Amide substituted triheterocyclic guanidino compounds as PRMT5 inhibitors

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

PATENT Atorney Docket No.052326-581001WO Client Ref. No.2024-004-B-PCT AMIDE SUBSTITUTED 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 No.63 / 549,390 filed February 2, 2024, the contents of which is incorporated by reference in its entirety for al 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 efects are not restricted to cancer cels and adverse side efects can occur within normal tissues. Consequently, novel strategies are needed to beter target cancer cels.

[0005] Synthetic lethality arises when a combination of deficiencies in the expression or activity of two or more genes leads to cel 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 cel 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 cels that render them vulnerable to synthetic-lethality approaches. These tumor- specific genetic defects lead to the use of targeted agents that induce the death of tumor cels while sparing normal cels.

[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 activity of PRMT5 has been associated with development and cancer as wel 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 chalenge for these inhibitors is that the SAM-PRMT5 complex forms in both normal and cancer cels, making it dificult to selectively inhibit PRMT5 in only cancer cels.

[0008] Chromosome 9p21 encompasses, among others, CDKN2A (cyclin dependent kinase inhibitor 2A), and homozygous deletion of 9p21 genomic locus is implicated in about 15% of al 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’methylthioadenosine (MTA) in the cel.

[0009] Seemingly due to structural similarities between SAM and MTA, PRMT5 is competitively inhibited by MTA. Cels with an MTAP deletion have increased levels of MTA, thereby partialy 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, efectively inhibiting PRMT5 in MTAP deleted cels, while leaving normal cels relatively unafected. Inhibition of PRMT5 with MTA cooperative inhibitors leads to cel 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):(I) or a pharmaceuticaly acc or Y1, X1, X2, X3, R4, n, R7 and R8 are further described herein.

[0012] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, or a subembodiment thereof, and one or more pharmaceuticaly 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 therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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 nul cancer in a patient in need thereof comprising administering to the patient a therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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, a reduced function of MTAP protein, or combination thereof, comprising administering to the subject a therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0016] In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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 pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceuticalcomposition 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 pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an MTAP nul cancer.

[0019] In another aspect, provided herein is a compound of Formula (I) or a pharmaceuticaly 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 combination thereof.

[0020] In another aspect, provided herein is a compound of Formula (I) or a pharmaceuticaly 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 pharmaceuticaly 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 pharmaceuticaly 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 pharmaceuticaly 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 nul cancer.

[0024] In another aspect, provided herein is a compound of Formula (I) or a pharmaceuticaly 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 combination thereof.

[0025] In another aspect, provided herein is a compound of Formula (I) or a pharmaceuticaly 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 pharmaceuticaly 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 efect.

[0027] In another aspect, provided herein is the use of a compound of Formula (I) or a pharmaceuticaly 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 efect.

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

[0029] In another aspect, provided herein is a method of inhibiting cel proliferation in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound of Formula (I) or a pharmaceuticaly 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 pharmaceuticaly acceptable salt thereof, or a subembodiment thereof as defined herein.

[0032] In another aspect, provided herein is a compound of Formula (I) or a pharmaceuticaly 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 prefered, 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 smaler ranges may independently be included in the smaler ranges, and are also encompassed within the invention, patient to any specificaly 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, al technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skil 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 diferent from the actual publication dates, which may need to be independently confirmed. GENERAL

[0039] Provided herein are compounds of Formula (I) or a pharmaceuticaly 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 inhibition of PRMT5. Further provided herein are methods treating or preventing a disease, disorder or condition, or a symptom thereof treatable by inhibition ofPRMT5.DEFINITIONS

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

[0041] 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.

[0042] 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. C1-8 means one to eight carbons). Alkyl can include any number of carbons, such as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, 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.

[0043] 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 diferent 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.

[0044] The term "cycloalkyl" refers to a non-aromatic, saturated hydrocarbon ring having the indicated number of ring atoms (e.g., C3-6 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.

[0045] The term “cycloalkenyl” refers to a non-aromatic, unsaturated hydrocarbon ring having the indicated number of ring atoms (e.g., C3-6 cycloalkenyl). Cycloalkenyl groups have 1, 2, or 3 one carbon-carbon double bonds. In some embodiments, cycloalkenyl groupshave 1 carbon-carbon double bond. Ilustrative examples of cycloalkenyl groups include, but are not limited to, cyclopenten-3-yl, cyclohexen-4-yl and the like.

[0046] The term "halo" or "halogen," by itself or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0047] The term "haloalkyl," refers to alkyl, as defined above, that is substituted having one or more halogen atoms, which may be the same or diferent, at one or more carbon atoms of an alkyl and includes monohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0048] The terms "alkoxy," and "haloalkoxy" refer to alkyl and haloalkyl groups respectively, each as defined herein, that is atached to the remainder of the molecule via an oxygen atom, for example –O–alkyl or –O–haloalkyl.

[0049] The term “aryl” refers to a monocyclic or bicyclic, hydrocarbon, aromatic radical. An aryl group may contain 6 to 14 carbon atoms. For example, “C6-10 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.

[0050] 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 atached 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, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrolyl, thiazolyl, furyl, thienyl and the like.

[0051] The term "5- or 6-membered heteroaryl” 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 from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain three heteroatoms.Exemplary groups include, but are not limited to, furanyl, thienyl, pyrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0052] The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partialy 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 optionaly oxidized, and the nitrogen atom(s) are optionaly 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 pyrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, , and the like. A heterocycloalkyl group can be atached to the remainder of the molecule through a ring carbon or a heteroatom.

[0053] The term "hydroxyalkyl," refers to an alkyl, as defined above, that is substituted with one or two hydroxy. For example, the term “hydroxyC1-4 alkyl” or “C1-4 hydroxyalkyl” is meant to include hydroxymethyl, 1-, or 2-hydroxyethyl, 1,2-dihydroxyethyl, hydroxypropyl, and the like.

[0054] The term “optionaly 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 atached 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 diferent.

[0055] The term "oxo" refers to an oxygen atom with a double bond to the point of atachment (O=).

[0056] As used herein, a wavy line, " ", that intersects a single, double or triple bond in any chemical structure depicted herein, represent the point atachment of the single, double, or triple bond to the remainder of the molecule. Additionaly, a bond extending to the center of a ring (e.g., a phenyl ring) is meant to indicate atachment at any of the available ring vertices. One of skil in the art wil understand that multiple substituents shown as beingatached to a ring wil occupy ring vertices that provide stable compounds and are otherwise stericaly compatible.

[0057] The term “pharmaceuticaly 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, iritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0058] As used herein, the term “pharmaceuticaly acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological efects. Such pharmaceuticaly 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 suficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceuticaly-acceptable inorganic bases include aluminum, ammonium, calcium, copper, feric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc. Salts derived from pharmaceuticaly-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturaly-occuring amines, such as arginine, betaine, cafeine, choline, N,N’-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a suficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceuticaly 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 wel 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 alow the compounds to be converted into either base or acid addition salts.

[0059] 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 difers 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.

[0060] 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 al intended to be encompassed within the scope of the present disclosure. When a stereochemical depiction is shown, it is meant to refer the compound in which one of the isomers is present and substantialy free of the other isomer. ‘Substantialy 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 wil be present in an amount of at least 99%.

[0061] Certain compounds of Formula (I) can exist in unsolvated forms as wel 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 crystaline or amorphous forms. In general, al physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0062] Certain compounds of the present disclosure can exist as tautomers and / or geometric isomers. Al possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure.

[0063] 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, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 1251, 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. Additionaly, isotopic variants of Formula (I) or a subembodiment thereof can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or eficacy during treatment. Isotopicaly-labeled compounds (e.g., those labeled with 3H and 14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., 3H) 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 aford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life 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 14C-enriched carbon. Positron emiting isotopes such as 15O, 13N, 11C, and 15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopicaly labeled compounds can generaly be prepared by folowing procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopicaly labeled reagent for a non-isotopicaly labeled reagent. Al 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.

[0064] 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.

[0065] “Disease” as used herein is intended to be generaly synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that al reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typicaly manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0066] “In need of treatment” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or wil 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.

[0067] The terms “administration”, “administer” and the like, as they apply to, for example, a subject, cel, tissue, organ, or biological fluid, refer to contact of, for example, a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a pharmaceutical composition comprising same, or a diagnostic agent to the subject, cel, tissue, organ, or biological fluid. In the context of a cel, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cel, as wel as contact of a reagent to a fluid, where the fluid is in contact with the cel.

[0068] The terms “proliferative disorder,” “proliferative condition,” and “cel proliferation” are used interchangeably herein and pertain to an unwanted or uncontroled celular proliferation of excessive or abnormal cels 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 celular 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 cel may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, gastric, liver, pancreas, brain, and skin.

[0069] 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 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 aflicting a patient, or at least one of the symptoms associated with a disease, disorder, condition aflicting 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.

[0070] 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 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 (asdetermined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generaly 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.

[0071] 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.

[0072] The phrase “therapeuticaly efective amount” as used herein means the amount of a compound of Formula (I) or a pharmaceuticaly 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 efect 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 therapeuticaly effective amount can be ascertained by measuring relevant physiological efects, 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 pharmaceuticaly acceptable salt thereof (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeuticaly efective amount has been used.

[0073] The term “antibody” means an immunoglobulin and is a molecule containing an antigen-binding site immunospecificaly 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, IgG2, IgG3, IgG4, IgAl, and IgA2 and is preferably IgGl or IgG2. The antibody may be derived from any species, and prefered 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 wel-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 tumorcels. 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 cel, a property of binding to a tumor cel, a property of internalizing in a tumor cel, and a property of damaging a tumor cel. 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 cel. 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 (ErbB1), ErbB2, ErbB3, EGFRvII, FGFR, EpCAM, HER-2, HER-3, tissue factor (TF), CD19, CD22, CD25, ILR2, ANTXR1, ROR1, 5T4, CD30, CD33, CD79b, CD74, CD138, CD56, CD70, CD166, CEACAM5, GPNMB, Claudin-18, folate receptor alpha (FRα), 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

[0074] In some aspects, provided herein are compounds of Formula (I) (I) or a pharmaceuticalyY1 is O, NRy, S, S(O), or S(O2);H, C1-4 alkyl, halo, or C1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl; or two R4 groups when atached to the same carbon atom combine to form oxo or C3-6 cycloalkyl; R7 is (i) –CH2Ar;Ar is phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein phenyl and heteroaryl are each independently substituted with 0, 1, or 2 R7a; each R7a is independently –CN, halo, C alkyl, C haloalkyl, 7a1 7a2 7a3 1-6 1-6 –OR , –NR R , –C(O)NR7a2R7a3, –SO2, –SO2C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, or heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 halo, C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, or –OC3-7 cycloalkyl; each R7a1 is H or C1-6 alkyl, wherein C1-6 alkyl is substituted with 0, 1, or 2 halo or oxetanyl; each R7a2 and R7a3 is independently H, C1-6 alkyl, or C1-6 haloalkyl; or (i) a moiety selected from ;–S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –CN, C1-6 alkoxy, C1-6 haloalkoxy, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, pentafluorosulfanyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heteroaryl is substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo; m is 0, 1, 2, 3, or 4; R7f is C alkyl, halo, or C haloalkyl, wherei 7f 1-6 1-6 n R can be on any available ring vertex in either ring system of (a7), (b7), or (c7); R8 is –CHR8aR8b, C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are each independently substituted with 0, 1, or 2 –CN or C3-6 cycloalkyl;R8a and R8b are each independently H, C alkyl, C alkynyl, – 8c 1-6 1-6 CH2(OR), C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, wherein each R8c is independently H, C1-6 alkyl, or C1-6 haloalkyl, and wherein C1-6 alkyl, C1-6 alkynyl, –CH2(OR8c), C3-10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a1; alternatively, R8a and R8b and the carbon atom to which they are atached combine to form C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, C6-10 aryl, or heteroaryl having 5 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, C6-10 aryl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a2; each R8a1 is independently halo, C al 8d 8e 1-6 kyl, –C(O)NR R, –OH, C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein R8d and R8e are each independently H, C1-6 alkyl, or C1-6 haloalkyl; and each R8a2 is independently C alkyl 8f 8f 1-6 , C1-6 alkynyl, halo, –CN, –OR, or –CH2(OR), wherein each R8f is independently H, C1-6 alkyl, or C1-6 haloalkyl.

[0075] In some aspects, provided herein are compounds of Formula (I) (I) or a pharmaceuticalyY1 is O, NRy, S, S(O), or S(O2);Ry, R1, R2, and R3 are each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl; or two R4 groups when atached to the same carbon atom combine to form oxo or C3-6 cycloalkyl; R7 is (i) –CH2Ar; Ar is phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein phenyl and heteroaryl are each independently substituted with 0, 1, or 2 R7a; each R7a is independently –CN, halo, C 7a1 7a2 7a3 1-6 alkyl, C1-6 haloalkyl, –OR , –NR R , –C(O)NR7a2R7a3, –SO2, –SO2C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, or heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 halo, C1-6 alkyl, – C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, or –OC3-7 cycloalkyl; each R7a1 is H or C1-6 alkyl, wherein C1-6 alkyl is substituted with 0, 1, or 2 halo or oxetanyl; each R7a2 and R7a3 is independently H, C1-6 alkyl, or C1-6 haloalkyl; or (i) a moiety selected from ;–S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –CN, C1-6 alkoxy, C1-6 haloalkoxy, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, pentafluorosulfanyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, orS, and wherein the heteroaryl is substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo; m is 0, 1, 2, 3, or 4; R7f is C alkyl, halo, or C haloalkyl 7f 1-6 1-6 , wherein R can be on any available ring vertex in either ring system of (a7), (b7), or (c7); R8 is –CHR8aR8b, C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionaly substituted with one or more groups, each group is independently –CN or C3-6 cycloalkyl; R8a and R8b are each independently H, C 8c 1-6 alkyl, C1-6 alkynyl, –CH2(OR), C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, wherein each R8c is independently H, C1-6 alkyl, or C1-6 haloalkyl, and wherein C1-6 alkyl, C1-6 alkynyl, –CH2(OR8c), C3-10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a1; alternatively, R8a and R8b and the carbon atom to which they are atached combine to form C3- 10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, C6-10 aryl, or heteroaryl having 5 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, C6-10 aryl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a2; each R8a1 is independently halo, C1-6 alkyl, –C(O)NR8dR8e, –OH, C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein R8d and R8e are each independently H, C1-6 alkyl, or C1-6 haloalkyl; and each R8a2 is independently C 8f 8f 1-6 alkyl, C1-6 alkynyl, halo, –CN, –OR, or –CH2(OR), wherein each R8f is independently H, C1-6 alkyl, or C1-6 haloalkyl.

[0076] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y1 is O or S.

[0077] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y1 is S.

[0078] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y1 is O.

[0079] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1 is N.

[0080] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1 is C(R1) and R1 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0081] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1 is C(R1) and R1 is H, methyl, ethyl, fluoro, chloro, or bromo.

[0082] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1 is C(R1) and R1 is H, methyl, fluoro, chloro, or trifluoromethyl.

[0083] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1 is CH.

[0084] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2 is N.

[0085] In some embodiments, the compound or the pharmaceuticaly 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, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0086] In some embodiments, the compound or the pharmaceuticaly 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.

[0087] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2 is C(R2) and R2 is H, methyl, fluoro, chloro, or trifluoromethyl.

[0088] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2 is CH, CF, or N.

[0089] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2 is CH or CF.

[0090] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2 is CH.

[0091] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2 is CF.

[0092] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3 is N.

[0093] In some embodiments, the compound or the pharmaceuticaly 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, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0094] In some embodiments, the compound or the pharmaceuticaly 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.

[0095] In some embodiments, the compound or the pharmaceuticaly 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.

[0096] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3 is CH or CF.

[0097] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3 is CH.

[0098] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3 is CF.

[0099] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl.

[0100] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R4 is independently C1-4 alkyl, halo, or C1-4 haloalkyl.

[0101] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 0, 1, or 2.

[0102] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 0 or 1.

[0103] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 0.

[0104] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 2; and each R4 is independently fluoro (F).

[0105] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7 is (i) –CH2Ar.

[0106] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Ar is phenyl substituted with 0, 1, or 2 R7a.

[0107] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Ar is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S substituted with 0, 1, or 2 R7a.

[0108] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl substituted with 0, 1, or 2 R7a.

[0109] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Ar is pyrolyl or pyrazolyl substituted with 0, 1, or 2 R7a.

[0110] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Ar is pyridinyl substituted with 0, 1, or 2 R7a.

[0111] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, halo, C alkyl, C haloalkyl, –OR7a1, –NR7a2R7a3, –C 7a2 7a3 1-6 1-6 (O)NR R , =S, –SO2, –SO2C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, or –C(O)OC1-6 alkyl.

[0112] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, halo, C alkyl, C haloalkyl, –OR7a1, –NR7a2R7a3 7a2 7a3 1-6 1-6 , –C(O)NR R , – C(O)H, –C(O)C1-6 alkyl, or –C(O)OC1-6 alkyl.

[0113] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, halo, C1-6 alkyl, or C1-6 haloalkyl.

[0114] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, C1-6 alkyl, or C1-6 haloalkyl.

[0115] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently C1-6 haloalkyl.

[0116] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, methyl, or trifluoromethyl.

[0117] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently trifluoromethyl.

[0118] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently .the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein at least one R7a is heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 halo, C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, –OC3-7 cycloalkyl.

[0120] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein at least one R7a is pyrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 halo, C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, –OC3-7 cycloalkyl.

[0121] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7a1 is H.

[0122] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a1 is C1- 4 alkyl.

[0123] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a2 is H.

[0124] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7a2 is C1-4 alkyl.

[0125] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7a3 is H.

[0126] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7a3 is C1-4 alkyl.

[0127] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7 is (i) a moiety selected from .thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7 is .

[0129] In someacceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7 is .

[0130] In someacceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7 is .

[0131] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4 is O.

[0132] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4 is C(R7bR7c).

[0133] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7b and R7c are each independently H, C1-4 alkyl, or halo.

[0134] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7b and R7c are each H.

[0135] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X5 is N.

[0136] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X5 is C(R7d).

[0137] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7d is H, C1-4 alkyl, or halo.

[0138] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7d is H.

[0139] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is C1-6 alkyl, halo, C1-6 haloalkyl, –S(O)2C1-6alkyl, –S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –CN, C1-6 alkoxy, C1-6 haloalkoxy, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, or pentafluorosulfanyl.

[0140] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is C1-6 alkyl, halo, C1-6 haloalkyl, –CN, C1-6 alkoxy, or C1-6 haloalkoxy.

[0141] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is H, C1-6 haloalkyl, –CN, or C1-6 haloalkoxy.

[0142] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is C1-6 haloalkyl, –CN, or C1-6 haloalkoxy.

[0143] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is H, trifluoromethyl, –CN, or difluoromethoxy.

[0144] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is trifluoromethyl, –CN, or difluoromethoxy.

[0145] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is –S(O)2C1-6alkyl, –S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, or pentafluorosulfanyl.

[0146] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is C3-6 cycloalkyl.

[0147] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heteroaryl is substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo.

[0148] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7e is pyrolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo.

[0149] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7f is C1-4 alkyl, halo, or C1-4 haloalkyl.

[0150] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7f is C1-4 methyl, chloro, or fluoro.

[0151] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein m is 0.

[0152] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R7 is a moiety selected from .

[0153] Insalt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8 is C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C1-6 cycloalkyl are optionaly substituted with one or more groups, each group is independently –CN or C3-6 cycloalkyl.

[0154] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8 is C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C1-6 cycloalkyl are substituted with 0, 1, or 2 –CN or C3-6 cycloalkyl.

[0155] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8 is methyl, ethyl, or cyclopropyl.

[0156] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8 is – CHR8aR8b.

[0157] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b are each independently H, C alkyl, C 8c 8a 8b 1-6 1-6 alkynyl, –CH2(OR), provided that R and R are notboth H, and wherein C1-6 alkyl, C1-6 alkynyl are each independently substituted with 0, 1, or 2 R8a1.

[0158] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8a is H or C1-6 alkyl and R8b is C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, and wherein C3-10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a1.

[0159] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b are each independently H, C1-6 alkyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, and wherein heteroaryl are each independently substituted with 0, 1, or 2 R8a1.

[0160] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b are each independently H, C 8a 8b 1-6 alkyl, pyrimidinyl, or pyridinyl, provided that R and R are not both H, and wherein C1-6 alkyl, pyrimidinyl, and pyridinyl are each independently substituted with 0, 1, or 2 R8a1.

[0161] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b are each independently H, C 8a 8b 1-6 alkyl, oxazolyl, thiophenyl, or thiazolyl, provided that R and R are not both H, and wherein C1-6 alkyl, oxazolyl, thiophenyl, and thiazolyl are each independently substituted with 0, 1, or 2 R8a1.

