeOH (14 mL) and ammonium hydroxide (28% in water) (140 mL), the mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum to afford a 1 :1 mixture of (5S,6S)-5- amino-2-chloro-5,6,7,8-tetrahydroquinolin-6-ol and (5R,6R)-5-amino-2-chloro-5, 6,7,8- tetrahydroquinolin-6-ol (8.1 g, crude) as a yellow solid. MS ESI calculated for C9H11CIN2O [M+H]⁺, 199.06: found, 199.05.

Step 4: 1 : 1 mixture of N-|(5S,6S)-2-chloro-6-hydroxy-5,6,7,8-tetrahydroquinolin-5- yl]benz amide and N ■ [(5R,6R)-2-chloro-6-hydroxy-5,6,7,8"tetrahydroquinolin-5- vljbenzamide

[0892] To a stirred solution of a 1:1 mixture of (5S,6S)-5-amino-2-chloro-5, 6,7,8- tetrahydroquinolin-6-ol and (5R,6R)-5-amino-2-chloro-5,6,7,8-tetrahydroquinolin-6-ol ( 14. 10 g, 70.47 mmol) and EtsN (21.39 g, 211.42 mmol) in DCM (140 mL) was added benzoyl chloride (6.93 g, 49.33 mmol) at 0°C. The reaction was poured into water/ice. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSO^ After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford a 1: 1 mixture of N-[(5S,6S)-2-chloro-6-hydroxy- 5,6,7,8-tetrahydroquinolin-5-yl]benzamide and N-[(5R,6R)-2-chloro-6-hydroxy-5, 6,7,8- tetrahydroquinolin-5-yl]benzamide (8.90 g, 41%) as a brown solid. MS ESI calculated for CieHisClNbCh lM+Hf , 303.08; found, 303.05.

Step 5: 1: 1 mixture of (3aR,9bS)-7-chloro-2-phenyl-3a,4,5,9b-tetrahydrooxazolo[4,5- fjquinoline and (3aS.9bR)-7-chloro-2-phenyI-3a,4,5,9b-tetrahydrooxazolo[4,5-f]quinoline

[0893] To a stirred solution of a 1: 1 mixture of N-[(5S,6S)-2-chloro-6-hydroxy-5, 6,7,8- tetrahydroquinolin-5-yl]benzamide and N-[(5R,6R)-2-chloro-6-hydroxy-5, 6,7,8- tetrahydroquinolin-5-yl]benzamide (8.90 g, 29.39 mmol) in DCM (180 mL) was added Thienyl chloride (8.74 g, 73.47 mmol) dropwise at room temperature. The reaction was poured into water/ice at room temperature. The mixture was basified to pH 7 with NaHCCh (sat.). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSCU- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (3aR,9bS)-7-chloro-2-phenyl-3a,4,5,9b-tetrahydrooxazolo[4,5-f]quinoline and (3aS,9bR)-

7-chloro-2-phenyl-3a,4,5,9b-tetrahydrooxazolo[4,5-f]quinoline (4.90 g, 58%) as a white solid. MS ESI calculated for CRJ-IBCINSO [M+H]⁺, 285.07; found, 285.05.

Step 6: 1:1 mixture of (5S,6R)-5-amino-2-chloro-5,6,7,8-tetrahydroquinolin-6-ol and (5R,6S)-5-amino-2-chloro-5,6,7,8-tetrahydroquinolm-6-ol

[0894 ] A solution of a 1 : 1 mixture of (3aR,9bS)-7-chloro-2-phenyl-3a,4,5,9b- tetrahydrooxazolo[4,5-f]quinoline and (3aS,9bR)-7-chloro-2-phenyl-3a,4,5,9b- tetrahydrooxazolo[4,5-f]quinoiine (4.80 g, 16.85 mmol) and HC1 (cone., 10 mL) in 1,4- dioxane (40 mL) was stirred at 100 °C for 16 h. The resulting mixture was concentrated under vacuum to afford a 1:1 mixture of (5S,6R)-5-amino-2-ch1oro-5, 6,7,8- tetrahydroquinolin-6-ol and (5R,6S)-5-amino-2-chloro-5,6,7,8-teirahydroquinolin-6-ol (5.8 g, crude) as a yellow oil. MS ESI calculated for C9H11CIN2O [M+H]⁺, 199.06; found, 199.10.

Step 7: 1 : 1 mixture of tert-butyl ((5S,6R)-2-chloro-6-hydroxy-5,6,7,8-tetrahydroquinolin-5- yl)carbamate and tert-butyl ((5R,6S)-2-chloro-6-hydroxy-5,6,7,8-tetrahydroquinolin-5- yl)carbamate

[0895] To a stirred solution of a 1 : 1 mixture of (5S,6R)-5-amino-2-chloro-5, 6,7,8- tetrahydroquinolin-6-ol and (5R,6S)-5-amino-2-chloro-5,6,7,8-tetrahydroquinolin-6-ol (5.80 g, 29. 19 mmol) and EtjN (8.86 g, 87.59 mmol) in MeOH (60 mL) was added di-tert-butyl dicarbonate (12.74 g, 58.39 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl ((5S,6R)-2-chloro-6-hydroxy-5, 6,7,8- tetrahydroquinolin-5-yl)carbamate and tert-butyl ((5R,6S)-2-chloro-6-hydroxy-5, 6.7,8- tetrahydroquinolin-5-yl)carbamate (3.03 g, 34%) as a colorless oil. MS ESI calculated for C U HCIVO; [M+H] ^f, 299.11; found, 299.11.

Step 8: 1: 1 mixture of tert-butyl ((5S,6R)-2-chloro-6-((S)-2-hydroxypropoxy)-5,6,7,8- tetrahydroquinolin-5-yl)carbamate and tert-butyl ( (5R,6S)-2-chloro-6-((S)-2- hydroxypropoxy)-5,6,7,8-tetrahydroquinolin-5-yl)carbamate

[0896] To a stirred solution of a 1:1 mixture of tert-butyl ((5S,6R)-2-chloro-6-hydroxy-

5.6.7.8-tetrahydroquinolin-5-yl)carbamate and tert-butyl ((5R,6S)-2-chloro-6-hydroxy-

5.6.7.8-tetrahydroquinolin-5-yl)carbaraate (2.00 g, 6.69 mmol) in DCM (40 mL) were added tetrabutylazanium hydrogen sulfate (0.45 g, 1.33 mmol) and NaOH (1.87 g, 46.75 mmol), this was followed by the addition of (4S)-4-methyl- 1,3, 2-k-6-dioxathiolane-2, 2-dione (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1) (1.20 g, 8.70 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water. The mixture was neutralized to pH 7 with HC1 (cone.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSO-i. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 2-methoxy-2- methylpropane (90 mL), then ITO (3 mL, 166.52 mmol), TsOH (0.70 g, 4.08 mmol) and dioxane (25 mL, 295.09 mmol) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 40 °C for 2 h. The reaction was quenched with water/ice. Hie mixture was neutralized to pH 7 with NaHCOs (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl ((5S,6R)-2-ch1oro-6-((S)-2- hydroxypropoxy)-5,6,7,8"tetrahydroquinolin-5-yl)carbamate and tert- butyl ((5R,6S)-2- chloro-6-((S)-2-hydroxypropoxy)-5,6,7,8-tetrahydroquinolin-5-yl)carbaniate (1.20 g, 47%) as a white solid. MS ESI calculated for CJ7H25CIN2O4 [M+H]⁴, 357.15; found, 357.10.

Step 9: (2R,4aS,10bR)-8-chloro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[3,2- fjquinoline, isomer 1 (A17, isomer 1):

A17, isomer

(2R,4aR,l()bS)-8-chloro-2-methyl-2,3,4a,5,6,i0b-hexahydro-l H-[l ,4]oxaz.ino[3,2- flquinoline, isomer 2 (A 17, isomer 2)

A17, isomer 2

[0897] To a stirred solution of a 1:1 mixture of tert-butyl ((5S,6R)-2-chloro-6-((S)-2- hydroxypropoxy)-5,6,7,8-tetrahydroquinolin-5-yl)carbamate and tert-butyl ((5R,6S)-2- chloro-6-((S)-2-hydroxypropoxy)-5,6,7,8-tetrahydroquinolin-5-yl)carbamate (2.00 g, 5.60 mmol) and TEA (1.70 g, 16.81 mmol) in DCM (24 mL) was added MszO (1.46 g, 8.40 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h, The reaction was quenched by water. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NaiSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (24 mL), then TFA (8 mL) was added to the mixture at room temperature. The resulting mixture was stirred al room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in MeCN (20 mL), this was followed by the addition of 1 ,2,2,6,6-pentamethylpiperidine (8.70 g, 56.05 mmol) at. room temperature. The resulting mixture was stirred at 60 °C for additional 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0- 50% ethyl acetate in petroleum ether to afford a mixture isomers, which was further purified by Prep-Achiral SFC with the following conditions (Column: DAICEL DCpak P4VP 3*25 cm, 5 pm; Mobile Phase A: CO?, Mobile Phase B: IP A (20 mM NH?,); Flow rate: 60 mL/min; Gradient: isocratic 32% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wave Length: 220 nra; RT1 (min): 3.90; RT2 (min): 6.50; Sample Solvent: MeOH; Injection Volume: 1.5 mL; Number Of Runs: 10.0) to afford (2R,4aS,10bR)-8-chloro-2-methyl- 2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[3,2-f]quinoline (A17, isomerl) (460 mg, 34%) as a white solid. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for CirHisClN.O [M+H]⁺, 239.09; found, 239.15. ^!H NMR (400 MHz, DMSO-rfc) 3 8.13 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.17 - 4.16 (m, 1H), 3.94 3.93 (m, 1H), 3.69 - 3.67 (in, 1H), 3.29 - 3.12 (m, 1H), 2.97 - 2.80 (m, 1H), 2.74 - 2.53 (m, 2H), 2.08 - 2.07 (m, 1H), 1 .99 - 1.83 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H).

[0898] The Achiral SFC purification also afford (2R,4aR,10bS)-8-chloro-2-methyl- 2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[3,2-f]quinoline (A17, isomerl) (500 mg, 37%) as a yellow oil. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for CnHisCINiO [M+H]⁺, 239.09; found, 239.15. ‘H NMR (400 MHz, DMSO-dt,) 37.90 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 4.63 - 4.62 (m, 1H), 4.33 - 4.32 (m, 1H), 3.86 - 3.62 (m, 1H), 3.48 - 3.47 (m, 2H), 2.99 - 2.97 (m, 2H), 2.76 - 2,57 (m, 1H), 1.81 - 1.80 (m, 1H). 1.19 (br, 3H).

Intermediate A18, isomer 1: rel-(4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro- lH-isochromeno[4,3-b]pyridine, isomer 1 (Al 8, isomer 1):

A18, isomer 1 . _anj Intermediate A18, isomer 2: rel-(4aR,10bR)-8-(trifluorometliyl)-2,3,4,4a,6,l0b-hexahydro- lH-isochromeno[4,3-b]pyridine, isomer 2 (A 18, isomer 2):

A18, isomer 2

Step-1: methyl 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate

[0899] To a stirred mixture of methyl 2-bromo-5-(trifluoromethyl)benzoate (50.20 g, 177.35 mmol) and BPD (49.54 g, 195.09 mmol) in dioxane (500 mL) were added AcOK (34.81 g, 354.71 mmol) and PdidppfJCh-CFbCh (14.45 g, 17.73 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 85 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford methyl 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboro1an-2-y1)-5-(trifluoromethyl)benzoate (49.20 g, 84%) as a light yellow solid. MS ESI calculated for CT5H18BF3O4 [M+H]⁺, 331.13; found, 331.05.

S tep-2 : 2-bromo-3 -(methoxymethoxy (pyridine

[0909] To a stirred solution of 2-bromopyridin-3-ol (50.00 g, 287.36 mmol) and K 2CO3 (79.43 g, 574.72 mmol) in MeCN (500 mL) was added bromofmethoxy (methane (39.50 g, 316.09 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) with a 330 g silica gel column eluted with 0-34% ethyl acetate in petroleum ether to afford 2-bromo-3-(meihoxymetboxy (pyridine (38.50 g, 60%) as a white solid. MS ESI calculated for CvHsBrNOz [M+H]⁺, 217.97, 219.97; found, 217.80, 219.80.

Step-3: methyl 2-[3-(methoxymethoxy)pyridin-2-yl]-5-(trifluoromethyl)benzoate

[0901] To a stirred solution of methyl 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)benzoate (20.10 g, 60.88 mmol) and 2-bromo-3-(niethoxymethoxy)pyridine (13.28 g, 60.88 mmol) in dioxane (200 mL) were added K2CO3 (16.83 g, 121.77 mmol) and PdtdppDCl’-CH₂Ch. (4.96 g, 6.089 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0-25% ethyl acetate in petroleum ether to afford methyl 2-[3-(methoxymethoxy)pyridin-2-yl]-5- (trifluoromethyl)benzoate (18.70 g, 89%) as a yellow oil. MS ESI calculated for C16H14F3NO4 [M+H]⁺, 342.09; found, 342.30.

Step-4: 8-(trifluoromethyl)isochromeno[4,3-b]pyridin-6-one

[0902] To a stirred solution of methyl 2-[3-(methoxymethoxy)pyridin-2-yl]-5- (trifluoromethyl)benzoate (18.70 g, 54.79 mmol) in DCM (180 mL) was added TEA (60 ml) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. Hie reaction was concentrated under vacuum. The residue was diluted by water and extracted with CH2CI2. The combined organic layers were washed with NaHCOs (sat.), dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure to afford 8-(trifluoromethyl)isochromeno[4,3-b]pyridin-6-one (8.60 g, 58%) as a yellow solid. MS ESI calculated for CrsHsFsNOz [M+HJ+, 266.04; found, 266.00. Step-5: 8-(trifluoromethyl)-6H-isochromeno[4,3-b]pyridine

[0903] To a stirred solution of 8-(trifluoromethyl)isochromeno[4,3-b]pyridin-6-one (8.60 g, 32.42 mmol) and NH3-BH3 (2.00 g, 64.85 mmol) in EtzO (100 mL) was added TiCL (12.30 g, 64.85 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of water/ice at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO-j. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography with a 120 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford 8-(trifluoromethyl)-6H-isochromeno[4,3-b]pyridine (3.80 g, 46%) as a white solid. MS ESI calculated for CBHSFSNO [M+H]⁺, 252.06; found, 251.95.

Step-6: 1:1 mixture of (4aS,I0bS)-8-(triiluoromethyl)-2,3,4,4a,6.10b-hexaliydro-lH- isochromeno[4,3-b]pyridine and (4aR,10bR)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-

1 H-isocbromeno[4,3-b]pyridine (A18)

[6904] To a stirred solution of 8-(trifluoromethyl)-6H-isochromeno[4,3-b]pyridine (3.80 g, 15. 12 mmol) in AcOH (30 mL) was added PtCh (0.34 g, 1.51 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was basified with NaHCCh (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of (4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine and (4aR, 1 ObR)-8-( trifluoromethyl)-2,3,4,4a,6, 10b-hexahydro-lH-isochromeno[4,3- b [pyridine (3.00 g, 70%) as a light grey solid. MS ESI calculated for C13H14F3NO [M+Hf; 258.10; found, 258.05. ’H NMR (300 MHz, DMSO-&) 8 7.59 - 7.48 (m, 2H), 7.44 (d, 7 = 1.8 Hz, 1H), 4.98 - 4.67 (m, 2H), 3.64 - 3.53 (m, 2H), 2.93 - 2.82 (m, 1H). 2.70 - 2.61 (m, III), 2.03 - 1.91 (m, 1H), 1.83 - 1.67 (m, 1H), 1.65 - 1.52 (m, 1H), 1.40 - 1.28 (m, 1H).

Step-7: iel-(4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-bexabydro-lH-isochromeno[4,3- bjpyridine, isomer 1 (A18, isomer 1):

A18, isomer iel-(4aR,10bR)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- bjpyridine, isomer 2 (Al 8, isomer 2):

Al 8, isomer 2

[0905] A 1:1 mixture of (4aS,10bS)-8-(trifluorometliyl)-2,3,4,4a,6,10b-hexahydro-lH- isocliromeiio[4,3-bjpyridme and (4aR,10bR)-8-(trilluoromethyl)-2,3,4,4a,6,10b-hexahydro-

1 H-tsochromeno[4,3-bjpyridtne (980 mg) was purified by Prep-chiral SFC with the following conditions [Column: Column: CHIRALPAK IG, 3*25 cm, 5 pm; Mobile Phase A: CO?, Mobile Phase B: MEOH (0.1% 2M NHs-MeOH); Flow rate: 80 mL/min; Gradient: isocratic 15% B; RTl(min): 4; RT2(min): 7: Sample Solvent: MeOH; Injection Volume: 1.5 ml; Number Of Runs: 20] to afford rel-(4aSJ0bS)-8-(trifluoromethyl)-2, 3, 4,4a, 6,10b- hexahydro-lH-isochromeno[4,3-bJpyridine, isomer 1 (A18, isomer 1 ) (205 mg, 22%) as a yellow oil. MS ESI calculated for CBH14F3NO [M+H]⁺, 258.10: found, 258.05. ’H NMR (400 MHz, DMSO-4) 5 7.57 - 7.49 (m, 2H), 7.46 (s, 1H), 4.92 (d, 7 = 15.6 Hz, 1H), 4.72 (d, J = 15.6 Hz, IH), 3.61 - 3.60 (m, HI), 3.57 - 3.56 (m, IH), 2.90 - 2.85 (m, IH), 2.72 - 2.59 (m, IH), 1.99 - 1.93 (m, I H), 1.79 - 1.72 (m, 1 H), 1.61 - 1.51 (m, 1H), 1.36 - 1.30 (m, IH). Absolute stereochemistry was not determined.

[0906] The chiral resolution also afford rel-(4aR,10bR)-8-(trif1uoromethyl)-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine, isomer 2 (Al 8, isomer 2) (305 mg, 33%) as a yellow oil. MS ESI calculated for Ci _3i Ii 4F3NO [M+Hf, 258.10; found, 258.05. 'H NMR (400 MHz, DMSO-cfc) 5 7.57 - 7.49 (m, 2H), 7.46 (s, 1H), 4.92 (d, J = 15.6 Hz, IH), 4.72 (d, J = 15.6 Hz, IH), 3.61 - 3.60 (m, IH), 3.57 - 3.56 (m. IH), 2.90 - 2.85 (m, IH), 2.72 - 2.59 (m, IH), 1.99 - 1.93 (m, IH), 1.79 - 1.72 (m, IH), 1.61 - 1.51 (m, IH), 1.36 - 1.30 (m, IH).

/Absolute stereochemistry was not determined.

Intermediate A19: rel-(4aS, 10bS)-8-(difJuoromethoxy)-2,3,4,4a,6, lOb-hexahydro- 1H- pyranof 3,2-b:5,4-b']dipyridine

Step- 1 : methyl 3-bromo-6-(difluoromethoxy)pyridine-2-carboxylale

[0907] To a stirred mixture of methyl 3-bromo-6-hydroxypyridine-2-carboxy1ate ( 10.00 g, 43. 10 mmol) in DMF (100 mL) were added K2CO3 (11.91 g, 86.19 mmol) and sodium 2- chloro-2,2-difluoroacetate (7.88 g, 51.72 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 4 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% EtOAc in PE to afford methyl 3-bromo-6- (difluoromethoxy)pyridine-2-carboxylate (9.58 g, 78%) as a white solid. MS ESI calculated for Cd b.Bd- XCn. [MW, 281.95, 283.95; found, 282.05, 284.00. 'H NMR (400 MHz, DMSO-<%) 8 8.33 (d, J - 8.8 Hz, 1H), 7.64 (t, 7- 71.6 Hz, HI), 7.28 (d, J - 8.8 Hz, 1 H ), 3.92 (s, 3H).

Step-2: methyl (E)-3-(5-((tert-butyldiphenylsily1)oxy)pent-l-en-l-yl)-6-

(difluoromethoxy)picolinate

[0908] To a stirred mixture of methyl 3-bromo-6-(difluoromethoxy)pyridme-2-carboxylate (9.58 g, 33.97 mmol) and tert-butyldiphenyl ] [(4E)-5-(4,4,5,5-tetrajnethyl-l,3,2- dioxaborolan-2-yl)pent-4-en-l-yl]oxyjsiiane (16.83 g, 33.36 mmol) in dioxane ( 100 mL) and H2O ( 10 mL) were added K2CO3 (9.39 g, 67.93 mmol) and Pd(dppf)Ch (2.49 g, 3.39 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSO.j. The residue was purified by silica gel column chromatography, eluted with 0-10% EtOAc in PE to afford methyl (E)-3-(5-((tert-butyldiphenylsilyl)oxy)peni-l-en-l-yl)-6-(difluoromethoxy)picolinate (15.00 g, 84%) as a yellow oil. MS (ESI) calculated for C29H33F2NO4S1 [M+HJ⁺, 526.21 ; found, 526.25.

Step-3: rel-tert-butyl N-[(5S,6S)-6-{3-[(tert-butyldiphenylsilyl)oxy]propyl}-2-

(di fluoromethoxy )-8-oxo-5H,6H-pyrano[3,4-b]pyridin-5-yl]carbamate [0909] To a stirred solution of BocNHi (10.35 g, 88.47 mmol) in n-PrOH (225 mL.) was added a solution of NaOH (3.09 g, 77.04 mmol) in HaO (195 mL), then l,3-dich!oro-5,5- dimethylimidazolidine-2, 4-dione (8.43 g, 42.81 mmol) was added to above mixture at room temperature under nitrogen atmosphere. After stirring for 30 min, a solution of (DHQ)?- PHAL (2.22 g, 2.85 mmol) in n-PrOH (30 mL) and a solution of methyl (E)-3-(5-((tert- butyldiphenylsilyl)oxy)pent-l-en-l-yl)-6-(difluoroniethoxy)picolinate (15.00 g, 28.53 mmol) in n-PrOH (30 mL) were added sequentially. Then a solution of K2OSO4.2H2O (1.05 g, 2.85 mmol) and NaOH (0.4 N, 7 mL) -was added dropwise at 0 °C. After that, the resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4. After filtration, the filtrate was concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography, eluted with 0-16% EtOAc in PE to afford rel-tert-butyl N-[(5S,6S)-6-{ 3-[(tert-butyldiphenylsilyi)oxy]propyl}-2- (difluoroniethoxy)-8-oxo-5H,6H-pyrano[3,4-b]pyridin-5-yl]carbamate (5.90 g, 31%) as a yellow oil. MS ESI calculated for CssH^FzNzOsSi [M+H] ⁺, 627.26; found, 627.35. ^!H NMR (400 MHz, DMSO-tfc) 5 8.03 - 7.94 (m. 1H), 7.76 - 7.72 (m, IHj, 7.65 - 7.58 (m, 5H), 7.48 - 7.37 (m, 7H), 4.95 - 4.92 (m, 1H), 4.76 - 4.72 (m, 1H), 3.73 - 3.71 (m, 2H), 1.84 - 1.70 (m, 4H), 1 .42 (s, 9H), 1 .01 (s, 9H). Absolute stereochemistry was not determined.

Step-4: rel-tert-butyl N-[(5S,6S)-6-{3-[(tert-butyldiphenylsilyl)oxy]propyl}-2- (difk]oromethoxy)-5H,6H,8H-pyrano[3,4-b]pyridin-5-yl]carbamate

[0910] To a stirred mixture of rel-tert-butyl N-[(5S,6S)-6- { 3-[(tert- butyldiphenylsilyl)oxy]propyl }-2-(difluoromethoxy)-8-oxo-5H,6H-pyrano[3,4-b]pyridin-5- yl]carbamate (5.90 g, 9.41 mmol) in THF (60 mL) were added BF3-Et2O (10.69 g, 75.30 mmol) and NaBHt (2.85 g, 75.30 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction was quenched with water, and extracted with EtOAc. The residue was purified by silica gel column chromatography, eluted with 0- 11% EtOAc in PE to afford rel-tert-butyl N-[(5S,6S)- 6-{3-[(tert-butyldiphenylsilyl)oxy]propyl}-2-(difluoromethoxy)-5H,6H,8H-pyrano[3,4- b]pyridin-5-yl]carbamate (1 .59 g, 27%) as a colorless oil. MS ESI calculated for C33H42F2N2OsSi [M+H]⁺, 613.28; found, 613.35. Absolute stereochemistry was not determined.

Step-5: rel- tert-butyl N-[(5S,6S)-2-(difluoromethoxy)-6-(3-hydroxypfopyl)-5H,6H,8H- pyrano[3,4-b]pyridin-5-yl]carbamate

[0911] To a stirred mixture of rel-tert-butyl N-[(5S,6S)-6-{ 3-[(tert- butyldipheny1silyl)oxy]propyl}-2-(difluoromethoxy)-5H,6H,8H-pyrano[3,4-b]pyri din-5- yljcarbamate (1.59 g, 2.59 mmol) in THF (16 ml) was added TBAF (1.02 g, 3.89 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in PE to afford rel-tert-butyl N-[(5S,6S)-2-(difluoromethoxy)-6-(3-hydroxypropyl)-5H,6H,8H- pyrano[3,4-b]pyridin-5-yl]carbamate (700 mg, 72%) as a colorless oil. MS ESI calculated for C17H24F2N2O5 [M+H] ⁺, 375.17; found, 375.15. *H NMR (400 MHz, DMSO-&) 5 7.74 (d, J = 8.4 Hz. 1H), 7.65 (t, J = 72.8 Hz. 1H), 7.08 (d, 7 - 9.4 Hz, 1H), 6.96 (d, 7 = 8.4 Hz, 1H), 4.70 - 4.49 (m, 3H), 4.39 (t, ./ - 5.2 Hz, 1 H), 3.73 - 3.61 (m, 1H), 3.49 - 3.38 (m, 2H), 1.62 - 1.51 (m, 4H), 1 .40 (s, 9H). Absolute stereochemistry was not determined.

Step-6: rel-tert-butyl (4aS,10bS)-8-(difluoromethoxy)-2,3,4,4a,6,10b-bexahydro-lH- pyranof 3 ,2-b: 5 ,4-b'Jdipyridine- 1 -carboxylate

[0912] To a stirred mixture of rel-tert-butyl N-[(5S,6S)-2-(difluoromethoxy)-6-(3- hydroxypropyl)-5H,6H,8H-pyrano[3,4-b]pyridm-5-yl]carbamate (700 mg, 1.87 mmol) in toluene (7 mL) was added CMBP (902 mg, 3.74 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. Hie residue was purified by silica gel column chromatography, eluted with 0-13% EtOAc in PE to afford rel-tert-butyl (4aS, 10bS)-8-(difluoromethoxy)-2, 3, 4,4a, 6,10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate (570 mg, 85%) as a colorless oil. MS ESI calculated for C17H22F2N2O4 [M+HJ* 357. 15; found, 357.20. Absolute stereochemistry was not determined.

Step-7: rel-(4aS,10bS)-8-(difluoromethoxy)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5.4- b’Jdipyridine hydrochloride (A 19)

[0913] To a stirred mixture of rel-tert-butyl (4aS, 10bS)-8-(difluoromethoxy)- 2,3,4,4a,6, 10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (570 mg, 1.77 mmol) in DCM (3 mL) was added HC1 (4 M in 1,4-dioxane, 3 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford rel- (4aS,10bS)-8-(dinuoromelhoxy)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b'Jdipyridine hydrochloride (500 mg, 96% yield, 94% e.e.) as a white solid. MS ESI calculated for C2H14F2N2O2 [M+H]⁺, 257.10; found, 257.00. ^JH NMR (400 MHz, DMSO- d_(>) 8 10.12 (d, J = 11.2 Hz, 1H), 8.78 - 8.75 (m, 1H), 8.17 (d, J = 8.4 Hz. 1H), 7.70 (t, J = 72.8 Hz, TH), 7.11 (d, J = 8.4 Hz, 1H), 4.78 (s, 2H), 4.40 (d, J = 10.4 Hz, 1H), 4.06 - 4.05 (in, 1H), 3.23 - 2.99 (m, 2H), 2.02 - 1.99 (m, 1H), 1.93 - 1.77 (m, 2H), 1.70 - 1.66 (m, 1H). Absolute stereochemistry was not determined.

Intermediate A21: (2R,4aS,10bS)-8-chloro-2-methyl-l,2,3,4a,5,10b- hexahydrochromeno[3,4-b][ l,4]oxazine hydrochloride (A21)

Step-1: 1: 1 mixture of (S)-3-bromo-7-chloro-2,3-dihydro-l-benzopyran-4-one and (R)-3- bromo-7-chloro-2,3-dihydro-l-benzopyran-4-one

[0914] To a solution of 7-chloro-2,3-dihydro- 1 -benzopyran-4-one (50.00 g, 273.82 mmol) in Et20 (500 mL) was added Br? (15.01 mL, 292.99 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The mixture was allowed to cool down to 0 °C, then was quenched by the addition of sat. NacSOs (aq.) at 0 °C. The precipitated solids were collected by filtration. Hie solids were purified by trituration with Et?O. The precipitated solids were collected and dried over vacuum to afford a 1 : 1 mixture of (S)-3-bromo-7-chloro-2,3-dihydro-l-benzopyran-4-one and (R)-3-bromo-7- chloro-2,3-dihydro-l-benzopyran-4-one (63.00 g, 87%) as an off-white solid. MS (ESI) calculated for (CgHsBrClCh) [M+H]⁺, 260.92, 262.92; found, 261.00, 263.00.

Step-2: 1 :1 mixture of (3S,4S)-3-bromo-7-chlorochroman-4-ol and (3R,4R)-3-bromo-7- chlorochrom an-4-ol

[0915] To a solution of 3-bromo-7-chloro-2,3-dihydro-l-benzopyran-4-one (64.00 g, 244.74 mmol) in MeOH (1 L) was added NaBHt (4.63 g, 122.37 mmol) in portions at 0 °C.

The resulting mixture was warmed at room temperature and stirred for 2 h. The reaction was quenched with water at 0 °C. The organic solvent was removed under vacuum. The precipitated solids were collected by filtration and washed with water. The solids were dried over vacuum to afford a. 1 : 1 mixture of (3S,4S)-3-bromo-7-cblorochroman-4-ol and (3R,4R)- 3-bromo-7-chlorochroman-4-ol (63.00 g. 97%) as an off-white solid. MS (ESI) calculated for (C₉H₈BrC102) [M+H]⁺, 262.94, 264.94; found, 263.00, 265.00. *H NMR (400 MHz, DMSO- d₆) 8 7.32 (d, 8.4 Hz, 1H), 6.98 (dd, J - 8.4, 2.0 Hz, 1H), 6.86 (d, J- 2.0 Hz, 1H), 6.05

(d, J - 5.8 Hz, 1H), 4.90 -- 4.79 (m, 1H), 4.71 - 4.68 (m, 1H), 4.58 - 4.54 (m, 1H), 4.34 (dd, J 12.0, 6.0 Hz, 1H).

Step-3: 1:1 mixture of (3S,4S)-4-amino-7-chloro-3,4-dihydro-2H-l-benzopyran-3-ol and

(3R,4R)-4-aniirio-7-chloro-3,4-dihydro-2H-l-benzopyran-3-ol

[0916] To a solution of 3-bromo-7-chloro-3,4-dihydro-2H-l-benzopyran-4-ol (100.00 g, 379.47 mmol) in acetonitrile ( 1 L) was added cone. H2SO4 (74.43 g, 758.95 mmol) dropwise at 0 °C. The resulting mixture was heated at 50 °C for 2 h with stirring. The mixture was cooled at 0 °C, H?O (1 I..) was added slowly to the mixture. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was concentrated under reduced pressure to remove most of MeCN. The resulting mixture was filtered, the filter cake was washed with water.

The filtrate was neutralized to pH 7 with NaOH (4 N). The precipitated solids were collected by filtration to afford a 1: 1 mixture of (3S,4S)-4-amino-7-chloro-3,4-dihydro-2H-l- benzopyran-3-ol and (3R,4R)-4-amino-7-chloro-3,4-diltydro-2H-l-benzopyran-3-ol (81.00 g, 94%) as a white solid. MS (ESI) calculated for (C9H10CINO2) [M+H]⁺, 200.04; found,

200.00.

Step-4: 1:1 mixture of tert-butyl N- [(3S,4S)-7-chloro-3 -hydroxy-3,4-dihydro-2H-l - benzopyran-4-yi]carbamate and tert-butyl N-[(3R.4R)-7-chloro-3-hydroxy-3,4-dihydro-2H-l- benzopyran-4-yl]carbamate

[0917] To solution of a 1: 1 mixture of (3S,4S)-4-amino-7-chloro-3,4-dihydro-2H-l- benzopyran-3-ol and (3R,4Rj-4-amino-7-chloro-3,4-dihydro-2H-l -benzopyran-3-ol (64.00 g, 320.59 mmol) in MeOH (1 L) was added TEA (97.33 g, 961.77 mmol), this was followed by the addition of BOC2O (76.97 g, 352.65 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-5% methanol in dichloromethane to afford a 1:1 mixture of tert-butyl N-[(3S,4S)-7-chloro-3- hydroxy-3 ,4-dihydro-2H- 1 -benzopyran-4-yl Jcarbamate and tert-butyl N- [(3 R,4R)-7 -chloro-3- hydroxy-3,4-dihydro-2H-l-benzopyran-4-yl]carbamate (52.00 g, 54%) as a white solid. MS (ESI) calculated for (CrsHigClNOr) [M+H]⁺, 300.09; found, 300.05.

Step-5: 1:1 mixture of (S)-l-(((3S,4S)-4-amino-7-chlorochroman-3-yl)oxy)propan-2-ol and (S)-l-(((3R.4R)-4-amino-7-chlorochroman-3-yl)oxy)propan-2-ol

[0918] To a solution of a 1 : 1 mixture of tert-butyl N-|(3S,4S)-7-chloro-3-hydroxy-3,4- dihydro-2H- 1 -benz.opyran-4-y1]carbamate and ten-butyl N-[(3R,4R)-7-chloro-3-hydroxy-3,4- dihydro-2H-l-benzopyran-4-yI]carbamate (79.00 g, 263.55 mmol) in DCM (800 mL) were added NaOH (73.79 g, 1844.87 mmol) and tetrabutylazanium hydrogen sulfate (134.23 g, 395.32 mmol), then (4S)-4-methyl-l , 3, 2-A-6-dioxathiolane-2, 2-dione (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1 ) (54.61 g, 395.32 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was redissolved in water (800 mL), and cone. H2SO4 (258.47 g, 2635.53 mmol) was added slowly to the mixture at 0 °C. The resulting mixture was stirred at 60 °C overnight. The reaction mixture was cooled down to room temperature and neutralized with NaOH (aq.) to pH 7. The aqueous layer was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford a 1: 1 mixture of (S)-l-(((3S,4S)-4- amino-7-chlorochroman-3-yl)oxy)propan-2-o1 and (S)-l-(((3R,4R)-4-amino-7- chlorochroman-3-yl)oxy)propan-2-ol (60.00 g, crude) as a yellow solid, which was used directly. MS (ESI) calculated for (C12H16CINO3) [M+H]⁺, 258.08; found, 258.05.

Step-6: 1:1 mixture of tert-butyl ((3S,4S)-7-chloro-3-((S)-2-hydroxypropoxy)chroman-4- yl)carbamate and tert-butyl ((3R,4R)-7-chloro-3-((S)-2-hydroxypropoxy)chroman-4- yl)carbamate

[(1919] To a solution of a 1 : 1 mixture of (S)- 1 -(((3S,4S)-4-amino-7-chlorochroman-3- yl)oxy)propan-2-ol and (S)-1 -(((3R,4R)-4-amino-7-chlorochroman-3-y1)oxy)propan-2-ol (60.00 g, 232.82 mmol) in methanol (600 ml) was added di -tert-butyl dicarbonate (60.98 g, 279.38 mmol), the mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl ((3S,4S)-7-chloro-3-((S')-2-hydroxypropoxy)chroman-4-yl)carbamate and ert- butyl ((3R,4R)-7-chloro-3-((S)-2-hydroxypropoxy)chroman-4-yl)carbamate (28.00 g, 30% over two steps) as a white solid. MS (ESI) calculated for (C17H24CINO5) [M+H]*, 358.13; found, 358.05.

Step-7 : tert-butyl (2R,4aS, 10bS)-8-chloro-2-methyl-2,3,4a, 10b-tetrahydrochromeno[3,4- b][l,4]oxazine-l(5H)-carboxylale, isomer 1 and tert-butyl (2R,4aR,10bR)-8-chloro-2-methyl-2,3,4a,10b-tetrahydrochromeno[3,4- b] [ 1 ,4]oxazine- l(5H)-carboxylate, isomer 2

[0920] To a solution of a 1: 1 mixture of tert-butyi ((3S,4S)-7-chloro-3-((S)-2- hydroxypropoxy)chroman-4-yl)carbamate and tert-butvl ((3R,4R)-7 -chloro-3-((S)-2- hydroxypropoxy)chroman-4-yl)carbamate (28.00 g, 78.24 mmol) in anhydrous toluene (280 mL) was added 2-(tributyl-??-pbosphaneylidene)acetonitrile (28.33 g, 117.37 mmol) (CAS No. 157141-27-0) at 0 °C. The resulting mixture was stirred at 110 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted -with 0-10% ethyl acetate in petroleum ether to afford tert-butyl (2R,4aS,10bS)-8-chloro-2-metbyl-2,3,4a,10b- tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate. isomer 1 (9.00 g, 34%) as a colorless oil as the second eluting peak. Absolute stereochemistry was confirmed by NOE. MS (ESI) calculated for (C17H22CINO4) [M+Hp, 340.12; found, 340.10. H NMR (300 MHz, DMSO-do) 87.09 - 6.92 (m, 2H), 6.85 (s, 1H), 5.24 - 5.14 (m, 1H), 4.35 - 4.25 (m, 2H), 4.07 - 4.00 (m, 1H), 3.82 - 3.80 (m, 1H), 3.72 - 3.61 (m, 2H), 1.51 (s, 9H), 0.78 - 0.62 (m, 3H).

[0921] The purification also afford tert-butyl (2R,4aR,10bR)-8-chloro-2-methyl- 2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate, isomer 2 (11.20 g, 42%) as a colorless oil as the first eluting peak. MS (ESI) calculated for (C17H22CINO4) i M+H L . 340.12; found, 340.10. ‘H NMR (300 MHz, DMSO-d₆) 3 7.00 - 6.99 (m, 2H), 6.87 (s, 1H), 5.25 - 5.24 (m, 1H), 4.33 - 4.22 (m, 3H), 3.54 - 3.50 (m, 2H), 3.40 - 3.34 (m, 1H), 1.49 is, 9H), 1.35 - 1.33 (m, 3H).

Step-8: (2R,4aS,10bS)-8-chloro-2-methyl-l,2.3,4a,5,10b-hexahydrochromeno[3,4- b] [ 1 ,4]oxazine hydrochloride ( A21 )

A21

[0922] To a solution of tert-butyl (2R,4aS, 10bS)-8-cbloro-2-methyl-2,3,4a, 10b- tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate, isomer 1 (9.00 g, 26.49 mmol) in 1,4-dioxane (100 mL) was added HC1 (10 mL, 4M in dioxane), the mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford

(2R,4aS , 10bS)-8-chloro-2-methyl- 1 ,2, 3, 4a, 5 , 10b-hexahydrochromeno[3 ,4-b] [ 1 ,4]ox azine hydrochloride (A21) (6.00 g, 96%) as a white solid. MS (ESI) calculated for (C12H14CINO2) [M+H]⁺, 240.07; found, 240.10. ^SH NMR (300 MHz, DMSO-d₆) 8 10.81 (hr, 1H), 9.67 (br, 1 H), 7.79 (d, .J = 8.4 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 1H), 7.02 (s, 1H), 4.80 - 4.72 (m, 2H), 4.48 - 4.41 (m, 1H), 4.23 - 4.18 (m, 1H), 3.87 - 3.81 (m, 1H), 3.59 - 3.52 (m, 2H), 1.20 (d, J

= 6.0 Hz, 3H).

Intermediate A22: (2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl- 1,2,3, 4a, 5,1 Ob- hexahydrochromeno[3,4 -b] [ 1 ,4]oxazine (A22)

A22

Step- 1 : 7-(difluoromethoxy)-2,3-dihydro- 1 •■benzopyran- 4-one [0923] To a stirred solution of 7-hydroxy-2,3-dihydro-l-benzopyran-4-one (50.10 g, 304.58 mmol) in DCM (100 mL) was added 20% w/w KOH aqueous solution (102.53 g. 1.82 mol) at 0 °C. Then (bromodifluoromethyl)trimethylsilane (123.72 g, 609.16 mmol) was added dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NajSCH- After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether to afford 7-(difluoromethoxy)-2,3-dihydro-l-benzopyran-4-one (40.60 g, 62%) as a yellow oil. MS ESI calculated for C10H8F2O3 [M+H]⁺, 215.04; found, 215.05. ’H NMR (400 MHz, DMSO-rfc) 5 7.81 (d, J - 8.6 Hz, IH), 7.40 (t, J - 73.2 Hz, IH), 7.01 - 6.77 (m, 2H), 4.57 (t, .7 - 6.4 Hz, 2H), 2.79 (t, .7 - 6.4 Hz, 2H).

Step-2: 1 : 1 mixture of (S)-3-bromo-7-(difluoromethoxy)-2,3-dihydro-l-benzopyran-4-one and (R)-3-bromo-7-(difluoromethoxy)-2,3-dihydro-l-benzopyran-4-one

[0924] To a stirred solution of 7-(ditluoromethoxy)-2,3-dihydro-l-benzopyran-4-one (34.10 g, 158.75 mmol) in Diethyl ether (340 mL) was added Biy (8.1 mL, 158.08 mmol) dropwise ar. 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by NaS2Ch (sat.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether within 20 min to afford a 1:1 mixture of (S)-3-bromo-7- (difluoromethoxy)-2,3-dihydro-l-benzopyran-4-one and (R)-3-bromo-7-(difluoromethoxy)- 2.3-dihydro-l-benzopyran-4-one (41.35 g, 75%) as a yellow solid. MS ESI calculated for CioH7BrF₂Ch [M+H]⁺, 292.95: found, 292.80. 'H NMR (400 MHz, DMSO-J₆) 67.90 (d, J - 8.6 Hz, 1H), 7.46 (t, J - 73.0 Hz, IH), 6.95 (d, .7 - 8.6 Hz. 2H), 5.02 (t, .7 - 3.2 Hz, IH), 4.90 (dd, 7 = 13.4, 2.8 Hz, IH), 4.67 (dd, .7 = 13.4, 3.8 Hz, IH). Step-3: 1:1 mixture of (3S,4S)-3-bromo-7-(difluorometlioxy)chroman-4-ol and (3R,4R)-3- bromo-7-(di fluoromethoxy )chroman-4-ol

[0925] To a stirred solution of a 1:1 mixture of (S)-3-bromo-7-(difluoromethoxy)-2,3- dihydro-l-beiizopyran-4-oiie and (R)-3-bromo-7-(difluoromethoxy)-2,3-dihydro- 1- benzopyran -4-one (41.30 g, 141.43 mmol) in EtOH (400 mL) was added NaBHa (2.82 g, 70.72 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by water at 0 °C. The EtOH was removed under vacuum. The remaining aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford a 1:1 mixture of (3S,4S)-3-bromo-7-(difhjoromelhoxy)chroman-4-ol and (3R,4R)-3-bromo-7-(difluoromethoxy)chroman-4-ol (42.50 g, crude) as a white solid, which was used without further purification. MS ESI calculated for CiuHyBrFzOa [M+H]⁺, 294.97, 296.97; found, 294.97, 296.97.

Step-4: 1 :1 mixture of (3S,4S)-4-amino-7-(difluoromethoxy)chroman-3-ol and (3R,4R)-4- amino- 7 - (difluoromethoxy)chroman- 3 -ol

[0926] To a mixture of a 1: 1 mixture of (3S,4S)-3-bromo-7-(difluoromethoxy)chroman-4- ol and (3R,4R)-3-bromo-7-(ditluororaethoxy)chroman-4-ol (42.50 g, 183.98 mmol) in ACN (430 mL) was added HzSO^conc.) (36.06 g, 367.96 mmol) at 0 °C. The resulting mixture was stirred at 50 °C for 2 h. Then the mixture was cooled down to room temperature, then H2O (400 mL) was added to the mixture. The resulting mixture was stirred at 75 °C for 12 h. The organic solvent was removed under reduced pressure. The resulting aqueous layers was basified with NaOH (aq., 25%) to pH 12. The precipitated solids were collected by filtration and fried under vacuum to afford the product. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford another batch of product. The workup was totally afford a 1 : 1 mixture of (3S,4S)-4-amino-7-(difluoromethoxy)chroman-3-ol and (3R,4R)-4-amino-7-(difluoromethoxy)chroman-3-o1 (28.50 g, 65%) as a white solid. MS ESI calculated for CioHnFzNCh [M+H]⁺, 232.07; found, 232.00.

Step-5: 1:1 mixture of tert-butyl N-[(3S,4S)-7-(difluoromethoxy)-3-hydroxy-3,4-dihydro-2H-

1 -benzopyran-4-yl]carbamate and tert-butyl N-[(3R,4R)-7-(difluoromethoxy)-3-hydroxy-3,4- dihydro-2H-l-benzopyran-4-yl]carbamate

[0927] To a stirred solution of a 1: 1 mixture of (3S,4S)-4-amino-7- (difluoromethoxy)chroman-3-ol and (3R,4R)-4-amino-7-(difluororaethoxy)chroman-3-ol (28.50 g, 122.84 mmol) in MeOH (300 mL) were sequentially added TEA (18.61 g, 184.2.7 mmol) and Boc?O (29.45 g, 135.12 mmol) at room temperature. The resulting solution was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl N-[(3S,4S)-7- (difluoromethoxy)-3-hydroxy-3,4-dihydro-2H-l -benzopyran-4-yl [carbamate and tert-butyl N-[(3R,4R)-7-(difluoromethoxy)-3-hydroxy-3,4-dihydro-2H-l-benzopyran-4-yl]carbamate (19.78 g, 50%) as a white solid. MS ESI calculated for CisHigF^NOs [M+H] *, 332.12; found, 332.00.

Step-6: 1: 1 mixture of tert-butyl ((3S,4S)-7-(difluorometlioxy)-3-((S)-2- hydroxypropoxy)chroman-4-yl)carbamate and tert-butyl ((3R,4R)-7-(difiuoromethoxy)-3-

((S)-2-hydroxypropoxy)chroman-4-yl)carbamate

[0928] To a mixture of a 1: 1 mixture of tert-butyl N-[(3S,4S)-7-(difluoromethoxy)-3- hydroxy-3,4-dihydro-2H-l-benzopyran-4-yl]carbamate and tert-butyl N-[(3R,4R)-7- (difluoromethoxy)-34iydroxy-3,4-dihydro-2H- Lbenzopyran-4-yl]carbamate (19.50 g, 60.56 mmol) in DCM (200 mL) were added NaOH (14.53 g, 363.3 mmol), tetrabutylazauium hydrogen sulfate (4.10 g, 12.11 mmol) and (4S)-4-methyl-L3,2-A-6-dioxathiolane-2, 2-dione (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1) (10.28 g, 72.62 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. Then the solvents were evaporated under vacuum and the residue was diluted with water. Then the aqueous solution was acidified with HC1 (2N) to PH~7 and extracted with ethyl acetate. The combined organic layers were concentrated under vacuum. The residual was dissolved with tBuOMe (800 mL), then HjO (32 mL) and a solution of pTsOH (2.08 g, 12.1 1 mmol) in 1,4-dioxane (320 mL.) were added. The resulting mixture was stirred at 40 °C for 16 h. The reaction mixture was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-70% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl ((3S,4S)-7-(difluoromethoxy)-3-((S)-2-hydroxypropoxy)chroman-4- yl)carbamate and tert-butyl ((3R,4R)-7 -(difluoromethoxy)-3-((S)-2- hydroxypropoxy)chroman-4-yl)carbamate (14.43 g, 63%) as a white solid. MS ESI calculated for C1SH25F2NO6 [MW, 390.16; found, 390.10.

Step-7: tert-butyl (2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl-2,3,4a,10b- tetrdhydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate, isomer 1:

tert-butyl (2R,4aR,10bR)-8-(difluoromethoxy)-2-methyl-2,3,4a,10b-tetrahydrochromeno[3,4- b][l,4]oxazine-l(5H)-carboxy1ate, isomer 2:

[0929] To a mixture of a 1:1 mixture of tert-butyl ((3S,4S)-7-(difluoromethoxy)-3-((S)-2- hydroxypropoxy)chroman-4-yI)carbamate and tert-butyl ((3R,4R)-7-(difluoromethoxy )-3- ((S)-2-hydroxypropoxy)chroman-4-yl)cafbamate (14.43 g, 37.1 1 mmol ) in toluene (200 mL) was added 2-(tributyl-/?-phosphaneylidene)acetonitrile (17.89 g, 74.23 mmol) (CAS No.

157141-27-0). The mixture was stirred at 110 °C for 1 h under nitrogen atmosphere. The solvents were moved under vacuum. The residue was dissolved with ethyl acetate and washed with water. The combined organic layers dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford lert-butyl (2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl- 2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate, isomer 1 (3.16 g, 22%) as a yellow solid with the second eluting peak. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for C18H23F2NO5 [M+H]⁺, 372.15; found, 372.05.

[0930] Ute purification also afford ten-butyl (2R,4aR,10bR)-8-(dilluoromethoxy)-2- methyl-2,3,4a,l0b-tetrahydrochromeno[3,4-b][1 ,4]oxazine-l(5H)-carboxylate, isomer 2 (3.30 g, 24%) as a yellow solid with the first eluting peak. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for C18H23F2NO5 [M+H]⁺, 372.15; found, 372.05. Step-8: (2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl-l,2,3,4a,5,10b- hexahydrochromeno[3,4-b][l,4]oxazine (A22)

[0931] To a stirred solution of tert-butyl (2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl- 2.3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazine-1(5H)-carboxylate, isomer 1 (6.8 g, 18.31 mmol) in DCM (68 niL) was added Zinc bromide (8.25 g, 36.62 mmol) at 25 °C. The resulting solution was stirred at 40 °C for 2 h. The mixture was concentrated under vacuum. The residue was diluted by water and was extracted with EtOAc. The combined organic layers were washed with brine, then dried over anhydrous NazSOzi. After filtration, the filtrate was concentrated under reduced pressure to afford (2R,4aS,10bS)-8-(difluoromethoxy)-2- methyl-1 ,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l,4]oxazme (A22) (4.6 g, 73%) as a yellow solid. MS ESI calculated for CBHISFZNOS [M+Hf, 272.10; found, 272.05. NMR (400 MHz, DMSO-cfc) 5 (ppm) 7.45 - 6.98 (m, 2H), 6.71 (dd, J = 8.4, 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.65 (t, J - 1 1 .2 Hz, 1 H), 4.02 - 3.94 (m, 2H), 3.88 - 3.84 (m. 1 H), 3.48 (dd, J = 10.8, 3.2 Hz, 1 H), 3.16 (t, ./ = 10.4 Hz, 1 H), 2.99 - 2.89 (m. 1H), 2.59 (s, 1H), 0.87 (d, ,Z = 6.4 Hz, 3H).

Intermediate A23, isomer 1 : rel-(4bS,8aS)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-

5H-cyciopenta[T,2-b:3,4-b’]dipyridine, isomer 1:

A23, isomer 1 . _an<j Intermediate A23, isomer 2: rel-(4bR,8aR)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro- 5H-cyclopenta[l,2-b:3,4-b’]dipyridine, isomer 2

A23, isomer 2

Step 1 : 2-hydroxy-6H,7H-cyclopenta[b]pyridin-5-one

HO

K

[0932] A mixture of ethyl 2-chloro-5-oxo-6H,7H-cyclopenta[b]pyridine -6 -carboxylate (60.00 g, 250.36 mmol) and H3PO4 (600 ml) was stirred at 180 °C for 3 h under nitrogen atmosphere. After cooling down, the mixture was poured into ice/water, and neutralized with NaOH (aq.) to pH 6-7. The resulting mixture was extracted with EtOAc, and the combined organic layers were concentrated under reduced pressure to afford 2-hydroxy-6H,7H- cyclopenta[b]pyridin-5-one (100 g, crude) as a yellow solid. MS ESI calculated for CglbNO.? [M+H] ^h, 150.05; found, 150.00.

Step 2: 2-(difluoromethoxy)-6H,7H-cyclopenta[b]pyridin-5-one

[0933] To a stirred mixture of 2-hydroxy-6H,7H-cyclopenta[b]pyridin-5-one ( 1 1.60 g, 77.77 mmol) and K2CO3 (32.25 g, 233.32 mmol) in DMF (150 mL) was added sodium 2- chloro-2.2-difluoroacetate (17.79 g, 116.66 mmol) in portions at room temperature. The resulting mixture was stirred at 90 °C for 4 h. After cooling down, the mixture was poured into water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NacSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford 2- (difluoromethoxy)-6H,7H-cyclopenta[b]pyridin-5-one (3.10 g, 30% over two steps) as a yellow solid. MS ESI calculated for C9H7F2NO2 [M+Hf', 200.04; found, 200.15.

Step 3: 1: 1 mixture of tert-butyl (S)-(3-(2-(difluoromethoxy)-5-oxo-6,7-dihydro-5H- cyclopenta[b]pyridin-6-yl)propyl)carbamate and tert-butyl (R)-(3-(2-(difluoromethoxy)-5- oxo-6, 7-dihydro-5H-cyclopema[b]pyridin-6-yl)propyl)carbamate

[0934] To a stirred solution of 2-(difluoromethoxy)-6H,7H-cyc1openta[b]pyridin-5-one (13.00 g. 65.28 mmol) and tert-butyl N-(3-hydroxypropyl)carbamate (34,31 g, 195.83 mmol) in toluene (200 mL) were added t-BuOLi (1.05 g, 13.06 mmol) and dichloro(pentamethylcyclopentadienyl)ruthemum(III) polymer (2.01 g, 3.26 mmol). The resulting mixture was stirred at 110 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl (S)-(3-(2-(difluoromethoxy)-5-oxo-6,7-dihydro-5H- cyclopenta[b]pyridin-6-yl)propyl)carbamate and tert-butyl (R)-(3-(2-(difluoromethoxy)-5- oxo-6, 7-dihydro-5H-cyclopenia[b]pyridin-6-yl)propyl)carbamate (6.90 g, 30%) as a yellow oil. MS ESI calculated for C17H22F2N7O4 [M+H]⁺, 357.15; found. 357.20.

Step 4: 1: 1 mixture of (S)-2-(difluoromethoxy)-7,8,8a,9-tetrahydro-6H-cyclopenia[l,2-b:3,4- b'Jdipyridine and (R)-2-(difluoromethoxy)-7,8,8a,9-tetrahydro-6H-cyclopenta[l,2-b:3,4- b’Jdipyridine [0935] To a solution of a 1 : 1 mixture of terl-butyl (S)-(3-(2-(difluorometlioxy)-5-oxo-6,7- dihydro-5H-cyclopenta[b]pyridin-6-yl)propyl)carbamaie and tert-butyl (R)-(3-(2-

(difluoromethoxy)-5-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)propyl)carbamate (4.00 g, 11.22 mmol) in DCM (30 mL) was added trifluoroacetic acid (15 mL). The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (40 mL), and 4 A molecular sieves (1 g) was added. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to afford a 1 :1 mixture of (S)-2-(difluoromethoxy)-7,8,8a,9-tetrahydro-6H- cyclopenta[l,2-b:3,4-b']dipyridine and (R)-2-(difluoromethoxy)-7,8,8a,9-tetrahydro-6H- cyclopenta[l,2-b:3,4-b']dipyridine (4.70 g, crude) as a yellow oil, which was used directly without purification. MS ESI calculated for CizHnFiNsO [M+H]⁺, 239.09; found, 239.05.

Step 5: 2:2:3:3 mixture of tert-butyl (4bR,8aS)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro- 5H-cyclopenta| l,2-b:3,4-b']dipyridine-5-carboxylate, tert-butyl (4bS,8aR)-2-

(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-5H-cyc1openta[l,2-b:3,4-b']dipyridine-5- carboxylate, tert-butvl (4bS,8aS)-2-(difluorometboxy)-4b, 6,7, 8,8a, 9-hexahydro-5H- cyclopenta[l,2-b:3,4-b']dipyridine-5-carboxylate, and tert-butyl (4bR,8aR)-2-

(difluoiomethoxy)-4b,6,7,8,8a,9-hexahydfo-5H-cyclopenta[1.2-b:3,4-b']dipyridine-5- carboxylate

[0936] To a stirred solution of a 1 : 1 mixture of (S)-2-(difluorornethoxy)-7,8,8a,9- tetrahydro-6H-cyclopenta[l,2-b:3,4-b‘Jdipyridine and (R)-2-(difluoromethoxy)-7,8,8a,9- tetrahydro-6H-cyclopenta[l,2-b:3,4-b']dipyridine (4.70 g, crude) in methanol (47 mL) was added Pd/C (400 mg, 10%) at room temperature. The resulting mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered. TEA (2.43 g, 24.07 mmol) and di -tert -butyl dicarbonate (3.95 g, 18.11 mmol) were added to the filtrate at 0 °C. The resulting mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-25% ethyl acetate in petroleum ether to afford a 2:2:3:3 mixture of tert-butyl (4bR,8aS)-2-(difluoromelhoxy)-4b,6,7,8,8a,9-hexahydro-5H- cyclopenta[1.2-b:3.4-b']dipyridine-5-caiboxylate, tert-butyl (4bS,8aR)-2-(difluoromethoxy)- 4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3,4-b']dipyridine-5-carboxylate, tert-butyl (4bS,8aS)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-5H-cyc1openta[l ,2-b:3,4- b']dipyridine-5-carboxylate, and tert-butyl (4bR,8aR)-2-(difluoromethoxy)-4b,6,7,8,8a,9- hexahydro-5H-cyclopenta[l,2-b:3,4-b’]dipyridine-5-carboxylate (2.20 g, 57% over two steps) as a colorless oil. MS ESI calculated for C17H22F2N2O3 [M+H]⁺, 341.16; found, 341.15.

Step 6: rel-(4bS,8aS)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3,4- b'Jdipyridine, isomer 1 (A23, isomer 1):

A?3 corner 1 . _and rel-(4bR,8aR)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3,4- b'Jdipyridine, isomer 2 (A23, isomer 2)

A23, isomer 2

[0937] To a stirred solution of a 2:2:3:.3 mixture of tert-butyl (4bR,8aS)-2- (difluofomethoxy)-4b,6,7.8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3.4-b']dipyridine-5- carboxylate, tert-butyl (4bS,8aR)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-5H- cyclopenta[l,2-b:3,4-b']dipyridine-5-carboxylate, tert-butyl (4bS,8aS)-2-(difIuoromethoxy)- 4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3,4-b‘]dipyridine-5-carboxylate, and tert-butyl (4bR,8aR)-2-(diiluoromethoxy)-4b,6J,8,8a,9-hexahydro-5H-cyclopenta| l,2-b:3,4- b']dipyridine-5-carboxylate(2.20 g, 6.46 mmol) in DCM (11 ml.,) was added HC1 (4 M in 1 ,4- dioxane, 11 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water. The mixture was basified with saturated NaHCCh (aq. ) to pH 8. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOr. After filtration, the filtrate was concentrated under reduced pressure to afford a mixture product (1.45 g, 93%) as a colorless oil.

[0938] The mixture product (2. 16 g) was separated by Prep- Achiral- SFC with the following conditions: [Column: DAICEL DCpak P4VP 3*25 cm, 5 pm; Mobile Phase A: CO?, Mobile Phase B: MeOH(20mM NHs-MeOH); Flow rate: 60 mL/min; Gradient: isocratic 20% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 254 nm; RTl(niin): 3.90; RT2(min): 5.13; Sample Solvent: MEOH; Injection Volume: 1 mL; Number Of Runs: 7.0] to afford fraction A (786 mg, 36%) with the first peak on Achiral SFC, which was trans racemic based on NOESY.

[0939] The Achiral resolution also afford fraction B (1.17 g, 54%) with the second peak on Achiral SFC, which was cis racemic based on NOESY.

[0949] The fraction B (130 mg) was separated by Prep-Chiral -HPLC with the following conditions: [Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NHs-MeOH), Mobile Phase B: MeOH: DCM=1: 1; Flow rate: 20 mL/min; Gradient: 10% B to 10% B in 12 min; Wave Length: 220/254 nm; RTl(min): 9.09; RT2(min): 10.65; Sample Solvent: EtOH: DCM-1: 1— HPLC; Injection Volume: 0.25 mL; Number Of Runs: 15] to afford (4bS,8aS)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3,4- b’jdipyridine, isomer 1 (A23, isomer 1) (50 mg) as a yellow oil. MS ESI calculated for C..4 HF-N -O [M+Hy, 241.11 ; found, 241.10. ^!H NMR (400 MHz, DMSO-de) 3 7.75 (d, 7 = 8.0 Hz, 1H), 7.66 (t, J = 73.2 Hz, 1H), 6.84 (d, 7 = 8.0 Hz, 1H), 4.16 (d, 7 = 5.6 Hz, 1H), 2.88 - 2.79 (m, 1H), 2.66 - 2.54 (m, 2H), 2.49 - 2.41 (m, 1H), 2.40 - 2.31 (m. 1H), 1.75 - 1.65 (m, I H), 1 .44 - 1.20 (m, 3H). Absolute stereochemistry was not determined.

[0941] The chiral resolution of fraction B also afford (4bR,8aR)-2-(difluororaethoxy)- 4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3,4-b']dipyridine, isomer 2 (A23, isomer 2) (40 mg) as a yellow oil with the second peak on chiral HPLC. MS ESI calculated for C12H14F2N2O [M+H]⁺, 241.11; found, 241.10. ^!H NMR (400 MHz, DMSO-de) 6 7.75 (d, 7 = 8.0 Hz, 1H), 7.66 (t, 7 = 73.2 Hz, 1H), 6.84 (d, 7= 8.0 Hz, 1H), 4.16 (d, 7 = 5.6 Hz, 1H), 2.88 - 2.79 (m, 1H), 2.66 - 2.54 (m, 2H), 2.49 - 2.41 (m, 1H), 2.40 - 2.31 (rn, 1H), 1.75 - 1.65 (m, 1H), 1.44 - 1.20 (m, 3H). Absolute stereochemistry was not determined.

Intermediate A24, isomer 1: (4aS,10bS)-8-(difluoromethoxy)-2,3,4.4a,6,10b-hexahydro- lH-isochromejio[4,3-b]pyridine, isomer 1:

A24, isomer

Intermediate A24, isomer 2: (4aR,10bR)-8-(.difluoromeliioxy)-2,3,4,4a,6,10b-hexahydro- lH-isocbromeno[4,3-b]pyridine, isomer 2:

A24, isomer 2 Step 1: methyl 2-bromo-5-(difluoromethoxy)benzoate

[0942] To a stirred solution of methyl 2-bromo-5-hydroxybenzoate (120.00 g, 519.48 mmol) in DMF (500 mL) were added K2CO3 (215.06 g, 1558.44 mmol) and sodium 2- chloro-2,2-difluoroacetate (236.88 g, 1558.44 mmol) at 0 °C. The resulting solution was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4- The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5/1) to afford methyl 2-bromo-5-(difluoromethoxy)benzoate (75.70 g, 78%) as a yellow solid. MS (ESI) calculated for (CgHyBrFsOs) [M+H]⁺, 280.95, 282.95; found, 280.95, 283.00.

Step 2: methyl 5-(difluoromethoxy)-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y1)benzoate

[0943] To a stirred solution of methyl 2-bromo-5-(difluoromethoxy (benzoate (75.70 g, 270.41 mmol) in 1 ,4-dioxane (760 ml..) were added BPD (103.00 g, 405.62 mmol), AcOK (79.62 g, 811.2.4 mmol) and Pd(dppf)Ch (19.79 g, 27.04 mmol). The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4- The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5/1 ) to afford methyl 5-(difluoromethoxy)-2-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2-yl)benzoate (72.60 g, 82%) as a colorless oil. MS (ESI) calculated for (C15H19BF2O5) [M+H]⁺, 329.13; found, 329.10.

Step 3: methyl 5-(dinuoromeihoxy)-2-(3-iluoropyridin-2-yl)benzoate

[0944] To a stirred solution of methyl 5-(difluoromethoxy)-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (33.00 g, 100.57 mmol) in 1,4-dioxane (330 mL) and H2O (33 mL) were added 2-chloro-3-fluoropyridine (13.23 g, 100.57 mmol), K2CO3 (41.70 g, 301.72 mmol) and Pd(dppf)Ch (7.36 g, 10.06 mmol). The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. Hie resulting mixture was diluted with water. Hie resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCri. The resulting mixture was concentrated under reduced pressure. Hie residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3/1) to afford methyl 5-(difluoromethoxy)-2-(3-fluoropyridin-2-yl)benzoate (15.25 g, 51%) as a yellow oil. MS (ESI) calculated for (C32H42N6O4S) [M+H]⁺, 298.06; found, 298.10.

Step 4: [2-(3-fluoro-6-methylpyridin-2-yl)-5-(trifluoromethyl)phenyl]methanol

[0945] To a stirred solution of methyl 5-(difluoromethoxy)-2-(3-fluoropyridin-2- yllbenzoate (15.25 g, 51 .31 mmol) in THF (150 mL) was added LAH (3.89 g, 102.61 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by the addition of water (4 mL) and NaOH (aq, 10%) (4 mL) at 0 °C. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The resulting mixture was washed with brine to afford [5-(difluoromethoxy)"2-(3-fluoropyridin-2-yl)phenyl]methanol (15.70 g, etude) as a brown solid. MS (ESI) calculated for (C_{; 3}H_]0F 6NO_Z) [M+H]⁺, 270.07; found, 270.05.

Step 5: 2-methyl-8-(trifluoromethyl)-6H-isochromeno[4,3-b]pyridine

[0946] To a stirred solution of [5-(difluoromethoxy)-2-(3-fluoropyridin-2- yl)phenyl]raethanol ( 15.70 g, 58.32 mmol) in DMF (150 mL) was added K2CO3 (40.30 g,

291.58 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1/1) to afford 8-(difluoromethoxy)-6H- isochromeno[4,3-b]pyridiite (7.58 g, 52%) as a yellow solid. MS (ESI) calculated for (CBH9F2NO2) [M+H] h 250.06; found, 250.05.

Step 6: 1: 1 mixture of (4aS,10bS)-8-(difluoromethoxy)-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine and (4aR,10bR)-8-(difiuoromethoxy)-2,3,4,4a,6,10b-hexahydro-

1 H-isochromeno[4,3-b]pyridine formate (A24)

[0947] To a solution of 8-(difluoromethoxy)-6H-isochromeno[4,3-blpyridine (2.00 g, 8.02 mmol) in AcOH (20 mL) was added PtOz (200 mg) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 16 h under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase flash column chromatography with 5-20%- acetonitrile in water (0.1 % FA) to afford a 1:1 mixture of (4aS,10bS)-8-(difluoromethoxy)- 2,3.4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine formate and (4aR,10bR)-8- (difluoromethoxy)-2.3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine formate (2.10 g, 87%) as a white solid. MS (ESI) calculated for (CBHISFZNOZ) [M+H]⁺. 256.1 1 ; found, 256.15. ^!H NMR (400 MHz, DMSO-rf₆) S 8.32 (s, 1 H), 7.60 - 7.50 (m, 1H), 7.42 - 7.05 (m, 2H), 7.04 - 6.87 (m, 1H), 4.92 - 4.88 (m, 1H), 4.79 - 4.73 (m, 1H), 3.98 - 3.96 (m, 1H), 3.79 - 3.78 (m, 1H), 3.10 - 2.98 (m, 1H), 2.92 - 2.83 (m, 1H), 2.02 - 1.96 (rn, 1H), 1.86 - 1.66

(m, 2H), 1.53 - 1.42 (m, 1 H).

Step 7 : (4aS, 10bS)-8-(difluoromethoxy)-2,3,4,4a,6, 10b-hexahydro-lH-isochromeno[4,3- b jpyridine, isomer 1 :

A24. isomer

(4aR, lObR) ■ 8 -(difluoromethoxy )-2, 3 ,4, 4a, 6, lOb-hexahydro- lH-isochromeno[4,3-b]pyridme, isomer 2:

A24, isomer 2

[0948] A 1:1 mixture of (4aS, 10bS)-8-(difluoromethoxy)-2,3, 4,4a, 6, lOb-hexahydro- 1H- isochromeno[4,3-b]pyridine and (4aR,10bR)-8-(difluoromethoxy)-2,3,4,4a.6,10b-hexahydro- lH-isochromeno[4,3-b]pyridine (1.17 g, 4.58 mmol) was purified by Prep-Chiral SFC with the following conditions (Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: CCh, Mobile Phase B: MEOH; Flow rate: 110 mL/min; Gradient: isocratic 15% B; Wave Length: 220 nm; RTl(min): 3.8; RT2(min): 4.9: Sample Solvent: MeOH) to afford (4aS,10bS)-8-(difluoromethoxy)-2,3,4,4a,6,10b-hexahydro-lH-isocbromeno[4,3-b]pyridine (530 mg), isomer 1 (A24, isomer 1) as a white solid with the first peak on chiral SFC. MS (ESI) calculated for d i .WAO - ! [M+H]⁺, 256.11; found, 256.20. H NMR (400 MHz, DMSO-cfe) 8 7.43 - 7.02 (m, 3H), 6.92 (d, 7 = 2.4 Hz, 1H), 4.85 (d, 15.6 Hz, 1H), 4.69 (d,

J = 15.6 Hz, 1H), 3.69 - 3.62 (m, 2H). 2.98 - 2.89 (m, 1H), 2.78 - 2.66 (m. 1H), 2.01 - 1.92 (m, 1H), 1.84 - 1.70 (m, 1 H), 1.68 - 1.52 (m, 1H). 1.45 - 1.34 (m, IH).

[0949] Absolute stereochemistry of A24 isomer 1 was determined by crystallography based on the co-crystal structure of Example 31 with PRMT5 enzyme, where the example 31 was prepared using A24 isomer 1.

[0950] The chiral separation also afford (4aR,10bR)-8-(difluoromethoxy)-2,3,4,4a,6.10b- hexahydro-lH-isochromeno[4,3-b]nyridine (470 me), isomer 2 (A24, isomer 2) as a white solid with the second peak on chiral SFC. MS (ESI) calculated for (Ci 3H15F2NO2) [M+H]⁺, 256.11; found, 256.20. ^!H NMR (400 MHz, DMSO-cfe) 3 7.43 - 7.02 (m, 3H), 6.92 (d, J = 2.4 Hz, 1H), 4.85 (d, J = 15.6 Hz, 1H), 4.69 (d, J = 15.6 Hz, 1H), 3.69 - 3.62 (m, 2H), 2.98 - 2.89 (m, 1H), 2.78 - 2.66 (m, 1H), 2.01 - 1.92 (m, 1H), 1.84 - 1.70 (m, 1H), 1.68 - 1.52 (m, III), 1.45 - 1.34 (m, 1H)

Intermediate A25: rel-(4aS,10bS)-8-cyclopropoxy-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-bjpyridine hydrochloride

[6951] To a stirred solution of methyl 2-bromo-5-chlorobenzoate (30.00 g, 120.25 mmol) and (E)-tert-butyldiphenyl((5-(4, 4, 5, 5 -tetramethyl- 1 ,3,2- -dioxaborolan-2- yl)pent-4 -en- 1 - yl)oxy)silane (59.59 g, 132.27 mmol) in 1,4-dioxane (300 mL) and H2O (30 rnL) were added K2CO3 (33.24 g, 240.49 mmol) and PdldppfjCk-CHzCl? (9.82 g, 12.03 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h, The reaction mixture was quenched by the addition of water/ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography eluted with 0-8% ethyl acetate in petroleum ether to afford methyl (E)-2-(5-((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-5-ch1orobenzoate (58.10 g, 97%) as a light yellow oil. MS ESI calculated for CipEfaClChSi [M+H]⁺, 493.19; found, 493.20. ^;H NMR (300 MHz, DMSCfoL) 6 7.83 - 7.74 (m, 1H), 7.65 - 7.53 (m, 6H), 7.47 - 7.40 (m, 6H), 6.98 (dd, 16.0, 1.6 Hz, 1H), 6.24 (dt, J = 15.8. 6.8 Hz, 1H), 3.84 (s, 3H), 3.67 (t, / = 6.0 Hz, 2H), 2.36 2.15 (m, 2H), 1.76 - 1.61 (m, 2H), 1.00 (s, 9H). Absolute stereochemistry was not determined.

Step-2:

[0952] To a stirred solution of tert-butyl carbamate (23.05 g, 196.77 mmol) in propan-l-ol (490 mL) was added a solution of NaOH (6.96 g, 173.92 mmol) in HjO (436 mL) at room temperature. The resulting mixture was stirred at room temperature for 10 minutes. Then 1,3- dichloro-5,5-dimethylimidazolidine-2, 4-dione (18.76 g, 95.21 mmol) was added to the mixture at room temperature. After stirring at room temperature for 30 minutes, potassium osmate(VI) dihydrate (2.34 g, 6.35 mmol) was added to the mixture, this was followed by the addition of a solution of (DHQhPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (4.94 g, 6.35 mmol) in propan-l-ol (64 mL) and a solution of methyl (E)-2-(5- ((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-5-cblorobenzoate (31.30 g, 63.47 mmol) in propan-l-ol (60 mL) drop wise at 0°C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography with a 330 g silica gel column eluted with 0 - 15% ethyl acetate in petroleum ether to afford rel-tert-butyl ((3S,4S)-3-(3-((tert- butyldiphenylsilyl)oxy)propyl)-7-chloro-1 -oxoisochroman-4-yl)carbatnate (17.40 g, 46%) as a brown oil. MS ESI calculated for CsrH^oClNOsSi [M+H]⁺, 594.24; found, 594.15. ^!H NMR (300 MHz, DMSO-cL) 5 7.88 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 8.0, 2.4 Hz, 1H), 7.64 - 7.62 (m, 5H), 7.50 - 7.40 (m, 7H), 4.88 (d, J - 9.4 Hz, 1H), 4.66 - 4.65 (m, 1H), 3.77 - 3.71 (m, 2H), 1.80 - 1.76 (m, 4H), 1.38 (s, 9H), 1.00 (s, 9H). Absolute stereochemistry was not determined. Step-3:

[0953] To a stirred solution of rel-tert-butyl ((3S,4S)-3-(3-((tert- buty]diphenylsilyl)oxy)propyl)-7-chloro-1 -oxoisochroman-4-yl)carbamate ( 17.40 g, 29.28 mmol) in THF (170 mL) was added NaBHj (5.54 g, 146.41 mmol) at 0 °C, then boron trifiuoride dimethyl etherate (18 mL, 146.41 mmol) was added dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of water/ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography with a 120 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford rel-tert-butyl ((3S,4S)-3-(3-((tert-butyldiphenylsilyl)oxy)propyl)-7- chloroisochroman-4-yl)carbamate (6.40 g, 37%) as a colorless oil. MS ESI calculated for The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography with an 80 g silica gel column eluted with 0-8% ethyl acetate in petroleum ether to afford rel-tert-butyl ((3S,4S )-7-chloro-3-(3-hydroxypropyl)isochroman-4- yl)carbamate (2.98 g, 79%) as a colorless oil. MS ESI calculated for C17H24CINO4 [M+H]*, 342.14; found, 342.05. ^!H NMR (400 MHz, DMSO-rfo) 5 7.30 - 7.23 (m, 2H), 7.18 (d, J = 2.0 Hz, 1H), 6.96 (d, ./ = 9.6 Hz, 1 Hi, 4.76 (d, ./ = 15.6 Hz, 1 H), 4.64 - 4.54 (m, 2H), 4.39 (t, J = 5.2 Hz, 1H), 3.62 - 3.59 (m, 1 H), 3.44 - 3.37 (ra, 2H), 1 .60 - 1.51 (m, 4H), 1 .39 (s, 9H). Absolute stereochemistry was not determined.

Step- 5:

[0955] To a stirred solution of rel-tert-butyl ((3S,4S)-7-chloro-3-(3- hydroxypropyl)isochroman-4-yl)carbamate (2.50 g, 7.31 mmol) in toluene (25 mL) was added 2-(tributy]-X^J-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (3.53 g, 14.63 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with a 40 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford rel-tert-butyl (4aS,10bS)-8- chloro-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine-l-carboxylate (1.65 g, 69%) as a light yellow oil. MS ESI calculated for C17H22CINO3 [M+HJT 324.13; found, 324.05. ^:H NMR (300 MHz, DMSO-cfc) 57.36 (dd, J = 8.4, 2.2 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.27 (d, J = 6.0 Hz, 1H), 4.81 - 4.65 (m, 2H), 4.08 - 3.99 (m, 1H), 3.81 (d, J - 13.4 Hz, 1H), 2.31 (t, J = 12.4 Hz, 1H), 1.76 - 1.52 (m, 4H), 1.47 (s, 9H). Absolute stereochemistry was not determined.

Step-6:

[9956] To a stirred solution of rel-tert-butyl (4aS, 10bS)-8-chloro-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine-l-carboxylate (200 mg, 0.62 mmol) and K2CO3 (1 135 mg, 8.22 mmol) in DMF (18 mL) and H2O (2 ml) were added Herrmann's palladacycle (50 mg, 0.05 mmol) and l-BuXPhos (92 mg, 0.22 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 3 h. The mixture was allowed to cool at room temoerature and diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. 'The residue was purified by silica gel column chromatography, eluted with 0 - 20% EtOAc in PE to afford rel-tert-butyl (4aS,10bS)-8-hydroxy-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- b]pyridine-l -carboxylate (200 mg, 42%) as a colorless oil. MS ESI calculated for C17H23NO4 [ M+H f) 306.16; found, 306.15. Absolute stereochemistry was not determined.

Step-7 :

[0957] To a stirred solution of rel-tert-butyl (4aS,10bS)-8-hydroxy-2,3,4,4a,6,10b- hexahydro- lH-isochromeno[4,3-b]pyridine-l -carboxylate (120 mg, 0.39 mmol) and CS2CO3 (384 mg, 1.18 mmol) in DMF (5 mL) was added iodocyclopropane (99 mg, 0.59 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120 °C for overnight. Hie mixture was allowed to cool at room temperature and diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 ~ 25% EtOAc in PE to afford rel-tert-butyl (4aS,10bS)-8-cyclopropoxy-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine-l -carboxylate (130 mg, 57%) as a colorless oil, MS ESI calculated for C20H27NO4 [M+H]*', 346.19; found, 346.20. Absolute stereochemistry was not determined.

Step-8:

A25

[0958] To a solution of rel-tert-butyl (4aS, 10bS)-8-cyclopropoxy-2, 3, 4,4a, 6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine-l -carboxylate (130 mg, 0.38 mmol) in DCM (2.5 mL) was added HC1 (4M in 1,4-dioxane) (2.5 mL). The mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford rel-(4aS,10bS)-8-cyclopropoxy-2,3,4,4a,6,10b-hexahydro-lH- isochrorneno[4,3-b]pyridine hydrochloride (A25) (75 mg, 96%) as a while solid. MS ESI calculated for C15H19NO2 [M+Hf, 246.14; found, 246.15. ^;H NMR (400 MHz, DMSO-ds) 8 9.70 (d, J = 11.2 Hz, 1H), 8.53 (d, J = 11.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.4, 2.8 Hz, 1H), 6.90 (d, .7 - 2.4 Hz, 1H), 4.97 - 4.72 (m, 2H), 4.22 (d, J= 10.0 Hz, 1H), 3.94 - 3.93 (rm 1H), 3.89 - 3.81 (m, 1H), 3.19 - 2.93 (m, 2H), 2.04 - 1.92 (m, 1H), 1.92 - 1.73 (m, 2H). 1.73 - 1.59 (m, 1H), 0.86 - 0.75 (m, 2H), 0.70 - 0.58 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A26: rel-(4aS,9bS)- ■/•(trifluoromethyl)- 1,2, 3, 4,4a, 9b-hexahydrofuro[2,3-b:4, 5- b']dipyridine, isomer 2

A2®, isomer rel-(4aR,9bR)-7-(tri fluoromethyl)- 1,2, 3 ,4, 4a, 9b-hexahydrofuro[2,3-b:4,5-b']dipyridme, isomer 1

A26, isomer 1

Step- 1 :

[09S9] To a stirred mixture of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (25.00 g, 95.99 mmol), (E)-tert-butyldiphenyi((5-(4,4,5,5-tetramethy1-l,3,2-dioxaborolan-2-yl)pent-4- en-l-yl)oxy)silane (51.89 g, 115.18 mmol) and K2CO3 (39.80 g, 287.97 mmol) in 1,4- dioxane (300 mL) and H2O (30 mL) was added Pd(dppf)C12 (7.84 g, 9.59 mmol) at room temperature under nitrogen atmosphere. Then the mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted by water and extracted with EtOAe. The combined organic layers were washed with water, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 10-20% ethyl acetate in petroleum ether to afford (E)-3- (5-((tert-butyldiphenylsilyl)oxy)pent- l-en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine (48 g, 99%) as a yellow oil. MS ESI calculated for C27H29CIF3NOS! [M+H]⁺, 504.17; found, 504.15.

Step-2: [0960] To a stirred mixture of tert-butyl carbamate (16.73 g, 142.83 mmol) in propan-l-ol (200 mL) was added a solution of NaOH (5.14 g, 128.55 mmol) in HjO (200 mL) at 0 °C and then stirred for 15 minutes. 1.3-dichloro-5,5-dimethylimidazolidine-2, 4-dione ( 14.07 g. 71.41 mmol) was added to the mixture, the mixture was stirred at 0 °C for 30 minutes. Then (E)-3- (5-((teri-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-2-chloro-6-(trifluorornethyl)pyridine (24.00 g, 47.61 mmol), (DHQjjPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (3.71 g, 4.76 mmol) and Potassium osmate(VI) dihydrate (1.75 g, 4.76 mmol) were added to the mixture. The mixture was stirred at room temperature for 12 h. The resulting mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous NajSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-11% ethyl acetate in petroleum ether to afford a 4: 1 mixture of rel- tert-butyl (( IS ,2S) -5 ■ ((tert-butyldiphenylsilyl)oxy )■• 1 ■ (2 -chloro ■ 6-(trifhioromethyl)pyridin-3 - yl)-2-hydroxypentyl)carbamate isomer 2 and rel-tert-butyl ((lR,2R)-5-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-y1)-2- hydroxypentyl)carbamate isomer 1 (10.0 g, 32%) as a yellow solid. MS ESI calculated for C₃2H4oClF3N₂04Si [M+H]⁺, 637.24; found, 637.20.

Step-3 :

[0961] To a stirred mixture of a 4: 1 mixture of rel-tert-butyl (( 1 S,2S)-5-( ( terl- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2- hydroxypentyl)carbamate isomer 2 and rel-tert-butyl ((lR,2R)-5-((tert- butyldiphenylsilyl)oxy)-l -(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2- hydroxy pentyllcarbamate isomer 1 (9.90 g, 15.53 mmol) and CS2CO3 (15.19 g, 46.60 mmol) in toluene (100 ml..) were added JohnPhos (0.93 g, 3.10 mmol) and Pd(OAc)?. (0.35 g, 1.55 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. Tire precipitated solids were filtered, the filler cake was washed with DCM. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with 10-20% ethyl acetate in petroleum ether to afford a 4: 1 mixture of rel- tert-butyl ((2S,3S)-2-(3-((tert-buty1diphenylsilyl)oxy)propy])-6-(trifIuoromet.hyl)-2,3- dihydrofuro[2,3-b]pyridin-3-yl)carbaniate isomer 2 and rel-tert-butyl ((2R,3R)-2-(3 -((tert- buty ldiphenylsilyl)oxy)propyl) -6-(trifluoromethyl)- 2 ,3 -dihydrofuro[2,3 -b]pyridin-3 - yl)carbamate isomer 1 (3.90 g, 41%) as a yellow solid. MS ESI calculated for C₃2H3₉F₃N2O4Si [M+H]⁺, 601.26; found, 601.24.

[0962] To a 4:1 mixture of rel-tert-butyl ((2S,3S)-2-(3-((tert- butyldiphenylsilyl)oxy)propyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- yljcarbamate isomer 2 and rel-tert-butyl ((2R,3R)-2-(3-((tert-butyldiphenylsily1)oxy)propyl)- 6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate isomer 1 (3.90 g, 6.49 mmol) in THE (40 mL) was added TBAF (3.39 g, 12.98 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and then washed with brine. The organic layer was dried over anhydrous NajSCU, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 30-50%’ ethyl acetate in petroleum ether to afford a 4: 1 mixture of rel-tert-butyl ((2S,3S)-2-(3- hydroxypropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate isomer 2 and rel-tert-butyl ((2R,3R)-2-(3-hydroxypropyI)-6-(trifiuoromethyl)-2,3-dihydrofuro[2,3- b]pyridin-3-yl)carbamate isomer 1 (1.90 g, 80%) as a yellow solid. MS ESI calculated for C.d hT' .X'.-O: [M-rHJh 363.15; found, 363.18.

Step- 5: [0963] To a stirred a 4: 1 mixture of rel-tert-butyl ((2S,3S)-2-(3-hydroxypropyl)-6- (trifluoromethyl)-2,3-dibydrofuro[2,3-b]pyridin-3-yl)carbamate isomer 2 and rel-tert-butyl ((2R,3R)-2-(3-hydroxypropyl)-6-(trifluoromethyl)-2,3-dihydroftiro[2,3-b]pyridin-3- yl)carbamate isomer 1 (1.90 g, 5.24 mmol) in toluene (20 mL) was added 2-(tributyl-A?- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (3.80 g, 15.73 mmol) at room temperature, and then the mixture was stirred at 110 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 10-20% ethyl acetate in petroleum ether to afford a 4: 1 mixture of rel- tert-butyl (4aS,9bS)-7-(trifluoromethy1)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b‘]dipyridine- l(2H)-carboxylate isomer 2 and rel-tert-butyl (4aR,9bR)-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate isomer 1 (1.40 g, 77%) as a light yellow solid. MS ESI calculated for CisHigF^Ch [M+H]⁺, 345. 13: found, 345. 15.

Step-6:

[0964] A mixture of 4:1 mixture of tert-butyl (4aS,9bS)-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine- l(2H)-carboxylate and tert-butyl (4aR,9bR)-7- (trifluoromethy1)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridine- l(2H)-carboxylate (1.40 g, 4.06 mmol) and HQ (4M in 1,4-dioxane) (20 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford a 4:1 mixture of (4aS,9bS)-7-(trifluorornethyl)-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b']dipyridine and (4aR,9bR)-7-(trifluororaetliyl)-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b’]dipyridine hydrochloride (1.8 g, crude) as a yellow solid. MS ESI calculated for C11H11F3N2O [M+HJ⁺, 245.08: found, 245.00.

Step-7 :

A26, isomer 2 _aRj

A26, isomer 1

[6965] A 4:1 mixture of rel-(4aS, 9bS)-7-(trifluoromethyl)-l, 2,3,4, 4a,9b- liexahydrofuro[2,3-b:4,5-b']dipyridine isomer 2 and rel-(4aR,9bR)-7-(trifluoromethyl)- 1, 2, 3, 4,4a, 9b-hexahydrofuro[2,3-b:4,5-b']dipyridine hydrochloride isomer 1 (1.80 g, 7.37 mmol) was purified by Prep-SFC with the following conditions (Column: CHIRALPAK PAK AD-H, 30*250mm; Mobile Phase B: ETOH (0.1 % 2M NH3-MEOH); Flow rate: 100 mL/min: Gradient: isocratic 20% B; RTl (min): 2.6; RT2(min): 4; Sample Solvent: MEOH; Injection Volume: 2 mL; Number Of Runs: 20) to afford rel-(4aR,9bR)-7-(trifluoromethyl)- l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b']dipyridine, isomer 1 (A26 isomer 1) (170 mg) as a white solid with shorter retention time. MS ESI calculated for Ci iHnFsNiO [M+H]⁺, 245.08; found, 245.00. *H NMR (400 MHz, DMSO-Je) 6 8.01 (d, 8.0 Hz, IH), 7.47 (d, 8.0

Hz, IH), 4.81 - 4.72 (m, 2H), 3.00 •- 2.80 (m, 2H), 2.19 - 1.92 (m, 2H), 1.16 - 1.47 (m, 2H).

[0966] The chiral resolution also afford rel-(4aS,9bS)-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine, isomer 2 (A26, isomer 2) (500 mg) as a while solid with longer retention time. MS ESI calculated for C11H11F3N2O [M+H]⁺, 245.08; found, 245.00. ^:,H NMR (400 MHz, DMSO-zfc) 8 8.01 (d, J = 8.0 Hz. IH), 7.47 (d, 8.0 Hz, IH),

4.81 - 4.72 (m, 2H), 3.00 - 2.80 (m, 2H), 2.19 - 1.92 (m, 2H), 1.16 - 1.47 (m, 2H).

[0967] Absolute stereochemistry of A26 isomer 2 was now determined by single crystal crystallography of a compound prepared using A26 isomer 2. A26 isomer 2 is now’ represented by the structure: chemical name of (4aS,9bS)-7-(trifluoromethyI)-l, 2,3,4, 4a.9b- hexahydrofuro[2,3-b:4,5-b']dipyridine.

[0968] Accordingly, A26 isomer 1 is represented by the structure: chemical name of (4aR,9bR)-7-(trifluoromethyl)-J ,2,3,4,4a,9b- hexahydrofuro 12 ,3 ■ b: 4, 5 ■■ b' ] dipyridine.

Intermediate A27: 1:1 mixture of rel-(4aR,9bR)-l_>2,3,4,4a,9b-hexahydrobenzofuro[3,2- bJpyridme-7-carbonitrile isomer 1 and rel-(4aR,9bR)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- b]pyridine-7-carbonitriIe hydrochloride isomer 2

[0969] To a stirred mixture of (4-chloro-2-hydroxyphenyl)boronic acid ( 10.00 g, 58.01 mmol) and 2-bromo-3-fluoropyridine (10.21 g, 58.01 mmol) in 1,4-dioxane (LOO mL) and H₂O (10 mL) were added Pd(dppf)Ch (4.24 g, 5.80 mmol) and K2CO3 (24.05 g, 174.04 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 2 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-60% ethyl acetate in petroleum ether to afford 5-chloro-2-(3-fluoropyridin-2-yl)phenol (10.70 g, 82%) as a yellow solid. MS ESI calculated for C11H7CIFNO [M+l]⁺, 224.03: found, 224. 10.

Step-2:

[0970] A mixture of 5-chloro-2-(3-fluoropyridin-2-yl)phenol (10.70 g, 47.84 mmol) and K2CO3 (19.84 g, 143.51 mmol) in DMF (100 mL) was stirred at 120 °C for 3 h. The precipitated solids were filtered off by filtration and washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCX After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to afford 7-chlorobenzofuro[3,2-b]pyridine (8.00 g, 82%) as a white solid. MS ESI calculated for CnHsClNO 204.01; found, 204.05.

Step-3:

[0971] To a stirred mixture of 7-chlorobenzofuro[3,2-b]pyridine (9.10 g, 44.68 mmol) and B(C6Fs)3 (2.29 g, 4.46 mmol) in toluene (90 mL) were added HBpin (28.60 g, 223.44 mmol) and PhjNH (30.25 g, 178.75 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH₂Clj/MeOH (5:1 ) to afford a 1:1 mixture of rel-(4aS,9bS)-7-chIoro-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(4aR,9bR)-7-chloro-l, 2,3,4, 4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2 (6.90 g, 73%) as a yellow solid. MS ESI calculated for C11H12CINO [M+H]⁺, 210.06; found, 210.15. Relative and absolute stereochemistry was not determined.

Step-4:

[0972] To a stirred 1 : 1 mixture of rel-(4aS,9bS)-7-chloro- 1 .2, 3, 4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(4aR,9bR)-7-chloro-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2 (4.70 g, 22.41 mmol) and BOC2O (4.89 g. 22.41 mmol) in methanol (47 mL) was added TEA (6.81 g, 67.24 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (5:1) to afford a 1:1 mixture of rel-tert- butyl (4aS,9bS)-7-chloro-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridine-l(2H)-carboxylate isomer 1 and rel-tert-butyl (4aR,9bR)-7-chloro-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridine-l(2H)-carboxylate isomer 2 (6.00 g, 86%) as a white solid. MS ESI calculated for CieHzoCJNOs [M+l ]⁺, 310.11; found, 310.20. Relative and absolute stereochemistry was not determined.

Step-5:

[0973] To a stirred 1: 1 mixture of rel-tert-butyl (4aS,9bS)-7-chloro-3,4,4a,9b- tetrahydrobenzofuro[3,2-b]pyridine-l(2H)-carboxylate isomer 1 and rel-tert-butyl (4aR,9bR)- 7-chloro-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridine-l(2H)-carboxylate isomer 2 (3.00 g, 9.68 mmol) in DMF (30 mL) were added Zn(CN)? (3.41 g, 29.05 mmol), XPhos (0.46 g, 0.96 mmol) and Zinc powder (2.53 g, 38.73 mmol). The resulting mixture was stirred at 130 °C for 2 h under nitrogen atmosphere. The mixture was filtered. The filtrate was purified directly by reverse phase flash column chromatography, eluted with 10 - '70 % acetonitrile in water to afford a 1: 1 mixture of rel-tert-butyl (4aS,9bS)-7-cyano-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridine-l(2H)-carboxylate isomer 1 and rel-tert-butyl (4aR,9bR)-7-cyano-3,4,4a,9b- tetrahydrobenzofuro[3,2-b]pyridine-l(2H)-carboxylate isomer 2 (2.00 g, 68%) as a white solid. MS ESI calculated for C17H20N2O3 [M+H]⁺, 301.15; found, 301.20. Relative and absolute stereochemistry was not determined.

Step-6:

[0974] A mixture of 1 :1 mixture of rel-tert-butyl (4aS,9bS)-'7-cyano-3,4,4a,9b- tetrahydrobenzofuro[3,2-b]pyridine-l(2H)-carboxylate isomer 1 and rel-tert-butyl (4aR,9bR)- 7-cyano-3,4,4a,9b-tetrahydrobenzofiiro[3,2-b]pyridine-l(2H)-carboxylate isomer 2 (2.00 g, 6.65 mmol) and HC1 (4M in 1,4-dioxane) (20 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography, eluted with 10—80 % acetonitrile in water to afford a 1:1 mixture of rel-(4aR,9bR)- 1 , 2,3,4, 4a,9b-hexahydrobenzofuro[3,2-b]pyridine-7- carbonitrile isomer 1 and rel-(4aR, 9bR)- l, 2,3, 4,4a, 9b-hexahydrobenzofuro[3,2-b]pyridine-7- carbonitrile hydrochloride isomer 2 (A27) (1.00 g, 75%) as a white solid. MS ESI calculated for CicHizNsO [M+lf, 201.09; found, 201.20. ^!H NMR (400 MHz, DMSO-de) 6 10.74 (br, 1H), 8.75 (br, 1 H), 7.81 (d, 7 = 7.6 Hz, 1H), 7.56 (d, 7 = 1.2 Hz, 1H). 7.52 (dd, 7 = 8.0, 1.2 Hz, 1H), 4.90 - 4.80 (m, 2H), 3. 11 - 3.07 (m, 1H), 2.94 - 2.88 (m, 1H), 2.24 - 2.18 (m, 1H), 2.12 - 2.00 (m, 1H), 1.77 - 1.70 (in, 2H). Relative and absolute stereochemistry was not determined.

Step-7: A r 2

[0975] A 1:1 mixture of rel-(4aS,9bS)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine-7- carbonitrile isomer 1 and rel-(4aR,9bR)-l,2,3,4,4a,9b-hexahydrobenzofui'o|3,2-b]pyridine-7- carbonitrile hydrochloride isomer 2 (1.5 g) was separated by prep-chiral SFC with die following conditions: [Column: NB_CHIRALPAK AD, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 100 mL/rnin: Gradient: isocratic 30% B; Wave Length: 220 nm; RTl(min): 3.34; RT2(min): 4.23; Sample Solvent: MEOH; Injection Volume: 1 .5 mL] to afford rel-(4aR,9bR)-l,2,3,4,4a,9b-bexahydrobenzofaro[3,2-b]pyridine- 7-carbonitrile, isomer 2 (A27, isomer 2) (570 mg, 40%) as a white solid with shorter retention time. Relative and absolute stereochemistry was not determined.

[0976] The chiral resolution also afford rel-(4aR,9bR)-l ,2, 3, 4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine-7-carbonitrile, isomer J (A27, isomer 1) (630 mg, 44%) as a white solid with longer retention time. Relative and absolute stereochemistry was not determined.

[0977] rel-(4aR,9bR)-l ,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine-7-carbonitri1e, isomer 2: MS ESI calculated for C -H -N -O [M+l]⁺, 201.09; found, 201.20. H NMR (400 MHz, DMSO-a'e) 6 7.46 (d, 7 = 7.6 Hz, 1H), 7.34 (dd. J = 7.6, 1.6 Hz, 1H), 7.29 (d, 7 - 1.2 Hz, 1 H), 4.56 - 4.52 (m, 1H), 4.30 (d, .7 - 6.4 Hz, 1H), 2.59 - 2.55 (m, 2H), 1.94 -1.90 (m, 2H), 1.46 -1.40 (m, 2H).

[0978] rel-(4aR,9bR)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine-7-carbonitrile, isomer 1: MS ESI calculated for C12H12N2O [M+l]⁺, 201.09; found, 201.20. ^!H NMR (400 MHz, DMSO-ds) 6 7.46 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.6, 1.6 Hz, 1H), 7.29 (d, 7 - 1.2 Hz. 1H), 4.56 - 4.52 (m, 1 H), 4.30 (d, J = 6.4 Hz, 1H), 2.59 - 2.55 (m, 2H), 1 .94 -1.90 (m, 2H), 1.46 -1.40 (m, 2H). Intermediate A28: rel-(4aS,10bS)-8-isopropoxy-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine hydrochloride

Step-1:

[0979] To a stirred solution of rel-tert-butyl (4aS,10bS)-8-hydroxy-2,3,4,4a,6,10b- hexaliydro-lH-isochromeno[4,3-b]pyridine-l -carboxylate (200 mg. 0.65 mmol) and 2- iodopropane (167 rag, 0.98 mmol) in DMF (5 mL) were added K.-CO; (271 mg, 1.96 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h. The mixture was allowed to cool at room temperature and diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCE- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 ~ 20% EtOAc in PE to afford rel-tert-butyl (4aS,10bS)-8-isopropoxy-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine-l -carboxylate (105 mg, 46%) as a colorless oil. MS ESI calculated for C20H29NO4 [M+H]⁺, 348.21; found, 348.15. Absolute stereochemistry was not determined.

Step-2:

A28

[0980] To a stirred mixture of rel-tert-butyl (4aS,10bS)-8-isopropoxy-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine-l -carboxylate (140 mg, 0.40 mmol) in DCM (1 mL) was added HC1 (4M in 1 ,4-dioxane) (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford rel-(4aS,10bS)-8-isopropoxy-2,3,4,4a,6,l0b-hexahydro-lH- isochromeno[4,3-b]pyridine hydrochloride (A28) (104 nig, 94%) as a white solid. MS ESI calculated for C15H21NO2 [M+H]⁺, 248.16; found, 248.15. TI NMR (400 MHz, DMSO-de) 6 9.57 (d, J = 11.2 Hz, 1 H), 8.51 (d, J - 11.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.89 (dd, J = 8.4, 2.4 Hz, 1H), 6.75 (d, J - 2.4 Hz, 1H), 4.95 - 4.75 (m, 2H), 4.71 - 4.58 (m, 1H), 4.20 (d,

./ - 10.0 Hz, 1H), 3.93 - 3.92 (m, 1H), 3.19 - 2.92 (m, 2H), 2.05 - 1.93 (m, 1H), 1.91 - 1.74 (m, 2H), 1 .72 - 1.58 (m, 1H), 1.26 (d, J = 6.0 Hz, 6H). Absolute stereochemistry was not determined. Intermediate A29: rel-(4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b']dipyridine hydrochloride

A29

Step- 1 : [0981] To a stirred solution of methyl 3-bromo-6-chloropicoliiiate (10.00 g, 39.92 mmol) and Nal (17.95 g, 119.76 mmol) in MeCN (100 mb) was added TMSC1 (5.20 g, 47.90 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combi Flash (Biotage Isolera Prime) with a 120 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford methyl 3-bromo-6-iodopicolinate (6.1 g, 44% yield) as a white solid. MS ESI calculated for C₇H₅BrINO₂ [M+H]⁺, 341.85, 343.85; found, 341.80, 343.80.

Step-2:

[0982] To a stirred solution of methyl methyl 3-bromo-6-iodopicolinate (6.00 g, 17.54 mmol) and Cui (5.35 g, 28.07 mmol) in NMP (60 mL) were added KF (1.53 g, 26.32 mmol) and trimethyl(trifluoromethyl)silane (3.74 g, 26.32 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combi Flash (Biotage Isolera Prime) with a 120 g silica gel column eluted with 0-15% ethyl acetate in petroleum ether to afford methyl 3-bromo-6-(trifluoromethyl)picolinaie (2.1 g. 42% yield) as a lightyellow oil. MS ESI calculated for CgHsBrFjNCh [M+H]⁺, 283.95, 285.95; found, 283.95, 285.95.

Step-3:

[0983] To a stirred solution of methyl 3-bromo-6-(trifluoromethyl)picolinate (20.00 g, 70.41 mmol) and (E)-ten-butyldiphenyl((5-(4,4,5,5-tetramethy1- 1 ,3,2-dioxaboro]an-2- y])pent-4-en-l-yl)oxy)silane (31.72 g, 70.41 mmol) in 1,4-dioxane (80 mL) and H2O (8 mL) were added K2CO3 (29.19 g, 211.24 mmol) and Pd(dppf)Ch-CH2C12 (5.75 g, 7.04 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO^ After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combi Flash (Biotage Isolera Prime) with a 330 g silica gel column eluted with 0-15% ethyl acetate in petroleum ether to afford methyl (E)-3-(5-((tert-butyldiphenylsilyl)oxy)penl-l-en-l-yl)-6- (trifluoromethyl)picolinate (31 g, 83% yield) as a yellow oil. MS ESI calculated for C29H32F3NO3S1 [M+H]⁺, 528.21 ; found, 528.25.

Step-4:

[0984] To a stirred solution of tert-butyl carbamate (30.28 g, 258.50 mmol) in propan- l-ol (323 mL) and a solution of NaOH (9.01 g, 225.14 mmol) in H2O (282 mL), then 1,3- dichloro-5,5-dimetliylimidazolidine-2, 4-dione (32.86 g, 166.77 mmol) was added at room temperature. After stirring at room temperature for 20 minutes, a solution of (DHQ)₂PHAL (supplier: Shanghai Accela ChemBio Co.. Ltd. CAS# 140924-50-1) (6.50 g, 8.33 mmol) in propan- l-ol (83 mL), a solution of methyl (E)-3-(5-((tert-butyldiphenylsilyi)oxy)penH-en-l- yl)-6-(trifluoromethyl)picolinate (44.00 g, 83.38 mmol) in propan- l-ol (44 mL) and Potassium osmate(Vl) dihydrate (3.07 g, 8.33 mmol) were added to the mixture at 0 °C. Hie resulting mixture was stirred for 16 h at room temperature. Hie reaction mixture was diluted by water and extracted with ElOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. Hie residue was dissolved in DCM (300 niL), then DCC (11.05 g, 53.57 mmol) and DMAP (0.60 g, 4.87 mmol) were added to the mixture at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Combi Flash (Biotage Isolera Prime) with a 330 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford rel-tert-butyl N-[(5S,6S)-6-{3-[(tert-butyldipheny1silyl)oxy]propyl}-8-oxo-2- (trifluoromethyl)-5H,6H-pyrano[3,4-b]pyridin-5-yl]carbaniate (28 g, 53% yield) as a brown oil. MS ESI calculated for C33H39F3N2O5S1 [M+H]⁺, 629.26; found, 629.30. Absolute stereochemistry was not determined.

Step-5 :

[0985] To a stirred solution of rel-tert-butyl ((5S,6S)-6-(3-((tert- butyldiphenylsilyl)oxy)propyl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate (30.00 g, 47.71 mmol) in methanol (300 raL) was added NaBI-ff (3.25 g, 85.88 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with ice water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCff After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) with a 330 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether to afford rel-tert-butyl ((1 S,2S)-5- ((tert-butyldiphenylsilyl)oxy)-2-hydroxy-l-(2-(hydroxymethyl)-6-(trifluorometbyl)pyri din-3- yllpentyl [carbamate (14.4 g, 47% yield) as a yellow oil. MS ESI calculated for CaaHisFsNzOsSi [M+H]*, 633.29; found, 633.25. Absolute stereochemistry was not determined.

Step-6;

[0986] To a stirred solution of rel-tert-butyl ((lS,2S)-5-((tert-butyldiphenylsilyl)oxy)-2- hydroxy-l-(2-(hydroxymethyl)-6-(trifluorojtnethyl)pyridin-3-y1)pentyl)carbamate (14.40 g, 22.75 mmol) in toluene (144 ml.,) was added 2-(tributyl-X^s-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (10.98 g, 45.51 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 1 10 "C for 16 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by Combi Flash (Biotage Isolera Prime) with a 120 g silica gel column eluted with 0-15% ethyl acetate in petroleum ether to afford rel-tert-butyl ((5S,6S)-6-(3-((tert-butyldiphenylsilyl)oxy)propyl)- 2-(trifluoromethyl)-5₎8-dihydro-6H-pyrano[3,4-b]pyridin-5-y1)carbamate (4.5 g, 32% yield) as a brown oil. MS ESI calculated for C33H41F3N2O4S1 [M+HJ⁺, 615.28; found, 615.25.

Absolute stereochemistry was not determined.

Step-7 :

[0987] To a stirred solution of rel-tert-butyl ((5S,6S)-6-(3-((tert- butyldiphenyIsilyl)oxy)propyl)-2-(trifluoronietbyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5- yl)carbamate (4.50 g, 7.32 mmol) in THE (45 mL) was added TBAF (2.30 g, 8.78 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was purified by Combi Flash (Biotage Isolera Prime) with a 120 g silica gel column eluted with 0-60% ethyl acetate in petroleum ether to afford rel-tert-butyl ((5S.6S)-6-(3-hydtx>xypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate (1.70 g, 61% yield) as a brown oil. MS ESI calculated for C17H23F3N2O4 [M-t-H]*, 377.16; found, 377.10. Absolute stereochemistry was not determined. Step-8:

[0988] To a stirred solution of rel-tert-butyl ((5S,6S)-6-(3-hydroxypropyl)-2- (trifluoromethyl')-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (1.70 g, 4.51 mmol) in toluene (17 ml) was added 2-(tributyl-X⁵-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (2.18 g, 9.03 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 3 h under nitrogen atmosphere. 75% desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 80 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether within 25 min to afford rel-tert-butyl (4aS,10bS)-8-(trilluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b']dipyridine4 -carboxylate (1.1 g, 85% e.e.) as a white solid, which was purified by Prep-Chiral-SFC with the following conditions [Column: CHIRALPAK IG, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA (0.1 % 7M NH3-MeOH); Flow rate: 80 mL/min; Gradient (B%): isocratic 10% B; RTl(min): 4.8; RT2(min): 6; Sample Solvent: MEOH] to afford rel-tert-butyl (2S,7S)-12-(trifluororoelhyl)-8-oxa-3,l 1- diazatricyclo[8.4.0.0^A]2,7}]tetradeca-l(14).10,12-triene-3-carboxylate (940 mg, 99%) as a white solid with longer retentiontime. MS ESI calculated for C17H21F3N2O3 [M+H]⁺, 359.15; found, 359.10. Absolute stereochemistry was not determined.

Step-9:

A29

[0989] A mixture of rel-tert-butyl (4aS, lObS) ■8-(trifluoromethyl)-2,3,4,4a,6, 10b- hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridine-l-carboxylate ( 1.70 g, 4.74 mmol) and hydrogen chloride (4.0 M in ethyl acetate) (17 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to afford rel-(4aS,10bS)-8- (tifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridine hydrochloride (A29) (1.1 g, 78% yield) as a white solid. MS ESI calculated for CnHuFabhO f.M+H]⁺, 259.10; found, 259.10. *H NMR (400 MHz, DMSO-d₆) 8 10.40 (br, 1H), 8.93 (br, 1H), 8.41 (d, 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 5.09 - 4.80 (m, 2H), 4.55 - 4.54 (m, 1H), 4.14

(s, 1H), 3.25 - 3.24 (m, 1H), 3.07 - 3.06 (m, 1H), 2.14 - 1.58 (m, 4H).

[0990] Absolute stereochemistry of A29 was determined by single crystal X-ray crystallography of a compound, prepared using A29. A29 is now represented by the structure: A²® , having the chemical name of (4aS,10bS)-8-(trilluoromethyl)-2,3,4,4a,6,10b- hexahydro- 1 H-pyrano [ 3 ,2-b : 5 ,4-b’ jdipyridine hydrochloride.

Intermediate A30: (3R,4aR*,10bR*)-8-(difluoromethoxy)-3-rnetboxy-2,3,4,4a,6,10b- hexahydro- lH-isochromeno| 4,3 -bjpyridine [0991] To a stirred solution of trimethylsilylacetylene (7.80 g, 79.64 mmol) in THF (400 mL) were added n-Butyllithium (2.5 M in n-hexane) (32.00 mL, 80.00 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 20 minutes. Then boron trifluoride diethyl etherate (11.3 g. 79.64 mmol) was added dropwise at -78 °C. After stirring at -78 °C for additional 40 minutes, a solution of (R)-tert-butyldiraethyl(oxiran- 2-yimethoxy)silane (supplier: Shanghai Haohong Pharmaceutical Co., Ltd. CAS#124150-87- 4) (5.00 g, 26.54 mmol) in THF (100 mL) was added dropwise to above mixture at -78 °C. The resulting mixture was allowed to warm at room temperature with stirring for overnight. The reaction was quenched by the addition of NaHCCh (sat.) at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous N32SO4. After filtration, the filtrate was concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography, eluted with 0-70% ethyl acetate in petroleum ether to afford (R)-l-((tert-butyldimethylsilyl)oxy)-5-(trimethylsilyl)pent-4-yn-2- ol (7.6 g, 65%) as a yellow oil. MS ESI calculated for CuHjoOiSii [M+H]⁺, 287.18. found, 287. 15. (400 MHz, DMSO-ds) 5 4.87 (d, J = 4.8 Hz, 1H), 3.62 - 3.57 (m, 1H), 3.56 - 3.50 (m, 2H), 2.43 - 2.20 (m, 2H), 0.88 (s, 9H), 0.11 (s, 9H), 0.05 (s, 6H).

Step-2:

[0992] To a mixture of (R)-l-((tert-butyldimethylsilyl)oxy)-5-(trimethylsilyl)pent-4-yn-2- ol (7.00 g, 24.42 mmol) and N¹,N¹,N⁸,N⁸-tetramethylnaphthalene-l,8-diamine (10.5 g, 48.85 mmol) DCM (70 mL) was added Trimethyloxonium tetrafluoroborate (7.20 g, 48.85 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether to afford (R)- tert-butyl((2-methoxy-5-(trimethylsilyl)pent-4-yn-l-yl)oxy)dimethylsilane (5.20 g, 70%) as a yellow oil. MS ESI calculated for CisILcChSii [M+H]⁺, 301.19. found, 301. 10. ^!H NMR (400 MHz, DMSO-Je) 5 3.73 - 3.60 (m, 2H), 3.33 - 3.27 (m, 4H), 2.42 (d, J - 6.0 Hz, 2H), 0.88 (s, 9H), 0.11 (s, 9H), 0.05 (s, 6H).

Step-3:

[0993] To a solution of (R)-tert-butyl((2-methoxy-5-(trinaethylsilyl)pent-4-yn- 1- yl)oxy)dimethylsilane (8.50 g, 28.27 mmol) in methanol (85 mL) was added K2CO3 (7.80 g, 56.55 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford (R)-tert-butyl((2-methoxypent-4-yn-l-yl)oxy)dimethylsi1ane (2.80 g, 43%) as a yellow oil. MS ESI calculated for CfoffoXhSi [M+H]⁺,229.15. found, 229. 10. 'H NMR (400 MHz, DMSO-tfc) 5 3.69 - 3.59 (m, 2H), 3.34 - 3.28 (m, 4H), 2,80 (t, ./ = 4.0 Hz, 1H), 2,45 - 2,27 (m, 2H), 0.87 (s, 9H), 0.05 (s, 6H).

Step-4:

[0994] To a stirred mixture of 4,4.5,5-tetramethyl- l ,3,2-dioxaborolane (5.60 g, 43.78 mmol) and (R)-tert-butyl((2-methoxypent-4-yn-l-yl)oxy)dimethylsilane (4.00 g, 17.51 mmol) were added bis(cyclopenta-l,3-dien- l-yl)zirconiunibis(ylium) chloride hydride (0.90 g, 3.50 mmol) and EtaN (1.00 g, 10.50 mmol) at room temperature. The resulting solution was stirred at 60 °C for 16 h. The reaction mixture was purified by silica gel column, eluted with 0-30% ethyl acetate in petroleum ether to afford (R,E)-tert-butyl((2-methoxy-5-(4, 4,5,5- tetraniethyl- l,3,2-dioxaborolan-2-yl)pent-4-en-l-yl)oxy)dirnethylsilane (2.30 g, 36%) as a colorless oil. MS ESI calculated for CisHs-BOrSi [M+H]⁺, 357.26. found, 357.20. ’ll NMR (400 MHz, DMSO-rfc) 5 6.55 - 6.47 (m, 1H), 5.38 (dl, J = 18.0, 1.6 Hz, 1H), 3.60 - 3.50 (m, 2H). 3.36 - 3.31 (m, 4H), 2.37 - 2.20 (m, 2H), 1,19 (s, 12H), 0.87 (s, 9H), 0.04 (s, 6H).

Step-5 :

[0995] To a stirred solution of (R,E)-tert-butyl((2-methoxy-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy)dimethylsilane (2.30 g, 6.45 mmol) in dioxane (23 mL) and H?O (2.3 mL) were added methyl 2-bromo-5-(difluoromethoxy)benzoate (2.20 g, 7.74 mmol), Pd(dppf)Ch (0.47 g, 0.64 mmol) and K2CO3 (2.70 g, 19.36 mmol) at room temperature. The resulting solution was stirred at 100 °C for 16 h. The solvents were removed under vacuum. The residue was purified by silica gel column chromatography, eluted with 0- 50% ethyl acetate in petroleum ether to afford methyl (R,E)-2-(5-((tert- butyldimethylsilyl)oxy)-4-methoxypent-l-en-l-yl)-5-(difluoromethoxy (benzoate (1.70 g, 61%) as a colorless oil. MS ESI calculated for CisHrrBCLSi [M+H]*, 431 .20.; found, 431.20.

Step-6:

[0996] A solution of tert-butyl carbamate (3.71 g, 31.68 mmol) and NaOH (1.10 g, 27.59 mmol) in propan- l-ol (102 mL) and H2O (69 mL) was stirred at room temperature for 10 minutes, then DCDMH (3.02 g, 15.33 mmol) was added in portions at room temperature. After stirring at room temperature 30 minutes, a solution of methyl (R,E)-2-(5-((tert- butyldirnethylsilyl)oxy)-4-methoxypent-l-en-l-yl)-5-(difluoromethoxy)benzoate (4.4 g, 10.22 mmol) in propan- l -ol (102 mL), (DHQ)iPHAL (supplier: Shanghai Accela ChemBio

Co., Ltd. CAS# 140924-50-1) (0.80 g, 1.02 mmol) and Potassium osmate(Vl) dihydrate (0.38 g, 1.02 mmol) were added to the mixture at 0 °C. The resulting mixture -was stirred at room temperature for 16 h. The reaction was quenched with brine at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-70% ethyl acetate in petroleum ether to afford tert-butyl ((3R*,4R*)-3-((R)-3-((tert- butyldimethylsilyl)oxy)-2-methoxypropyl)-7-(difluoromethoxy)-l-oxoisochroman-4- yljcarbamate (2.40 g, 44%) as a yellow oil. MS ESI calculated for CzsHiw^NOvSi [M+H]⁺, 532.25: found, 532.25. Absolute stereochemistry was not determined.

Step-7 :

[0997] To a stirred solution of tert-butyl ((3R*,4R*)-3-((R)-3-((tert- butyldimethylsilyI)oxy)-2-methoxypropyl)-7-(difluoromethoxy)-l-oxoisochroman-4- yl)carbamate (2.40 g, 4.51 mmol) in THF (25 mL) were added NaBlli (0.85 g, 22.47 mmol) and boron trifluoride diethyl etherate (3.20 g, 22.57 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford tertbutyl ((3R*,4R*)-3-((R)-3-((tert-bulyldimelhylsilyl)oxy)-2-methoxypropyl)-7- (difluoromethoxy)isochroman-4-yl)carbamate (1.40 g, 60%) as a yellow oil. MS ESI calculated for CcsIEiFjNOeSi 518.27; found, 518.35. .Absolute stereochemistry was not determined.

Step-8:

[0998] To a stirred solution of tert-butyl ((3R*,4R*)-3-((R)-3-((tert- butyldimethylsilyl)oxy)-2-methoxypropyl)-7-(difluoromethoxy)isochroman-4-yl (carbamate (1.00 g, 1.93 mmol) in THF (10 mL) was added TBAF (0.76 g, 2.90 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography , eluted with 0-80% ethyl acetate in petroleum ether to afford tertbutyl ((3R*,4R*)-7-(difluorome1hoxy)-3-((R)-3-hydroxy-2-methoxypropyl)isochroman-4- yl)carbamate (0.70 g, 90%) as a yellow oil. MS ESI calculated for CwHj^FzNOe [M+H]’, 404.18; found, 404.10. Absolute stereochemistry was not determined.

Step-9:

[0999] To a stirred solution of tert-butyl ((3RMR*)-7-(difluoromethoxy)-3-((R)-3- hydroxy-2-methoxypropyl)isocbroman-4-yl)carbamate (480 mg, 1.19 mmol) in toluene (5 niL) was added 2-(tributyl-X⁵-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (574 mg, 2.38 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 1 10 °C for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford tert-butyl (3R,4aR*,10bR*)-8-(difluoromethoxy)-3-methoxy- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine-l -carboxylate (350 mg, 76%) as a yellow oil. MS ESI calculated for Cs^FiNOs [M+H]\ 386.17; found, 386.15. Absolute stereochemistry was not determined.

Step- 10:

[1000] A solution of tert-butyl (3R,4aR*,10bR*)-8-(difluoromethoxy )-3-methoxy- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine-l -carboxylate (350 mg, 0.91 mmol) and hydrogen chloride (4.0 M in ethyl acetate) (4 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford (3R,4aR* , 10bR*)-8-(difluoromethoxy)-3-methoxy-2,3,4,4a,6, 1 Ob-hex ahydro- 1 H- isochromeno[4,3-b]pyridine (A30) (300 mg, crude) as a grey oil. MS ESI calculated for C14HI7F2NO3 [M+H]⁺, 286.12; found, 286.15. ’H NMR (400 MHz, DMSO-cfc) 8 9.86 (br, 1H), 8.64 (br, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 73.8 Hz, 1H), 7.17 (dd, J = 8.4, 2.6 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 4.97 - 4.61 (m, 2H), 4.35 - 4.31 (m, 1H), 3.97 - 3.96 (m, 1H), 3.68 - 3.67 (m, 1H), 3.30 - 3.23 (m, 5H). 2.37 - 2.32 (m, 1H), 2.02 - 1.99 (m, 1H). Absolute stereochemistry was not determined.

Intermediate A32, isomer 1: rel- tert-butyl (4aR,10bR)-8-(trifluoromethyl)-l,2,3,4a,5,10b- hexahydro-4H-chromeno[3,4-b]pyrazine-4-carboxylate, isomerl

A32, isomer 1

Step-1 :

[1001] To a solution of 7-( trifluoromethyl)chroman-4-one (24.00 g, 111.02 mmol) in MeOH (240 mL) was added NaBHa (8.40 g, 222.05 mmol) in portions at 0 °C. The mixture was sdrred at room temperature for 2 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-48% ethyl acetate in petroleum ether to afford 7- (trifluoromethyl)chroman-4-ol (23.20 g, 95%) as a white solid. MS ESI calculated for Cs-Hfo .O - [M+H]⁺, 219.06; found, 219.05.

Step-2:

[1002] To a solution of 7-(trifluoromethyl)chronian-4-ol (22.20 g, 101.75 mmol) in toluene

(220 mL) was added TsOII (35.04 g, 203.50 mmol) at room temperature. The mixture was stirred at 100 °C for 0.5 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed 'with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-60% ethyl acetate in petroleum ether to afford 7-(trifluoromethyl)- 2H-chromene ( 10.10 g, 49%) as a colorless oil. MS ESI calculated for CioHvFrO 201.04; found, 201.00.

Step-3 : [1003] A solution of 7-(trifluoromethyl)-2II-chromene ( 10.10 g, 50.46 mmol) in THF (75.0 mL) and H2O (25.0 mL) was added NBS (9.88 g, 55.50 mmol) at. 0 °C, then the mixture was stirred at 0 °C for 16 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0 - 45% ethyl acetate in petroleum ether to afford intermidiate (8.70 g) yellow oil. which was dissolved in MeOH (8.0 mL), then ammonium hydroxide (28% in water) (80.0 mL) was added. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue -was purified by flash column chromatography with 0 ~ 45% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of (3R,4S)-4-amino-7- (trifluoromethyl)chroman-3-ol and (3S,4R)-4-amiiio-7-(trifluoroniethyl)chroman-3-ol (4.8 g, 74%) as a colorless oil. MS ESI calculated for C10H10F3NO2 [M+H]⁺, 234.07; found, 234.10.

Step-4:

[1004] A solution of a 1: 1 mixture of (3R,4S)-4-amino-7-(irifluoromethyl)chroman-3-ol and (3S,4R)-4-amino-7-(trifluoromethyl)chroman-3-ol and tert-butyl N-(2- oxoethyl (carbamate (2.18 g, 13.72 mmol) in MeOH (40.0 mL) was stirred at room temperature for 2 h. NaBH4 (1.04 g, 27.44 mmol) was added in portions to above solution.

Then the mixture was stirred at room temperature for 2 h. The mixture was quenhed by water and extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-80% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl (2-(((3R,4S)-3- bydroxy-7-(trifiuoromethyl)chroman-4-yl)ainino)ethyl)carbamate and tert-butyl (2-(((3S,4R)~ 3-hydroxy-7-(trifTuoromethyl)chroman-4-yl)aniino)ethyl)carbamate (3.10 g, 60%) as a white solid. MS ESI calculated for C17II23F3N2O4 [M+H]⁺, 377.16, found, 377.20.

[1005] To a solution of a 1 : 1 mixture of tert-butyl (2-(((3R,4S)-3-hydroxy-7- (trifiuoromethyl)chroman-4-yl)amino)ethyl)carbamate and tert-butyl (2-(((3S,4R)-3-hydroxy- 7-(trifluoromethyl)chroman-4-yl)aniino)ethyl)carbamate and NaHCO3 (9.44 g, 112.38 mmol) in 1,4-dioxane (150.0 mL) was added CbzCl (9.59 g, 56.19 mmol) drop wise at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by Hash column chromatography with 0 ~ 60% ethyl acetate in petroleum ether to afford a 1 : 1 mixtire of benzyl (2-((tert-butoxycartxmyl)amino)ethyl)((3R,4S)-3-hydroxy-7-

(trifluoromethyl)chroman-4-yl)carbamate and benzyl (2-((tert- butoxycarbonyl)aminojethyl)((3S,4R)-3-hydroxy-7-(lrifluoromethyl)chroman-4-yl)carbamate (15.4 g, 80%) as a colorless oil. MS ESI calculated for C25H29F3N2O6 [M+H]⁺, 511.20; found, 511.20. Step-6:

[1006] A solution of a 1 : 1 mixtire of benzyl (2-((lert- butoxycarbonyl)aniino)ethyl)((3R,4S)-3 -hydroxy ■■7-(trifluoromethyl)chronian-4-yl)carbamate and benzyl (2-((tert-butoxycarbonyl)amino)ethyl)((3S,4R)-3-hydroxy-7- (trifluorornethyl)chroman-4-yl)carbamate (15.00 g, 29.38 mmol) and HC1 (4M in 1,4- dioxane) ( 150.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated to afford a 1:1 mixture of benzyl (2-aminoethyl)((3R,4S)-3-hydroxy-7- (trinuoromethyl)chroman-4-yl)carbamate and benzyl (2-aminoethyl)((3S,4R)-3-hydroxy-7-

(trifluoromethyl)chroman-4-yl)carbamate (15.00 g, crude) as a yellow oil. MS ESI calculated for C20H21F3N2O4 [M+Hf^l, 411.15; found, 411.15.

Step-7 :

[1007] To a solution of a 1 : 1 mixture of benzyl (2-aminoethyl)((3R,4S)-3-hydroxy-7- (trifluoromethyl)chroman-4-yl)carbamate and benzyl (2-aminoethyl)((3S,4R)-3-hydroxy-7- (trifluoromethyl)chroman-4-yl)carbamate (15.00 g, 36.550 mmol) and pyridine (8.67 g, 109.65 mmol) in DCM (150.0 mL) was added 2-nitrobenzenesulfonyl chloride (9.72 g, 43.86 mmol) at 0 °C. Then the mixture was stirred at room temperature for 4 h. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-80% ethyl acetate in petroleum ether to afford a 1: 1 mixture of benzyl ((3R,4S)-3 -hydroxy-7-

(trifluoromethyl)chroman-4-yl)(2-((2-nitrophenyl)sulfonamido)ethyl)carbamate and benzyl ((3S,4R)-3-hydroxy-7-(trifluoromethyl)chroman-4-yl)(2-((2- nitrophenyl)sulfonamido)ethyl)carbamate (6.80 g, 31%) as a yellow oil. MS ESI calculated for CreHcrFsNaOsS [M+H]⁺, 596.12; found. 596.15.

Step-8: [1008] To a solution of a 1 : 1 mixture of benzyl ((3R,4S)-3-hydroxy-7- (trifluoromethyl)chroman-4-yl)(2-((2-nitrophenyl)sulfonamido)ethyl)carbamate and benzyl ((3S,4R)-3-hydroxy-7-(trifluoromethyl)chroman-4-yl)(2-((2- nitropbenyl)sulfbnaniido)ethyl)carbamate (6.80 g, 5.03 mmol) and PPhs (4.48 g, 7.55 mmol) in TITF (68.0 ml.,) was added DIEA (4.42 g, 15.1 1 mmol) at 0 °C under nitrogen atmosphere.The mixture was stirred at room temperature for 4 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-25% ethyl acetate in petroleum ether to afford a 1: 1 mixture of benzyl (4aS,10bS)-4-((2-nitrophenyl)sulfonyl)-8-

( tritluoromethyl)-3, 4,4a, 10b-tetrahydro-2H-chronieno[3,4-b]pyrazine-1 (5H)-carboxy late and benzyl (4aR,10bR)-4-((2-nitrophenyl)sulfonyl)-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro- 2H-chromeno[3,4-b]pyrazine-l(5H)-carboxylate (4.10 g, 79%) as a yellow oil. MS ESI calculated for C26H22F3N3O7S [M+H]⁺, 578.11; found, 578.10.

Step-9:

[1009] To a stirred solution of a 1 : 1 mixture of benzyl (4aS, 10bS)-4-((2- nitrophenyJ)sulfonyl)-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[3,4- b]pyrazine- 1(5H) -carboxylate and benzyl (4aR,10bR)-4-((2-nitrophenyl)sulfonyl)-8- (trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[3,4-b|pyrazine-l(5H)-carboxylate (4.10 g, 0.69 mmol) in DMF (40.0 ml.,) were added LiOH (1 .70 g, 6.93 mmol) and 2- sulfanylacetic acid (3.80 g, 4.15 mmol) at room temperature. The mixture was stirred at room temperature for 4 h under nitrogen atmosphere. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-55% ethyl acetate in petroleum ether to afford a 1: 1 mixture of benzyl (4aS,10bS)-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[3,4- bjpyrazine- 1 (5H)-carboxylate and benzyl (4aS, 10bS)-8-(trifluoromethyl)-3,4,4a, 10b- tetrahydfo-2H-chromeno[3,4-b]pyrazine-1(5H)-carboxylale (1.90 g, 73%) as a yellow oil.

MS ESI calculated for C 20H :■% 3N2O3 [M+H] ⁺, 393.13; found, 393. 15.

Step- 10:

[1010] To a stirred solution of a 1: 1 mixture of benzyl (4aS,10bS)-8-(trifluoromethyl)- 3,4,4a,10b-tetrahydro-2H-chromeno[3,4-b]pyrazine-l(5H)-carboxylate and benzyl (4aS,10bS)-8-(trifluoromethyl)-3,4,4a, 10b-tetrahydro-2H-chromeno[3,4-b]pyrazine-l(5H)- carboxylate (1.90 g, 4.84 mmol) in THE (20.0 ml) were added TEA (1.47 g, 14.52 mmol) and BocsO (1.59 g, 7.26 mmol) at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-55% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of 1- benzyl 4- (tert-butyl) (4aS,10bS)-8-(trifluoromethyl)-2,3,4a,10b-tetraliydro-4H-chromeno[3,4- b]pyrazine-l,4(5H)-dicarboxylate and 1 -benzyl 4-(tert-butyl) (4aR,10bR)-8- (trinuoromethyr)-2,3,4a,10b-tetrahydro-4H-chromeno[3,4-b]pyrazine-l,4(5H)-dicarboxylate (1.50 g, 63 %) as a yellow oil. MS ESI calculated for C25H27F3N2O5 [M+H]⁺, 493.19; found, 493.19.

Step- 1 1 :

[1011] A 1 :1 mixture of 1 -benzyl 4-(tert-butyl) (4aS, 10bS)-8-(trifiuoromethyl)-2,3,4a, 10b- tetrahydro-4H-chromeno[3,4-b]pyrazine-1 ,4(5H)-dicarboxylate and 1 -benzyl 4-(tert-butyl) (4aR,10bR)-8-(trifluoromethy1)-2,3,4a, 10b-tetrahydro-4H-chromeno[3,4-b]pyrazine-l,4(5H)- dicarboxylate (1.5 g, 3.04 mmol) was separated by Prep-Chiral SFC with the following conditions [Column: CHIRALPAK PAK AD-H, 30*250mm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 100 mL/niin: Gradient (B%): isocratic 20% B; RTl(min): 2.6; RT2(min): 4.8; Sample Solvent: MEOH] to afford rel-l-benzyl 4-(tert-butyl) (4aR,10bR)-8- (trifluoromethyl)-2,3,4a,10b-tetrahydro-4H-chromeno[3,4-b]pyrazine-l ,4(5H)-dicarboxylate, isomer 1 (600 mg, 40%) as a colorless oil. MS ESI calculated for C25H27F3N2O5 [M+l]⁺. 493.19; found, 493.20. TI NMR (400 MHz, DMSO-O 57.52 - 7.24 (m, 7H), 7.23 - 7.17 (m, IH), 5.77 (d, 7 = 6.8 Hz, 1H), 5.34 - 5.16 (m, 2H), 4.55 - 4.49 (m, 1H), 4.40 - 4.26 (m, 2H), 3.97 - 3.84 (m, 1H), 3.55 - 3.49 (m, 1H), 3.21 - 3.15 (m, 1H), 2.68 - 2.59 (m, 1H), 1.44 (s, 9H). Absolute stereochemistry was not determined.

[1012] The chiral resolution also afford rel- 1 -benzyl 4-(tert-butyl) (4aR,10bR)-8- (trifluoromethyl)-2,3,4a,10b-tetrahydro-4H-chromeno[3,4-b]pyrazine-l ,4(5H)-dicarboxylate. isomer 2 (610.0 rng, 41 % ) as a colorless oil. MS ESI calculated for C25H27F3N2O5 [M+ 1 ]⁺, 493.19; found, 493.20. ^!H NMR (400 MHz, DMSO-de) 8 7.52 - 7.24 (m, 7H), 7.23 - 7.17 (m, IH), 5.77 (d, 7 = 6.8 Hz, 1H), 5.34 - 5. 16 (m, 2H), 4.55 - 4.49 (m, 1H), 4.40 - 4.26 (m, 2H), 3.97 - 3.84 (m, IH), 3.55 - 3.49 (m, IH), 3.21 - 3.15 (m. 1H), 2.68 - 2.59 (m, 1H), 1.44 (s, 9H). Absolute stereochemistry was not determined.

A32, isomer 1

[1013] To a solution of rel- 1 -benzyl 4-(tert-butyl) (4aR,10bR)-8-(trifluoromethyl)-

2,3,4a,10b-tetrahydro-4H-chromeno[3,4-b]pyrazine-l,4(5H)-dicarboxylate, isomer 1 (100 mg, 0.40 mmol) in isopropanol (2.0 mL) was added Pd/C (5% active on carbon) (22 mg) at room temperature. The mixture was stirred at room temperature for 4 h under hydrogen atmosphere (1 atm.). The solids were filtered off. The filtrate was concentrated under vacuum to afford rel-tert-butvl (4aR,10bR)-8-(trifluoromethvl)-l,2,3,4a,5,10b-hexahydro-4H- chromeno[3,4-b]pyrazine-4-carboxylate, isomer 1 (A32, isomer 1) (100.0 nig, crude) as a colorless oil that was used directly in next reaction. MS ESI calculated for C17H21F3N2O3 [M+H]\ 359.15; found, 359.15. Absolute stereochemistry was not determined.

Intermediate A32, isomer 2: rel-tert-butyl (4aR,10bR)-8-(trifluoromethy1)-l,2,3,4a,5,10b- hexahydro-4H-chromeno[3,4-b]pyrazine-4-carboxylale, isomer 2

A32, isomer 2

[1014] To a solution of rel- 1 -benzyl 4-(tert-butyl) (4aR, 10bR)-8-(trifluoromethyl)-

2,3,4a, 10b-tetrahydro-4H-chromeno[3,4-b]pyrazine-l,4(5H)-dicarboxylate, isomer 2 ( 100 mg, 0.40 mmol) in isopropanol (2.0 mL) was added Pd/C (5% active on carbon) (21 mg) at room temperature. The mixture was stirred at room temperature for 4 h under hydrogen atmosphere (1 atm.). The solids was filtered off. The filtrate was concentrated under vacuum to afford rel-tert-butyl (4aR,10bR)-8-(trifluoroniethyl)-l,2,3,4a,5,10b-hexahydro-4H- chromeno[3,4-b]pyrazine-4-carboxylate. isomer 2 (A32, isomer 2) (100.0 mg, crude) as a colorless oil. MS ESI calculated for C17H21F3N2O3 [M+H]⁺, 359.15; found, 359.15. Absolute stereochemistry was not determined.

Intermediate A33: rel-(4aS,9bS)-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b’]dipyridine-7- carbonitrile

A33

Step-1 :

[1015] To a stirred solution of 3-bromo-2,6-dichloropyridine (25.00 g, 110. 19 mmol) and (E)-tert-butyldiphenyl((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pent-4-en-l- yl)oxy)silane (54.60 g, 121.20 mmol) in dioxane (250 mL) and H2O (25 mL) were added Pd(dppf)C12 (8.06 g, 1 1 .01 mmol) and K2CO3 (45.69 g, 330.57 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% EtOAc in PE to afford (E)-3-(5-((tert- butyldiphenylsilyl)oxy)pent-l-en-l-yl)-2,6-dichloropyridine (44.6 g, 94%) as a yellow oil. MS ESI calculated for Cj/TBClzNOSi [M+H]⁺, 470.14 ; found, 470.20.

Step-2:

[1016] To a stirred solution of tert-butyl carbamate (34.42 g, 293.85 mmol) in propan- l -ol (368 mL) was added a solution of NaOH (10.24 g, 255.93 mmol) in H2O (322 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 minutes. Then DCDMH (37.35 g, 189.58 mmol) was added in portions at room temperature. After stirring for 30 minutes, a solution of (DHQ^PHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (7.38 g, 9.47 mmol) in propan- l-ol (95 mL), a solution of (E)-3-(5-((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yI)-2,6- dichloropyridine (44.60 g. 94.79 mmol) in propan- l-ol (95 mL) and Potassium osmate (VI) dihydrate (3.49 g. 9.47 mmol) were added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCL- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% EtOAc in PE to afford rel-tert-butyl ((lS,2S) -5-((tert-butyldiphenvlsilvl)oxy)-l-(2,6-dichloropvridin-3-vl)- 2-hydroxypentyl)carbamate (16.00 g, 95%) as a green oil. MS ESI calculated for C31H40C12N2O4S1 [M+H]⁺, 603.21 ; found, 603.25. Absolute stereochemistry was not determined.

Step-3:

[1017] To a stirred solution of rel -tert-butyl ((lS,2S)-5-((tert-butyldiphenylsilyl)oxy)-l- (2,6-dichloropyridin-3-yJ)-2-hydroxypentyl)carbamate (3.00 g, 4.97 mmol) in THE (30 mL) was added TBAF (2.60 g, 9.94 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-80% EtOAc in PE to afford rel-tert-butyi ((1S,2S)- 1- (2,6-dichloropyridin-3-yD-2_>5-dihydroxypentyl)cafbaniate (1.30 g, 98%) as a yellow oil. MS ESI calculated for CJ5H22C12N2O4 [M+H]⁺, 365.10; found, 365.10. Absolute stereochemistry was not. determined.

Step-4:

[1018] To a stirred solution of rel-tert-butyi ((l S,2S)-l-(2,6-dichloropyridin-3-yl)-2,5- dihydroxypentyllcarbamate ( 1.30 g, 3.55 mmol) and Imidazole (0.97 g, 14.23 mmol) in DCM (13 mL) was added TBSC1 (0.80 g, 5.33 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by water and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NajSCM. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-24% EtOAc in PE to afford rel-tert-butyi ((lS,2S)-5-((tert-butyldimethylsilyl)oxy)-l -(2,6- dichloropyridin-3-yl)-2-hydroxypentyl)carbamate (1.44 g, 99%) as a light, yellow oil. MS ESI calculated for CiiHssCiiNsCLSi [M+H]⁺, 479.18; found, 479.25. Absolute stereochemistry was not determined.

Step-5:

[1019] To a stirred solution of rel-tert-butyl ((lS,2S)-5-((tert-butyldimethylsilyl)oxy)-l- (2,6-dichloropyridm-3-yl)-2-hydroxypenlyl)carbamale (1.40 g, 2.92 mmol) and tert- butyl(chloro)diphenylsilane (1.20 g, 4.38 mmol) in DCM (14 mL) was added imidazole (0.80 g, 11 .68 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. lire reaction was quenched by water and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na^SOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 20% EtOAc in PE to afford rel-tert- butyl ((lS,2S)-5-((tert-butyldimethylsilyl)oxy)-2-((tert-butyldiphenylsilyl)oxy)-l-(2,6- dichloropyridin-3-yl)pentyl)carbamate (1.88 g, 73%) as a light yellow oil. MS ESI calculated for CwHsaCENzCUSb [M+H]⁺, 717.30 ; found, 717.35. Absolute stereochemistry was not determined.

Step-6:

[1020] To a stirred solution of rel-tert-butyl ((lS,2S)-5-((tert-butyldimethylsilyl)oxy)-2- ((tert-butyldipheny1silyl)oxy)-l -(2,6-dichloropyridin-3-yl)pentyl)carbamate (1.88 g, 2.61 mmol) in methanol (20 mL) was added T'sOH (0.05 g, 0.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 ~ 30% EtOAc in PE to afford rel-tert-butyl ((lS,2S)-2-((tert- butyldipbenylsilyl)oxy)-l-(2,6-dichloropyridin-3-yl)-5-hydroxypentyl)carbamate (882 mg, 99%) as a colorless oil. MS ESI calculated for C • i foCi N.'Ofoi [M+H]⁺, 603.21; found, 603.20. Absolute stereochemistry was not determined.

[1021] To a stirred solution of rel-tert-butyl ((lS,2S)-2-((tert-butyldiphenylsilyl)oxy)-l- (2,6-dichloropyridin-3-yl)-5-hydroxypentyl)carbarnate (830 mg, 1.37 mmol) in toluene (10 mL) was added 2-(tributyl-X⁵-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (663 mg, 2.75 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 1 10 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0- 10% EtOAc in PE to afford rel-tert-butyl (2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-(2,6- dichloropyridin-3-yl)piperidine-l-carboxyIate (703 mg, 90%) as a white solid. MS ESI calculated for C31H38C12N2O3S1 [M+H] ¹’, 585.20; found, 585.35. Absolute stereochemistry was not determined.

