Tricyclic amidino 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

TRICYCLIC AMIDINO COMPOUNDS AS PRMT5 INHIBITORSCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Nos. 63 / 549,386 filed February 02, 2024 and 63 / 745,533 filed January 15, 2025, the contents of each is incorporated by reference in its entirety for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] NOT APPLICABLEREFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK

[0003] NOT APPLICABLEBACKGROUND

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

[0005] Synthetic lethality arises when a combination of deficiencies in the expression or activity of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The concept of synthetic lethality originates from studies in drosophila model systems in which a combination of mutations in two or more separate genes leads to cell death (in contrast to viability, which occurs when only one of the genes is mutated or deleted). More recently, a multitude of studies have explored maladaptive genetic changes in cancer cells that render them vulnerable to synthetic-lethality approaches. These tumorspecific genetic defects lead to the use of targeted agents that induce the death of tumor cells while sparing normal cells.

[0006] Protein arginine N-methyltransferase 5 (PRMT5) is a methyl transferase that uses s- adenosyl methionine (SAM) as a methyl donor. PRMT5 catalyzes symmetrical dimethylarginine in a number of substrates including histone and non-histone proteins. The activity of PRMT5 has been associated with development and cancer as well as other biological functions.

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

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

[0009] Seemingly due to structural similarities between SAM and MTA, PRMT5 is competitively inhibited by MTA. Cells with an MTAP deletion have increased levels of MTA, thereby partially inhibiting PRMT5. A new generation of PRMT5 inhibitors targeting the MTA-PRMT5 complex in MTAP deleted cancers are being developed. These MTA cooperative inhibitors selectively bind to the MTA-PRMT5 complex, effectively inhibiting PRMT5 in MTAP deleted cells, while leaving normal cells relatively unaffected. Inhibition of PRMT5 with MTA cooperative inhibitors leads to cell 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):or a pharmaceutically acceptable salt thereof. The definitions for X1, X2, X3, X4, X5, X6, ring A, ring B, R7, p, R8, q, and R9are further described herein.

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

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

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

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

[0016] In another aspect, provided herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0017] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5).

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

[0019] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer 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.

[0020] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer.

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

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

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

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

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

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

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

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

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

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

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

[0032] In another aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0033] In another aspect, provided herein are novel intermediates as defined herein which are suitable for use in any one of the synthetic methods as set out herein.

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

[0035] NOT APPLICABLEDETAILED DESCRIPTION OF THE INVENTION

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

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

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

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

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

[0041] Unless specifically indicated otherwise, the group “as used jnanyone of the structures in Table 1, the Examples, or moieties disclosed herein, refers to methyl (-CH3) where the wavy line is the point of attachment to the remainder of the molecule.

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

[0043] The term "alkyl", by itself or as part of another substituent, refers to, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms designated i.e. C1-8 means one to eight carbons). Alkyl can include any number of carbons, such as C1-2, C1.3, CM, 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.

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

[0045] The term “alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond and having the number of carbon atom indicated (i.e., C2-6 means to two to six carbons). Alkynyl can include any number ofcarbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl,1.3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl,1.4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.

[0046] The term "cycloalkyl" refers to a non-aromatic, saturated hydrocarbon ring having the indicated number of ring atoms (e.g., 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.

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

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

[0049] The term “haloalkyl(OH),” refers to haloalkyl, as defined above, that is further substituted with a hydroxy (OH) group.

[0050] The terms "alkoxy," and "haloalkoxy" refer to alkyl and haloalkyl groups respectively, each as defined herein, that is attached to the remainder of the molecule via an oxygen atom, for example -O-alkyl or -O-haloalkyl.

[0051] The term “aryl” refers to a monocyclic or bicyclic, hydrocarbon, aromatic radical. An aryl group may contain 6 to 14 carbon atoms. For example, “Ce-io 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.

[0052] 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 attachedto 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, pyrrolyl, thiazolyl, furyl, thienyl and the like.

[0053] 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, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0054] The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially unsaturated 3 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N, O, and S and the remaining ring atom being carbon. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized and one or two ring carbon atoms of the heterocyclic ring may be replaced by -C=(O) group. However, heterocycloalkyl groups are not aromatic. Non limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, , and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

[0055] The term "hydroxyalkyl," refers to an alkyl, as defined above, that is substituted with one or two hydroxy. For example, the term “hydroxyCi-4 alkyl” or “C1-4 hydroxyalkyl” is meant to include hydroxymethyl, 1-, or 2-hydroxy ethyl, 1,2-dihydroxy ethyl, hydroxypropyl, and the like.

[0056] The term “optionally substituted” indicates that a group may be unsubstituted or substituted with one or more substituents as defined herein. The term “substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced by one of the defined substituents. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

[0057] The term "oxo" refers to an oxygen atom with a double bond to the point of attachment (O=).