[0162] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8a is C alkyl or C c 8b 8c 1-6 3-10 ycloalkyl; and R is –CH2(OR) or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein R8c is H, C1-6 alkyl, or C1-6 haloalkyl, and wherein C3-10 cycloalkyl and heteroaryl are each independently substituted with 0, 1, or 2 R8a1.

[0163] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8a is methyl or cyclopropyl; and R8b is –CH2(OCH3) or pyrimidinyl.

[0164] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8a1 is independently halo, C 8d 8e 1-6 alkyl, or –C(O)NR R, –OH.

[0165] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8d and R8e is independently H or methyl.

[0166] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8a1 is independently C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, and heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S.

[0167] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b and the carbon atom to which they are atached combine to form C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, C6-10 aryl, heteroaryl having 5 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, C aryl, and heteroaryl are each independently substituted with 0, 1, or 8a2 6-10 2 R .

[0168] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8a2 is independently C1-6 alkyl, C1-6 alkynyl, or halo.

[0169] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y1 is O; X1 is CH; X2 is C(R2) or N;X3 is CH; R2 is H, or halo; n is 0; R7 is (i) –CH2Ar; Ar is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, substituted with 1 R7a; R7a is –CN, C1-6 alkyl, or C1-6 haloalkyl; or (i) a moiety selected from ;m is 0; R8 is –CHR8aR8b or C1-6 alkyl; and R8a and R8b are each independently C1-6 alkyl,–CH2(OR8c), C3-10 cycloalkyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein each R8c is independently C1-6 alkyl.

[0170] In some embodiments, the compound or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Y1 is O; X1 is CH; X2 is CH, CF, or N; X3 is CH; n is 0; R7 isor macceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the compound is selected from Table 1.

[0172] 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 pharmacologicaly active 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 metabolicaly hydrolyzed to the carboxylic acid, the active entity. Additionaly, 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.

[0173] A number of compounds in Table 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 wedged solid ( ) and / or dashed ( ) chemical bond(s) at the stereocenter without any markings or with the label of” or “(S)”. When the absolute stereochemistry of one or more stereocenters in an isolated compound isnot known, the folowing labels are indicated at the stereocenter of the displayed structure: “&” (e.g., “&1”); or “or” (e.g., “or1”, “or2”, or “or3”). Each of these labels is further described below.

[0174] The chemical names in the present application are generated from the corresponding structures using software, for example, CHEMDRAW.

[0175] The label “&” in the structures in the present disclosure refers to both chiral centers being present in the mixture. When multiple stereocenters are labeled with “&1” the relative stereochemistry between them is determined. The term “rac” in the chemical names denotes a racemic mixture.

[0176] 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 labeled with diferent labels, the relative stereochemistry between them is not determined. For example, in a compound with stereocenters labeled as “or1” and “or2”, the relative stereochemistry between the diferently labeled stereocenters is not determined. When multiple stereocenters are labeled with the same label, the relative stereochemistry between the same labeled stereocenters is determined but not the absolute stereochemistry. For example, for al stereocenters labeled “or1”, the relative stereochemistry between those stereocenters labeled “or1” is determined but not the absolute stereochemistry.

[0177] Unless otherwise indicated, Isomer 1 refers to the first eluting isomer and Isomer 2 refers to the second eluting isomer during chiral chromatographic separation. 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 of Formula (I) Ex. Ex. Structure Structure2PHARMACEUTICAL COMPOSITIONS

[0178] The compounds of Formula (I) or pharmaceuticaly 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 pharmaceuticaly acceptable salt thereof, or a subembodiment thereof, and one or more pharmaceuticaly acceptable excipients. The pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, thepharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.

[0179] 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.

[0180] The pharmaceutical compositions containing the active ingredient (e.g., a compound of Formula (I), a pharmaceuticaly 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 insuflation (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).

[0181] 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 pharmaceuticaly 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 pharmaceuticaly 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, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[0182] The pharmaceutical compositions typicaly comprise a therapeuticaly effective amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, and one or more pharmaceuticaly acceptable excipient. Suitable pharmaceuticaly acceptableexcipients 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, filers, bulking agents, detergents, bufers, 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 bufered saline or saline mixed with serum albumin are further exemplary vehicles. Those skiled in the art wil readily recognize a variety of bufers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical bufers include, but are not limited to, pharmaceuticaly acceptable weak acids, weak bases, or mixtures thereof. As an example, the bufer 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 bufering agents include, for example, a Tris bufer, N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N- Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), and N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0183] 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.

[0184] Any drug delivery apparatus may be used to deliver the compounds, pharmaceuticaly acceptable salts thereof, or pharmaceutical compositions described herein including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, al of which are known in the art.

[0185] An efective amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof for use in therapy is an amount suficient to treat or prevent a proliferativecondition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0186] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) wil naturaly 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 wel-known principles of medicine.

[0187] Al the compounds and pharmaceutical compositions provided herein can be used in al the methods provided herein. For example, the compounds and pharmaceutical compositions provided herein can be used in al the methods for treatment and / or prevention of al diseases or disorders provided herein. Thus, the compounds and pharmaceutical compositions provided herein are for use as a medicament. THERAPEUTIC USES AND APPLICATIONS

[0188] Provided herein are compounds that function as inhibitors of protein arginine N- methyltransferase 5 (PRMT5).

[0189] The present disclosure therefore provides a method of inhibiting PRMT5 enzyme activity in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0190] 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 therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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.

[0191] 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 therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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.

[0192] The present disclosure also provides a method of treating an MTAP nul cancer in a patient comprising administering to the patient a therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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.

[0193] The present disclosure also provides a method of treating a cancer deficient in CDKN2A in a patient comprising administering to the patient a therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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.

[0194] The present disclosure also provides a method of treating a 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 therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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.

[0195] The present disclosure also provides a method of treating a cancer in a patient comprising administering to the patient a therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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.

[0196] The present disclosure also provides a method of inhibiting cel proliferation, in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0197] 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 therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In an embodiment, the proliferative disorder is cancer.

[0198] Provided herein is a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0199] Provided herein is a compound of Formula (I) or a pharmaceuticaly 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.

[0200] Provided herein is a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the inhibition of PRMT5 enzyme activity.

[0201] Provided herein is a compound of Formula (I) or a pharmaceuticaly 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.

[0202] Provided herein is a compound of Formula (I) or a pharmaceuticaly 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.

[0203] Provided herein is a use of a compound of Formula (I) or a pharmaceuticaly 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.

[0204] Provided herein is a use of a compound of Formula (I) or a pharmaceuticaly 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.

[0205] Provided herein is a use of a compound of Formula (I) or a pharmaceuticaly 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.

[0206] Provided herein is a use of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as definedherein in the manufacture of a medicament for the treatment of a disease or disorder in which PRMT5 activity is implicated.

[0207] Provided herein is a use of a compound of Formula (I) or a pharmaceuticaly 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.

[0208] In another aspect, the present disclosure provides a method of treating a cancer in a patient, comprising: (i) determining if the cancer is MTAP nul; and (i) if the cancer is MTAP nul, administering to the patient a therapeuticaly effective amount of a compound as disclosed herein or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0209] 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.

[0210] 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, medulary thyroid carcinoma, papilary thyroid carcinoma, renal carcinoma, kidney parenchym 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, meduloblastoma and peripheral neuroectodermal tumors), Hodgkin lymphoma, non-Hodgkin lymphoma, Burkit lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cel leukemia, hepatocelular carcinoma, gal bladder carcinoma, bronchial carcinoma, smal cel lung carcinoma, non- smal cel lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroideamelanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma or plasmocytoma.

[0211] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is lung cancer, non-smal cel lung (NSLC) cancer, bronchioloalveolar cel 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 falopian tubes, carcinoma of the endometrium, carcinoma of the vagina, carcinoma of the vulva, cancer of the smal 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 cel carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocelular 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, meduloblastomas, meningiomas, squamous cel carcinomas, pituitary adenomas, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers.

[0212] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is leukemia, glioma, melanoma, pancreatic, non-smal cel lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non- Hodgkin lymphoma or mesothelioma.

[0213] 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, difuse large B cel lymphoma (DLBCL), acute lymphoblastic leukemia (ALL) or mantle cel lymphoma (MCL).

[0214] 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 someembodiments, 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.

[0215] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-smal cel 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. In some embodiments, the cancer is non-smal cel lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.

[0216] 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 cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC); e.g., lung squamous or lung adenocarcinoma), astrocytoma, undiferentiated pleiomorphic sarcoma, lymphoma (e.g., difuse large B-cel lymphoma (DLBCL), leukemia, head and neck cancer (e.g., head and neck squamous cel carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0217] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is an MTA-accumulating cancer. In some embodiments, the cancer treatedby the methods, uses, or medicaments described herein is an MTAP-deficient cancer. In some embodiments, the cancer is treatable by inhibition of PRMT5.

[0218] 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 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- nul cels 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-nul associated disease and / or condition through inhibiting PRMT5 in MTAP-nul cels by said compounds. In some embodiments the chromosome 9p21 deletion or MTAP-nul associated disease or condition is aleviated by inhibition of PRMT5 in MTAP-nul cels.

[0219] In some embodiments, provided herein is a method of treating and / or preventing a MTAP-nul or chromosome 9p21 deletion associated disease or condition in a patient in need thereof, comprising administering to the patient a therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0220] In some embodiments, the chromosome 9p21 deletion or MTAP-nul 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, dediferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cel 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 cel 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., Baret's esophagus, dysplasia and adenocarcinoma); • gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromaltumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cel 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 papilary mucinous neoplasms (IPMN), intraductal oncocytic papilary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cel cystadenoma, acinar cel cystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, coloid carcinoma, medulary carcinoma, hepatoid carcinoma, signet ring cel carcinoma, undiferentiated carcinoma, undiferentiated carcinoma with osteoclast-like giant cels, acinar cel carcinoma, neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including smal cel or large cel NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid- pseudopapilary neoplasms (SPN), pancreatoblastoma); • gal bladder (e.g., carcinoma of the galbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma); • neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas); • thyroid (e.g., anaplastic (undiferentiated) carcinoma, medulary carcinoma, oncocytic tumors, papilary carcinoma, adenocarcinoma); • liver (e.g., adenoma, combined hepatocelular and cholangiocarcinoma, fibrolamelar carcinoma, hepatoblastoma, hepatocelular carcinoma, mesenchymal, nested stromal epithelial tumor, undiferentiated carcinoma; hepatocelular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, rhabdoid tumor); • kidney (e.g., ALK-rearanged renal cel carcinoma, chromophobe renal cel carcinoma, clear cel renal cel carcinoma, clear cel sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cel carcinoma, nephroma, nephroblastoma (Wilms tumor), papilary adenoma, papilary renal cel carcinoma, renal oncocytoma, renal cel carcinoma, succinate dehydrogenase- deficient renal cel carcinoma, colecting duct carcinoma); • breast (e.g., invasive ductal carcinoma, including without limitation, acinic cel carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cel, inflammatory carcinoma, lipid-rich carcinoma, medulary carcinoma, metaplastic carcinoma, micropapilarycarcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papilary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cel carcinoma; • peritoneum (e.g., mesothelioma; primary peritoneal cancer); • female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, germ cel tumors, sex cord-stromal tumors), Falopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cel adenocarcinoma, transitional cel carcinoma, squamous cel carcinoma, undiferentiated carcinoma, Mülerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cel tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cel carcinoma, mucinous carcinoma, squamous cel carcinoma, transitional carcinoma, smal cel carcinoma, undiferentiated 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 mulerian 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 cel tumors, spermatocytic seminoma), penis; • bladder (e.g., squamous cel 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 cel carcinoma (SCC) (e.g., glotic carcinoma, supraglotic carcinoma, subglotic carcinoma, transglotic carcinoma), carcinoma in situ, verucous, spindle cel and basaloid SCC, undiferentiated 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., smal cel carcinoma (SCLC), non-smal cel lung carcinoma (NSCLC), includingsquamous cel carcinoma (SCC), adenocarcinoma and large cel carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cel carcinomas, spindle cel carcinomas, pleuropulmonary blastoma); • lymph (e.g., lymphomas, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (NHL), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, Epstein-Bar virus (EBV)-associated lymphoproliferative diseases, including B cel lymphomas and T cel lymphomas (e.g., Burkit lymphoma; large B cel lymphoma, difuse large B-cel lymphoma (DLBCL), mantle cel lymphoma, indolent B-cel lymphoma, low grade B cel lymphoma, fibrin-associated difuse large cel lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK / T cel lymphoma, nasal type; peripheral T cel lymphoma, cutaneous T cel lymphoma, angioimmunoblastic T cel lymphoma; folicular T cel lymphoma; systemic T cel lymphoma), lymphangioleiomyomatosis); • central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cel astrocytoma, pleomorphic xanthoastrocytoma, difuse astrocytoma, fibrilary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cel glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapilary ependymoma, ependymomas (e.g., celular, papilary, clear cel, 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, meduloblastoma, meningeal tumors, primary CNS lymphomas, germ cel tumors, Pituitary adenomas, cranial and paraspinal nerve tumors, stelar 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 medula (pheochromocytomas) and extra- adrenal paraganglia (extra-adrenal) paragangliomas); • skin (e.g., clear cel hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and • soft tissues (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cel sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, smal round cel tumor, desmoplastic smal round cel tumor, elastofibroma, embryonalrhabdomyosarcoma, Ewing's tumors / primitive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, 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, undiferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undiferentiated sarcoma, wel- diferentiated liposarcoma.

[0221] In some embodiments, the chromosome 9p21 deletion or MTAP-nul associated disease or condition is a cancer selected from lung cancer, urothelial cancer, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cel 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.

[0222] In some embodiments, the chromosome 9p21 deletion or MTAP-nul associated disease or condition is a cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic, and bladder cancer.

[0223] 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 refered to herein as "triple negative breast cancer".

[0224] In further aspects, a breast cancer can be a lobular carcinoma in situ (LCIS), a ductal carcinoma in situ (DOS), an invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phylodes tumor, Angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medulary carcinoma, mucinous carcinoma, papilary carcinoma, tubular carcinoma, metaplastic carcinoma, micropaparycarcinoma, 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.

[0225] In an embodiment, the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer.

[0226] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is NSCLC (non-smal cel lung carcinoma. In one embodiment, the NSCLC can be squamous NSCLC. In another embodiment, it can be adenocarcinoma.

[0082] 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.

[0227] In some aspects, one or more compounds described herein are useful for treating any PRMT5- mediated or PRMT5-responsive proliferative cel disorder, for example a cancer that is PRMT5 responsive.

[0228] In one aspect, a cancer that lacks p53 (e.g., a p53 nul 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 nul cancer) than a p53 positive cancer.

[0229] 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.

[0230] 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 nul cancer). In some embodiments, a p53 negative cancer (e.g., a p53 nul 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 nul cancer) is treated with a therapeutic agent that is not a PRMT5 inhibitor.

[0231] By "sample" is meant any biological sample derived from the subject, includes but is not limited to, cels, tissues samples, body fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), cancer cels, 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 bloting, etc., or any combination of thereof.

[0232] 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, lymphangioendotheliosarcoma, hemangio sarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g. , cholangiocarcinoma), bladder cancer, brain cancer (e.g., meningioma; glioma, e.g. , astrocytoma, oligodendroglioma; meduloblastoma), 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 hemorhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g. , adenocarcinoma of the esophagus, Baret' s adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gal bladder cancer, gastric cancer (e.g. , stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cel carcinoma, oral cancer (e.g., oral squamous cel 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-cel ALL, T-cel ALL), acute myelocytic leukemia (AML) (e.g. , fl- cel! AML, T-cel AML), chronic myelocytic leukemia (CML) (e g. , B-cel CML, T-cel CML), and chronic lymphocytic leukemia (CLL) (e.g. , B-cel CLL, T- cel CLL), folicular lymphoma, chronic lymphocytic leukemia / smal lymphocytic lymphoma (CLL / SLL), marginal zone B-cel lymphomas (e.g. , mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cel lymphoma, splenic marginal zone B-cel lymphoma), primary mediastinal B-cel lymphoma, Burkit lymphoma, lymphoplasmacytic lymphoma (e.g., "Waldenstrom's macro globulinemia"), hairy cel leukemia (HCL), immunoblastic large cel ly mphoma, precursor B -1ymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cel NHL such as precursor T- 1ymphoblastic lymphoma / leukemia, peripheral T-cel lymphoma (PTCL) (e.g., cutaneous T- cel lymphoma (CTCL) (e.g. , mycosis fungiodes, Sezary syndrome), angioimmunoblastic T- cel lymphoma, extranodal natural kiler T-cel lymphoma, enteropathy type T-cel lymphoma, subcutaneous panniculitis-1ike T-cel lymphoma, anaplastic large cel 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 cel carcinoma), liver cancer (e.g. , hepatocelular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, smal cel lung cancer (SCLC), non-smal cel 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 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g. , cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papilary 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 cel carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cel carcinoma (BCC), smalbowel 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., papilary carcinoma of the thyroid, papilary thyroid carcinoma (PTC), medulary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).

[0233] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is spinal cord cancer. COMBINATION THERAPY

[0234] The present disclosure contemplates the use of compounds of a compound of Formula (I) or a pharmaceuticaly 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 diferent, complementary mechanisms of action. Such combination therapy may be especialy advantageous by alowing 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 efect on the underlying disease, disorder, or condition.

[0235] 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”).

[0236] In certain embodiments, compounds of Formula (I) or pharmaceuticaly acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered or applied sequentialy, e.g., where one agent is administered prior to one or more other agents. In other embodiments, compounds of Formula (I) or pharmaceuticaly 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 separateformulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentialy or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.

[0237] The present disclosure also contemplates the use of the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with at least one additional therapeutic agent as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0238] 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 therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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.

[0239] The present disclosure also provides a method of treating an MTAP nul cancer in a patient comprising administering to the patient a therapeuticaly efective amount of (a) a compound of Formula (I) or a pharmaceuticaly 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

[0240] The present disclosure also provides a method of treating a cancer deficient in CDKN2A in a patient comprising administering to the patient (a) a therapeuticaly efective amount of a compound of Formula (I) or a pharmaceuticaly 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.

[0241] The present disclosure also provides a method of treating a 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) a therapeuticaly efective amount of a compound of Formula (I) or apharmaceuticaly 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.

[0242] The present disclosure provides methods for treating a cancer with (a) a compound of Formula (I) or a pharmaceuticaly 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

[0243] The disclosure provides one or more additional therapeutic agents for use with a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof and one or more pharmaceuticaly 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

[0244] In an embodiment, the additional therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents include alkylating agent, microtubule inhibitors, antimetabolites, anti-tumor antibiotics, as wel as corticosteroids.

[0245] In some embodiments, the chemotherapeutic agent is an alkylating agent. In some embodiments, the alkylating agent is altretamine, bendamustine, busulfan, improsulfan, piposulfan, procarbazine, mechlorethamine, carmustine, lomustine, semustine chlorambucil, cyclophosphamide, thiotepa, ifosfamide, dacarbazine, temozolomide, or perfosamide. In some embodiments, the alkylating agent is mechlorethamine. In some embodiments, the alkylating agent is perfosamide.

[0246] 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.

[0247] In some embodiments, the chemotherapeutic agent is a microtubule inhibitor. In an embodiment, the microtubule inhibitor is eribulin, ixabepilone, cabazitaxel, enfortumab 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, podophylotoxin, or abraxane (protein-bound paclitaxel). In some embodiments, the chemotherapeutic agent is paclitaxel.

[0248] In some embodiments, the chemotherapeutic agent is an antimetabolite. 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 antimetabolite is clofarabine. In an embodiment, the antimetabolite is cytarabine. In an embodiment, the antimetabolite is gemcitabine. In an embodiment, the antimetabolite is floxuridine.

[0249] 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.

[0250] In some embodiments, the chemotherapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is prednisone, methylprednisolone, or dexamethasone.