Step-8:

[1022] To a stirred solution of rel-tert-butyl (2S,3S)-3-((tert-buiyldiphenylsilyl)oxy)-2-(2,6- dichloropyridin -3 -yljpiperi dine- 1 -carboxylate (680 mg, 1.16 mmol) in THF (7 mL) was added TBAF (607 mg, 2.32 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in PE to afford rel-tert-butyl (2S,3S)-2-(2,6-dichloropyridin-3-yl)- 3-hydroxypiperidine-l-carboxylate (255 mg, 99%) as a white solid. MS ESI calculated for C15H20CI2N2O3 [M+H]⁺, 347.09; found, 347.10. Absolute stereochemistry was not determined.

Step -9:

[1023] To a stirred solution of rel-tert-butyl (2S,3S)-2-(2,6-dichloropyridin-3-yl)-3- hydroxypiperidine-1 -carboxylate (220 mg, 0.63 mmol) in THF (5 mL) was added NaH (60% in mineral oil) (22 mg, 0.5'7 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% EtOAc in PE to afford rel-tert-butyl (4aS,9bS)-7-chloro- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (216 mg, 80%) as a colorless oil. MS ESI calculated for C15H19CIN2O3 [M+H] ¹, 311.11 ; found, 311.15. Absolute stereochemistry was not determined.

Step-10:

[1024] To a stirred solution of rel-tert-butyl (4aS,9bS)-7-cbloro-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b'ldipyridine-l(2H)-carboxylate (252 mg, 0.81 mmol) and Zn(CN)? (190 mg, 1.62 mmol) in DMF (3 mL) were added Zn powder (212 mg, 3.24 mmol), XPhos (38 mg, 0.08 mmol) and XPhos Pd G3 (68 mg, 0.08 mmol) al room temperature under nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 16 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% EtOAc in PE to afford rel-tert-butyl (4aS,9bS)-7-cyano-3,4,4a,9b-tetrahydrofuro[2,3- b:4,5-b']dipyridine-l(2H)-carboxylate (156 mg, 99% yield) as a colorless oil. MS ESI calculated for CisHioNsOa [M+H]⁺, 302.14 ; found, 302.20. Absolute stereochemistry was not determined. Step-11:

A33

[1025] To a stirred solution of rel -tert-butyl (4aS,9bS)-7-cyano-3.4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (126 mg, 0.41 mmol) in TEA (1 mL) and DCM (3 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting residue was purified by reverse phase flash column chromatography with 5-50% acetonitrile in water (10 mM NH4HCO3) to afford rel- (4aS,9bS )- 1 ,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b’]dipyridine-7-cafbonitrile (A33) (80.6 mg, 99% yield, 86% e.e.) as a white solid. MS ESI calculated for C11H11N3O [M+H]⁺, 202.09 ; found, 202.15. ’H NMR (400 MHz, DMSO-tfc) 6 8.09 (d, J = 7.4 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1 H), 5.07 - 4.90 (m, 2H), 3.21 - 3.16 (m, 1 H), 3.03 - 2.96 (m, 1H), 2.32 - 2.20 (m, 1 H), 2.11 - 2.04 (m, 1H), 1.86 - 1.61 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A34: (2R,4aS,10bS)-8-melhoxy-2-methyl-l,2,3,4a,5,10b- hexahydropyrido[3\2fo,6]pyrano[3,4-b][l,4]oxazme hydrochloride

Step- 1 :

[1026] To a stirred mixture of 6-fluoro-5-iodopyridm-2-amine (50 g, 210.08 mmol) and H2SO4 (250 g, 255.10 mmol) in H2O (500 mL) was added a solution of NaNCL (28.98 g, 420.03 mmol) in H2O (100 mL) dropwise at -5 °C under nitrogen atmosphere. The mixture was allowed to warm at room temperature for 16 h with stirring. The precipitated solids were collected by filtration and washed with H2O. The solids were dried under vacuum to afford 6- fluoro-5-iodopyridin-2-ol (53 g, crude) as a light yellow solid that is used directly in next reaction. MS ESI calculated for Cd hfoXO [M+l]⁺, 239.92; found, 239.90. ^]H NMR (400 MHz. DMSO-rfc) 8 (ppm) 1 1.62 (s, 1H), 8.09 (dd, J = 9.2, 8.4 Hz, 1H), 6.45 (dd, 8.4, 1.6 Hz, 1H).

[1027] To a solution of 6-fluoro-5-iodopyridin-2-ol (53 g, 220.83 mmol) in DMF (530 mL.) were added NaOH (17.74 g, 443.53 mmol) at room temperature. Then the mixture was stirred at 50 °C for 0.5 h. The reaction mixture was allowed to cool at room temperature. Then dimethyl sulfate (55.94 g, 443.53 mmol) was added dropwise to the reaction mixture at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-10% ethyl acetate in petroleum ether to afford 2-fluoro-3-iodo-6-niethoxypyridine (23.6 g, 42%) as a white solid. MS ESI calculated for C₆H₅FINO [M+l ]⁺, 253.94; found, 253.95. 'H NMR (400 MHz, DMSO-db) 5 (ppm) 8.19 (t, ./ = 8.4 Hz, 1H), 6.66 (dd, 7 = 8.4, 1.6 Hz, 1H), 3.83 (s, 3H).

Step-3:

[1028] To a stirred mixture of 2-fluoro-3-iodo-6-methoxypyridine (23.6 g, 92.91 mmol), Pd(PPh3)₂Ch (13.10 g, 18.65 mmol) and Cui (7.10 g, 37.31 mmol) in TEA (236 mL) was added tert-butyldimethyl(prop-2-yn-l-yloxy)silane (47.66 g, 279.82 mmol). The mixture was stirred at 100 °C under nitrogen atmosphere for 16 hours. The reaction mixture was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether and further purified by reverse phase flash column chromatography with 5%~90% MeCN in water to afford 3-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn-l-yl)-2- fluoro-6-methoxypyridine (20 g, 72%) as a brown oil. MS ESI calculated for C15H22FNO2S1 [M+l]⁺, 296.14; found, 296.15. 'H NMR (400 MHz, DMSO-de) 5 (ppm) 7.97 - 7.91 (m, 1H), 6.83 - 6.79 (ni, 1H), 4.57 (s, 2H), 3.87 (s, 3H), 0.89 (s, 9H). 0.13 (s, 6H).

Step-4:

[1029] To a solution of 3-(3-((tert-butyldimethylsilyDoxy)prop- 1-yn- 1 ■yl)-2-fluoro-6- methoxypyridine (20 g, 67.69 mmol) in THF (200 ml) was added TBAF (25.56 g, 101.54 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography with 0-100% ethyl acetate in petroleum ether to afford 3-(2-fluoro-6- methoxypyridin-3-y])prop-2-yn-l-ol (13.6 g, 73%) as a light yellow solid. MS ESI calculated for CaHsFNO?. [M-fo ]⁺, 182.05; found, 182.15.

Step-5 :

[1030] To a solution of 3-(2-fluoro-6-methoxypyridin-3-yl)prop-2-yn-l-ol (13.6 g, 74.72 mmol) in THF (136 ml.,) were added Lindlar catalyst (6.3 g, 59.17 mmol) and quinoline (9.56 g, 73.96 mmol) at room temperature. The mixture was stirred for 1 hour under hydrogen atmosphere (1 atm. ). The mixture was filtered, the filtrate was concentrated under vacuum. The residue was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-100% ethyl acetate in petroleum ether to afford (Z)-3-(2-fluoro-6- methoxypyridin-3-yl)prop-2-en- l-ol (22 g, crude) as a red oil MS ESI calculated for C9H10FNO2 [M+l f, 184.07; found, 184.05. Step-6:

[1031] To a solution of (Z)-3-(2-fluoro-6-methoxypyridin-3-yl)prop-2-en-l-ol (22 g, 121.10 mmol) in DMF (800 mL) were added NaH (60% in mineral oil) (3.6 g, 90 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-80% ethyl acetate in petroleum ether to afford 7-methoxy-2H- pyrano[2,3-b]pyridine (5.39 g, 44%, over 2 steps) as a light yellow oil. MS ESI calculated for C9H9NO2 [M+l ]’, 164.06; found, 164.10. ^]H NMR (400 MHz, DMSO-tfc) 8 (ppm) 7.39 id, J - 8.0 Hz, 1H), 6.44 - 6.40 (m, IH), 6.33 (d, 7 - 8.0 Hz, 1 H), 5.71 - 5.67 (m, 1H), 4.98 - 4.96 (m, 2H), 3.76 (s, 3H).

Step-7:

[1032] A mixture of tert-butyl carbamate (11.79 g, 100.69 mmol) and NaOH (3.49 g, 87.69 mmol) in propan-1 -ol (249 mL) and H2O (218 mL) was stirred at room temperature for 10 minutes. Then l,3-dichloro-5,5-dimetliylimidazolidine-2₍ 4-dione (9.59 g, 48.72 mmol) was added to above mixture at room temperature. After stirring at room temperature for 30 minutes, (DHQD)jPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140853-10-7) (2.51 g. 3.24 mmol), 7-methoxy-2H-pyrano[2,3-b]pyridine (5,30 g, 32.48 mmol) and Potassium osmate(VI) dihydrate (1.19 g, 3.24 mmol) were added to the mixture at 0 °C. The resulting mixture was allowed to warm at room temperature and stirred for 16 h. The reaction mixture was diluted by NaHCCh (sat.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-15% ethyl acetate in petroleum ether to afford 3:1 mixture of tert- butyl ((3S,4S)-3-hydroxy-7-methoxy-3,4-dihydTO-2H-pyrano[2,3-b]pyridin-4-yl)carbamate and tert-butyl ((3R,4R)-3-hydroxy-7-metboxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4- yDcarbaniate (1.31 g, 13%) as a white solid. MS ESI calculated for C14H20N2O5 (M+l]⁺, 297.14; found, 297.10. %I NMR (400 MHz, DMSO-d₆) 8 (ppm) 7.40 (d, ./ = 8.0 Hz, 1H), 6.69 (d, J = 9.2 Hz, 1H), 6.39 (d, J - 8.0 Hz, 1H), 5.28 (d, J - 4.0 Hz, 1H), 4.83 - 4.76 (m, 1H), 4.26 - 4.14 (m, 2H), 3.98 - 3.92 (m, 1H), 3.75 (s, 3H), 1.44 (s, 9H).

[1033] To a stirred 3:1 mixture of tert-butyl ((3S,4S)-3-hydroxy-7-methoxy-3,4-dihydro- 2H-pyrano[2,3-b]pyridin-4-yl)carbamate and tert-butyl ((3R.4R)-3-hydroxy-7-methoxy-3,4- dihydro-2H-pyrano[2,3-b]pyridin-4-yl)carbamate (1.3 g, 4.38 mmol) and NaOH (1.22 g, 30.71 mmol) in DCM (7.5 mb) were added (Bu4N)HSCU (297 mg, 0.87 mmol) and (S)-4- methyl-l,3,2-dioxathiolane 2,2-dioxide (supplier; Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1) (787 mg, 4.56 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. Then H2O (5 ml) and H2SO4 (8.6 g, 87.75 mmol) was added to the residue at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was basified with NaOH (aq.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (5 ml..), then TEA (1.32 g, 13.14 mmol) and Boc?O (946 mg, 4.38 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure, The residue was purified by flash column chromatography with 0-100% ethyl acetate in petroleum ether to afford 3:1 mixture of tert-butyl ((3S,4S)-3-((S)-2-hydroxypropoxy)-7- methoxy-3.4-dihydro-2H-pyrano[2,3-b]pyridm-4-yl)carbamate and tert-butyl ((3R,4R)-3- ((S)-2-hydroxypropoxy)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)carbamate (1 .12 g, 72%) as a white solid. MS ESI calculated for CwftsNrCE [M+l]*, 355.18; found, 355.20.

Step -9:

[1034] To a solution of 3: 1 mixture of tert-butyl ((3S,4S)-3-((S)-2-hydroxypropoxy)-7- methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)carbamate and tert-butyl ((3R,4R)-3- ((S)-2-hydroxypropoxy)-7-methoxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yi)carbamate (1.12 g, 3.15 mmol) in toluene (10 mL) was added 2-(tributyl-/?- phosphaneylidene)acetonitrile (1.52 g, 6.30 mmol) at room temperature. The mixture was stirred at 1 10 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-100% ethyl acetate in petroleum ether to afford tert-butyl (2R,4aS,10bS)-8-methoxy-2-methyl-2,3,4a,10b- tetrahydropyrido[3'.2':5,6]pyrano[3,4-b]fl,4]oxazine-l(5H)-carboxylate (470 mg, 44%) as a light yellow semi-solid with longer retention time on flash column chromatography. MS ESI calculated for C17H24N2O5 [M+l]⁺, 337.17; found, 337.20.

[1035] The purification also afford tert-butyl (2R,4aR,10bR)-8-methoxy-2-methyl-

2,3,4a, 10b-telrahydropyrido[3',2’:5,6]pyraao[3,4-b][l ,4]oxazine-l(5H)-carboxylale (168 mg,

15%) as a brown oi 1 with shorter retention time on flash column chromatography. MS ESI calculated for C17H24N2O5 337.17: found, 337.20.

Step- 10:

[1036] A mixture of tert-butyl (2R,4aS, 10bS)-8-methoxy-2-methyl-2,3,4a, 10b- tetrahydropyrido[3',2':5,6]pyrano[3,4-b][l,4]oxazine- 1 (5H)-carboxylate (470 mg, 1.39 mmol) and hydrogen chloride (gas, 4.0 M in ethyl acetate) (5 ml.) was stirred at room temperature for 16 h. The mixture was concentrated under vacuum to afford (2R,4aS,10bS)-8-methoxy-2- methyl-l,2,3,4a,5,10b-hexahydropyrido[3’,2':5,6]pyrano[3,4-b][l,4]oxazjne hydrochloride (A34) (370 mg, crude) as a white solid. Absolute stereochemistry' was confirmed by NOE.

MS ESI calculated for CnHieNsOa [M+l]*, 237.12; found, 237.15. ^SH NMR (400 MHz, Methanol-iA) 5 (ppm) 7.86 (d, J- 8.4 Hz, 1H), 6.59 (d, 8.4 Hz, 1H), 4.81 - 4.68 (m, 2H), 4.58 - 4.52 (m, 1H), 4.44 - 4.39 (m, 1H), 4.01 - 3.91 (m, 1 H), 3.90 (s, 3H), 3.77 - 3.62 (m, 2H), 1.38 - 1.26 (m, 3H).

Intermediate A35: (2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl- 1 , 2, 3,4a, 5,10b- hexahydropyrido[3’,2' : 5 ,6]pyrano [3 ,4-b j [ 1 ,4]oxazine

Step- 1 :

[1037] To a stirred solution of H2SO4 (0.84 M) (1.25 L) was added 6-fluoro-5-iodopyridin- 2-amine (50.00 g, 210.08 mmol) at -5 °C under nitrogen atmosphere. The mixture was stirred at -5 °C for 10 min. A solution of NaNCb (28.99 g, 420.16 mmol) in H2O (250 mL) was added dropwise at -5 °C. The resulting mixture was stirred at -5 °C for 2 h. The precipitated solids were collected by filtration and washed with H2O. The solids were dried under reduced pressure to afford 6-fluoro-5-iodopyridin-2-ol (46.9 g, 93% yield) as a brown solid. MS ESI calculated for (C5H3FINO) [M+H]⁺, 239.92; found, 239.90.

Step-2:

3 /4

[1038] To a stirred solution of 6-fluoro-5-iodopyridin-2-ol (46.90 g, 196.24 mmol) in DCM (500 mL) was added a solution of KOH (66.06 g, 1177.46 mmol) in H2O (264 mL) dropwise at 0 °C. Then (bromodifluoromethyl)trimethylsilane (79.72 g, 392.49 mmol) was added dropwise to above mixture at. 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography w'ith a 330 g silica gel column eluted with 0- 8% ethyl acetate in petroleum ether to afford 6-(difluoromethoxy)-2-fluoro-3-iodopyridine (28.3 g, 49% yield) as a yellow oil. MS ESI calculated for CeHsFsINO [M+H]⁺, 289.92; found, 290.00. ^rH NMR (400 MHz, DMSO-rfc) 8 8.45 - 8.42 (m, 1H), 7.76 ~ 7.40 (m, 1H), 6.92 (dd, J = 8.2, 1.2 Hz, HI).

Step-3:

[1039] To a stirred solution of 6-(difluoromethoxy)-2-fluoro-3-iodopyridine (28.30 g, 97.93 mmol) and tert-butyldimethyl(prop-2-yn-l-yloxy (silane (50.04 g. 293.78 mmol) in Et₃N (300 mL) were added Pd(PPh₃)₂Cl₂ (13.75 g, 19.59 mmol) and Cui (7.46 g, 39.17 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0-8% ethyl acetate in petroleum ether to afford 3-(3-((tert- butyldimethylsilyl)oxy)prop- 1 -yn- 1 -yl)-6-(difluoromethoxy)-2-fluoropyridine (37.9 g, 70% yield) as a brown oil. MS ESI calculated for C15H20F3NO2SL |M+H]⁺, 332.12; found, 332.15.

3/5 Step-4:

[1040] To a stirred solution of 3-(3-((tert-butyIdimethylsilyl)oxy)prop-l-yn-l-yl)-6- (difluoromethoxy)-2-fluoropyridine (32.90 g, 99.27 mmol) in THE (350 mL) was added HC1 (aq., IM) (35 mL) at. room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with NaHCOs (sat.) and brine. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether to afford 3-(6-(difluoromethoxy)-2-fIuoropyridin-3-yl)prop-2-yn- l-ol (1 1.5 g, 53% yield) as a brown oil. MS ESI calculated for C9H6F3NO2 [M+H]⁺, 218.04; found, 218.00.

Step -5:

[1041] To a solution of 3-(6-(difluoromethoxy )-2-fluoropyridin-3-yl)prop-2-yn- 1 -ol ( 1 1.50 g, 52.96 mmol) in i-PrOH (350 mL) was added Lindlar catalyst (2.30 g, 4.77 mmol) at room temperature. The mixture was placed under hydrogen atmosphere with a balloon (1 atm.). The reaction mixture was degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford (Z)-3-(6-(difluoroinethoxy)-2-fluoropyridin-3-yl)prop-2-en-l-ol (1 1.5 g, crude) as a brown oil, which was used in next reaction directly. MS ESI calculated for C9H8F3NO2 [M+H]⁺, 220.05; found, 220.05. ^!H NMR (400 MHz, DMSO-tfc) 5 7.96 (dd, J = 10.0, 8.0 Hz, 1H), 7.62 (t, ./ = 72.0 Hz, 1H), 7.08 (dd, ./ = 8.0, 0.8 Hz, 1H), 6.30 - 6.32 (m, 1H), 6.05 - 5.97 (m, 1H), 4.98 - 4.95 (m, 1H), 4.26 - 4.01 (m, 2H).

Step-6:

3 /6

[1042] To a stirred solution of (Z)-3-(6-(difluoromethoxy)-2-fluoropyridin-3-yl)prop-2-en- l-ol (11.50 g, 52.47 mmol) in DMF (150 mL) was added CS2CO3 (25.64 g, 78.71 mmol) al room temperature. The resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched by the addition of water and extracted witir ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with a 120 g silica gel column eluted with 0-8% ethyl acetate in petroleum ether to afford 7-(difluororaethoxy)-2H-pyrano[2,3-b]pyridine (3.8 g, 36% yield) as a light yellow oil. MS ESI calculated for C9H7F2NO2 [M+H]⁺, 200.04; found, 200.05. ^rH NMR (400 MHz, DMSO-dy) 3 7.81 - 7.22 (m, 2H), 6.57 (d, J = 7.6 Hz, 1H), 6.50 - 6.47 (m, 1H), 5.85 - 5.81 (m, 1H), 5.06 (dd, J - 3.4, 2.0 Hz, 2H).

Step-7:

[1043] To a stirred solution of tert-butyl carbamate (7.48 g, 63.82 mmol) in propan- 1 -ol (80 mL) was added a solution of NaOH (2.22 g, 55.59 mmol) in H2O (70 mL.) at room temperature. The mixture was stirred at room temperature for 10 minutes, then 1,3-dichloro- 5.5-dimethylimidazolidine-2, 4-dione (6.08 g, 30.88 mmol) was added at room temperature. After stirring at room temperature for 30 minutes, a solution of (DHQDljPHAL (1.60 g, 2.06 mmol) (supplier: ShangHai Accel a ChemBio Co., Ltd. CAS# 140853-10-7) in propan- l-ol (21 mL) and a solution of 7-(difluoromethoxy)-2H-pyrano[2,3-b]pyridine (4.10 g, 20.59 mmol) in propan- l -ol (9 mL) were added dropwise at 0 °C. This was followed by the addition of Potassium osmate(VI) dihydrate (759 mg, 2.06 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of brine and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography eluted with 0-50% ethyl acetate in petroleurn ether to afford a 5:1 mixture of tert-butyl ((3S,4S)-7-(difluoromethoxy)-

37 / 3-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)carbamate and tert-butyl ((3R,4R)-7- (difluoromethoxy)-3-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)caibamaie (1,27 g, 19% yield) as a white solid. MS ESI calculated for C14H18F2N2O5 [M+H]⁺, 333.12; found, 63

[1044] To a stirred solution of 5:1 mixture of tert-butyl ((3S,4S)-7-(difluoromethoxy)-3- hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)carbamate and tert-butyl ((3R,4R)-7- (difluoromethoxy)-3-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)carbamate (1.07 g, 3.22 mmol) in DCM (20 mL) were added Tetrabutylammonium sulfate (50 wu% in H2O) (374 mg, 0.64 mmol), NaOH (901 mg, 22.54 mmol) and (4S)-4-methyl-l,3,2-z.-6- dioxathiolane -2, 2-dione (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30- 1 ) (578 mg, 4.19 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was concentrated under vacuum. Ute residue was acidified to pH 7 with HC1 (aq., I M). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO<u After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (10 mL), Citric acid (653 mg, 3.40 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water. The mixture was basified with NaHCOj (sat.) to pH 7. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated tinder reduced pressure. The resulting residue was purified by normal phase flash column chromatography eluted with 0—50% ethyl acetate in petroleum ether to afford a 5:1 mixture of tert-butyl ((3S,4S)-7-(difluoromethoxy)-3-((S)-2- hydroxypropoxy)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)carbamate and tert-butyl

3 /8 ((3R,4R)-7-(difluoromethoxy)-3-((S)-2-hydroxypropoxy)-3,4-dihydro-2H-pyrano[2,3- b]pyridin-4-yl)carbamate (527 mg. 64% yield) as a while solid. MS ESI calculated for C17H24F2N2O6 l.M+H]⁺, 391.16; found, 391.20.

Step-9:

[1045] To a stirred solution of a 5: 1 mixture of tert-butyl ((3S,4S)-7-(dilluoromethoxy)-3- ((S)-2-hydroxypropoxy)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)carbamate and terl-butyl ((3R,4R)-7-(difluoromethoxy)-3-((S)-2-hydroxypropoxy)-3,4-dihydro-2H-pyrano[2,3- b]pyridin-4-yl)carbamate (527 mg, 1.35 mmol) in toluene (6 mL) was added 2-(tributyl-k'- phosphaneylidenejacetonitrile (CAS No. 157141-27-0) (651 mg, 2.70 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 16 h. The resulting mixture was concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography eluted with 0-25% ethyl acetate in petroleum ether to afford terl-butyl (2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl-2,3,4a,10b- tetrabydropyrido[3',2’:5,6]pyrano[3,4-b][l,4]oxazine-l (5H)-carboxylate (378 mg, 75% yield) as a light yellow solid. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for C17H22F2N2O5 [M+H]⁺, 373.15: found. 373.15. ^;H NMR (400 MHz, DMSO-d6) 8 7.83 - 7.36 (m, 2H), 6.72 - 6.66 (tn, 1H), 5.28 - 5.19 (m, 1H), 4.53 - 4.36 (m, 2H), 4.04 - 3.90 (m, 1H), 3.84 - 3.83 (m, 1H), 3.78 ■■■ 3.59 (m, 2H), 1.50 (s, 9H), 0.71 - 0.66 (m, 3H).

[1046] The column purification also afford a 3:2 mixture of tert-butyl (2R,4aR,10bR)-8- (difluoromethoxy)-2-methyl-2,3,4a,10b-ieirahydropyrido[3’.2':5,6]pyrano[3,4-b][l,4]oxazme- l(5H)-carboxy1ate and tert-butyl (2R,4aS,10bS)-8-(difluoromethoxy)-2-methy1-2,3,4a,10b- tetrahydropyrido[3',2':5,6]pyrano[3,4-b][l,4]oxazine-l(5Il)-cai‘boxylate (160 mg) as a yellow oil.

Step- 10:

[1047] To a stirred solution of tert-butyl (2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl- 2,3,4a,10b-tetrahydropyrido[3’,2':5,6]pyrano[3,4-b][l ,4]oxazine-l(5H)-carboxylate (378 mg, 1.02 mmol) in ethyl acetate (3 mL) was added hydrogen chloride (4.0 M in ethyl acetate) (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford (2R,4aS,10bS)-8- (difluoromethoxy)-2-methyl-l,2,3,4a,5,10b-hexahydropyrido[3’,2’:5,6]pyrano[3,4- b][l,4]oxazine hydrochloride (A35) (290 mg, 92% yield) as a light yellow solid. MS ESI calculated for CJ2H14F2N2O3 [M+H]⁺, 273. 10; found, 273.10. ‘H NMR (400 MHz. DMSO- de.) 6 10.91 (s, 1H), 9.77 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 72.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.04 - 4.85 (m, 1H), 4.68 - 4.67 (m, 1H), 4.56 - 4.42 (m, 1H), 4.36 - 4.22 (m, 1H), 3.87 (dd, J - 12.0, 3.2 Hz, 1H), 3.67- 3.40 (m, 2H), 1.19 (d, .7 - 6.4 Hz, 3H).

Intermediate A38: (2R,4aR,10bS)-2-methyl-8-(trifluoromethyl)-2,3,4a,5,6,10b-hexahydro- 1 H-[l,4]oxazino[3,2-f]quinolme

A38

Step-1: [1048] To a stirred solution of 3-aminocyclohex-2-en-l-one (100.00 g, 899.73 mmol) and (E)-4-ethoxy-l ,l,l-trifluorobut-3-en-2-one (302.52 g, 1799.47 mmol) in MeCN (1000 mL) were added FeCh (14.59 g, 89.97 mmol) and pyrrolidine hydrochloride (48.40 g, 449.87 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 8 h under nitrogen atmosphere. Hie solvent was removed under reduced pressure. The residue was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-30% ethyl acetate in petroleum ether to afford 2-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one (20.60 g, 11%) as a brown oil. MS ESI calculated for CioHsFjNO [M+H]⁺, 216.06; found, 216.10.

Step-2:

[1049] To a stirred solution of 2-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one (20.60 g, 95.74 mmol) in methanol (300 ml.) was added NaBFU (7.24 g, 191.47 mmol) in portions at. 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by water at 0 °C. The MeOH was removed under vacuum, the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography with 0-50%: ethyl acetate in petroleum ether to afford a 1:1 mixture of (S)-2-(trifluoromethyI)-5,6,7,8-tetrahydroquinolin-5-ol and (R)-2- (trifluoromethyD-5,6,7,8-tetrahydroquinolin-5-ol (10.80 g, 52%) as a colorless oil. MS ESI calculated for C: J fo.F NO [M+l]⁺, 218.07; found, 218.15.

Step-3:

[1050] A solution of a 1 : 1 mixture of (S)-2-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-5- ol and (R)-2-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-5-ol ( 10.80 g, 49.73 mmol) in PPA (100 mL) was stirred at 110 ^,JC for 4 h. The residue was diluted by water and basified to pH 8 with NH3-H2O (aq.). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-70% ethyl acetate in petroleum ether to afford 2-(trifiuoromethyl)-7,8-dihydroquinoline (7.10 g, 72%) as a colorless oil. MS ESI calculated for C10H8F3N [M+H]⁺, 200.06; found, 200.10.

Step-4:

[1051] To a solution of tert-butyl carbamate (12.35 g, 105.44 mmol) in propan- l-ol (260 mL) were sequentially added NaOH (aq., 0.4 M) (260 mL) and tert-butyl hypochlorite (1 1.45 g, 105.44 mmol). The resulting mixture was stirred at room temperature for 30 min. Then a solution of (DHQDhPHAL (supplier: ShangHai Accela ChemBio Co., Ltd. CAS# 140853- 10-7) (2.74 g, 3.52 mmol) in propan-l -ol (40 mL) was added to above mixture at 0 oC. After stirring at 0 °C for 30 min. 2-(trifluoromethyl)-7,8-dihydroquinoline (7.00 g, 35.15 mmol) and Potassium osmate (VI) dihydrate (1.29 g, 3.56 mmol) were added to above mixture at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Hie residue was purified by reverse phase flash with 5-50% acetonitrile in water to afford a 2:1 mixture of tert-butyl ((5S,6R)-6- hydroxy-2-(trifluoromethyl)-5,6.7,8-tetrahydroquinolin-5-yl)carbaniate and tert-butyl ((5R,6S)-6-hydroxy-2-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-5-yl)carbamate (1.90 g, 16%) as a yellow oil. MS (ESI) calculated for C15H19F3N2O3 [M+H]⁺, 333.13; found. 333.20.

Step-5 :

[1052] To a solution of a 2: 1 mixture of tert-butyl ((5S,6R)-6-hydroxy-2-(triiluoromethyl)- 5,6,7,8-tetrahydroquinolin-5-yl)carbamate and tert-butyl ((5R,6S)-6-hydroxy-2- (trifluoromethyl)-5,6,7,8-tetrahydroquinolin-5-yl)carbamate (1.90 g, 5.72 mmol) in DCM (30 mL) were added (Bu4N)HSO4 (0.39 g, 1.14 mmol), NaOH (1.60 g, 40.02 mmol) and (4S)-4-methyl-l, 3, 2-k-6-dioxathiolane-2, 2-dione (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1) (1.03 g, 7.43 mmol) at 0 °C with stirring. The resulting mixture was stirred at room temperature for 2 h. Then H?O (20 mL) and H2SO4 (1.32 g, 13.50 mmol) were added to the reaction mixture at 0 °C. The resulting mixture was stirred at 80 °C for 16 h. Then the mixture was diluted with water and basified by NaOH (aq., 30%) to pH 8. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford a 2: 1 mixture of (S)-l-(((5S,6R)-5-amino-2- (trifluoromethyl)-5,6,7,8-tetrahydroqumolin-6-yl)oxy)propan-2-ol and (S)-l-(((5R,6S)-5- aniino-2-(trilluoromethyl)-5,6,7,8-tetrahydroquinolin-6-yl)oxy)propaii-2-ol (2.10 g, crude) as a yellow oil. MS ESI calculated for [M+H]⁺, 291.12; found, 291.10.

Step-6:

[1053] To a solution of’ a 2: 1 mixture of (S)-l-(((5S,6R)-5-amino-2-(trifluoromethyl)-

5,6,7,8-tetrahydroquinolin-6-yl)oxy)propan-2-ol and (S)-l-(((5R,6S)-5-amino-2-

(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-6-yl)oxy)propan-2-ol (1.90 g, 6.54 mmol), TEA (1.99 g, 19.64 mmol) in MeOH (20 mL) was added BoczO (1 .43 g, 6.54 mmol). The resulting mixture was stirred at room temperature for 2 h. The solvent was concentrated under vacuum. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford a 2:1 mixture of tert-butyl ((5S,6R)-6-((S)-2-hydroxypropoxy)-2- (tifluoromethyl)-5,6,7,8-tetrahydroquinolin-5-yl)carbamate and tert-butyl ((5R,6S)-6-((S)-2- hydroxypropoxy)-2-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-5-yr)carbamate (1.50 g, 59%) as an off-white solid. MS ESI calculated for C18H25F3N2O4 [M+H]⁺, 391.18: found, 391.15.

Step-7:

[1054] To a solution of a 2:1 mixture of tert-butyl ((5S,6R)-6-((S)-2-hydroxypropoxy)-2- (trifIuoromethyl)-5,6,7,8-tetrahydroquinolin-5-yl)carbamate and tert-butyl ((5R,6S)-6-((S)-2- hydroxypropoxy)-2-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-5-ybcarbamate (1.60 g, 4.09 mmol) in toluene (20 ml..) was added 2-(tributy]->,³-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (1.98 g, 8.19 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 5 h. The solvent was removed under vacuum. The residue was purified by flash column chromatography with 0-40% ethyl acetate in petroleum ether to afford a 2:1 mixture of tert-butyl (2R,4aR,10bS)-2-methyl-8-(trifluoromethyl)-2, 3,4a, 5,6, lOb-hexahydro-lH- [l,4]oxazino[3,2-f]quinoline- 1 -carboxylate and tert-butyl (2R,4aS,10bR)-2-methyl-8- (tritluoromethyl)-2, 3, 4a, 5, 6, 10b-hexahydro-lH-[l,4]oxazino[3,2-f]quinoline-l -carboxylate (1.20 g, 78%) as a yellow oil. MS ESI calculated for CjgHjoFsNiCh [M+H]⁺. 373.17; found, 373.20.

Step-8:

A38

[1055] A 2:1 mixture of tert-butyl (2R,4aR,10bS)-2-methyl-8-(trifluoromelhyl)-

2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[3,2-f]quinoline- l-carboxylate and tert-butyl

(2R,4aS,10bR)-2-methyl-8-(trifluoromethyl)-2,3,4a,5,6,10b-hexahydro-lH-[l ,4]oxazino[3,2- f]quinoline-l -carboxylate (1.2 g. 3.22 mmol) and HC1 (4M in 1,4-dioxane) (10 mL) was stirred at. room temperature for 1 h. The resulting mixture was concentrated under vacuum. The crude product (1100 mg) was separated by Prep-chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: MEOH: DCM=1: 4-HPLC; Flow rate: 20 mL/min; Gradient (B%): 7% B to 7% B in 9 min; Wave Length: 220/254 nm; RTl(min): 6.28; RT2(min): 7.76; Sample Solvent: MeOH; EtOH=l; 1--HPLC; Injection Volume: 0.26 mL; Number Of Runs: 25) to afford (2R,4aS,10bR)-2-meihyl-8-(tnfluoroinethyl)- 2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[3,2-f]quinoline (220 mg, 30%) as a white solid as the first eluting peak. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for Ci3H_!5F3N₂O [M+H]⁺, 273. 1 1; found, 273.05. ^:H NMR (300 MHz, DMSO-rfc) 8 8.38 (d, J= 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1 H), 4.07 - 3.85 (m, 2H), 3.65 - 3.60 (m, 1H), 3.18 - 3.11 (m, 1H), 3.05 - 2.90 (m, 1H), 2.85 - 2.72 (m, 1H), 2.47 - 2.35 (m, 1H), 2.18 - 1.90 (m, 21 b. 0.87 (d, J ~ 6.4 Hz, 3H).

[1056] The chiral resolution also afford (2R,4aR,10bS)-2-methyl-8-(t.rifluoromethyD- 2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[3,2-f]quinolme (A38) (400 mg, 55%) as a white solid as the second eluting peak. Absolute stereochemistry was confirmed by NOE. MS ESI calculated for C13H15F3N2O [M+H]⁺, 273.11; found, 273.05. ’H NMR (300 MHz, DMSO-tfc) 5 8.38 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 4.07 - 3.85 (m, 2H), 3.65 - 3.60 (m, 1H), 3.18 - 3.11 (m, 1H), 3.05 - 2.90 (m, 1H), 2.85 - 2.72 (m, 1H), 2.47 - 2.35 (m, 1H), 2.18 - 1.90 (m, 2H), 0.87 < d. 7 -- 6.4 Hz, 3H).

Intermediate A39: 1:1 mixture of rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-fluoro- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-7- (difluoromethoxy)-3-fluoro-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-bjpyridine isomer 2 Step-1:

[1057] To a stirred solution of 4-chloro-2- hydroxyphenyl boronic acid (10.00 g, 58.01 mmol) and K.’CO, (24.05 g, 174.04 mmol) in 1,4-dioxane (150 mL) were added 2-bromo- 3,5-dilluoropyridine ( 12.38 g, 63.81 mmol) and Pd(dppf)Ch-CH2C12 (4.74 g, 5.80 mmol) at 25°C. The resulting mixture was stirred at 90°C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-25% EtOAc in petroleum ether to afford 5-chloro- 2-(3,5-difluoropyridin-2-yl)phenol (13.5 g, 96% yield) as a white solid. MS (ESI) calculated for (C11H6CIF2NO) [M+H]⁺, 242.01; found, 242.00.

[1058] To a stirred solution of 5-chloro-2-(3,5-dilluoropyridm-2-yl)phenol (13.50 g, 55.87 mmol) in DMF (140 mL) were added K2CO3 (15.44 g, 111.74 mmol) at 30 °C. The resulting mixture was stirred at 120 °C for 3 h. The resulting mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4- After filtration, the filtrate was concentrated under reduced pressure to afford 7-chloro-3-fluorobenzofuro[3,2-b]pyridine (10.8 g, 87% yield) as a white solid. MS (ESI) calculated for (C11H5CIFNO) [M+H] ⁺, 222.00: found, 221.95.

Step-3:

[1059] To a stirred solution of 7-chloro-3-tluorobenzofuro[3,2-b]pyridine (9.25 g, 41 .73 mmol) and Herrmann's catalyst (1.96 g, 2.08 mmol) in DMF (504 ml.,) and H2O (56 mL) were added t-BuXPhos (3.54 g, 8.34 mmol) and K2CO3 (44.99 g, 325.55 mmol) at 30 °C. The resulting mixture was stirred at 120°C for 2 h under nitrogen atmosphere. The mixture was quenched by water and acidified with HC1 (aq.) to pH 3. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, then dried over anhydrous NaaSO^n After filtration, the filtrate was concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography, eluted with 0-50%' EtOAc in petroleum ether to afford 3-fluorobenzofuro[3,2-b]pyridin-7-ol (5.6 g, 66% yield) as a white solid. MS (ESI) calculated for (Ct jHsFNOa) [M+H]⁺, 204.04; found, 204.05.

Step-4:

[1060] To a stirred solution of 3-tluorobenzofuro[3,2-b]pyridin-7-ol (35.00 g, 172.26 mmol) in DMF (350 ml) were added sodium 2-chloro-2,2-difluoroacetate (31.52 g, 206.72 mmol) and K2CO3 (47.62 g, 344.53 mmol) at 30 °C. The resulting mixture was stirred at 90 °C for 3 h. The mixture was cooled and diluted by water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in PE to afford 7-(difluoromethoxy)-3-fluorobenzofuro[3,2-b]pyridine (11.00 g, 25% yield) as an off-white solid. MS (ESI) calculated for (CizIfeFsNO?) [M+H]⁺, 254.04; found, 254.05. Step-5:

A39

[1061] To a stirred solution of 7- (difluoromethoxy)-3-fluorobenzofuro[3,2-b]pyridine (6.40 g, 25.27 mmol) in THF (60 mL) were added HC1 (cone.) (2.21 g, 60.667 mmol) and Palladium hydroxide (Pd 20% on carbon powder, nominally 50% water) (2.55 g) in portions at 30 °C. The resulting mixture was stirred at 70 °C for 16 h under hydrogen atmosphere (50 atm.). The resulting mixture was filtered, the filter cake was washed with mixture of MeOH and water. The filtrate was concentrated under reduced pressure. The residue was dissolved in H2O (60 mL). The mixture was acidified with HCJ (aq.) to pH 4. The resulting mixture was extracted with EtOAc. The water layers were collected and basified NaHCOa (sat.) to pH 8. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO-j. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC- Actus Triart Cl 8 ExRS, 20*250 ram, 5pm; Mobile Phase A: Water (10 mmol/L NH3HCO3), Mobile Phase B: ACN; Flow rate: 20 ml., /min; Gradient: 35% B to 50% B in 10 min; Wave Length: 253/220 nm) to afford a 1:1 mixture of rel- (3R,4aS,9bS)-7-(difluoromethoxy)-3-fluoro-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine isomer 1 and (3R,4aS,9bS)-7-(difluoromelhoxy)-3-fluoro-l ,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2 (A39) (160 mg, 2% yield) as a white solid. MS (ESI) calculated for (C12H12F3NO2) [M+H]⁺, 260.08; found, 260.10. H NMR (400 MHz, DMSO-df,) 87.33 (d, .7 - 7.8 Hz, 1H), 7.20 (t, .7- 74.4 Hz, HI), 6.73 - 6.63 (m, 2H), 4.81 - 4.62 (m, 1H), 4.66 - 4.57 (m, 1H), 4.29 (d, J - 6.4 Hz, 1H), 2.94 - 2.84 (m, 1 H), 2.72 - 2.57 (m, 1H), 2.39 - 1.97 (rn, 3H). Relative and absolute stereochemistry was not determined.

Intermediate A39 isomer 1: rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-fluoro-1 ,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine, isomer 1

A39, Isomer

Intermediate A39 isomer 2: reI-(3R,4aS,9bS)-7-(difluoroniethoxy)-3-fluorO"l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine, isomer 2

A39, Isomer 2

[1062] The racemic mixture (2.8 g) was separated by Prep-Chiral SFC with the following conditions (Column: CHLRALPAK IG, 3*25 cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH: ACN=1: 1; Flow rate: 100 mL/min; Gradient: isocratic 30% B; Wave Length: 220 nm; RTl(min): 2.5; RT2(min): 4.5; Sample Solvent: MEOH) to afford rel- (3R,4aS,9bS)-7-(difluoromethoxy)-3-fluoro-l,2,3,4,4a,9b-hexaliydrobenzofuro[3,2- bjpyridine, isomer 2 (A39 isomer 2) (840 mg, 30% yield) as a white solid with the first peak on SFC. MS (ESI) calculated for (C12H12F3NO2) [M+H]⁺, 260.08; found, 260.10. ^!H NMR (400 MHz, DMSCMA) 5 7.33 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 74.4 Hz, 1H), 6.73 - 6.63 (m, 2H), 4.81 - 4.62 (m, 1H), 4.66 - 4.57 (m, 1H), 4.29 (d, J= 6.4 Hz, 1H), 2.94 •■■■ 2.84 (m, 1H), 2.72 - 2.57 (m, 1H), 2.39 - 1.97 (m. 3H). The relative and absolute stereochemistry for A39 isomer 2 was not determined.

[1063] The above chiral resolution also afford rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3- fluoro-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine, isomer 1 (A39 isomer 1) (860 mg, 30% yield) as a colorless oil with the second peak on SFC. MS (ESI) calculated for (C12H12F3NO2) [M+H ] 7 260.08; found, 260.10. I I NMR (400 MHz, DMSO-tfo) 5 7.33 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 74.4 Hz, 1H), 6.73 ■■■ 6.63 (m, 2H), 4.81 - 4.62 (m, 1H), 4.66 - 4.57 (m, 1H), 4.29 (d, 7 - 6.4 Hz, 1H), 2.94 - 2.84 (m, HI), 2.72 - 2.57 (m, 1H), 2.39 - 1.97 (m, 3H). The relative and absolute stereochemistry for A39 isomer 1 was not determined.

Intermediate A40: rel-(4aS, 1 ()bS)-8-chloro-2,3,4,4a,6, 1 Ob-hexahydro- 1 H-pyrano[3,2-b:5,4- b'Jdipyridine hydrochloride

A40

Step-1:

[1064] To a stirred solution of methyl 3-bromo-6-chloropicolinate (50.0 g, 199.61 mmol) in 1 ,4-dioxane (500 mL) and H.?O (50 mL) were added (E)-tert-butyldiphenyl«.5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pent-4-en-l-yl)oxy)silane (124.10 g, 275.47 mmol), Pd(dppf)Ch (14.61 g, 19.96 mmol) and K2CO3 (82.76 g, 598.85 mmol) at room temperature. The reaction mixture was stirred at. 80 °C for 3 h under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford methyl (E)-3-(5-((tert- butykliphenylsilyl)oxy)pent- 1 -en-1 -yl)-6-chloropicolinate (42.5 g, 43%) as a light yellow oil. MS ESI calculated for CesH^ClNCKSi [M+H]⁺, 494.18; found, 494.25.

Step-2:

[1065] To a stirred solution of BocNHz (20.58 g, 175.67 mmol) in propan- 1-oi (580 mL) was added a solution of NaOH (6.14 g, 153.57 mmol) in water (510 mL), then 1 ,3-dichloro- 5, 5-dimethylimidazo1idine-2, 4-dione (22.33 g, 113.33 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 30 min. This was followed by the addition of (DHQh-PHAL (6.07 g, 7.79 mmol, 0.1 M in propan- l-ol) (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1), then a solution of methyl (E)-3-(5-((tert- butyldiphenylsilyl)oxy)pent-l-en-l -yl)-6-chloropicolinate (39 g, 79.08 mmol) in propan-l-ol (440 mL) was added dropwise at 0 °C, after that, K2OSO4.2H2O (2.09 g, 5.66 mmol) was added in portions at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to afford rel-tert -butyl ((5S,6S)-6-(3-((tert- butyldiphenylsilyl)oxy)propyl)-2-chloro-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5- yl)carbaniate (9.2 g, 27%) as a green oil. MS ESI calculated for C^HaaCdhOOsSi [M+H] ⁺, 595.23; found, 595.30.

Step-3 :

[1066] To a stirred solution of rel -tert-butyl ((5S,6S)-6-(3-((tert- buty ldiphenylsilyl)oxy)propyl)-2-chloro-8-oxo-5, 8-dihydro-6H-pyrano[3,4-b]pyri din-5- yl)carbamate (17.00 g, 28.56 mmol) in THE (170 mL) was added NaBEU (1.08 g, 28.56 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3/1) to afford rel-tert-butyl ((lS,2S)-5- ((tert-butyldiphenylsilyl)oxy)-l-(6-chloro-2-(hydroxymethyl)pyridin-3-yl)-2- hydroxypentyDcarbamate (12.00 g, 70%) as a colorless oil. MS ESI calculated for C . -I U ;( TvChSi [M+Hf, 599.26; found, 599.25.

Step-4:

[1067 ] To a stirred solution of rel-tert-butyl ((lS,2S)-5-((tert-butyldiphenylsilyl)oxy)-l-(6- chloro-2-(hydroxymethyl)pyridin-3-yl)-2-hydroxypentyl)carbamate (12.00 g, 20.03 mmol) in Toluene (120 mL) was added 2-(tributyl-X⁵-phosphaneylidene)acetonitrile (CAS No. 157141- 27-0) (9.67 g, 40.05 mmol ) at room temperature. The resulting mixture was stir red at 110 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10/1) to afford rel-tert-butyl ((5S,6S)-6-(3-((tert-butyldiphenylsilyl)oxy)propyl)-2- chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (6.04 g, 52%) as a white solid. MS ESI calculated for C^H^CINpOaSi [M+H] ⁺, 581.25; found, 581 .25.

Step-5:

[1068] To a stirred solution of rel-tert-butyl ((5S,6S)-6-(3-((tertbutyldiphenylsilyl)oxy)propy])-2-chlofo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5- yl)carbamate (6.04 g, 10.39 mmol) in THE (60 mL) was added TBAF (5.43 g, 20.78 mmol) at room temperature. Tire resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10/1) to afford rel- tert-butyl ((5S,6S)-2- chloro-6-(3-hydroxypropyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yi)carbamate (3.32 g, 93%) as a colorless oil. MS ESI calculated for (C16H23CIN2O4) [M+H]⁺, 343.13; found, 343.15.

Step-6:

[1069] To a stirred solution of rel-tert-butyl ((5S,6S)-2-chloro-6-(3-hydroxypropyl)-5,8- dihydro-6H-pyrano[3,4-b]pyridin- 5-yl)carbamate (3.32 g, 9.68 mmol) in Toluene (33 mL) was added 2-(tiibutyl-X^s-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (4.67 g, 19.37 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5/1) to afford rel-tert-butyl (4aS,l()bS)-8-chloro-2,3,4,4a,6, 10b-hexahydro-lH-pyrano[3,2-b:5,4- b’Jdipyridine-1 -carboxylate (2.76 g, 88%) as a white solid. MS ESI calculated for (Ci6H₂iClN₂O3) 325.12: found, 325.15.

Step-7 : [1070] To a stirred solution of rel-tert-butyl (4aS, 10bS)-8-chloro-2,3,4,4a,6, 10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (2,76 g, 8.50 mmol) in HO in 1,4-dioxane (4,0 M) (28 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The racemic compound was separated by Prep-Chiral SFC with the following conditions: [Column: CHIRAL ART Amylose-SA, 5*25 cm, 5 pm; Mobile Phase A: CO?., Mobile Phase B: MEOH (0.1% 2M NH3-MEOH); Flow' rate: 140 mL/min: Gradient ): isocratic 20% B;

RTl(min): 7.8: RT2(min): 1 1 ; Sample Solvent: MEOH] to afford rel-(4aS,WbS)-8-chloro- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine (A40) (1.63 g, 67%) as a white solid with retention time at 11 minute. MS ESI calculated for (C11H13CIN2O) [M+H]⁺, 225.07; found, 225.15. ‘H NMR (400 MHz, DMSO-tfc) 6 8.20 (d, J= 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 4.87 - 4.77 (m, 2H), 4.40 (s, 1H), 4.06 - 4.04 (m, IH), 3.22 - 3.17 (m, 1H). 3.06 - 2.98 (m, IH), 2.03 - 1.98 (m, IH), 1.93 - 1.84 (m, 2H), 1.69 - 1.64 (m, IH).

[1071] The absolute stereochemistry of A40 was determined as S, S-configuration, by single crystal crystallography of a compound prepared using A40. Accordingly, A40 is represented by the structure:

Intermediate A41 isomer 1: rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6-methyl- 2, 3, 4, 4a, 6, 1 Ob-hexahydro- lH-isochromeno[4,3-b]pyridine, isomer 1

Isomer 1 _and,

Intermediate A41 isomer 2: rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6-methy1-

2, 3, 4, 4a, 6,1 Ob-hexahydro- lH-isochromeno[4,3-b]pyridine, isomer 2 and,

Intermediate A41 isomer 3: rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6-niethyl- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine, isomer 3 and, Intermediate A41 isomer 4: reI-(4aR,6S,10bS)-8-(difluoroniethoxy)-6-methyl-

2, 3, 4.4a, 6, lOb-hexahydro- lH-isochromeno[4,3-b]pyridme, isomer 4 isomer 4

Step-1: [1072] To a stirred solution of 2-bromo-5-hydroxybenzaldehyde (30.0 g, 149.24 mmol) and

K2CO3 (61.9 g, 447.72 mmol) in DMF (300 mL) was added sodium 2-chloro-2,2- difluoroacetate (68.3 g, 447.72 mmol). The resulting mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. Hie filtrate was concentrated under reduced pressure. The mixture was diluted with water. The aqueous layer was extracted with ethyl acetate. Hie combined organic layers were washed with brine, dried over anhydrous N&2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford 2-bromo-5-

(difluoromethoxy)benzaldehyde ( 11 .0 g, 29%) as a white semi-solid. MS ESI calculated for

CsH^BrFjOz [M+H]⁺, 250.94, 252.94; found, 250.90, 252.85. Step-2:

[1073] To a stirred solution of 2-bromo-5-(difluoromethoxy)benzaldehyde (10.5 g, 52.23 mmol) in THE (50 ml,) was slowly added methylmagnesium bromide (3M in 2-MeTHF) (78 mL, 234 mmol) at -40 °C under nitrogen atmosphere. The mixture was stirred at -40 °C for 3 h. The mixture was quenched with NH4CI (sat.). The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NajSOr. Hie resulting mixture was concentrated under reduced pressure. The residue was purified byflash column chromatography with 0-20% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of (R)-1 -(2-bromo-5-(difluoromethoxy)phenyl)ethan-1 -ol and (S)-l -(2-bromo-5- (difluoromethoxy)phenyl)ethan-l-ol (8.5 g, 65%) as a yellow- oil. MS ESI calculated for C₉HyBrF₂O2 [M+H]⁺, 266.98/268.98; found, 266.85/268.95.

Step-3: [1074] To a stirred solution of a 1 : 1 mixture of (R)- 1 -( 2-bromo-5- (difluoromethoxy)phenyl)ethan- l-ol and (S )- ■ -(2-bromo-5-(difluorojnethoxy)phenyJ)ethan- 1- ol (3.5 g, 13.09 mmol) and 3-fluoro-2-(tributylstannyl)pyridine (6.0 g, 15.72 mmol) in DMF (30 ml) were added Pd(PPhj)4 (1-5 g, 1.30 mmol) and CuO (0.2 g, 2.63 mmol). The mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-80% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (R)-l-(5-(difluoromethoxy)-2-(3- fluoropyridin-2-yl)phenyl)ethan-l-ol and (S)-l-(5-(difluoromethoxy)-2-(3-fluoropyridin-2- yl)phenyl)ethan-l-ol (2.8 g, 75%) as a yellow oil. MS ESI calculated for C14H12F3NO2 [M+H]⁺, 284.08; found, 283.95.

Step-4:

[1075] To a stirred solution of a 1:1 mixture of (R)-l-(5-(difluoromethoxy)-2-(3- f]uoropyridin-2-yl)phenyl)ethan- l-ol and (S)- l-(5-(difluoromethoxy)-2-(3-fluoropyridin-2- y])phenyl)ethan-l -ol (2.8 g, 9.89 mmol) in DMF (30 mL) was added NaH (60% in mineral oil) (0.4 g, 10 mmol) at 0 °C. The mixture was stirred at 80 °C for 2 h. The resulting mixture was quenched with ice water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaaSCU. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-80% ethyl acetate in petroleum ether to afford a 1:1 mixture of (R)-8-(difluoromethoxy)-6-methyl-6H-isochromeno[4_t3-b]pyridine and (S)-8- (dinuoromethoxy)-6-methyl-6H-isochromeno[4,3-b]pyridine (2.2 g, 84%) as a yellow oil. MS ESI calculated for C14H11F2NO2 [M+Hf, 264.08; found, 264.00.

Step-5:

[1076] To a stirred solution of a 1 : 1 mixture of (R)-8-(difluoromethoxy)-6-methyl-6H- isochromeno[4,3-b]pyridine and (S)-8-(difluoromethoxy)-6-methyl-6H-isochrorneno[4,3- bjpyridine (2.5 g, 9.50 mmol) and HC1 (cone. 5 mL) in methanol (50 mL) was added PtCh (2.50 g, 1 1 .02 mmol). The mixture was stirred at 20 °C for 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford a 1 : 1 :8: 8 mixture of rel-(4aR,6S,10bS)-8- (ditluoromethoxy)-6-meihyl-2,3,4,4a,6, 10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 1 and rel-(4aR,6S, 10bS)-8-(difluoromethoxy)-6-niethyl-2,3,4,4a,6, lOb-hexabydro- lH-isochromeno[4,3-b]pyridine isomer 2 and rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6- methyl-2,3,4,4a,6,10b-hexahydro-lH-isochrorneno[4,3-bjpyridine isomer 3 and rel- (4aR,6S, 10bS)-8-(difluorornethoxy)-6-methyl-2,3,4,4a,6, 1 Ob-hex ahydro- 1 H- isochromeno[4,3-b]pyridine isomer 4 (2.2 g, crude) as a white solid. MS ESI calculated for

[1077] The 1 : 1 :8:8 mixture of rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6-methyl-

2,3.4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 1 and rel-(4aR,6S,10bS)-8- (difluoromethoxy)-6-methyl-2,3,4.4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 2 and rel-(4aR,6S ,10bS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,l0b-hexahydro- 1 H-isochromeno[4,3-b]pyridine isomer 3 and rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6- methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 4 (2.2 g) was separated by Prep- Achiral-SFC with the following conditions: [Column: GreenSep Basic 3*15 cm, 5 pmL; Mobile Phase A: CO2, Mobile Phase B: IP A (20mM NH3): Flow rate: 75 mL/min; Gradient (B%): isocratic 23% B: Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 2.45; RT2(min): 3.10; Sample Solvent: MEOH] to afford a 1 : 1 mixture of rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6-methyl-2,3.4,4a,6,10b- hexahydro-iH-isochromeno[4,3-b]pyridine isomer 1 and rel-(4aR,6S,10bS)-8- (difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 2 (220 mg) as a yellow oil.

[1078] The chiral resolution also afforded a 1: 1 mixture of rel-(4aR,6S,10bS)-8- (difluoromethoxy )-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno|4,3-b|pyridine isomer 3 and rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro- lH-isochromeno[4,3-b]pyridine isomer 4 (1.1 g) as a yellow oil.

[1079] A 1: 1 mixture of rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine isomer 1 and rel-(4aR,6S,10bS)-8- (difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 2 (220 mg) was separated by Prep-Chiral- HPLC with the following conditions: [Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: ETOH: DCM=1: 1; Flow rate: 20 mL/min; Gradient (B%): 5% B to 5% B in 13 min; Wave Length: 220/254 nm; RTl(min): 9.31 : RT2(min): 10.79: Sample Solvent: EtOH: DCM-l : 1-HPLC] to afford rel-(4aR,6S, l()bS)-8-(difiuoromethoxy)-6-methyl- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 1 (A41 isomer 1) (40 mg) as a white solid with shorter retention time and rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6- methyl-2,3, 4, 4a, 6 JOb-hexahydro- lH-isochromeno[4,3-b]pyridine isomer 2 (A41 isomer 2) (40.2 mg) as a yellow solid with longer retention time.

[1080] rel-(4aR,6SJ0hS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,Wb-hexahydro- 1 H- isochromeno[4,3-b]pyridine isomer 1 (A41 isomer 1): MS ESI calculated for C14H17F2NO2 [M+H]⁺, 270.12: found, 270.10. ^!H NMR (400 MHz, DMSO-cfc) 5 7.59 - 7.53 (m, 1H), 7.20 (t, J = 74.4 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.96 (d, 7 = 2.4 Hz, 1H), 4.91 - 4.84 (m, 1H), 3.34 - 3.27 (m, 1H), 3.17 - 3.09 (m. 1H), 3.03 - 2.94 (m, 1H), 2.61 - 2.53 (m, 1H). 2.46 - 2.29 (in, III), 2.04 - 1.96 (m, 1H), 1.73 - 1.64 (m, 1H), 1.50 - 1.36 (m, 4H). The relative stereochemistry of two centers labeled with “orl” was determined by NOESY.

[1081] rel-(4aR,6S,10bS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine isomer 2 (A41 isomer 2): MS ESI calculated for C14H17F2NO2 [M+H]⁺, 270.12; found, 270.10. (400 MHz, DMSO-Js) 5 7.59 - 7.53 (m, 1H), 7.20 (t, J = 74.4 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.96 (d, J = 2.4 Hz, 1H), 4.91 - 4.84 (m, 1H), 3.34

- 3.27 (m, 1H). 3.17 - 3.09 (m, 1H), 3.03 - 2.94 (m, 1H), 2.61 - 2.53 (m, 1H), 2.46 2.29 (m, 1H), 2.04 - 1.96 (m, 1H), 1.73 - 1.64 (m, 1H), 1.50 - 1.36 (m. 4H). The relative stereochemistry of two centers labeled with ‘■‘orl” was determined by NOESY.

[1082] A 1 : 1 mixture of rel-(4aR,6S,l0bS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,10b- hexahydro- lH-isochromeno|4,3-b]pyridine isomer 3 and rel-(4aR,6S,10bS)~8- (difluoTomethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 4 (1 100 mg) was separated by Prep-Chiral-SFC with the following conditions:

[Column; CHIRALPAK IG, 3*25 cm, 5 pm; Mobile Phase A; CO2, Mobile Phase B: MEOH (0.1% 2M NH3-MEOH); Flow rate: 80 mL/min; Gradient (B%): isocratic 20% B; RTl(min): 3.5; RT2(min): 6; Sample Solvent: MEOH] to afford rel-(4aR,6S,10bS)-8-(difiuoromethoxy)- 6-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b|pyridine isomer 3 (A41 isomer 3) (423 mg) as a white solid with shorter retention time and rel-(4aR,6S,10bS)-8- (difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-bexahydro-lH-isochromeno[4,3-b]pyridine isomer 4 (A41 isomer 4) (428 mg) as a white solid with longer retention time.

[1083] rel-(4aR,6S,10bS)-8-(difluoroniethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine isomer 3 (A41 isomer 3): MS ESI calculated for C14H17F2NO2 [M+H]\ 270.12; found, 270.10. ^!H NMR (400 MHz, DMSO-Js) 5 7.44 - 7.22 (m, 2H), 7.07

- 6.99 (111, 2H), 4.76 (q, J = 6.4 Hz, 1H), 3.63 -■ 3.62 (m, 1H), 3.53 - 3.52 (m, 1H), 2.99 - 2.92 (m, 1H), 2.74 - 2.63 (no, 1H), 2.01 - 1.92 (m, 1H), 1.79 - 1.69 (m, 1H), 1.67 - 1.57 (m, 1H), 1.51 (d, J - 6.4 Hz, 3H), 1.40 - 1.31 (m, 1H). The relative stereochemistry of two centers labeled with ‘‘orl ” was determined by NOESY.

[1084] rel-(4aR,6S, lObS) ■ 8-(difluoromethoxy)-6- methyl-2,3,4,4a,6, lOb-hexahydro- 1H- isochromeno[4,3-b]pyridine isomer 4 (A41 isomer 4): MS ESI calculated for C14H17F2NO2 [M+H]⁺, 270.12; found, 270.10. ^!H NMR (400 MHz, DMSO-ds) 3 7.44 - 7.22 (m, 2H), 7.07

- 6.99 (m, 2H), 4.76 (q, 6.4 Hz, 1H), 3.63 - 3.62 (m, 1H), 3.53 - 3.52 (m, 1H), 2.99 -

2.92 (m, 1H), 2.74 - 2.63 (tn, 1H), 2.01 - 1.92 (m, 1 H), 1.79 - 1.69 (m, 1H), 1.67 - 1.57 (m, 1 H), 1 .51 (d, J ~ 6.4 Hz, 3H), 1.40 - 1.31 (m, 1H). The relative stereochemistry of two centers labeled with “orl" was determined by NOESY.

Intermediate A42: 1 : 1 mixture of rel-(2R,4aR,9bR)-2-methyl-7-(trifluoromethy1)-

2,3,4,4a,5,9b-hexahydro-lH-indeno[l ,2-bJpyridine isomer 2 and rel-(2S,4aS,9bS)-2-methyl-

7-(lrifluoromethyl)-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine isomer 1

A42

Step- 1 :

[1085] A mixture of (4-(trifluoromethy1)pheny1)boronic acid (19 g, 100.04 mmol), methyl 2-chloro-6-meihylnicotinate (22.28 g, 120.04 mmol), NajCOs (41.48 g, 300.11 mmol) and tetrakis(triphenylphospliine)palladium (2.31 g, 2.00 mmol) in a mixture of toluene (100 mL), H2O (50 mL) and EtOH ( 100 ml.) was stirred al 120°C for 16 h under nitrogen atmosphere. The resulting mixture was quenched by water and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SO.j. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0 - 15% ethyl acetate in petroleum ether to afford methyl 6-meihy]-2-(4-(trifluoromethyl)phenyl)nicotinate (19.5 g, 44%) as an off-white oil. MS ESI calculated for CisHirFsNCh [M+H]⁺, 296.08; found, 296.10.

Step-2:

[1086] To a stirred solution of methyl 6-methyl-2-(4-(trifIuoromethyl)phenyl)nicotinate (19.50 g, 66.38 mmol) and CaCh (1 1.05 g, 99.57 mmol) in THF (150 ml) and EtOH (150 mL) was added NaBlTi (6.28 g, 165.96 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water/ice. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCfo After filtration, the filtrate w-as concentrated under reduced pressure to afford (6-methy1-2-(4-(trifluoromethyl)phenyl)pyridin-3-y1)methanol (17 g, 86%) as a white solid. MS ESI calculated for C14H12F3NO [M+H]\ 268.09; found, 268.15.

Step-3:

[1087] To a stirred solution of (6-methyl-2-(4-(trifluoromethyl)phenyl)pyridin-3- yl)rnethanol (17 g, 63.61 mmol) in DCM (200 mL) was added SOCI2 (14 mL, 190.83 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford 3-(chloromethyl)-6-metbyl-2-(4-

(trifluoromethyl)phenyl)pyridine (23.4 g, crude) as a yellow oil. MS ESI calculated for

[1088] To a stirred solution of 3-(cbloromethyl)-6-methyJ-2-(4-

(trifluoromethyl)phenyl)pyridine (23.40 g, 81.91 mmol) and Na2COs (34.72 g, 327.63 mmol) in DME (250 mL) were added P(m-Tol)3 (4.99 g, 16.38 mmol) and Pd(0Ac')₂ (1.84 g, 8.19 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 16 h. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford 2-methyl-7-(trifluoromethyI)-5H-indeno[l,2-b]pyridine (9.0 g, 43%) as a light yellow solid. MS ESI calculated for CHHJOFJN [M+H]⁺, 250.08; found, 250.20. 'H NMR (400 MHz, DMSO-zfc) 8 8.11 (d, 8.0 Hz, 1H), 8.07 - 7.98 (m,

1H), 7.94 (d, J = 7.8 Hz, 1 H), 7.79 (dd, J = 7.6, 1.6 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1H), 4.00 (s, 2H), 2.60 (s, 3H).

Step-5 :

[1089] To a stirred solution of 2-methyl-7-(trifluoromethyl)-5H-indeno[l,2-b]pyridine (2.8 g, 11.23 mmol) in Toluene (28 rnL) were added N-phenylaniline (7.60 g, 44.94 mmol) and tris(2,3,4,5,6-pentafluorophenyi)borane (575 mg, 1.12 mmol) at 20 °C. The resulting mixture was stirred at 1 10 °C for 16 h. The mixture was basified with NaHCOs (sat.) to pH 8 and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash chromatography with a 120 g silica gel column eluted with 0—10% methanol in dichloromethane, the product was further purified by Prep-Achiral-SFC with the following conditions: [Column: YMC-Actus Triart Diol-HILIC 3*25 cm, 5 pm; Mobile Phase A: COz, Mobile Phase B: MeOH (20mM NH3.M); Flow rate: 75 mL/mm; Gradient: isocratic 13% B; Column Temperature! °C ): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 4.88; RT2(min): 5.62; Sample Solvent: MEOH] to afford a 1: 1 mixture of rel-(2R,4aR,9bR)-2-methyl-7-(trifluoromethyl)-2,3,4,4a,5,9b- hexahydro-lH-indeno[l,2-b]pyridine isomer 1 and rel-(2R,4aR,9bR)-2-methyl-7- (trifluoromethyl)-2,3,4,4a,5,9b-hexahydro-lH-indeno| 1 ,2-bJpyridine isomer 2 (489 rag, 88% purity) as a light yellow oil with retention time at 5.62 minute. MS ESI calculated for C14H_!6F3N [M+HT, 256.12; found, 256.10. ‘H NMR (400 MHz, DMSO-zfo) 8 7.69 - 7.40 (m, 3H), 4.06 (d, J = 5.2 Hz, 1H). 3.06 - 2.89 (m, 1H), 2.82 ■■■■ 2.57 (m. 2H), 2.40 - 2.22 (m, 1H), 1.91 - 1.68 (m, 2H), 1.57 - 1.41 (rn, 1H), 1.31 - 1.10 (m, 1H), 1.04 - 0.90 (m, 3H).

Intermediate A42 isomer 1: rel-(2R,4aR,9bR)-2-melhyl-7-(trifluoromethyl)-2,3,4,4a,5,9b- hexahydro-lH-indeno[l,2-b|pyridine isomer 1:

Intermediate A42 isomer 2: rel-(2R,4aR,9bR)-2-methyl-7-(trifluoroniethyl)-2,3,4,4a,5,9b- hexaliydro-lH-indeno[l,2-b]pyridine isomer 2:

[1090] Intermediate A42 (489 mg) was separated by Prep-Chiral -HPLC with the following conditions: [Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NIL-MeOH), Mobile Phase B: MEOH: DCM=i: 1— HPLC; Flow rate: 20 mL/min; Gradient: 2% B to 2% B in 11.5 min; Wave Length; 220/254 nm; RTl(min): 4.87; RT2(min): 7.03;

Sample Solvent: EtOH: DCM-1: 1-HPLC] to afford rel-(2R,4aR,9bR)-2-methyl-7- (trifluoromethyl)-2,3.4,4a,5,9b-hexahydro-lH-indeno[1.2-b]pyridme isomer 1 (.442 isomer 1) (66 rag, 14% yield) as a light yellow oil with retention time at 4.87 minute. MS ESI calculated for C14H16F3N [M+H]\ 256.12; found, 256.10. ^!H NMR (400 MHz, DMSO-cfc) 5 7.66 - 7.37 (m, 3H), 3.99 (d, J = 5.2 Hz, IH), 3.03 - 2.97 (m, IH), 2.84 - 2.70 (m, 1 H), 2.64 - 2.52 (m, IH), 2.34 - 2.19 (m, IH), 1.89 - 1.66 (m, 2H), 1.52 - 1.36 (m, IH), 1.26 - 1.07 (ra, IH), 0.94 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was not determined.

[1091] The chiral resolution also afforded rel-(2R,4aR,9bR)-2-methyl-7-(trifluoromethyl)- 2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine isomer 2 (A42 isomer 2) (61 mg, 12% yield) as a light yellow oil with retention time at 7.03 minute. MS ESI calculated for CriHi₆F₃N [M+H]⁺, 256.12; found, 256.10. ^!H NMR (400 MHz, DMSO-Js) 5 7.66 - 7.37 (m, 3H), 3.99 (d, J = 5.2 Hz, IH), 3.03 - 2.97 (m, HI), 2.84 - 2.70 (m, IH), 2.64 - 2.52 (m, IH), 2.34 - 2.19 (tn, IH), 1.89 - 1.66 (m, 2H), 1 .52 - 1.36 (m, IH), 1.26 - 1.07 (m, IH), 0.94 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A43: iel-(4aS,10bS)-8-isopropyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b : 5 ,4- b’ ]dipyri dine hy drochlori de

A43

Step-1 : [1092] To a stirred solution of rel-tert-butyl (4aS, 10bS)-8-chloro-2,3,4,4a,6, 10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (from intermediate A40) (1.0 g, 3.07 mmol) and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (0.62 g, 3.69 mmol) in Dioxane (10 mL) were added Pd(dppf)C12-CH2Ch (0.25 g, 0.30 mmol) and K2CO3 (1.28 g, 9.23 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. Hie combined organic layers were washed with EtOAc, dried over anhydrous NasSO-i. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE / EtOAc (5: 1) to afford rel-tert-butyl (4aS,10bS)-8-(prop-l-en-2-yl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b^,]dipyridine- 1 -carboxylate (910 mg, 89%) as a colorless oil. MS ESI calculated for C19H26N2O3 [M+H]⁺, 331.19; found, 331.15.

Step-2:

[1093] To a solution of rel-tert-butyl (4aS,10bS)-8-(prop-l-en-2-yl)-2,3,4,4a,6,10b- hexaliydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (850 mg, 2.57 mmol) in methanol (10 ml..) was added Pd/C (273 mg, 10% active on carbon). The mixture was stirred at 20 °C for 2 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EtOAc (5: 1) to afford rel-tert-butyl (4aS,10bS)-8-isopropyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- bjdipyridine-l -carboxylate (790 mg, 92%) as a colorless oil. MS ESI calculated for C19H28N2O3 [M+H]⁺, 333.21 : found, 333.15.

Step-3:

[1094] A mixture of rel-tert-butyl (4aS, 10bS)-8-isopropyl-2,3,4,4a,6. lOb-hexahydro- 1 H- pyrano[3,2-b:5,4-b']dipyridine-1 -carboxylate (700 mg, 2.10 mmol) and HC1 (4M in dioxane) (2 ml.) was stirred at 20 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford rel-(4aS.10bS)-8-isopropyI-2, 3, 4, 4a, 6, lOb-hexahydro- lH-pyrano[3, 2- b:5,4-b’]dipyridine hydrochloride (A43) (760 mg, crude) as a white solid, which was used directly without purification. MS ESI calculated for C14H20N2O [M+H]⁺, 233.16; found, 233.15. ^;H NMR (400 MHz, DMSO-d₆) 8 10.79 (br, 1H), 8.87 (br, 1H), 8.44 (d, J= 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 5. 18 - 4.84 (m, 2H), 4.58 - 4.38 (m, 1H), 4.09 - 4.08 (m, 1H), 3.36 - 3.11 (m, 2H), 3.02 (q, 11.8 Hz, 1 H), 2.14 - 1.53 (m, 4H), 1.44 - 1.13 (m, 6H).

[1095] The absolute stereochemistry of A43 was determined as S, S-configuration, prepared from A40, the absolute stereochemistry of which was confirmed. Accordingly, A43 is represented by the structure:

Intermediate A44: rel-(4aS, 10bS)-8-cyclopropyl-2, 3,4, 4a, 6, lOb-hexahydro- lH-pyrano[3, 2- b:5,4-b’]dipyridine hydrochloride Step-1:

[1096] To a stirred mixture of rel-tert-butyl (4aS,10bS)-8-chloro-2.3,4,4a,6,10b-hexahydro- lH-pyrano|3,2-b:5.4-b']dipyridine-l-carboxylate (from intermediate A40) (1.0 g, 3.07 mmol) and K3PO4 (1.96 g, 9.23 mmol) in toluene (20 mL) and H?O (2 mL) were added Pd(OAc)₂ (69 mg, 0.30 mmol) and cyclopropylboronic acid (661 mg, 7.69 mmol) at room temperature under nitrogen atmosphere. Hie resulting mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1 ) to afford rel-tert-butyl (4aS,10bS)-8- cycfopropyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (1.0 g, 98%) as a colorless oil. MS ESI calculated for C_:jH .-.X ■() . [M+H]⁺, 331.19; found, 331.20.

A44

[1097] A mixture of rel-tert-butyl (4aS, 10bS)-8-cyclopropyl-2,3,4,4a,6, lOb-hexahydro- 1H- pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (1.0 g, 3.02 mmol) and HC1 (4M in dioxane) (10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford rel-(4aS,10bS)-8-cyclopropyl-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b']dipyridine hydrochloride (A44) (870 mg, crude) as an off-white solid, which was used in the next step directly without further purification. MS ESI calculated for CMH_!8N2O [M+H]⁺, 231.14; found, 231.25. ‘H NMR (400 MHz, DMSO-dg) 5 10.29 (s, 1H), 8.72 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.31 (d, J =■■ 8.0 Hz, 1H), 4.92 - 4.66 (m, 2H), 4.34 (d, J = 10.6 Hz, 1H), 4.03 - 4.02 (m, 1H), 3.18 (d, J = 12.4 Hz, 1H), 3.01 (q. J - 11.8 Hz, 1H), 2.22 - 2.16 (m, 1H), 2.05 - 1.58 (m, 4H), 1.15 - 0.88 (m, 4H).

[1098] The absolute stereochemistry of A44 was determined as S, S-configuration, prepared from A40, the absolute stereochemistry of which was confirmed. Accordingly, A44 is represented by the structure:

Intermediate A45 isomer 1: (4aS,6R, 10bS)-6-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b- hexahydro- 1 H-pyrano[3,2-b:5,4-b']dipyridine

A45 isomer 1

Step - 1 :

[1099] To a stirred solution of methyl 3-bromo-6-(trifluoromethyl)picolinate (25.0 g, 88.02 mmol) in THF (250 mL) and IfcO (50 mL) was added LiOH (4.22 g, 176.04 mmol) at room temperature . The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified with HC1 (aq., IN) to PH 1. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure to afford 3-bromo-6- (trifluoromethyl)picolinic acid (42 g, crude) as a white solid. MS ESI calculated for (CrHsBrFsNOr) 269.93, 271.93; found, 270.05, 272.05. Step-2:

[1100] To a stirred solution of 3-bromo-6-(trifluoromethyl)picolinic acid (42 g, 155.55 mmol) and N,O-dimethylhydroxylamine hydrochloride (18.21 g, 186.66 mmol) in DMF (500 mL) were added HATU (70.98 g, 186.66 mmol) and DIEA (60.31 g, 466.66 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-25% ethyl acetate in petroleum ether to afford 3-bromo-N-methoxy-N-methyl-6- (trifluorornethyl)picolinamide (29 g, 60%) as a yellow oil. MS ESI calculated for (CQH- BrHVO 2) [M+H]⁺, 312.97, 314.97; found, 313.05, 315.05.

Step-3:

[1101] To a stirred solution of 3 -bromo-N -methoxy -N-methy 1-6- (trifluoromethyl)picolinamide (29 g, 92.63 mmol) in Diethyl ether (300 mL) was added MeMgBr (3M in Et.2O) (93 ml.., 279 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford 1- (3-bromo-6-(trifluoromeihyl)pyridm-2-yl)ethan-l-one (13.8 g, 56%) as a brown oil. MS ESI calculated for CxH5BrF3NO [M+HJ⁺, 267.95, 269.95; found, 268.00, 270.00.

Step-4:

[1102] To a stirred solution of l-(3-bromo-6-(trifluoromethyl)pyridin-2-yl)ethan-l-one (13.30 g, 49.62 mmol) and (E)-tert-bulyldiphenyl((5-(4,4,5,5-tetrametbyl-l ,3,2-dioxaborolan- 2-yl)pent-4-en-l-yl)oxy)siiane (28.26 g, 59.54 mmol) in Dioxane (150 mL) and H2O (15 mL) were added K2CO3 (13.72 g, 99.24 mmol) and PdidppftCL-CHiCh (4.05 g, 4.96 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-8% ethyl acetate in petroleum ether to afford (E)-l-(3-(5-((tert-butyldiphenylsilyl)oxy)pent- 1-en-l-yl)- 6-(trifluoromethyl)pyridin-2-yl)ethan-l-one (17.6 g, 69%) as a yellow oil. MS ESI calculated for C29H32F3NO2S1 [M+H]⁺, 512.22; found, 512.25.

[1103] To a stirred solution of (E)- l-(3-(5-((teit-butyldiphenylsilyJ)oxy)pent- 1 -en- 1-yl) -6- (trifluoromethyl)pyridin-2-yl)ethan- 1 -one (17.6 g, 34.40 mmol) in methanol (300 mL) was added NaBH4 (1.95 g, 51.60 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford a 1 :1 mixture of (R,E)-l-(3-(5-((tert- butyldipbenylsilyl)oxy)pent-l-en-l-yl)-6-(trifluoroniethyl)pyridin-2-yl)ethan-l-ol and (S,E)- 1 -(3 -( 5 ■ ((tert-butyldiphenylsilyl)oxy )pent- 1 ■ en- 1-yl)- 6- ( trifli3oromethyl)pyridin-2-yl)ethan- 1 ■ ol (15.4 g, 87%) as a yellow oil. MS ESI calculated for C₂9H;uF₃NO₂Si [M+H]⁺, 514.23; found, 514.30.

Step-6:

[1104] To a stirred solution of tert-butyl carbamate (10.89 g, 92.94 mmol) in propan-l-ol (116 mL) was added a solution of NaOH (3.24 g, 80.95 mmol) in H₂O (110 niL) at room temperature. The mixture was stirred at room temperature for 10 min. Then l,3-dichloro-5,5- dimethylimidazolidine-2, 4-dione (8.86 g, 44.97 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 30 min. This was followed by the addition of a solution of (DHQ)₂PHAL (2.34 g, 2.99 mmol) (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50- 1) in propan-l-ol (30 mL) and a solution of 1 : 1 mixture of (R,E)-l-(3-(5-((tert-butyldiphenylsilyl)oxy)pent-l-en- 1 -yl)-6-(trifluoromethyl)pyridin-2- yl)ethan- l-ol and (S,E)- 1 -(3-(5-((tert-butyldiphenylsilyI)oxy)pent- 1 -en-l-yl)-6- (tritluoromethyl)pyridin-2-yl)ethan-l-ol (15.4 g, 29.980 mmol, 1 equiv) in propan-l-ol (20 mL) at 0 °C. Then Potassium osmate(VI) dihydrate (1 ,10 g, 2.99 mmol) was added at at 0 °C. Hie resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of brine and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford tert-butyl ((lS,2S)-5-((tert-butyddiphenylsi]yl)oxy)-2-hydroxy-l-(2-((S)-l-hydroxyethyl)-6- (trifluorometliyl)pyridin-3-yl)pentyl)carbamate (8.3 g, 43%) as a yellow oil as the second eluting peak. MS ESI calculated for C34H45F3N2O5S1 |M+H]⁺, 647.30; found, 647.20.

[1105] The purification process also afforded tert-butyl (( lS,2S)-5-((tert- butyldiphenyisilyl)oxy)-2-hydroxy-l-(2-((R)-l-hydroxyethyl)-6-(trifluoromethyl)pyridin-3- yl)pentyl)carbamate (6.9 g, 36%) as a yellow oil as the first eluting peak. MS ESI calculated for CMH45F3N2O5S1 [M+H]⁺, 647.30; found, 647.20.

[1106] To a stirred solution of tert-butyl ((lS,2S)-5-((tert-butyldiphenylsilyl)oxy)-2- hydroxy-l-(2-((S)-l-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)pentyl)carbamate (8.3 g, 12.83 mmol) in toluene (100 mL) was added 2-(tributyl-A⁵-phosphaneylidene)acetonitrile (CAS No. 157141 -27-0) (6.19 g, 25.67 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The resulting mixture was concentrated under vacuum. Tire residue was purified by normal phase flash column chromatography with a 120 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford tert-butyl ((5S,6S,8R)-6-(3-((tert-butyldiphenylsilyl)oxy)propyl)-8-methyl-2- (trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (2.45 g, 30%) as a light yellow oil. MS ESI calculated for CsrlEuFsNiChSi [M+H]⁺, 629.29; found, 629.45.

Step-8:

[1107] To a stirred solution of tert-butyl ((5S,6S,8R)-6-(3-((tert- butyldiphenylsilyl)oxy)propyl)-8-methyl-2-(trifluoromethyl)-5,8-dihydro-6Ifopyrano[3,4- b]pyridin-5-yl)carbamate (2.45 g, 3.90 mmol) in THF (30 mL) was added TBAF (1.22 g, 4.68 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under vacuum. The residue was purified by normal phase flash column chromatography with an 80 g silica gel column eluted with 0-60% ethyl acetate in petroleum ether to afford tert-butyl ((5S,6S,8R)-6-(3-hydroxypropyl)-8-methyl-2-

(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-bjpyridin-5-yl)cart>amate (1.36 g, 89%) as a light yellow oil. MS ESI calculated for C18H25F3N2O4 [M+H]⁺, 391.18; found, 391.15.

Step-9:

[1108] To a stirred solution of ((5S,6S,8R)-6-(3-hydroxypropyl)-8-methyl-2- (trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (1.36 g, 3.48 mmol) in toluene ( 15 mL) was added 2-(tributy1-A³-phosphaneylidene)acetonitrile (CAS No.

157141-27-0) (1.68 g, 6.97 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by normal phase flash column chromatography with an 80 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford tert-butyl (4aS,6R,10bS)-6-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b'Jdipyridiiie-1 -carboxylate ( 1.2 g, 93%) as a yellow oil. MS ESI calculated for C1SH23F3N2O3 [M+H]⁺, 373.17; found, 373.10. Step-10:

A45 isomer 1

[1109] A mixture of tert-butyl (4aS,6R,10bS)-6-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b- bexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-1 -carboxylate (1.10 g, 2.95 mmol) and HC1 (4M in 1,4 -dioxane) (10 mL) was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to afford (4aS,6R,10bS)-6-niethyl-8-(trifluoromethyl)- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine hydrochloride (A45 isomer 1 ) (crude, 925 mg) as a white solid. MS ESI calculated for CBH45F3N2O 273.11 ; found, 273.10. 'H NMR (400 MHz, DMSO) 5 10.66 (s, 1H), 8.80 (s, 1H), 8.44 (dd, J = 8.0, 3.0 Hz, 1H), 7.96 (d, J - 8.0 Hz, 1H), 4.99 - 4.92 (m, HI), 4.53 (d, - 10.4 Hz, HI), 4.15 -

4.14 (m, 1H), 3.26 - 3.05 (m, 2H), 2.15 - 1.95 (m, 1H), 1.95 - 1.76 (in, 2H), 1.76 - 1.53 (m, 4H). Absolute stereochemistry was determined by NOESY.

Intermediate A45 isomer 2: (4aS,6S,10bS)-6-methyl-8-(trifluoromethyl)-2, 3,4, 4a, 6,1 Ob- hex ahy dro- 1 H-pyrano [3 ,2-b : 5 ,4 -b'ldipy ridine

A45 isomer 2

Step-1 : [1110] To a stirred solution of tert-butyl ((1 S,2S)-5-((lert-butyldiphenylsiIyl)oxy)-2- hydroxy-l-(2-((R)-l-hydroxyet,hyl)-6-(trifluoromethyl)pyridin-3-y])pentyl)carbamate (8.4 g, 12.99 mmol) in toluene (100 mL) was added 2-(tributyl-A⁵-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (6.27 g, 25.97 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by normal phase flash column chromatography with an 120 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford tert-butyl ((5S,6S,8S)-6-(3-((tert-butyldipheny1silyl)oxy)propyl)-8- methyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (3.05 g, 37%) as a light yellow oil. MS ESI calculated for CMEUsFjNzO-tSi [M+H]⁺, 629.29; found, 629.35.

[1111] To a stirred solution of tert-butyl ((5S,6S,8S)-6-(3-((tert- butyldiphenylsilyl)oxy)propyl)-8-methyl-2-(trifluoroniethyl)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate (3.05 g, 4.85 mmol) in THE (30 mL) was added TBAF (1.52 g, 5.82 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by normal phase flash column chromatography with a 120 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford tert-butyl ((5S,6S,8S)-6-(3-hydroxypropyl)-8-methyl-2- (trifIuoromethyl)-5,8-dihydro-6H-pyrano| 3,4-b]pyridin-5-yl)carbamate (1.3 g, 69%) as a light yellow oil. MS ESI calculated for CssEhsFtNiCU [M+H]*, 391.18; found, 391.25.

Step-3 :

[1112] To a stirred solution of tert-butyl ((5S,6S,8S)-6-(3-hydroxypropyl)-8-methyl-2- (tritluoromethyl)-5,8-dihydro-6H-pyrano[3,4-bjpyridin-5-yl)carbamate (1.30 g, 3.33 mmol) in toluene (20 mL) was added 2-(tributyl-)?-phosphaneylidene)acetonitrile (CAS No.

157141-27-0) (1.61 g, 6.66 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under vacuum.

The residue was purified by normal phase flash column chromatography with an 80 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford tert ■•butyl (4aS,6S,10bS)-6-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b']dipyridine-l -carboxylate (1.02 g, 82%) as a yellow oil. MS ESI calculated for C18H23F3N2O3 [M+H]⁺, 373.17; found, 373.10.

A45 isomer 2

[1113] A mixture of tert-butyl (4aS,6S,10bS)-6-methy1-8-(trifluoromethyl)-2,3,4,4a,6,10b- hexaliydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate (1.02 g, 2.74 mmol) and HC1 (4M in 1,4-dioxane) (10 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by Prep- HPLC with the following conditions: [Column: XB ridge Prep OBD Cl 8 Column30*150 mm: Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min, 23% B to 43% B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.9-9.4] to afford ((4aS,6S,10bS)-6-methyl-8-(trifiuoromethyl)- 2,3,4,4a,6.10b-hexahydro-iH-pyrano[3,2-b:5,4-b']dipyridine (A45 isomer 2) (470 mg, 63%) as a white solid. MS ESI calculated for C13H15F3N2O [M+H]⁺, 273.1 1 ; found, 273. 10. ‘H NMR (400 MHz, DMSO) 8 8.04 (d, J = 7.6 Hz, 1H), 7.73 (dd, J - 8.0, 2.8 Hz, 1H), 5.12 - 34.93 (m, 1H), 4.08 - 3.88 (m, 1H), 3.76 (d, J = 2.8 Hz, 1H), 2.85 - 2.55 (m, 2H), 2.24 - 2.23 (m, 1H), 1.93 - 1.67 (ni, 2H), 1.67 - 1.22 (m, 5H). Absolute stereochemistry was determined by NOESY.

Intermediate A46 isomer 1: (4S,4aR,10bS)-4-fluoro-8-(trifluoromelhyi)-2,3,4,4a,6,10b- hexahydro- 1 H-pyr ano [3 ,2-b : 5 ,4-b’ jdipyridine isomer 1

A46 isomer 1

Step-1: HO''"^Sx^^x’OTBDPS

[1114] To a stirred solution of propane- 1,3-diol (100.00 g, 1314.15 mmol) in DCM (200 mL.) were added imidazole (223.66 g, .3285.37 mmol) and TBDPSC1 (397.33 g, 1445.56 mmol) al 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCh. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (0 - 10%) to afford 3-((tert- buty1diphenylsilyl)oxy)propan-1 -ol (136.9 g, 33%) as a colorless oil. MS ESI calculated for Ci9H₂6O₂Si [M+H]⁺, 315.17; found, 315.15.

Step-2:

[1115] To a stirred solution of 3-((tert-butyldiphenylsilyl)oxy)propan-l-ol (40.00 g, 127.19 mmol) in DCM (400 mL) was added TEA (38.61 g, 381.56 mmol) at room temperature. To the above mixture was added a solution of Py-SCh (40.49 g. 254.37 mmol) in DMSO (200 mL.) at 0°C. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 15% EtOAc in petroleum ether to afford 3- ((tert - butyldiphenylsilyl)oxy)propanal (31.00 g, 78%) as a colorless oil. MS ESI calculated for CM HO-Si [M+H] \ 313.15; found, 313.15.

Step-3:

[1116] To a stirred solution of 3-((tert-butyldiphenylsilyljoxy)propanal (31.00 g, 99.21 mmol) in THE (310 mL) was added Ethynyimagnesium bromide (0.5 M solution in THF) (39'7 mL, 198.41 mmol) at 0 ° C dropwise under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with NHiCl (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 10% EtOAc in petroleum ether to afford a 1 : 1 mixture of (S)-5-((tert-butyldipheny1silyl)oxy)pent-l-yn-3-ol and (R)-5-((tert- butyldiphenylsilyl)oxy)pent- l-yn-3-ol (19.20 g, 57%) as a yellow oil. MS ESI calculated for C2jH₂₆O₂Si [M+H]⁺, 339.17: found, 339.10.

Step-4:

[1117] To a stirred solution of a 1:1 mixture of (S)-5-((tert-butyldiphenylsilyl)oxy)pent-l- yn-3-ol and (R)-5-((tert-butyldiphenylsilyl)oxy)pent-l-yn-3-ol (19.10 g, 56.42 mmol) in DCM (200 mL) were added imidazole (7.68 g, 112.84 mmol) and TBSC1 (10.20 g, 67.71 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 5% EtOAc in petroleum ether to afford a 1 :1 mixture of (S)-5-ethynyl-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-4,8-dioxa-3,9- disilaundecane and (R)-5-ethynyl-2,2,3,3 ,10,10-hexametbyl-9,9-diphenyl-4,8-dioxa-3,9- disilaundecane (20.45 g, 80%) as a yellow oil. MS ESI calculated for CrrHioChSir [M+H]⁺, 453.26; found, 453.25.

Step-5 :

[1118] A mixture of 1:1 mixture of (S)-5-ethyny1-2, 2.3, 3,10, 10-hexamethyl-9, 9-dipbenyl- 4,8-dioxa-3,9-disilaundecane and (R)-5-ethynyl-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-4,8- dioxa-3,9-disilaundecane (20.00 g, 44.17 mmol), TEA (0.89 g, 8.83 mmol), Schwartz's reagent (2.27 g, 8.83 mmol) and HBpin (3.39 g, 26.50 mmol) was stirred at 60 °C for 4 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography, eluted with 0 - 40% DCM in petroleum ether to afford a 1:1 mixture of (R,E)-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-5-(2- (4,4,5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)vinyl)-4,8-dioxa-3,9-disiIaundecane and (S,E)- 2,2,3,3,10,10-hexamethyl-9,9-diphenyl-5-(2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)vinyl)-4,8-dioxa-3,9-disilaundecane (17.80 g, 69%) as a colorless oil. MS ESI calculated for C .. I E . BO AT [M+H]⁺, 581.36; found, 581.45.

Step-6:

[1119] To a stirred solution of 1: 1 mixture of (R,E)-2,2,3,3,10,10-hexamethyl-9,9- diphenyl-5-(2-(4,4,5,5-tetrametbyl-1 ,3,2-dioxaborolan-2-yl)vinyl)-4,8-dioxa-3,9- disilaundecane and (S,E)-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-5-(2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)vinyl)-4,8-dioxa-3,9-disilaundecane (15.30 g, 26.35 mmol) in 1,4- dioxane ( 140 rnL) and H2O (14 mL) were added methyl 3-bromo-6- (trifliioromethyl)picolinate (6.80 g, 23.95 mmol), K2CO3 (9.93 g, 71.85 mmol) and Pd(dppf)C1₂ (1 -75 g, 2.40 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with waler and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 10% EtOAc in petroleum ether to afford a 1: 1 mixture of methyl (S,E)-3-(3-((tert-butyldimethylsilyl)oxy)-5- ((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-6-(trifluoromethyl)pico1inate and methyl (R,E)- 3-(3-((tert-butyldimethylsilyl)oxy)-5-((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-6- (tritluoromethyl)picolinaie (14.20 g, 90%) as a yellow oil. MS ESI calculated for C35H46F₃NO4Si2 [M+H]⁺, 658.29; found, 658.30. ^!H NMR (400 MHz, DMSO-rfe) 5 8.38 (d, ./ = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.63 - 7.56 (m, 4H), 7.47 - 7.36 (m, 6H), 6.89 (d, J = 15.6 Hz, 1H), 6.63 (dd, J - 16.0, 5.6 Hz, 1H), 4.64 - 4.59 (m, 1H), 3.88 (s, 3H), 3.82- 3.71 (m, 210. 1.84 - 1.77 (m, 210. 0.99 - 0.75 ( m. 18H), 0.03 - 0.02 (m, 6H).

Step-7:

[1120] To a stirred solution of 1: 1 mixture of methyl (S,E)-3--(3-((tert- butyldimethylsilyl)oxy)-5-((tert-butyldiphenylsilyl)oxy)pent- l-en-l-yl)-6- (trilluoromethyl)picolinate and methyl (R,E)-3-(3-((tert.-butyldimethylsilyl)oxy)-5-((tert- butyldipbenylsilyl)oxy)pent-l-en- 1 -yl)-6-(trifluoromethyl)picolinate (14.20 g, 21.58 mmol) in THE (60 rnL) were added AcOH (180 mL) and H2O (60 mL) at room temperature. The resulting mixture was stirred at room temperature for 32 h. The mixture was basified with saturated NajCOz (sat.) to pH 8. The resulting mixture was extracted with EtOAc. The combined organic layers w^rere washed with brine, dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with 0 ~ 30% EtOAc in petroleum ether to afford a 1 : 1 mixture of methyl (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-hydroxypent- 1-en- 1 -y1)-6- (trifluoromethyl)picolinate and methyl (R,E)-3-(5-((tert-butyIdiphenylsilyl)oxy)-3- hydroxypent-l-en-l-yl)-6-(trifluoromethyl)picolinate (6.57 g, 56%) as a yellow oil. MS ESI calculated for C₂9H₃₂F₃NO4Si [M+H]t 544.21 ; found. 544.25. Step-8:

[1121] To a stirred solution of 1: 1 mixture of methyl (S,E)-3-(5-((tert- buty1dipheny1si1yl)oxy)-3-hydroxypent- 1 -en-l-yl)-6-(trifluoromethyl)picolinate and methyl (R,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-hydroxypent-l-en-l -yl)-6-

(trinuoromethyl)picolinate (6.57 g, 12.09 mmol) in DCM (70 mL) was added DA ST (3.90 g, 24.17 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with ice water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Nai’SCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 10% EtOAc in petroleum ether to afford a 1 : 1 mixture of methyl (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent- 1 -en- 1 -yl)~6~ (trifluoromethyl)picolinate and methyl (R,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3- fluoropent-l-en-l-yl)-6-(trifluoromethyl)picolinate (4.78 g, 72%) as a colorless oil. MS ESI calculated for C M fo Efot LSi [M-t-Hf, 546.20; found, 546.25. ’H NMR (400 MHz, DMSO- d₆) 5 8.45 (d, J - 8.4 Hz, 1 H), 8. 10 (d, J = 8.4 Hz, 1 H), 7.65 - 7.61 (m, 4H), 7.49 - 7.38 (m, 6H), 7.11 (d, ./ - 16.0 Hz, 1H), 6.75 - 6.64 (m, 1H), 5.5.3 - 5.34 (m, 1 H), 3.91 (s, 3H), 3.87 - 3.76 (m, 2H), 2.09 - 1.98 (m, 2H), 1.01 - 0.99 (m, 9H).

Step -9:

[1122] A mixture of BocNH2(2.52 g, 21.48 mmol, 0.8 M in n-PrOH) and NaOH (0.75 g, 18.71 mmol, 0.8M) was stirred at 0 °C for 10 min. Then DCDMH (2.05 g, 10.39 mmol) was added to the mixture at 0 °C. After stirring for 30 min. This was followed by the addition of (DHQhPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (0.54 g, 0.69 mmol, 0.1 M in n-PrOH), a solution of 1: 1 mixture of methyl (S,E)-3-(5-('(ten- butyldipbenylsilyl)oxy)-3-fluoropent- 1 -en- l-yl)-6-(tifluoromethyl)picolinate and methyl (R,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent- 1-en- 1 -yl)-6- (trifluoromethyl)picolinate (3.78 g, 6.93 mmol) in n-PrOH(30 mL) and K2OSO4.2H2O (0.26 g, 0.69 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with waler and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaaSOa- After filtration, the filtrate was concentrated under reduced pressure.

[1123] The residue was dissolved in DCM 140 mL), then DMAP (0.19 g, 1.55 mmol) and DCC (3.21 g, 15.54 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 30% EtOAc in petroleum ether to afford a 1: 1 mixture of tert-butyl ((5S,6R)-6-((S)-3-((tert- butyldipbenylsilyl)oxy)-l-fluoropropyl)-8-oxo-2-(trifluoromethy1)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate and tert -butyl <.(5S,6R)-6-((S)-3-((tert- butyldiphenylsilyl)oxy)-l -fluoropropyl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate (2.10 g, 43%) as a yellow solid. MS ESI calculated for C33H38F4N₂O₅Si [M+H p , 647.25; found, 647.30.

Step-10:

[1124] To a stirred solution of 1: 1 mixture of tert-butyl ((5S,6R)-6-((S)-3-((tert- butyldiphenylsilyl)oxy)-l-fluoropropyl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate and lert-butyl ((5S,6R)-6-((S)-3-((ten- butyldiphenylsilyl)oxy)-l-fluoropropyl)-8-oxo-2-(trifluoromethy1)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate (2.10 g, 3.25 mmol) in THE (20 mL) was added NaBth (0.25 g. 6.49 mmol) in portions at 0 °C. The resulting mixture was stirred at 0°C for 2 h. Ute reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 ~ 30% EtOAc in petroleum ether to afford tert-butyl ((lS,2R,3S)-5-((tert-butyldiphenylsilyl)oxy)-3-fluoro-2-hydroxy-1-(2- (hydroxymethyl)-6-(trifluoronietliyl)pyridin-3-yl)pentyl)carbaniate (720 mg, 34%) as a colorless oil with first eluting peak on column purification. MS ESI calculated for CssHrcfoNrOsSi [M+H]L 651.28; found, 651.30.

[1125] The purification also afforded lert-butyl ((lS,2R,3R)-5-((tert- butyldiphenylsilyl)oxy)-3-fluoro-2-hydroxy-l-(2-(hydroxymethyl)-6- (trifluoromethyl)pyridin-3-yl)pentyl)carbamate (700 mg, 33%) as a colorless oil with the second eluting peak on column purification. MS ESI calculated for CssHtiF^NsOsSi [M+H]⁺, 651.28; found, 651.30.

Step- 1 1 :

[1126] To a solution of tert-butyl ((lS,2R,3S)-5-((tert-butyldiphenylsilyl)oxy)-3-fluoro-2- hydroxy-l-(2-(hydroxymethyl)-6-(trifiuoromethyl)pyridin-3-yl)pentyl)carbarnate (720 mg, 1.11 mmol) in toluene (8 mL) was added 2-(tributyl-??-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (534 mg, 2.21 mmol). The resulting mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. Hie resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 ~ 20% EtOAc in petroleum ether to afford tert-butyl ((5S,6R)-6-((S)-3-((tert-butyldiphenylsilyl)oxy)-l- fluoropropyr)-2-(trifluoromethyl)-5,8“dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbarnate (500 mg, 71%) as a yellow oil. MS ESI calculated for C33H4oF4N204Si [M+H]*, 633.27: found, 633.30.

Step- 12:

[1127] To a solution of tert- butyl ((5S,6R)-6-((S)-3-((tert-butyldiphenylsilyl)oxy)-l- fluoropropyl)-2-(trifiuoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbarnate (500 mg, 0.79 mmol) in T'HF (5 mL) was added TBAF (499 mg, 1.58 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 ~ 50% EtOAc in petroleum ether to afford tert-butyl ((5S,6R)-6-((S)-l-fluoro-3- hydroxypropyl)-2-(trifluorometbyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (180 mg, 58%) as a white solid. MS ESI calculated for C17H22F4N2O4 IM+H]⁺, 395.15; found, 395.15.

Step-13:

[1128] To a stirred solution of tert-butyl ((5S,6R)-6-((S)-l-fluoro-3-bydroxypropyJ)-2- (trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-y1)carbamate (180 mg, 0.46 mmol) in Toluene (1.8 mL) was added 2-(tributyl-X⁵-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (220 mg, 0.91 mmol). The resulting mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 - 20% EtOAc in petroleum ether to afford tert-butyl (4S,4aR,10bS)-4-fluoro-8-(trifiuoromethyl)- 2, 3, 4.4a, 6, 10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate (129 mg. 75%) as a yellow oil. MS ESI calculated for C17H20F4N2O3 fM+H]⁺, 377.14; found, 377.15. ’H NMR (400 MHz, DMSO-dfc) 6 7.84 ( 8.4 Hz, IH), 7.71 (d, J = 8.0 Hz, IH), 5.43 (d, J =

6.8Hz, IH), 5.26 - 5.11 (m, IH), 5.05 - 4.87 (m, 2H), 4.35 - 4.22 (m, IH), 3.89 - 3.80 (m. IH), 2.77 - 2.70 (m, IH), 1 .96 - 1.81 (m, 2H), 1.46 (s, 9H). Absolute stereochemistry was determined by NOESY.

Step-14:

A46 isomer 1

[1129] A mixture of tert-butyl (4S,4aR, 10bS)-4-fluoro-8-(trifluorometbyl)-2,3,4,4a,6, 10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridiiie-l -carboxylate (129 mg, 0.34 mmol) and HC1 (4.0 M in 1,4-dioxane) (1 mL) was stirred at 0 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford (4S,4aR,10bS)-4-fluoro-8-(trifluorojnethyl)- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b'ldipyridine hydrochloride (A46 isomer 1) (100 mg, crude) as a white solid. MS ESI calculated for C12H12E1N2O [M+H]⁺, 277.09; found, 277.15. *H NMR (400 MHz, DMSO-Js) 6 10.89 (s, IH), 9.08 (s, IH), 8.44 (d, J = 8.0 Hz, IH), 7.98 (d, J = 8.0 Hz, IH), 5.18 - 4.91 (m, 3H), 4.67 - 4.66 (m, IH), 4.48 - 4.45 (m, IH), 3.42 - 3.10 (m, 2H), 2.14 - 2.11 (m, 2H). Absolute stereochemistry was determined by NOESY.

Intermediate A46 isomer 2: (4R,4aR, 10bS)-4-fluoro-8-(trifluoromethyl)-2,3,4,4a,6, 10b- hexahydro- 1 H-pyrano [3 ,2-b : 5 ,4-b' Jdipyridine

A46 isomer 2 Step-1:

[1130] To a solution of tert-butyl ((lS,2R,3R)-5-((tert-buty1diphenylsiJyl)oxy)-3-fluoro-2- hydroxy-l -(2-(hydroxymethyJ)-6-(trifluoromethyl)pyridin-3-yl)pentyl)carbamate (700 mg, 1.08 mmol) in toluene (8 mL) was added 2-(tributyl->?-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (519 mg, 2.15 mmol). The resulting mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 - 20% EtOAc in petroleum ether to afford tert-butyl ((5S,6R)-6-((R)-3-((tert-butyldiphenylsilyl)oxy)-l- nuoropropyl)-2-(trinuoromethyl)-5,8-dihydro-6I-I-pyrano[3,4-b]pyridin-5-yl)carbamate (428 mg, 63%) as a yellow oil. MS ESI calculated for CrsH^oEiNjCUSi [M+H]⁺, 633.27; found, 633.30.

Step-2:

[1131] To a solution of tert-butyl ((5S,6R)-6-((R)-3-((tert-butyldiphenylsilyl)oxy)-l- fluoropropyl)-2-(trifiuorometbyl)-5,8-dihydro-6H-pyrano|3,4-b|pyridin-5-yl)carbamate (420 mg, 0.66 mmol) in THF (5 mL) was added TBAF (419 mg, 1.33 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0

- 50% EtOAc in petroleum ether to afford tert-butyl ((5S,6R)-6-((R)-l-fluoro-3- hydroxypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate

(150 mg, 57%) as a white solid. MS ESI calculated for C17H22F4N2O4 [M+H]⁺, 395.15; found, 395.10. Step-3:

[1132] To a stirred solution of tert-butyl ((5S,6R)-6-((R)- l-f1uoro-3-hydroxypropyl)-2- (trifluoromethyl)-5,8-dibydro-6H-pyrano[3,4-b]pyridin-5-yl)earbamate (150 mg, 0.41 mmol) in Toluene (1.6 mL) was added 2-(tributyl-A⁵-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) ( 196 mg, 0.81 mmol). The resulting mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 - 20% EtOAc in petroleum ether to afford tert-butyl (4R,4aR,10bS)-4-fluoro-8-(trifluoromethyl)- 2,3,4.4a,6,l()b-hexahydro-lH-py£ano[3,2-b:5,4-b']dipyridme-l-carboxylate (117 mg, 77%) as a yellow oil. MS ESI calculated for C17H20F4N2O3 [M+H]⁺, 377.14; found, 377.15. ’H NMR (400 MHz, DMSO-ho) 6 7.87 (d, 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 5.61 - 5.59 (m,

1H), 5.04 - 4.84 (m, 3H), 4.24 - 4.17 (m, 1H), 3.96 - 3.92 (m, 1H), 2.05 - 1.99 (m, 1H), 1.70

- 1 .69 (m, 211), 1 .46 (s, 9H). Absolute stereochemistry was determined by NOESY.

Step-4:

[1133] A mixture of tert-butyl (4R,4aR, 10bS)-4-fluoro-8-(trifluoromethy I)-2,3,4,4a,6, 10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (1 17 mg, 0.31 mmol) and HCl (4.0 M in 1,4-dioxane) (1 mL) was stirred at 0 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford (4R,4aR,10bS)-4-fluoro-8-(trifluoromethyl)- 2, 3,4, 4a, 6, 10b-hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridine hydrochloride (A46 isomer 2) (100 mg, crude) as a white solid. MS ESI calculated for C12H12F4N2O [M+H]⁺, 277.09; found, 277.15. ^lH NMR (400 MHz, DMSO) 6 10.71 (br, 1H). 9.28 (br, 1H), S.49 - 8.46 (m,

1H), 8.01 (d, J = 8.0 Hz, 1H), 5.18 - 4.98 (m, 3H), 4.74 (s, 1H), 4.39 - 4.33 (m, 1H), 3.27 -

3.14 (m. 2H), 2.17 - 1.92 (m, 2H). Absolute stereochemistry was determined by NOESY.

Intermediate A47 isomer 1: (4S,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6,10b-hexahydro-

1 H-pyrano [3 ,2-b:5 ,4-b’]dipyridine

A47 isomer 1 . _anj

Intermediate A47 isomer 2: (4R,4aR,10bS)-8-chloro-4-fluoiio-2,3,4,4a,6,10b-hexahydro- rH-pyrano|3,2-b:5,4-b' |dipyridine

A47 isomer 2

Step- 1 :

[1134] To a stirred mixture of 3-bromo-6-chloropicolinic acid (50 g, 211.46 mmol) and

K2CO3 (58.45 g, 422.92 mmol) in DMF (500 mL) was added Mel (33.02 g, 232.61 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc.

The combined organic layers were washed with brine, dried over anhydrous Na^SCfo After filtration, the filtrate was concentrated under reduced pressure to afford methyl 3-brorno-6- chloropicolinate (45.8 g, crude) as a yellow solid. MS ESI calculated for C7H5B1CINO2 [M+Hf , 249.92, 251.92; found, 249.90, 251.90.

Step-2:

[1135] To a stirred solution of methyl 3-bromo-6-chloropicolinate (25 g, 99.81 mmol) and a 1:1 mixture of (R,E)-2,2,3,3,10,10-hexamethyl-9,9-diphenyL5-(2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)vinyl)-4,8-dioxa-3,9-disilaundecane and (S,E)-2,2,3,3.10,10- hexamethyl-9,9-diphenyl-5-(2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yi)vinyl)-4,8-dioxa- 3,9-disilaundecane (57.96 g, 99.81 mmol) in 1,4 -Dioxane (250 mL) and H2O (25 mL) were added PdidppfiCb-CHrCh (8.15 g, 9.98 mmol) and K2CO3 (41.38 g, 299.42 mmol). The resulting mixture was stirred at 80 °C for 4 h under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCL- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10: 1 ) to afford a 1:1 mixture of methyl (S,E)-3-(3- ((tert-butyldimethylsilyl)oxy)-5-((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-6- chloropicolinate and methyl (R,E)-3-(3-((tert-buty1dimethy1silyl)oxy)-5-((tert- butyldiphenylsilyl)oxy)pent-l-en-l-yl)-6-chloropicolinate (42.7 g, 68%) as a yellow oil. MS ESI calculated for C^xiH/jsClNO/iSiz [M+H]⁺, 624.27; found, 624.25.

Step-3 :

[1136] To a stirred solution of 1 : 1 mixture of methyl (S,E)-3-(3-((tert- buiyldimethylsilyl)oxy)-5-((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-6-ch]oropicolinaie and methyl (R,E)-3-(3-((tert-butyldimethylsilyl)oxy)-5-((tert-butyldiphenylsilyl)oxy)pent-l- en-l-yD-6-chloropicolinate (42 g. 67.27 mmol) in THF (168 mL) were added AcOII (504 mL) and H2O <168 ml..) at room temperature. The resulting mixture was stirred at room temperature for 48 h. The resulting mixture was concentrated under reduced pressure. The mixture was basified with NazCOa (sat.) to pH 7. The resulting mixture was extracted with EtOAc, The combined organic layers were washed with brine, dried over anhydrous NazSO.-r After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford a 1 :1 mixture of methyl (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-hydroxypent-1-en-l-yl)-6-chloropicoHnate and methyl (R.E)-3-(5-((tert-butyldiphenyisilyi)oxy)-3-hydroxypent- l-en-l-yl)-6- chloropicolinate (22 g, 64%) as a yellow oil. MS ESI calculated for CzsHszONOrSi [M+H]⁺, 510.18; found, 510.15.

Step-4:

[1137] To a stirred solution of 1: 1 mixture of methyl (S,E)-3-(5-((tert- butyldiphenylsilyl)oxy)-3-hydroxypent- 1-en- 1 -yl)-6-ch1oropicolinate and methyl (R,E)-3-(5- ((terl-butyldiphenylsilyl)oxy)-3-hydroxypent-l-en-l-ylj-6-chloropicolinate (22 g, 43.13 mmol) in THF (220 niL) was added DAST (13.90 g, 86.26 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 ^CC for 1 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10: 1) to afford a 1 :1 mixture of methyl (S,E)-3-(5- ((tert-butyldiphenylsilyl)oxy)-3-fluoropent-l-en-l-yl)-6-chloropicolinate and methyl (R,E)-3- (5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent- 1-en- 1 -yl)-6-chloropicolinate (12.4 g, 56%) as a yellow oil. MS ESI calculated for CssHsiCIFNOsSi [M+H]⁺, 512.17; found, 512.15. *H NMR (400 MHz, DMSO-ife) 6 8.23 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.64 - 7.60 (m, 4H), 7.48 - 7.39 (m, 6H), 7.1 1 - 7.06 (m, 1H), 6.63 - 6.54 (m, 1H), 5.47 - 5.33 (m, 1H), 3.88 (s, 3H), 3.84 - 3.74 (m, 2H), 2.07 - 1.96 (m, 2H), 1.00 (s, 9H).

Step-5 :

[1138] To a solution of BocNffc (8.79 g, 75.06 mmol) in n-PrOH (90 mL) was added a solution of NaOH (2.61 g, 65.38 mmol) in water (80 mL) at 0 °C. After stirring at 0 °C for 10 minutes, DCDMH (7.16 g, 36.32 mmol) was added in portions at 0 °C. The mixture was stirred at 0 °C for 30 minutes. This was followed by the addition of a solution of (DHQhPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (1.89 g, 2.42 mmol) in n-PrOH (24 mL), a solution of 1 : 1 mixture of methyl (S,E)-3-(5-((tert- butyldiphenylsilyl)oxy)-3-fluoropent-l-en-l-yl)-6-chloropicolinate and methyl (R,E)-3-(5- ((tert-butyldiphenylsilyl)oxy)-3-fluoropent- 1-en- 1 -yl)-6-chloropicolinate ( 12.4 g, 24.21 mmol) in n-PrOH(50 mL) and lC.2OsO4.2H2O (0.89 g, 2.42 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 4 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SOr- After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM (140 mL), then DCC (9. 15 g, 44.36 mmol) and DMAP (0.54 g, 4.43 mmol) were added to the mixture at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1: 1 ) to afford a 1 :1 mixture of tert-butyl ((5S,6R)-6-((S)-3-((tert-butyldiphenylsilyl)oxy)-l-fluoropropyl)-2- chloro-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5S,6R)-6- ((R)-3-((tert-butyldiphenylsilyl)oxy)-l-fluoropropyl)-2-chloro-8-oxo-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate (9.6 g, 35%) as a white solid. MS ESI calculated for C32H38ClFN₂O₅Si [M+Hf; 613.22; found, 613.25.

[1139] To a stirred solution of 1: 1 mixture of tert-butyl ((5S,6R)-6-((S)-3-((tert- butyldiphenylsiIyr)oxy)-l-fluoropropyl)-2-chloro-8-oxo-5,8-diliydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate and tert-butyl ((5S,6R)-6-((R)-3-((ten-butyldiphenylsilyl)oxy)-l- fiuoropropyl)-2-chloro-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbatnate (9.6 g, 15.65 mmol) in THE (100 mL) was added NaBHL (1.18 g, 31.31 mmol) in portions at 0^c'C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (4:1) to afford a 1:1 mixture of tert-butyl ((lS,2R,3S)-5-((tert-butyldiphenylsilyl)oxy)-l-(6-chloro-2-(hydroxymethyi)pyridin-3-yl)-3- fluoro-2-hydroxypentyl)carbamate and tert-butyl ((lS,2R,3R)-5-((tert- butyldiphenylsilyl)oxy)-l-(6-chloro-2-(hydroxymethyl)pyridin-3-yl)-3-fluoro-2- hydroxypentyDcarbamate (6.3 g, 65%) as a while solid. MS ESI calculated for C32H42CIFN2O5S! [M+HF, 617.25; found, 617.25.

Step-7 :

[1140] To a stirred solution of 1: 1 mixture of tert-butyl (( 1 S,2R,3S)-5-((tert- butyldiphenylsilyl)oxy)-l-(6-chloro-2-(hydroxymethyl)pyridin-3-yl)-3-fluoro-2- hydroxypentyl)carbamate and tert-butyl ((! S,2R,3R)-5-((tert-butyldiphenylsilyl)oxy)- 1 -(6- chloro-2-(hydroxymethyl)pyridin-3-yl)-3-fluoro-2-hydroxypentyl)carbamate (6.3 g, 10.21 mmol) in toluene (63 mL) was added 2-(tributyl-A³-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (4.93 g, 20.41 mmol) at room temperature. The resulting mixture was stirred at 1 10 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford a 1:1 mixture of tert-butyl ((5S,6R)-6-((S)-3-((tert-butyldiphenylsilyl)oxy)-l-fluoropropyl)-2- chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5S,6R)-6-((R)- 3-((tert-butyldipbenylsilyl)oxy)-l-fluoropropyl)-2-chloro-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate (870 mg, 14%) as a yellow oil. MS ESI calculated for C₃₂H4oClFN₂04Si [M+HF, 599.24; found, 599.25.

Step-8:

[1141] To a stirred solution of 1 : 1 mixture of tert-butyl ((5S,6R)-6-((Sj-3-((tert- butyldiphenylsilyl)oxy)- 1 -fluoropropyl) -2 -chloro-5,8- dihydro-6H-pyrano [3, 4-bjpyridin- 5 ■ yl)carbamate and tert-butyl ((5S,6R)-6-((R)-3-((tert-butyldiphenylsilyl)oxy)- 1 -fluoropropyl)- 2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (870 mg, 1.45 mmol) in THF (10 mL) was added TBAF (759 mg, 2.90 mmol) in portions at room temperature. The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford a 1:1 mixture of tert-butyl ((5S,6R)-2-chloro-6-((S)-l-fluoro-3- hydroxypropyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5S,6R)-2-chloro-6-((R)-l-fluoro-3-hydroxypropyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5- yl)carbamate (500 mg, 95%) as a yellow oil. MS ESI calculated for C16H22CIFN2O4 [M+H]⁺, 361.13; found, 361.10.

Step-9:

[1142] To a stirred solution of 1 : 1 mixture of tert-butyl ((5S,6R)-2-chloro-6-((S)-1-fluoro- 3-hydroxypropyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5S,6R)-2-chloro-6-((R)-l-fluoro-3-hydroxypropyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5- yl)carbamate (500 mg, 1.38 mmol) in toluene (5 ml.) was added 2-(tributyl-/?- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (669 mg, 2.77 mmol) at room temperature. The resulting mixture was stirred at 1 10 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford a 1 :1 mixture of teri-butyl (4S.4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b']dipyridine-l -carboxylate and tert-butyl (4R,4aR,10bS)-8-chloro-4-fluoro-2, 3,4, 4a, 6,10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (400 mg, 84%) as a colorless oil.

MS ESI calculated for C16H20CIFN2O3 [M+H]⁺, 343.11; found, 343.10.

Step- 10: [1143] A solution of 1 : 1 mixture of tert-butyl (4S,4aR,10bS)-8-chloro-4-fluoro-

2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate and tert-butyl (4R,4aR,l0bS)-8-chloro-4-fluoro-2,3,4,4a,6,l0b-hexahydro-1H-pyrano[3,2-b:5,4- b']dipyridine-l -carboxylate (400 mg, 0.67 mmol) and HC1 (4M in 1,4-dioxane) (2 mL) was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to afford a 1:1 mixture of (4S,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b']dipyridine and (4R,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6,10b- liexaliydro- lH-pyrano|3,2-b:5,4-b']dipyridine hydrochloride (A47) (400 nig, crude) as a white solid. MS ESI calculated for C11H12CIFN2O [M+H]⁺, 243.06; found, 243.00.

Step- 1 1 :

A47 isomer 2

[1144] The intermediate A47 (400 mg) was purification by Perp-Chiral HPLC with the following conditions (Column: CHIRAL ART Cellulose- SC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5%' 2M NH₃-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 10% B to 10% in 16min; Wave Length: 220/254 nm; RTl(min): 8.89: RT2(min): 12.61: Sample Solvent: MeOH: DCM=1: 1-HPLC) to afford (4R,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a.6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b']dipyridine (A47 isomer 2) (90 mg, 22%) as a yellow oil with retention time at 8.89 minutes. MS ESI calculated for Ci 1H12CIFN2O [M+H]⁺, 243.06; found, 243.00. ^!H NMR (400 MHz, DMSO-tfe) 5 7.88 (d, ./ = 8.4 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1H), 5.00 - 4.71 (m. 3H), 3.93 - 3.92 (m, 1H). 3.85 - 3.81 (m, 1 H), 2.91 - 2.84 (m, 1H). 2.74 - 2.69 (m, 1H), 1.92 - 1.70 (m, 2H). Absolute stereochemistry was determined by NOESY.

[1145] The chiral resolution also afforded (4S,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6,10b- hexttliydro-lH-pyrano[3,2-b:5,4-b']dipyridine (A47 isomer 1) (140 mg, 35%) as a yellow solid with retention time at 12.61 minutes. MS ESI calculated for CnHuOFNcO [M+H]⁺, 243.06; found, 243.00. ^!H NMR (400 MHz, DMSO-zfc) 5 7.79 (d, J= 8.0 Hz, 1 H), 7.39 (d, .7 = 8.0 Hz, 1H), 4.92 - 4.67 (m, 3H), 3.99 - 3.96 (m, 1H), 3.67 - 3.66 (m, 1H), 3.05 - 2.98 (m, 1 H), 2.70 - 2.61 (m, 1H), 1.84 - 1.75 (m, 2H). Absolute stereochemistry was determined by NOESY.

Intermediate A48: (2R,4aS , 10bS)-2-methyl-8-(trifluoromethyi)- 1 ,2,3 ,4a, 5 , 10b- hexahydrochromenof 3,4-b] [ L ,4]oxazine [1146] To a mixture of a 1:1 mixture of (3S,4S)-4-amino-7-(trinuorometliyI)chroman-3-ol and (3R,4R)-4-amino-7-(trifluoromethyl)chroman-3-ol (13.0 g, 55.74 mmol) (From A4) in MeOH (130 mL) was added TEA ( 11.3 g, 111.47 mmol) and BOC2O (13.38 g, 61.32 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE in EtOAc (0-80%) to afford a 1: 1 mixture of tert-butyl ((3S,4S)-3-hydroxy-7- (tiifluoromethyl)chroman-4-yl)carbamate and tert-butyl ((3R,4R)-3-hydroxy-7- (trifluoromethyl)chroman-4-yl)carbamate (6.5 g, 35 %) as a yellow solid. MS ESI calculated

[1147] To a mixture of a 1: 1 mixture of tert-butyl ((3S,4S)-3-hydroxy-7- (trinuoromethyl)chroman-4-yl)carbamate and tert-butyl ((3R,4R)-3-hydroxy-7- (trifluoromelhyl)chroman-4-yl)carbamate (5.1 g, 15.00 mmol), letrabutylazanium hydrogen sulfate (1.02 g, 3.00 mmol) and NaOH (4.20 g, 105.00 mmol) in DCM (50 mL) was added (4S)-4-methyl-l, 3, 2-L-6-dioxathiolane-2, 2-dione (2.69 g, 19.50 mmol) (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1) at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 2 h. Then H2O (50 mL) and H2SO4 (10 mL) were added slowly to above mixture at 0 °C. The resulting mixture was stirred at 60 °C overnight. The reaction mixture was basified with NaOH (sat.) to pH -8 and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a 1:1 mixture of (S)-l-(((3S,4S)-4-amino-7-(trifluoromethyi)chroman-3-yl)oxy)propan-2-ol and (S)-l-(((3R,4R)-4-amino-7-(trifluoromethyl)cbroman-3-yl)oxy)propan-2-ol (4. 1 g, 91%) as a brown oil. MS ESI calculated for C13H16F3NO3 [M+H]*, 292.11; found, 292.10.

Step-3:

[1148] To a 1 : 1 mixture of a mixture of (S)- 1 -(((3S,4S)-4-amino-7-

(trifluoromethyl)chroman-3-yl)oxy)propan-2-ol and (S)-l-(((3R,4R)-4-amino-7- (trilluoromethy1)chrornan-3-y1)oxy)propan-2-ol (4.1 g, 13.73 mmol) in MeOH (40 ml) were added DMAP (0.17 g, 1.37 mmol), TEA (2.08 g, 20.59 mmol) and Boc?.O (3.30 g, 15.10 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (0-60%) to afford a 1 :1 mixture of tert-butyl ((3S,4S)-3-((S)-2-hydroxypropoxy)-7-(trifluoromethyl)chroman-4-yl)carbaniate and tertbutyl ((3R,4R)-3-((S)-2-hydroxypropoxy)-7-(trifluoromethyl)chroman-4-yl)carbamate (3.5 g, 65%) as a yellow solid. MS ESI calculated tor C18H24F3NO5 [M+ 1]⁺, 392.16: found, 392.10.

Step-4:

[1149] To a 1 : 1 mixture of tert-butyl ((3S,4S)-3-((S)-2-hydroxypropoxy)-7- (trifluoromethyl)chroman-4-y1)carbamate and tert-butyl ((3R,4R)-3-((S)-2-hydroxypropoxy)- 7-(trifluoromethyl)chroman-4-yl)carbamate (3.5 g, 8.94 mmol) in DCM (35 mL) were added TEA (4.52 g, 44.71 mmol) and methanesulfonyl methanesulfonate (4.67 g, 26.82 mmol) at 0 °C. The mxiture was stirred at 25 °C for 1 h. The resulting mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na^SCU After filtration, the filtrate was concentrated under reduced pressure to afford a 1: 1 mixture of (S)-l-(((3S,4S)-4-((tert-butoxycarbonyI)amino)-7- (lrifIuoromethy1)chroman-3-y1)oxy)propan-2-yl methanesulfonate and (S)-l-(((3R,4R)-4- ((tert-butoxycarbonyl)amino)-7-(trifluoromethyl)chroman-3-yl)oxy)propan-2-yl methanesulfonate (4.0 g, crude) as a brown oil. MS ESI calculated lor C19H26F3NO7S [M+l]⁺, 470.14; found, 470.05. Step-5:

[1150] To a 1:1 mixture of a mixture of (S)-l-(((3S,4S)-4-((tert-butoxycarbonyl)amino)-7- (trifluoromethyl)chroman-3-yl)oxy)propan-2-yl methanesulfonate and (S)-l-(((3R,4R)-4- ((ierl-butoxycarbonyl)antino)-7-(triiluoromethyl)chroman-3-yl)oxy)propan-2-yl methanesulfonate (4.4 g, 9.37 mmol) in DCM (44 ml..) was added TP A (15 ml.., 201.94 mmol) at 0 °C. The mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeCN (88 mL), this was followed by the addition of l;2,2,6,6-pentamethylpiperidine (4.3 g, 28.14 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaaSOa. After filtration, the filtrate -was concentrated under reduced pressure. The resultant oil was purified by prep-HPLC with the following conditions: [Column: XB ridge Prep OBD C18 Column, 30* 150 mm, 5 urn; Mobile Phase A: Water) lOmmol/L NH4HCO3). Mobile Phase B: ACN; Flow rate: 60 mL/min: Gradient: 39% B to 54% B in 10 min; Wave Length: 254/220 nm] to afford (2R,4aR,10bR)-2-mechyl-8-(trifluoromethyl)-l,2,3,4a,5,10b- hexahydrochromeno[3,4-b][l,4]oxazine (400 mg, 15 %) as a white solid with shorter retention time. MS ESI calculated for C13H14F3NO2 [M+HJ+, 274.10; found, 274.00. ^SH NMR (400 MHz, DMSO) 5 7.82 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.02 (d, 7 = 1.8 Hz, 1H), 4.24 (d, J = 2.0 Hz, 2H), 4.07 (d, 7= 3.2 Hz, 1H), 3.80 (dt, J = 3.6, 1.8 Hz, 1H), 3.60 (dd, 7 = 10.6, 3.2 Hz, 1H), 3.10 (t, 7 = 10.6 Hz, 1H), 2.48 - 2.39 (m, 1H), 0.84 (d, 7 = 6.4 Hz, 3H). Absolute stereochemistry was determined by NOESY. [1151] The purification also afford (2R,4aS,10bS)-2-meihy1-8-(irifluoromethyl)- l ,2,3,4a,5,10b-hexahydrochromeno[3,4-bj[l,4]oxazine (A48) (400 mg, 15%) as a white solid with longer retention time, MS ESI calculated for C13H14F3NO2 [M+HJ+, 274.10; found, 274.05. ^SH NMR (400 MHz, DMSO) 6 7.55 (d, 8.0 Hz, 1H), 7.23 (dd, J - 8.2, 1.8 Hz,

1H), 7.09 (d, ,7- 1.8 Hz, 1H), 4.80 - 4.50 (m, 1 H), 4. 11 - 3.97 (m, 2H), 3.95 (d, .7 - 3.8 Hz, 1 H), 3.51 (dd, J - 10.8, 3.2 Hz, 1H), 3.19 (dd, J = 10.8, 9.2 Hz, 1H), 3.01 - 2.91 (m, 1H), 0.86 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was determined by NOES Y.

Intermediate A49: 1:1 mixture of (4S,4aS,10bR)-4-methy]-8-(trifluoromeihyl)- l,3,4,4a,5,10b-hexahydro--2H“Chromeno[4,3--b]pyridine and (4R,4aR,10bS)-4-methyl-8- (trifluoromeihyl)-l,3,4,4a,5, l0b-hexahydro-2H-chromeno[4,3-b]pyridine

[1152] To a degassed solution of ethyl 2- chloro- 4- methylnicotinate (5.0 g, 25.05 mmol) in dioxane (50 mL) and H2O (5 mL) were added (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (8.26 g, 37.57 mmol), K2CO3 (10.38 g, 75.11 mmol) and PdidppDCh-CHaCh (2.04 g, 2.50 mmol). The resulting solution was stirred at 100 °C for 16 b under nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. Tire combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 120 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford ethyl 2-(2-melhoxy-4-(trif]uoromethyl)phenyI)-4-methylnicotinate (8.60 g. 92%) as a yellow oil. MS ESI calculated for C17H16F3NO3 [M+H]⁺, 340.11; found, 340.13.

Step-2:

[1153] To a stirred solution of ethyl 2-(2-methoxy-4-(trifluorometbyl)phenyl)-4- methylnicotinate (8.60 g, 25.35 mmol) in DCM (80 ml) was added BBn (1 M in DC.M) (88 niL, 88.00 mmol) at 0 °C. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 120 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford 4-methyl-8-(trifluoromethyl)-5H- chromeno[4,3-b]pyridin-5-one (8.60 g, 97%) as a white solid. MS ESI calculated for C iH .b .NO- [M+Hf, 280.05: found, 280.10.

Step-3 :

[1154] To a stirred solution of 4-methyl-8-(tritluoromethyl)-5H-chromeno[4,3-b]pyridin-5- one (8.70 g, 31.16 mmol) in Diethyl ether (100 raL) were sequentially added NH3.BH3 (2.41 g, 78.21 mmol) and TiClr (8.6 ml.., 78.21 mmol) at 0 °C. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of ice water and extracted with ethyl acetate. The combined organic layers were washed -with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 120 g silica gel column eluted with 0-60% ethyl acetate in petroleum ether to afford 4-methyl-8-(lrifluoromethyl)- 5H-chromeno[4,3-b]pyridine (2.10 g, 23%) as a white solid. MS ESI calculated for Ci fo.EXO I M- Hi . 266.07; found, 266.11.

Step-4:

A49

[1155] To a solution of 4-methyl-8-(trifluoTomethyl)-5H-chromeno[4,3-b]pyridine (2.10 g, 7.92 mmol) in AcOH (20 mL) was added Pt/C (5%) (220 mg) at room temperature. The mixture was placed under hydrogen atmosphere with a balloon. The reaction mixture degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at room temperature for 48 h under hydrogen atmosphere (1 atm.). The suspension was filtered. The filtrate was collected and concentrated under vacuum. Tire residue was purified by prep-HPLC with the following conditions: [Column: XBridge Prep OBD C18 Column. 30*150 mm, 5 pm; Mobile Phase A: Water) lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 62% B to 77% B in 10 min; Wave Length: 254/220 nm; RTl(min): 6.9] to afford a 1: 1 mixture of (4S,4aS,10bR)-4-methyl-8-(tri fluoromethyl)- 1 ,3, 4, 4a,5,10b-hexahydro-2H-chromeno[4, 3- b [pyridine and (4R,4aR, 10bS)-4-methyl-8-(trifluoromelhyl)- 1,3, 4, 4a, 5, 1 Ob-hex ahydro-2H- chromeno[4,3-b]pyridine (A49) (400 mg, 18%) as a white solid. MS ESI calculated for Ci4H_!6F₃NO [M+H]⁺,272.12; found, 272.15. ^]H NMR (400 MHz, DMSO-rfc) 6 7.41 (d, 7 = 7.6 Hz, 1H), 7.15 (dd, 7 = 8.0, 1.2 Hz, 1H), 7.05 (s, 1H), 4.52 - 4.34 (m, 1H), 4.20 - 4.11 (m, 1H), 3.63 - 3.58 (m, 1H), 3.03 - 2.91 (m, 1H), 2.76 - 2.61 (m, 1H), 2.02 - 1.83 (m, 2H), 1.42 - 1.28 (m, 1H), 1.24 - 1.07 (m, 1H), 0.99 (d, ./ = 6.8 Hz, 3H). The relative configuration was determined by NOESY.

Intermediate A49 isomer 1: rel-(4R,4aR,10bS)-4-methyl-8-(trifluoromethyl)- l,3,4.4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 1

Isomer 1 _and

Intermediate A49 isomer 2: rel-(4R,4aR,10bS)-4-methyl-8-(trifluoromethyl)- 1 ,3,4,4a,5,10b-hexahydro-2H-chromeno[4.3-b]pyridine isomer 2

Isomer 2

[1156] 1:1 mixture of (4S,4aS,10bR)-4-methyl-8-(trifluoromethyl)-l ,3,4,4a,5,l0b- hexahydro-2H-chromeno[4,3-b]pyridine and (4R,4aR,10bS)-4-methyl-8-(trifluoromethyl)- l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-bjpyridine (A49) (350 mg) was purified by Prep-Chiral HPLC with following condition [Column: CHIRALPAK IF, 2*25 cm, 5 um; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: MEOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient (B%): 15% B to 15% B in 9 min; Wave Length: 220/254 nm; RTl(min): 5.82; RT2(min): 6.85; Sample Solvent: EtOH: DCM=1: 1 — HPLC] to afford rel-(4R,4aR, 10bS)-4-methyl-8-(irifluoromeihyl)- 1 ,3,4, 4a, 5, 10b-hexahydro-2H- chromeoo[4,3-b]pyridine isomer 1 (A49 isomer 1) (120 mg) as a white solid with retention time at 5.82 minute. MS ESI calculated for C14H16F3NO [M+H]⁺,272. 12: found, 272.15. ’H NMR (400 MHz, DMSO-rfc) 8 7.41 (d, J= 7.6 Hz, 1H), 7.15 (dd, J = 8.0, 1 .2 Hz, 1H), 7.05 (s, 1H), 4.52 - 4.34 (m, 1H), 4.20 - 4.11 (m, 1H), 3.63 - 3.58 (m, 1H), 3.03 - 2.91 (m, 1H), 2.76 - 2.61 (m, 1H), 2.02 - 1.83 (m, 2H), 1.42 - 1.28 (m, 1H), 1.24 - 1.07 (m, 1H), 0.99 (d, J = 6.8 Hz, 3H). Absolute stereochemistry was not determined.

[1157] The chiral resolution also afford rel-(4R ,4aR, 10bS)-4-methyl-8-(trifluoromethyl)- 1 ,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 2 (A49 isomer 2) (120 mg) as a white solid with retention time at 6.85 minute. MS ESI calculated for C14H16F3NO [M+H]⁺,272.12; found, 272.15. ^;H NMR (400 MHz, DMSO-tfe) 5 7.41 (d, J = 7.6 Hz, 1H), 7.15 (dd, 8.0, 1.2 Hz, 1H), 7.05 (s, 1H), 4.52 - 4.34 (m, 1H), 4.20 - 4.11 (m, 1H), 3.63 - 3.58 (m, 1H), 3.03 - 2.91 (m, 1H), 2.76 - 2.61 (tn, 1H), 2.02 - 1.83 (m, 2H), 1.42 - 1.28 (m, 1H), 1.24 - 1.07 (m, 1H), 0.99 (d, J - 6.8 Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A50: (3R,4aS,9aR)-3-methyl-2,3,4,4a,9,9a-hexahydroindeno[2,l- b|[l,4]oxazine

Step 1 :

[1158] A mixture of (lS,2R)-1-amino-2,3-dihydro-lH-inden-2-ol (10.0 g, 67.02 mmol) (supplier: Accela ChemBio Co., Ltd. CAS# 126456-43-7), TEA (13.57 g, 134.10 mmol) and BociO (21 .94 g, 100.54 mmol) in MeOH (100 mL) was stirred at. room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified byflash column chromatography with 0-33% EtOAc in PE to afford tert-butyl ((lS,2R)-2- hydroxy-2,3-dihydro-lH-inden-l-yl)carbamate (16.7 g, 99%) as a white solid. MS ESI calculated for CuHisjNOs [M+Hf, 250.14; found, 250.25. ^:H NMR (300 MHz, DMSO-cfc) 6 (ppm) 7.24 - 7. 18 (m, 4H), 6.39 (d, J - 8.7 Hz, 1H), 5.00 (d, J ~ 4.2 Hz, 1H), 4.93 - 4.84 (m, 1 H), 4.44 - 4.36 (m, 1H), 3.06 - 2.95 (m, 1 H), 2.83 - 2.75 (m, 1H), 1.45 (s, 9H).

■Step-2: [1159] To a stirred solution of tert-butyl ((1 S,2R)-2-hydroxy-2,3-dihydro-lH-inden-l- yl)carbamate (16.7 g, 68.18 mmol), tetrabutylazanium hydrogen sulfate (4.63 g, 13.63 mmol) and NaOH (19.09 g, 477.31 mmol) in DCM (170 mL) was added (S)-4-methyl- 1,3,2- dioxathiolane 2,2-dioxide (12.25 g, 88.64 mmol) (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (170 mL), this was followed by the addition of H2SO4 (66.87 g, 681.88 mmol) slowly at 0 °C. The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was basified with NaOH (aq.) to pH -8 and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford (S)- 1 - (((l S,2R)-l-amino-2,3-dihydro-lH-inden-2-y1)oxy)propan-2-ol (17.8 g, 68% yield, 54% purity) as a brown oil. MS ESI calculated for C^HpNOi 208.13; found, 208.15.

[1160] A mixture of (S)-1 -(((1 S,2R)-l-amino-2,3-dihydro-lH-inden-2-yl)oxy)propan-2-ol (5.0 g, 24.12 mmol), BoczO (7.9 g, 36.18 mmol) and TEA (4.88 g, 48.24 mmol) in MeOH (50 mL) was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0- 50% EtOAc in PE to afford tert-butyl ((lS,2R)-2-((S)-2-hydroxypropoxy)-2,3-dihydro-1H- inden-l-yl)carbamate (2.98 g, 40%) as a white solid. MS ESI calculated for C17H25NO4 [M+H]⁺, 308.18; found, 308.10.

Step 4:

[1161] To a solution of tert-butyl ((!S,2R)-2-((S)-2-hydroxypropoxy)-2,3-dihydro-lH- inden-l-yl)carbamate (2.98 g, 9.69 mmol) and TEA (4.91 g. 48.47 mmol) in DCM (30 mL) was added methanesulfonyl methanesulfbnate (6.75 g, 38.78 mmol ) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHCCh (aq.) and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL.) and trifluoroacetic acid (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. Then the residue was dissolved acetonitrile (60 mL), this was followed by the addition of 1,2.2,6,6-pentamethylpiperidine (4.52 g, 29.10 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 10% ~ 60% Me-CN in water (10 mmol/L NH4HCO3) to afford (3R,4aS,9aR)-3-melhyl-2,3,4,4a,9,9a-hexahydroindeno[2,l- b][l,4]oxazine (A50) (473 nig, 23%) as a brown oil. MS ESI calculated for CizHisNO [M+H]⁺, 190.12; found, 190.05. ^!H NMR (400 MHz, DMSO-ris) 6 (ppm) 7.34 - 7.30 (m, 1H), 7.29 - 7.11 (m, 3H), 4.22 - 4.15 (m, 1 H), 3.98 (d, J = 5.2 Hz, 1H), 3.53 - 3.49 (m, 1H),

3.30 - 3.16 (m, 2H), 2.84 - 2.70 (m, 2H), 0.84 (d, J= 6.4 Hz, 3H).

Intermediate A51, isomer 1: rel-(3R,4aS,9bR)-7-(difluoromethoxy)-3-methoxy-

2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridme isomer 1

A51 isomer 1 _anj

Intermediate A51, isomer 2: rel- rel-(3S,4aR,9bS)-7-(difiuoromethoxy)-3-metboxy-

2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-bjpyridme isomer 2

A51 isomer 2 _anj Intermediate A51, isomer 3: rel-(3S,4fhS,9bR)-7-(difluoromethoxy)-3-metboxy-

2,3,4,4a,5,9b-hexahydro- lH-indeno[l,2-b]pyridine isomer 3

A51 isomer 3 _anj

Intermediate A51, isomer 4: rel- (3R,4aR,9bS)-7-(difluoromethoxy)-3-methoxy-

2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine isomer 4

[1162] To a stirred solution of methyl 5-bromo-2-chloronicotinate (200.0 g, 798.46 mmol) and 4,4,4',4’,5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (202.7 g, 798.46 mmol) in 1 ,4- dioxane (2000 mL) were added AcOK (155.9 g, 1588.94 mmol) and Pd(dppf)C12 -CH2CI2

(65.0 g, 79.84 mmol) in portions at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-20% ethyl acetate in petroleum ether to afford methyl 2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinate (95.0 g, 28%) as a light green solid. MS ESI calculated for C13H17BCINO4 [M+H]⁺, 298.10; found. 298.05.