[0058] The term "fused tricyclic moiety" refers to a ring system comprising three fused rings having the number of ring atoms and heteroatoms indicated, wherein each ring in the fused system can be unsaturated, partially unsaturated, or saturated. Therefore, each ring in the fused tricyclic moiety can be aromatic or non aromatic.

[0059] As used herein, a wavy line, ">~w ", that intersects a single, double or triple bond in any chemical structure depicted herein, represent the point attachment of the single, double, or triple bond to the remainder of the molecule. Additionally, a bond extending to the center of a ring (e.g., a phenyl ring) is meant to indicate attachment at any of the available ring vertices. One of skill in the art will understand that multiple substituents shown as being attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible.

[0060] The term “pharmaceutically acceptable” refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0061] As used herein, the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of thedesired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines, such as arginine, betaine, caffeine, choline, N,N" -dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethyhnorpholine, 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 sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydriodic, or phosphorous acids, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic. Also included are salts of amino acids such as arginate, and salts of organic acids like glucuronic or galactunoric acids (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0062] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0063] Certain compounds of Formula (I) possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within thescope of the present disclosure. When a stereochemical depiction is shown, it is meant to refer to the compound in which one of the isomers is present and substantially free of the other isomer. “Substantially free of’ another isomer indicates at least an 80 / 20 ratio of the two isomers, more preferably 90 / 10, or 95 / 5 or more. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0064] Certain compounds of Formula (I) can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of Formula (I) may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0065] Certain compounds of the present disclosure can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure.

[0066] 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 as2H,3H,nC,13C,14C,13N,15N,150,170,180,32P,33P,35S,18F,36C1,123I, and1251, respectively. Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Additionally, isotopic variants of Formula (I) or a subembodiment thereof can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. Isotopically-labeled compounds (e.g., those labeled with3H and14C) 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 afford certaintherapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo halflife or reduced dosage requirements). In some embodiments, in compounds disclosed herein, including in Table 1 below one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,nC, and15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. All isotopic variations of Formula (I) or a subembodiment thereof, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0067] 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.

[0068] “Disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0069] “In need of treatment” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver’s expertise.

[0070] The terms “administration”, “administer” and the like, as they apply to, for example, a subject, cell, tissue, organ, or biological fluid, refer to contact of, for example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, or a diagnostic agent to the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.

[0071] The terms “proliferative disorder,” “proliferative condition,” and “cell proliferation’ are used interchangeably herein and pertain to an unwanted or uncontrolled cellularproliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, gastric, liver, pancreas, brain, and skin.

[0072] The terms “treat”, “treating”, treatment” and the like refer to a course of action (such as administering an inhibitor of PRMT5 or a pharmaceutical composition comprising the same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a patient, or at least one of the symptoms associated with a disease, disorder, condition afflicting a patient. Thus, treatment includes inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.

[0073] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a PRMT5 inhibitor or a pharmaceutical composition comprising the same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a patient’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a patient predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition, or inhibiting progression thereof to a harmful or otherwise undesired state.

[0074] 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.

[0075] The phrase “therapeutically effective amount” as used herein means the amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive effect on any symptom, aspect, or characteristic of a disease, disorder or condition when administered to the patient. It may vary depending on the compound, the disease and its severity and the age and weight of the subject to be treated. The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the patient’s condition, and the like. By way of example, measurement of the serum level of a compound Formula (I) or a pharmaceutically acceptable salt thereof (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been used.

[0076] The term “antibody” means an immunoglobulin and is a molecule containing an antigen-binding site immunospecifically binding to an antigen. The class of the antibody of the present disclosure may be any of IgG, IgE, IgM, IgD, IgA, and IgY and is preferably IgG. The subclass of the antibody of the present disclosure may be any of IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2 and is preferably IgGl or IgG2. The antibody may be derived from any species, and preferred examples of the species can include humans, rats, mice, and rabbits. When the antibody is derived from other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody of the present disclosure may be a polyclonal antibody or a monoclonal antibody. In an embodiment, the antibody is a monoclonal antibody. The antibody of the present disclosure is capable of targeting tumor cells. In an embodiment, the antibody of the present disclosure is conjugated with an antitumor compound having antitumor activity via a linker, the antibody preferably possesses one or more of a property of recognizing a tumor cell, a property of binding to a tumor cell, a property of internalizing in a tumor cell, and a property of damaging a tumor cell. In an embodiment, the antibody is a monoclonal antibody that is reactive with a target antigen or epitope of an antigen expressed on a cancer or malignant cell. Techniques for preparing monoclonal antibodies against target antigen are known in the art. Non limiting target antigens are B7-H3, B7-H4, Trop-2, PSMA, BCMA, folate receptor, AXL, EGF receptor (ErbBl), ErbB2, ErbB3, EGFRvIII, 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 (FRa), c-Met,Nectin-4, Mesothelin, delta-like ligand 3 (DLL3), PTK7, GPNMB, Ley, CA6, CanAng, Av integrin, SLC44A4, CEACAM5, AGS- 16, Anti-Cripto, Carbonic Anhydrase 9, Mesotheilin, TENB2, 5T4, VEGF, insulin-like growth factor (ILGF), MUC1 and TA-MUC1.COMPOUNDS