[0251] Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chiorambucil, chlornaphazine, 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, esorubicin, idarubicin, marcelomycin, 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, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 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; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; eliptinium acetate; etoglucid; galium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophylinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; 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; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceuticaly 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-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and pharmaceuticaly acceptable salts, acids or derivatives of anyof the above. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent. i) Cel Cycle Checkpoint Inhibitors

[0252] In an embodiment, the additional therapeutic agent is a cel cycle checkpoint inhibitor. In some embodiments, the cel cycle checkpoint inhibitor is KU60019, AZD0156, Ceralasertib, Camonsertib, VE821, AZD7762, SRA737, Rabusertib, Prexasertib, SCH900776, or Adavosertib. In some embodiments, the cel cycle checkpoint inhibitor is KU60019. In some embodiments, the cel cycle checkpoint inhibitor is AZD0156. In some embodiments, the cel cycle checkpoint inhibitor is ceralasertib. In some embodiments, the cel cycle checkpoint inhibitor is camonsertib. In some embodiments, the cel cycle checkpoint inhibitor is VE821. In some embodiments, the cel cycle checkpoint inhibitor is AZD7762. In some embodiments, the cel cycle checkpoint inhibitor is SRA737. In some embodiments, the cel cycle checkpoint inhibitor is rabusertib. In some embodiments, the cel cycle checkpoint inhibitor is prexasertib. In some embodiments, the cel cycle checkpoint inhibitor is SCH900776. In some embodiments, the cel cycle checkpoint inhibitor is adavosertib. ii) Immune Checkpoint Inhibitors

[0253] 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 TIGIT inhibitor.

[0254] 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-1 inhibitor is retifanlimab. In an embodiment, the PD-1 inhibitor is atezolizumab.

[0255] In an embodiment PD-1 / PD-L1 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.

[0256] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is relatlimab.

[0257] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In some embodiments, the ipilimumab or tremelimumab

[0258] In some embodiments, the immune checkpoint inhibitor is a BTLA inhibitor.

[0259] 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), or LY3321367 (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).

[0260] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor. In some embodiments, the TIGIT inhibitor is tiragolumab, domvanalimab, vibostolimab, etigilimab, M6223, or ociperlimab. In some embodiments, the TIGIT inhibitor is tiragolumab. In some embodiments, the TIGIT inhibitor is domvanalimab. 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

[0261] 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

[0262] In some embodiments, the additional therapeutic agent is an anti-CD20 therapeutic agent. In some embodiments, the anti-CD20 therapeutic agent is rituximab, arzera, gazyva, ibritumomab tiuxetan, obinutuzumab, ofatumumab, riabni, rituxan, ruxience, truxima, zevalin, or tositumomab. vi) Hormonal Therapeutic Agent

[0263] 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, leuprorelin, fulvestrant, 4- hydroxytamoxifen, trioxifene, keoxifene, onapristone, toremifene; flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, or goserelin. vi) PARP Inhibitors

[0264] In some embodiments, the additional therapeutic agent is a PARP inhibitor. In some embodiments, the PARP inhibitor is niraparib, rucaparib, olaparib, talazoparib, or veliparib. vii) MAT2A Inhibitors

[0265] In some embodiments, the additional therapeutic agent is a MAT2A inhibitor. In some embodiments, the MAT2A inhibitor is AG- or. In some embodiments, the MAT2A inhibitor is a compound disclosedthe contents of which is incorporated herein by reference for al purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2018 / 045071, the contents of which is incorporated herein by reference for al 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 al purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2021 / 1259815, WO2023 / 066283,WO2024 / 217502, WO2020 / 139991, WO2020 / 139992, WO2018 / 045071, WO2018 / 039972, WO2019191470, WO2024 / 002024, or WO2024 / 217493, the contents of which are incorporated herein by reference for al purposes. In some embodiments, the MAT2A inhibitor is ISM3412 or S095035. In some embodiments, the MAT2A inhibitor is ,WO2022 / 268180, the contents of which are incorporated herein by reference for al purposes.

[0267] In some embodiments, the MAT2A inhibitor is pharmaceuticaly acceptable salt thereof.

[0268] In some embodiments, the additional therapeutic agent is radiation therapy. x) VEGF Inhibitors

[0269] In some embodiments, the additional therapeutic agent is a VEGF inhibitor. In some embodiments, the VEGF inhibitor is Bevacizumab, aflibercept, ranibizumab, sorafenib, dasatinib, sunitinib, nilotinib, pazopanib, pegaptanib, axitinib, lenvatinib, ramucirumab, or regorafenib.xi) Tyrosine Kinase Inhibitors

[0270] 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, pyrotinib, panitumumab, nimotuzumab, necitumumab, mobocertinib, vandetanib, lenvatinib, pazopanib, mubritinib, fostamatinib, calquence, pertuzumab, acalabrutinib, alectinib, cabozantinib, ceritinib, capmatinib, or crizotinib. xi) mTOR Inhibitors

[0271] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is rapamycin, everolimus, sirolimus, temsirolimus, everolimus, or sirolimus. xii) AKT Inhibitors

[0272] 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

[0273] 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. xv) PI3K Inhibitors

[0274] In some embodiments, the additional therapeutic agent is a PI3K inhibitor. In some embodiments, the PI3K inhibitor is idelalisib, alpelisib, leniolisib, duvelisib, or copanlisib. xvi)JAK Inhibitors

[0275] In some embodiments, the additional therapeutic agent is a JAK inhibitor. In some embodiments, the JAK inhibitor is tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, filgotinib, or abrocitinib.xvi) Inhibitors of Cereblon (Ubiquitin Ligase)

[0276] In some embodiments, the additional therapeutic agent is a inhibitor of cereblon. In some embodiments, the inhibitor of cereblon is thalidomide, lenalidomide. xvii) MAPK / ERK Inhibitors

[0277] 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, selumetinib, SML-8-731, tipifarnib, lonafarnib, trametinib, ulixertinib, WX-554, or cobimetinib. xix)Wnt / β-catenin Inhibitors

[0278] In some embodiments, the additional therapeutic agent is a Wnt / β-catenin inhibitor. In some embodiments, the Wnt / β-catenin inhibitor is capmatinib, resibufogenin, or isoquercitrin. xx) Proteosome Inhibitors

[0279] In some embodiments, the additional therapeutic agent is a proteosome inhibitor. In some embodiments, the proteosome inhibitor bortezomib, carfilzomib, or ixazomib. xxi)Histone Deacetylase Inhibitors

[0280] In some embodiments, the additional therapeutic agent is a histone deacetylase inhibitor. In some embodiments, the histone deacetylase inhibitor vorinostat, romidepsin, panobinostat, or belinostat. xxi) Recombinant IL-2

[0281] In some embodiments, the additional therapeutic agent is a recombinant IL-2. In some embodiments, the recombinant IL-2 is aldesleukin. xxii) RANKL Inhibitors

[0282] In some embodiments, the additional therapeutic agent is a RANKL inhibitor. In some embodiments, the RANKL inhibitor is Denosumab or AS2676293. xxiv) B4GALNT1 Inhibitors

[0283] In some embodiments, the additional therapeutic agent is a B4GALNT1 inhibitor. In some embodiments, the B4GALNT1 inhibitor is Dinutuximab.xxv) SLAMF7 Inhibitors

[0284] In some embodiments, the additional therapeutic agent is a SLAMF7 inhibitor. In some embodiments, the SLAMF7 inhibitor is elotuzumab. xxvi) IDH2 / IDH1 Inhibitors

[0285] In some embodiments, the additional therapeutic agent is a IDH2 / IDH1 inhibitor. In some embodiments, the IDH2 / IDH1 inhibitor is enasidenib, ivosidenib, AGI-6780, AG- 221, FT-2102, IDH305, GSK 321, or BAY1436032. xxvi) BTK Inhibitors

[0286] In some embodiments, the additional therapeutic agent is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib. xxvii) FLT3 Inhibitors

[0287] In some embodiments, the additional therapeutic agent is a FLT3 inhibitor. In some embodiments, the FLT3 inhibitor is sunitinib, midostaurin, lestaurtinib, KW-2449, crenolanib, or gilteritinib. xxix) PDGFRα Inhibitors

[0288] In some embodiments, the additional therapeutic agent is a PDGFRα inhibitor. In some embodiments, the PDGFRα inhibitor is olaratumab, avapritinib, ayvakit, imatinib, ripretinib, or regorafenib. xxx) Smoothened (Smo) Inhibitors

[0289] 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

[0290] 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. xxxi) Cel Based Therapy

[0291] In some embodiments, the additional therapeutic agent is a cel based therapy. In some embodiments, the cel based therapy is tumor-infiltrating lymphocyte (TIL) therapy;engineered t cel receptor (TCR) therapy; chimeric antigen receptor (CAR) T cel therapy; Natural Kiler (NK) cel therapy; or sipuleucel-T. xxxii) OX40 Inhibitors

[0292] In some embodiments, the additional therapeutic agent is a OX40 inhibitor. In some embodiments, the OX40 inhibitor is ivuxolimab, cudarolimab, utomilumab, or INBRX- 106. xxxiv) 41BB (CD137) Inhibitors

[0293] In some embodiments, the additional therapeutic agent is a 41BB (CD137) inhibitor. In some embodiments, the 41BB (CD137) inhibitor is urelumab. xxxv) VISTA Inhibitors

[0294] In some embodiments, the additional therapeutic agent is a VISTA inhibitor. In some embodiments, the VISTA inhibitor is hmbd-002. xxxvi) CD96 Inhibitors

[0295] In some embodiments, the additional therapeutic agent is a CD96 inhibitor. In some embodiments, the CD96 inhibitor is GSK6097608. xxxvi) TGFβ Inhibitors

[0296] In some embodiments, the additional therapeutic agent is a TGFβ inhibitor. In some embodiments, the TGFβ inhibitor is SAR-439459. xxxvii) CD19 Inhibitors

[0297] 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

[0298] 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

[0299] 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

[0300] In some embodiments, the additional therapeutic agent is a CD39 inhibitor. In some embodiments, the CD39 inhibitor is pur001, ES002023, TTX-030, IPH5201, or SRF617. xli) CD52 Inhibitors

[0301] In some embodiments, the additional therapeutic agent is a CD52 inhibitor. In some embodiments, the CD52 inhibitor is alemtuzumab. xlii) CD73 Inhibitors

[0302] 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 triammonium, dalutrafusp alfa, BK50164, mupadolimab, uliledlimab, MRS4620, BMS-986179, NZV930, AK119, SYM024, INCA00186, or ORIC-533. xliv) A2AR Inhibitors

[0303] In some embodiments, the additional therapeutic agent is an A2AR inhibitor. In some embodiments, the A2AR inhibitor is istradefyline, vipadenant, CVT-6883, enprofyline, ciforadenant, imaradenant, etrumadenant, NIR178, EOS100850, CS3005, PBF- 999, or INCB106385. xlv)A2BR Inhibitors

[0304] In some embodiments, the additional therapeutic agent is an A2BR inhibitor. In some embodiments, the A2BR inhibitor is pbf-1129, QAF805, LAS101057 AB928, ISAM140, or TT-4. xlvi) IDO1 & TDO2 Inhibitors

[0305] 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. xlvi) Arginase Inhibitors

[0306] In some embodiments, the additional therapeutic agent is an arginase inhibitor. In some embodiments, the arginase inhibitor is numidargistat, pegzilarginase, or INCB001158. xlvii) B7-H3 Inhibitors

[0307] 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

[0308] In some embodiments, the additional therapeutic agent is a B7-H4 inhibitor. In some embodiments, the B7-H4 inhibitor is mt-1660, FPA150, or AZD8205. l) Signal Transduction Inhibitor (STI)

[0309] 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); (i) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (ii) her-2 / neu receptor inhibitors (e.g., HERCEPTIN); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cel cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositol kinase inhibitors. li) Spicing Inhibitor Sulfonamides (SPLAMs)

[0310] In some embodiments, the additional therapeutic agent is a Spicing inhibitor sulfonamide (SPLAM).

[0311] In some embodiments, the SPLAM is indisulam or E7820. li) Additional Therapeutic Agents

[0312] 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-cel adjuvant, bone marow transplant, or antigen presenting cels (e.g., dendritic cel therapy).

[0313] 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 therapeuticagent disclosed herein. In an embodiment, the antitumor compound is a chemotherapeutic agent disclosed herein.

[0314] 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 (bcl2 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). DOSING

[0315] A compound of Formula (I) or a pharmaceuticaly 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, for 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 efects associated with the agent(s) being administered.

[0316] An efective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired efect 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 efect 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 efect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration al relevant factors. Thus, in some situations the efective amount is more than the calculated ED50, in other situations the efective amount is less than the calculated ED50, and in stil other situations the efective amount is the same as the calculated ED50. ROUTES OF ADMINISTRATION

[0317] A compound of Formula (I), a subembodiment thereof, or a pharmaceuticaly acceptable salt thereof or pharmaceutical compositions comprising this compound may be administered to a patient by any convenient route of administration, whether systemicaly / peripheraly or topicaly (i.e., at the site of desired action).

[0318] 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 insuflation therapy using e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; 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

[0319] The compounds of the curent application can be further described by the folowing non-limiting embodiments:

[0320] Embodiment 1. A compound of Formula (I): (I) or a pharmaceuticalyY1 is O, NRy, S, S(O), or S(O2); X1 is C(R1) or N; X2 is C(R2) or N; X3 is C(R3) or N; Ry, R1, R2, and R3 are each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl; or two R4 groups when atached to the same carbon atom combine to form oxo or C3-6 cycloalkyl; R7 is (i) –CH2Ar;Ar is phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein phenyl and heteroaryl are each independently substituted with 0, 1, or 2 R7a, each R7a is independently –CN, halo, C alky 7a1 7a2 7a3 1-6 l, C1-6 haloalkyl, –OR , –NR R , –C(O)NR7a2R7a3, –SO2, –SO2C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, or heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 halo, C1-6 alkyl, – C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, or –OC3-7 cycloalkyl; each R7a1 is H or C1-6 alkyl, wherein C1-6 alkyl is substituted with 0, 1, or 2 halo or oxetanyl; each R7a2 and R7a3 is independently H, C1-6 alkyl, or C1-6 haloalkyl; or (i) a moiety selected from ;R7e is C1-6 alkyl, C3-6 cycloalkyl, halo, C1-6 haloalkyl, –S(O)2C1-6alkyl, –S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –CN, C1-6 alkoxy, C1-6 haloalkoxy, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, pentafluorosulfanyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heteroaryl is substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo; m is 0, 1, 2, 3, or 4; R7f is C alkyl, halo, or C haloalkyl, 7f 1-6 1-6 wherein R can be on any available ring vertex in either ring system of (a7), (b7), or (c7);R8 is –CHR8aR8b, C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionaly substituted with one or more groups, each group is independently –CN or C3-6 cycloalkyl; R8a and R8b are each independently H, C 8c 1-6 alkyl, C1-6 alkynyl, –C(OR), C3-10 cycloalkyl, C3- 10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, wherein each R8c is independently H, C1-6 alkyl, or C1-6 haloalkyl, and wherein C1-6 alkyl, C1-6 alkynyl, –C(OR8c), C3-10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a1; alternatively, R8a and R8b and the carbon atom to which they are atached combine to form C3- 10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, C6-10 aryl, heteroaryl having 5 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, C6-10 aryl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a2; each R8a1 is independently halo, C alkyl, 8d 8e 1-6 –C(O)NR R, –OH, C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, and heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein R8d and R8e are each independently H, C1-6 alkyl, or C1-6 haloalkyl; and each R8a2 is independently C al 8f 8f 1-6 kyl, C1-6 alkynyl, halo, –CN, –OR, or –C(OR), wherein each R8f is independently H, C1-6 alkyl, or C1-6 haloalkyl.

[0321] Embodiment 2. The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, wherein Y1 is O or S.

[0322] Embodiment 3. The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, wherein Y1 is S.

[0323] Embodiment 4. The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, wherein Y1 is O.

[0324] Embodiment 5. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 4, wherein X1 is N.

[0325] Embodiment 6. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 4, wherein X1 is C(R1) and R1 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0326] Embodiment 7. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 4, wherein X1 is C(R1) and R1 is H, methyl, ethyl, fluoro, chloro, or bromo.

[0327] Embodiment 8. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 4, wherein X1 is C(R1) and R1 is H, methyl, fluoro, chloro, or trifluoromethyl.

[0328] Embodiment 9. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 4, wherein X1 is CH.

[0329] Embodiment 10. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 9, wherein X2 is N.

[0330] Embodiment 11. The compound or a pharmaceuticaly 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.

[0331] Embodiment 12. The compound or a pharmaceuticaly 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.

[0332] Embodiment 13. The compound or a pharmaceuticaly 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.

[0333] Embodiment 14. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 9, wherein X2 is CH or CF.

[0334] Embodiment 15. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 9, wherein X2 is CH.

[0335] Embodiment 16. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 9, wherein X2 is CF.

[0336] Embodiment 17. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 16, wherein X3 is N.

[0337] Embodiment 18. The compound or a pharmaceuticaly 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.

[0338] Embodiment 19. The compound or a pharmaceuticaly 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.

[0339] Embodiment 20. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 16, wherein X3 is C(R3) and R3 is H, methyl, fluoro, chloro, or trifluoromethyl.

[0340] Embodiment 21. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 16, wherein X3 is CH or CF.

[0341] Embodiment 22. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 16, wherein X3 is CH.

[0342] Embodiment 23. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 16, wherein X3 is CF.

[0343] Embodiment 24. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 23, wherein each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl.

[0344] Embodiment 25. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 23, wherein each R4 is independently C1-4 alkyl, halo, or C1-4 haloalkyl.

[0345] Embodiment 26. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 25, wherein n is 0, 1, or 2.

[0346] Embodiment 27. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 25, wherein n is 0 or 1.

[0347] Embodiment 28. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 25, wherein n is 0.

[0348] Embodiment 29. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 25, wherein n is 2 and each R4 is independently F.

[0349] Embodiment 30. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29, wherein R7 is (i) –CH2Ar.

[0350] Embodiment 31. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 30, wherein Ar is phenyl substituted with 0, 1, or 2 R7a.

[0351] Embodiment 32. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 30, wherein Ar is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S substituted with 0, 1, or 2 R7a.

[0352] Embodiment 33. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 30, wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl substituted with 0, 1, or 2 R7a.

[0353] Embodiment 34. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 30, wherein Ar is pyrolyl or pyrazolyl substituted with 0, 1, or 2 R7a.

[0354] Embodiment 35. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, wherein R7a is –CN, halo, C 7a1 1-6 alkyl, C1-6 haloalkyl, –OR , –NR7a2R7a3, –C(O)NR7a2R7a3, =S, –SO2, –SO2C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, or – C(O)OC1-6 alkyl.

[0355] Embodiment 36. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, wherein R7a is –CN, halo, C alkyl, C haloalky 7a1 1-6 1-6 l, –OR , –NR7a2R7a3, –C(O)NR7a2R7a3, –C(O)H, –C(O)C1-6 alkyl, or –C(O)OC1-6 alkyl.

[0356] Embodiment 37. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, wherein R7a is –CN, halo, C1-6 alkyl, or C1-6 haloalkyl.

[0357] Embodiment 38. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, wherein R7a is heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 halo, C1-6 alkyl, –C(O)H, – C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, –OC3-7 cycloalkyl.

[0358] Embodiment 39. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, wherein R7a is pyrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 halo, C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, –OC3-7 cycloalkyl.

[0359] Embodiment 40. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 36, wherein R7a1 is H.

[0360] Embodiment 41. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 36, wherein each R7a1 is C1-4 alkyl.

[0361] Embodiment 42. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 36, 40, and 41, wherein each R7a2 is H.

[0362] Embodiment 43. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 36, 40, and 41, wherein R7a2 is C1-4 alkyl.

[0363] Embodiment 44. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 36 and 40 to 43, wherein each R7a3 is H.

[0364] Embodiment 45. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 36 and 40 to 43, wherein R7a3 is C1-4 alkyl.

[0365] Embodiment 46. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29, wherein R7 is (i) a moiety selected from .

[0366] Embodiment 47. The compound or a pharmaceuticaly acceptable salt thereof of embodiment 46, wherein R7 is7).

[0367] Embodiment 48. T ceuticaly acceptable salt thereof of embodiment 46, wherein R7 is .

[0368] Embodiment 49.acceptable salt thereof of embodiment 46, wherein R7 is .

[0369] Embodiment 50.acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 49, wherein X4 is O.

[0370] Embodiment 51. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 49, wherein X4 is C(R7bR7c).

[0371] Embodiment 52. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 51, wherein R7b and R7c are each independently H, C1-4 alkyl, or halo.

[0372] Embodiment 53. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 51, wherein R7b and R7c are each H.

[0373] Embodiment 54. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 53, wherein X5 is N.

[0374] Embodiment 55. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 53, wherein X5 is C(R7d).

[0375] Embodiment 56. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 55, wherein R7d is H, C1-4 alkyl, or halo.

[0376] Embodiment 57. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 55, wherein R7d is H.

[0377] Embodiment 58. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 57, wherein R7e is C1-6 alkyl, halo, C1-6 haloalkyl, –S(O)2C1-6alkyl, –S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –CN, C1-6 alkoxy, C1-6 haloalkoxy, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, or pentafluorosulfanyl.

[0378] Embodiment 59. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 57, wherein R7e is C1-6 alkyl, halo, C1-6 haloalkyl, – CN, C1-6 alkoxy, or C1-6 haloalkoxy.