Step-2:

[1163] To a stirred solution of methyl 2-chloro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-

2-yl)nicotinate (95.0 g. 319.28 mmol) in EtOH (1000 mL) and H2O ( 1000 mL) was added sodium perborate (5.6 g, 69.23 mmol) in portions al 0 °C. The resulting mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was was quenched with water and acidified with HC1 (aq., 2 N) to pH 5-6. The mixture was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford methyl 2-chIoro-5-hydroxynicotinate (95.0 g, crude) as a brown solid. MS ESI calculated for C₇H₆C1NO3 [M+H]⁺, 188.00; found, 188.01 .

Step-3 :

[1164] To a stirred solution of methyl 2-chloro-5-hydroxynicotinaie (95.0 g, 506.45 mmol) and K2CO3 (210.0 g, 1519.35 mmol) in DMF (2000 mL) was added Mel (86.26 g, 607.74 mmol ) at 0 °C. The mixture 'was stirred at room temperature for 4 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NasSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford methyl 2-chloro-5- methoxynicotinate (45.0 g, 44%) as a yellow solid. MS ESI calculated for CsHsClNOs [M+H]⁺, 202.02: found, 202.04.

Step-4:

[1165] To a degassed solution of methyl 2-cbloro-5-methoxyaicotinate (45.0 g, 223.20 mmol) and (4-(difluoromethoxy)phenyl)boronic acid (43.2 g, 229.89 mmol) in DME (500 mL) and H2O (100 mL) were added Pd(PPhj)4 (25.7 g, 22.32 mmol) and Na2CCh (71.9 g, 678.53 mmol). The mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na^SOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-30% ethyl acetate in petroleum ether to afford methyl 2-(4-(difluoromethoxy)phenyl)-5- methoxynicotinate (45.0 g, 57%) as a white solid. MS ESI calculated for C15H13F2NO1 [M+H]⁺, 310.08; found, 310.02. Step-5 :

[1166] To a stirred solution of methyl 2-(4-(difluoromethoxy)phenyl)-5-methoxynicotinate (45.0 g, 145.50 mmol) and CaCl₂ (24.2 g, 218.25 mmol) in THF (300 mL) and EtOH (300 mL) was added NaBH.s ( 16.5 g, 436.51 mmol) in portions at 0 °C. The mixture was stirred at room temperature for 16 h. The reaction was quenched with ice water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-40% ethyl acetate in petroleum ether to afford (2-(4- (difluoromethoxy (phenyl )-5-methoxypyridin-3-yl)methano] (38.0 g, 93%) as a white solid. MS ESI calculated for C14H13F2NO3 [M-t-H]⁴, 282.09; found, 282.04.

Step-6:

[1167] To a stirred solution of (2-(4-(dilluoromethoxy)phenyl)-5-methoxypyridin-3- yl)methanol (34.0 g, 120.88 mmol) in DCM (400 mL) was added Thionyl chloride (71.9 g, 604.42 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was treated with NaHCCh (sat.) and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NasSCU After filtration, the filtrate was concentrated under reduced pressure afford 3-(chloromethy])-2-(4-(difluoromethoxy)phenyl)-5-methoxypyridine (30.0 g, crude) as a yellow oil. MS ESI calculated for CuHi^CMNO: [M+H]¹’, 300.05; found, 300.02.

Step-7:

[1168] To a degassed solution of 3-(chloromeihyl)-2-(4-(difluoromeihoxy)phenyl)-5- methoxy pyridine (30.0 g, 100.10 mmol) in DME (300 niL) were added Pd(OAc)₂ (2.2 g, 10.01 mmol), tris(3-methylphenyl)phosphane (6.1 g, 20.02 mmol) and Na'zCOj (31.8 g,

300.30 mmol). The mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was quenched with water and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-40% ethyl acetate in petroleum ether to afford 7-(difluoromethoxy)-3-methoxy-5H-indeno[l,2-b]pyridine ( 11.2 g, 42%) as a white solid. MS ESI calculated for CuHnFzNQs [M+H]⁺, 264.08; found, 264.04.

Step-8:

[1169] To a solution of 7-(difluoromethoxy)-3-methoxy-5H-indeno[ 1 ,2-b]pyridine (11.0 g, 41.78 mmol) in i-PrOH (100 mL) was added PdfOHfi/C (20% active in carbon, wetted with ca. 50% water) (11.7 g, 83.57 mmol). The mixture was stirred at 50 °C for 72 h under hydrogen atmosphere (20 atm). The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-20% dichloromethane in methanol to afford the mixture (7.5 g, 67%) as a colorless oil.

[1170] The mixture (7.5 g) was separated by Prep-Achiral-SFC with the following conditions [Column: GreenSep Basic 3* 15 cm, 5 pm: Mobile Phase A: CO2, Mobile Phase B: IPA (1% 2M NH3-MEOH); Flow rate: 75 mL/min; Gradient (B%): isocratic 32% B; Column Temperature(20 °C): 35; Back Pressure(bar): 100; Wave Length: 254 nm; RTl(min): 3.88; RT2(min): 4.33; Sample Solvent: MeOH-HPLC] to afford fraction A that is a 1:1 mixture of rel-(3S,4aS,9bR)-7-(difluoromethoxy)-3-methoxy-2,3,4,4a,5,9b-hexahydro-IH-indeno[l,2- b]pyridine and rel- (3R,4aR,9bS)-7-(difluoromethoxy)-3-methoxy-2,3,4,4a,5,9b-hexahydro- lH-indeno[l,2-b]pyridine (0.7 g, 8%) as a brown oil. MS ESI calculated for CirHnFiNCh [M+H]⁺, 270.12: found, 270.08. ‘H NMR (400 MHz, DMSO-J&) 5 7.38 - 6.94 (m, 4H), 4.11 (d, J = 5.6 Hz, 1H), 3.27 (s, 3H), 3.22 - 3.17 (m, 1H), 2.88 ~ 2.77 (m, 1H), 2.69 - 2.61 (m, 2H), 2.57 - 2.43 (m, 3H), 1.78 - 1.66 (m, 1H), 1.57 - 1.39 (m, 1H). [1171] The Achiral SFC process also afford fraction B that is a 1 : 1 mixture of rel- (3R,4aR,9bS)-7 -(difluoromethoxy )-3-methoxy-2, 3,4, 4a, 5,9b-hexahydro-lH-indeno[ 1,2- bjpyridine and rel-(3S,4aR,9bS)-7-(difluoromethoxy)-3-methoxy-2,3,4.4a,5,9b-hexahydro- lH-indeno[l,2-b]pyridine (4.0 g, 53%) as a brown oil. MS ESI calculated for C14H17F2NO2 [M+H]⁺, 270.12; found, 270.08. ^!H NMR (400 MHz, DMSO-E₆) 8 7.37 - 6.98 (m, 4H), 4.18 (d, J - 6.0 Hz, 1H), 3.19 (s, 3H), 3.14 - 3.04 (m, 1H), 2.93 - 2.84 (m, 2H), 2.48 - 2.39 (m, 2H), 2.11 - 1.90 (m, 2H), 1.38 - 1.17 (m, 1H), 0.88 - 0.74 (m, 1H).

Step-9:

A51 isomer 2

[1172] The fraction B (4.0 g) was separated by Prep-Chiral-HPLC with the following conditions [Column: CHIRAL ART Celiulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NHj-MeOH), Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min: Gradient (B%): 5% B to 5% B in 12 min: Wave Length: 220/254 nm; RTl (min): 8.2; RT2(min): 9.93; Sample Solvent: EtOH; DCM=1: 1— HPLC] to afford rel-(3R,4aR,9bS)- 7-(difluoromethoxy)-3-methoxy-2,3₎4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine isomer 1 (A51 isomer 1) (1.6 g, 40%) as a brown oil with shorter retention time. MS ESI calculated for (C14H17F2NO2) [M+l]⁺, 270.12; found, 270.08. 'H NMR (400 MHz, DMSO-cfc) 6 7.37 - 6.98 (m, 4H), 4.18 (d, J = 6.0 Hz, 1H), 3.19 (s, 3H), 3.14 - 3.04 (m, 1H), 2.93 - 2.84 (m, 2H), 2.48 - 2.39 (m, 2H), 2.1 1 - 1.90 (m, 2H), 1.38 - 1.17 (m, 1 H), 0.88 - 0.74 (m, 1H). NOESY shows all the groups of pyridine are cis, but the absolute configuration is undetermined. [1173] The chiral resolution also afford rel-(3S,4aR,9bS)-7-(difluoromethoxy)-3-methoxy- 2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine (A51 isomer 2) (2.0 g, 50%) as a brown oil with longer retention time. MS ESI calculated for (C14H17F2NO2) |M+1]⁺, 270.12; found, 270.08. NMR (400 MHz, DMSO-de) 57.37 - 6.98 (m, 4H), 4.18 (d, J = 6.0 Hz, 1H), 3.19 (s, 3H), 3.14 - 3.04 (m, 1H), 2.93 - 2.84 (m, 2H), 2.48 - 2.39 (m, 2H), 2.11 - 1.90 (m, 2H), 1.38 - 1.17 (m, 1H), 0.88 - 0.74 (m, 1H). NOESY shows all the groups of pyridine are cis, but the absolute configuration is undetermined.

Step- 10:

A51 isomer 4

[1174] The fraction A (660 mg) was separated by Prep-Chiral-HPLC with the following conditions [Column: CHIRALPAK IG, 5*25 cm, 10 pm; Mobile Phase A: Hex--HPLC-, Mobile Phase B: MEOH: DCM=1: 1(1% 2M NH3-MEOH); Flow rate: 100 niL/min; Gradient (B%): isocratic ; Wave Length: 220 nm; RTl(min): 6.54; RT2(min): 8.45; Sample Solvent: Hex--HPLC] to afford rel-(3S,4aS,9bR)-7-(difluoromethoxy)-3-methoxy-2,3,4,4a,5,9b- hexahydro-lH-indeno[l,2-b]pyridine (A51 isomer 3) (200 nig, 31%) as a colorless oil with shorter retention time. MS ESI calculated for C14H17F2NO2 [M+H]\ 270.12; found, 270.08. ‘H NMR (400 MHz, DMSO-tfc) 37.38 - 6.94 (m, 4H), 4.11 (d, J = 5.6 Hz, 1H), 3.27 (s, 3H), 3.22 - 3.17 (m, 1H), 2.88 - 2.77 (m, 1H), 2.69 - 2.61 (m. 2H), 2.57 - 2.43 (m, 3H), 1.78 - 1.66 (m, 1H), 1.57 - 1.39 (m, 1H). NOESY shows the -OMe group is at the trans position, but the absolute configuration is undetermined. [1175] The chiral resolution also afford rel-(3R,4aR,9bS)-7-(difluoromethoxy)-3-methoxy- 2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine (A51 isomer 4) (210 mg, 32%) as a colorless oil with longer retention time. MS ESI calculated for C14H17F2NO2 1M+H]⁴, 270.12; found, 270.08. ’H NMR (400 MHz, DMSO-4) S 7.38 - 6.94 (m, 4H), 4.11 (d, 5.6 Hz,

1H), 3.27 (s, 3H), 3.22 - 3.17 (m, 1 H), 2.88 - 2.77 (m, 1H), 2.69 - 2.61 (m, 2H), 2.57 - 2.43 (m, 3H), 1.78 - 1.66 (m, 1H), 1.57 - 1.39 (m, 1H). NOESY shows the -OMe group is at the trans position, but the absolute configuration is undetermined.

Intermediate A52: 1:1 mixture of rel-(3R,4aS,9bR)-7-(difluoromethoxy)-3-fluoro- 2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine isomer 1 and rel-(3R,4aS,9bR)-7- (difluoromethoxy)-3-fluoro-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine isomer 2

A52

Step-1:

[1176] To a stirred solution of 2-chloro-5-fluoronicotinic acid (20.00 g, 114 mmol) in THE (200 mL) was added BHj-THF (1.0M in THF, 341 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. Then the reaction was quenched by the addition of ice water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na^SCU. After filtration, the filtrate was concentrated under reduced pressure to afford (2-chloro-5-fluoropyridin-3-y])methanol (18.70 g, crude) as a yellow oil. MS ESI calculated for CeHsCIFNO [M+Hj⁺, 162.00; found, 162.10.

Step-2:

[1177] To a stirred solution of (2-chloro-5-fluoropyridin-3-yl)methanol (9.40 g, 58 mmol) and (4-(difluoromethoxy )phenyT)boronic acid (12.03 g, 64.00 mmol) in DME ( 120 mL) and HcO (40 mL) was added Na2COs (24.67 g, 232.73 mmol) and PdjPPhsJa ( 13.95 g, 12.07 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight. The mixture was allowed to cool down to room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 ~ 30% EtOAc in PE to afford (2-(4- (difluoromethoxy)phenyl)-5-fluoropyridin-3-yl)methanol (7.00 g, 44%) as a yellow solid. MS

[1178] To a stirred solution of (2-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-3- y])methanol (26.00 g, 96.57 mmol) in DCM (300 mL) were added SOCh (46.8 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched by the addition of water at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCfo After filtration, the filtrate was concentrated under reduced pressure to afford 3-(chloromethyl)-2- (4-(difluorornethoxy)phenyl)-5-fluoropyridine (25.10 g, crude) as a yellow oil. MS ESI calculated for C13H9CIF3NO [M+H] ^h, 288.03; found, 288.05.

Step-4: [1179] To a stirred solution of 3-(chloromethyl)-2-(4-(difluoromethoxy)phenyl)-5- fluoropyridine (25.10 g, 87.25 mmol) and Na₂CO3 (36.99 g, 349.01 mmol) in DME (335 niL) were added Pd(OAc)₂ (1.96 g, 8.72 mmol) and P( m-Tol )a (5.31 g, 17.45 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 ~ 20% EtOAc in PE to afford 7-(difluoromethoxy)-3-fluoro- 5H-indeno[l,2-b]pyridine (16.00 g, 73%) as a yellow solid. MS ESI calculated for C25H27F3N4O3 [M+H] , 489.20; found, 489.20.

Step-5 :

A52

[1180] To a solution of 7-(difluoroniethoxy)-3-fluoro-5H-indeno[l,2-b]pyridine (7.50 g,

29.86 mmol) in THF (100 mb) and H₂O (100 mL) was added H₂SO₄ (7.03 g. 71.65 mmol) and Pd(OH)₂/C (59t>) (2.10 g, 14.93 mmol). The mixture was stirred at 40 °C under hydrogen pressure (50 atm.) overnight. Tire mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The resulting mixture was quenched with water and basified with NaOH (aq.) to PH 9. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NajSCH After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with, 5% to 50% MeCN in water to afford a 1 :1 mixture of rel-(3R,4aS,9bR')-7-(difluoromethoxy )-3-fluoro-2,3,4,4a,5,9b-hexahydro-lH- indeno [ 1 ,2-b]py ridine isomer 1 and rel-(3R,4aS,9bR)-7-(difluoromethoxy)-3-fluoro- 2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine isomer 2 (A52) (960 mg, 12% yield) as a yellow oil. MS ESI calculated for CssHuFsNO [M+H]⁺, 258.10; found. 258.10. 'H NMR (400 MHz, DMSO-d₆) 6 7.41 - 6.98 (m, 4H), 4.70 - 4.51 (rn, 1H), 4.24 - 4.21 (m, 1 Hi, 3.07 - 2.79 (m, 2H), 2.72 - 2.40 (m, 3H), 2.35 - 1.84 (m, 1H), 1.48 - 1.21 (m, 1H).

Intermediate A52 isomer 1: rel-(3R,4aS,9bR)-7-(difluoroniethoxy)-3-fluoro-2,3,4,4a,5,9b- hexahydro- 1 H-indeno[ 1 ,2-b]py ridine isomer 1 A52 isomer

Intermediate A52 isomer 2: rel-(3R,4aS,9bR)-7-(ditluoromethoxy)-3-fiuoro-2,3,4,4a,5.9b- hexahydro- 1 H-indeno[ 1 ,2-b]pyridine isomer 2

A52 Isomer 2

[1181] 1 : 1 mixture of rel-(3R,4aS_!9bR)-7-(ditluoromeihoxy)-3-fluoro-2.3,4,4a,5,9b- hexahydro-lH-indeno[l,2-b]pyridine isomer 1 and rel-(3R,4aS,9bR)-7-(difluoromethoxy)-3- fluoro-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridine isomer 2 (350 mg) was separated by prep-chiral SFC with the following conditions: [Column: YMC- Actus Triart Diol-HILIC 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH (20 mM NH3); Flow rate: 75 mL/min; Gradient: isocratic 15% B; Column Temperature! °C): 35; Back Pressure(bar): 100; Wave Length: 254 nm; RTl (min): 4.40; RT2(min): 6.27; Sample Solvent: MEOH] to afford rel-(3R,4aS,9bR)-7-(difluoromethoxy)-3-fluoro-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2- bjpyridine isomer 1 (A52 isomer 1) (124 mg, 35% yield) as a yellow oil with retention time al 4.40 minute. MS ESI calculated for C13H14F3NO [M+H]⁺, 258.10; found, 258.10. ‘H NMR (400 MHz, DMSO) 5 7.40 - 6.95 (m, 4H), 4.62 - 4.35 (m, 1H), 4.16 (t, J = 5.2 Hz, 1H), 2.97 - 2.69 (m, 3H), 2.60 - 2.53 (m, 1H), 2.34 - 2.28 (m, 1H), 2.10 - 1.94 (m. 1H), 1.22 - 1.07 (m, 1H).

[1182] The chiral resolution also afford rel-(3R,4aS,9bR)-7-(difluoromethoxy')-3-tluoro- 2,3,4,4a,5,9b-hexahydro-1H-indeno[1 ,2-b]pyridine isomer 2 (A52 isomer 2) (124 mg, 35% yield) as a yellow oil with retention time at 6.27 minute. MS ESI calculated for C13H14F3NO [M+H]⁺, 258.10; found, 258.10. TI NMR (400 MHz, DMSO) S 7.40 - 6.95 (m, 4H), 4.62 - 4.35 (m, HI), 4.16 (t, J - 5.2 Hz, 1H), 2.97 - 2.69 (m, 3H), 2.60 - 2.53 (m, 1H), 2.34 - 2.28 (m, 1H), 2.10 - 1.94 (m, 1H), 1.22 - 1.07 (m, 1H). Intermediate A53: (3R,4aS,9aR)-3,7-dimethyl-2,3,4,4a,9,9a-hexahydroindeno[2,l- b][l,4]oxazine

[1183] A mixture of 5 methyl-2,3-dihydro-lH-inden-l-one (20.0 g, 136.81 mmol) and Br- (21.86 g, 136.81 mmol) in EtaO (200 mL) was stirred al room temperature for 0.5 h. The reaction mixture was quenched with sodium thiosulfate (sat.) at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na^SCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatograph 0-25% EtOAc in PE to afford a 1: 1 mixture of (R)-2-bromo-5-methyi-2,3-dihydro-lH-inden-l-one and (S)-2- bromo-5-methyl-2,3-dihydro-lH-inden-l-one (27.0 g, 85%) as a yellow solid. MS ESI calculated for C_!0H₉BrO [M+H]⁺, 224.98; found, 224.95. ‘H NMR (300 MHz, DMSO-tA) 5 (ppm) 7.65 (d, J = 7.8 Hz, lH), 7.39 (s, I H), 7.33 (d, J = 7.8 Hz, 1H), 5.02 - 4.97 (m, 1 H), 3.89 - 3.79 (m, 1H), 3.32 - 3.24 (rn, 1H), 2.43 (s, 3H).

[1184] To a solution of 1 : 1 mixture of (R)-2-bromo-5-methyl-2,3-dihydro-lH-inden-1 -one and (S)-2-bromo-5-methyl-2,3-dihydro-lH-inden-l-one (27.0 g, 119.96 mmol) in EtOH (270 mL) was added NaBH* (2.27 g, 59.98 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water at room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na^SOr. After filtration, the filtrate was concentrated under reduced pressure to afford a 1:1 mixture of (lS,2R)-2-bromo-5-methyl-2,3-dihydro-lH- inden-l-ol and (lR,2S)-2-bromo-5-methy1-2,3-dihydro-lH-inden-l-ol (32.00 g, crude) as a white solid. MS ESI calculated for CioHj jBrO [M+l]⁺, 227.00, 229.00; found, 226.95, 228.95.

Step-3

[1185] A mixture of 1:1 mixture of (lS,2R)-2-bromo-5-methyl-2,3-dihydro-lH-inden-l-ol and (lR,2S)-2-bromo-5-methyl-2,3-dihydro-lH-inden-l-ol (32.0 g, 140.91 mmol), ACN (17.35 g, 422.72 mmol) and H2SO4 (20.73 g, 211.36 mmol) in DCE (320 rnL) was stirred at 50 °C for 1 h. Then H2O (213 mL) was added to the mixture at 50 °C. The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was basified with NaOH to pH 12. The precipitated solids were collected by filtration and washed with water to afford a 1 :1 mixture of (lS,2R)-l-amino-5-methyl-2,3-dihydro-lH-inden-2-ol and ( 1R,2S)- l-amino-5-methy 1-2,3- dihydro- lH-inden-2-ol (6.9 g, 35% over 2 steps) as a white solid. MS ESI calculated for

[1186] A solution of 1 : 1 mixture of (lS_!2R)-l-amino-5-metbyl-2,3-dihydro-lH-inden-2-ol and (lR,2S)-l-ammo-5-methyi-2,3-dihydro-lH-inden-2-ol (6.90 g, 42.27 mmol), B0C2C)

(13.84 g, 63.41 mmol) and TEA (8.56 g, 84.55 mmol) in MeOH (70 mL) was stirred at room temperature for Ih. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-30% EtOAc in PE to afford a 1 :1 mixture of tert-butyl ((lS,2R)-2-hydroxy-5-methyl-2,3-dihydro-lH-inden-l-yl)carbamate and tert-butyl ((lR,2S)-2-hydroxy-5-methyl-2,3-dihydro-lH-inden-l-yl)carbamate (6.89 g, 59%) as a white solid. MS ESI calculated for C15H21NO3 [M+H]⁴, 264, 15; found, 264.10. ‘H

NMR (400 MHz, DMS0-</₆) 6 (ppm) 7.06 (d, 7.6 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.29 (d, ./

- 8.8 Hz, 1H), 4.94 (d, 7 - 4.8 Hz, 1 H), 4.86 - 4.80 (m, 1 H), 4.44 - 4.35 (m, 1H), 2.99 - 2.93 (m, 1H), 2.77 - 2.71 (m, 1H), 2.27 (s, 3H), 1.45 (s, 9H).

Step-5:

[1187] To a mixture of 1 : 1 mixture of tert-butyl ((lS,2R)-2-hydroxy-5-methyl-2,3-dihydro- lH-inden-l-yl)carbamate and tert-butyl ((lR,2S)-2-hydroxy-5-metbyl-2,3-dihydro-lH-inden- 1 -yl)carbamate (6.87 g, 26.09 mmol), (4S)-4-methyl-l,3,2-X-6-dioxathiolane-2.2-dione (4.68 g, 33.91 mmol) (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1 ) and NaOH (7.30 g, 182.62 mmol) in DCM (70 ml.,) was added tetrabutylazanium hydrogen sulfate (1.77 g, 5.22 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. Then the residue was dissolved in H2O (70 mL), then H2SO4 (25.58 g, 260.88 mmol) was added. The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was basified with NaOH to pH 8 The precipitated solids were collected by filtration and washed with H?O to afford a 1: 1 mixture of (S)- l-(((l S,2R)-l-amino-5-methyl-2,3-dihydro-lH-ioden-2-yl)oxy)propan-2-ol and (S)-l-(((lR,2S)-l-amino-5-methyl-2,3-dihydro-lH-inden-2-yl)oxy)propan-2-oi (6.0 g, crude) as a white solid. MS ESI calculated for C13H19NO2 [M+H]⁺, 222.14; found, 222.10. [1188] A solution of 1 :1 mixture of (S)-l -(((lS,2R)-l-amino-5-methyl-2,3-dihydro-lH- mden-2-yl)oxy)propan-2-ol and (S)-l-(((lR,2S)-l-amino-5-melhyl-2,3-dihydro-lH-inden-2- yl)oxy)propan-2-ol (6.0 g, 27.11 mmol), BocsO (8.88 g, 40.67 mmol), TEA (5.49 g. 54.23 mmol) and DMAP (0.33 g, 2.71 mmol) in MeOH (50 mL) was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-60% EtOAc in PE to afford a 1:1 mixture of tert-butyl (( lR,2S)-2-((S)-2-hydroxypropoxy)-5-methyl-2,3-dihydro- 1 H-inden- 1- yl)carbamate and tert-butyl ((lS,2R)-2-((S)-2-hydroxypropoxy)-5-methyl-2,3-dihydro-lH- inden-l-yl)carbamate (1.48 g, 17%) as a white solid. MS ESI calculated for C18H27NO4

[1189] To a stirred 1:1 mixture of tert-butyl ((lR,2S)-2-((S)-2-hydroxypropoxy)-5-methyl- 2, 3 -dihydro- 1 H-inden- l-yl)carbaniate and tert-butyl ((lS,2R)-2-((S)-2-hydroxypropoxy)-5- melhyl-2,3-dihydro- l H-inden- l -yl)carbamate (1.48 g. 4.61 mmol) and E13N (2.33 g, 23.03 mmol) in DCM (15 mL) was added methanesulfonic anhydride (3.21 g, 18.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was basified with NaHCCh (sat.) to pH 8 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NajSCh. After filtration, the filtrate was concentrated under reduced pressure. Then the residue was dissolved in DCM (15 mL) and trifluoroacetic acid (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. Then the residue was dissolved in acetonitrile (10 ml), 1,2,2,6,6-pentamethylpiperidine (2.15 g, 13.82 mmol) was added to the mixture at room temperature. Then the mixture was heated at 80 °C for 16 h with stirring. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 5% -- 15% MeCN in water (0.1% FA) and further purified by Prep-Achiral SFC with the following conditions: [Column: YMC-Actus Triart Diol-HILIC 3*25 cm, 5 gm; Mobile Phase A: CO?, Mobile Phase B: IPA (20 mM NH?); Flow rate: 75 mL/niin; Gradient: isocratic 13% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nra; RTl(min): 4.87;

RT2(min): 6.17; Sample Solvent: MEOH] to afford (3R,4aR,9aS)-3, 7-dimethy 1-2,3, 4, 4a, 9.9a- hexahydroindeno[2,l-b][l,4]oxazine (350 mg, 38%) as a white solid with retention time at 4.87 minute.

[11911] The achiral separation also afford (3R,4aS,9aR)-3,7-dimethyl-2,3,4.4a,9_t9a- hexahydroindeno[2,1 -b] [ 1 ,4]oxazine (A53) (245 mg, 26%) as a yellow oil with retention time at 6.17 minute. MS ESI calculated for C13H17NO [M+H]⁺, 204.13; found, 204. 15. ’H NMR

(400 MHz, DMSO-tfe) 6 (ppm) 7.19 (d, 7 = 7.6 Hz, 1H), 7.05 (s, 1H), 6.98 (d, 7 = 7.6 Hz, 1H), 4.20 - 4.14 (m, 1H), 3.96 (d, 7 = 5.2 Hz, 1H), 3.53 - 3.49 (m, 1H), 3.29 - 3.13 (m, 2H), 2.88 - 2.65 (m, 2H), 2.27 (s, 3H), 0.85 (d, 7 = 6.4 Hz, 3H). Absolute stereochemistry was de t eim ined by NOESY.

Intermediate A54: (2R ,4aR , 1 ObS )-8-chloro-2-methyl-2,3 ,4a, 5 ,6, 1 Ob-hexahydro- 1 H- naph tho[2, 1 -b] [ 1 ,4]oxazine

A54

Step-1 :

[1191] To a stirred solution of 6-chloro-3,4-dihydronaphthalen-l (2H)-one (15.00 g, 83.04 mmol) in ethyl acetate (300 niL) was added CuBrz (27.82 g, 124.57 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography , eluted with 0-30% ethyl acetate in petroleum ether to afford a 1:1 mixture of (S )-2-bromo-6-chloro-3,4-dihydronaphthalen- 1 (2H)-one and (R)-2-bromo-6-chloro-3,4-dihydronaphthalen-l(2H)-one (17.10 g, 79%) as a light yellow solid. MS ESI calculated for CioHsBiClO [M+H]⁺, 258.94, 260.94; found, 259.00, 261.00.

Step-2:

[1192] To a stirred solution of a 1:1 mixture of (S)-2-bromo-6-chloro-3,4- diliydronaphthalen-l(2H)-one and (R)-2-bronio-6-chloro-3,4-dihydronaphthalen-l(2H)-one (17.10 g, 65.89 mmol) in MeOH (170 mL) was added NaBH4 (2.49 g, 65.82 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction was quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaiSOn After filtration, the filtrate was concentrated under reduced pressure. This resulted in a 1:1 mixture of (lR,2S)-2-bromo-6-chloro-l,2,3,4-tetrahydronaphthalen-l-ol and (lS,2R)-2- bromo-6-chloro-l ,2,3,4-tetrahydronaphthalen-l-ol (17.10 g, crude) as a light yellow solid. MS ESI calculated for CioHioBrClO [M+H]⁺, 260.96, 262.96; found, 261 .05, 263.05.

Step-3:

[1193] To a stirred solution of a 1 : 1 mixture of ( 1 R,2S)-2-bromo-6-chloro- 1,2,3 ,4- tetrahydronapbthalen-l-ol and (lS,2R)-2-bromo-6-ch1oro-l,2,3,4-tetrahydronaphthalen-l-ol (17.10 g, 65.38 mmol) in acetonitrile (170 mL) was added cone. H2SO4 (12.82 g, 130.76 mmol) dropwise at 0 °C. The resulting mixture was stirred at 50 °C for 1 h. Then water (170 mL) was added to the mixture at 50 °C. The mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature, filtered, and the filter cake was washed with CH2CI2. The filtrate was extracted with CH2CI2. The aqueous layer was basifted with NaOH (aq., 20%) to PH 12 and extracted with CH2O2. The combined organic layers were washed with brine, dried over anhydrous Na^SCU- After filtration, the filtrate was concentrated under reduced pressure. This resulted in a 1: 1 mixture of (1R, 2S)-1 -arnino- 6- chloro- 1,2, 3,4- tetrahydronaphthalen-2-ol and ( 1 S,2R)- 1 -amino-6-chloro- 1 ,2,3 ,4-tetrahydronaphthalen-2-ol (9.1 g, crude) as a white solid. MS ESI calculated for CioHnCINO [M+H]⁺, 198.06; found, 198.00.

Step-4:

[1194] To a stirred solution of a 1:1 mixture of ( 1R, 2S)-l-amino-6-chloro-l, 2,3,4- tetrahydronaphthalen-2-ol and ( 1 S,2R)- 1 -amino-6-chloro- 1 ,2,3 ,4-tetrahydronaphthalen-2-ol (9.10 g, 46.04 mmol) and EtjN (9.32 g, 92.08 mmol) in methanol (91 mL) was added BocoO (10.05 g, 46.04 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by the addition of water. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NazSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% MeOH in CH2CI2 to afford a 1 :1 mixture of tert-butyl ((lR,2S)-6-chloro-2-hydroxy- 1 .2.3.4-tetrahydronaphthalen-l -yl)carbamate and tert-butyl ((lS,2R)-6-chloro-2-hydroxy-

1.2.3.4-tetrahydronaphthalen-l-ylicarbamate (11.3 g, 82%) as an orange oil. MS ESI calculated for C_{; 3}H₂OC1N0₃ [M+H]⁺, 298.11 ; found, 298.15.

Step-5 :

[1195] To a stirred solution of a 1 : 1 mixture of tert-butyl ( ( 1R,2S )-6-chloro-2-hydroxy-

1 .2.3.4-tetrahydronaphthalen-l -yl)carbamate and tert-butyl (( lS,2R)-6-chloro-2-hydroxy-

1 .2.3.4-tetrahydronaphthalen-l -yl)carbamate (8.80 g, 29.55 mmol) and NaOH (8.27 g, 206.86 mmol) in DCM (83 niL) were added (BruNjHSO?, (2.01 g, 5.91 mmol) and (4S)-4-methyl- l,3,2-k-6-dioxathioIane-2, 2-dione (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1) (5.31 g, 38.42 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water and neutralized with HC1 (aq) to PH~7. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NajSOn After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 2-methoxy-2- methylpropane (350 mL) and H₂O (12 niL), then TsOH (3.05 g, 17.7.3 mmol) was added at room temperature. The mixture was stirred at 40 °C for 4 h. The resulting mixture was quenched with water and basified with NaHCOj (sat.). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₃. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl ((lR,2S)-6-chloro-2-((S )-2- hydroxypropoxy)-!, 2, 3, 4-tetrahydronaphthalen-l-yl (carbamate and tert-butyl ((1 S,2R)-6- chloro -2-((S) -2-hydroxypropoxy) ■ 1 ,2,3,4- tetrahydronaphthalen- 1 -yl)carbamate (6.4 g, 61 %) as a white solid. MS ESI calculated for CI₃H₁₈C1NO₂ [M+H]⁺, 256.10; found, 256.00.

Step-6:

[1196] To a stirred solution of a 1: 1 mixture of tert-butyl ((lR,2S)-6-chloro-2-((S)-2- hydroxypropoxy)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)carbamate and tert-butyl (( lS,2R')-6- chloro-2-((S)-2-hydroxypropoxy)-l,2,3,4-tetrahydronaphthalen-l-yl)carbamate (6.63 g, 18.64 mmol) in toluene (150 mL) was added 2-(tributyl-X³-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (9.00 g, 37.29 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl (2R,4aS,10bR)-8-chloro- 2-methyl-2,3,4a,5,6,10b-hexahydro-lH-naphtho[2,l-b][l,4]oxazine-l-carboxylate and tertbutyl (2R,4aR, 10bS)-8-chloro-2-methyl-2, 3,4a, 5, 6, lOb-hexahydro- lH-naphtho[2, l- b][l,4]oxazine-l -carboxylate (5.53 g, 88%) as a light yellow oil. MS ESI calculated for C1SH24CINO3 [M+H]⁺, 338.14; found, 338.05.

Step-7 :

[1197] To a stirred solution of 1 : 1 mixture of tert-butyl (2R,4aS, 10bR)-8-chloro-2- methyl- 2.3 ,4a, 5 ,6, lOb-hexahydro- lH-naphtho[2, 1 -b] [ 1 ,4]oxazine- 1 -carboxylate and tert -butyl (2R,4aR,l0bS)-8-chIoro-2-methyl-2,3,4a,5,6,l0b-hexahydro-lH-naphtho[2,1-b][l,4]oxazine- 1 -carboxylate (5.53 g, 16.37 mmol) in DCM (52 niL) was added trifluoroacetic acid (17.3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography with 5% to 25% MeCN in Water (0.1% TEA) to afford a 1: 1 mixture of (2R,4aS,10bR)-8-chloro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH- naphtho[2,l-b][l,4]oxazme and (2R,4aR,l()bS)-8-chloro-2-methyl-2,3,4a,5,6,10b-hexahydro- lH-naphtho[2,l-b][l,4]oxazine (3.7 g) as a white solid. The mixture was purified by Prep- Achiral-SFC with the following conditions [Column: GreenSep Basic 3*15 cm, 5 tt; Mobile Phase A: CO?, Mobile Phase B: MeOH(20mM NH3.M); Flow rate: 75 mL/rnin; Gradient: isocratic 15% B; Column Temperature(25 °C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 2.13; RT2(niin): 3.60; Sample Solvent: MeOHj to afford (2R,4aS,10bR)- 8-chloro-2-methy 1-2, 3,4a, 5, 6 J Ob-hexahydro- 1 H-naphtho[2 J -b][l ,4]oxazine (1.0 g, 25% yield) as a light yellow solid with the first peak on Achiral SFC. MS ESI calculated for CI₃H₁₆C1NO [M+Hf, 238.09; found, 238.10. ^! H NMR (400 MHz, DM St )■<■/..? 5 7.71 (d, J = 8.4 Hz, 1H), 7.24 (dd, J - 8.3, 2.3 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 3.94 - 3.78 (m, 2H), 3.61 (dd, 10.8, 3.2 Hz, 1H), 3.12 (t, / = 10.6 Hz, 1 H), 2.91 - 2.79 (m, 1H), 2.63 - 2.45 (m, 2H). 2.01 - 1.91 (m, 1H), 1.88 - 1.75 (m, 1H), 0.87 (d, J = 6.4 Hz, 3H).

[1198] The separation also afford (2R,4aR,10bS)-8-chloro-2-methyl-2,3,4a,5,6,10b- hexahydro-lH-naphtho[2,l-b][l,4]oxazine (A54) (884 mg, 22%) as a white solid with the second peak on Achiral SFC. MS ESI calculated for CBHIGCINO [M+H]⁺, 238.09; found, 238.10. ^!H NMR (400 MHz, DMSO-J₆) 87.49 - 7.40 (m, 1H), 7.38 - 7.26 (m, 2H), 4.48 - 3.99 (m, 2H), 3.92 - 3.57 (m, 1 Hi, 3.48 - 3.36 (m, 1H), 3.13 - 2.66 (m. 3Hi, 2.65 - 2.52 (m, 1 H), 1 .76 - 1.58 (m, 1H), 1.18 — 0.98 (m, 3H). Absolute stereochemistry was determined by NOESY.

Intermediate A55: (2R,4aR,10bS)-8-fluoro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH- naphtho[2, 1 -b][l,4]oxazine

Step- 1 :

11199] To a mixture of 6-fluoro-3,4-dihydronaphthalen-l (2H)-one (30.50 g, 185.77 mmol) in Diethyl ether (300 ml) was dropwise added Br? (9.5 mL, 185.77 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by saturated NaSzCh aq. and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 330 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether within 20 min to afford a 1:1 mixture of (R)-2-bromo-6-fluoro-3,4- dihydronaphthalen-l(2H)-one and (S)-2-bromo-6-fluoro-3,4-dihydronaphthalen-l(2H)-one (33.10 g, 73%) as a yellow oil. MS ESI calculated for CioHsBrFO [M+H]⁺, 242.97; found,

242.85.

[1200] To a 1: 1 mixture of (R)-2-bromo-6-fluoro-3,4-dihydronaphthalen-l(2H)-one and (S)-2-bromo-6-fluoro-3,4-dihydronaphtha1en-l(2H)-one (10 g, 41.14 mmol) in EtOH (100 mL) was added NaBFU (0.78 g, 20.57 mmol) in portions af 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched slowly by water at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a 1: 1 mixture of ( lR,2S)-2-bromo-6-iluoro- 1 ,2,3,4-tetraliydronaphthalen- l-ol and (lS,2R)-2-bromo-6-lluoro- 1,2,3.4-tetahydronaphthalen-l-ol (9.30 g, 93% yield) as a white solid. MS ESI calculated for CwHioBrFO [M+H]⁺, 244.99, 246.99; found, 245.00, 247.00.

Step- 3:

[1201] To a 1 : 1 mixture of 1 : 1 mixture of (lR,2S)-2-bromo-6-fluoro-l ,2.3,4 tetrahydronaphthalen- 1 -ol and (1 S,2R)-2-brorao-6-fluoro- 1 ,2,3,4-tetraliydronaphthalen-l -ol (9.10 g, 37.13 mmol) in ACN (90 mL) was slowly added H2SO4 (7.28 g, 74.26 mmol) at. 0 °C. The mixture was stirred at 50 °C for 1 h. Then H O (90 mL) was added to the mixture, the mixture was stirred at 80 °C for 16 b. The mixture was concentrated under vacuum. The residue was was basified with NaOH (2 M) to pH and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a 1:1 mixture of (lS,2R)-l-amino-6-fluoro- 1 ,2,3 ,4-tetrahydronaphthalen-2-ol and ( 1 R,2S)- 1 -amino-6-fluoro- 1 ,2,3 ,4- tetrahydronaphthalen-2-ol (4.10 g, 43%) as a white solid. MS ESI calculated for C10H12FNO [M+H]⁺, 182.09; found, 182.00.

[1202] To a 1 : 1 mixture of ( 1 S,2R)-l-amino-6-fluoro-l ,2,3,4-tetrahydronaphthalen-2-ol and (lR,2S)-l-amino-6-fluoro-l,2,3,4-tetrahydronaphthalen-2-ol (4.10 g, 22.62 mmol) in MeOH (40 mL) were added EtsN (3.43 g, 33.94 mmol) and di-tert-butyl dicarbonate (5.43 g, 24.89 mmol). The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 80 g silica gel column eluted with 0-70% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl ((lS,2R)-6-fluoro-2-hydroxy- 1,2,3, 4-teirahydronaphthalen- 1 -yl)carbamate and tert-butyl (( 1 R,2S)-6-fluoro-2-hydroxy- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - yl)carbamate (4.70 g. 66%) as a white solid. MS ESI calculated for C15H20FNO3 [M+H]⁺, 282.14; found, 282.15.

Step-5:

[1203] To a 1: 1 mixture of tert •■butyl ((lS,2R)-6-fluoro-2-hydroxy-l,2,3,4- tetrahydronaphthalen - 1-yl (carbamate and tert-butyl ((lR,2S)-6-fluoro-2-hydroxy-l,2,3,4- tetrahydronaphthalen-l-yl)carbamate (3.4 g, 12.08 mmol) in DCM (30 mL) were added (4S)~ 4-niethyl- 1, 3, 2-A-6-dioxathiolane-2, 2-dione (2.2 g, 15.92 mmol) (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1 ), NaOH (3.4 g. 85.00 mmol) and tetrabuiylazanium hydrogen sulfate (0.82 g, 2.41 mmol). The resulting mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum. The residue was diluted with H2O (50 mL), then H2SO4 (7 mL) was added. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was basified with NaOH (aq., 4N) to pH 8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCfo After filtration, the filtrate was concentrated under reduced pressure to afford a 1: 1 mixture of (S)- 1 -((( 1 S.2R)- 1 -amino-6-fluoro-l .2,3,4-tetrahydronaphthalen-2-yl)oxy)propan-2-ol and (S)- 1 -((( 1 R,2S)- l-amino-6-fluoro-l ,2,3,4-tetrahydronaphthalen-2-yl)oxy)propan-2-ol (2.9 g, 95%) as a yellow oil. MS ESI calculated for C12H16FNO2 [M+H]⁺, 240.13; found, 240.00.

Step-6:

[1204] To a 1: 1 mixture of (S)-l-(((lS,2R)-l-amino-6-fluoro-l,2,3,4-tetrahydronaphthalen- 2-yl)oxy)propan-2-ol and (S)-l-(((lR,2S)-l-amino-6-fluoro- 1,2,3, 4-tetrahydronaphthalen-2- yl)oxy)propan-2-ol (2.1 g, 8.77 mmol) in MeOH (20 mb) were sequentially added EtaN (1 .33 g, 13.16 mmol) and di-tert-butyl dicarbonate (1.92 g, 8.77 mmol) at room temperature. The resulting solution was stirred at room temperature for 4 h. The solvents were removed under vacuum. The resulting residue was purified by Combi Flash using a 80 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl ((lS,2R)-6-fluoro-2-((S)-2-hydroxypropoxy)-l,2,3,4-tetrahydronaphlhalen-l-yl)carbaniate and tert-butyl ((lR,2S)-6-fluoro-2-((S)-2-hydroxypropoxy)-l,2,3,4-tetrahydronaphthalen-l- yl)carbamate (1.75 g, 53%) as a white solid. MS ESI calculated for CisIIreFNCb [M+H]*, 340.18; found, 340.10.

Step-7:

[1205] To a 1 : 1 mixture of tert-butyl (( lS,2R)-6-fluoro-2-((S j-2-hydroxypropoxy)- 1 ,2,3,4- tetrahydronaphthalen-l-yl)carbamate and tert-butyl ((lR,2S)-6-fiuoro-2-((S)-2- hydroxypropoxy)-! ,2,3, 4-tetrahydronaphthalen-l-yDcarbamate (1.7 g, 5.00 mmol) in toluene

(20 mL) was added 2-(irihutyl-A^s-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (2.4 g, 10.55 mmol). The resulting mixture was stirred at 110 °C for 3 h. The solvents were removed under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / ElOAc (4:1 ) to afford a 1: 1 mixture of tert-butyl (2R.4aS,10bR)-8-fluoro-2- methyl-2, 3, 4a, 5, 6, 10b-hexahydro-lH-naphtho[2,l-b][l,4]oxazine-l -carboxylate and tertbutyl (2R,4aR,10bS)-8-fluoro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH-naphtho[2,l- b][l,4]oxazine-l-carboxylate (1.5 g, 84%) as a yellow oil. MS ESI calculated for C1SH24FNO3 [M-t-Hf, 322.17 found, 322.10.

Step-8:

[1206] To a solution of 1 : 1 mixture of tert-butyl (2R,4aS,10bR)-8-fluoro-2-methyl- 2,3,4a,5,6,10b-hexahydro-lH-naphtho[2,l-b][l ,4]oxazine-l -carboxylate and tert-butyl (2R,4aR,10bS)-8-fluoro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH-naphtho[2,l-b][l,4]oxazine- 1 -carboxylate (1.5 g, 4.62 mmol) in DCM (15 ml) was added Zinc bromide (2.07 g, 9.24 mmol). The resulting mixture was stirred at 40 °C for 16 h. Tire mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase Hash with the 5-35% MeCN in HsO (10 mM NH4HCO3) to afford a 1 :1 mixture of (2R,4aR,l0bS)-8-fluoro-2-methyl-2,3,4a,5,6,10b- hexahydro-lH-naphtho[2,l-b][l,4]oxazine and (2R,4aS,10bR)-8-fluoro-2-methyl- 2,3,4a,5,6,10b-hexahydro-lH-naphtho[2,l-b][l,4]oxazine (990 mg), which was separated by prep-Achiral SFC with the following conditions: [Column: YMC-Pack Poly amine II 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (20 mM NHr); Flow rate: 75 mL/min; Gradient (B%): isocratic 18% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 254 nm; RTl(min): 2.44; RT2(min): 3.34; Sample Solvent: MeOH— HPLC] to afford (2R,4aS,10bR)-8-fluoro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH- naphtho[2,l-b][l,4]oxazine (560 mg, 56% ) as a white solid with retention time at 2.44 minute. MS ESI calculated for CsHieFNO [M+H]⁺, 222.12; found, 222.05.

[1207] The separation also afford (2R,4aR,10bS)-8-fluoro-2-methyl-2,3,4a,5,6,l()h- hexahydro-lH-naphtho[2,l-b][l,4]oxazine (A55) (280 mg, 28%) as a white solid with retention time at 3.34 min. MS ESI calculated for CisHjgFNO [M+H]\ 222.12; found, 222.05. ^SH NMR (400 MHz, DMSO) 8 7.34 - 7.28 (m, 1H), 7.02 - 6.94 (m, 1H), 6.91 (dd, J = 10.2, 2.8 Hz, 1 H), 3.86 - 3.78 (m, 2H), 3.41 (dd, J = 10.8, 3.2 Hz, 1H), 3.19 (t, J = 10.8 Hz, 1 H), 2.98 - 2.87 (m, 1H), 2.87 - 2.83 (m, 1H), 2.82 - 2.70 (m, 1H), 2.66 - 2.53 (m, 1H), 2.26

- 2.03 (m, 1H), 1.57 - 1.46 (m, 1H), 0.87 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was determined by NOESY.

Intermediate ASG isomer 1 : (2R,4aR*,l 1 bR*)-2-rnethyl-9-(trifluoromethyl)-2,3,4a,5,7,l 1b- hexahydro-lH-benzo[5,6joxepino[3,4-b][l,4]oxazine isomer 1

‘^someM and

Intermediate ASG isomer 2: (2R,4aR*,llbR*)-2-niethyl-9-(trifluoromethyl)-2,3,4a,5,7,llb- hexahydro-lH-benzo[5,6]oxepino[3,4-b][l,4]oxazine isomer 2

Isomer 2

Step-1:

[1208] To a stirred solution of (2-bromo-5-(trif]uoromethyl)phenyl)methanol (5.00 g, 19.60 mmol) and ethenyltrifluoro-Z-4- borane potassium (3.94 g, 29.41 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) were added K2CO3 (89.4 g, 646.96 mmol) and Pd(dppf)C12-CH2C12 (1.43 g, 1 .96 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. Hie mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford (5- (trifluorotnethyr)-2-vinylphenyl)methanol (3.65 g, 89%) as a white solid. MS ESI calculated for C10H9F3O [M+H]⁺, 201 .06; found, 201 .00. ‘H NMR (400 MHz, DMSO-tfc) 87.86 - 7.71 (m, 2H), 7.62 - 7.57 (m, 1H), 7.01 (dd, J = 17.2, 11.2 Hz, 1H), 5.88 (dd, 17.6, 1.2 Hz, 1H), 5.56 - 5.31 (m, 2H), 4.64 (d, J = 5.6 Hz, 2H)

Step-2:

[1209] To a solution of (5 -(trifluoromethyl) -2-vinylphenyl)methanol (6.85 g, 33.88 mmol) in THF (70 mL) was added Nall (1.63 g, 40.65 mmol, 60% in mineral oil) at 0 °C, the mixture was stirred at 0 °C for 30 min. This was followed by the addition of 3-bromoprop-l- ene (4.92 g, 40.65 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at 0 °C and extracted with EtOAc. The organic layer was dried over anhydrous NaiSOj. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford 2- ((allyloxy)methyl)-4-(trifluoromethyl)-l -vinylbenzene (7.66 g, 93%) as a yellow' liquid. MS ESI calculated for C13H13F3O [M+H]⁺, 243.09; found, 243.00. ’H NMR (400 MHz, DMSO- O 3 7.90 - 7.73 (m, 1H), 7.73 - 7.60 (m, 2H), 7.01 (dd, J = 17.6, 11.2 Hz, 1H), 6.06 - 5.86 (m, 2H), 5.51 (dd, / - 11.2, 1.2 Hz, 1H), 5.32 - 5.26 (m, I H), 5.20 - 5.16 (m, 1H), 4.62 (s, 2H), 4.06 (dt, ./ = 5.2, 1 .6 Hz. 2H).

Step-3 :

[1210] A solution of 2-((allyloxy)methyl)-4-(trifluoromethyl)-l-vinylbenzene (3.44 g,

14.20 mmol) and Grubbs 2nd (3.01 g, 3.55 mmol) in DCM (35 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford 8-(trifluoromethyl)-l,3- dihydrobenzo[c]oxepine (2.55 g, 81%) as a brown solid. MS ESI calculated for C11H9F3O [M+H]⁺, 215.06; found, 215.05. ^!H NMR (400 MHz, DMSO-<fe) 8 7.71 - 7.55 (rn, 2H), 7.52 (d, J - 8.0 Hz, 1H), 6.60 - 6.56 (m, 1H), 6.11 (dt, .J = 12.4, 2.8 Hz, 1H), 4.70 (s, 2H), 4.54 (t, J = 2.8 Hz, 2H).

Step-4:

[1211] To a solution of S-(trifluoromethyl)- 1 ,3-dihydrobenzo[c]oxepine ( 1 .23 g, 5.74 mmol) in DMSO (15 niL) and H2O (3 mb) was added NBS (1.02 g, 5.74 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The resulting mixture was quenched with water and extracted with ElOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCM. After filtration, the filtrate was concentrated under reduced pressure to afford a 1: 1 mixture of (4S,5S)-4-bromo-8-(trifluoromethyl)-l, 3,4,5- tetrahydrobenzo[c]oxepin-5-ol and (4R,5R)-4-bromo-8-(trifluoromethyl)-l, 3,4,5- tetrahydrobenzo[c]oxepin-5-ol (1.66 g, crude) as a brown oil. MS ESI calculated for CnHioBrFsOt [M+H]⁺, 310.98, 312.98: found, 311.00, 313.00.

[1212] A solution of a 1 : 1 mixture of (4S,5S)-4-bromo-8-(trifluorometliyl)-l ,3,4,5- tetrahydrobenzo[c]oxepin-5-ol and (4R,5R)-4-bromo-8-(trifluoromethyl)-l, 3,4,5- tetrahydrobenzo[cjoxepin-5-ol (1.66 g, 5.33 mmol) and Ammonium hydroxide (28% in water) (1.61 g, 45.89 mmol) in MeOH ( 17 mL) was stirred al room temperature for 2 days under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (17 mL). The filtrate was concentrated under reduced pressure to afford a 1:1 mixture of (4S,5R)-5-amino-8-(trifluoromethyl)-l,3,4,5-tetrahydrobenzo[c]oxepin-4-ol and (4R,5S)-5-amino-8-(trifluoromeihyl)-l,3,4,5-tetrahydrobenzo[c]oxepin-4-ol (870 mg, 62%) as a white solid. MS ESI calculated for Ci IHSJFJNOZ [M+H]\ 248.08; found, 248.10. *H NMR (400 MHz, DMSOm'e) g 7.77 (d, ./ = 8.0 Hz, 1H), 7.66 - 7.62 (m, 1H), 7.56 - 7.54 (m, 1 H), 5.17 (s, 1H), 4.83 (d, 7 = 13.6 Hz, 1H), 4.61 (d, J - 13.6 Hz, 1H), 4.23 - 3.99 (m, 2H), 3.69 - 3.63 (m, 1H), 3.30 - 3.24 (m, 1H).

Step -6

[1213] To a stirred solution of a 1: 1 mixture of (4S,5R)-5-amino-8-(trifluoromethyl)- l,3,4,5-tetrahydrobenzo[c]oxepin-4-ol and (4R,5S)-5-amino-8-(trifluoromethyl)-l ,3,4,5- telrahydrobenzo|c]oxepin-4-ol (5.30 g, 21.43 mmol) and TEA (2.82 g, 27.87 mmol) in DCM (100 mL) was added benzoyl chloride (3.01 g, 21.43 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% methanol in dichloromethane to afford a 1: 1 mixture of N-((4S,5R)-4-hydroxy-8-(trifluoromethyl)-l,3.4,5-tetrahydrobenzo[cjoxepin-5- yl)benzamide and N-((4R,5S)-4-hydroxy-8-(tifJuoromethyl)- 1 ,3,4,5- tetrahydrobenzo[c]oxepin-5-yl)benzamide (5.10 g, 65%) as a white solid. MS ESI calculated for CisHieFjNOj [M+Hf, 352.11; found, 352.10.

Step-7:

[1214] To a stirred solution of a 1: 1 mixture of N-((4S,5R)-4-hydroxy-8-(trifluoromethyl)- l,3.4,5-tetrahydrobenzo[c]oxepin-5-yl)benzamide and N-((4R,5S)-4-hydroxy-8-

( trifluoromethyl)-!, 3, 4, 5-tetrahydrobenzo|c]oxepin-5-yl)benzamide (620 mg, 1.76 mmol) in DCM (12 mL) was added SOCI2 (419 mg, 3.53 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with NaHCCh (aq.) and extracted with CH2CI2. The organic layer was dried over anhydrous NazSCfi. After filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of (3aS,10bS)-2-phenyl-8-(trifluoronieihyl)-3a,4,6,10b-tetrahydrobenzo[5,6]oxepino[4,3- djoxazoie and (3aR,10bR)-2-phenyl-8-(trifluoromethyl)-3a,4,6,10b- tetahydrobenzo[5,6]oxepino[4,3-djoxazole (447 mg, 69%) as a yellow solid. MS ESI calculated for CtsHuFiNOi [M+H]t 334.10; found, 334.15.

Step-8:

[1215] To a stirred solution of a 1: 1 mixture of (3aS,10bS)-2-phenyl-8-(tritluoromethyl)- 3a,4,6,10b-tetrahydrobenzo[5,6]oxepino[4,3-d]oxazole and (3aR,10bR)-2-phenyl-8- (triiluoromethyl)-3a,4,6,10b-tetrahydrobenzo[5,6]oxepino[4,3-d]oxazole (518 mg, 1.55 mmol) in 1,4-dioxane (3 mL) was added HC1 (6 mb) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The mixture was allowed to cool down to room temperature and partitioned between CH2CI2 and water. The mixture was extracted with CH2CI2. The aqueous phase was collected and basified with NaOH to pH 10. The aqueous layer was then extracted with CH2CI2. The organic layer was dried over anhydrous NaiSOr.

After filtration, the filtrate was concentrated under reduced pressure to afford a 1:1 mixture of (4S,5S)-5-amino-8-(trifluoromethyl)- 1 ,3 ,4,5-tetrahydrobenzo[c]oxepin-4-ol and (4R,5R)-5- amino-8-(trifluoromethyl)-l,3,4,5-tetrahydrobenzo[c]oxepin-4-ol (300 mg, 78%) as a white solid. MS ESI calculated for CI IH_!2F₃NO₂ [M+H]⁺, 248.08; found, 248.05.

Step-9:

[1216] To a stirred solution of a 1:1 mixture of (4S,5S)-5-amino-8-(trifluoromethyl)- l,3,4,5-tetrahydrobenzo[c]oxepin-4-ol and (4R,5R)-5-amino-8-(trifluoromethyl)-l,3,4,5- tetrahydrobenzo[c]oxepin-4-ol (1.40 g, 5.66 mmol) and Et₃N (1.15 g, 11.32 mmol) in MeOH (20 ml..) was added BOC2O (1.61 g, 7.36 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-60% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl ((4S,5S)-4-hydroxy-8- (trifluoromethyl)-l,3,4,5-tetrahydrobenzo[c]oxepin-5-yl)carbamate and tert-butyl ((4R,5R)-4- hydroxy-8-(trifluoromethyl)-l,3,4,5-tetrahydrobenzo[c]oxepin-5-yl)carbamate (1.71 g, 85%) as a white solid. MS ESI calculated for C16H20F5NO4 [M+H]⁺, 348.13: found, 348.10.

[1217] To a stirred solution of a 1:1 mixture of tert-butyl ((4S,5S)-4-hydroxy-8-

(trifluoromethyl)- 1 ,3,4,5-tetrahydrobenzo[c]oxepiri-5-yl)carbarnate and tert-butyl ((4R,5R)-4- hydroxy-8-( trifluoromethyl)-!, 3, 4, 5-tetrahydrobenzo[c]oxepin-5-yl)carbamate (1 .21 g, 3.48 mmol) in DCM (12 mL) were added NaOH (975 mg, 24.38 mmol) and (S)-4-methyl-l,3,2- dioxathiolane 2,2-dioxide (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953- 30-1) (625 mg, 4.52 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The residue was quenched with water. The mixture was neutralized with HO (cone.) to pH 7. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Tire residue was dissolved in 2-raethoxy-2-methylpropane (51 mL) and H?O (1.7 mL), this was followed by the addition of TsOH (359 mg, 2.09 mmol) and dioxane (14.4 mL) at room temperature. The resulting mixture was stirred at 40 °C for 2. h under nitrogen atmosphere. The resulting mixture was quenched with waler and neutralized by NaHCOs (aq,). to pH 8. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-60% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl ((4S,5S)-4-((S)-2-hydroxypropoxy)-8-(trifluoromethyl)-l ,3,4,5- tetrahydrobenzo[c]oxepin-5-yl)carbamate and tert-butyl ((4R,5R)-4-((S)-2-hydroxypropoxy)- 8-(trifluoromelhyl)-l ,3,4,5-tetrahydrobenzo[c]oxepin-5-yl)carbamate (1.01 g, 67%) as a white solid. MS ESI calculated for C19H26F3NO5 [M+H]⁴, 406.18; found, 406.15.

Step-11:

[1218] A solution of a 1 : 1 mixture of tert-butyl ((4S,5S)-4-((S)-2-hydroxypropoxy)-8-

( trifluoromethyl)-!, 3, 4, 5-tetrahydrobenzo[c]oxepin-5-yl)carbamate and tert-butyl ((4R,5R)-4- ((S)-2-hydroxypropoxy)-8-(trifluorornethyl)- 1,3,4, 5-tetrahydrobenzo[c]oxepin-5- yljcarbamate (273 mg, 0.67 mmol) and 2-(tributyl-X⁵-phosphaneylidene)acetonitri]e (CAS No. 157141-27-0) (325 mg, 1.34 mmol) in toluene (5 mL) was stirred at 110 °C for 16 h under nitrogen atmosphere. Hie mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl (2R,4aS , 11 bS) - 2.-methyl-9- (trifluoromethyl) -2,3 ,4a, 5 ,7, 1 lb-hexahydro- 1 H- benzo[5,6]oxepino[3,4-b][l,4]oxazine-l-carboxylate and tert-butyl (2R,4aR,l lbR)-2-methyl- 9-(trifluoromethyl)-2,3,4a,5,7,l lb-hexahydro-lH-benzo[5,6]oxepino[3,4-b][l ,4]oxazine-l- carboxylate (200 mg, 74%) as a white solid. MS ESI calculated for C19H24F3NO4 [M+H]⁺, 388.18: found, 388.15.

Step- 12:

A56 isomer 2

[1219] To a solution of tert-butyl (2RS,4R,7RS)-4-methyl-13-(lrifluoromethyl)-6,9-dioxa- 3-azatricyclo[9.4.0.0^A{2,7 }]pentadeca-l(15),l l,13-triene-3-carboxylate (627 mg, 1.61 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was basified with NaHCOs (aq.) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions [Column: Xcelect CSH F-pheny OBD Column 19*250 mm, 5m; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 niL/min: Gradient: 10% B to 20% B in 10 min; Wave Length: 254/220 nm: RTl(min): 9.0; RT2(min): 9.5] to afford (2R,4aR*,l lbR*)-2-methyl-9-(trifluoromethyl)- 2,3, 4a, 5, 7,1 lb-hexahydro-lH-benzo[5,6]oxepino[3,4-b][l,4]oxazine (A56, isomer 1) (177 mg) as a white solid with the first peak on HPLC. MS ESI calculated for C14I I i&FjNCh [M+H]⁺, 288.11 ; found, 288.10. ^!H NMR (400 MHz, DMSCfofc) 8 7.65 - 7.54 (m, 3H), 4.85 (d, J = 13.2 Hz, 1H), 4.77 - 4.64 (m, 2H), 4.27 (d, .7 - 3.2 Hz, 1H), 3.91 - 3.84 (m, 1H), 3.78 - 3.72 (m, 1H), 3.46 and 3.43 (d, J = 4.0 Hz, 1H), 3.37 (d, J = 10.8 Hz, 1H), 3.08 - 2.99 (m, 1H), 2.55 2.52 (m, 1H), 0.93 (d, J - 6.4 Hz, 3H). Absolute stereochemistry was not determined.

[1220] The separation also afford (2R,4aR*,l lbR*)-2-methyl-9-(trifluoromethyl)- 2,3, 4a, 5, 7,1 lb-hexahydro-lH-benzo[5,6]oxepino[3,4-b][l,4]oxazine (A56, isomer 2) (121 mg) as a light yellow solid with the second peak on HPLC. MS ESI calculated for C14H16F3NO2 [M+H]⁺, 288.11 ; found, 288.10. ^JH NMR (400 MHz, DMSO-Js) 6 7.90 (d, J = 8.0 Hz, 1H), 7.72 - 7.60 (m, 1 H), 7.56 - 7.52 (m, 1H), 4.84 - 4.78 (m, 1H), 4.72 - 4.65 (m, 1H), 4.37 (s, 1H), 3.95 and 3.92 (d, J = 3.6 Hz, 1H), 3.86 (q, J = 3.6 Hz, 1H), 3.80 - 3.66 (m, 2H), 3.14 (t, J = 10.0 Hz, 1H), 3.08 - 2.97 (m, 2H), 0.94 (d, ./ = 5.6 Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A57: 2:2: 1:1 mixture of rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-methyl- l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 1 and rel-(2R,4aS,10bR)-8-

(difluoromethoxy)-2-methyl-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 2 and rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-methyl-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine isomer 3 and rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-methyl-

1,3, 4, 4a, 5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 4

A57

Step - 1 ;

[1221] To a stirred solution of (2,4-diraethoxyphenyl)boronic acid (10 g, 54.95 mmol) and methyl 2-chloro-6-methylnicotinate (10.20 g, 54.95 mmol) in 1,4-dioxane (100 mL) and H?O (10 mL) were added Pd(dppl)Ch (4.02 g, 5.49 mmol) and K2CO3 (22.78 g, 164.85 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to afford methyl 2-(2,4-dimethoxyphenyl)-6-methylnicotinate (12 g, 72%) as a yellow solid. MS ESI calculated for Ci6Hi7NO₄ [M+H]*, 288.12; found, 288.10.

[1222] To a stirred solution of methyl 2-(2,4-dimethoxyphenyl)-6-methylnicotinaie (12.9 g, 44.89 mmol) in DCM (130 mL) was added BBn ( 1 M in DCM) (225 mL, 225 mmol) dropwise at 0 °C. The resulting solution was stirred at 0 °C for 3 h. The reaction was quenched with MeOH at -40 °C. The resulting mixture was concentrated under reduced pressure to afford 8-hydroxy-2-methyl-5H-chromeno[4,3-b]pyridin- 5-one (12 g, crude) as a yellow solid. MS ESI calculated for CT3H9NO3 |M+Hf, 228.06; found, 228.00.

Step-3 :

[1223] To a stirred solution of 8-hydroxy-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (10 g, 44.01 mmol) and K2CO3 (9.12 g, 66.02 mmol) in DMF (100 mL) was added sodium 2- chloro-2,2-difluoroacetate (13.42 g, 88.02 mmol) at 0 °C. The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was quenched with waler. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 : 1) to afford 8-(difluoromethoxy)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (2.4 g, 18%) as a yellow solid. MS ESI calculated for C14H9F2NO3 IM+Hf, 278.06; found, 278.00.

Step-4:

[1224] To a stirred solution of 8-(difluoromethoxy)-2-methyl-5H-cliromeno[4,3-b]pyridin- 5-one (2.4 g, 8.65 mmol) in THF (24 mL) was added LiAlH4(0.66 g, 17.31 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of water (0.7 mL) and NaOH (aq. IN) (0.7 mL) at 0 °C, The resulting mixture was filtered, the filter cake was washed with EtOAc. The ft] terate was collected and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCL. After filtration, the filtrate was concentrated under reduced pressure to afford 5 - (difluoromethoxy)-2-(3-(hydroxymethyl)-6-methylpyridin-2-yl)phenol (2.2 g, crude) as a yellow solid. MS ESI calculated for C14IL3F2NO3 [M+H]⁺, 282.09; found, 282.00.

Step-5 :

[1225] To a stirred solution of 5-(difluoromethoxy)-2-(3-(hydroxyniethyl)-6- methylpyridin-2-yl)phenol (2.2 g, 7.82 mmol) and PPI13 (4.10 g, 15.64 mmol) in THF (22 mL) was added DIAL) (3.16 g, 15.64 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1 ) to afford 8-(difluoromethoxy)-2-methy1-5H- chromeno[4,3-b]pyridine (1.4 g, 62%) as a yellow oil. MS ESI calculated for C14H11F2NO2 [M+H]⁺, 264.08; found, 264.10.

Step-6:

[1226] To a solution of 8-(difluoromethoxy)-2-methyl-5H-chromeno[4,3-b]pyridine (2.90 g, 11.01 mmol) in i-PrOH (300 mL) and AcOH (30 mL) were added Pd/C (10%, 0.12 g) and Pd(OH)₂/'C (20%, 0.15 g). The mixture was hydrogenated at 50 °C under 30 psi of hydrogen pressure for 48 h. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with 10% - 50% MeCN in Water (10 mmol/L NH4HCO3) to afford a 2:2: 1:1 mixture of re]-(2R,4aS,10bR)-8-(difluoromethoxy)-2-methyl-l, 3, 4, 4a, 5, 10b- hexahydro-2H-chromeno[4,3-b]pyridine isomer 1 and rel-(2R,4aS,10bR)-8- (difluoromethoxy)-2-meihyl-l,3,4,4a,5, 10b-hexaliydro-2H-chromeno[4,3-b]pyridine isomer 2 and rel-(2R,4aS, 10bR)-8-(difluoromethoxy)-2-metbyl- 1 ,3, 4,4a, 5, 10b-hexahydro-2H- chromeno[4,3-b]pyridine isomer 3 and rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-methyl- l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 4 (A57) (1.3 g, 42%) as a yellow oil. MS ESI calculated for C_!4Hi7F₂NO2 [M+H]⁺, 270.12; found, 270.05

Intermediate A57 isomer 1: rel-(2R,4aS,10bR) -8 -(difluoromethoxy)-2- methyl- 1 ,3,4.4a,5,10b-hexahydro-2H-chronieiio[4,3-b]pyridine isomer 1 Intermediate A57 isomer 2: rel-(2R,4aS,10bR)-8-(difiuoroniethoxy)-2-methyl-

1 ,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 2

Isomer 2

Intermediate A57 isomer 3: rel-(2R,4aS,10bR)-8-(difluoromelhoxy )-2-methyl- 1,3, 4, 4a, 5 ,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 3

Isomer S _and?

Intermediate A57 isomer 4: rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-methy]-

1,3, 4, 4a, 5, 10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 4

[1227] 2:2: 1 : 1 mixture of reJ-(2R,4aS,l0bR)-8-(difluorometboxy)-2-methy1-l,3,4₅4a,5,l0b- hexahydro-2H-chromeno[4,3-b]pyridine isomer 1 and rel-(2R,4aS,10bR)-8-

(difluoromethoxy)-2-methyl-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 2 and rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-meihy]-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine isomer 3 and rel-(2R,4aS,10bR)-8-(difiuoromethoxy)-2-methyl- l,3,4.4a,5,10b-hexahydro-2H-chromeno|4,3-b]pyridine isomer 4 ( 1 .3 g) was separated by Prep-Chiral HPLC with the following conditions: [Column: CHIRALPAK IG, 3*25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MEOH (0.1% 2M NH3-MEOH); Flow rate: 100 mL/min; Gradient: isocratic 10% B; RT1 (min): 6,7; RT2 (min): 7.9; RT3 (min): 10.5; RT4 (min): 15.2; Sample Solvent: MEOH] to atford rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2- methyl-l ,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 1 (A57 isomer 1 ) (170 mg, 13%) as a pink oil with retention time at 6.7 min.; rel-(2R,4aS,10bR)-8- (ditluoromethoxy)-2-methyl-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3-b]pyridine isomer 2 (A57 isomer 2) ( 120 mg, 9%) as a white solid with retention time at 7.9 min.; rel- (2R,4aS,10bR)-8-(difluoromethoxy)-2-methyl-l,3,4,4a,5,10b-hexahydro-2H-chromeno[4,3- bjpyridine isomer 3 (A57 isomer 3) (90 mg, 7%) as a white solid with retention time at 10.5 min.; reH2R,4aS, 10bR)-8-(difluorometIioxy)-2-methyl- 1,3, 4,4a, 5,10b-hexahydro-2H - chromeno[4,3-b]pyridine isomer 4 (A57 isomer 4) (210 mg, 15.6%) as a white solid with retention time at 15.2 min.

[1228] rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-niethyl-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine isomer 1 (A57 isomer 1): MS ESI calculated for C14H17F2NO2 [M+H]*, 270. 12; found, 270, 15. ^;H NMR (400 MHz, DMSO-cfc) 5 7.36 - 6.99 (m, 2H), 6.64 (dd, J = 8.4, 2.8 Hz, IH), 6.55 (d, J = 2.8 Hz, IH), 4.49 - 4.43 (m, IH), 3.97 - 3.91 (m, IH), 3.66 (d, J = 3.2 Hz, IH), 2.76 - 2.69 (m, 1H), 1.99 - 1.94 (m, 2H), 1.83 - 1.71 (m, 2H), 1.40 - 1.32 (m, IH), 0.98 (d, J = 6.4 Hz, 3H).

[1229] rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-methyl-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine isomer 2 (A57 isomer 2): MS ESI calculated for CirHnFzNCh [M+l ]⁺, 270.12; found, 270.15. *H NMR (400 MHz. DMSO-d₆) 8 7.46 (dd, J= 8.8, 1.2 Hz, IH), 7.17 (t, 74.4 Hz, IH), 6.66 (dd, J= 8.4, 2.4 Hz, IH), 6.53 (d, J = 2.4 Hz, IH), 4.34

(d, J = 4.4 Hz, IH), 4.15 (dd, J = 10.8, 3.6 Hz, IH), 3.89 - 3.82 (m, IH), 3.43 - 3.40 (m, IH), 2.79 - 2.69 (m, IH), 2.17 (s, HI), 1.78 - 1.65 (m, 2H), 1.58 - 1.45 (m, IH), 1.09 (d, J= 6.4 Hz, 3H).

[1230] rel-(2R,4aS,10bR)-8-(difluoromethoxy)-2-niethyl-1 ,3, 4, 4a, 5,10b-hexahydro-2H- chromeno[4,3-b]pyridine isomer 3 (A57 isomer 3): MS ESI calculated for C14H17F2NO2 [M+H]⁺, 270.12: found, 270.15. ^!H NMR (400 MHz, DMSO-rfc) 3 7.47 (dd, 7 = 8.4, 1.2 Hz, IH), 7.17 (t, J = 74.4 Hz, IH), 6.66 (dd, J = 8.4, 2.8 Hz, IH), 6.53 (d, J = 2.4 Hz, IH), 4.15 (dd, J = 10.4, 3.6 Hz. IH), 3.85 (t, J = 12.0 Hz, IH). 3.43 - 3.32 (m, 2H), 2.74 (s, IH), 2.17 (s, IH), 1.76 - 1.68 (tn, 2H), 1.58 - 1.45 (m, IH), 1.09 (d, ./ = 6.4 Hz, 3H). [1231] rel-(2R,4aS,10bR)-8-(diiluoromethoxy)-2-methyl-l,3,4,4a,5,10b-hexahydro-2H- chromeno[4,3-b]pyridine isomer 4 (A57 isomer 4): MS ESI calculated for Cj^lnFzNOi [M+H?, 270.12; found, 270.15. ^!H NMR (400 MHz, DMSO- d&) 5 7.36 - 6.99 (m, 2H), 6.64 (dd, 7 = 8.4, 2.8 Hz, IH), 6.55 (d, 7= 2.4 Hz, 1H), 4.49 - 4.43 (m, IH), 3.98 - 3.92 (m, IH), 3.67 - 3.64 (m, IH), 2.76 - 2.68 (m, IH), 2.05 - 1.68 (m, 4H), 1.40 - 1.34 (m, IH), 0.98 (d, 7 = 6.0 Hz, 3H }.

Intermediate ASS: 1:1 mixture of (4aR,9bR)-7-methoxy-l ,2, 3.4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine and (4aS,9bS)-7-methoxy- 1 , 2, 3, 4, 4a, 9b- hexahydrobenzofuroj 3,2-b]pyridine

A58

Step- 1 :

[1232] To a stirred solution of (2-fluoro-4-methoxyphenyl)boronic acid (10 g, 58.84 mmol) and 2-bromo-3-(methoxymethoxy)pyridine (12.83 g, 58.84 mmol) in 1,4-dioxane (200 mL) were added K2CO3 (24.40 g, 176.52 mmol) and PdfdppflCh-CHzCh (4.81 g, 5.88 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine, dried over anhydrous NazSO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0- 40% ethyl acetate in petroleum ether to afford 2-(2-fluoro-4-methoxyphenyl)-3- (methoxymethoxy)pyridme (13.1 g, 84% yield) as a brown oil. MS ESI calculated for Cl 4H_!4FNO₃ [M-t-HJ y 264.10; found, 264.30. Step-2:

[1233] To a stirred solution 2-(2-fluoro-4-methoxyphenyl)-3-(methoxymethoxy)pyridine (13.1 g. 49.75 mmol) in DCM (90 ml_) was added trifluoroacetic acid (56.74 g, 497.59 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum to afford 2-(2- fluoro-4-methoxyphenyl)pyridin-3-ol (23.3 g, crude) as a brown oil. The crude product was used in the next step directly without further purification. MS ESI calculated for C12H10FNO2 [M+H]⁺, 220.07: found, 220.00.

Step-3:

[1234] To a stirred solution of 2-(2-fluoro-4-methoxyphenyl)pyridin-3-ol (23.3 g, 106.28 mmol) was added K2CO3 (44.07 g, 318.86 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120 °C overnight. The reaction was quenched with water at. room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCfi- After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography with a 330 g silica gel column eluted with 0-40% ethyl acetate in petroleum ether to afford 7-methoxybenzofuro[3,2-b]pyridine (9 g, 42% yield) as a light yellow solid. MS ESI calculated for C12H9NO2 [M+H]⁺, 200.06; found, 199.95.

Step-4:

[1235] To a stirred solution of 7-methoxybenzofuro[3,2-b]pyridine (2 g, 10.04 mmol) in toluene (20 ml) was added diphenylamine (6.80 g, 40.16 mmol), 4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (6.42 g, 50.20 mmol) and tris(pentafluorophenyl)boraiie (0.51 g, 1.00 mmol) at room temperature. The resulting mixture was stirred at 110 °C overnight. The reaction mixture was quenched by the addition of water and basified with NaHCOs (sat.) to pH ~8, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography eluted with 0- 24% methanol in dichloromethane to afford a 1: 1 mixture of (4aR,9bR)-7-methoxy- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine and (4aS,9bS)-7 -methoxy- 1,2,3, 4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine (A58) (1.12 g, 54% yield) as a yellow solid. MS ESI calculated for CirH^NO?. [M+H]T 206.11; found, 206.05. ^!H NMR (300 MHz, DMSO-&) 8 7.26 - 6.98 (m, 1H), 6.43 - 6.40 (m, 2H), 4.42 - 4.37 (m, 1H), 4.10 (d, J = 5.8 Hz, 1H), 3.71 (s, 3H), 2.72 - 2.43 (m, 2H), 2.08 - 1.76 (m, 2H), 1.56 - 1.26 (m, 2H).

Intermediate A58 isomer 1: rei-(4aR,9bR)-7-methoxy-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-bjpyridine isomer 1

Isomer i _a<

Intermediate A58 isomer 2: rel-(4aR,9bR)-7-metboxy-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2

isomer 2

[1236] 1:1 mixture of (4aR,9bR)-7 -methoxy- 1,2, 3, 4,4a, 9b-hexahydrobenzofuro[3, 2- bjpyridine and (4aS,9bS)-7-methoxy-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-bjpyridine (A58) (4.6 g, 22.411 mmol) was separated by prep-chiral SFC with the following conditions:

[Column: CHIRALPAK IG, 7*25cm, 10 pm; Mobile Phase A: CO?, Mobile Phase B: MEOH (0.1% 7M NHj-MeOH); Flow rate: 250 mL/min: Gradient (B%): isocratic 2.5% B; Column Temperature ('C): 35; Back Pres sure( bar): 100; Wave Length: 220 nm; RTl(min): 9.23;

RT2(min): 12.39; Sample Solvent: MEOH] to afford rel-(4aR,9bR)-7-me-thoxy-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 (A58 isomer 1) (1.45 g, 31% yield) as a yellow solid with retention time at 9.23 minute. MS ESI calculated for CIJHJSNO? [M+H]⁺, 206.1 1 ; found, 206.05. ’H NMR (300 MHz, DMSO-rfc) 5 7.26 - 6.98 (m, 1H), 6.43 - 6.40 (m, 2H), 4.42 - 4.37 (m, 1H), 4.10 (d, 5.8 Hz, 1H), 3.71 (s, 3H), 2.72 - 2.43 (m, 2H), 2.08 - 1.76

(tn, 2H), 1.56 - 1.26 (m, 2H). Absolute stereochemistry -was not determined. [1237] The chiral resolution also afford rel-(4aR,9bR)-7-methoxy-l,2,3,4,4a,9b- hexaliydrobenzofuro[3,2-bjpyridine isomer 2 (A58 isomer 2) (1.8 g, 39% yield) as a yellow solid with retention time at 12.39 minute. MS ESI calculated for C12H15NO2 [M+H]⁺, 206. 1 1 ; found, 206.05. *H NMR (300 MHz, DMSO-ifc) 6 7.26 - 6.98 (m, 1H), 6.43 - 6.40 (m, 2H), 4.42 - 4.37 (m, 1H), 4.10 (d, J - 5.8 Hz, 1H), 3.71 (s, 3H), 2.72 - 2.43 (m, 2H), 2.08 - 1.76

(m, 2H), 1.56 - 1.26 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A59: 1 : 1 mixture of rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-methyl- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-7- (difluoromethoxy)-3-methyl-1 ,2,3, 4,4a, 9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2

Step-1: [1238] To a mixture of (2,4-dimethoxyphenyl)boronic acid (10.05 g, 55.22 mmol), 2- chloro-3-fluoro-5-methy1pyridine (8.84 g, 60.74 mmol), Pd(dppf)C12-CH2C12 (2.25 g. 2.75 mmol) and K2CO3 (11.45 g, 82.84- mmol) in Dioxane (100 ml) was added Water (10 mL).

The mixture was stirred at 100 °C for 1 h. The solvents were removed under vacuum and purified directly. The resulting residue was purified by normal phase flash chromatography using a 330 g silica gel column eluted with 0-40% ethyl acetate in petroleum ether within 20 min to afford 2-(2,4-dimethoxyphenyl)-3-fluoro-5 ■methylpyridine (11.10 g, 81%) as a yellow solid. MS ESI calculated for C14H14FNO2 [M+H]⁺, 248.10; found, 248.05.

Step-2:

[1239] To a stirred solution of 2-(2,4-dimethoxyphenyl)-3-fluoro-5-methylpyridine (11.10 g, 44.48 mmol) in DCM (110 mL) was added a solution of BBi ■ (IM in DCM) (135 mL, 135.00 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction was quenched with water and basified to pH '7 with saturated NaHCOj (aq.). The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaiSO4, filtered, and concentrated under vacuum. The residue was purified bysilica gel column chromatography, eluted with PE / EtOAc (3: 1) to afford 4-(3-fluoro-5- methylpyridin-2-yl)benzene-l,3-diol (6.0 g, 61%) as a yellow solid. MS ESI calculated for C12HI0FNO2 i M - H l . 220.07; found, 220.00.

Step-3:

[1240] To a stirred solution of 4-(3-fluoro-5-methylpyridin-2-yi)benzene-1 ,3-diol (6.0 g, 27.37 mmol) in N-methyl-2-pyrrolidone (60 mL) was added t-BuOK (6.14 g, 54.74 mmol) at room temperature. The resulting solution was stirred at 150 °C for 3 h. The reaction was cooled to 0 °C and acidified with HO (aq., 2N) to pH ~7. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by Combi Flash with a 330 g C 18 column, eluted with 5-80% acetonitrile in water (10 mM NH4HCO3) to afford 3-methylbenzofuro[3,2-bJpyridin-7-ol (3.8 g, 70%) as a yellow solid. MS ESI calculated for C12H9NO2 [M+H]⁺, 200.05; found, 200.06.

Step-4:

[1241] To a stirred solution of 3-methylbenzofuro[3,2-b]pyridin-7-ol (3.8 g, 19.07 mmol) and K2CO3 (15.82 g, 1 14.45 mmol) in DMF (50 mL.) was added sodium 2-chloro-2,2- difluoroacetate (11.63 g, 76.30 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 5 h. The resulting mixture was filtered, the filler cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography with a 120 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether to afford 7-(difluoromethoxy)-3-methylbenzofuro[3,2-b]pyridine (1.7 g, 28%) as a brown solid. MS ESI calculated for C13H9F2NO2 [M+H]⁺, 250.06; found, 250.00. Isomer 1 Isomer 2

A59

[1242] To a 40 inL of screw cap vial was placed a solution of 7-(difluorometlioxy)-3- methylbenzofuro[3,2-b]pyridine (500 mg, 2.00 mmol) and N-phenylaniline (2.03 g, 12.01 mmol) in toluene (8 mL). Then 4,4,5,5-tetamethyl-l ,3,2-dioxaboro1ane (1.29 g, 10.15 mmol) and tris(pentafluorophenyl)borane (103 mg, 0.20 mmol) were added at room temperature.

The resulting mixture was stirred at 110 °C for 4 h under nitrogen atmosphere. The reaction was cooled to room temperature and quenched with water. The mixture was quenched with NaHCOj (sat.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by Combi Flash with a 40 g silica gel column eluted with 0-25% methanol in dichloromethane to afford a 1 :1 mixture of rel-(3R,4aS,9bS)-7- (difluoromethoxy )-3-methyl-l, 2, 3,4, 4a,9b-bexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-7-(difluoromeihoxy)-3-methyl-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine isomer 2 (350 mg, 23%) as a yellow oil. MS ESI calculated for C13H15F2NO2 [M+H]⁺, 256.1 1 : found, 256.15. ^!H NMR (400 MHz, DMSO) 5 7.45 - 6.92 (m, 2H), 6.76 - 6.57 (m, 2H), 4.45 - 4.40 (m, 1H), 3.99 (d, 4.8 Hz, 1H), 2.73 - 2.59 (m, 1H), 2,23 - 2.15 (m, 1H), 2.13 - 2.05 (m, 2H), 1.66 - 1.54 (m, 1H), 1.53 - 1.44 (m, 1H), 0.83 (d, 7 = 6.4 Hz,

3H). Stereochemistry was not determined.

Intermediate A59 isomer 1: rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-methyl- 1,2,3, 4,4a, 9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 and,

Intermediate A59 isomer 2: rel-(3R,4aS,9bS)-7-(difluoromethoxy)- -3 -methyl- 1,2,3 ,4,4a, 9b hexahydrobenzofuro[3,2-b]pyridine isomer 2 isomer 2

At>9 isomer 2

[1243] A 1:1 mixture of rei-(3R,4aS,9bS)-7-(difluoromethoxy)-3-niethyl- 1,2,3, 4, 4a, 9b- hexaiiydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3- methyl-L2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2 (350 mg) was separated by prep-chiral HPLC with the following conditions: [Column: CHIRAL PAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1 -HPLC; Flow rate: 20 rnL/min; Gradient (B% ): 15% B to 15% B in 10.5 min; Wave Length: 220/254 nm; RTl(min): 5.894; RT2(min): 8.921; Sample Solvent: MeOH: DCM=1: 1-HPLC] to afford rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-methyl- 1,2, 3, 4, 4a, 9b- hextdiydrobenzofuro[3,2-b]pyridine isomer 1 (A59 isomer 1) (70 mg, 20%) as a white solid with retention time at 5.894 minute. MS ESI calculated for CBHJSFINOS [M+H]⁺, 256.11; found, 256.10. *H NMR (400 MHz, DMSO) 6 7.45 - 6.92 (m, 2H), 6.76 - 6.57 (m, 2H), 4.45 - 4.40 (m, lH), 3.99 (d, J = 4.8 Hz, 1 H), 2.73 - 2.59 (m, 1H), 2.23 - 2.15 (m, 1 H), 2.13 - 2.05 (m, 2H), 1.66 - 1.54 (m, H i ). 1.53 - 1.44 (m, 1H), 0.83 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was not determined.

[1244] The separation also afford rel-(3R,4aS,9bS)-7-(diiluoromethoxy)-3-nielhyl-

1,2,3, 4,4a, 9b-hexaliydrobenzofuro[3,2-b]pyridine isomer 2 (A59 isomer 2) (80 mg, 23%) as a white solid with retention time at 8.921 min. MS ESI calculated for C13H15F2NO2 [M+H]⁺, 256.11; found, 256.15. ^!H NMR (400 MHz, DMSO) 5 7.45 - 6.92 (m, 2H), 6.76 - 6.57 (m, 2H), 4.45 - 4.40 (m, 1H), 3.99 (d, 7 = 4.8 Hz, 1H), 2.73 - 2.59 (m, 1H), 2.23 - 2.15 (m, 1H), 2.13 - 2.05 (m, 2H), 1.66 - 1.54 (m, 1 H), 1 .53 - 1.44 (m, 1H), 0.83 (d, J= 6.4 Hz, 3H).

Absolute stereochemistry was not determined.

Intermediate A60: 1 : 1 :3:3 mixture of rel-(4R,4aR,9bR)-7-chloro-4-methyl- 1 , 2,3,4, 4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(4R,4aR,9bR)-7-chloro-4-melhyl- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2 and rel-(4R,4aR,9bR)-7-chloro-4- methyl-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 3 and rel-(4R,4aR,9bR)-7- chloro-4-methyl- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 4 isomer 1 isomer 2 isomer 3 isomer 4

A60

Step-1:

[1245] To a stirred mixture of (4-ch1oro-2-hydroxyphenyl)boronic acid (6.60 g, 38.29 mmol) in 1,4-dioxane (120 mL) and H?O (12 mL) were added 2-chloro-3-lluoro-4- methylpyridine (5.57 g, 38.29 mmol), K2CO3 (15.88 g, 114.87 mmol) and Pd(dppf)Ch (2.80 g, 3.83 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 4 h. The resulting mixture was quenched -with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO<i. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford 5-chloro-2-(3-fIuoro-4-metbylpyridin-2-yl)phenol (4.80 g, 52%) as a green solid. MS ESI calculated for C12H9CIFNO [M+H]⁺, 238.04; found, 238.05. Step-2:

[1246] The mixture of 5-chloro-2-(3-fluoro-4-methyipyridin-2-yl)phenol (4.80 g, 20.20 mmol) and K2CO3 (8.37 g, 60.59 mmol) in DMF (50 mL) was stirred at 120 °C for 2 h under nitrogen atmosphere. The reaction mixture was allowed to cool down to room temperature. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NajSO.j. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-25% ethyl acetate in petroleum ether to afford 7- chloro-4-methylbenzofuro[3,2-b]pyridine (3.30 g, 75%) as a white solid. MS ESI calculated for Ci₂H₈ClNO [M+H]⁺, 218.03: found, 217.95.

Step-3: isomer 1 isomer 2 isomer 3 isomer 4

A60

[1247] To a stirred solution of 7-chloro-4-methylbenzofuro[3,2-b]pyridine (3.50 g. 16.08 mmol) in toluene (50 mL) were added PhjNH (10.89 g, 64.32 mmol), HBpin (10.29 g, 80.41 mmol) and BfCeFsh (0.82 g. 1.61 mmol) at room temperature under nitrogen atmosphere.

The resulting mixture was stirred at 110 °C for 16 h. The mixture was allowed to cool down to room temperature and quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NajSOr- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography with 5% to 60% MeCN in Water (0. 1% TFA) to afford a 1: 1:2:2 mixture of rei-(4R,4aR,9bR)-7-chloro-4-methyl-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(4R.4aR,9bR)-7-chloro-4-methyl- 1 ,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2 and rel-(4R,4aR,9bR)-7-chloro-4- ffiethyl-l,2.3,4.4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 3 and rel-(4R,4aR,9bR)-7- chloro-4-methyb-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridme isomer 4 (A60) (3.07 g, 85%) as a white solid. MS ESI calculated for C12H14CINO [M+H]⁺, 224.08; found, 224.00.

Intermediate AGO isomer 1: rel-(4R,4aR,9bR)-7-chloro-4-methyl-l,2,3,4,4a,9b- hexahydrobeiizofuro|3,2-b]pyridine isomer 1

Intermediate AGO isomer 2: rel-(4R,4aR,9bR)-7-chloro-4-methyl-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2 isomer 2 _and)

Intermediate AGO isomer 3: rel-(4R,4aR,9bR)-7-chloro-4-methyM,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 3 isomer 3 _and

Intermediate AGO isomer 4: rel-(4R,4aR,9bR)-7-chloro-4-methyl-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 4

[1248] The 1: 1:2:2 mixture of rel-(4R,4aR, 9bR)-7-chloro-4-methyl-l, 2,3,4, 4a, 9b- hexahydrobenzofuro[3,2-blpyridine isomer I and rel-(4R,4aR,9bR)-7-chloro-4-meihyl- 1 ,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2 and rel-(4R,4aR,9bR)-7-chloro-4- niethyl- •l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-bjpyridine isomer 3 and rel-(4R,4aR,9bR)-7- chloro-4-methyl-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 4 (A60) (3.0 g) was separated by Prep-Achiral-SFC with the following conditions: [Column: DAICEL DCpak P4VP 3*25 cm, 5 pm; Mobile Phase A: CCh, Mobile Phase B: MeOH(20mM NH₃); Flow rate: 60 mL/min; Gradient: isocratic 22% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 254 nm; RTl(min): 4.24; RT2(min): 5.04; Sample Solvent: MeOH— HPLC; Injection Volume: 1.5 mL; Number Of Runs: 18.0] to afford fraction A (380 mg) with retention time at 4.2.4 minute and fraction B (660 mg) with retention time at 5.04 minute.

[1249] The fraction A was separated by Prep-Chiral -HPLC with the following conditions: [Column: CHIRALPAK AS-H, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH₃- MeOH), Mobile Phase B: MeOH: EtOH=l : 1-HPLC; Flow rate: 20 mL/min; Gradient: 1% B to 1% B in 8 min; Wave Length: 220/254 nm; RTl(min): 5.82; RT2(rnin): 6.07; Sample Solvent: EtOH: DCM=1 : 1— HPLC; Injection Volume: 0.17 ml..; Number Of Runs: 28] to afford rel-(4R,4aR,9bR) -7 -chloro-4-methyl- 1 ,2,3 ,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 1 (A60 isomer 1) (100 nig) as a yellow solid with shorter retention time and rel- (4R,4aR,9bR)-7-chloro-4-methyI- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2 (A60 isomer 2) (120 mg) as a yellow solid with longer retention time.

[1250] rel-(4R,4aR,9bR)-7-chloro-4-methyl-L2,3,4,4a,9b-hexahydrobenzofuro[3,2- b]pyridine isomer 1 (A60 isomer 1): MS ESI calculated for C12H14CINO [M+H]⁺, 224.08; found, 224.10. ’H NMR (400 MHz, DMSO-cfc) 5 7.34 (d, J - 7.9 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H), 6.97 (dd, J = 7.9, 1.9 Hz, 1H), 4.40 (t, 7 - 4.3 Hz, 1H), 4.30 (d, 7 - 5.1 Hz, 1H), 2.86 - 2.77 (m, 1H), 2.69 - 2.61 (m, I H), 2.10 - 1.98 (m, 1H), 1.58 - 1.50 (nt, 1H), 1.32 - 1.22 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H). Absolute stereochemistry was not determined.

[1251] rel-(4R,4aR,9bR)-7-chloro-4-methyl-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine isomer 2 (A60 isomer 2): MS ESI calculated for C12H14CINO [M+H]⁺, 224.08; found, 224.10. ’H NMR (400 MHz, DMSO-zfc) 5 7.34 (d, J - 7.9 Hz, 1H), 7.03 (d, 7 = 1.9 Hz, 1H), 6.97 (dd, 7 - 7.9, 1.9 Hz, 1H), 4.40 (t, 7 = 4.3 Hz, 1H), 4.30 (d, J - 5.1 Hz, 1H), 2.86 - 2.77 (m, 1H), 2.69 - 2.61 (m, 1H), 2.10 - 1.98 (m, 1H), 1.58 - 1.50 (m, 1H), 1.32 - 1.22 (m, 1H), 1.14 (d, J ~ 6.9 Hz, 3H). Absolute stereochemistry was not determined.

[1252] The fraction B (450 mg) was separated by Prep-Chiral -HPLC with the following conditions: [Column: CH1RALPAK IG, 2*25 cm, 5 pro; Mobile Phase A: Hex(0.5% 2M NHs-MeOH), Mobile Phase B: EtOH: DCM-1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 10% B to 10% B in 12 min; Wave Length: 220/254 nm; RTl(min): 8.75: RT2(min): 10.33; Sample Solvent: EtOH: DCM-1: 1-HPLC; Injection Volume: 0.2 mL; Number Of Runs: 26] to afford rel-(4R,4aR,9bR)-7-chloro-4-methyl-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine isomer 3 (A60 isomer 3) ( 140 mg) as a yellow solid with shorter retention time and rel-(4R,4aR,9bR)-7-chloro-4-methyl-l ,2,3,4,4a,9b-hexahydrobenzofiiro[3,2-b]pyridine isomer 4 (A60 isomer 4) (160 mg) as a yellow solid with longer retention time.

[1253] rel-(4R,4aR,9bR)-7-chloro-4-methyl-l,2,3,4,4a,9b-hexaliydrobenzofuro[3,2- bjpyridine isomer 3 (A6(i isomer 3): MS ESI calculated for C12H14CINO [M+H]*, 224.08; found, 224.10. *H NMR (400 MHz, DMSO-tfc) 6 7.31 (d, 7 - 8.5 Hz, 1H), 7.00 - 6.93 (m, 2H), 4.60 (d, 7 = 7.2 Hz, 1H), 4.28 (t, 7 - 7.4 Hz, 1H), 2.87 - 2.79 (m, 1H), 2.71 - 2.63 (m, 1H), 1.87 - 1.75 (m, 1H), 1.67 - 1.57 (m, 1H), 1.28 - 1.14 (m, 1H). 1.08 (d, ./ - 6.8 Hz, 3H). Absolute stereochemistry was not determined. [1254] rel-(4R,4aR,9bR)-7-chloro-4-methyl-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine isomer 4 (AGO isomer 4): MS ESI calculated for C12H14CINO fM+H] ⁺, 224.08; found, 224.10. ^JH NMR (400 MHz, DMSO-d₆) 5 7.31 (d, J = 8.5 Hz, 1H), 7.00 - 6.93 (m, 2H), 4.60 (d, J = 7.2 Hz, 1 H), 4.28 (t, J = 7.4 Hz, 1H), 2.87 - 2.79 (m, 1 H), 2.71 - 2.63 (m, 1H), 1.87 - 1.75 (m, 1H), 1.67 - 1.57 (m, 1H), 1.28 - 1.14 (m, 1H), 1.08 (d, J - 6.8 Hz, 3H)

Absolute stereochemistry was not determined.

Intermediate A61 : (2R,4aR, 10bS)-8-chloro-2-methyl-2,3 ,4a, 5 ,6, 1 Ob-hexahydro- 1 H-

[l,4]oxazino[2,3-h]isoquinoline

Step- 1 :

[1255] To a stirred solution of 3-chloro-6,7-dihydroisoquinolin-8(5H)-one (5.0 g, 27.5 mmol) in methanol (100 mL) was added NaBHi (1.56 g, 41 .3 mmol) at 0 ^CC. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water, and the methanol was removed under reduced pressure. The remained mixture was extracted with ethyl acetate. The organic layers were dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. This resulted in a 1:1 mixture of (R)-3- chloro-5,6,7,8-tetrahydroisoquinoIin-8-ol and (S)-3-chloro-5,6,7,8-tetrahydroisoquinolin-8-ol (5.7 g, crude) as a yellow oil. MS ESI calculated for C9H10CINO [M+H]⁺, 184.05; found, 184.15.

Step-2:

[1256] A solution of a 1: 1 mixture of (R)-3-chIoro-5,6,7,8-tetrahydroisoquinolin-8-ol and (S)-3-chloro-5,6,7,8-tetrahydroisoquinolin-8-ol (27.0 g, 147 mmol) in PPA (300 mL) was stirred at 120 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched with water. The mixture was basified to PH 7-8 with Na^COa (sat.) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na^SCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford 3-chloro-5,6-dihydroisoquinoline (5.8 g, 23%) as a colorless liquid. MS ESI calculated for CLILCTN [M+H]⁺, 166.03; found, 166.15.

Step-3 :

[1257] To a stirred solution of tert-butyl carbamate (10.3 g, 87.9 mmol) in propan-l -ol (220 ml..) w'as added a solution of a solution of NaOH (3.06 g, 76.6 mmol) in H2O (190 mL) at room temperature and then stirred for 15 minutes. l,3-dichloro-5,5-dimethylimidazolidine- 2, 4-dione (8.39 g, 42.5 mmol) was added to the mixture, the mixture was stirred at room temperature for 30 minutes. Then (DHQJ2PHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (2.21 g, 2.83 mmol), 3-chloro-5.6-dihydroisoquinoline (4.70 g, 28.3 mmol) and Potassium osmate(VI) dihydrate (1 .05 g, 2.83 mmol) were added to the mixture. The mixture w'as stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate. The organic layers were dried over anhydrous NajSCL- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions [Column: XBridge Prep OBD CI S Column, 30* 150 mm, 5pm;

Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2/% B to 47% B in 14 min; Wave Length: 254/220 nm; RTl(min): 9] to afford a 1:4 mixture of tert-butyl ((7R.8S)-3-chloro-7-hydroxy-5,6,7,8-tetrahydroisoquinolin- 8-yl)carbamate and tert-butyl <.(7S, 8R)-3-chloro-7-hydroxy -5,6,7, 8-tetrahydroisoquino1in-8- yl)carbamate (3.7 g, 43%) as a grey solid. MS ESI calculated for C14H19CIN2O3 [M+H] ⁺, 299.11; found, 299.05.

Step-4:

[1258] To a solution of a 1 :4 mixture of tert-butyl ((7R,8S)-3-chloro-7-hydroxy-5, 6,7,8- tetraliydroisoquinolin-8-yl)carbamate and tert-butyl ((7S, 8R)-3-chloro-7-hydroxy-5, 6,7,8 - tetrahydroisoquinolin-8-yl)carbamale (2.70 g, 9.03 mmol) in DCM (30 mL) were sequentially added (Bu4N)HSO4 (613 mg, 1.80 mmol), NaOH (2.53 g, 63.2 mmol) and (4S)- 4-methyl-1 , 3, 2-X-6-dioxathiolane-2, 2-dione (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1) (1.62 g, 11.7 mmol). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and neutralized with HC1 (aq. ) to PH~7. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.

[1259] The residue was dissolved in 2-methoxy-2-methy1propane (21 mL) and H2O (0.07 mL), than TsOH (17 mg, 0.10 mmol) and 1,4-dioxane (0.6 mL) were added. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure. Tire residue was dissolved in methanol (30 mL), this was followed by the addition of EtiN (2.74 g, 27.1 mmol) and BOC2O (2.96 g, 13.5 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-60% ethyl acetate in petroleum ether to afford a 1:4 mixture of tert-butyl ((7R,8S)-3-chloro-7-((S)- 2-hydroxypropoxy)-5,6,7,8-tetrahydroisoquinolin-8-yl)carbamate and tert-butyl ((7S,8R)-3- chloro-7-((S)-2-hydroxypropoxy)-5,6,7,8-tetrahydroisoquinolin-8-yl)carbamate (2.85 g, 88%) as a white solid. MS ESI calculated for C17H25GN2O4 [M+H]⁺, 357.15; found, 357.05.

Step-5:

[1260] To a stirred solution of a 1:4 mixture of tert-butyl ((7R,8S)-3-chloro-7-((S)-2- liydroxypropoxyj-5,6,7,8“tetrahydroisoquinolin-8-yl)carbamate and tert-butyl ((7S,8R)-3- chloro-7-((S)-2-hydroxypropoxy)-5,6,7,8-tetrahydroisoquinolin-8-yl)carbamate (3.75 g, 10.5 mmol) and TEA (4.25 g, 42.0 mmol) in DCM (40 mL) was added MsjO (3.11 g, 17.8 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with DCM. The organic layers were dried over anhydrous NazSCU After filtration, the fillrate was concentrated under reduced pressure.

[1261] The residue was dissolved in DCM (30 mL), and then TFA (10 mL) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was dissolved in MeCN (120 mL), and then 1 ,2, 2,6,6- pentamethylpiperidine (21.1 g, 136 mmol) was added. The resulting solution was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions [Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 pm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACM; Flow rate: 60 mL/'min: Gradient (B%): 5% B to 40% B in 12mm; Wave Length: 254/220 nm; RTl(min): 8.1 ; RT2(min): 9.1 ] to afford (2R,4aR, 10bS)-8-ch]oro-2-methyl- 2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[2_>3-h]isoquinoline ( A61) (290 mg, 10%) as a white solid as the first eluting peak by Prep-HPLC. MS ESI calculated for C12H15CIN2O [M+H]⁺, 239.09: found, 239.15. ‘H NMR (400 MHz, DMSCMs) 6 8.29 (s, 1H), 7.27 (s, 1H), 3.94 - 3.89 (rm 1H), 3.87 - 3.81 (m, 1 H), 3.47 - 3.40 (ra, 1H), 3.20 (t, J = 10.4 Hz, 1H), 2.97 - 2.87 (m, 2H), 2.81 - 2.71 (m, 1H), 2.63 - 2.52 (m, 1H), 1 .59 - 1 .50 (rn, 1H), 0.86 (d, J = 6.4 Hz. 3H). Absolute stereochemistry was determined by NOESY.

Intermediate A62: (2R,4aR,10bS)-8-bromo-2-methyl-2,3,4a,5,6,1 Ob-hexahydro-1 H-

[1,4] ox azi no [2 , 3 -h ] quinoli ne

A62

Step-1 :

[1262] To a stirred solution of 3-bromo-6,7-dihydroquinolin-8(5H)-one (4.30 g, 19. 11 mmol) in methanol (40 mL) was added NaBHi (863 mg, 22.93 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SCU. After filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of (R)-3-bromo-5,6,7,8-tetrahydroquinolin-8-ol and (S)-3-bromo- 5,6,7,8-tetrahydroquinolin-8-ol (4.34 g, crude) as a colorless oil. MS ESI calculated for CyHioBrNO [M+H]⁺, 227.99, 229.99; found, 228.00, 229.95.

Step-2:

[1263] A solution of a 1: 1 mixture of (R)-3-bromo-5,6,7,8-tetrahydroquinolin-8-ol and (S)- 3-bromo-5,6,7,8-tetrahydroquinolin-8-ol (4.34 g, 19.11 mmol) in PPA (30 mL) was stirred at 120 °C for 1 h. The mixture was allowed to cool down to room temperature and quenched with water. The mixture was basified with saturated Na^COs (aq.) to PH 7~8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NasSCU After filtration, the filtrate was concentrated under reduced pressure to afford 3-bromo-5,6-dihydroquinoline (3.70 g, crude) as a colorless oil. MS ESI calculated for CyllsBrN [M-t-HJL 209.98, 21 1.98; found, 209.95, 211.95.

Step-3 :

[1264] To a stirred solution of 3-bromo-5,6-dihydroquinoline (3.70 g, 17.61 mmol) in DMSO (40 mL) and HiO (8 mL) was added NBS (3.76 mg, 21.13 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (6 mL), then ammonium hydroxide (28% in water) (60 mL) was added. The mixture was stirred at room temperature for 20 h. The resulting mixture was concentrated under reduced pressure to afford a 1:1 mixture of (7S,8S)-8-amino-3-bronio- 5,6,7,8-tetrahydroquinolin-7-ol and (7R,8R)-8-amino-3-bromo-5,6,7,8-tetrahydroquinolin-7- ol (5.47 g, crude) as a brown solid. MS ESI calculated for CoHuBrNLO [M+H]⁺, 243.01, 245.01; found, 243.00, 245.00.

Step-4:

[1265] To a stirred solution of a 1: 1 mixture of (7S,8S)-8-amino-3-bromo-5, 6,7,8- tetrahydroquinolin-7-ol and (7R,8R)-8-amino-3-bromo-5,6,7,8-tetrahydroquinolin-7-o1 (4.20 g, 17.28 mmol) in DCM (50 mL) were added TEA (5.24 g, 51.83 mmol) and benzoyl chloride (2.67 g, 19.00 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% methanol in dichloromethane to afford a 1: 1 mixture of N-((7S,8S)-3-bromo-7-hydroxy-5,6,7,8-telrahydroquinolin-8-y1)benzamide and N-((7R,8R)- 3-bromo-7-hydroxy-5,6,7,8-tetrahydroquinohn-8-yl)benzamide (5.90 g, 98%) as a brown solid. MS ESI calculated for CWTsBrN^Ch [M+H]⁺, 347.03, 349.03; found, 347.05, 349.00.

[1266] To a stirred solution of a 1 : 1 mixture of N-((7S,8S)-3-bromo-7-hydroxy-5, 6,7.8- tetrahydroquinolin-8-yl)benzamide and N-((7R,8R)-3-bromo-7 -hydroxy-5, 6,7,8- tetrahydroquinolin-8-yl)benzamide (5.70 g, 16.43 mmol) in DCM (60 niL) was added SOCh (3.88 g, 32.85 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr- After filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of (3aR,9bS)-7-bromo-2-phenyl- 3a,4,5,9b-tetrahydrooxazolo[5,4-h]quinoline and (3aS,9bR)-7-bromo-2-phenyl-3a,4,5,9b- tetrahydrooxazolo[5,4-h]quinoline (5.50 g, crude) as a brown oil. MS ESI calculated for Ci6H_!3BrN₂O [M+HJ⁺, 329.02, 331.02: found, 328.95, 331.00.

Step-6:

[1267] To a mixture of a 1:1 mixture of (3aR,9bS)-7-bromo-2-phenyl-3a,4 ,5,9b- tetrahydrooxazolo|5,4-h]quinoline and (3aS,9bR)-7-bromo-2-phenyl-3a,4,5,9b- tetrahydrooxazolo[5,4-h]quinoline (5.00 g, 15.19 mmol) in FLO (25 mL) and 1 ,4-dioxane (25 mL) was added HC1 (cone.) (25 mL). The resulting mixture was stirred at 80 °C for 16 h. After cooling drown, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (60 mL), and then TEA (7.59 g, 74.38 mmol) and BociO (8. 1 1 g, 37. 19 mmol) were added at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl ((7R,8S)-3-bromo-7-hydroxy-5, 6,7,8- tetrahydroquinolin-8-yl)carbamate and tert-butyl ((7S, 8R)-3-bromo-7-hydroxy-5, 6,7,8- tetrahydroquinolin-8-yl)cafbamate (1.00 g, 12%) as a yellow oil. MS ESI calculated for Ci4Hi9BrN2O₃ [M+H]⁺, 343.06, 345.06; found, 343.05, 345.00.

Step-7 :

[1268] To a stirred solution of a 1 :1 mixture of tert-butyl ((7R,8S )-3-bromo-7 -hydroxy- 5,6, 7, 8-tetrahydroquinolin-8-yl)carbamate and tert-butyl ((7S,8R)-3-bromo-7-hydroxy- 5,6,7,8-tetrahydroquinolin-8-yl)carbamate (940 mg, 2.74 mmol) in DCM (10 mL) were added (BtuNlHSOa (186 mg, 0.55 mmol), NaOH (767 mg, 19.17 mmol) and (4S)-4-methyl- l,3,2-X-6-dioxathiolane-2,2-dione (supplier: Suzhou spark Biotechnology Co.. Ltd. CAS# 174953-30-1 ) (492 mg, 3.56 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure and quenched with water. The mixture was neutralized with HC1 (aq.) to PH~7. The mixture was concentrated under reduced pressure. The residue was dissolved in 2-methoxy-2- methylpropane (45 mL) and EbO (1.5 mL). then TsOH (283 mg, 1.64 mmol) and 1,4-dioxane (6 mL) were added. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), and then TEA (300 mg, 8.84 mmol) and Bocj0 (970 g, 4.42 mmol) were added. The resulting mixture was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl ((7R,8S)-3-bromo-7-((S)-2-hydroxypropoxy)-5, 6,7,8- tetrahydroquinohn-8-yl)carbamate and tert-butyl ((7S,8R)-3-bromo-7-((S)-2- hydroxypropoxy)-5,6,7,8-tetrahydroquinolin-8-yl)carbamate (740 mg, 63%) as a yellow oil. MS ESI calculated for CnEksBrN^CU [M+H]⁺, 401.10, 403.10; found, 401.05, 403.05.

Step-8:

[1269] To a stirred solution of a 1:1 mixture of tert-butvl ((7R,8S)-3-bromo-7-((S)-2- hydroxypropoxy ) ■ 5 ,6,7,8 -tetrahydroquinolin- 8-yl)carbamate and tert- butyl ((7S , 8R)-3 - bromo-7-((S)-2-hydroxypropoxy)-5,6,7,8-tetrahydroqumolin-8-yl)carbamate (500 mg, 1.25 mmol) and TEA (378 mg, 3.74 mmol) in DCM (5 mL) was added Ms?O (369 mg, 2. 12 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by water and extracted with CH2CI2. The combined organic layers were dried over anhydrous NaaSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL), and then TEA (2 mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. The mixture was concentrated under reduced pressure. The residue was dissolved in MeCN (10 mL), and then 1,2,2,6,6-pentamethylpiperidine (1.98 g, 12.72 mmol) was added. The resulting mixture was stirred at 60 °C for 16 h. The mixture was concentrated under reduced pressure. Hie residue was purified by Prep-HPLC with the following conditions [Column: XSelect CSH Prep Cl 8 OBD Column, 19*250 mm, 5pm: Mobile Phase A: Water (10 mmol/'L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20% B to 30% B in 10 min, 30%' B to 30% B in 20 min: Wave Length: 254/220 nm; RTl(min): 1 1.43; RT2(mm): 15.6] to afford (2R,4aR, 10bS)-8-bromo-2-methyl-2,3,4a,5,6, lOb-hexahydro- 1H- [l ,4]oxazino[2,3-h]quinoline (A62) (160 mg, 45%) as a white solid with the first peak on HPLC. MS ESI calculated for C^HisBrNiO [M+H]⁺, 283.04, 285.04; found, 283.00, 285.00. ^!H NMR (400 MHz, Chloroform-d) 6 8.47 (s. 1H), 7.60 (s, 1H), 4. 10 - 4.01 (m, 2H), 3.63 - 3.56 (m, 1H), 3.45 - 3.38 (m, 1H), 3.20 - 3,09 (m, 1H), 2.95 - 2.86 (m, 1H), 2.85 - 2.74 (m, 1H), 2.70 - 2.57 (m, 1H), 1.81 - 1.73 (m, 1H), 0.94 (d, 6.4 Hz, 3H).

[1270] The separation also afford (2R,4aS,10bR)-8-bromo-2-methyl-2,3,4a,5,6,10b- hexahydro-lH-[l,4]oxazino[2.3-h]quinolone (134 mg, 37%) as a white solid with the second peak on HPLC. MS ESI calculated for Ci₂H_i5BrN₂O [M+H]⁺, 283.04, 285.04; found, 283.00, 285.00. ^;H NMR (400 MHz, Chloroform-d) 8 8.50 (s, 1H), 7.56 (s, 1H), 4.20 - 4.14 (ni, 1H), 3.80 - 3.75 (m, HI), 3.69 - 3.63 (m, 1H), 3.32 (t, J - 10.6 Hz, 1H), 3.17 - 3.04 (m, 1H), 2.67 - 2.58 (m, 1H), 2.57 - 2.47 (m, 1H), 2.22 - 2.13 (m, 1H), 1.90 - 1.79 (m. 1H), 0.92 (d, J = 6.4 Hz, 3H).

Intermediate A63: 1 :1 :3:3 mixture of rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-methoxy-

1 ,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-7- (difluorornethoxy) -3 -methoxy- 1 ,2,3.4, 4a, 9b -hexahydrobenzofuro] 3,2-b]pyridine isomer 2 and rel-(3R,4aR,9bR)-7-(difluoromethoxy)-3-methoxy-l,2,3,4,4a,9b- bexahydrobenzofuro[3,2-b]pyridine isomer 3 and re1-(3R,4aR,9bR)-7-(difluoromethoxy)-3- methoxy-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 4

Isomer 1 Isomer 2 Isomer 3 Isomer 4

A63

Step-1:

[1271] To a stirred solution of 6-chloro-5-fluoropyridin-3-ol (24.70 g, 167.42 mrnol) and CS2CO3 (109.10 g, 334.84 mmol) in MeCN (250 mL) was added CH3I (21 mL, 337.32 mmol) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford 2-chloro-3-fluoro-5-me(hoxypyridine (24.00 g, 88%) as a yellow oil. MS ESI calculated for CsHsClFNO jM+Hf’, 162.00; found, 162.10.

Step-2:

[1272] To a stirred solution of 2-chloro-3-fluoro-5-methoxypyridine (28.00 g, 173.31 mmol) and (4-ch1oro-2-hydroxyphenyl)boronic acid (35.85 g, 207.97 mmol) in 1 ,4-dioxane (280 mL) and H2O (28 mL) were added K2CO3 (71.86 g, 519.93 mmol) and Pd(dppf)Ch-

CH2CI2 (14.15 g. 17.33 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C tor 2 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCU After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with 0-20% ethyl acetate in petroleum ether to afford 5-chloro-2-(3-fluoro-5-methoxypyridin-2-yl)phenol (31.50 g, 71 %) as a light yellow solid. MS ESI calculated for C12H9CIFNO2 [M+H]⁺, 254.03; found. 254.00.

[1273] To a stirred solution of 5-chloro-2-(3-fluoro-5-methoxypyridin-2-yl)phenol (30.00 g, 118.26 mmol) in DMF (300 ml) was added K2CO3 (49.04 g, 354.80 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 2 h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSOj. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with 0-20% ethyl acetate in petroleum ether to afford 7 -chloro- 3- methoxybenzofuro[3,2-b]pyridine (20.00 g, 72%) as a yellow solid. MS ESI calculated for CnHsCINCh [M+HD 234.02; found, 234.15.

Step-4:

[1274] To a stirred solution of 7-chloro-3-methoxybenzofuro[3,2-b]pyridine (1 1 .00 g, 47.07 mmol) and BPD (11.96 g, 47.07 mmol) in 1,4-dioxane (110 mL) were added AcOK (13.86 g, 141.23 mmol) and Pd(dppf)Ch-CH2C12 (3.84 g, 4.70 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred al 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / PE (1:10) to afford 3-methoxy-7- (4,4,5,5-letramethyl-l,3,2-dioxaboro1an-2-y1)benzofuro[3,2-b]pyridine (7.9 g, 51%) as a white solid. MS ESI calculated for C18H20BNO4 [M+HJ*. 326. 15; found, 326.20.

Step-5 :

[1275] To a stirred solution of 3-methoxy-7-(4,4,5,5-tetrameihyl-l,3,2-dioxaborolan-2- yl)benzofuro[3,2-b]pyridine (14.80 g, 45.51 mmol) in H2O (38 mL) and THF (150 mL) was added NaBChAHjO (10.50 g, 68.27 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-methoxybenzofuro[3.2-b]pyridin-7-ol (13 g, crude) as a white solid. MS ESI calculated for Ci 2H9NO? [M+H]⁺, 216.06; found, 216.15.

Step-6:

[1276] To a stirred solution of 3-methoxybenzofuro[3,2-b]pyridin-7-ol (10 g, 46.46 mmol)

DCM ( 100 mL) was added a solution of KOH ( 15.64 g, 278.80 mmol) in H2O (66 mL), then TMSCFzBr (28.31 g, 139.40 mmol) was added at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na^SCU- After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography with 0-31 % ethyl acetate in petroleum ether to afford 7-(difluoromethoxy)-3-methoxybenzofuro[3,2-b]pyridine ('7.00 g, 56%) as a yellow solid. MS ESI calculated for C13H9F2NO3 [M+HJ*. 266.06; found, 266.10.

Step-6:

Isomer ! Isomer 2 Isomer 3 Isomer 4

A63

[1277] To a stirred solution of 7-(difluoromethoxy)-3-methoxybenzofuro[3,2-b]pyridine (700 mg, 2.63 mmol) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.68 g, 13.19 mmol) in toluene (7 mL) were added N-phenylaniiine (1.78 g, 10.55 mmol) and tris(pentafluorophenyl)borane (135 mg, 0.26 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 16 h. The resulting mixture was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SOa. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 20 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford a 1 : 1 : 3 : 3 mixture of rel-(3R,4aS ,9bS)-7 -(difluoromethoxy) -3-methoxy- 1,2,3 , 4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3- methoxy-1 ,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2 and rel-(3R,4aR,9bR)-7- (difluoromethoxy)-3-methoxy-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 3 and rel-(3R,4aR,9bR)-7-(difluoromethoxy)-3-methoxy-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 4 (A63) (500 mg, 69%yield) as a yellow oil. MS ESI calculated for C13H15F2NO3 [M+l]⁺, 272.10; found, 272.15. ^JH NMR (400 MHz, DMSO-ifc) 67.41 - 6.93 (m, 2H), 6.78 - 6.54 (m, 2H), 4.74 - 4.55 (m, 2H), 4.15 (d, 5.8

Hz, 1H), 3.93 (s, 3H), 3.35 - 3.31 (m, 1H), 2.86 - 2.82 (m, 1 H), 2.44 - 2.22 (m, 1H), 1.86 ~ 1.80 (m. 1H).

Intermediate A63 isomer 1: rel-(3R,4aS,9bS)-7-(difluoTomethoxy)-3-methoxy- l,2,3,4_>4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 1 isomer 1 _and;

Intermediate A63 isomer 2; rel-(3R,4aS,9bS)"7-(difluoromethoxy)"3-methoxy- l,2,3.4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2

Isomer z _and_

Intermediate A63 isomer 3: rel-(3R,4aR,9bR)-7-(difluoromethoxy)-3-methoxy- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 3

Isomer 3 _a<

Intermediate A63 isomer 4: rel-(3R,4aR,9bR)-7-(difluoromethoxy)-3-methoxy- 1 ,2,3.4.4a,9b-bexahvdrobenzofuro[3,2-b]ovridine isomer 4

[1278] A 1 : 1 :3: 3 mixture of rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-methoxy- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-bjpyridine isomer 1 and rel-(3R,4aS,9bS)-7- (difluoromethoxy )-3-metboxy- 1,2, 3, 4, 4a, 9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2 and rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-methoxy-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 3 and rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3- methoxy-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 4 (A63) (7.7 g) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150 mm, 5 urn; Mobile Phase A: Water (0. 1 % FA), Mobile Phase B: ACN: Flow rate: 60 mL/min; Gradient: isocratic 3-19; Wave Length: 254 nm / 220 nm; RTl(min): 5 minute; RT2(min): 8 minute) to afford fraction A (540 mg, 7%) as a white solid as the first eluting peak at 5 min and fraction B (1.30 g, 18%) as a white solid as the second eluting peak at 8 min. [1279] The fraction A (540 mg) was separated by prep-chiral SFC with the following conditions: [Column: CHIRALPAK IG, 3*25 cm, 10 gm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 100 mL/min; Gradient: isocratic 20% B; Wave Length: 220 nm; RTl(min): 4.5; RT2(min): 6.35; Sample Solvent: MEOH] to afford rel-(3R,4aS,9bS)-7- (difluoromethoxy)-3-methoxy-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine, isomer 1 (A63 isomer 1) (150 mg, 27%) as a white solid with retention time at 4.5 minute. And the chiral resolution of fraction A also afford rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-methoxy- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine, isomer 2 (A 63 isomer 2) (180 mg, 33%) as a white solid with retention time at 6.35 minute.

[1280] rel-( 3R,4aS,9bS)-7-(difluoromethoxy)-3-methoxy- 1.2, 3,4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine, isomer 1 (A 63 isomer 1): MS (ESI) calculated for (C13H15F2NO3) [M+Hr, 272.10; found, 272.10. ^;H NMR (400 MHz, DMSO-d₆) 87.39 - 6.98 (m, 2H), 6.70 - 6.62 (m, 2H), 4.62 (q, J = 6.4 Hz, 1H), 4.34 (d, J = 6.4 Hz, 1H), 3.30 - 3.23 (m, 1H), 3.21 (s, 3H), 2.84 (dd, J = 12.8, 4.0 Hz, 1H), 2.48 - 2.39 (m, 1H). 2.23 - 2.15 (m, 1H), 1.83 - 1.77 (m, 1H). The OMe group is at cis position based on NOESY.

[1281] rel-(3R,4aS,9bS)-7-(difluoromethoxy)-3-methoxy-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine, isomer 2 (A63 isomer 2): MS (ESI) calculated lor (C13H15F2NO3) [M+H]*, 272.10; found, 272.10. ^:H NMR (400 MHz, DMSO-cfc) 57.39 - 6.98 (m, 2H), 6.70 - 6.64 (m, 2H), 4.62 (q, J = 6.0 Hz, 1H), 4.32 (d, J = 6.8 Hz, 1H). 3.26 - 3.22 (m, 1H), 3.20 (s, 3H), 2.82 (dd, ./ = 13.2, 4.4 Hz, 1H), 2.45 - 2.39 (m, 1H), 2.23 - 2.17 (m, 1H), 1 .82 - 1.74 (m, 1H). The OMe group is at cis position based on NOESY.

[1282] The fraction B (900 mg) was separated by prep-chiral SEC with the following conditions: [Column: CHIRALPAK PAK AD-H, 30*250 mm; Mobile Phase A: CO2, Mobile Phase B: MEOH (0.1% 2M NH3-MEOH); Flow rate: 100 mL/min: Gradient: isocratic 40% B; RTl(min): 2.5; RT2(min): 4; Sample Solvent: MEOH] to afford rel-(3R,4aR,9bR)-7- (difluorometlioxy)-3-methoxy-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine, isomer 3 (A63 isomer 3) (400 mg, 44%) as a while solid with retention time at 2.5 minute. And the chiral resolution of fraction B also afford rel-(3R,4aR,9bR)-7-(difluoromethoxy)-3-methoxy- 1 ,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine, isomer 4 (A63 isomer 4) (370 mg, 41 %) as a white solid with retention time at 4 minute.

[1283] rel-(3R,4aR,9bR)-7-(difluoromeihoxy)-3-methoxy-l , 2, 3, 4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine, isomer 3 (A63 isomer 3): MS (ESI) calculated for (C13H15F2NO3) [M+H]⁺, 272.10; found, 272. 15. ^:H NMR (400 MHz, DMSO-cfe) 57.37 - 7.00 (m, 2H), 6.67 - 6.65 (tn, 2H), 4.68 - 4.63 (m, HI), 4.15 (d, ./ = 5.6 Hz, 1 H), 3.36 - 3.33 and 3.31 - 3.28 (m, IH), 3.25 (s, 3H), 2.83 (dd, J = 12.4, 4.4 Hz, IH), 2.41 - 2.25 (m, 2H), 1 .86 - 1.79 (m, IH).

[1284] rel-(3R,4aR,9bR)-7-(difluoromethoxy)-3-methoxy-l, 2,3,4, 4a,9b- hexahydrobenzofuro[3,2-b]pyridine, isomer 4 (A63 isomer 4): MS ESI calculated for

C d Ld- .XO, [M+H]\ 272.10; found, 272.15. ^JH NMR (400 MHz, DMSO-d₆) 8 7.37 - 7.00 (m, 2H), 6.70 - 6.61 (m, 2H), 4.67 - 4.63 (m, I H), 4.15 (d, J - 6.0 Hz, IH), 3.37 - 3.33 and 3.32 - 3.28 (m, IH), 3.25 (s, 3H), 2.83 (dd, J = 12.0, 4.0 Hz, IH), 2.41 - 2.21 (m, 2H), 1.88 ■ 1.78 (m, IH).

Intermediate A64: 1: 1 mixture of rel-(2R,4aS,9bS)-7-methoxy-2-methyl-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(2R,4aS,9bS)-7-methoxy-2-methyl- 1 ,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2

A64

Step- 1 :

[1285] To a stirred mixture of 2,4-dimethoxyphenylboronic acid (10.00 g, 54.95 mmol) and 2-chloro-3-fluoro-6-methylpyridine (8.00 g, 54.95 mmol) in 1,4-dioxane (100 mL) and H?O (10 mL) were added PdldppfiCL-CHxCh (4.49 g, 5.49 mmol) and K2CO3 (22.78 g, 164.85 mmol) at 25 °C. The resulting mixture was stirred at. 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford 2-(2,4-dimethoxyphenyl)-3-fluoro-6-methylpyridine (12.10 g, 89%) as a pink solid. MS ESI calculated Ibr CnHrtFNO? [M+H]⁺, 248.10; found, 248.05. Step-2:

[1286] To a stirred solution of 2-(2,4-dimethoxyphenyl)-3-fluoro-6-methylpyridine (12.00 g, 48.53 mmol) in DCM (120 mL) were added BBrj (IM in DCM) (48.53 mL, 48.53 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched with water at 0°C. The resulting mixture was extracted -with CH2CI2. The combined organic layers were dried over anhydrous NazSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue w’as purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford 2-(3- fluoro-6-methylpyridin-2-yl)-5-methoxyphenol (9.00 g, 79%) as a yellow oil. MS ESI calculated for C13H12FNO2 [M+H]⁺, 234.09; found, 234.10.

Step-3:

[1287] To a stirred mixture of 2-(3-fluoro-6-methylpyridin-2-yl)-5-methoxypheno1 (9.00 g, 38.59 mmol) in DMF (30 mL) was added K2CO3 (21.33 g, 154.35 mmol) at 25 °C. The resulting mixture was stirred at 120 °C for 16 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were dried over anhydrous NazSCU.

After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% methanol in dichloromethane to afford 7-methoxy-2-methylbenzofuro[3,2-b]pyridine (3.40 g, 41%) as a brown solid. MS ESI calculated for CHHJ JNOZ [M+H]⁺, 214.08; found, 214. 10.

Step-4:

A64

[1288] To a stirred mixture of 7-melhoxy-2-metbylbenzofuro[3,2-b]pyridine (500 mg, 2.35 mmol) and N -phenylaniline (1.59 g, 9.38 mmol) in toluene (5 niL) were added 4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (1.50 g, 11.73 mmol) and tris(pentafluorophenyl)borane ( 120 mg, 0.24 mmol) slowly at 25 °C. The resulting mixture was stirred at 110 °C for 16 h. The mixture was allowed to cool down to room temperature. The mixture was basified with saturated NaHCOs (aq.) to pH 9. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous NaaSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with 3% to 100% MeCN in Water ( lOmmol/L NH4HCO3 to afford a 1 :1 mixture of rel-(2R,4aS,9bS)-7-methoxy-2-methyl-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2- bjpyridine isomer 1 and rel-(2R,4aS,9bS)-7-methoxy-2-methyl-l,2,3,4,4a,9b- hexaliydrobenzofuro[3,2-bjpyridine isomer 2 (A64) (115 mg, 22%) as a yellow oil. MS ESI calculated for C13H17NO2 [M+l]⁺, 220.13; found. 220.15. ‘H NMR (400 MHz. DMSO-tfc) 5 7.17 (d, J = 8.0 Hz, 1H), 6.45 - 6.38 (m, 2H), 4.30 - 4.22 (m, 1H), 3.99 (d, J = 4.8 Hz, 1H), 3.71 (s, 3H), 2.61 - 2.52 (ni, 1H), 2.23 - 2.12 (m, 1H), 1.94 - 1.83 (m, 1H), 1.51 - 1.43 (m, 1H), 1.17 - 1.05 (m, 1H), 1.00 - 0.96 (m, 1H), 0.93 (d, J - 6.4 Hz, 3H).

Intermediate A65: rel-(4aS, 10bS)-8-cbloro-2,3,4.4a.6, lOb-bexahydro- lH-isochrotneno[4,3- b]pyridine

A65

[1289] To a stirred solution of rei-tert- butyl (4aS,10bS)-8-chloro-2, 3.4, 4a, 6,10b- hexaliydro-lH-isochromenol4,3-b]pyridine-l-carboxylate (intermediate from A25) (1.53 g, 4.73 mmol) in DCM (15 mL) was added Zinc bromide (2.13 g, 9.45 mmol) at 25 °C. The resulting mixture was stirred at 40 °C for 16 h. The resulting mixture was concentrated under reduced pressure and the residue was quenched with water. The mixture was basified to pH 8 with NaHCCh (sat.). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford rel-(4aS,10bS)-8-chloro- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine (A65) (1.02 g, 96%) as a light brown oil. MS ESI calculated for C12H14CINO [M+H]⁺, 224.08; found, 224.05. ’H NMR (300 MHz, DMSO-tfe) 8 7.31 (d, 7 - 8.1 Hz, 1H), 7.24 (dd, J - 8.1, 2.1 Hz, 1H), 7.16 (d. J = 2.1 Hz, 1 H), 4.86 - 4.62 (m, 2H), 3.55 (q, 7= 3.0 Hz, 1 H), 3.48 (d, J - 2.0 Hz, 1 H), 2.90 - 2.86 (m, 1H), 2.65 - 2.60 (m, H i ). 2.01 - 1 .91 (m, 1H), 1.84 - 1.68 (m, 2H), 1 .57 - 1 .51 (m,

1H), 1.35 - 1.29 (m, 1H).

Intermediate A66: rel-(4aS,10bS)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- b]pyridine-8-carbonitrile

Step-1 :

[1290] A mixture of rel-tert-butyl (4aS, lObS) -8-chloro-2,3,4,4a,6, lOb-hexahydro- 1H- isocbromeno[4,3-b]pyridine- 1 -carboxylate (from A25) ( 13.01 g, 40.17 mmol), Zinc cyanide (9.06 g, 77.14 mmol), XPhos-Pd G3 (3.74 g, 4.41 mmol), XPhos (1.92 g, 4.01 mmol) and Zinc (10.38 g, 158.69 mmol) in DMF (130 mL) was stirred at 130 °C for 2 h under nitrogen atmosphere. The reaction mixture was cooled down at room temperature, the mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography eluted with 0-50% ethyl acetate in petroleum ether to afford rel-tert-butyl (4aS, 10bS)-8-cyano-2, 3, 4, 4a, 6, lOb-hexahydro- lH-isochromeno[4,3-b]pyridine-l -carboxylate (7.6 g, 60%) as a colorless oil. MS ESI calculated for C18H22N2O3 [M+H]⁺, 315.16; found,

315.10.

Step-2:

[1291] To a mixture of rel-tert-butyl (4aS,10bS)-8-cyano-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine-l -carboxylate (1.70 g, 5.40 mmol) in ethyl acetate (10 mL) was added hydrogen chloride (4.0 M in dioxane) (10 mL) at 0 °C. Ute mixture was stirred at room temperature for 16 h. The solvents were removed under vacuum to afford rel- (4aS, lObS )-2, 3, 4, 4a, 6, 10b-hexahydro- lH-isochromeno[4,3-b]pyridine-8-carbonitrile hydrochloride (A66) (1.3 g, 96%) as a white solid. MS ESI calculated for C13H14N2O [M+H]⁺, 215.11; found, 215.15. ^SH NMR (400 MHz, DMSO-rfe) 5 10.04 (s, HI), 8.80 (s, 1H), 7.84 - 7.85 (m, 2H), 7.78 (d, J = 1.2 Hz, 1H), 5.07 - 4.77 (m, 2H), 4.41 (d, 9.6 Hz, 1 H), 4.00 (d, J- 3.2 Hz, 1 H), 3.20 - 3.18 (m, 1H), 3.07 - 3.04 (m, 1H), 2.02 - 1.99 (m, HI),

1.94 - 1.74 (m, 2H), 1.69 - 1.66 (m, 1H).

Intermediate A67: 1 : 1 mixture of rel-(2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl-

2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 1 and rel-(2R,4aS,10bS)-8-

(difluoromethoxy)-2-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 2

[1292] To a stirred mixture of methyl 5"(difluoromethoxy)-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (11.00 g, 33.52 mmol) in 1,4-dioxane (100 mL) and HzO (10 mL) were added K2CO3 (13.90 g, 100.57 mmol), 2-bromo-3-fluoro-6-methylpyridine (7.64 g, 40.23 mmol) and Pd(dppf)Ch (2.74 g, 3.35 mmol). The resulting solution was stirred at 100 °C for 15 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford methyl 5-(difiuoromethoxy)-2-(3-fluoro-6-methylpyridin-2-yl)benzoate (6.50 g, 81%) as an orange oil. MS ESI calculated for C15H12F3NO3 [M+H]* , 312.26; found, 312.05.

Step-2:

[1293] To a stirred solution of methyl 5-(dilluoromethoxy )-2-(3-fluoro-6-methyIpyridin-2- yl)benzoate (6.80 g, 2'1.85 mmol) in THF (68 mL) was added L1AIH4 (1.66 g, 43.69 mmol) in portions at 0 °C. The resulting solution was stirred at. 0 °C for additional 2 h. The reaction was quenched with ice water (1.6 mL) and NaOH (aq., 10%) (1.6 mL) at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaxSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford [5-(difluoromethoxy)-2-(3-tluoro-6-methylpyridin- 2-yl)phenyl]methanol (4.80 g, 88%) as an off-white solid. MS ESI calculated for C14H.2F3NO2 |M+HJ⁺ , 284.25; found, 284.05.

[1294] To a stirred solution of [5-(difluorometlioxy)-2-(3-fluoro-6-methylpyridin-2- yl)phenyl]methanol (4.80 g, 16.95 mmol) in DMF (50 mL) was added NaH (60% in mineral oil) (0.81 g. 20.25 mmol) at 0 °C, The resulting solution was stirred at 0 °C for 4 h. The reaction was quenched with water at 0 °C and extracted with EtOAc. The combined organic layers -were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford 8- (difluoromethoxy)-2-methyl-6H-isochromeno[4,3-b]pyridine (3.50 g, 85%) as a white solid. MS ESI calculated for Ci4H_{; !}F₂NO₂ [M+H]*, 264.03; found, 264.05.

Step-4:

[1295] To a solution of 8-(difluoromethoxy )-2-methyl-6H-isochromeno[4,3-b]pyridine (4.00 g, 15.20 mmol) in AcOH (100 mL) was added Pladnum(IV) oxide (0.35 g, 1.52 mmol). The mixture was hydrogenated at 50 °C under hydrogen pressure (50 atm.) for 18 h. The resulting mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. 'The residue was basified with NarCCfi (sat.) to pH 7-8. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1: 1 mixture of rel-(2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl- 2,3,4.4a,6, lOb-hexahydro- lH-isochromeno[4,3-b]pyridine isomer 1 and rel-(2R.4aS,10bS)-8- (difluoromethoxy)-2-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 2 (A67) (1.30 g, 98%) as a yellow oil. MS ESI calculated for C14HJ7F2NO2 [M+H]⁺ , 270.12; found, 270.15. ^!H NMR (400 MHz, DMSO-<) 37.37 - 6.99 (m, 3H), 6.88 (cl, ./ = 2.4 Hz, 1H), 4.85 - 4.64 (m, 2H), 3.50 - 3.49 (m, 2H), 2.77 - 2.68 (m, 1H), 2.02 - 1.95 (m, 1H), 1 .83 - 1 .72 (m, 1 H), 1 .39 - 1 .36 (m, 1 H), 1 .28 - 1.16 (m, 1 H), 0.97 (d, J = 6.4 Hz, 3H).

Intermediate A67 isomer 1: rel-(2R,4aS,10bS)-8-(difluoromeihoxy)-2-methyi-

2, 3, 4, 4a, 6, lOb-hexahydro- lH-isochromeno[4,3-b]pyridine isomer 1

Isomer 1 _and> Intermediate A67 isomer 2: rel-(2R,4aS,10bS)-8-(difluoromeihoxy)-2-methyl-

2,3,4,4a,6,10b-hexahydro-lH-isocliromeno[4,3-b]pyridine isomer 2 [1296] A 1:1 mixture of rel-(2R,4aS,l0bS)-8-(difluoromethoxy)-2-methyl-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridine isomer 1 and rel-(2R,4aS,10bS)-8- (difluoromethoxy)-2-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4.3-b]pyridine isomer 2 (A 67) (1.30 g) was separated by prep-Chiral SFC with the following conditions: [Column; CHIRALPAK IH 5*25 cm, 5 pm; Mobile Phase A: CO₂, Mobile Phase B: MEOH: ACN=1: 1(0.1% 7M NHs-MeOH); Flow rate: 250 mL/min; Gradient (B%): isocratic 30%' B; Column Temperaturef'C ): 35; Back Pressure(bar): 100: Wave Length: 220 nm; RTl(min): 4; RT2(min): 7] to afford rel-(2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl-2,3,4,4a,6,l0b- hexahydro-lH-isochromeno[4,3-b]pyridine isomer 1 (A67 isomer 1) (580 mg) as a yellow solid with retention time at 4 minute. MS ESI calculated for C14H17F2NO2 |.M+Hj⁺ , 270.12; found. 270.15. NMR (400 MHz, DMSO-afo 5 7.39 - 7.30 (m, IH), 7.18 (t. /= 72.0 Hz, I H), 7.04 - 6.97 (m, IH), 6.88 (d, J 2.6 Hz, IH), 4.82 (d, .7 - 15.6 Hz, IH), 4.66 (d, J - 15.6 Hz, 1H), 3.54 - 3.47 (m, 2H), 2.78 - 2.67 (m, 1H), 2.02 - 1.92 (m, 1H), 1.85 - 1.70 (m. 1 H), 1.40 - 1.36 (m, 1H), 1.28 - 1.13 (m, 1H), 0.97 (d, J - 6.4 Hz, 3H). Absolute stereochemistry’ was not determined.