[0077] In one aspect, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinX1is C(RlaRlb), O, or NR1;X2is C(R2aR2b), O, or NR2;X3is C(R3aR3b), O, or NR3;X4is C(R4aR4b), O, NR4, S, S(O), or S(O)2;X5is C(R5aR5b), O, NR5, S, S(O), or S(O)2;X6is C(R6aR6b), O, NR6, S, S(O), or S(O)2;R1, R2, and R3are each independently H or Ci-4 alkyl;Rla,Rlb, R2a,R2b, R3a, and R3bare each independently H, Ci-4 alkyl, halo, or Ci-4 haloalkyl;R4, R5, and R6are each independently H, Ci-4 alkyl, or Ci-4 hydroxyalkyl;R4a,R4b, R5a>R5b>R6a, and R6bare each independently H, Ci-4 alkyl, C1-4 haloalkyl, CH hydroxyalkyl, or C1-4 haloalkyl(OH); ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is Ce-io aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R7is independently C1-6 alkyl, C1-6 haloalkyl, halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, or -C(O)OCi-6haloalkyl;each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, OH, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, - C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, -C(O)OCi-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6 cycloalkyl, -O-C3-6 cycloalkyl, and heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently C1.4 alkyl, halo, C1-4 haloalkyl, CN, OH, or C1-4 alkoxy; alternatively, one R7attached to ring A and one R8attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a, and ring A, ring B, and ring C form a fused tricyclic moiety; each R7ais independently C1-4 alkyl, halo, C1-4 haloalkyl, OH, or C1-4 alkoxy; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; and R9is H, Ci-4 alkyl, halo, or C1-4 haloalkyl.

[0078] In some aspects, provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, whereinX1is C(RlaRlb), O, or NR1;X2is C(R2aR2b), O, or NR2;X3is C(R3aR3b), O, or NR3;X4is C(R4aR4b), O, NR4, S, S(O), or S(O)2;X5is C(R5aR5b), O, NR5, S, S(O), or S(O)2;X6is C(R6aR6b), O, NR6, S, S(O), or S(O)2;R1, R2, and R3are each independently H or C1-4 alkyl;Rla,Rlb, R2a,R2b, R3a, and R3bare each independently H, C1.4 alkyl, halo, or C1.4 haloalkyl;R4, R5, and R6are each independently H, C1-4 alkyl, or C1-4 hydroxyalkyl;R4a, R4b, R5a,R5b, R6a, and R6bare each independently H, Ci-4 alkyl, Ci-4 haloalkyl, C hydroxyalkyl, or Ci-4 haloalkyl(OH); ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is Ce-io aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R7is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, Ci-6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, or -C(O)OCi-6haloalkyl; each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, C3- 6 cycloalkyl, -O-C3-6 cycloalkyl, -C(O)Ci-6 alkyl, -C(O)Ci-6 haloalkyl, -C(O)OCi-6 alkyl, -C(O)OCi-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently C1-4 alkyl, halo, or C1-4 haloalkyl; alternatively, one R7attached to ring A and one R8attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a, and ring A, ring B, and ring C form a fused tricyclic moiety; each R7ais independently C1-4 alkyl, halo, or C1-4 haloalkyl; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; and R9is H, C1.4 alkyl, halo, or C1-4 haloalkyl.

[0079] In some aspects, provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein X1is C(RlaRlb), O, or NR1;X2is C(R2aR2b), O, or NR2;X3is C(R3aR3b), O, or NR3;X4is C(R4aR4b), 0, NR4, S, S(O), or S(O)2;X5is C(R5aR5b), O, NR5, S, S(O), or S(O)2;X6is C(R6aR6b), O, NR6, S, S(O), or S(O)2;R1, R2, and R3are each independently H or C1-4 alkyl;Rla,Rlb, R2a,R2b, R3a, and R3bare each independently H, C1.4 alkyl, halo, or C1.4 haloalkyl;R4, R5, and R6are each independently H, C1-4 alkyl, or C1-4 hydroxyalkyl;R4a, R4b, R5a,R5b, R6a, and R6bare each independently H, C1-4 alkyl, C1-4 haloalkyl, CH hydroxyalkyl, or C1-4 haloalkyl(OH); ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is Ce-io aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R7is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, or -C(O)OCi-6haloalkyl; each R8is independently C1-6 alkyl, C1-6 haloalkyl, halo, Ci-6 alkoxy, C1-6 haloalkoxy, - C(O)Ci-6alkyl, -C(O)Ci6haloalkyl, -C(O)OCi6alkyl, -C(O)OCi-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently C1.4 alkyl, halo, or C1.4 haloalkyl; alternatively, one R7attached to ring A and one R8attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a, and ring A, ring B, and ring C form a fused tricyclic moiety; each R7ais independently C1-4 alkyl, halo, or C1-4 haloalkyl; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; and R9is H, Ci-4 alkyl, halo, or C1-4 haloalkyl.