[0379] Embodiment 60. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 57, wherein R7e is–S(O)2C1-6alkyl, –S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, or pentafluorosulfanyl.

[0380] Embodiment 61. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 57, wherein R7e is C3-6 cycloalkyl.

[0381] Embodiment 62. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 57, wherein R7e is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heteroaryl is substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo.

[0382] Embodiment 63. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 57, wherein R7e is pyrolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo.

[0383] Embodiment 64. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 63, wherein R7f is C1-4 alkyl, halo, or C1-4 haloalkyl.

[0384] Embodiment 65. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 29 and 46 to 63, wherein R7f is C1-4 methyl, chloro, or fluoro.

[0385] Embodiment 66. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 65, wherein R8 is C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C1-6 cycloalkyl are optionaly substituted with one or more groups, each group is independently –CN or C3-6 cycloalkyl.

[0386] Embodiment 67. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 65, wherein R8 is methyl, ethyl, or cyclopropyl.

[0387] Embodiment 68. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 65, wherein R8 is –CHR8aR8b.

[0388] Embodiment 69. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 65, wherein R8a and R8b are each independently H, C1-6 alkyl, C alkynyl, –C(OR8c), provided that R8a a 8b 1-6 nd R are not both H, and wherein C1-6 alkyl, C1-6 alkynyl are each independently substituted with 0, 1, or 2 R8a1.

[0389] Embodiment 70. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 68, wherein R8a is H or C 8b 1-6 alkyl and R is C3-10 cycloalkyl, C3- 10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, and wherein C3-10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with0, 1, or 2 R8a1.

[0390] Embodiment 71. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 68, wherein R8a and R8b are each independently H, C1-6 alkyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, and wherein heteroaryl are each independently substituted with 0, 1, or 2 R8a1.

[0391] Embodiment 72. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 68, wherein R8a and R8b are each independently H, C1-6 alkyl, pyrimidinyl, or pyridinyl, provided that R8a and R8b are not both H, and wherein C1-6 alkyl, pyrimidinyl, and pyridinyl are each independently substituted with 0, 1, or 2 R8a1.

[0392] Embodiment 73. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 68, wherein R8a and R8b are each independently H, C1-6 alkyl, oxazolyl, thiophenyl, or thiazolyl, provided that R8a and R8b are not both H, and wherein C1-6 alkyl, oxazolyl, thiophenyl, and thiazolyl are each independently substituted with 0, 1, or 2 R8a1.

[0393] Embodiment 74. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 73, wherein each R8a1 is independently halo, C1-6 alkyl, or –C(O)NR8dR8e, –OH.

[0394] Embodiment 75. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 74, wherein each R8d and R8e is independently H or methyl.

[0395] Embodiment 76. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 73, wherein each R8a1 is independently C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, and heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S.

[0396] Embodiment 77. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 68, wherein R8a and R8b and the carbon atom to which they are atached combine to form C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, C6-10 aryl, heteroaryl having 5 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, C6-10 aryl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a2.

[0397] Embodiment 78. The compound or a pharmaceuticaly acceptable salt thereof of embodiment 77, wherein each R8a2 is independently C1-6 alkyl, C1-6 alkynyl, or halo.

[0398] Embodiment 79. The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, wherein the compound is selected from Table 1.

[0399] Embodiment 80. A pharmaceutical composition comprising a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, and a pharmaceuticaly acceptable excipient.

[0400] Embodiment 81. 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 therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80.

[0401] Embodiment 82. The method of embodiment 81, wherein the disease is cancer.

[0402] Embodiment 83. A method of treating an MTAP nul cancer in a patient comprising administering to the patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80.

[0403] Embodiment 84. 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 therapeuticaly efective amount of a compound or pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80.

[0404] Embodiment 85. A method of treating cancer in a patient comprising administering to the patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80.

[0405] Embodiment 86. The method of any one of embodiments 82 to 85, wherein the cancer is an MTAP-deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0406] Embodiment 87. The method of embodiment 82 or 86, wherein the cancer is deficient in CDKN2A.

[0407] Embodiment 88. The method of any one of embodiments 82 to 87, wherein the cancer is a solid tumor.

[0408] Embodiment 89. The method of embodiment 88, wherein the solid tumor is malignant.

[0409] Embodiment 90. The method of embodiment 82 to 89, wherein the patient is in recognized need of such treatment.

[0410] Embodiment 91. The method of any one of embodiments 82 to 90, 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 cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undiferentiated pleiomorphic sarcoma, lymphoma (e.g., difuse large B-cel lymphoma (DLBCL), leukemia, head and neck cancer (e.g., head and neck squamous cel carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0411] Embodiment 92. The method of any one of embodiments 82 to 90, wherein the cancer is selected from the group consisting of leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-smal cel 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.

[0412] Embodiment 93. The method of any one of embodiments 82 to 90, wherein the cancer is selected from the group consisting of non-smal cel lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

[0413] Embodiment 94. A compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80, for use in therapy.

[0414] Embodiment 95. A compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80, for use in the treatment cancer.

[0415] Embodiment 96. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of embodiment 95, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0416] Embodiment 97. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of embodiment 95 or 96, wherein said cancer is deficient in CDKN2A.

[0417] Embodiment 98. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 95 or 97, wherein said cancer is an MTAP nul cancer.

[0418] Embodiment 99. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 95 to 97, 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.

[0419] Embodiment 100. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 95 to 99, wherein said cancer is a solid tumor.

[0420] Embodiment 101. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of embodiment 100, wherein the solid tumor is malignant.

[0421] Embodiment 102. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 95 to 101, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undiferentiated pleiomorphic sarcoma, lymphoma (e.g., difuse large B-cel lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cel carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0422] Embodiment 103. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 95 to 101, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-smal cel 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.

[0423] Embodiment 104. Use of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80, in the manufacture of a medicament for use in therapy.

[0424] Embodiment 105. Use of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80, in the manufacture of a medicament for use in the treatment of cancer.

[0425] Embodiment 106. The use of embodiment 105, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0426] Embodiment 107. The use of embodiment 105 or 106, wherein said cancer is deficient in CDKN2A.

[0427] Embodiment 108. The use of any one of embodiments 105 to 107, wherein said cancer is an MTAP nul cancer.

[0428] Embodiment 109. The use of any one of embodiments 105 to 107, 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.

[0429] Embodiment 110. The use of any one of embodiments 105 to 109, wherein said cancer is a solid tumor.

[0430] Embodiment 111. The use of embodiment 110, wherein said solid tumor is malignant.

[0431] Embodiment 112. The use of any one of embodiments 105 to 111, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladderurothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undiferentiated pleiomorphic sarcoma, lymphoma (e.g., difuse large B-cel lymphoma (DLBCL), leukemia, head and neck cancer (e.g., head and neck squamous cel carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0432] Embodiment 113. The use of any one of embodiments 105 to 111, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-smal cel 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.

[0433] Embodiment 114. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80.

[0434] Embodiment 115. A method of inhibiting cel proliferation, in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80.

[0435] Embodiment 116. A method for inhibiting PRMT5 activity in a cel, comprising contacting the cel in which inhibition of PRMT5 activity is desired with an efective amount of a compound or pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 79, or a pharmaceutical composition of embodiment 80. EXAMPLES

[0436] The folowing examples are put forth so as to provide those of ordinary skil in the art with a complete disclosure and description of how 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 the experiments below were performed or that they are al of the experiments that may be performed. It is to be understood that exemplary descriptionswriten 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. Eforts 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 PdCl2(dppf)-DCM adduct - paladium chloride-1,1-ferrocenediyl-bis(diphenylphosphino)- dichloromethane adduct K2CO3 – potassium carbonate APhos Pd G3 – paladium G3-(4-(N,N-Dimethylamino)phenyl)di-tert-butylphosphine, [4- (Di-tert-butylphosphino)-N,N-dimethylaniline-2-(2′-aminobiphenyl)]paladium(I) methanesulfonate dppf Pd G3 – methanesulfonato 1,1-ferocenediyl-bis(diphenylphosphino) (2′-amino-1,1′- biphenyl-2-yl) paladium(I) DI H2O – deionized water (4,4′-dtbbpy)NiCl2 – [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (I) dichloride [Ir(dtbbpy)(ppy)2]PF6 – [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[2-(2- pyridinyl-N)phenyl-C]iridium(II) hexafluorophosphate Aminosupersilane – N-(Adamantan-1-yl)-1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2- amine DPPF Pd G3 - Methanesulfonato 1,1-ferocenediyl-bis(diphenylphosphino) (2′-amino-1,1′- biphenyl-2-yl) paladium(I) Na2CO3 – sodium carbonate AcCN – acetonitrile TsOH - p-Toluenesulfonic acid i-PrOH – isopropanol THF – tetrahydrofuran DMF – N,N-dimethylformamide DCM –dichloromethane TFA – trifluoroacetic acid NaH - sodium hydride TIPSOTf - Trisopropylsilyl trifluoromethanesulfonateNH4Cl – ammonium chloride EtOAC – ethyl acetate DBU - 1,8-diazabicyclo(5.4.0)undec-7-ene Synthesis Examples Carboxylic Acid (CA) intermediate synthesis Intermediate # Structure Intermediate # Structure CA1 CA1 isomer 1,,, y [1,4]oxazino[4,3-c]quinazoline-10-carboxylic acid and (R)-6-amino-9-fluoro-1,3,4,11b- tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylic acidStep 1: methyl 4-ami

[0437] To a stired solution of (200 g, 1.18 mol) inCHCl3 (2.5 L) was added N- g, 1.18 mol) in portions at 0 °C. The resulting mixture was stired 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 aford methyl 4- amino-5-bromo-2-fluorobenzoate (256 g, 87%) as a white solid. MS ESI calculated for CH + 8 7BrFNO2 [M+H], 247.96, 249.96; found, 248.00, 250.00. Step 2: methyl 5-bromo-4-(tert-butoxycarbonyl)amino)-2-fluorobenzoate

[0438] A solution of methyl(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 stired at 40 ℃ 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 aford methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-2- fluorobenzoate (35 g, 47%) as a white solid. MS ESI calculated for C + 13H15BrFNO4 [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-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate

[0439] To a stired mixture of methyl 5-bromo-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)Cl2 (4.20 g, 5.74 mmol) at room temperature. The resulting mixture was stired at 100 ℃ 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 aford 32.00 g white solid. The residue was further purified by trituration with petroleum ether to aford methyl 4-((tert-butoxycarbonyl)amino)-2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (30.8 g, 68%) as a white solid. MS ESI calculated for C H BFNO + 19 27 6 [M+H], 396.19; found, 396.10. Step 4: tert-butyl 5-(2-(tert-butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)- 2,3-dihydro-4H-1,4-oxazine-4-carboxylate

[0440] To a stired mixture ofamino]-2-fluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (30.8 g, 77.9 mmol) and tert-butyl 5- (diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-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)Cl2.CH2Cl2 (6.4 g, 7.8 mmol) at room temperature. The resulting mixture was stired at 100 ℃ 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- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)-2,3-dihydro-4H-1,4-oxazine- 4-carboxylate (18.9 g, 54%) as an of-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-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate and tert-butyl (R)-3-(2-(tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate

[0441] To a stired 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 stired at 50 ℃ 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 aford a 1:1 mixture of tert-butyl (S)-3-(2-(tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)morpholine-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 C H FNO [M+H]+, 455 1 22 31 2 7 .21; found, 455.30.H NMR (400 MHz, Chloroform-d) δ 9.19 (br, 1H), 8.59 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 14.2 Hz, 1H), 5.04 (d, J = 3.9 Hz, 1H), 4.34 (d, J = 12.1 Hz, 1H), 3.99 (dd, J = 11.1, 3.1 Hz, 1H), 3.96 – 3.88 (m, 4H), 3.77 – 3.69 (m, 1H), 3.65 – 3.56 (m, 1H), 3.11 – 3.02 (m, 1H), 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

[0442] To a stired(tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate and tert-butyl (R)-3-(2-(tert-butoxycarbonyl)amino)-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 stired 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 NaHCO3 (aq). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to aford 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 C + 12H15FN2O3 [M+H], 255.11; found, 255.20.Step 7: 1:1 mixture of methyl (S)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylate and methyl (R)-6-amino-9-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylate

[0443] A 1:1 3-yl)benzoate andmethyl (R)-4- and BrCN (1.46 g, 15.8 mmol) in 1,4-dioxane (40 mL) was stired at 80 ℃ 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-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline- 10-carboxylate and methyl (R)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylate (3.05 g, 71%) as a white solid. MS ESI calculated for C H14FN3O3 [M + 13 +H], 280.10; found, 280.15. Step 8: 1:1 mixture of (S)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylic acid and (R)-6-amino-9-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylic acid (CA1)

[0444] To a stired9-fluoro-1,3,4,11b- tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate and methyl (R)-6-amino-9-fluoro- 1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate (3.05 g, 10.92 mmol) in THF (40 mL), MeOH (20 mL) and H2O (20 mL) was added LiOH (780 mg, 32.76 mmol) at room temperature. The resulting mixture was stired at 40 ℃ for 3 h. The organic solvents were removed under reduced pressure. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was filtered, and the filter cake was washed with H2O to aford a 1:1 mixture of (S)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10- carboxylic acid and (R)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylic acid (1.80 g, 62%) as a white solid. MS ESI calculated for C H FNO [M+H]+, 266 1 12 12 3 3 .09; found, 266.20.H NMR (400 MHz, DMSO-d6) δ 12.63 (br,1H), 8.42 (br, 2H), 7.73 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 11.4 Hz, 1H), 4.96 – 4.90 (m, 1H), 4.23 – 4.11 (m, 2H), 3.95 – 3.88 (m, 1H), 3.66 – 3.54 (m, 2H), 3.31 – 3.24 (m, 1H). Intermediates CA1 isomer 1 and CA1 isomer 2: (R)-6-amino-9-fluoro-1H,3H,4H,11bH- [1,4]oxazino[4,3-c]quinazoline-10-carboxylic acid, isomer 1 and (S)-6-amino-9-fluoro- 1H,3H,4H,11bH-[1,4]oxazino[4,3-c]quinazoline-10-carboxylic acid, isomer 2 Step 1: tert-(methoxycarbonyl)phenyl)morpholine-4-carboxylate, isomer 1 and tert-butyl (S)-3-(2-(tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate, isomer 2

[0445] The-4-fluoro-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate (10.00 g, 22.00 mmol) was separated by Prep-Chiral-SFC with the folowing conditions [Column: (S, S)-Whelk-O 15μm Kromasil, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 100 mL / min; Gradient: isocratic 20% B; RT1(min): 5; RT2(min): 7; Sample Solvent: MEOH; Injection Volume: 3.5 mL; Number Of Runs: 70] to aford tert-butyl (R)-3-(2-((tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate, isomer 1 (4.40 g, 44%) as a white solid with the first peak on Chiral SFC and tert-butyl (S)-3- (2-(tert-butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)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]+, 455.21; found, 455.15. Step 2: methyl (R)-4-amino-2-fluoro-5-(morpholin-3-yl)benzoate, isomer 1

[0446] To a stired 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 TFA (10 mL) at room temperature. The resulting mixture was stired 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 NaHCO3 (aq.). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to aford tert-butyl (R)-3-(2-((tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)morpholine-4-carboxylate, isomer 1 (3.20 g, crude) as a brown solid. MS ESI calculated for C + 12H15FN2O3 [M+H], 255.11; found, 255.10. Step 3: methyl (R)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline- 10-carboxylate, isomer 1

[0447] A mixture of methyl (R)-4-amino-2-fluoro-5-(morpholin-3-yl)benzoate, isomer 1 (3.20 g, crude) and BrCN (1.33 g, 12.59 mmol) in 1,4-dioxane (35 mL) was stired at 80 ℃ for 16 h. After cooling down, the reaction mixture was filtered, and the filter cake was colected and washed with 1,4-dioxane to affordmethyl (R)-6-amino-9-fluoro-1,3,4,11b- tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate, isomer 1 (2.57 g, 73%) as a white solid. MS ESI calculated for C + 13H14FN3O3 [M+H], 280.10; found, 280.10. Step 4: (R)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10- carboxylic acid, isomer 1 (CA1 isomer 1)

[0448] To a stired mixture of methyl (R)-6-amino-9-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylate, isomer 1 (2.57 g, 9.20 mmol) in MeOH (10 mL), THF (20 mL) and H2O (10 mL) was added LiOH (660 mg, 27.6 mmol) at room temperature. The resulting mixture was stired at 40 ℃ for 2 h. The reaction solution was concentrated under reduced pressure. The mixture was acidified to pH 6 with HCl (2 N). The resulting mixture was filtered, and the filter cake was colected and washed with H2O to aford (R)-6-amino-9-fluoro-1,3,4,11b-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, 266.00.1H NMR (300 MHz, DMSO-d6) δ 12.38 (br, 1H), 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, 1H), 3.94 (dd, J = 11.0, 3.3 Hz, 1H), 3.86 – 3.75 (m, 2H), 3.57 – 3.40 (m, 2H), 3.15 – 3.04 (m, 1H). Step 5: methyl (S)-4-amino-2-fluoro-5-(morpholin-3-yl)benzoate, isomer 2

[0449] To a stired 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 mL) was added TFA (10 mL) at room temperature. The resulting mixture was stired 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 NaHCO3 (aq.). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to aford 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+H]+, 255.11; found, 255.15. Step 6: methyl (S)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10- carboxylate, isomer 2

[0450] A mixture of methyl (S)-4-amino-2-fluoro-5-(morpholin-3-yl)benzoate, isomer 2 (2.90 g, crude) and BrCN (1.21 g, 11.41 mmol) in 1,4-dioxane (35 mL) was stired at 80 ℃ for 16 h. After cooling down, the reaction mixture was filtered, and the filter cake was washed with 1,4-dioxane to aford methyl (S)-6-amino-9-fluoro-1,3,4,11b-tetrahydro- [1,4]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-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10- carboxylic acid, isomer 2 (CA1 isomer 2)

[0451] To a stired mixture of methyl (S)-6-amino-9-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylate, isomer 2 (2.74 g, 9.81 mmol) in MeOH (10 mL), THF (20 mL) and H2O (10 mL) was added LiOH (700 mg, 29.43 mmol) at room temperature. The resulting mixture was stired at 40 ℃ for 2 h. The reaction solution was concentrated under reduced pressure. The mixture was acidified to pH 6 with HCl (2 N). The resulting mixture was filtered, and the filter cake was colected and washed with H2O to aford (S)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]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, 266.00.1H NMR (300 MHz, DMSO-d6) δ 12.38 (br, 1H), 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, 1H), 3.94 (dd, J = 11.0, 3.3 Hz, 1H), 3.86 – 3.75 (m, 2H), 3.57 – 3.40 (m, 2H), 3.15 – 3.04 (m, 1H).

[0452] The absolute stereochemistry of CA1 isomer 2 was determined by single crystal X- ray crystalography. The absolute stereochemistry of CA1 isomer 2 was further confirmed by crystalography based on the co-crystal structure of selected compounds disclosed herein with PRMT5 enzyme, where the compounds were prepared using CA1 isomer 2. As such, CA1 isomer 2 has the S-configuration represented by:.