[1297] The chiral separation also afford rel-(2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 2 (A 67 isomer 2) (560 mg) as a yellow oil with retention time at 7 minute. MS ESI calculated for C14H17F2NO2 [M+H]⁺ , 270.12; found, 270.15. ^!H NMR (400 MHz, DMSO-ffc) 5 7.39 - 7.30 (m, 1H), 7.18 (t, J = 72.0 Hz. 1H). 7.04 - 6.97 (m, 1H), 6.88 (d, 2.6 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), 4.66

(d, J = 15.6 Hz, 1H), 3.54 - 3.47 (m, 2H), 2.78 - 2.67 (m, 1H), 2.02 - 1.92 (m, 1H), 1.85 - 1.70 (m, 1H), 1.40 - 1.36 (m, 1H), 1.28 - 1.13 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A68 isomer 1: rel-(4R,4aR,9bR)-4-methy]-7-(irifluorometbyl)-1 , 2, 3, 4 ,4a, 9b- hexahydrofuro|2,3-b:4,5-b']dipyridiiie isomer 1

[1298] To a stirred solution of 3-bromo-2-chloro-6-(trif'luoromethyl)pyridine (18.33 g, 70.39 mmol) and (E)-tert-butyl((3-methyl-5-(4,4,5,5-tetramethyl- 1 „3,2-dioxaborolan-2- yl)pent-4-en-l-yl)oxy)diphenylsilane (32.70 g, 70.39 mmol) in Dioxane (450 mL) and H?O (45 mL) were added K2CO3 (29.19 g, 211.18 mmol) and PdCdppfjCh-CHrCh (5.75 g, 7.04 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase Hash chromatography with a 330 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (S,E)-3-(5-((terl- butyldiphenyIsilyl)oxy)-3-methylpent-l-en-l-yl)-2-chloro-6-(trifiuoromethyl)pyridine and (R,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-metliylpent-l-en-l-yl)-2-chloro-6- (trifltioromethyl)pyridine (33.0 g, 90%) as a yellow oil. MS ESI calculated for C J foCIHXOSi i M ■ 11 f . 518.18; found, 518.15.

Step-2:

[1299] To a stirred solution of tert-butyl carbamate (14.04 g, 119.86 mmol) in propan- l -ol (197 mL) was added a solution of NaOH (4.26 g, 106.54 mmol) in FbO (130 mL) at room temperature. The mixture was stirred at room temperature for 10 min. Then 1,3-dichloro-5,5- dimethylimidazolidine-2, 4-dione (1 1.81 g, 59.93 mmol) was added to the mixture at room temperature. After stirring at room temperature for 30 min, this was followed by the addition of a solution of (DHQAPHAL (supplier: Shanghai Accela CheniBio Co., Ltd. CAS# 140924- 50-1) (2.07 g, 2.66 mmol) in propan-l-ol (27 mL) and a solution of 1:1 mixture of (S,E)-3-(5- ((tert-butyldiphenylsilyl)oxy)-3-methylpent-l-en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine and (R.E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-methylpent-l-en-l-yl)-2-chloro-6- (trifluoromethyl)pyridine in propan-l-ol (20 mL) at O °C. Then Potassium osraate(VT) dihydrate (0.98 g, 2.66 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of brine and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by normal phase flash chromatography with a 330 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford rel-teri-butyl ((lR,2R,3R)-5-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridiii-3-yl)-2-hydroxy-3- methylpentyljcarbamate isomer 1 (8.0 g, 46%) as a yellow oil as the first eluting peak. MS ESI calculated for C33H42ClF3N?O4Si [M+H]⁺, 651.26; found, 651.15. Absolute stereochemistry was not determined.

[1300] The purification process also affords rel-tert-butyl ((lR,2R,3R)-5-((teri- buiyldiphenylsilyl)oxy)-l -(2-chloTO-6-(trifluoromeihyl)pyridin-3-yl)-2-hydroxy-3- methylpentylicarbamate isomer 2 (9.5 g, 54%) as a yellow oil as the sencond eluting peak. MS ESI calculated for CjslUCIFsNiChSi [M+H]⁺, 651.26; found, 651.25. Absolute stereochemistry was not determined.

Step-3: isomer 1

[1301] To a stirred solution of rel -tert-butyl ((lR,2R,3R)-5-((tert-butyldiphenylsilyl)oxy)- l-(2-chloro-6-(trifluoromethyl}pyridin-3-yl)-2-liydroxy-3-methylpentyl)carbamate isomer 1 (5 g, 7.68 mmol) and CS2CO3 (5.00 g, 15.36 mmol) in Toluene (50 mb) were added Pd(OAc)₂ (172 nig, 0.77 mmol,) and JohnPhos (458 mg, 1.54 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by normal phase flash column chromatography with a 120 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford rel-teri-butyl ((2R,3R)-2-((R)-4-((tert- buty]diphenylsilyl)oxy)butan-2-yl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- yl)earbamate isomer 1 (870 mg, 18%) as a yellow oil. MS ESI calculated for C33H41F3N2O4S1 [M+Hf , 615.28; found, 615.25.

Step-4: isomer 1 isomer 1 [1302] To a stirred solution of rel-tert-butyl ((2R,3R)-2-((R)-4-((tert- butyldiphenylsiIyl)oxy)butan-2-yl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- yl)carbamate isomer 1 (840 mg, 1.37 mmol) in THE (9 mL) was added TBAF (715 mg, 2.73 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h.

The mixture was concentrated under vacuum. The residue was purified by normal phase flash column chromatography with an 40 g silica gel column eluted with 0—50% ethyl acetate in petroleum ether to afford rel-tert-butyl ((2R,3R)-2-((R)-4-hydroxybutan-2-yl)-6- (trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate isomer 1 (410 mg, 80%) as a yellow oil. MS ESI calculated for Ci7H23F3N₂O4 [M+HJA 377.16; found, 377.20.

Step-5 :

[1303] To a stirred solution of rel-tert-butyl ((2R,3R)-2-((R)-4-hydroxybutan-2-yl)-6- (trifluorometliyr)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate isomer 1 (410 mg, 1.09 mmol) in toluene (5 mL) was added 2-(tributyl-??-phosphaneylidene)acetoniirile (CAS No. 157141-27-0) (526 mg, 2.18 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred al 100 °C tor 16 h. The reaction mixture w'as concentrated under vacuum. The residue was purified by normal phase flash column chromatography with an 40 g silica gel column eluted with 0—15% ethyl acetate in petroleum ether to afford rel-tert- butyl (4R,4aR,9bR)-4-methyl-7-(trifluoromethy1)-3,4,4a,9b-tetraliydrofuro[2,3-b:4,5-b']dipyridine- l(2H)-carboxylate isomer I (330 mg, 83%) as a yellow oil. MS ESI calculated for C -H; H.X (T. [M+H] \ 359.15; found, 359.15. isomer 1 A68 isomer 1

[1304] A mixture of rel-tert-butyl (4R,4aR,9bR)-4-methyl-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxylate isomer 1 (330 mg, 0.92 mmol) and HC1 (4.0 M in ethyl acetate) (4 ml..) was stirred at room temperature for 2 h. The mixture was concentrated under vacuum to afford rel-(4R,4aR,9bR)-4-methyl-7-(trifluoromethyl)- 1,2, 3,4.4a, 9b-hexahydrofuro[2,3-b:4,5-b’jdipyridine hydrochloride isomer 1 (A68 isomer 1) (crude, 285 mg) as a white solid. MS ESI calculated for C12H13F3N2O [M+H]⁺, 259.10; found, 259.10. *H NMR (400 MHz, DMSO) 3 10.62 (s, 1H), 8.73 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 5.09 - 4.93 (m, 1H), 4.88 •■■■ 4.76 (m, 1H), 3.2.4 - 3.08 (m, 1H), 3.06 - 2.90 (m, 1 H), 2.33 - 2.19 (m, 1H), 1.83 - 1.69 (in, 1H), 1.60 - 1.43 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A68 isomer 2: rel-(4R,4aR,9bR)-4-methyl-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine isomer 2 isomer 2

[1305] A solution of rel-tert-butyl ((1 R,2R,3R)-5-((tert-butyldiphenylsi1yl)oxy)-l-(2-chloro- 6-(trifluoromethyl)pyridm-3-yl)-2-hydroxy-3-methylpentyl)carbamaie isomer 2 (8 g, 12.28 mmol) Pd(OAch (0.28 g, 1.22 mmol), JohnPhos (0.73 g, 2.45 mmol) and CS2CO3 (10.01 g, 30.71 mmol) in toluene (80 ml.,) was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by normal phase flash chromatography using a 330 g silica gel column eluted with 0-15% ethyl acetate in petroleum ether to afford rel-tert-butyl ((2R,3R)-2-((R)-4-((tert- butyldipbenylsilyl)oxy)butan-2-yl)-6-(trifluoromethyl)-2,3-dibydrofuro[2,3-b]pyridin-3- ylicarbamate isomer 2 (1.3 g, 17%) as a yellow oil. MS ESI calculated for (C33H41F3N2O4SO [M+H]⁺, 615.28; found, 615.30.

Step 2: isomer 2 isomer 2 [1306] A solution of rel-tert-butyl ((2R,3R)-2-((R)-4-((tert-butyldiphenylsilyl)oxy)buian-2- yJ)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbaniate isomer 2 (1.3 g, 2.11 mmol) and TBAF (0.83g, 3.17 mmol) in THF (10 ml_) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by normal phase flash chromatography using a 40 g silica gel column eluted with fl- 50% ethyl acetate in petroleum ether to afford rel-tert-butyl ((2R,3R)-2-((R)-4-hydroxybutan- 2-yl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)cafbamate isomer 2 (600 mg,

75%) as a white solid. MS ESI calculated for CjrHmEtNzOr [M+H]⁺, 377.16; found, 377.20.

Step 3:

[1307] A solution of rel-tert-butyl ((2R,3R)-2-((R)-4-hydroxybutan-2-yl)-6-

(trifluoromethyl)-2,3-dibydrofuro[2,3-b]pyridin-3-yl)carbamate isomer 2 (600 mg, 1 .59 mmol) and 2-(tributyl-/v⁵-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (769 mg,

3.18 mmol) in toluene (10 mL) was stirred at 100°C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase flash column chromatography, eluted with 5~70% acetonitrile in water (10 mM NH4HCO3) to afford rel-tert-butyl (4R,4aR,9bR)-4-methyl-7-

(trifluoromethyI)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxy1ate isomer

2 (340 mg, 66%) as a yellow oil. MS ESI calculated for CurH/jFsNzCh [M+H]⁴, 359.15; found, 359.10.

Step 4: isomer 2 A68 isomer 2

[1308] A mixture of tert-butyl (4R*,4aS,9bS)-4-methyl-7-(trifluoromethyI)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxylate (340 mg, 0.94 mmol) and hydrogen chloride (4.0 M in ethyl acetate) (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford rel-(4R,4aR,9bR)-4-methyl-7- (trifluoromethyl)- 1 ,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b’]dipyridine hydrochloride isomer 2 (301 mg, crude) as a light yellow solid. MS ESI calculated for C12H13F3N2O [M+H]*, 259.10; found, 258.95. ^JH NMR (400 MHz, DMSO-&) 5 10.81 (s, 1H), 9.36 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 5.14 - 5.13 (m, 1H), 4.71 (t, ./ = 7.6 Hz, 1H), 3.15 - 3.14 (m, 2H), 2.21 - 2.18 (m, 1H), 1.89 - 1.85 (m, 1 H), 1.58 - 1.51 (m, 1H), 1.16 (d, 7 - 6.6 Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A69: (3R,4aS.9aR)-3-methyl-2.3,4,4a,9,9a-hexahydroindeno[2,l- b][l,4]oxazine-7-carbonitrile

[1309] To a stirred mixture of (3R,4aS,9aR)-7-chloro-3-methyl-2,3, 4,4a, 9,9a- hexahydroindeno[2,1 -b][l ,4]oxazine (1 .0 g, 4.47 mmol), Zn(CN')₂ (584 mg, 8.94 mmol), Zinc (1169 mg, 17.88 mmol) in DMF (15 ml) were added XPhos Pd G3 (567 mg, 0.67 mmol) and XPhos (319 mg, 0.67 mmol). The resulting mixture was stirred at 130 °C for 3 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. The residue was purified byreverse phase flash column chromatography with 5-90% ACN in water to afford (3R,4aS,9aR)-3-methyl-2,3,4,4a,9,9a-hexahydroindeno[2,l-b][l,4]oxazine-7-carbonitrile (A69) (320 mg, 33% yield) as a yellow oil. MS ESI calculated for CBHUNIO [M+H]⁺, 215.11; found, 215. 10. ^;H NMR (300 MHz, DMSO-rfc) 8 7.76 - 7.46 (m, 3H), 4.25 (d, J = 3.6 Hz, 1H), 4.13 (t, ./ = 3.6 Hz, HI), 3.42 (dd, J = 10.8, 3.0 Hz, 1H), 3.06 - 2.88 (m, 3H), 2.73 (d, 16.5 Hz, 1H), 0.86 (d, J= 6.3 Hz, 3H). Intermediate A70 isomer 1: rei-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro-

2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 1 isomer 1 Intermediate A70 isomer 2: rel-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro-

2,3,4,4a,6,10b-hexahydro-lH-isocliromeno[4,3-b]pyridine isomer 2 isomer 2 _and?

Intermediate A70 isomer 3: iel-(3R,4aS,l0bS)-8-(difluoromethoxy)-3-fluoro-

2, 3, 4, 4a, 6, 1 Ob-hexahydro- lH-isochromeno[4,3-b]pyridine isomer 3 isomer S _and,

Intermediate A70 isomer 4: rel-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro-

2,3,4.4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 4

isomer 4

Step-1 :

[1310] To a stirred mixture of 2-bromo-5-bydroxybenza1dehyde (12 g, 59.69 mmol) in DCM (200 mL) was added KOH (20%, aq.) (200 niL, 358.17 mmol) at 0 °C, then TMSCFsBr (24.25 g, 119.39 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was extracted with DCM. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Ute residue was purified by flash column chromatography with 10-30%’ ethyl acetate in petroleum ether to afford 2-bromo-5-(difluoromethoxy)benzaldehyde (13 g, 86%) as a light yellow oil. MS ESI calculated for CsHsBrFjO? [M+H]⁺, 250.94, 252.94; found, 250.90. 252.95. [1311] To a stirred mixture of 2-bromo-5-(difluoromethoxy)benzaldehyde (5 g, 19.91 mmol) in THE (50 mL) was added NaBH/, (1.51 g, 39.83 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of water at 0 °C. The mixture was extracted with DCM, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (2-bromo-5-(difluoromethoxy)pheny1)meliianol (4.9 g, crude) as a white solid. MS ESI calculated for CsHrBrFzOz [M+l ]⁺, 252.96, 254.96; found, 252.85, 254.85.

Step-3:

[1312] To a stirred mixture of (2-bromo-5-(difluoromethoxy)phenyl)methanol (4.9 g, 19.36 mmol) in DCM (50 mL) were added TEA (5.87 g, 58.08 mmol) and AcjO (2.17 g, 21.30 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 10-30% ethyl acetate in petroleum ether to afford 2-bromo-5- (difluoromethoxy)benzyl acetate (4.9 g, 85%) as a white solid. MS ESI calculated for CsoHyBrFzOs [M+l ]⁺, 294.97, 296.97; found, 294.95, 297.00.

Step-4:

[1313] To a stirred mixture of 2-bromo-5-(difluoromethoxy)benzyl acetate (4.9 g, 16.60 mmol), AcOK (4.89 g, 49.81 mmol) and BPD (4.64 g, 18.26 mmol) in 1,4-dioxane (50 mL) was added Pd(dppl)Ch (0.92 g, 1.66 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature, this was followed by the addition of a mixture of K2CO3 (5.94 g, 42.96 mmol), 2-bromo-3,5-difluoropyridine (3.33 g, 17.18 mmol) and Pd(dppf)C12 (1.17 g, 1.43 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The mixture was diluted with ethyl acetate, washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 10-30% ethyl acetate in petroleum ether to afford 5-(difluoromethoxy)-2-(3,5- difluoropyridin-2-yl)benzyl acetate (2.1 g, 44%) as a yellow oil. MS ESI calculated for C_i5HiiF₄NO3 [M+H] L 330.07; found, 330.05.

Step-5 ;

[1314] To a stirred mixture of 5-(difluoromethoxy)-2-(3,5-difluoropyridin-2-yl)benzyl acetate (2.1 g, 6.37 mmol) in H2O (6 mL.) and THF (18 mL) was added LiOH (0.61 g, 25.51 mmol) at room temperature. The resulting mixture was stirred at room temperature for 48 h. The aqueous solution was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NhoSOr. After filtration, the filtrate was concentrated under reduced pressure to afford (5-(difluoromethoxy)-2-(3,5- difluoropyridin-2-yl)phenyl)methanol (1.6 g, crude) as a yellow oil. MS ESI calculated for C13H9F4NO2 [M+l]⁺, 288.06; found. 288.05.

Step-6:

[1315] To a solution of (5-(difluoromethoxy)-2-(3,5-difluoropyridin-2-yl)phenyl)methanol (1.6 g, 5.57 mmol) in THF (20 mL) was added NaH (0.27 g, 6.75 mmol, 60% in mineral oil) in portions at 0 °C. The mixture was allowed to warm at room temperature and stirred for 16 h. The reaction mixture was quenched by water and extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 20-50% ethyl acetate in petroleum ether to afford 8- (difiuoromethoxy)-3-fluoro-6H-isochromeno[4,3-b]pyridine (1.3 g, 87%) as a white solid. MS ESI calculated for C d kb .M b i MM H . 268.05: found, 268.05.

[1316] To a solution of 8-(difluoromethoxy)-3-fluoro-6H-isochromeno[4_!3-b]pyridine (500 mg, 1.87 mmol) in THF (5 mL) were added HC1 (con.) (163 mg, 4.49 mmol) and H2O (5 ml,), then Pd(OH)?/C (5%;) (500 mg, 3.56 mmol) was addded. The mixture was hydrogenated at room temperature under hydrogen atmosphere (50 atm.) for 24 h. The mixture was filtered through a Celite pad. The filtrate -was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30* 150 mm 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5%' B in 2 min, 3% B to 16%' B in 15 min; Wave Length: 254/220 nm; RTl (min): 4.5-10.2) to afford fraction A ( 150 mg) as a white solid as the first eluting peak and fraction B (50 mg) as a white solid as the second eluting peak.

[1317] The fraction A was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NHs-MeOH), Mobile Phase B: MEOH : DCM=1:1-HPLC; Flow rate: 20 niL/min; Gradient: 15% B to 15% B in 20 min; Wave Length: 220/254 nra; RTl(min): 12.85; RT2(min): 15.54; Sample Solvent: EtOH : DCM=1 : 1— HPLC; Injection Volume: 0.2 mb; Number Of Runs: 18) to afford rel-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro-2₎3,4,4a,6.10b-hexahydro-lH- isochromeno[4,3-b]pyridine isomer 1 (A70 isomer 1) (50 mg, 33%) as a white solid with retention time at 12.85 min. and rel-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 2 (A70 isomer 2) (50 mg, 33%) as a white solid with retention time at 15.54 min.

[1318] rel-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine isomer 1 (A70 isomer 1): MS ESI calculated for CJSHUFJNO? [M+H]\ 274.10; found, 274.15. ‘H NMR (300 MHz, DMSO-ds) 8 (ppm) 5 7.45 - 6.99 (m, 3H), 6.94 - 6.87 (m, 1H), 4.78 (d, J = 15.6 Hz, 1H), 4.69 - 4.45 (m, 2H), 3.65 - 3.59 (m, 1H),

3.56 (s, 1H), 3.06 - 2.79 (m, 2H), 2.21 - 1.84 (ra, 3H). Absolute stereochemistry was not determined.

[1319] rel-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine isomer 2 (A70 isomer 2): MS ESI calculated for C13H14F3NO2 [M+H]\ 274.10; found, 274.15. (300 MHz, DMSO-cfe) 3 (ppm) 6 7.47 - 6.97 (m, 3H), 6.95 - 6.87 (m, 1H), 4.78 (d. J = 15.6 Hz, 1H), 4.69 - 4.45 (m, 2H), 3.67 - 3.59 (m, 1H),

3.57 (s, 1H), 3.03 - 2.79 (rn, 2H), 2.23 - 1.95 (m, 3H). Absolute stereochemistry was not determined.

[1320] The fraction B (300 mg) was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A; Hex (0.5% 2M NH₃-MeOH)-HPLC, Mobile Phase B: EtOH : DCM=1:1-HPLC; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 13 min; Wave Length: 220/254 nm; RTl(min): 8.91 ;

RT2(min): 11.83; Sample Solvent: EtOH ; DCM=1:1--HPLC; Injection Volume: 0.5 mb;

Number Of Runs: 10) to afford rel-(3R,4aS,10bS)-8-(dilluoromethoxy)-3-lluoro- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 3 (A70 isomer 3) (70 mg, 23%) as a white solid with retention time at 8.91 min. and rel-(3R,4aS,10bS)-8- (difluoronietiioxy)-3-fluoro-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine isomer 4 (A70 isomer 4) (70 mg, 23% )as a white solid with retention time at 1 1.83 min.

[1321] rel-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine isomer 3 (A70 isomer 3): MS ESI calculated for CfoHisNO [M+H]⁺, 190.12; found, 190.05. ^jH NMR (300 MHz, DMSO-d₆) 8 (ppm) 8 7.60 (d, 8.7 Hz, IH), 7.47 - 6.92 (rn, 2H), 6.91 - 6.89 (m, IH), 4.82 (t, 7 - 16.5 Hz. 2H), 4.72 - 4.42 (m, 1 H), 3.38 - 3.31 (m, 1H), 3.29 - 3.13 (m, 2H), 2.68 - 2.55 (m, 2H), 2.49 - 2.43 (m, 1H), 1.70

- 1.52 (m, IH). Absolute stereochemistry was not determined.

[1322] rel-(3R,4aS,10bS)-8-(difluoromethoxy)-3-fluoro-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridine isomer 4 (A70 isomer 4): MS ESI calculated for C12H15NO [M+H]⁺, 190.12; found, 190.05. ^!H NMR (300 MHz, DMSO-zfc) 8 (ppm) 6 7.60 (d, J = 8.4 Hz, IH), 7.47 - 6.92 (m, 2H), 6.91 •■■ 6.89 (m, IH), 4.82 (t, J = 16.2 Hz, 2H), 4.72 - 4.42 (m, IH), 3.38 - 3.31 (m, IH). 3.29 - 3.13 (m, 2H), 2.68 - 2.55 (m. 2H), 2.49 - 2.43 (m, 1H), 1.70

- 1.52 (m, IH). Absolute stereochemistry was not determined.

Intermediate A71: rel-(4aR,9bR)-7-(difluoromethoxy)-l,2,3,4,4a,9b-hexahydrofuro[2,3- b:4,5-b']dipyridine

Step- 1 :

[1323] To a stirred solution of 5-bromo-6-chloropyridin-2-amine (70 g, 168.70 mmol) in

H2SO4 (1400 mL, 20%) was added a solution of NaNCh (46.56 g, 337.41 mmol) in H2O (700 mL) dropwise at 0 °C. The resulting mixture -was stirred at 0 °C for 1 h. The precipitated solids were collected by filtration and washed with water. The filter cake was concentrated under reduced pressure to afford 5-bromo-6-chloropyridiB-2-ol (68 g, crude) as a light brown solid. MS ESI calculated for C5H3B1CINO [M+HJ⁺, 207.91 , 209.91 ; found, 207.95, 209.95.

Step-2:

[1324] To a stirred solution of 5-bromo-6-chloropyridin-2-ol (62 g, 297.45 mmol) in DMF (620 mL) and H2O (62 mL) were sequentially added K2CO3 (82.22 g, 594.89 mmol) and sodium 2-chloro-2,2-difluoroacetate (68.02 g, 446.17 mmol) at 0 °C. The mixture was stirred al 100 °C for 2 h. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was quenched with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO-i. The residue was purified by silica gel column chromatography, eluted with PE / DCM (10: 1) to afford 3- bromo-2-chloro-6-(difluoromethoxy (pyridine (71 .2 g, 92%) as a colorless oil. MS ESI calculated for CeHaBrCIFzNO [M+H]⁺, 257.91, 259.90; found, 257.95, 259.95.

Step-3:

[1325] To a stirred solution of 3-bromo-2-chloro-6-(difluoromethoxy)pyridine (33 g, 127.68 mmol) and (E)-tert-butyldiphenyI((5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)penl-4-en-l-yl)oxy)si1ane (57.52 g, 127.68 mmol) in 1,4-dioxane (330 mL) and HzO (33 mb) were added K2CO3 (52.94 g, 383.05 mmol) and Pd(dppf)Cl?-CH2Cb (10.43 g, 12.77 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO^ After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / PE ( 1: 10) to afford (E)-3-(5- ((tert-butyldiphenylsilyl)oxy)pent-l-en-l -yl)-2-chioro-6-(difluoromethoxy)pyridine (36.4 g, 57%) as a yellow oil. MS ESI calculated for CzrEboClFyNOcSi [M+H]⁴, 502.17; found, 502.15. Step-4:

[1326] To a stirred mixture of BocNEh (15.87 g, 135.64 mmol, 0.4 M in n-PrOH) and NaOH (5.42 g, 135.64 mmol, 0.4 M aq.) was added DCD.MH (26.72 g, 135.64 mmol) in portions at 0 °C. The resulting solution was stirred at 25 °C for 0.5 h. Then (DHQftPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (3.52 g, 4.52 mmol, 0.1 M in n-PrOH) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for additional 20 min. Then (E)-3-(5-((t.ert-butyldiphenylsilyl)oxy)pent-l-en-l-y])-2-chloro-6- (difluoromethoxy (pyridine (22.7 g, 45.21 mmol) and K2OSO4-2H2O (1.67 g, 4.52 mmol) were added at 0 °C. The resulting mixture was stirred at room temperature for additional 16 h. The resulting mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSO/n After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford rel-tert-butyl ((lS,2S)-5-((tert-butyldiphenylsilyl)oxy)-l-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-2- hydroxy pent yDcarbamate ( 12.2 g, 42%) as a yellow solid. MS ESI calculated for C₃2H4iCIF2N₂O5Si [M+H]⁺, 635.24; found, 635.25.

Step-5 :

[1327] To a stirred solution of rel-tert-buty] ((1 S,2S)-5-((tert-butyldiphenylsilyl)oxy)-l-(2- chloro-6-(difluoromethoxy)pyridin-3 -yl)-2-hydroxypentyl)carbamate (4.4 g, 6.93 mmol) in THF (45 mL) was added TBAF (3.62 g, 13.85 mmol) in portions at 0 °C. The resulting solution was stirred at 25 °C for 2 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to afford rel-tert-butyl ((lS,2S)-l-(2-chloro-6-(difluoroinethoxy)pyridin-3-yl)-2,5- dihydroxypentyl)carbamate (1.3 g, 47%) as a white solid. MS ESI calculated for C16H23CIF2 N2O5 [M+H]⁺, 397.13; found, 397.15.

Step-6:

[1328] To a stirred solution of rel-tert-butyl ((lS,2S)-l-(2-chloro-6- (difluoromethoxy)pyridin-3-yl)-2,5-dihydroxypentyl)carbamate (1.3 g, 3.27 mmol) and imidazole (0.45 g, 6.55 mmol) in DCM (13 mL) was added TBSC1 (0.74 g, 4.91 mmol) at 0 °C. The resulting solution was stirred at 25 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc ( 1:1 ) to afford rel-tert-butyl ((1 S,2S)-5-((tert- butyldimethylsilyl)oxy)-l-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-2- hydroxypentyljcarbamate ( 1.3 g. 77%) as a colorless oil. MS ESI calculated for

[1329] To a stirred solution of rel-tert-butyl ((lS,2S)-5-((tert-buty1dimethy1silyl)oxy)-l-(2- chloro-6-(difluoromethoxy)pyridin-3-yl)-2-hydroxypentyl)carbamate (1.3 g, 2.54 mmol) and imidazole (0.35 g, 5.09 mmol) in DCM (1.3 mL) was added TBDPSC1 (1.05 g, .3.81 mmol) at

0 °C. The resulting solution was stirred at 25 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / PE (1: 1) to afford rel -tert-butyl ((lS,2S)-5-((tert- butyldimethy]silyl)oxy)-2-((teri-butyldipheny]silyr)oxy)-l-(2-chloro-6-

(difluoromethoxy)pyridin-3-yl)pentyl)carbamate (380 mg, 20%) as a colorless oil. MS ESI calculated for CasHssCWWsSii [M+Hj⁺, 749.33; found, 749.35.

[1330] To a stirred solution of rel-tert-butyl ((l S,2S)-5-((tert-biHy]dimethylsilyl)oxy)-2- ((tert-butyldiphenylsilyl)oxy)-l-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)pentyl)carbamate (330 mg, 0.44 mmol) in methanol (3 mL) was added TsOH (15 mg, 0.09 mmol) at room temperature. The resulting solution was stirred at 25 °C for 2 h. The resulting mixture was concentrated under reduced pressure . The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford rel-tert-butyl ((lS,2S)-2-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-5- hydroxypentyljcarbamate (22.0 mg, 78%) as a colorless oil. MS ESI calculated for C₃2H4iClF2N₂O5Si [M+H]⁺, 635.24; found, 635.15.

Step-9:

[1331] To a stirred solution of rel-tert-butyl ((lS,2S)-2-((tert-butyldiphenylsilyl)oxy)- 1 -(2- chloro-6-(difluoromethoxy)pyridin-3-yl)-5-hydroxypentyl)cafbamate (200 mg, 0.31 mmol) in toluene (4 mL) was added 2-(tributyl-V-phosphaneylidene)acetonitrile (CAS No. 157141-27- 0) (152 mg, 0.63 mmoJ) dropwise at room temperature under nitrogen atmosphere. The resulting solution was stirred at 110 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / ElOAc (10: 1) to afford rel-tert-butyl (2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-(2- chloro-6-(difluoromethoxy)pyridin-3-yl)piperidine-l-carboxy1ate (150 mg, 77%) as a white solid. MS ESI calculated for C₃2H₃₉ClF2N2O4Si [M+H]⁺, 617.23: found, 617.10.

Step- 10:

[1332] To a stirred solution of rel-tert-butyl (2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-(2- chloro-6-(difluoromethoxy)pyridin-3-yI)piperidine-l-carboxy1ate (150 mg, 0.24 mmol) in THF (2 mL) was added TBAF (127 mg, 0.48 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EtOAc (5: 1) to afford rel-tert-butyl (2S,3S)-2-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-3- hydroxypiperidine-1 -carboxylate (60 mg, 65%) as a colorless oil. MS ESI calculated for C16H21CIF2N2O4 [M+H]⁺, 379.12; found, 379.05.

Step- 1 1 :

[1333] To a stirred solution of rel-tert-butyl (2S,3S)-2-(2-chloro-6-

(difluoromethoxy)pyridin-3-yl)-3-hydroxypiperidine-l-carboxylate (55 nig, 0.14 mmol) in

THF (1 mL) was added NaH (2 mg, 0.06 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred at 0 °C for 1 h. The reaction was quenched by the addition of ice water at 0 ° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford rel-tert-butyl (4aS,9bS)-7- (difluoromethoxy)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-1 (2H)-carboxylate (25 mg, 50%) as a white solid. MS ESI calculated for C16H20F2N2O4 [M+H]⁺, 343.14; found, 343.10.

Step- 12:

[1334] A mixture of rel-tert-butyl (4aS,9bS)-7-(difluoromeihoxy 1-3, 4, 4a, 9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (25 mg, 0.12 mmol) and HCl (4.0 M in 1,4-dioxane) (1 niL) was stirred at 25 ⁰ C for 1 h. The resulting mixture was concentrated under reduced pressure to afford rel44aS,9bS)-7-(difluorornethoxy)-

1, 2, 3, 4, 4a, 9b-hexahydroturo[2,3-b:4,5-b']dipyridine hydrochloride (A71) (40 mg, crude) as a white solid . MS ESI calculated for Ci 1 H12F2N2O2 [M+H]⁺, 243.09; found, 243.10. >H NMR (400 MHz, DMSO-ds) 5 9.95 (br, 1H), 8.59 (br, 1H), 8.02 (d, 8.0 Hz 1H), 7.65 (t, J =

71.6 Hz, 1H), 6.74 (d, J = 8.0 Hz 1H), 4.94 - 4.89 (m, 1H), 4.87 - 4.82 (m, 1H), 3.18 - 3.07 (ra, 1H), 2.99 - 2.88 (m, 1 H), 2.29 - 2.19 (m, 1H), 2.11 - 1.99 (m, 1 H), 1.83 - 1.66 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A72: rel-(2R,4aS,9bS)-7-rnethoxy-2-methyl-l,2,3,4,4a,9b-hexahydrofuro[2,3- b:4,5-b']dipyridine

[1335] A mixture of 3-bromo-2-chloro-6-methoxypyridine (25.0 g, 112.37 mmol). Pd(OAc>2. (5.04 g, 22.47 mmol), TBAC (34.36 g, 12.3.61 mmol), AcOK (33.08 g. 337.122 mmol) and hex-5-en-2-one (12.14 g, 123.61 mmol) in DMF (1750 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched with saturated NaHCCh (aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue -was purified by flash column chromatography with 0-10% EtOAc in PE to afford (E)-6-(2-chloro-6-methoxypyridin-3-yl)hex-5-en-2-one (13.2 g, 48%) as a yellow oil. MS ESI calculated for C12H14CINO2 [M+H]⁺, 240.07; found, 240.10.

Step-2:

[1336] A mixture of (E)-6-(2-ch]oro-6-methoxypyridin-3-yl)hex-5-en-2-one (13.2 g, 55.06 mmol) and NaBH4 (4.17 g, 110.14 mmol) in methanol (132 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of ice water at 0 °C and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-20% EtOAc in PE to afford a 1:1 mixture of (R,E)-6-(2-chloro-6-methoxypyridin-3-yl)hex-5-en-2-ol and (S,E)-6-(2- chloro-6-methoxypyridin-3-yl)hex-5-en-2-ol (9.2 g, 69% j as a yellow oil. MS EST calculated for Ci2H_!6ClNO2 [M+H]⁺, 242.09; found, 242.10. Step 3:

[1337] To a stirred solution of a 1 : 1 mixture of (R,E)-6-(2-chloro-6-methoxypyridin-3- yl)hex-5-en-2-oi and (S,E)-6-(2-chloro-6-meihoxypyridin-3-yl)hex-5-en-2-o1 (9.2 g, 38.06 mmoi) in DCM (92 mL) were added Imidazole (5.18 g, 76.12 mmol) and tert- butyl(chloro)dimethylsilane (7.46 g, 49.48 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-10% EtOAc in PE to afford a 1 : 1 mixture of (R,E)-3-(5-((tert-butyldimethylsilyl)oxy)hex-l-en-1-y1)-2-chloro-6-methoxypyridine and (S,E)-3-(5-((tert-butyldimethylsilyl)oxy)hex-l-en-l -yl)-2-chloro-6-methoxypyridine (13.2 g, 97%) as a yellow oil. MS ESI calculated for CisHaoCINOzSi [M+H]⁺, 356.17; found, 356. 15.

Step 4:

[1338] A mixture of a 1:1 mixture of (R,E)-3-(5-((tert-butyldimethylsilyl)oxy)hex-l-en-l- yl)-2-chloro-6-methoxypyridine and (S,E)-3-(5-((tert-butyldimethylsilyl)oxy)hex-l-en-l-yl)- 2-chloro-6-methoxypyridine (11.2 g, 3 1 .43 mmol), sodium (tert-butoxycarbonyDchloroamide (16.89 g, 97.44 mmol), 1-[(R)-[(2R,4S,5R)-5-ethyl-l-azabicyclo[2.2.2]octan-2-yl](6- methoxyqumolm-4-yl)methoxy]-4-[(lS)-l-(pyridin-4-yl)propoxy]phthalazine ((supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1)) (2.49 g, 3.14 mmol) and Potassium osmate(VI) dihydrate (2.32 g. 6.28 mmol) in propan- 1 -ol (125 ml) and HzO (62 mL) was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction mixture was quenched with saturated NaHCCL (aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 10% ~ 80% MeCN in Water (10 mmol/L NH4HCO3) to afford a 1:1 mixture of tert-butyl (( 1 R*,2R*,5R)-5-((tert-butyldimethylsilyl)oxy)- 1 -(2-chloro-6- methoxypyridin-3-yl)-2-hydroxyhexyl)carbamate and tert-butyl ((lR*,2R*,5S)-5-((tert- butyldimethylsilyl)oxy)-l-(2-chloro-6-metiioxypyridin-3-yl)-2-hydroxyhexyl)carbamate (6.9 g, 44%) as a brown oil. MS ESI calculated for CzsEkiClNiOsSi [M+H]⁺, 489.25; found, 489.30.

Step 5:

[1339] A mixture of 1 : 1 mixture of tert-butyl ((lR*,2R*,5R)-5-((tert- butyldimethylsilyl)oxy)-l-(2-chloro-6-methoxypyridin-3-yl)-2-hydroxyhexyl)carbaniate and tert-butyl ((lR*,2R*,5S)-5-((.tert-butyldimethylsilyl)oxy)-l-(2-chloro-6-methoxypyridin-3- yl)-2-hydroxyhexy1)carbamate (6.9 g, 14.10 mmol), PdiOAch (633 mg, 2.82 mmol), JohnPhos (1.68 g, 5.64 mmol) and CsjCCh (13.8 g, 42.31 mmol) in toluene (75 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0 - 20% EtOAc in PE to afford a 1 : 1 mixture of tert-butyl ((2R*,3R*)-2-((R)-3-((tert-butyidimethylsilyl)oxy)butyl)-6-methoxy-2,3-dihydrofuro[2,3- b]pyridin-3-yl)carbamate and tert-butyl ((2R*,3R*)-2-((S)-3-((tert- butyldimethylsilyl)oxy)butyl)-6-methoxy-2,3-dihydrofiiro[2,3-b]pyridin-3-yl)carbamate (3.9 g, 61%) as a light yellow oil. MS ESI calculated for CzsH^NiOsSi [M+H]⁺, 453.27; found, 453.35.

[1340] To a mixture of a 1: 1 mixture of tert- butyl ((2R*,3R*)-2-((R)-3-((tertbutyldimethylsilyl)oxy)butyl)-6-methoxy-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tert-butyl ((2R^t:;,3R*)-2-((S)-3-((tert-butyldimethylsiiyl)oxy)butyi)-6-meihoxy-2,3- dihydrofuro[2,3-bjpyridin-3-yl)carbamate (3.9 g, 8.61 mmol) in methanol (80 mL) was added hydrogen chloride (4.0 M in ethyl acetate) (39 mL). The mixture was stirred at room temperature for 0.5 b. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (80 mL), EtsN (17.44 g, 172.32 mmol) and BociO (4.70 g, 21.54 mmol) were added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 16 h. Ute reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-80% EtOAc in PE to afford a 1: 1 mixture of tert-butyl ((2R*,3R*)-2-((R)-3-hydroxybutyl)-6-methoxy-2,3- dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tert-butyl ((2R*,3R*)-2-((S)-3-hydroxybutyl)- 6-methoxy-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (2.3 g, 79%) as a white solid. MS ESI calculated for C17H26N2O5 [M+H]⁺, 339.18; found, 339.15.

Step 7:

[1341] A mixture of a 1: 1 mixture of tert-butyl ((2R*,3R*)-2-((R)-3-hydroxybutyl)-6- methoxy-2.3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tert-butyl ((2R*,3R*)-2-((S)-3- hydroxybutyl)-6-methoxy-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (2.3 g, 6.79 mmol) and 2-(tributyl%''-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (3.28 g, 13.59 mmol) in toluene (23 mL) was stirred at 110 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0 ~ 10% EtOAc in PE to afford a 1:1 mixture of tert-butyl (2S,4aR^SK,9bR*)-7-metlioxy-2-methyl-3,4,4a,9b-tetraliydrofuro[2,3-b:4,5-b’]dipyridine- l(2H)-carboxylate and tert-butyl (2R,4aR*,9bR*)-7-mdhoxy-2-methyl-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (1,8 g, 82%) as a yellow oil. MS ESI calculated for C17H24N2O4 321.17; found, 321.15.

Step 7 ;

[1342] The 1: 1 mixture of tert-butyl (2S,4aR*,9bR*)-7-methoxy-2-methyl-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-cart>oxylate and tert-butyl (2R,4aR*,9bR*)-7- methoxy-2-methyl-3₎4,4a,9b-tetrahydrofuro[2,3-b:4,5-b^,]dipyridine-l(2H)-carboxylate (1.8 g) was separated by Prep-chiral SFC with the following conditions: [Column: CHIRALPAK IG, 5*25 cm, 10 pm; Mobile Phase A: CO₂, Mobile Phase B: MEOH: MTBE=1: 1 (0.1 % 2M NH3M); Flow rate: 100 mL/min; Gradient (B%): isocratic 20% B; RTl(min): 7; RT2(min): 9; Sample Solvent: MEOH] to afford fraction A with retention lime at 7 minute. The fraction A was further separated by Prep-chiral SFC with the following conditions: [Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 80 mL/min; Gradient (B%): isocratic 15% B; RTl(min): 4.2; RT2(min): 5.5; Sample Solvent: MEOH] to afford rel-tert-butyl (2R,4aS,9bS)-7-methoxy-2-methyl- 3,4,4a,9b-tetTahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate isomer 1 (500 rag) as a light yellow solid with retention time at 5.5 minute.

[1343] Ute first chiral resolution also afford rel-tert-butyl (2R,4aS,9bS)-7-methoxy-2- methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxylate isomer 2 (800 mg) as a light, yellow solid with retention time at 9 minute.

[1344] rel-tert-butyl (2R,4aS,9bS)-7-methoxy-2-methyl-3,4,4a,9b-tetrahydrofiiro[2,3-b:4,5- b']dipyridine-l (2H)-carboxylate isomer 1: MS ESI calculated for C17H24N2O4 [M+H]⁺, 321.17; found, 321.15. ^:H NMR (400 MHz, DMSO-Jc) 5 (ppm) 7.43 (d, 7 - 8.0 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 5.87 (d, J - 10.4 Hz, 1H), 5.18 - 5.12 (m, 1H), 3.96 - 3.86 (m, 1H), 3.79 (s, 3H), 1.90 - 1.74 (m, 2H), L70 - 1.56 (in, 1H), 1.47 (s, 9H), 1.21 - 1.06 (m, 1H), 0.81 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was not determined.

[1345] rel-tert-butyl (2R,4aS,9bS)-7-methoxy-2-methy]-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b']dipyridine-l(2H)-carboxylate isomer 2: MS ESI calculated for C17H34N2O4 [M+l]⁺, 321.17; found, 321.15. ^!H NMR (400 MHz, DMSO-db) 3 (ppm) 7.76 (d, J = 8.0 Hz, 1H), 6.29 (d, J = 8.0 Hz, 1H), 5.30 - 5.18 (m, 1H), 5.02 - 4.96 (m, 1H), 3.87 - 3.75 (m, 4H), 2.05 - 1.86 (m, 2H), 1.77 - 1.66 (m. 1H), 1.51 - 1.40 (m, 10H), 1.20 (d. J = 6.4 Hz, 3H).

Absolute stereochemistry was not determined.

Step 8:

[1346] To a mixture of rel-ten-butyl (2R,4aS,9bS)-7-meihoxy-2-methyl-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b'|dipyridine-l(2H)-carboxylate isomer 1 (500 mg, 1.56 mmol) in ethyl acetate (5 mL) was added hydrogen chloride (4.0 M in ethyl acetate) (5 mL) was stirred at room temperature for 16 h. Hie resulting mixture was concentrated under reduced pressure to afford rel-(2R,4aS,9bS)-7-methoxy-2-methyl-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5- b’Jdipyridine hydrochloride (A72) (450 mg, crude) as a yellow semi-solid. MS ESI calculated for C12H16N2O2 [M+Hj⁺, 221.12; found, 221.10. ^]H NMR (400 MHz, DMSO-ifc) 8 (ppm) 10.37 (br, 1H), 7.98 (br, 1H), 7.84 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 4.85 - 4.68 (m, 2H), 3.83 (s, 3H), 3.26 - 3.10 (m, 1H), 2.13 - 1.97 Im, 2H), 1.81 - 1.71 (m, 1H), 1.59 - 1.48 (m, 1H), 1.22 (d, J ~ 6.4 Hz, 3H). Relative stereochemistry was determined by NOESY. Absolute stereochemistry was not determined.

Intermediate A73 isomer 1: rel-(5aR,8R,9aR)-3-methoxy-8-methyl-5a, 6,7,8,9,9a- hexahy dropyrido [2' , 3 ’ : 4, 5 ]f uro [2, 3 -b] pyrazine i somer 1 isomer 1 _and>

Intermediate A73 isomer 2: iel-(5aR,8R,9aR)-3-methoxy-8-methyl-5a,6,7,8,9,9a- hexahydropyrido[2',3’;4,5]furo[2,3-b]pyrazine isomer 2

Isomer 2

Intermediate A73 isomer 3: rel-(5aR,8R,9aR)-3-methoxy-8-methyl-5a,6,7,8,9,9a- hexahydropyrido[2’,3':4,5]furo[2,3-b]pyrazine isomer 3 i^{somer 3} and, Intermediate A73 isomer 4: reI-(5aR,8R,9aR)-3-methoxy-8-methyl-5a,6,7,8,9,9a- hexahydropyrido[2\3':4,5]furo[2,3-b]pyrazine isomer 4

Step-1 :

[1347] To a stirred solution of 5-bromo-6-chloropyrazin-2-amine (350.0 g, 1679.14 mmol) in H2SO4 (875 mL) was added a solution of Sodium nitrite (129.8 g, 1880.63 mmol) in water ( 100 mL) dropwise at 0 °C. The resulting solution was then stirred at 0 °C for 1 h. The reaction was quenched by ice water. The precipitated solids were collected by filtration and washed with water to afford 5-bromo-6-chloropyrazin-2-ol (302.2 g, 85%) as a yellow solid.

MS ESI calculated for C4H2B1CIN2O [M-l]", 206.90/208.90; found, 206.85/208.85.

Step-2:

[1348] To a stirred solution of 5-bromo-6-chloropyrazin-2-ol (300.0 g, 1432.46 mmol), methanol (91.8 g, 2864.92 mmol), PPI13 (751.5 g, 2864.92 mmol) in THE (3000 ml..) was added DIAD (579.3 g, 2864.92 mmol) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was diluted and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO,i. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0 - 20% petroleum ether in ethyl acetate to afford 2-bromo-3-chloro-5-methoxypyrazine (201 .1 g, 62%) as a white solid. MS ESI calculated for CsH^BrClNcO [M+H]*, 222.92/224.92; found, 222.90/224.85.

Step-3:

[1349] A mixture of 2-bromo-3-chloro-5-methoxypyrazine (200. 1 g, 895.05 mmol), 1- hexen-5-one (175.7 g, 1790.11 mmol), Pd(OAc)₂ (10.0 g, 44.75 mmol), AcOK (87.8 g, 895.05 mmol) and tetrabutyl(chloro)aniine (746.3 g, 2685.16 mmol) in DMF (3000 niL) was stirred at. 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaaSO*. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0 ~ 20% petroleum ether in ethyl acetate to afford (E)-6-(3-chloro-5-methoxypyrazin-2-yl)hex-5-en-2-one (37.2 g, 17 %) as a brown oil. MS ESI calculated for Ci 1H13CIN2O2 [M+H]⁺. 241.07; found, 241.00.

Step-4:

[1350] To a stirred solution of tert-butyl carbamate (54.3 g, 463.66 mmol) in propan-l-ol (730 mL) was slowly added NaOH (aq. 0.4 M) (730 mL), the mixture was stirred at 0 °C for 15 min. Then l,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione (45.7 g, 231.83 mmol) was added. The resulting mixture was stirred at 0 °C for additional 30 min. This was followed by the addition of a solution of (DHQh-PHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (12.0 g, 15.45 mmol) in propan-l-ol (154 mL), after stirring at 0 °C for 20 min., (E)-6-(3-ch1oro-5-methoxypyrazin-2-yl)hex-5-en-2-one (37.2 g, 154.55 mmol) and K?OsO42H2O (5.7 g, 15.45 mmol) were sequentially added at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The mixture was purified by reverse phase flash column chromatography with 5~50% acetonitrile in water to afford rel-tert-butyl ((lS,2S)-l-(3-chloro-5-methoxypyrazin-2-yl)-2-hydroxy-5-oxohexyl)carbamate (5.1 g, 8%) as a yellow oil. MS ESI calculated for C16H24CIN3O5 [M+H]⁺, 374.14; found, 374.05.

Step-5:

[1351] To a stirred solution of rel-tert-butyl ((lS,2S)-l-(3-chloro-5-methoxypyrazin-2-y1)-

2-hydroxy-5-oxohexyl)carbamate (5.1 g, 13.64 mmol) and CsjCOs (1.8 g, 5.45 mmol) in toluene (100 mL) were added JohnPhos (3.3 g, 10.91 mmol) and Pd(OAc)₂ (9.2 g, 40.92. mmol). The resulting mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The mixture was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaaSOa. The resulting mixture was concentrated under reduced pressure. The mixture was purified by reverse flash chromatography with 5-30% acetonitrile in water to afford rel-tert-butyl ((6S,7S)-3-methoxy-6-(3-oxobutyl)-6,7-dihydrofiiro[2,3- b]pyrazin-7-yl)carbamate (1 .2 g, 26%) as a white solid. MS ESI calculated for C16H23N3O5 [M+H] ^h, 338.16 found, 338.10.

Step-6:

[1352] To a stirred solution rel-tert-butyl ((6S,7S)-3-methoxy-6-(3-oxobutyl)-6,7- dihydrofuro[2,3-b]pyrazin-7-yl)carbamate (1.1 g, 3.26 mmol) in methanol (20mL) was added NaBILi (0.4 g, 9.78 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The residue was quenched by ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography with 0 - 80% petroleum ether in ethyl acetate to afford a 1 :1 mixture of tert-butyl (<6R*,7R*)-6-((R)-3- hydroxybutyl)-3-methoxy-6,7-dihydrofuro[2,3-b]pyrazm-7-yl)carbamate and tert-butyl ((6R*,7R*)-6-((S)-3-hydroxybutyl)-3-methoxy-6,7-dihydrofuro[2,3-b]pyrazin-7- yl)carbaniate (0.8 g, 71%) as a yellow oil. MS ESI calculated for C16H25N3O5 [M+H]⁺,

340.18; found, 340.1b.

Step-7 :

[1353] To a stirred solution of 1:1 mixture of tert-butyl ((6R*,7R*)-6-((R)-3- hydroxybutyl)-3-methoxy-6,7-dihydrofuro[2,3-b]pyrazin-7-yl)carbamate and tert -butyl ((6R*,7R*)-6-((S)-3-hydroxybuty])-3-methoxy-6,7-dihydrofuro[2,3-b]pyrazin-7- yl)carbamate (750 mg, 2.21 mmol) in toluene (15 mL) was added 2-(tributyl-/?- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (1066 nig, 4.42 mmol). The resulting mixture was stirred at 100 °C for 5 h. The resulting mixture was concentrated under vacuum.

The crude was purified by reverse phase flash column chromatography with 5 ~ 60% acetonitrile in water to afford a 1 : 1 mixture of tert-butyl (5aR*,8R,9aR'^s)-3-methoxy-8- methyl-5a, /,8,9a-tetrahydropyrido[2',3':4,5]furo[2,3-b]pyrazine-9(6H)-carboxylate and tertbutyl (5aR*,8S,9aR*)-3-methoxy-8-methyl-5a,7,8,9a-tetrahydropyrido[2',3':4,5]furo[2,3- b]pyrazine-9(6H)-carboxylate (430 mg, 61%) as a yellow oil. MS ESI calculated for Ci6H₂₃N₃Qj [M+H]⁺, 322.17; found, 322.10.

Step-8:

[1354] A mixture of 1 : 1 mixture of tert-butyl (5aR*,8R,9aR*)-3-raethoxy-8-methyl- 5a,7,8,9a-tetrahydropyrido[2',3':4,5]furo[2,3-b]pyrazine-9(6H)-carhoxylate and tert-butyl (5aR*,8S,9aR*)-3-methoxy-8-methyl-5a,7,8,9a-tetrahydropyrido[2',3':4,5]furo[2,3- b]pyrazine-9(6H)-carboxylate (430 mg, 1.34 mmol) and HC1 in dioxane (4 mL, 4M) was stirred at 20 "C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was separated by Prep-Achiral SFC with the following conditions: [Column: GreenSep Basic 3*15 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH(1% 2M NH3-MEOH); Flow rate: 75 mL/min; Gradient (B%): isocratic 12% B; Column Temperature

(°C): 35; Back Press ure(bar): 100; Wave Length: 220 nm; RTl(min): 1.85; RT2(tnin): 2.75;

Sample Solvent: MEOH] to afford fraction A (110 mg, 31%) with retention time at 1.85 minute and fraction B (95 mg, 27%) with retention time at 2.75 minute [1355] The fraction A was separated by Prep-Chiral HPLC with the following conditions: [Column: CHIRAL ART Amylose-SC 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3- MeOH). Mobile Phase B: MEOH: DCM=1: 1--HPLC: Flow rate: 20 mL/min; Gradient (B%): 10% B to 10%' B in 20 min; Wave Length: 220/254 nm; RTl(min): 7.813; RT2(min): 14.583; Sample Solvent: MeOH: EtOH-1: 1— HPLC] to afford rel-(5aR,8R,9aR)-3-methoxy- 8-methyl-5a,6,7,8,9,9a-hexahydropyrido[2’,3':4,51furo[2,3-b]pyrazine isomer 1 (A73 isomer 1) (31 mg, 28% ) with retention time at 7.813 minute and rel-(5aR,8R.9aR)-3-methoxy-8- methyl-5a,6,7,8,9,9a-hexahydropyrido[2^!,3’:4,.5]furo[2,34r]pyrazine isomer 2 (A73 isomer 2) (30 mg. 27%) with retention time at 14.583 minute. Relative stereochemistry in Isomer 1 and isomer 2 were determined by NOESY. Absolute stereochemistry was not determined.

[1356] Ute fraction B was separated by Prep-Chiral HPLC with the following conditions: [Column: CHIRALPAK LG. 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)- HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient (B%): 15%' B to 15% B in 11.5 min; Wave Length: 220/254 nm; RTl(min): 7.85; RT2(min): 9.51 ; Sample Solvent: MeOH: DCM=1: 1-HPLC] to afford rel-(5aR,8S,9aR)-3-methoxy-8- methyl-5a,6,7,8,9,9a-hexahydropyrido[2\3':4,5]furo[2,3-b]pyrazine isomer 3 (A73 isomer 3) (22 nig, 22%) with retention time at 7.85 minute and rel-(5aR,8S,9aR)-3-methoxy-8-methyl- 5a,6,7,8,9,9a-hexahydropyrido[2',3':4,5]furo[2,3-b]pyrazine isomer 4 (A73 isomer 4) (32 mg, 34%) with retention time at 9.51 minute. Relative stereochemistry in Isomer 3 and isomer 4 were determined by NOESY. Absolute stereochemistry was not determined.

[1357] rel-(5aR,8R,9aR)-3-methoxy-8-methyl-5a,6,7,8,9,9a- hexahydropyrido[2',3’:4,5]furo[2,3-b]pyrazine isomer 1 (A73 isomer 1 j: MS ESI calculated for CnHssNsOj [M+Hj⁺, 222.12; found, 222.10. 'HNMR (400 MHz, DMSO-Je) S 7.73 (s, 1H), 4.93 - 4.89 (m, IH), 4.50 (d, 7 = 7.8 Hz, 1H), 3.84 (s, 3H), 2.61 - 2.54 (m, IH), 2.10 - 2.00 (tn, IH), 1.78 - 1.65 (m, IH), 1.63 - 1.56 (m, IH), 1.14 - 1.06 (rn, IH), 0.99 (d, 7 = 6.4 Hz, 3H). Absolute stereochemistry was not determined.

[1358] rel-(5aR,8R,9aR)-3-methoxy-8-methyl-5a,6,7,8,9,9a- hexahydropyrido[2^!,3':4,5]furo[2,3-b]pyrazine isomer 2 (A73 isomer 2): MS ESI calculated for CnHisNsCh [M+H]⁺, 222.12; found, 222.10. ’HNMR (400 MHz, DMSO-d₆) 8 7.73 (s, IH), 4.93 - 4.89 (m, IH), 4.50 (d, 7 = 7.8 Hz, IH), 3.84 (s, 3H), 2.61 - 2.54 (m, IH), 2.10 - 2.00 (m. IH), 1.78 - 1.65 (m, IH), 1.63 - 1.56 (m, IH), 1.14 - 1.06 (m, IH), 0.99 (d, 7 = 6.4 Hz, 3H). Absolute stereochemistry was not determined. [1359] rel-(5aR,8S,9aR)-3-meihoxy-8-methyl-5a,6,7,8,9,9a- hexahydropyrido[2‘,3':4,5]furo[2,3-b]pyrazine isomer 3 (A73 isomer 3): MS ESI calculated for C11H15N3O2 |M+H]⁺, 222.12; found, 222.10. 'H NMR (400 MHz, DMSO-d_f.) 3 7.69 (s, 1H), 4.64 - 4.58 (m, 1H), 4.12 (d, 4.8 Hz, 1H), 3.85 (s, 3H), 2.63 - 2.59 (m, 1H), 2.23 -

2.18 (m, 1H), 2.02 - 1.82 (m, 1H), 1.54 - 1.48 (m, 1H), 1.16 - 1.11 (m, III), 0.94 (d, J - 6.3 Hz, 3H). Absolute stereochemistry was not determined.

[1360] rel-(5aR,8S,9aR)-3-methoxy-8-methyl-5a,6,7,8,9,9a- hexahydropyrido[2',3':4,5]furo[2,3-b]pyrazine isomer 4 (A73 isomer 4): MS ESI calculated for CiiHssNjCh [M+H]⁺, 222.12; found, 222.10. ‘H NMR (400 MHz, DMSO-de) 8 7.69 (s, 1H), 4.64 - 4.58 (m, 1H), 4.12 (d, J= 4.8 Hz, 1H), 3.85 (s, 3H), 2.63 •■■■ 2.59 (m, 1H), 2.23 - 2.18 (m, 1H), 2.02 - 1.82 (no, 1H), 1.54 - 1.48 (m, 1H), 1.16 - 1.11 (m, 1H), 0.94 (d, 6.3

Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A74: rel-(4aR,10bR)-8-cyclopropoxy-2,3,4,4a,6,10b-hexahydro-lH- pyrano [3 ,2-b: 5 ,4-b']dipyridine

[1361] To a stirred mixture of rel-tert-butyl (4aR, 10bR)-8-chloro-2,3,4,4a,6, 10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate (from A40) (600 mg, 1.84 mmol) and cyclopropanol (321 nig, 5.54 mmol) in Dioxane (10 niL) were added CS2CO3 (2.41 g, 7.38 mmol), r,3',5'-triphenyl-5-{ [(lr,3R,5S,7s)-adainantan-l-yIJ[(3R,5S,7s)- adarnantan-l-yl]phosphanyl)-rH-l,4'-bipyrazole (183 mg, 0.27 mmol) and Pd2(dba)3-CHCh (286 mg, 0.27 mmol) al room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with Dioxane (10 mL), The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with 40% to 70%? MeCN in Water to afford rel- tert-butyl (4aR,10bR)-8-cyclopropoxy- 2, 3, 4, 4a, 6, lOb-hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridine- 1 -carboxylate (120 mg, 18% yield) as a colorless oil. MS ESI calculated for C19H26N2O4 [M+H]⁺, 347.19; found, 347. 10.

Step-2:

[1362] A mixture of rel-tert -butyl (4aR, 10bR)-8-cyclopropoxy-2,3,4,4a,6, lOb-hexahydro- lH-pyrano[3,2-b:5,4-b‘]dipyridine-l-carboxy]ate (55 mg, 0.15 mmol) and TIG in 1 ,4-dioxane (4.0 M) (1 mL) was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under vacuum to afford rel-(4aR,10bR)-8-cycIopropoxy-2,3,4,4a,6,l0b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine hydrochloride (A74) (50 mg, crude) as a white solid. MS ESI calculated for CixHigN-Or [M+H]⁺, 247.14; found, 247.10.

[1363] The absolute stereochemistry of A74 was determined as S, S-configuration, prepared from A40, the absolute stereochemistry of which was confirmed. Accordingly, A74 is represented by the structure:

Intermediate A75: rel-(4aS_!9bS)-7-isopropyl-l,2,3,4,4a,9b-hexahydrofbro[2,3-b:4,5- b'Jdipyridine

Step-1

[1364] A mixture of rel-tert-butyl (4aS,9bS)-7-chloro-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b'jdipyridine-l (2H)-carboxylate (180 mg, 0.58 mmol), 4,4,5,5-tetrarnethyl-2-(prop-l-en-2- yl)-l,3,2-dioxaborolane ( 197 mg, 1.17 mmol), PdldppffCii-CHhCl?. (42 mg, 0.05 mmol) and K.2CO3 (152 mg, 1.10 mmol) in Dioxane (2 mL) and H2O (0.5 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by normal phase flash chromatography with a 25 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether to afford rel-tert-butyl (4aS,9bS)-7-(prop-l-en-2-y1)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxyiate (130 mg, 71%) as a white solid. MS ESI calculated for C.d i >\ ( ) [M+H]⁺, 317.18; found, 317.15.

Step-2:

[1365] To a solution of rel-tert-butyl (4aS,9bS)-7-(prop- 1 -en-2-yl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b ]dipyridine-l(2H)-carboxylate (130 mg, 0.41 mmol) in methanol (5 mL) was added Pd/C (10% active on carbon) (130 mg) at room temperature. The mixture was degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The mixture was filtered through a Celite pad. The filtrate was collected and concentrated under vacuum to afford to afford rel-tert-butyl (4aS,9bS)-7- isopropyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (160 nig, crude) as a white solid. MS ESI calculated for ChsHicNgCh [M+H]⁺, 319.19; found, 319.15.

[1366] To a mixture of rel-tert-butyl (4aS,9bS)-7-isopropyl-3,4,4a,9b-letrahydrofuro[2,3- b:4,5-b']dipyridine-l(2H)-carboxylate (160 mg, 0.50 mmol) in Dioxane (1 mL) was added HC1 (4M in 1 ,4-dioxane) (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum to afford rel-(4aS,9bS)- 7-isopropyl-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b'ldipyridine hydrochloride (A75) (190 mg) as a white solid, which was used in the next step without further purification. MS ESI calculated for CfoHjs^O 219.15; found, 219.15. ^;H NMR (400 MHz, DMSO) 8 10.44 (s, 1H), 8.54 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 6.97 (d, 7 = 7.6 Hz, 1H), 4.84 - 4.72 (m, 2H), 3.25 - 3.03 (m, 1H), 2.96 - 2.77 (m, 1H), 2.26 - 2.17 (m, 1H), 2.12 - 1.94 (m, 1H), 1.80 - 1.64 (m, 3H), 1.21 (d, J = 6.8 Hz, 6H). Absolute stereochemistry was not determined.

Intermediate A76: rel-(5aR,l lbS)-9-(difluoromethoxy)-2,3,5,5a,7,l Ib-hexahydro-lH- isochromejio[4,3-e] [ 1 ,4]oxazepine

A76

Step-1:

[1367] To a stirred mixture of 2-((tert-buiy1dimethylsilyl)oxy)ethan-1 -ol (50.00 g, 143.96 mmol) in THE (500 mL) was added NaH (60% in mineral oil) (5.18 g, 129.5 mmol) in portions at 0 °C. After stirring at 0 °C for 1 h, 3 -bromoprop- 1-yne (40.58 g, 215.95 mmol) was added dropwsie at 0 °C. The resulting mixture was stirred at 50 °C for additional 16 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na^SCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-20% DCM in PE to afford tert-butyldimethyl(2-(prop-2-yn-l- yloxy)ethoxy (silane (49.40 g, 80%) as a yellow oil. MS ESI calculated for CnEbzCfeSi [M+H]⁺,215. 14: found.215.13.

Step-2:

[1368] To a mixture of tert-butyldimethyl(2-(prop-2-yn-l-yloxy)ethoxy)silane (49.40 g, 230.43 mmol), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (30.97 g, 241.95 mmol) and EtjN (2.33 g, 23.04 mmol) was added bis(cyclopenta-l,3-dieri-l-yl)zirconiumbis(ylium) chloride hydride (5.92 g, 23.04 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h under nitrogen atmosphere. The reaction mixture was treated with PE ( 100 mL), then the mixture was filtered, the filter cake was washed with PE. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0- 50% DCM in PE to afford (E)-tert-butyldimethyl(2-((3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)allyl)oxy)ethoxy (silane (24.51 g, 31%) as a yellow oil. MS ESI calculated for Ci7H₃5BO₄Si [M+H]⁺, 343.24; found, 343.23.

Step-3 : [1369] To a stirred mixture of (E)-tert-butyldimethyl(2-((3-(4,4,5,5-tetrametIiyl-l ,3,2- dioxaborolan-2-yl)allyl)oxy)ethoxy)silane (24.50 g, 71.56 mmol) and K2CO3 (29.67 g, 214.69 mmol) in dioxane (140 mL) and H2O (14 mL) was added Pd(dppf)Ch (5.24 g, 7.16 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 ^C’C for 1 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The fillrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% DCM in PE to afford methyl (E)-2-(3-(2-((tert- butyldimethylsilyljoxy )ethoxy)prop-l-en- 1 -yl)-5-(difluoromethoxy)benzoate (24.80 g, 83%) as a yellow oil. MS ESI calculated for C2oH3oF?.05Si [M+H]⁺, 417.18; found,417.17.

Step-4:

[1370] To a stirred mixture of tert-butyl carbamate (9.20 g, 78.50 mmol) in propan-l-ol (178 mL) were added a solution of NaOH (2.83 g, 70.65 mmol) in H2O (178 mL) at room temperature. After stirring al room temperature for 5 minutes, DCDMH (7.73 g, 39.25 mmol) was added at 0 °C. The resulting mixture was stirred at 0 °C for additional 30 minutes, this was followed by the addition of (DHQLPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1 ) (2.04 g, 2.61 mmol). Potassium osmate(VI) dihydrate (0.96 g, 2.61 mmol) and methyl (E)-2-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)prop- 1-en-l -yl)-5- (difluoromethoxy)benzoate (10.9 g, 26.16 mmol) at 0 °C. The resulting mixture was stirred at room temperature for additional 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaaSOa. After filtration, the filtrate was concentrated under reduced pressure.

[1371] The residue was dissolved in DCM (100 mL), then DCC (10.80 g, 52.33 mmol) and DMAP (643 mg, 5.22 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for additional 2 h. Tire resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:3) to afford rel -tert-butyl ((3R,4S)-3-((2-((tert- butyldimethylsilyl)oxy)ethoxy)methyI)-7-(difluoromethoxy)-l-oxoisochroman-4- yl)carbamate (10.5 g, 77% yield) as a yellow oil. MS ESI calculated for CzrHioFsNOrSi [MW, 518.23; found, 518.24.

Step-5:

[1372] To a stirred mixture of rel-tert-butyl ((3R,4S)-3-((2-((tert- butyldimethylsilyl)oxy)ethoxy)metbyl)-7-(difluoromethoxy)-l-oxoisochroman-4- yDcarbaniate (23.60 g, 45.59 mmol) in THF (240 mL) were added NaBHt (5.17 g. 136.77 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h. The reaction was quenched by the addition of water at 0 °C. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous NajSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford re! -tert-butyl ((lR,2S)-3-(2-((tert-butyldimethylsi1yl)oxy)ethoxy)-l-(4-(difluoromethoxy)-2- (hydroxymethyl)phenyl)-2-hydroxypropyl)carbamate (17.93 g, 75%) as a colorless oil. MS ESI calculated for (C24H4iF₂NO7Si) [M+H]⁺, 522.26; found, 522.25.

Step-6:

[1373] A solution of rel-tert-butyl ((lR,2S)-3-(2-((tert-butyidimethylsilyl)oxy)ethoxy)-l- (4-(difluoromethoxy)-2-(hydroxymethyl)phenyl)-2-hydroxypropyl)carbamate (17.80 g, 34.25 mmol) and 2-(tributyl-A.⁵-phosphaneylidene)acetonitriie (CAS No. 157141-27-0) (16.53 g, 68.50 mmol) in toluene (180 mL) was stirred at 110 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford rel-tert-butyl ((3R,4S)-3-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-7- (difluoromethoxy)isochroman-4-yl)carbamate (10.84 g, 62%) as a brown oil. MS ESI calculated for C 24H [M+H]⁺, 504.25; found, 504.24.

Step-7:

[1374] To a mixture of rel-tert-butyl ( (3R,4S)-3-((2-((tert- butyldimethylsilyl)oxy)etboxy)methy])-7-(difluoromethoxy)isochroman-4-yl)carbamate

(10.70 g, 20.59 mmol) in THF (110 mL) was added TBAF (10.77 g, 41.18 mmol). The mixture was stirred at room temperature for 16 h. The reaction was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford rel-tert-butyl ((3R,4S)-7-(difluoromethoxy)-3-((2- hydroxyethoxy)methyl)isochroman-4-yI)carbamate (6.53 g, 81%) as a yellow solid. MS ESI calculated for CisfeFzNOe 390.16: found, 390.15

Step-8:

[1375] To a stirred mixture of rel-tert-butyl ((3R,4S)-7-(difluoromethoxy)-3-((2- hydroxyethoxy)methyl)isochroman-4-yl)carbamate (4.40 g, 8.47 mmol) and TEA (4.28 g, 42.33 mmol) in DCM (45 mL) was added methanesulfonyl methanesulfonate (5.90 g, 33.86 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of NaHCOs (sat.) at 0 °C. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (45 mL), then TFA (15 mL) was added at room temperature. The resulting mixture was stirred at room temperature tor additional 30 min. The reaction mixture was concentrated under vacuum. The residue was dissolved in acetonitrile (80 mL), then 1 ,2, 2,6,6- pentamethylpiperidine (3.94 g, 25.39 mmol) was added at room temperature. The resulting mixture was stirred at 80 °C for additional 16 h. The mixture was concentrated under vacuum. The residue was purified by reverse phase flash column chromatography with 10- 40% acetonitrile in water to afford rel-(5aR, llbS)-9-(difluoromethoxy)-2,3,5,5a,7, l 1b- hexahydro-lH-isocliromeno[4,3-ej[l,4]oxazepaiie (A76) (1.20 g, 36%) as a yellow oil. MS ESI calculated for C13H15F2NO3 [M+H]⁺, 272.10; found, 272.05. Tl NMR (400 MHz, DMSO-cfo) 57.46 (d, 8.4 Hz, 1H), 7.36 - 6.92 (m, 2H), 6.87 (d, J = 2.4 Hz, 1H), 4.75 -

4.50 (m. 2H), 4.15 - 4.10 (m, 1H), 3.92 ■■■ 3.80 (m, 2H), 3.64 (d, J = 3.6 Hz. 1H). 3.53 - 3.52 (rn, 1 H), 3.49 (d, / = 7.8 Hz, 1H), 3.45 - 3.39 (m, 1 H), 3.05 - 2.87 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A77: rel-(2R,4aS,9bS)-7-isopropyl-2-methyl-l,2_!3,4_f4a,9b-hexahydrofuro[2,3- b:4,5-b’]dipyridine

Step-1 :

[1376] To a stirred solution of 2,6-dichloro-3 -iodopyridine (10.0 g, 36.51 mmol) and hex- 5-en-2-one (3.94 g, 40.16 mmol) in DMF (100 mL) were added AcOK (10.75 g, 109.53 mmol), teteabutylazanium chloride (11.16 g. 40.16 mmol) and Pd(OAc)₂ ( 1.64 g, 7.30 mmol) at room temperature. Ihe resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and then quenched with water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSGr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford (E)-6-(2,6- dichloropyridin-3-yl)hex-5-en-2-one (3.46 g, 38%) as a yellow oil. MS ESI calculated for Ci iH iiChNO [M-f-H]⁺, 244.02: found, 244.00.

[1377] To a stirred solution of tert-butyl carbamate (20.83 g, 177.78 mmol) in propan- l ol (445 mL) was added a solution of NaOH (6.19 g, 154.84 mmol) in H2O (.387 mL) at room temperature. The mixture was stirred at room temperature for 10 min., then DCDMH (16.95 g, 86.02 mmol) was added at room temperature. After stirring at room temperature for 30 min., this was followed by the addition of a solution of (DHQLPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1 ) (4.47 g, 5.73 mmol) in propan- 1-oi (57 mL), a solution of (E)-6-(2,6-dichloropyridin-3-yl)hex-5-en-2-one (14 g, 57.34 mmol) in propan- 1- ol (57 mL) and a mixture of potassium osmate(VI) dihydrate (2.11 g, 5.73 mmol) and NaOH (0.4 N in H2O, 14 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-60% ethyl acetate in petroleum ether to afford rel-tert-butyl ((lS,2S)-l-(2,6-dicbloropyridin-3-yl)-2-hydroxy-5- oxohexyl)carbamate (6.05 g, 28%) as a yellow oil. MS ESI calculated for C16H22CI2N2O4

[M+Hf^h, 377.10; found, 377.00.

Step-3:

[1378] To a solution of rel-tert-butyl ((1 S,2S)- 1 -(2,6-dichloropyridin-3-yl)-2-hydroxy-5- oxohexyDcarbamate (2.0 g, 5.30 mmol) in DCM ( 18 ml) was added TFA (6 mL). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was basified with saturated NaHCOa (aq.) to pH 8. Tire mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in i-PrOH (20 mL), then Pt/C (10%, 30 mg) was added. The mixture was hydrogenated at room temperature overnight under hydrogen atmosphere. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford rel-(2R,3R,6S)-2-(2,6- dichloropyridin-3-yl)-6-methylpiperidin-3-oi (1.02 g, crude) as a brown oil. MS ESI calculated for CnHuChNiO [M+H]⁺, 261.05; found, 261.00.

Step-4:

[1379] To a solution of rel-(2R,3R,6S)-2-(2,6-dichloropyridin-3-yl)-6-methylpiperidin-3-ol (980 mg, 3.75 mmol) in tert-Amyl alcohol (40 niL) was added t-BuOK. (505 mg, 4.50 mmol). The mixture was stirred at 60 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum and then quenched with water. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous NacSOr. After filtration, the filtrate was concentrated under reduced pressure. Hie residue was purified by reverse phase flash column chromatography with 5% to 50% MeCN in water (10 mmol/L NH4HCO3) to afford re]-(2R,4aS,9bS)-7-chloro-2-me!hyl-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5- b'jdipyridine (313 mg, 37%) as a yellow solid. MS ESI calculated for C11H13CN2O |M+H]⁺, 225.07: found, 225.00.

Step -5

[1380] To a stirred solution of rel-(2R,4aS,9bS)-7-chlofo-2-methyl-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine (710 mg, 3.16 mmol) and 4,4,5,5-tetramethyl-2-(prop- l-en-2-yl)- l,3,2-dioxaborolane (796 mg, 4.74 mmol) in 1,4-dioxane ( 10 mL) and H?.O (2 mL) were added K2CO3 (655 mg, 4.74 mmol) and PdfdppfiCls-CHoCh (258 mg, 0.31 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched with water. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous NaiSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 10% methanol in di chloromethane to afford rel-(2R,4aS,9bS)-2-methyl-7-(prop-l-en-2-yl)- 1,2.3, 4,4a, 9b- hexahydrofuro[2,3-b:4,5-b']dipyridine (950 mg, crude) as a brown oil. MS EST calculated for [M+Hf, 231.14; found, 231.10.

Step-6

[1381] To a solution of rei-(2R,4aS,9bS)-2-melhyl-7-(prop-l-en-2-yl)-l , 2, 3, 4, 4a, 9b- hexahydrofuro|2,3-b:4,5-b'jdipyridine (950 mg. 4.12 mmol) in i-PrOH (10 mL) was added Pd/C (10%) (439 mg). The mixture was hydrogenated at room temperature for 16 h under hydrogen atmosphere. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 5% to 50% MeCN in Water (10 mmol/L NH4HCO3) to afford rel- (2R,4aS,9bS)-7-isopropyl-2-methyl- 1, 2.3, 4, 4a, 9b-hexahydrofuro[2,3-b:4,5-b']di pyridine (420 mg, 56% over two steps) as a yellow solid. MS ESI calculated for C14H20N2O [M+H]⁺, 233.16; found, 233.10. ^!H NMR (400 MHz, DMSO-tfc) 57.56 (d, J = 7.2 Hz, 1H), 6.74 (d, J

= 7.2 Hz, 1H), 4.34 - 4.30 (m, I H), 4.11 - 4.07 (m, 1H), 2.92 - 2.83 (m, I H), 2.61 - 2.54 (m, 1 H), 2.24 - 2.15 (m, 1H). 1.92 - 1.82 (m, I H), 1 .70 (s, I H), 1 .52 - 1.43 (m. 1H), 1.26 ~ 1. 10 (m, 7H), 0.94 (d, J = 6.4 Hz, 3H). Absolute stereochemistry’ was not determined. Intermediate A78: (4aS,6R,10bS)-8-chloro-6-methyl-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b’]dipyridine hydrochloride

A78

Step 1 : [1382] To a stirred solution of 3-bromo-6-chloropico]inic acid (50 g, 211.46 mmol) and N,O-dimethylhydroxylamine hydrochloride (24.75 g, 253.75 mmol) in DMF (500 mL) were added DIEA (81.99 g, 634.38 mmol) and HATU (96.49 g, 253.75 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCE- After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Tsolera Prime) with a 330 g silica gel column eluted with 0-40% ethyl acetate in petroleum ether to afford 3-bromo-6-chloro-N-methoxy-N-methylpicolinamide (41.9 g, 70% yield) as a white solid. MS ESI calculated for CgHgBrClNjCh [M+H] 278.95, 280.95; found, 278.85, 280.85.

[1383] To a stirred solution of 3-bromo-6-chloro-N-methoxy--N-methylpicolinamide (40.9 g, 146.32 mmol) in THF (200 mL) was added chloro(methyl)magnesium (3M in EtzO) (146 mL, 438 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 330 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether to afford l--(3-bromo -6 -chloropyridin-2-yl)ethan-l - one (20 g, 58% yield) as a yellow oil. MS ESI calculated for CrHsBrClNO [M+H]⁺, 233.92, 235.92; found, 233.95, 235.95.

Step 3:

[1384] To a stirred solution of 1 -(3-bromo-6-chloropyridin-2-yl)ethan-l -one (19.5 g, 83.16 mmol) in methanol (200 mL) 'was added NaBFL (6.29 g, 166.32 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 b. The reaction was quenched by the addition of ice water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCU- After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 330 g silica gel column eluted with 0-25% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (R)-l - (3-bromo-6-chloropyridiii-2-yl)ethan-l-ol and (S)-l-(3-bromo-6-chloropyridin-2-yDethan-l- ol (19 g, 96% yield) as a white solid. MS ESI calculated for CrHrBrClNO [M+H]⁺, 235.94, 237.94; found, 235.95, 237.95.

Step 4:

[1385] To a stirred solution of 1: 1 mixture of (R)-l-(3-bromo-6-chloropyridin-2-yl)ethan-

1-ol and (S)-l-(3-bromo-6-chloropyridin-2-yl)ethan-l-ol (18.5 g, 78.22 mmol) and Imidazole (10.65 g, 156.45 mmol) in DCM (5 mL) was added tert-butyl(chloro)dimethylsilane (11.79 g, 78.22 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 330 g silica gel column eluted with 0-15% ethyl acetate in petroleum ether to afford a 1:1 mixture of (R)-3-bromo-2-(l-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridine and (S)-3-bromo-

2-(l-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridine (27 g, 98% yield) as a colorless oil. MS ESI calculated for CnH^BrClNOSi [M+H]⁺, 350.02, 352.02 ; found, 350.00, 352.00.

Step 5:

[1386] To a stirred solution of 1 : 1 mixture of (R)-3-bromo-2-(1 -((tert- butyldimethylsilyl)oxy)ethyl )-6-chloropyridine and (S)-3-bromo-2-(l -((tertbutyldimethylsilyl)oxy)ethyl)~6-chloropyridine (16 g, 45.61 mmol) and tert-butyl 3- oxopiperidine- 1 -carboxylate (9.09 g, 45.61 mmol) in toluene (340 mL) were added K3PO4 (23.24 g, 109.47 mmol) and Pdtt-BusP)? (1.63 g, 3.19 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 60 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was quenched with water and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 330 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford a 1 : 1 : 1 : 1 mixture of tert-butyl (S)-2-(2-((R)-l-((tert-butyldimethylsilyl)oxy)ethy1)-6- chloropyridin-3-yl)-3-oxopiperidine-l-carboxylate and tert-butyl (S)-2-(2-((S)-l-((tert- butyldimeihy1silyl)oxy)ethyl)-6-chloropyridin-3-y1)-3-oxopiperidine-l -carboxylate and tertbutyl (R)-2-(2-((S)-l-((tert-buiyldimethylsily])oxy)ethyl)-6-chloropyridin-3-yl)-3- oxopiperidine-1 -carboxylate and tert-butyl (R)-2-(2-((R)- l-((tert- butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-3-yl)-3-oxopiperidine-l-carboxylate (3.3 g, 15% yield) as a yellow oil. MS ESI calculated for CisHjrCINzChSi [M+Hf , 469.22; found, 469.20.

[1387] To a stirred solution of 1 : 1 : 1 : 1 mixture of tert-butyl (S)-2~(2-((R)- 1 -((tert- butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-3-yl)-3-oxopiperidine-l-carboxylate and tertbutyl (S)-2-(2-((S)-l -((tert-butyldimethylsi1yl)oxy)ethy1)-6-ch1oropyridin-3-yl)-3- oxopiperidine- 1 -carboxy! ate and tert-butyl (R)-2-(2-((S )- 1 -((tertbutyldimethylsilyl)oxy)ethyl)-6-chloropyridin-3-yl)-3--oxopiperidine-l- carboxylate and tertbutyl (R)-2-(2-((R)-l-((tert-butyldimethylsilyr)oxy)ethyl)-6-chloropyridin-3-yl)-3- oxopiperidine- 1-carboxylate (3.30 g, 7.03 mmol) and 1 ,4-diazabicyclo[2.2.2]octane hexahydrate (8.37 g, 37.98 mmol) in MeCN (20 mL) were added HCOOH (0.94 g, 20.40 mmol) and RuCl(p-cymene)[(S,S)-Ts-DPEN] (0.13 g, 0.21 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 3 h. The resulting mixture was quenched by water extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCln After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 120 g silica gel column eluted with 0—25% ethyl acetate in petroleum ether to afford tert-butyl (2S,3S)-2-(2-((R)-l-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-3-yl)-3- hydroxy piperidine- 1-carboxylate (780 nig, 23% yield) as white solid. MS ESI calculated for CM foClMO sSi [M+H]⁺, 471.24; found, 471.40.

[1388] The purification process also afford tert-butyl (2S ,3S)-2-(2-((S)- 1 -((tert- butyldimethy1siiyl)oxy)ethyl)-6-chloropyridin-3-yl)-3-hydroxypiperidine- 1-carboxylate (960 mg, 28% yield) as white solid. MS ESI calculated for CcsI-hgClNzOrSi [M+H]⁺, 471.24; found, 471.40.

[1389] To a stirred solution of tert-butyl (2S,3S)-2-(2-((S)-l-((tert- butyldimethylsilyl)oxy)ethyl)-6-chloropyridin-3-yl)"3-hydroxypiperidiiie- 1-carboxylate (960 mg, 2.03 mmol) in THF (10 mL) was added TBAF (639 mg, 2.44 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 40 g silica gel column eluted with 0-70% ethyl acetate in petroleum ether to afford tert-butyl (2S,3S)-2-(6-chloro-2-((S)-l- hydroxyethyl)pyridin-3-yl)-3-hydroxypiperidine-l-carboxylate (750 mg, 96% yield) as a white solid. MS ESI calculated for C17H25CIN2O4 [M+H]⁺, 357.15; found, 357,15.

Step 8:

[1390] To a stirred solution of tert-butyl (2S,3S)-2-(6-chloro-2-((S)-l- hydroxyethyl)pyridin-3-yl)-3-hydroxypiperidine-l -carboxylate (750 mg, 2.10 mmol) in toluene (8 mL) was added 2-(tributyl-??-phosphaneylidene)acetonilrile (CAS No. 157141-27- 0) (1014 mg, 4.20 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 1 10 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Combi Flash (Biotage Isolera Prime) using a 40 g silica gel column eluted with 0—12% ethyl acetate in petroleum ether to afford tert-butyl (4aS,6R,10bS)-8-chloro-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b']dipyridine-l -carboxylate (540 mg, 75% yield) as a yellow oil. MS ESI calculated for C17H23QN2O3 [M+H]⁺, 339.14; found, 339.10. Absolute stereochemistry was determined by NOESY.

Step 9:

A78

[1391] A mixture of tert-butyl (4aS,6R, 10bS)-8-chloro-6-methyl-2,3,4,4a,6, 1 Ob- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (540 mg, 1.59 mmol) and HCi in 1,4-dioxane (4,0 M) (5.5 mL) was stirred at room temperature for 2 h. The resuiting mixture was concentrated under reduced pressure to afford (4aS,6R,10bS)-8-chIoro-6-methyl- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine hydrochloride (A78) (crude, 373 mg) as a white solid. MS ESI calculated for C12H15CIN2O [M+H]⁺, 239.09; found, 239.10. 'H NMR (400 MHz, DMSO-nfo 8 10.37 (s, 1H), 8.66 (s, 1H). 8.14 (d, ./ - 8.0 Hz, 1H), 7.56 (d, ./ = 8.0 Hz, 1H), 4.88 - 4.82 (m, 1H), 4.41 (d, .7 - 7.2 Hz, 1 H), 4.11 - 4.02 (m, 1H), 3.27 - 3.18 (ra, 1H), 3.12 - 2.96 (m, 1 H), 2.09 - 1.94 (m, 1H), 1.94 - 1.78 (m, 2H), 1.77 - 1.64 (m, 1H).

1.58 (d, J = 6.8 Hz, 3H).

Intermediate A79 isomer 1: re1-(4R,4aS,9bR)-4-fluoro-7-(trifluoromethyl)-l , 2,3,4, 4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine isomer 1

[1392] To a stirred solution of 3-bromo-2-chloro-6-(trif!uoromethyl)pyridine (10 g, 38.40 mmol) in 1,4-dioxane (100 niL) and H2O (10 mL) were sequentially added PdtdppfjCb- CH2CI2 (3.14 g, 3.84 mmol), a 1: 1 mixture of (R,E)-2,2,3,3,10,10-hexamethyl-9,9-diphenyl- 5-(2-(4,4,5,5-tetramethy]-l,3,2-dioxaborolan-2-yl)vinyl)-4,8-dioxa-3,9-disilaujidecane and (S,E)-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-5-(2-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2- yl)vinyl)-4,8-dioxa-3,9-disilaundecane (from A46) (22.30 g, 38.40 mmol) and K2CO3 (15.92 g, 115.19 mmol). The resulting solution was stirred at 100 °C for 16 h. The resulting solution was quenched with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SOr. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10:1) to afford a 1 : 1 mixture of (R,E)-3-(3-((tert-butyldimethylsilyl)oxy)-5-((tert-butyldiphenylsilyl)oxy)pent-l- en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine and (S,E)-3-(3-((tert-butyldimethylsilyl)oxy)-5- ((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine ( 11.50 g, 72%) as a yellow oil. MS ESI calculated for C33H43CIF3NO2S12 [M+H]⁺, 634.25; found, 634.15. Step-2:

[1393] To a stirred solution of 1: 1 mixture of (R,E)-3-(3-((tert-butyklimethylsilyl)oxy)-5- ((tert-butyldiphenyisilyl)oxy)pent-l-en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine and (S,E)- 3-(3-((tert-butyldimethylsilyl)oxy)-5-((tert-butyldiphenylsilyr)oxy)pent-l-en-l -yl)- 2- chloro- 6-(trifkioromethyl)pyridine (11.50 g, 18.13 mmol) in THF (5 mL) were added AcOH (15 mL) and H2O (5 mL). The resulting solution was stirred at room temperature for 16 h. The resulting solution was quenched with water. The mixture was neutralized to pH 8 with NaHCCh (sat.). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCL. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to afford a 1:1 mixture of (R,E)-5-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifltioromethyl)pyridin-3-y])pent-l-en-3-ol and (S.E)- 5 -((tert-bu ty Jdiphenylsily l)oxy )- 1 -(2-chloro-6-(trifluoromethy Dpyridin- 3 -yl)pen t- 1 -en -3 -ol (5.50 g. 68%) as a yellow oil. MS ESI calculated for CTrHjgClFsNOzSi [M+H]⁺, 520.16; found, 520.15.

Step-3 :

[1394] To a stirred solution of a 1:1 mixture of (R,E)-5-((tert-butyldiphenylsilyl)oxy )- 1 -(2- chloro-6-(trifluoromethyi)pyridin-3-yl)pent- l -en-3-ol and (S,E)-5-((tert- buty1diphenylsilyl)oxy)- 1 -(2-chloro-6-(trifluoromet.hyl)pyridin-3-yl)pent.-1 -en-3-ol (5.50 g,

10.58 mmol) in DCM (55 mL) was added DAST (3.41 g, 21.15 mmol) dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. The resulting solution was quenched with water at 0 °C. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO₄. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10: 1) to afford a 1 : 1 mixture of (R,E)-3-(5-((tert- butyldiphenylsilyl)oxy)-3-fluoropent-l-en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine and (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent-l-en-l-yl)-2-chloro-6- (trifltioromethyl)pyridine (3.50 g, 74%) as a yellow' oil. MS ESI calculated for C -I KCH • _iNOSi [M+H]E 522.16; found, 522.15.

[1395] To a stirred solution of BocNHj (557 mg, 4.75 mmol, 0.4 M in i-PrOH) were sequentially added NaOH (165 mg, 4.14 mmol, 0.4 M in water) and DCDMH (429 mg, 2. 18 mmol) at 0 °C and was at 0 °C for 20 min. Then to above the mixture were sequentially added (DHQjaPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (119 mg, 0.15 mmol, 0.1 M in i-PrOH), a solution of 1:1 mixture of (R,E)-3-(5-((tert- butyldiphenylsilyl)oxyj-3-fluoropent-l-en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine and (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-fluoropent-l-en-l-yl)-2-chloro-6- (trifluoromethyl)pyridine (800 mg, 1.53 mmol) in n-PrOH (5 mL) and K2OSO4.2H2O (56 mg, 0.15 mmol) at 0 °C. The resulting solution was stirred at room temperature for 16 h. The resulting solution was quenched with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2.SO4.The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to afford a 1: 1 mixture of tertbutyl ((lR*,2S*,3R)-5-((tert-butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluorometliyl)pyridin- 3-yl)-3-fiuoro-2-hydroxypentyl)carbamate and tert-butyl (( 1R *,2S*,3S)-5-((tert- butyldiphenylsiiyi)oxy)- l~(2-chloro-6-(trifluoromethyi)pyridin-3-yl)-3“fluoro-2- hydroxypentyl)carbamate (600 mg, 80%) as a colorless oil, MS ESI calculated for CrcHwClFTNaOaSi [M+H]⁺, 655.23; found, 655.15.

Step-5:

[1396] To a stirred solution of a 1:1 mixture of tert-butyl ((lR*,2S*,3R)-5-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-3-fluoro-2- liydroxypentyDcarbamate and tert-butyl ((lR*,2S*,3S)-5-((.tert-butyldiphenylsilyl)oxy)- 1 -(2- chloro-6-(trifluoromethyl)pyridin-3-yJ)-3-fluoro-2-hydroxypentyl)carbamate (1.00 g, 1.53 mmol) in toluene (10 mL) were added CS2CO3 11.49 g, 4.58 mmol), JohnPhos (0.05 g, 0.15 mmol) and Pd(OAc)₂ (0.03 g, 0.15 mmol). The resulting solution was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting solution was quenched with water and extracted with EtOAc, The combined organic layers were washed with brine, dried over anhydrous NasSO.i. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (8:1) to afford a 1 : 1 mixture of tert-butyl ((2R*,3S*)-2-((R)-3-((tert-bulyldiphenylsilyl)oxy)-l-fluoropropyl)-6- (trifluoromethyD-2,3-dihydrofuro[2,3-bjpyridin-3-yl)carbamate andtert-butyl ((2R*,3S*)-2- ((Sj-3-((tert-butyldiphenylsilyl)oxy)-1 -fluoropropyl)-6-(trifluoromethy1)-2,3-dihydrofuro[2,3- b]pyridin-3-yl)carbamate (260 mg, 88%) as a yellow' oil. MS ESI calculated for CrvHiyCIFsNChSi [M+H]⁺, 618.25; found, 618.15.

Step-6: [1397] To a stirred solution of a 1 : 1 mixture of tert-butyl ((2R*,3S*)-2-((R)-3-((tert- butyldiphenylsilyl)oxy)-l-fluoropropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- yDcarbamate andtert ■ butyl ((2R*,3 S *)-2-((S )-3 -((tert-butyldiphenylsilyl)oxy ) - 1 - fluoropropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)cafbamate (1.30 g, 2. 10 mmol) in THE (13 mL) was added TBAF (1.37 g, 5.25 mmol) at 0 °C. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 : 1) to afford a 1 : 1 mixture of tert-butyl ((2R*,3S*)-2-((R)-l-fluoro-3- hydroxypropyl)-6-(trifluoromethyj)-2,3-dihydrofuro[2,3-blpyridin-3-y])carbamate and tertbutyl ((2R*,3S*)-2-((S)-l-fluoro-3-hydroxypropyl)-6-(trifluoromethyl)-2,3-dihydiofuro[2,3- b]pyridin-3-yl)carbamate (900 mg, 80%) as a yellow oil. MS ESI calculated for (CJ6H2OF4N₂04) [M+H]⁺, 381.14; found, 381 .15.

Step-7 :

[1398] To a stirred solution of a 1:1 mixture of tert-butyl ((2R*,3S"')-2- ((R)- l-fluoro- 3- hydroxypropyD-6-(trif]uorometliyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tertbutyl ((2R*,3S*)-2-((S)-l-fluoro-3-hydroxypropyl)-6-(trifluoromelhyl)-2,3-dihydrofuro[2,3- b]pyridin-3-yl)carbamate (900 mg, 2.37 mmol) in toluene (10 mL) was added 2-(tributyl-X³- phosphaneylidene)acetonitrile (46.54 g, 192.82 mmol) (CAS No. 157141-27-0) (1.14 g, 4.73 mmol). The resulting solution was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3: 1 ) to afford rel -tert-butyl (4R,4aS,9bR)-4-fluoro-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridine- 1 (2H)-carboxy1ate isomer 1 (140 mg, 75%) as a white solid with the first eluting peak. MS

ESI calculated for CisHisFrNsOs [M+H]⁺, 363. 13; found, 363. 15. ‘H NMR (400 MHz, DMSO- fo) 87.75 (d, J - 7.6 Hz, 1H), 7.51 (d, 7= 7.2 Hz, 1H), 6.13 (d, 7 = 9.2 Hz, IH), 5.17 - 5.04 (m, IH), 4.92 - 4.70 (m, IH), 4.08 - 3.89 (m, IH), 2.79 - 2.77 (m, 1 H), 1.99 - 1.89 (m, IH), 1.81 - 1.66 (m, IH), 1.48 (s, 9H).

[1399] The purification process also afford rel-terl-butyl (4R,4aS,9bR)-4-fluoro-7- (trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b'jdipyridine-l(2H)-carboxylate isomer

2 (90 mg, 62% ) as a white solid with the second eluting peak. MS ESI calculated for CieHigfoNzOs [M+H]⁺, 363.13; found, 363.20. NMR (400 MHz, DMSO-rfe) 6 7.73 (d, 7 = 7.6 Hz, IH), 7.46 (d, 7= 7.2 Hz, IH), 5.98 (d, 7 = 9.2 Hz, IH), 5.30 - 5.02 (m, 2H), 3.85 - 3.84 (m, IH), 2.99 - 2.76 (m, IH), 1.98 - 1.83 (m, 2H), 1.48 (s, 9H).

Step-8: 1

[1400] A mixture of rel-tert-butyl (4R,4aS.9bR)-4-fluoro-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4.5-b']dipyridine-l(2H)-carboxylate isomer 1 (140 mg, 0.39 mmol) and

HC1 (4.0 M in 1 ,4-dioxane) (2 mL) was stirred at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure to afford rel-(4R,4aS,9bRj-4-fluoro-7-(trifluoromethyl)- 1, 2, 3, 4, 4a, 9b-hexaltydrofuro|2,3-b:4,5-b'ldipyridine hydrochloride isomer 1 (A79 isomer 1 ) (120 mg, crude) as a yellow solid. MS ESI calculated for C11H10F4N2O [M+H]⁺, 263.07; found, 263.15. ’H NMR (400 MHz, DMSO- -de) 8 11.09 (br, IH), 9.63 (br, 1H), 8.37 (d, J = 7.6 Hz, IH), 7.67 (d, J = 7.6 Hz, 1H), 5.42 - 5.23 (m, 2H), 5.16 - 5.05 (m, IH), 3.26 - 3.11 (ra, 2H), 2.2'2 - 2.09 (m, 2H). Absolute stereochemistry -was not determined.

Intermediate A79 isomer 2: reI-(4R,4aS,9bR)-4-fluoro-7-(trifluoromethyl)-l , 2, 3, 4, 4a, 9b- hexahydrofuro[2,3-b:4,5-b’]dipyridine isomer 2

A79 isomer 2

Step-1: isomer 2 A79 isomer 2

[1401] A mixture of rel-tert-butyl (4R,4aS,9bR)-4-fluoro-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’jdipyridine-l(2H)-carboxylate isomer I (90 mg, 0.25 mmol) and HC1 (4.0 M in ! ,4-dioxane) (2 mL) was stirred at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure to afford rel-(4R,4aS,9bR)-4-fluoro-7-(trifluoromethyl)- 1 ,2,3.4,4a,9b-hexahydrofuro[2,3-b:4,5-b']dipyridine hydrochloride isomer 2 (A79 isomer 2) (60 mg. crude) as a yellow solid. MS ESI calculated for CnHioF4N?0 [M+H]⁺, 263.07; found, 263.15. ^JH NMR (400 MHz, DMSO-d₆) 8 1 1.11 (br. 1H), 9.12 (br, i l l s. 8.30 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 5.44 - 5.18 (m, 3H), 3.29 - 3.19 (m, 1H), 3.18 - 3.10 (m, 1 H), 2.27 - 2.03 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A80 isomer 1: rel-(4R,4aS ,10bS)-4-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b- hexahydro- 1 H-pyrano[3,2-b:5,4-b']dipyridine isomer 1

A80 isomer 1

Step-1:

[1402] To a mixture of 1:1 mixture of (R)-3-methyldihydrofuran-2(3H)-one and (S)-3- methyldihydrofuran-2(3H)-one (30 g, 299.65 mmol) in DCM (600 mL) was added DIBAL-H (1.0 M in DCM) (389 mL, 389 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at. -78 °C for 1 h under nitrogen atmosphere. The reaction mixture was quenched by the addition of ice water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper, and concentrated under vacuum to afford a 1: 1 : 1:1 mixture of (2R,3R)-3-methyltetrahydrofiiran-2-ol and (2S,3S)-3-methyltetrahydrofuran-2-ol and (2R,3S)-3-methyltetrahydrofuran-2-ol and (2S,3R)-3-methyltelrahydrofuran-2-ol (26.4 g, crude) as a yellow oil. H NMR (400 MHz, DMSO-cfo) 5 6.05 - 5.63 (m, 1H), 5. 18 - 4.67 (rn, 1H), 3.99 - 3.50 (m, 2H), 2.20 - 1.81 (m, 2H), 1.64 - 1.28 (m, 1H), 1.00 - 0.89 (m, 3H).

Step-2:

[1403] To a mixture of 1 : 1 : 1: 1 mixture of (2R,3R)-3-methyltetrahydrofiiran-2-ol and (2S,3S)-3-methyltetrahydrofuran-2-ol and (2R,3S)-3-methyltetrahydrofuran-2-ol and (2S,3R)-3-methyitetrahydrofuran-2-ol (25.40 g, 248.69 mmol) and dimethyl (l-diazo-2- oxopropyl)phosphonate (52.55 g, 273.56 mmol) in methanol (1250 mL) was added K2CO3 (68.74 g, 497.39 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford a 1:1 mixture of (R)-3-methylpent-4-yn-l-ol and (S)-3-methylpent-4-yn-l-o1 (15.90 g, 65%) as a yellow oil. >H NMR (400 MHz, CDCh) 5 3.96 - 3.70 (m, 2H), 2.75 - 2.52 (m, 1H), 2.10 (d, ./ - 2.4 Hz, 1 H), 1 .96 - 1 .86 (m, 1 H), 1.77 - 1 .58 (m, 2H), 1 .24 (d, J = 6.8 Hz, 3H).

Step-3 : [1404] To a mixture of 1:1 mixture of (R)-3-methylpent-4-yn-l-ol and (S)-3-methylpent-4- yn-l-ol (22.9 g, 233.33 mmol) and TBDPSC1 (70.55 g, 256.66 mmol) in DMF (340 mL) was added imidazole (63.54 g, 933.31 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10: 1) to afford a 1 : 1 mixture of (R)-tert-butyl((3-methylpent-4-yn-l-yl)oxy)diphenylsilane and (S)- tert-butyl((3-methylpent-4-yn-l-yl)oxy)diphenylsilane (62 g, 78%) as a colorless oil. ’H NMR (400 MHz, DMSO) 8 7.75 - 7.56 (m, 4H), 7.50 - 7.38 (m, 6H), 3.87 - 3.66 (m, 2H), 2.84 (d, J - 2.4 Hz, 1H), 2.70 - 2.62 (m, 1H), 1.80 - 1.54 (m, 2H), 1.12 (d, J - 7.2 Hz, 3H), 1.00 (s, 9H).

Step-4:

[1405] To a 1 : 1 mixture of (R)-tert-butyl((3-methylpeni-4-yn-l-yl)oxy)di phenylsilane and (S)-tert-butyl((3-methylpent-4-yn- l-yl)oxy)diphenylsilane (31.10 g, 92.41 mmol) and Schwartz reagent (4.75 g, 18.48 mmol) were added 4,4,5,5-tetramethyl-l,3,2- dioxaborolane (29,57 g, 231.02 mmol) and EtjN (5.61 g, 55,44 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to afford a 1 : 1 mixture of (R,E)-tert-butyl((3-methyl-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pent-4- en-l-yl)oxy)dipbenylsilane and (S,E)-terc-butyl((3-methyl-5-(4, 4,5, 5 -tetramethyl- 1 ,3,2- dioxaborolan-2-yl)penl-4-en-l-yl)oxy)diphenylsilane (34 g. 79%) as a light yellow oil. MS ESI calculated for CzsEkiBChSi [M+H]⁺, 465.29; found, 465.35.

Step-5:

[1406] To a mixture of (R,E)-tert-butyl((3-methyl-5-(4,4,5,5-tetrametbyl-1 ,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy)diphenylsilane and (S,E)-tert-butyl((3-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pent-4-en-l-yl)oxy)diphenylsnane (10.29 g, 22.14 mmol) and ethyl 3-bromo-6-(Lrifluor0methyl)picolinate (5.50 g, 18.45 mmol) in dioxane (70 ml.,) and H2O (7 mb) were added Pd(dppf)C12-CH2Ch (1.51 g, 1.84 mmol) and K2CO3 (7.65 g, 55.36 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (4: 1) to afford a 1 : 1 mixture of ethyl (S,E)-3-(5-((lert- butyldiphenylsilyl)oxy)-3-methylpent-i-en-l-yr)-6-(trifluoromethyl)picolinate and ethyl (S,E)-3-(5-((tert.-butyldiphenylsilyl)oxy)-3-methy1pent-l-en-l-yl)-6-

(trifiuoromethyl)picolinate (9.5 g, 92%) as a yellow oil. MS ESI calculated for ChiHseFaNOsSi [M+H]\ 556.24; found, 556.20.

Step-6:

[1407] To a mixture of BocNIh (3.27 g, 27.89 mmol) in n-PrOH (35 ml..) were added a solution of NaOH (0.97 g, 24.29mmol) in H2O (30.5 mb). Then l,3-dichloro-5,5- dimethylimidazolidine-2, 4-dione (2.66 g, 13.49 mmol) was added at room temperature. After stirring at room temperature for additional 30 min, a solution of (DHQ)₂PHAL (supplier: Shanghai Accela ChemBio Co., bid. CAS# 140924-50-1) (0.70 g, 0.90 mmol) in n-PrOH (9 mb), a solution of 1:1 mixture of ethyl (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3- methylpent-l-en-l-yl)-6-(trifluoromethyl)picolinate and ethyl (S,E)-3-(5-((tert- butyldipheny1silyl)oxy)-3-methylpent- 1 -en- l-yl)-6-(trifluoromethy1)picolinate (5 g, 8.99 mmol) in propan- l-ol (50 mb) and Potassium osmate(VI) dihydrate (0.33 g, 0.90 mmol) were added sequentially at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NajSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (110 mb), then DCC (2.78 g, 13.49 mmol) and DMAP (0.11 g, 0.90 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 4 h. Use reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous NaiSOn After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3: 1) to afford a 1 :1 mixture of tert-butyl ((5R*,6R*)-6-((S)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-8- oxo-2-(tifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-8-oxo-2-(tritluoromethyl)-5₍8- dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (2.40 g, 41%) as a brown oil. MS ESI calculated for C uH ■ j-hX-CnSi [M+H]⁺, 643.27; found, 643.20.

Step-7:

[1408] To a 1: 1 mixture of tert-butyl ((5R*,6R*)-6-((S)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4- bJpyridin-5-yDcarbamate (2.70 g, 4.20 mmol) in THF (54 mL) was added NaBFL (238 mg, 6.30 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with ice water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaaSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 : 1) to afford a 1 : 1 mixture of tert-butyl ((lR*,2R*,3S)-5-((tert- butyldiphenylsilyl)oxy )■ 2 -hydroxy- 1 -(2- (hydroxymethyl) - 6- (trifluorometliyl)pyridin-3-yl) -3 - methylpentyl)carbamaie and tert-butyl ((lR*,2R*,3R)-5-((tert-buty1diphenylsily1)oxy)-2- hydroxy-l-(2-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)-3-methylpentyl)carbamate (2.40 g, 88%) as an off-white solid. MS ESI calculated for CsaHtsFsNsOsSi [M+H]⁺, 647.30; found, 647.70.

Step-8:

[1409] To a stirred solution of 1: 1 mixture of tert-butyl ((lR*,2R*,3S)-5-((tert- butyldiphenylsilyl)oxy)-2-hydroxy-l-(2-(hydioxymethyl)-6-(trifluoromethyl)pyridin-3-yl)-3- meihylpentyl)carbamate and tert-butyl ((lR*,2R*,3R)-5-((tert-butyldiphenylsi1yr)oxy)-2- hydroxy-l-(2-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)-3-methy1pentyl)carbamate (1.40 g, 2.16 mmol) in toluene (15 mL) was added 2-(tributyl-X³- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (0.78 g, 3.24 mmol) at room temperature. The resulting mixture was stirred at 1 10 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2: 1) to afford a 1 :1 mixture of tert-butyl ((5R*,6R*)-6-((S)-4-((tert-butyldiphenylsilyl)oxy)buian-2- yJ)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-2-(trifluoromethyl)-5,8- dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbaniate (420 mg, 30%) as an off-white solid. MS ESI calculated for CMHrsFsNrChSi [M+H]⁺, 629.29; found, 629.25.

Step-9:

[1410] To a stirred solution of 1 : 1 mixture of tert-butyl ((5R*,6R*)-6-((S)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin- 5-yl)carbamate and tert -butyl ((5R*,6R*)-6-((R)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)- 2-(trinuoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbajnate (400 mg, 0.64 mmol) in THF (4 mL) was added TBAF (332 mg, 1.27mmol) at 25 °C. The resulting solution was stirred at 25 °C for 16 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaiSO4.

After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl ((5R^:ii,6R*)-6-((S)-4-hydroxybutan-2-yl)-2- (trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-y])carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-hydroxybutan-2-yl)-2-(trifluoromethyi)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yi)carbamate (120 mg, 48%) as a white solid. MS ESI calculated for C18H25F3N2O4 [M+H]L 391.18; found, 391.10 Step-10: isomer 1

[1411] To a 1: 1 mixture of tert-butyl ((5R*,6R*)-6-((S)-4-hydroxybutan-2-yl)-2- (trifluoromelhyl)-5,8-dibydro-6H-pyrano[3,4-b]pyridin-5-y1)carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-hydroxybutan-2-yl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate (370 mg, 0.95 mmol) in toluene (8 mL) was added 2-(tributyl-)?- pbosphaneylidene)aeetonitrile (CAS No. 157141-27-0) (343 mg, 1.42 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. Hie resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the folio-wing conditions (Column: XBridge Prep OBD C 18 Column30*150 mm; Mobile Phase A: WaterflO mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min, 52% B to 72% B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.9-9.6) to afford rel-tert-butyl (4R,4aS,10bS)-4-methyl-8- (trinuoromethy!)-2, 3, 4, 4a, 6, 10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate isomer 1 (105 mg, 29%) as a colorless oil as the first eluting peak. MS ESI calculated for C18H23F3N2O [M-i-H] \ 373.17; found, 373.10.

[1412] rel- tert-butyl (4R,4aR, 10bR)-4-methyl-8-(trifluoromethyl)-2,3,4,4a,6, 10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate isomer 2 (105 mg, 29%) as a colorless oil as the second eluting peak. MS ESI calculated for C18H23F3N2O 373.17; found, 373.10 Step- 11:

A80 isomer 1

[1413] A mixture of tert-butyl (4R,4aS,10bS)-4-methyl-8-(trifluoroniethyl)-2,3,4,4a,6,10b- hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate ( 140 nig, 0.37 mmol) and hydrogen chloride(4.0 M in ethyl acetate) (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford rel- (4R,4aS, 10bS)-4-inethyl-8-(trilluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b'ldipyridine hydrochloride isomer 1 (A80 isomer 1) (130 mg, crude) as a white solid. MS ESI calculated for CBHISFSNJO.HCI [M+H]⁺, 273.1 1 ; found, 273.15. ‘H NMR (400 MHz, DMSO) 5 10.66 (br, 1H), 9.01 (br, 1 H), 8.46 (dd, ./ = 8.8, 3.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1 H), 5.07 - 4.82 (m, 2H), 4.72 (s, 1H), 3.88 (t, 2.0 Hz, 1H), 3.25 - 3.12 (m, 1H), .3.09 -

3.00 (m, 1H), 2.28 - 2.16 (m, 1H), 2.12 - 1.97 (m, 1H), 1.60 - 1.41 (m, 1H), 1.13 (d, J = 7.2 Hz, 3H). Relative stereochemistry’ was determined by NOESY. Absolute stereochemistry was not determined.

Intermediate A80 isomer 2: rei-(4R,4aR,10bR)-4-methyl-8-(trifluoroniethyl)-

2, 3, 4.4a, 6, lOb-hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridine isomer 2

A80 isomer 2

■Step-1:

[1414] A mixture of rel-tert-butyl (4R,4aR,10bR)-4-methyl-8-(trifluoromethyl)- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate isomer 2 (130 mg, 0.35 mmol) and hydrogen chloride (4.0 M in ethyl acetate) (2 ml) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford rel- (4R,4aR,l0bR)-4-metbyl-8-(trifluoromethyl)-2,3,4,4a,6,l0b-hexahydro-1H-pyrano[3,2-b:5,4- b'Jdipyridine hydrochloride isomer 2 (A80 isomer 2) (120 nig, crude) as a white solid. MS ESI calculated for Cj3H1.sF3N2O.HCl [M+H]⁺, 273.11; found, 273.152H NMR (400 MHz, DMSO) 5 10.69 (br, 1H), 8.85 (br, 1H), 8.54 - 8.34 (m, 1H), 7.96 (d, J = 8.0 Hz, TH), 5.00 (d, J = 16.4 Hz, 1H), 4.85 (d, J - 16.4 Hz, 1H), 4.54 (s, 1H), 4.00 - 3.83 (m, 1H), 3.22 (d, J =

12.8 Hz, 1H), 3.09 (s, 1H), 2.12 - 2.01 (m, 111), 1.70 - 1.53 (m, 2H), 1.08 (d, J - 6.8 Hz, 3H). Relative stereochemistry was determined by NOESY. Absolute stereochemistry was not determined. Intermediate A81 isomer 1: rel-(4R,4aR,9bS)-4-methoxy-7-(trifluoromethyl)- 1,2,3.4,4a, 9b-

A81 isomer 1 _an£j

Intermediate A81 isomer 2: rel-(4S,4aR,9bS)-4-methoxy-7-(trifluoromethyl)-l, 2,3,4, 4a, 9b- hexahydrofuro[2,3-b:4,5-b’]dipyridine isomer 2

A81 isomer 2

Step-1: " HO'^^'OTBDPS

[1415] To a stirred solution of propane- 1 ,3-diol (100.00 g, 1314.15 mmol) in DCM (200 mL) were added imidazole (223.66 g, 3285.37 mmol) and TBDPSC1 (397.33 g, 1445.56 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (0 - 10%) to afford 3-((tert- butyldiphenylsilyl)oxy)propan-l-ol (136.9 g, 33%) as a colorless oil. MS ESI calculated for CioHreOsSi [M+H]⁺, 315.17; found, 315.15.

Step-2:

[1416] To a stirred solution of 3-((tert-butyldiphenylsi1yi)oxy)propan-l-ol (40.00 g, 127.19 mmol) in DCM (400 mL) was added TEA (38.61 g, 381.56 mmol) at room temperature. To the above mixture was added a solution of Py-SOs (40.49 g, 254.37 mmol) in DMSO (200 mL) at 0 “ C. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCri. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 15% EtOAc in PE to afford 3-((tert- butyldiphenylsilyl)oxy)propanal (31.00 g, 78%) as a colorless oil. MS ESI calculated for Ci₉H24O₂Si [M+H]L 313.15; found, 313.15.

Step-3:

[1417] To a stirred solution of 3-(( tert-butyldiphenyisilyl)oxy')propanal (31.00 g, 99.21 mmol) in THF (310 mL) was added Ethynyl magnesium bromide (0.5 M solution in THF) (397 tnL, 198.41 mmol) al 0 ° C dropwise under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with NEUC1 (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 ~ 10% EtOAc in PE to afford a 1 : 1 mixture of (S)-5-((tert- buiyldiphenylsilyl)oxy)pent-l-yii-3-ol and (R)-5-((tert-butyldiphenylsi1yl)oxy)pent-l-yn-3-ol (19.2.0 g, 57%) as a yellow oil. MS ESI calculated for CeiEWhSi [M+Hf; 339.17; found, 339.10.

Step-4:

[1418] To a stirred mixture of NaH (2.38 g, 59.5 mmol, 60% in mineral oil) in THE (100 mL) was added a solution of a 1: 1 mixture of (S)-5-((iert-butyldiphenylsilyl)oxy)pent-l-yn-3- ol and (R)-5-((tert-butyldipbeny]silyl)oxy)pent-l-yn-3-ol (28.00 g, 82.71 mmol) in THF (200 mL.) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min, then CH₂I (17.61 g, 124.07 mmol) was added dropwise at 0 °C. The resulting solution was stirred room temperature for 3 h. The mixture was quenched with water at 0 °C. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to afford a 1:1 mixture of (S)-tert-buty]((3-methoxypent-4-yTi-l-yl)oxy)diphenylsilane and (R)-tert-butyl((3- methoxypent-4-yn-l-yl)oxy)diphenyIsilane (25 g, 55%) as a yellow oil. MS ESI calculated for C22H2sO₂Si [M+H]⁺, 353.19: found, 353. 15.

Step-5:

[1419] To a 1 : 1 mixture of (S)-tert-butyl((3-methoxypent-4-yn- l-yl)oxy)diphenylsilane and (R)-tert-butyl((3-methoxypent-4-yn-l -yl)oxy)diphenylsilane (25.00 g, 70.91 mmol) was added EtjN (0.72 g, 7.09 mmol), Schwartz's reagent (18.15 g, 141.82 mmol) and HBpin (1.82 g, 7.09 mmol). The mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (6: 1 ) to afford a 1: 1 mixture of (R,E)- tert-butyl((3-methoxy“5"(4,4,5,5-tetramethyi-l,3,2-dioxaborolan-2-yl)pent-4-en-l- yl)oxy)diphenylsilane and (S,E)-tert-butyl((3-metlioxy-5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy)diphenylsilajne (20 g, 54%) as a yellow oil. MS ESI calculated for CjstuBO/iSi [M+H]⁺, 481.29; found, 481.15. ^!H NMR (400 MHz, DMSO-ifc) 6 7.65 - 7.57 (m, 4H), 7.48 - 7.35 (m, 6H), 6.34 (dd, J= 18.4, 6.4 Hz, 1H), 5.50 (dd, J = 18.0, 0.8 Hz, 1H), 3.86 - 3.79 (m, 1H), 3.76 - 3.60 (m, 2H), 3.13 (s, 3H), 1.78 - 1.65 (m, 2H), 1.21 (s, 12H), 0.99 (s, 9H).

Step-6:

[1420] To a stirred solution of a 1: 1 mixture of (R,E)-tert-butyl((3-methoxy-5-(4,4.5,5- tetramethyl-l,3,2-dioxaboro1an-2-y1)pent-4-en-l-y1)oxy)diphenylsilane and (S.E)-ten- buiyl((3-melhoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pent-4-en-l- yl)oxy)diphenylsilane (46.00 g, 95.73 mmol) and 3-bromo-2-chloro-6-

(trifluoromethyl)pyridine (24.93 g, 95.73 mmol) in 1,4-di oxane (460 mL) and HjO (46 ml) were added K2CO3 (39.69 g, 287.18 mmol) and Pd(dppf)CE (7.00 g, 9.57 mmol). The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 0-5% EtOAc in PE to afford a 1 : 1 mixture of (R,E)- 3-(5-((tert-butyldiphenylsilyl)oxy)-3-methoxypent-l-en-l-yl)-2-chloro-6- (trifluoromethyl)pyridine and (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-methoxypent-l-en- l-yl)-2-chloro-6-(trilluoromethyl)pyridine (15 g, 95%) as a yellow oil. MS ESI calculated for C28H3iClF₃NO₂Si [M+H]⁺, 534.18; found, 534.15.

[1421] To a mixture of BocNHi ( 10.20 g, 87.06 mmol) in n-PrOH (220 mL) was added NaOH (aq. 0.4 M) ( 190 mL). The mixture was stirred at 0 °C for 10 minutes. DCDMH (7.86 g, 39.88 mmol) was added in portions to the mixture at 0°C. After stirring at 0 °C. for 30 minutes, (DHQ)₂PHAL (supplier: Shanghai Accel a ChemBio Co., Ltd. CAS# 140924-50-1) (2.19 g, 2.81 mmol), a solution of methyl 3-[(lE)-5-[(tert-butyldiphenylsilyl)oxy]-3- methoxypent-l-en-l-y]]-2-chloro-6-(triiluoromethyI)pyridine ( 15 g, 28.09 mmol) in n- PrOH(5() mL) and K₂OsO42H₂O (0.89 g, 2.42 mmol) were added to above mixture at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to afford a 1 : 1 mixture of tert-butyl ((lS*,2R*,3R)-5-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-3- methoxypentyl)carbamate and tert-butyl ((lS*,2R*,3S)-5-((tert-butyldipheny1silyl)oxy)-l-(2- chloro-6-(triiluoromethyl)pyridin-3-yl)-2-hydroxy-3-methoxypentyl)carbamate (17.00 g, 67%) as a yellow oil. MS ESI calculated for C^ITeClFsNiOsSi [M+H]⁺, 667.20; found, 667.15.

Step-8:

[1422] To a stirred solution of a 1: 1 mixture of tert-butyl ((lS*,2R’\3R)-5-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridiii-3-y])-2-hydroxy-3- methoxypentyl)carbamate and tert-butyl ((1 S*,2R*,3S)-5-((tert-butyldiphenylsilyl)oxy)-1 -(2- chloro-6-(trifluoronietliyi)pyridin-3-yl)-2-liydroxy-3-niethoxypentyl)carbamate (7.00 g, 10.49 mmol) in toluene (70 mL) were added CS2CO3 (10.25 g, 31.47 mmol), JohnPhos (0.31 g, 1.05 mmol) and Pd(OAc)₂ (0.24 g, 1.05 mmol). The resulting solution was stirred at 100 °C for IS b under hydrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was quenched with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NacSOa- The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5: 1) to afford a 1:1 mixture of tert-butyl ((2R*,3S*)-2-((R)-3-((tert-butyldiphenylsilyl)oxy)-l-methoxypropyl)-6-(tTifluoTomethyl)- 2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tert-butyl ((2R*,3S*)-2-((S)-3-((tert- butyldiphenylsilyl)oxyj-l-methoxypropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3“ b]pyridin-3-yl)carbamate (3.3 g, 66%) as a yellow oil. MS ESI calculated for C M LJoX d n.Si [M+HJT 631.27; found, 631.15.

Step-9:

[1423] To a stirred solution of a 1: 1 mixture of tert-butyl ((2R*,3S*)-2-((R)-3-((tertbutyldiphenylsilyl)oxy)-l-mefhoxypropyl)-6-(trifluoromethyJ)-2,3-dihydrofiiro[2,3- b|pyridin-3-yl)carbamate and tert-butyl ((2R*,3S*)-2-((S)-3-((tert-butyldiphenylsilyJ)oxy)-l- methoxypropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (3.40 g, 5.39 mmol) in THF (35 mL) was added TBAF (3.52 g, 13.48 mmol) at 0 °C. The resulting solution was stirred at room temperature for 2 h. The mixture was quenched with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /

EtOAc (5:1) to afford a 1: 1 mixture of tert-butyl ((2R*,3S*)-2-((R)-3-hydroxy-l- methoxypropy1)-6-(trifluoTomethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)cafbamate and tert- butyl ((2R*,3S*)-2-((S)-3-hydroxy-l-methoxypropyl)-6-(irifluoromethyl)-2,3- dihydrofuro[2,3-bJpyridin-3-yDcarbamate (1.6 g, 64%) as a yellow oil. MS ESI calculated for

C17H23F3N2O5 [M+Hr, 393.16; found, 393.15.

Step- 10: isomer 1 [1424] To a stirred solution of a 1 : 1 mixture of tert-butyl ((2R*,3S*)-2-((R)-3-hydroxy-l- methoxypropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and ten- butyl ((2R*.3S*)-2-((S)-3-hydroxy-l-methoxypropyl)-6-(trifluoromethyl)-2,3- dihydrofuro[2,3-b]pyridin-3-yl)carbamate (1.6 g, 4.08 mmol) in toluene ( 160 ml) was added 2-(iributyl-V-phosphaneyIidene)acetonitrile (CAS No. 157141-27-0) (1.97 g, 8.16 mmol). The resulting solution was stirred at 110 °C for 18 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (8:1 ). And then purified by prep-chiral HPLC with the following conditions: [Column: CHIRAL ART Cellulose-SC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2 M NH₃-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1:1- HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 10% B to 10% in lOmin: Wave Length: 220/254 nm; RTI (min): 6.02; RT2(min): 7.31; Sample Solvent: MeOH:DCM=l:l- HPLC] afford rel-tert-butyl (4R,4aR,9bS)-4-methoxy-7-(trifluoromethyl)-3 , 4, 4a, 9b- tetrahydrofuro[2,3-b:4.5-b']dipyridine-l(2H)-carboxylate, isomer 1 (150 mg, 93%) as a white solid with retention time at 6.02 minutes. MS ESI) calculated for C17H21F3N2O4 [M+H]⁺, 375.15; found, 375.20. ^!H NMR (400 MHz, DMSO-d₆) 8 7.74 (d, J = 7.2 Hz. 1H). 7.48 (d, J = 7.6 Hz, 1 H), 6.00 (d, 9.6 Hz, 1 H), 4.90 (dd, J = 9.6, 6.4 Hz, 1H), 4.01 - 3.76 (m, 1H),

3.47 - 3.37 (m, 1H), 3.35 (s, 3H), 2.89 - 2.62 (m, 1H), 1.92 - 1.76 (m, 1 H), 1.56 - 1.39 (s, 10H). Relative stereochemistry was determined by NOESY.

[1425] The chiral resolution also afford rel-tert-butyl (4S,4aR,9bS)-4-methoxy-7- (tafluoromethyl)-3,4,4a,9b-tetrahydrofufo[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate, isomer 2 (330 mg, 97%) as a white solid with retention time at 7.31 minutes. MS ESI calculated for C17H21F3N2O4 [M+H]⁺, 375.15; found, 375.15. ^!H NMR (400 MHz, DMSO-rfe) 8 7.74 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 6.00 (d, J ~ 9.2 Hz, 1H), 5.26 (dd, J = 9.2, 3.2 Hz, 1H), 3.76 - 3.65 (m, 2H), 3.29 (s, 3H), 2.85 - 2.64 (ra, 1H), 1.96 - 1 .84 (m, 1 H), 1 .69 - 1.57 (m, 1H), 1.47 (s, 9H). Relative stereochemistry was determined by NOESY.

Step-11:

A81, isomer 1

[1426] A stirred solution of rel-tert-butyl (4R,4aR,9bS)-4-methoxy-7-(trifluoromethyl)- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b^,]dipyridine-l(2H)-carboxyiate (150 mg, 0.-40 mmol) and HC1 (4M in 1 ,4-dioxane) (2 mL) was stirred at 0 °C for 3 h. The resulting mixture was concentrated under reduced pressure to afford rel-(4R,4aR,9bS)-4-methoxy-7-

( trifluoromethyl)- 1, 2, 3, 4, 4a, 9b-hexahydrofuro[2,3-b:4,5-b‘]dipyridme hydrochloride, isomer 1 (A81 isomer 1) (100 mg, crude) as a white solid. MS ESI calculated for C11H10F4N2O [M+H]⁺, 263.07; found, 263.20. ^SH NMR (400 MHz, DMS0-<fe) 8 10.81 (br, 1H), 9.29 (br, 1H), 8.31 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 4.94 - 4.89 (m, 1H), 3.96 - 3.89 (rn, 1H), 3.15 - 3.04 (m, 2H), 2.03 - 1.93 (m, 2H).

Step- 12:

A81 , isomer 2

[1427] A stirred solution of rel-tert-butyl (4S,4aR,9bS)-4-methoxy-7-(trifluoromethyl)- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxy]ate (330 mg, 0.88 mmol) and HC1 (4M in 1 ,4-dioxane) (4 mL) was stirred at. 0 °C for 3 h. The resulting mixture was concentrated under reduced pressure to afford rel-(4S,4aR,9bS)-4-methoxy-7-

( trifluoromethyl)-!, 2,3,4, 4a, 9b-hexahydrofuro[2,3-b:4,5-b’]dipyridine hydrochloride, isomer 2 (A81 isomer 2) (200 mg, crude) as a white solid. MS ESI calculated for C12H13F3N2O2 [M+H]⁺, 275.09; found, 275.15. ^!H NMR (400 MHz, DMSO-tfc) 8 11.06 (br, 1H), 8.84 (br, 1H), 8.27 (d. J = 7.6 Hz, 1H), 7.62 (d, J ~ 7.6 Hz, 1H), 5.19 - 5.09 (m, 2H), 3.98 - 3.91 (m, 1 H), 3.40 (s, 3H), 3.23 - 3. 15 (m, 1H), 3.09 - 2.98 (m, 1 H), 2.08 - 1.98 (m, 1H), 1.88 - 1 .75 (m, 1H). Absolute stereochemistry was not determined. Intermediate A82: rel-(2R,4aS,9bS)-2-methyl-7-(trifluoromethy1)- 1,2,3, 4, 4a, 9b- hexahydrofuro[2,3-b:4,5-b’]dipyridine

[1428] To a stirred solution of 3-bromo-2-chloro-6-(triiluorometliyl)pyridme (30.0 g, 115.19 mmol) and hex-5-en-2-one (13.5 g, 138.22 mmol), AcOK (33.9 g, 345.57 mmol) and TBAC (3.2 g, 11.51 mmol) in DMF (300 mL) was added Pd(OAc)? (2.6 g, 11.51 mmol). The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was filtered, the filler cake was washed with ethyl acetate. The filtrate was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaiSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0 ■■ 10% ethyl acetate in petroleum ether to afford (E)-6-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)hex-5-en-2-one (15.0 g, 46%) as a brown oil. MS ESI calculated for C12H11CIF3NO [M+H]⁺, 278.05; found, 278.00.

Step-2: [1429] To a stirred solution of tert-butyl carbamate (18.3 g, 156.30 mmol) in propan-l-ol (194 mL) was slowly added NaOH (aq., 0.4 M) (168 ml,) at 0 °C. The mixture was stirred at 0 °C for 10 min., then DCDMH (14.9 g, 75.63 mmol) was added at room temperature. After stirring at room temperature for 30 min., this was followed by the addiotn of a solution of (DHQ)₂-PHAL (supplier: Shanghai Accel a ChemBio Co., Ltd. CAS# 140924-50-1) (3.9 g, 5.04 mmol) in propan-l-ol (1 mL) and a solution of (E)-6-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)hex-5-en-2-one (14.0 g, 50.42 mmol) in propan-l-ol (100 mL) dropwise at 0 °C, after that, Potassium osmate(Vf) dihydrate (1.8 g, 5.04 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography with 0-60% ethyl acetate in petroleum ether to afford re! -tert- butyl ((1S,2S)- l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-5-oxohexyl)carbaniate (8.3 g, 40%) as a yellow solid. MS ESI calculated for Ci 7H22CIF3N2O4 [M+l]⁺, 411.12: found, 41 1.00.

Step-3:

[1430] To a stirred solution of rel-tert-butyl ((lS,2S)-l-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)-2-hydroxy-5-oxohexyl)carbamaie (9.0 g, 21.90 mmol) in DCM (90 mL) was added TEA (30 ml,) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was basified with NaHCOs (sat.) and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.

[1431] The above residue was dissolved in iPrOH (50 mL), then Pd/C ( 1.0 g, 10% active on carbon)- The mixture was hydrogenated at room temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake w^;as washed with IPrOH. The filtrate was collected and concentrated under vacuum to afford rei-(2R,3R,6S)-2-(2-chloro-6- (trinuoromethyl)pyridin-3-yl)-6-meihylpiperidin-3-ol (4.6 g, crude) as a brown solid. MS ESI calculated for C12H14CIF3N2O [M+H]⁺, 295.07; found, 295.00.

Step-4

[1432] To a solution of rel-(2R,3R,6S)-2-(2-chloro-6-(trifluoroniethyl)pyridin-3-yl)-6- niethylpiperidin-3-o] (4.6 g, 15.27 mmol) in toluene (90 ml) was added NaH (60%) (0.7 g, 17.50 mmol) at room temperature. The mixture was stirred at 80 °C for 8 h. The reaction mixture was quenched by the addition of water at 0 °C. The mixture was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase flash column chromatography with 5-80% acetonitrile in water to afford rel-(2R,4aS,9bS)-2-methyl-7- (trifluoromethyl)-l, 2,3,4, 4a, 9b-hexahydrofuro[2,3-b:4,5-b']dipyridine (A82) (1.8 g, 45%) as a yellow solid. MS ESI calculated for C12HBF3N2O [M+H]⁺, 259.10; found, 259.05. ^;H NMR

(300 MHz, DMSO-cfc) 5 7.89 (d, J = 7.2 Hz, IH), 7.39 (d, J = 7.2 Hz, IH), 4.55 - 4.51 (m,

1H), 4.24 (d, J = 4.8 Hz, IH), 2.66 - 2.56 (m, IH), 2.34 - 2.18 (m, IH), 2.12 (br, IH), 1.96 -

1 .90 (m, IH), 1.54 - 1.56 (m, 1 H), 1 .32 - 1 .03 (m, IH), 0.94 (d, J = 6.3 Hz, 3H). Cis Relative stereochemistry was determined by NOESY. Absolute stereochemistry was not determined.

Intermediate A83 isomer 1: rel-(4R,4aR.10bR)-8-chloro-4-niethyl-2,3,4,4a.6,10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine isomer 1

A83 isomer , and

Intermediate A83 isomer 2: rel-(4R,4aR,10bR)-8-chloro-4-methyi-2,3,4,4a,6,10b- hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridine isomer 2

A83 isomer 2

Step-1:

[1433] To a stirred solution of 3-bromo-6-chloropicolinic acid (25.0 g, 105.73 mmol) and K2CO3 (29.2 g, 21 1.46 mmol) in DMF (200 ml) was added Mel (16.5 g, 1 16.30 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NazSCU. The resulting mixture was concentrated under reduced pressure to afford methyl 3-bromo-6-chloropico1inate (26.0 g, crude) as a yellow solid. MS ESI calculated for CzHsBrClNOzllM+H]⁴, 249.92, 251.92; found, 249.90, 251.90.

Step-2:

[1434] To a stirred solution of methyl 3-bromo-6-chloropicolinate (25.0 g, 99.80 mmol) and K2CO3 (41.3 g, 299.42 mmol) in dioxane (300 mL) and H?O (30 mL) were added 1:1 mixture of (S, E)-tert-bulyl((3-melhyl-5-(4, 4,5, 5-tetramethy 1-1,3, 2-dioxaborolan-2-y I)pent-4- en- l-yl)oxy)diphenylsilane and (R,E)-tert-butyl((3-methyl-5-(4, 4,5, 5-tetramethy J- 1,3,2- dioxaborolan-2-yl)pent-4-en-1 -yl)oxy)diphenylsilane (51 .0 g, 109.78 mmol) and PdtdppfiCh-CHzCk (8.1 g, 9.98 mmol). The resulting mixture was stirred at 80 °C for 8 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NazSOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford a 1: 1 mixture of methyl (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-methylpenl- 1 -en- 1 -yl)-6- chloropicolinate and methyl (R,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-methylpent-l-en-l- yl)-6-chloropicolinate (44.0 g, 75%) as a yellow oil. MS ESI calculated for C29H34CINO3S1 [M+Hf, 508.20; found, 508.25.

[1435] To a solution of tert-butyl carbamate (30.43 g, 259.77 mmol) in propan- l-ol (59.5 mL) and H2O (59.5 mL) was added NaOH (9.35 g, 233.79 mmol) at room temperature. After stirring for 5 minutes, DCDMH (25.59 g, 129.88 mmol) was added in portions at 0 °C, and then the mixture w'as stirred at 0 °C for additional 30 min. This was followed by the addition of (DHQl’PHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (6.75 g, 8.65 mmol), Potassium osmate(VI) dihydrate (3.19 g, 8.65 mmol) and 1: 1 mixture of methyl (S,E)-3-(5-(.(tert-butyldiphenylsi1yl)oxy)-3-methylpent-l -en-l-yl)-6-chIoropicolinate and methyl (R,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-methylpent-l-en-l-yl)-6-chloropicolinate (44 g, 86.59 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with H?O, then dried over anhydrous NajSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (300 mL), then DCC (35.7 g, 173.23 mmol) and DMAP (2 g, 16.26 mmol) were added at 0 °C. The mixture was stirred at room temperature for 6 h. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAv ( 1:1) to afford a 1:1 mixture of tert-butyl ((5R*,6R*)-6-(.(S)-4-((tert-butyldiphenylsilyl)oxy)butan-2- yl)-2-chloro-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-((tert-butyIdiphenylsilyl)oxy)butan-2-yl)-2-chloro-8-oxo-5,8-dihydro- 6H-pyrano[3,4-b]pyridm-5-yl)carbamate (22 g, 41% yield) as a yellow oil. MS ESI calculated for C33H41CIN2O5S1 [M+Hf , 609.25; found, 609.20.

Step-4:

[1436] To a stirred solution of 1 : 1 mixture of tert-butyl ((5R*,6R*)-6-((.S)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)-2-ch1oro-8-oxo-5,8-dihydro-6H-pyrano[3,4-blpyridin-5- yl)carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-2- chloro-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (22.0 g, 36.1 1 mmol) in THF (440 mL) was added NaBHt (5.4 g, 144.44 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched by ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-100% ethyl acetate in petroleum ether to afford a 1 :1 mixture of tert-butyl (( iR*,2R*,3S)-5-((tert-butyldiphenylsilyl)oxy)-l -(6-chloro-2- (hydroxymethyl)pyridin-3-yl)-2-hydroxy-3-methylpentyl)carbamate and tert-butyl ((lR*,2R*,3S)-5-((tert-butyldiphenylsilyl)oxy)-l-(6-chloro-2-(hydroxyniethyl)pyridin-3-yl)- 2 -hydroxy -3 -methylpentyl )carbamate (8.0 g, 95%) as a white solid. MS ESI calculated for CrrHrsClNrOsSi [M+H]⁺, 613.28; found, 613.30.

[1437] To a stirred solution of 1: 1 mixture of tert-butyl (( lR*,2R*,3S)-5-((tert- butyJdiphenylsilyl)oxy)-l-(6-chloro-2-(hydroxymeihyl)pyridin-3-yl)-2-hydroxy-3- methylpentyllcarbaniate and tert-butyl ((lR*,2R*,3S)-5-((tert-butyldiphenylsilyl)oxy)-l-(6- chloro-2-(hydroxymethyl)pyridin-3-yl)-2-hydroxy-3-rnethylpentyl)carbamate (8.0 g, 13.05 mmol) in toluene (100 mL) was added 2-(tributyl-L⁵-phosphaney]idene)acetonitrile (CAS No. 157141-27-0) (6.3 g, 26.09 mmol). The resulting mixture was stirred at 1 10 °C overnight. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography with 0-60% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tertbutyl ((5R*,6R*)-6-((S)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-2-chloro-5,8-dihydro- 6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)-2-ch1oro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5- yl)carbamate (3.3 g, 95%) as a yellow oil. MS ESI calculated for Css^jClNsCflSi [M+H]⁺, 595.27; found, 595.30.

Step-6:

[1438] To a stirred solution of 1 : 1 mixture of tert-butyl ((5R*,6R*)-6-((S)-4-((tert- butyldiphenylsilyl)oxy)butan-2-yl)-2-chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5- yl)carbamate and tert-butyl ((5R*,6R*)-6-((R)-4-((tert-butyidiphenylsilyl)oxy)butan-2-yl)-2- chloro-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (3.2 g, 5.46 mmol) in THE (40 mL) was added tetrabutylazamum fluoride (3.4 g, 10.92 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-80% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of tert-butyl ((5R*,6R*)-2-ch1oro-6-((S)-4-hydroxybutan-2-yl)-5,8-dihydro-6H- pyrano|3,4-b]pyridin-5 -yl)carbamate and tert -butyl ((5R*,6R*)-2-chloro-6-((R)-4- hydroxybutan-2-yl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (2.0 g, 96%) as a yellow oil. MS ESI calculated for CnHzsClNzCh [M+H]⁺, 357.15; found, 357.15.

Step-7 :

isomer 2

[1439] To a stirred solution of 1 : 1 mixture of tert-butyl ((5R*,6R*)-2-chloro-6-((S)-4- hydroxybutan-2-yl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5R*,6R*)-2-chloro-6-((R)-4-hydroxybutan-2-yl)-5,8-dihydro-6H-pyrano[3,4-blpyridin-5- yl)carbamate (1.9 g, 5.46 mmol) in toluene (20 mL) was added 2-(tributyl-X⁵- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (2.6 g, 10.92 mmol). The resulting mixture was stirred at 110 °C for 5 h. The resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with 0-70% ethyl acetate in petroleum ether to afford crude product. The crude product was separated by Prep-Chiral SFC with the following conditions: [Column: CH1RALPAK 1C, 3*25 cm, 5 ttm; Mobile Phase A: CO2, Mobile Phase B: IPA (1% 2M NHs-MEOH); Flow rate: 100 mL/min;

Gradient (B%): isocratic 15% B; RTl(min): 4; RT2(min): 6: Sample Solvent: MEOH; Injection Volume: 2 mL; Number Of Runs: 10] to afford rel- tert-butyl (4R,4aR,10bR)-8- chloro-4-methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b‘]dipyridine- 1 -carboxylate isomer 1 (0.4 g, 34%) as a white solid with retention time at 4 minute. MS ESI calculated for C-HisClNbO [M+H]⁺, 339.14: found, 339.00.

[1440] The chiral resolution also afford rel- tert-butyl (4R,4aR,10bR)-8-chloro-4-methyl- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate isomer 2 (0.3 g, 23%) as a yellow oil. MS ESI calculated for C12H15CIN2O [M+H]⁺, 339.14; found, 339.00.

Step-8:

[1441] A mixture solution of rel-tert-butyl (4R,4aR,10bR)-8-chloro-4-methyl- 2,3.4_s4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b'Jdipyridine-l-carboxylate isomer 1 (100 mg, 0.29 mmol) and HC1 in 1,4-dioxane (3 niL, 4M) was stirred at room temperature for 30 min. The resulting mixture -was concentrated under vacuum to afford rel-(4R,4aR, 10bR)-8- chloro-4-methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridine hydrochloride isomer 1 (A83 isomer 1) (130 mg, crude) as a white solid. MS ESI calculated for C12H15CIN2O [M+H]⁺, 239.09; found, 239.10.