[0080] In some embodiments of Formula (I), one R7attached to ring A and one R8attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a, and ring A, ring B, and ring C form a fused tricyclic moiety.

[0081] In some embodiments, the compound is represented by Formula (la):or the pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; q is 0, 1, or 2; and ring A, ring B, ring C, X1, X2, X3, X4, X5, X6, R7, R7a, R8, and R9are each defined in Formula (I) and described in any one of the embodiments thereof.

[0082] In some aspects, provided herein are compounds of Formula (la):or a pharmaceutically acceptable salt thereof, whereinX1is C(RlaRlb), O, or NR1;X2is C(R2aR2b), O, or NR2;X3is C(R3aR3b), O, or NR3;X4is C(R4aR4b), O, NR4, S, S(O), or S(O)2;X5is C(R5aR5b), O, NR5, S, S(O), or S(O)2;X6is C(R6aR6b), O, NR6, S, S(O), or S(O)2;R1, R2, and R3are each independently H or C1.4 alkyl;Rla,Rlb, R2a,R2b, R3a, and R3bare each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl;R4, R5, and R6are each independently H, C1-4 alkyl, or C1-4 hydroxyalkyl;R4a, R4b, R5a,R5b, R6a, and R6bare each independently H, Ci-4 alkyl, Ci-4 haloalkyl, C hydroxyalkyl, or Ci-4 haloalkyl(OH); ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S; ring B isphenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, or 2; q is 0, 1, or 2; each R7is independently C1-6 alkyl, C1-6 haloalkyl, halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6 haloalkyl, -C(O)OCi-6 alkyl, or -C(O)OCi-6haloalkyl; each R7ais independently C1-4 alkyl, halo, CM haloalkyl, OH, or C1-4 alkoxy; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; each R8is independently C1-6 alkyl, C1-6 haloalkyl, halo, OH, CN, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, - C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, -C(O)OCi-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6 cycloalkyl, -O-C3-6 cycloalkyl, and heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently C1.4 alkyl, halo, C1-4 haloalkyl, CN, OH, or C1-4 alkoxy; and R9is H, C1.4 alkyl, halo, or C1-4 haloalkyl.

[0083] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein: each R7is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, or -C(O)OCi-6haloalkyl; each R7ais independently C1.4 alkyl, halo, or C1.4 haloalkyl; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; each R8is independently C1-6 alkyl, C1-6 haloalkyl, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, C3- 6 cycloalkyl, -O-C3-6 cycloalkyl, -C(O)Ci-6 alkyl, -C(O)Ci-6 haloalkyl, -C(O)OCi-6alkyl, -C(O)OCi-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently Ci-4 alkyl, halo, or Ci-4 haloalkyl; andR9is H, Ci-4 alkyl, halo, or Ci-4 haloalkyl.

[0084] In some embodiments, the compound is represented by Formula (Ial-1):or the pharmaceutically acceptable salt thereof, wherein Xais O, NH, N(CI-4 alkyl), CH2, or CHR7; p is 0, 1, or 2; q is 0, 1, or 2; and ring C, X1, X2, X3, X4, X5, X6, R7, R7a, R8, and R9are each defined in Formula (I) and described in any one of the embodiments thereof.

[0085] In some embodiments, the compound is represented by Formula (la 1-2):(Ial-2), or the pharmaceutically acceptable salt thereof, wherein Xais O, NH, N(CI-4 alkyl), CH2, or CHR7; p is 0, 1, or 2; q is 0, 1, or 2; and ring C, X1, X2, X3, X4, X5, X6, R7, R7a, R8, and R9are each defined in Formula (I) and described in any one of the embodiments thereof.

[0086] In some embodiments, the compound is represented by Formula (Ia2-1):or the pharmaceutically acceptable salt thereof, wherein Xais O, NH, N(CI-4 alkyl ), CH2, or CHR7; X7aand X7bare each independently absent, O, CH2, or CHR7a, provided that X7aand X7bare not each O; p is 0, 1, or 2; q is 0, 1, or 2; and X1, X2, X3, X4, X5, X6, R7, R7a, R8, and R9are each defined in Formula (I) and described in any one of the embodiments thereof.

[0087] In some embodiments, the compound is represented by Formula (Ia2-2):or the pharmaceutically acceptable salt thereof, wherein Xais O, NH, N(CI-4 alkyl), CH2, or CHR7; X7aand X7bare each independently absent, O, CH2, or CHR7a, provided that X7aand X7bare not each O; p is 0, 1, or 2; q is 0, 1, or 2; and X1, X2, X3, X4, X5, X6, R7, R7a, R8, and R9are each defined in Formula (I) and described in any one of the embodiments thereof.