[0453] Accordingly, the CA1 isomer 1 has the R-configuration represented by:. Intermediate CA2: 1:1 mixture of (S)-6-amino-8-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylic acid and (R)-6-amino-8-fluoro-1,3,4,11b- tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylic acid Step 1: methyl 4-2-yl)benzoate)

[0454] To a stired solution5-fluorobenzoate (50.00 g, 201.6 mmol) in dioxane (500 mL) were sequentialy added BPD (76.8 g, 302.4 mmol), AcOK (59.4 g, 604.7 mmol) and Pd(dppf)Cl2 (14.75 g, 20.15 mmol). The resulting solution was stired at 80 oC 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 Na2SO4. The residue was purified by trituration with ethyl ether. The precipitated solids were colected by filtration and washed with petroleum ether to afordmethyl 4-amino-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (23.93 g, 24%) as a grey solid. MS ESI calculated for C + 14H19BFNO4 [M+H], 296.14; found, 296.00. Step 2: tert-butyl 3-[2-amino-3-fluoro-5-(methoxycarbonyl)phenyl]-5,6-dihydro-oxazine-4- carboxylate

[0455] To a solution of tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate g, (100 mL) and H2O (25 mL) were sequentialy added tert-butyl 3-[(diphenoxyphosphoryl)oxy]-5,6-dihydro-oxazine-4- carboxylate (8.72 g, 20.11 mmol), K3PO4 (11.7 g, 54.9 mmol) and Pd[(t-Bu)3P]2 (0.93 g, 1.82 mmol). The resulting mixture was stired at 65 ℃ for 16 h under nitrogen atmosphere. The mixture was quenched with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to aford tert-butyl 3-[2-amino-3-fluoro-5-(methoxycarbonyl)phenyl]-5,6- dihydro-oxazine-4-carboxylate (2.70 g 33%) as a yelow solid. MS ESI calculated for C17H21FN2O5 [M-100+H]+, 353.14; found, 353.25. Step 3: methyl 4-amino-3-(5,6-dihydro-2H-1,4-oxazin-3-yl)-5-fluorobenzoate

[0456] A solution of tert-butyl(methoxycarbonyl)phenyl]-5,6- dihydro-oxazine-4-carboxylate (1.45 g, 4.11 mmol) in DCM (10 mL) and TFA (5 mL) was stired at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to aford methyl 4-amino-3-(5,6-dihydro-2H-1,4-oxazin-3-yl)-5-fluorobenzoate (2.55 g, crude) as a brown oil. MS ESI calculated for C + 12H15FN2O2 [M+H], 253.09; found, 253.10. Step 4: 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

[0457] To a stired s H-1,4-oxazin-3-yl)-5- fluorobenzoate (2.55 g, 10.109 mmol) in DCM (25 mL) was added NaBH(AcO)3 (4.29 g, 20.3 mmol) at 0 °C. The resulting mixture was stired at 40 °C for 4 h. The mixture was quenched with water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography with 0-100% EtOAc in petroleum ether to aford 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 (210 mg g, 6%) as a brown solid. MS ESI calculated for C12H15FN2O3 [M+H]+, 255.11; found, 255.10. Step 5: 1:1 mixture of methyl (S)-6-amino-8-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylate and methyl (R)-6-amino-8-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylate

[0458] To a3-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 stired at 80 °C for 16 h. The precipitated solids were colected by filtration and washed with EtOAc to afford a 1:1 mixture of methyl (S)-6-amino-8-fluoro- 1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate and methyl (R)-6-amino- 8-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate (626 mg, 90%) as a white solid. MS ESI calculated for C H FNO [M+H]+, 280.10; found, 280. 1 13 14 3 3 20.H NMR (400 MHz, DMSO-d6) δ 8.05 (br, 2H), 7.79 – 7.75 (m, 2H), 5.07 (dd, J = 10.4, 3.2 Hz, 1H), 4.24 (dd, J = 11.2, 3.2 Hz, 1H), 4.07 (d, J = 13.2 H, 1H), 3.97 (dd, J = 12.0, 3.2 Hz, 1H), 3.85 (s, 3H), 3.69 – 3.59 (m, 2H), 3.41 – 3.31 (m, 1H).Step 6: 1:1 mixture of (S)-6-amino-8-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylic acid and (R)-6-amino-8-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylic acid (CA2)

[0459] To a stired 8-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate and methyl (R)-6-amino-8-fluoro- 1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate (630 mg, 2.25 mmol) in THF (4 mL) and H2O (1 mL) was added LiOH (108 mg, 4.51 mmol) at room temperature. The resulting mixture was stired at 40 °C for 16 h. The mixture was acidified to pH 5 with HCl (2 M). The precipitated solids were colected by filtration and dried under vacuum to aford a 1:1 mixture of (S)-6-amino-8-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylic acid and (R)-6-amino-8-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylic acid (325 mg, 46%) as a white solid. MS ESI calculated for C H FNO [M+H]+, 266.09; found, 266. 1 12 12 3 3 20.H NMR (400 MHz, DMSO-d6) δ 7.37 (dd, J = 11.6, 2.0 Hz, 1H), 7.32 (s, 1H), 6.70 (s, 2H), 4.68 (dd, J = 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-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylic acid and (R)-6-amino-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylic acid Step 1: tert-butyl 5-oxazine-4-carboxylate

[0460] To a stired 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 stired 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 alowed to warm slowly to 25 °C and stired for 6 h under nitrogen. The reaction mixture was quenched by the addition of sat. NH4Cl (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 Na2SO4. 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 aford tert-butyl 5- (diphenylphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (69 g, 58.3%) as a colorless oil. Step 2: methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0461] To a stired mixture(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)Cl2.CH2Cl2 (1.77 g, 2.17 mmol). The resulting mixture was stired at 100 ℃ 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 aford methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate (6.00 g, 65%) as an orange solid. MS (ESI) calculated for (C H B + 14 20 NO4) [M+H], 278.15; found, 278.20. Step 3: methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0462] To a stired mixture oftetramethyl-1,3,2-dioxaborolan- 2-yl)benzoate (5.90 g, 21.3 mmol) and tert-butyl 3-[(diphenylphosphoroso)oxy]-5,6-dihydro- oxazine-4-carboxylate (7.12 g, 17.7 mmol) in MeCN (60 mL) and H2O (15 mL) were addedPd[(t-Bu)3P]2 (0.91 g, 1.77 mmol) and K3PO4 (11.30 g, 53.2 mmol). The resulting mixture was stired at 65 ℃ 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 Na2SO4. 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 of-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-amino-5-(methoxycarbonyl)phenyl)morpholine-4- carboxylate and tert-butyl (R)-3-(2-amino-5-(methoxycarbonyl)phenyl)morpholine-4- carboxylate

[0463] To aphenyl]-5,6- dihydro-oxazine-4-carboxylate (650 mg, 1.94 mmol) in MeOH (5 mL) were added Pd / C (47.6 mg, 10%) and Pd(OH)2 / C (240 mg, 20%). The resulting mixture was stired at 25 ℃ for 16 h under hydrogen atmosphere (1 atm). The resulting mixture was filtered, the filter cake was washed with CH2Cl2. The filtrate was colected and concentrated under reduced pressure to aford a 1:1 mixture of tert-butyl (S)-3-(2-amino-5- (methoxycarbonyl)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 (C H NO) [M+H]+ 17 24 2 5 , 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

[0464] To a stiredamino-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate and tert-butyl (R)-3-(2-amino-5- (methoxycarbonyl)phenyl)morpholine-4-carboxylate (680 mg, crude) in DCM (6 mL) wasadded TFA (2 mL) dropwise at 25 ℃. The resulting mixture was stired at 25 ℃ for 16 h. The resulting mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to aford 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, 84%) as a brown solid. MS (ESI) calculated for (C12H16N2O3) [M+H]+, 237.12; found, 237.20. Step 6: 1:1 mixture of methyl (S)-6-amino-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylate and methyl (R)-6-amino-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxylate

[0465] To a 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 stired at 80 ℃ for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the folowing 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 aford a 1:1 mixture of methyl (S)-6-amino-1,3,4,11b- tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate and methyl (R)-6-amino-1,3,4,11b- tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate (300 mg, 68%) as an of white solid. MS (ESI) calculated for (C13H15N3O3) [M+H]+, 262.11; found, 262.05. Step 7: 1:1 mixture of (S)-6-amino-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10- carboxylic acid and (R)-6-amino-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10- carboxylic acid (CA3)

[0466] To a stired1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxylate and methyl (R)-6-amino-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxylate (250 mg, 0.96 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH (46 mg, 1.91 mmol) slowly at 25 ℃. The resulting mixture was stired for at 25 ℃ 16 h. The resulting mixture was concentrated under reduced pressure to aford a 1:1 mixture of (S)-6-amino-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10- carboxylic acid and (R)-6-amino-1,3,4,11b-tetrahydro-[1,4]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, 248.25.1H NMR (400 MHz, DMSO-d6) δ 7.57 (dd, J = 8.1, 1.8 Hz, 1H), 7.42 (s, 1H), 6.50 (d, J = 8.0 Hz, 1H), 4.48 (dd, J = 10.0, 3.2 Hz, 1H), 3.95 (dd, J = 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-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acidStep-1: methyl 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2- carboxylate

[0467] A mixture of methyl 5-(25.00 g, 164.31 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (31.54 g, 246.46 mmol) in anhydrous THF (200 mL) was stired 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(COD)(OMe)]2 (1.63 g, 2.47 mmol) in anhydrous THF (200 mL) at 25 °C under nitrogen atmosphere. The mixture was stired 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 aford methyl 5-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-2-carboxylate (62.4 g, crude) as a brown solid. MS (ESI) calculated for(C13H19BN2O4) [M+H]+, 279.14; found, 279.15.1H NMR (400 MHz, Chloroform-d) δ 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-yl]-5,6-dihydro-oxazine-4- carboxylate

[0468] A mixture of methyl 1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate g, , 3-[(diphenoxyphosphoryl)oxy]- 5,6-dihydro-oxazine-4-carboxylate (37.79 g, 87.19 mmol), Pd(dppf)Cl2 (6.38 g, 8.72 mmol) and K2CO3 (24.10 g, 174.39 mmol) in dioxane (1000 mL) and H2O (200 mL) was stired at 90 °C for 2 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 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 tert- butyl 3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]-5,6-dihydro-oxazine-4-carboxylate (19.3 g, 33%) as a brown solid. MS (ESI) calculated for (C + 16H21N3O5) [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

[0469] To a4-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 Paladium hydroxide (20% active on carbon, nominaly 50% water) (4.19 g) were added to above mixture. The mixture was stired at 50 oC for 16 h under hydrogen atmosphere (30 atm.). The resulting mixture was filtered, the filter cake was washed with methanol. The filtrate was colected and concentrated under reduced pressure to aford a 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 (18.2 g, crude) as a yelow solid. MS (ESI) calculated for (C + 16H23N3O5) [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- morpholine-4-carboxylate

[0470] The racemic 2-(methoxycarbonyl)pyridin-4-yl]morpholine-4-carboxylate (19.00 g) was separated by prep-chiral SFC with the folowing conditions: [Column: CHIRAL ART Celulose-SZ, 5*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 200 mL / min; Gradient: isocratic 60% B; Wave Length: 220 nm; RT1(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]morpholine-4-carboxylate (8.7 g, 45%) as a brown solid with the second peak on Chiral SFC. MS (ESI) calculated for (C + 16H23N3O5) [M+H], 338.16; found, 338.15. Step-5: methyl 5-amino-4-[(3R)-morpholin-3-yl]pyridine-2-carboxylate (6)

[0471] To a stired solution of2-(methoxycarbonyl)pyridin-4- yl]morpholine-4-carboxylate (8.50 g, 25.14 mmol) in DCM (75 mL) was added trifluoroacetic acid (25 mL) at 25 oC. The resulting solution was stired at 25 oC for 2 h. The solvents were removed under vacuum to aford methyl 5-amino-4-[(3R)-morpholin-3-yl]pyridine-2-carboxylate (17.8 g, crude) as a brown oil. MS (ESI) calculated for (C11H15N3O3) [M+H]+, 238.11; found, 238.05. Step-6: methyl (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carboxylate

[0472] To a stired solution -morpholin-3-yl]pyridine-2-carboxylate (17.8 g, crude from (400 mL) was added carbononitridic bromide (7.95 g, 75.02 mmol) at 25 oC. The resulting solution was stired at 80 oC for 16 h. The precipitated solid was colected by filtration and washed with isopropanol to aford methyl (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carboxylate (5.4 g, 26%) as a white solid. MS (ESI) calculated for (C H + 12 14N4O3) [M+H], 263.11; found, 263.10. Step-7: (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10- carboxylic acid (CA4)

[0473] To a stired mixture of methyl (R)-6-amino-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate (5.40 g, 20.59 mmol) in THF (40 mL) and H2O (20 mL) was added LiOH (1.48 g, 61.77 mmol) at 25 °C. The resulting mixture was stired at 25 oC for 1 h. The organic solvent was removed under vacuum. The aqueous layer was acidified with HCl (6 N) to pH ~6. The suspension was filtered through paper. The filter cake was colected and dried under vacuum to aford (R)-6- amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (5.00 g, 90%) as a white solid. MS (ESI) calculated for (C11H12N4O3) [M+H]+, 249.09; found, 249.10.1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.54 (s, 1H), 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, 1H), 3.56 – 3.42 (m, 2H), 3.11 – 3.00 (m, 1H).

[0474] The absolute stereochemistry of CA4 was determined by crystalography based on the single-crystal X-ray structure of compound 22 that was prepared using intermediate CA4. Intermediate CA4 (Method 2): (R)-6-amino-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid Step-1: (R)-N-[(1E)-2-[(tert--2-methylpropane-2- sulfinamide

[0475] To a stired solution of 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 CuSO4 (114.45 g, 717.09 mmol) at 20 °C. The resulting solution was stired at 20 °C for 16 h. The suspension was filtered through celite. The filtrate was colected and concentrated under vacuum. The residue was purified by flash column chromatography with 0–50% ethyl acetate in petroleum ether to aford (R)-N-[(1E)-2-[(tert-butyldimethylsilyl)oxy]ethylidene]-2- methylpropane-2-sulfinamide (62.00 g, 77%) as a colorless oil. MS ESI calculated for C H27NO + 12 2SSi [M+H], 278.15;Step-2: tert-butyl (4-(R)-2-(tert-butyldimethylsilyl)oxy)-1-((R)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate tert-butyl (4-(S)-2-((tert-butylsulfinyl)amino)ethyl)-6- chloropyridin-3-yl)carbamate

[0476] To a stired solution of yridin-3-yl)carbamate (20.00 g, 87.46 mmol) and N,N,N',N'-Tetramethylethylenediamine (30.49 g, 262.37 mmol) in Diethyl ether (400 mL) was added butylithium (1.6 M in n-hexane) (164 mL, 262.40 mmol) dropwise at - 78 °C under nitrogen atmosphere. The resulting mixture was stired at -78 °C for 1 h under nitrogen atmosphere. Then a solution of (R)-N-[(1E)-2-[(tert- butyldimethylsilyl)oxy]ethylidene]-2-methylpropane-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 stiring for 16 h. The reaction was quenched with water at 0 oC. 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 flash column chromatography with 0–30% ethyl acetate in petroleum ether to aford tert-butyl (4-(R)-2-(tert-butyldimethylsilyl)oxy)-1- ((R)-tert-butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate (24.7 g, 55%) as a yelow oil and tert-butyl (4-(S)-2-(tert-butyldimethylsilyl)oxy)-1-((R)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate (8.80 g, 19%) as a yelow oil. MS ESI calculated for C22H40ClN3O4SSi [M+H]+, 506.22; found, 506.25.

[0477] tert-butyl (4-(R)-2-((tert-butyldimethylsilyl)oxy)-1-((R)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate : MS ESI calculated for C H ClNOSSi [M+H]+, 506. 1 22 40 3 4 22; found, 506.25.H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.43 (s, 1H), 7.54 (s, 1H), 5.29 (d, J = 6.4 Hz, 1H), 4.71 (q, J = 6.0 Hz, 1H), 3.87 – 3.77 (m, 2H), 1.46 (s, 9H), 1.12 (s, 9H), 0.82 (s, 9H), -0.02 (s, 3H), -0.03 (s, 3H).

[0478] tert-butyl (4-(S)-2-((tert-butyldimethylsilyl)oxy)-1-((R)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate: MS ESI calculated for C H ClNOSSi [M+H]+, 506.22; found, 506. 1 22 40 3 4 25.H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.40 (s, 1H), 7.61 (s, 1H), 5.86 (d, J = 8.2 Hz, 1H), 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

[0479] A mixture of tert-butyl ( imethylsilyl)oxy)-1-((R)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate (12.10 g, 23.94 mmol) and HCl (4M in dioxane) (15 mL) was stired at 25 oC for 1 h. The organic solvent was removed under vacuum. The residue was triturated with Et2O to aford (2R)-2-amino-2-(5-amino-2- chloropyridin-4-yl)ethanol hydrochloride (6.00 g, crude) as a yelow solid. MS ESI calculated for C7H10ClN3O [M+H]+,188.05; found, 188.10. Step-4: N-[(1R)-1-(5-amino-2-chloropyridin-4-yl)-2-hydroxyethyl]-2-chloroacetamide

[0480] To a stired solution of2-chloropyridin-4-yl)ethanol hydrochloride (6.00 g, 26.78 mmol) in DCM (400 mL) was added Et3N (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 oC. The resulting solution was stired at 25 oC for 16 h. The organic solvent was removed under vacuum. The residue was purified by flash column chromatography with 0– 15% methanol in dichloromethane to afford N-[(1R)-1-(5-amino-2-chloropyridin-4-yl)-2- hydroxyethyl]-2-chloroacetamide (5.40 g, 85% over two steps) as a yelow solid. MS ESI calculated for CH Cl + 9 11 2N3O2 [M+H], 264.02; found, 264.10. Step-5: (5R)-5-(5-amino-2-chloropyridin-4-yl)morpholin-3-one

[0481] To a stired solution of N-[chloropyridin-4-yl)-2-hydroxyethyl]- 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 stired at 20 °C for 16 h. The reaction was quenched by the addition of NH4Cl (sat.). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried overanhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to aford (5R)-5-(5-amino-2-chloropyridin-4-yl)morpholin-3-one (1.80 g, 20%) as a yelow solid. MS ESI calculated for C9H10ClN3O2 [M+1]+, 228.04; found, 228.15. Step-6: 6-chloro-4-[(3R)-morpholin-3-yl]pyridin-3-amine

[0482] To a stired mixture of 4-yl)morpholin-3-one(1.46 g, 6.41 mmol) and boron (2.73 g, 19.24 mmol) in THF (20 mL) was added NaBH4 (73 mg, 19.24 mmol) in portions at 0 oC under nitrogen atmosphere. The resulting mixture was stired at 40 °C for 16 h under nitrogen atmosphere. The mixture was alowed to cool down to room temperature. The reaction was quenched by water at room temperature. The mixture was acidified to pH 2 with HCl (4 M). The aqueous layer was extracted with EtOAc. The aqueous layer was colected and basified to pH 9 with Na2CO3 (sat.). The nixture was extracted with EtOAc. The organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to aford 6- chloro-4-[(3R)-morpholin-3-yl]pyridin-3-amine (320 mg, crude) as a yelow solid, which was used in next step without further purification. MS ESI calculated for C + 9H12ClN3O [M+1], 214.06; found, 214.25. Step-7: (R)-10-chloro-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazin-6- amine

[0483] A mixture of 6-chloro-4-[3-amine (320 mg, 1.50 mmol) and carbononitridic bromide (159 mg, 1.50 mmol) in 1,4-dioxane (5 mL) was stired 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 colected by filtration and dried under vacuum to afford (R)-10-chloro-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazin-6-amine (290 mg, 81%) as a yelow solid. MS ESI calculated for C + 10H11ClN4O [M+H], 239.06; found, 239.15.Step-8: (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10- carbonitrile

[0484] To a stired mixture oftetrahydropyrido[3',4':4,5]pyrimido (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 stired at 130 °C for 1 h under nitrogen atmosphere. The reaction mixture was applied to a 40 g C18 column and purified by Combi Flash (Biotage Isolera Prime), eluted with 5~70% acetonitrile in water (10 mM NH4HCO3) to aford (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10- carbonitrile (230 mg, 45%) as a light yelow solid. MS ESI calculated for C11H11N5O [M+H]+, 230.09; found, 230.25.1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.53 (s, 1H), 6.77 (s, 2H), 4.69 (dd, J = 10.4, 3.2 Hz, 1H), 4.21 – 3.98 (m, 1H), 3.92 – 3.73 (m, 2H), 3.58 – 3.43 (m, 2H), 3.12 – 3.00 (m, 1H). Step-9: (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10- carboxylic acid (CA4)

[0485] A mixture of (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carbonitrile (230 mg, 1.00 mmol) and HCl (conc., 3 mL) was stired at 80 oC for 2 h. The resulting mixture was concentrated under reduced pressure to aford (R)-6- amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (CA4) (250 mg, crude) as a yelow solid. MS ESI calculated for C + 11H12ClN4O3 [M+H], 249.09; found, 249.10.1H NMR (300 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.48 (s, 2H), 8.33 (s, 1H), 7.96 (s, 1H), 5.04 (dd, J = 10.5, 3.6 Hz, 1H), 4.28 (dd, J = 11.1, 3.3 Hz, 1H), 4.14 (d, J = 13.5 Hz, 1H), 3.97 – 3.92 (m, 1H), 3.78 – 3.54 (m, 2H), 3.43 – 3.13 (m, 1H).