Step-9: isomer 2 A83 isomer 2

[1442] A mixture of rel-tert-butyl (4R,4aR,10bR)-8-chJoro-4-melhyl-2,3,4,4a,6,10b- hexahydro-lH-pyrano[3, 2-b:5,4-b’]dipyridine-l -carboxylate isomer 2 (230 mg, 0.67 mmol) and HC1 (4.0 M in 1 ,4-dioxane) (2 niL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to afford rel-(4R,4aR,10bR)-8-chloro-4- methyl-2,3,4,4a,6,I0b-hexahydro- 1 H-pyrano[3,2-b:5,4-b']dipyridine hydrochloride isomer 2 (A83 isomer 2) (190 mg) as a white solid. MS ESI calculated for CizH’sCINhO [M+H]\ 239.09; found, 239.10. Absolute stereochemistry was not determined.

Intermediate A84: rel-(4R,4aR,9bR)-7-chloro-4-methyl- 1 ,2,3,4,4a,9b-hexahydrofuro[2,3- b:4,5-b’ldipyridine isomer 1 and rel-(4R,4aR,9bR)-7-chloro-4-methyl-l,2.3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine isomer 2

[1443] To a stirred solution of 3-bromo-2,6-dichloropyridine (10 g, 44.07 mmol) and 1:1 mixture of (R,E)-tert-butyl((3-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)peni-4- en-l-yl)oxy)diphenylsilane and (S.E)-tert-buty]((3-methyl-5-(4, 4,5, 5-tetramethyJ- 1,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy)diphenylsilane (22.52 g, 48.48 mmol) in dioxane (90 mL) and H2O (18 mL) were added K2CO3 (18.27 g, 132.22 mmol) and Pd(dppf)Ch (3.23 g, 4.40 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 16 h. The reaction was cooled down to room temperature and quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford a 1:1 mixture of (R,E)-3-(5-((tert- butyldiphenylsilyl)oxy)-3-methylpent-l-en-l-yl)-2,6-dichloropyridine and (S,E)-3-(5-((ten- butyldiphenylsilyl)oxy)-3-methylpent-l-en-l-yl)-2,6-dichloropyridine (20.6 g, 90%) as a yellow oil. MS ESI calculated for CziHssCoNOSi [M+H]⁺, 484.16; found, 484.15. [1444] To a stirred solution of tert-butyl carbamate (15.44 g, 131.79 mmol) in propan-l-ol (166 mL) was added a solution of NaOH (4.59 g, 114.79 mmol) in HjO (144 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 min. Then l,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione (16.75 g, 85.03 mmol) was added in portions at room temperature. After stirring at room temperature for additional 30 minutes, a solution of (DHQlsPHAL (3.31 g, 4.25 mmol) (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) in propan-l-ol (42 mL), a 1: 1 mixture of (R,E)-3-(5-((tert-buiyldiphenylsilyl)oxy)-3-methylpent-l-en-l-yl)-2,6- di chloropyridine and (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-methylpent-l-en-l-yl)-2,6- dichloropyridine (20.6 g, 42.51 mmol) in propan- l-ol (42 mL) and a mixture of Potassium osmate! VI) dihydrate ( 1.57 g, 4.25 mmol) and NaOH (aq., 0.4M) at 0 °C. The resulting mixture was stirred at room temperature for additional 16 h. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (0-20%) to afford a 1: 1 mixture of tert-butyl ((lS*,2S*.3R)-5-((tert-butyldiphenyIsilyl)oxy)-l-(2,6- dichloropyridin-3-yl)-2-hydroxy-3-methylpentyI)carbamate and tert-butyl ((lS*,2S*,3S)-5- ((tert-but.yldiphenylsilyl)oxy)-l-(2,6-dichloropyridin-3-yl)-2-hydroxy-3- methylpenlyl)carbamate (15.3 g, 90%) as a green oil. MS ESI calculated for C32H42CI2N2O/1S1 [M+H]⁺, 617.23; found, 617.20.

Step-3 :

[1445] To a stirred solution of 1: 1 mixture of tert-butyl ((lS*,2S*,3R)-5-((tert- butyldiphenylsilyl)oxy)-l-(2,6-dichloropyridin-3-yl)-2-hydroxy-3-rnethylpentyl)carb- arnate and tert-butyl ((lS*,2S*,3S)-5-((tert-butyldipheriylsilyl)oxy)-l-(2,6-dichloropyridin-3-yl)-2- hydroxy-3-methylpentyl)carbamate (18.1 g, 29.30 mmol) in THE (155 mL) was added TBAF (15.32 g, 58.60 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-100% to EtOAc in PE afford a 1:1 mixture of tert-butyl ((lS*,2S*,3S)-l-(2,6-dichloropyridin-3-yl)-

2,5-dihydroxy-3-melhylpentyl)carbamate and tert-butyl ((1S*,2S*,3R)- 1-(2,6- dichloropyridin-3-yl)-2,5-dihydroxy-3-methylpentyl)carbamate (1.5 g, 95%) as a yellow oil.

MS ESI calculated for C16H24C12N2O4 [M+H]⁺, 379.11; found, 379.10.

Step-4:

[1446] To a stirred solution of 1: 1 mixture of tert-butyl ((lS*,2S*,3S)-l-(2,6- dichloropyridin-3-yl)-2,5-dihydroxy-3-methylpentyl)carbaniate and tert-butyl ((1S*,2S*,3R)- l-(2,6-dichloropyridin-3-yl)-2,5-dihydroxy-3-methylpentyl)carbamate (1.5 g, 3.95 mmol) and TEA (1.20 g, 11.86 mmol) in DCM (15 mL) was added MS2O (0.47 g, 4.74 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with ice water and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (16 mL), then TFA (10 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissloved in ACN (28 mL), this was followed by the addition of 1,2,2,6,6-pentamethylpiperidine (9.74 g, 62.70 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 16 h. The mixture was concentrated under vacuum. The resulting residue was purified by reverse phase flash column chromatography with an 80 g C18 column eluted with 5-100% acetonitrile in water (10 mmol/L NII4HCO3) to afford a 1:6 mixture of rel-(2S,3S,4S)-2-(2,6-dichloropyridin-3-yl)-4- methylpiperidin-3-ol isomer 1 and rel-(2S.3S,4R)-2-(2,6-dichloropyridin-3-yl)-4- methylpiperidin-3-o] isomer 2 (217 mg. 95%) as a yellow oil. MS ESI calculated for C iiH_; sCrX O [M+H]⁺, 261.05; found, 261.05.

Step-5 :

[1447] To a stirred solution of 1:6 mixture of rel-(2S,3S,4S)-2-(2,6-dichloropyridin-3-yl)- 4-methylpiperidin-3-ol isomer 1 and rel-(2S,3S,4R)-2-(2,6-dichloropyridin-3-yl)-4- methylpiperidin-3-ol isomer 2 (207 mg, 0.79 mmol) in MeOH (2 mL) was added BocsO (259 mg, 1 .19 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (0- 30%) to afford a 1:6 mixture of rel-tert-butyl (2S,3S,4S)-2-(2,6-dichloropyridin-3-yl)-3- hydroxy-4-methylpiperidine-l-carboxylate isomer 1 and rel-tert-butyl (2S,3S,4R)-2-(2,6- dichloropyridiii-3 -yl)-3-hydroxy-4-methylpiperidiiie- l -carboxylate isomer 2 (199 nig, 98%) as a colorless oil. MS ESI calculated for C16H22G2N2O3 [M+H]⁺, 361.10; found, 361.10.

Step-6:

[1448] To a stirred solution of 1 :6 mixture of rel-tert-butyl (2S,3S,4S)-2-(2,6- dichloropyridin-3-yl)-3-hydroxy-4-metbylpiperidine-l -carboxylate isomer 1 and rel-tert-butyl (2S,3S,4R)-2-(2,6-dicliloropyridin-3-yl)-3-hydroxy-4-methylpiperidine-l-carboxylate isomer 2 (179 mg, 0.49 mmol) in tert-Amyl alcohol (10 ml) was added t-BuOK. (1 1 1 mg, 0.99 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 16 h. The resulting mixture cooled down to room temperature and quenched with water. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum to afford a 1:6 mixture of rel-tert-butyl (4S,4aS,9bS)-7-chloro-4-methyl-3,4,4a,9b-tetrahydrofttro[2,3-b:4,5- b']dipyridine-l (2H)-carboxylate isomer 1 and rel-tert-butyl (4R,4aS,9bS)-7-chloro-4-methyl- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate isomer 2 (crude, 124 mg) as a white solid. MS ESI calculated for CisftjClNzOs [M+H1⁺, 325.12; found, 325.10.

Step-7:

A84 [1449] A mixture of 1:6 mixture of rel-tert-butyl (4S,4aS,9bS)-7-chloro-4-metliyl-

3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine- 1 (2H)-carboxylate isomer 1 and rel-tert- butyl (4R,4aS,9bS)-7-chloro-4-methyl-3,4,4a_>9b-tetrahydroftiro[2,3-b:4,5-b^,]dipyridine- l(2H)-carboxylate isomer 2 ( 114 mg, 0.35 mmol) and HC1 in dioxane (2 rnL, 4M) was stirred at room temperature for 16 b. The resulting mixture was concentrated under vacuum to afford a l :6 mixture of rel-(4S,4aS,9bS)-7-chloro-4-methy1-l ,2,3,4,4a,9b-hexahydrofurol2,3-b:4,5- b'Jdipyridine hydrochloride isomer 1 and rel-(4R,4aS,9bS)-7-chloro-4-methyl- 1, 2, 3, 4, 4a, 9b- hexahydrofuro[2,3-b:4,5-b']dipyridine isomer 2 hydrochloride (A84) (crude, 94 mg) as a white solid. MS ESI calculated for C11H13CIN2O [M+H] ⁺, 225.07; found, 225.10. Intermediate ASS: (2R,4aS,10bS)-2-methyl-8-(prop-2-yn-l-yloxy)-l,2,3,4a,5,10b- hexahydrochromeno[3,4-b][l ,4]oxazine

A85

Step - 1 : [1450] A solution of 7-bromochroman -4-one (10 g, 44.04 mmol) and CuBr? (19.67 g, 88.08 mmol) in EtOAc (100 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was filtered. The filtrate was concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography with 0-20% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of (S)-3,7-dibromochroman-4-one and (R)-3,7- dibromochroman-4-one (12.6 g, 86%) as a white solid. MS ESI calculated for CyHsBrjO?. [M+H]⁺, 304.87, 306.87: found, 304.95, 304.95.

Step-2:

[1451] To a solution of 1: 1 mixture of (S)-3,7-dibromochroman-4-one and (R)-3,7- dibromochroman-4-one (25.3 g, 82.69 mmol) in EtOH (250 mL) was added NaBIL (3.13 g, 82.69 mmol) in porstions at 0 °C. The mixture was stirred at 25 °C for 2. h under nitrogen atmosphere. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO-j. After filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of (3R,4S)-3,7- dibromochroman-4-ol and (3S,4R)-3.7-dibromochroman-4-ol (28 g, crude) as a while solid. ^!H NLMR (300 MHz, DMSO-d's) 87.26 (d, 9.0 Hz, 1H), 7.13 - 7.02 (m, 1 H), 7.00 - 6.95

(m, i H i. 6.04 (s, 1 H), 4.84 (d, J= 6.0 Hz, 1H), 4.73 - 4.66 (m, 1H), 4.60 - 4.51 (m, 1H), 4.33 (dd, J = 12.0, 6.0 Hz, 1H).

Step

[1452] To a solution of 1: 1 mixture of (3R,4S)-3,7-dibromochroman-4-ol and (3S,4R)-3,7- dibromochroman-4-ol (28 g, 90.91 mmol) in CHsCN (280 mL) was added H2SO4 (17.83 g, 181.83 mmol) dropwise at 0 °C. The resulting mixture was stirred at 50 °C for I h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in HzO (200 mL) and heated at 100 °C for 16 h with stirring. The mixture was cooled and basified by NaOH (30% aq.) to pH 10. The precipitated solids were collected by filtration and washed with water to afford a 1: 1 mixture of (3S,4S)-4-amino-7-bromochroman-3-ol and (3R,4R)-4-amino-7-bromochroman-3-ol (21 g, 69%) as a white solid. MS ESI calculated for G;H loBrNOe [M+H]⁺, 243.99, 245.99; found, 244.15, 246.10.

[1453] To a solution of a 1:1 mixture of (3S,4S)-4-amino-7-bromochroman-3-ol and (3R,4R)-4-amino-7-bromochroman-3-ol (14 g, 57.36 mmol.) in MeOH (140 mL) were added TEA (17.46 g, 172.07 mmol) and BociO (13.77 g, 63.09 mmol). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2:1) to afford a 1: 1 mixture of tert-butyl ((3S,4S)-7-bromo-3-hydroxychroman-4-yI)carbamate and tert-butyl ((3R.4R)-7-bromo-3-hydroxychroman-4-yl)carbamate (14.30 g, 71%) as an off- white solid. MS ESI calculated for Ci4Hi₈BrNO₄ [M+H]⁺, 344.04, 346.04; found, 344.05, 346.05.

[1454] To a solution of a 4:3 mixture of tert-butyl ((3S,4S)-7-bromo-3-hydroxychroman-4- yllcarbaniate and tert-butyl ((3R,4R)-7-bromo-3-hydroxychroman-4-yl)carbamate (14.30 g.

41.55 mmol) in DCM (143 mL) were sequentially added (Bu4N)HSO₄ (2.82 g, 8.31 mmol), NaOH (11.63 g, 290.82 mmol) and (S)-4-methy1-l,3,2-dioxathioIane 2,2-dioxide (7.46 g, 54.01 mmol) (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30-1 ). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in H2O (29 mL), and H2SO4 (214 mL) was added at 0 °C with stirring. The resulting mixture was stirred at 80 °C for 16 h. The mixture was cooled and basified with NaOH (a.q.) to pH 8. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4- After filtration, the filtrate was concentrated under reduced pressure to afford a 1:1 mixture of (S)-l-(((3S,4S)-4-amino-7-bromochroman-3-yl)oxy)propan-2-ol and (S)-l -(((3R,4R)-4-aniino-7-bromochroman-3-yl)oxy)propan-2-ol (14.3 g, crude) as a brown solid. MS ESI calculated for C^HicBrNCh [M+H]⁺, 302.03, 304.03; found, 302.00, 304.00.

Step-6:

[1455] To a solution of a 1:1 mixture of (S)-l-(((3S,4S)-4-anuno-7-bromochroman-3- yl)oxy)propan-2-ol and (S)-l-(((3R,4R)-4-amino-7-bromochroman-3-yl)oxy)propan-2-ol in methanol (89 mL.) were added TEA (8.89 g, 87.86 mmol) and BOC2O (7.03 g. 32.22 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:2) to afford a 1: 1 mixture of tert-butyl ((3S,4S)-7-bromo-3-((S)-2- hydroxypropoxy)chroraan-4-y!)carbamate and tert-butvl ((3R,4R)-7-bromo-3-((S)-2- hydroxypropoxy)chroman-4-yl)carbamate (8. 1 g, 68%) as a white solid. MS ESI calculated for (Ci7H₂4BrNO₅) [M+H]⁺, 402.08, 404.08; found, 402.00, 404.05.

Step-7:

[1456] To a solution of a 1 :1 mixture of tert-butyl ((3S,4S)-7-bromo-3-((S)-2- hydroxypropoxy)chroman-4-yl)carbamate and tert-butyl ((3R,4R)-7-bromo-3-((S)-2- hydroxypropoxy)chroman-4-yI)carbamate (8.1 g, 20.38 mmol) in toluene (82 mL) were added 2-(tributyl-/3-phosphaneylidene)acetonitrile (CAS No. 157141 -27-0) (9.27 g, 40.77 mmol). The resulting mixture was stirred at 110 °C for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (4:1 ) to afford tert-butyl (2R,4aR,10bR)-8- bromo-2-methy1-2,3,4a,10b-tetrahydrochromeno[3,4-b][1 ,4]oxazine- 1 (5H)-carboxylate (2.63 g, 33%) as a yellow oil as the first eluting peak. MS ESI calculated for Ci?H22BrNO4 [M+H]⁺, 384.07, 386.07; found, 384.25, 386.20. ’H NMR (400 MHz. DMSO) 8 7.43 (d, 7 = 8.0 Hz, 1H), 6.75 - 6.68 (m, 1H), 6.51 (s, 1H), 4. 19 - 4.07 (m, 2H), 3.94 (d, J = 3.2 Hz, IH), 3.74 - 3.71 (m, IH), 3.57 (dd, J = 10.8, 3.2 Hz, IH), 3.07 (t, J = 10.4 Hz, IH), 2.49 - 2.46

(m, IH), 2.21 (s, 9H), 0.82 (d, J - 6.4 Hz, 3H). Absolute stereochemistry was determined by NOESY.

[1457] The purification process also afford tert-butyl (2R,4aS,10bS)-8-bromo-2-methyl- 2,3.4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazine-l(.5H)-carboxylate (3.67 g, 46%) as a yellow oil with the second peak on flash. MS ESI calculated for CnlfeBrNOa [M+H]⁺, 384.07, 386.07; found, 384.25, 386.20. *H NMR (400 MHz, DMSO) 5 7.14 (d, J = 7.6 Hz, IH), 6.70 (dd, J = 7.6, 1.2 Hz, 1H), 6.58 (s, 1H), 4.66 - 4.59 (m, IH), 3.99 - 3.89 (m, 2H), 3.85 - 3.79 (m, 1H), 3.46 (dd, 7 - 10.4, 3.2 Hz, IH), 3.15 (t, 7 = 10.4 Hz. IH), 2.99 - 2.88 (ra, 1H), 2.21 (s, 9H), 0.87 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was determined by NOESY.

[1458] A solution of tert-butyl (2R,4aS, 10bS)-8-bromo-2-methyl-2,3,4a, 10b- tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxy1ate (500 mg, l,3mmol) in DMSO (8 mL) and H2O (2 mL) were added N,N'-bis(4-hydroxy-2,6-dimethylphenyl)ethanediamide (854 mg, 2.6 mmol) and Cu(acac)₂ (681 mg, 2.6 mmol) at room temperature, this was followed by the addition of NaOH (104 mg, 2.6 mmol) in portions at room temperature. The resulting mixture was heated to 110 °C with stirring overnight. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-30% ethyl acetate in petroleum ether to afford tert-butyl (2R,4aS,10bS)-8-hydroxy-2-methyl-2,3,4a,10b- tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate (450 rng, 95%) as a yellow oil. MS ESI calculated for C17H23NO5 [M+H]\ 322.16; found, 322.05.

Step 9:

[1459] To a solution of tert-butyl (2R,4aS,10bS)-8-hydroxy-2-methyl-2,3,4a,10b- tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate (500 mg, 1 .56mmol) in DMF (5 mL) were added K2CO3 (537 mg, 3.89mmo1) and propargyl bromide (555 mg, 4.67mmol) at room temperature with stirring. The resulting mixture was stirred at 80 °C for 8 hours under nitrogen atmosphere. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-30% ethyl acetate in petroleum ether to afford tertbutyl (2R,4aS,10bS)-2-methyl-8-(prop-2-yn-l-yloxy)-2,3.4a,10b-tetrahydrochromeno[3,4- bj[l,4]oxazine-l(5H)-carboxy1ate (350 mg, 50%) as a yellow oil. MS ESI calculated for C20H2.5NO5 [M+H]⁺, 360.17; found, 360.15.

Step 10:

A85

[1460] A mixture of tert-butyl (2R,4aS,10bS)-2-methyl-8~(prop-2-yn- 1 -yloxy)-2,3,4a,10b- tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate (300 mg, 0.84 mmol) and HC1 (g) in dioxane (4M, 10 ml.) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford (2R,4aS,10bS)-2-methyl-8-(prop-2-yii-l- yloxy)-l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l,4joxazine hydrochloride (A85) (240 mg, 76%) as a yellow solid. MS ESI calculated for CjsHnNOs [M+H]⁺, 260.12; found, 260.10.

M NMR (300 MHz, DMSO-zfe) 5 10.71 (br, IH), 9.40 (br, IH). 7.67 (d, 7 = 8.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.6 Hz, IH), 6.52 (d. 2.6 Hz, 1H), 4.81 (d, 2.4 Hz, 2H), 4.70 (t, J = 10.8

Hz, IH), 4.57 - 4.55 (m, IH), 4.47 - 4.40 (m, IH), 4.19 - 4.14 (m, HI), 3.85 - 3.82 (m, IH), 3.57 - 3.51 (m, 3H), 1.20 (d, 5.6 Hz, 3H).

Intermediate A86: (2R,4aS,10bS)-8-ethynyl-2-methyl- 1,2, 3.4a, 5,10b- hexahydrochromeno[3,4-b][ l,4]oxazine

Step 1:

[1461] To a stirred mixture of tert-butyl (2R,4aS, 10bS)-8-bromo-2-methyl-2.3,4a, 10b- tetrahydrochromeno[3,4-b][ l,4joxazine-l(5H)-carboxylate (500 rag, 1.30 mmol) and trimethylsilylacetylene (639.00 mg, 6.50mmol) were added PdfPPhsli (451.09 mg, 0.39mmol), Cui (247.81 mg, 1.30mmol) and EtsN (25.00 mL, 179.84 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford tert-butyl (2R,4aS,10bS)-2-methyl-8-((triniethylsilyl)etliynyl)-2,3,4a,10b-tetrahydrocliromeno[3.4- b][l,4]oxazine-l(5H)-carboxylate (526 mg, 86.5%) as a yellow oil. MS ESI calculated for

[1462] To solution of tert-butyl (2R,4aS,10bS)-2-methyl-8-((trimethylsilyl)ethynyl)- 2,3,4a,10b-tetrahydrochromeno[3,4-bJll,4]oxazine- l(5H)-carboxylate (500 mg. 1.25mmol) in methanol (30 ml.,) was added K2CO3 (516 mg, 3.74mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solids were filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford tertbutyl (2R,4aS,l0bS)-8-ethynyl-2-methyl-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazine- 1 (5H)-carboxy1ate (400 rag, 87%) as a yellow oil. MS ESI calculated for C19H23NO4 [M+H]⁺, 330.16; found, 330.15.

Step 3:

A86 [1463] A mixture of tert-butyl (2R,4aS,l0bS)-8-ethynyl-2-methyl-2,3_!4a,10b- teiraIiydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate (400 mg, 1 .2Immol) and HC1 (g) in 1 ,4-dioxane (4.0 M, 30 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. This resulted in (2R,4aS,10bS)-8-ethynyl-2- methyl-l ,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l ,4]oxazme hydrochloride (A86) (312 rag, 89%) as a yellow solid. MS ESI calculated for C14H15NO2 [M+H]⁺, 230. 11; found, 230.10.

^!H NMR (400 MHz, DMSO-fife) 5 10.73 (s, 1H), 9.58 (s, 1H), 7.77 - 7.72 (m, 1H), 7.16 - 7.01 (m, 1H), 7.01 (d, J = 1.8 Hz, 1H), 4.80 - 4.58 (m, 2H), 4.48 - 4.43 (m, 1H), 4.36 - 4.16 (m, 2H), 3.87 - 3.83 (m, 1H), 3.58 - 3.83 (m, 2H), 1.48 - 0.93 (m, 3H). Intermediate A87: (2R,3R,4aS,9bS)-3-niethoxy-2-methyl-7-(trifIuoromethyl)-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine

A87

Step- 1 :

[1464] To a stirred solution of (R,Ej-tert-butyl((2-metboxy-5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)peni-4-en-l-yl)oxy)dimethylsilane (10.00 g, 28.06 mmol) and 3-bromo-2- chloro-6-(trifluoromethyl)pyridine (7.31 g, 28.06 mmol) in dioxane (100 mL) and EbO (10 mL) were added K2CO3 (11.63 g, 84.18 mmol) and Pd(dppf)Ch (2.05 g, 2.81 mmol) at room temperature under nitrogen atmosphere. The resulting mixture w'as stirred at 100 °C for 16 h. The mixture was allowed to cool down to room temperature and quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NazSCU- Alter filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% EtOAc in PE to afford (R,E)-3-(5-((tert-butyldimethylsiIyl)oxy)-4-methoxypent- 1-en- 1 -yl)-2-chloro-6-(trilluoromethyl)pyridine (9.00 g, 78%) as a brown oil. MS ESI calculated fos - Ci sHjrClFsNOzSi [M+Hf; 410.15; found, 410.15.

Step-2:

[1465] To a stirred solution of (R,E)-3-(5-((tert-butyldimetliylsilyl)oxy )-4-methoxypent-l- en-l-yl)-2-chloro-6-(trifluoromethy])pyridine (20.60 g, 50.25 mmol) and DMP (31.97 g, 75.38 mmol) in DMSO (200 mL) was added TsOH (0.87 g, 5.03 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 2 h. The mixture was allowed to cool down to room temperature and quenched with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NasSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-32% EtOAc in PE to afford (R,E)-5-(2- chloro-6-(trifluoromethyl)pyridin-3-yl)-2-methoxypent-4-enal (1 1.00 g, 74%) as a brown oil.

MS ESI calculated for C12H11CIF3NO2 [M+H]⁺, 294.04; found, 294.05.

[1466] To a stirred solution of (R,E)-5-(2-chloro-6-(triiluoromethyl)pyridin-3-yl)-2- methoxypent-4-enal (1 1.00 g, 37.46 mmol) and 4 A molecular sieve in THF ( 100 mL) was added MeMgBr (1 M/L in THF) (93 mL, 93.00 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by NH4CI (sat.) at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na?.SOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-55% EtOAc in PE to afford a 1:4 mixture of (2R,3R,E)-6-(2-chloro-6-(trifluoromelhyl)pyridin-3-yl)-3-methoxyhex-5-en-2-oi and (2S,3R,E)-6-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-3"methoxyhex-5"en-2-ol (1.87 g, 16%) as a brown oil. MS ESI calculated for C13H15CIF3NO2 [M+H]⁺, 310.07; found, 310.05.

Step-4:

[1467] To a stirred solution of a 1:4 mixture of (2R,3R,E)-6-(2- chloro- 6-

(trifluoromethyl)pyridin-3-yl)-3-methoxyhex-5-en-2-ol and (2S,3R,E)-6-(2-chloro-6-

(tritluoromethyl)pyridin-3-yl)-3-methoxyhex-5-en-2-ol (1.87 g, 6.13 mmol) and imidazole (1.25 g, 18.41 mmol) in DCM (20 mL) was added TBDPS-C1 (2.53 g, 9.20 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NasSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% EtOAc in PE to afford a 1:4 mixture of 3-((4R,5R ,E)-5-(( tert-butyldlphenylsilyl)oxy )-4-methoxyhex- 1 -en- 1 -y l)-2-chloro- 6-(trifluoromethyl)pyridine and 3-((4R,5S,E)-5-((tert-butyldiphenylsi1yl)oxy)-4-methoxyhex- l-en-l-yI)-2-chloro-6-(trifluoromechyl)pyridine (.2.20 g, 65%) as a colorless oil. MS ESI calculated for CsJ-feCIFsNOzSi [M+H]⁺, 548.19; found, 548. 15.

Step-5:

[1468] To a stirred solution of BocNEb (0.4 M/L in i-PrOH) (39 mL, 12.44 mmol) were sequentially added NaOH (0.4 M, aq.) (28 mL) and DCDMH (149 g, 6.02 mmol) at 0 °C. After stirring at 0 °C for 20 min., (DHQ)?PHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (0.1 M/L in i-PrOH) (39 mL, 0.15 mmol), a 1:4 mixture of 3- ((4R,5R,E)-5-((tert-butyldiphenylsilyl)oxy)-4-methoxyhex-l-en-l-yl)-2-chloro-6- (trifluoromeihyl)pyridine and 3-((4R,5S,E)-5-((tert-butyldiphenylsilyl)oxy)-4-methoxyhex-l- en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine (2.20 g, 4.01 mmol) and K2OSO4.2H2O (0.15 g, 0.40 mmol) were added at 0 °C. The resulting solution was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaiSOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-22% EtOAc in PE to afford a 1:4 mixture of tert- butyl ((lS,2S,4R,5R)-5-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-4- methoxyhexyl)carbamate and teri-butyl (( lS,2S,4R,5S)-5-((teri-butyldiphenylsilyl)oxy)-l-(2- chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-4-methoxyhexyl)carbamate (1.50 g, 55%) as a colorless oil. MS ESI calculated for CarHuCIFsN^OsSi [M+H]⁺, 681.27; found, 681.30.

Step-6:

[1469] To a stirred mixture of a 1:4 mixture of tert-butyl ((lS,2S,4R,5R)-5-((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-4- methoxyhexyljcarbarnate and tert-butyl ((lS,2S,4R,5S)-5-((tert-butyldiphenylsily1)oxy)-l-(2- cliloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-4--methoxyhexyl)carbaniate (468 mg, 0.69 mmol) in toluene (5 mL) were added CS2CO3 (448 mg, 1.37 mmol), JohnPhos (20 mg, 0.07 mmol) and Pd(OAc)?. (15 mg, 0.07 mmol) at. room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The mixture was diluted with ethyl acetate. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0—15% EtOAc in PE to afford a 1:4 mixture of tertbutyl ((2S,3S)-2-((2R,3R)-3-((tert-butyldiphenylsilyl)oxy)-2-methoxybutyl)-6- (trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tert-butyl ((2S,3S)-2- ((2R,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-methoxybutyl)-6-(trifluoromethyr)-2,3- dihydrofuro[2,3-b]pyridin-3-yl)carbamate (110 mg, 25%) as a yellow oil. MS ESI calculated for C34H43F3N2O5S1 |M+Hf, 645.29: found, 645.20.

[1470] To a stirred mixture of 1 :4 mixture of tert-butyl ((2S,3S)-2-((2R,3R)-3-((tert- butyldiphenylsilyl)oxy)-2-methoxybutyl)-6-(trifluorojnethyl)-2,3-dihydrofuro[2,3-b]pyridin- 3-yl (carbamate and tert-butyl ((2S,3S)-2-(.(2R,3S)-3-((tert-buiy]diphenylsilyl)oxy)-2- methoxybutyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-blpyridin-3-yl)carbamate (425 mg, 0.66 mmol) in THF (5 mL) was added TBAF (344 mg, 1.32 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-53% EtOAc in PE to afford a 1:4 mixture of tert-butyl ((2S,3S)-2-((2R,3R)-3-hydroxy-2-methoxybutyl)-6- (trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tert-butyl ((2S,3S)-2- ((2R,3S)-3-hydroxy-2-methoxybutyl)-6-(trif1uoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- yl)carbamate (179 mg, 67%) as a white solid. MS ESI calculated for C18H2.5F3N2O5 [M+H]*, 407.17; found, 407.15.

[J 471] A solution of a 1 :4 mixture of tert-butyl ((2S,3S)-2-((2R,3R)-3-hydroxy-2- methoxybutyl)-6-(irifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tertbutyl ((2S ,3 S)-2-((2R,3S) ■ 3 -hydroxy-2-methoxybutyl) -6-(trifluoromethyl)-2, 3 ■ dihydrofuro[2,3-b]pyridin-3-yl)carbamate (220 mg, 0.54 mmol) and 2-(tributyl-X⁵- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (392 mg, 1.62 mmol) in toluene (6 mb) was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% EtOAc in PE to afford a 1 :4 mixture of tert-butyl (2R,3R,4aS,9bS)-3- methoxy-2-methyj-7-(lrinuoromethyl)-3,4,4a,9b-l.etrahydrofuro[2,3-b:4,5-b']dipyridine- l(2H)-carboxylate and tert-butyl (2S,3R,4aS,9bS)-3-niethoxy-2-rnethyl-7-(trifluoromethyl)- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (120 mg, 57%) as a brown oil. MS ESI calculated for C18H23F3N2O4 [M-t-H]⁺, 389.16; found, 389.15.

Step-9:

[1472] To a stirred mixture of a 1:4 mixture of terl-butyl (2R,3R,4aS,9bS)-3-methoxy-2- methyl-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)- carboxylate and tert-butyl (2S,3R,4aS,9bS)-3-methoxy-2-methyi-7-(trifluoromethyl)- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (120 mg, 0.31 mmol) in EtOAc (2 ml..) was added HC1 in 1,4-dioxane (4.0 M, 2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-Chiral -HPLC with the following conditions [Column: CHIRALPAK IB, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)- HPLC, Mobile Phase B: EtOH: DCM=1: 1 --HPLC; Flow' rate: 20 mL/min; Gradient (B%): isocratic 15% B to 15% in 7min; Wave Length: 220/254 nm; RTl(min): 4.84; RT2(min): 5.96; Sample Solvent: MeOH: DCM=1: 1-HPLC] to afford (2R,3R.4aS,9bS)-3-methoxy-2- methyl-7-(trifluoromethyl)-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b']dipyridine, isomer 1 ( A87) (29 mg) as a yellow solid with retention time at 4.84 minute. MS ESI calculated for C13H15F3N2O2 [M+H]⁺, 289.11; found, 289.15. ^!H NMR (400 MHz, DMSO-de) 5 7.95 (d, J = 7.2 Hz, 1H), 7.39 (d, J - 7.2 Hz, 1H), 4.57 - 4.49 (m, 1H), 4.34 (d, J= 5.2 Hz, 1H), 3.48 (s, 3H), 3.20 - 3.14 (m, 1H), 2.88 - 2.77 (m, 1H), 2.68 - 2.58 (m, 1H), 2.04 - 1.93 (m, 1H), 1.61 (br, 1 H), 0.97 (d, J ~ 6.8 Hz, 3H). Absolute stereochemistry is determined by NOESY.

Intermediate A88: (2R,3S,4aS,9bS)-3-methoxy-2-methyl-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrofurol^.S-b^^-b'Jdipyridine

A88

Step-1:

[1473] To a stirred solution of ethynyltrimethylsilane (10,0 g, 101.81 mmol) in THF (100 mL) was added n-BuLi (1.6 M/L in n-hexane) (63.5 ml.,, 101.81 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 40 minutes under nitrogen atmosphere. Then a solution of boron trifluoride diethyl etherate (9.63 g, 67.87 mmol) in THF ( 10 mL) was added dropwise, this was followed by the addition of a solution of (Sj-tert-butyldimethyl(oxiran-2-ylmethoxy (silane (6.39 g, 33.93 mmol) in THF (10 mL) at -78 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by NHjCl (sat.) at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford (S )■• l-((tert- butyldimethy]silyl)oxy)-5-(trimethylsilyl)pent-4-yn-2-ol (8.8 g, 90%) as a brown oil. ^JH NMR (400 MHz, DMSO-d₆) 0 4.87 (d, J = 4.8 Hz, 1H), 3.61 - 3.51 (m, 3H), 2.42 - 2.23 (m, 2H), 0.88 (s, 9H), 0.11 (s, 9H), 0.05 (s, 6H).

Step-2:

[1474] To a stirred solution of (S)-l-((tert-buty]dimethylsilyl)oxy)-5-(trimetliylsilyl)peni.-4- yn-2-ol (8.3 g, 28.96 mmol) and N’‘,N¹,N⁸,N^s-tetramethylnaphthalene-l,8-diarnine (18.62 g, 86.89 mmol) in DCM (83 mL) were added MesO-BF4 (10.71 g, 72.41 mmol) and 4A molecular sieve (8.3 g) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford (S)- tert-butyl((2-meihoxy-5-(trimethylsilyl)pent-4-yn-l-yl)oxy)dimethylsilane (7.7 g, 88%) as a brown oil. 'H NMR (400 MHz, DMSO-de) 6 3.73 - 3.58 (m, 2H), 3.36 - 3.26 (m, 4H), 2.42 (d, J = 6.0 Hz, 2H), 0.88 (s, 9H), 0. 12 (s, 9H), 0.06 (s, 6H).

Step-3:

[1475] To a stirred solution of (S)-tert-butyl((2-methoxy-5-(trimeihylsilyl)pent-4-yn-l- yl)oxy)dimethylsilane (8.1 g, 26.94 mmol) in MeOH (90 mL) was added KzCO3 (7.45 g, 53.89 mmol) in portions at 0 °C. Hie resulting mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate -was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford (S)-tert- butyl((2-niethoxypent-4-yn-l-yl)oxy)dimethylsilane (4.3 g, 69%) as a yellow oil. 'H NMR (400 MHz, DMSO-<fc) 5 3.73 - 3.55 (m, 2H), 3.33 - 3.31 (m, 4H), 2.78 (t, J= 2.8 Hz, 1H), 2.43 - 2.29 (m, 2H), 0.88 (s, 9H), 0.05 (s, 6H).

Step-4:

[1476] A mixture of (S)-tert-butyl((2-methoxypent-4-yn-l-yl)oxy)dimethylsilane (16.2 g, 70.92 mmol), TEA (717 mg, 7.09 mmol), bis(cyclopeiita-l,3-dieii-l-yl)zirconiumbis(yiium) chloride hydride (1 .82 g. 7.09 mmol) and 4.4,5,5-tetramethyl-l,3,2-dioxaborolane (13.62 g, 106.38 mmol) was stirred at 60°C for 16 h under nitrogen atmosphere. The mixture was allowed to cool down io room temperature. The reaction mixture was purified by silica gel column chromatography, eluted with 0-20%; ethyl acetate in petroleum ether to afford (S,E)- tert-butyl((2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yDpent-4-en-l- yl)oxy)dimethylsilane (14.4 g, 56%) as a yellow oil. MS ESI calculated for CisHbrBC^iSi

[M+H]⁺, 357.26; found, 357.20.

Step-5 :

[1477] To a stirred solution of (S,E)-tert-butyl((2-methoxy-5-(4,4₅5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy klimethylsilane (24.4 g, 68.46 mmol) and 3-bromo-2- chloro-6-(trifluoromethyl)pyridine (17.83 g, 68.46 mmol) in 1 ,4-dioxane (300 mL) and H?Q (30 ml..) were added K2CO3 (28.39 g, 205.39 mmol) and Pd(dppf)Cl?-CH2Cl? (5.59 g, 6.84 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica, gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether to afford (S,E)-3-(5-((tert- butyldimethylsilyl)oxy)-4-methoxypent-l -en-l-yl)-2-chloro-6-(trifluoromethy])pyridine (25.2 g, 89%) as a yellow oil. MS ESI calculated for CisHcrClFsNOzSi [M+H]⁺, 410.15; found, 410.05.

Step-6:

[1478] To a stirred solution of (S,E)-3-(5-((tert-butyldirnethylsilyl)oxy)-4-methoxypent- 1 - en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine (20.0 g, 48.78 mmol) and l ,l-bis(acetyloxy)-3- oxo-3H- ll^A[5],2-benziodaoxol-l-yl acetate (31.04 g, 73.17 mmol) in DMSO (300 mL) was added 4-methylbenzene-l -sulfonic acid hydrate (927 mg, 4.87 mmol) at room temperature.

The resulting mixture was stirred at 50 °C for 2 h. The mixture was allowed to cool down to room temperature and quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCH. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether to afford (S,E)-5-(2-chloro-6-(trifluoromethyI)pyridin-3-yl)-2-methoxypent-4-enal (8.8 g, 61%) as a yellow oil. MS ESI calculated for CnHnCJFsNO? [M+H]⁺, 294.04; found, 294.00.

Step-7:

[1479] To a stirred solution of (S,E)-5-(2-chloro-6-(trifluorc>methyl)pyridin-3-yl)-2- methoxypent-4-enal (8.8 g, 29.96 mmol) and 4A molecular sieve (8 g) in THF (100 ml) was added methylmagnesium bromide(l .0 M in THF) (89.90 mL, 89.90 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for additional 16 h. The reaction was quenched with NH4CI (sat.) at 0 °C. The mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was extracted with EtOAc. Hie organic layer was dried over anhydrous Na^SCfo After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford a 10: 1 mixture of (2R,3S,E)-6-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-3-methoxyhex-5-en-2-ol and (2S,3S,E)-6-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-3-methoxyhex-5-en-2-ol (7.36 g, 79%) as a yellow oil. MS ESI calculated for C13H15CIF3NO2 [M+H]*, 310.07; found, 310.00.

Step-8:

[1480] To a stirred solution of a 10: 1 mixture of (2R,3S,E)-6-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)-3-methoxyhex-5-en-2-ol and (2S,3S,E)-6-(2-chloro-6- (trifIuoromethyl)pyridin-3-yl)-.3-meihoxyhex-5-en-2-ol (7.36 g, 23.76 mmol) and imidazole (4.85 g, 71.29 mmol) in DCM (80 mL) was added tert-butyl(ch1oro)diphenylsi1ane (9.80 g, 35.64 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford a 10:1 mixture of 3-((4S,5R, E)-5-((tert-butyldiphenylsilyl)oxy)-4- methoxyhex-l-en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine and 3-((4S,5S,E)-5-((tert- butyldiphenylsilyl)oxy)-4-methoxyhex-l-en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine (12.3 g, 94%) as a colorless oil. MS ESI calculated for CjgH-o.CIFsNOsSi [M+H]⁺, 548.19; found, 548.25.

Step-9:

[1481] To a stirred solution of tert-butyl carbamate (8.15 g, 69.56 mmol) in propan-l-ol (174 mL) was added a solution of NaOH (2.42 g, 60.58 mmol) in H2O (152 mL) at room temperature. The mixture was stirred at room temperature for 10 minutes, thenl ,3-dicbloro- 5, 5-dimethylimidazolidine-2, 4-dione (6.63 g, 33.66 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. This was followed by the addition of a solution of (DHQjzPH.AL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (1.75 g, 2.244 mmol) in propan-l-ol (22.5 mL) and a solution of a 10:1 mixture of 3-((4S,5RJE)-5-((tert-butyldiphenylsilyl)oxy)-4-methoxyhex-l-en-l-y])-2-chloro-6- (trifluoromethyl)pyridine and 3-((4S,5S,E)-5-((teit-butyldiphenylsilyl)oxy)-4-methoxyhex-l- en-l-yl)-2-chloro-6-(trifluoromethyl)pyridine (12.3 g, 22.44 mmol) in propan- l-ol (22.5 mL) dropwise at 0 °C, and then a solution of potassium osmate(Vl) dihydrate (826 nig, 2.24 mmol) in NaOH (0.4 N in FLO, 5.6 mL) was added. The resulting mixture was stirred at room temperature for 16 h. The organic solvent was removed under reduced pressure. The remined mixture was extracted with EtOAc. The organic layer was dried over anhydrous NaoSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford a 10:1 mixture of tert-butyl ((lS,2S,4S,5R)-5-((tert- buty]diphenylsilyl)oxy)-l -(2-chloTO-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-4- methoxyhexyljcarbamate and tert-butyl ((lS,2S,4S,5S)-5-((tert-butyldipheny1sily1)oxy)- l -(2- chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-4-methoxyhexyl)carbamate (7.25 g, 47%) as a white solid. MS ESI calculated for Cs^ClFj^OsSi [M+H]⁺, 681.27: found, 681.30.

Step-10:

[1482] To a stirred solution of 10: 1 mixture of tert-butyl ((lS,2S,4S,5R)-5-((tert- butyldiphenylsilyl)oxy)-l -(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-4- methoxyhexyljcarbamate and tert-butyl ((lS,2S,4S,5S)-5-((tert-butyldipheny1silyl)oxy)- l-(2- chloro-6-(trifluoroniethyl)pyridin-3-yl)-2-hydroxy-4-methoxyhexyl)carbamate (7.25 g, 10.64 mmol) and CS2CO3 (6.93 g, 21.28 mmol) in Toluene (80 mL) were added Pd(OAc)₂ (2.38 mg, 1.06 mmol) and JohnPhos (317 mg, 1.06 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford a 10:1 mixture of tert-butyl ((2S,3S)-2-((2S,3R)-3- ((tert-butyldiphenylsilyl)oxy)-2-methoxybutyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3- b]pyridin-3-yl)carbamate and tert-butyl ((2S,3S)-2-((2S,3S)-3-((tert-butyldiphenylsilyl)oxy)- 2-methoxybutyl)-6-(irifluoromelhyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (4.32 g, 62%) as a yellow oil. MS ESI calculated for C^HrsFsNzOsSi [M+H]⁺, 645.29; found, 645.25 [1483] To a solution of a 10: 1 mixture of tert-butyl ((2S,3S)-2-((2S,3R)“3-((tert- butyldiphenylsilyl)oxy)-2-methoxybutyl)-6-(trifluoroniethyl)-2,3-dihydrofuro[2,3-bjpyridin- 3-yl)carbamate and tert-butyl ((2S,3S)-2-((2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2- methoxybutyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbaniate (4.72 g, 7.32 mmol) in THE (50 mL) was added TBAF (3.83 g, 14.64 mmol). The mixture was stirred at room temperature 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-80% ethyl acetate in petroleum ether to afford a 10: 1 mixture of tert-butyl ((2S,3S)-2-((2S,3R)-3- hydroxy-2-methoxybutyl)-6-(trinuoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tert-butyl ((2S,3S)-2-((2S,3S)-3-hydroxy-2-meihoxybutyJ)-6-(trifluoromethyl)-2,3- dihydrofuro[2,3 -b]pyridin-3-yl)carbaniate (2.2 g, 73%) as a white solid. MS ESI calculated for CisH 25F3N2O5 [M+H]⁺, 407.17: found, 407.15.

Step- 12: [1484] A solution of 10:1 mixture of tert-butyl ((2S,3S)-2-((2S,3R)-3-hydroxy-2- meLhoxybutyl)-6-(trifluoromeihyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tertbutyl ((2S,3S)-2-((2S.3S)-3-hydroxy-2-methoxybutyl)-6-(trifluoromethyl)-2,3- dihydrofuro[2,3-b]pyridin-3-yl)carbaniate (2.0 g, 4.92 mmol) and 2-(tributyl-/.⁵- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (3.56 g, 14.76 mmol) in Toluene (40 mL) was stirred at 1 10 °C for 5 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0- 50% ethyl acetate in petroleum ether to afford tert-butyl (2R,3S.4aS,9bS)-3-methoxy-2- methyl-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)- carboxylate, isomer 1 (1.67 g, 87%) as a yellow oil. MS ESI calculated for C18H23F3N2O4 [M+H]⁺, 389.16; found, 389.10.

[1485] The separation also afford tert-butyl (2S,3S,4aS,9bS)-3-methoxy-2-methyl-7- (trifiuoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate , isomer

2 (148 mg, 7%) as a colorless oil. MS ESI calculated for C1SH23F3N2O4 [M+H]⁺, 389.16; found, 389.10.

Step-13:

[1486] To a stirred solution of tert-butyl (2R,3S,4aS,9bS)-3-methoxy-2-methy1-7- (trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2I-I)-carboxylate, isomer 1 (1.67 g, 4.30 mmol) in EtOAc (18 mL) was added HC1 (4.0 M in 1,4-dioxane) (18 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum and then quenched with ■water. The mixture was basified by NaHCCh (aq.) to pH 8 and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (2R,3S,4aS,9bS)-3-metitoxy-2-methyl-7-(trifluoromethyl)- L2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine (A88) (1.02 g, 82%) as a yellow solid. MS ESI calculated for C13H15F3N2O2 [M+H]⁺, 289.11; found, 289.00. 'H NMR (400 MHz, DMSO- do) 5 8.30 (d, ,7- 7.6 Hz, 1H), 7.62 (d, J - 7.6 Hz, 1 H), 5.15 (q, .7 - 5.6 Hz, 1H), 5.04 - 4.93 (m, 1H), 3.49 ~ 3.40 (m, 2H), 3.36 (s, 3H), 3.30 - 3.19 (m, 1H), 2.33 - 2.22 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H). Absolute stereochemistry is determined by NOESY.

Intermediate A89: 1:1 mixture of (lR,2R)-2-((2R,4aS,l0bS)-2-methyl-1 , 2, 3, 4a, 5,10b- hexahydrochromeno[3,4-b][ 1 ,4]oxazin-8-yl)cyclopropane-l -carbonitrile and (1 S,2S)-2- ((2R,4aS,10bS)-2-methyl-l,2,3,4a,5,10b-hexahydrochromeno[3,4-b]| l,4]oxazin-8- yl)cyclopropane- 1 -carbonitrile

[1487] To a solution of tert-butyl (2R,4aS,10bS)-8- bromo -2-methyl-2,3,4a,10b- tetrahydrochromeno[3,4-b|[l,4]oxazine-l(5H)-carboxylate (800 nig, 2.08 mmol) in toluene (8 raL) and H2O (1 niL) were added potassium rac-((1R,2R)-2- (ethoxycarbonyl)cyclopropyl)tri fluoroborate (687 mg, 3.12 mmol), di(l-adamantyl)-N- butylphosphine (37 nig, 0.10 mmol), CS2CO3 (1.35 g, 4.16 mmol) and Pd(AcO)₂ (23 mg, 0.10 mmol) at room temperature. The reaction was stirred at 90 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by Combi Flash (Biotage Isolera Prime) using a 40 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford to afford a 1 : 1 mixture of tert-butyl (2R,4aS,10bS)- 8-((lR,2R)-2-(ethoxycarbonyl)cyclopropy1)-2-metliyl-2,3,4a,10b-tetahydrochromeno[3,4- b][l,4]oxazine-l(5H)-carboxylate and tert-butyl (2R,4aS,10bS)-8-((i S,2S)-2- (ethoxycarbonyl)cyclopropyl)-2-methyl-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazine- l(5H)-carboxylate (700 mg, 80%) as a white solid. MS ESI calculated for C23H31NO6 [M+l ]⁺, 418.22; found, 418.20.

Step-2:

[1488] To a stirred solution of 1 : 1 mixture of tert-butyl (2R,4aS,10bS)-8-((lR,2R)-2- (ethoxycarbony l)cy clopropyl)-2-methyl-2,3 ,4a, l()b-tetrahydrochromeno[3 ,4-b] [ 1 ,4]oxazine- 1 (5H)-carboxylate and tert-bulyl (2R,4aS,l0bS)-8-((lS,2S)-2-(ethoxycarbonyl)cyclopropyl)- 2-metbyl-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate (800 mg, 1.91 mmol) in methanol (2 mL) and H2O (2 mL) was added LiOH (92 mg, 3.83 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 1 h. The resulting mixture was concentrated under vacuum to afford to afford a 1:1 mixture of (lR,2R)-2- ((2R,4aS,10bS)-l-(tert-butoxycarbonyl)-2-methyl-l,2,3,4a,5,10b"hexahydrochromeno[3,4- b][l,4]oxazin-8-yl)cyclopropane-l -carboxylic acid and (lS,2S)-2-((2R,4aS,10bS)-l-(tert- butoxycarbonyi)-2-methyl-l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l ,4]oxazin-8- yllcyclopropane- 1 -carboxy lie acid (750 mg, crude) as a white solid. MS ESI calculated for C2JH27NO6 [M+ l]*, 390 18; found, 390.15.

Step-3: [1489] To a stirred solution of 1 : 1 mixture of (lR,2R)-2-((2R,4aS,10bS)-l-(tert- butoxycarbonyl)-2-methyl-l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l ,4]oxazin-8- yDcyclopropane- 1 -carboxy lie acid and (lS,2S)-2-((2R,4aS,10bS)-l-(tert-butoxycarbonyl)-2- methyl-l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l,4]oxazin-8-yl)cyclopropane-l- carboxylic acid (750 mg, 1.91 mmol) in DMF (4 mL) were added HATH (1.09 g, 2.87 mmol), DIEA (742 mg, 5.74 mmol) and ammonium chloride (205 mg, 3.83 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous NaiSCh. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 40 g silica gel column eluted with 0- 50% ethyl acetate in petroleum ether to afford to afford a 1:1 mixture of tert-butyl (2R,4aS,10bS)-8-((lR,2R)-2-carbamoylcyclopropyl)-2-methyl-2,3,4a,10b- tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)-carboxylate and tert-butyl (2R,4aS,10bS)-8- ((lS,2S)-2-carbamoylcyclopropyl)-2-methyJ-2,3,4a,10b-tetrahydrochroroen-o[3,4- b][l,4]oxazine-l(5H)-carboxylate (700 mg, 94%) as a white solid. MS ESI calculated for C- H A (1 [M+ 1 ]⁺, 389.20; found, 389.15.

Step-4:

[1490] To a stirred solution of 1: 1 mixture of tert-butyl (2R,4aS,10bS)-8-((lR,2R)-2- carbamoylcyclopropyl)-2-methyl-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)- carboxylate and tert-butyl (2R,4aS,10bS)-8-((lS,2S)-2-carbamoylcyclopropyr)-2-metbyl- 2,3,4a,10b-tetrahydrochromen-o[3,4-bj[l,4]oxazine-l(5H)-carboxylate (800 mg, 2.06 mmol) and pyridine (651 mg, 8.23 mmol) in DCM (8 mL) was added phosphoryl trichloride (237 mg, 1.54 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at. room temperature for 16 h. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) using a 40 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford to afford a 1:1 mixture of tert-butyl (2R,4aS, 10bS)-8-((lR,2R)-2-cyanocycIopropyl)-2-methyl-2,3,4a,10b- tetrahydrochromeno[3,4"bJ[l,4]oxazine-l(5H)-carboxylate and tert-butyl (2R,4aS,10bS)-8-

((lS,2S)-2-cyanocyclopropyl)-2-methyl-2,3,4a,10b-tetrahydrochromeno- [3,4- b][l,4]oxazine-l(5H)-carboxylate (400 rag, 52%) as a yellow oil, MS ESI calculated for C? 1H2.6N2O4 fol+ l i . 371.19; found, 371.15.

A89

[1491] A solution of 1 : 1 mixture of tert-butyl (2R,4aS,10bS)-8-((lR,2R)-2- cyanocycIopropyl)-2-niethyl-2,3,4a, 10b-tetrahydrochromeno[3,4-b][l,4]oxazine-l(5H)- carboxylate and tert-butyl (2R,4aS,10bS)-8-((lS,2S)-2-cyanocyclopropyl)-2-methyl- 2,3,4a,10b-tetrahydrochiomeno-[3,4-b][l,4joxazine-l(5H)-carboxylate (100 mg, 0.27 mmol) and HC1 in 1,4-dioxane (4.0 M) (1 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford a 1 : 1 mixture of (lR,2R)-2- ((2R,4aS,10bS)-2-methyl-l,2,3,4a,5.10b-hexahydrochromeno[3,4-b][l,4]oxazin-8- yl)cyclopropane- 1-carbonitrile hydrochloride and (lS,2S)-2-((2R,4aS,10bS)-2-methyl- 1 ,2, 3, 4a,5,10b-hexahydrochrorneno[3,4-b][l ,4]oxazin-8-yl)cyclopropane- 1 -carbonitrile hydrochloride (A89) (100 mg, crude) as a white solid. MS ESI calculated for CisHisbhO? [M+H]⁺, 271.14; found, 271.15.

Intermediate A90: rel-(4aR,9bR)-7-chloro- 1 ,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5- b'Jdipyridine

[1492] A mixture of rel-ten-butyl (4aS,9bS)-7-chloro-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b'Jdipyridine-1 (2H)-carboxylate (400 mg, 1.28 mmol) and HC1 (4M in dioxane) (4 mL) was stirred at 25 °C for 1 h. The solvents were removed under vacuum to afford rel-(4aR,9bR)-7- chloro-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b']dipyrtdine hydrochloride (A90) (380 mg) as white solid. MS ESI calculated for CioHi iCINzO [M+H]⁺, 211.06; found, 211.00. *H NMR (300 MHz, DMSO- A) 8 10.75 (hr, 1H), 8.87 (br, 1H). 8.05 (d. J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 5.04 - 4.76 (m, 2H), 3.25 - 2.75 (m, 2H), 2.33 - 1.94 (m, 2H), 1.89 - 1.60 (m, 2H).

Intermediate A91 isomer 1: rel-(3R,4aS,9bS)-3-fluoro-7-(trifluoroniethyl)-l, 2,3,4, 4a, 9b- bexahydrofuro[2,3-b:4,5-b']dipyridine isomer 1

Isomer 1 Intermediate A91 isomer 2: rel-(3R,4aR,9bR)-3-fluoro-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine isomer 2

[1493] To a solution of dimethyl 2-fluoromalonate ( 100 g, 666.20 mmol) in N,N- dimethylacetamide (30 ml.) was added CS2CO3 (217 g, 666.20 mmol) at 0 °C. After stirring at 0 °C for 10 minutes, then 3-bromoprop-l-yne (79.2 g, 666.20 mmol) was added slowly. The mixture was stirred at 20 °C for 1.5 h. The reaction was quenched by the addition of NH4CI (sat.) at 20 °C and extracted with EtOAc. The combined organic layers were washed with EtOAc, dried over anhydrous NaiSOr. After filtration, the filtrate was concentrated under reduced pressure. Then the residue was dissolved in DMSO (40 niL) and H2O (1.4 mb), LiCl (84.72 g, 1998.60 mmol) was added. The resulting mixture was stirred at 1 10 °C for additional Ih. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na^SCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford a 1:1 mixture of methyl (R)-2-fluoropent-4-ynoate and methyl (S)-2-fluoropent-4-ynoate (35 g, 40% yield) as a yellow oil. T-I NMR (400 MHz, CDCh-d) 8 5.13 - 4.90 (m, IH), 3.83 (s, 3H), 2.90 - 2.74 (m, 2H), 2.11 (t, 7 = 2.8 Hz, IH).

Step [1494] To a stirred solution of 1 : 1 mixture of methyl (R)-2-fluoropent-4-ynoate and methyl (S)-2-fluoropent-4-ynoate ((100 g, 768.5 mmol) and 4,4,5,5-tetramethyl- l,3,2-dioxaborolane (118.0 g, 922.2. mmol) in THF (50 mL) were added EtsN (7.8 g, 76.8 mmol) and bis(cyclopenta-l,3-dien- l-yl)zirconiumbis(ylium) chloride hydride (19.7 g, 76.8 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2 h). The reaction was quenched by water and extracted with CH2CI2. The combined organic layers were washed with water, dried over anhydrous Na?SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (20:1 ) to afford a 1:1 mixture of methyl (R, E)-2- fluoro-5"(4,4,5,5-tetramethyl-l,3,2-dioxaborolaii-2-yl)peiit-4-eiioate and methyl (S,E)-2- fluoro-5-(4,4,5,5-tetramethyM,3,2-dioxaborolan-2-yl)pent-4-enoate (80 g, 34%) as a yellow oil. MS ESI calculated for C12H20BFO4 [M+H]⁺, 259.14; found, 259.00. ^!H NMR (300 MHz, CDCh) 6 6.60 - 6.40 (m, IH), 5.64 - 5.44 (m, 1H), 5.14 - 4.77 (m, 1H), 3.75 (s, 3H), 2.79 - 2.59 (m, 2H), 1.22 (s, 12H).

Step-3:

[1495] To a stirred solution of 1: 1 mixture of methyl (R, E)-2-fluoro-5-(4, 4,5,5 ■■ tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pent-4-enoate and methyl (S, E)-2-fluoro-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pent-4-enoate (30.0 g, 116.234 mmol) and 3-bromo-2- chloro-6-(trifluoromethyl)pyridine (30.27 g, 116.234 mmol) in Dioxane (300 mL) and water (30 mL) were added K. CO . (1.61 g, 1 1.62 mmol) and PdfdppfjCb-CH₂Ch (9.49 g, 1 1.62 mmol). The resulting mixture was stirred at 90 °C for 2 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford a 1:1 mixture of methyl (R,E)-5-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2- fluoropent-4- enoate and methyl (S,E)-5-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2- fluoropent-4-enoate (30 g, 82%) as a brown oil. MS ESI calculated for C^HioClE+NOj [M+H]\ 312.03; found, 312.05. Step-4:

[1496] To a stirred solution of 1: 1 mixture of methyl (R, E)-5-(2-chIoro-6- (trifluoromethyl)pyridin-3-yl)-2-fluoropent-4-enoate and methyl (S,E)-5-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)-2-fluoropent-4-enoate (10 g, 32.1 mmol) in THF (100 mL) was added CaCh (3.56 g, 32.1 mmol) at 0°C . Then NaBH< (2.43 g, 64.172 mmol) was added in portions at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction was quenched by the addition of NH4CI (sat.) at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1 : 1 mixture of (R,E)-5-(2-chloro-6-(tifluoromethyl)pyridin-3-yl)-2-fluoropent-4-en-l-ol and (S,E)-5-(2- chloro-6-(trifluoromethyl)pyridin-3-yI)-2-fiuoropent-4-en-l-ol (7 g, 77%) as a yellow oil. MS ESI calculated for C12H10CIF4NO2 [M+H]⁺, 284.04; found, 284.10.

Step-5:

[1497] To a stirred solution of 1: 1 mixture of (R,E)-5-(2-chloro-6-(trifluoromethyI)pyridiii- 3-y1)-2-fluoropent-4-en-1 -oJ and (S,E)-5-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2- fluoropent-4-en-l-ol (30 g, 105.76 mmol) in DCM (300 mL) were added imidazole (21.60 g, 317.3 mmol) and tert-butyl(chloro)diphenylsilane (32.0 116.3 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography with PE/EtOAc (20/1) to afford a 1 : 1 mixture of (R,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-4- fluoropent-l-en-l-yI)-2-chloro-6-(trifluoroniethyl)pyridine and (S,E)-3-(5-((tert- bulyldiphenylsilyl)oxy)-4-fluoropent-l-en-l-yl)-2-chIoro-6-(trinuoromethyl)pyridine (45 g, 81% yield) as a colorless oil. MS ESI calculated for CiiHisClBtNChSi 522.16; found, 522.10.

Step-6: [ 1498] To a stirred solution of tert-butyl carbamate (20.2 g, 172.4 mol) in propan- 1 -ol (144 mL) was added a solution of NaOH (6.9 g, 172.4mmol) in water (144 mb), then DCDMH (33.97 g, 172.39 mmol) was added in portions at 0 °C. After stirring at room temperature for 30 minutes, (DHQLPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50- 1) (4.48 g, 5.747 mmol) was added in portions at 0 °C. This was followed by the addition of 1 : 1 mixture of (R ,E)-3-(5-((tert-butyldiphenyl silyl)oxy)-4-fluoropent- 1 -en- 1 -yl)-2-chloro-6- (trifluoromethyl)pyridine and (S,E)-3-(5-((tert-butyIdiphenylsilyl)oxy)-4-fluoropent- 1-e-n- 1 - y])-2-chloro-6-(trifluoromethyl)pyridine (30.0 g, 57.47 mmol) and Potassium osmate(VI) dihydrate (2.12 g, 5.747 mmol) at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with PE/EtOAc (20/1) to afford a 1: 1 mixture of tert-butyl ((lR*,2R*,4R)-5-((tert-butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)- 4-fluoro-2-hydroxypent.yl)carbamate and tert-butyl (( lR*,2R*,4S)-5-((tert- butyldipheiiylsilyl)oxy)- l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-4-fluoro-2- hydroxypentyl)carbamate (30 g, 79% yield) as a colorless oil. MS ESI calculated for C ;;H %llio\O,Si [M-rH]⁺, 655.23; found, 655.25

[1499] To a stirred solution of 1: 1 mixture of tert-butyl ((lR*,2R*,4R)-5 -((tert- butyldiphenylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-4-fluoro-2- hydroxypentyl)carbamate and tert-butyl ((lR*,2R*,4S)-5-((tert-butyldiphenylsilyl)oxy)-l-(2- chloro-6-(trifluoromethyl)pyridin-3-yl)-4-fluoro-2-hydroxypentyl)carbamate (30 g, 10.53 mmol) in toluene (300 mL) were added CS2CO3 (10.29 g, 31.593 mmol), Pd(AcO)₂ (236 mg, 1 .05 mmol) and JohnPhos (0.31 g. 1.05 mmol). The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash column chromatography with 10%~50% MeCN in Water to afford a 1 : 1 mixture of tert-butyl ((2R*,3R*)-2-((R)-3-((tert- butykliphenylsilyl)oxy)-2-fluoropropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- yl)carbamate and tert-butyl ((2R*,3R*)-2-((S)-3-((tert-butyldiphenyIsi1yl)oxy)-2- fluoropropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamaie (2.1 g, 32% yield) as a yellow oil. MS ESI calculated for CiiHagEiN^OaSi [M+H]⁺, 619.25: found, 619.15

[1500] To a solution of 1 : 1 mixture of tert-butyl ((2R*,3R*)-2-((R)-3-((tert- butyldiphenylsilyl)oxy)-2-fluoropropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- yl)carbamate and tert-butyl ((2R*,3R*)-2-((S)-3-((tert-buiyldiphenylsilyl)oxy)-2- lluoropropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (12 g, 19.39 mmol) in THF (50 mL) was added TBAF (1.0 M in THF) (20 mL, 20 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford a 1:1 mixture of tert-butyl ((2R*,3R*)-2-((R)-2-fluoro-3-hydroxypropyl)-6-(trifluoromethyl)-2,3-dihydroftiro[2.3- b]pyridin-3-yl)carbamate and tert-butyl ((2R*,3R*)-2-((S')-2-fluoro-3-hydroxypropyl)-6- (trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (6.8 g, 92%) as a brown oil. MS ESI calculated for C16H20F4N2O4 [M+H]⁺, 381.14; found, 381.05. ^;H NMR (400 MHz, CDCh) 67.84 (d, 7= 7.6 Hz, 1H), 7.32 (dd, 7 = 7.6, 2.4 Hz, 1H). 5.61 - 5.47 (m, 1H), 5.15 - 4.71 (m, 3H), 4.00 - 3.66 (m, 2H), 2.31 - 2.17 (m, I H), 2.03 - 1.86 (m, 2H), 1.49 (s, 9H).

Step-9:

[1501] A mixture of 1 : 1 mixture of tert-butyl ((2R*,3R*)-2-((R)-2-fluoro-3- hydroxypropyl)-6-(irifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tertbutyl ((2R*,3R*j-2-((S)-2-fluoro-3-hydroxypropyl)-6-(trifluoromethyl)-2,3-dibydrofuro[2,3- b]pyridin-3-yl)carbamate (12.0 g, 31.55 mmol) and 2-(tributyl-/?- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (15.23 g, 63.10 mmol) in Toluene (120 mL) was stirred at 110 °C for 2 h. Ute resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford rel-tert-butyl (3R,4aS,9bS)-3-fluoro-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate isomer 1 (1.8 g, 33%) as a yellow solid and rel-tert-butyl (3R,4aR,9bR)-3-fluoro-7-(trifluoroniethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine- l(2H)-carboxylate isomer 2 (1.35 g, 25%) as a yellow solid.

[1502] rel-tert-butyl (3R,4aS,9bS)-3-lluoro-7-(trilluororaethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b‘]dipyridine-l(2H)-carboxylate isomer 1 (1.8 g) was further purified by Prep-chiral SFC with following condition [(S, S)- WHELK-01 SFC, 3*25 cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 80 mL/min; Gradient (B%): isocratic 15% B; RTl(min): 3.8; RT2(min): 5; Sample Solvent: MEOH] to afford rel-tert- butyl (3R,4aS,9bS)-3-fluoro-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b']dipyridine-l(2H)-carboxylate isomer 1 (1.5 g) with retention time at 3.8 minute.

[1503] rel-iert-butyl (3R,4aS,9bS)-3-fluoro-7-(trinuoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b‘]dipyridine- l(2H)-carboxylate isomer 1: MS ESI calculated for C16H18E1N2O3 |.M+H]⁺, 363.13; found, 363.00. ^SH NM\R (400 MHz, CDCI3) 8 7.82 (s, 1 H), 7.31 (d, .7 - 7.4 Hz, 1H), 6.05 - 5.65 (m, 1H), 5.20 - 5.05 (m, 1H), 5.03 - 4.70 (m, 1H), 4.45 - 3.98 (m, 1H), 2.99 - 2.43 (m, 2H), 2.35 - 2.07 (m, 1H), 1.53 (s, 9H).

[1504] rel-tert-butyl (3R,4aR,9bR)-3-fluoro-7-(trifluoromethyI)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxylate isomer 2: MS ESI calculated for C16H-₁₈F₄N2O3 [M+H]⁺, 363.13; found, 363.00. ^!H NMR (400 MHz, CDCh) 8 7.75 (s, 1H), 7.29 (d, 7 - 7.6 Hz, 1H), 6.03 - 5.63 (m, 1H), 5.25 - 5.05 (m, 1H), 5.09 - 4.77 (m, 1H), 4.48 ... 4.14 (m, 1H). 3.00 - 2.63 (m, 1H), 2.60 - 2.34 (m, 1H), 2.33 - 2.06 (m, 1H), 1.52 (s, 9H).

Step- 10:

[1505] To a mixture of rel-tert-butyl (3R,4aS,9bS)-3-fluoro-7-( trifluoromethyl)-3,4,4a,9b- tetrahydrot'uro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxylate isomer 1 (1.1 g, 3.03 mmol) in Dioxane (10 mL) was added HC1 (4.0 M in 1,4-dioxane) (5 ml..) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to afford rel-(3R,4aS,9bS)-3-fluoro-7-(trifluoromethyl)- 1 ,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine hydrochloride isomer 1 (A91 isomer 1 ) (1.1 g, crude) as a white solid. MS ESI calculated for CnHioEfffoO [M+H]⁴, 263.07; found, 263.05. ‘H NMR (400 MHz, DMSO-</₆) 8 10.36 (br, 2H), 8.38 (d, ./ = 7.6 Hz, 1H), 7.62 (d, J - 7.6 Hz, 1H), 5.38 - 5.05 (m, 3H), 3.63 - 3.40 (m, 1H), 3.35 - 3.08 (m, 1H), 2.73 - 2.67 (m, 1H), 2.55 - 2.37 (m, 1H). Absolute stereochemistry was not determined.

Step-11: [1506] To a solution of rel-iert-butyl (3R,4aR,9bR)-3-fiuoro-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b‘]dipyridine-l(2H)-carboxylate isomer 2 (1.3 g, 3.58 mmol) in Dioxane (10 mb) was added HC1 (4.0 M in 1,4-dioxane) (5 mb) at room temperature. The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated under reduced pressure to afford rel-(3R,4aR,9bR)-3-fluoro-7-(trifluoromethyl)-l , 2, 3, 4, 4a, 9b- hexahydrofuro[2,3-b:4,5-b']dipyridine isomer 2 (A91 isomer 2) (1.2 g, crude) as a brown solid. MS ESI calculated for C11H10F4N2O [M+H]⁺, 263.07; found, 263.05. ^!H NMR (400 MHz, DMSO-de) 8 11.52 (br, 1H), 9.16 (br, HI), 8.29 (d, 7= 7.6 Hz, 1H), 7.61 (d, .7 - 7.6 Hz, 1H), 5.31 - 4.96 (m, 3H), 3.51 - 3.24 (m, 2H), 2.71 - 2.63 (m, 1H), 2.49 - 2.30 (m, 1H). /Absolute stereochemistry was not determined.

Intermediate A92 isomer 1: rel-(4R,4aS,9bR)-7-cliloro-4-methoxy-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine isomer 1 isomer 1 Intermediate A92 isomer 2: rel-(4R,4aR,9bS)-7-cHoro-4-methoxy-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine isomer 2 isomer 2

Step ■ 1 :

[1507] A mixture of 1:1 mixture of (R,E)-tert-butyl((3-methoxy-5-(4_!4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pent-4-en-l-yl)oxy)dipheny]silane and (S,E)-tert-butyl((3-methoxy- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pent-4-en-l-yl)oxy)diphenylsilane (30 g, 62.43 mmol), 3-bromo-2, 6- dichloropyridine (12.75 g, 56.19 mmol), AcOK (18.38 g, 187.29 mmol) and Pd(dppf)C12-CH2C12 (5.10 g, 6.24 mmol) in dioxane (300 mL) and H2O (30 mL) was stirred at 100 °C for 2 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The solvents were removed under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford to afford a 1:1 mixture of (R,E)-3-(5-(<tert-butyldiphenylsilyl)oxy)-3-methoxypent-l-en-l-yl)-2.6- dichloropyridine and (S,E)-3-(5-((tert-butyldipheny1silyl)oxy)-3-methoxypent-l-en-l-yl)-2,6- dichloropyridine (21 g, 67%) as a yellow oil. MS ESI calculated for C27H31CI2NO2S1 [M+H]⁺, 500.15; found, 500.15.

[1508] A solution of tert-butyl carbamate (16.15 g, 137.85 mmol) and NaOH (5.51 g,

137.85 mmol) in propan-1 -ol (125 mL) and H2O (125 mL) was stirred at 0 °C for 10 minutes, then DCDMH (27.16 g, 137.85 mmol) was added in portions over 2 min at 0 °C. After stirring at 0 °C for additional 30 minutes, (DHQisPHAL (supplier: Shanghai Accela

ChemBio Co., Ltd. CAS# 140924-50-1) (3.58 g, 4.59 mmol), 1:1 mixture of (R,E)-3-(5-

((tert-butyldiphenylsilyl)oxy)-3-methoxypent-l-en-l-yi)-2,6-dichloropyridine and (S,E)-3-(5- ((tert-butyldiphenylsily])oxy)-3-meihoxypent-l-en-l-yl)-2,6-dichl0ropyridine (21 g, 41.96 mmol) and Potassium osmate(VI) dihydrate (1.69 g, 4.59 mmol) were added to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for additional 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleurn ether to afford a 1 :1 mixture of tert-butyl ((lR*,2S*.3R)-5- ((tert-butyldipheny1silyl)oxy)-l -(2,6-dichloropyridin-3-yl)-2-hydroxy-3- methoxypentyl)carbamate and tert-butyl ((lR*,2S*,3S)-5-((tert-butyldiphenylsilyl)oxy)-l- (2,6-dichloropyridin-3-yl)-2-hydroxy-3-methoxypentyl)carbamate (28.9 g, 99%) as a brown oil. MS ESI calculated for C32M42CI2N2O5S3 [M+H]⁺, 633.22; found, 633.25.

[1509] To a solution of 1: 1 mixture of tert-butyl ((lR*,2S*,3R')-5-((lert- butyldiphenyisilyl)oxy)-l"(2,6"dichloropyridin-3-yl)"2-hydroxy-3-methoxypentyl)carbamate and tert-butyl ((lR*,2S*.3S)-5-((tert-butyldiphenylsilyl)oxy)-l-(2,6-dichloropyridin-3-yl)-2- hydroxy-3-methoxypentyl)carbamate (28.9 g, 45.71 mmol) in THE (289 ml..) was added TBAF (17.89 g, 68.41 mmol) at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The solvents were removed under vacuum. The residue was purified by silica gel column chromatography , eluted with 0-30% ethyl acetate in petroleum ether to afford a 1: 1 mixture of tert-butyl ((1R*,2S*,3R)-l-(2,6-dichloropyridin-3-yl)-2,5- dihydroxy-3-methoxypentyl)carbamate and tert -butyl ((lR*,2S*,3S)-l-(2,6-dichloropyridin- 3-yl)-2,5-dihydroxy-3-methoxypentyl)carbamate (8.8 g, 48%) as a yellow oil. MS ESI calculated for CsI^ChNrOs [M+H]⁺, 395. 11; found, 395.10.

Step-4:

[1510] To a 1 : 1 mixture of tert-butyl (( 1R*,2S*,3R)- 1 -(2,6-dichloropyridin-3-ylj-2,5- dihydroxy-3-methoxypentyl)carbamate and tert-butyl ((lR*,2S*,3S)-l-(2,6-dichloropyridin- 3-yl)-2,5-dihydroxy-3-methoxypentyl)carbamate (7.5 g, 18.97 mmol) in DCM (84 mL) was added EtjN (5.76 g, 56.92 mmol) at room temperature. Then Ms^O (2.64 g, 15.17 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The solvents were removed under vacuum. The residue was dissolved in DCM (84 mL), this was followed by the addition of trifluoroacetic acid ( 84 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum. The residue was dissolved in MeCN (153 mL), then 1 ,2,2,6,6-pentamethylpiperidine (56 g, 360.62 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The reaction was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a 1:1 mixture of rel-(2R,3S,4R)-2-(2,6-dichloropyridin-3-yl)-4-methoxypiperidin-3-ol and rel-(2R,3S,4S)-2-(2,6-dichloropyridin-3-yl)-4-methoxypiperidin-3-ol (20 g) as a yellow semisolid. MS ESI calculated for Ci iHjrChNzOs. |M+H]⁺, 277.15; found, 277.05.

[1511] To a solution of 1: 1 mixture of rel-(2R,3S,4R)--2-(2,6-dichloropyridin-3-yl) -4 - medioxypiperidin-3-ol and rel-(2R,3S,4S)-2-(2,6-dichloropyridin-3-yI)-4-methoxypiperidin- 3-ol (7.8 g, 28.144 mmol) in methanol (78 mL) was added BOC2O (6.14 g, 28.144 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum. The residue was purified by normal phase flash column chromatography using a 330 g silica gel column eluted with 0-40% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of rel-tert-butyl (2R,3S,4S)-2-(2,6-dichloropyridin-3- yl)-3-hydroxy-4-melhoxypiperidine- 1 -carboxylate and rel-tert-butyl (2R,3S,4R)-2-(2,6- dichloropyridin-3-yl)-3-hydroxy-4-methoxypiperidine-l-carboxylate (2.8 g, 26%) as a yellow oil. MS ESI calculated for C16H22CI2N2O4. [M+H]⁺, 377. 10: found, 377.15.

Step-6:

[1512] To a solution of 1: 1 mixture of rel- tert-butyl (2R,3S,4S)-2-(2,6-dichloropyridin-3- yl)-3-hydroxy-4-methoxypiperidine-l -carboxylate and rel-tert-butyl (2R,.3S,4R)-2-(2,6- dichloropyridin-3-yl)-3-hydroxy-4-meihoxyp!peridine-l -carboxylate (2.7 g, 7.157 mmol) in tert-Amyl alcohol (108 mL) was added t-BuOK (0.88 g, 7.873 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. Hie reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by normal phase flash column chromatography using a 120 g silica gel column eluted with 0-50% ethyl acetate in petroleum ether to afford rel-tert-butyl (4R,4aR,9bS)-7-chloro-4-methoxy-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)- carboxylate isomer 2 (600 mg. 49%) as the first eluting peak. MS ESI calculated for C16H21CIN2O4. [M+H]⁺, 341.12: found. 341.15 [1513] The process also affords rel-tert-butyl (4R,4aS,9bR)-7-chloro-4-methoxy-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b‘]dipyridine-l(2H)-carboxylate isomer 1 (600 mg, 49%) as a colorless oil as the second eluting peak. MS ESI calculated for C16H21CIN2O4. [M+H]⁺, 341.12; found, 341.15

Step-7 :

[1514] To a stirred solution of rel-tert-butyl (4R,4aS,9bR)-7-chloro-4-methoxy-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b‘]dipyridine-l(2H)-carboxylate isomer 1 (600 mg, 1.76 mmol) in ethyl acetate (115 mL) was added hydrogen chloride(4.0 M in ethyl acetate) (6 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to afford rel-(4R,4aS,9bR)-7-chIoro-4-methoxy- 1, 2, 3, 4, 4a, 9b-hexahydrofuro[2,3-b:4,5-b’]dipyridine hydrochloride isomer 1 (A92 isomer 1) (335 mg) as a white solid. MS ESI calculated for Ci iHuClNbCh [M+H]⁺, 241.07; found, 241. 10. ’H NMR (400 MHz, DMSO-J₆) 8 10.40 (s. 1H), 8.61 (s, 1H), 7.99 (d, 7 = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 5.11 (t, 7= 4.8 Hz, 1H), 5.01 (d, 7 = 5.6 Hz, 1H), 3.94 -

3.86 (m, 1H), 3.40 (s, 3H), 3.24 - 3.11 (m, 1H), 3.07 - 2.97 (m, 1H), 2.10 - 1.93 (m, 1H),

1.87 - 1.70 (m, 1H). Absolute stereochemistry was not determined.

Step-8; 2

[1515] To a stirred solution of rel-tert-butyl (4R,4aR,9bS)-7-chloro-4-methoxy-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxylate isomer 2 (600 mg, 1.76 mmol) in ethyl acetate (115 mL) was added hydrogen chloride(4.0 M in ethyl acetate) (6 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 b. The mixture was concentrated under vacuum to afford rel-(4R,4aR,9bS)-7-chloro-4-methoxy-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b’]dipyridine hydrochloride isomer 2 (A92 isomer 2) (374 nig) as a white solid. MS ESI calculated for CnHuClNiCh [M+H]⁺, 241.07; found, 241.10. *H NMR (400 MHz, DMSO-db) 6 10.22 (s, 1H), 8.98 (s, 1H), 8.02 (d, J - 7.8 Hz, HI), 7.24 (d, J - 7.8 Hz, 1H), 5.01 (d, J ----- 6.4 Hz, 1H), 4.92 - 4.81 (m, 1H), 3.92 - 3.91 (m, 1 H i. 3.41 (s, 3H), 3.08 - 3.06 (in, 2H), 2.01 - 1.91 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A93 isomer 1: fel-(3aR,8bR)-6-(trifluoromethyl)“2,3,3a,8b-tetrahydro-lH- benzofuro[3,2-b]pyrrole isomer 1 isomer 1

Intermediate A93 isomer 2: rel-(3aR,8bR)-6-(trifluoromethyr)-2,3,3a,8b-tetrahydro-lH- benzofuro[3,2-b]pyrrole isomer 2 isomer 2

Step-1:

[1516] To a stirred solution of 2-hydroxy-4-(trifluoromethyl)benzaldehyde (5.0 g, 26.29 mmol) and ethyl propiolate (3.35 g, 34.18 mmol) in DCM (100 mL) was added NMM (532 mg, 5.26 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford ethyl (E)-3-(2-formyl-5-

(tifluoromethyl)phenoxy)acrylate (5.8 g, 76%) as an off-white solid. MS ESI calculated for C_i3HiiF₃O4 [M+H]⁺, 289.06; found, 289.00.

Step-2:

[1517] A solution of 2-(perfluoropbenyl)-6,7-dihydro-5H-pyrrolo[2,l-c][l,2,4]triazol-2- ium tetrafluoroborate (466 mg, 1.28 mmol) in THF (58 ml) was treated -with TEA (129 mg, 1.28 mmol) at room temperature for 5 minutes, this was followed by a addition of ethyl 2-(3- oxo-6-(tifluoromethyl)-2,3-dihydrobenzofuran-2-yI)acetate (6.17 g, 21.40 mmol) in THF (116 niL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with NILiCl (aq.) at 0 °C. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous NazSOr.

After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of ethyl (R)-2-(3-oxo-6-(trifluoromethyl)-2,3-dihydrobenzofuran-2- yliacetate and ethyl (S)-2-(3-oxo-6-(trifluoromethyl)-2,3-dihydfobenzofuran-2-yl)acetate (4.7 g, 76%) as a colorless oil. MS ESI calculated for CBHRFJCU [M+H]⁺, 289.06; found, 289.00.

Step-3:

[1518] To a stirred solution of 1: 1 mixture of ethyl (R)-2- (3-oxo -6-(trifluoromethyl)-2,3 - dihydrobenzofuran-2-yl)acetate and ethyl (S)-2-(3-oxo-6-(trifluoromethyl)-2,3- dihydrobenzofuran-2-yl)acetate (6.3 g, 21.85 mmol) in EtOH (70 mL) were added hydroxylamine hydrochloride (3.04 g, 43.71 mmol) and AcONa (3.59 g, 43.71 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The mixture was allowed to cool down to room temperature. The mixture was filtered, and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOH (70 mL), and then Pd/C (10%, 500 mg) was added. The mixture was hydrogenated at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0—15% methanol in dichloromethane to afford a 1:1 mixture of (3aS,8bS)-6-(trifluoromethyl)-l,3,3a,8b- tetrahydro-2H-benzofuro[3,2-b]pyrrol-2-one and (3aR,8bR)-6-(trifluorornethyl)- l,3,3a,8b- tetrahydro-2H-benzofuro[3,2-b]pyrrol-2-one (2.82 g, 53%) as an off-white solid. MS ESI calculated for CuHgFyNOj 244.05; found, 243.95.

Step-4:

A93 isomer 2

[1519] To a stirred solution of 1:1 mixture of (3aS,8bS)-6-(trifluoromethyl)-l,3,3a,8b- tetrahydro -2H-benzofuro [3 ,2-b ] pyrrol-2-one and (3aR, 8bR) ■ 6- (trifluoromethyl)- 1,3,3 a,8b- tetrahydro-2H-benzofuro[3,2-b]pyrrol-2-one (2.66 g, 10.93 mmol) in THF (30 mL) was added BHs-THF (I M in THF) (22 mL., 22 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 16 h. The mixture was allowed to cool down to room temperature and quenched with MeOH at 0 °C. Then HC1 (cone., 15 mL) was added the mixture at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was quenched with water and extracted with ethyl acetate. The aqueous layer was collected and basifted with saturated NaHCCh (aq.) to pH 8. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure to afford a 1: 1 mixture of (3aS,8bS)-6-(trifluoromethyl)-2,3,3a,8b-tetrahydro-lH-benzofuro[3,2-b]pyrrole and (3aR,8bR)-6-(trifluoromethyl)-2,3,3a,8b-tetrahydro-lH-benzolhro[3,2-b]pyrrole (1.86 g) as a brown solid.

[1520] The 1: 1 mixture of (3aS,8bS)-6-(tifluoroniethyl)-l,3,3a,8b-tetrahydro-2H- benzofuro[3,2-b]pyrrol-2-one and (3aR,8bR)-6-(trifluoromethyl)- 1,3,3a, 8b-tetrahydro-2H- benzofuro[3,2-b]pyrrol-2-one (1 .86 g) was separated by prep-chiral HPLC with the following conditions [Column: CH1RALPAK IG, 5*25 cm, 10 pm; Mobile Phase A: Hex- -HPLC, Mobile Phase B: EtOH: DCM==1: 1 : Flow rate: 100 mL/min; Gradient (B%): isocratic 10% B; Wave Length: 220 nm; RTl (rnin): 10.9; RT2(min): 15: Sample Solvent: EtOH-HPLC: Injection Volume: 10 mL] to afford rel-(3aR,8bR)-6-(trifluoromethyl)-2,3,3a,8b-tetrahydro- lH-benzofuro[3,2-b]pyrrole (A93, isomer 1) (1.1 g, 62%) as a brown solid as the first peak on chiral HPLC. MS ESI calculated for C11H10F3NO [M+H]⁺, 230.07; found, 230.05. ^]H NMR (400 MHz, CDCh-di) 57.42 (d, 7 = 7.6 Hz, IH), 7.23 - 6.91 (m, 2H), 5.37 (t, J = 6.4 Hz, IH), 5.04 (d, 7= 6.4 Hz, 1H), 3.15 - 3.08 (m, 1H), 2.75 - 2.66 (m, IH), 2.29 - 2.22 (m, IH), 2.02 - 1.92 (m, IH). Absolute stereochemistry -was not determined.

[1521] The separation also affords rel-(2R,6R)-10-(trifluoromethyl)-7-oxa-3- azalricyclo[6,4.0.0^A{2,6 }]dodeca-l(12),8,10-triene (A93, isomer 2) (1.4 g, 79%) as a brown solid as the second peak on chiral HPLC. MS ESI calculated for Ci 1H10F3NO [M+H]⁺, 230.07; found, 230.05. ^;H NMR (400 MHz, CDCh-Ji) 8 7.44 (d, J = 7.6 Hz, 1 H), 7.24 - 6.94 (m, 2H), 5.37 (t, J = 6.4 Hz, IH), 5.05 (d, J= 6.4 Hz, 1H), 3.16 - 3.10 (m, IH), 2.75 - 2.65 (rn, IH), 2.29 - 2.23 (m, IH), 2.04 - 1.93 (m, IH). Absolute stereochemistry was not determined.

Intermediate A94: (3R,4aS,9bS)-3-methoxy-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine

Step 1:

[1522] To a stirred solution of ethynyl trimethylsilane (50.00g, 509.06 mmol) in THF (300 mL) were added n-BuLi (2.5M in hexane) (203 mL, 507.5 mmol) dropwise at -78°C under nitrogen atmosphere. After stirring at -78 °C for 1 hour under nitrogen atmosphere, Boron trifluoride diethyl etherate (48.17 g, 339.37 mmol) was added dropwise at -78 °C, this was followed by the additon of a solution of (R)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane (supplier: Shanghai Haohong Scientific Co., Ltd. CAS# 124150-87-4 ) (31.96 g, 169.69 mmol) in THF (50 mL) dropwise at -78 °C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with NH4CI (aq.) at room temperature and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford (R)-l-((tert-butyldimethylsilyl)oxy)-5-(trimethylsilyl)pent-4-yn-2- ol (37.5 g, 69%) as a brown oil. MS ESI calculated for CwHsoChSiz [M+H]⁺, 287.18 ; found,

287.18.

[1523] To a stirred solution of (R)-l-((tert-butyldimethylsilyl)oxy)-5-(trimethylsiiyl)pent-

4-yn-2-ol (135.00 g, 471.10 mmol) and Nl,Nl,N8,N8-tetramethyInaphthalene- l,8-diamine (302.89 g, 1413.31 mmol) in DCM (700 mL) were added trimetbyloxonium tetrafluoroborate (174.20 g, 1177.74 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford (R)-tert-butyl((2-methoxy-5-(trimethylsilyi)pent-4- yn-l-yl)oxy)dimethylsilane (210.00 g. 74%) as a yellow oil. MS ESI calculated for C d foO.-Sn [M+H]⁺, 301.19; found, 301.19.

Step 3:

[1524] To a stirred solution of (R)-tert-butyl((2-methoxy-5-(trimethylsilyl)pent-4-yn-l- yl)oxy)dimethylsilane (240.00 g, 798.43 mmol) in methanol (1500 mL) was added K2CO3 (220.69 g, 1596.86 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered, the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford (R)-tert-butyl((2-methoxypent-4-yn-l- yl)oxy)dimethylsilane (180.00 g, 98%) as a yellow oil. MS ESI calculated for CizHj^OzSi [M+H]⁺, 229.15 ; found, 229.15.

Step 4:

[1525] To a mixture of (R)-tert-butyl((2-methoxypent-4-yn- 1 -yl)oxy)diniethylsilane (180.00 g, 788.07 mmol) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (151.29 g, 1 182.10 mmol) was added bis(cyclopenta-l,3-dien-l-yl)zirconiumbis(yliutn) chloride hydride (20.24 g, 78.81 mmol) at 0 °C, this was followed by the addition of EtjN (7.97 g, 78.81 mmol) dropwises at. 0 °C. The mixture was heated to 60 °C for 16 h with stirring. Hie reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCri. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford (R,E)-tert-butyl((2-methoxy-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pent-4-en-l-yl)oxy)diniethylsilane (110 g, 39%) as a brown oil. MS ESI calculated for CislToBOaSi [M+H]⁺, 357.26 : found, 357.26.

Step 5 :

[1526] To a stirred solution of (R,E)-tert-butyi((2-methoxy-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy)dimethylsilane (62.00 g, 173.97 mmol) and 3-bromo- 2-chloro-6-(trifluoromethyl)pyridine (45.31 g, 173.97 mmol) in Dioxane (600 niL) and H?O (60 ml) were added K2CO3 (72.13 g, 521.90 mmol) and Pd(dppf)C12 (12.73 g, 17.39 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated to 100 °C with stirring for 16 h. The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SCri. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford (R,E)-3-(5- ((tert-butyldimethyisilyl)oxy)-4-methoxypent-l-en- l-yl)-2-chloro-6-(trifluoromethyl)pyridine (58.4 g, 81%) as a brown oil. MS ESI calculated for CisIfcvClFjNOzSi [M+H]⁺, 410.15 ; found, 410.15.

Step 6:

[1527] To a stirred solution of NaOH (14.75 g, 368.83 mmol) in H2O (922 mL) was added a solution of tert-butyl carbamate (49.61 g, 423.47 mmol) in propan- l-ol (1058 mL), then 1 ,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione (53.83 g, 273.20 mmol) was added in portions at room temperature under nitrogen atmosphere. After stirring at room temperature for 0.5 hour, a solution of (DHQLPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (10.64 g, 13.66 mmol) in propan-l-ol (137 mL) and a solution of (R,E)- 3-(5-((tert-butyldimethylsi1yl)oxy)-4-methoxypent-1 -en-l-yl)-2-chloro-6- (trifluoromethyl)pyridine (56.00 g, 136.60 mmol) in propan-l-ol (137 mL) was added at 0 °C, after that, Potassium osmates VI) dihydrate (5.03 g, 13.660 mmol) was added in portions at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaaSCU- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford a 1:8 mixture of tert-butyl ((lR,2R,4R)-5-((tert- butyldimethylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-4- methoxypentyl)carbamate and tert-butyl ((lS,2S,4R)-5-((tert-butyldimethylsilyl)oxy)-l-(2- chloro-6-(triiluoromethyl)pyridin-3-yl)-2-hydroxy-4-methoxypentyl)carbamate (49.8 g, 67%) as a yellow oil. MS ESI calculated for CrsHssClFsNrOsSi [M+H]⁺, 543.22 ; found, 543.25.

Step 7 : [1528] A mixture of 1 :8 mixture of tert-butyl ((lR,2R,4R)-5-((tert-butyldimethylsilyl)oxy)- l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-bydroxy-4-meihoxypentyl)caibamaie and tertbutyl ((lS,2S,4R)-5-((tert-butyldimethylsilyl)oxy)-l-(2-chloro-6-(trifluoromethyl)pyridin-3- yl)-2-hydroxy-4-methoxypentyl)carbamate (20 g, 36.82 mmol), Pd(OAc)₂ (1.65 g, 7.36 mmol), CS2CO3 (36.00 g, 110.47 mmol) and JobnPhos (2.2 g, 7.36 mmol) in Toluene (50 mL) was stirred at 100 °C for 16 b under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSOr After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford a 1 :8 mixture of tert-butyl ((2R,3R)-2-((R)-3-((teri- butyldimeihylsilyl)oxy)-2-meihoxypropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3- b]pyridin-3-yl)carbamate and tert-butyl ((2S,3S)-2-((R)-3-((tert-butyldimethylsilyl)oxy)-2- methoxypropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (11 g, 58% yield) as a yellow oil. MS ESI calculated for CisHnFsNaOsSi [M+H] A 507.24 ; found, 507.15.

Step 7 :

[1529] To a solution of 1:8 mixture of tert-butyl ((2R,3R)-2-((R)-3-((tert- butyldimethylsilyl)oxy)-2-methoxypropyl)-6-(trifluoromethyl)-2,3“dihydrofuro[2,3- b]pyridin-3-yl)carbamate and tert-butyl ((2S,3S)-2-((R)-3-((tert-butyldimethylsilyl)oxy)-2- methoxypropyl)-6-(trilluoromethyl)-2,3-dihydrofuro[2,3“b]pyridin-3-yl)carbaniate (23.00 g, 45.40 mmol) in THF (300 mL) was added TBAF (23.74 g, 90.79 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford a 1:8 mixture of tert-butyl ((2R,3R)-2-((R)-3-hydroxy-2-methoxypropyl)-6-(trifluoromethyl)-2,3- dibydrofuro[2,3-b]pyridin-3-yl)carbamate and tert-butyl ((2S,3S)-2-((R)-3-hydroxy-2- meihoxypropyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)caTbamate (17.00 g, 95%) as a brown oil. MS ESI calculated for C17H23F3N2O5 [M+H]⁺, 393.16 ; found, 393.05.

[1530] To a solution of 1:8 mixture of tert-butyl ((2R,3R)-2-((R)- 3 -hydroxy -2- methoxypropyl[-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate and tert- butyl ((2S,3S)-2-((R)-3-hydroxy-2-methoxypTopyl)-6-(trifluoromethyl)-2,3-dihydrofuro[2,3- b]pyridin-3-yl)carbamate (17.00 g, 45.87 mmol) in Toluene (200 mL) was added 2-(tributyl- k⁵-phosphaneylidene)acetonitrile (CAS No. 157141-2.7-0) (22.14 g, 91.75 mmol) at room temperature. The mixture was heated to 110 °C for 16 h with stirring. The mixture was allowed to cool down to room temperattire. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford a 1:8 mixture of tert -butyl (3R,4aR,9bR)-3- meihoxy-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)- carboxylate and tert-butyl (3R,4aS,9bS)-3-methoxy-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxylate (15.1 g, 72%) as a brown oil. MS ESI calculated for CnlE^NzCh [M+H]⁺, 375.15 ; found, 375. 15.

Step 9:

[1531] A 1 :8 mixture of tert- butyl (3R,4aR,9bR)-3-methoxy-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b\]dipyridine- 1 (2H [-carboxylate and tert-butyl (3R,4aS,9bS[-3- methoxy-7-(trifluoromethyl[--3,4,4a,9b-tetrahydrofuro[2,3 -b:4,5-b']dipyridine--l(2H[ - carboxylate (15.1 g, 40.33 mmol) and HC1 (g) (4.0 M in 1,4-dioxane, 150 mL) was stirred at room temperature for 1 hour. 'The resulting mixture was concentrated under reduced pressure. The resude was purified by Prep-Chiral SFC with the following conditions (Column: CHIRALPAK AD-H, 5*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH: Flow rate: 180 mL/min; Gradient (B%): isocratic 40% B; Wave Length: 220 nm; RTl(min): 3.25; RT2(min): 6.35; Sample Solvent: MEOH) to afford (3R,4aS,9bS)-3-methoxy-7- (tafluoromethyl)-i,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b']dipyridine (A94) (8.4 g, 79%) as a brown solid with retention time at 6.35 minute. MS ESI calculated for C12H13F3N2O2 [MW, 275.09; found, 275.05. ^!H NMR (300 MHz, DMSO) 5 7.95 (d, J = 7.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 4.85 - 4.80 (m, 1H), 4.61 (d, J = 7.2 Hz, 1H), 3.40 - 3.31 (m, 1H), 3.21 (s, 3H), 2.99 - 2.92 (m, 1 H), 2.47 (d, J = 6.2 Hz, 1H), 2.33 - 2.25 (m, 1 H), 1 .92 - 1.80 (m, 1H). Absolute stereochemistry was determined by NOE-SY.

Intermediate A9S: rel-(4aR,9bR)-7-(difluoromethyl)-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5- b']dipyridine

Step- 1 :

[1532] To a stirred mixture of methyl 5-bromo-6-chloropicolinate (25.00 g, 99.81 mmol) and CaCl'2 (16.62 g, 149.71 mmol) in THF (200 mL) and EtOH (200 mL) was added NaBILi (9.44 g, 249.52 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCri. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5/1) to afford (5-bromo-6-chloropyridin-2- yl)methanol (20.00 g, 90% yield) as a white solid. MS ESI calculated for C6H5B1CINO [M+H]⁺, 221.92, 223.92; found, 221.90. 223.90.

Step-2:

[1533] To a stirred solution of (5-bromo-6-chloropyridin-2-yl)methanol (20.00 g. 89.90 mmol) in DCM (200 ml..) was added MnCh (78.16 g, 899.00 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. This resulted in 5-bromo-6-chloropicolinaldehyde (17.00 g, 85% yield) as an off-white solid. MS ESI calculated for C6H3B1CINO [M+H]*, 219.91, 221.91: found, 219.90, 221.90.

Step-3:

[1534] To a stirred solution of 5-bromo-6-chloropicolinaldehyde (17.00 g, 77.12 mmol) in DCM (150 mL) was added Diethylaminosulfur trifluoride (24.86 g, 154.23 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with ice water at 0 °C. The mixture was basified with NaHCCb (sat.) to pH 7. The mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NaaSCri. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5/1) to afford 3-bromo-2-chloro-6- (difluoromethyl)pyridine (15.00 g, 80.2% yield) as a light yellow oil. MS ESI calculated for

[1535] To a stirred mixture of 3-bromo-2-chIoro-6-(difhioromethyl)pyridine ( 1 1.00 g, 45.37 mmol) and (E)-tert-buty1diphenyl((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pent--4-eii-l-yl)oxy)silane (30.66 g, 68.06 mmol) in Dioxane (150 mL) and H2O (15 mL) were added Pd(dppl)C12-CH2C12 (3.70 g, 4.54 mmol) and K2CO3 (18.81 g, 136.11 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated to 100 °C with stirring for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO-t. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1/1) to afford (E)-3-(5-((t.ert- butyldiphenyisiiy Doxy (pent- 1-en- 1 ■yl)-2-chloro-6- (difluoromethyl)pyridine (20.00 g, 90% yield) as a light yellow oil. MS ESI calculated for C27H3₀ClF₂NOSi [M+H]% 486.18, 488.18; found, 486.15, 488.15.

Step-5:

[1536] To a stirred solution of NHzBoc (14.94 g, 127.55 mmol) in propan- l-ol (212 mL) were added a solution of NaOH (4.44 g, 111.09 mmol) in H2O (185 ml..). After stirring al 0

°C for 30 minutes, DCDMH (12.16 g, 61.72 mmol) was added in portions at room temperature. This was followed by the addition of (DHQhPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (3.21 g, 4.12 mmol) in propan- l-ol (55 mL), a solution of (E)-3-(5-((tert-butyldiphenylsilyl)oxy)pent-l-en-l-yl)-2-chloro-6- (difluoroinethyl)pyridine (20.00 g, 41.15 mmol) in propan- l-ol (20 mL) and Potassium osmate(VI) dihydrate (1.52 g, 4. 12 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1/1) to afford rel-tert- butyl ((lR,2R)-5-((tert-buty1diphenylsilyljoxy)-i-(2-chloro-6-(dif1uoromethyl)pyridin-3-yl)- 2-hydroxypentyl)carbamate (30.00 g, crude) as a green semi-solid. MS ESI calculated for C32H₄iClF₂N2O4Si [ M+H ]^!, 619.25; found, 619.20.

Step-6:

[1537] To a stirred mixture of rel -tert-butyl (( | R,2R )-5-((tert-butyldiphen ylsilyljoxy)- 1 -(2- chloro-6-(difluoromethyl)pyridin-3-yl)-2-hydroxypentyi)carbamate (30.00 g, 48.45 mmol) and CS2CO3 (47.36 g, 145.34 mmol) in toluene (300 mL) were added JohnPhos (2.17 g, 7.27 mmol) and Pd/OAch (1.09 g, 4.85 mmol) at room temperature under nitrogen atmosphere.

The resulting mixture was stirred at 90 ^CC overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5/1) to afford rel-tert-butyl ((2R,3R)-2-(3-((tert- butyldipheny]silyr)oxy)propyl)-6-(difiuoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- yj)carbamate (10.00 g, 41% over 2 steps) as a light brown oil. MS ESI calculated for C₃2H4oF₂N₂04Si [M+H]⁺, 583.27; found, 583.25.

Step 7 :

[1538] To a stirred solution of rel-tert-butyl ((2R,3R)-2-(3-((tert- butyldiphenylsilyl)oxy)propyl)-6-(difluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3- ylicarbamate (10.00 g, 17.16 mmol) in THF (100 mL) was added TBAF (8.97 g, 34.32 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1/1) to afford rel-tert-butyl ((2R,3R)-6- (difluoromethyl)-2-(3-hydroxypropyl)-2,3-dihydrofuro[2,3-blpyridin-3-yl)carbamate (4.00 g, 67% yield) as a light-yellow solid. MS (ESI) calculated for C16H22F2N2O4 |M+H|⁺, 345.15; found, 345.10.

Step 8:

[1539] To a stirred solution of rel-tert-butyl ((2R,3R)-6-(difluororaethyl)-2-(3- hydroxypropyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (4.00 g, 1 1.62 mmol) in toluene (50 mL) was added 2-(tributyl-X⁵-phosphaneylidene)acetonitrile (CAS No. 157141- 27-0) (5.61 g, 23.23 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1/1) to afford rel-tert-butyl (4aR,9bR)-7-(difluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b’]dipyridine-l(2H)-carboxylate (2.50 g, 65% yield) as a light yellow solid. MS (ESI) calculated for C16H20F2N2O3 [M+H]⁺, 327.14; found, 327.10.

Step 9:

[1540] A solution of rel-tert-butyl (4aR,9bR)-7-(difluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b‘]dipyridine-l(2H)-carboxylate (2.50 g, 7.66 mmol) and HC1 (4M in dioxane) (30 niL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-Chiral-SFC with the following conditions (Column: CHIRALPAK IF 3*25 cm, 5 gm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 100 niL/min; Gradient (B%): isocratic 50% B; Back Pressure(bar): 100: Wave Length: 220 nm; RTl(min): 2.1 : RT2(min): 3.32: Sample Solvent: MEOH) to afford rel-(4aR,9bR)-7-(difluoromethyl)- 1 , 2,3,4, 4a,9b- hexahydrofuro[2,3-b:4,5-b’]dipyridine (1.00 g, 57% yield) as a yellow oil with retention time at 3.32 minute. MS ESI calculated for (' i f ■! ' X ( ) [M+H]⁺, 227.09; found, 227.01. ‘H NMR (300 MHz, DMSO) 0 7.82 (d, J = 7.2 Hz, 1H), 7.21 (d, 7 = 7.2 Hz, 1H), 6.81 (t, 7 = 55.0 Hz, IH), 4.66 - 4.55 (m. 1H), 4.35 (d, 7 = 6.0 Hz, 1H), 2.83 (br, 1H), 2.70 - 2.52 (m, 2H), 2.01 - 1.89 (ni, 2H), 1.55 - 1.38 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A96: (4aS,9bS)-7-( trifluoromethoxy)- 1,2,3, 4,4a, 9b-hexahydrofuro[2,3-b:4, 5- b']dipyridine

A96

Step- 1:

[1541] To a stirred solution of LDA (2.0 M in THF, 14 mL) in THF (84 mL) was added a solution of 2-chloro-6-(trifluoromethoxY)pyridine (5.00 g, 25.31 mmol) in THF (5 mL) at -78 °C under nitrogen atmosphere. After stirring at -78 °C for 1.5 b, a solution of TMSC1 (3.02 g, 27.84 mmol) in THF (28 mL) was added dropwise at -78 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was poured into water at room temperature and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NajSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-3% EtOAc in PE to afford 6-chloro-2-(trifluoromethoxy)-3-(trimethylsilyl)pyridine (4.91 g, 71%) as a colorless liquid. MS ESI calculated for CyHnClFsNOSi 270.03; found, 270.00.

Step-2:

[1542] To a stirred mixture of LDA (2.0 M in THF, 10 mL) in THF (70 mL) was added a solution of 6-chloro-2-(trifluoromethoxy)-3-(trimethylsilyl)pyridine (4.70 g, 17.42 mmol) in THF (24 mL) dropwise at -78 °C under nitrogen atmosphere. After stirring at -'78 °C for 2 h, a solution of h (4.87 g, 19.16 mmol) in THF (24 mL) was added dropwise at -78 °C. The resulting mixture was stirred at room temperature for additional 16 h. The reaction was poured into NH4CI (sat.) at room temperature. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous NaiSOr. After filtration, the filtrate was concentrated under reduced pressure to afford 2-chloro-3- iodo-6-(trifluoromethoxy )-5-(trimethylsily])pyridine (8.23 g, crude) as a brown oil. MS ESI calculated for C₉HioClF₃INOSi [M+HJ⁺, 395.92; found, 395.80.

Step-3 :

6/4 [1543] To a stirred mixture of 2-chloro-3-iodo-6-(trifluoromethoxy)-5- (trimethy1silyl)pyridine (8.23 g, 20.80 mmol) in THF (80 mL) was added TBAF (10.88 g, 41.60 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by water and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na^SCfo After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford 2-chloro-3-iodo-6- (trifluoromethoxy)pyridine (3.82 g, 56%) as a white solid. MS ESI calculated for C6H2CIF3INO [M+H]⁺, 323.88; found, 323.85.

Step-4:

[1544] To a stirred mixture of 2-chloro-3-iodo-6-(trifluoromethoxy)pyridine (3.0 g, 9.27 mmol) and tert-butyl 3- oxopiperidine- 1 -carboxylate (2.77 g, 13.91 mmol) in toluene (30 mL) were added K3PO4 (4.73 g, 22.26 mmol) and Pd(t-Bu3P)₂ (0.33 g. 0.64 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The mixture was allowed to cool down to room temperature. The mixture was filtered, the filter cake was washed with EtOAc. Tire filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% EtOAc in PE to afford tert-butyl 2-(2-chloro-6-(trifluoromethoxy)pyridin-3-yl)-3-oxopi peri dine- 1- carboxylate (1.70 g, 46%) as a yellow oil. MS ESI calculated for CisHisClF^NrOr [M+H]*, 395.09; found, 395.00.

Step-5:

6/5 [1545] To a stirred mixture of tert-butyl 2-(2-chloro-6-(trifIuoromethoxy )pyridin-3-yl)-3- oxopiperidine-l-carboxylate (1.70 g, 4.30 mmol) and DABCO (2.61 g. 23.25 mmol) in MeCN (40 mL) was added HCOOH (0.59 g, 12.91 mmol) and RuCl(p-cymene)[(S,S)-Ts- DPEN] (0.08 g, 0.13 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The mixture was basified with saturated NaHCOs (aq.) to pH 8. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCU. After filtration, the filtrate was concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography, eluted with 0-28% EtOAc in PE to afford terc-butyl (2S,3S)-2-(2-chloro-6-(trifluoromethoxy)pyridin-3- yl)-3-hydroxypiperidine- 1- carboxylate (1.37 g, 80%) as a yellow oil. MS ESI calculated for Ci6H₂oClF3N₂04 [M+HK, .397.11; found, 397.05.

Step-6:

[1546] To a stirred mixture of tert-butyl (2S,3S)-2-(2-chloro-6-(trifluoromethoxy)pyridin- 3-yl)-3-hydroxypiperidine-l-carboxylate (1.25 g, 3.15 mmol) in THE (30 mL) was added t- BuOK (0.53 g, 4.72. mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 2 h. The reaction was allowed to cool down to room temperature and quenched with NH4CI (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-24% EtOAc in PE to afford tert-butyl (4aS,9bS)-7-(trifluoromethoxy)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)- carboxylate (0.83 g, 73%) as a white solid. MS ESI calculated for Ci6Hi9F3N₂O4 [M+H]⁺, 361.13; found, 361.10.

Step-7 :

6/6

[1547] To a stirred mixture of tert-butyl (4aS,9bS)-7-(trifluoromethoxy)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (830 mg, 2.30 mmol) in EtOAc (4 mL) was added HC1 (4 M in 1 ,4-dioxane, 12 mL) al room temperature. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure to afford (4aS,9bS)-7-(trifluoromethoxy)-l,2,3,4,4a,9b-hexahydrofuro[2,3- b:4,5-b’]dipyridine hydrochloride (A96) (550 mg, 91%) as a white solid. MS ESI calculated for C11H11F3N2O2 [M+H]⁺, 261.08; found. 261.00. ^!H NMR (400 MHz, DMSO-cfo) 6 10.77 (br, 1H), 8.83 (br, 1H), S 8.20 (d, J = 8.0 Hz, 1H), 6.95 (d, 7 - 8.0 Hz, 1H), 4.99 - 4.88 (m, 2H). 3.14 - 3.09 (m, I H), 2.96 - 2.89 (m, 1H), 2.25 - 2.20 (m, 1H), 2.12 - 1.71 (m, 1H), 1.78

- 1.71 (m, 2H).

Intermediate A97: (3R,4aR*,10bR*)-3-niethoxy-8-(trifluoromethyl)-2,3,4,4a,6,10b- hexahydro- 1 H -pyrano [3 ,2 -b : 5 ,4-b' ] dipyridin e

Step-1:

[1548] To a stirred solution of (R,E)-tert-butyl((2-methoxy-5-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)peni-4-en-l-yl)oxy)dimethylsilane (20.0 g, 56.75 mmol) in dioxane (200 mL) and H2O (20 mL) were added ethyl 3-bromo-6-(trifluoromethyl)pyridine-2-carboxylate (25.37 g, 85.12 mmol), Pd(dppf)Cb (4.15 g, 5.68 mmol) and K2CO3 (23.53 g, 170.24 mmol) al 25 °C. The resulting solution was stirred at 100 °C for 2 h. The solvents were removed under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 ~ 40% EtOAc in petroleum ether to afford ethyl (R,E)-3-(5-((tert-butyldimethylsilyl)oxy)-4- methoxypenl-l-en-l-yl)-6-(trifluoromethyl)picolinate (9.0 g, 35%) as a yellow oil. MS ESI calculated for C -4 L i-'-NtLSi [M-t-Hf, 448.21; found, 448.20.

Step-2:

[1549] To a stirred solution of NH2B0C (7.55 g, 64.42 mmol) in i-PrOH ( 194 mL) was added a solution of NaOH (2.24 g, 56.10 mmol) in H?O (69 mL) at 25 °C. The resulting solution was stirred at 25 °C for 10 minutes, then l,3-dichloro-5,5-dimethylimidazolidine- 2, 4-dione (4.91 g, 24.94 mmol) was added at 25 °C. After stirring at 25 °C tor 30 minutes, a solution of (DHQ)₂PHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50- 1) (1.62 g, 2.08 mmol) in i-PrOH (194 mL), a solution of ethyl (R,E)-3-(5-((tert- butyldimethylsilyl)oxy)-4-metlioxypent-l-en-l-yl)-6-(trifluoromethyl)picolinate (9.30 g, 20.78 mmol) in i-PrOH (194 mL) and Potassium osmate(VI) dihydrate (0.77 g, 2.08 mmol) were added at 0 °C. The mixture was stirred al 25 °C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper, and concentrated under vacuum.

[1550] The above residue was dissolved in DCM (220 mL), DCC (9.03 g, 43.79 mmol) and DMAP (9.73 g, 79.61 mmol) were added at 0 °C. The resulting solution was stirred at 25 °C for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 ~ 45% EtOAc in petroleum ether to afford tert-butyl ((5R*,6R*)-6-((R)-3-((tert-butyldimethylsilyDoxy)-2-methoxypropyl)-8-oxo-2- (trifIuoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (3.40 g, 15%) as a white solid. MS ESI calculated for CnHjrFaNzOeSi [M+Hf‘, 535.24; found, 535.25.

Step- 3:

[1551] To a stirred solution of tert-butyl ((5R*,6R*)-6-((R)-3-((tert- butyldimethylsilyl)oxy)-2-methoxypropyl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate (3.40 g, 6.36 mmol) in THE (36 mL) and EtOH (9 mL.) were added CaCb (847 mg, 7.63 mmol) and NaBIU (722 mg, 19.07 mmol) at 0 °C. The resulting solution was stirred at 25 °C for 4 h. The reaction mixture was quenched by the addition of water at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 ~ 50% EtOAc in petroleum ether to afford tert-butyl ((lR*,2R*,4R)-5-((tert-buty1dimethylsily1)oxy)-2-hydroxy-l-(2-(hydroxymethyl)-6- (trifluoromethyl)pyridin-3-yl)-4-methoxypentyl)carbamate (1.0 g, 29%) as a white solid. MS ESI calculated for Cz^LiFsN^ObSi [M+H]⁺, 539.27: found, 539.30.

Step-4:

[1552] To a stirred solution of tert-butyl ((lR*,2R*,4R)-5-((tert-butyldmiethylsilyl)oxy)-2- hydroxy-1 -(2-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)-4-methoxypentyl)carbamate (600 mg, 1.11 mmol) in toluene (6 mL) was added 2-(tributyl-X⁵- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (538 mg, 2.23 mmol) at 25 °C. The resulting solution was stirred at 110 °C for 16 h. The solvents were removed under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 ~ 35% EtOAc in petroleum ether to afford tert-butyl ((5R*,6R*)-6-((R)-3-((tert-butyldimethylsilyl)oxy)-2- methoxypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (210 mg, 36%) as a white solid. MS ESI calculated for Cz^FsNoOsSi [M+Hf, 521 .26; found, 521 .30.

Step-5 :

[1553] To a stirred solution of tert-butyl ((5R*,6R*)-6-((R)-3-((tertbutyldimethylsilyl)oxy)-2-methoxypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate (210 mg, 0.40 mmol) in THF (3 mL) was added TBAF (210 mg,

0.80 mmol) at. 25 °C. The resulting solution was stirred at 25 °C for 2 b. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 - 50% EtOAc in petroleum ether to afford tert-butyl ((5R*,6R*)-6-((R)-3-hydroxy-2-melhoxypropyr)-2-(trifluoromediyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridm-5-yl)carbamate (110 mg, 67%) as a colorless oil. MS ESI calculated for C18H25F3N2O5 [M+H]⁺, 407.17; found, 407.15.

Step-6:

[1554] To a stirred solution of tert-butyl ((5R*,6R*)-6-((R)-3-hydroxy-2-niethoxypropyl)- 2-(trifluorome1hyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridm-5-y1)carbajnaie (210 mg, 0.51 mmol) in toluene (3 mb) was added 2-(tributyl-/v⁵-phosphaneylidene)acetonitrile (CAS No.

157141 -27-0) (2.49 mg, 1.03 mmol) at 25 °C. Hie resulting solution was stirred at 110 °C for 16 h. The solvents were removed under vacuum. The residue was purified by silica gel column chromatography , eluted with 0 ~ 50% EtOAc in petroleum ether to afford tert-butyl (3R,4aR*,l0bR*)-3-methoxy-8-(trifluoromethy1)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-b']dipyridine-l-carboxylate (100 nig, 49%) as a yellow oil. MS ESI calculated for ('J EHMh [M+H]⁺, 389.16; found, 389.25.

Step-7:

[1555] A mixture of tert-butyl (3R,4aR*,10bR*)-3-methoxy-8-(trifluoromethy1)- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (100 mg, 0.26 mmol) and hydrogen chloride (4.0 M in ethyl acetate) (2 ml) was stirred at 25 °C for 1 h. The solvents were removed under vacuum to afford (3R,4aR*,10bR*)-3-methoxy-8- (trinuoromethyl)-2,3,4,4a,6,10b-hexahydro-l H-pyrano[3,2-b:5,4-b']dipyridine hydrochloride (A97) (100 mg, crude) as a yellow solid. MS ESI calculated for C13H15F3N2O2 [M+H]⁺, 289.11; found, 289.05. ’H NMR (400 MHz, DMSO) 8 10.75 (br, 1H), 8.87 (s, 1H). 8.57 - 8.54 (m, 1H), 7.95 (d, ./ - 8.0 Hz, H i t 5.04 - 4.66 (m, 2H), 4.57 - 4.56 (m. 1 H), 4.21 - 4.12 (m, 1H), 3.70 - 3.69 (m, 1H), 3.37 - 3.35 (m, 5H), 2.43 - 2.33 (m, 1H), 2.1 1 - 2.00 (m, 1H).

Absolute stereochemistry was not determined.

Intermediate A98 isomer 1: rel-(4R,4aS,10bR)-4-methoxy-8-(trifluoromethyl)-

2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine isomer 1

A98 isomer 1

Intermediate A98 isomer 2: rel-(4R,4aR,10bS)-4-methoxy-8-(trifluoromethyl)-

2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine isomer 2

[1556] To a stirred solution of ethyl 3-bromo-6-(trifluorornethyl)picoiinate (30 g, 100.65 mmol) and 1: 1 mixture of (R,E)-tert-butyl((3-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaboro1an-2-y1)pent-4-en-l-yl)oxy)diphenylsilane and (S,E)-ten-butyl((3-meihoxy-5- (4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)penl-4-en-l-yl)oxy)diphenylsilane (58.04 g, 120.78 mmol) in dioxane (300 mD/HiO (30 niL) were added AcOK (29.63 g, 301.95 mmol) and Pd(dppf)Ch (8.22 g, 10.06 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCU. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi Flash using a 330 g silica gel column eluted with 0-10% ethyl acetate in petroleum ether to afford a 1: 1 mixture of ethyl (R,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3- methoxypent- 1 ■en-l-yl)-6-(trifluoromethyi)picolinate and ethyl (S,E)-3-(5-((tert- butyldiphenylsilyl)oxy)-3-methoxypent- 1-en- 1 -yl)-6-( trifluoromethyl)picolinate (50 g, 86%) as a yellow oil. MS ESI calculated for CnHxsFsNOxSi [M+H]*, 572.24; found, 572.15.

Step-2

[1557] To a stirred solution of tert-butyl carbamate (32.56 g, 277.93 mmol) in propan- l-ol (330 rnL) was added a solution of NaOH (9.68 g, 242.01 mmol) in HzO (290 rnL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 minutes, l,3-dichloro-5,5-dimethylinudazolidine-2, 4-dione (26.50 g,

134.48 mmol) was added at room temperature. After stirring at room temperature for additional 30 minutes, (DHQlsPHAL (supplier: Shanghai Accel a ChemBio Co., Ltd. CAS# 140924-50-1) (6.98 g, 8.96 mmol) and 1:1 mixture of ethyl (R,E)-3 -(5 -((tert- butyldiphenylsilyl)oxy)-3-methoxypent-l-en-l-yl)-6-(trifluorornethyl)picolinate and ethyl (S,E)-3-(5-((tert-butyldiphenylsilyl)oxy)-3-methoxypent-l-en-l-yl)-6-

(trifluoromethyl)picolmate (50 g, 89.65 mmol) were added to the mixture at 0 °C, this was followed by the addition of Potassium osmate(VI) dihydrate (3.3 g, 8.96 mmol). The resulting mixture was stirred at room temperature for additional 16 h. Hie resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSO^. After filtration, the filtrate was concentrated under reduced pressure. [1558] The above residue was dissolved in DCM (500 mL), this was followed by the addition of DCC (32.86 g, 159.27 mmol) and DMAP (1.77 g, 14.48 mmol) at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by Combi Flash using a 330 g silica gel column eluted with 0-30% ethyl acetate in petroleum ether to aff ord a 1 : 1 mixture of tert-butyl ((5R*,6S*)-6-((R)-3-((tert- butyldiphenylsilyl)oxy)-l-methoxypropyl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridm-5-yl)cafbamate and tert-butyl ((5R*,6S*)-6-((S)-3-((tert- butyldiphenylsilyl)oxy)-l-methoxypropyl)-8-oxo-2-(trifluoromethyl)-5,8-dibydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate (52 g, 54%) as a yellow solid. MS ESI calculated for C34H₄iF₃N2O6Si [M+H]\ 659.27; found, 659.15.

Step-3 :

[1559] To a stirred solution of 1: 1 mixture of tert-butyl ((5R*,6S*)-6-((R)-3-((tert- butyldiphenylsilyl)oxy)-l-methoxypropyl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate and tert-butyl ((5R*,6S*)-6-((S)-3-((tert- butyldiphenylsilyl)oxy)-l -metho xypropyl)-8-oxo-2-(trifluoromethyl)-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate (52 g, 78.93 mmol) in THF (500 mL) was added NaBH4 (2.99 g, 78.93 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford a 1:1 mixture of tert-butyl ((iR*,2S*,3R)-5-((tert-butyldiphenylsilyl)oxy)-2-hydroxy-l-(2-(hydroxymethyl)-6- (lrifluoromethyl)pyridin-3-yl)-3-methoxypentyl)carbamate and tert-butyl ((lR*,2S*,3S)-5- ((teit-butyIdiphenylsilyl)oxy)-2-hydroxy-l-(2-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3- y])-3-melhoxypentyl)carbamale (50 g, crude) as a brown oil. MS ESI calculated for C34H45F3N2O6S1 [M+HJL 663.30; found, 663.35.

Step-4:

[1560] To a stirred solution of 1 : 1 mixture of tert-butyl (( 1 R*,2S*,3R)-5-((tert- butyldiphenylsilyl)oxy)-2-hydroxy-l-(2-(bydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)-3- methoxy pentyl)carbamate and tert-butyl ((lR*,2S*,3S)-5-((tert-butyldiphenylsilyl)oxy)-2- hydroxy-l -(2-(hydroxymethyl)-6-(trilluoroTnethy1)pyridin-3-yr)-3-methoxypentyl)carbamate (50 g, 75.43 mmol) in toluene (500 mL) was added 2-(tributyl-/?- phosphaneylidene)acetonitriie (CAS No. 157141-27-0) (36.41 g, 150.87 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 1 10 °C for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford a 2: 1 mixture of rel-tert-butyl ((5R,6S)-6-((S)-3-((tert-butyldiphenylsilyl)oxy)- 1 -methoxypropyl)- 2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate isomer 1 and rel- tert-butyl ((5R,6S)-6-((S)-3-((tert-butyldiphenylsilyl)oxy)-l-methoxypropyl)-2- (ti’ifluoromethyr)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate isomer 2 (5.2 g, 10%) as a yellow oil. MS ESI calculated for CsaHxiFrNrOsSi [M+H]⁺, 645.29; found, 645.30.

Step-5:

[1561] To a stirred solution of 2: 1 mixture of rel-tert-butyl ((5R,6S)-6-((S)-3-((tert- butyldiphenylsilyl)oxy)-l-methoxypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4- b]pyridm-5-yI)carbamate isomer 1 and rel-tert-butyl ((5R.6S)-6-((S)-3-((tert- butyldiphenylsilyl)oxy)-l-metlioxypropyl)-2-(trifluorometbyl)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate isomer 2 (5.2 g, 8.06 mmol) in THF (50 mL) was added TBAF

(2.53 g, 9.67 mmol) at room temperature. Hie resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by Combi Flash using a 120 g silica gel column eluted with 0- 80% ethyl acetate in petroleum ether to afford a 2: 1 mixture of rel- tert-butyl ((5R,6S)-6-((S)- 3-hydroxy-l-methoxypropyl)-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5- yl)carbamate isomer 1 and rel-tert-butyl ((5R,6S)-6-((R)-3-hydroxy-l-methoxypropyl)-2-

(lrifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate isomer 2 (2.3 g, 70%) as a yellow oil. MS ESI calculated for CjgHjxFsNrOs [M+H]⁺, 407.17; found, 407.20.

[1562] To a stirred solution of 2: 1 mixture of rel-tert-butyl ((5R,6S)-6-((S)-3-hydroxy-l- methoxypropyl)-2-(triiluoromethyl)-5,8-dihydro-6H-pyrano[3,4-bjpyridin-5-yl)carbamate isomer 1 and rel-tert-butyl ((5R,6S)-6-((R)-3-hydroxy-l-methoxypropyl)-2-(trifluoromethyl)- 5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate isomer 2 (2.2 g, 5.41 mmol) in toluene (22 mL) was added 2-(tributyl-V-phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (2.61 g, 10.81 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by Combi Flash using a 80 g silica gel column eluted with 0-20% ethyl acetate in petroleum ether to afford a 2: 1 mixture of rel-tert-butyl (4R,4aS,10bR)-4-methoxy-8- (trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate isomer 1 and rel-tert-butyl (4R,4aR,10bS)-4-methoxy-8-(trifiuoromethyl)-2,3,4,4a,6.10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate isomer 2 (1.3 g, 61%) as a yellow oil. [1563] The above mixture was separated by Prep-HPLC with the following conditions [Column: Xselect CSH OBD Column 30* 150mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 44% B to 66% B in 8mm; Wave Length: 254/220 nm; RTl(min): 6; RT2(min): 6.5] to afford rel-tert-butyl (4R,4aS,l0bR)-4-methoxy-8-(trifluorometbyl)-2,3,4,4a,6,10b-hexahydro- lH-pyrano[3,2- b:5,4-b']dipyridine-l-carboxylate isomer 1 (558 mg, 42%) as a yellow solid as the second eluting peak. MS ESI calculated for C18H23F3N2O4 [M+HJ+, 389.16; found, 389.20. Relative stereochemistry was determined by NOESY.

[1564] The purification also affords rel-tert-butyl (4R,4aR,10bS)-4-methoxy-8- (trifluoroniethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridine-l-carboxylate isomer 2 (130 mg, 10%) as a yellow solid as the first eluting peak. MS ESI calculated for CJ8H23F3N2O4 [M+HJ+, 389.16; found, 389.20. Relative stereochemistry was determined by NOESY.

Step-7 :

[1565] A mixture of rel-tert-butyl (4R,4aS,10bR)-4-methoxy-8-(trifluoromethyl)- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate isomer 1 (558 mg, 1.43 mmol) and HC1 (4.0 M in 1 ,4-dioxaiie) (10 niL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford rel-(4R,4aS,10bR)-4- methoxy-8-(irifluoromethyl)-2,3,4,4a,6,l0b-hexahydro-lT-I-pyrano[3,2-b:5,4-b']dipyridine hydrochloride isomer 1 (510 mg, crude)(A98 isomer 1 ) as a yellow solid. MS ESI calculated for C13H15F3N2O2 [M+H]⁺, 289.11; found, 289.05. ^!H NMR (400 MHz, DMSO) 5 10.90 (s, 1H), 8.97 (s, 1H), 8.46 (d, 7 - 8.0 Hz, 1H), 7.96 (d, J - 8.0 Hz, 1H), 4.93 - 4.8S (m, 2H), 4.58 (s, 1H), 4.36 (t, •/ = 2.0 Hz, 1H), 3.73 - 3.62 (m, 1 H), 3.57 (s, 3H), 3.32 - 3.20 (m, 1H), 3.12 - 3.10 (m, 1H), 1.97 ■ 1.83 (m, 2H). Absolute stereochemistry was not determined.

Step-8: 2

[1566] A mixture of rel-tert-butyl (4R,4aR,10bS)-4-methoxy-8-(trifluoromethyl)- 2,3,4,4a,6,10b-hexahydro- ■lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate isomer 2 (130 mg, 0.33 mmol) and HC1 (4.0 M in 1,4-dioxane) (3 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford rel-(4R,4aR,10bS)-4- methoxy-8-(trifluoromethyl)-2,3,4,4a,6,10b-bexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine hydrochloride isomer 2 (90 mg, crude)(A98 isomer 2) as a yellow solid. MS ESI calculated for C13H15F3N2O2 [M+H]⁺, 289.11 ; found. 289.05. ^!H NMR (300 MHz, DMSO) 3 10.74 (s, 1H), 9. 10 (s, 1H), 8.58 - 8.47 (m, I H), 7.97 (d, J = 8.1 Hz, 1H), 4.97 (s, 2H), 4.52 - 4.50 (m, 1H), 4.23 - 4.21 (m, 1H), 3.71 - 3.70 (m, 1H), 3.40 (s, 3H), 3.10 - 3.09 (m, 2H), 2.01 ■■ 1.94

(in, 2H). Absolute stereochemistry was not determined.

Intermediate A99 isomer 1: (3R,4aS,9bS)-7-(difluoromethoxy)-3-methyl- 1 , 2, 3, 4, 4a, 9b- hexahydrofuro[2,3-b:4,5-b']dipyridine, isomer 1 isomer 1

Intermediate A99 isomer 2: (3S,4aS,9bS)-7-(difluoromethoxy)-3-methyl-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine, isomer 2

isomer 2

Step- 1 :

[1567] To a stirred mixture of 5-bromo-6-chloropyridin-2-amine (20.0 g, 96.40 mmol) in H2SO4 (450 mL) was added a solution of NaNO? (18.62 g, 269.93 mmol) in H?O (200 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2>SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5 -bromo-6-chloropyridin-2~ol (23 g, crude) as a brown solid. MS ESI calculated for CjThBrClNO [M+H]⁺, 207.91 ; found, 207.95.

Step-2:

[1568] A mixture of 5-bromo-6-chloropyridin-2-ol (20.0 g, 95.95 mmol), sodium 2-chloro- 2,2-difluoroacetate (29.26 g, 191.90 mmol) and K2CO3 (15.91 g, 115.14 mmol) in DMF (400 mL) was stirred at 100 °C for 2 h. The mixture was allowed to cool down to room temperature and quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na-iSO*. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford 3-bromo-2-chloro-6-(difluoromethoxy)pyridine (18.1 g, 72% over 2 steps) as a colorless oil . MS ESI calculated for CsHsBrCIFaNO [M+H]⁺, 257.91; found, 257.80.

[1569] To a stirred solution of 3-bromo-2-chloro-6-(difluoromethoxy)pyridine (2.0 g, 7.73 mmol) and 1: 1 mixture of tert-butyl (R)-3-methyl-5-oxopiperidine-l-carboxylate and tertbutyl (S)-3-methyl-5-oxopiperidine-l -carboxylate (2.48 g, 11.60 mmol) in toluene (40 mL) were added K3PO4 (3.29 g. 15.47 mmol) and P(t-Bu)s Pd Ch (395 mg, 0.77 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h under nitrogen atmosphere. Tire mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% ethyl acetate in petroleum ether to afford a 1:1 :1: 1 mixture of tert-butyl (2S,5R)-2-(2-chloro-6- (difluoromethoxy)pyridin-3-yl)-5-methyl-3-oxopiperidine-l-carboxylate and tert-butyl (2S,5S)-2-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-5-methyl-3-oxopiperidine-l- carboxylate and tert-butyl (2R,5R)-2-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-5-nielhyl-3- oxopiperidine- 1 -carboxylate and tert-butyl (2R,5S)-2-(2-chloro-6-(difluoromethoxy)pyridin- 3-yl)-5-methyl-3-oxopiperidine-l -carboxylate (1.81 g, 59%) as a brown oil. MS ESI calculated for C17H21CIF2N2O4 [M+H]⁺, 391.12; found, 391.10.

[1570] To a stirred solution of 1 : 1 : 1 : 1 mixture of tert-butyl (2S ,5R)-2-(2-chloro-6- (difluoromethoxy)pyridin-3-yl)-5-methyl-3-oxopiperidine-l -carboxylate and tert-butyl (2S,5S)-2-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-5-methyl-3-oxopiperidine-l- carboxylate and tert-butyl (2R,5R)-2-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-5-methyl-3- oxopiperidine-l-carboxylate and terl-butyl (2R,5S)-2-(2-chloro-6-(difluoromethoxy)pyTidin- 3-yl)-5-methyl-3-oxopiperidine4 -carboxylate- ( 1.8 g, 4.60 mmol) in ACN (20 mL) were added DABCO (5.07 g, 23.03 mmol), HCOOH (635 mg, 13.81 mmol) and RuCl[(S,S- TsDPEN)](p-cymene) (146 mg, 0.23 mmol) al 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous NasSCfi. Alter filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-70% ethyl acetate in petroleum ether to afford a 1:1 mixture of tert-butyl (2S,3S,5R)-2-(2-chloro-6-(difluoromethoxy)pyridin-3-yl)-3-hydroxy-5- methylpiperidine- 1 -carboxylate and tert-butyl (2S,3S,5S)-2-(2-chloro-6- (difhjoromethoxy)pyridin-3-yl)-3-hydroxy-5-methylpiperidine- 1 -carboxylate ( 1.02 g, 56% ) as a yellow' oil. MS ESI calculated for C17H23CIF2N2O4 393.13; found, 393.10.

Step-5 :

[1571] A solution of a 1 : 1 mixture of tert-butyl (2S,3S,5R)-2-(2-chloro-6- (ditluororaethoxy)pyridin-3-yl)-3-hydroxy-5-methylpiperidine-l-carboxylate and tert-butyl (2S,3S,5S)-2-(2-chloro-6-(difluoromethoxy)pyridio-3-yl)-3-hydroxy-5-methylpiperidine-l- carboxylate (1.0 g, 2.54 mmol) and t-BuOK (428 mg, 3.81 mmol) in THE (20 mL) was stirred at 70 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether to afford a 1 :1 mixture of tert-butyl (3R,4aS,9bS)-7-(difluoromethoxy)-3-methyl-3,4,4a,9b- teirahydrofuro[2,3-b:4,5-b’]dipyridine- l(2H)-carboxylale and tert-butyl (3S,4aS,9bS)-7- (difluoromethoxy)-3-meihyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)- carboxylate (586 mg, 64%) as a white solid.

[1572] The 1 : 1 mixture of tert-butyl (3R,4aS,9bS)-7-(difluoromethoxy)-3-methyl- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate and tert-butyl (3S,4aS,9bS)-7-(difluoromethoxy)-3-niethyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b']dipyridine-l(2H)-carboxylate (580 mg) was separated by prep-chiral HPLC with the following conditions [Column: CH1RALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1 : 1-HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 10% B to 10% in lOniin; Wave Length: 220/254 nm;

RTl(min): 5.56; RT2(min): 7.35; Sample Solvent: MeOH: DCM-1 : 1-HPLC] to afford tertbutyl (3R,4aS,9bS)-7-(difluoromethoxy)-3-methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b']dipyridine-l(2H)-carboxylate, isomer 1 (230 mg, 39%) as a white solid as the first peak on chiral HPLC. MS ESI calculated for C17H22F2N2O4 [M+H]⁺, 357.15: found, 357.15.

[1573] The separation also afford tert-butyl (3S,4aS,9bS)-7-(difluoromethoxy)-3-methyl- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxy1ate, isomer 2 (220 mg, 38%) as a colorless oil as the second peak on chiral HPLC. MS ESI calculated for C17H22F2N2O4 [M+H]⁺, 357.15; found, 357.15.

Step-6:

A99 isomer 1

[1574] To a mixture of tert-butyl (3R,4aS,9bS)-7-(difluoromethoxy)-3-methyl-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b^,]dipyridine-l(2H)-carboxyiate (230 mg, 0.64 mmol) in ethyl acetate (2 mL) was added HC1 (4.0 M in 1,4-dioxane) (2 niL). The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum to afford (3R,4aS,9bS)-7-(difluoromethoxy)-3-methyLl,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5- b’]dipyridine, hydrochloride (A99, isomer 1 ) (220 mg, crude) as a white solid. MS ESI calculated for C12H14F2N2O2 [M+H]⁺, 257.10; found, 257.10. ^rH NMR (400 MHz, DMSO- d₆) 8 10.29 (s, 1H), 9.21 (s, 1H), 8.12 (d. 8.0 Hz, 1H), 7.65 (t, J = 72.4 Hz, 1H), 6.73 (d, J

= 8.0 Hz, 1 H), 5.18 - 4.92 (m, 2H), 3.26 - 3.17 (m, 1H), 2.68 - 2.58 (m, 1H). 2.36 - 2.20 (m, IH), 2.07 - 2.00 (m, 1H), 1.74 - 1.63 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H).

Step-7 :

A99 isomer 2

[1575] To a solution of tert-butyl (3S.4aS,9bS)-7-(difluoromethoxy)-3-methyl-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’]dipyri.dine-l(2H)-carboxylate isomer 2 (220 mg, 0.61 mmol) in ethyl acetate (2 ml.,) was added HC1 (4.0 M in 1,4-di oxane) (2 mL). The mixture was stirred at room temperature for 16 h. Hie resulting mixture was concentrated under vacuum to afford (3S,4aS,9bS)-7-(difluoromethoxy)-3-methy]-l,2,3,4,4a.9b-hexahydrofuro[2,3-b:4,5- b']dipyridine, hydrochloride (A99, isomer 2) (145 mg, crude) as a white solid. MS ESI calculated for CJ3H14F2N2O2 [M+H]⁺, 257.10; found, 257.10. *H NMR (400 MHz, DMSO- <A) 8 10.58 (s, HI), 8.69 (s, IH), 8.06 (d, 7 - 8.0 Hz, III), 7.65 (t, J - 72.4 Hz, IH), 6.74 ( d, J = 8.0 Hz, 1 H), 5.01 - 4.72 (m, 2H), 3. 10 - 2.91 (m, IH), 2.68 - 2.56 (m, IH), 2.36 - 2.24 (m, 1H), 2.04 - 1.90 (m. 1H), 1.77 - 1.66 (m, IH), 0.98 (d. ./ = 6.8 Hz, 3H).

Intermediate A100: rel-(4aR,10bR)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b ] dipyridine- 8 -c arbonitrile

[1576] To a stirred solution of rel-(4aR,10bR)- 8-chloro-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b']dipyridine (500 mg, 2.22 mmol), Zn(CN)₂ (496 mg, 4,22 mmol) and XPhos (106 mg, 0.22 mmol) in DMF (10 mL) were added XPhos Pd G3 (188 mg, 0.22 mmol) and Zinc (581 mg, 8.90 mmol) al room temperature under nitrogen atmosphere. The resulting mixture was stirred at 130 °C for overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous N»2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with 5%--95%MeCN in Water (10 mmol/L NH4IICO3) to afford rel-(4aR,10bR)-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b']dipyridine-8-carbonitrile (A 100) (110 mg, 22% yield) as a colorless semi-solid, MS ESI calculated for C12H13N3O [M+H]⁺, 216. 1 1 : found, 216. 10, 'H NMR (400 MHz, DMSO-d₆) 87.96 (d, J= 7.8 Hz, 1 H), 7.90 (d, 7 - 7.8 Hz, 1 H), 4.94 - 4.55 (m, 2H),

3.73 - 3.62 (m, 2H), 2.97 - 2.80 (m, 1H), 2.67 - 2.63 (m, TH), 2.04 - 1.87 (m, 1H), 1.79 -

1.74 (m, 1H), 1.59 - 1.54 (m, 1H), 1.37 - 1.31 (m, 1H).