[0088] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), or any one of subformulae (e.g., (la), (Ial-1), (lal- 2), (Ia2-1), (Ia2-2), (lb), and (Ibl)), or a subembodiment thereof, wherein no more than two of X1, X2, and X3are N. In some embodiments, no more than two of X1, X2, and X3are O. In some embodiments, at least one of X1, X2, and X3comprises a carbon atom (e.g., X1is C(RlaRlb), X2is C(R2aR2b), or X3is C(R3aR3b)). In some embodiments, X1is C(RlaRlb); X2is C(R2aR2b), O, or NR2; and X3is C(R3aR3b). In some embodiments, X1is NR1; X2is C(R2aR2b); and X3is O.

[0089] Unless specifically indicated otherwise, embodiments or subembodiments related to Formula (I) are applicable to any one of Formulae (la), (Ial-1), (Ial-2), (Ia2-1), (Ia2-2), (lb), (Ibl), (Ila), (Ila- 1), and (IIa-2).

[0090] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is C(RlaRlb) or NR1.

[0091] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is NR1.

[0092] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R1is H or methyl.

[0093] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R1is H.

[0094] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is NR1; and R1is H. In some embodiments, X1is NH.

[0095] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is C(RlaRlb).

[0096] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R1aand Rlbare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0097] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Rlaand Rlbare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0098] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Rlaand Rlbare each H.

[0099] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is C(RlaRlb); and Rlaand Rlbare each H. In some embodiments, X1is CH2.

[0100] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein Rlais methyl, and Rlbis H.

[0101] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is O.

[0102] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2is NR2. In some embodiments, R2is H or methyl. In some embodiments, R2is H.

[0103] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2is NR2; and R2is H. In some embodiments, X2is NH.

[0104] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2is C(R2aR2b) or O.

[0105] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2is O.

[0106] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2is C(R2aR2b).

[0107] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R2aand R2bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0108] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R2aand R2bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0109] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R2aand R2bare each H.

[0110] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X2is C(R2aR2b); and R2aand R2bare each H. In some embodiments, X2is CH2.

[0111] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R2ais methyl, and R2bis H.

[0112] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3is C(R3aR3b) or NR3.

[0113] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3is NR3.

[0114] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R3is H or methyl.

[0115] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3is C(R3aR3b).

[0116] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R3aand R3bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0117] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R3aand R3bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0118] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R3aand R3bare each H.

[0119] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3is C(R3aR3b); and R3aand R3bare each H. In some embodiments, X3is CFh.

[0120] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R3ais methyl, and R3bis H.

[0121] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X3is O.

[0122] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is C(RlaRlb); X2is C(R2aR2b), O, or NR2; and X3is C(R3aR3b). In some embodiments, X1is CH2; X2is O, NH, or CH2; and X3is CH2.

[0123] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), or any one of subformulae (e.g., (la), (Ial-1), (lal- 2), (Ia2-1), (Ia2-2), (lb), and (Ibl)), or a subembodiment thereof, wherein no more than two of X4, X5, and X6are N. In some embodiments, no more than two of X4, X5, and X6are O. In some embodiments, at least one of X4, X5, and X6comprises a carbon atom (e.g., X4is C(R4aR4b), X5is C(R5aR5b), or X6is C(R6aR6b)). In some embodiments, X4is C(R4aR4b); X5is O or NR4; and X6is C(R6aR6b). In some embodiments, X1is X4is C(R4aR4b); X5is O; and X6is C(R6aR6b).

[0124] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4is C(R4aR4b), O, or NR4.

[0125] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4is O.

[0126] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4is NR4.

[0127] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R4is H or methyl.

[0128] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R4is H.

[0129] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4is C(R4aR4b).

[0130] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R4aand R4bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0131] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R4aand R4bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0132] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R4aand R4bare each H.

[0133] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4is C(R4aR4b); and R4aand R4bare each H. In some embodiments, X4is CH2.

[0134] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R4ais methyl, and R4bis H.

[0135] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4is C(R4aR4b); R4ais methyl; and R4bis H. In some embodiments, X4is CH(CH3).

[0136] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X5is C(R5aR5b), O, or NR5.

[0137] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X5is O.

[0138] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X5is NR5.

[0139] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R5is H or methyl.

[0140] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R5is H.

[0141] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X5is C(R5aR5b).

[0142] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R5aand R5bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0143] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R5aand R5bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0144] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R5aand R5bare each H.

[0145] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X5is C(R5aR5b); and R5aand R5bare each H. In some embodiments, X5is CH2.

[0146] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R5ais methyl, and R5bis H.

[0147] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X5is C(R5aR5b); R5ais methyl; and R5bis H. In some embodiments, X5is CH(CH3).

[0148] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X6is C(R6aR6b), O, or NR6.

[0149] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X6is O.

[0150] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X6is NR6.

[0151] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R6is H or methyl.

[0152] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R6is H.

[0153] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X6is C(R6aR6b).

[0154] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R6aand R6bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0155] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R6aand R6bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0156] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R6aand R6bare each H.

[0157] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X6is C(R6aR6b); and R6aand R6bare each H. In some embodiments, X6is CFh.

[0158] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R6ais methyl, and R6bis H.