[0486] 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 CA5: (4S,11bS)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid; and Intermediate CA6: (4S,11bR)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acidStep-1: tert-butyl (3S)-3-

[0487] 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-tert-butyl dicarbonate (28.52 g, 130.67 mmol) at room temperature. The mixture was stired 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 aford tert-butyl (3S)-3-methyl-5-oxomorpholine-4- carboxylate (17.31 g, 88%) as a colorless oil. MS ESI calculated for C H NO + 10 17 4 [M+H], 216.12; found, 216.15.1H NMR (400 MHz, Chloroform-d) δ 4.35 – 4.15 (m, 3H), 3.86 – 3.76 (m, 2H), 1.57 (s, 9H), 1.41 (d, J = 6.6 Hz, 3H). Step-2: tert-butyl (5S)-3-[(diphenoxyphosphoryl)oxy]-5-methyl-5,6-dihydro-oxazine-4- carboxylate

[0488] To a mixture of tert-butyl xomorpholine-4-carboxylate (17.30 g, 80.37 mmol) in THF (170 mL) was added LiHMDS (83 ml, 83.00 mmol, 1M in THF) dropwise at -30 °C under nitrogen atmosphere. After stiring at -30 °C for 1 h, a solution of diphenyl chlorophosphonate (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 alowed to warm to room temperature for 1 h with stiring. 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 aford tert-butyl (5S)-3-[(diphenoxyphosphoryl)oxy]-5-methyl-5,6- dihydro-oxazine-4-carboxylate (29.90 g, 83%) as a yelow solid. MS ESI calculated for C + 1 22H26NO7P [M+H], 448.14; found, 448.10.H NMR (400 MHz, DMSO-d6) δ 7.49 – 7.37 (m, 4H), 7.30 – 7.22 (m, 6H), 6.49 (d, J =Hz, 1H), 4.49 – 4.43 (m, 1H), 4.01 (dd, J = 11.2, 1.2 Hz, 1H), 3.61 (dd, J = 11.2, 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

[0489] To a stired solutionoxy]-5-methyl-5,6- dihydro-oxazine-4-carboxylate (30.50 g, 67.05 mmol) and methyl 5-amino-4-(4,4,5,5- tetramethyl-1,3,2-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(dppf)Cl2-CH2Cl2 (5.48 g, 6.70 mmol) at room temperature. The resulting mixture was stired 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 aford tert-butyl (5S)-3-[5-amino-2- (methoxycarbonyl)pyridin-4-yl]-5-methyl-5,6-dihydro-oxazine-4-carboxylate (11.50 g, 49%) as a yelow solid. MS ESI calculated for C + 1 17H23N3O5 [M+H], 350.16; found, 350.05.HNMR (400 MHz, DMSO-d6) δ 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, J = 10.8, 1.2 Hz, 1H), 3.90 (dd, J = 10.8, 2.8 Hz, 1H), 3.77 (s, 3H), 1.24 (d, J = 6.8 Hz, 3H), 1.05 (s, 9H). Step-4: methyl 5-amino-4-[(3R,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate and methyl 5-amino-4-[(3S,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate

[0490] To a pyridin-4-yl]-5-methyl-5,6- g, (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 stired at 60 °C for 16 h under hydrogen atmosphere (50 atm). The mixture was filtered through a Celite pad. The filtrate was colected and concentrated under vacuum. The 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-methylmorpholin-3-yl]pyridine-2-carboxylate (1.20 g, 31%) as a yelow solid with the first eluting peak and methyl 5-amino-4-[(3S,5S)-5-methylmorpholin-3-yl]pyridine- 2-carboxylate (2.20 g, 57%) as a white solid with the second eluting peak.

[0491] Methyl 5-amino-4-[(3R,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate: MS ESI calculated for C17H25N3O5 [M+H]+, 352.18; found, 352.15.1H NMR (400 MHz, DMSO- d6) δ 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).

[0492] Methyl 5-amino-4-[(3S,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate: MS ESI calculated for C H N + 1 17 25 3O5 [M+H], 352.18; found, 352.20.H NMR (400 MHz, DMSO- d6) δ 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, 1H), 1.24 (d, J = 6.6 Hz, 3H), 1.10 (s, 9H). Step-5a: methyl 5-amino-4-[(3S,5S)-5-methylmorpholin-3-yl]pyridine-2-carboxylate

[0493] To a mixture of tert-butyl (3S,5S)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]-5- methylmorpholine-4-carboxylate (2.20 g, 6.26 mmol) in DCM (25 mL) was added TFA (7 mL). The mixture was stired at room temperature for 1 h. The solvents were removed under vacuum. The residue was basified with NaHCO3 (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 aford methyl 5-amino-4-[(3S,5S)-5- methylmorpholin-3-yl]pyridine-2-carboxylate (1.51 g, crude) as a yelow solid. MS ESI calculated for C H NO [M+H]+, 252.13; fo 1 12 17 3 3 und, 252.15.H NMR (400 MHz, Methanol- d4) δ 8.11 (s, 1H), 8.01 (s, 1H), 4.17 (dd, J = 5.6, 3.6 Hz, 1H), 3.95 (dd, J = 11.8, 5.6 Hz, 1H), – = –carboxylate (1.51 g, crude from previous step) in isopropanol (20 mL) was added carbononitridic bromide (757 mg, 7.21 mmol). The mixture was stired at 80 °C for 16 h. The suspended solids were colected by filtration and dried under vacuum to afford methyl (4S,11bS)-6-amino-4-methyl-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carboxylate (1.35 g, crude) as a white solid. MS ESI calculated for C H NO [M+H]+, 272.12; found, 272. 1 13 16 4 3 10.H NMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 7.99 (s, 1H), 5.37 – 5.33 (m, 1H), 4.49 (dd, J = 11.4, 3.6 Hz, 1H), 4.20 – 4.09 (m, 1H), 3.98 (s, 3H), 3.93 – 3.81 (m, 2H), 3.78 – 3.67 (m, 1H), 1.55 (d, J = 6.9 Hz, 3H). Step-7a: (4S,11bS)-6-amino-4-methyl-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carboxylic acid (CA5)

[0495] To a mixture of methyl (4S,11bS)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]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 stired at 50 °C for 1 h. The organic solvent was removed under vacuum. The remaining aqueous layer was neutralized with HCl (aq., 2N) to pH ~7. The suspended solids were colected by filtration and dried under vacuum to aford (4S,11bS)-6-amino-4-methyl- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (CA5) (1.10 g, 60% over 3 steps) as a yelow solid. MS ESI calculated for C + 12H14N4O3 [M+H], 263.11; found, 263.10.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.02 (br, 2H), 7.82 (s, 1H), 5.19 (dd, J = 10.4, 3.6 Hz, 1H), 4.38 (dd, J = 11.2, 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).

[0496] The absolute stereochemistry of CA5 was determined by crystalography 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

[0497] To a mixture of tert-(methoxycarbonyl)pyridin-4-yl]-5- methylmorpholine-4-carboxylate (1.20 g, 3.41 mmol) in DCM (12 mL) was added TFA (4 mL). The mixture was stired at room temperature for 1 h. The solvents were removed under vacuum. The residue was basified with NaHCO3 (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 aford methyl 5-amino-4-[(3R,5S)-5- methylmorpholin-3-yl]pyridine-2-carboxylate (700 mg, crude) as a yelow solid. MS ESI calculated for C12H17N3O3 [M+H]+, 252.13; found, 252.15.1H NMR (400 MHz, Methanol- d4) δ 7.99 (s, 1H), 7.98 (s, 1H), 4.11 (dd, J = 10.4, 3.2 Hz, 1H), 3.90 (s, 3H), 3.79 (dd, J = 11.0, 3.2 Hz, 2H), 3.43 (t, J = 10.6 Hz, 1H), 3.19 (t, J = 10.6 Hz, 1H), 3.10 – 3.03 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H). Step-6b: methyl (4S,11bR)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate

[0498] To a mixture of methy 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 stired at 80 °C for 16 h. The suspension was filtered. The filter cake was colected and dried under vacuum to aford methyl (4S,11bR)-6-amino-4- methyl-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate (620 mg, crude) as a yelow solid. MS ESI calculated for C + 13H16N4O3 [M+H], 272.12; found, 272.10.1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 7.96 (s, 1H), 5.59 – 5.43 (m, 1H), 4.77 (dd, J = 10.8, 4.2 Hz, 1H), 4.44 (dd, J = 12.4, 3.2 Hz, 1H), 4.26 (t, J = 11.0 Hz, 1H), 4.16 – 4.14 (m, 1H), 3.98 (s, 3H), 3.77 (dd, J = 12.4, 3.0 Hz, 1H), 1.49 (d, J = 6.4 Hz, 3H). Step-7b: (4S,11bR)-6-amino-4-methyl-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carboxylic acid (CA6)

[0499] To a mixture of1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate (620 mg, 2.24 mmol) in THF (5 mL) and H2O (5 mL) was added LiOH (107 mg, 4.46 mmol). The mixture was stired at 50 °C for 1 h. The organic solvent was removed under vacuum. The remained aqueous layer was neutralized with HCl (aq., 2N) to pH ~7. The suspended solids were colected by filtration and dried under vacuum to aford (4S,11bR)-6-amino-4-methyl- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (CA6) (580 mg, 65% over 3 steps) as a yelow solid. MS ESI calculated for C + 12H14N4O3 [M+H], 263.11; found, 263.10.1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 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, J = 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-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acidStep-1:

[0500] To a pyridin-4-yl) g, was added trifluoroacetic acid (210 mL) at room temperature. The resulting mixture was stired at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to aford methyl (S)-5-amino-4-(morpholin-3-yl)picolinate (160 g, crude) as a yelow oil. MS ESI calculated for C + 12H16N2O3 [M+H], 238.11; found, 238.20. Step-2:

[0501] To(55.80 g, 235.18 mmol) in isopropanol (800 mL) was added Cyanogen bromide (26.16 g, 246.94 mmol). The resulting mixture was stired at 80 °C for 16 hours. The precipitated solids were colected by filtration and washed with isopropanol (500 mL), the solids were dried under vacuum to aford methyl (S)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]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:

[0502] To a stired mixture of methyl (S)-6-amino-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]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 stired at the room temperature for 1 hour. The organic solvent was removed under vacuum. The aqueous layer was acidified with HCl (6 M) to pH ~6. The suspended solids were colected by filtration, then wash by water. The filter cake was dried under vacuum to aford (S)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carboxylic acid (CA7) (13.3 g, 46% yield) as a white solid. MS ESI calculated for C H NO [M+H]+, 249.09; found, 2 1 11 12 4 3 49.20.H NMR (300 MHz, DMSO-d6) δ 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[6,1-c][1,4]oxazine-10-carboxylic acidStep-1:

[0503] To a stired solution of 2-(50.00 g, 286.84 mmol) in DCM (500 mL) were added (S)-2-methylpropane-2-sulfinamide (38.24 g, 315.52 mmol) (supplier: Accela ChemBio Co., Ltd. CAS# 343338-28-3) and CuSO4 (114.45 g, 717.09 mmol) at 20 °C. The resulting solution was stired at 20 °C for 16 h. The suspension was filtered through celite. The filtrate was colected and concentrated under vacuum. The residue was purified by flash column chromatography with 0–50% ethyl acetate in petroleum ether to aford (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2- methylpropane-2-sulfinamide (62 g, 77%) as a colorless oil. MS ESI calculated for C12H27NO2SSi [M+H]+, 278.15; found, 278.15. Step-2:

[0504] 0.00 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 stired 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 THF (50 mL) was added dropwise to above mixture at -78 °C. The resulting mixture was alowed to warm at room temperature with stiring for additional 16 h. The reaction was quenched with NH4Cl (sat.) at 0 oC. 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 flash column chromatography with 0–30% ethyl acetate in petroleum ether within 30 min to aford 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-butyldimethylsilyl)oxy)-1-((S)-tert-butylsulfinyl)amino)ethyl)-6- chloropyridin-3-yl)carbamate (13.1 g, 25%) as an orange oil.

[0505] tert-butyl (4-(S)-2-((tert-butyldimethylsilyl)oxy)-1-((S)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate: MS ESI calculated for C H ClNOSSi [ + 1 22 40 3 4 M+H], 506.22; found, 506.15.H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.43 (s, 1H), 7.55 (s, 1H), 5.29 (d, J = 6.4 Hz, 1H), 4.71 (q, J = 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).

[0506] tert-butyl (4-(R)-2-((tert-butyldimethylsilyl)oxy)-1-((S)-tert- butylsulfinyl)amino)ethyl)-6-chloropyridin-3-yl)carbamate: MS ESI calculated for C H ClNOSSi [M+H]+, 506. 1 22 40 3 4 22; found, 506.20.H NMR (400 MHz, DMSO-d6) δ 8.84 (s,1H), 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). Step-3:

[0507] A (S)-tert-- g, and HCl (4.0 M in 1,4-dioxane) (150 mL) was stired at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with Et2O (50 mL). The precipitated solids were colected by filtration and washed with Et2O to aford (S)-2-amino-2-(5-amino-2-chloropyridin-4-yl)ethan-1-ol hydrochloride (9.4 g, crude) as a brown solid. MS ESI calculated for C + 7H10ClN3O [M+H],188.05; found, 188.15. Step-4:

[0508] Toyl)ethan-1-ol hydrochloride (6.90 g, 36.78 mmol) and Et3N (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 stired 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 aford (S)-N-(1-(5-amino-2- chloropyridin-4-yl)-2-hydroxyethyl)-2-chloroacetamide (3.2 g, 32%) as a brown semi-solid. MS ESI calculated for CH ClNO [M+ + 9 11 2 3 2 H], 264.02; found, 264.00. Step-5:

[0509] To a stired l)-2-hydroxyethyl)-2- chloroacetamide (7.30 g, 27.64 mmol) in THF (30 mL) and isopropanol (120 mL) was added t-BuOK (12.41 g, 110.56 mmol) in portions at 0 °C. The resulting mixture was stired 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to aford (S)-5-(5-amino-2-chloropyridin-4-yl)morpholin-3-one (1.30 g, crude) as a brown oil. MS ESI calculated for CH ClNO [M + 9 10 3 2 +H], 228.05; found, 228.10. Step-6:

[0510] To a3-one (1.30 g, 5.71 mmol) in THF (15 mL) were added boron trifluoride diethyl etherate (2.43 g, 17.13 mmol) and NaBH4 (648 mg, 17.13 mmol) at 0 °C. The resulting mixture was stired at 40 °C for 16 h. The reaction was quenched with water at 0 °C. The mixture acidified by HCl (4 M) to pH 2~4. The resulting mixture was extracted with EtOAc. The aqueous layer was colected and basified to pH 9~10 with NaHCO3 (sat.), then 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 aford (S)-6-chloro-4- (morpholin-3-yl)pyridin-3-amine (450 mg, crude) as a yelow solid. MS ESI calculated for CH ClN + 9 12 3O [M+H], 214.07; found, 214.15. Step-7:

[0511] To a stired solution of (S)-6-chloro-4-(morpholin-3-yl)pyridin-3-amine (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 stired at 80 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was trituration with DCM to aford (S)-10-chloro- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazin-6-amine (470 mg, crude) as a yelow solid. MS ESI calculated for C10H11ClN4O [M+H]+, 239.06; found, 239.10. Step-8:

[0512] Totetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazin-6-amine (500 mg, 2.10 mmol) and Zinc cyanide (369 mg, 3.14 mmol) in N-methyl-2-pyrolidone (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 stired 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 aford (S)-6-amino-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonitrile (160 mg, 33%) as a yelow solid. MS ESI calculated for C + 1 11H11N5O [M+H], 230.10; found, 230.20.H NMR (300 MHz, DMSO-d6) δ 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, J = 11.1, 3.3 Hz, 1H), 3.90 – 3.69 (m, 2H), 3.59 – 3.40 (m, 2H), 3.19 – 2.99 (m, 1H). Step-9:

[0513] A[6,1- c][1,4]oxazine-10-carbonitrile (100 mg, 0.44 mmol) and HCl (conc.) (1.5 mL) was stired at 80 °C for 1 h. The resulting mixture was concentrated under vacuum to afford (S)-6-amino- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (CA7)(128 mg, crude) as a brown solid. MS ESI calculated for C + 11H12N4O3 [M+H], 249.09; found, 249.20.1H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.60 (s, 2H), 8.30 (s, 1H), 7.95 (s, 1H), 5.05 (dd, J = 10.5, 3.3 Hz, 1H), 4.35 – 4.13 (m, 2H), 3.93 (dd, J = 12.0, 3.0 Hz, 1H), 3.73 – 3.50 (m, 2H), 3.38 – 3.21 (m, 1H). Intermediate CA8: (4R,11bS)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acidStep-1:

[0514] To a mixtureShanghai Balmxy. Pharmaceutic Co. Ltd. CAS# 119844-67-6) (10.00 g, 86.85 mmol) and DMAP (1.06 g, 8.68 mmol) in THF (100 mL) was added di-tert-butyl dicarbonate (28.43 g, 130.28 mmol) slowly. The mixture was stired 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 aford tert-butyl (R)-3-methyl- 5-oxomorpholine-4-carboxylate (17.90 g, 95%) as a colorless oil. MS ESI calculated for C10H17NO4 [M+H]+, 216.12; found, 216.15.1H NMR (400 MHz, DMSO) δ 4.28 – 3.99 (m, 3H), 3.91 – 3.69 (m, 2H), 1.47 (s, 9H), 1.27 (d, J = 6.6 Hz, 3H). Step-2:(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 stiring at -30 °C for 1 h, a solution ofdiphenyl chlorophosphonate (27.11 g, 100.90 mmol) in THF (50 mL) was added to the above mixture at -30 °C. The mixture was alowed to warm to room temperature for 1 h with stiring. 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 aford tert-butyl (R)- 5-(diphenoxyphosphoryl)oxy)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (26.10 g, 69%) as a yelow solid. MS ESI calculated for C + 22H26NO7P [M+H], 448.14; found, 448.10. 1H NMR (400 MHz, DMSO) δ 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:

[0516] methyl-2,3- dihydro-4H-1,4-oxazine-4-carboxylate (26.10 g, 58.39 mmol) and methyl 5-amino-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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)Cl2-CH2Cl2 (5.48 g, 6.70 mmol) at room temperature. The resulting mixture was stired 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 aford tert-butyl (R)-5-(5-amino-2- (methoxycarbonyl)pyridin-4-yl)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (8.5 g, 41%) as a yelow solid. MS ESI calculated for C + 17H23N3O5 [M+H], 350.16; found, 350.05. Step-4:

[0517] yl)pyridin-4- yl)-3-methyl-2,3-dihydro-4H-1,4-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 Pd(OH)2 / C (6.83 g, 2.43 mmol, 5% active on carbon). The mixture was stired at 50 °C for 72 h under hydrogen atmosphere (50 atm.). The mixture was filtered through a Celite pad. The filtrate was colected and concentrated under vacuum. The resulting residue was purified by normal phase flash column chromatography eluted with 0–5% methanol in dichloromethane to aford tert-butyl (3S,5R)-3-(5-amino-2-(methoxycarbonyl)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-methylmorpholine-4-carboxylate (4.28 g, 50%) as a white solid as the second eluting peak.

[0518] Tert-butyl (3S,5R)-3-(5-amino-2-(methoxycarbonyl)pyridin-4-yl)-5- methylmorpholine-4-carboxylate: MS ESI calculated for C + 17H25N3O5 [M+H], 352.18; found, 352.20.1H NMR (400 MHz, DMSO) δ 8.18 (s, 1H), 8.02 (s, 1H), 6.32 (s, 2H), 4.90 (d, J = 4.4 Hz, 1H), 4.27 – 4.19 (m, 1H), 4.20 – 4.06 (m, 1H), 3.79 – 3.76 (m, 3H), 3.76 – 3.62 (m, 2H), 3.18 – 3.16 (m, 1H), 1.38 (s, 9H), 1.05 (d, J = 1.8 Hz, 3H). Absolute stereochemistry was determined by NOESY.