Intermediate A101: 7:2 mixture of rel-(3R,4aS,9bS)-6-fluoro-7-methoxy-3-methyl- l,2,3,4,4a,9b-hexahydrobeiizofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-6-fluoro-7- methoxy-3-methyl-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 2 [1577] To a stirred solution of l-bromo-2,3-difluoro-4-methoxybenzene (3 g, 13.452 mmol) and tert-butyl 3-methyl-5-oxopiperidine-l-carboxylate (2.87 g, 13.452 mmol) in Toluene (60 mL) were added K3PO4 (6.85 g, 32.285 mmol) and P(l-Bu)3 Pd Gs (0.48 g, 0.942 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60°C tor 16h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2:1) to afford a

1 : 1 : 1 : 1 mixture of tert-butyl (2S,5R)-2-(2,3-difluoro-4-methoxyphenyl)-5-methyl-3- oxopiperidine- l-carboxylate and tert-butyl (2R,5S)-2-(2,3-difluoro-4-methoxyphenyl)-5- methyl-3-oxopiperidme- 1 -carboxylate and tert-butyl (2R,5R)-2-(2,3-difluoro-4- methoxyphenyl)"5-methyl-3-oxopiperidine-l -carboxylate and tert-butyl (2S,5S)-2-(2,3- difluoro-4-methoxyphenyl)-5-methyl-3-oxopiperidine-l-carboxy]ate (1.3 g, 27. 19%yield, 85%purity) as a yellow oil. MS ESI calculated for C18H23F2NO4 356.16; found,

356.05.

Step 2: [1578] To a stirred solution of 1:1:1: 1 mixture of tert-butyl (2S ,5R)-2-(2,3-difluoro-4- meihoxypheny1)-5-melhyl-3-oxopiperidme-l-carboxylate and tert-butyl (2R,5S)-2-(2,3- difluoro-4-methoxyphenyl)-5-methyl-3-oxopiperidine- 1 -carboxylate and tert-butyl (2R,5R)- 2-(2,3-difluoro-4-methoxyphenyl)-5-niethyl-3-oxopiperidine- 1 -carboxylate and tert-butyl (2S,5S)-2-(2,3-difluoro-4-methoxyphenyl)-5-methyl-3-oxopiperidine-l-carboxylate (1.3 g, 3.658 mmol,) and DABCO (4.43 g, 20.119 mmol) in MeCN (20 ml) were added RuCl[(S,S- TsDPEN)](p-cymene) (0.06 g, 0.091 mmol) and HCOOH (0.51 g, 10.974 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The mixture was basified with saturated NaHCO?, (aq.) to pH 8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSOr- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to afford a 7:2 mixture of rel- tert- butyl (2R,3R,5S)-2-(2,3-difluoro-4-methoxyphenyl)-3-hydroxy-5-methylpiperidme-l- carboxylate isomer 1 and rel-tert-butyl (2R,3R,5S)-2-(2,3-difluoro-4-methoxyphenyi)-3- hydroxy-5-methylpiperidine-l-carboxylate isomer 2 (700 mg, 53%) as a yellow oil. MS ESI isomer 1 isomer 2 isomer 1 isomer 2

[1579] A solution of 7:2 mixture of rel-tert-butyl (2R,3R,5S)-2-(2,3-difluoro-4- methoxypheiiyl)-3-hydroxy-5-methylpiperidine-l-carboxylate isomer 1 and rel-tert-butyl (2R,3R,5S)-2-(2,3-difluoro-4-methoxyphenyl)-3-hydroxy-5-methylpiperidine-l-carboxylate isomer 2 (700 mg, 1.959 mmol) and t-BuOK (439 mg, 3.91 mmol) in THE (6 mL) was stirred at 70 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to afford a 7:2 mixture of rel-tert-butyl (3R,4aS,9bS)-6-fluoro-7-meihoxy-3- methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridine-l(2H)-carboxylate isomer 1 and rel- tert-butyl (3R,4aS,9bS)-6-fhioro-7-methoxy-3-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridine-l(2H)-carboxylate isomer 2 (300 mg, 45%’ yield) as a yellow oil. MS ESI calculated for C18H24FNO4 [M+H]⁺, 338.17; found, 338.35.

A101

[1580] A solution of 7:2 mixture of rel-tert-butyl (3R,4aS,9bS)-6-fluoro-7-meihoxy-3- methyl-3,4.4a,9b-tetrahydrobenzofuro[3,2-b]pyridine-l(2H)-carboxylate isomer 1 and rel- tert-butyl (3R,4aS,9bS)-6-fluoTO-7-methoxy-3-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridine-l(2H)-carboxylate isomer 2 (300 mg, 0.84 mmol) and HCl (4M in dioxane) (5 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum to afford a 7:2 mixture of rel-(3R,4aS,9bS)-6-fluoro-7-methoxy-3-methyl-

1 ,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-6-fluoro-7- methoxy-3 -methyl- 1,2, 3, 4,4a, 9b-hexahydrobenzofuro[3,2-b]pyridine hydrochloride isomer 2 (A101) (320 mg, crude) MS ESI calculated for C_!3Hi6FNO₂ [M+H]⁺, 238.12; found, 238.15. !H NMR (400 MHz, DMSO-<fe) 8 10.73 (s, IH). 9.21 (s. 1 Tri), 7.48 - 7.37 (m, IH), 6.87 - 6.74 (m, IH), 4.97 - 4.86 (m, IH), 4.85 - 4.57 (m, IH), 3.86 (s, 3H), 3.26 - 3.10 (m, IH), 2.61 - 2.54 and 2.39 - 2.29 (m, IH), 2.28 - 2.16 (m, IH), 2.07 - 1.88 (m, IH), 1.81 - 1.60

(ra, IH), 1.08 - 0.98 (m, 3H).

Intermediate A101 isomer 1: rel-(3R, 4aS,9bS)-6-fluoro-7-methoxy-3-methyl-l, 2,3,4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1

Al 01 isomer 1 Intermediate A101 isomer 2: rel-(3R,4aS,9bS)-6-fluoro-7-methoxy-3-methyl-l, 2,3,4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2

Al 01 isomer 2 [1581] A 7:2 mixture of rel-(3R,4aS,9bS)-6-fluoro-7-methoxy-3-methyl-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 and rel-(3R,4aS,9bS)-6-fluoro-7-methoxy-3- methyl-1, 2,3.4, 4a, 9b-hexahydrobenzofuro[3,2-b]pyridine hydrochloride isomer 2 ( A101) (270 mg) by prep-Chiral HPLC with the following conditions: [Column: CH1RALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 10% B to 10% in 21min% B; Wave Length: 220/254 nm; RTl(min): 10.49; RT2(niin): 14.08; Sample Solvent: MeOH: DCM~1: 1-HPLCi to afford rel-(3R,4aS,9bS)-6-fluoro-7-methoxy-3-methyl- l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine isomer 1 (Al 01 isomer 1) (77 mg, 38% yield) as a white solid and rei-(3R,4aS,9bS)-6-fluoro-7-methoxy-3-methyl-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2 (A101 isomer 2) (29 mg, 14%' yield) as a white solid. [1582] rel-(3R,4aS,9bS)-6-fluoro-7-methoxy-3-methyl-l , 2, 3, 4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine isomer 1 (A101 isomer 1): MS ESI calculated for C13H.6FNO2 [M+H]⁺, 238.12; found, 238.15. 'H NMR (300 MHz, DMSO-Je) 5 7.03 - 6.89 (rn, 1 H), 6.71 - 6.52 (m, 1H), 4.75 - 4.65 (m, 1H), 4.48 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 2.81 - 2.61 (m, 2H), 2.10 - 1.91 (m, 2H), 1.58 - 1.42 (m, 1H), 1.33 - 1.12 (m, 2H), 0.80 (d, J - 8.0 Hz, 3H), Absolute stereochemistry was not determined.

[1583] rel-(3R.4aS,9bS)-6-fluoro-7-methoxy-3-methyl-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine isomer 2 (A101 isomer 2): MS ESI calculated for Ci ₃H_{; 6}FNO₂ i M-H i . 238.12; found, 238.15. ‘H NMR (300 MHz, DMSO-cfc) S 7.03 - 6.96 (m, 1H), 6.65 - 6.50 (m, IHj, 4.51 - 4.47 (m, 1H), 4.06 - 3.93 (m, 1H), 3.81 (s, 3H), 2.75 - 2.61 (m, 1H), 2.29 - 2.04 (m, 2H), 1.69 - 1.42 (m, 2H), 0.81 (d, ./ = 8.0 Hz, 3H). Absolute stereochemistry was not determined.

Intermediate A102 (2R,3R,4aS,9bS)-3-methoxy-2-methyl-7- (trifluoromethyl)- 1,2, 3, 4, 4a, 9b- hexahydrobenzofuro[3,2-b]pyridine

Step 1:

[1584] To a stirred solution of (R,E)-tert-butyl((2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy)dimethylsilane(20 g, 56.11 mmol) and l-bromo-2- lluoro-4-(trifluoromethyl)benzene (15.00 g, 61.73 mmol) in Dioxane (100 mL) and H₂O (10 mL) were added K2CO3 (23.27 g, 168.35 mmol) and Pd(dppf)CI₂ (4.11 g, 5.61 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford (R,E)-tert-butyl(5-(2-fluoro-4- (trifluoromethyl)phenyl)-2-methoxypent-4-enyIoxy)dimethylsilane (.10 g, 45%) as a brown oil. MS ESI calculated for CwH^CKSi [M+H]⁺, 393.18; found, 393.15.

Step 2:

[1585] To a stirred solution of (R,E)-tert-butyl(5-(2-fluoro-4-(trifluoromethyl)phenyI)-2- methoxypent-4-enyloxy)dimeihylsilane (10 g, 25.47 mmol) in DMSO (30 mL) were added Dess-Martin periodinane (16.21 g, 38.21 mmol) and TsOH (0.44 g, 2.54 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 h. The mixture was allowed to cool down to room temperature. Hie resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford (R,E)-5-(2-fluoro-4- (trifluoromethyl)phenyl)-2-methoxypent-4-enal (5.7 g, 80%) as a brown oil. MS ESI calculated for C 4112F4O2 [M+H]⁺, 277.08; found, 277.05.

Step 3 :

[1586] To a stinted solution of (R,E)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-2- methoxypent-4-enal (5.7 g, 20.63 mmol) in THF (10 mL) was added MeMgBr (IM in THF) (80 mL, 80 mmol) dropwise at -78 °C under nitrogen atmosphere, i be resulting mixture was stirred at room temperature overnight. The reaction was quenched with NH4CI (sat.) at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford a 1 : 1 mixture of (2S,3R,E)-6-(2-fluoro-4-(trifluoromeihyl)pbenyl)- 3-methoxyhex-5-en-2-ol and (2R,3R,E)-6-(2-fluoro-4-(trifluoromethyl)phenyl)-3- methoxyhex-5-en-2-ol (2 g, 33%) as a colorless oil. MS ESI calculated for CuHseFiO? [M+H]⁺, 293.11 : found, 293.10.

Step 4:

[1587] To a solution of (2S,3R,E)-6-(2-fluoro-4-(trifluoromethyl)phenyl)-3-methoxyhex-5- en-2-ol (2 g, 6.84 mmol) in DCM (10 naL) was added Dess-Martin periodinane (4.35 g, 10.26 mmol) at room temperature. The mixture was stin'ed at room temperature overnight. The reation mixture was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford (R,E)-6-(2- fJu0ro-4-(trifluorornethyl)phenyl)-3-meth0xyhex-5-ei)-2-one (1 g, 50%) as a yellow oil. MS ESI calculated for C14H14F4O2 [M+H]*', 291.09; found, 291.10.

Step 5 :

[1588] To a stirred solution of NaOH (0.28 g, 6.88 mmol) in ITO (400 mL) was added a solution of tert-butyl carbamate (0.93 g, 7.90 mmol) in propan- l-ol (400 mL), thne 1,3- dichloro-5,5-dimethylimidazolidine-2, 4-dione (1.00 g, 5.09 mmol) was added in portions at room temperature. After stirring at room temperature for 0.5 h, this was followed by the addition of a solution of (DHQjjPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (0.20 g, 0.25 mmol) in propan- l-ol (400 mL), a solution of (R,E)-6-(2-fluoro- 4fttrifluoromethyl)phenyl)-3-rnethoxyhex-5-en-2-one (1 g, 2.54 mmol) in propan-l-ol (400 mL) and a mixture of Potassium osmate(VI) dihydrate (0.09 g, 0.25 mmol) in NaOH (aq, 0.4 M, 1 mL) at 0 °C. The resulting mixture was stirred at room temperature for additional 16 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (400 mL) and extracted with DCM. The organic layer was dried over anhydrous Na?.SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford (lS,2S,4R)-l-(2-fluoro-4-(trifluororaeihyl)phenyl)-2-hydroxy-4- methoxy-5-oxohexylcarbamate (1 g, 92%) as a yellow oil. MS ESI calculated for C19H25F4NO5 [M+H]⁺, 434.17; found, 434.17.

Step 6:

[1589] To a solution of tert-butyl (1 S,2S,4R)- 1 -(2-fluoro-4-(trifluoromethyl)phenyl)-2 - hydroxy-4-methoxy-5-oxohexylcarbainate (1 g, 2.36 mmol) in DCM (10 mL) was added TFA (5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The residue was basified with saturated NaOH (aq.) to pH 8 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in i-PrOH (10 mL), then Pd/C (500 mg, 10% active on carbon) was added at room temperature. The mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with i-PrOH (10 mL). The filtrate was concentrated under reduced pressure to afford (2S,3S,5R,6R)-2-(2-fluoro-4- (lrifluorometliyl)phenyl)-5-methoxy-6-methylpiperidin-3-ol (400 mg, 55%) as a colorless oil. MS ESI calculated for C14TT7F4NO2 [M+H] \ 308. 12; found, 308. 10.

Step 7:

[1590] To a solution of (2S,3S,5R,6R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-5-methoxy- 6-methylpiperidin-3-ol (400 mg, 1 .30 mmol) in tert-Amyl alcohol (4 mL) was added t-BuOK (292 mg, 2.60 mmol) at room temperature. The mixture was stirred at 60 °C for 16 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50-80% ethyl acetate in petroleum ether to afford (2R,3R,4aS,9bS)-3-methoxy-2-methyl-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine (A102) (100 mg, 269b) as a yellow oil. MS ESI calculated for C14H16F3NO2 [M+H]⁺, 288.11; found, 288.10. ^]H NMR (400 MHz, DMSO) S 7.53 (d, J - 7.6 Hz, HI), 7.21 (d, 7 - 8.0 Hz, IH), 7.15 (d, J - 1.6 Hz, IH), 4.40 (t, J - 5.2 Hz, 1H), 4.27 - 4.16 (m, 1H), 3.30 (s, 3H), 3.15 (t, 7 = 3.2 Hz, 1H), 2.80 (d, J = 7.2 Hz, IH), 2.61 (d, J = 16.0 Hz, IH), 1.97 (d, J = 15.6 Hz, IH), 1.04 - 0.93 (m, 3H). Absolute stereochemistry was determined by NOESY.

Intermediate A103 (2R.3R,4aS,9bS)- /-chloro-3-methoxy-2-methyl-l,2,3,4,4a,9b- hexaliydrobenzofuro[3,2-b]pyridine

Step- 1 :

[1591] To a solution of (R,E)-tert-butyl((2-methoxy-5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy)dimethylsilane (20.00 g, 56.12 mmol), l-bromo-4- chloro-2-fluorobenzene (10.68 g, 51.02 mmol) and K2CO3 (21.15 g, 153.05 mmol) in 1,4- dioxane (200 ml) and H2O (20 mL) were added Pd(dppf)C12-CH2C12 (4.17 g, 5.10 mmol). The mixture was stirred at 100 °C for 16 h. The mixture was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford (R,E)-tert- butyI((5-(4-chloro-2-fluorophenyl)-2-methoxypent-4-en-l-y1)oxy)dimethylsilane (16.00 g, 87%) as a yellow oil. MS ESI calculated for CigHaaClFOiSi [M+H]⁺, 359.15; found, 359.15.

Step-2:

[1592] To a solution of (R,E)-tert-butyl((5-(4-chloro-2-fluorophenyl)-2-methoxypent-4-en- 1 -yl)oxy)dimethylsilane (16.00 g, 44.57 mmol) in DMSO (160 mL) were added Dess-Martin periodinane (28.36 g, 66.86 mmol) and 4-methylbenzene-l -sulfonic acid hydrate (850 mg, 4.45 mmoll. The mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-17% ethyl acetate in petroleum ether to afford (R,E)-5-(4- chloro-2-fluorophenyl)-2-methoxypent-4-enal (10.20 g, 94%') as a colorless oil. MS ESI calculated for C12H12CIFO2 [M+H ]⁺, 243.05; found, 243.10.

Step-3 :

[1593] To a solution of (R,E)-5-(4-chloro-2-fluorophenyl)-2-methoxypent-4-enal (10.50 g, 43.27 mmol) in THE (100 mL) was added methylmagnesium bromide (1.0 M in THE, 130 mL) dropwise at -78 °C. The mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction was quenched by the addition of NH4CI (sat.) at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford a 1: 1 mixture of (2S,3R,E)-6-(4-chloro-2- fluorophenyl)-3-methoxyhex-5-en-2-ol and (2R,3R,E)-6-(4-chloro-2-fluorophenyl)-3- methoxyhex-5-en-2-ol (5.80 g, 52%) as a yellow oil. MS ESI calculated for CisHieClFOi [M+H]⁺, 259.08; found, 259.10.

Step-4:

[1S94] To a solution of 1: 1 mixture of (2S,3R,E)-6-(4-chloro-2-fluorophenyl)-3- methoxyhex-5-en-2-ol and (2R,3R,E)-6-(4-chloro-2-fiuorophenyl)-3-methoxyhex-5-en-2-ol (5.80 g, 22.42 mmol) in DCM (60 mL) was added Dess-Martin periodinane (14.26 g, 33.63 mmol). The mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water at 0 °C and extracted with EtOAc. The combined organic layers were dried over anhydrous NarSOr. After filtration, the filtrate was concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography, eluted with 0—10% ethyl acetate in petroleum ether to afford (R,E)-6-(4-chloro-2-fluorophenyl)-3-rnethoxyhex-5- en-2-one (4.80 g, 83%) as a yellow oil. MS ESI calculated for CnrHuClKh [M+H]⁺, 257.07; found, 257.05.

Step-5:

[1595] To a solution of NH2B0C (6.89 g, 58.81 mmol) in propan-l-oi (145 mL) was added

NaOH (4 M in H2O, 126 mL). The mixture was stirred at room temperature for 10 min. Then DCDMH (5.61 g, 28.46 mmol) was added, the mixture was stirred at room temperature for 30 min. This was followed by the addition of a solution of (DHQjiPHAL (supplier: Shanghai Accela CheniBio Co., Ltd, CAS# 140924-50-1) (1.48 g, 1.90 mmol) in propan- l-ol (19 mL). a solution of (R,E)-6-(4-chloro-2-fluorophenyl)-3-methoxyhex-5-en-2-one (4.87 g. 18.97 mmol) in propan-l-ol (19 mL) and Potassium osmate(VI) dihydrate (0.70 g, 1.90 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water. The aqueous layer was extracted with EtOAc. The residue was purified by silica gel column chromatography, eluted with 0-35% ethyl acetate in petroleum ether to afford tert-butyl ((lS,2S,4R)-l-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methoxy-5- oxohexyl)carbamate (4.90 g, 66%) as a colorless oil. MS ESI calculated for C18H25CIFNO5 [M+H]⁺, 390.14; found, 390.10.

Step-6:

[1596] To a solution of tert-butyl ((lS,2S,4R)-l-(4-chloro-2-fluorophenyl)-2-hydroxy-4- melhoxy-5-oxohexyl)carbamate (4.90 g, 12.57 mmol) in DCM (50 mL) was added TFA (15 mL, 0.13 mmol). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in i-PrOH (.80 mL), then Pt/C (5% active on carbon) (3.05 g) was added. The mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The mixture was filtered. The filtrate was diluted by NaaHCOj (aq.) and extracted with EtOAc. The organic layer was dried over anhydrous NasSO-i. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 5% to 50% MeCN in Water (10 mmol/L NH4HCO3) to afford (2S,3S,5R,6R)-2-(4-chloro-2-fluorophenyl)-5-methoxy-6- methylpiperidin-3-ol (620 mg, 6%) as a colorless oil. MS ESI calculated for C13H17CIFNO2 |M+11]⁺, 274.09; found, 274.10.

Step-7:

[1597] To a solution of (2S,3S,5R,6R)-2-(4-chloro-2-fluorophenyl)-5-methoxy-6- methylpiperidin-3-ol (587 mg. 2.14 mmol) in THF (2 mb) was added t-BuOK (481 mg, 4.29 mmol). The mixture was stirred at 70 °C for 5 h. The resulting mixture was diluted with water and extracted with EtOAc. Ute combined organic layers dried over anhydrous Na^SOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 5% to 50% MeCN in Water ( 10 mmoi/L NH4HCO3) to afford (2R,3R,4aS,9bS)-7-chloro-3-methoxy-2-methyl-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine (A103) (240 mg, 44%) as a yellow oil. MS ESI calculated for Ci ₃H₁₆C1NO₂ [M+H]⁺, 254.09; found, 254.10. ^!H NMR (400 MHz, DMSO-&)

57.30 (d, J= 7.6 Hz, 1H), 6.96 - 6.83 (m, 2H), 4.61 (q, J = 4.8 Hz, 1H), 4.10 (d, J = 5.2 Hz, IHj, 3.28 (s, 3H), 2.99 - 2.91 (m, 1H), 2.49 - 2.39 (m, 1H), 2.O7 - 1.92 (m, 1H). 1.85 - 1.72 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was determined by NOESY. Intermediate A104: (3R,4aR*,9bR*)-7-(difluorome±oxy)-3-methoxy- 1, 2, 3, 4, 4a, 9b- hexahydrofuro[2,3-b:4,5-b']dipyridine

Step 1 :

[1598] To a stirred solution of (R,E)-tert-butyl((2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pent-4-en-l-yl)oxy)dimethylsilane (8.04 g, 30.87 mmol) in Dioxane (200 mL) and H2O (20 mL) were added K2CO3 (23.27 g, 168.35 mmol), 3-bromo-2-chIoro-6- (difluoromelhoxy)pyridine (7.93 g, 30.87 mmol) and Pd(dppl)C12 (4.11 g, 5.62 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was heated to 100 °C with stirring for 16 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford (R,E)-3-(5-((tert-butyldimethylsilyl)oxy)-4-methoxypent-l -en-l-yl)-2-chloro-6- (difluoromethoxy)pyridine (21.00 g, 99%) as a brown oil. MS ESI calculated for

[1599] To a stirred solution of NaOH (5.45 g, 136.34 mmol) in H2O (340 ml) was added a solution of tert-butyl carbamate (18.34 g, 156.54 mmol) in propan- l-ol (391 mL), then 1,3- dichloro-5,5-dimethylimidazolidine-2,4-dione (19.90 g, 100.99 mmol) was added in portions al room temperature under nitrogen atmosphere. After stirring at room temperature for 0.5 hour, this was followed by the addition of a solution of (DHQ)₂PHAL (supplier: Shanghai AcceJa ChemBio Co., Ltd. CAS# 140924-50-1) (3.93 g, 5.05 mmol) in propan- l-ol (51 mL), a solution of (R,E)-3-(5-((tert-butyldimethylsilyl)oxy)-4-methoxy^fpent-l-en-l-yl)-2-chloro-6- (difluoromethoxy)pyridine (20.60 g, 50.25 mmol) in propan- l-ol (51 mL) and Potassium osmate(VI) dihydrate (1.86 g, 5.05 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O and extracted with DCM. The combined organic layers were washed -with brine, dried over anhydrous Na^SCL- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% ethyl acetate in petroleum ether to afford tert-butyl ((lS*,2S*,4R)-5-((ten-butyldimethylsilyl)oxy)-l-(2-chloTO-6-(difluoromethoxy)pyri din-3- yl)-2-hydroxy-4-methoxypentyl)carbamate (13.00 g, 45%) as a yellow oil. MS ESI calculated for C23H3₉ClF₂N2O₆Si [M+Hj⁴, 541.22 ; found, 541.20.

[1600] To a solution of tert-butyl ((lS*,2S*,4R)-5-((tert-butyldimethylsilyl)oxy)-l-(2- chloro-6-(difluoromethoxy)pyiidin-3-yD-2-hydroxy-4-methoxypentyl)carbamate (13.00 g, 24.02 mmol) in Toluene (150 mL) were added Pd(OAc)₂ (1.08 g, 4.80 mmol), JohnPhos (1 .43 g, 4.81 mmol) and CS2CO3 (23.48 g, 72.07 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0- 10% ethyl acetate in petroleum ether to afford tert-butyl ((2S*,3S*)-2-((R)-3-((tert-butyldinaethylsilyl)oxy)-2-methoxypropyl)-6- (difluoromethoxy)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (8.7 g, 71%) as a yellow oil. MS ESI calculated for C23H38F2N2O6S1 [M+Hj⁴, 505.25 ; found, 505.20. Step 4:

[1601] To a solution of tert- butyl ((2S*,3S*)-2-((R)-3-((tert-butyldimethylsilyl)oxy)-2- methoxypropyl)-6-(difluoromethoxy)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)carbamate (8.7 g, 17.24 mmol) in THF ( 100 ml..) was added TBAF (9.02 g, 34.48 mmol). The mixture was stirred at. room temperature for 2 hours. The reaction was quenched by water and extracted with EtOAc. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% MeOH in CH2CI2 to afford tert-butyl ((2S*,3S*)-6-(difluoromethoxy)-2-((R)-3-hydroxy-2-metboxypropyl)-2,3- dihydrofuro[2,3-b]pyridin-3-yl)carbamate (5.8 g, 86%) as a pink solid. MS ESI calculated for

[1602] A solution of tert-butyl ((2S*,3S*)-6-(difluoromethoxy)-2-((R)-3-hydroxy-2- methoxypropyl)-2,3-dihydroftiro[2,3-b]pyridin-3-yl)carbamate (5.8 g, 14.86 mmol) and

CMBP (7.17 g, 29.71 mmol) in Toluene (60 mL) was stirred at 100°C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleurn ether to afford tert-butyl (3R.4aS*,9bS*)-7-(difluoromethoxy)-3-methoxy-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b ]dipyridine-l(2H)-carboxylate (4.3 g, 61%) as a yellow oil. MS

ESI calculated for CJ7H22F2N2O5 373.15 ; found, 373.10. Step 6:

[1603] A mixture of tert-butyl (3R,4aS*,9bS*)-7 -(difluoromethoxy )-3-methoxy-3,4, 4a, 9b- tetrahydrofuro[2,3-b:4,5-b‘]dipyridine-l(2H)-carboxylate (4.3 g, 11.55 mmol) and HC1 (g) (4M in 1,4-dioxane, 50 mL) was stirred at room temperature for 1 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved with DCM (50 mL) and MeOH (5 mL), then K2CO3 (4.78 g, 34.65 mmol) as added. The resulting mixture was stirred at room temperature for 1 hours. The resulting mixture was filtered, the filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure and afford (3R,4aS*,9bS*)-7-(difluoromelhoxy)-3-methoxy-l,2,3,4,4a,9b-hexahydrofuro[2,3- b:4,5-b’]dipyridine (A104) (3.4 g, 97%) as a brown oil. MS ESI calculated for C12H14F2N2O3 [M+H]⁺, 273.10: found, 275.05. ‘H NMR (300 MHz, DMSO) 57.88 - 7.29 (m, 2H), 6.56- 6.49 (m, 1H), 4.98 - 4.63 (m, 1 H), 4.40 - 4.30 (m, 1H), 3.31 - 3.25 (m, 1H), 3.21 (d, J = 3.2 Hz, 3H), 2.97 - 2.77 (m, 1H), 2.44 - 2.08 (m, 2H), 2.05 - 1.40 (m, 2H). Absolute stereochemistry was not determined.

Intermediate A106 isomer I: (3R,4aS,9bS)-3-methyl-7-( trifluoromethyl)-! , 2,3, 4, 4a, 9b- hexaliydrofuro [2,3 -b:4 , 5 ■ b’J dipyridine

Intermediate A106 isomer 2: (3S,4aS,9bS)-3-methyl-7-(trifluoromethyl)-l,2,3,4,4a,9b- hexahy drof uro [2,3 -b:4,5 -b’J dipyridine

[1604] To a stirred solution of 3-bromo-2-chloro-6-(trifluoromethyl)pyridine (5.0 g, 19.20 mmol) in toluene (50 mL) were added tert-butyl 3-methyl-5-oxopiperidine-l-carboxylate (8.19 g, 38.40 mmol), P(t-Bu)3Pd G3 (981 nig. 1.92 mmol) and KsPCT (10.19 g, 47.99 mmol) at 25 °C. The resulting solution was stirred at 90 °C for 1 h under nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 - 40% EtOAc in petroleum ether to afford a 1: 1 : 1:1 mixture of tert-butyl (2S,5R)-2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-5-methyl-3-oxopiperidine-l- carboxylate and tert- bu tyl (2R,5 S) -2 ■ (2-chloro -6-(trifluoromethy l)pyridin-3 -yl) ■ 5 -methyl- 3 ■ oxopiperidine- 1 -carboxylate and tert-butyl (2S,5S)-2-(2-chloro-6-(trifluoromethyl)pyridin-3- yl)-5-methyl-3-oxopiperidine-l-carboxylate and tert-butyl (2R,5R)-2-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)-5-methyl-3-oxopiperidine- l -carboxylate (3.50 g, 19%) as a yellow oil. MS ESI calculated for C_{; ?}H 20CIF3N 2O3 [M+H]⁺, 393.11; found, 393.05.

Step-2: [1605] To a stirred solution ofl : 1 : 1 : 1 mixture of tert-butyl (2S,5R)-2-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)-5-methyl-3-oxopiperidine-l -carboxylate and tert-butyl (2R,5S)-2-(2-chloro-6-(trifluoromethyl)pyridm-3-yl)-5-methyl-3-oxopiperidine-l- carboxylate and tert-butyl (2S,5S)-2-(2-chloro-6-(trifluorometbyl)pyridin-3-yl)-5-methyl-3- oxopiperidine-1 -carboxylate and tert-butyl (2R,5R)-2-(2-chloro-6-(trifluoromethyl)pyridin-3- yl)-5-methyl-3-oxopiperidine-l-carboxylate (3.52 g, 8.91 mmol) in MeCN (40 mL) were added RuCl[(S,S-TsDPEN)](p-cymene) (142 mg, 0.22 mmol). HCOOH (1.24 g, 26.73 mmol) and DABCO (5.53 g, 49.00 mmol) at 0 °C. The resulting solution was stirred at 25 °C for 16 h. The resulting mixture was quenched by the addition of NaHCOr (sat.) and extracted with EtOAc. Th e combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 - 20% EtOAc in petroleum ether to afford a 1:1 mixture of tert-butyl (2S,3S,5R)-2-(2-chloro-6-(trifluoroniethyl)pyridin-3-yl)-3-hydroxy-5- methylpiperidine-l-carboxylate and tert-butyl (2S,3S,5S)-2-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)-3-hydroxy-5-methylpiperidine-l -carboxylate (1.50 g, 50%) as a white solid. MS ESI calculated for CnH^ClFsN/Ch [M+H]⁺,395.13 ;found, 395.20.

[1606] To a stirred solution of 1: 1 mixture of tert-butyl (2S.3S,5R)-2-(2-chloro-6- (trifluoromethyl)pyridin-3-yl)-3-bydroxy-5-methylpiperidine-l -carboxylate and tert-butyl (2S,3S,5S)-2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-3-hydroxy-5-methylpiperidine-l- carboxylate (1.50 g, 3.80 mmol) in THE (20 mL) was added t-BuOK (639 mg, 5.70 mmol) at 25 °C. The resulting solution was stirred at 25 °C for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0 - 30% EtOAc in petroleum ether, then purified by prep-chiral SFC with the following conditions: [Column: CHIRALPAK IF 3*25 cm, 5 pm; Mobile Phase A: CO?, Mobile Phase B: MeOH; Flow rate: 100 mL/min; Gradient (B%): isocratic 20% B; RTl(min): 2.5; RT2(min): 4; Sample Solvent: MEOH; Injection Volume: 2 mb; Number Of Runs: 15] to afford tert-butyl (3R,4aS,9bS)-3-methyl-7-(trifluoromethy1)-3,4.4a,9b- tetrahydrofuro[2,3-b:4,5-b‘]dipyridine-l(2H)-carboxylate isomer 1 (420 mg, 43%) as a yellow solid with retention time at 4.0 minutes. MS ESI calculated for C17H21CIF3N2O3 [M+H]⁺, 359.15 ; found, 359.10.

[1607] The chiral resolution also affords tert-butyl (3S,4aS,9bS)-3-methyl-7- (trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b^,]dipyridine-l(2H)-carboxylate isomer 2 (410 mg, 45%) as a yellow solid with retention time at 2.5 minutes. ESI calculated for C17H21CIF3N2O3 [M+Hf, 359.15;found, 359.10.

[1608] A mixture of tert-butyl (3R,4aS,9bS)-3-methyl-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b']dipyridine-l(2H)-carboxylate (420 mg, 1.17 mmol) and hydrogen chloride (4.0 M in ethyl acetate) (5 mL) was stirred at room temperature for I h. The resulting mixture was concentrated under vacuum to afford (3R,4aS,9bS)-3-methyl-7-

( trifluoromethyl)-!, 2, 3, 4, 4a, 9b-hexahydrofuro[2,3-b:4,5-b’]dipyridine hydrochloride isomer 1 (A106 isomerl) (400 mg, crude) as a yellow solid. MS ESI calculated for C12H13F3N2O [M+H]⁺, 259.10; found, 259.05. ‘H NMR (300 MHz, DMSO) 5 10.81 (s, 1H), 9.65 (s, 1H), 8.38 (d, 7 = 7.5 Hz, 1H), 7.60 (d, 7 = 7.5 Hz, 1H), 5.29 - 4.94 (m, 2H), 3.30 - 3.17 (m, 1H), 2.75 - 2.58 (m, 1H), 2.36 - 2.21 (rn, 1H), 2.10 - 1.95 (m, 2H), 1.79 - 1.54 (m, 1H), 1.01 (d, J ~ 6.6 Hz, 3H). Absolute stereochemistry was determined by NOESY. Step-6: [1609] A mixture of tert-butyl (3S,4aS,9bS)-3-methyl-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4,5-b’]dipyridine-l(2H)-carboxylate (400 nig, 1.12 mmol) and hydrogen chloride(4.0 M in ethyl acetate) (4 mL) was stirred at room temperature for 1 h. Ute resulting mixture was concentrated under vacuum to afford (3S,4aS,9bS)-3-methyl-7- (trifluoromethyl)-l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b’]dipyridine hydrochloride isomer 2 (A106, isomer2) (350 mg, crude) as a yellow solid. MS ESI calculated for C12H13F3N2O

[M+H]⁺, 259.10; found, 259.05. ^SH NMR (300 MHz, DMSO) 5 11.04 (s, 1H), 8.91 (s, 1H), 8.26 (d. J = 7.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 5.03 - 4.80 (m, 2H), 3.08 (d. J = 12.6 Hz, 1H), 2.63 - 2.62 (m, 1H), 2.36 (d. J = 15.0 Hz, 1H), 2.09 - 1.52 (m, 2H). 0.99 (d, J = 6.6 Hz, 3H). Absolute stereochemistry -was determined by NOESY.

Intermediate A 107: (4aS,6R,10bS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,10b- hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridine

Step-1:

[1610] To a stirred solution of tert-butyl (4aS,6R,10bS)-8-chloro-6-methyl-2,3,4,4a,6,10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate (from A78) (300 mg, 0.89 mmol) and KOH (99 mg, 1.77 mmol) in Dioxane (5 mL) and H?O (1 mb) were added t- BuXPhos (38 mg, 0.09 mmol) and Pd2(dba)a (81 mg, 0.09 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 ^C’C for 16 h. The resulting mixture was concentrated under vacuum. The residue was purified by normal phase flash column chromatography which applied to 40 g silica gel column eluted with 0-15% methanol in dichloromethane to afford tert-butyl (4aS,6R,10bS)-8-hydroxy-6-metbyl-2,3,4,4a,6,10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate (254 mg, 90% yield) as a yellow solid. MS ESI calculated for C17H24N2O4 [M+H]⁺, 321.17; found. 321.15.

Step-2:

[1611] To a stirred solution of tert-butyl (4aS,6R,10bS)-8-hydroxy-6-methyl- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (250 mg. 0.78 mmol) and K2CO3 (129 mg, 0.94 mmol) in DMF (5 ml..) was added sodium chlorodi fluoroacetate (238 mg, 1.56 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography which applied to 25 g silica gel column eluted with 0-15% ethyl acetate in petroleum ether to afford tert-butyl (4aS,6R,10bS) 8-(difluoromethoxy)-6-niethyl-2,3,4,4a,6,10b hexahydro- lH-pyrano[3,2- b:5,4-b']dipyridine-l -carboxylate (160 mg, 55% yield) as a light yellow oil. MS ESI calculated for C18H24F2N2O4 [M+H]⁺, 371.17; found, 371.20.

Step-3:

[1612] A solution of tert-butyl (4aS,6R,10bS)-8-(difluoromethoxy)-6-methyl - 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (160 mg, 0.43 mmol) and HC1 (4.0 M in 1,4-dioxane) (2 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to afford (4aS,6R,10bS)-8- (difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine hydrochloride (A107) (crude, 103 mg) as a white solid. MS ESI calculated for C]3Hi6F2NzO2 [M+H]⁺, 271.12; found, 271.15. ^!H NMR (400 MHz, DMSO) 8 10.52 (s, 1 H), 8.63 (hr, 1H), 8.23 (dd, 8.8, 1.6 Hz, 1H), 7.96 - 7.58 (m, 1H), 7.10 (d, 8.4 Hz, 1H), 4.85 - 4.75 (m,

1H), 4.37 (d, J = 10.4 Hz, 1H), 4.06 (d, J= 2.4 Hz,lH), 3.20 (d, J = 12.4 Hz, 1H), 3.02 (d, J = 11.4 Hz, 1H), 2.09 - 1.77 (m, 3H), 1.73 - 1.39 (m, 4H).

Intermediate A 108: (3R,4aR*,10bR*)-8-(difluoromethoxy)-3-methoxy-2,3,4,4a,6,10b- hexahydro- 1 H- pyrano [3 ,2 - b : 5 ,4 -b'jdipyridine

Step- 1 :

[1613] To a stirred solution of methyl 3-bromo-6-(difluoromethoxy)picolinate (17.20 g, 61.98 mmol) in 1,4-dioxane (200 mL) and H2O (20 mL) were added (R,E)-tert-butyl((2- methoxy-5-(4,4,5,5"tetramethyl-l,3,2-dioxaborolan-2-yi)pent-4-en- l-yl)oxy)dimethylsilane (23.91 g, 67.08 mmol), PdfdppDCh-CITCb (4.98 g, 6.10 mmol) and K2CO3 (25.28 g, 182.95 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na^SCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% ethyl acetate in petroleum ether to afford methyl (R,E)-3-(5-((tert- butyldimethylsilyl)oxy)-4-methoxypent-l-en-l-yl)-6-(difluoromethoxy)picolinate (4.50 g, 45%) as a brown oil. MS ESI calculated for CcoHsiFaNOsSi [M+H]⁺, 432. 19; found 432.20.

Step-2:

[1614] To a mixture of BocNH? (3.79 g, 32.32 mmol) in n-PrOH (40 mL) were added a solution of NaOH (1.13g, 24.29mmol) in H2O (34 mL). After stirring at room temperature for 10 minutes, l,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione (3.08 g, 15.64 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for additional 30 min. This was followed by the addition of a solution of (DHQhPHAL (supplier: Shanghai Accela ChemBio Co., Ltd. CAS# 140924-50-1) (0.81 g, 1.04 mmol) in n- PrOH (9 mL), a solution of methyl (R,E)-3-(5-((tert-butyldimetliylsilyl)oxy)-4-niethoxypent- l-en-l-yI)-6-(difluoromethoxy)picolinate (4.50 g, 10.43 mmol) in propan- l-ol (45 mL) and Potassium osmate(VI) dihydrate (0.38 g. 1,04 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaiSOr. Alter filtration, the filtrate was concentrated under reduced pressure.

[1615] The residue was dissolved in DCM (65mL), then DCC (6.43 g, 31.16 mmol) and DMAP (6.92 g, 56.66 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous NazSO^ After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 30% EtOAc in petroleum ether to afford tert-butyl ((5R*,6R*)-6-((R)-3-((tert-butyldimethylsilyl)oxy)-2-nietboxypropyl)-2- (difluoromethoxy)-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (3.0 g, 22%) as a yellow solid. MS ESI calculated for (C24H38F2N2O7S1) [M+H]⁺, 533.24; found: 53.3.25.

Step-3:

[1616] To a stirred solution of tert-butyl ((5R*,6R*)-6-((R)-3-((tert- butyldimethylsilyljoxy)-2-methoxypropyl)-2-(difluoroniethoxy)-8-oxo-5,8-dihydro-6H- pyrano[3,4-b]pyridin-5-yl)carbamate (3.0 g, 5.63 mmol) in THE (30 mL) was added NaBIE (320 mg, 8.45 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaiSOn After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 ~ 40% EtOAc in petroleum ether to afford tert-butyl ((1 S*,2S*,4R)-5-((tert- butyldimethylsilyi)oxy)-l-(6-(difluoromethoxy)-2-(hydroxymethyl)pyridin-3-yl)-2-hydroxy- 4-raeth0xypentyl)caibamate (1.10 g, 48%) as a colorless oil. MS ESI calculated for (C24H42F2N2O7S1) [M+H]⁺, 537.27; found: 537.35.

Step-4:

[1617] To a stirred solution of tert-butyl ((lS*,2S*,4R)-5-((tert-butyldimethylsilyl)oxy)-l- (6-(difluoromethoxy)-2-(hydroxymethyl)pyridin-3-yl)-2-hydroxy-4- methoxypentyl)carbamate (1.0 g, 1.86 mmol) in toluene ( 15 mL) was added CMBP (899 mg, 3.72 mmol) at 25 °C. The resulting solution was stirred at 100 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% EtOAc in petroleum ether to afford tert-butyl ((5S*,6vS*)-6-((R)-3-((tert-buty1dimethy1sily1)oxy)-2-methoxypropyl)-2-(difluoromethoxy)- 5,8-dihydro-6H-pyrano[3,4-bjpyridin-5-yl)carbamate (420 mg, 48%) as a yellow oil. MS ESI calculated for CcfoLoFiN^OsSi [M+H]⁺, 519.26; found: 519.25.

Step-5:

[1618] To a stirred solution of tert-butyl ((5S*,6S*)-6-((R)-3-((tert- butyldimethylsilyl)oxy)-2-methoxypropyl)-2-(difluoromethoxy)-5,8-dihydro-6H-pyrano[3,4- b]pyridin-5-yl)carbamate (420 mg, 0.81 mmol) in THE (5 mL) was added TBAF (423 mg, 1 .62 mmol) at 25 °C. The resulting mixture was stirred at room temperature tor 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in petroleum ether to afford tert-butyl ((5S*,6S*)-2-(difluoromethoxy)-6-((R)- 3-hydroxy-2-methoxypropyD-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (220 mg, 89%) as a yellow solid. MS ESI calculated for C 1 >11 „i^;-N ■( >■. [M+H]⁺, 405.18; found:405.15.

Step-6:

[1619] To a stirred solution of tert-butyl ((5S*,6S*)-2-(difluoromethoxy)-6-((R)-3- hydroxy-2-methoxypropyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)carbamate (220 mg, 0.54 mmol) in toluene (3 mL) was added 2-(tributyl-X⁵-phosphaneylidene)acetonitrile (CAS

No. 157141-27-0) (197 mg, 0.82 mmol) at 25 °C. The resulting solution was stirred at 100 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-10% EtOAc in petroleum ether to afford tert-butyl (3R,4aS*,10bS*)-8-(difluoromethoxy)-3-methoxy-2, 3, 4,4a, 6,10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (140 mg, 76%) as a yellow oil. MS ESI calculated for C18H24F2N2O5 [M+H]⁺, 387.17; found: 387.20.

Step-7: [1620] A mixture of tert-butyl (3R,4aS*, 1 ObS*)-8-(difluoromethoxy)-3-methoxy- 2,3,4,4a,6,10b-hexabydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l -carboxylate (130 mg, 0.34 mmol) and hydrogen chloride (4.0 M in ethyl acetate) (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford (3R,4aS*,10bS*)-8-(difluoromethoxy)-3-methoxy-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-b']dipyridine hydrochloride (A 108) (120 mg, crude) as a yellow solid. MS ESI calculated for CBH16F2N2O3 [M+HJ*. 287.1 1 ; found, 287.15. *H NMR (300 MHz. DMSO) 6 10.13 (br, 1H), 8.81 (br, 1H), 8.23 (d, J - 8.4 Hz, 1H), 7.69 (t, J - 72.6 Hz, 1H), 7.10 (d, J ~ 8.4 Hz, 1H), 4.69 (s, 2H), 4.40 - 4.39 (m, 1H), 4.06 - 4.05 (m, 1H), 3.69 - 3.68 (m, 1H), 3.39 - 3.16 (m, 5H), 2.36 (d, J - 15.6 Hz, 1H), 2.17 - 1.86 (m, 1H). Absolute stereochemistry at two “orl” centers was not determined.

Intermediate A 109: (4aS,6R,10bS)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-bJdipyridine-8-carbonitrile

A109

Step-1:

[1621] To a stirred solution of tert-butyl (4aS,6R,10bS)-8-chloro-6-methyl-2,3,4,4a,6,10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (from A78) (150 mg, 0.44 mmol) and ZntCNh (155 mg, 1.32 mmol) in THF (1 mL) and H2O (1 mL)were added t- BuXPhos Pd G3 (52 mg, 0.06 mmol) at 25°C under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by normal phase flash column chromatography which applied to 25 g silica gel column eluted with 0-55% ethyl acetate in petroleum ether to afford tert-butyl (4aS,6R,10bS)-8-cyano-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b’]dipyridine-l -carboxylate (120 mg, 82% yield) as a white solid. MS ESI calculated for C18H23N3O3 [M+H]⁺, 330.17; found, 330.15.

Step-2:

[1622] To a solution of tert-butyl (4aS,6R,10bS)-8-cyano-6-methyl-2, 3, 4,4a, 6,10b- hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridine-l-carboxylate (120 mg, 0.36 mmol) in 1,4- dioxane (2 mL) was added HC1 (4.0 M in 1 ,4-dioxane) (2 mL) at 25 °C under nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 1 b. The resulting mixture was concentrated under vacuum to afford (4aS,6R,10bS)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b']dipyridine-8-carbonitrile hydrochloride (A109) (crude, 100 mg) as a white solid. MS ESI calculated for C13H15N3O [M+HJ⁺, 230.12; found, 230.15JH NMR (300 MHz, DMSO-efe) 8 10.20 (s, 1H), 8.74 (br, 1H), 8.29 (d, 7 = 8.1 Hz, 1H), 8.09 (d, 7 = 8.1 Hz, 1H), 4.92 (q, J = 6.6 Hz, 1H), 4.53 - 4.52 (m, 1H), 4.14 - 4.13 (m, 1H), 3.17 - 3.07 (m, 2H), 1.87 - 1.82 (m, 2H), 1.62 (d, J = 6.6 Hz. 3H), 1.29 - 1.07 (in, 2H).

Intermediate Al 10 isomer 1 : (2R,4aR.9bS)-7-(difluoromethoxy)-2-methyl- 1.2,3.4a,5,9b- hexah ydropyrido[3' ,2* : 3,4]cyclopenta [ 1 ,2-b] [1 ,4]oxazine

At 10 isomer ! _an(j

Intermediate A110 isomer 2: (2R,4aS,9bR)-/-(difluoromethoxy)-2-methyl-l,2,3,4a,5,9b- hexahydropvrido[3’,2':3,4]cvclopenta| l,2-b][l,4joxazine

A110 isomer 2

Step- 1 :

[1623] A mixture of 2-(difluoromethoxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (6.20 g, 31.13 mmol) and CuBry (10.43 g, 46.69 mmol) in EtOAc (120 mL) was stirred at

80 °C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1 ) to afford a 1:1 mixture of (R)-6-bromo--2- (difluoromethoxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one and (S)-6-bromo-2-(difluoromethoxy)-6,7-dihydro-5H-cyclope.nta[b]pyridin-5-one (5.00 g, 57%) as a white solid. MS ESI calculated for CyHsBrFsNOs [M+H]⁺, 277.95, 279.95; found,

278.00. 280.00.

Step-2:

[1624] To a stirred solution of 1: 1 mixture of (R)-6 ■bromo-2-(difluoromethoxy)-6,7- dihydro-5H-cyclopenta[b]pyridin-5-one and (S)-6-bromo-2-(difluoromethoxy)-6,7-dihydro-

5H-cyclopema[b]pyridin-5-one (5.00 g, 17.98 mmol) in MeOH (50 mL) was added NaBHi (1.36 g, 35.96 mmol) in portions at 0 °C. The resulting mixture was stirred at 25 °C for 4 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to afford a 1 : 1 mixture of (5S,6R)-6-bromo-2-(difluoromethoxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol and (5R,6S)-6-bromo-2-(difluoromethoxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol (4.40 g, 87%) as a white solid. MS ESI calculated for C₉H₈BrF₂NO₂ [M+HJ *, 279.97, 281.97; found, 280.00, 282.00.

Step-3:

[1625] To a stirred a 1:1 mixture of (5S,6R)-6-bromo-2-(difluoromethoxy)-6,7-dihydro- 5H-cyclopenta[b]pyridin-5-ol and (5R,6S)-6-bromo-2-(difluoromethoxy)-6,7-dihydro-5H- cyclopenta[b]pyridin-5-ol (3.30 g, 11.78 mmol) in MeCN (40 rnL) was added H2SO4 (1.73 g, 17.67 mmol) dropwise at 0 °C. The resulting mixture was stirred at 70 °C for 3 h. The reaction mixture was diluted by H2O (40 mL) and the resulting mixture was stirred at 70 °C for 16 h. The resulting mixture was basified to with NaOH (aq., 30%) to pH 1 1-12. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4. After filtration, the filtrate was concentrated under reduced pressure to afford a 1 : 1 mixture of (5S,6R)-5-amino-2-(difluoromethoxy)-6,7-dihydro-5H- cyclopenta[b]pyridin-6-ol and (5R,6S)-5-amino-2-(difluoromethoxy)-6,7-dihydro-5H- cyclopenta[b]pyridin-6-ol (2.20 g, crude) as a brown solid. MS ESI calculated for C₉HIOF₂N₂0₂ [M+H]⁺, 217.07; found, 217.20.

Step-4:

[1626] To a stirred a 1 :1 mixture of (5S,6R)-5-amino-2-(difluoromethoxy)-6,7-dihydro-5H- cyclopenta[b]pyridin-6-o! and (5R,6S)-5-amiiio-2-(diiluoromethoxy)-6,7-dihydro-5H- cyclopenta[b]pyridin-6-ol (2.00 g, 9.25 mmol) in methanol (5 mL) were added Et?,N ( 1.87 g, 18.50 mmol) and B0C2C) (3.03 g, 13.87 mmol) at room temperature. The resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1: 1) to afford a 1: 1 mixture of tert- butyl ((5S,6R)-2-(difluoromethoxy)-6-hydroxy-6,7-dihydro-5H- cyclopenta[b]pyridin-5-yI)carbamate and tert-butyl ((5R,6S)-2-(difluoromethoxy)-6-hvdroxy- 6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)carbamate (2.00 g, 68%) as an off-white solid. MS ESI calculated for C14H18F2N2O4. [M+H]⁺, 317.12; found, 317.15.

Step-5:

[1627] To a stirred a 1 :1 mixture of tert-butyl ((5S,6R)-2-(difluoromethoxy)-6-hydroxy- 6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)carbamate and tert-butyl ((5R,6S )-2- (difluoromethoxy)-6-hydroxy-6,7-dihydro-5H-cyclopenta[bJpyridin-5-yl)carbaniate (2.00 g, 6.32 mmol) in DCM (30 mL) were sequentially added NaOH (1.78 g, 44.26 mmol), (B«4N)HSO4 (429 mg, 1.26 mmol) and (S)-4-methyl-L3,2-dioxathioIane 2,2-dioxide (supplier: Suzhou spark Biotechnology Co., Ltd. CAS# 174953-30- 1) (1.14 g, 8.22 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in 2-methoxy-2- methylpropane (140 mL) and H2O (4.4 mL), then a solution of TsOH (544 mg, 3.16 mmol) in 1 ,4-dioxane (25.5 mL) was added. The resulting mixture was stirred at 40 °C for 16 h. The reaction was quenched with NaHCCh (aq., 20%) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated tinder reduced pressure to afford a 1: 1 mixture of tert-butyl ((5S,6R)-2-(difluoromethoxy)-6-((S)-2-hydroxypropoxy)-6,7-dihydro-5H- cyclopenta[b]pyridin-5-yl)carbamate and tert-butyl ((5R,6S)-2-(difluoromethoxy)-6-((S)-2- hydroxypropoxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)carbamate (2.00 g, crude) as a light brown solid. MS ESI calculated for CnH24F2N2.O5. [M+H]⁺, 375. 17; found, 375.25.

Step-6:

[1628] To a stirred a 1 :1 mixture of tert-butyl «5S,6R)-2-(difluoromethoxy)-6-((S)-2- hydroxypropoxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)carbamate and tert-butyl ((5R,6S)-2-(difluoromethoxy)-6-((S)-2-hydroxypropoxy)- 6, 7 -dihydro-5 H- cycIopenta[b]pyridin-5-yl)carbamate (500 mg, 1.33 mmol) in toluene (10 mL) was added 2- (tributyl-X³-phosphaneyIidene)acetonitrile (CAS No. 157141-27-0) (644 mg, 2.67 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1 ) to afford tert-butyl (2R,4aS,9bR)-7- (difluoromethoxy)-2-melhyl-2,3,5,9b-tetrahydropyrido[3',2’:3,4]cyclopenta[l ,2- b][l,4]oxazine-l(4aH)-carboxylate ( 150 mg, 31%) as a light yellow oil as the first eluting peak and tert-butyl (2R,4aR,9bS)-7-(difluoromethoxy)-2-methyl-2,3,5,9b- tetrahydropyrido[3\2':3,4]cyclopenta[l,2-b][l ,4]oxazine-l(4aH)-carboxylate (170 mg, 35%) as a light brown oil as the second eluting peak. MS ESI calculated for C17H22F2N2O4 [M+HJA357.15; found, 357.10.

Step-7:

At 10 isomer 1

[1629] To a stirred solution of tert-butyl (2R,4aR,9bS)-7-(difluoromethoxy)-2-metliyl- 2.3,5,9b-teirahydropyrido[3’,2’:3,4jcyclopenta[l,2-b][l,4]oxazine-1(4aH)-carboxylate (170 mg, 0.47 mmol) in DCM (2 mL) was added Zinc bromide (2.14 mg, 0.95 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 4 h. The reaction was diluted with water at room temperature and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOzi- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 :1 ) to afford (2R,4aR,9bS)-7-(difluoromethoxy)- 2-methyl-l,2,3,4a,5,9b-bexahydropyrido[3',2^,:3,4]cyclopenta[l,2-bj[l,4]oxazine isomer 2 (A110 isomer 1) (100 nig, 81%) as a light brown oil. MS ESI calculated for C12H14F2N2O2 [M+H]⁴, 256.10; found, 257.15. ‘H NMR (400 MHz, DMSO-O 8 7.86 - 7.48 (m, 2H), 6.89 - 6.48 (m, 1 H), 4.29 - 4.22 (m, 1H), 4.05 ( t, J - 4.8 Hz, HI), 3.53 (dd, J = 10.8, 2.8 Hz, 1 H), , 2H), 0.84 (d,

[1630] To a stirred solution of tert-butyl (2R,4aS,9bR)-7-(difluoromethoxy)-2-methyl- 2,3,5,9b-tetrahydropyrido[3‘,2':3,4]cyclopenta[l,2-b][l,4]oxazine-l(4aH)-carboxylate (150 mg, 0.42 mmol) in DCM (2 mL) was added ZnBrj (189 mg, 0.84 mmol) at room temperature. The resulting mixture was stirred at 40 °C for 4 h. The reaction was diluted with water at room temperature and extracted with EtOAc. The combined organic layers w'ere washed with brine, dried over anhydrous NacSOa- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford (2R,4aS,9bR)-7-(difluoromethoxy )-2-methyl-l , 2, 3, 4a, 5,9b- hexahydropyrido[3‘,2':3,4]cyclopenta[l,2-b][l ,4]oxazine (AHO isomer 2) (80 rag, 74%) as a light brown oil. MS ESI calculated for C12H14F2N2O2 257.10; found, 257.15. ‘H

NMR (400 MHz, DMSO-</₆) 6 7.87 - 7.49 (m, 2H), 6.87 (d, J = 8.0, 4.0 Hz, IH), 4.24 - 4.20 (m, IH), 4.17 - 4.13 (m, IH), 3.43 (dd, 10.8, 2.8 Hz, IH), 3.05 (dd, - 16.8, 4.0 Hz, IH), 3.00 - 2.93 (m, 2H), 2.58 - 2.53 (m, IH), 0.85 (d, J = 6.4 Hz, 3H). Absolute stereochemistry was determined by NOESY.

Intermediate Alli: rel-(4R,4aS,9bR)-7-(trifluoromethyl)-l,2,3,4,4a,9b-hexahydrofuro[2,3- b : 4 , 5 -b' ]dipyridin-4-ol

[1631] To a stirred solution of rel-(4S,4aR,9bS)-4-methoxy-7-(trifluoromethyl)-

1 ,2, 3, 4,4a, 9b-hexahydrofuro[2,3-b:4,5-b']dipyridine - hydrochloride (200 mg, 0.64 mmol) in MeOH (2 mL) and DCM (0.2 mb) was added K2CO3 (267 mg, 1.93 mmol) at room temperature. The resulting mixture was stirred at 25 °C for 30 min. The suspension was filtered. The filtrate was collected and concentrated under vacuum.

[1632] The residue was dissolved in DCM (1 mL), Then BBn (1.5 mL, 1.50 mmol, IM in

DCM) was added at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 40 °C for 16 h. The reaction was quenched by the addition of ice water at 0 °C. The resulting mixture was concentrated under reduced pressure to afford (4S,4aR,9bS)-7-(trifluoromethyl)- 1 ,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b']dipyridin-4-o1 (Al 11) (120 mg, crude) as a yellow oil. MS ESI calculated for CoHnFidSEOz [M+H]⁺, 261.08; found, 261.15.

Final Compound Synthesis

Example 1: rel-((R)-6-amino-9-fluoro-l,3,4,Hb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-

10-yl)((4aS,i0bS)-8-(trifiuoromethyi)-2,3,4a,10b-telrahydrochromeno[3,4-b][l,4]oxazin- l(5H)-yl)methanone formate, isomer 4:

Isomer 4 ; and

Example 2: rel-((R)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-| l,4]oxazino[4,3-c]quinazolin-

10-yI)((4aS, 10bS)-8-(trifluoromethyl)-2,3,4a, 10b-tetrahydrochromeno[3,4-b] [1 ,4]oxazin- l(5H)-yl)methanone formate, isomer 2: isomer 2

Step 1: A 1:1: 1:1 mixture of rel- ((R)-6-amino-9- fluoro- 1, 3,4,1 Ib-tetrahydro-

[ 1 ,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS, 10bS)-8-(lrifluoromeiliyl)-2,3 ,4a, 10b- tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 1, and rel-((R)- 6-amino-9-fluoro-l,3,4,llb-tetrahydro-|l,4|oxazino[4,3-cjquinazolm-10-yl)((4aS,10bS)-8- (trifluoromethyl)-2,3,4a,10b-tetrahydrochi‘omeno[3,4-b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 2, and rel-((R)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3- c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4- b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 3, and rel-((R)-6-amino-9-fluoro- 1 ,3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)- 2,3,4a,10b-tetrahydrochromeno[3,4-bl[l,4]oxazin-l(5H)-yl)methanone formate, isomer 4: isomer 2 isomer 4

[1633] To a stirred solution of intermediate A4 (60 mg, 0.23 mmol) in DMAC (1 mL) was added TEA (72 mg, 0.71 mmol), intermediate CAI (61 mg, 0.23 mmol) at 0 °C. The resulting solution was stirred at 2.5 ^C’C for 16 h. The reaction solvent was purified by prep- HPLC with the following conditions: [Column: Xselect CSH C18 OBD Column 30* 150mm 5pm; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 10% B to 30% B in 15 min; Wave Length: 254/220 nm; RTl(min): 13.5] to afford a 1 : 1 : 1 : 1 mixture of reI-((R)-6-amino-9-fluoro-l,3,4,llb- tetahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS')-8-(trifluoromelliy])-2,3,4a,10b- tetrahydrochromeno[3,4-bHl,4|oxazin-l(5H)-yI)metbanone formate, isomer 1. and rel-((R)- 6-amino-9-fluoro- 1 ,3 ,4, 11 b-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8- (trinuoromethyl)-2,3,4a,l()b-tetrahydrochromeno[3,4-b][l,4]oxazin-1 (5H)-yl)methanone formate, isomer 2, and rel-((R)-6-amino-9-fluoro-l,3,4,llb-tetaihydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)-2.3,4a,10b-tetrahydrochromeno[3,4- b][l,4]oxazin-l(5H)-yDmethanone formate, isomer 3, and rel-((R)-6-amino-9-fluoro- l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)- 2,3,4a,10b-tetrahydrochromeno[3,4-bj[l,4]oxazin-l(5H)-yl)methanone formate, isomer 4 (8. 1 mg, 6%) as a white solid. MS ESI calculated for C24H22F4N4O4 [M+H]⁺, 507. 16; found, 507.15. TI NMR (400 MHz, Methanol-^) 8 8.56 (s, 1 H), 7.55 - 7.41 (m, IH), 7.39 - 7.31 (m, 1H), 7.29 - 7.22 (m, 1H), 7.14 - 7.04 (m, IH), 6.92 - 6.83 (m, IH), 6.00 (s, 1H), 5.02 - 4.92 (m, 2H), 4.49 - 4.34 (m, 2H), 4.32 - 4.23 (m, IH), 4.10 - 3.91 (m, 3H), 3.86 - 3.59 (m, 4H), 3.54 - 3.39 (m, IH), 3.19 - 3.01 (m, IH).

Step 2: rel-((R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)- yl)rnethanone formate, isomer 2:

Isomer 2 _; and rel-((R)-6-amino-9 -fluoro- l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4a,10b-teti‘aliydrochromeno[3,4-b][l,4]oxazin-l(5H)- yl)raethanone formate, isomer 4:

Isomer 4

[1634] The 1 : 1 : 1: 1 mixture ofrel-((R)-6-amino-9-tIuoro-l,3,4,llb-tetrahydro- [l,4]oxazino[4_>3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoroniethyl)-2,3,4a,10b- teirahydrochromeno[3,4-b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 1, and rel-((R)- 6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-cjquinazolin-10-yl)((4aS,10bS)-8- (trifluoromethyl)-2,3₅4a40b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 2, andre]-((R)-6-amino-9-fluoro-1 ,3,4, 1 1 b-ietrahydro-[ 1 ,4]oxazino[4,3- c]quinazolin-l0-yl)((4aS,l0bS)-8-(trifluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4- b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 3, and rel-((R)-6-amino-9-fluoro-

1 ,3,4, 1 lb-teirahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)- 2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 4 (40 mg) was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK SZ 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% IP AMIN), Mobile Phase B: EtOH:DCM=l:l-HPLC; Flow rate: 20 ml., /min; Gradient: 25% B to 25% B in 24 min; Wave Length: 220/2.54 nm: RT1 (min): 15.08; RT2 (min): 20.53: Sample Solvent:

EtOH:DCM~l :1-HPLC; Injection Volume: 0.8 mL; Number Of Runs: 4] to afford fraction A with retention time 15.08 rain and fraction B with retention time 20.53 min. [1635] The fraction A was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% IP AMIN), Mobile Phase B: EtOH:DCM==l:l-HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 18 min; Wave Length: 220/254 nm; RT1 (min): 11.27; RT2 (min): 14.64: Sample Solvent: EtOH:DCM~l:l , HPLC; Injection Volume: 0.7 mL; Number Of Runs: 4] to afford rel-((R)- 6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-l0-y1)((4aS,l0bS)-8- (trifluoromethyl)-2,3,4a,l()b-tetrahydrochromeno[3,4-b][L4]oxazin-l(5H)-yi)methanone formate, isomer 1 (6.7 mg, 17%) as a ■white solid with retention time 1 1.27 min and rel-((R)- 6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8- (trifluoromethyi)-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 2 (6.7 mg, 17%) as a white solid with retention time 14.64 min.

[1636] The fraction B was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.3% IP AMIN), Mobile Phase B: EtOH:DCM=l:l, HPLC: Flow rate: 20 mL/min; Gradient: 25% B to 25%: B in 18 min; Wave Length: 220/254 nm; RTl (min): 11.27; RT2(min): 14.64; Sample Solvent: EtOH:DCM=l : 1, HPLC; Injection Volume: 0.7 mL; Number Of Runs: 4] to afford rel-((R)- 6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8- (tritluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)-yl)methanone formate, isomer 3 (6.9 mg, 17%) as a white solid retention time 11.27 minute and reI-((R)-6- amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8- (tfifluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4-b][L4]oxazin-l(5H)-yDmethanone formate, isomer 4(5.6 mg, 16%) as a white solid -with retention time 14.64 minute.

[1637] rel-((R)-6-amino-9-fluoro-l,3,4,l1b-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-l0- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)- yljmethanone formate, isomer 1: MS (ESI) calculated for (C24H22F4N4O4) [M+H]⁺, 507.16 found, 507.05. ’H NMR (400 MHz, DMSO-nL) 5 8.31 (s, 1H), 7.36 - 7.05 (m, 4H), 6.51 - 6.41 (m, 1H), 5.94 - 4.98 (m, 1H), 4.72 - 4.53 (m, 1H), 4.50 - 4.25 (m, 2H), 4.23 - 3.95 (m, 2H), 3.92 - 3.70 (m, 3H), 3.68 - 3.50 (m, 3H), 3.33 - 3.03 (m, 2H), 2.94 - 2.80 (m, 1H). Absolute stereochemistry was not determined.

[1638] rel-((R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4-bj[l,4]oxazin-l(5H)- yljmethanone formate, isomer 2 (Example 2): MS (ESI) calculated for (C24H22F4N4O4) [M+H]⁺, 507.16 found, 507.10. 'H NMR (400 MHz, DMSO-Jo) 6 8.31 (s, ITT). 7.36 - 7.05 (m, 4H), 6.51 - 6.41 (m, 1H), 5.94 - 4.98 (m, 1H), 4.72 - 4.53 (m, 1H), 4.50 - 4.25 (m, 2H), 4.23 - 3.95 (m, 2H), 3.92 - 3.70 (m, 3H), 3.68 - 3.50 (m, 3H), 3.33 - 3.03 (m, 2H). 2.94 - 2.80 (m, HI). Absolute stereochemistry was not determined.

[1639] rel-((R)-6-amino-9-f]uoro- 1,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)- yl)methanone formate, isomer 3: MS (ESI) calculated for (C24H22F.4N4O4) [M+H]⁺, 507.16 found. 507.05. Hl NMR (400 MHz, DMSO-ffc) 6 8.31 (s, 1H), 7.36 - 7.05 (m, 4H), 6.51 - 6.41 (m, 1H), 5.94 - 4.98 (m, 1H), 4.72 - 4.53 (m, 1H), 4.50 - 4.25 (m, 2H), 4.23 - 3.95 (m, 2H), 3.92 - 3.70 (m, 3H), 3.68 - 3.50 (m, 3H), 3.33 - 3.03 (m, 2H), 2.94 - 2.80 (m, 1H). Absolute stereochemistry was not determined.

[1640] rel-((R)-6-amino-9-f]uoro-l,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((4aS,10bS)-8-(trifluorometbyl)-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)- yl)methanone formate, isomer 4 (Example 1): MS (ESI) calculated for (C24H22F4N4O4) [M+H]⁺, 507.16 found, 507.20. ^]H NMR (400 MHz, DMSO-a’s) 8 8.31 (s, 1H), 7.36 - 7.05 (m, 4H), 6.51 - 6.41 (m, 1H), 5.94 - 4.98 (m, 1H), 4.72 - 4.53 (m, 1H), 4.50 - 4.25 (m, 2H), 4.23 - 3.95 (m, 2H), 3.92 - 3.70 (m, 3H), 3.68 - 3.50 (m. 3H), 3.33 - 3.03 (m, 2H), 2.94 - 2.80 (m, HI). Absolute stereochemistry was not determined.

Example 3: rel-((R)-6-amirio-9-fluoro-l ,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3- b|pyridin-l(5H)-yl)methanone, isomer 3:

Example 4: rel-((R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-

10-yl)((3R,4aS,10bR)-3-methyl-8-(trilluoromethyl)-3,4,4a, 10b-tetrahydro-2H-chronieno[4,3- bjpyridin- 1 (5H)-yl)methanone, isomer 2:

Step 1 : A 1:1: 1 :1 Tnixture of rel-((R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)- 3,4,4a,10b-tetrahydro-2H-chromeno[4,3-b]pyridin-l(5H)-yl)methanone, isomer 1, and rel- ((R)-6-aniino-9-fluoro-l, 3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((3R,4aS,10bR)-3-melhyl-8-(lrilluoromelhyl)-3,4,4a,10b-te(rahydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 2, and rel-((R)-6-amino-9-fluoro-l,3,4,llb- tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((3R,4aS,10bR)-3-methy1-8- (trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3-b]pyridin-l(5H)-yl)methanone, isomer 3, and rel-((R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-3,4,4a,10b-tetraliydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 4

[1641] To a stirred solution of intermediate A9 (50 mg, 0.18 mmol) and intermediate CAI (49 mg, 0.18 mmol) in D M AC (1.5 mL) were added TEA (56 mg, 0.55 mmol) and PyBrOP (129 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by prep-HPLC with the following conditions: [Column: XBridge Prep OBD C IS Column, 30*150 mm, 5pm; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 60% B in 10 min; Wave Length: 254/220 nm; RTl(min): 7] to afford a 1:1 :1 :1 mixture of rel-((R)-6-araino-9-fluoro-l,3,4,l Ib-tetrahydro- [1 ,4]oxazino[4,3-c]quinazolin-10-yl)((3R,4aS,10bR)-3-methy1-8-(trifluoromethyl)- 3,4,4a,10b-tetrahydro-2H-chromeno[4,3-b]pyridin-l(5H)-yl)methanone, isomer 1, and rel- ((R)-6-amino-9-fluoro- 1 ,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((3R,4aS,10bR)-3-methy]-8-(trifluoromethyl)-3,4,4a,l0b-tetraliydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 2, and rel-((R)-6-amino-9-fluoro- l,3,4,l 1b- tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((3R,4aS,10bR)-3-methyl-8- (trifluoromethyl)-3,4,4a,10b-t;etrahydro-2H-chromeno[4,3-bjpyridin-l(5H)-yl)methanone, isomer 3, and rel-((R)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin- 10-yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-3,4,4a, 10b-tetrahydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 4 (25 nig, 25%) as a white solid. MS ESI calculated for (C26H26F4N4O3) [M+H]⁺, 519.19; found, 519.10. *H NMR (400 MHz, DMSO-tfc) 8 7.31 - 7.22 (m, 2H), 7.12 - 7.08 (m, 2H), 6.41 - 6.32 (m, 1H), 6.05 (s, 1H), 4.72 - 4.40 (m, 2H), 4.25 - 3.94 (m, 2H), 3.85 - 3.72 (m, 2H), 3.63 - 3.35 (m, 3H), 3.16 - 2.95 (m, 1H), 2.38 - 2.04 (m, 2H), 1.82 - 1.68 (m, 2H), 1.23 - 1.07 (m, 1H), 0.83 and 0.69 (d, J = 6.4 Hz, 3H).

Step 2: rel-((R)-6-amino-9-fluoro-l ,3,4, 1 lb-tetraliydro-[l,4]oxazino[4,3-c]quinazolin-10- yJ)((3R,4aS,10bR)-3-methyl-8-(trifluofomelhyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 2: rel-((R)-6-amino-9-fluoro- 1,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 3 [1642] The 1 : 1: 1 : 1 mixture of rel-((R)-6-ammo-9-fluoro-l ,3,4,llb-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)- 3,4,4a,10b-tetrahydro-2H-chromeno[4,3-b]pyridin-l(5H)-yl)methanone, isomer 1, and rel- ((R)-6-amino-9-fluoro- 1 ,3 ,4, 1 Ib-tetrahydro- [1 ,4]oxazino[4,3-c]quinazolin- 10- yl)((3R,4aS,10bR)-3-inethyl-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chronieno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 2, and rel-((R)-6-amino-9-fluoro-l,3,4,l lb- tetrahydro-Ll,4]oxazino[4,3-c]quinazolin-l()-yl)((3R,4aS,10bR)-3-methy]-8- (trifluoromethyl)-3,4,4a,l()b-tetrahydro-2H-chromeno[4,3-b]pyridin-l(5H)-yl)raethanone, isomer 3, and rel-((R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-3,4,4a,10b-tetahydro-2H-chromeno[4,3- b]pyridin-i(5H)-yl)methanone, isomer 4 (25 mg) was separated by Prep-Chiral-HPLC with the following conditions: [Column: CHIRALPAK IC, 2*25 cm, 5 urn; Mobile Phase A: Hex(0.3% IPAMIN), Mobile Phase B: EtOH:DCM=l:l, HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 21 min; Wave Length: 220/254 nm; RT l(min): 8.39; RT2 (min): 10.44; Sample Solvent: EtOH:DCM=l:l, HPLC; Injection Volume: 0.65 mL; Number Of Runs: 4] to afford rel-((R)-6-amino-9-fluoro- l,3,4,llb-tetrahydro- [l,4]oxazino[4,3 - c]quinazolin- 10-yl)((3R,4aS , 10bR)-3-methyl-8-(trifluoromethy1)-3 ,4,4a, 10b-tetrahydro-2H- chromeno[4,3-b]pyridin-l(5H)-yl)methanone, isomer 1 (3.2 mg, 13%) as a white solid with retention time at 8.39 minute and rel-((R)-6-amino-9-fluoro-l,3,4,l Ib-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)- 3,4,4a,10b-tetrahydro-2H-chromeno[4,3-b]pyridin-l(5H)-yl)methanone, isomer 2 (4.1 mg, 16%) as a white solid with retention time at 10.44 minute.

[1643] The above chiral resolution also afforded a mixture of two additional unresolved isomers (12.3 mg), which was separated by Prep-Chiral-HPLC with the following conditions: [Column: CHIRALPAK ID, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.3% IPAMIN), Mobile Phase B: MEOH:DCM=1: I, HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 24 min; Wave Length: 220/254 nm; RT1 (min): 13.36; RT2 (min): 17.74; Sample Solvent: EtOH:DCM~l :1, HPLC; Injection Volume: 0.6 mL; Number Of Runs: 2] to afford rel-((R)- 6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((3R,4aS,10bR)- 3-methyl-8-(tifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3-b]pyridin-l(5H)- yljmethanone, isomer 3 (3.3 mg, 13%) as a white solid with retention time at 13.36 minute and rel-((R)-6-amino-9-fluoro-1 ,3,4,1 lb-tetrahydro-[1 ,4]oxazino[4,3-c]quinazolin-l0- yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-cliromeno[4,3- b]pyridin-l(5H)-y1)metlianone, isomer 4 (4.2 mg, 17%) as a white solid with retention time at 17.74 minute. Absolute stereochemistry was not determined.

[1644] rel-((R)-6"amino-9-fluoro-i,3,4,llb-tetrahydro-[ l,4]oxazino[4,3-c]quinazoiin-10- yl)((3R,4aS,10bR)-3-meihyl-8-(trif1uoromethy1)-3,4,4a,10b-tetrahydTO-2H-chromeno[4,3- b]pyridin-l(5H)-yl)metbanone, isomer 1 : MS ESI calculated for (C26H26F4N4O3) [M+H]*, 519.19; found, 519.25. ^!H NMR (400 MHz, Methanol-^) 8 7.44 - 7.15 (m, 3H), 7.14 - 6.98 (m, 1H), 6.72 - 6.57 (rn, IH), 6.18 (s, 1H), 4.86 - 4.70 (m, 2H), 4.44 - 4.41 (m, IH), 4.32 - 4.10 (m, 2H), 4.01 - 3.82 (m, 2H). 3.72 - 3.63 (m, 2H), 3.34 - 3.33 (m. 2H), 2.50 - 2.20 (m, 2H), 1 .86 - 1.84 (m, 2H), 0.93 - 0.76 (m, 3H). Absolute stereochemistry was not determined.

[1645] rel-((R)-6-aniino-9-fluorO"l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazoliii- 10- yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)metbanone, isomer 2 (Example 4): MS ESI calculated for (C26H26F4N4O3) [M+HJ+, 519.19; found, 519.25. ^!H NMR (400 MHz, Methanol-^) 8 7.44 -

7.15 (m, 3H), 7.14 - 6.98 (m, IH), 6.72 - 6.57 (m, IH), 6.18 (s, IH), 4.86 - 4.70 (m, 2H), 4.44 - 4.41 (m, IH), 4.32 - 4.10 (m, 2H), 4.01 - 3.82 (m, 2H), 3.72 - 3.63 (m, 2H), 3.34 - 3.33 (m, 2H), 2.50 - 2.20 (m, 2H), 1.86 ■■■ 1.84 (m, 2H), 0.93 - 0.76 (m, 3H). Absolute stereochemistry was not determined.

[1646] rel-((R)-6-amino-9-f]uoro- 1,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R,4aS,10bR)-3-methy]-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 3 (Example 3): MS ESI calculated for (C26H26F4N4O3) [M+H]+, 519.19; found, 519.20. ^!H NMR (400 MHz, Methanol-^) 8 7.39 - 7.20 (m, 2H), 7.18 - 7.00 (m, 2H), 6.60 - 6.44 (m, IH), 6.18 (s, IH), 4.76 - 4.64 (m, 2H), 4.44 ... 4.41 (m, IH), 4.32 - 4.16 (m, 1H), 4.12 - 4.09 (m, IH), 3.94 - 3.82 (m, 2H), 3.75 - 3.55 (m, 2H), 3.41 - 3.14 (m, 2H), 2.35 - 2.26 (m, IH), 1.85 - 1.82 (m, 2H), 1.33 - 1.24 (m, IH), 0.92 - 0.76 (m, 3H). Absolute stereochemistry was not determined.

[1647] rel-((R)-6-amino-9-lluoro-l,3,4,rib-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R,4aS,10bR)-3-methyl-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3- b]pyridin-l(5H)-yl)methanone, isomer 4: MS ESI calculated for (C26H26F4N4O3) [M+H]+, 519.19; found, 519.25. NMR (400 MHz, Methanol-^) 8 7.39 - 7.20 (m, 2H), 7.18 - 7.00 (m, 2H), 6.60 ~ 6.44 (m, 1 H), 6.18 (s, IH), 4.76 - 4.64 (rn, 2H), 4.44 - 4.41 (m, IH), 4.32 -

4.16 (m, IH), 4.12 - 4.09 (m, IH), 3.94 - 3.82 (m, '.'H i. 3.75 - 3.55 (m, 2H), 3.41 - 3.14 (m, :H), 2.35 - 2.26 (m, 1H), 1.85 - 1.82 (m, 2H), 1.33 - 1.24 (m, 1H), 0.92 - 0.76 (m, 3H).

Absolute stereochemistry was not determined.

Example 5: rel-((R)-6-ammo-8-fluofo-l, 3,4,1 lb-tetrahydro-[ l,4]oxazino[4,3-c]quinazolin- 10-yl ')((4aS , 10bS)-8-(trifluoromethyl)-2,3,4,4a,6, 1 Ob-hexahydro- 1 H-isochromenol4,3- b]pyridin-l-yl)metbanone, isomer 4: isomer 4 . _aj, j

Example 6: rel-((R)-6-amino-8-fluoro- 1,3,4, Hb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS, 10bS)-8-(trifluoromethyl)-2,3,4,4a,6, 1 Ob-hexahydro- lH-isochromeno[4,3- bjpyridin-l-yl)methanone, isomer 1: isomer 1

Step 1: A 1:1:1:1 inixture of rel-((R)-6-amino-8-iluoro-l,3,4,llb-tetrahydro-

[1.4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethy1)-2,3,4,4a,6,10b- hexahydro-lH-isoclrromeno[4,3-b]pyridin-l-yl)methanone, isomer 1, and rel-((R)-6-amino- 8-fluoro-l,3,4,llb-tetiahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8- (trinuoromethyl)-2,3,4,4a,6, lOb-hexahydro- 1 H-isochromeno[4,3-b]pyridin- 1 -yl)methanone, isomer 2, and rel-((R)-6-amino-8-fluoro-l,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS, 10bS)-8 -(trifluoromethyl)-2, 3, 4, 4a, 6, lOb-hexahydro- lH-isochromeno[4, 3- b]pyridin-l-yl)methanone, isomer 3, and rel-((R)-6-amino-8-fluoro-l,3,4,l Ib-tetrahydro-

[1.4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethy1)-2, 3, 4,4a, 6,10b- hexahydro- lH-isochromeno[4,3-bjpyridin-l-yl)methanone, isomer 4

[1648] To a stirred solution of intermediate A2 (150 nig, 0.583 mmol), intermediate AC2 (185.6 mg, 0.70 mmol) and TEA (177.01 mg, 1.749 mmol) in DMAc (3 mL) was added PyBrOP (326.19 mg, 0.700 mmol) in portions at. room temperature. The resulting mixture was stirred at room temperature for 2 h. Hie resulting mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?.SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with die following conditions: (Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5 uni; Mobile Phase A: Water (lOmmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 55% B in 10 min; Wave Length: 254/220 nm; RT1 (min): 8.9) to a 1:1:1 :1 mixture of rel- ((R)-6--amino-8-fluoro- 1 ,3 ,4, 11 b- tetrahydro - [ 1 ,4]oxazino[4,3 -cjquinazolm- 10- yl)((4aS,l()bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridiri- 1 -yl (methanone, isomer 1 , and rel-((R)-6-amino-8-fluoro- 1,3,4, 1 Ib-tetrahydro- [l,4]oxaziiio[4,3-cjquinazolin-10-yl)((4aS,10bS)--8-(trifluoromethyl)-2,3,4,4a,6,10b- hexahydro-lH~isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 2, and rel-((R)-6-amino- 8-fluoro-l ,3,4, 1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazohn- 10-yl)((4aS, 10bS)-8- (lrifluoromethyl)-2,3,4,4a,6,l0b-hexahydro-lH-isochromenoj4,3-b|pyridin-1 -yl)methanone, isomer 3, and rel-((R)-6-amino-8-fluoro-l ,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS, 10bS)-8-(tritluoromeihyl)-2,3,4,4a,6, 1 Ob-hexahydro- lH-isochroraeno[4,3- b]pyridin-l-yl)meihanone, isomer 4 (54.8 mg, 18.35%) as a white solid. MS ESI calculated for C25H24F4N4O3 [M+Hp, 505.18: found, 505.15. ^!H NMR (400 MHz, DMSO-ffc) 8 (ppm) 7.65 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.48 (d, .7 - 8.4 Hz, 1 H), 7.10 (d, .7 - 11.2 Hz, 1H), 6.96 (s, HI), 6.48 (s, 2H), 5.67 (br, 1H), 4.90 - 4.76 (m, 2H), 4.65 - 4.63 (m, 1H), 4.23 - 4.14 (m, 1H), 4.01 - 3.99 (m, 1H), 3.86 - 3.74 (m, 2H), 3.57 - 3.42 (m, 2H), 3.31 - 3.30 (m, 1H), 3.14 - 3.02 (m, 1H), 2.47 - 2.46 (m, 1H), 1.85 - 1.75 (m, 1H), 1.71 - 1.53 (in, 3H).

Step 2: rel-((R)-6-amino-8-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazmo[4,3-c]quinazolin-10- yJ)((4aS, 10bS)-8-(lrifluoromethyJ)-2, 3, 4, 4a, 6, 1 Ob-hexahydro- lH-isochromeno[4,3-b]pyridin- l-yl)niethanone, isomer 1: rel-((R)-6-amino-8 -fluoro- l,3,4,Hb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,l0bS)-8-(trifluoromethyl)-2,3,4,4a.6,10b-hexahydro-lH-isochromeno[4,3-b]pyridiii- l-yl)methanone, isomer 4 isomer 4

[1649] The 1:1 :1: 1 mixture ofrel-((R)-6-amino-8-fiuoro-l,3,4,llb-tetrahydro-

[1.4]oxazino[4_>3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoroniethyl)-2,3,4,4a,6,10b- hexahydro-lH-isochromejno[4,3-b]pyridin-l-yl)methanone, isomer 1, and rel-((R)-6-amino- 8-fluoro-l ,3,4, Hb-tetrabydro-[l,4]oxazino[4,3-c]quinazoliji-10-yl)((4aS,10bS)-8- (trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-bJpyridin-l-yl)methanone, isomer 2, and rel-((R)-6-amino-8-fluoro-l ,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- b]pyridin-l-yl)methanone, isomer 3, and rel-((R)-6-aniino-8-fluoro-l,3,4,llb-tetrahydro-

[1.4]oxazino[4,3-c]quinazolm-10-yl)((4aS,10bS)-8-(trifluorometliyl)-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 4 (54.8 mg) was separated by Prep-Chiral HPLC with the following conditions (Column: CH1RALPAK 1C, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.2% IPAMine), HPLC, Mobile Phase B: MeOH:DCM=l:l, HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 19.5 min; Wave Length: 220/254 nm; RTl(min): 11.24; RT2(min): 13.36; Sample Solvent: MeOH:DCM=l:l, HPLC; Injection Volume: 0.65 mL; Number Of Runs: 4) to afford rel-((R)-6-amino-8-fluoro-

1 ,3,4, 1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)- 2,3,4,4a,6,10b-hexahydro-lH-isodiromeno[4,3-b]pyridin-l-yl)methanone, isomer 1 (7.7 mg, 14%) as a while solid with retention time at 1 1 .24 minute and rel-((R)-6-amino-8-lluoro- 1 ,3,4, 1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quin azolin- 10-yl)((4aS,10bS)-8-(trifluoromethyI)- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 2 (8.2 mg, 15%) as a white solid with retention time at 13.36 minute.

[1650] Ute above chiral separation also affords a mixture of two additional isomers, which was further purified by Prep-Chiral HPLC with the following conditions (Column: CHIRAL ART Cellulose-SZ 2*25 cm. 5 urn; Mobile Phase A: Hex (0.2% IPAMine)-HPLC, Mobile Phase B: EtOH:DCM=l: l, HPLC: Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 13 min; Wave Length: 220/254 nm; RTl(min): 7.97; RT2(nrin): 11.73; Sample Solvent: EtOH:DCM=l:l, HPLC; Injection Volume: 1.0 mL; Number Of Runs: 2) to afford rel-((R)- 6-amino-8-fluoro- 1 ,3,4, Hb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS, 10bS)-8- (tritluoromethyl)-2,3,4,4a,6,l0b-hexahydro-lH-isochromeno[4,3-b]pyridin-1 -yl)methanone, isomer 3 (7.5 mg, 14%) as a white solid with retention time at 7.97 minute and rel-((R)-6- arnino-8-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8- (trifluoromethyl)-2,3,4,4a,6, lOb-hexahydro- 1 H-isochromeno[4,3-b]pyridin- 1 -yl)methanone, isomer 4 (5. 1 mg, 9%) as a white solid with retention time at 11.73 minute.

[1651] rel-((R)-6-amino-8-fluoro-l,3,4,llb-tetrahydro-| l,4]oxazmo[4,3-c]quinazoliii-10- yl)((4aS,10bS)-8-(trifluoromethyl)-2, 3, 4, 4a, 6, lOb-hexahydro- lH-isochronieno[4,3-b]pyridin- l-yl)methanone, isomer 1 (Example 6): MS (ESI) calculated for (C25H24F4N4O3) [M+H]⁺, 505.18; found, 505.20. ^!H NMR (400 MHz, DMSO-ffe) 5 (ppm) 7.65 (d, J = 8.0 Hz, 1H), 7.55 (s, HI), 7.48 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 11.2, 2.0 Hz, IK). 6.96 (s, 1H), 6.48 (s, 2H), 5.68 (hr, 1H), 4.91 - 4.76 (m, 2H), 4.64 (dd, J = 10.4, 4.0 Hz, 1H), 4.21 - 4.16 (m, 1 H), 4.01 - 3.98 (m, 1H), 3.84 - 3.76 (m, 2H), 3.60 - 3.39 (m, 3H), 3.15 - 3.04 (m, 1H), 2.46 - 2.45 (m, 1H), 1.81 - 1.78 (m, 1H), 1.70 - 1.55 (m, 3H). Absolute stereochemistry was not determined.

[1652] rel-((R)-6-amino-8-fluoro- 1,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6, lOb-hexahydro- 1 H-isochromeno[4,3-b]pyridin- 1 -yljmethanone, isomer 2: MS (ESI) calculated for (C25H24F4N4O3) [M+H]⁺, 505.18; found, 505.20. ^:H NMR (400 MHz, DMSO-<%) 5 (ppm) 7.65 (d, J= 8.4 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 11.2, 2.0 Hz, 1H), 6.95 (s, 1H), 6.49 (s, 2H), 5.75 (hr, 1H), 4.89 - 4.76 (m, 2H), 4.63 - 4.61 (m, 1H), 4.21 - 4.15 (m, 1H), 4.03 - 3.99 (m, 1H), 3.84 - 3.77 (m, 2H), 3.56 - 3.45 (m, 3H), 3. 16 - 3.05 (m, 1H), 2.56 - 2.55 (m, 1H), 1 .82 - 1.78 (m, 1H), 1.70 - 1.55 (m, 3H). Absolute stereochemistry was not determined.

[1653] rel-((R)-6"amino-8-fluoro-l,3,4,llb-tetrahydro-[ l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6. IOb-hexahydro-lH-isochn)meno[4.3-b]pyridin- l-yl)methanone, isomer 3: MS (ESI) calculated for (C25H24F4N4O3) [M+H]⁺, 505.18; found, 505.20. ^!H NMR (400 MHz, DMSO-d₆) 5 (ppm) 7.65 (d, J= 8.0 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.10 (dd, 11.2. 2.0 Hz, 1H), 6.96 (s, 1H), 6.48 (s, 2H), 5.68 (br, 1H), 4.91 - 4.76 (m, 2H), 4.64 (dd, J = 10.4, 4.0 Hz, 1 H), 4.21 - 4.16 (m, 1H), 4.01 - 3.98 (m, 1H), 3.84 - 3.76 (m, 2H), 3.60 - 3.39 (m, 3H), 3.15 - 3.04 (m, 1H), 2.46 - 2.45 Im, 1H), 1.81 - 1.78 (m, 1H), 1.70 - 1.55 (m, 3H). Absolute stereochemistry was not determined.

[1654] rel-((R)-6-amino-8-fluorO"l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin- l-yl)methanone, isomer 4 (Example 5): MS (ESI) calculated for (C25H24F4N4O3) [M+H]⁺, 505.18; found, 505.20. ^!H NMR (400 MHz, DMSO-4₆) 8 (ppm) 7.65 (d, 8.4 Hz, 1H),

7.55 (s, 1H), 7.48 (d, 8.0 Hz, 1H), 7.10 (dd, 7 = 11.2, 2.0 Hz, 1H), 6.95 (s, 1H), 6.49 (s,

2H), 5.75 (br, 1H), 4.89 - 4.76 (m, 2H), 4.63 - 4.61 (m, 1H), 4.21 - 4.15 (m, 1H), 4.03 - 3.99 (m, 1H), 3.84 - 3.77 (m, 2H), 3.56 - 3.45 (m, 3H), 3.16 - 3.05 (m, 1H), 2.56 - 2.55 (m, 1H), 1.82 - 1.78 (m, 1 H), 1.70 - 1.55 (ni, 3H). Absolute stereochemistry was not determined.

Example 7: rel-(R)-6-amino-9-fluoro-1 ,3,4,1 1b-tetrahydro-[1 ,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin- 1 -yl)methanone, isomer 1

Isomer 1

Step 1: A 1: 1 : 1 : 1 mixture of rel~(R)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridin- 1 -yl)methanone, isomer 1 , and rel-(R)-6-amino-9-fluoro- l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8-(trilluoromethyl)- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 2, and rel- (R)-6-amino-9-fluoro-l,,3,4, l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS,10bS)-

8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l- yDmethanone, isomer 3, and rel-(R)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazoIin-10-yl)((4aS,10bS)-8-(trifluoromethyI)-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 4

[1655] To a stirred solution of intermediate CAI (300 mg, 1.13 mmol), intermediate A2 (290 mg, 1.13 mmol) and TEA (321 mg, 3.17 mmol) in DM AC (3 mL) was added PyBrOP (739 mg, 1.59 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was quenched by water and extracted with EtOAc. The combined organic layers were dried over anhydrous NajSCfo After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography with the following conditions: (column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5%' to 45% gradient in 40 min; detector, UV 254 nm) to afford a 1 :1: 1:1 mixture of rel-(R)-6-amino-9-fluoro-l,3,4, 1 lb-tetrahydro-[l ,41oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(trifluoromethy1)-2,3,4,4a,6,10b-hexahydro- 1H-isochromeno[4,3-b]pyridin- l-yl)raethanone, isomer 1, and rel-(R)-6-amino-9-fluoro-l,3,4,l Ib-tetrahydro- [l,4]oxazino[4,3-clquinazolin-10-yl)((4aS,10bS)-8-(trifluoromeihyl)-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 2, and rel-(R)-6-amino-9- fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,l()bS)-8- (trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 3, and rel-(R)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- b]pyridin-1 -yilmethanone, isomer 4 (25 mg, 4%) as a white solid. MS ESI calculated for C25H24F4N4O3 [M+H]⁺, 505.18; found, 505.10. ^!H NMR (400 MHz, DMSO-d₆) 8 8.28 (s, 1H), 7.66 (d, 7= 7.6 Hz, 1H), 7.57 (br, 1H), 7.41 (br, 1H), 7.22 (br, 1H), 6.50 (br, 1H), 5.90 and 4.33 (br, 1H), 4.92 - 4.59 (m, 3H), 4.17 - 4.03 (m, 2H), 3.90 - 3.76 (m, 2H), 3.61 - 3.45 (m, 2H), 3.34 ~ 3.07 (m, 2H), 2.70 - 2.58 (m, 1H), 1.84 - 1.75 (m, 1 H), 1 .72 - 1.44 (m, 3H). Step 2: rel-(R)-6-amino-9-fluoro- 1,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS, 10bS)-8-(trifluoromethyl)-2, 3, 4, 4a, 6, lOb-hexahydro- lH-isochromeno[4,3-b]pyridin- l-yl)methanone, isomer 1

Isomer 1

[1656] The 1:1:1: 1 mixture of rel-(R)-6-amino-9“fluoro-l,3,4,l lb-tetraliydro-

[1.4]oxazino[4,3-cjquinazolin-10-yl)((4aS, 10bS)-8-(trifluoromethyl)-2, 3, 4,4a, 6,10b- hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 1 , and rel-(Rj-6-amino-9- fluoro-1 ,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazo1in-10-yl)((4aS,10bS)-8- (trifluoromethyl)-2,3,4,4a,6,l0b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 2, and rel-(R)-6-amino-9-fluoro-l,3,4,l lb-tetraliydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((4aS ,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- b]pyridin-l-yl)methanone, isomer 3, and rel-(R)-6-amino-9-fluoro- 1,3,4, llb-tetrahydro-

[1 .4]oxazino[4,3-c]quinazolin-l0-yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,l0b- hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 4 (25 mg, 0.05 mmol) was separated by Prep-Chiral-HPLC with the following conditions [Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase. A: Hex (0.3% IPAMIN), Mobile Phase B:

EtOH:DCM=l:l, HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 22 min; Wave Length: 220/254 nm: RT1 (min): 9.17; RT2 (min): 13.47; RT3 (min): 13.47; Sample Solvent: EtOH:DCM=l, HPLC; Injection Volume: 0.25 mL; Number Of Runs: 5] to afford rel-(R)-6- ammo-9-fluoro- 1 ,3,4, 1 1 b-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin- 10-yl )((4aS , 10bS)- 8- (trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-bJpyridin- l-yl)methanone, isomer 1 (2.6 mg, 10%) as a white solid with the first peak on Chiral HPLC, a mixture of rel- (R)-6-amino-9-tluoro-l ,3,4, 1 lb-teirahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)- 8-(trifluoromethyl)-2,3,4,4a,6, 10b-bexahyd.ro- lH-isochromeno[4,3-b]pyridin-1 - yl)methanone, isomer 2 and rel-(R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridin-l-yl)melhanone, isomer 3 (6 rag, 24%) with the second peak on Chiral HPLC, and rel-(R)-6-amino-9- fluoro- 1,3, 4,1 lb-tetrahydro-[l,4]oxazino[4, 3- c]quinazolin- 10-yl)((4aS, 10bS)-8-(trifluoromethyl)-2,3,4,4a,6, lOb-hexahydro- 1H- isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 4 (3 mg, 13%) with the third peak on Chiral HPLC as a white solid.

[1657] rel-(R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(triiluoromethyl)-2,3,4,4a,6, 10b-hexahydro-l H-isochromeno[4,3-b]pyridin- l-yl)methanone, isomer 1 (Example 7): MS ESI calculated for C25H24F4N4O3 [M+H]⁺, 505.18; found, 505.15. ^!H NMR (400 MHz, Methanol-^) 8 7.62 (d, J= 8.2 Hz, IH), 7.49 - 7.47 (m, 2H), 7.29 - 7.27 (m, IH), 6.68 (d, J = 10.9 Hz, 1H), 6.08 and 4.50 (br, 1H), 5.02 - 4.81 (m, 2H), 4.25 - 4.16 (m. 2H). 3.99 - 3.86 (m, 2H), 3.76 - 3.61 (m, 3H), 3.46 - 3.35 (m, 2H), 2.91 - 2.41 (m, IH), 1.97 - 1.88 (m, 1H), 1.87 - 1.76 (m, IH), 1.68 - 1.63 (m, 2H).

Absolute stereochemistry was not determined.

[1658] Mixture of rel-(R)-6-amino-9 -fluoro- 1 ,3 ,4, 1 Ib-tetrahydro- [ 1 ,4]oxazino[4,3- c]quinazolin- 10-yl)((4aS, 10bS)-8-(tritluoromethyl)-2_!3,4,4a,6, 1 Ob-hexahydro- 1H- isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 2, and rel-(R)-6-amino-9-fluoro-

1, 3, 4,1 Ib-tetrahydro- [l,4]oxazmo[4,3-c]quinazolin-10-yl)((4aS,10bS)-8-(trifluoromethyl)- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone, isomer 3: MS ESI calculated for C25H24F4N4O3 [M+H]’, 505.18; found, 505.15. ^JH NMR (400 MHz, Methanol- cW) 6 7.62 M 7 - 8.2 Hz, IH), 7.54 - 7.42 (m, 2H), 7.26 (br, IH), 6.67 (d. J = 11.0 Hz, IH), 6.09 and 4.50 (br, IH), 5.03 - 4.94 (tn, 2H), 4.59 (br, IH), 4.25 - 4.16 (tn, 2H), 3.99 - 3.86 (m, 2H), 3.76 - 3.61 (m, 2H), 3.46 - 3.35 (m, 2H), 2.91 - 2.41 (m, IH), 1.97 - 1.88 (m, IH), 1.87 - 1.76 (m, IH), 1.67 - 1.65 (m, 2H). /Absolute stereochemistry was not determined.

[1659] rel-(R)-6-ammo-9- fluoro- 1,3, 4,1 Ib-tetrahydro- ■[l,4]oxazino[4,3-c]quinazolin- 10- yl)((4aS,10bS)-8-(trifluoromethyl)-2,3,4,4a,6,l0b-hexahydro-lH-isochromeno[4,3-b]pyridin- 1 -yl)methanone, isomer 4: MS ESI calculated for C25H24F4N4O3 [M+H] *, 505. 18; found, 505.15. ^;H NMR (400 MHz, Methanol- Ja) 87.62 (d, J = 8.2 Hz, IH), 7.49 - 7.47 (m, 2H), 7.33 - 7.31 (m, IH), 6.73 (d, J = 10.6 Hz, IH), 6.08 and 4.50 (br, IH), 5.02 - 4.81 (m, 2H), 4.25 - 4.16 (m, 2H), 4.01 - 3.88 (m, 2H), 3.76 - 3.61 (m, 3H), 3.46 - 3.35 (m, 2H), 2.91 - 2.41 (m, IH), 1 .97 -- 1 .88 (m, 1 H), 1 .87 - 1 .76 (m, IH), 1 .68 - 1 .64 (m, 2H). Absolute stereochemistry was not determined.

Example 8: ((R*)-6-amino-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- y])((2R,5S)-5-rnethyl-2-(2-(l-rnetbylpiperidin-4-yl)benzo[d]thiazo]-5-yl)piperidin-l- yj)methanone, isomer 2:

Example 9: ((R*)-6-amino-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-l- yljraethanone, isomer 1:

Step 1: 1: 1 mixture of ((R*)-6-amino-l,3,4,l lb-tetrahydro-[l,4|oxazino|4,3-cjquinazolin-10- yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-l- yl)methanone, isomer 1, and ((R*)-6-arnino-l,3,4,l lb-tetrahydro-[l ,4]oxazino[4,3- c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methyIpiperidin-4-yl)benzo[d]thiazol-5- yl)piperidin-l- yljmethanone, isomer 2

Isomer 1 ^{isomer 2}

[1660] To a stirred solution of intermediate CA3 (100 mg, 0.40 mmol) and intermediate A3 (133.27 mg, 0.40 mmol) in DMF (2 mL) were added NMI (99.62 mg, 1.21 mmol) and TCFH (136.17 mg, 0.48 mmol) at 0 °C. The resulting mixture was stirred for at room temperature 16 h. The reaction mixture (2 mL) was purified by prep-HPLC with the following conditions: [Column: Xcelect CSH F-pheny OBD Column 19*250 mm, 5 urn; Mobile Phase A; Water (0.1%FA), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 5% B to 20% B in 10 min; Wave Length: 254/220 nm] to afford 1: 1 mixture of ((R*)-6-amino-l,3,4,Hb- tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin- 4-yl)benzo[d]tliiazol-5-yl)piperidin-l-yl)methanone, isomer 1 , and ((R*)-6-amino-l,3,4,l lb- tetahydro-[l,4]oxazino[4,3-c]quinazoIin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin- 4-yI)benzo[d]thiazoI-5-yr)piperidin-l-yl)methanone, isomer 2 formate (20 mg, 7.45% ) as a white solid. MS (ESI) calculated for (CMTsNeCFS) [M+H]⁺, 559.28; found, 559.30

Step 2: ((R*)-6-amino-l_!3,4,llb-tetrahydro-[l,4]oxazino[4_!3-c]quinazolin-10-yl)((2R,5S)-5- met.hyl-2-(2-(l-met.hylpiperidin-4-yl)benz.o[d]thiazol-5-yl)piperidin-l-yl)met.hanone, isomer 1 , and

((R*)-6-amino-l, 3,4,1 lb-tetrahydro-[l,4]oxazino[4_!3-c]quinazolin-10-yr)((2R,5S)-5-methyl- 2-(2-(1-methylpiperidin-4-yl)benzo[d]tbiazol-5-yl)piperidin-l-yl)methanone, isomer 2

[1661] The 1:1 mixture ((R*)-6-amino-l,3,4,llb-tetrahydro-[T,4joxazino[4,3-c]quinazolin- 10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]tiuazol-5-yl)piperidin-l- yl)methanone formate (20 mg) was purified by Prep-Chiral HPLC with the following conditions (Column: CHIRALPAK 1C, 2*2.5 cm, 5 pm; Mobile Phase A: Hex(0.2% Isopropyl amine)— HPLC, Mobile Phase B: IPA: DCM-1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 80% B to 80% B in 20 min; Wave Length: 220/254 ran; RTl(min): 16.16; RT2(min): 17.56; Sample Solvent: IPA: DCM-1: 1— HPLC; Injection Volume: 0.5 ml..; Number Of Runs: 5) to afford ((R*)-6-amino-l,3 ,4,1 lb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)(('2R,5S)"5-niethyl-2-(2-(l-methylpiperidin-4-yl)benzo|d]thiazol-5- yl)piperidin-l-yl)methanone, isomer 1 (1.2 mg, 6%) as a white solid with the first peak on chiral - HPLC with retention time at 16.16 minute and ((R*)-6-amino-l,3,4,llb-tetrabydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4- yl)benzo[djthiazol-5-yI)piperidin-l-yl)methanone, isomer 2 (2.4 mg, 12%) as a white solid with the second peak on chiral - HPLC with retention time at 17.56 minute.

[1662] ((R*)-6-amino-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)- 5 ■■methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-l--yl)methanone, isomer 1 (Example 9):MS ESI calculated for (C31H38N6O2S) [M+H]⁺, 559.28; found, 559.30. ^SH NMR (400 MHz, Met.hanol-d₄) 68.02 (d, J = 8.4 Hz, 1H), 7.9 i (s, 1H). 7.44 (d, ./ = 8.3 Hz, 2H), 7.28 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 5.68 - 5.66 (m, 1H), 4.97 - 4.92 (m, 2H), 4.18 - 3.90 (m, 3H), 3.75 - 3.62 (m, 2H), 3.57 - 3.37 (m, 3H), 3.31 - 3.14 (m, 3H), 2.62 - 5.28 (m, 1H), 2.55 (s, 3H), 2.32 - 2.30 (m, 3H), 2.17 - 2.01 (m, 2H), 1.99 - 1.78 (m, 2H), 1.54 - 1.39 (m, 1H), 1.31 ~ 1.28 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H).

[1663] ((R*)-6-amino- 1,3,4, llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolm-10-yl)((2R,5S)-

5-methyl-2-(2-( 1 -methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin- 1 -yl)methanone, isomer 2 (Example 8): MS ESI calculated for (CsiEbsNeChS) [M+H]⁺, 559.28; found, 559.30. ’H NMR (400 MHz, Methanol-d^) 6 8.00 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.41 - 7.39 (m, 2H), 7.24 (s, 1H), 6.93 (d, 8.2 Hz, 1H), 5.67 - 5.64 (m, 1H), 4.81 - 4.78 (m, 1H),

4.18 - 4.11 (m, 1H), 3.99 - 3.82 (m, 3H), 3.68 - 3.63 (m, 2H), 3.23 - 3.14 (m, 2H), 3.04 - 3.01 (m, 2H), 2.42 - 2.13 (m, 9H), 2.07 - 1.83 (m, 5H), 1.46 - 1.42 (m, 1H), 1.08 6.7

Hz, 3H).

Example 10: ((R*)-6-amino-8-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methyl-2-(2-(l-metfiy1piperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-l- yl)methanone, isomer 1

Isomer 1

Step 1 : 1 : 1 mixture of ((R*)-6-amino-8-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yJ)((2R,5S)-5-methyl-2-(2-(l -methylpiperidin-4-yl)benzo[d]thiazol-5- yl)piperidin-l-yl)methanone, isomer 1, and ((R*) -6-amino-8-fluoro-l,3,4,llb-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4- yl)benzo[d]thiazol-5-yi)piperidin-l-yl)methanone, isomer 2

Isomer 1 Isomer 2

[1664] To a stirred solution of intermediate A3 (70 mg, 0.21 mmol) and intermediate CA2 (84 mg, 0.32 mmol) in DMF (1.5 mL) was added NMI (52 mg, 0.63 mmol) and TCFH (71 mg, 0.25 mmol). The resulting mixture was stirred at room temperature for 3 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na^SCU. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 niL/niin; Gradient: 34% B to 44% B in 10 min; Wave Length: 254/220 nm; RTl (min): 5.58) to afford a 1 :1 mixture of ((R*)-6-amino-8-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((2R,5S)-5-metliyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-l - yl)methanone, isomer 1, and ((R*)-6-amino-8-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5- yl)piperidin-l-yl)methanone, isomer 2 (27.3 mg, 27%) as a white solid. MS ESI calculated forC3iH37FN₆O₂S [M+H]⁺, 577.27; found, 577.20. *H NMR (400 MHz, DMSO-tfc) 5 8.05 (dd, J = 8.4, 1.6 Hz, 1H), 7.85 (s, 1H), 7.36 (d, 8.4 Hz, 1H), 7.02 ■■■ 6.95 (m, 1H), 6.87 -

6.83 (m, 1H), 6.43 (s, 2H), 5.49 (s, 1H), 4.65 - 4.56 (m, 1H), 3.99 - 3.67 (m, 4H), 3.55 - 3.45 (m, 2H), 3.39 - 3.34 (m, 1H), 3.16 - 3.02 (m, 3H), 2.88 - 2.83 (m, 2H), 2.26 - 2.15 (m, 4H), 2.10 - 2.01 (m, 4H), 1.87 - 1.76 (m, 3H), 1.72 - 1.64 (m, 1H), 1.35 - 1.32 (m, 1H), 0.97 (d, J =■- 7.2 Hz, 3H).

Step 2: ((R*)-6-amino-8-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- y1)((2R,5S)-5-metbyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazoJ-5-yl)piperidin-l- yllmethanone, isomer 1

Isomer 1

[1665] Tiie 1 : 1 mixture of ((R*)-6-amino-8-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5- ylipiperidin- l-yl)methanone, isomer 1 , and ((R*)-6-aniino-8-fluoro- 1 ,3,4, 1 lb-tetrahydro- [ 1 ,4]oxazino[4,3-c]quinazolin- 10-yl)((2R,5S)-5-methyl-2-(2-(l -methylpiperidin-4- yI)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 2 (27.3 mg) was separated by Prep- Chiral HPLC with the following conditions: (Column: CHIRAL ART Cellulose- SZ 2*25 cm, 5 pm; Mobile Phase A: Hex (0.2% IPAMine)— HPLC, Mobile Phase B: EtOH:DCM=l : 1, HPLC; Flow rate: 20 ml, /min; Gradient: 50% B to 50% B in 12 min; Wave Length: 220/254 nm; RT1 (min): 8.56; RT2 (min): 10.94: Sample Solvent: EtOH:DCM=l:l, HPLC: Injection Volume: 0.75 mL; Number Of Runs: 3) to afford ((R*)-6-amino-8-fluoro-l,3,4,Hb- tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin- 4-yl)benzo[djthiazol-5-yl)piperidin-l-yl)methanone, isomer 1 (9.3 nig, 35%) as a white solid with retention time at 8.56 minute and ((R*)-6-amino-8-fluoro-L3,4,llb-tetrahydro- [1 ,4]oxazino[4,3-c]quinazolin-l0-yl)((2R,5S)-5-methyl-2-(2-(1 -methylpiperidin-4- yl)benzo[d]thiazo1-5-yl)piperidin-l -yl)methanone, isomer 2 (9.3 mg, 35%) as a white solid with retention time at 10.94 minute.

[1666] ((R* )-6-amino-8-fluoro- 1 ,3,4, 1 lb-tetrahydro-[ l,4]oxazino[4,3-c]qumazolin- 10- yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5-y1)piperidin-l- yljmethanone, isomer 1 (Example 10): MS (ESI) calculated for (C31H37FN6O2S) [M+H]⁺, 577.27; found, 577.20. ^!H NMR (400 MHz, DMSO-d₆) 5 8.06 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.36 (dd, / = 8.4, 2.0 Hz, 1H), 6.98 (dd, 11.2, 1.6 Hz, 1H), 6.84 (s, 1H), 6.45 (s, 2H), 5.50 (s, 1H), 4.63 - 4.61 (m, 1H), 3.87 - 3.68 (m, 4H), 3.55 - 3.45 (m, 2H), 3.16 - 3.02 (m, 3H), 2.88 - 2.83 (m, 2H), 2.23 - 2.15 (m, 5H), 2.10 - 2.01 (m, 4H), 1.87 - 1.76 (m, 3H), 1.72

- 1.64 (m, 1H), 1.33 - 1.28 (m, 1H), 0.97 (d, J = 6.0 Hz, 3H).

[1667] ((R*)-6-amino-8-fluoro- ■l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methy]-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiaz.ol-5-yl)piperidin-l- yljmethanone, isomer 2: MS (ESI) calculated for (C31H37FN6O2S) [M+H] ¹', 577.27; found, 577.20. ^!H NMR (400 MHz, DMSO-d₆) 5 8.05 (d, J =8.4 Hz, 1H), 7.85 (s, 1H), 7.36 (dd, J = 8.4, 1.6 Hz, 1H), 6.98 (dd, 7 - 11.2, 1.6 Hz, 1H), 6.88 (s, 1H), 6.43 (s, 2H), 5.49 (s, 1H), 4.62

- 4.60 (m, 1H), 3.97 - 3.95 (m, 1H), 3.84 - 3.67 (m, 3H), 3.55 - 3.45 (m, 2H), 3.16 - 2.99 (m, 3H), 2.93 - 2.79 (m, 2H), 2.23 - 2.15 (m, 5H), 2.10 - 2.01 (m, 4H), 1.87 - 1.76 (m, 3H), 1.72 - 1.64 (m, 1 H), 1.33 - 1.28 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H).

Example 11: ((R*)-6-amino-9- fluoro- 1,3, 4, 1 lb-tetraliydro-[l,4]oxazino[4,3-c]quinazolin-10- yI)((2R,5S)-5-methy]-2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l- yl)methanone, isomer 4: isomer 4

Example 12: ((R*)-6-amino-9-fluoro-l,3,4,l lb-tetraliydro-[l,4]oxazino[4,3-c]quinazolin-10- yI)((2R,5S)-5-methyJ-2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l- yl)methanone, isomer 3:

isomer 3

Example 13: ((R*)-6-amino-9-fluoro- 13,4, 1 lb-tetahydro-[l ,4]oxazino[4,3-c]quinazolin- 10- y1)((2R,5S)-5-methyl-2-(2-((R*)-l-methylpiperidin-3-y1)benzo[d]thiazol-5-yl)piperidin-l- yl)methanone, isomer 2: isomer 2 ; and

Example 14: ((R*)-6-amino-9-fluoro-l,3,4,llb-tetahydro-[l,4joxazino[4,3-c]quinazolin-10- y1)((2R,5S)-5-metbyl-2-(2-((R*)-l-methylpiperidin-3-y1)benzo[dlihiazol-5-yl)piperidin-l- yl)methanone, isomer 1: isomer 1 Step 1: 1: 1: 1: 1 mixture of ((R*)-6-amino-9-fluoro-l,3,4,llb-telrahydro-[l,4]oxazino[4,3- cJquinazolin-10-yl)((2R,5S)-5-methyl-2-(2-((R*)-l-methylpiperidin-3-yl)benzold]thiazol-5- y])piperidin-l-yl)meihanoiie, isomer 1, and ((R*)-6-amino-9-fluoro- 13,4,1 Ib-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-meihy]-2-(2-((R*)4-methylpiperidin-3- yl)benzo[d]thiazo1-5-yl)piperidin-l -yl)methanone, isomer 2, and ((R*)-6-amino-9-fluoro- 1 ,3.4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazohn-10-yl)({2R.,5S)-5-methyl-2-(2-((R*)-l- methylpiperidin-3-yl)benzo[dJthiazol-5-yi)piperidin-l-yl)methanone, isomer 3, and ((R*)-6- amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-y])((2R,5S)-5-niethyl- 2-(2-((R*)-l-methylpiperidir!-3-yl)beiizo[d]thiazo]-5-yl)piperidin-l-yl)methanone, isomer 4 isomer 1 Isomer 2 Ssornftf 3 4

[1668] To a stirred solution of intermediate A8 (200 mg, 0.60 mmol) and intermediate CAI (209 mg, 0.78 mmol) in DMAC (2 mL) was added PyBrOP (424 mg, 0.91 mmol) and TEA (307 mg, 3.03 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous NaiSCL- After filtration, the filtrate was concentrated under reduced pressure. The reaction mixture (2 mL) was purified by prep- HPLC with the following conditions: [Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 10 min; Wave Length: 254/220 nm] to afford a 1 :1 : 1: 1 mixture of ((R*)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4joxazino[4,3- cJquinazolin-10-yD((2R,5S)-5-methyl-2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5- y])piperidin- l-yl)methanone, isomer 1, and ((R*)-6-amino-9-fluoro-l ,3,4,l Ib-telrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-((R*)-l-methylpiperidin-3- yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 2, and ((R*)-6-amino-9-fluoro- l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-((R*)-l- methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l -yllmethanone, isomer 3, and ((R*)-6- amino-9-fluoro- 1,3,4,11 b -tetrahydro ■ [ 1 ,4]oxazino[4,3 -c]quinazolin- 10-yl)((2R,5S)-5-methyI- 2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 4 (10.1 mg, 2%) as a whi te solid. MS ESI calculated for C31H37FN6O2S [M+H]⁺, 577.27; found, 577.30. ^]H NMR (400 MHz, DMSO-tfc) 8 (ppm) 8.05 (d, J = 8.4 Hz, 1H), 7.87 - 7.86 (m, 1 H), 7.35 - 7.34 (m, 1H), 6.97 - 6.96 (m, 1H), 6.42 - 6. 17 (m, 3H). 6.01 - 5.71 (m, 1 H), 4.54 - 4.53 (m, 1H), 4.02 - 3.65 (m, 3H), 3.57 - 3.39 (m, 3H), 3.03 - 3.01 (m, 2H), 2.72 - 2.61 (m, 2H), 2.33 - 2.23 (m, 6H), 2.09 - 2.01 (m, 3H), 1.89 - 1.48 (m. 5H), 1.37 - 1.32 (m, 1H), 0.98 - 0.91 (m, 3H).

Step 2: ((R*)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4Joxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methyl-2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l- yl)methanone, isomer 1: isomer 1

((R* )-6-amino-9-fluoro- 1 ,3,4, 1 lb-tetrahydro-[ 1 ,4]oxazinol4,3-c]quinazolin- 10-yl)((2R,5S)- 5-metbyl-2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-1 -yl)methanone, isomer 2: isomer 2

((R*)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[1 ,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-

5-methyl-2-(2-((R*)-l-methylpiperidin-3-y])beiizo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 3:

'^{somsr S} ; and ((R*)-6--amino-9-fluorO"l,3,4,llb-tetrahydrO"|l,4]oxazino[4,3-c]quinazoliii-10-yl)((2R,5S)-

5-methyl-2-(2-((R^)-l-niethylpiperidin-3-yl)beiizo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 4

Isomer 4

[1669] Hie 1 : 1 : 1 : 1 mixture of ((R*)-6-amino-9-f1uoro- 1 ,3,4, 1 Ib-tetrahydro-

[1 ,4]oxazino[4,3-c]quinazolin- 10-yl)((2R,5S)-5-metbyl-2-(2-((R*)- 1 -methylpiperidin-3- yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 1, and ((R*)-6-amino-9-fluoro- l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-((R*)-l- meihylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l-yl)meihanone, isomer 2. and ((R*)-6- amino-9-fluoro- 1 ,3,4, 1 1 b-telrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin- 10-yl)((2R,5S)-5-methyl- 2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 3, and ((R*)-6-amino-9-fluoro-l ,3,4,1 lb-tetTahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methyl-2-(2-((R*)-l-melhy1piperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l- yljmethanone, isomer 4 (80 rag) was separated by prep-chiral HPLC with the following conditions: [Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% isopropyl amine), Mobile Phase B: EtOH:DCM-l:L HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 13 min; Wave Length: 220/254 nm; RT1 (min): 7.65; RT2 (min): 10.41; Sample Solvent: EtOH; DCM=1: 1-HPLC; Injection Volume: 0.55 mL; Number Of Runs: 12] to afford fraction A as the first peak on chiral HPLC and fraction B as the second peak on chiral HPLC.

[1670] The fraction A was further separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IE, 2*25 cm, 5 pm: Mobile Phase A: MTBE(0.3% IPAMIN), Mobile Phase B: EtOH, HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 33 min; Wave Length: 220/254 nm; RT1 (min): 19.67; RT2 (min): 27.31 ; Sample Solvent: EtOH:DCM=l:l, HPLC; Injection Volume: 0.9 mL; Number Of Runs: 3 J to afford ((R*)-6- amino-9-fluoro-l,3,4,llb-ietrahydro-[l,4]oxaz.ino[4,3-c]quinazolin-10-y])(.(2R,5S)-5-methyl- 2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 1 (9.2 nig, 11%) as a white solid with retention time at 19.67 and ((R*)-6-amino-9-fluoro- 1 ,3,4.11b-tetrahydfo-[l ,4]oxazino[4,3-c]quinazolin- 10-yl)((2R,5S)-5-methyl-2-(2-((R*)-l- methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 2 (8.7 mg, 10%) as a while solid with retention time at 27.31. [1671] The fraction B was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.3% IP AMIN), Mobile Phase B: IPA:DCM=1:L HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 21 min; Wave Length: 220/254 nm; RTl(min): 10.76: RT2 (min): 16.23; Sample Solvent: EtOH:DCM~l:l , HPLC; Injection Volume: 0.5 niL; Number Of Runs: 4] to afford ((R*)-6- amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-niethyl- 2-(2-((R*)-l-methylpiperidin-3-yl)benzo[dJthiazol-5-yl)piperidin-l-yI)methanone, isomer 3 (7.3 mg, 8%;) as a white solid with retention time at 10.76 and ((R*)-6-amino-9-fluoro- 1 ,3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyI-2-(2-((R*)-l- methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l -yl)methanone, isomer 4 (9.0 nig, 10%) as a white solid with retention time at 16.23.

[1672] ((R*)-6-amino-9-fluoro-l,3,4,Llb-tetahydro-[l,4]oxazino[4,3-cJqumazolin-10- yI)((2R,5S)-5-methy1-2-(2-((R*)-1-methylpiperidjn-3-yl)benzo[d]thiazol-5-yl)piperidin-l- yl)rnethanone, isomer 1 (Example 14): MS (ESI) calculated for (C31H37FN6O2S) [M+H]⁺, 577.27; found, 577.35. TI NMR (400 MHz, DMSO-rfc) 5 (ppm) 8.04 (d, J- 8.4 Hz, 1H),

7.83 - 7.82 (m, 1H), 7.34 - 7.33 (m, 1H), 6.97 (d, 7 = 7.6 Hz, 1H), 6.38 - 6.36 (m. 3H), 5.98

- 5.80 (m, 1H), 4.54 - 4.53 (m, 1H), 3.95 - 3.78 (m, 2H), 3.49 ■■■ 3.24 (m, 4H), 3.16 - 2.87 (m, 2H), 2.74 - 2.57 (m, 2H), 2.31 - 2.18 (m, 6H), 2.17 - 1.99 (m, 4H), 1.86 - 1.48 (m, 6H), 1.35 - 1.32 (m, 1H), 0.94 - 0.84 (m, 1H).

[1673] ((R*)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methyl-2-(2-((R*)-l-methyipiperidin-3-yl)benzo[d]thiazoL5-yl)piperidin-l- y1)methanone, isomer 2 (Example 13): MS (ESI) calculated for (CiMTwFNcCLS) [M+H]⁺, 577.27; found, 577.25. ^!H NMR (400 MHz, DMSO-Jd) 5 (ppm) 8.04 (d, J = 8.4 Hz, 1H),

7.83 - 7.82 (m, 1H), 7.34 - 7.33 (m, 1H), 6.97 (d, 7 = 7.6 Hz, 1H), 6.38 - 6.36 (m, 3H), 5.98

- 5.80 (m, 1H), 4.54 - 4.53 (m, 1H). 3.95 - 3.78 (m, 2H), 3.49 - 3.24 (m. 4H), 3.16 - 2.87 (m, 2H), 2.74 - 2.57 (m, 2H), 2.31 - 2.18 (m, 6H), 2.17 - 1.99 (m, 4H), 1.86 - 1.48 (m, 6H), 1.35 - 1.32 (m, 1H), 0.94 - 0.84 (m, 1H).

[1674] ((R*)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methyl-2-(2-((R*)-l-methylpiperidin-3-y1)benzo[d]thiazol-5-yl)piperidin-l - yl)methanone, isomer 3 (Example 12):: MS (ESI) calculated for (C31H37FN6O2S) [M+H]⁺, 577.27; found, 577.25. NMR (400 MHz, DMSO-ffs) 8 8.05 (d, J = 8.4 Hz, 1H), 7.85 -

7.84 (m, 1H), 7.35 - 7.34 (m, 1H), 6.98 - 6.97 (m, 1H), 6.40 - 6.38 (m, 3H), 5.98 - 5.80 (m, 1H), 4.57 - 4.56 (m, 1H), 3.98 - 3.72 (m, 3H), 3.50 - 3.48 (m, 1H), 3.12 - 2.99 (m, 3H), 2.68

- 2.67 (m, 1H), 2.33 - 2.28 (m, 6H), 2.10 - 2.07 (m, 4H), 1.82 - 1.59 (m, 6H), 1.33 - 1.32 (m, 1H), 0.94 - 0.82 (ni, 3H).

[1675] ((R*)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[1 ,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methy]-2-(2-((R*)-l-methylpiperidin-3-yl)benzo[d]thiazol-5-yl)piperidin-l- yl)methanone, isomer 4 (Example 11): MS (ESI) calculated for (CjjH^FNsChS) [M+H]⁺, 577.27; found, 577.25. ^!H NMR (400 MHz, DMSO-rfo) 58.05 (d, J= 8.4 Hz, 1H), 7.85 - 7.84 (m, 1H), 7.35 - 7.34 (m, 1H), 6.98 - 6.97 (m, 1H), 6.40 - 6.38 (m. 3Hi, 5.98 - 5.80 (m, 1H), 4.57 - 4.56 (m, 1H), 3.98 - 3.72 (m, 3H), 3.50 - 3.48 (m, 1H), 3.12 - 2.99 Im, 3H), 2.68

- 2.67 (m, 1H), 2.33 - 2.28 (m, 6H), 2.10 - 2.07 (m, 4H), 1.82 - 1.59 (m, 6H), 1.33 - 1.32 (m, 1H), 0.94 - 0.82 (m, 3H).

Example 15: ((S)-6-amino-9-fluoro-l ,3,4.1 lb-tetrahydro-[l,4]oxaz.ino[4,3-c]quinazo1in-10- yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-l-yl)methanone:

Example 16: ((R)-6-ammo-9-fluoro-l,3,4,i lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-l-y1)methanone:

Step 1: A 1:1 mixture of ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-ineihylpiperidin-l-yl)methanone and ((R)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l_!4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-2- (benzo[d] thi azol-5 -y l)-5 -methylpi peridin- 1 -y Ijmethanone

[1676] To a stirred solution of intermediate CAI <100 mg, 0.37 mmol) and intermediate A7 (86 mg, 0.37 mmol) and NMT (77 mg, 0.94 mmol) in DMF (5 mL) was added TCFH (106 mg, 0.37 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction solution was then purified by reverse phase column chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 m.M NH4HCO3), 5% to 70% gradient in 30 min; detector, UV 254 nm] to afford a 1:1 mixture of ((S)-6-amino-9- fluoro-l,3,4,llb-tetrahydro-[l,4joxazino[4,3-c]quinazolin-10-yl)((2R,5S)-2- (benzo[d]thiazol-5-yl)-5-methylpiperidin-l-yl)methanone and ((R)-6-amino-9-fluoro- 1,3,4, 1 lb-tetrahydro-[i,4]oxazmo[4,3-c]quinazolin- 10-yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)- 5 -niethylpiperidin-l-yDniethanone (34 rng, 19%) as an off-white solid. MS ESI calculated for C25H26FN5O2S [M+H]⁺, 480.18; found, 480.10. ^!H NMR (400 MHz, DMSO-J_fi) 89.41 (s, 1H), 8.18 (d, J - 8.4 Hz, 1H), 8.00 - 7.98 (m, 1H), 7.45 - 7.43 (m, 1H), 7.11 - 7.10 (m, 1H), 6.52 - 6.48 (m, 1H), 5.92 (br, 1H), 4.65 - 4.58 (m, 1H), 4.06 - 3.99 (m, 1H), 3.87 - 3.79 (m,

2H), 3.59 - 3.43 (m, 3H), 3.17 - 3.06 (m, 2H), 2.36 - 2.25 (m, 1H), 2.22 - 2.10 (m, 1H), 1.82

- 1.79 (m, 1H), 1.75 - 1.64 (m, 1H), 1.40 - 1.31 (m, 1H), 0.98 - 0.88 (m, 3H).

Step 2:

[1677] The 1:1 mixture of ((S)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4Joxazino[4,3- c]quinazolin-10-yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-meihylpiperidin-l-yl)methanone and ((R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-2- (benzo[d]thiazol-5-yl)-5-methy1piperidin-l-yl)methanone (32 mg) was separated by Prep-

Chiral-HPLC with the following conditions: [Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.2% isopropyl amine), HPLC, Mobile Phase B:

EtOH:DCM=l:l, HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 12 min; Wave Length: 220/254 nm; RTl(min): 7.37; RT2(min): 9.8; Sample Solvent: EtOH:DCM=l: l, HPLC; Injection Volume: 0.5 mL; Number Of Runs: 6] to afford ((R)-6-amino-9-fluoro-

1 ,3,4,1 lb-tetrahydro-[l ,4]oxazmo[4,3-c]quinazolin-10-yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)- 5-rnethylpiperidin-l-yl)methanone (8.7 mg) as a white solid with the first peak on chiral HPLC and ((S)-6-amino-9-fluoro-1.3,4,l lb-tetrahydro-1 l,4|oxazino|4.3-c]quinazolin-10- yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-l-yl)methanone (4.7 mg) as a white solid with the second peak on chiral HPLC.

[1678] ((R)-6-amino-9-fluoro- 1,3,4. llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin- 1 -yl)methanone (Example 16): MS ESI calculated for C25H26FN5O2S [M+H]⁺, 480.18: found, 480.10. *H NMR (400 MHz, DMSO-dd) 89.40 (s, 1H), 8.17 (d, 7 - 8.4 Hz, IH), 8.01 - 7.99 (m, 1H), 7.44 - 7.42 (m, IH), 7.00 - 6.98 (m, 1H), 6.42 - 6.37 (m, 3H), 5.89 - 5.87 (m, IH), 4.58 - 4.48 (m, 1H), 4.03 - 3.92 (m, 1H), 3.86 - 3.72 (m, 3H), 3.57 - 3.40 (m, 2H), 3.17 - 2.98 (m. 2H), 2.37 - 2.26 (m, IH), 2.24 - 2.09 (m, IH), 1.82 - 1.78 (m, 1H), 1.74 - 1.63 (m, IH), 1.41 - 1.30 (m, 1H), 0.96 - 0.88 (m, 3H).

[1679] ((S)-6-aminO"9-fluoro-l, 3,4,1 lb-tetrahydro-[l, 4]oxazino[4, 3-c]quinazolin-10- yl)((2R,5S)-2-(benzo[d]thiazol-5-y1)-5-methylpiperidin- 1 -yl)methanone (Example 15): MS ESI calculated for C25H26FN5O2S [M+H]⁺, 480. 18; found, 480.10. ‘H NMR (400 MHz, DMSO-4) 59.41 (s, IH), 8.17 (d, J = 8.4 Hz, 1H), 8.00 - 7.98 (m, IH), 7.45 7.42 (m, IH), 6.96 - 6.94 (m, IH), 6.38 - 6.35 (m, 3H), 5.86 - 5.84 (m, IH), 4.55 - 4.53 (m, IH), 4.03 - 3.62 (m, 4H), 3.55 - 3.43 (m, 2H), 3.12 - 2.94 (m, 2H), 2.35 - 2.24 (m, IH), 2.20 - 2.09 (m, IH), 1.82 - 1.79 (m, IH), 1.75 - 1.63 (m, IH), 1.41 - 1.30 (m, IH), 0.98 - 0.92 (m, 3H).

[1680] The absolute stereochemistry of Example 15 was determined by crystallography based on the co-crystal structure of the compound with PRMT5 enzyme.

Example 17: ((R*)-6-amino-l ,3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-2-(benzo[d]thiazol-5-y1)-5-methyJpiperidin-l-yl)methanooe, isomer 2, and

Isomer 2

Example 18: ((R*)-6-amino-l, 3,4,1 lb-tetrahydro-[l, 4]oxazino[4, 3-c]quinazo1in-10- yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-l-yl)methanone, isomer 1 isomer 1

Step I : 1:1 mixture of ((R*)-6-amino- 1 ,3, 4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin- 10-yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-metbylpiperidin-l-yl)metbanone, isomer 1 and ((R*)-6-amino-l , 3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-2- (benzo[d]thiazol-5-yl)-5-methylpiperidin-l-y])methanone, isomer 2

Ssorner 1 Isomer 2

[1681] To a stirred solution of intermediate CA3 (100 mg, 0.39 mmol) and intermediate A7 (91 mg, 0.39 mmol) in DMF (2 mL) was added NMI (9'7 mg, 1.18 mmol) and TCFH (166 mg, 0.59 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was quenched water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaaSCU. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5pm; Mobile Phase A: Water ( 10 mrnol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 80% B to 90% B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.6) to afford a 1: 1 mixture of ((R*)-6-amino-l,3,4,llb-tetraliydro-[l,4]oxazino[4,3-cjquinazolin- 10-yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-l-yl)methanone, isomer 1 and ((R*)-6-amino-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-2- (benzo[d]thiazol-5 -yl)-5-methylpiperidin~l-yl)methanone, isomer 2 (5.0 mg, 5%) as a white solid. MS ESI calculated for C25H27N5O2S [M+H]⁺, 462.19: found, 462.25. ^!H NMR (400 MHz, Methanol-cL) 89.30 (s, 1 H), 8.20 ~ 7.95 (m, 2H), 7.53 8.4 Hz, 1H), 7.37 - 7.27

(m, 1H), 7.14 - 7.12 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.68 - 5.62 (m, 1H), 4.76 (d, J = 10.4 Hz, 1H), 4.09 - 4.02 (m. 1 Hi, 3.99 - 3.77 (m, 3H), 3.73 - 3.55 (m. 2H), 3.47 (t, J = 10.8 Hz, 1H), 3.25 - 3.22 (m, 1H), 2.33 - 2.30 (m, 2H), 2.02 - 1.78 (m, 2H), 1.56 - 1.37 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H).

Step 2: ((R*)-6-amino-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-cJquinazolin-10-yl)((2R,5S)-2- (benzo[d]thiazol-5-yl)-5-methylpiperidin-i -yDmethanone, isomer 1 : isomer 1 ; _and

((R*)-6-amino-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-2-

(benzo[dJthiazol-5-yl)-5-methylpiperidin- 1 -yljmethanone, isomer 2:

Isomer 2

[1682] The 1:1 mixture of ((R*)-6-amino-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((2R,5S)-2-(benzo[djthiazol-5-yl)-5-methylpiperidin-l-yr)methanone, isomer 1 and ((R*)-6-amino-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methyIpiperidin-l-yl)methanione, isomer 2 (13 mg, 0.02 mmol) was separated by prep-chiral HPLC with the following conditions: [Column: Lux 5um Cellulose-4, 2.12*25 cm, 5 pm; Mobile Phase A: Hex(0.2% IPAMine), HPLC, Mobile Phase B: MeOH:EtOH=1 : 1, HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 20 min; Wave Length: 220/254 nm; RT1 (min): 10.02; RT2 (min): 15.5; Sample Solvent: MeOH:EtOH=l:l, HPLC: Injection Volume: 0.8 mL; Number Of Rims: 4] to afford ((R*)-6- amino- 1, 3,4,1 lb-tetraliydro-[L4]oxazino[4,3-c]quinazolin-10-yI)((2R,5S)-2- (benzo[d]thiazol-5-yi)-5-methylpiperidin-l-yl)methanone, isomer 1 (3.0 mg, 21%) as a white solid with the first peak on chiral HPLC and ((R*)--6-amino-l,3,4,llb-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-l- y])methanone, isomer 2 (3.2 mg, 23%) as a white solid with the second peak on chiral HPLC.

[1683] ((R*)-6-amioo- 1,3,4, 1 lb-tetrahydro-[l,4Joxazioo[4,3-c]quinazolin-10-yl)((2R,5S)- 2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-l-yl)methanone, isomer 1 (Example 18): MS (ESI) calc’d for (C25H27N5O2S) [M+H]⁺, 462.19: found, 462.25. ^!H NMR (400 MHz, Methano1-d₄) 89.30 (s, 1H), 8.14 (d, J - 8.4 Hz, 1H), 8.06 (s, 1H), 7.59 - 7.47 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7. 10 (s, 1H), 6.90 - 6.77 (m, 1H), 5.68 ~ 5.66 (m, 1H), 4.74 (d, J = 10.4 Hz, 1H), 3.98 ■■■■ 3.75 (m, 4H), 3.73 - 3.56 (m, 2H), 3.52 ■■■■ 3.40 (m, 1H), 3.29 - 3.12 (m, 1H), 2.32 (t, J - 4.8 Hz, 2H), 1.99 - 1.81 (m, 2H), 1.55 - 1.38 (m, 1H), 1.09 (d, 7 - 6.8 Hz, 3H). [1684] ((R*)-6-amino-l ,3,4,11b-teirahydro-[1 ,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-

2-(benzo[d]diiaz.oi-5-yl)-5-methylpiperidin-l -y])melhanone, isomer 2 (Example 17): MS (ESI) calc’d for (C25H27N5O2S) [M+H]⁺, 462.19; found, 462.25. ^:H NMR (400 MHz, Methanol-^) 59.30 (s, 1 H), 8.13 (d. J = 8.4 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.53 (dd, J = 8.4, 1.6 Hz, 1H), 7.31 (dd, 8.0, 1.0 Hz, 1H), 7.14 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.72 - 5.70 (m, 1H), 4.78 - 4.60 (m, 1H), 4.06 (dd, J = 11.2, 3.2 Hz, 1H), 3.94 - 3.77 (m, 3H), 3.75

- 3.56 (m, 3H), 3.28 - 3.15 (m, 1H). 2.36 - 2.34 (rn, 2H), 2.01 - 1.83 (m. 2H), 1.47 - 1.45 (m, 1 H), 1 .08 (d, ./ - 6.8 Hz, 3H).

Example 19: ((R*)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin- l- yl)methanone, isomer 2:

Isomer 2 ; and

Example 20: ((R*)-6-amino-9-fluoro- 1,3,4, 1 lb-tetrahydro- [l,4joxazino[4,3--c]quinazoliir-

10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-l- yljmethanone, isomer 1:

teomer 1

Step 1: 1: 1 mixture of ((R*)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l -methylpiperidin-4-yl)benzo[d]tbiazol-5- yl)piperidin-l-yl)methanone, isomer 1 and ((R*)-6-ammo-9-fluoro-l,3,4,llb-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((.2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4- yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 2 isomer 1 Isomer 2

[1685] To a stirred mixture of intermediate CAI ( 100 mg, 0.38 mmol) and intermediate A3 (124 mg, 0.38 mmol) and NMI (93 mg, 1.13 mmol) in DMAC (5 mL) was added TCFH (127 rag, 0.45 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was purified by reversed-phase column chromatography with the following conditions: [column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 5% to 40% gradient in 30 min] to afford a 1 : 1 mixture of ((R*)-6-amino-9-fluoro- 1,3,4, 11b- tetrahydro-[l,4]oxazioo[4,3-c]quinazolin-l0-yl)((2R,5S)-5-methyl-2-(2-(l-metbylpiperidin- 4-yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 1 and ((R*)-6-amino-9- fluoro- 1 ,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l- methyIpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 2 (70 mg, 28% ) as a white solid. MS ESI calculated for C31H37FN6O2S [M+H]⁺, 577.27; found. 577.35.

Step 2: ((R*)-6-amino-9"fluoro- 1,3,4, llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((2R,5S)-5-methy]-2-(2-(l-methy1piperidin-4-yl)benzo[d]thiazol-5-y])piperidin-l- yl)methanone, isomer 1:

. _and

((R*)-6-amino-9-fluoro-1 ,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)- 5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazol-5"yl)piperidin-l-yl)methanone, isomer 2: d cd M o r'V^ly^,>[4-s' U , XU* R Isomer 2

[1686] Hie 1:1 mixture of ((R*)-6-ammo-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-y1)benzo[d]thiazo1-5- yl)piperidin-l-yl)methanone, isomer 1 and ((R*)-6-amino-9-fluoro-l, 3,4,1 Ib-tetrahydro- [l,4joxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4- yl)benzo[d]thiazol-5-yl)piperidin-l-yl)methanone, isomer 2 (70 mg) was separated by Prep- Chiral HPLC with the following conditions: [Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.2% Isopropylamine), HPLC, Mobile Phase B: EtOH:DCM~l:L HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 20 min; Wave Length: 220/254 nra; RT1 (min): 13.17: RT2 (rain): 17.8: Sample Solvent: EtOH:DCM=l : 1, HPLC; Injection Volume: 0.8 mL; Number Of Runs: 6] to afford ((R*)-6-amino-9 -fluoro- 1,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyI-2-(2-( 1- methylpiperidin-4-yl)benzo[d]tbiazol-5-y1)piperidin-l-yl)methanone, isomer I (16.0 mg, 24%) as a white solid with the first peak on chiral HPLC and ((R*)-6-amino-9-fluoro- l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,5S)-5-methyl-2-(2-(l- methylpiperidin-4-yl)benzo[d]thiazo1-5-yl)piperidin-l -yl)methanone, isomer 2 (15.4 mg, 23%) as a white solid with the second peak on chiral HPLC.