[0159] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X6is C(R6aR6b); R6ais methyl; and R6bis H. In some embodiments, X6is CH CHs).

[0160] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X4is C(R4aR4b); Xsis O; X6is C(R6aR6b); and R4a, R4b, R6a, and R6bare each independently H or Ci-4 alkyl. In some embodiments, X4is CHR4a; X5is O; X6is CHR6a; and R4aand R6aare each independently H or C1-4 alkyl. In some embodiments, X4is CHR4a; X5is O; X6is CH2; and R4ais H or C1-4 alkyl. In some embodiments, X4is CH2 or CH(CH3); X5is O; and X6is CH2 or CH(CH3). In some embodiments, X4is CH2; X5is O; and X6is CH2. In some embodiments, X4is CH(CH3); X5is O; and X6is CH2.

[0161] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is CH2; X2is O, NH, or CH2; X3is CH2; X4is CHR4a; X5is O; X6is CH2; and R9is H.

[0162] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S.

[0163] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 1 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S.

[0164] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additionalheteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0165] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0166] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0167] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0168] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl.

[0169] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

[0170] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is piperidinyl, substituted with 1 or 2 R7.

[0171] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is piperazinyl, substituted with 1 or 2 R7.

[0172] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is morpholinyl, substituted with 1 or 2 R7.

[0173] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein, when ring C is present (i.e., formed by one R7attached to ring A and one R8attached to ring B, as defined herein), ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R7. In some embodiments, when ring C is present, ring A is piperidinyl substituted with 0, 1, or 2 R7. In some embodiments, when ring C is present, ring A is piperazinyl substituted with 0, 1, or 2 R7. In some embodiments, when ring C is present, ring A is morpholinyl substituted with 0, 1, or 2 R7.

[0174] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R7. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with 0, 1, or 2 R7. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperazinyl substituted with 0, 1, or 2 R7. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with 0, 1, or 2 R7.

[0175] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or Ci-6 haloalkoxy.

[0176] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is independently C1.4 alkyl, Ci-4 haloalkyl, or halo.

[0177] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7isindependently Ci-4 alkyl, halo, or Ci-4 alkoxy. In some embodiments, each R7is independently Ci-4 alkyl, halo, OH, or Ci-4 alkoxy.

[0178] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0179] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is independently methyl, ethyl, fluoro, chloro, bromo, methoxy, or ethoxy.

[0180] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is independently methyl, fluoro, or methoxy.

[0181] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is independently methyl or fluoro.

[0182] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is independently methyl, fluoro, OH, or methoxy.

[0183] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is independently methyl or methoxy.

[0184] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R5is independently methyl or methoxy.

[0185] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is methyl.

[0186] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is fluoro.

[0187] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is OH.

[0188] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7is methoxy.

[0189] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein, when ring C is present (i.e., formed by one R7attached to ring A and one R8attached to ring B, as defined herein), ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R7; and each R7is independently methyl, fluoro, or methoxy.

[0190] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein, when ring C is present, ring A is piperidinyl substituted with 0 R7. In some embodiments of Formula (I) or any one of the embodiments thereof, when ring C is present, ring A is piperidinyl substituted with one R7; and R7is methyl, fluoro, or methoxy. In some embodiments of Formula (I) or any one of the embodiments thereof, when ring C is present, ring A is piperidinyl substituted with one R7; and R7is methyl. In some embodiments of Formula (I) or any one of the embodiments thereof, when ring C is present, ring A is piperidinyl substituted with one R7; and R7is fluoro. In some embodiments of Formula (I) or any one of the embodiments thereof, when ring C is present, ring A is piperidinyl substituted with one R7; and R7is methoxy.

[0191] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein, when ring C is present, ring A is morpholinyl substituted with 0 R7. In some embodiments of Formula (I) or any one of the embodiments thereof, when ring C is present, ring A is morpholinyl substituted with one R7; and R7is methyl or fluoro. In some embodiments of Formula (I) or any one of the embodiments thereof, when ring C is present, ring A is morpholinyl substituted with one R7; and R7is methyl.

[0192] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (la):wherein, ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; q is 0, 1, or 2; and ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0193] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or (la), or a subembodiment thereof, wherein: X1is C(RlaRlb);X2is C(R2aR2b), O, or NR2; R2is H or Cu alkyl;X3is C(R3aR3b);X4is C(R4aR4b); X5is O; X6is C(R6aR6b);Rla, Rlb, R2a, R2b, R3a, R3b, R4a, R4b, R6a, and R6bare each independently H or C1-4 alkyl; ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is N or O; ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; ring C is C5-7 cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a; p is 0 or 1; q is 1;R7is C1-4 alkyl, halo, or C1-4 alkoxy;R8is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, or C3-6 cycloalkyl; and R9is H.

[0194] Unless specifically indicated otherwise, embodiments or subembodiments related to Formula (la) are applicable to any one of Formulae (Ial-1), (Ial-2), (Ia2-1), (Ia2-2), (II), (Ha), (Ha-1), and (Ha-2).