[0519] Tert-butyl (3R,5R)-3-[5-amino-2-(methoxycarbonyl)pyridin-4-yl]-5- methylmorpholine-4-carboxylate: MS ESI calculated for C + 17H25N3O5 [M+H], 352.18; found, 352.20.1H NMR (400 MHz, DMSO) δ 7.97 (s, 1H), 7.68 (s, 1H), 6.12 (s, 2H), 4.71 – 4.65 (m, 1H), 4.14 – 3.98 (m, 2H), 3.83 – 3.65 (m, 5H), 3.19 – 3.16 (m, 1H), 1.24 (d, J = 6.6 Hz, 3H), 1.10 (s, 9H). Absolute stereochemistry was determined by NOESY. Step-5:

[0520] T pyridin-4-yl)-5- methylmorpholine-4-carboxylate (1.8 g, 5.12 mmol) in DCM (18 mL) was added trifluoroacetic acid (6 mL). The mixture was stired at room temperature for 3 h. The solvents were removed under vacuum. The residue was basified with NaHCO3 (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 aford methyl 5-amino- 4-(3S,5R)-5-methylmorpholin-3-yl)picolinate (1.7 g, crude) as a yelow solid. MS ESI calculated for C12H17N3O3 [M+H]+, 252.13; found, 252.15. Step-6:

[0521] 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 colected and dried under vacuum to afford methyl methyl (4R,11bS)-6-amino-4- methyl-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate (700 mg, crude) as a yelow solid. MS ESI calculated for C + 13H16N4O3 [M+H], 277.12; found, 272.15. Step-7:

[0522] To a mixture of methyl methyl (4R,11bS)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]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 stired at room temperature for 2 h. The organic solvents were removed under vacuum. Theremained aqueous layer was neutralized with HCl (aq., 2N) to pH ~7. The suspended solids were colected by filtration and dried under vacuum to aford (4R,11bS)-6-amino-4-methyl- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (CA8) (560 mg, 42% over 3 steps) as a yelow solid. MS ESI calculated for C + 12H14N4O3 [M+H], 263.11; found, 263.05.1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 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, J = 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 CA9: (4R,11bR)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid-5- methylmorpholine-4-carboxylate (4.28 g, 12.19 mmol) in DCM (45 mL) was added TFA (10 mL). The mixture was stired at room temperature for 1 h. The solvents were removed under vacuum. The residue was basified with NaHCO3 (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 aford methyl 5-amino-4-(3R,5R)-5- methylmorpholin-3-yl)picolinate (4.60 g, crude) as a yelow solid. MS ESI calculated for C H NO [M+H+ 12 17 3 3 ], 252.13; found, 252.15. Step-2:

[0524] 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 stired at 80 °C for 16 h. The suspended solids were colected by filtration and dried under vacuum to aford methyl (4R,11bR)-6-amino-4-methyl- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate (3.17 g, crude) as a white solid. MS ESI calculated for C H NO [M+ + 13 16 4 3 H], 277.12; found, 277.15. Step-3:

[0525] To a mixture of methyl (4R,11bR)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate (3.17 g, 11.47 mmol) in THF (30 mL) and H2O (15 mL) was added LiOH (0.82 g, 34.41 mmol). The mixture was stired at 50 °C for 2 h. The organic solvent was removed under vacuum. The remaining aqueous layer was neutralized with HCl (aq., 2N) to pH ~7. The suspended solids were colected by filtration and dried under vacuum to aford (4R,11bR)-6-amino-4-methyl- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (CA9) (1.9 g, 58% over 3 steps) as a yelow solid. MS ESI calculated for C + 12H14N4O3 [M+H], 263.11; found, 263.05.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.02 (br, 2H), 7.82 (s, 1H), 5.19 (dd, J = 10.4, 3.6 Hz, 1H), 4.38 (dd, J = 11.2, 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,11bR)-6-amino-4-(difluoromethyl)-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid and (4R,11bS)-6- amino-4-(difluoromethyl)-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine- 10-carboxylic acidStep-1: a- nitrogen atmosphere. The resulting mixture was stired 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 stired at -78 °C for additional 30 minutes. Then Et3N (585.91 g, 5.79 mol) was added dropwise to the mixture over 20 minutes at -78 °C. The resulting mixture was stired at -78 °C for additional 1 h. Then the mixture was warmed to room temperature for 16 h with stiring. The reaction mixture was quenched by NaHCO3 (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 aford a 1:1 mixture of (S)-4- benzylmorpholine-3-carbaldehyde and (R)-4-benzylmorpholine-3-carbaldehyde (38.90 g, 39%) as a yelow oil. MS ESI calculated for C + 12H15NO2 [M+H], 206.11; found, 206.15. Step-2:

[0527] 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 stired at room temperature for 2 h. The reaction mixture was quenched carefuly by NaHCO3 (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 aford a 1:1 mixture of (S)-4-benzyl-3-(difluoromethyl)morpholine and (R)-4-benzyl-3-(difluoromethyl)morpholine (17.80 g, 42%) as a yelow oil. MS ESI calculated for C + 12H15F2NO [M+H], 228.11; found, 228.15. Step-3: (R)-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. The mixture was placed under hydrogen atmosphere with a baloon (1 atm.). The reaction mixture was degassed via vacuum evacuation, then backfiled with hydrogen, and this process was repeated three times. The reaction mixture was stired at room temperature for 16 h under hydrogen atmosphere. The mixture was filtered through a Celite pad. The filtrate was colected and concentrated under vacuum to aford to aford a 1:1 mixture of tert-butyl (S)-3-(difluoromethyl)morpholine-4-carboxylate and tert-butyl (R)-3- (difluoromethyl)morpholine-4-carboxylate (17.0 g, crude) as a yelow oil. MS ESI calculated for C10H17F2NO3 [M+H]+, 238.12; found, 228.25. Step-4:4- carboxylate and tert-butyl (R)-3-(difluoromethyl)morpholine-4-carboxylate (17.80 g, 75.02 mmol) in THF (170 mL) were added trichlororuthenium hydrate (3.38 g, 15.00 mmol) and H2O (170 mL). Then NaIO4 (48.30 g, 225.83 mmol) was added in portions. The resulting mixture was stired at room temperature for 16 h. The suspension was filtered. The filtrate was colected and concentrated under vacuum. The residue was purified by normal phase flash column chromatography using a 330 g silica gel column eluted with 0 60% ethyl acetate in petroleum ether to aford a 1:1 mixture of tert-butyl (R)-3-(difluoromethyl)-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 C + 10H15F2NO4 [M+H], 252.10; found, 252.15.Step-5:oxomorpholine-4-carboxylate and tert-butyl (S)-3-(difluoromethyl)-5-oxomorpholine-4- carboxylate (6.80 g, 27.06 mmol) in THF (70 mL) was added LiHMDS(1.0 M in THF) (32.5 mL, 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 stired at -30 °C for additional 1 h, then the mixture was warmed to room temperature and stired 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- (difluoromethyl)-5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate and tert-butyl (R)-3-(difluoromethyl)-5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4- oxazine-4-carboxylate (5.90 g, 45%) as a yelow oil. MS ESI calculated for C22H24F2NO7P [M+H]+, 484.13; found, 484.10. Step-6:(diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate and tert-butyl (R)-3- (difluoromethyl)-5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (5.90 g, 12.20 mmol), Pd(dppf)Cl2-CH2Cl2 (1.00 g, 1.22 mmol) and K2CO3 (3.37 g, 24.41 mmol) in Dioxane (60 mL) was added H2O (6 mL). The resulting mixture was stired 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 columneluted with 0 80% ethyl acetate in petroleum ether to aford a 1:1 mixture of tert-butyl (S)- 5-(5-amino-2-(methoxycarbonyl)pyridin-4-yl)-3-(difluoromethyl)-2,3-dihydro-4H-1,4- oxazine-4-carboxylate and tert-butyl (R)-5-(5-amino-2-(methoxycarbonyl)pyridin-4-yl)-3- (difluoromethyl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (4.10 g, 87%) as a yelow solid. MS ESI calculated for C17H21F2N3O5 [M+H]+, 386.14; found, 386.15. Step-7:- - carboxylate and tert-butyl (R)-5-(5-amino-2-(methoxycarbonyl)pyridin-4-yl)-3- (difluoromethyl)-2,3-dihydro-4H-1,4-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 Paladium hydroxide (5% active on carbon) (4.08 g, 1.45 mmol) at room temperature. The reaction mixture was stired at 50 oC for 16 h under hydrogen atmosphere (30 atm.). The mixture was filtered through a Celite pad. The filtrate was colected 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 aford a 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-(difluoromethyl)morpholine-4-carboxylate (2.70 g, 67%) as a white solid. MS ESI calculated for C + 17H23F2N3O5 [M+H], 388.16; found, 388.20. Trans relative stereochemistry was determined by NOESY. Step-8:(methoxycarbonyl)pyridin-4-yl)-5-(difluoromethyl)morpholine-4-carboxylate and tert-butyl (3S,5R)-3-(5-amino-2-(methoxycarbonyl)pyridin-4-yl)-5-(difluoromethyl)morpholine-4- carboxylate (2.7 g, 6.97 mmol) in DCM (30 mL) was added trifluoroacetic acid (6 mL). The resulting mixture was stired at room temperature for 3 h under air atmosphere. The solventswere removed under vacuum to aford 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 yelow oil, which was used in the next step without further purification. MS ESI calculated for C + 12H15F2N3O3 [M+H], 288.11; found, 288.10. Step-9:- (difluoromethyl)morpholin-3-yl)picolinate (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 stired 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 C18 column eluted with 5 40% acetonitrile in water to afford a 1:1 mixture of methyl (4S,11bR)-6-amino-4- (difluoromethyl)-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10- carboxylate and methyl (4R,11bS)-6-amino-4-(difluoromethyl)-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate (700 mg, 32%) as a yelow solid. MS ESI calculated for C13H14F2N4O3 [M+H]+, 313.10; found, 313.05. Step-10:

[0535] A 1:1 mixture of methyl (4S,11bR)-6-amino-4-(difluoromethyl)-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylate and methyl (4R,11bS)-6-amino-4-(difluoromethyl)-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carboxylate (100 mg, 0.32 mmol) and HCl (aq., 2N) (2 mL) was stired at 60 oC for 16 h. The solvents were removed under vacuum to aford a 1:1 mixture of (4S,11bR)-6-amino-4-(difluoromethyl)-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carboxylic acid and (4R,11bS)-6-amino-4-(difluoromethyl)-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (CA10) (110 mg, crude) as a yelow solid, which was used in the next step without further purification. MS ESIcalculated for C H FNO3 [M+H]+, 299.09; fo 1 12 122 4 und, 299.15.H NMR (400 MHz, DMSO) δ 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, 1H), 4.43 (dd, J = 11.2, 3.6 Hz, 1H), 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 # Structure Intermediate # Structure AC1 AC1 isomer 1,,, , , oline- 10-carbonyl chloride

[0536] A mixture of 6-[1,4]oxazino[4,3-c]quinazoline-10- carboxylic acid (500 mg, 1.88 mmol) and HCl (gas) (4M in 1,4-dioxane) (7 mL) was stired at 25 °C for 30 minutes. The resulting mixture was concentrated under reducedpressure. The residue was dissolved in SOCl2 (7 mL). The resulting mixture was stired at 60 °C for 1.5 h. The mixture was cooled. The precipitated solids were colected by filtration and washed with DCM to aford 6-amino-9-fluoro-1H,3H,4H,11bH-[1,4]oxazino[4,3- c]quinazoline-10-carbonyl chloride hydrochloride (280 mg, 52%) as a brown solid. Intermediate AC1 isomer 1: (R)-6-amino-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carbonyl chloride, isomer 1

[0537] A mixture of CA1, isomer 1 (930 mg, 3.49 mmol) and HCl (4M in dioxane) (10 mL) was stired at room temperature for 1 h. The mixture was concentrated under vacuum. Then SOCl (10 mL) was added to the residue. The mixt o 2 ure was stired at 50C for 3 h. The mixture was concentrated under vacuum to aford (R)-6-amino-9-fluoro-1,3,4,11b- tetrahydro-[1,4]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-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carbonyl chloride, isomer 2

[0538] A mixture of CA1, isomer 2 (960 mg, 3.60 mmol) and HCl (4M in dioxane) (10 mL) was stired at room temperature for 1 h. The mixture was concentrated under vacuum. Then SOCl (10 mL) was a o 2 dded to the residue. The mixture was stired at 50C for 3 h. The mixture was concentrated under vacuum to aford (S)-6-amino-9-fluoro-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carbonyl chloride, isomer 2 (930 mg, crude) as a white solid that is used directly in subsequent reactions.

[0539] The absolute stereochemistry of AC1 isomer 2 was determined based on its precursor acid (i.e., CA1 isomer 2). The absolute stereochemistry of AC1 isomer 2 was further confirmed by crystalography 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:.

[0540] Accordingly, AC1 isomer 1 has the R-configuration represented by:. Intermediate AC4: (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carbonyl chloride

[0541] A mixture of CA4 (10 g, 40.28 mmol) and hydrogen chloride (4.0 M in 1,4- dioxane) (50 mL) was stired 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 oC. The resulting mixture was stired at 25 oC for 1 h. The solvents were removed under vacuum to aford (R)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carbonyl chloride (13.5 g, crude) as a light yelow solid that is used directly in subsequent reactions.

[0542] The absolute stereochemistry of AC4 was assigned as the same absolute stereochemistry of precursor CA4.Intermediate AC5: (4S,11bS)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride

[0543] A mixture of CA5 (50 (4M in 1,4-dioxane) (0.5 mL) wasstired 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 stired at 25 oC for 1 h. The solvents were removed under vacuum to aford (4S,11bS)-6-amino-4-methyl- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride (50 mg) as a yelow solid that is used directly in subsequent reactions.

[0544] The absolute stereochemistry of AC5 was determined by crystalography based on the co-crystal structure of selected compounds disclosed herein with PRMT5 enzyme, where the compounds were prepared using intermediate AC5. Intermediate AC6: (S)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1- c][1,4]oxazine-10-carbonyl chloride

[0545] A solution of (S)-6-[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 folowed by the addition of Oxalyl chloride (3.58 g, 28.20 mmol) dropwise at 0 °C. The resulting mixture was stired at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to aford (S)-6-amino-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride (AC6) (2 g) as a yelow solid that is used directly in subsequent reactions. Intermediate AC7: (4S,11bR)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride

[0546] A mixture of - tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (100 mg, 0.43 mmol) in HCl in 1,4-dioxane(4.0 M) (2 mL) was stired at room temperature for 10 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 stired at room temperature for 1 h. The solvents were removed under vacuum to aford (4S,11bR)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride (AC7) (110 mg, crude) as a yelow solid, which was used in the next step without further purification. Intermediate AC8: (4R,11bS)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride

[0547] A mixture of (4R,11bS)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (117 mg, 0.44mmol) and HCl in 1,4-dioxane(4.0 M) (2 mL) was stired 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 stired at room temperature for 1 h. The solvents were removed under vacuum to aford (4R,11bS)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride (AC8) (110 mg) as a yelow solid, which was used in the next step without further purification. Intermediate AC9: (4R,11bR)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride

[0548] tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxylic acid (100 mg, 0.43 mmol) and HCl in 1,4-dioxane(4.0 M) (2 mL) was stired 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, folowed by the addition of DMF (one drop). The mixture was stirred at room temperature for 1 h. The solvents were removed under vacuum to aford (4R,11bR)-6-amino-4-methyl-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carbonyl chloride (AC9) (110 mg, crude) as a yelow solid, which was used in the next step without further purification.Amine intermediate synthesis Intermediate Structure Intermediate Structure # #Intermediate A1: (R)-1-cyclopropyl-2-methoxy-N-(5-(trifluoromethyl)pyridin-2- yl)methyl)ethan-1-amineStep 1: tert-butyl (R)-(1-cyclop thyl)carbamate

[0549] To a stired mixture of (2R) hydrochloride(Pharmablock, PBZ5602 g, 65.40 mmol) in THF (50 mL) and H2O (50 mL) were added Boc2O (15.70 g, 71.94 mmol) and NaHCO3 (10.99 g, 130.80 mmol) at room temperature. The resulting mixture was stired 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 the filtrate was concentrated under vacuum to aford tert-butyl N-[(1R)-1-cyclopropyl-2- hydroxyethyl]carbamate (13.80 g, crude) as a light yelow oil. MS (ESI) calculated for (C H NO) [M + 10 19 3 +H], 202.1; found, 202.1 Step 2: tert-butyl (R)-(1-cyclopropyl-2-methoxyethyl)carbamate

[0550] To a stired mixture of2-hydroxyethyl]carbamate (13.80 g, 68.57 mmol) in MeCN (150 mL) were added Ag2O (23.83 g, 102.85 mmol) and MeI (97.32 g, 685.66 mmol) at 0 °C. The resulting mixture was stired at 50 °C for 16 h. The suspension was filtered. The filtrate was colected and concentrated under vacuum to aford tert-butyl N-[(1R)-1-cyclopropyl-2-methoxyethyl]carbamate (14.20 g, crude) as a yelow oil. MS (ESI) calculated for (C11H21NO3) [M+H]+, 216.1; found, 216.2. Step 3: (R)-1-cyclopropyl-2-methoxyethan-1-amine

[0551] To a stired mixture ofcyclopropyl-2-methoxyethyl]carbamate (13.80 g, 64.10 mmol) in MeOH (70 mL) was added HCl (gas in ethyl acetate, 4M) (70 mL,301.27 mmol) at room temperature. The mixture was stired at room temperature for 16 h. The resulting mixture was concentrated under vacuum to aford (1R)-1-cyclopropyl-2- methoxyethanamine hydrochloride (14.20 g, crude) as a yelow oil. MS (ESI) calculated for (C6H13NO) [M+H]+, 116.0; found, 116.0. Step 4: (R)-1-cyclopropyl-2-methoxy-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1- amine A1

[0552] To a stired mixture2-methoxyethanamine (5.00 g, 43.41 mmol) and 5-(trifluoromethyl)pyridine-2-carbaldehyde (6.08 g, 34.73 mmol) in MeOH (50 mL) was added TEA (6.59 g, 65.12 mmol) at room temperature. The resulting mixture was stired at room temperature for 1 h. Then NaBH4 (3.61 g, 95.51 mmol) was added to the above mixture at 0 °C. The resulting solution was stired at 25 oC 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 through paper, and concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) with a 40 g C18 column, eluted with 5~70% acetonitrile in water (10 mM NH4HCO3) within 25 min to aford [(1R)-1-cyclopropyl-2-methoxyethyl]({[5- (trifluoromethyl)pyridin-2-yl]methyl})amine (3.40 g, 27%) as a yelow oil. MS (ESI) calculated for (C H FNO) [M+H]+, 275.1; found 1 13 173 2 , 275.1.H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.4 Hz, 1H), 8.15 (dd, J = 8.4, 2.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 4.12 – 3.96 (m, 2H), 3.46 – 3.27 (m, 2H), 3.25 (s, 3H), 2.54 – 2.53 (m, 1H), 2.03 – 1.93 (m, 1H), 0.67 – 0.54 (m, 1H), 0.52 – 0.38 (m, 1H), 0.38 – 0.28 (m, 1H), 0.23 – 0.13 (m, 1H), 0.13 – 0.03 (m, 1H). Intermediate A2: 1:1 mixture of (R)-N-methyl-7-(trifluoromethyl)chroman-4-amine and 1:1 mixture of (S)-N-methyl-7-(trifluoromethyl)chroman-4-amine

[0553] Intermediate A res available in the literature. Intermediate A3: (S)-4-(methylamino)isochromane-7-carbonitrile

[0554] Intermediate A3 is synthesized from standard procedures available in the literature. Intermediate A4: 1:1 mixture of (R)-N-methyl-2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-5-amine and (S)-N-methyl-2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-5-amine

[0555] To a stired mixture5H-cyclopentafb]pyridin-5- one (1.50 g, 7.46 mmol) and aminomethane (2 M solution in THF) (9.32 mL 18.64 mmol) in DCM (7 mL) was added acetic acid (1.120 g, 1.076 mL, 18.64 mmol). The resulting mixture was stired at rt for 10 min before sodium triacetoxyborohydride (2055 g, 9.69 rnmol) was added in one po1tion as a solid. The resulting mixture was stired at rt for 42 h. The reaction was quenched with methanol. The volatiles were removed in vacuo and the residue was basified at O cc with ammonium hydroxide, directly loaded onto a silica gel precolumn (25 g), and subjected to combi-flash column chromatography on a 24-g ISCO gold column eluting with MeOH (with 0.5% ammonium hydroxide) / DCM (0 to 20%) (2 x) to give 1:1 mixture of (R)-N-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine and (S)-N-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine A4(1.40 g, 6.48 mmol, 87 % yield) as a dark-colored solid. m / z (ESI): 217.20 (M+H)+, 1H NMR (CHLOROFORM-d, 400 MHz) o 7.78 (d, 1H,J=7.7 Hz), 7.52 (d, lH,1=7.7 Hz), 4.26 (t, lH, 1=6.9 Hz), 3.1-3.2 (m, lH), 3.0-3.1 (m, lH), 2.5-2.6 (m, 4H), 1.9-2.0 (m, lH), 1.31 (br s, lH). 19F NMR (CHLOROFORM-d, 376 MHz) o -67.39 (s, 3F). Intermediate A5: 1:1 mixture of (S)-6-(difluoromethoxy)-N-methyl-2,3-dihydrobenzofuran- 3-amine and (R)-6-(difluoromethoxy)-N-methyl-2,3-dihydrobenzofuran-3-amine

[0556] Intermediate A5 is available in the literature.Intermediate A6: (R)-1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethan- 1-amine