/66 [1687] ((R*)-6-atnino-9-fluoro- 1 ,3,4, 1 1 b-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin- 10- yl)((2R,5S)-5-methyl-2-(2-(l-methylpiperidin-4-yl)benzo[d]thiazoT5-yl)piperidin-l- yl)methanone, isomer 1 (Example 20): MS ESI calculated for C31H37FN6O2S [M+H]⁺, 577.27; found, 577.30. ^:,H NMR (400 MHz, DMSO-<fc) 8 8.07 (d, J = 8.4 Hz, 1 H), 7.87 (br, 1H), 7.37 (br, 1H), 7.25 (d, J - 7.1 Hz, 1H), 6.68 (d, J - 10.8 Hz, 1H), 5.90 - 5.84 (m, 1 H), 4.75 - 4.69 (m, 1H), 4.11 - 4.05 (m, 1H), 3.95 - 3.85 (m, 2H), 3.62 - 3.49 (m, 2H), 3.23 - 3.13 (m, 2H), 3.05 - 3.01 (m, 2H), 2.43 - 2.25 (m, 8H), 2.20 - 2.09 (m, 3H), 1.95 - 1.77 (m, 3H), 1 .74 - 1.63 (m, 1H). 1.39 - 1.30 (m, 1 H), 0.95 - 0.94 (m, 3H).

[1688] ((R*)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,5S)-5-methyl-2-(2-( 1 -methylpiperidin-4-yl)benzo[d]thiazol-5-yl)piperidm- 1 ■■ yl)methanone, isomer 2 (Example 19): MS ESI calculated for C31H37FN6O2S [M+H]⁺, 577.27: found, 577.35. ^:H NMR (400 MHz, DMSO-J5) 6 8.05 (d, 7 - 8.4 Hz. 1H), 7.85 (s, IH), 7.35 (br, IH), 6.99 (br, 1H), 6.56 (br, IH), 6.40 (d, J = 1 1.6 Hz, 1 H ), 5.88 (br, IH), 4.58 (d, 7 = 10.2 Hz, IH), 3.93 - 3.90 (m, IH), 3.84 - 3.72 (m, 2H), 3.58 - 3.42 (m, 2H), 3.12 - 3.00 (m, 2H), 2.90 - 2.82 (m, 2H), 2.44 - 2.36 (m, IH), 2.30 - 2. 18 (m, 4H), 2.17 - 1.93 (m, 6H), 1 .87 - 1.75 (m, 3H), 1.74 - 1.61 (m, 1 H), 1 .37 - 1.28 (m, IH), 0.94 - 0.92 (m, 3H).

Example 21: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((2RMaS*,10bS*)-2-methyl-8-(trtluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridin- 1 -yl)methanone

[1689] To a stirred mixture of Intermediate A14, isomer 1 (500 nig, 1.84 mmol) and DIEA (714 mg, 5.52 mmol) in N,N-Diraethylacetamide (12 mL) was added Intermediate AC4 (558 mg, 1.84 mmol) in portions at 0 °C. The resulting mixture was stirred at. room temperature for 1 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4.

After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (5: 1), then further purified by Prep-HPLC with the following conditions [Column: XBridge Prep OBD Cl 8 Column,

/67 30*150 mm, 5 pm; Mobile Phase A: Water (10 rnmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate; 60 mL /min; Gradient: 53% B to 73% B in 14 min; Wave Length: 254/220 nm;

RTl(miii): 9] to afford ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3’,4’:4,5]pyrimido[6,l- c][l ,4]oxazin-10-yl)((2R*,4aS*,10bS*)-2-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b- hexahydro-lH-isochromeno[4,3-b]pyridin-l-y1)methanone (40.7 mg, 4%) as a white solid. MS ESI calculated for C25H2.6F3N5O3 [M+l]⁺, 502.20; found, 502.15. ’H NMR (400 MHz, DMSO-tfc) 57.92 - 7.29 (m, 5H), 6.48 (s, 21 L. 5.95 - 5.76 (m, IH), 5.00 - 4.86 (nt, IH), 4.80 - 4.65 (m, 2H), 4.25 - 4.06 (m, 3H), 3.86 - 3.75 (ra, 2H), 3.56 - 3.49 (m, 2H), 3.10 - 2.98 (m, IH), 2.10 - 1.96 (m, IH), 1.83 - 1.63 (m, 2H), 1.60 - 1.47 (m, IH), 0.74 (d, J = 6.8 Hz, 3H).

Example 22: ((R)-6-amino- 1,3,4, llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((3R,4aS,9aR)-7-(difluoromethoxy)-3-methy1-2,3,9,9a4etrahydroindeno[2,l- b] [ 1 ,4]oxazin-4(4aH)-yl)methanone

[1690] To a stirred solution of Intermediate A15, isomer 2 (50 mg, 0.196 mmol) and CS2CO3 (319.1 mg, 0.980 mmol) in DMAC (1 ml.,) was added Intermediate AC4 (78.3 mg, 0.294 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaaSCU- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (5:1) to afford ((R)-6-arnino-l ,3,4,11b- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l ,4]oxazin-10-yl)((3R,4aS,9aR)-7- (difluoromethoxy )-3-methyl-2, 3, 9, 9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- yl)methanone (40.0 mg, 42%) as a white solid. (Example 22): MS (ESI) calculated for (C24H25F2N5O4) [M+HF, 486.19; found, 486.20. ^!H NMR (400 MHz, DMSCMs) 6 (ppm) 7.89 and 7.71 (s, IH), 7.50 - 7.33 (m, IH), 7.33 - 7.09 (m, 2H), 7.09 - 6.90 (rn, 2H), 6.59 (s, 2H), 5.71 - 5.54 (m, IH), 4.75 - 4.59 (m, I H), 4.54 - 4.09 (m, 3H), 3.93 - 3.70 (m, 2H), 3.70

- 3.42 (m, 4H), 3.25 - 2.98 (m, 2H), 2.97 - 2.77 (m, IH), 0.94 - 0.71 (m, 3H).

[1691] The absolute stereochemistry of Example 22 was determined by single-crystal X- ray structure. Example 23: ((S)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R,4aS,9aR)-7-chloro-3-methyl-2,3,9,9a-tetrahydromdeno[2, l-b][l,4]oxazin-4(4aH)- yl)methanone

[1692] To a stirred solution of Intermediate A16 (47 mg, 0.21 mmol) and Intermediate AC1, isomer 2 (50 mg, 0.18 mmol) in N,N-Dimethylacetamide (I mL) was added EtaN (107 mg, 1.06 mmol) al 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSOa- After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min;

Gradient: 35% B to 45% B in 10 min; Wave Length: 254/220 nm; RTI (min): 7.2) to afford ((S) -6- amino -9 -fluoro - 1 , 3 ,4, 11 b -tetrahydro ■ [ 1 ,4]oxazino[4, 3 ■ c]quinazolin - 10- yl)((3R,4aS ,9aR)-7 -chloro-3-methy l-2,3,9,9a-tetrahydroindeno[2, 1 -b] [ 1 ,4]oxazin-4(4aH)- y1)methanone (16.0 mg, 19%) as a white solid. MS (ESI) calculated for (C24H24CIFN4O3) [MW, 471.15; found, 471.15. ^SH NMR (400 MHz, Methanol-A) 5 7.40 - 7.21 (m, 3H), 7.13 (d, J - 7.2 Hz, IH), 6.59 - 6.34 (m, IH), 5.68 (d, 4.4 Hz, IH), 4.77 - 4.50 (m, 2H),

4.48 - 4.32 (m, IH), 4.21 - 3.96 (rn, IH), 3.95 - 3.55 (m, 6H), 3.31 - 3.15 (m, 2H), 3.1 1 - 2.78 (m, IH), 1.12 - 0.70 (m, 3H). Example 24: ((R)-6-amino-l,3,4,llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((2R,4aR,10bS)"8"Chloro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH-[T,4]oxazino[3,2- f]quinolin- l-yl)methanone

[1693] To a stirred solution of Intermediate A17 isomer 2 (70 mg, 0.29 mmol) and NaHCOs (148 mg, 1.76 mmol) in THF (2 mL) and water (0.5 mL) was added Intermediate AC4 (94 mg, 0.35 mmol) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was quenched -with water and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSOi. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC with the following conditions: (Column: XSelect CSH Prep CIS OBD Column, 19*250 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient: 45% B to 55% B in 10 min, 55% B to 55% B in 20 min; Wave Length: 254/220 am; RTl(min): 1 1.37) to afford ((R)-6-amino- 1 ,3,4,1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R,4aR,l0bS)-8- chlorO"2-methyl-2,3,4a,5,6,10b-hexahydro-lH-[l,4joxazino[3,2-f]quinolin-l -yi)methanone (21.9 mg, 16%) as a white solid. (Example 24); MS ESI calculated for (C2.3H25CIN6O3) [M+HT, 469.17, 471.16; found, 469.15, 471.20. ’H NMR (400 MHz, DMSO-cfc) 8 (ppm) 7.83 (s, 1H), 7.72 - 7.45 (m, 1H), 7.41 - 7.28 (m, 2H), 6.49 (s, 2H), 5.73 - 5.54 (m, 1H), 4.71 - 4.54 (m, 1H), 4.21 - 4.06 (m, 2H), 4.00 - 3.84 (m, 2H), 3.81 - 3.46 (m, 5H), 3.13 - 2.96 (m, 2H), 2.78 - 2.61 (m, 1 H), 2.38 - 1.89 (m, 2H), 0.72 and 0.67 (d, J = 6.8 Hz, 3H).

Example 25: ((R)-6-amino-1 ,3,4,llb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4aR*,10bR*)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- b jpyridin- 1 -yl)rnethanone

[1694] To a stirred solution of Intermediate A18, isomer I (57 mg, 0.22 mmol) and

Intermediate CA4 (61 nig, 0.24 mmol) in DMF (1.5 mL) were added DIEA (86 mg, 0.67 mmol) and HATU (126 mg, 0.33 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in DMF (1.5 ml.,) and was purified by Prep-HPLC with the following conditions; [Column: XSelect CSH Prep CIS OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 50% B in 12 rain; Wave Length: 254/220 mn; RTl(min): 1 1.3] to afford ((R)-6-amino-l ,3,4,llb- tetrahydropyrido[3',4’:4,5]pyriniido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8" (tritluoromethyl)-2,3,4,4a,6, 10b-hexahydro-lH-isochromeno[4,3-b]pyridin- l-yl)methanone (25.6 mg, 24%) as a white solid. (Example 25); MS ESI calculated for (Cc^aFiNsO?) [M+H]⁺, 488.18; found, 488.25. ^!H NMR (400 MHz, DMSO-rfe) 5 (ppm) 7.88 and 7.73 (s, 1H), 7.81 - 7.63 (m, 1H), 7.62 - 7.27 (m, 3H), 6.57 (s, 2H), 5.90 - 5.63 (m, 1H), 4.97 - 4.59 (m, 3H), 4.21 - 4.03 (m, 2H), 3.98 - 3.71 (m, 3H), 3.60 ~ 3.47 (m, 2H), 3.15 - 2.98 (m, 1H), 2.66 - 2.18 (m, 1H), 1.87 - 1.75 (m, 1H), 1.73 - 1.42 (m. 3H).

Example 26: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4‘:4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((4aR*,10bR*)-8-(difluoromethoxy)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4 b'Jdipy ridin- 1 -yljmelhanone

[1695] To a stirred mixture of Intermediate A 19 (50 mg, 0. 17 mmol) in DMAC (2 ml,) were added K2CO3 (118 mg, 0.85 mmol), 4A molecular sieves (3 g) and Intermediate AC4 (59 mg, 0.22 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h under nitrogen atmosphere. The reaction was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NarSCL. After filtration, the filtrate was concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography, eluted with 0-20% MeOH in DCM to afford ((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8- (difluoromethoxy)-2,3,4,4a,6,10b-hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone (32 mg, 38%) as a white solid. MS ESI calculated for C23H24F2N6O4 [M+H]⁺, 487.18; found, 487.10. ^!H NMR (400 MHz, DMSO-d₆) 8 7.99 - 7.92 (m, 1H), 7.85 - 7.80 (m, 1H), 7.72 - 7.68 (m, 1H), 7.48 - 7.40 (m, 1H), 7.06 (d, J - 8.4 Hz, 1H), 6.93 (br, 2H), 5.87 - 5.46 (ni, 1H), 4.80 - 4.49 (m, 3H), 4.37 - 3.72 (m, 5H), 3.55 (t, 7 - 10.8 Hz, 2H), 3.18 - 3.06 (m, 1H), 2.65 - 2.18 (m, 1H), 1.83 - 1.43 (m, 4H).

Example 27 (Method 1): ((R)-6-amino-l,3,4,llb-letrahydropyrido[3\424,5]pyrimido[6,l- cl[ l,4]oxazin-10-yi)((2R,4aS,10bS)-8-chloro-2-methyl-2,3,4a,10b-tetrahydrochromeno[3,4- b j [1 ,4]oxazin- 1 (5H)-yl)methanone

[1696] To a stirred mixture of Intermediate A21 (269.6 mg, 1.12 mmol) and TEA (455.3 mg, 4.50 mmol) in DM AC (10 mL) was added Intermediate AC4 (prepared by Method 1) (300 mg, 1.12 mmol) in portion at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NfoSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-20% MeOH in DCM to afford ((R)-6-amino-l,3,4,llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- c] [ 1 ,4]oxazin- 10-yl)(( 2R,4aS , 10bS)-8-chloro-2-methyl-2,3 ,4a, 1 Ob-tetrahy drochromeno[3 ,4- b][l,4]oxazin-l (5H)-yl)methanonee (Example 27) (140 mg, 26%) as a brown solid. MS ESI calculated for C₂?H_MC1N₅O4 [M+H]⁺, 470.15; found, 470.20. ^!H NMR (400 MHz, DMSO- <! 5 7.89 (s, 1H), 7.35 (s, 1H), 7.16 (d, ./ = 8.4 Hz, 1H), 7.00 - 6.82 (m, 2H), 6.67 (br, 2H), 5.83 - 5.71 (m, 1H), 4.75 - 4.64 (m, 1 H), 4.60 - 4.06 (m, 4H), 3.95 - 3.60 (m, 5H), 3.59 - 3.47 (m, 2H), 3.14 - 3.02 (m, 1 H), 0.82 - 0.70 (m, 3H). Example 27 (Method 2): ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3‘,4':4,5]pyrimido[6,l- c][l,4]oxazin-10-yl)((2R,4aS,10bS)-8-chloro-2-methyl-2,3,4a,10b-teirahydrochromeno[3,4- b] [1 ,4joxazin- 1 (5H)-yl)methanone

[1697] To a stirred solution of Intermediate A21 (110 mg, 0.40 mmol) and Intermediate CA4 (prepared by Method 2) (LOO nig, 0.40 mmol) in DMF (1 mL) were added DIEA (157 mg, 1.22 mmol) and HATU (231 mg, 0.61 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure, The residue was purified by prep-HPLC with the following conditions: [Column: Xselect CSH CI8 OBD Column 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 5% B to 25% B in 15 min; Wave Length; 254/220 nm; RTl(min): 12.5] to afford product with e.e. 77%, which was purified by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IK 2*25 cm, 5 um; Mobile Phase A: Hex (0.2%;

IPAMine)— HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 17 min; Wave Length: 220/254 nm; RTl(min): 8.63;

RT2(min): 11.07; Sample Solvent: EtOH: DCM=1: 1-HPLC; Injection Volume: 0.55 mL; Number Of Runs: 4] to afford ((R)-6-amino-l,3,4,l l b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][T,4]oxazin-10-yl)((2R,4aS,10bS)-8-chloro-2- methyl-2,3,4a,10b-tetrahydrochroraeno[3,4-b][l ,4]oxaziml (5H)-yl)methanone (Example 27) (6.8 mg, 3%) as a white solid with the second peak on chiral HPLC. MS ESI calculated for C23H24CIN5O4 [M+Hf, 470.15; found, 470.20. H NMR (400 MHz, DMSO-d₆) 5 7.89 (s, 1 H), 7.35 (s, 1H), 7.16 (d, J ~ 8.4 Hz, 1H), 7.00 - 6.82 (m, 2H), 6.67 (br, 2H), 5.83 - 5.71 (m, 1H), 4.75 - 4.64 (m, 1H), 4.60 - 4.06 (m, 4H), 3.95 - 3.60 (m, 5H), 3.59 - 3.47 (m, 2H), 3.14 - 3.02 (m, 1H), 0.82 - 0.70 (m, 3H).

Example 28: ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4’:4,5 ]pyrimido[6, 1 -c] [ 1 ,4]oxazin- l()-yl)((2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl-2,3,4a,10b-tetrahydrochromeno[3,4- b] [ 1 ,4]oxazm- 1 (5H)-yl)methanone

[1698] To a stirred mixture of intermediate A22 (100 mg, 0.37 mmol) in N,N- Dimethylacetarnide (2 mL) -was added EtjN (1 1 1 mg, 1.10 mmol). Then Intermediate AC4 (175 mg, 0.66 mmol) was added slowly at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (1 mL) and was purified directly by prep-HPLC with the following conditions: [Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Watert lO mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 38% B in 10 min; Wave Length: 254/220 nm; RTl(niin): 9.12] to afford ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- c] [ 1 ,4]oxazin- 10-y1)((2R,4aS, 10bS)-8-(difluorornethoxy)-2-methyl-2,3,4a, 10b- tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)-yl)methanone (Example 28) (28.7 mg, 15%) as a yellow solid. MS ESI calculated for C24H25F2N5O5 [M+l]⁺, 502.18; found, 502.15. ^!H NMR (400 MHz, DMSO-Je) 6 7.86 - 7.27 (m, 1H), 7.49 - 7.00 (ra, 3H), 6.78 - 6.65 (m, 1H), 6.63 - 6.54 (m, 1H), 6.52 - 6.42 (m, 2H), 5.83 - 5.71 (m, 1H), 4.70 - 4.61 (m, 1 H), 4.58 - 4.05 (m, 4H), 3.97 - 3.45 (m, 7H), 3.14 - 3.00 (m, 1H), 0.80 - 0.71 (m, 3H).

Example 29: ((R)-6-amino-l,3,4,l lb--tetrahydropyrido[3',4':4,5Jpyrimido[6,l-c][l,4]oxazin- 10-yl)((3R,4aS,9aR)-7-chloro-3-methyl-2.3,9,9a-tetrahydroindeno[2,l-b][1 ,4]oxazin-4(4aH)- yljmethanone

[1699] To a solution of Intermediate A16 (178 mg, 0.67 mmol) and Intermediate AC4 (100 mg, 0.45 mmol) in N,N-Dimeihylacetamide (2.5 mL) was added EtjN (136 mg, 1.34 mmol) al 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr- After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 35% B in 10 min, 35% B to 35% B in 20 min: Wave Length: 254/220 nm; RTl(min): 13.6) to afford ((R)-6-amino-l,3,4,Hb- tetrahydropyrido[3^,,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((3R,4aS,9aR)-7-chloro-3- methyl-2,3,9,9a-tetrahydroindeno[2,l-bJ[l,4joxazin-4(4aH)-yl)methanone (Example 29) (36.8 mg, 18%) as a white solid. MS ESI calculated for (C23H24CIN5O3) [M+H]⁺, 454. 16; found, 454.19. *H NMR (300 MHz, DMSO-d₆) 5 7.97 and 7.68 (s, 1H), 7.46 - 7.16 (m, 4H), 6.44 (s, 2H), 5.87 - 5.42 (m, 1H), 4.68 (d, J = 9.0 Hz, 1H), 4.62 - 4.04 (m, 3H), 3.90 - 3.72 (m, 2H), 3.70 - 3.41 (m, 4H), 3.26 - 2.99 (m, 2H), 2.98 - 2.78 (m, 1H), 0.92 - 0.80 (m, 3H).

Example 30: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4bR*,8aR*)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[ l,2-b:3,4- b']dipyridin-5-yl)methanone

[1700] To a stirred mixture of Intermediate A23, isomer 2 (40 mg, 0.17 mmol), K2CO3 (46 mg, 0.33 mmol) and 4A molecular sieves (100 mg) in DMAC (1 mL) was added Intermediate AC4 (6! mg, 0.22 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NazSOr- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: [Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(l0 mmol/L NH4HCO3). Mobile Phase B: ACN; Flow' rate: 60 mL/min; Gradient: 44% B to 64% B in 14 min; Wave Length: 254/220 nm; RTl(min): 9] to afford ((R)-6-amino-1 ,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4bR*,8aR*)-2- (difluoromethoxy)-4b, 6,7, 8,8a, 9-hexahydro-5H-cyclopenta[1 ,2-b:3,4-b']dipyridin-5- yl)methanone (Example 30) (33 mg, 42%) as a white solid. MS ESI calculated for C23H24F2N6O3 [M+H]⁺, 471.19; found, 417.15. ^!H NMR (400 MHz, DMSO-A) 5 8.02 - 7.44 (m, 3H), 7.43 - 7.34 (m, 1 H), 7.02 - 6.54 (m, 3H), 5.99 - 5.45 (m, 1H), 4.79 - 4.64 (m, 1H), 4.53 - 3.73 (m, 4H), 3.63 - 3.47 (m, 2H), 3.25 - 2.90 (m, 2H), 2.74 - 2.61 (m, 2H). 2.43 - 2.32 (m, 1H), 1.86 - 1.69 (m, 1H), 1.62 - 1.28 (m, 2H), 1.16 - 0.92 (m, 1H).

Example 31: ((4S.1 lbS)-6-amino-4-metbyl- 1 ,3,4, 11b- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,10bS)-8-

(difluoromethoxy)- 2, 3, 4, 4a, 6, 10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone formate

[1701] To a stirred solution of intermediate CA5 (100 mg, 0.38 mmol) and intermediate A24, isomer 1 (97 mg, 0.38 mmol) in DMF (3 mL) were added DIEA (246 mg, 1 .91 mmol) and HATU (319 mg, 0.84 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: [Column: Xselect CSH C18 OBD Column 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 8% B to 25% B in 15 min; Wave Length: 254/220 nm; RTl(min): 12.51 to afford ((4S,l lbS)-6-amino-4-methyl-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,10bS)-8- (difluoromethoxy)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone formate (51.3 mg, 24%) as an off-white solid. MS ESI calculated for C25H27F2N5O4 [M+H]⁺, 500.20; found, 500.15. ^!H NMR (400 MHz, Methanol- J₄) 8 8.54 (s, 1H), 8.30 - 8.10 (m, 1H), 7.62 - 7.32 (m, 2H), 7.18 - 6.62 (m, 3H). 6.03 - 5.16 (m, 2H), 4.82 - 4.33 (m. 3H). 4.23 - 4.04 (m, 2H), 3.92 - 3.78 (m, 2H), 3.76 - 3.58 (m, 2H), 2.90 - 2.44 (m, 1H), 1.93 -

1.61 (m, 4H), 1.53 (d, J - 6.8 Hz, 3H). Example 32: ((4S, 1 lbR)-6-amino-4-methyl- 1,3,4, 11b- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,10bS)-8-

(difluoromethoxy)-2,3,4,4a,6,10b-hexahydro- lH-isochromeno[4,3-b]pyridin-l-yl)methanone

[1702] To a stirred solution of intermediate CA6 (100 mg, 0.38 mmol) and intermediate A24, isomer 1 (97 mg, 0.38 mmol) in DMF (3 ml.) were added DIEA (246 mg, 1.91 mmol) and HATU (319 mg, 0.84 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: [Column: Xselect CSH Cl 8 OBD Column 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 8% B to 25% B in 15 min; Wave Length: 254/220 nm; RTl(min): 12.5] to afford ((4S,llbR)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,10bS)-8- (difluoromethoxy)-2,3.4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)metbanone (17.3 mg, 9%) as an off-white solid with retention time at 11.69 minute. MS ESI calculated for C25H27F2N5O4 [M+H]⁺, 500.20; found, 500.20. ^!H NMR (400 MHz, Methanol-J₄) 6 8.22 - 8.06 (m, 1H), 7.54 - 7.32 (m, 2H), 7.14 - 6.61 (m, 3H), 6.00 - 5.30 (m, 1H), 5.14 - 5.08 (m, 1H), 4.82 - 4.37 (rn, 3H), 4.33 - 4.27 (m, 1H), 4.23 ■■■ 4.15 (m, 2H), 4.02 - 3.93 (m, 1H), 3.74 > 3.6O (m, 2H), 2.88 - 2.44 (m, 1 H), 1 .96 - 1 .56 (m, 4H), 1 .40 (d, J = 6.4 Hz, 3H ).

Example 33: ((4S,l lbS)-6-amino-4-methyl-l,3,4,l lb- teirahydropyrido[3',4':4,5]pyrimido[6, l-c][l,4]oxaz.in- 10-yl)((3R,4aS,9aR)-7-

(difluoromethoxy)-3-methyl-2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- yl)methanone formate

[1703] To a stirred solution of intermediate CA5 (100 mg, 0.38 mmol) and intermediate A15, isomer 2 (81 mg, 0.32 mmol) in DMF (10 mL) were added DTEA (164 mg, 1.27 mmol) and HATU (181 mg, 0.48 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched -with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Hie residue was purified by Prep-HPLC with the following conditions: [Column: Xselect CSH C18 OBD Column 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B; ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 8% B to 25% B in 15 min; Wave Length: 254/220 nm; RTl(min): 12.5] to afford ((4S,llbS)-6-amino-4-methyl-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6, 1-c] [ 1 ,4]oxazin-10-yl)((3R,4aS,9aR)-7- (dif!uoromethoxy)-3-metbyl-2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- yl)rnethanone formate (46.8 mg, 27%) as an off-white solid. MS ESI calculated for C25H27F2N5O4 [M+H]⁺, 500.20; found, 500.25. TI NMR (400 MHz, Methanol-d₄) 8 8.54 (s, 1H), 8.26 - 8.10 (m, 1H), 7.67 ~ 7.59 (m, TH), 7.45 - 7.31 (m, 1H), 7.14 - 6.58 (m, 3H), 5.77 - 5.21 (m, 2H), 4.70 - 4.31 (m, 3H), 4.14 - 4.02 (m, 1H), 3.94 - 3.52 (m, 5H), 3.31 - 2.91 (m, 2H), 1 .56 - 1.49 (m, 3H), 1.06 - 0.96 (m, 3H).

Example 34: ((4S. 1 lbS)-6-amino-4-methyl- 1 ,3,4, 11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l -c][l,4]oxazin-10-yl)((3R,4aS,9aR)-7-cbloro-3- methyl-2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)-yl)methanone formate [1704] To a stirred solution of intermediate CA5 (100 mg, 0.38 mmol) and intermediate A16 (71 mg, 0.32 mmol) in DMF (10 mL) were added DIEA (164 mg, 1.27 mmol) and HATH (181 mg, 0.48 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep- HPLC with the following conditions: [Column: Xselect CSH CIS OBD Column 30* 150 mm 5 pm; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: ACN; Flow' rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 8% B to 25% B in 15 min; Wave Length: 254/220 nm; RTl(min): 12.5] to afford ((4S,llbS)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6, l-c][l ,4]oxazin-10-yl)((3R,4aS,9aR)-7-chloro-3- methyL2,3,9,9a-letrahydroindenor2,l-b][l,4]oxazin-4(4aH)-yl)methanone formate (40.6 mg, 24%) as an off-white solid. MS ESI calculated for C24H26CIN5O3 [M+Tj\ 468.17; found, 468.15. TI NMR (400 MHz, Methanol-^) 5 8.53 (s, 1H), 8.24 - 8.08 (m, 1H), 7.66 - 7.59 (m, 1H), 7.48 - 7.14 (m, 3H), 5.74 - 5.24 (m, 2H), 4.70 - 4.34 (m, 3H), 4.14 - 4.02 (m, 1H), 3.96 - 3.52 (m, 5H), 3.29 - 2.89 (m, 2H), 1.55 - 1.49 (m. 3H), 1.05 - 0.95 (m, 3H).

Example 35: ((4S,1 lbR)-6-aniino-4 -methyl- 1,3,4, lib- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((3R,4aS,9aR)-7-chloro-3- methyl-2,3,9,9a-letrahydroindeno[2,l -b][l,4]oxazin-4(4aH)-yl)methanone

[1705] To a stirred solution of intermediate CA6 (100 mg, 0.38 mmol) and intermediate A16 (85 mg, 0.38 mmol) in DMF (3 mL) were added DIEA (246 mg, 1.91 mmol) and HATH (318 mg, 0.84 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep- HPLC with the following conditions: [Column: Xselect CSH C18 OBD Column 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 5% B to 25% B in 15 min; Wave Length: 254/220 nm; RTl(min): 12.5] and further purified by Prep-chiral HPLC with the following conditions: [Column: CHIRAL. ART Cellulose-SZ 2*25 era, 5 um; Mobile Phase A: Hex (0.3% 1PAMIN), Mobile Phase B: MEOH: DCM=1: 1; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 14 min; Wave Length: 220/254 nm; RTl(min): 6.48; RT2(min): 10.64; Sample Solvent: EtOH: DCM-1 : 1— HPLC; Injection Volume: 0.7 mL; Number Of Runs: 3] to afford ((4S,llbR)-6-amino-4-methy1-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- cJ[i,4]oxazin-10-yl)((3R,4aS,9aR)-7-chloro-3-methyl-2,3,9,9a-tetrahydroindeno[2,l- b][l,4]oxazin-4(4aH)-yl)methanone (18.5 mg, 10%) as an off-white solid with retention time al 10.64 minute. MS ESI calculated for C24H26CIN5O3 [M+l]⁺, 468.17; found, 468.15. *H NMR (400 MHz, Methanol-dt) 5 8.19 - 8.01 (111, 1H), 7.58 - 7.44 (m, 1H), 7.43 - 7.14 (m, 3H), 5.74 - 5.50 (m, 1 H), 5.09 - 5.02 (m, 1H), 4.71 - 4.57 (m, 1H), 4.47 - 4.38 (m. 1H), 4.34 - 4.05 (m, 3H), 4.01 - .3.90 (m. 1H), 3.85 - 3.52 (m, 3H), 3.29 - 2.88 (m. 2H), 1.41 - 1.35 (ni, 3H), 1.06 0.90 (m, 3H).

Example 36: ((S)-6-amino-l,3,4,llb-ietrahydropyrido[3',4':4,5]pyriniido[6,l-c][l,4]oxazin-

10-yl)((3R,4aS,9aR)-7-(difluoromethoxy)-3-methyl-2,3,9,9a-tetrahydroindeno[2,lb ] [ 1 ,4]oxazin-4(4aH)-yl)raethanone

[1706] To a stirred mixture of intermediate A 15, isomer 2 (300 mg, 1 .03 mmol), 4A molecular sieve (1 g) and CS2CO3 (1340 mg, 4.11 mmol) in N,N-dimetbylacetamide (8 mL) was added intermediate AC6 (374 mg, 1.23 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of water at room temperature and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 21% MeOH in DCM to afford((S)-6-amino- l,3,4,llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((3R,4aS,9aR)-7- (difluorornethoxy)-3-meihyl-2,3,9,9a-ietrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- yl)methanone (148.2 mg, 29% yield) as a white solid. MS ESI calculated for C24H25F22N5O4 [M+Hf , 486.19; found, 486.20. H NMR (400 MHz, DMSO-tfe) 5 7.93 - 7.68 (m, 1H), 7.54 - 6.92. (m, 5H), 6.62 (br, 2H), 5.65 - 5.54 (m, 1H), 4.76 ■■■• 4.62 (m, 1H), 4.53 - 4.09 (m, 3H), 3.91 - 3.70 (m, 2H), 3.69 - 3.59 (m, 1H), 3.58 - 3.48 (m, 2H), 3.43 - 3.39 (m, 1H), 3.24 - 2.99 (m, 2H), 2.95 - 2.78 (m, 1 H), 0.92 - 0.79 (m, 3H).

Example 37: ((S)-6-amino-l,3,4,llb-tetrahydropyrido[3',4‘:4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((3R,4aS,9aR)-7-chloro-3-methyl-2,3.9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- y])methanone

[1707] To a stirred mixture of intermediate A16 ( 300 mg, 1.15 mmol ), CS2CO3 (1.13 g, 3.46 mmol) and 4A molecular sieve (1 g) in MeCN (10 ml) was added intermediate AC6 (350 mg, 1.15 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched by water and extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2.SO4- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% MeOH in CH2CI2 to afford ((S)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((3R,4aS,9aR)-7-chloro-3- methyl-2,3,9,9a-tetrahydroindeno[2_!l-b][l,4]oxazin-4(4aH)-yl)methanone (204.7 mg, 39% yield) as a white solid. MS ESI calculated for C23H24CIN5O3 [M+Hj⁺, 454.16; found, 454.25. ^!H NMR (400 MHz, DMSO-Js) 87.91 and 7.75 (s, 1H), 7.48 - 7.14 (m, 4H), 6.77 (br, 2H), 5.61 - 5.54 (m, 1H), 4.78 - 4.66 (in, 1H), 4.50 - 4. 12 (m, 3H), 3.91 - 3.74 (m, 2H), 3.67 - 3.60 (m, 1H), 3.59 - 3.50 (m, 2H), 3.49 - 3.41 (m, 1H), 3.24 ■■■■ 3.00 (m, 2H), 2.95 - 2.79 (m, 1 H), 0.90 - 0.79 (m, 3H).

Example 38: ((S)-6-amino-1 ,3,4,llb-ietrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl-2,3,4a,10b-tetrahydrochronieno[3,4- b] [ 1 ,4]oxazin- 1 (5H)-yl)methanone

[1708] To a stirred mixture of intermediate A22 (300 mg, 0.98 mmol), CS2CO3 (953 mg, 2.93 mmol) and 4A molecular sieve (1 g) in MeCN (10 mL) was added intermediate AC6 (296 mg, 0.98 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched by water and extracted with EtOAc. The- combined organic layers were dried over anhydrous Na2SCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-20% MeOH in CH2CI2 to afford ((S)-6-amino-l ,3,4, 11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R,4aS,10bS)-8- (dinuoromethoxy)-2-methyl-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)- yl)methanone (209.8 mg, 42%) as a white solid. MS ESI calculated for C24H25F2N5O5 [M+H]⁺, 502.18; found, 502.25. ^!H NMR (400 MHz, DMSO-tfe) 5 7.90 and 7.81 (s, 1H), 7.52 - 7.00 (m, 3H), 6.99 - 6.51 (m, 4H), 5.80 - 5.64 (m, 1H), 4.79 - 4.67 (m, 1H), 4.58 - 4.26 (m, 2H), 4.24 - 4.06 (m, 2H), 3.97 - 3.59 (m, 5H), 3.58 - 3.42 (m, 2H), 3.15 - 3.04 (m,

1H), 0.82 - 0.71 (m, 3H).

Example 39: ((R)-6-amino-i,3,4,l lb-letrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4aR*,10bR*)-8-cyclopropoxy-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- bjpyridin- 1 ■■ yl)methanone

[1709] To a stirred mixture of intermediate A25 (50 mg, 0. 17 mmol) in DMAC (5 mL) were added K2CO3 (122 mg, 0.88 mmol), 4 A molecular sieve (700 mg) and intermediate AC4 (64 mg, 0.21 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature tor 4 h. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-15% MeOH in DCM to afford ((R)-6-amino-l,3,4, l lb-tetrahydropyrido[3’,4’:4,5]pyrimido[6,l- cJ[l,4]oxazin-10-yl)((4aR*,10bR*)-8-cyc1opropoxy-2,3,4,4a,6,10b-hexahydro-lH- isochromenoL4,3-bjpyridin-l-yl)methanone (26.5 mg, 31% yield) as a white solid. MS ESI calculated for C26H29N5O4 [M+H]⁺, 476.22; found, 476.20. ^;H NMR (400 MHz, DMSO-d₆) 8 7.90 - 7.79 (m, 1H), 7.39 - 6.67 (m, 6H), 5.77 - 5.45 (m, 1H), 4.94 - 4.58 (m, 3H), 4.30 - 3.80 (m, 6H), 3.55 - 3.50 (m, 2H), 3.17 - 3.09 (m, 1H), 2.68 - 2.27 (m, 1H), 1.72 - 1.56 (m, 4H), 0.78 - 0.76 (m, 2H), 0.64 - 0.62 (m, 2H).

Example 40: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((4aR*,9bR*)-7-(trifluoromethyl)-3,4,4a,9b-tetraliydrofuro[2,3-b:4,5-b']dipyridin-

1 (2H)-y1)methanone isomer 1

Isomer 1

[1710] To a stirred solution of intermediate A26, isomer 2 (50 mg, 0.20 mmol) and intermediate AC4 (54 mg, 0.20 mmol) in N,N-dimethyJacetamide (2 mL) was added DIEA (79 mg, 0.61 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD CIS Coiumn30'^:T50 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 23% B to 43%; B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.9) to afford ((R)-6- amino-l ,3,4,llb-tetrahydropyrido[3’,4^>:4,5]pyrimido[6,l -c][l,4]oxazin-10-yl)((4aR*,9bR*)- 7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3“b:4,5“b’]dipyridin-l(2H)-yl)metlianone isomer 1 (5.7 mg, 6%) as a white solid. MS ESI calculated for C22H21F3N6O3 [M+H]⁺, 475.16; found, 475.15. ^;H NMR (400 MHz, DMSO-J6) 8 8.22 - 7.83 (m, 2H), 7.48 - 7.33 (m, 2H), 6.53 (br, 2H), 6.21 - 6.19 (m, 1H), 5.23 - 5.13 (m, 1H), 4.69 (d, J = 10.4 Hz, 1H), 4.22 - 3.95 (m, 1H), 3.84 - 3.69 (m, 2H), 3.54 - 3.47 (m, 3H), 3.09 - 3.05 (m, 1H), 2.84 -

2.52 (m, 1H), 1.83 - 1.57 (m, 4H).

Example 41 : ((R)-6-amino-l ,3,4, 1 lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][1 ,4]oxazin- 10-yl)((4aR*,9bR*)-7-(trifluoTomethyl)-3,4,4a,9b-tetrahydrofuTo[2,3-b:4,5-b']dipyridin- l(2H)-yl)methanone isomer 2

[1711] To a stirred mixture of intermediate A26, isomer 1 (50 mg, 0.20 mmol) and CS2CO3 (200 mg, 0.61 mmol) in acetonitrile (2 mL) was added intermediate AC4 (70 mg, 0.26 mmol) at 0 °C. The solvent was removed under vacuum. The residue was purified by flash column chromatography with 5- 15% MeOH in DCM to afford ((R)-6-amino-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido|6,l-c][l,4]oxazin-10-yl)((4aR*,9bR*)-7-

(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)-yl)methanone isomer 2 (9.2 mg, 9%) as a white solid. MS ESI calculated for C22H21F3N6O3 [M+H]⁺, 475.16; found, 475.10. 'H NMR (400 MHz, DMSO-&) 8 8.27 - 7.79 (m, 2H), 7.56 - 7.32 (m, 2H), 6.82 (br, 2H), 6.31 - 6.05 (in, 1H), 5.31 - 5.04 (m, 1H), 4.75 - 4.68 (m, 1H). 4.26 - 4.10 (m, 1 H), 3.94 - 3.78 (m, 2H), 3.60 - 3.49 (m, 3H), 3. 16 - 3.04 (m, 1 H), 2.87 - 2.67 (m, i H), 1 .97 - 1.57 (m, 4H).

Example 42: (4aR*,9bR*)-l-((R)-6-amino-l,3,4,l lb- t.etrahydropyrido|3',4’:4,5]pyrimido[6, l-c]| 1 ,4]oxazine-10-carbonyl)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine-7 -carbonitrile, isomer 1 isomer 1

[1712] To a stirred mixture of intermediate A27, isomer 2 (80 mg, 0.40 mmol) in DMAC (2 mL) were added 4A molecular sieve (20 mg), K2CO3 (221 mg, 1.60 mmol) and intermediate AC4 (106 mg, 0.40 mmol) at 0 °C with stirring. The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCM. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 5-30% MeCN in H2O (0.1% FA) to afford (4aR*,9bR*)-l-((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- cl[l,4]oxazine-10-carbonyl)-l,2,3,4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine-7-carbonitrile, isomer 1 (75.7 mg, 44%) as a light-yellow solid. MS ESI calculated for C23H22N6O3 [M+H]⁺, 431.18; found, 431.15. ^!H NMR (400 MHz, Methanol-^) 5 8.16 (s, 1H), 7.89 - 7.45 (m, 2H), 7.34 (dd, 7.6, 1 .2 Hz, 1H), 7.20 (s, 1H), 6.37 - 5.93 (m, 1H), 5.15 - 5.14 (m, 1H), 4.99 - 4.97 (m, 1H), 4.60 - 4.26 (m, 1H), 4.03 - 3.91 (m, 3H), 3.72 - 3.66 (m, 2H), 3.47 - 3.36 (m, 1H), 2.91 - 2.72 (m, 1H), 2. 15 - 1.57 (m, 4H).

Example 43: (4aR*,9bR*)-l-((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-cafbonyl)-l,2,3,4,4a,9b- hexahydrobenzofuro[3,2-b]pyridine-7-carbonitrile, isomer 2

Isomer 2

[1713] To a stirred solution of intermediate A27, isomer 1 (60 mg, 0.30 mmol) in DMAC

(2 mL) were added 4A molecular sieve (20 mg), K CO . ( 165 mg. 1.20 mmol) and intermediate AC 4 (96 mg, 0.36 mmol) at 0 °C with stirring. The resulting solution was stirred al 25 °C for 1 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-20% MeOH in DCM to afford (4aR*,9bR*)-i-((R)-6- amino-1 ,3,4, llb-teirahydropyrido[3’,4';4,5]pyrimido[6,l-c][l,4]oxaz.ine-10-carbonyl)- L2,3.4,4a,9b-hexahydrobenzofuro[3,2-b]pyridine-7-carbonitrile, isomer 2 (33.2 mg, 26%) as a white solid. MS ESI calculated for C23H22N6O3 [M+H]⁺, 431.18; found, 431. 15. NMR (400 MHz, DMSO-^e) 8 7.93 (s, 1H), 7.73 - 7.37 (m, 4H), 6.88 (br, 2H), 6.20 - 6.05 (m, 1H), 5.13 - 5.02 (rn, 1H), 4.73 (dd, J = 10.4, 3.6 Hz, 1H), 4.18 (d, 7 = 10.8 Hz, 1H), 3.89 - 3.82 (m, 3H), 3.57 - 3.54 (m, 2H), 3.15 - 3.07 (m, 1 H), 2.75 - 2.46 (m, 1H), 1.95 - 1.57 (m, 4H).

Example 44: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4aR*,10bR*)-8-isopropoxy-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- b]pyridin- 1 -yl)methanone

[1714] To a stirred solution of intermediate A28 (40 mg, 0. 14 mmol) and K2CO3 (97 mg, 0.71 mmol) in DMAC (2 mL) were added 4A molecular sieve (400 mg) and intermediate AC4 (45 mg, 0. 17 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSCU- After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions:[Column: XBridge Prep OBD C18 Column30*150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 25% B to 45% B in 10 min; Wave Length: 254/220 nm; RTl (min): 8.9] to afford ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l ,4]oxazin-10- yl)(.(4aR*,10bR*)-8-isopropoxy-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l- yl)methanone (22.9 mg, 34%) as a white solid. MS ESI calculated for C26H31N5O4 [M+H]⁺, 478.24; found, 478.30. ^!H NMR (400 MHz, DMSO-cfe) 3 8.21 - 7.65 (m, 1H), 7.49 - 7.02 (m, 2H), 6.95 - 6.44 (ni, 4H), 5.84 - 5.33 (m, 1H), 4.89 - 4.48 (ni, 4H), 4.38 - 3.69 (m, 5H), 3.60 - 3.45 (m, 2H), 3.17 - 3.01 (m, 1H), 2.75 - 2.23 (m, 1H), 1.82 - 1.39 (m, 4H), 1.25 (d, J - 6.0 Hz, 6H).

Example 45: ((S)-6-amino-9- fluoro- 1 ,3,4, 1 lb-tetrahydro-[ 1 ,4]oxazino|4,3-c]quinazolin-10- yl)((4aR*.10bR*)-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b']dipyridin-l-yl)methanone

[1715] To a stirred solution of intermediate A29 (50 mg, 0. 17 mmol) in N,N- dimethylacetamide (1 mL) were added CS2CO3 (552 mg, 1.70 mmol) and intermediate ACT isomer 2 (48 mg, 0.17 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. Hie resulting mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSOr. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC with the following conditions: [Column: XBridge Prep OBD C18 Column30* 150 mm; Mobile Phase A: Water (TO mmol/L NH4HCO3), Mobile Phase B: ACN; Flow' rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min, 26% B to 46% B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.9] to afford ((S)-6-amino-9- fluoro-1,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-ylX(4aR*,10bR*)-8- (lrifluoromethyl)-2,3,4,4a,6, !0b-hexahydro4H-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone (22.9 mg 26% yield) as a white solid. MS ESI calculated for C24H23F4N5O3 [M+H]⁺, 506.17: found, 506.15. ^!H NMR (400 MHz, DMSO-ds) 6 7.87 (s, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.70 - 6.30 (m, 3H), 5.97 - 5.96 (m, 1H), 4.84 - 4.83 (m, 2H), 4.70 - 4.50 (m, 1H), 4.40 - 4.20 (m, 1H), 4.05 - 4.04 (m, 1H), 3.89 ■■■ 3.69 (m, 2H), 3.51 - 3.49 (m, 3H), 3.18 - 3.00 (m, 1H), 2.74 - 2.31 (m, 1 H ), 1.92 - 1.31 (m, 4H). Example 46: ((R)-6-amino- 1 ,3,4,llb-tetrahydropyrido[3’,4‘:4,5]pyrimido[6, 1 -c][l,4]oxazin- 10-yl)((3R,4aR*,10bR*)-8-(difluoromethoxy)-3-methoxy-2,3,4,4a,6,10b-hexahydro-lH- isochromeno [4,3 ■ bjpyridin- 1 -yl)methanone

[1716] To a stirred solution of intermediate A30 (50 mg, 0.18 mmol) in DMAC (2 mL) were added CS2CO3 (286 mg, 0.88 mmol) and intermediate AC4 (70 mg, 0.26 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NazSCh. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm; Mobile Phase A: Water (10 mniol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min. 22% B to 42% B in 10 min; Wave Length: 254/220 nm;

RTl(min): 8.9) to afford ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3^,,4’:4,5]pyrimido[6,l- c][l,4]oxazin-10-yl)((3R.4aR*,10bR*)-8-(difluoromethoxy)-3-methoxy-2,3,4,4a,6.10b- hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone (35.5 mg, 39%) as a white solid. MS ESI calculated for C25H27F2N5O5 [M+H]⁺, 516.20; found, 516.20. TI NMR (400 MHz, DMSO-rfo) 5 7.92 and 7.72 (s, 1H), 7.51 - 7.32 (m, 2H), 7.26 - 6.87 (m, 3H), 6.53 (s, 2H), 5.75 - 5.59 (m, 1H), 4.90 - 4.64 (m, 3H), 4.63 - 4.05 (m, 3H), 3.93 - 3.68 (m, 2H), 3.61 - 3.44 (m, 3H), 3.29 and 3.19 (s, 3H), 3.12 - 2.99 (m, 1H), 2.38 - 1.95 (m, 2H), 1 .53 - 1.47 (ra, TH).

Example 47 : ((S)-6-amino-9-fluoro- 1 ,3,4, 1 lb-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin- 10- yl)((3R,4aR*, 1 ObR* )-8-(difluoromethoxy)-3-methoxy-2,3,4,4a,6, iOb-hexahydro- 1 II- isochromeno[4,3-b]pyridin- 1 -yl)niethanone

[1717] To a stirred solution of intermediate A30 (50 mg, 0.17 mmol) and CsiCCh (256.96 mg, 0.78 mmol) in N,N-dimethylacetamide (0.5 mL) was added intermediate AC1 isomer 2 (74 mg, 0.26 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC with the following conditions: [Column: XBridge Prep OBD C18 Column 30*150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient:

5% B to 5% B in 2 min, 27% B to 47% B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.9] to afford ((S)-6-amino-9-fluoro-l ,3,4,1 lb-tetrabydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R,4aR*_s10bR*)-8-(difluoromethoxy)-3-methoxy-2,3,4,4a.6,10b-hexahydro- 1H- isochromeno[4,3-b]pyridin-l-yl)methanone (35.5 mg, 38% yield) as an off-white solid. MS ESI calculated for C26H27F3N4O5 [M+H]⁺, 533. 19; found, 533. 15. ^:H NMR (400 MHz, DMSO-d₆) 87.46 - 6.85 (m, 5H), 6.37 (m, 3H), 5.78 - 3.77 (m, 1H), 4.80 ■■■■ 4.58 (m, 4H), 4.17 - 4.16 (m, 1H), 4.10 - 3.90 (m, 1H), 3.87 - 3.60 (m, 2H), 3.59 - 3.42 (m, 2H), 3.29 - 3.06 (m, 5H), 2.42 - 2.27 (rn, 1H), 2.28 - 2.09 (m, 1H), 1.50 - 1.47 (m, 1H).

Example 48: ((R)-6-amino-l,3,4,llb-tetrahydropyrido[3\4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((S)-3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[1718] To a stirred solution of (S)-3-(4”(trifIuoromethyl)phenyl)morpholine A31 (500 mg,

2.16 mmol, prepared according to a known procedure) and intermediate AC4 (865 mg, 3.24 mmol) in N,N-dimethylacetamide (10 mL) was added EtaN (875 mg, 8.65 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with 0-20% methanol in dichloromethane to afford ((R)-6-amino- l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-cj[l,4]oxazin-10-yl)((S)-3-(4- (triflrioromethyl)phenyl)morpholino)methanone (327.1 mg, 33%) as an off-white solid. MS ESI calculated for C22H22F3N5O3 [M+H]⁺, 462.17; found, 462.15. ^!H NMR (400 MHz, DMSO-cfc) 8 8.05 - 7.50 (m, 5H), 7.36 (s, 1H), 6.61 (s, 2H), 5.70 5.69 (s, 1H), 4.78 - 4.58 (m, 1H), 4.50 (d, .J = 12.4 Hz, 1H), 4.36 - 3.89 (m, 2H), 3.88 - 3.61 (m, 4H), 3.60 - 3.43 (m. 3H), 3.22 - 2.99 (m, 21 b.

Example 49: ((4S,llbR)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4aR*,10bR*)-8-

(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l- yDmethanone formate

[1719] To a stirred solution of intermediate A29 (90 mg, 0.31 mmol) and intermediate CA6 (96 mg, 0.37 mmol) in N,N-dimethy1formamide (10 mL) were added N,N- diisopropylethylamine (158 mg, 1.22 mmol) and O-(7-Azabenzotriazol-l-yl)-N,N,N,N- tetramethyluronium Hexafluorophosph ate (174 mg, 0.46 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: [Column: Xselect CSH OBD Column 30* 150mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 60 mL/min; Gradient (B%): 23% B to 40 % B in 10 min; Wave Length: 254/220 nm; RTi (min): 5] to afford ((4S,1 lbR)-6-amino-4-methyl-l, 3,4,11b- teiraliydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4aR*,10bR*)-8- (tifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l- yDniethanone formate (78.6 mg, 46%) as an off-white solid. MS ESI calculated for C24H25F3N6O3 [M+H]⁺, 503.19; found, 503.30. ^SH NMR (400 MHz, DMSO-O 8 (ppm) 8.18 (s, 1H), 8.17 - 7.76 (m, 3H), 7.39 - 7.38 (m, 1H), 6.91 (br, 2H), 5.98 - 5.66 Cm, ill), 4.95 - 4.65 (m, 3H), 4.56 - 4.50 (m, 1H), 4.38 ~ 4.30 (m, 1H), 4.27 - 3.72 (m, 5H), 2.65 - 2.20 (m, 1H), 1.88 - 1.50 (m, 4H), 1.19 (d, J = 6.0 Hz. 3H).

Example 50: ((4S,llbS)-6-amino-4-methyl-l ,3,4,11b- tetrahydropyrido[3',4':4,5]pyriniido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8-

(trifluoromethyl)-2,3,4,4a,6,l0b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l- yl jmethanone formate

[1720] To a stirred solution of intermediate A29 (90 mg, 0.31 mmol) and intermediate CA5 (96 mg, 0.37 mmol) in N,N-dirnethylformamide ( 10 mL) were added N,N- diisopropylethylamine (158 mg, 1.22 mmol) and O-(7-Azabenzotriazol-l-yl)-N,N,N,N- tetramethyluronium Hexafluorophosphate (174 mg, 0.46 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: [Column: Xselect CSH OBD Column 30* 150mm, 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate; 60 mL/min; Gradient: 22% B to 37% B in 10 min; Wave Length: 254/220 nm; RTl(min): 4.3] to afford ((4S, 1 lbS)-6-amino-4-methyl-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c][l ,4]oxazin-10-yl)((4aR*, 10bR*)-8- (trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l- yl)methanone formate (68.7 rng, 41%) as a yellow solid. MS ESI calculated lor C24H25F3N6O3 [M+H]⁺,503.19; found, 503.25. ^:H NMR (400 MHz, Methanol-d₄) 8 (ppm) 8.55 (s, 1H), 8.35 - 7.95 (m, 2H), 7.77 (d, J - 8.0 Hz, 1 H), 7.57 (s, 1H), 6.15 - 5.55 (m, 1H), 5.26 - 5.22 (m, 1H), 4.96 - 4.42 (m, 4H), 4.36 - 4.18 (m, 1H), 4.10 - 4.03 (m, 1H), 3.93 -

3.78 (m, 2H), 3.74 - 3.65 (m, 1H), 2.85 - 2.30 (tn, JH), 2.02 - 1.61 (m, 4H), 1.52 (d, J - 6.8 Hz, 3H).

Example 51: tert-butyl (4aR*,10bR*)-l -((R)-6-amino- 1,3,4, 11b- tetrahydropyrido[3^,,4':4,5]pyrimido[6,l-c][l,4]oxazine-l0-carbonyl)-8-(trifluoromethy1)- l,2,3,4a,5,10b-hexahydro-4H-chromeno[3,4-b]pyrazine-4-carboxyIate, isomer 1

Step-1 : isomer 1

[1721] To a mixture of intermediate A32, isomer 1 ( 100 mg, 0.27 mmol) and CS2CO3 (272 mg, 0.83 mmol) in MeCN (3.0 ml) was added intermediate AC4 (89.3 mg, 0.33 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The solid was filtered. The solvent was removed under vacuum. The residue was purified by reverse phase flash column chromatography with 5~8()% acetonitrile in water to afford tert-butyl (4aR*,10bR*)-l-((R)-6- amino- 1 ,3,4, 1 1 b-tetrahydropyrido[3’,4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazine- 10-carbonyl)-8- (trifliioromethyl)-l,2,3,4a,5,10b-hexahydro-4H-chromeno[3,4-b]pyrazine-4-carboxyiate, isomer 1 (84 mg, 51%) as a yello w solid. MS ESI calculated for C28H31F3N6O5 [M+H]⁺, 588.20; found, 588.30.

Step-2:

isomer 1

[1722] A mixture of tert-butyl (4aR*,10bR*)-l-((R)-6-amino-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-cafbonyl)-8-(trifluoromethyl)- l,2,3,4a,5J 0b-hexahydro-4H-chromeno[3,4-b]pyrazine-4-carboxylate, isomer 1 (80 mg, 0.13 mmol) and HC1 (4M in dioxane) (1.0 mb) was stirred at room temperature for 4 h. The solvent was removed under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: XB ridge Prep OBD C 18 Colurnn30*150 mtn; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min, 18% B to 38% B in 10 min; Wave Length: 254/220 nm;

RTl (min): 8.9) to afford tert-butyl (4aR*,10bR*)-l-((R)-6-amino-l,3,4J lb- tetrahydropyrido[3^,,4':4,5]pyrimido[6,l -c][l,4]oxazine- 10-carbonyl)-8-(trifluoromeihy1)- l,2,3,4a,5,10b-hexahydro-4H-chromeno[3,4-b]pyrazine-4-carboxylate, isomer 1 (40.9 mg, 61%) as a white sloid. MS ESI calculated for C23H23F3N6O3 [M+H]⁺, 489.18; found, 489.15. ^;H NMR (400 MHz, DMSO-<A) d 7.86 and 7.72 (s, 1H), 7.52 - 7.01 (m, 4H), 6.48 (s, 2H), 5.72 - 5.55 (m, 1H), 4.73 - 4.59 (m, 1H), 4.47 - 4.06 (m. 3H), 3.90 - 3.69 (m, 3H), 3.60 - 3.41 (m, 2H), 3.13 - 2.98 (m, 2H), 2.94 - 2.57 (m,3H).

Example 52: tert-butyl (4aR*,10bR^!i!)-l-((R)-6-amino-l,3,4,llb- tetraliydropyrido[3',4':4,5]pyrimido[6,l-cJ[l,4]oxazine-10“Carbonyi)-8-(trifluoromethyl)

1 ,2,3.4a,5, 10b-hexahydro-4H-chromeno[3.4-b]pyrazine-4-carboxylate, isomer 2

Step-1:

isomer 2

[1723] To a mixture of intermediate A32, isomer 2 (100 mg, 0.27 mmol) and CsjCO? (272 mg, 0.83 mmol) in MeCN (3.0 ml..) was added intermediate AC4 (89 mg, 0.33 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The solids were filtered. The filtrate was concentrated under vacuum. The residue was purified by re verse phase Hash column chromatography with 5~80% acetonitrile in water to afford tert-butyl (4aR*,10bR*)-l-((R)-6- amino-l,3,4,l lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)-8- (trifluorometliyl)-l,2,3,4a,5,10b-hexahydro-4H-chromeno[3,4-b]pyrazine-4-cart>oxylate, isomer 2 (69 mg, 42%) as a white solid. MS ESI calculated for C ■ j fo I [M+H]⁺, 589.20; found, 589.30.

Step-2:

[1724] A mixture of tert-butyl (4aR*,10bR*)-l-((R)-6-aniino- 1,3,4, 11b- tetrahydropyrido[3',4’:4,5]pyrimido[6, 1 -c] [1 ,4]oxazine- 10-carbonyl)-8-(trifluoromethyl)- 1 ,2,3,4a,5,10b-hexabydro-4H-chromeno[3,4-b]pyrazine-4-carboxylate, isomer 2 (69 mg, 0. 12 mmol) and HC1 (4M in dioxane) (1.0 rnL) was stirred at room temperature for 1 h. The solvent was removed under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30* 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min. 18% B to 38% B in 10 min; Wave Length: 254/220 nm;

RTl(min): 8.9) to afford tert-butyl (4aR*,10bR*)-l-((R)-6-amino-l, 3,4,11b- teiraliydropyrido[3',4’:4,5]pyrimid0[6,l-c][l,4]oxazine-lO-carb0riyl)-8-(trifluoromethyl)- 1 ,2,3,4a,5,10b-hexahydro-4H-chromeno[3,4-b]pyrazine-4-carboxyIaie, isomer 2 (38.5 mg, 66%) as a white sloid. MS ESI calculated for C23H23F3N6O3 [M+H]⁺, 489.18; found, 489.15. ^!H NMR (400 MHz, DMSO-ds) # 7.86 and 7.72 (s, 1H). 7.52 - 7.01 (m, 4H), 6.48 (s, 2H), 5.72 - 5.55 (m, 1H), 4.73 - 4.59 (m, 1H), 4.47 - 4.06 (m, 3H), 3.90 - 3.69 (m, 3H), 3.60 - 3.41 (m, 2H), 3.13 - 2.98 (m, 2H), 2.94 - 2.57 (m,3H).

Example 53: ((R)-6-amino-l ,3,4.11b-tetrahydropyrido[3’,4':4.5]pyrimido[6,l-c][l,4]oxazin- l0-yl)((4aR*,10bR*)-8-(trifluoromethyl)-2,3,4,4a,6,l0b-hexahydro-lH-pyrano[3,2-b:5,4- b'Jdipyridin- 1 -yl) methanone

[1725] To a stirred solution of intermediate A29 (50 mg, 0.19 mmol), 4 A molecular sieve (100 mg) and CS2CO3 (252 mg, 0.77 mmol) in N,N-dimethylacetamide (1 ml..) was added intermediate CA4 (72 mg, 0.27 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC with the following conditions: [Column: XBridge Prep OBD C18 Column 30* 150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 inL/min; Gradient: 5% B to 5% B in 2 min, 20% B to 40% B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.9] to afford ((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c][ 1 ,4]oxazin- 10-yl)((4aR*,10bR*)-8- (trifluoromethyl)-2,3,4,4a,6, 10b-hexahydro-l H-pyrano[3,2-b:5,4-b']dipyridin-l- yj)methanone (13.4 mg, 14% yield) as a white solid. MS ESI calculated for C23H23F3N6O3 [M+H]⁺, 489.18; found, 489.10. ’ll NMR (400 MHz, DMSO-<fe) 8 8.19 - 7.62 (m, 3H), 7.42 - 7.37 (m, 1H), 6.51 (s, 2H), 5.94 - 5.80 (m, 1H), 4.99 - 4.57 (m, 3H), 4.40 - 4.05 (m, 3H), 3.96 - 3.75 (m, 2H), 3.54 - 3.49 (m. 2H), 3.09 - 3.06 (m, 1H), 2.52 - 2.12 (m, 1H), 1.89 ~ 1.39 (m, 4H). Example 54: (4aR*,9bR*)-l -((S)-6-amino-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c]ll,4]oxazme-10-carbonyr)-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine-7-carbonitrile

[1726] To a stirred solution of intermediate A33 (80 nig, 0.39 mmol, 86% e.e.) and intermediate CA7 (118 mg, 0.47 mmol) in DMF (2 mL) were added D1EA (154 mg, 1.19 mmol) and HATU ( 181 mg, 0.47 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at. room temperature for 2 h. The resulting mixture was diluted by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NarSOa. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-12% MeOH in DCM to afford (4aR*,9bR*)-l"((S)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6, l-c][L4]oxazine- 10-carbonyl)- 1,2,3, 4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine-7-carbonitrile (22 mg) as a white solid, which was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NHvMeOH), Mobile Phase B: MEOH: DCM-1 : 1--HPLC; Flow rate: 20 mL/min; Gradient (B%): 60% B to 60% B in 10 min; Wave Length: 220/254 nm; RTl(min): 6.56; RT2(min): 7.58; Sample- Solvent: MeOH: EtOH=l : 1 — HPLC] to afford (4aS,9bS)-1 -((S)-6-amino- 1,3,4, 1 1b- tetrahydropyrido[3^,,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)-l,2,3,4,4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridine-7-carbonitrile (13.0 mg, 59% yield) as a white solid with the second peak on chiral HPLC. MS ESI calculated for C22H21N7O3 [M+Hf , 432.17; found, 432.15. ^JH NMR (400 MHz, DMSO-rA) 8 8.25 - 7.80 (m, 2H), 7.65 (d, J- 7.2 Hz, 1H), 7.40 - 7.39 (m, 1H), 6.66 (s, 2H), 6.24 - 6.14 (m, TH), 5.22 - 5.11 (m, 1H), 4.80 - 4.59 (m, 1H), 4.32 - 3.62 (m, 4H), 3.57 - 3.45 (m, 2H), 3.19 - 3.00 (m, 1H), 2.99 - 2.53 (m, 1H), 2.09 - 1.55 (m, 4H). Example 55: ((S)-6-amino-l,3,4,Hb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((2R,4aS,10bS)-8-methoxy-2-meihyl-2,3,4a,10b-telrahydropyrido[3',2‘:5,6]pyrano[3,4- b] [ 1 ,4]oxazin- 1 (5H)-yl)methanone

[1727] A mixture of intermediate A34 (80 mg, 0.29 mmol), intermediate CA7 (100 mg, 0.41 mmol), triethylamine (342 mg, 3.39 mmol) and bis(2-oxo-l,3-oxazolidin-3- yl)phosphinoyl chloride (129 mg, 0.51 mmol) in N,N-dimethylacetamide (8 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The- residue was purified by Prep-HPLC with the following conditions: [Column: XBridge Prep OBD Cl 8 Column 30*150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min, 9% B to 29% B in 10 min; Wave Length: 254/220 nra; RTl(min): 8.9] to afford ((S)-6-amino- 1,3,4, 1 1b- tetrahydropyndo[3’,4':4,5]pyrimido[6, 1 -c][1 ,4]oxazin-10-yl)((2R,4aS,l0bS)-8-methoxy-2- methyl-2,3,4a,10b-tetrahydropyrido[3’,2':5,6]pyrano[3,4-b][l,4]oxazin-l(5H)-yl)methanone (10.5 mg, 6*%:) as an off-white solid. MS ESI calculated for C23H26N6O5 [M+H]⁺, 467.20; found, 467.20. *H NMR (400 MHz, DMSQ-d₆) 3 (ppm) 7.84 - 7.75 (m, 1H), 7.61 - 7.43 (m, 1H), 7.36 - 7.25 (m, 1H). 6.47 - 6.36 (m, 3H), 5.69 - 5.39 (m. 1H), 4.71 - 4.64 (m, 1 H), 4.49 - 4.29 (m, 2H), 4.23 - 4.07 (m, 2H), 3.87 - 3.66 (m, 7H), 3.65 - 3.38 (m, 3H), 3.15 - 3.04 (m, 1 H), 0.73 - 0.68 (m, 3H).

Example 56: ((S)-6-amino-l,3,4,llb-tetrahydropyrido[3',4‘:4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((2R,4aS, 10bS)-8-(difluoromethoxy)-2-methyl-2,3,4a.10b- teirahydropyrido[3',2':5,6]pyrano[3,4-b][l,4]oxazin-l(5H)-yl)methanone

[1728] To a stirred solution of intermediate A35 (57 mg, 0.21 mmol), K2CO3 (415 mg, 3.00 mmol) and 4A molecular sieve (100 mg) in N.N-dimethylacetamide (2 mL) was added intermediate AC6 (80 mg, 0.30 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by normal phase flash column chromatography eluted with 0-30% methanol in di chloromethane to afford ((S)-6-amino-l,3,4,l lb-tetrahydropyrido[3‘,4’:4,5]pyrimido[6,l- c][l,4joxazin-10-yl)((2R,4aS,10bS)-8-(difluoromethoxy)-2-methyl-2,3,4a,10b- tetrahydropyrido[3',2':5,6]pyrano[3,4-b][l,4]oxazin-l(5H)-yl)methanone (12.6 mg, 8% yield) as a white solid. MS ESI calculated for C23H24F2N6O5 [M+H]¹’, 503.18; found, 503.15. ‘H NMR (400 MHz, DMSO-d₆) 8 7.90 (s, 1 H), 7.84 - 7.23 (m, 3H), 6.69 - 6.64 (m, 3H), 5.83 - 5.53 (m, 1H), 4.74 - 4.71 (m, 1H), 4.61 - 4.31 (m, 2H), 4.28 - 4.06 (m, 2H), 3.99 - 3.89 (m, 1H), 3.88 - 3.60 (m, 4H), 3.60 - 3.41 (m, 2H), 3.18 - 2.98 (m, 1H), 0.77 - 0.74 (m, 3H).

Example 57: ((S)-6-amino-l,3,4,llb-tetrahydropyrido|3^,,4':4,5|pyriniido|6,l-c]| 1.4joxazin-

10-yr)((4aR*,9bR*)-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2.3-b:4,5-b']dipyridin- l(2H)-yl)methanone

[1729] A mixture of intermediate A26, isomer 2 ( 60 mg, 0.24 mmol), intermediate CA7 (73 mg, 0.29 mmol), BOP (163 mg, 0.37 mmol) DIEA (127 rag, 0.98 mmol) in DMF (2 mL) was stirred at 25 °C for 4 h. The reaction mixture was purified by Prep-HPLC with the following conditions [Column: XB ridge Prep OBD C18 Column30*150 mm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min, 20% B to 40% B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.9] to afford ((S)-6-ainiiio-l,3,4,l lb-tetrahydropyrido[3^!,4':4,5]pyriniido[6,l- c] [ 1 ,4]oxazin-10-yl)((4aR*,9bR*)-7-(trinuoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b’]dipyridin-l(2H)-yl)methanone (49.4 mg, 42% yield) as a white solid. MS ESI calculated for C22H21F3N6O3 [M+H]⁺, 475.16; found, 475.15. ^SH NMR (400 MHz, DMSCMg) 8 8.19 - 8.04 (m, I FI), 7.83 (s, IH), 7.49 (d, 7.4 Hz, IH), 7.34 - 7.33 (m, 1H), 6.53 (s, 2H), 6.50 -

6.00 (m, IH), 5.21 - 5.17 (m, IH), 4.67 - 4.64 (m, LH), 4.13 - 4.10 (m, IH), 3.85 - 3.83 (m, IH), 3.76 - 3.73 (m, IH), 3.56 - 3.49 (m, 3H), 3.17 - 2.98 (m, IH), 2.93 - 2.54 (m, IH), 2.07 - 1.44 (m, 4H).

Example 58: ((S)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((2R,4aR,10bS)-2-methyl-8-(trilluoromethyl)-2,3,4a,5,6,10b-hexahydro-lH-

[ 1 ,4]oxazino[3 ,2-fjquinolin- 1 -yljmethanone

[1730] To a stirred mixture of intermediate A38 (50 mg, 0.20 mmol), IDEA (130 mg, 1 .00 mmol) and intermediate CA7 (54 mg, 0.20 mmol) in DMAC (2 mL) was added bis(2-oxo- l ,3-oxazolidin-3-yl)phospbinoy! chloride (76 mg, 0.30 mmol) at room temperature. The resulting mixture was stirred at room temperature for I h. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5pm; Mobile Phase A: Water) 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient (B%): 29%' B to 39% B in 10 min; Wave Length: 254/220 nm; RTl (min): 15) to afford ((S)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin- l()-yl)((2R,4aR,10bS)-2-methyI-8-(trilluoromethyl)-2,3,4a,5,6,10b-hextd'iydro-lH- [l,4]oxaz.ino[3,2-f]quinolin-l-yl)methanone (10.4 mg, 10%’) as a white solid. MS ESI calculated for C • d l MLNAL [M+H]⁺, 503.19; found, 503.15. H NMR (400 MHz, DMSO- do) 5 8.1 1 - 7.62 (m, 3H), 7.51 - 7.32 (m, 1H), 6.52 (br, 2H), 5.86 - 5.63 (m, 1H), 4.75 - 4.57 (m, 1H), 4.21 - 4.08 (m, 2H), 4.00 - 3.92 (m, 1H), 3.89 - 3.67 (m, 3H), 3.60 - 3.59 (m, 1H), 3.58 ... 3.44 (m_t 2H), 3.17 - 3.02 (m, 2H), 2.89 - 2.73 (m, 1H), 2.32 - 2.12 (m, 2H). 0.75 - 0.60 (m, 3H).

Example 59: ((S)-6-amino-l,3,4,1 lb-tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,41oxazin- 10-yl)((3R*,4aS*,9bS*)-7-(difluorometlioxy)-3-fluoro-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridin-l(2H)-yl)methanone, isomer 1

Isomer 1

[1731] To a stirred mixture of Intermediate A39, isomer 2 (50 mg, 0.19 mmol), intermediate CA7 (50 mg, 0.19 mmol) and DIEA (50 mg. 0.38 mmol) in N.N- dimethylacetamide (1.5 mL) was added HATU (1 10 mg, 0.29 mmol) at 30 °C. The resulting mixture was stirred at 30 °C for 3 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na^SOa. After nitration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% MeOH in DCM to afford 33 mg of light yellow solid, which was purified by reversed- phase flash column chromatography with following condition: (Phase A: 75% i-PrOH+25% MeCN, Phase B: Water (10 mmol/L NH4HCO3); 5% to 100% B in A gradient in 30 minutes) to afford ((S)-6-amino- 1,3,4, 1 lb-tetrahydropjtrido[3',4':4,5]pyrimido[6,l- cj [ 1 ,4]oxazin- 10-yl)((3R* ,4aS* ,9bS*)-7- -(difluoromethoxy)-3-fluoro-3 , 4, 4a, 9b- tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone, isomer 1 (17 mg, 18% yield) as a white solid. MS (ESI) calculated for (C23H22F3N5O4) [M+H]⁺, 490.16; found, 490.20. ^JH NMR (400 MHz, DMSO-de) 6 7.90 - 7.74 (m, 1H), 7.48 - 7.00 (m, 3H), 6.87 - 6.43 (m. 4H), 5.95 (br, 1H), 5.37 - 5.01 (m, 2H), 4.71 - 4.24 (m, 2H), 4.12 (dd. 11.2, 3.4 Hz, 1H), 4.00 - 3.69 (m, 2H), 3.53 - 3.51 (m, 2H), 3.06 (t, J = 12.6 Hz, 1H), 2.42 - 2.13 (m, 3H). Example 60: ((S)-6-amino- 1,3,4, llb-tetrahydropyrido[3‘,4':4,5]pyrimido[6, l-c][l,4]oxazin- 10-yl)((3R^!i!,4aS*.9bS*)-7-(difluoromethoxy)-3-fluoro-3,4,4a,9b-tetrahydrobenzofuro[3,2- bjpyridin-l(2H)-yl)niethanone, isomer 2

Isomer 2

[1732] To a stirred solution of Intermediate A39, isomer 1 (50 mg, 0.193 mmol, 1 equiv) and Intermediate CA7 (47 mg, 0.19 mmol) in N,N-dimethylacetamide (2 mL) were added N,N-Diisopropylethylamine (99 mg, 0.77 mmol) and HATU (110 nig, 0.29 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4- After fillration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with C^Ch/MeOH (8: 1) to afford ((S)-6-amino-l,3,4,l lb-tetrahydropyrido[3‘,4’:4,5]pyrimido[6,l-c][i,4]oxazin-10- yl)((3R*,4aS*,9bS*)-7-(difluoromethoxy)-3-tluoro-3,4,4a,9b-tetrahydrobenzofuro[3,2- bJpyridin-1 (2H)-yl)methanone, isomer 2 ( 18.5 mg, 19% yield) as a light pink solid. MS (ESI) calculated for (C23H22F3N5O4) [M+H]*, 490.16; found, 490.25. ^lH NMR (400 MHz, DMSO- d₆) 6 8.27 - 8.24 (m, 1H), 7.93 (s, 2H), 7.82 - 7.62 (m, 1H), 7.52 - 7.00 (m, 2H), 6.90 - 6.68 (m, 2H), 5.96 - 5.77 (m, 1H), 5.39 - 4.99 (m, 3H), 4.61 ~ 3.94 (m, 4H), 3.64 - 3.56 (m, 2H), 2.70 - 2.52 (m, 2H), 2.45 - 2.13 (m, 2H).

Example 61: ((S)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[1 ,4]oxazino[4,3-c]quinazo1in-10- yl)((4aR*,9bR*)-7-(difluoromelhoxy)-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridin-l- yl)methanone, isomer 2

[1733] Followed the procedure of Example 23 with intermediate AC 1 isomer 2 (50 mg, 0.16 mmol) and intermediate A12 (37 mg, 0.16 mmol) to afford a 1 : 1 mixture of ((S)-6- amino-9-fluoro- 1,3,4, 1 lb-tetrahydro-[l,4]oxazinol4,3-c]quinazolin-10-y])((4aR*.9bR*)-7- (difluoromethoxy)-2,3,4,4a,5,9b-hexahydro-l H-indeno[l,2-b]pyridin-l-yl)methanone, isomer 1 and ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aR*,9bR*)-7-(difluoromethoxy)-2,3,4_!4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridin-l- yl)methanone, isomer 2 (16.1 mg, 19%) as a white solid. This mixture was separated by Prep- Chiral-HPLC with the following conditions: [Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% 1PAMIN), Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/rnin; Gradient (B%): 40% B to 40% B in 14 min; Wave Length: 220/254 nm: RTl (min): 8.31; RT2(min): 11.38; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.6 mL; Number Of Runs: 3] to afford f(S)-6-amino-9-fluoro- 1,3,4, l lb-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((4aR*,9bR*)-7-(difluoromethoxy)-2,3,4,4a,5,9b- hexahydro-lH-indeno[l ,2-b]pyridin-l -yl)methanone, isomer 2 (Example 61) (4.3 mg, 28%) as a white solid with retention time at 1 1.38 minute on chiral HPLC. MS ESI calculated for C25H25F3N4O3 [M+H]⁺, 487.19; found, 487.20. ^SH NMR (400 MHz, DMSO-tfc) 5 7.48 - 6.89 (m, 5H), 6.63 - 6.32 (m, 1H), 6.04 - 4.88 (m, HI), 4.88 - 4.30 (m, 1H), 4.17 - 3.95 (m, 1 H), 3.95 - 3.72 (m, 2H), 3.59 - 3.45 (m, 2H), 3.41 - 3.37 (m, 1H), 3.19 - 3.03 (m, 2H), 2.97 -

2.65 (m, 1H), 2.60 - 2.55 (m, 1H), 2.45 - 2.19 (m, 1H), 1.78 -• 1.68 (m, 1H), 1.63 - 1.15 (m, 2H), 1.10 - 0.89 (m, 1H). Absolute stereochemistry at two “orl” centers was not determined. Example 62: ((S)-6-amino-9-fluoro- 1 ,3,4,1 lb-tetrahydro-[ 1 ,4]oxazino[4,3-c Jquinazolin- 10- yl)((4aR*,9bR®)-7-(difluoromethoxy)-3.4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)- yljmethanone isomer 2

[1734] Followed the procedure of Example 23 with intermediate ACl isomer 2 (65 nig, 0.23 mmol) and intermediate All (50 mg, 0.21 mmol) to afford a 1: 1 mixture of ((S)-6- amino -9 -fluoro - 1,3,4,11 b -tetrahydro - [ 1 ,4]oxazino[4,3-c]quinazolin- 10-yl)((4aR*,9bR"')-7 - (difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)niethanone isomer 1 and ((S)-6-amino-9-lluoro- L3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- y1)((4aR*,9bR*)-7-(difluorometboxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)- yl)methanone isomer 2 (21 mg, 20%) as a white solid.

[1735] The above mixture was purified by Prep-Chiral HPLC with following condition [Column: CHIRALPAK IC, 2*25 cm, 5 pm: Mobile Phase A: Hex (0.3% IPAMIN), Mobile Phase B: EtOH; DCM=1: 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 17 min: Wave Length: 220/254 nm; RT1 (min): 11.15: RT2 (min): 13.44; Sample Solvent: EtOH: DCM-1: 1— HPLC; Injection Volume: 0.85 mL: Number Of Runs: 6] to afford ((S)-6- amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aR*,9bR*)-7- (difluoromethoxy)-3,4,4a,9b-tetrahydrobeiizofuro[3,2-b]pyridin-l(2H)-yl)methanone isomer 2 (Example 62) (4.7 mg, 25%) as an off-white solid with retention time at. 13.44 minute. MS ESI calculated for (C24H23F3N4O4) [M+H ]⁺, 489.16; found 489.15. NMR (400 MHz,

Methanol-cL) 87.41 - 7.12 (m, 2H), 7.04 - 6.80 (m, 1H), 6.76 - 6.66 (ni, 2H), 6.64 (s, 1H), 6.26 (s, 1H), 5.53 - 5.07 (in, 1H), 4.78 - 4.50 (m, 1 H), 4.39 - 4.14 (m, HI), 4.02 - 3.88 (m, 2H), 3.77 - 3.57 (m, 3H), 3.44 - 3.34 (m, 1H), 2.98 - 2.69 (m, 1H), 2.16 ~ 1.89 (m, 2H), 1.87 - 1.65 (m, 2H). Absolute stereochemistry at two “orl” centers was not determined.

Example 63: ((R)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10- yl)((4aR*,9bR*)-7-(difluoromethoxy)-3,4,4a,9b-letrahydrobenzofuro[3,2-b]pyridin-l(2H)- yljmethanone isomer 2

[1736] Followed the procedure of Example 23 with intermediate AC 1 isomer 1 (65 mg, 0.23 mmol) and intermediate Al 1 (50 mg, 0.21 mmol) to afford a 1: 1 mixture of ((R)-6- amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-y1)((4aR*,9bR^!i:)-7- (difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone isomer 1 and ((R)-6-amino-9-fluoro- 1 ,3,4, 1 lb-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin-10- y])((4aR*,9bR*)-7-(difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)- yl)methanone isomer 2 (21 mg, 20%) as a white solid.

[1737] lite above mixture was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IH, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.2% IPAMine)— HPLC, Mobile Phase B: MeOH: Et.OH-1: 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 27 min; Wave Length: 220/254 nm: RT1 (min): 15.92; RT2 (min): 23.65; Sample Solvent: MeOH: EtOH=4: 1-HPLC; Injection Volume: 1.0 mL;

Number Of Runs: 3) to afford ((R)-6-amino-9-fluoro-l,3,4.11b-tetrahydro-[l,4]oxazino[4,3- c]quiTiazolin-10-yl)((4aR*,9bR*)-7-(difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridin-l(2H)-yl)methanone isomer 2 (Example 63) (3.9 mg, 19%) as a white solid with retention time at 23.65 minute. MS ESI calculated for (C24H23F3N4O4) [M+Hp, 489.17; found 489.20. 'H NMR (400 MHz, Methanol-a’4) 8 7.45 - 7.05 (m, 2H), 7.01 - 6.47 (m, 4H), 6.28 - 5.40 (m, 1H), 5.08 - 5.07 (m, 1H), 4.80 - 4.72 (m, 1 H), 4.34 - 4.05 (m, 1H), 4.00 - 3.54 (m, 4H), 3.44 - 3.39 (m, 1H), 3.33 - 3.24 (m, 1H), 2.98 - 2.62 (m, 1H), 2.15 - 1.92 (m, 2H), 1.88 - 1.62 (m, 2H). Absolute stereochemistry at two “or I” centers was not determined.

Example 64: ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-clquinazolin-10- yl)((4aS,10bS)-8-methoxy-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l- yl)methanone

[1738] Followed the procedure of Example 23 with intermediate AC1 isomer 2 (84 mg, 0.30 mmol) and intermediate .Al (50 mg, 0.23 mmol) to afford a 1: 1 mixture of ((S)-6-amino 9-fluoro- 1, 3,4,1 lb-tetr ahydro-[l, 4 joxazino[4, 3 -c]qumazolin-10-yl)((4aS,10bS)-8 -methoxy- 2,3,4,4a,6,10b-hexahydro-lH-isochroraeno[4,3-b]pyridm-l-yl)rnethanone and ((S)-6-amino- 9-fluoro-l, 3/M lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aR,10bR)-8-methoxy- 2,3,4,4a,6,10b-hexahydro- ■lH-isochromeno[4,3-b]pyridin-l-yl)methanone (36 mg, 33%) as a w'hite solid.

[1739] Tiie above mixture was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IF, 2*25 cm, 5 gm; Mobile Phase A: Hex (0.3%

IP AMIN), Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 16 min; Wave Length: 220/254 nm; RTl(min): 10.47: RT2(min): 12.63: Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.4 mL; Number Of Runs: 7] to afford ((S)-6-amino-9-fluoro-l₍3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aR,10bR)-8-methoxy-2,3,4,4a,6.10b-hexahydro-lH-isochromeno[4.3-b]pyridin-l- yljraethanone isomer 1 (5.8 mg, 16%) as a white solid with retention time at. 10.47 minute. MS ESI calculated for (C25H27FN4O4) [M+H]⁺, 467.20; found 467.20. ^!H NMR (400 MHz, DMSO-tfc) 57.18 - 7.02 (m, 2H), 6.87 (dd, ./ = 8.4, 2.4 Hz, 1H), 6.71 - 6.59 (m, 2H), 6.52 - 6.32 (m, 2H), 5.79 - 5.78 (m, 1H), 4.86 - 4.46 (m, 3H), 4.03 (d, J = 10.8 Hz, 2H), 3.87 - 3.72 (m, 5H), 3.60 - 3.37 (m, 3H), 3.11 - 3.06 (m, 1H), 2.68 - 2.64 (m, 1 H), 1 .75 - 1.61 (m, 2H), 1.59 - 1.37 (m, 2H).

[1740] The chiral separation also afford ((S)-6-amino-9-fluoro-l,3,4,l Ib-tetrahydro- [ l,4Joxaz.ino[4,3-c]quinazo1in-10-yl)((4aS,10bS)-8-methoxy-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridin-l-yl)methanone isomer 2 (Example 64) (8.2 mg, 23%) as a white solid with retention time at 12.63 minute. MS ESI calculated for (C25H27FN4O4) [M+H]⁺, 467.20; found 467.20. Tl NMR (400 MHz, DMSO-ds) 8 7.13 - 7.07 (m, 2H), 6.87 (dd, J = 8.4, 2.4 Hz, 1H), 6.70 - 6.69 (m, 2H), 6.55 ~ 6.02 (m, 2H), 5.79 - 5.78 (m, 1H), 4.82 ~ 4.53 (m, 3H), 4.36 - 3.94 (m, 2H), 3.88 - 3.75 (m, 5H), 3.54 - 3.41 (m, 2H), 3.33 - 3.19 (m, 1H), 3.14 - 3.03 (m, 1 H), 2.66 - 2.61 (m, 1H), 1.84 - 1.40 (m, 4H). Absolute stereochemistry was determined by crystallography based on the co-crystal structure of the compound with PRMT5 enzyme.

Example 65: ((S)-6-amino-9-fluoro-1 ,3,4, 1 lb-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin-10- y1)((4aR*,9bS*)-7-(difluoromethoxy)-2,3,5,9b-tetrahydropyrido[3\2’:3,4]cyclopenta[1 ,2- b][l,4joxaziii-l(4aH)-yl)methanone, isomer 2

[1741] Followed die procedure of Example 23 with intermediate AC1 isomer 2 (43 mg, 0.15 mmol) and intermediate A13 (48 mg, 0.20 mmol) to afford a 1: 1 mixture of ((S)-6- amino-9-fluoro- 1 ,3.4,1 lb-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin- 10-yl)((4aR*,9bS*)-7- (difluoromethoxy)-2,3,5,9b-tetrahydropyrido[3’,2':3,4]cyclopenta[l ,2-b][l ,4]oxazin-1(4aH)- yllmethanone, isomer 1 and ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((4aR*,9bS*)-7-(difluoromethoxy)-2,3,5,9b- tetrahydropyrido[3',2':3,4]cyclopenta[l,2-b][l ,4]oxazin-l(4aH)-yl)methanone, isomer 2 (1 1.1 mg, 20%) as a white solid. Ibis mixture (10 mg) was separated by prep-chiral HPLC with the following conditions: [Column: CH1RALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% IP AMIN), Mobile Phase B: EtOH: DCM=1: 1-HPLC; How rate: 20 mL/min;

Gradient: 40% B to 40% B in 12 min; Wave Length: 220/254 nm; RTl(min): 6.71; RT2(min): 9.28; Sample Solvent: EtOH: DCM-1: 1-HPLC; Injection Volume: 0.5 niL; Number Of Runs: 2] to afford ((S)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4joxazino[4,3- cjquinazolin-10-yl)((4aR*,9bS*)-7-(difluoromethoxy)-2,3,5,9b- tetrahydropyrido [ 3 ' ,2 ' : 3 ,4]cyclopenta[ 1 ,2-b] [ 1 ,4]oxazin- 1 (4aH)-yl [methanone, isomer 2 (Example 65) (1.2 mg, 12%) as a white solid with the retention time at 9.28 min. MS ESI calculated for C24H23F3N4O4 [M+H]⁺, 489.17; found, 489.20. *H NMR (400 MHz, DMSO- dh) 3 7.42 - 6.97 (m, 5H), 6.58 (br, 2H), 6.39 - 6.25 (m, 1H), 5.76 and 4.98 (br, 1H), 4.62 - 4.56 (m, 1H), 4.43 - 4.15 (m, 1H), 4.12 ■■• 3.95 (m, 1H), 3.89 - 3.58 (ni, 3H), 3.58 - 3.39 (m, 3H), 3.30 - 3.02 (m, 4H), 2.78 - 2.62 (m, 1H).

Example 66: ((S)-6-amino-9-fluoro-l ,3,4,11b-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,4aS,10bS)-2-methyl-8-(trifluorometliyl)-2,3,4a,10b-tetraliydrochromeno[3,4- b] [ 1 ,4]oxazin- 1 (5H)-yl)methanone

[1742] Followed the procedure of Example 23 with intermediate AC1 isomer 2 (103 nig, 0.36 mmol) and intermediate A48 (100 mg, 0.36 mmol) to afford ((S)-6-amino-9-fluoro-

1, 3,4,1 lb- tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,4aS,10bS)-2-methy1-8- (trifluoromethyl)-2,3,4a,10b-tetrahydrochromeno[3,4-b][l,4joxaziii-l(5H)-yl)methanone (Example 66) (73 mg, 38%) as a white solid. MS ESI calculated for C25H24F4N4O4 [M+H]⁺, 521.17 found, 521.10. NMR (400 MHz, DMSO-d₆) 8 (ppm) 7.55 - 7.02 (m, 4H), 6.55 - 6.27 (m, 3H), 5.89 - 4.97 (m, 1H), 4.60 (dd, J ~ 10.0, 3.6 Hz, 1H), 4.44 - 4.30 (m, 2H), 4.06

(dd, J = 11.2, 3.2 Hz, 1H), 3.91 - 3.89 (m, 1H), 3.86 - 3.61 (rn, 5H), 3.59 - 3.43 (m, 2H), 3.14 - 3.00 (m, 1 H), 0.72 and 0.61 (d, J - 7.2 Hz, 3H).

Example 67: ((S)-6-amino-9- -fluoro- 1 ,3,4,1 lb-tetrahydro-[l ,4]oxazinoL4,3-c]quinazolin-10- y1)((4S,4aS,10bR)-4-methyl-8-(trifluoromethyl)-3,4,4a,10b-tetrahydro-2H-chromeno[4,3- b]pyridin- 1 (5H)-yl)methanone, isomer 2

[1743] Followed the procedure of Example 23 with intermediate AC1 (104 mg, 0.36 mmol) and intermediate A49 ( 100 mg, 0.36 mmol), and purified by Prep-Chiral -HPLC with the following conditions: [Column: CHIRALPAK IC, 2*25 cm, 5 urn; Mobile Phase A: Hex (0.3% IP AMIN), Mobile Phase B: EtOH: DCM=1: 1- -HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 11 min; Wave Length: 220/254 am; RT1 (min): 5.7; RT2 (min): 7.2; RT3 (min): 8.52; Sample Solvent: EtOH: DCM=1: 1— HPLC; Injection Volume: 0.45 mL; Number Of Runs: 8] to afford ((S)-6-amino-9- fluoro-l,3,4₍llb-tetrahydro- [l,4]oxazino[4,3-c]quinazolin-10-yl)((4S,4aS,10bR)-4-metliyl-8-(trifluoromethyl)- 3,4,4a,l()b-tetrahydro-2H-chromeno[4,3-b]pyridin-l(5II)-yl)methanone, isomer 2 (Example 67) (9.3 mg, 15%) as a white solid with the retention time at 7.2 minute. MS ESI calculated for C26H26F4N4O3 [M+H]⁺, 519.19; found, 519.20. ^SH NMR (400 MHz, DMSO-tfc) 8 7.23 (s, 2H), 7.15 - 6.97 (m, 2H), 6.68 - 6.29 (m, 3H), 6. 10 - 5.55 (br, 1H), 4.65 - 4.49 (m, 2H), 4.45 - 4.32 (m, 1H), 4.09 - 3.96 (m, 1H), 3.90 - 3.67 (m, 2H), 3.59 - 3.37 (m, 3H), 3.14 - 2.98 (m, 1H), 2.96 - 2.75 (in, 1H), 2.32 - 2.30 (m, 1H), 2.24 - 2.22 (m, 1H), 1.86 - 1.67 (m, 1H), 1 .41 - 1 .29 (m, 1H), 0.84 (d, J = 7.2 Hz, 3H). Absolute stereochemistry was confirmed by crystallography.

Example 68: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,i-c][l,4]oxazin-

10-yl)((2R,4aS,10bS)-2-methyl-8-(trifluoromethyl)-2,3,4a, 10b-tetrahydrochromeno[3,4- b H 1 ,4 [oxazin- 1 (5H)-yl)methanone

[1744] To a mixture of intermediate CA4 (59 mg, 0.23 mmol.) in N,N- Dimethylacetamide (2 mL) were added intermediate A48 (50 mg, 0. 18 mmol), EtjN (27 mg, 0.26 mmol) and HATU (90 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in MeOH (1 mL) and was purified by prep-HPLC with the following conditions: | Column: Kinetex EVO Cl 8, 21.2*250mm, 5pm; Mobile Phase A; Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to45% B in 14 min: Wave Length: 254/227 nrn; RTl(min): 9.5] to afford ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4’:4,5]pyrimido[6,l- c][l,4]oxazin-10-yl)((2R,4aS,10bS)-2-methyl-8-(trifluoromethyl)-2,3,4a,10b- tetrahydrochromeno[3,4-b][l,4]oxazin-l(5H)-yDmethanone (Example 68) (9.1 mg, 10%) as a white solid. MS (ESI) calculated for C24H24F3N5O4 [M+H]L504.18 found, 504.20. ^!H NMR (400 MHz, DMSO-db) 8 (ppm) 7.87 - 7.70 (m, 1H), 7.58 - 7.30 (m, 2H), 7.29 - 7.16 (m, 1H), 7.15 - 7.04 (m, 1H), 6.55 - 6.40 (m, 2H), 5.92 - 5.78 (m, 1H), 4.74 - 4.50 (m, 1H), 4.48 - 4.25 (m. 2H), 4.24 - 4.07 (m, 2H), 4.00 - 3.89 (m, 1H), 3.88 - 3.67 (rn, 3H), 3.66 - 3.59 (m, 1H), 3.58 - 3.43 (m, 2H), 3.14 - 2.97 (m, 1H), 0.78 - 0.65 (m, 3H).

Example 69: ((S)-6-amino-9-fluoro- 1,3,4.1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R,4aS,9aR)-3-methyl-2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- yl)methanone formate

[1745] Followed the procedure of Example 23 with intermediate AC1, isomer 2 (45 mg, 0.16 mmol) and intermediate A50 (30 mg, 0.16 mmol) to afford ((S)-6-amino-9-fluoro- 1 ,3,4,1 lb-tetrahydfo-[l ,4]oxazino[4,3-c]quinazolin-10-yI)((3R,4aS,9aR)-3-methyl-2,3,9,9a- tetrahydroindeno[2,l -b]| ,l,4]oxazin-4(4aH)-yl)methanone formate (Example 69) (22.2 mg, 29%) as a white solid. MS ESI calculated for C24H25FN4O3 [M+H]*, 437.19; found, 437.30. ^!H NMR (400 MHz, DMSO-<%>) 8 (ppm) 8.33 - 8.23 (m, 1H), 7.51 - 7.1 1 (m, 5H), 6.66 - 6.46 (m, 1H), 5.63 - 4.81 (tn, 1H), 4.80 - 4.37 (m, 2H), 4.36 - 4.23 (m, 1H), 4.22 - 4.06 (m, 1H), 3.98 - 3.76 (m, 2H), 3.71 - 3.45 (m, 5H), 3.24 - 3.03 (m, 2H), 2.98 - 2.73 (m, 1H), 0.90

- 0.70 (m, 3H).

Example 70: ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R* ,4aS * ,9bR*) -7 -(difluoromethoxy)-3 -methoxy-2,3,4,4a,5 ,9b-hexahydro- 1H- indeno[l,2-b]pyridin-l-yl)meihanone

[1746] To a stirred solution of intermediate A51 isomer 1 (15 mg, 0.056 mmol) in THF (0.65 mL) were added H2O (0.2 mL) and NaHCO, (15 mg, 0.18 mmol), then intermediate ACT isomer 2 (15.8 mg, 0.056 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 35% B to 50% B in 12 min; Wave Length: 254/220 nm; RTl(min): 7) to afford((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R*,4aS*,9bR*)-7-(difluoromethoxy)-3-methoxy-2,3,4,4a,5,9b-hexahyclro-lH- indetto[l ,2-b]pyridm-l -yl)methanone isomer 1 (Example 70) (7.0 mg, 24% yield) as a white solid. MS (ESI) calc’d for C26H27F3N4O4 [M+H]⁺, 517.20; foursd,517.20. ‘H NMR (400 MHz, DMSO-ds) 3 7.47 - 6.99 (m, 6H), 6.52 - 6.40 (m, 1H), 6.00 - 4.88 (m, 1H), 4.69 - 4.60 (m, 1H), 4.13 - 3.78 (m, 1H), 3.87 - 3.77 (m, 2H), 3.60 - 3.45 (m, 3H), 3.33 (s, 3H), 3.21 - 3.07 (m, 3H), 3.07 - 2.91 (m, 1H), 2.73 - 2.57 (m, 2H), 2.42 - 2.31 (m, 1H), 2.1 1 - 2.08 (m, 1H), 0.83 - 0.79 (m, 1 H).

Example 71: ((S)-6-amino-9-fluoro-l, 3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((3R*,4aS*,9bR*)-7-(difluoromethoxy)-3-lluoro-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2- b]pyridin-l-yl)metlianone, isomer 2

[1747] Followed the procedure of Example 70 with intermediate AC I isomer 2 (33 mg, 0.116 mmol) and intermediate A52 (50 mg, 0.194 mmol), then separated by Prep-chiral HPLC with the following conditions (Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.3% IP AMIN). Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 35% B to 35% B in 27 min; Wave Length: 220/254 nm;

RTl(min): 15.91; RT2(min): 23.72; Sample Solvent: EtOH; DCM=1: 1-HPLC; Injection Volume: 0.5 mL; Number Of Runs: 6) to afford ((S)-6-anuno-9-fluoro-l,3,4,llb-tetrahydro- [l ,4]oxazino[4,3-c]quinazolin-10-yr)((3R*,4aS*,9bR*)-7-(difluoTomethoxy)-3-fluoro- 2,3,4,4a,5,9b-bexahydro-lH-indeno[l,2-b]pyridin-l-yl)methanone isomer 2 (Example 71) (2.6 mg, 2% yield) as a white solid with the retention time at 23.72 min. MS ESI calculated for C25H24F4N4O3 [M+H]⁺, 505.18; found. 505.20. ^!H NMR (400 MHz, Methanol-^) 8 7.40 - 7.19 (m, 4H), 7.13 - 6.62 (m, 2H). 6.15 - 5.02 (m, 1H), 4.85 - 4.60 (m, 2H), 4.20 - 3.60 (ni, 5H), 3.22 - 3.10 (m, 1H), 3.05 - 2.66 (m, 4H), 2.24 - 2.21 (m, 1H). 1.39 - 1.24 (m, 2H).

Example 72: ((S)-6-amino-9-fluoro-l, 3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-I0- yl)((3R,4aS,9aR)-3,7-dimethyL2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- yljmethanone

[1748] Followed the procedure of Example 23 with intermediate AC1 isomer 2 (56 mg, 0.20 mmol) and intermediate A53 (40 mg, 0.20 mmol) to afford ((S)-6-amino-9-fluoro- 1,3,4, 1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10-yl)((3R,4aS,9aR)-3,7-diniethyl-

2,3,9,9a-tetrabydroindeno[2,l-b][l,4]oxazin-4(4aH)-yJ)methanone (Example 72) (28.3 mg, 31%) as an off-white solid. MS ESI calculated for C25H27FN4O3 [M+Hf', 451.21; found, 451.15. ^:H NMR (400 MHz, DMSCfofo) 5 (ppm) 7.26 - 6.91 (m, 4H), 6.42 - 6.28 (m, 3H), 5.58 - 4.78 (m, 1H), 4.65 - 4.51 (m, 1H), 4.43 - 4.22 (m, 1H), 4.13 - 3.96 (m, 1 H), 3.88 - 3.69 (m. 2H), 3.65 - 3.40 (m, 4H), 3.30 - 2.97 (m, 3H), 2.93 ■■■ 2.66 (m, 1H), 2.34 - 2.24 (m,

3H), 0.89 - 0.70 (m, 3H).

Example 73: ((S)-6-amino-9-fluoro-l ,3,4.1 lb-teirahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aR*,9bS*)-7-(difluoromethoxy)-2,3,5,9b-tetrahydropyrido[3',2':3,4]cyclopenta[l,2- b][l,4]oxazin-l(4all)-yl)methanone, isomer 2

[1749] To a stirred mixture of intermediate A23 ( 100 mg, 0.41 mmol), NaHCCh ( 138 mg, 1.65 mmol) and H?O (0.5 mL) in 1,4-dioxane (2 mL) was added intermediate AC1. isomer 2 (109 nig, 0.41 mmol) in portions at 0 °C. The result mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na?SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue purified by reverse phase flash with the following conditions: (Column: Xselect CSH C18 OBD Column 30*150 mm 5 urn; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 5% B to 25% B in 15 min; Wave Length: 254/220 nm; RTl(min): 12.5) to afford a 1: 1 mixture of ((S)-6-amino-9-fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((4aR*,9bS*)-7-(difluoromethoxy)-2,3,5,9b- tetrahydropyrido[3‘,2':3,4]cyclopenta[l,2-b][l ,4 loxazin- l(4aH)-yl)methanone, isomer 1 and ((S)-6-amino-9-fluoro4,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)(.(4aR*,9bS*)-7-(difluoromethoxy)-2,3,5,9b-tetrahydropyrido[3’,2':3,4]cyclopenta[l,2- b][1.4]oxazin-l(4aH)-yl)methanone, isomer 2 (65 mg, 32%) as a white solid. This mixture was separated by Prep-Chiral HPLC with the following conditions: (Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% IPAMIN), Mobile Phase B: EtOH: DCM=1 :1--HPLC; Flow rate; 20 mL/min; Gradient; 40% B to 40% B in 10.5 min; Wave Length: 220/254 nm: RTl(min): 7.08; RT2(min): 8.37; Sample Solvent: EtOH : DCM=1:1- HPLC; Injection Volume: 0.45 mL; Number Of Runs: 9) to afford ((S)-6-amino-9-fluoro- 1 ,3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((4aR*,9bS*)-7-(difluoromethoxy)- 2,3 ,5 ,9b-tetrahydropyrido[3',2’:3,4]cyclopenta[ 1 ,2-b] [ 1 ,4]oxazin- 1 (4aH)-yl)methanone, isomer 2 (Example 73) (31.1 mg, 47%) as a white solid with retention time at 8.37 minute. MS (ESI) calculated for C23H22F3N5O4 [M+H]⁺, 490.16; found, 490.10. ^!H NMR (400 MHz, DMSO-,% - D₂O) 5 7.83 - 7.40 (m, 2H), 7.26 - 7.24 (m, 1H), 7.00 - 6.92 (m, 1H), 6.66 - 6.60 (m, 1I-I), 5.78 and 4.95 (s. 1H), 4.77 - 4.69 (m, 1H), 4.46 - 4.34 (m, 1H), 4.30 - 4.11 (m, 1 H), 3.94 - 3.77 (m, 2H), 3.67 - 3.46 (m, 4H), 3.34 - 3.09 (m, 3H), 3.00 - 2.98 (m, 1H), 2.80 - 2.64 (m, 1 H ).

Example 74: ((S)-6-amino-9-fluoro-1 ,3,4,1 lb-tetrahydro-[l ,4]oxazino[4.3-c]quinazolin-10- yl)((3R*,4aR*,9bS*)-7-(difluoromethoxy)-3-methoxy-2,3,4,4a,5,9b-hexahydro-lH- indeno [ 1 , 2-b jpyridi n- 1 -yljmethanone, i somer 4

[1750] Followed the procedure of Example 68 with intermediate CAI, isomer 2 (16 mg, 0.059 mmol) and intermediate A51 isomer 4 (20 mg, 0.074 mmol) to afford ((S)-6-aniino-9- fluoro-l,3,4,llb-tetahydro-[l,4|oxazino[4,3-c|quinazolin-10-yl)((3R*,4aR*,9bS*)-7- (difluoromethoxy)-3-methoxy-2,3,4,4a,5,9b-hexahydro- 1 H-indeno[ 1 ,2-b]pyridin- 1 - yl)raethanone formate, isomer 4 (Example 74) (14.4 rag, 37% yield) as a white solid. MS ESI calculated for C26H27F3N4O4 [M+H]⁺, 517.20; found, 517.20. ^!H NMR (400 MHz, DMSO-ds+DjO ) 6 8.30 (s, 1H), 7.54 - 6.91 (m, 5H), 6.56 - 6.52 (m, 1 Hi, 6.10 - 5.90 and 5.05 - 4.89 (m, 1H), 4.78 - 4.70 (m, 1 H), 4.11 - 3.86 (m, 2H). 3.85 - 3.56 (m, 3H), 3.52 - 3.07 (m, 7H), 2.87 - 2.64 (m, 3H), 1.95 - 1.79 (m, 1H), 1.16 - 0.97 (m, 1H).

Example 75: ((S)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R,4aS,9aR)-7-(difluoromethoxy)-3-jneihy1-2,3,9,9a-tetahydroindeno[2,l- b][l ,4]oxazin-4(4aH)-yl)methanoBe

[1751] To a stirred solution of intermediate A15, isomer 2 (500 mg, 1.96 mmol) and CS2CO3 (1.91 g, 5.87 mmol) in MeCN (15 mL) was added intermediate AC1, isomer 2 (0.56 g, 1.96 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography using a 40 g silica gel column eluted with 0-20% methanol in dichloromethane to afford ((S)-6-amino-9-fluoro-l,3,4,llb-tetrahydro- [l,4]oxazino[4_>3-c]quinazolin-10-yl)((3R,4aS,9aR)-7-(difluoromethoxy)-3-methyl-2,3,9,9a- tetrahydroindeno[2, l -b][l ,4]oxaziri-4(4aH)-yl)methanone (Example 75) (129.5 mg, 13%) as a white solid. MS ESI calculated for C25H25F3N4O4 [M+H]⁺, 503. 18; found, 503. 15. ^;H NMR (400 MHz, DMSO-ds) 87.49 - 6.91 (m, 5H), 6.50 (br, 2H), 6.38 - 6.24 (m, 1H), 5.56 (d, J = 4.2 Hz, 1H), 4.95 - 4.52 (m, 1H), 4.50 - 4.20 (m, 1H), 4.18 - 3.95 (m, 1H), 3.90 - 3.70 (m, 2H), 3.66 - 3.42 (m, 4H), 3.25 - 2.75 (m, 3H), 0.87 and 0.71 (d, J = 6.8 Hz, 3H).

Example 76: ((S)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazo1in- l 0- yl)((2R,4aR,10bS)-8-chloro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH-naphtho[2,l- b] [ 1 ,4]oxazin- 1 -yl)methanone

A54

[1752] To a solution of intermediate A54 (50 mg, 0.21 mmol) and DIEA (81 mg, 0.63 mmol) in N,N-Dimelhylacetamide (2 mL) was added intermediate AC1 isomer 2 (59 mg, 0.21 mmol) in portions at 0 °C. The resulting mixture was stirred for I h at room temperature. The mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NazSO-j. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD CIS Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 50% B in 10 min; Wave Length: 254/220 nm; RTl(min): 8.95) to afford ((S)-6-amino-9-fluoro- 1 ,3 ,4, 1 1 b-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin- 10- yl)((2R,4aR, 10bS)-8-chloro-2-methyl-2,3,4a,5,6, lOb-hexahydro- lH-naphtho[2,l - b][l,4]oxaz.in-l-yl)methanone (Example 76) (38.6 mg, 37%) as a white solid. MS (ESI) calc’d for (C.-d %,C%\ _;CM [M-t-Hp, 485.2; found, 485.2. H NMR (400 MHz, DMSO-zfc) 8 7.27 - 7.09 (m, 4H), 6.60 - 6.20 (rn, 3H), 5.30 - 4.60 (m, 2H), 4.07 - 3.44 (m, 9H), 3.12 - 2.94 (m, 2H), 2.67 - 2.63 (m, 1H), 2.11 - 1.93 (m, 2H), 0.71 - 0.60 (m, 3H)

Example 77: ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[1.4]oxazino[4,3-c]quinazolin-10- yl)((2R,4aR,10bS)-8-fluoro-2-methyl-2, 3 ,4a, 5, 6, lOb-hexahydro- lH-naphtho[2,l- b][l,4]oxazin-l-yl)methanone formate

A55

[1753] Followed the procedure of Example 23 with intermediate AC 1 isomer 2 (46 mg, 0.16 mmol) and intermediate A55 (30 mg, 0.14 mmol) to afford ((S)-6-amino~9-fluoro- 1 ,3,4.11b-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((2R,4aR,10bS)-8-fiuoro-2-methyl-

2,3 ,4a, 5, 6, lOb-hexahydro- lH-naphtho[2, 1 -b] [ 1 ,4]oxazi n- 1 -yl)methanone formate (Example 77) (18.6 mg, 26%) as a white solid. MS ESI calculated for C25H26F2N4O3 [M+H]⁺, 469.20; found, 469.20. 'H NMR (400 MHz, Methanol-^) 6 (ppm) 8.54 (s, IH), 7.74 - 7.17 (m, 2H), 7.04 - 6.76 (m, 3H), 5.73 (s, IH), 5.04 - 4.94 (m, IH), 4.37 - 4.16 (m, I H), 4.14 - 3.95 (m, 3H), 3.96 - 3.60 (m, 6H), 3.24 - 3.07 (m, IH), 2.75 - 2.57 (m, IH), 2.34 - 2.17 (m, IH), 2.08

- 1.81 (m, IH), 0.81 (dd, ./ - 41.2, 7.0 Hz, 3H).

Example 78: ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yI)((2R,4aR*,l lbR*)-2-methyl-9-(trifluoromethyl)-2, 3,4a, 5,7,1 Ib-hexahydro-lH- benzo[5,6]oxepino[3.4-b][ ! ,4]oxazin- 1 -yl)methanone formate

A56 isomer 1

[1754] Followed the procedure of Example 76 with intermediate AC1 isomer 2 (49 mg, 0.17 mmol) and intermediate A56 isomer 1 (50 mg, 0.17 mmol) to afford ((S)-6-amino-9- fluoro-l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]quinazo1in-10-yl)((2R,4aR*,llbR*)-2- methyl-9-(trifluoromethyl)-2,3,4a,5,7,llb-hexahydro-lH-benzo[5,6]oxepiiio[3,4- b][l,4]oxazin-l-yl)methanone formate (Example 78) (2.7 mg, 2%) as a white solid. MS ESI calculated for C A KEIXIO ; [M+H]⁺, 535.19; found, 535.20. ’H N MR (400 MHz, DMSO- d₆) 6 8.33 - 8.21 (m, 1H), 7.80 - 7.48 (m, 3H), 7.36 - 6.82 (m, 1H). 6.64 - 5.93 (m, 1H), 5.05 - 5.02 (m, 1H), 4.87 - 4.69 (m, 1H), 4.62 - 4.47 (m, 1H), 4.14 - 4.11 (m, 1H), 3.99 - 3.13 (m, UH), 3.06 - 3.05 (m, 1H), 1.21 - 0.64 (m, 3H).

Example 79: ((S)-6-amino-9-tluoFO- 1 ,3,4, 1 lb-tetrahydro-[ 1 ,4]oxazino[4,3-c]quinazolin- 10- yl)((2R*,4aS*,l 0bR*)-8-(dituoromethoxy)-2-methyl-3,4,4a,10b-teirahydro-2H- chromeno[4,3-b]pyridin-l(5H)-yl)methanone formate, isomer 2 [1755] To a stirred solution of intermediate A57 isomer 1 (30 mg, 0.11 mmol) in THF (0.5 mL) was added LiHMDS ( 1.0 M in THF) (0.13 mL, 0.13 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 min, then intermediate AC1 isomer 2 (37 mg, 0.13 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NasSCL. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30* 150mm 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 10% B to 30% B in 15 min; Wave Length: 254/220 nm; RTl(mm): 12.5) to afford ((S)-6-amino-9- fluoro-1,3,4,1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolm-10-yl)((2R*,4aS*,10bR*)-8- (dilluoromethoxy)- 2- methyl-3 ,4 ,4a, 10b-tetrahydro-2H-chromeno[4,3 -bjpyridin- 1 (5H) ■ yl)rnethanone formate (Example 79) (2.2 mg, 3%) as a white solid. MS ESI calculated for C26H27F3N4O4 [M+H]⁺, 517.20; found, 517.35. *H NMR (400 MHz, DMSO-cfc) 5 8.32 (s, 1H), 7.44 - 6.99 (m, 3H), 6.76 - 6.65 (m, 1H), 6.63 - 6.45 (m, 2H), 5.97 and 4.54 (s, 1H), 4.86 - 4.59 (m, 2H), 4.36 - 4.03 (m, 3H), 3.95 - 3.73 (m, 3H), 3.62 - 3.47 (m, 2H), 3.24 - 3.04 (m, 2H), 2.03 - 1.98 (rn, 1H), 1.87 - 1.47 (m, 4H), 0.78 - 0.53 (rn, 3H).

Example 80: ((S)-6-amino-9- fluoro- 1 ,3,4, 1 lb-tetrahydro-[ 1 ,4]oxazino|4,3-cjquinazolin-10- yl)((4bR*,8aR*)-2-(difluoromethoxy)-4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3,4- b’]dipyridin-5-yl)methanone isomer 3

Isomer 3

ACL isomer 2 isomer 3

[1756] Followed the procedure of Example 76 with intermediate AC L isomer 2(200 mg, 0.62 mmol) and intermediate A23 isomer 2 (150 mg, 0.62 mmol) to afford ((S)-6-amino-9- fluoro- l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3“C]quinazolin-10-yl)((4bR*,8aR*)-2-- (difluoroniethoxy)-4b,6,7,8,8a,9-hexahydro-5H-cyclopenta[l,2-b:3,4-b']dipyridin-5- yl)methanone isomer 3 (123 mg, 40%) as a white solid. MS ESI calculated for C24H24F3N5O3 [M+Hf , 488.18; found, 488.10. ^!H NMR (400 MHz, DMSO-ds) 5 7.90 - 7.44 (m, 2H), 7.08 (d, ./ = 7.6 Hz, IH), 6.92 (d, J= 8.0 Hz, IH), 6.50 - 6.20 (m, 3H), 6.05 - 5.00 (m, 1H), 4.63 - 4.37 (m, IH), 4.13 - 3.90 (m, I H), 3.90 - 3.70 (m, 2H), 3.70 - 3.39 (m, 4H), 3.26 - 2.95 (m, 2H), 2.78 - 2.59 (m, IH), 2.45 - 2.28 (m, IH), 1.87 - 1.71 (m, I H), 1.62 - 1.30 (m, 2H), 1.13

- 0.92 Im, IH).

Example 81: ((S)-6-amino-9-fluoro-l, 3.4,1 lb-tetrahydro-[ L4]oxazino[4,3-c]quinazolin-10- y1)((4aR*,9bR*)-7-methoxy-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)- yl)methanone, isomer 1

Isomer 1

[1757] Followed die procedure of Example 23 with intermediate AC 1 isomer 2 (41 mg, 0.15 mmol) and intermediate A58 isomer 1 to afford ((S)-6-amino-9-fluoro-l,3,4,l lb- tetrahydrc>-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((4aR*,9bR*)-7-methoxy-3,4,4a,9b- tetrahydrobenzofuro[3,2-b]pyridin-1 (2H)-yl)methanone, isomer 1 (Example 81) (24.4 mg, 36%) as a white solid. MS ESI calculated for C24H25FN4O4 [M+H]“, 453.19; found, 453.20.

NMR (400 MHz, DMSO-cfo) 7.31 - 6.85 (m. 2H), 6.49 - 6.45 (m, 2H), 6.43 - 6.41 (m, 3H), 6.07 - 5.01 (m, 1H), 5.00 - 4.98 (m, HI), 4.55 - 4.53 (m, 1H), 4.27 - 4.03 (m. 1 H), 3.84

- 3.67 (m, 5H), 3.57 - 3.36 (m, 2H), 3.27 - 3.21 (m, 1H), 3.11 - 2.98 (m, 1H), 2.83 - 2.64 (ni, 1H), 1.94 - 1.46 (m, 4H).

Example 82: ((S)-6-amino-9-fluoro-l, 3.4,1 lb-tetrahydro-[ l,4]oxazino[4,3-c]quinazolin-10- y])((4aS,10bS)-8-(difhioromethoxy)-2,3,4,4a,6, lOb-hexahydro- 1 H-isochromeno[4,3- bjpyridin- l-yl)methanone, isomer 4

Isomer 4

A24 isomer 1 isomer 4

[1758] Followed the procedure of Example 23 with intermediate AC 1 isomer 2 (43 mg, 0.15 mmol) and intermediate A24, isomer 1 (30 nig, 0.12 mmol) to afford ((S)-6- aminosfluoro- 1,3, 4,1 lb-ietrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((4aS,10bS)-8- (difluoromethoxy)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridiD-l-yl)metbanone, isomer 4 (Example 82) (20.1 mg, 34%) as a white solid. MS (ESI) calculated for C25H25F3N4O4 [M+Hr, 503.18; found, 503.18. ^!H NMR (400 MHz, DMSO-Je) 6 7.48 - 7.01 (m, 4H), 6.98 (s, 1H), 6.35 (br, 3H), 5.82 (s, 1H), 4.85 - 4.66 (m, 2H), 4.60 - 4.53 (m, 1H), 4.39 - 3.94 (m, 2H), 3.87 - 3.70 (m. 2H), 3.56 - 3.39 (m, 2H), 3.25 - 3.23 (m, 1H), 3.06 (t, J = 12.8 Hz, 1H), 2.70 - 2.58 and 2.36 - 2.23 (m, 1H), 1.84 - 1.40 (m, 4H).

Example 83: ((S)-6-amino-9-fluoro-l, 3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R*,4aS*,9bS*)-7-(difluoromethoxy)-3-methyl-3,4,4a,9b-teirahydrobenzofuro[3,2- bjpyridin-l(2H)-yl)niethanone, isomer 2 isomer 2

A59 isomer 2 Isomer 2

[1759] Followed the procedure of Example 23 with intermediate AC1 isomer 2 (16 mg, 0.03 mmol) and intermediate A59, isomer 2 (10 mg, 0.04 mmol) to afford ((S)-6-amino-9- fluoro-l,3,4,llb-tetrahydro-[l,4Joxazino[4,3-c]quinazolin-10-yl)((3R*,4aS*,9bS*)-7- (difluoromethoxy)-3-mefhyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l (2H)- yljmethanone, isomer 2 (Example 83) (4.1 mg, 19%) as a white solid. MS ESI calculated for C25H25F3N4O4 [M+H]⁺,503.18 found, 503.20. ^!H NMR (400 MHz, DMSO-ffc) 5 (ppm) 7.46 - 6.94 (m, 4H), 6.77 - 6.11 (m, 3H), 6.36 - 5.26 (tn, 1H), 5.25 - 5.01 (m, 1H), 4.74 - 4.59 (m, 1H), 4.20 - 3.94 (tn, 1H), 3.92 - 3.64 (m, 2H), 3.63 - 3.40 (m, 3H), 3.23 - 3.05 (m, 1H), 3.03 - 2.58 (m, 2H), 2.07 - 1.92 (m, 1H), 1.90 - 1.72 (m, 1H), 1.56 - 1.40 (m, 1H), 1.10 - 0.63

(m, 3H).

Example 84: ((S)-6-amino-9-fluoro-1 ,3,4,llb-tetrabydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4R*,4aR*,9bR*)-7-chloro-4-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)- yl) methanone isomer 2

A60 isomer 1 isomer 2

[1760] Followed the procedure of Example 76 with intermediate A60 isomer 1 (40 mg, 0.18 mmol) and intermediate AC! isomer 2 (51.5 mg, 0.16 mmol) to afford ((S)-6-amino-9- fluoro- 1 ,3,4, 1 lb-tetrahydro-[l ,4]oxazino[4,3-c]quinazolin-10-yl)((4R*,4aR*,9bR*)-7-chloro- 4-niethyl-3.4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin- l(2H)-yl)methanone formate isomer 2. (Example 84) (42.3 mg, 45% yield) as a white solid. MS ESI calculated tor C24H24CIFN4O3 [M+H]⁺, 471.15: found, 471.15. ^!H NMR (400 MHz, DMSO-J₆) 6 8.30 (s, 1H), 7.34 - 7.08 (m, 2H), 6.96 - 6.88 (m, 2H), 6.60 - 6.56 (m, 1H), 6.24 - 5.40 (m, 1 H), 4.94 - 4.92 (m, 1H), 4.78 - 4.75 (m, 1H), 4.14 - 4.11 (m, 1H), 3.96 - 3.84 (m, 2H), 3.73 - 3.60 (m, 3H), 3.41 - 3.23 (m, 2H), 2.85 - 2.68 (m, 1H), 2.08 - 1.84 (m, 21 i 1. 1.25 - 1.27 (m, 3H).

Example 85: ((S)-6-amino-9-fluoro-l ,3,4,1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4R*,4aR*_>9bR*)-7-chloro-4-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)- yl)methanone, isomer 4 [1761] Followed the procedure of Example 76 with intermediate A60, isomer 3 (60 mg, 0.26 mmol)and intermediate AC1, isomer 2 (77 mg, 0.24 mmol) to afford ((S)-6-ammo-9- fluoro- 1,3,4,11 b-tetrahydro ■ [ 1 ,4 Joxazino [4,3 ■ c]quinazolin- 10-yl)((4R*,4aR* ,9bR* )-7-chloro- 4-methyl-3.4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone isomer 4 (Example 85) (34.4 mg, 27% yield) as a white solid. MS ESI calculated for C24H24CIFN4O3 [M+H]⁺, 471.15; found, 471.15. ^!H NMR (400 MHz, Methanol-J₄) 67.15 - 7.07 (m, 2H), 6.97 - 6.94 (m, 1H), 6.87 - 6.83 (m, I H), 6.53 (d, 11.6 Hz, 1H), 6.36 - 5.51 (m, 1H). 4.73

- 4.70 (m, 1H), 4.55 - 4.42 (m, 1H), 4.09 - 4.07 (m, 1H), 3.93 - 3.90 (m, 1H), 3.84 - 3.81 (m, 1H), 3.71 - 3.50 (m, 3H), 3.30 - 3.24 (m, 1H), 3.03 - 2.75 (m, 1H), 1.77 - 1.65 (m, 2H), 1.43 - 1.28 (m, 1H), 1.17 (d, J = 6.4 Hz. 3H).

Example 86: ((S)-6-amino-9-fluoro-l ,3,4.1 lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin- 10- yl)((2R,4aR,10bS)-8-chloro-2-methyl-2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[2,3- h]isoquinolin-l-yl)methanone

[1762] Followed the procedure of Example 23 with intermediate AC 1 isomer 2 (71 mg, 0.25 mmol) and intermediate A61 (60 mg, 0.25 mmol) to afford ((S)-6-amino-9-fluoro-

1 ,3,4, 11 b-tetrahydro- [ 1 ,4]oxazmo[4,3-c]quinazolin-10-yl)((2R,4aR, 10bS)-8-chloro-2- methyl-2,3,4a,5,6, 1 Ob-hexahydro- lH-[ l,4]oxazino[2,3-h]isoquinolin- l-yl)methanone (Example 86) (54 mg, 44%) as a white solid. MS ESI calculated for C24H25CIFN5O3 [M+H]⁺, 486.16; found, 486.10. ^!H NMR (400 MHz, DMSO-cfe) 58.30 - 8.06 (m, 1H), 7.37 - 7.26 (m, 1H), 7.25 - 7.05 (m, 1H), 6.54 - 6.28 (m, 3H), 5.68 ~ 4.68 (m, 1H), 4.77 - 4.46 (m, 1H), 4.09 - 3.99 (m, 1H), 3.94 - 3.87 (m, 1H), 3.86 - 3.58 (ni, 5H), 3.58 - 3.39 (m, 2H), 3.14 - 3.02 (m, 1H), 3.01 - 2.86 (m, 1H), 2.76 - 2.59 (m, 1H), 2.21 - 1.88 (m, 2H), 0.76 - 0.57 (m, 3H).

Example 87 : ((S)-6-amino-9- fluoro- 1 ,3,4, 1 lb-tetrahydro- [ 1 ,4]oxazino|4,3-c]quinazolin-10- y])((2R,4aR,10bS)-8-bromo-2-methyl-2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[2,3- hjquinoli n- l-yl)methanone

[1763] Followed the procedure of Example 23 with intermediate AC1 isomer 2 (45 nig, 0.16 mmol) and intermediate A62 (30 mg, 0.11 mmol) to afford ((S)-6-amino-9-fIuoro- 1,3,4, 1 lb-tetrahydro-! l,4|oxazino|4,3-c|quinazolin- 10-yJ)((2R,4aR,10bS)-8-bromo-2- methyl-2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[2,3-h]quinolin-l-yl)niethanone (Example 87) (26 mg, 46%) as a white solid. MS ESI calculated for C^thsBrFNsOr [M+H]⁺, 530.11 , 532. 11: found, 530. 15, 532.15. ^!H NMR (400 MHz, DMSC !-</,,) 8 8.57 - 8.45 (m, 1H), 7.88 - 7.71 (m, 1H), 7.24 - 6.87 (m, 1H), 6.52 - 5.57 (m, 3H), 4.63 - 4.45 (m, 2H), 4.36 - 4.23 (m, 1H), 4.07 - 3.88 (m, 2H), 3.83 - 3.75 (m, 1H), 3.74 - 3.66 (m. 2H), 3.63 - 3.38 (m, 2H), 3.28 - 3.16 (m, 1H), 3.16 - 2.88 (m, 2H), 2.76 - 2.57 (m, 1H), 2.17 - 1.89 (m, 2H), 0.59 - 0.47 (m, 3H). Example 88: ((4S,11bR)-6-amino-4-methyI-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][1.4]oxazm-10-yl)((4aR*,9bR*)-7-

(difluorometiioxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridm-l(2H)-yl)methanone isomer

1

[1764] Followed the procedure of Example 23 with intermediate AC7 (58 mg, 0.20 mmol) and intermediate Al l isomer 1 (25 mg, 0.10 mmol) to afford ((4S,1 lbR)-6-amino-4-methy1- 1,3, 4,1 lb-lelrahydropyrido[3',4':4,5]pyriniido[6,l-c][l,4]oxazin-10-yl)((4aR*,9bR*)-7- (difluoromethoxy)-3,4»4a,9b-teirahydrobenzofuro[3,2-b]pyridin-l(2H)-yr)methanone formate isomer 1 (Example 88) (7.0 mg, 12.4%) as a white solid. MS (ESI) calculated for C24H25F2NSO4 [M+H]⁺,486.19 found, 486.15. ^!H NMR (400 MHz, Methanol-^) 5 (ppm) 8.56 (s, 1H), 8.34 - 8.11 (m, 1H), 7.73 - 7.29 (m, 2H), 7.07 - 6.54 (m, 3H), 6.26 - 5.77 (m, 1H), 5.34 - 4.95 (m, 2H), 4.74 - 4.59 (m, 1H), 4.42 - 4.26 (m, 1H), 4.25 - 4.1 1 (m, 1H), 4.10

- 3.93 (m, IH), 3.92 - 3.60 (m, 2H), 3.02 - 2.62 (m, 1H), 2.24 - 1.84 (m, 3H), 1.82 - 1.60 (m, 1 H), 1.41 6.3 Hz, 3H).

Example 89: ((4R,1 lbS)-6-ammo-4-methyl-l,3,4,l lb- tetrahydropyrido[3',4':4,5]Dvrimido[6.1-c][l,4]oxazin-10-yl)((4aR*,9bR*)-7- (difluoTomethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yr)methanone isomer [1765] Followed the procedure of Example 23 with intermediate AC8 (43 mg, 0.15 mmol) and intermediate All isomer 1 (20 mg, 0.08 mmol) to afford ((4R,l lbS)-6-amino-4-methyl-

I,3,4, 1 lb-letrahydropyrido[3’,4':4,5]pyTimido[6,l-c][l,4]oxazin-10-yl)((4aR*,9bR*)-7- (difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-bjpyridin-l(2H)-yl)methanone formate isomer 2 (Example 89) (4.6 mg, 10%) as a white solid. MS (ESI) calculated for C24H25F2N5O4 [M-t-Hp, 486.19 found, 486.20. ^!H NMR (400 MHz, Methanol-^) 5 (ppm)

8.57 (s, IH), 8.19 (s, 1H), 7.73 - 7.29 (m, 3H), 7.05 - 6.55 (m, 3H), 6.32 - 6.73 (m, 1H), 5.30

- 4.92 (m, 2H), 4.65 (dd, 11.0, 4.2 Hz, IH), 4.30 (dd, J = 12.0, 3.6 Hz, IH), 4.18 (t, J =

I I.0 Hz, IH), 4.04 - 3.90 (m, IH), 3.66 (dd, J = 12.0, 4.2 Hz, I H), 3.06 - 2.58 (m, IH), 2.26

- 1 .60 (nt, 4H), 1.40 (d, J = 6.3 Hz, 3H).

Example 90: ((4S,llbS)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4aR*,9bR*)-7-

(difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yJ)metbanone isomer 3

[1766] Followed the procedure of Example 23 with interniediate AC5 (43 nig, 0.15 mmol) and intermediate A 11 isomer I (25 mg, 0. 10 mmol) to afford ((4S, 1 1 bS)-6-ammo-4-methyl- 1,3,4, 1 lb-tetrahydropyrido[3^,,4';4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,9bR*)-7-

(difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone formate isomer 3 (Example 90) (14.5 mg, 26%) as a white solid. MS (ESI) calculated for C24H25F2N5O4 [M+H]⁺, 486.19 found, 486.15. NMR (400 MHz, Methano1-d₄) 8 (ppm) 8.55 (s, 1H), 8.14 (s, IH), 7.70 - 7.26 (m, 2H), 7.05 - 6.56 (m, 3H), 6.33 - 5.70 (m, 1H), 5.22 (dd, J = 10.6, 3.6 Hz, 1 H), 5.15 - 4.93 (m, IH), 4.44 (dd, - 11 .4, 3.6 Hz, IH), 4.38 - 3.98 (m, IH), 3.96 - 3.78 (m, 2H), 3.77 - 3.55 (m, 2H), 3.02 - 2.64 (ra, IH), 2.25 - 1.82 (m, 3H),

1.81 - 1.62 (m, IH), 1.51 (d, J = 6.8 Hz, 3H).

Example 91: ((4R,1 lbR)-6-amino-4-methyl- 1,3,4, 11b- teirahydropyrido[3',4':4,5]pyrimido[6,l-c]Ll,4]oxazin-10-yI)((4aR*,9bR^1!:)-7- (difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone isomer 4

[1767] Followed the procedure of Example 23 with intermediate AC9 (43 nig, 0.15 mmol) and intermediate A 11 isomer I (25 mg, 0.10 mmol) to afford ((4R,1 lbR)-6-amino-4-methyl- 1,3,4, 1 lb-tetrahydropyrido[3^,,4';4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,9bR*)-7-

(difluoromethoxy)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone formate isomer 4 (Example 91) (9.5 mg, 17%) as a white solid. MS (ESI) calculated for C24H25F2N5O4 [M+H]⁺,486.19 found, 486.20. NMR (400 MHz, Methanol- J₄) 8 (ppm) 8.57 (s, 1H), 8.13 (s, 1H), 7.65 - 7.32 (m, 2H), 7.04 - 6.58 (m, 3H), 6.27 - 5.81 (m, 1H), 5.24 (d, J = 10.4 Hz, 1H), 5.18 - 4.92 (m, 1H), 4.42 (d, J = 1 1.0 Hz, 1H), 4.10 - 3.97 (nt, IH),

3.92 > 3.77 (m, 2H), 3.76 - 3.58 (m, 2H), 3.02 - 2.66 (m, 2H), 2.22 - 1.62 (ra, 3H), 1.51 (d, J = 6.8 Hz, 3H).

Example 92: ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((2R,4aR,l0bS)-8-chloro-2-methyl-2,3_!4a,5,6,l0b-hexahydro-l H-[1 ,4]oxazino[3,2- f]quinolin-l-yl)methanone, isomer 2

A17 isomer 2 isomer 2

[1768] Followed the procedure of Example 76 with intermediate A 17 isomer 2 (100 mg, 0.42 mmol) and intermediate AC1, isomer 2 (119 mg, 0.42 mmol) to afford ((S)-6-amino-9- fluoro- 1,3, 4, l ib- •tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10-yl)((2R,4aR,10bS)-8-chloro-2- methyl-2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[3,2-f]quinoiin-l-yl)methanone, isomer 2 (Example 92) (47.2 mg, 23%) as a white solid. MS ESI calculated for C24H25CIFN5O3 [ M+H]⁺, 486.16; found, 486.15. ^j H NMR (400 MHz, DMSO-Je) 8 7.72 - 7.00 (rn, 3H), 6.49 - 6.27 (m, 3H), 5.64 (s, 1H), 4.74 - 4.45 (m, 1H), 4.12 - 3.95 (m, 1H), 3.96 - 3.59 (m, 6H), 3.58 - 3.41 (m, 2H), 3.15 - 2.91 (rn, 2H), 2.82 - 2.66 (m, 1H), 2.27 - 2.02 (m, 2H), 0.68 and

0.59 ( 6.8 Hz, 3H).

Example 93: ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((3R*,4aS*,9bS*)-7- (difluoromethoxy) -3-methoxy- 3, 4, 4a, 9b-tetrahydrobenzofuro[3, 2- b]pyridin-l(2H)-yl)methanone, isomer 2

Example 94: ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3-c]quioazolin- 10- yl)((3R*,4aS*,9bS*)-7-(difluoromethoxy)-3-methoxy-3,4,4a,9b-tetrahydrobenzofuro[3,2- bjpyridin- 1 (2H )-yl)methanone, isomer 4

[1769] To a stirred solution of intermediate A63 (100 mg, 0.36 mmol) and CS2CO3 (71.7 mg, 0.22 mmol) in N,N-Dimethylacetamide (0.5 ml) was added intermediate AC1, isomer 2 (73.21 mg, 0.25 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction mixture was filtered. The filtrate was purified by prep-HPLC with the following conditions: [Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient: 60% B to 70% B in 10 min, 70%' B to 70% B in 20 min; Wave Length: 254/220 nm; RTl(min): 1 1 .4 - 12.5] to afford fraction A (9.5 mg) with retention time at 11.4 min on prep-HPLC and fraction B (24.4 mg) with retention time at 12.5 min on prep-HPLC.

[1770] The fraction A (9.5 mg) was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IK 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% lPAMine)-HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient; 40% B to 40% B in 10 min; Wave Length: 220/254 nm; RT1 (min): 6.929; RT2 (min): 8.431 ; Sample Solvent: MeOH: DC.M-1: 1— HPLC; Injection Volume: 0.3 ml..; Number Of Runs: 3] to afford ((S)-6-amino-9-fluoro-l ,3,4,llb-tetrahydro-[l,4]oxazino[4,3- c]quinazolin-10-yl)((3R*,4aS*,9bS*)-7-(difluoromethoxy)-3-methoxy-3,4,4a,9b- tetrahydrobenzofuro[3,2-b]pyridin-l (2FI)-yl)methanone, isomer 2 (Example 93) ( 1.8 mg, 18% yield) as a white solid with the second peak on chiral-HPLC with retention time at 8.431 minute. MS ESI calculated for (C25H25F3N4O5) [M+H]⁺, 519.18; found, 519.20. 'H NMR (400 MHz, Methanol-J₄) 5 7.49 - 7.04 (m, 2H), 7.05 - 6.71 (in, 1H), 6.72 - 6.62 (m, 1H), 6.61 - 6.55 (m, 2H), 6.19 - 5.32 (m, 1H), 5.18 - 5.02 (m, 1 H), 4.77 - 4.60 (m, 1H), 4.16 - 4.10 (m, 1H), 3.96 - 3.84 (tn, 2H). 3.80 - 3.50 (m, 3H), 3.29 - 3.20 (m, 5H), 2.71 - 2.56 (m, 1 H), 2.30 - 2.08 (m, 2H). Stereochemistry at “orl”, “or2”, and “or3” centers was not determined.

[1771] The fraction B (24.4 mg) was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IK 2*25 cm, 5 jrm: Mobile Phase A: Hex(0.3% IPAMine)-HPLC, Mobile Phase B: MeOH: DCM=1: 1— HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 9.5 min; Wave Length: 220/254 nm; RTl(min): 6.026;

RT2(mm): 7.617; Sample Solvent: MeOH: DCM=1: 1-HPLC; Injection Volume: 0.4 mL;

Number Of Runs: 6] to afford ((S)-6-amino-9-fluoro-l,3,4,l lb-tetrahydro-[l,4]oxazino[4,3- c]quinazohn-10-yl)((3R*,4aS*,9bS*)-7-(difluoromeihoxy)-3-methoxy-3,4,4a,9b- tetrahydrobenzofuro|3,2-b|pyridin-1 (2H)-yl)methanone, isomer 4 (Example 94) (6.1 mg, 64% yield) as a white solid with the second peak on chiral-HPLC with retention time at 7.617 minute. MS ESI calculated for C25H25F3N4O5 [M+H]⁺, 519.18; found, 519.20. ^lH NMR (400 MHz, Methanol-da) 8 7.48 - 7.05 (m, 2H), 7.04 - 6.46 (m, 4H), 6.26 - 5.33 (m, 1H), 5.16 - 5.08 (m, 1H), 4.82 - 4.55 (m, 1H), 4.11 - 4.04 (m, 1H), 3.95 - 3.82 (m, 2H), 3.76 - 3.45 (m, 4H), 3.40 - 3.35 (m, 1H), 3.19 - 3.10 (m, 2H), 3.03 - 2.93 (m, 2H), 2.86 - 2.16 (m, 1H), 1.99

- 1.83 (m, 1H). Stereochemistry at “orl”, “or2”, and “or3” centers was not determined.

Example 95: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((3RMaS*,9bR*)-7-(difluoromethoxy)-3-fluoro-2,3,4,4a,5,9b-hexahydro-lH- indeno[1.2-b]pyridin-l-yl)methanone isomer 2

[1772] Followed the procedure of Example 23 with intermediate AC4 (103 mg, 0.39 mmol) and intermediate A52 (100.00 mg, 0.39 mmol) and purified by Prep-HPLC with the following conditions (Column: CHIRAL ART Cellulose- SC, 2*25 cm, 5 pm; Mobile Phase

A: Hex(0.2% IPAMine)— HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 30 min; Wave Length; 220/254 nm; RTl(min): 8.499;

RT2(min): 1 1.898; Sample Solvent: EtOH; DCM=1 : 1— HPLC; Injection Volume: 1.0 mL; Number Of Runs: 2) to afford a 1 :1 mixture of ((R)-6-amino-l,3,4,l lb- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10-yI)((3R*,4aS*,9bR*)-7- (difluoromethoxy)-3-fluoro-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridin-l- yl)methanone isomer 1 and ((R)-6-amino-l,3,4,llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- c][l,4]oxazin-10-y1)((3R*,4aS*,9bR*)-7-(difluoromethoxy)-3-fluoro-2,3,4,4a,5,9b- hexahydro-lH-indeno[l,2-b]pyridin-l-yl)methanone isomer 2 (22.31 mg, 3%) as a yellow solid.

[1773] The above mixture was purified by Prep-HPLC with the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.3% IP AMIN), Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 12 min; Wave Length: 220/254 nm: RTl(min): 7.93; RT2(min): 9.41; Sample Solvent: EtOH: DCM=1: 1--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 3) to afford ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxaz.in-10-yl)((3R*,4aS*,9bR*)-7- (difluoroniethoxy)-3-fluoro-2,3,4,4a,5,9b-hexahydro-lH-indeno[l,2-b]pyridin-l- yl)methanone isomer 2 (Example 95) (1.90 mg, 6%) as a white solid with retention time at 9.41 minute. MS ESI calculated for (C24H24F3N5O3) [M+H]M88.18; found, 488.25. ^:H NMR (400 MHz, Methanol-^) 8 8.01 - 7.93 (m, 1H), 7.44 - 7.25 (m, 2H), 7.19 - 6.90 (m, 2H), 6.81 (t, J = 74.0 Hz, 1H), 6.01 - 5.54 (m, 1H), 4.86 - 4.54 (m, 2H), 4.21 - 4.20 (m, 1H), 3.97 - 3.94 (m, 1H), 3.84 - 3.83 (m, 1H), 3.77 - 3.40 (m, 3H), 3.16 - 2.48 (m, 4H), 2.26 - 2.22 (m, 1H), 1.31 - 1.30 (rn, 2H). Stereochemistry at “orl”, “or2”, and “or3" centers was not determined.

Example 96: ((R)-6-amino-l ,3,4,1 lb-tetrahydropyrido[3’,4‘:4,5]pyrimido[6,l -c][l,4]oxazin-

10-yl)((2R*,4aS*,9bS*)-7-methoxy-2-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin- l(2H)-yl)methanone isomer 2

[1774] To a stirred solution of intermediate A64 (220 mg, 1.00 mmol) and CS2CO3 (654 mg, 2.00 mmol) in N,N-Dimethylacetamide (2 mL) was added intermediate AC4 (267 mg, 1.00 mmol) in portions at 0 °C. The resulting mixture was stirred at 25 °C for 1.5 h. The reaction was quenched by water and extracted with EtOAc and dried over anhydrous NazSO-r. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% methanol in dichloromethane to afford to afford a 1: 1 mixture of ((R)-6-ammo-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-cj[l ,4]oxazin-10-yl)((2R*,4aS*,9bS*)-7-methoxy-2- methyl-3.4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone isomer 1 and ((R)- 6 -amino- 1,3, 4,1 lb-tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((2R*,4aS*,9bS*)-7-methoxy-2-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin- 1 (2H)-yl)methanone isomer 2 (57 mg, 13%) as a white solid.