[0195] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la), or a subembodiment thereof, wherein: ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is independently N or O; ring B is phenyl or heteroaryl having 6 ring members with 1 to 2 nitrogen atom ring vertices; and ring C is C5-6 cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

[0196] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la), or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl. In some embodiments, ring A is piperidinyl, piperazinyl, or morpholinyl.

[0197] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la), or a subembodiment thereof, wherein ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring B is phenyl or pyridyl.

[0198] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R7; and each R7is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R7; and each R7is independently methyl, fluoro, or methoxy.

[0199] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl substituted with 0 R7. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R7; and R7is methyl, fluoro,OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R7; and R7is methyl, fluoro, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R7; and R7is methyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R7; and R7is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R7; and R7is OH. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R7; and R7is methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R7; and R7is OH.

[0200] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is morph olinyl substituted with 0 R7. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with one R7; and R7is methyl or fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with one R7; and R7is methyl.

[0201] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl substituted with 2 vicinal R7; and each R7is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R7; one R7is methyl; and the other R7is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R7; one R7is methyl; and the other R7is OH. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R7; one R7is methyl; and the other R7is methoxy.

[0202] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl substituted with 2 geminal R7; and each R7is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R7; one R7is methyl; and the other R7is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R7; one R7is methyl; and the other R7is OH. Insome embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R7; one R7is methyl; and the other R7is methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R7; and each R7is methyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R7; and each R7is fluoro.

[0203] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperazinyl, substituted with 2 vicinal R7or 2 geminal R7, wherein each R7is any one of embodiments described herein.

[0204] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is morpholinyl substituted with 2 vicinal R7or 2 geminal R7, wherein each R7is any one of embodiments described herein.

[0205] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ial-1):wherein:Xais O, NH, CH2, or CHR7; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0206] In some embodiments, In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ial-2):or the pharmaceutically acceptable salt thereof, wherein, Xais O, NH, CH2, or CHR7; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0207] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ial-1):wherein,Xais O, CH2, or CHR7; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0208] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C4-7 cycloalkyl substituted with 0, 1, 2, or 3 R7a.

[0209] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C4-6 cycloalkyl substituted with 0, 1, 2, or 3 R7a.

[0210] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C5-6 cycloalkyl substituted with 0, 1 , or 2 R7a.

[0211] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is Ce cycloalkyl substituted with 0, 1, or 2 R7a.

[0212] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C5 cycloalkyl substituted with 0, 1, or 2 R7a.

[0213] With reference to any one of Formulae (I), (la), (Ial-1), and (Ial-2), or any one of embodiments thereof, in some embodiments, ring C is C5-6 cycloalkyl substituted with 0, 1, or 2 R7a. In some embodiments, ring C is C6 cycloalkyl substituted with 0, 1, or 2 R7a. In some embodiments, ring C is C5 cycloalkyl substituted with 0, 1, or 2 R7a.

[0214] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0215] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 4 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0216] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0217] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a.

[0218] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0219] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0220] With reference to any one of Formulae (I), (la), (Ial-1), and (Ial-2), or any one of embodiments thereof, in some embodiments, ring C is heterocycloalkyl having 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a. In some embodiments, ring C is heterocycloalkyl having 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a. In some embodiments, ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a.

[0221] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring C is C5-6 cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O. In some embodiments of Formula (la) or any one of theembodiments thereof, ring C is C5-6 cycloalkyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

[0222] In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is C5-6 cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is C5-6 cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0223] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydropyranyl substituted with 0, 1, or 2 R7a.

[0224] In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl, each of which is independently substituted with 0 or 1 R7a. In some embodiments, ring C is tetrahydrofuranyl substituted with 0 or 1 R7a. In some embodiments, ring C is tetrahydropyranyl substituted with 0 or 1 R7a. In some embodiments, ring C is oxepanyl substituted with 0 or 1 R7a.

[0225] With reference to any one of Formulae (I), (la), (Ial-1), and (Ial-2), or any one of embodiments thereof, in some embodiments, ring C is tetrahydropyranyl substituted with 0, 1, or 2 R7a. In some embodiments, ring C is tetrahydropyranyl substituted with 0 or 1 R7a. In some embodiments, ring C is tetrahydropyranyl substituted with 0 R7a.

[0226] With reference to any one of Formulae (I), (la), (Ial-1), and (Ial-2), or any one of embodiments thereof, in some embodiments, ring C is tetrahydrofuranyl substituted with 0 or 1 R7a. In some embodiments, ring C is tetrahydrofuranyl substituted with 0 R7a.

[0227] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-1):wherein,Xais absent, O, CH2, or CHR7;X7ais absent, O or CH2, or CHR7a;X7bis absent, O or CH2, or CHR7a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0228] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, whereinXais O, CH2, or CHR7;X7ais O or CH2, or CHR7a;X7bis O or CH2, or CHR7a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0229] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-1):wherein,Xais O, NH, CH2, or CHR7;X7ais absent, O, CH2, or CHR7a;X7bis absent, O, CH2, or CHR7a; p is 0, 1, or 2; and q is 0, 1, or 2, provided that X7aand X7bare not each O.