[0557] To a mixture of 5-(3.02 g, 17.27 mmol) and (1R)- 1-pyrimidin-2-ylethanamine hydrochloride (Pharmablock, PBT0073-1) (3.2 g, 20.21 mmol) in DCM (50 mL) at RT was added acetic acid (1.11 g, 18.48 mmol). The mixture was stired at RT for 30 min then treated with sodium triacetoxyborohydride (5.49 g, 25.9 mmol). The mixture was stired at RT for 1 h then neutralized with saturated aqueous Na2CO3. The layers were separated and the aqueous layer was extracted with DCM. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc / EtOH (3 / 1) in heptane) to aford (R)-1- (pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine A6. m / z (ESI): 269.0 (M+H)+. Intermediate A7: N-methyl-1,2,3,4-tetrahydronaphthalen-1-amineNH

[0558] Intermediate A7 is procedures available in the literature. This intermediate corresponds toIntermediate A8: (R)-2-methyl-6-((1-(pyrimidin-2-yl)ethyl)amino)methyl)nicotinonitrile Step 1:

[0559] To a solution of 6-in dioxane (100 mL) and H2O (10 mL) were added potassium trifluoro(vinyl)borate (13.17 g, 98.31 mmol), Pd(dppf)Cl2-CH2Cl2 (5.34 g, 6.55 mmol), K2CO3 (18.12 g, 131.08 mmol) at room temperature. The mixture was stired at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was filtered. The filtrate was colected, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography with 0~20% ethyl acetate in petroleum ether to aford 6-ethenyl-2-methylpyridine-3- carbonitrile (9 g, 94%) as a yelow solid. MS ESI calculated for C + 9H8N2 [M+1], 145.07; found, 145.05. Step-2:

[0560] To a mixture of 2-methyl-6-vinylnicotinonitrile (9 g, 62.42 mmol) in THF (200 mL) and H2O (100 mL) were added OsO4 (1.59 g, 6.24 mmol) and NaIO4 (26.70 g, 124.84 mmol) at 0 °C. The mixture was stired at room temperature for 16 h. The reaction mixture was quenched by the addition of NaHCO3 aqueous solution 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 0~50% EtOAc in PE to aford 6-formyl-2-methylnicotinonitrile (4.47 g, 48%) as a white solid. MS ESI calculated for C + 1 8H6N2O [M+H], 147.05; found, 147.05.H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 2.79 (s, 3H). Step 3: N NH2 N HCl

[0561] A, AcOK (3.80 g, 33.83 mmol) and (R)-1-(pyrimidin-2-yl)ethan-1-amine hydrochloride ((supplier: PharmaBlock Inc. CAS# 2387560-79-2) (4.5 g, 28.19 mmol) in MeOH (40 mL) was stired at room temperature for 3 h. To the above mixture was added NaBH3CN (5.31 g, 84.57 mmol) at room temperature. The resulting mixture was stired at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was diluted by NaHCO3 aqueous solution 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 0-5% MeOH in DCM to aford (R)-2-methyl-6-((1-(pyrimidin-2-yl)ethyl)amino)methyl)nicotinonitrile (A8) (3.16 g, 44.%) as a yelow oil. MS ESI calculated for C + 1 14H15N5 [M+H], 254.13; found, 254.10.H NMR (400 MHz, DMSO-d6) δ 8.77 (s, J = 4.8 Hz, 2H), 8.15 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 4.8 Hz, 1H), 3.90 (q, J = 6.8 Hz, 1H), 3.82 – 3.68 (m, 2H), 2.61 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H).Final Compound Synthesis Example 1: 1:1 mixture of (R*)-6-amino-N-((R)-1-cyclopropyl-2-methoxyethyl)-N-((5- (trifluoromethyl)pyridin-2-yl)methyl)-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline- 10-carboxamide

[0562] To a and intermediate A1(44 mg, 0.16 were mg, and TCFH (85 mg, 0.30 mmol). The resulting mixture was stired at 25 ℃ for 2 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the folowing conditions (Column: XBridge Prep Phenyl OBD Column19*250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 26% B to 36% B in 10 min; Wave Length: 254 / 237 nm; RT1(min): 10.6) to aford 1:1 mixture of (R*)-6-amino-N-((R)-1- cyclopropyl-2-methoxyethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4,11b- tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxamide (1 mg, 1%) as a white solid. MS (ESI) calculated for (C H FNO) [M+H]+, 504.21; found, 504 1 25 283 5 3 .25.H NMR (300 MHz, Methanol-d4) δ 8.84 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.41 – 7.28 (m, 2H), 6.90 (d, J = 8.1 Hz, 1H), 4.89 – 4.82 (m, 3H), 4.14 – 4.09 (m, 1H), 4.02 – 3.84 (m, 2H), 3.78 – 3.61 (m, 1H), 3.61 – 3.56 (m, 4H), 3.30 – 3.22 (m, 4H), 1.04 – 0.84 (m, 1H), 0.67 – 0.55 (m, 1H), 0.48 – 0.33 (m, 1H), 0.21 – 0.06 (m, 2H). Example 2: 1:1:1:1 mixture of (R*)-6-amino-9-fluoro-N-methyl-N-(R*)-7- (trifluoromethyl)chroman-4-yl)-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10- carboxamide

[0563] Example 2 is synthesized using same procedure as used in Example 1, wherein intermediate CA3 is changed for CA1 and intermediate A1 is changed for A2. Example 3: 1:1 mixture of (R*)-6-amino-N-((S)-7-cyanoisochroman-4-yl)-9-fluoro-N- methyl-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline-10-carboxamide

[0564] 1, wherein intermediate CA3 is changed for CA1 and intermediate A1 is changed for A3. Example 4: 1:1:1:1 mixture of (R*)-6-amino-9-fluoro-N-methyl-N-(R*)-2- (trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-1,3,4,11b-tetrahydro- [1,4]oxazino[4,3-c]quinazoline-10-carboxamideintermediate CA3 is changed for CA1 and intermediate A1 is changed for A4. Example 5: 1:1:1:1 mixture of (R*)-6-amino-10-((R*)-6-(difluoro-l3-methoxy)-2,3- dihydrobenzofuran-3-yl)(methyl)carbamoyl)-9-fluoro-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline

[0566] Example 5 is synthesized using same procedure as used in Example 1, wherein intermediate CA3 is changed for CA1 and intermediate A1 is changed for A5.Example 6: 1:1 mixture of (R*)-6-amino-N-((R)-1-(pyrimidin-2-yl)ethyl)-N-(5- (trifluoromethyl)pyridin-2-yl)methyl)-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3-c]quinazoline- 10-carboxamide

[0567] 1, whereinintermediate A6. Example 7: 1:1 mixture of (R*)-6-amino-N-((R)-1-cyclopropyl-2-methoxyethyl)-9-fluoro-N- (5-(trifluoromethyl)pyridin-2-yl)methyl)-1,3,4,11b-tetrahydro-[1,4]oxazino[4,3- c]quinazoline-10-carboxamide

[0568] 1, wherein intermediate CA3 is changed for CA1 and intermediate A1 is changed for A8. Example 8: 1:1 mixture of (R)-6-amino-N-methyl-N-(S)-1,2,3,4-tetrahydronaphthalen-1-yl)- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxamide and (R)-6- amino-N-methyl-N-(R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxamide

[0569] T ermediate A7 (supplier: Beijing Feilongrui Trading Co., Ltd. CAS:10409-15-1) (46.19 mg, 0.186 mmol) in N,N-dimethylacetamide (1 mL) were added N,N-Disopropylethylamine (72.14 mg, 0.558 mmol) and N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophospate (106.11 mg, 0.279 mmol). The resulting mixture was stired at room temperature for 1 h. The reaction mixture was purified by Prep-HPLC with the folowing 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 (B%): 5% B to 5% B in 2 min, 21% B to 41% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 9.1] to aford a 1:1 mixture of (R)-6-amino-N-methyl-N-(S)-1,2,3,4-tetrahydronaphthalen-1-yl)- 1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxamide and (R)-6- amino-N-methyl-N-(R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxamide (Example 8) (17.2 mg, 23.62%) as a white solid. MS ESI calculated for C22H25N5O2 [M+H]+, 392.20; found. 392.2; 1H NMR (400 MHz, DMSO-d6) δ 7.86 and 7.78 (s, 1H), 7.29 (s, 1H), 7.19 – 7.09 (m, 4H), (br, 2H), 5.80 – 5.32 (m, 1H), 4.68 – 4.65 (m, 1H), 4.16 – 4.12 (m, 1H), 3.85 – 3.83 (m, 1H), 3.79 – 3.73 (m, 1H), 3.53 – 3.32 (m, 2H), 3.07 – 3.04 (m, 1H), 2.76 – 2.72 (m, 1H), 2.68 (d, J = 4.0 Hz, 2H), 2.60 (s, 2H), 2.04 – 1.84 (m, 4H). Example 9: (R)-6-amino-N-(5-cyano-6-methylpyridin-2-yl)methyl)-N-(R)-1-(pyrimidin-2- yl)ethyl)-1,3,4,11b-tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxamide N

[0570] g,. mmol) in DMAc (4 mL) were added TEA (360 mg, 3.60 mmol) and PyBrOP (276 mg, 0.60 mmol). The resulting mixture was stired at room temperature for 1 h. After completion of the reaction, 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 crude product was purified by Prep-HPLC with the folowing 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, 12% B to 22% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 9.6] to aford (R)-6-amino-N-((5-cyano-6- methylpyridin-2-yl)methyl)-N-((R)-1-(pyrimidin-2-yl)ethyl)-1,3,4,11b- tetrahydropyrido[3',4':4,5]pyrimido[6,1-c][1,4]oxazine-10-carboxamide (Example 9) (10.7 mg, 5%) as a white solid. MS ESI calculated for C + 25H25N9O2 [M+H], 484.21; found, 484.20. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.73 (s, 2H), 8.14 – 8.03 (m, 1H), 7.85 – 7.55 (m, 1H), 7.42 – 7.29 (m, 2H), 7.26 – 7.15 (m, 1H), 6.50 – 6.40 (m, 2H), 6.05 – 5.64 (m, 1H), 5.22 – 4.32 (m, 3H), 4.13 – 3.96 (m, 1H), 3.87 – 3.70 (m, 2H), 3.57 – 3.44 (m, 2H), 3.11 – 2.98 (m, 1H), 2.62 – 2.54 (m, 3H), 1.66 – 1.52 (m, 3H). Biological Examples Biological Example 1: Cel viability assay in HCT116 MTAP - / - cels

[0571] The cel viability was determined by doing cel nuclear counts; cel nuclei were labeled with a fluorescent protein kit using the manufacturer’s protocol (Sartorius).

[0572] HCT116 MTAP- / - (ATCC) were cultured in DMEM / F12 with GlutaMAX (Gibco) supplemented with 10% Fetal Bovine Serum (FBS, Gibco) and 2ug / mL puromycin (Gibco).Cels were seeded in 384-wel plates, at a density of 166 cels / wel in 50µL of cel culture media without puromycin. Cel plates were incubated overnight at 37°C with 5% CO2. After the overnight incubation, cels were imaged in a confocal microscope with nuclear count capabilities for the pre-treatment data set.

[0573] Cels were treated starting at a 20µM in 9-points and 4-fold serial dilutions for test compounds; the negative control was DMSO. Al compounds and the negative control had a final DMSO concentration of 0.2%. Cels were incubated for 5 days at 37°C with 5% CO2. On day 5, cels were imaged, and nuclei were counted for the post-treatment data set.

[0574] 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 fited and the EC50 was estimated using the Levenberg- Marquardt algorithm.

[0575] The EC50 of a representative compound in Table 1 above is disclosed in Table 2 below: A <= 0.1 µM; Table 2: Cel Viability Assay Results Ex # HCT116-MTAP nul EC50 (µM) Biological Example 2: PRM

[0576] The PRMT5 biochemical assay was conducted in 384-wel, assay-ready compound plates (PerkinElmer, Inc.; catalog number 6007290) with a final enzymatic reaction volume of 16 µL; 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 al reagents aside from PRMT5 protein, and the High Control contained al reagents plus PRMT5.

[0577] The enzymatic reaction was caried 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 bufer and incubated for 60 minutes at 37 °C, in the presence and absence of 100 nM MTA (EMD Milipore, Inc.; catalog number260585); the mixture consisted of 2 µM S-adenosyl-methionine (Promega, Inc.; catalog number V7601), 2.3 µM ful-length histone H2A (New England Biolabs, Inc.; catalog number M2502) or 1.5 µM ful-length histone H2A (Active Motif, Inc.; catalog number 31890) in assay bufer; assay bufer 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), 0.01% Tween-20 (EMD Milipore, 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 bufer, 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.

[0578] 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 fited and the IC50 was estimated using Levenberg-Marquardt algorithm.

[0579] The IC50 of a representative number of compounds in Table 1 above are disclosed in Table 3 below, where 1.5 µM ful-length histone H2A (Active Motif, Inc.; catalog number 31890) was used: A < 0.1 µM Table 3: PRMT5 Biochemical Assay Results Ex # PRMT5 Biochemical )

[0580] Although teoegog e o asee esc e soe detail by way of ilustration and example for purposes of clarity of understanding, one of skil in the art wil 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 inits entirety to the same extent as if each reference was individualy incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shal dominate.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I): (I) or a pharmaceuticaly 1 yY is O, NR, S, S(O), or X1 is C(R1) or N; X2 is C(R2) or N; X3 is C(R3) or N; Ry, R1, R2, and R3 are each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C cyclo 4 3-6 alkyl; or two R groups when atached to the same carbon atom combine to form oxo or C3-6 cycloalkyl; R7 is (i) –CH2Ar; Ar is phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein phenyl and heteroaryl are each independently substituted with 0, 1, or 2 R7a; each R7a is independently –CN, halo, C alkyl, C haloalkyl, 7a1 7a2 7a3 1-6 1-6 –OR , –NR R , –C(O)NR7a2R7a3, –SO2, –SO2C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, or heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 halo, C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, or –OC3-7 cycloalkyl; each R7a1 is H or C1-6 alkyl, wherein C1-6 alkyl is substituted with 0, 1, or 2 halo or oxetanyl; each R7a2 and R7a3 is independently H, C1-6 alkyl, or C1-6 haloalkyl; or (i) a moiety selected fromc7); –S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –CN, C1-6 alkoxy, C1-6 haloalkoxy, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, pentafluorosulfanyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heteroaryl is substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo; m is 0, 1, 2, 3, or 4; R7f is C alkyl, halo, or C ha 7f 1-6 1-6 loalkyl, wherein R can be on any available ring vertex in either ring system of (a7), (b7), or (c7); R8 is –CHR8aR8b, C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are each independently substituted with 0, 1, or 2 –CN or C3-6 cycloalkyl; R8a and R8b are each independently H, C1-6 alkyl, C1-6 alkynyl, –CH2(OR8c), C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, wherein each R8c is independently H, C1-6 alkyl, or C1-6 haloalkyl, and wherein C alkyl, C al 8c 1-6 1-6 kynyl, –CH2(OR), C3-10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a1; alternatively, R8a and R8b and the carbon atom to which they are atached combine to form C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, C6-10 aryl, or heteroaryl having 5 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein C3-10cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, C6-10 aryl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a2; each R8a1 is independently halo, C1-6 alkyl, –C(O)NR8dR8e, –OH, C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein R8d and R8e are each independently H, C1-6 alkyl, or C1-6 haloalkyl; and each R8a2 is independently C alkyl, C alkynyl, halo, –CN, –OR8f, 8f 1-6 1-6 or –CH2(OR), wherein each R8f is independently H, C1-6 alkyl, or C1-6 haloalkyl.

2. The compound or a pharmaceuticaly acceptable salt thereof of claim 1, wherein Y1 is O.

3. The compound or a pharmaceuticaly acceptable salt thereof of claim 1 or 2, wherein X1 is CH.

4. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 3, wherein X2 is CH or CF.

5. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 3, wherein X2 is N.

6. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 5, wherein X3 is CH.

7. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 6, wherein n is 0.

8. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7, wherein R7 is (i) –CH2Ar.

9. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 8, wherein Ar is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S substituted with 0, 1, or 2 R7a.

10. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 8, wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl substituted with 0, 1, or 2 R7a.

11. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 8, wherein Ar is pyridinyl substituted with 0, 1, or 2 R7a.

12. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 11, wherein each R7a is independently –CN, C1-6 alkyl, or C1-6 haloalkyl.

13. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 12, wherein each R7a is independently –CN, methyl, or trifluoromethyl.

14. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 13, . 15.acceptable salt thereof of any one of claims 1 to 7, wherein R7 is (i) a moiety selected from .or a 15, wherein R7 is .

17. The compound or a pharmaceuticaly acceptable salt thereof of claim 15, wherein R7 is .

18. Theacceptable salt thereof of claim 15, wherein R7 is .

19. Theacceptable salt thereof of any one of claims 1 to 7 and 15 to 18, wherein X4 is O.

20. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7 and 15 to 18, wherein X4 is C(R7bR7c).

21. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7, 15 to 18, and 20, wherein R7b and R7c are each H.

22. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7 and 15 to 21, wherein X5 is N.

23. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7 and 15 to 21, wherein X5 is C(R7d).

24. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7, 15 to 21, and 23, wherein R7d is H.

25. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7 and 15 to 24, wherein R7e is H, C1-6 haloalkyl, –CN, or C1-6 haloalkoxy.

26. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7 and 15 to 25, wherein m is 0.

27. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 7 and 15 to 26, wherein R7 is a moiety selected from .thereof of any one of claims 1 to 27, wherein R8 is methyl, ethyl, or cyclopropyl.

29. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 27, wherein R8 is –CHR8aR8b.

30. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 27 and 29, wherein R8a is C 8b 8c 1-6 alkyl or C3-10 cycloalkyl; and R is –CH2(OR) or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein R8c is H, C1-6 alkyl, or C1-6 haloalkyl, and wherein C3-10 cycloalkyl and heteroaryl are each independently substituted with 0, 1, or 2 R8a1.

31. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 27, 29, and 30, wherein R8a is methyl or cyclopropyl; and R8b is –CH2(OCH3) or pyrimidinyl.

32. The compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 27, and 29 to 31, wherein R8 is .

33. The compound or a pharmaceuticaly acceptable salt thereof of claim 1, wherein Y1 is O; X1 is CH;X2 is C(R2) or N; X3 is CH; R2 is H, or halo; n is 0; R7 is (i) –CH2Ar; Ar is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, substituted with 1 R7a; R7a is –CN, C1-6 alkyl, or C1-6 haloalkyl; or (i) a moiety selected from ;m is 0; R8 is –CHR8aR8b or C1-6 alkyl; and R8a and R8b are each independently C 8c 1-6 alkyl,–CH2(OR), C3-10 cycloalkyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein each R8c is independently C1-6 alkyl.

34. The compound or a pharmaceuticaly acceptable salt thereof of claim 1, wherein Y1 is O; X1 is CH; X2 is CH, CF, or N; X3 is CH; n is 0; R7 isor msalt thereof of claim 1, wherein the compound is selected from Table 1.

36. A pharmaceutical composition comprising a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 35, and a pharmaceuticaly acceptable excipient.

37. 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 therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 35, or a pharmaceutical composition of claim 36.

38. The method of claim 37, wherein the disease is cancer.

39. A method of treating an MTAP nul cancer in a patient in need thereof comprising administering to the patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 35, or a pharmaceutical composition of claim 36.

40. A method for 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 ofthe 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 therapeuticaly efective amount of a compound or pharmaceuticaly acceptable salt thereof of any one of claims 1 to 35, or a pharmaceutical composition of claim 36.

41. A method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 35, or a pharmaceutical composition of claim 36.

42. The method of any one of claims 38 to 4141, wherein the cancer isMTA-accumulating cancer.

43. The method of claim 38 or 42, wherein the cancer is deficient in CDKN2A.

44. The method of any one of claims 38 to 43, wherein the cancer is a solid tumor.

45. The method of claim 44, wherein the solid tumor is malignant.

46. The method of any one of claims 38 to 45, 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 cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undiferentiated pleiomorphic sarcoma, lymphoma (e.g., difuse large B-cel lymphoma (DLBCL), leukemia, head and neck cancer (e.g., head and neck squamous cel carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

47. The method of any one of claims 38 to 45, wherein the cancer is selected from the group consisting of leukemia, esophageal cancer, glioma, melanoma,pancreatic, non-smal cel 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.

48. The method of any one of claims 38 to 45, wherein the cancer is selected from the group consisting of non-smal cel lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

49. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 35, or a pharmaceutical composition of claim 36.

50. A method of inhibiting cel proliferation, in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 35, or a pharmaceutical composition of claim 36.

51. A method for inhibiting PRMT5 activity in a cel, comprising contacting the cel in which inhibition of PRMT5 activity is desired with an efective amount of a compound or pharmaceuticaly acceptable salt thereof of any one of claims 1 to 35, or a pharmaceutical composition of claim 36.

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