[1775] The mixture (57 mg) was separated by Prep-HPLC with the following conditions (Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.3% IPAMine)-HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 19 min; Wave Length: 220/254 nm; RTl(min): 12.434; RT2(min): 15.028; Sample Solvent: MeOH: DCM=1: 1 -HPLC; Injection Volume: 0.4 mL; Number Of Runs: 4) to afford ((R)-6-amino-l,3,4,llb-tetrahydropyrido[3',4':4,5]pyriinido[6,l-c][l,4]oxazin-10- yl)((2R%4aS%9bS*)-7-methoxy-2-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridm- l(2H)-yl)methanone isomer 2 (Example 96) (20 mg, 35%) as a white solid with retention time at 15.028 minute. MS ESI calculated for C24H27N5O4 [M+H]⁺, 450.21: found, 450.20. ^!H NMR (400 MHz, DMSO-Js) 8 7.98 (s, 1 Hi, 7.48 - 7.08 (m, 4H), 6.50 - 6.35 (m, 2H), 6.35 - 5.75 (m, 1H), 5.20 - 4.98 (m, 1H), 4.69 - 4.61 (m, 1H), 4.46 - 4.33 (m, 1H), 4.25 - 4.17 (m, 1H), 3.93 - 3.83 (m, 2H), 3.72 (s, 3H), 3.63 - 3.48 (m, 2H), 3.22 - 3.07 (m, 1 H), 1 .89 - 1.47 (m, 3H), 1.32 - 1.16 (m, 1H), 0.92 - 0.58 (m, 3H). Stereochemistry at “or I”, “or2”, and “or3” centers was not determined.

Example 97: re1-((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l- c][l,4]oxazin-10-yl)((4aS,10bS)-8-chloro-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- b Jpyridin- 1 ■■yl)methanone

[1776] Followed the procedure of Example 96 with intermediate A65 (112 mg, 0.50 mmol) and intermediate AC4 (200 mg, 0.75 mmol) to afford to afford rel-((R)-6-amino-l,3,4,l ib- teirahydropyrido[3',4':4,5]pyrimido[6, l-c][1 ,4]oxazin-10-yJ)((4aS,l0bS)-8-chloro- 2,3,4,4a,6,10b-hexahydro- 1H-isochromeno[4,3-b]pyridin-l -yl)methanone (Example 97) (23.9 mg, 10% yield) as a white solid. MS ESI calculated for C23H24CIN5O3 [M+H]⁺, 454.16; found, 454.15. ‘H NMR (400 MHz, DMSO-a'e) 8 7.91 - 7.72 (m, 1H), 7.36 - 7.20 (m, 4H), 6.48 (s, 2H), 5.78 - 5.57 (m, I H), 4.82 - 4.66 (m, 3H), 4.3 ! - 3.75 (m, 5H), 3.55 - 3.38 (m, 2H), 3.09 ■■ 3.06 (m, 1H), 2.61 - 2.25 (m, 1H), 1.78 ■ 1.51 (m, 4H). Absolute stereochemistry at two “or!” centers was not determined.

Example ((R)-6-ammo-l ,3,4, llb-tetrahydropyrido[3',4‘:4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((3R*,4aS*,9bS*)-7- (difluoromethoxy )-3-methyl -3, 4, 4a, 9b- tetrahydrobenzofurol 3, 2- b jpyridin - 1 (2H )-yl)niethanone

A59 isomer 1

[1777] Followed the procedure of Example 96 with intermediate A59 isomer 1 (40 mg, 0.16 mmol) and intermediate AC4 (84 mg, 0.31 mmol) to afford ((R)-6-amino- 1,3, 4,Hb- tetrah ydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((3R*,4aS*,9bS*)-7-

(dinuoromelhoxy)-3-meihyl-3,4,4a,9b-ietrahydrobenzofuro[3,2-b]pyridin-l(2H)- yDniethanone (Example 98) ( 14.6 mg, 19%) as a white solid. MS ESI calculated for C24H25F2N5O4 [M+H]⁺, 486.19; found, 486.20. ^!H NMR (400 MHz, CD3OD) 3 7.99 (s, 1H), 7.63 - 7.22 (m, 2H), 7.03 - 6.49 (m, 3H), 6.39 - 5.94 (m, 1 H), 5.23 - 5.01 (m, 1H), 4.85 - 4.76 (m, 2H), 4.24 - 4.11 (m, 1H), 4.01 - 3.91 (m, 1H), 3.88 - 3.76 (m, 1H), 3.74 - 3.56 (m,

2H), 3.31 - 3.14 (m, 1H), 3.10 - 2.78 (m, 1H), 2.20 - 2.08 (m, 1H). 2.07 - 1.89 (m, 1H), 1.63 - 1.48 (m, 1H), 1.02 - 0.98 (m, 3H). Stereochemistry at “orl”, “or2”, and “or3” centers was not determined. Example 99: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4‘:4,5]pyrimido[6,l-c][1.4]oxazin-

10-yl)((4aS,10bS)-8-(difluoromethoxy)-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3- bjpyridin- 1 -yl)methanone

A24, isomer 1

[1778] Followed the procedure of Example 23 with intermediate AC4 (154 mg, 0.51 mmol) and intermediate A24 isomer 1 (100 mg, 0.39 mmol) to afford ((R)-6-amino-l,3,4,l 1b- tetrahydropyrido[3’,4':4,5]pyrimido[6,l -c][l,4]oxazin- 10-yl)((4aS,10bS)-8-

(difluoroniethoxy)-2,3,4,4a,6,10b-hexahydro-lH-isochromeiio[4,3“b]pyridin-l-yl)methanone (Example 99) (31.2 mg, 16%) as a light yellow solid. MS ESI calculated for (C24H25F2N5O4) [MW, 486.19; found, 486.25. ^SH NMR (400 MHz, DMSO-<%) 5 8.19 - 8.07 (m, 1H), 7.81 (br, 2H), 7.67 - 7.58 (m, 1H), 7.47 - 7.03 (m, 3H), 7.03 - 6.91 (m, 1H), 5.79 - 5.23 (m, 1H), 5.00 - 4.88 (m, 1H), 4.87 - 4.57 (m, 2H), 4.37 - 4.22 (m, 1 H), 4.16 - 4.05 (m, 1H), 4.04 -

4.89 (m, 2H), 3.69 - 3.53 (m, 3H). 3.28 - 3.16 (m, 1H), 2.70 -• 2.25 (m, 1H), 1.84 - 1.43 (m,

4H).

Example 100: rel-(4aS,10bS)-l-((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)-2,3,4,4a,6,10b- hexaliydro-lH-isochromeno[4,3-b]pyridine-8-carbonitrile

[1779] Followed the procedure of Example 23 with intermediate AC 4- (373 mg, 1.40 mmol) and intermediate A66 (150 mg, 0.70 mmol) to afford rel-(4aS,10bS)-l-((R)-6-amino-

1,3,4, 1 lb- tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridine-8-carbonitrile (Example 100) (19.6 mg, 6.30%) as a white solid. MS ESI calculated for C24H24N6O3 [M+l]⁺, 445.19; found, 445.35. ^JH NMR (400 MHz, DMSO-d₆) 8 7.96 - 7.22 (m, 5H), 6.67 - 6.40 (m, 2H), 5.92 - 5.64 (m, 1H), 4.91 - 4.59 (m, 3H), 4.38 - 4.30 (m, 2H), 3.98 - 3.69 (m, 3H), 3.61 - 3.43 (m, 2H), 3.15 - 3.97 (m, 1H), 2.70 - 2.53 (m, 1H), 1.88 - 1.38 (m, 4H). Absolute stereochemistry at two “orl” centers was not determined.

Example 101: ((R)-6-amino- 1,3,4, 1 lb-tetahydropyrido| 3’ ,4' : 4,5 Ipyrimidoj 6, 1-c | [ 1 ,4 joxazin- 10-yl)((2R*,4aS*,10bS*)-8-(difluoromethoxy)-2-methyl-2,3,4,4a,6,10b-hexahydro-lH- isochromen o [4,3 -bjpyridin- 1 -y 1) methanone, i somer 1 isomer 1

A67 isomer 1 Isomer 1

[1780] To a stirred solution of intermediate A67 isomer 1 (500 mg, 1.86 mmol), K (770 mg, 5.57 mmol) and 4A molecular sieve in DMAC (12.5 mL) was added intermediate AC4 (675 mg, 2.23 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with water at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na?SO4- After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 5% to 35% MeCN in water (10 mmol/L NH4HCO3) to afford (( R )-6- amino- l,3,4,llb-tetrahydropyrido[3’,4’:4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((2R*,4aS*,10bS*)-8-(dilluoromethoxy)-2-methyl-2,3,4,4a,6,10b-hexahydro- 1H- isochromeno[4,3-b]pyridin-l-yl)methanone formate, isomer 1 (Example 101) (20.0 mg, 2% yield) as a white solid. MS ESI calculated for C25H27F2N5O4 [M+H]⁺, 500.20; found, 500.20. ^!H NMR (400 MHz, DMSO-ds) 5 8.38 - 8.20 (m, 1 H), 8.07 - 7.72 (m, 1H), 7.73 - 6.73 (m, 7H), 5.99 - 5.41 (m, 1H), 4.95 - 4.51 (m, 3H), 4.28 - 3.96 (m, 3H), 3.98 - 3.78 (m, 2H), 3.61 - 3.49 (m, 2H), 3.22 - 3.01 (m, 1H), 2.15 - 1.90 (m, 1H), 1.82 -• 1.37 (m, 3H), 0.76 (d, J = 6.4 Hz, 3H). Stereochemistry at “orl”, “or2”, and “or3" centers was not determined.

Example 102: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxa zin- 10-yl)((2R*,4aS*,10bR*)-8-(difluoromethoxy)-2~methyl-3,4,4a,10b-tetrahydro-2H- cliromeno[4,3-b]pyridin-l(5H)-yl)methanone isomer 1

AS/ isomer 1 Isomer 1

[1781] To a stirred solution of intermediate A57 isomer 1 (50 mg, 0.18 mmol) in THF (1 mL) was added LiHMDS (1.0 M in THF) (0.2 mL, 0.20 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min. Then intermediate AC4 (59 mg, 0.22 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched with water/ice at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCfo After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Cl 8 OBD Column 30*150 mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 10% B to 30% B in 15 min; Wave Length; 254/220 nm; RTl(min): 12.5 to afford ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1-c] [1 ,4]oxazin- 10- yl)((2R*,4aS*, 10bR*)-8-(dilluoromethoxy)-2-methyl-3,4,4a,10b-tetrahydro-2H- chromeno[4,3-b]pyridin-l(5H)-yl)methanone, isomer 1 (Example 102) (2.7 mg, 3%) as a white solid. MS ESI calculated for C25H27F2N3O4 [M+H]⁺, 500.20; found, 500.20. ^JH NMR (400 MHz, DMSO-&+ D₂O) 8 8.19 and 8.06 (s, 1H), 7.59 - 7.47 (m, 1H), 7.40 - 6.96 (m, 2H), 6.73 - 6.66 (m, 1H), 6.60 - 6.53 (m, 1 H), 5.95 and 5.29 (s, 1H), 4.99 - 4.70 (m, 1H), 4.30 - 4.05 (m, 3H), 3.94 - 3.91 (m, 3H), 3.72 - 3.63 (m, 2H), 3.30 - 3.22 (m, 1 H), 2.13 - 2.04 (m, III), 1.82 - 1.47 (m, 4H), 0.73 - 0.65 (m, 3H). Stereochemistry at “orl”, “or2”, and “or3” centers was not. determined.

Example 103: ((R)-6-amino-l ,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyriniido[6,l-c][l ,4]oxazin-

10-yl)((3R*,4aS*,9bS*)-7-(difluoromeihoxy)-3-niethoxy-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridin-l(2H)-yl)methanone isomer 3

[1782] Followed the procedure of Example 96 with intermediate A63 (200 mg, 0.73 mmol) and intermediate CA4 (196 mg, 0.73 mmol) and separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IK 2*25 cm, 5 pm; Mobile Phase A: Hex (0.3% IPAMIN), Mobile Phase B: MEOH: DCM=1: 1-HPLC: Flow rate: 20 mL/min;

Gradient: 40% B to 40% B in 24 min; Wave Length: 220/254 am; RT1 (min): 8.74: RT2 (min): 10.27; RT3 (min): 13.13; RT'4 (min): 20.81 ; Sample Solvent: EtOH: DCM=1: 1 — HPLC; Injection Volume: 0.5 mL; Number Of Runs: 5] to afford ((R)-6-amino-l,3,4,llb- teirahydropyrido[3',4':4,51pyrimido[6,l-c][l,4]oxazin-10-yl)((3R*,4aS*,9bS*)-7- (difluoromethoxy)-3-methoxy-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)- yljmethanone isomer 3 (Example 103) (2.5 mg, 6%) as a white solid as the third peak on chiral-HPLC with retention time at 13.13 minute. MS ESI calculated for C24H25F2N5O5 [M+H]⁺, 502.18; found, 502.20. ^!H NMR (400 MHz, Methanol-dj) 5 8.15 - 7.30 (m. 3H), 7.22 - 6.50 (m, 3H), 6.06 - 5.91 (m, 1 H), 5.17 - 5.02 (m, 1H), 4.82 - 4.54 (m, 1H), 4.22 - 4.04 (m, 2H), 3.98 - 3.87 (m, 1H), 3.87 - 3.75 (tn, JH), 3.73 - 3.58 (m, 3H), 3.43 - 3.34 (m, 2H), 3.29 3.20 (m, 2H), 2.62 - 2.39 (ni, 1H), 2.39 ■■■ 2,04 (m, 2H). Stereochemistry at “or I”, “or2”, and “or3” centers was not determined.

Example 104: (3R,4aS,9aR)-4-((R)-6-amino-l,3,4,l lb- tetahydropyrido[3',4':4,5]pyriniido[6,l-c][l,4]oxazine-10-carbonyl)-3-methyl-2,3,4,4a,9,9a- hex ally droi ndeno [2.1 -b] [ 1 ,4]oxazine-7-c arbon itri le

[1783] Followed the procedure of Example 76 with intermediate A69 (70 mg, 0.33 mmol) and intermediate AC4 (113 mg, 0.43 mmol) to afford (3R,4aS,9aR)-4-((R)-6-amino-

1 ,3,4,1 lb-tetrahydropyrido[3',4':4,5]pyriniido[6,l“C][l,4]oxazine-10-carbonyl)-3-methyl- 2,3,4,4a,9,9a-hexahydroindeno[2,l-b][l,4]oxazine-7-carboniirile (Example 104) (17.3 mg, 12%) as a white solid. MS ESI calculated for C2.4H24N6O3 [M+H]⁺, 445.19; found, 445.20. ‘H NMR (400 MHz, DMSO-de) 57.88 - 7.61 (m, 3H), 7.47 (d, J = 10.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 6.49 (s, 2H), 5.81 - 5.66 (m, 1H), 4.71 - 4.62 (m, 1H), 4.56 - 4.09 (m, 3H). 3.89 - 3.71 (m, 2H), 3.70 - 3.60 (m, 1H), 3.59 - 3.44 (m, 3H), 3.29 - 3.22 (m, 1H), 3.17 - 3.01 (m, 1H), 2.99 - 2.85 (m, 1H), 0.86 - 0.75 (m. 3H).

Example 105: ((S)-6-amino-9-fluoro- 1,3,4, i lb-tetrahydro-[l,4]oxazino[4,3-c]quinazolin-10- yl)((4aS,10bS)-8-(difluoromethoxy)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b'Jdipyridin- l-yl)methanone

A19

[1784] Followed the procedure of Example 76 with intermediate A 19 ( I 00 mg, 0.34 mmol ) and intermediate AC1 , isomer 2 (109 mg, 0.34 mmol) to afford ((S)-6-amino-9-fluoro- l,3,4,llb-tetrahydro-[l,4]oxazino[4,3-c]qumazolin-10-yl)((4aS,10bS)-8-(difluoromethoxy)- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l-yl)metlianone (Example 105) (99.3 mg. 57%) as a white solid. MS ESI calculated for C24H24F3N5O4 |M+H]⁺, 504.18; found, 504.10. ‘H NMR (400 MHz, DMSO-<%.) 8 7.82 - 7.46 (m, 2H), 7.11 - 7.04 (m, 2H), 6.48 - 6.36 (m, 3H), 5.84 - 4.84 (m, 1H), 4.73 - 4.55 (m, 3H), 4.30 - 4.03 (m, 2H), 3.83 - 3.75 (m, 2H), 3.54 - 3.42 (m, 3H), 3. 10 - 3.04 (m, 1H), 2.68 - 2.20 (m, 1H), 1.80 - 1.44 (m,

4H). Absolute stereochemistry was determined by single crystal crystallography.

Example 106: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-cj[l,4]oxazin- 10-yl)((4aS,6R,10bS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridin-l-yl)inethanone

[1785] Followed the procedure of Example 75 with intermediate A41 isomer 3 ( 100 mg, 0.48 mmol) and intermediate AC4 (128.7 mg, 0.48 mmol) to afford ((R)-6-amino-l,3,4,l 1b- tetrahydropyrido[3',4^,:4,5]pyrimido[6,l-c][l,4]oxazin-10-y])((4aS,6R,10bS)-8- (difluorometiioxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochfonieno[4,3-b]pyridin-l- yl)raethanone (Example 106) (49.2 mg, 26%) as a white solid. MS ESI calculated for C25H27F2N5O4 [M+H]⁺, 500.20; found, 500.20. ^!H NMR (400 MHz, DMSO-tfe) 8 7.84 (s, 1H), 7.51 - 7.26 (m, 3H), 7.27 - 7.05 (m, 2H). 6.58 (br, 2H), 5.59 (d, J = 6.4 Hz, 1H), 4.74 - 4.67 (m, 2H), 4.19 - 4.08 (m, 2H), 3.91 - 3.72 (rn, 3H), 3.65 - 3.38 (m, 2H), 3.14 - 2.83 (m, 2H), 1.81 - 1.46 (m, 7H). Absolute stereochemistry was determined by single crystal crystallography.

Example 107: ((4S,HbS)-6-amino-4-methy]-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,1 -c][l,4]oxazin-10-yl)((4aS,10bS)-8- (difluoromethoxy)-2,3,4»4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone [1786] Followed the procedure of Example 68 with intermediate A19 (150 mg, 0.58 mmol) and intermediate CA5 (168 mg, 0.64 mmol) to afford ((4S,l lbS)-6-amino-4-methyl- l,3,4,llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,10bS)-8- (difluorometiioxy)-2,3,4,4a,6,10b-hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone (Example 107) (108 mg, 37%) as a white solid. MS ESI calculated for C24H26F2N6O4 [M+H]⁺ 501.20; found, 501.20. ^!H NMR (400 MHz, DMSO-cfc) 8 7.93 - 7.46 (in, 3H), 7.36 (s, 1H), 7.06 (d, J = 8.4 Hz. 1H). 6.69 (s, 2H), 5.92 - 5.39 (m, 1H), 4.98 (d, J = 3.5 Hz. 1H), 4.78 - 4.69 (m, 2H), 4.40 - 4.23 (m, 1H), 4.20 - 4.01 (m, !H), 3.99 - 3.73 (m, 2H), 3.68 - 3.66 (m, 2H), 3.60 - 3.44 (m, 1H), 2.22 - 2.18 (m, 1H), 1.83 - 1.68 (m, 2H), 1.63 ... 1.44 (_m. 2H), 1.32 (d, J = 6.6 Hz, 3H).

Example 108: ((R)-6-amino- 1,3.4, 1 lb-tetrahydropyrido[3',4':4,5 ]pyrirnido[6, 1 -c] [ 1 ,4]oxazin- l0-yl)((3R*,4aS*,l0bS*)-8-(difluoromethoxy)-3-fiuoro-2,3,4,4a,6,l0b-hexahydro-1H- isochromeno[4,3-bjpyridin-l-yl)methanone isomer 1

[1787] Followed the procedure of Example 75 with intermediate A70 isomer 1 (40 nig, 0.14 mmol) and intermediate AC4 (46 mg, 0.17 mmol) to afford ((R)-6-amino-l ,3,4,l 1b- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((3R*,4aS*,10bS*)-8- (diiluoromelhoxy)-3-lluoro-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l- yl)methanone isomer 1 (Example 108; (31.8 mg, 43%) as a light yellow solid. MS ESI calculated for C24H24F3N5O4 [M+H]⁺, 504.18; found, 504.15. ^rH NMR (400 MHz, DMSO- <%.) 8 (ppm) 8.15 - 7.85 (m, 1H), 7.50 - 6.63 (m, 7H), 5.68 ■■■ 5.58 (m, 1H), 5.00 - 4.63 (m, 3H), 4.62 - 4.51 (m, 1H), 4.39 - 4.04 (m, 3H), 3.99 - 3.77 (m, 2H), 3.69 - 3.49 (m, 2H), 3.20 - 3.04 (m, 1H), 2.75 - 2.72 (m, 1H), 2.38 - 2.15 (m, 1H), 1.87 - 1.80 (m, 1H).

Stereochemistry at “oil”, ^u‘or2”, and “or3” centers was not determined.

Exampie 109 : ((4S, 1 lbR)-6-amino-4-methyl- 1 ,3,4, 1 1 b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][1 ,4]oxazin-10-y])((3R,4aS,9aR)-7-

(difluoromethoxy)-3-methyl-2₍3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- yl)inethanone

A !5 isomer 2

[1788] Followed the procedure of Example 68 with intermediate CA6 (100 mg, 0.38 mmol) and intermediate A 15 isomer 2 (81 mg, 0.32 mmol) to afford ((4S, 1 lbR)-6-amino-4-methyl- 1,3,4, 1 lb-tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((3R,4aS,9aR)-7- (difluoromethoxy)-3-methyl-2,3,9,9a-tetrahydroindeno[2,Eb][l,4]oxazin-4(4aH)- yl)methanone formate (Example 109) (39.6 mg, 22%) as a yellow solid. MS ESI calculated for C25H27F2N5O4 [M+H]⁺, 500.20; found, 500.25. ^!H NMR (400 MHz, DMSO-d₆+ D₂O) 8 (ppm) 8.23 (s, 1H), 8.02 - 7.82 (m, 1H), 7.47 - 6.90 (m, 5H), 5.60 - 5.49 (m, 1H), 4.91 - 4.77 (m, 1H), 4.63 - 4.41 (m, 1H), 4.38 ■■• 4.29 (m, 1H), 4.16 - 3.93 (m, 3H), 3.89 - 3.78 (m, 1H), 3.70 - 3.45 (m, 3H), 3.24 - 2.98 (m, 1H), 2.94 - 2.80 (m, 1H), 1 .23 - 1.17 (m, 3H), 0.89 - 0.80 (m, 3H). Example 110: ((4S,llbS)-6-anuno-4-methyl-l ,3,4,llb- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,6R,10bS)-8-

(difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-blpyridin-l- yl)methanone

[1789] Followed the procedure of Example 68 with intermediate A41 isomer 3 (80 mg, 0.29 mmol) and intermediate CA5 (62 mg, 0.24 mmol) lo afford ((4S,llbS)-6-amino-4- methyl- 1,3,4.1 lb-tetrahydropyrido[3\4':4,5]pyrimido[6. l-c][ l,4]oxazin- 10- yl)((4aS,6R,10bS)-8-(difluoromethoxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridin-l -yl)methanone (Example 110) (38.2 mg, 25%) as a white solid. MS ESI calculated for C26H29F2N5O4 [M+Hf, 514.22; found, 514.25. ^SH NMR (400 MHz, DMSO-d₆) 8 8.10 (s, 1 H), 7.77 - 7.25 (m, 4H), 7. 15 (dd, J = 8.4, 2.4 Hz, 1 H), 7. 11 - 7.03 (m, 1H), 5.59 - 5.57 (m, IH), 5.21 - 5.08 (m, 1H), 4.82 - 4.34 (m, 2H), 4.26 - 4.00 (m, 2H), 3.84 - 3.44 (m, 4H). 3.13 - 2.90 (m, 1H), 1.80 - 1.49 (m, 8H), 1.36 (d, ./ - 6.8 Hz, 3H).

Example 111 : ((4S,llbR)-6-amino-4-methyl-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yI)((4aS,10bS)-8-

(difluoromethoxy)-2.3,4»4a,6,10b-hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)raethanone

A19

[1790] Followed the procedure of Example 68 with intermediate A 19 (90 mg, 0.35 mmol) and intermediate CA6 (92 mg, 0.35 mmol) to afford ((4S,llbR)-6-amino-4-mechyl-l,3,4,l lb- tetraliydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,10bS)-8- (diiluoromethoxy)-2,3.4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridm-l- yl)methanone (Example 111) (25.8 mg, 14%) as a white solid. MS ESI calculated for C24H26F2N6O4 [M+H]⁺, 501.20; found, 501.15. ^!H NMR (400 MHz, DMSO-cfc) 8 7.97 - 7.46 (m, 3H), 7.33 - 7.30 (m, 1H), 7.06 (d, J= 8.4 Hz, 1H), 6.59 (s, 2H), 5.84 - 5.58 (m, 1H), 4.75 - 4.48 (m, 4H), 4.33 - 4.76 (m, 5H), 3.44 - 3.40 (m, 1H), 2.5S - 2. 17 (m, 1H), 1.80 - 1 .59 (m, 4H), 1.17 (d, J = 6.0 Hz, 3H).

Example 112: ((4S, 11 bR)-6-amino-4-methyl- 1,3,4,11b- teirahydropyrido[3',4':4,5]pyrimido[6,l-c][l ,4]oxazin-l0-y])((4aS,6R,10bS)-8-

(difluoromethoxy)-6-melhyl-2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-blpyridin-l- yDmethanone [1791] Followed the procedure of Example 68 with intermediate A41 isomer 3 ( 100 mg, 0.37 mmol) and intermediate CA6 (78 mg, 0.30 mmol) to afford ((4S, I lbR)-6-amino-4- methyl-1.3,4,llb-tetraliydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((4aS,6R,10bS)-8-(difluorometlioxy)-6-methyl-2,3,4,4a,6,10b-hexahydro-lH- isochromeno[4,3-b]pyridin-l-yl)methanone (Example 112) (44.5 mg, 23%) as a white solid. MS ESI calculated for C26H29F2N5O4 [M+H]⁺, 514.22; found, 514.25. ^!H NMR (400 MHz, DMSO-ds) 5 (ppm) 7.86 (s, 1H), 7.53 - 7.21 (m, 3H), 7.15 (dd, ./ = 8.4. 2.4 Hz, 1H), 7.07 (s, 1H), 6.52 (s, 2H), 5.60 (d, J - 6.4 Hz, 1 H), 4.77 - 4.69 (m, 1H), 4.65 - 4.60 (m, 1H), 4.51 - 4.45 (m, 1H), 4.20 - 4.13 (m, 1H), 4.08 - 4.03 (m, 1H), 4.00 - 3.69 (m, 3H), 3.44 - 3.38 (m, 1H), 3.05 - 2.85 (m, IH), 1.77 - 1.45 (m, 7H), 1.16 (d, J = 6.0 Hz, 3H).

Example 113: ((4S,1 lbR)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l -c][l,4]oxazin-10-yl)((2R,4aR,10bS)-8-chloro-2- methyl-2,3,4a,5,6, 1 Ob-hexahydro- lH-[ l,4]oxazino[3,2-f]quinolin- l-yl)methanone

[1792] Followed the procedure of Example 96 with intermediate A17 isomer 2 (102 mg, 0.42 mmol) and intermediate AC7 (120 mg, 0.42 mmol) to afford ((4S,llbR)-6-amino-4- melhyl-1,3,4,1 Ib-tetrahydropyMdolSfdM^JpyrimidoLb.l-cH lAloxaziii- lO- ylX^RAaRJObS^S-chloro^-methyl-^, 3,4a, 5, 6,1 Ob-hexahydro- lH-[l,4]oxazino[3, 2- f]quinolin-l-yl)methanone (Example 113) (41.8 mg, 98.4%) as a white solid. MS ESI calculated for C24H27CIN6O3 [M+HJt 483.18; found, 483.15. ^!H NMR (400 MHz, DMSO- d₆) 5 7.89 (s, 1H), 7.75 - 7.50 (m, 1H), 7.44 - 7.26 (m, 2H), 6.55 (s, 2H), 5.75 - 5.53 (m, 1 H), 4.70 - 4.60 (m, 1H), 4.59 - 4.4 (m, 1H), 4.15 - 4.01 (m, 2H), 3.98 - 3.85 (m, 2H), 3.83 - 3.60 (m, 3H), 3.45 - 3.35 (m, 1H), 3.11 - 2.96 (m, ITT), 2.82 - 2.61 (m, 1H), 2.24 - 2.05 (m, 2H), 1.16 (d, J = 6.4 Hz. 3H), 0.80 - 0.65 (m, 3H).

Example 114: ((4S, 1 lbS)-6-amino-4-methyl- i, 3,4,1 lb- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8-isopropoxy- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-blpyridin-l-yl)methanone

A28

[1793] Followed the procedure of Example 68 with intermediate A28 (50 mg, 0.18 mmol) and intermediate CA5 (42 mg, 0.16 mmol) to afford ((4S,ribS)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5jpyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8-isopropoxy- 2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone (Example 114) (22.8 mg, 26%) as an off-white solid. MS ESI calculated for C27H33N5O4 [M+H]⁺, 492.25: found, 492.20. *H NMR (400 MHz, DMSO-d₆) 3 8.18 - 8.82 (m, 1H), 7.77 - 6.97 (m, 4H), 6.88 - 6.79 (m, 1H), 6.74 - 6.56 (m. 1H), 5.84 - 4.98 (m, 2H), 4.84 - 4.49 (m, 3H), 4.47 - 4.20 (m, IH), 4.17 - 3.95 (m. 2H). 3.82 - 3.62 (m, 2H), 3.64 - 3.46 (m, 3H), 2.74 - 2.21 (m, 1H), 1.81 - 1.41 (m, 2H), 1.41 - 1.30 (m, 4H), 1.25 (d, 5.6 Hz, 6H). Absolute stereochemistry at two “orl” centers was not determined.

Example 115: ((4S,l lbS)-6-amino-4-methyl-l,3,4,l lb- tetrahydropyrido[3^,,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8-cyclopropoxy-

2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridin-l-yl)methanone

[1794] Followed the procedure of Example 68 with intermediate A25 (50 mg, 0. 17 mmol) and intermediate CA5 (46 mg, 0.17 mmol) to afford ((4S, llbS)-6-amino-4-methyl-l, 3,4,11b- tetrahydropyrido[3\4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8-cyclopropoxy-

2,3,4,4a,6,10b-hexahydro-lH-isochromeno[4,3-b]pyridm-l-yl)methanone (Example 115) (44.8 mg, 51%) as a white solid. MS ESI calculated for C27H31N5O4 [M+HJ⁺, 490.24; found, 490.20. ^!H NMR (400 MHz, DMSO-de) 8 8.15 - 7.94 (m, 1 H), 7.78 - 6.65 (m, 5H), 5.82 -

5.08 (m, 2H), 4.86 - 4.20 (m, 4H), 4.16 - 3.98 (m, 2H), 3.88 - 3.66 (m, 3H), 3.62 - 3.41 (m, 2H), 2.72 - 2.26 (m, 1H), 1.83 - 1.44 (m, 4H), 1.40 - 1.30 (m, 3H), 0.87 - 0.56 (m, 4H).

Absolute stereochemistry at two “orl” centers was not determined.

Example 116: ((4R*,1 1 hS*)-6-amino-4-(difiuoromet.hyl)-1,3,4,1 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((3R,4aS,9aR)-7- (difluoromethoxy)-3-methy 1-2,3 ,9,9a-tetrahydroindeno[2, 1 -b] [ 1 ,4]oxazin-4(4aH)- yl)methanone, isomer 4

[1795] To a mixture of intermediate CA10 (40 mg, 0.13 mmol) and intermediate A15, isomer 2 (40 mg, 0.13 mmol) in DMF (1 mL) were added DIEA (52 mg, 0.40 mmol) and HATU (66 mg, 0.17 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture (1 ml..) was purified by prep-HPLC with the following conditions: [Column: Xselect CSH OBD Column 30* 150mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min, 9% B to 27% B in 10 min: Wave Length: 254/220 nm; RTl(min): 10] to afford a 1:1 mixture of ((4S , 1 IbR)- 6- amino -4-(difluoromethyl) - 1 ,3,4, 1 lb -tetrahydropyrido[3',4' :4,5]pyrimido[ .6, 1 - c][l,4]oxazin-10-yl)((3R,4aS,9aR)-7-(difluoromethoxy)-3-methyl-2,3,9,9a- tetrahydroindeno[2, 1 -b] [ 1 ,4]oxazin-4(4aH)-yl (methanone and ((4R , 11 bS)-6-amino-4- (difluoromethyl)-l,3,4,l lb-tetrahydropyrido[3’,4’:4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((3R,4aS,9aR)-7-(difluoromethoxy)-3-mefliy1-2,3,9,9a-tetrahydroindeno[2,l- b][l,4]oxazin-4(4aH)-yl)methanone (33 mg, 46%) as a white solid. This mixture was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IE. 2*25 cm, 5 pm: Mobile Phase A: Hex(0.2% IPAMine)-HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC: Flow rate: 20 mL/min ; Gradient (B%): 30% B to 30% B in 25 min; Wave Length: 220/254 nm; RTlfmin): 16.68; RT2(min): 21.74; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 1.0 mL; Number Of Runs: 3] to afford ((4R*,llbS*)-6-amino- 4-(difluoromethyl)- 1,3,4, 1 lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((3R,4aS,9aR)-7-(difluoromethoxy)-3-methy1-2,3,9,9a-tetrahydroindeno[2,l- b][l,4]oxazin-4(4aH)-yl)methanone, isomer 3 (7.0 mg, 23%) as a white solid as the first peak on chiral HPLC with retention time at 16.68 minute. MS ESI calculated for C25H25F4N5O4 [M+H]⁺, 536.18 found, 536.15. ’H NMR (400 MHz, DMSO-t/c.) 5 (ppm) 57.79 and 7.66 (s, 1H), 7.48 - 7.33 (m, 1H), 7.30 - 6.91 (m, 4H), 6.79 - 6.39 (m. 3H), 5.58 (dd, J = 16.8, 4.2 Hz, 1H), 5.25 - 5.11 (m, 1H), 4.50 - 4.10 (rn, 4H), 4.08 - 3.92 (m, 1 H ), 3.85 - 3.72 (m, 1H), 3.69 - 3.46 (m, 3H), 3.24 - 2.99 (m, 1H), 2.96 - 2.78 (m, 1 H), 0.85 and 0.82 (d, .7 - 6.8 Hz, 3H). [1796] The chiral separation also affords ((4R*,1 lbS*)-6-amino-4-(difluoromethyl)- 1 ,3,4, 1 lb-tetrahydropyrido[3',4’:4,5jpyriinido[6,l-cl[l,41oxazin-10-yl)((3R,4aS,9aR)-7- (difluoromethoxy)-3-methyl-2,3,9,9a-tetrahydroindeno[2,l-b][l,4]oxazin-4(4aH)- yl)methanone, isomer 4 (Example 116) (7.0 mg, 23%) as a white solid as the second peak on chiral HPLC with retention time at 21.74 minute. MS ESI calculated for C25H2.5F4N5O4 [M+H]⁺, 536.18 found, 536.30. 'H NMR (400 MHz, DMSO-de) 8 (ppm) 7.66 and 7.42 (s, 1H), 7.47 - 6.91 (m, 5H), 6.80 - 6.38 (nt, 3H), 5.65 - 5.60 (m, 1H), 5.21 - 5.10 (m, 1H), 4.56

- 4.10 (m, 4H), 4.01 (dd, J = 12.6, 6.0 Hz, 1H), 3.85 - 3.72 (m, 1H), 3.72 - 3.45 (m, 3H), 3.23 - 3.01 (m, 1H), 2.95 - 2.78 (m, 1H), 0.86 and 0.82 (d, J = 6.8 Hz, 3H). Absolute stereochemistry at two “orl” centers was not determined.

Example 117 : ((R)-6-amino- 1,3.4, 1 lb-tetrahydropyrido[3',4':4,5 ]pyrimido|6, 1 -c] [ 1 ,4]oxazin-

10-yl)((4aR*,9bR*)-7-(difluoromethoxy)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-

1 (2H)-yl)methanone, isomer 1 isomer 1

[1797] Followed the procedure of Example 76 with intermediate A71 (60% e.e.) (74 mg, 0.30 mmol) and intermediate AC4 (81 mg, 0.30 mmol) and purified by Perp-Chiral HPLC with the following conditions: (Column: CHIRALPAK IC, 2*25 cm, 5 um; Mobile Phase A: Hex (0.5% 2M NH₃-MeOH), Mobile Phase B: MeOH: DCM-1: 1-HPLC; Flow rate: 20 rnL/min; Gradient. : 40% B to 40% B in 15 min; Wave Length: 220/254 nm; RT1 (min): 8.075; RT2 (min): 11 .276; Sample Solvent: EtOH : DCM=1 : 1-HPLC; Injection Volume: 1 .5 mL; Number Of Runs: 2) to afford ((R)-6- amino- 1,3,4,11b- teiraliydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,9bR*)-7- (difluoromethoxy )-3, 4, 4a, 9b-tetrahydrofuro[2,3-b:4,5-b‘]dipyridin-l(2H)-yl)methanone, isomerl (Example 117) (10. 1 mg, 52%) as a white solid with retention time at 8.075 min.

MS (ESI) calculated for C22H22F2N6O4 [M+H]⁺, 473.17; found, 473.25. ^!H NMR (400 MHz, DMSO-dfi) 8 8.11 - 7.26 (m, 4H), 6.68 - 6.42 (m, 3H), 6.15 - 5.94 (m, 1H), 5.25 - 5.08 (m, 1H), 4.69 (d, J = 10.0 Hz, 1H), 4.25 - 3.75 (m, 4H), 3.55 - 3.46 (m, 2H), 3.11 - 3.03 (m, 1H), 2.80 - 2.78 (in, 1H), 2.05 - 1.49 (m, 4H). Absolute stereochemistry at two “orl” centers was not determined.

Example 118: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1-c] [ 1 ,4]oxazin-

10-yl)((2RMaS*,9bS*)-7-methoxy-2-methyl-3, 4,4a, 9b-tetrahydrofuro[2,3-b: 4,5- b' Jdipyridin- 1 (2H )-y 1 (methanone

A72

[1798] Followed the procedure of Example 96 with intermediate A72 (100 mg, 0.39 mmol) and intermediate AC4 (207 mg, 0.78 mmol) to afford ((R)-6-amino-l,3,4,llb- tetahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R*,4aS*,9bS*)-7-methoxy-2- methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)-yl)methanone (Example 118) (8.0 mg, 4%) as an off-white solid. MS ESI calculated for C23H26N6O4 451.20; found, 451.25. ‘H NMR (400 MHz, DMSO-d₆) 8 (ppm) 7.97 - 7.50 (m, 2H), 7.31 (s, 1H), 6.55 (s, 2H), 6.35 (d, J = 8.0 Hz, 1H), 6.30 - 5.89 (m, 1H), 5.25 - 5.05 (m, 1H), 4.71 - 4.65 (m, 1H), 4.47 - 4.35 (m, 1H), 4.16 - 4.08 (m, 1H), 3.89 - 3.72 (m, 5H), 3.60 - 3.43 (m, 2 H), 3.13 - 3.03 (m, 1 H), 1.93 - 1.73 (m, 2H), 1.67 - 1.55 (m, 1 H), 1.24 - 1.12 (m, 1H), 0.93 - 0.62 (m, 3H). Absolute stereochemistry at three “orl” centers was not determined. Example 119: ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4’:4,5 ]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((5aR*,8S*.9aR*)-3-methoxy-8-methyl-5a,7₍8,9a-tetrahydropyrido[2',3’:4,5]furo[2,3- bjpyrazin-9(6H)-yl)methanone isomer 3

[1799] Followed the procedure of Example 76 with intermediate A73 isomer 3 (20 rug, 0.09 mmol) and intermediate AC4 (28.9 mg, 0.1 1 mmol) to afford ((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((5aR*,8S*,9aR*)-3-methoxy-8- methyl-5a,7,8,9a-tetrahydropyrido[2',3’:4,5]furo[2,3-b]pyrazin-9(6H)-yl)methanone isomer 3 (Example 119) (5.1 mg, 12%) as a white solid. MS ESI calculated for C22H25N7O4 [M+H]⁺, 452.20; found, 452.20. ^SH NMR (400 MHz, DMSO-<%) 8 (ppm) 7.98 - 7.68 (m, 2H), 7.30 -

7.23 (m. 1H), 6.53 - 6.34 (m, 3H), 5.34 - 5.32 (m, 1H), 4.63 - 4.61 (m, 1H), 4.33 - 4.25 (m, 1H), 4.11 - 4.06 (m, 1H), 3.93 - 3.66 (m, 5H), 3.05 (t, J = 12.0 Hz, 1H), 2.00 - 1.69 (m, 4H),

1.24 - 0.66 (m, 5H). Absolute stereochemistry at three “orl” centers was not determined.

Example 120: ((R)-6-amino- 1 ,3,4- 1 Ib-tetrah ydropyrido[3',4‘:4,5 ]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yr)((4aR*,10bR*)-8-cyclopropoxy-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b']dipyridin- 1 -yl)methanone

A74

[1800] Followed the procedure of Example 76 with intermediate A74 (55 mg, 0.22 mmol) and intermediate AC4 (59 mg, 0.22 mmol) to afford ((R)--6-amino-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8-cyclopropoxy- 2 ,3 ,4,4a, 6, 1 Ob-hexahydro- lH-pyrano[3 ,2-b:5 ,4-b']dipyridin- 1 -yl)methanone (Example 120) (24.41 mg, 22%) as a white solid. MS ESI calculated for C25H2SN6O4 [M+H]\ 477.22; found 477.20. ^!H NMR (400 MHz, DMSO-<fo) 57.85 - 7.72 (tn, 1H), 7.50 (s, 1H), 7.36 - 7.33 (m, 1H), 6.84 (d, 7 - 8.4 Hz, 1H), 6.50 (s, 2H), 5.79 - 5.56 (m 1H), 4.96 - 4.41 (m, 3H), 4.54 - 3.91 (m, 4H), 3.99 - 3.62 (m, 2H), 3.55 - 3.48 (m, 2H), 3.10 - 3.03 (m, 1H), 2.57 - 2.68 and 2.33 - 2.24 (m, 1H), 1.95 - 1.19 (m, 4H), 0.75 (d, 7= 6.6 Hz, 2H), 0.67 (d, 7 = 3.6 Hz, 2H).

[1801] Absolute stereochemistry of Example 120 was determined based on the absolute stereochemistry of A74 Accordingly, Example 120 is represented by the structure: having the chemical name of ((R)-6-amino-l ,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,10bS)-8-cyclopropoxy-

2,3,4,4a,6,10b-hexahydro-lH-Dvrano[3,2-b:5,4-b']dipyridin-l-vl)methanone. Example 121: ((4S,llbR)-6-amino-4-methyl-l,3,4,l 1b- tetrahydropyrido[3',4^,:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R,4aR,10bS)-2-methyl-8-

(tifluoromethyl)-2,3,4a,5,6,10b-hexahydro-lH-[l,4]oxazino[3,2-f]quinolin-l-yl)methanone

[1802] Followed the procedure of Example 96 with intermediate A38 (40 mg, 0.14 mmol) and intermediate AC7 (40 mg, 0.15 mmol) to afford ((4S,llbR)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R,4aR,10bS)-2-methyl-8- (trifluoromethyl)-2.3,4a,5,6, lOb-hexahydro- 1 H-[ 1 ,4]oxazino[3,2-f]quinolin- 1 -yl)melhanone (Example 121) (10.6 mg, 13%) as a white solid. MS ESI calculated for C25H27F3N6O3 [M+H]⁺, 517.21; found, 517.20. ’ll NMR (400 MHz, DMSO-d₆) 8 8.24 - 7.63 (m, 3H), 7.47 - 7.26 (m, 1H), 6.60 (s, 2H), 5.86 - 5.66 (m, 1H), 4.73 - 4.60 (rn, 1H), 4.58 - 4.45 (m, 1H), 4.20 ~ 4.04 (m, 2H), 4.04 - 3.91 (m, 2H), 3.85 - 3.66 (m, 2H), 3.64 - 3.57 (m, 1H), 3.49 ~ 3.39 (m, 1H), 3.23 - 3.01 (m, 1H), 2.93 - 2.74 (m, 1H), 2.30 ■■■ 1.97 (m, 2H), 1.16 (d, J = 6.0 Hz, 3H), 0.67 (d, ./ - 6.8 Hz, 3H).

Example 122: ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4’:4,5 ]pyrimido[6, 1 -c] [ 1 ,4]oxazin-

10-yl)((4aR*,9bR*)-/-isopropyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b'jdipyridin-l(2H)- yl)methanone

[1803] Followed die procedure of Example 96 with intermediate A75 (100 mg, 0.46 mmol) and intermediate AC4 (120 mg, 0.46 mmol) to afford ((R)-6-aniino- l,3,4,Hb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,9bR*)-7-isopropyl- 3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)-yl)methanone (Example 122) (7.4 rag, 3.6%) as a white solid. MS ESI calculated for Cw-dExNeCh [M+H] 449.22,; found, 449.20. ^!H NMR (400 MHz, CD3OD) S 8.08 - 7.65 (m, 2H), 7.37 (br. 1H), 6.93 - 6.86 (m, 1H), 6.32 - 6.95 (m, 1H), 5.08 (br, 2H ), 4.44 - 4.08 (m, 2H), 3.99 - 3.88 (m, 1H), 3.87 - 3.75 (m, 1H), 3.75 - 3.58 (m, 2H), 3.30 - 3.18 (m, 1H), 3.04 - 2.62 (m, 2H), 2.19 - 1.84 (m, 3H), 1.82 - 1 .61 (m, 1H), 1.34 - 1.23 (m, 6H). Absolute stereochemistry at two “orl” centers was not determined.

Example 123: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4’:4,5]pyriniido[6, 1-c] [ 1 ,4]oxazin-

10-yl)((5aR*,l lbS*)-9-(difluoromethoxy)-2,3,5.5a.7, 1 Ib-hexahydro- lH-isochromeno[4,3- e] [ 1 ,4]oxazepin- l-yl)methanone

.A76

[1804] Followed die procedure of Example 76 with intermediate A76 (100 mg, 0.37 mmol) and intermediate AC4 (98 mg, 0.37 mmol) to afford ((R)-6-amino-l,3,4,l lb- tetrahydropyrido[3',4^,:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((5aR*,llbS*)-9- (difluoromethoxy)-2,3,5,5a,7 ,1 lb-hexahydro-lH-isochromeno[4,3-e][l,4]oxazepin-l- yDniethanone (Example 123) (19 mg, 14%) as a white solid. MS ESI calculated for C24H25F2N5O5 [M+H]⁺, 502.18; found, 502.15. ^!H NMR (400 MHz, DMSO-<fc) 8 7.78 (d, J = 1.8 Hz, 1H), 7.51 - 7.32 (m, 2H), 7.23 (d, ./ - 5.0 Hz, 1H), 7.11 (id, J - 8.2, 2.8 Hz, 1H), 7.06 - 6.97 (m, 1H), 6.47 (d, J = 9.8 Hz, 2H), 5.80 - 5.58 (m, 1H), 4.89 - 4.78 (m, 1H), 4.71 - 4.45 (m, 2H), 4.28 - 4.07 (m, 3H), 4.04 - 3.94 (m, 1H), 3.89 - 3.72 (m, 3H). 3.72 - 3.43 (m,

4H), 3.16 - 2.76 (m, 2H). Absolute stereochemistry at two “orl” centers was not determined.

Example 124: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5 jpyrimido[6, 1-c] [ 1 ,4]oxazin-

10-yl)((4aR*,10bR*)-8-isopropyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b' Idipyridin- 1 -yl)melhanone [1805] Followed the procedure of Example 76 with intermediate A43 (50 mg, 0.22 mmol) and intermediate AC4 (57 mg, 0.22 mmol) to afford ((R)-6-amino-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aR*,10bR*)-8-isopropyl- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l-yl)methanone (Example 124) (19.8 mg, 19%) as a white solid. MS ESI calculated for C25H30N6O3 [M+H]⁺, 463.24; found, 463.20. ^!H NMR (400 MHz, DMSO-tfc) 8 7.93 - 7.44 (m, 2H), 7.42 - 7.29 (m, 1H), 7.24 (d, 7 = 8.0 Hz, 1H), 6.52 (s, 2H), 5.93 - 5.54 (m, 1H), 4.83 - 4.50 (m, 3H). 4.44 - 3.98 (m, 3H), 3.91 - 3.68 (m, 2H), 3.60 - 3.43 (m, 2H), 3.16 - 2.92 (ra, 2H), 2.65 - 2.55 and 2.29 - 2.16 (m, IH), 1.85 - 1.46 (m, 4H), 1.23 (d, .J = 6.8 Hz, 6H).

[1806] Absolute stereochemistry of Example 124 was determined based on the absolute stereochemistry of A43. Accordingly, Example 124 is represented by the structure: having the chemical name of ((R)-6-amino-l, 3,4,1 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS, 10bS)-8-isopropyl-

2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l-yl)methanone.

Example 125: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrirnido[6, l-c][l ,4]oxazin-

10-yl)((4aR*,10bR*)-8-cyclopropyl-2,3,4,4a,6,l0b-hexahydro- IH-pyrano[3,2-b:5,4- b'Jdipyridin- 1 - yl)methanone

A44

[1807] Followed the procedure of Example 76 with intermediate A44 (50 mg, 0.22 mmol) and intermediate AC4 (64 mg, 0.24 mmol) to afford ((R)-6-amino-l,3,4,Hb- tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c][1 ,4]oxazin-10-yl)((4aR*, 10bR*)-8-cyclopropyl- 2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l-yl)methanone (Example 125) (23.7 mg, 24%) as a white solid. MS ESI calculated for CzsFbsNeOs [M+H] ^f . 461.22; found, 461.25. ^!H NMR (400 MHz, DMSO-de) 5 (ppm) 7.90 - 7.66 (m, 1H), 7.65 - 7.28 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 6.49 (s, 2H), 5.93 - 5.52 (m, 1H), 4.78 - 4.48 (m. 3H), 4.37 - 3.67 (m, 5H), 3.57 - 3.47 (m, 2H), 3.14 - 2.99 (m, 1H), 2.64 - 2.54 and 2.30 - 2.16 (m, 1H), 2.12 - 2.02 (m, 1H). 1.80 - 1.54 (tn, 4H), 0.99 - 0.73 (m, 4H).

[1808] Absolute stereochemistry of Example 125 was determined based on the absolute stereochemistry of A44. Accordingly, Example 125 is represented by the structure: having the chemical name of ((R)-6-amino-l,3,4,l 1b- teirahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxaz.in-10-yl)((4aS,10bS)-8-cyc]opropyl-

2,3,4,4a,6,10b-hexahydro- lH-pyrano[3,2-b:5,4-b'ldipyridin-l-yl)methanone.

Example 126: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3’,4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((2R*,4aS*,9bS*)-7-isopropyl-2-methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b’Jdipyridin- i(2H)-yl)niethanone

[1809] Followed the procedure of Example 76 with intermediate A77 (80 mg, 0,34 mmol) and intermediate AC4 (91 mg, 0.34 mmol) to afford ((R)-6-amino- 1,3,4, 11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-y])((2R*,4aS*,9bS*)-7-isopropyl-2- methyl-3,4_!4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridin-l(2H)-yl)methanone (Example 126) (17.1 mg, 10%) as a white solid. MS ESI calculated for C25H30N6O3 [M+H]⁺, 463.24; found, 463.25. ^!H NMR (400 MHz, DMSO-dfi) 5 7.91 (d, .7 = 7.2 Hz, 1 H), 7.82 - 7.74 (m, 1H), 7.55 and 7.32 (s, 1H), 6.82 (d, 7= 7.6 Hz, 1H), 6.48 (s, 2H), 6.33 - 6.02 (m, 1H), 5.17 - 5.00 (m, 1H), 4.75 - 4.58 (m, 1H), 4.43 (s, 1H), 4.12 (d, J = 11.2 Hz, 1H), 3.87 - 3.80 (m, 1H), 3.76

(d, J - 13.6 Hz, 1H), 3.55 - 3.45 (m, 2H), 3.13 - 2.99 (m, 1H), 2.94 - 2.84 (m, 1 H), 1.90 - 1.75 (m, 2H), 1.66 - 1.53 (m, 1H), 1.26 ■■• 1.08 (m, 7H), 0.93 - 0.61 (m, 3H). Absolute stereochemistry at three “orl” centers was not determined. Example 127 : ((R)-6-ammo- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1-c] [ 1 ,4]oxazin-

10-yl)((4aS,6R,10b)-6-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-b’]dipyridin-l-yl)methanone

[1810] To a stirred solution of intermediate A45 isomer 1 (50 mg, 0.18 mmol) and intermediate CA4 (55 mg, 0.22 mmol) in N,N-dimethylacetamide (2 mL) were added EtjN (93 mg, 0.92 mmol) and bis(2-oxo-l,3-oxazolidin-3-yl)phosphinoyl chloride (70 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was purified by prep-HPLC with the following conditions: [Column: XBridge Prep OBD Cl 8 Column 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 20% B to 55% B in 12min; Wave Length: 254/22011m; RTl(min): 10] to afford ((R)--6-amino- 1.3,4,Ilb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,6R,10bS)-6-methyl-8- (trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l- yl)methanone (Example 127) (26.7 mg, 29%) as a white solid. MS ESI calculated for C24H25F3N6O3 [M-rHF, 503.19; found, 503.10. ^:H NMR (300 MHz, DMSO-d₆) 58.15 (d, J = 8.1 Hz. IH), 7.88 (d, J = 8.1 Hz, 1 H), 7.82 (s, 1H), 7.36 (s, IH), 6.60 (s, 2H), 5.72 (d. 6.3

Hz, IH), 4.86 - 4.83 (m, IH), 4.73 - 4.68 (m, IH), 4.30 - 4.21 (m, IH), 4.16 - 4.10 (m, IH), 3.99 - 3.66 (rn, 3H), 3.65 - 3.44 (ni, 2H), 3.17 - 2.99 (m, IH), 2.98 - 2.79 (m, IH), 1.78 - 1.72 (m, 4H), 1.59 (d, ./ = 6.6 Hz, 3H).

Example 128: ((R)-6-ammo- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxa zin- 10-yl)((4aS,6S,10bS)-6-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-b']dipyridin-l-yl)methanone

[1811] Followed the procedure of Example 127 with intermediate CA4 (45 nig, 0. 18 mmol) and intermediate A45 isomer 2 (50 mg, 0. 18 mmol) to afford ((R)-6-amino-l,3,4,l 1b- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)(( 4aS,6S,10bS)-6-methyi-8- (trifluorometliyl)-2.3,4,4a,6,10b-hexahydfo-lH-pyrano[3,2-b:5,4-b’jdipyridin-l- y])methanone (Example 128) (15.8 mg, 17%) as a white solid. MS ESI calculated for C24H25F3N6O3 [M+H]⁺, 503. 19; found, 503. 15. ¹ H NMR (400 MHz, DMSO-d_f.) 6 8.33 - 7.57 (rn, 3H), 7.40 - 7.35 (m, 1H), 6.50 (s, 2H), 5.99 - 5.73 (m, 1H), 5.07 - 4.82 (m, 1H), 4.72 - 4.58 (m, 1H), 4.38 - 3.90 (m, 3H), 3.82 - 3.70 (m, 2H ), 3.56 - 3.48 (m, 2H), 3. 1 1 - 2.99 (m,

1H), 2.55 ~ 2.51 and 2.34 - 2.06 (m, 1H), 1.88 - 1.82 (m, 1H), 1.76 - 1.68 (m, 1 H), 1.68 -

1.43 (m, 5H).

Example 129: ((R)-6-amino- 1 ,3,4, 11b-tetrahydropyrido[3',4’:4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((4aS,6R,10bS)-8-chloro-6-methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- bjdipyridin- l -yl)methanone

[1812] Followed the procedure of Example 68 with intermedaite CA4 (50 mg, 0.20 mmol) and intermediate A78 (48 mg, 0.20 mmol) to afford ((R)-6-amino- 1,3,4, 11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,6R,10bS)-8-chioro-6" methyl-2,3,4,4a,6,10b-hexahydro- lH-pyrano[3,2-b:5,4-b’]dipyridin-l-yl)methanone isomer 1 (Example 129) (26.7 mg, 99.5%) as a white solid. MS (ESI) calc’d for C23H25CIN6O3 [M+H]⁺, 469.17; found, 469.15. ^!H NMR (400 MHz, DMSO-ds) 3 7.95 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.49 (d, J = 8.0 Hz. 1H), 7.33 (s, 1H), 6.49 (s, 2H), 5.58 (d, J = 6.4 Hz, 1H), 4.82 - 4.65 (m, 2H), 4.21 - 4.20 (m, 1H), 4.15 - 4.00 (m, 1H), 3.96 - 3.71 (m, 3H), 3.57 -

3.44 (m, 2H), 3.15 - 3.03 (m, 1H), 2.95 - 2.75 (m, 1H), 1.87 - 1.56 (m, 4H), 1.54 (d, J = 6.4 Hz, 3H).

Example 130: ((R)-6-amino- 1,3.4, 1 lb-letahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4R*,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6,10b-hexahydro-1 H-pyrano[3,2-b:5,4- b’]dipyridin-l-yl)methanone isomer 1 Example 131 : ((R)-6-amino- 1 ,3,4, 11 b-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((4R*,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6, 10b-hexahydro-lH-pyrano[3,2-b:5,4- b']dipyridin-l-yl)methanone isomer 2

[1813] To a solution of intermediate A47 (70 mg, 0.29 mmol) in DM Ac (1 mL) were added intermediate CA4 (72 mg, 0.29 mmol), DIEA (149 mg, 1.15 mmol) and CMPI (11 mg, 0.04 mmol). The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was purified by reversed-phase flash column chromatography with 0-5% MeCN in Water (10 mmol/L NH4HCO3) to afford a 1 : 1 mixture of ((R)-6-amino- 1,3 ,4, 11 b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-l0-yl)((4R*,4aR,10bS)-8-chloro-4- fluoro-2,3,4,4a.6,10b-hexahydro-rH-pyrano[3,2-b:5,4-b']dipyridin-l-yl)methaiioiie isomer 1 and ((R)-6-amino- 1,3,4, Hb-ietrahydropyrido[3',4':4,5]pyrimido[6, l-c][l,4]oxazin-10- yJ)((4R*,4aS*,10bR*)-8-chloro-4-fluoro-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b’]dipyridin-l-yl)methanone isomer 2 (50 mg, 36%) as a white solid. This mixture was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IB, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH₃-MeOH)-HPLC, Mobile Phase B: MeOH : DCM=1:1-- HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 45% B to 45% in 15min; Wave Length: 220/254 nm; RTl(min): 8.37; RT2(min): 13.21; Sample Solvent: MeOH : DCM=1:1-HPLC; Injection Volume: 1.5 niL; Number Of Runs: 2] to afford ((R)-6- amino- l,3,4,Hb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((4R*,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b’]dipyridin-l-yl)methanone isomer 1 (Example 130) (21.8 mg, 43%) as a white solid with the retention time at 8.37 min on chiral HPLC and ((R)-6-amino-l,3,4,llb- tetrahydropyrido[3\4’:4,5]pyrimido[6,l-c][l ,4]oxazin-10-yl)((4R*,4aS*,10bR*)-8-chloro-4- fluoro-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b^,]dipyridin-l-yl)mechanone isomer 1 (Example 131) (21.8 mg, 43%) as a white solid with the retention time at 13.21 min on chiral HPLC.

[1814] ((R)-6-amino- 1 ,3,4, 1 lb-teirahydropyrido[3’,4’:4,5]pyrimido[6, 1 -c ] [ 1 ,4]oxazin- 10- yl)((4R*,4aS*,10bR*)-8-chloro-4-fluoro-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4- b']dipyridin-l-yl)methanone isomer 1 (Example 130): MS ESI calculated for C22H22CIFN6O3 [M+H]⁺, 473.14; found, 473.10. ^!H NMR (400 MHz, DMSO-ds) 3 7.94 - 7.58 (m, 2H), 7.50 - 7.37 (m, 2H), 6.55 (s, 2H), 5.82 (d, 6.8 Hz, 1H), 5.32 - 5.12 (m, 1H), 4.99 - 4.90 (m,

1H), 4.84 - 4.65 (m, 2H), 4.29 - 4.26 (m, 1H), 4.14 - 3.90 (m. 2H), 3.82 - 3.72 (m, 2H), 3.61 - 3.46 (m, 2H), 3.15 - 3.02 (m, 1H), 3.00 - 2.82 and 2.49 - 2.44 (m, 1H), 2.17 - 1.79 (m, 2H). Absolute stereochemistry at “orl” center was not determined.

[1815] ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5|pyriniido[6,l-c][l,4]oxazin-10- yl)((4R*,4aR,10bS)-8-chloro-4-fluoro-2,3,4,4a,6,10b-hexahydro-LH-pyrano[3,2-b:5,4- b'Jdipyridin- l-yl)methanone isomer 2 (Example 131): MS ESI calculated for C22H22CIFN6O3 [M+Hf; 473.14; found, 473.10. H NMR (400 MHz, DMSO-d₆) 5 7.86 (s, 1H), 7.76 - 7.38 (rn, 3H), 6.58 (s, 2H), 6.07 - 5.87 (m, 1H), 5.13 ■■■ 4.94 (m, 1H), 4.90 - 4.68 (m, 3H), 4.50 - 4.06 (m, 3H), 3.89 - 3.73 (m, 2H), 3.58 - 3.46 (m, 2H), 3.13 - 3.01 (rn, 1H), 2.76 - 2.62 and 2.42 - 2.33 (m, 1 H), 2.18 - 1.56 (m, 2H). Absolute stereochemistry at ‘‘orl” center was not determined.

Example 132: ((R)-6-amino- 1 ,3,4, 11 b-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [1 ,4]oxazin- 10-yl)((4S,4aR,10bS)-4-fluoro-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-l H-pyrano[3,2- b : 5 ,4-b’ Jdipyridin- 1 -yl)methanone

[1816] Followed the procedure of Example 130 with intermediate A46 isomer 1 (50 mg, 0.18 mmol) and intermediate CA4 (45 mg, 0.18mmol) to afford ((R)-6-amino- 1,3, 4,11b- tetTahydropyrido[3^,,4':4,5]pyrimido[6,l-c][1 ,4]oxazin-10-y])((4S_!4aRJ0bS)-4-fluoro-8-

(frifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l- yl)methanone (Example 132) (12.3 nig, 13%) as a white solid. MS ESI calculated for C23H22F4N6O3 [M+H]*, 507.17; found, 507.15. ^!H NMR (400 MHz, DMSO-d₆) 8 8.13 - 7.62 (m, 3H), 7.43 (s, IH), 6.60 (br. 2H), 5.95 (d, J= 6.4 Hz, 1H), 5.35 - 5.17 (m, IH), 5.08 - 5.00 (m, IH), 4.96 - 4.84 (m, IH), 4.71 (dd, J = 10.4, 3.2 Hz ,1H), 4.41 - 4.21 (m, IH), 4. 18

- 3.96 (m, 2H), 3.90 - 3.74 (m, 2H), 3.60 - 3.47 (m, 211), 3.14 - 3.03 (m, IH), 3.02 - 2.57 (m, IH), 2.20 - 1.76 (m, 2H).

Example 133: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c]| .l,4]oxazin- 10-yl)((4R,4aR,10bS)-4-fluoro-8-(trifluorometbyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-b']dipyridin-l-yl)melhanone

A46 isomer 2

[1817] Followed the procedure of Example 130 with intermediate A46 isomer 2 (50 mg, 0.18 mmol) and intermediate CA4 (45 mg, 0.18 mmol) to afford ((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R,4aR,10bS)-4-fluoro-8- (trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone (26 mg, 29%) as a white solid. MS ESI calculated for C23H22F4N6O3 [M+H]⁺, 507.17; found, 507.10. ^!H NMR (400 MHz, DMSO-de) 5 8.10 - 7.68 (m, 3H), 7.46 - 7.43 (ra, 1H), 6.52 (s, 2H), 6. 10 (s, 1H), 5.14 - 4.88 (m, 311), 4.70 (d, J - 8.4 Hz , 1H), 4.43 - 4.24 (m, 2H), 4.11 (d, J = 10.4 Hz ,1H), 3.87 - 3.76 (m, 2H), 3.55 - 3.50 (m, 2H), 3.11 - 3.05 (m, 1H), 2.74 - 2.68 and 2.51 - 2.50 (m, 1H), 2.10 - 2.03 (ni, 1H), 1.80 - 1.67 (m. 1H).

Example 134: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4R*,4aS*,9bR^!i!)-4-fluoro-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b']dipyridin-l(2H)-yl)methanone isomer 1 [1818] Followed the procedure of Example 130 with intermediate A79 isomer (50 mg, 0. 19 mmol) and intermediate CA4 (47 mg, 0.19 mmol) to afford ((R)-6-amino-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazm-10-yl)((4R*,4aS*,9bR*)-4-fluoro-7- (trifluoromethyl)-3,4.4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)-yl)methanone isomer 1 (Example 134) (26.1 mg) as a white solid. MS ESI calculated for C22H20F4N6O3 [M+H]⁺, 493.15; found, 493.10. ^!H NMR (400 MHz, DMSO-d₆) 5 8.23 - 7.66 (m, 2H), 7.64 - 7.32 (m. 2H), 6.76 - 6.40 (m, 3H), 5.29 - 5.01 (m, 1H), 5.00 - 4.80 (m, 1H), 4.71 (dd. J = 10.4, 3.2 Hz, 1H), 4.57 - 4.25 (m, 1 H), 4.10 (dd, J - 11.2, 3.2 Hz. 1H), 3.93 - 3.70 (m, 2H), 3.60 - 3.44 (m, 2H), 3.15 - 2.58 (m, 2H), 2.12 - 1.65 (m, 2H). Absolute stereochemistry at “orl” and “or2” centers was not determined.

Example 135: ((R)-6-amino- 1,3,4, 1 Ib-letahydropyridol3’,4':4,5]pyrimidol6,l-c]| 1.4]oxazin- 10-yl)((4R*,4aS*,9bR*)-4-fkioro-7-(trifluoromethyl)-3,4,4a,9bAetrahydrofuro[2,3-b:4,5- b’Jdipyridin- l(2H)-yl)methanone isomer 2 isomer 2

A79 isomer2

[1819] Followed the procedure of Example 130 with intermediate A79 isomer 2 (50 mg, 0.19 mmol) and intermediate CA4 (47 mg, 0.19 mmol) to afford ((R)-6-arnino-l ,3,4,l 1b- tetrahydropyrido[3^,,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aS^!i!,9bR*)-4-fluoro-7- (trifluoromethyl)-3,4,4a.9b-tetrahydrofuro|2,3“b:4,5“b'Jdipyridin- l(2H)-yl)methanone isomer 2 (Example 135) (15.3 rag, 16.3%) as a white solid. MS ESI calculated for C22H20F4N6O3 [M+Hp; 493.15; found, 493.10. (400 MHz, DMSO-d₆) 5 8.23 - 7.76 (m, 2H), 7.57 - 7.32 (m, 2H), 6.61 (s, 2H), 6.36 (d, J - 8.8 Hz, 1H), 5.39 - 5.00 (m, 2H), 4.71 (d, J = 9.6 Hz, 1H), 4.47 - 4.03 (m, 2H), 3.91 - 3.73 (m, 2H), 3.59 - 3.45 (m, 2H), 3.16 - 2.66 (m, 2H), 2.25 - 1.86 (m, 2H). Absolute stereochemistry at “orl” and “or2” centers was not determined.

Example 136: ((R)-6-ammo- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1-c] [ 1 ,4]oxazin- 10-yl)((4R*,4aS*,10bS*)-4-methyl-8-(trifluorometiiyl)-2₎3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b']dipyridin- 1 -yl)methanone

[1820] Followed the procedure of Example 23 with intermediate A80 isomer 1 (50 mg, 0.18 mmol) and intermediate AC4 (73 mg, 0.28 mmol) to afford ((R)-6-amino-l,3.4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6, l-c][l ,4]oxazin-10-yl)((4R*,4aS*,10bS*)-4-methyl-8- (trifluoron)ethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone (Example 136) (25.1 mg, 27%) as a white solid. MS ESI calculated for C24H25F3N6O3 [M+H]⁺, 503.19; found, 503.15. HI NMR (400 MHz, DMSO-d₆) 0 8.20 - 7.82 (m, 2H), 7.81 - 7.63 (m, 1 H), 7.41 - 7.36 (m, 1H), 6.48 (d, 7 - 8.4 Hz. 2H). 6.12 - 5.70 (m, 1H), 4.92 - 4.62 (m, 3H), 4.46 - 3.90 (m, 2H), 3.87 - 3.64 (m, 3H), 3.59 - 3.45 (m, 2H), 3.16 - 2.97 (m, 1H), 2.73 - 2.57 and 2.39 - 2.21 (m, 1H), 1.82 (s, 1H). 1.74 - 1.49 (m, 1H), 1.42 - 1.15 (m, 1H), 6.8 Hz, 3H). Absolute stereochemistry at three “orl" centers was not determined. Example 137 : ((R)-6-amino- 1 ,3,4, 11 b-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((4R*,4aS*,9bR*)-4-methoxy-7-(trifluoromethyl)-3,4,4a,9b-telrahydrofuro[2,3-b:4,5- b’Jdipyridin- 1(2H) -yl)methanone

A81 isomer 2

[1821] Followed the procedure of Example 130 with intermediate A81 isomer 2 (40 mg, 0.15 mmol) and intermediate CA4 (36 mg, 0.15 mmol) to afford ((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yI)((4R*,4aS*,9bR*)-4-methoxy-7- (lrifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)-yl)methanone (Example 137) (19.2 mg, 24%) as a white solid. MS (ESI) calculated for C23H23F3N5O4 [M+1H⁺, 505.17; found, 505.20. ^!H NMR (400 MHz, DMSO-dr, + D₂O) 8 8.02 - 7.82 (m, 2H), 7.55 - 7.31 (m, 2H), 6.29 - 6.08 (m, 1 H), 5.39 - 5.14 (m, 1H), 4.78 (d, J - 10.4 Hz, 1H), 4.31 - 4.08 (m, 2H), 3.93 - 3.72 (m, 3H), 3.60 - 3.46 (m, 2H), 3.31 (s, 3H), 3.21 - 3.09 (m, 1H), 2.96 2.56 (rn, 1H), 2.12 - 2.06 (m, 1H), 1.68 ■■■ 1.56 (m, 1H). Absolute stereochemistry at three “orl” centers was not determined.

Example 138: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1-c] [ 1 ,4]oxazin- 10-yl)((4R*,4aR*,9bS*)-4-methoxy-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b']dipyridin-l(2H)-yl)raethanone

A81 isomer 1

[1822] Followed the procedure of Example 130 with intermediate A81 isomer 1 (40 mg, 0.15 mmol) and intermediate CA4 (36 mg, 0.15 mmol) to afford ((R)-6-amino-l, 3,4,1 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aR*,9bS*)-4-methoxy-7- (trifluorometliyl)-3.4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)-yl)methanone (Example 138) (17.1 mg, 21 %) as a white solid. MS ESI calculated for C23H23F3N6O4 [M+Hp’, 505.17; found, 505.15. ^SH NMR (400 MHz, DMSO-d₆ + D₂O) 8 8.16 - 7.73 (m, 2H), 7.59 - 7.34 (in, 2H), 6.47 - 6.20 (m, 1H), 5.01 - 4.79 (m, 1H), 4.75 (dd, J = 10.4, 3.2 Hz, 1H), 4.46 - 3.98 (m, 2H), 3.90 - 3.76 (m, 2H), 3.49 - 3.44 (m, 3H), 3.34 (s, 3H), 3.18 - 3.04 (m, 1H), 2.99 - 2.05 (m, 1 H), 1.93 - 1.90 (m, 1H), 1.59 - 1.42 (m, 1H). Absolute stereochemistry at three “orl” centers was not determined.

Example 139: ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((4R*,4aR*,10bR^si!)-4-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- pyranol3,2-b:5,4-b'ldipyridin-l-yl)methanone [1823] Followed the procedure of Example 23 with intermediate A80 isomer 2 (50 mg, 0.18 mmol) and intermediate AC 4 (73 mg, 0.28 mmol) to afford ((R)-6-amino-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6.1-c][1.4]oxazin-10-yl)((4R*,4aR*,10bR*)-4-niethyl-8- (trifluoromethyl)-2,3.4,4a,6,l0b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)raethanone (Example 139) (7.4 mg, 8%) as a white solid. MS ESI calculated for C A f-d- sNeOs | M-A I i ■. 503.19; found, 503.20. X.ViR (400 MHz, DMSO-de) 5 8.33 (s, 1H), 7.87 (d. J = 8.0 Hz, I H ), 7.81 (s, 1H), 7.34 (s, 1H), 6.48 (s, 2H), 5.56 is, 1H), 5.00 - 4.80 (m, 1FI), 4.69 (d, J = 12.8 Hz, 2H), 4. 15 - 4.03 (m, 2H), 3.94 - 3.70 (m, 3H), 3.58 - 3.42 (m, 2H), 3.07 (t, J = 12.8 Hz, 2H), 2.09 - 2.06 (m, 1H), 1 .93 - 1.72 (m, 1H), 1.24 - 1.18 (m, 1H), 1.12 (d, J ~ 6.8 Hz, 3H). Absolute stereochemistry at three "orl” centers was not determined.

Example 140: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxa zin- 10-yl)((4R*,4aR*,9bR*)-4-methyl-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofiiro[2,3-b:4,5- b’]dipyridin-l(2H)-yl)ineihanone isomer 1

[1824] Followed the procedure of Example 96 with intermediate A68 isomer 1 (78 mg, 0.30 mmol) and intermediate AC4 (120 mg, 0.45 mmol) to afford ((R)-6-amino-l,3,4,Hb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aS.9bS)-4-methyl-7- (tritluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridin-l(2H)-yl)methanone (35.6 mg, 29%) (ee. -80%) as a white solid, which was further purified by Prep-Chiral-HPLC with the following conditions: [Column: CHIRALPAK IB, 2*25 cm, 5 um; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: MeOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 40% B to 40% in 9min; Wave Length: 220/254 nm;

RTl(min): 6.61; RT2(min): 7.59; Sample Solvent: MeOH: DCM=1: 1-HPLC] to afford ((R)- 6-amino-l ,3,4, llb-tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((4R*,4aR*,9bR*)-4-methyl-7-(trifluoromethyr)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b’]dipyridin-l(2H)-y1)methanone isomer 1 (10.8 mg, 30%) as a white solid with retention time at 6.61 minute. MS ESI calculated for C23H23F3N6O3 |M+H]⁺. 489.18: found, 489.15.

NMR (300 MHz, DMSO-J₆) 8 7.78 (s. 1H), 7.73 - 7.65 (rn, 1H), 7.44 - 7.33 (m, HI), 7.29 (s, 1H), 6.48 (s, 2H), 4.88 - 4.74 (m, 1H), 4.70 - 4.58 (m, IH), 4.46 - 4.28 (m, 1H), 4.20 - 4.06 (m, 1H), 4.04 - 3.95 (ni, 1H), 3.85 ■■■ 3.68 (m, 2H), 3.54 - 3.46 (m, 3H), 3.10 - 3.01 (m, 1H), 1.91 - 1.76 (m, 1 H), 1.32 - 1.17 (ra, 2H), 1.13 (d, J - 6.3 Hz, 3H). Absolute stereochemistry at “orl” and ‘"or2” centers was not determined.

Example 141: ((R)-6-amino-l,3,4,llb-tetraliydropyrido[3',4':4,5]pyriniido[6,l-c][l,4]oxazin-

10-y1)((4R*,4aR*,9bR*)-4-methy1-7-(trifluoromethyl)-3,4,4a,9b-tetraliydrofuro[2,3-b:4,5- b\]dipyridin-l(2H)-yl)methanone isomer 2

A68 isomer 2 isomer 2

[1825] Followed the procedure of Example 96 with intermediate A68 isomer 2 (78 mg,

0.34 mmol) and intermediate AC4 (139 mg, 0.52 mmol) to afford ((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aR*,9bR*)-4-niethyl-7- (trifIuoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b‘]dipyridin-l(2H)-yl)methanone isomer 2 (29.5 mg, 20%) as a white solid. MS ESI calculated for C23H23F3N6O3 [M+H]⁺, 489.18; found, 489.15. *H NMR (300 MHz, DMS0-<fc) 5 8.11 - 7.57 (m, 2H), 7.55 ~ 7.42 (m, IH), 7.42 - 7.26 (m, 1H), 6.47 (s, 2H), 6.39 - 6.12 (m, 1H), 4.79 - 4.35 (m, 3H), 4.17 - 4.00 (m, 2H), 3.92 - 3.65 (m, 2H), 3.17 - 2.96 (m, 2H), 2.96 - 2.82 (m, IH), 1.81 - 1.54 (m, 2H), 1.47 - 1.18 (m, HI), 1.18 - 0.99 (m, 3H). Absolute stereochemistry at “orl” and “or2” centers was not determined.

Example 142: ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((2R^ls,4aS*,9bS*)-2-rriethyl-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5- b’Jdipyridin- 1(2H) -yl)methanone

A82

[1826] Followed the procedure of Example 76 with interinediate A82 (100 mg, 0.38 mmol) and intermediate AC4 (103 mg, 0.38 mmol) to afford ((R)-6-amino-l,3,4,l 1b- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R*,4aS^!!!,9bS*)-2-methyl-7- (trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’jdipyridin-l(2H)-yl)methanone (Example 142) (29.0 mg, 15%) as a light, yellow solid. MS ESI calculated for C23H23F3N6O3 [M+H r, 489.18; found, 489.20. 5 8.30 (d, J = 7.6 Hz, IH),

7.95 - 7.73 (m, IH), 7.53 - 7.26 (m, 2H), 6.52 (br, 2H), 6.24 (d, J = 10.6 Hz, IH), 5.39 - 5.18 (m, IH), 4.75 - 4.35 (m, 2H), 4.12 (d, J = 11.2 Hz, IH), 3.91 - 3.70 (m, 2H), 3.51 (m, 2H), 3.08 - 3.02 (m, IH), 2.01 - 1.79 (m, 2H), 1.75 - 1.58 (m, I H), 1.28 - 0.60 (m, 4H). Absolute stereochemistry at three “orl” centers was not determined. Example 143: ((R)-6-amino- 1 ,3,4- 1 lb-tetrahydropyrido[3',4’:4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin-

10-yD((4R^!!',4aR^,i,10bR“)-8-chlofo-4-methyl-2,3,4,4a,6,10b-hexahydro-lH-pyraiio[3,2-b:5,4- b'Jdipyridin- 1 -yl)methanone

A83, isomer 1

[1827] Followed the procedure of Example 76 with intermediate A83, isomer 1 (50 mg, 0.2 mmol) and intermediate AC4 (43 mg, 0.16 mmol) to afford ((R)-6-amino-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aR*,10bR*)-8-chloro-4- methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l-yl)methanone (Example 143) (2.3 mg, 3%) as a white solid. MS ESI calculated for C23H25CIN6O3 [M+H]⁺, 469.17; found, 469.20. ^!H NMR (400 MHz, DMSO-de) 8 8.19 - 7.70 (m, 2H), 7.47 (d, ./ = 8.0 Hz, 1H), 7.32 (s, 1 H), 6.45 (br, 2H), 5.49 - 5.28 (m, 1 H), 4.80 - 4.47 (m, 3H), 4.12 - 3.93 (m, 2H), 3.88 - 3.67 (m, 3H), 3.56 - 3.41 (m, 2H), 3.12 - 2.89 (m, 2H), 2.35 - 2.24 (m, 1H), 2.14 - 1.91 (m, 2H), 1.10 (d, J = 6.4 Hz. 3H). Absolute stereochemistry at “orl” and “or2” centers was not determined.

Example 144: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxa zin-

10-yl)((2R,4aR,9bS)-2-methyl-7-(trifluoroiiiethyl)-2,3,5,9b- teiraliydropyrido[3',2’:3,4]cyclopenta[l,2-b][l,4]oxazin-l(4aH)-yl)methanone

[1828] Example 144 was prepared by an amide coupling reaction using AC4 and a corresponding amine, for example according to the general procedure described in Example 76. LCMS [M+H]⁺: found 489. 15.

Example 145: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((4R*,4aR*,9bR*)-7-chIoro-4-methyl-3_!4,4a,9b-tetraliydrofuro[2.3-b:4,5-b’]dipyridin- I (2H)-yl) methanone isomer 1 and,

Example 146: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5 jpyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((4R*,4aR *,9bR*)-7-chloro-4-methy 1-3,4, 4a, 9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin- l(2H)-yl)methanone isomer 2 isomer 2

[1829] Followed the procedure of Example 96 with intermediate A84 (20 mg, 0.08 mmol) and intermediate AC4 (35 mg, 0.13 mmol) to afford a 1:7 mixture of ((R)-6-amino-l, 3,4,11b- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10-y])((4R*,4aR*,9bR*)-7-chloro-4- methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b^,]dipyridin-l(2H)-yl)methanone isomer 1 and ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1-c] [ 1 ,4Joxazin- 10- yl)((4R*,4aR*,9bR*)-7-chloro-4-methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin- l(2H)-yl)methanone isomer 2 (22.6 mg) as a white solid. This mixture was separated by prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IB, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH₃-MeOH)— HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient (B%): isocratic 40% B to 40% in 10 min; Wave Length: 220/254 nm; RT1 (min): 5.33; RT2 (min): 9.03; Sample Solvent: MeOH: DCM-l: 1-IIPLC] to afford ((R)-6-amino-l,3,4,llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- c][l,4]oxazin-10-y1)((4R*,4aR*,9bR*)-7-chIoro-4-methyl-3,4,4a,9b-tetrahydrofuro[2,3- b:4,5-b’]dipyridin-l(2H)-yl)methanone isomer 1 (Example 145) (2.1 mg, 9%) as a white solid with the retention time at 5.33 minute. The chiral resolution also affords ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aR*,9bR*)-7- chloro-4-methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b’]dipyridin-l(2H)-yl)methanone isomer 2 (Example 146) (14.9 mg, 65% ) as a white solid with the second peak on chiral HPLC with the retention time at 9.03 minute.

[1830] ((R)-6-amino-l ,3,4,llb-tetrahydropyrido[3’,4’:4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((4R*,4aR*,9bR*)-7-chloro-4-methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin- l(2H)-yl)methanone isomer 1 (Example 145): MS ESI calculated for C22H23CIN6O3 [M+H]’, 455. 15; found, 455.15. ^!H NMR (400 MHz, DMSO-d₆) 8 8.63 - 7.64 (m, 3H), 7.55 - 7.50 (m, 1H), 7.06 (s, 1H), 6.40 - 5.96 (m, 1H), 5.00 - 4.90 (m, 1H), 4.78 - 4.50 (m, 2H), 4.31 - 4.18 (m. 1H), 4.05 - 3.85 (m, 2H), 3.82 ■■■ 3.66 (m, 2H), 3.40 - 3.35 (m, 1H), 3.08 - 2.92 and 2.85 - 2.63 (m, 1 H), 1.89 - 1.60 (m, 2H), 1.60 - 1.40 (m, 2H), 1.19 - 1.15 (m, 3H). Absolute stereochemistry at “orl” and “or2” centers was not determined.

[1831] ((R)-6-amino-l ,3,4, 1 lb-tetrahydropyrido[3’,4*:4,5 ]pyrimido[6, 1 -c] [1 ,4]oxazin- 10- yl)((4R*,4aR*.9bR*)-7-chloro-4-methyl-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin- l(2H)-yl)methanone isomer 2 (Example 146): MS ESI calculated for C22H23CIN6O3 455.15; found, 455.15. ^!H NMR (400 MHz, DMSO-rf₆) 3 8.22 - 7.57 (m, 2H), 7.42 - 7.31 (m, 1H), 7.11 - 7.04 (ni, 1H), 6.64 (s, 2H), 6.21 - 5.85 (m, 1H), 4.76 - 4.64 (m, 1H), 4.63 - 4.35 (m, 1H), 4.20 - 3.99 (m, 2H), 3.90 - 3.70 (m, 2H), 3.60 - 3.40 (m, 2H), 3.15 - 2.79 (m, 1H), 2.58 - 2.5.3 and 2.36 - 2.32 (m, 1 H), 1 .80 - 1.55 (ra, 2H), 1.44 - 1.25 (m, 1 H), 1.08 (d. J - 6.8 Hz, 3H). Absolute stereochemistry at “orl” and “or2” centers was not determined.

Example 147: ((R)-6-amino-l,3,4,llb-tetraliydfopyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-

10-yl)((2R,4aS,10bS)-2-methyl-8-(prop-2-yn-l-yloxy)-2,3,4a,10b-tetrahydrochronieno[3,4- b] [ 1 ,4]oxazin- 1 (5H)-yl)methanone

[1832] Followed the procedure of Example 130 with intermediate A85 (80 mg, 0.31 mmol) and intermediate CA4 (46 mg, 0.19 mmol) to afford ( (R)- 6-aniino- 1,3,4,11b- tetahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R.4aS,10bS)-2-methyl-8- (prop-2-yn-l-yioxy)-2,.3,4a,10b-ietrahydrochromeno[3,4-b][l,4]oxazin-l (5H)-yl)met.banone (Example 147) (5.9 mg, 3%) as a white solid. MS ESI calculated for C16H27N5O5 [M+H]⁺, 490.20; found, 490.20. ^!H NMR (300 MHz, DMSO-d₆) 5 7.85 - 7.75 (m, 1H), 7.45 - 7.30 (m, HI), 7.12 - 7.04 (m, IH), 6.64 - 6.29 (m, 4H), 5.73 (s, IH), 4.78 - 4.70 (m, 2H), 4.68 - 4.64 (m, IH), 4.30 - 4.25 (m, 2H), 4.21 - 4.01 (m, 2H), 3.97 - 3.61 (m, 5H), 3.60 - 3.45 (m, 3H), 3.11 — 3.02 (m, IH), 0.79 - 0.74 (m, 3H).

Example 148: ((4S, 1 lbR)-6-amino-4-methyl- 1 ,3,4, 1 1 b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][1 ,4]oxazin-10-y])((4R*,4aR*,l0bR*)-4-meihy1-8- (trifluoromethyi)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridiii-l-- yl)methanone

A80 isomer 2

[1833] Followed the procedure of Example 130 with intermediate A80 isomer 2 (13 mg, 0.048 mmol)and intermediate CA6 (13 mg, 0.048 mmol) to afford ((4S,1 lbR)-6-amino-4- methyl-1,3,4,1 ib-tetrahydropyrido[3^,,4':4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((4R*,4aR*,10bR*)-4-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH- pyrano[3,2-b:5,4-b'!dipyridin-l-y])methanone (Example 148) (3.8 mg, 15%) as a white solid. MS ESI calculated for C25HO7F3N6O3 [M+H]⁺, 517.21; found, 517.25. ^!H NMR (400 MHz, DMSO-d₆) 8 8.34 (s, IH), 7.92 - 7.83 (m, 2H), 7.29 (s, IH), 6.54 (s, 2H), 5.56 (d, J = 5.6 Hz, IH), 4.89 - 4.85 (m, IH), 4.75 - 4.58 (m, 2H), 4.48 (dd, J = 10.8, 4.4 Hz, IH), 4.11 - 4.01 (m, 2H), 3.94 (t, 10.4 Hz, IH), 3.82 - 3.70 (m, 2H), 3.46 - 3.38 (m, IH), 3.13 - 3.01 (m, I H), 2.13 - 2.06 (m, IH), 1.89 - 1.68 (m, I H), 1.34 - 1.19 (m, IH), 1.18 - 1.07 (m, 6H).

Absolute stereochemistry at three “orl” centers was not determined.

Example 149: ((4S, 1 lbS)-6-amino-4-methyl- i, 3,4, 1 1b- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-cj[l ,4]oxazin-10-yl)((4R*,4aR*,10bR*)-4-methyl-8-

(trifluoromethyl)-2,3,4,4a,6, 10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone

A80 isomer 2

[1834] Followed the procedure of Example 130 with intermediate A80 isomer 2 (20 mg, 0.073 mmol) and intermediate CA5 (19 mg, 0.073 mmol) to afford ((4S,llbS)-6-amino-4- meihyl-1 ,3,4.1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10- yl)((4R*,4aR*,10bR*)-4-methy]-8-(trifluoromethyI)-2,3,4,4a,6,10b-hexahydro-lH- pyrano|3,2-b:5,4-b']dipyridiii-l-yl)methanone (Example 149) (6.0 mg, 15%) as a white solid. MS ESI calculated for C25H27F3N6O3 [M+H]⁺, 517.21 ; found, 517.25. ^SH NMR (400 MHz, DMSO-de) 8 8.34 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.77 (s, IH), 7.29 (s, IH), 6.46 (s, 2H), 5.53 (d, J = 6.0 Hz, 1H), 5.00 - 4.82 (m, 2H), 4.68 (d, J = 15.6 Hz, 1H), 4.32 (dd, J = 11.8, 3.6 Hz, IH), 4.06 (d, J = 6.0 Hz, IH), 3.93 (d, J = 7.2 Hz, IH), 3.68 (d. 2.0 Hz, 3H), 3.51

(t, J = 10.8 Hz, IH), 3.03 - 2.96 (m, IH), 2.06 (t, J = 10.4 Hz, IH), 1.89 - 1.80 (m, IH), 1.35 - 1.18 (m, 4H), 1.11 (d, J = 6.8 Hz, 3H). Absolute stereochemistry at three “orl” centers was not determined. Example 150: ((4S,llbR)-6-amino-4-methyl-l,3,4,l 1b- tetrahydropyrido[3',4^,:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,6R,10bS)-6-mediyl-8- (tifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone

A45 isomer 1

[1835] Followed the procedure of Example 68 with intermediate A45 isomer 1 (50 mg, 0.16 mmol) and intermediate CA6 (43 mg, 0.16 mmol) to afford ((4S,llbR)-6-amino-4- methyl-1,3,4,1 lb-te.traliydropyrido[3',4':4,5]pyriniido[6,l-c][l,4]oxaziti-10- yr)((4aS,6R,10bS)-6-methyl-8-(trifluoromeihyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-b’]dipyridin-l-yl)methanone (Example 150) (30.9 nig, 37%) as a white solid. MS ESI calculated for C25H27F3N6O3 [M+H]⁺, 517.21 ; found, 517.25. *H NMR (400 MHz, DMSO-

5 8.16 (s, 1H), 7.90 - 7.86 (m, 2H), 7.30 (s, 1H), 6.56 (s, 2H), 5.71 (d, J - 6.0 Hz, 1H), 4.86 - 4.85 (m, 1H), 4.67 - 4.63 (m, 1H), 4.51 - 4.47 (m, 1H), 4.29 - 4.26 (m, 1H), 4.08 - 4.04 (m, 1H), 3.97 - 3.74 (m, 3H), 3.45 (dd. J= 11.6. 6.0 Hz, 1H), 3.03 - 2.95 (m, 1H), 1.73 - 1 .65 (m, 4H), 1 .59 (d, J - 6.8 Hz, 3H), 1.16 (d, J = 6.0 Hz, 3H).

Example 151: ((4S,llbS)-6-amino-4-methyl- 1,3,4, 11b- tetrahydropyrido[3',4‘:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,6R,10bS)-6-meihyl-8-

(trinuoromethyr)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone

A45 isomer 1

[1836] Followed the procedure of Example 68 with intermediate A45 isomer 1 (40 mg, 0.15 mmol) and intermediate CAS (42 mg, 0.15 mmol) to afford ((4S,l lbS)-6-amino-4- methyl -1,3, 4,1 lb-ietrahydropyrido[3',4':4,5]pyrimido[6.1-c][l,4]oxaziri-10- yl)((4aS,6R,10bS)-6-methyl-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-b’]dipyridin-l-yl)methanone (Example 151) (22 mg, 27%) as a yellow solid. MS ESI calculated for C25H27F3N.6O3 [M+H]⁺, 517.21; found, 517.25. ’H NMR (400 MHz, DMSO- <7₆) 5 8.13 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.30 (s, 1H), 6.48 - 6.47 (m, 2H), 5.70 (d, J = 6.0 Hz, 1H), 4.94 (dd, J = 10.4, 3.6 Hz, 1H), 4.89 - 4.82 (m, 1H), 4.34 -

4.21 (m, 2H), 3.99 - 3.74 (m, 2H), 3.67 (s, 2H), 3.49 (t, J = 10.4 Hz, 1H), 3.13 - 2.75 (m, 1H), 1.71 - 1.56 (m, 4H), 1.58 (d, J= 6.4 Hz, 3H), 1.31 (d, J= 6.4 Hz, 3H). Absolute stereochemistry at three “orl” centers was not determined. Example 152: ((4S,l lbR)-6-amino-4-methyl-l,3,4,llb- tetrahydropyrido[3‘,4':4,51pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,6R,10bS)-8-chloro-6- methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l-yl)methanone .0.

A78

[1837] Followed die procedure of Example 68 with intermediate A78 (27 mg, 0.11 mmol) and intermediate CA6 (30 mg, 0.11 mmol) to afford ((4S,l lbR)-6-amino-4-metbyl-l ,3,4, l 1b- tetrahydropyrido[3',4*:4,5]pyrimido[6,l-c][l,4]oxazin-10-y])((4aS,6R,l0bS)-8-chloro-6- methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin- l-yijmethauone formate

(Example 152) (17.8 mg, 32%) as a white solid. MS ESI calculated for C24H27CIN6O3 [M+H]⁺,483.18; found, 483.15. ‘H NMR (400 MHz, Methanol-^) 5 (ppm) 8.54 (s, 1H), 8.22 (s, 1H), 8.06 (d, 7 = 8.0, 1H), 7.49 (s, 1H), 7.37 (d, 7 = 8.0, 1H), 5.62 - 5.55 (br, 1H), 5.28 - 5.23 (m, 1H), 4.78 - 4.62 (m, 2H), 4.37 - 4.32 (m, 1H), 4.30 - 4.25 (m, 1 H), 4.22 - 4.16 (m, 1H), 4.06 - 3.98 (m, 1H), 3.80 - 3.60 (m, 2H), 3.35 - 3.10 (br, IH), 2.06 - 1.90 (m, 2H), 1.88

- 1.70 (m, 2H), 1.64 (d, 7 = 6.4 Hz, 3H), 1.43 (d, 7= 6.4 Hz, 3H).

Example 153: ((4S,l lbS)-6-amino-4-methyl-l,3,4,l lb- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,6R,10bS)-8-chloro-6- methyl-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l-yl)methanone [1838] Followed the procedure of Example 68 with intermediate A78 (30 mg, 0.13 mmol) and intermediate CA5 (30 mg, 0.11 mmol) to afford ((4S,l lbS)-6-amino-4-methyl-l,3,4,Hb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4aS,6R,10bS)"8-chloro-6" methyl-2,3,4,4a,6,10b-hexahydro- lH-pyrano[3,2-b:5,4-b’]dipyridin-l-yl)methanone (Example 153) (I I.2 mg, 20%) as a white solid. MS ESI calculated for C24H27CIN6O3 [M+H]⁺, 483.18; found, 483.15. ^!H NMR (400 MHz, DMSO-de) 5 (ppm) 7.94 (d, 8.4 Hz,

IH), 7.76 (s, IH), 7.49 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 6.45 (s, 2H), 5.56 (d, J = 6.0 Hz, 1H), 4.95 - 4.90 (m, IH), 4.78 - 4.71 (m, I H), 4.33 - 4.28 (tn, IH), 4.25 - 4.17 (m, 1H), 3.96 - 3.64 (m, 4H), 3.52 - 3.45 (m, IH), 3.10 - 2.80 (m, IH), 1.87 - 1.64 (m, 3H), 1.63 - 1.51 (m, 4H), 1.31 (d, J - 6.8 Hz, 3H).

Example 154: ((R)-6-amino- 1,3.4, 1 lb-letrahydropyrido|3’,4':4,5 ]pyrimido|6, 1 -c] [ 1 ,4]oxazin-

10-yl)((2R ,4aS, 10bS)-8-ethynyl-2-metbyl-2,3 ,4a , 10b-tetrahydrochromeno[3,4-b ] [ 1 ,4]oxazin-

1 (5 H)-y l)methanone

A86

[1839] Followed the procedure of Example 130 with intermediate A86 (50 mg, 0.22 mmol) and intermediate CA4 (59.55 mg, 0.24 mmol) to afford ((R)-6-amino-l,3,4,l lb- tetahydropyrido[3\4':4,5]pyrimido[6,l-c][l,4joxazin-10-yl)((2R,4aS,10bS)-8-ethynyl-2- methyl-2,3,4a,10b-tetrahydrochromeno[3,4-b][1.4]oxazin-l(5H)-yl)methanone (Example

154) (6.1 mg, 5.8%’) as a off-white solid. MS ESI calculated for C25H25N5O4 [M+H]⁺, 460.19; found, 460.20. ‘H NMR (400 MHz, DMSO-d₆) 87.85 (s, 1H), 7.32 (s, 1H), 7.15 (d, J =1.2 Hz, 1H), 7.04 - 6.81 (m, 2H), 6.48 (d, J = 8.8 Hz, 2H), 5.82 (d, J = 4.2 Hz, 1H), 4.67 (d, J =3.6Hz, 1H), 4.34 (d, J = 1.8 Hz, 1H), 4.31 - 4.09 (m, 4H), 3.91 - 3.81 (m, 2H), 3.81 ■■■■ 3.59 (m, 3H), 3.59 - 3.47 (m, 2H), 3.13 - 3.01 (m, 1H), 0.75 (d, J= 6.8 Hz, 3H).

Example 155: ((R)-6-amino-l,3,4,llb-tetrahydropyrido[3',4':4,5]pyTimido[6,l-c][l,4]oxazin- 10-yl)((2R,3R,4aS,9bS)-3-methoxy-2-methyl-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro[2,3-b:4.5-b']dipyridin-l(2H)-yl)methanone

[1840] Followed the procedure of Example 75 with intermediate A87 (10 mg, 0.035 mmol) and intermediate AC4 (10 mg, 0.04 mmol) to afford ((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,I-c][l,4]oxazin-10-yl)((2R,3R,4aS,9bS)-3-methoxy-2- melhyl-7-(lrifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)- yDniethatione (Example 155) (5.3 mg, 29%) as a white solid. MS ESI calculated for C24H25F3N6O4 [M+H]⁺, 519.19; found, 519.25. ^SH NMR (400 MHz, CD3OD) 8 8.23 (d, ./ = 7.3 Hz, 1H), 7.94 (m, 1H), 7.41 (s, 1H), 7.36 (d, J = 7.4 Hz, 1H), 6.49 - 6.12 (m, 1H), 5.25 (m, 1H), 4.84 - 4.78 (m, 1H), 4.78 ~ 4.67 (m, 1H), 4.16 (m, 1H), 3.94 (m, 1H), 3.81 (m, 1H), 3.75 - 3.56 (m, 3H), 3.30 - 3.13 (m, 4H), 2.50 - 2.26 (m, 1H), 1.94 - 1.79 (m, 1H), 1.16 - 0.75 (m, 3H). Example 156: ((R)-6-amino- 1 ,3,4, 11 b-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin-

10-yl)((2R,3S,4aS,9bS)-3-methoxy-2-methyl-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro [ 2,3 -b : 4,5 -b‘] dipyridin ■ 1 (2H) ■ y 1 jmethanone

[1841] Followed the procedure of Example 130 with intermediate A88 (75 mg, 0.26 mmol) and intermediate CA4 (50 mg, 0.20 mmol) to afford ((R)-6-amino-l,3,4,l 1b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R,3S,4aS,9bS)-3-methoxy-2- methyl-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)- yl)methanone (Example 156) (29.4 mg, 28%) as a yellow solid. MS ESI calculated for C24H25F3N6O4 [M+H]⁺, 519.19; found, 519.15. ^;H NMR (400 MHz, DMSO-rfg) 5 8.40 - 7.70 (m, 2H), 7.57 - 7.29 (m, 2H), 6.53 (s, 2H), 6.45 - 6.17 (m, 1H), 5.37 - 5.23 (m, 1H), 4.70 (dd, J = 10.2, 3.2 Hz, 1H), 4.53 - 4.36 (m, 1H), 4.21 - 4.07 (m, 1H), 3.90 - 3.73 (m, 2H), 3.62 - 3.42 (m, 2H), 3.22 (s, 3H), 3.20 - 3.00 (m, 2H), 2.31 - 1.68 (m, 2H), 0.99 - 0.77 (m, 3H).

Example 157: (lR*,2R*)-2-((2R,4aS, 10bS)-l-((R)-6-amino- 1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)-2-methyl- l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l,4]oxazin-8-yl)cyclopropane-l-carbonitrile, isomer 1

Example 158: (lR*,2R*)-2-((2R,4aS,10bS)-l-((R)-6-amino-l,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)-2-methyl- l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l,4]oxazin-8-yl)cyclopropane-l-carbonitrile, isomer 2

[1842] Followed the procedure of Example 130 with intermediate A89 (50 mg, 0.18 mmol) and intermediate CA4 (46 mg, 0.18 mmol) to afford to afford a 1 :1 mixture of (1R*,2R*)-2- ((2R,4aS,10bS)-l-((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrirnido[6,l- c][l,4joxazine-10-carbonyl)-2-methyl-l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l,4]oxazin- 8-yl)cyclopropane-l-carbonitrile, isomer 1 and (lR*,2R*)-2-((2R,4aS,10bS)-l-((R)-6-amino- 1,3, 4,1 lb-tetahydropyrido[3’,4':4,5]pyriniido[6,l-c][l,4]oxazine-10-carbonyl)-2-niethyl- 1 ,2, 3, 4a, 5, 10b-hexahydrochromeno[3,4-b][l,4joxazin-8-yl)cyclopropane-l ■carbonitrile, isomer 2 (50 mg, 54%) as a white solid. This mixture was separated by Prep-Chiral-HPLC with the following conditions: [Column: CHIRALPAK AD 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NHwMeOH), Mobile Phase B: IPA-HPLC; Flow rate: 20 niL/mm; Gradient (B%): 40% B to 40%' B in 27 min; Wave Length: 220/254 nm; RTl(min): 18.25; RT2(min): 21.46; Sample Solvent: EtOH-HPLC] to afford (IR*,2R*)-2-((2R,4aS,10bS)-l-((R)-6- amino-1 ,3,4, llb-tetrahydropyrido[3’,4’:4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)-2- methyl- 1 ,2,3,4a,5,10b-hexahydrochromeno[3,4-b] [l,4]oxazin-8-yl (cyclopropane- 1 ■ carbonitrile, isomer 1 (Example 157) (1.7 mg, 3%) as a white solid with retention time at 18.25 minute and (lR*,2R*)-2-((2R,4aS,l0bS)-l-((R)-6-armno-1,3,4,llb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)-2-methyl- 1 ,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l ,4]oxazin-8-y1)cyclopropane-l -carbonitrile, isomer 2 (Example 158) (1.9 mg, 3%) as a white solid with retention time at 21.46 minute.

[1843] (lR*,2R*)-2-((2R,4aS,10bS)- l-((R)-6-amino-l,3,4,l lb- tetrahydropyrido[3',4':4,5]pyrimido[6, i-c][l ,4]oxazine-10-carbonyl)-2-methyl- l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l,4]oxazin-8-yl)cyc1opropane-l-carbonitrile, isomer 1 (Example 157): MS ESI calculated for C27H28N6O4 [M+H]', 501.22; found, 501.20. ‘H NMR (300 MHz, DMSO-dg) 5 7.93 and 7.81 (s, 1H), 7.52 and 7.37 (s, 1H), 7.17 - 7.01 (tn, 1H), 6.85 - 6.69 (m, 3H), 6.63 - 6.48 (m, IH), 5.82 - 5.64 (m, IH), 4.78 - 4.64 (m, IH). 4.38 - 4.08 (m, 3H), 4.07 - 3.95 (m, IH), 3.92 - 3.70 (m, 4H), 3.65 - 3.58 (m, IH), 3.60 - 3.50 (m, 2H), 3.15 - 3.07 (m, IH), 2.77 - 2.61 (m, IH), 2.05 - 1.95 (m, IH), 1.62 - 1.59 (rn, IH), 1.49 - 1.42 (m, IH), 0.79 - 0.69 (in, 3H). Absolute stereochemistry at two “orl” centers was not determined.

[1844] (lR-*,2R*)-2-((2R,4aS, 1 ObS ) - 1 -(( R )-6-amino- 1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazine-10-carbonyl)-2-methyl- l,2,3,4a,5,10b-hexahydrochromeno[3,4-b][l,4]oxazin-8-yl)cyclopropane-l-carbonitrile, isomer 2 (Example 158); MS ESI calculated for C27H28N6O4 [M+H]⁺, 501 .22; found, 501 .25. ^!H NMR (300 MHz, DMSO) 5 7.98 and 7.86 (s, IH), 7.56 and 7.42 (s, IH), 7.12 - 6.87 (m, 3H), 6.78 - 6.68 (m, IH), 6.62 - 6.56 (in, IH), 5.77 - 5.66 (m, IH), 4.79 - 4.76 (m, IH), 4.30 - 4.28 (m, IH), 4.22 - 4.12 (m, 2H), 3.99 - 3.63 (m, 6H), 3.59 - 3.52 (m, 2H), 3.19 - 3.14 (m, IH), 2.67 - 2.60 (rn, IH), 2.06 - 1.97 (ni, IH), 1.63 ■■■ 1.55 (m, IH), 1.48 - 1.41 (in, IH), 0.76 -.0.73 (in, 3H). Absolute stereochemistry at two “orl” centers was not determined.

Example 159: ((R)-6-amino- 1 ,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((2R,3R,4aS,9bS)-3-methoxy-2-methyl-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone

[1845] To a mixture of intermediate A102 (50 mg, 0.17 mmol) and intermediate CA4 (47.53 mg, 0.19 mmol) were added CM Pi (88.93 mg, 0.34 mmol) and DIEA (67.48 mg, 0.52 mmol). The mixture was stirred at room temperature for 2h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2>SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5pm; Mobile Phase A: Water (lOmmol/L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient (B%): 72% B to 82% B in 10 min: Wave Length: 254/220 nm; RTl(min): 15) to afford ((RJ- 6-amino-l,3,4,l lb-tetrahydropyrido[3^,,4’:4,5]pyrimido[6,l-c][l,4]oxazin-10- yl)((2R,3R,4aS,9bS)-3-methoxy-2-methyl-7-(trifluoroniethyl)-3,4,4a,9b- tetrahydrobe.nzofuro[3,2-b]pyridin-l(2H)-yl)meihanone (Example 159) (39.2 mg, 43%) as a white solid. MS ESI calculated for C25H26F3N5O4 [M+H]⁺, 518.20; found, 518.20. ^!H NMR (400 MHz, DMSOA) 87.93 - 7.56 (m, 1H), 7.47 ■■■ 7.05 (m, 4H), 6.48 (br, 2H), 6.23 - 6.20 (m, 1H), 5.30 - 4.60 (m, 3H), 4.16 - 4.12 (m, 1H), 3.90 - 3.68 (m, 2H), 3.59 - 3.39 (m, 3H), 3.23 - 3.20 (m, 3H), 3.07 - 3.02 (m, 1H), 2.31 - 2.28 (m, 1H), 1.82 - 1.65 (m, 1H), 0.88 - 0.62 (m, 3H).

Example 160: ((R)-6-amino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin- 10-yl)((2R,3R,4aS,9bS)-7-chloro-3-methoxy-2-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2- b Ipyridin- l(2H)-yl)methanone

[1846] To a stirred solution of intermediate A103 (20 mg, 0.08 mmol) and intermediate CA4 (20 mg, 0.08 mmol) in DMF (0.5 mL) were added DIEA (31 mg, 0.24 mmol) and CMPI (30 mg, 0.12 mmol) at room temperature. The resulting mixture was stirred at room temperature for I h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2-SO4. After filtration, the filtrate was concentrated under reduced pressure. Hie crude product was purified by Prep-HPLC with the following conditions: (Column: XSelect CSH Prep Cl 8 OBD Column, 19*250 mm, 5 qm; Mobile Phase A: Water (l Ommol/L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 20 ml., /min; Gradient (B%); 76% B to 86% B in 10 min; Wave Length: 254/220 nm; RTl(min): 15) to afford ((R)-6-amino-l,3,4,l 1b- tetrahydropyrido[3‘,4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((2R,3R,4aS,9bS)-7-chloro-3- methoxy-2-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone (Example 160) (9 mg, 23%) as a white solid. MS ESI calculated for C24H26CIN5O4 [M+H]⁺, 484.17; found, 484.20. Tl NMR (400 MHz, DMSO-&) 5 7.85 - 7.74 (m, 1 H), 7.66 - 7.27 (m, 2H), 7.27 - 6.87 (m, 2H), 6.54 - 6.43 (m, 2H), 6.32 - 6.04 (m, IH), 5.26 - 5.16 (m, IH), 4.68 (d. J = 10.4 Hz, IH), 4.39 - 4.27 (m, IH), 4.20 - 4.05 (m, 1H), 3.84 - 3.76 (m, 2H), 3.60 - 3.43 (m, 2H), 3.27 (s, 211), 3.23 - 3.01 (m, 3H), 2.31 - 1.51 (m, 2H), 0.95 - 0.79 (m, 3H). Example 161 : ((R)-6-amino- 1 ,3,4, 11 b-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((3R*,4aS*,9bS*)-6-fluoro-7-methoxy-3-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridin-l(2H)-yl)methanone isomer 1 Example 162: ((R)-6-aniino- 1,3,4, 1 lb-tetrahydropyrido[3',4':4,5]pyrimido[6, 1-cJ [l,4joxazin-

10-yl)((3R*,4aS*,9bS*)-6-fluoro-7-methoxy-3-methyl-3,4,4a,9b-Letrahydrobenzofuro[3,2- b]pyridin-l(2H)-yl)methanone isomer 2

Isomer 2 [1847] To a stirred solution of intermediate A101 (50 mg, 0.21 mmol) and intermediate

CA4 (63 mg, 0.25 mmol) in DMAc (1 mL) were added DIEA (82 mg, 0.63 mmol) and CMPI (81 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 1 h. The residue was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaiSO-i. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions: (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5pm; Mobile Phase A: Water (lOmmol/L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 20 inL/min: Gradient (B%): 44% B to 54% B in 10 min: Wave Length: 254/220 nm; RTl(min): 12: RT2(min): 14) to afford ((R)-6-amino-1 ,3,4, 1 lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,1 - c|[l,4]ox azin- 10-yl)((3R*,4aS*,9bS*)-6-fluoro-7-methoxy-3-methyl-3, 4,4a, 9 b- tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone isomer 1 (Example 161) (16.5 nig, 17%) as an off-white solid as the first peak on prep-HPLC and ((R)-6-amioo-l, 3,4,1 1b- tetrahydropyrido[3',4':4,5]pyrimido[6, l-c][l,4]oxazin-10-yl)((3R*,4aS^iK,9bS*)-6-fluoro-7- methoxy-3-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yl)methanone isomer 2 (Example 162) (5.3 mg, 5%) as an off-white solid as the second peak on prep-HPLC.

[1848] ((Rj-6-amirio-l, 3,4,1 lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][l ,4]oxazin-l0- yJ)((3R*,4aS*,9bS^;K)-6-lluoro-7-methoxy-3-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridin-l(2H)-yl)methanone isomer 1 (Example 161): MS ESI calculated for C24H26FN5O4 [M+H]⁺, 468.20; found, 468.15. ^!H NMR (400 MHz, DMSO-de) 5 7.83 (s, 1H), 7.44 - 6.93 (m, 2H), 6.71 (s, TH), 6.49 (s, 2H), 6.11 - 5.94 (m, 1H), 5.20 - 4.92 (m, 1H), 4.76 - 4.60 (m, 1H), 4.32 - 3.84 (m, 3H), 3.84 - 3.72 (m, 4H), 3.63 - 3.43 (m, 2H), 3.19 - 2.99 (m, 1H), 2.42 - 1.79 (m, 3H), 1.61 - 1.39 (m, 1 H), 1.03 - 0.74 (m, 3H).

[1849] ((R)-6-amino-l ,3,4, 1 lb-tetrahydropyrido[3’,4':4,5]pyrimido[6,l-c][i ,4]oxazin- 10- y1)((3R*,4aS*,9bS*)-6-fluoro-7-methoxy-3-methyl-3,4,4a,9b-tetrahydrobenzofuro[3,2- b]pyridin-l(2H)-yl)methanone isomer 2 (Example 162): MS ESI calculated for C24H26FN5O4 [M+H]⁺, 468.20; found, 468.15. ‘H NMR (400 MHz, DMSO-dg) 8 7.83 (s, 1H), 7.54 - 6.91 (m, 2H), 6.69 (t, ./ - 8.4 Hz, HI), 6.47 (s, 2H), 6.10 (s, 1 H), 5.13 (s, 1 H), 4.68 - 4.66 (ra, 1H), 4.12 - 4.10 (m, 1H), 3.99 - 3.69 (m, 5H), 3.69 - 3.44 (ni, 2H), 3.19 - 2.94 (m, 1H), 2.90 - 2.60 (m, 2H), 2.06 - 2.03 (m, 1H), 1.96 - 1.70 (m, 1H), 1.43 - 1.41 (s, 1H), 1.10 - 0.77 (m, 3H).

Example 163: ((4S, 1 lbR)-6-amino-4-methyl- 1 ,3,4, 11b- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4S,4aR,10bS)-4-tluoro-8- (trifluorotnethyr)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b’]dipyridin-l- yl)methanone

A46 isomer 1

[1850] To a stirred mixture of intermediate A46 isomer 1 (30 mg, 0.10 mmol) and intermediate CA6 (28 mg, 0.10 mmol) in DMF (3 mL) were added CMPI (41 mg, 0. L6 mmol) and DIEA (42 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column30*150 mm; Mobile Phase A: Water(10 mniol/L NH4HCO3'), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min. 23% B to 43% B in 10 min; Wave Length: 254/220 nm; RTl(mio): 9.4) to afford ((4S,llbR)-6-amino-4- methyl- 1,3, 4,1 lb-tetrahydropyrido[3^!,4':4,5]pyrimido[6,l- c] [ l,4]oxazin- 10-yl)((4S,4aR, 10bS)-4-fluoro-8-(trifluorometliyl)-2,3,4,4a,6, 10b-hexahydro- lH-pyrano[3,2-b:5,4-b']dipyridin-l-yl)meihanone (Example 163) (4.3 mg, 7%) as a light yellow solid. MS ESI calculated for C24H24F4N6O3 [M+H]⁴, 521. 18; found, 521.25. ^!H NMR (400 MHz, DMSO-cfc) 5 8.18 - 7.64 (m, 3H), 7.36 (s, 1H), 6.59 (s, 2H), 5.94 (s, 1H), 5.41 - 5.23 (m, H-I), 5.11 - 4.99 (m, 1H), 4.93 - 4.90 (m, 1H), 4.73 - 4.63 (m, 1H), 4.56 - 4.48 (m, 1H), 4.42 - 4.22 (rn, 1H), 4.10 - 3.87 (m, 3H), 3.81 ■■■ 3.71 (m, 1H), 3.44 - 3.40 (m, 1H), 3.06 - 2.58 (m, 1H), 2.22 - 1.81 (m, 2H), 1.17 (d, ./ - 6.0 Hz, 3H). Example 164: ((R)-6-amino- 1 ,3,4, 11 b-tetrahydropyrido[3',4':4,5]pyrimido[6, 1 -c] [ 1 ,4]oxazin- 10-yl)((3aR*,8bR*)-6-(trifluoromethyl)-2, 3, 3a, 8b- tetrahydro- lH-benzofuro[3,2-b]pyrrol-l- yllmethanone

[1851] To a stirred solution of intermediate A93 isomer 1 (50 mg, 0.22 mmol) and intermediate CA4 in DMF (1 rnL) were added DIEA (85 mg, 0.65 mmol) and HATU (124 mg, 0.33 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NajSCU. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions [Column: Xselect CSH OBD Column 30* 150mm, 5pm;

Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%): 5% B to 5% B in 2 min, 16% B to 36% B in lOmin; Wave Length: 254/220 nm;

RTl(min): 7] to afford ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- c][l,4]oxazin-10-yl)((3aR*,8bR*)-6-(trifluoromethyl)-2,3,3a,8b-tetrahydro-lH- benzofuro[3,2-b]pyrrol-l-yl)rnethanone formate (Example 164) (26.3 mg, 26%) as a white solid. MS ESI calculated for C22H20F3N5O3 [M+H]⁴, 460.15; found, 460.15. ^!H NMR (400 MHz, DMSO-^s) 3 8.21 (s. 1H). 8.12 - 6.72 (m, 7H), 6.69 - 5.86 (m. 1H), 5.59 - 5.44 (m, 1H), 4.83 - 4.69 (m, 1H), 4.25 - 4.06 (m, 2H), 3.91 - 3.76 (m, 2H), 3.61 - 3.46 (m, 3H), 3.19 - 3.03 (m, 1H), 2.33 - 2.23 (m, 2H). Absolute stereochemistry at two “orl” centers was not determined. Example 165: ((4S,llbR)-6-amino-4-methyl-l,3,4,l 1b- tetrahydropyrido[3',4’:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R,4aR,10bS)-4-fluoro-8- (tifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2-b:5,4-b']dipyridin-l- yl)methanone

A46 isomer 2

[1852] Followed the procedure of Example 130 with intermediate A46 isomer 2 (30 mg, 0.109 mmol) and intermediate CA6 (28 mg, 0.109 mmol) to afford to afford ((4S,llbR)-6- amino-4-methyl- 1,3,4, nb-tetrahydropyrido[3',4':4,5]pyrimido|6,l-c]l l,4]oxazm~10- yl)((4R,4aR,10bS)-4-fluoro-8-(trifluoromethyl)-2,3,4,4a,6,10b-hexahydro-lH-pyrano[3,2- b:5,4-b']dipyridin-l-yl)methanone (Example 165) (5.8 mg, 10% yield) as a white solid. MS ESI calculated for C24H24F4N6O3 [M+H]⁺, 521.18; found, 521.2.0. ^!H NMR (400 MHz, DMSO-tfe) 58.14 - 7.71 (m, 3H), 7.39 - 7.36 (rn, 1H), 6.62 (s, 2H), 6.10 - 6.00 (m, 1H), 5.12 - 4.86 (m, 3H), 4.67 - 4.66 (m, 1 H), 4.52 - 4.51 (m. 1H), 4.49 - 4.08 (m, 3H), 3.95 - 3.92 (m, 1H), 3.95 - 3.94 (m, 1H), 3.41 -■ 3.37 (m, 1H), 2.67 - 2.38 (m, 1H), 2.33 - 2.31 (m, III), 1.85 - 1.70 (m, 1H), 1.16 (d, J- 6.4 Hz, 3H).

Example 166: ((4S,l lbR)-6-amino-4-methyl-l,3,4,lIb- tetrahydropyrido[3',4':4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aR*,9bS*)-4-niethoxy-7-

(trifluoromethyl)-3,4,4a,9b-tetrahydrofuro[2,3-b:4,5-b']dipyridin-l(2H)-yl)methanone

Step- 1 :

A81 isomer 1

[1853] To a stirred solution of intermediate A81 isomer 1 (20 nig, 0.07 mmol) in DMAc (0.5 mb) were added intermediate CA4, DIEA (47 mg, 0.36 mmol) and CMPI (28 mg, 0.11 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5 pm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min: Gradient (B% ): 42% B to 52% B in 10 min; Wave Length: 254/220 nm; RTl(min): 13) to afford ((4S,1 lbR)-6-amino-4-methyl-l,3,4,l lb- tetrahydropyrido[3',4':4,5jpyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aR*,9bS*)-4-methoxy-7- (tri tluororaethyl)-3, 4,4a, 9b-teirahydrofuro[2,3-b:4,5-b’]dipyridin-l(2H)-yl)methanone (Example 166) (3.4 mg, 8%) as a white solid. MS (ESI) calculated for C24H25F3N6O4 [M+H]⁺, 519.19; found, 519.25. ^!H NMR (400 MHz, DMSO-d₆) 3 8.16 - 7.72 (m, 2H), 7.57 - 7.56 (m, 1H), 7.36 - 7.28 (m, 1H), 6.62 (s, 2H), 6.42 - 6.25 (m, 1H), 5.02 - 4.78 (m, 1H),

4.73 - 4.62 (m, 1 H), 4.55 - 4.1 1 (m, 2H), 4.07 (dd, ./ = 11 .6. 4.0 Hz, 1 H), 3.99 - 3.86 (m, 1H), 3.79 - 3.71 (m, 1H), 3.53 - 3.45 (m, 1H), 3.43 - 3.37 (m, 1H), 3.35 (s, 3H), 3.00 - 2.54

(m, 1H), 2.01 - 1.89 (m, 1H), 1.58 - 1.39 (m, 1H), 1.15 (d, J 6.0 Hz, 3H). Example 167: ((R)-6-amino-l,3,4,llb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- c][ T,4]oxaz.in-10-yl)((4R*,4aS*,9bR*)-4-hydroxy-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrofuro [ 2,3 -b : 4,5 -b‘] dipyridin- 1 (2H) ■ y 1 (methanone

Step-1:

[1854] To a stirred solution of A81, isomer 2 (200 nig, 0.64 mmol) in MeOH (2 mL) and DCM (0.2 mL) was added K2CO3 (267 mg, 1.93 mmol) at room temperature. The resulting mixture was stirred at 25 °C for 30 min. The suspension was filtered. The filtrate was collected and concentrated under vacuum to afford (4S,4aR,9bS)-7-(trifluoromethyl)- l,2,3,4,4a,9b-hexahydrofuro[2,3-b:4,5-b']dipyridin-4-ol (200 mg, crude) as a yellow solid. MS (ESI) calculated for (C12H.3F3N2O2) [M+l?, 275.09; found, 275.15.

Step-2:

[1855] To a stirred solution of (4S,4aR,9bS)-7-(trifluoromethyl)-l,2,3,4.4a,9b- hexahydrofuro[2,3-b:4,5-b']dipyridin-4-ol (120 rag, 0.38 mmol) and intermediate CA4 (99 mg, 0.38 mmol) in DMF (1 mL) were added DIEA (248 mg, 1.92 mmol) and HATU (175 mg, 0.46 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was purified by reverse phase flash chromatography with 5-40% acetonitrile in water (10 mM NH4HCO3) to afford ((R)-6-amino-l ,3,4,l1 b- teirahydropyrido[3',4‘:4,5]pyrimido[6,l-c][l,4]oxazin-10-yl)((4R*,4aS*,9bR*)-4-hydroxy-7-

(tifluoromethyl)-3,4,4a,9b-letrahydrofuro[2,3-b:4,5-b’]dipyridin-l(2H)-yl)methanone

(Example 167) (32 nig, 17%) as a white solid. MS (ESI) calculated for C22H21F3N5O4 [M+H] ⁺, 491. 16 ; found, 491. 15.

Example 168: ((R)-6-amino-l,3,4,l lb-tetrahydropyrido[3',4':4,5]pyrimido[6,l- cJ[l,4]oxazin-10-yl)((2R,3R,4aS,9bS)-3-hydroxy-2-methyl-7-(trifluoromethyl)-3,4,4a,9b- tetrahydrobenzofuro[3,2-b]pyridin-l(2H)-yDmethanone

Example 159

[1856] To a stirred solution of Example 159 (5 mg, 0.009 mmol) in DCM (1 niL) was added Boron tribromide (IM in DCM) (0.4 rnL, 0.04 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 40 ⁰ C for 16 h under nitrogen atmosphere. The resulting mixture was quenched with water (0.5 mL) and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following 5% to 50% Water (10 mmol/L NH4HCO3) in MeCN to afford ((R)-6-amino- 1,3,4, ! lb-tetrahydropyrido[3’,4':4,5]pyrimido[6, l-c][l,4]oxazin-10-yl)((2R,3R,4aS,9bS)-3- hydroxy-2-methyl-7-(trifluoromethyl)-3,4,4a,9b-tetrahydrobenzofuro[3,2-b]pyridin-l(2H)- yl)methanone (Example 168) (0.4 mg, 9%) as a white solid. MS ESI calculated for C24H24F3N5O4 [M+H]⁺, 504.18; found. 504.20. Biological Examples

Biological Example 1: PRMT5 Biochemical Assay

[1857] The PRMT5 biochemical assay was conducted in 384-well, assay-ready compound plates (PerkinElmer, Inc.; catalog number 6007290) with a final enzymatic reaction volume of 16 pL; plates were prepared a priori, starting at 10 μM with 10 concentration points in a 3- fold serial dilution series for test compounds. The controls were defined as Low Control and High Control; Low Control contained all reagents aside from PRMT5 protein, and the High Control contained all reagents plus PRMT5.

[1858] The enzymatic reaction was carried out at a final concentration of PRMT5 (in complex with MEP50, Proteros, GmbH; catalog number PR-0376) of 1.2 nM (equal to the PRMT5 monomer concentration), in a reaction mixture buffer and incubated for 60 minutes at 37 °C, in the presence and absence of 100 nM MTA (EMD Millipore, Inc.; catalog number 260585); the mixture consisted of 2 μM S-adenosyl-methionine (Promega, Inc.; catalog number V7601), 2.3 μM full-length histone H2A (New England Biolabs, Inc.; catalog number M2502) or 1.5 μM full-length histone H2.A (Active Motif, Inc.; catalog number 31890) in assay buffer; assay buffer consisted of 50 mM Tris-HCl (pH 8) (ThermoFisher Scientific, Inc.; catalog number AM9856), 50 mM NaCl (ThermoFisher Scientific, Inc.; catalog number AM9759), 1 mM TCEP (Gold Biotechnology, Inc.; catalog number TCEP1), 0.019c Tween-20 (EMD Millipore, Inc.; 655206), 0.01% w/v bovine serum albumin (Perkin- Elmer, Inc.; catalog number CR84-100). After 60 minutes, the reaction was subjected to a detection procedure utilizing the MTase-Glo™ Methyltransferase Assay (Promega, Inc.; catalog number V7601). First, 4 uL of 5X MTase-Glo™ Reagent (Promega, Inc.; catalog number V7601), diluted from the original 10X stock with assay buffer, was added to added to the enzymatic reaction mixture and incubated for 30 minutes at room temperature. Second, 20 uL of 2X MTase-Glo™ Detection Solution (Promega, Inc.; catalog number V7601 ) was added, and the mixture was incubated for 30 minutes at room temperature. Signal was measured in a plate reader with luminescence capabilities.

[1859] Percent inhibition for each concentration of test compound was determined by calculating the ratio between the test compound, low control, and high control signals; the resulting data was fitted and the ICso was estimated using Levenberg-Marquardt algorithm. [1860] The ICso of a representative number of compounds in Table 1 above are disclosed in Table 2 A below, where 2.3 μM full-length histone H2A (New England Biolabs, Inc.; catalog number M2502) was used:

A < 0.1 μM

'Table 2A: PRMT5 Biochemical Assay⁷ Results

[1861] Hie ICso of a representati ve number of compounds in Table 1 above are disclosed in

Table 2B below, where 1.5 μM full-length histone H2A (Active Motif, Inc.; catalog number 31890) was used:

A < 0.1 μM Table 2B: PRMT5 Biochemical Assay Results

[1862] The ICso of a representative number of compounds in Table 1 above are disclosed in Table 2C below, where 1.5 μM full-length histone H2A (Active Motif, Inc.; catalog number 31890) was used: A < 0. 1 g M

Table 2C: PRMT5 Biochemical Assay Results

Biological Example 2: Cell viability assay in HCT116 WT and HCT116 MTAP cells

[1863] The cell viability was determined by doing cell nuclear counts; cell nuclei were labeled with a fluorescent protein kit using the manufacturer’s protocol (Sartorius).

[1864] HCT116 WT and HCT116 MTAP’⁷" (ATCC) were cultured in DMEM/F12 with

GlutaM.AX (Gibco) supplemented with 10% Fetal Bovine Serum (FBS, Gibco) and 2ug/mL puromycin (Gibco). Cells were seeded in 384-well plates, at a density of 166 cells/well in 50pL of cell culture media without puromycin. Cell plates were incubated overnight at 37 °C with 5%' COj. After the overnight incubation, cells were imaged in a confocal microscope with nuclear count capabilities for the pre-treatment data set.

[1865] Cells were treated starting at a 20μM in 9-points and 4-fold serial dilutions for test compounds; the negative control was DMSO. All compounds and the negative control had a final DMSO concentration of 0.2%. Cells were incubated for 5 days at 37°C with 5% CO2. On day 5, cells were imaged, and nuclei were counted for the post-treatment data set.

[1866] Percent inhibition for each concentration of test compound was determined by calculating the ratio between the post-treatment and pre-treatment nuclei count, and negative control; the resulting data was fitted and the EC50 was estimated using the Levenberg- Marquardt algorithm. [1867] The EC₅₀ of a representative number of compounds in Table 1 above are disclosed in Table 3 A below:

A <= 0.1 μM; 0.1 μM < B <= 0.25 μM; 0.25 μM < C <= 0.5 μM; 0.5 μM < D <= 1.0 μM;

1 .0 μM < E <= 2.0 μM; 2.0 μM < F <= 5.0 p M: 5.0 μM < G <= 10.0 μM; 10 μM < H

Table 3A: Ceil Viability Assay Results

[1868] The EC₅₀ of a representative number of compounds in Table 1 above are disclosed in Table 3B below:

A <= 0.1 μM; 0.1 μM < B 0.25 μM: 0.25 μM < C <= 0.5 μM; 0.5 μM < D <= 1.0 μM;

1 .0 μM < E <= 2.0 μM; 2.0 μM < F <= 5.0 μM; 5.0 μM < G <= 10.0 μM; 10 μM < H

Tabie 3B: Cell Viability Assay Results

[1869] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (la): or a pharmaceutically acceptable salt thereof, wherein:

Y¹ is O, NIC, S, S(O), or S(O;

X¹ is C(R^: ) or N:

X² is C(R²) or N;

X³ is C(R³) or N;

R^y, R¹, R², and R³ are each independently H, C_1-4 alkyl, halo, or C_1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R⁴ is independently Ci-6 alkyl, halo, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, or C_3-6 cycloalkyl; or two R⁴ groups when attached to the same carbon atom combine to form oxo or C_3-6 cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S; ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B: and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, or 2; q is 0, 1, or 2; each R⁵ is independently C_1-6 alkyl, C_1-6 haloalkyl, halo, OH, C_1-6 alkoxy, C_1-6 haloalkoxy, -C(0)C_1-6 alkyl, -C(O)C_1-6 haloalkyl, -C(0)OC_1-6 alkyl, or -C(O)OC_1-6 haloalkyl; each R^5a is independently C_1-4 alkyl, halo, C_1-4 haloalkyl, OH, or C_1-4 alkoxy; alternatively, two R'³ groups attached to the same carbon atom combine to form oxo; each R⁶ is independently Ci e> alkyl, Ci 6 haloalky 1, halo, OH, Ci-6 alkoxy, Ci-o haloalkoxy, CN, C_2-6 alkynyl, -O-C_2-6 alkynyl, C_3-6 cycloalkyl, -O-C_3-6 cycloalkyl, --C(O)C_1-6 alkyl, -C(O)Ci 6 haloalkyl, -C(0)OC_1-6 alkyl, -C(O)OCi-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C_3-6 cycloalkyl, -O--C_3-6 cycloalkyl, and heterocycloalkyl is independently substituted with 0, 1, or 2 R^6a; and each R^6a is independently C_1-4 alkyl, halo, C_1-4 haloalkyl, CN, OH, or C_1-4 alkoxy.

2. The compound or a pharmaceutically acceptable salt thereof of claim

1, wherein: each R⁵ is independently C_1-6 alkyl. C_1-6 haloalkyl, halo, C_1-6 alkoxy. C_1-6 haloalkoxy, -~C(O)C_1-6 alkyl, CtOsC haloalkyl, -C(O)OC_1-6 alkyl, or -C(O)OC_1-6 haloalkyl; each R'^,,; is independently C_1-4 alkyl, halo, or C 1-4 haloalkyl; alternatively, two R^5a groups attached to the same carbon atom combine to form oxo: each R⁶ is independently C_1-6 alkyl, C_1-6 haloalkyl, halo, C_1-6 alkoxy, C_1-6 haloalkoxy, CN, -O-C3 cycloalkyl, -C(O)C_1-6 alkyl, -C(O)Cw haloalkyl, -C(O)OC_1-6 alkyl, - C(O)OC_1-6 haloalkyl. or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1 , or 2 R^;>": and each R^6a is independently C_1-4 alkyl, halo, or C_1-4 haloalkyl.

3. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2, wherein Y¹ is O.

4. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein X¹ is CH; X* is C(R²) or N; and X^J is C(R³).

5. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 4, wherein ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O; ring B is phenyl or heteroaryl having 6 ring members with 1 to 2 nitrogen atom ring vertices; and ring C is Cs 6 cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

6. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 5, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl.

7. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 6, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

8. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

9. Ute compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 8, wherein ring C is C<6 cycloalkyl, tetrahydrofuranyl, te-trahydropyranyl, or oxepanyl .

10. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 9. wherein ring C is Cs-e cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl.

11. Tiie compound or a pharmaceutically acceptable salt thereof of any one of claims I to 10, having Formula (Ila): wherein: ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl;

X^a is O. NH, NR⁵, CH₂, CHR⁵, or C(R⁵)₂;

X^5a is absent, O, CH₂, or CHR⁵'¹;

X^5b is absent, O, ( i f-, or CHR^5a, provided that X^5a and X^5b are not each absent or O; and a total number of R⁵ groups is no more than 2.

12. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 11, wherein ring B is phenyl or pyridyl.

13. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 12, having Formula (IIa-1): wherein:

X^a is O, NH, N(C_1-4 alkyl), CH₂, CHR⁵, or C(R⁵)₂;

X^5a is absent, O, CH₂, or CHR'³; and

X^5b is absent, O, CH₂., or CHR^5a, provided that X^5a and X^5b are not each absent or 0; and a total number of R⁵ groups is no more than 2.

14. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 12, having Formula (IIa-2): wherein:

X^a is O, NH, Nt CT .4 alkyl), CH₂, CHR⁵, or C(R^S)₂;

X^5a is absent, O. CH₂. or CHR^5a; and

X^5b is absent, O, CS C. or CHR ^5a, provided that X^5a and X^5b are not each absent or O; and a total number of R⁵ groups is no more than 2.

15. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 14. wherein X² is C(R²) or N; and R² and R³ are each independently H or halo.

16. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 10, wherein

X¹ is CH; X² is N; and X³ is CH,

X¹ is CH; X² is CH; and X³ is CH or CF, or

X¹ is CH; X² is CF; and X³ is CH.

17. The compound or a pharmaceutically acceptable salt thereof of any one of claims 11 to 15, wherein

X² is N; and R³ is H,

X² is CH; and R³ is H or F, or

X² is CF; and R³ is H.

18. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 17, wherein each R⁴ is independently C;^ alkyl or Cj-4 haloalkyl.

19. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 18, wherein each R⁴ is independently methyl or -CHFH.

20. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 19, wherein each R⁴ is methyl.

21. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 10, wherein n is 0 or 1.

22. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 21, wherein n is 0 or R⁴ is absent.

23. Hie compound or a pharmaceutically acceptable salt thereof of any one of claims 11 to 22, wherein:

X^a is O, NH, CH₂, or CHR⁵;

X^5a is O, CH . or CHR⁵³;

X^5b is O, Cl b. or CHR^5a; and p is 0 or 1.

24. The compound or a pharmaceutically acceptable salt thereof of any one of claims 11. to 22, wherein:

X^a is O, NH, or CH₂;

X^5a is O, CH₂, or CHR^5a;

X ^5b is O, CH;, or CHR^5a; and p is 0, 1 , or 2.

25. 'Hie compound or a pharmaceutically acceptable salt thereof of any one of claims 11 to 22, wherein:

X^a is C(R⁵)₂;

X^5a is O, CH₂, or CHR^5a;

X^5b is O, CH₂, or CHR^5a; and p is 0.

26. The compound or a pharmaceutically acceptable salt thereof of any one of ciaims 11 to 23, wherein:

X^5a is O and X^5b is CH₂;

X^5a is CH₂ and X^5b is O;

X^5a is CH2 and X^5b is CH₂;

X^5a is absent and X^Sb is O.

27. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 26, wherein each R³ is independently C_1-4 alkyl, halo, OH, or C_1-4 alkoxy.

28. Tiie compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 27, wherein each R? is independently methyl, fluoro, OH. or methoxy.

29. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 28, wherein each R’ is independently methyl, fluoro, or methoxy .

30. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 29, wherein each R° is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, OH, Cs-6 alkoxy, Ci -6 haloalkoxy, CN, C_2-6 alkynyl, -O-C_2-6 alkynyl, C_3-6 cycloalkyl, or -O-C3 6 cycloalkyl, wherein the C_3-6 cycloalkyl and -O-C_3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

31. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 30, wherein q is 1; and R⁶ is C1-6 alkyl, Ci-r. haloalkyl, halo, OH, Ci-6 alkoxy, Ci-e haloalkoxy, CN, Ci-e alkynyl, -O-C24 alkynyl, C3-5 cycloalkyl, or -O-C3.<> cycloalkyl, wherein the C_3-6 cycloalky 1 and -O-C_3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

32. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 31, wherein q is 1; and R° is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, tri fluoromethyl, fluorometh yl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C~, or HC=C~ CH2-O -.

33. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 32, wherein q is 1 ; and R⁵ is chloro, trifluoromethyl, or difluoromethyl-O-.

34. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30, wherein q is 2; and each R⁶ is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

35. Hie compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 33, wherein the moiety has the formula:

wherein: X^a is O, NH, CH₂, or CHR⁵;

X^5a is O, CH₂, or CHR^5a;

X^5b is O, CH₂, or CHR^5a: each R^5a is independently C_1-4 alkyl; each R⁵ is independently F, OH, C_1-4 alkyl, or C_1-4 alkoxy; and R⁶ is C_1-4 alkyl. C_1-4 haloalkyl, halo, CN, C_1-4 alkoxy, C_1-4 haloalkoxy, C_2-4 alkynyl, -

O-C_2-4 alkynyl, C_3-6 cycloalkyl, or -O-C_3-6 cycloalkyl, wherein the C_3-6 cycloalkyl and -O- C_3-6 cycloalkyl are each independently unsubstituted or substituted with CN, provided that X^5a and X^5b are not each O.

36. The compound or a pharmaceutically acceptable salt thereof of claim 35, wherein X^a is O, NH, CH₂, CHF, C(CH₃), C(OH), or C(OCH₃); X^5a is O, CH₂, or

CH(CH₃); X^5b is O or CH₂; R⁵ is F, CH₃, OH, or OCH₃; and R° is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, iluorornethyl-O-, difluoromethyl- O-, trifluoromethyl-O- cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, CH=CH- or CH=CH-CH2-O-, provided that X^5aand X^5b are not each O.

37. The compound or a pharmaceutically acceptable salt thereof of claim or 36, wherein R⁶ is chloro, trifluoromethyl, or difluoromethyl-O-

38. The compound or a pharmaceutically acceptable salt thereof of any one

39. The compound or a pharmaceutically acceptable salt thereof of any one

4(1. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from Table 1.

41. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 40, and one or more pharmaceutically acceptable excipient.

42. A method for treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 40, or a pharmaceutical composition of claim 41.

43. The method of claim 42, wherein the disease is cancer.

44. A method of treating an MTAP null cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 40, or a pharmaceutical composition of claim 41.

45. A method for treating cancer in a patient in need thereof, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 40, or a pharmaceutical composition of claim 41.

46. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 40, or a pharmaceutical composition of claim 41.

47. The method of any one of claims 43 to 46, wherein the cancer is a MTA-accumulaling cancer.

48. The method of claim 43 or 47, wherein the cancer is deficient in CDKN2A.

49. Hie method of atty one of claims 43 to 48, wherein the cancer is a solid tumor.

50. Hie method of claim 49, wherein the solid tumor is malignant.

51. Hie method of any one of claims 43 to 50, wherein the cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC, e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, chol angiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and large intestine, or sarcoma.

52. The method of any one of claims 43 to 50, wherein the cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

53. Hie method of any one of claims 43 to 50, wherein the cancer is non- small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.

54. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 40, or a pharmaceutical composition of claim 41.

55. A method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 40, or a pharmaceutical composition of claim 41.

56. A method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired with an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 40. or a pharmaceutical composition of claim 41.