[0230] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-2):wherein,Xais O, NH, CH2, or CHR7;X7ais absent, O, CH2, or CHR7a;X7bis absent, O, CH2, or CHR7a; p is 0, 1, or 2; and q is 0, 1, or 2, provided that X7aand X7bare not each O.

[0231] In some embodiments of Formula (Ia2-1) or (Ia2-2), or any one of the embodiments thereof, X7aand X7bare not each absent.

[0232] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X7ais O; and X7bis CH2.

[0233] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X7ais CH2; and X71* is O.

[0234] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X7ais CH2; and X7’’ is CH2.

[0235] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X7ais absent; and X76is CH2.

[0236] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X7ais absent; and X711is O.

[0237] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7ais independently C1.4 alkyl, halo, or C1.4 haloalkyl.

[0238] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7ais independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0239] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R7ais independently methyl, fluoro, chloro, or trifluoromethyl

[0240] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein two R7agroups attached to the same carbon atom combine to form oxo.

[0241] In some embodiments of Formula (Ia2- 1 ) or (Ia2-2), or any one of the embodiments thereof, X7ais O, CH2, or CHR7a; and X7bis O, CH2, or CHR7a, provided that X7aand X7bare not each O. In some embodiments, R7ais C1-4 alkyl. In some embodiments, R7ais methyl.

[0242] In some embodiments of Formula (Ia2-1) or (Ia2-2), or any one of the embodiments thereof, X7ais O, and X7bis CH2. In some embodiments, X7ais CH2; and X7bis O. In some embodiments, X7ais CH2, and X7bis CH2. In some embodiments, X7ais O; and X7bis CH(CH3). In some embodiments, X7ais CH(CH3), and X7bis O. In some embodiments, X7ais CH2and X7bis CH(CH3); or X7ais CH(CH3) and X7bis CH2.

[0243] In some embodiments of Formula (Ia2-1) or (Ia2-2), or any one of the embodiments thereof, X7ais absent; and X7bis O.

[0244] In some embodiments of Formula (Ia2-1) or (Ia2-2), or any one of the embodiments thereof, X7ais absent; and X7bis CH2.

[0245] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, or C1-6 haloalkoxy.

[0246] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, or halo.

[0247] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0248] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is independently bromo or trifluoromethyl.

[0249] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), in some embodiments, each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, or C3-6 cycloalkyl. In some embodiments, each R8is independently C1-6 alkyl, Ci-6 haloalkyl, halo, C1-6 haloalkoxy, or C3-6 cycloalkyl.

[0250] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), in some embodiments, q is 1; and R8is Ci-6 alkyl, Ci-6 haloalkyl, halo, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, or C3-6 cycloalkyl. In some embodiments, q is 1; and R8is Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or C 1-6 haloalkoxy.

[0251] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), in some embodiments, q is 1 ; and R8is chloro, CN, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, or trifluoromethyl- O- . In some embodiments, q is 1; and R8is chloro, isopropyl, cyclopropyl, trifluoromethyl, or difluoromethyl-O-. In some embodiments, q is 1; and R8is chloro, trifluoromethyl, or difluoromethyl-O-. In some embodiments, q is 1 ; and R8is chloro. In some embodiments, q is 1 ; and R8is trifluoromethyl. In some embodiments, q is 1 ; and R8is difluoromethyl-O-. In some embodiments, q is 1; and R8is CN.

[0252] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, CN, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, or -O-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl and -O-C3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

[0253] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein each R8is independently chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-

[0254] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R8is Ci-6 alkyl, Ci-6 haloalkyl, halo, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, CN, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, or -O-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl and -O- C3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

[0255] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R8is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-.

[0256] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R8is chloro, trifluoromethyl, or difluoromethyl-O-.

[0257] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 2; and each R8is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

[0258] In some embodiments of Formula (I), or any one of the embodiments thereof, the moietyhas the formula:wherein:Xais O, NH, CH2, or CHR7;X7ais O, CH2, or CHR7a;X7bis O, CH2, or CHR7a; each R7ais independently C1-4 alkyl; each R7is independently F, C1-4 alkyl, or C1-4 alkoxy; andR8is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, or C3-5 cycloalkyl, provided that X7aand X7bare not each O.

[0259] In some embodiments of the above moieties 1 to 12, Xais O, NH, CH2, CHF, C(CH3), or C(OCH3); X7ais O, CH2, or CH(CH3); X7bis O or CH2; R7is F, CH3, or OCH3; R8is chloro, CN, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoromethyl-O- , or trifluoromethyl-O-, provided that X7aand X7bare not each O. In some embodiments of moieties 1 to 4, Xais CH2; X7ais CH2; X7bis O; and R8is chloro, CN, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoromethyl-O-, or trifluoromethyl-O-. In some embodiments of moieties 1 to 4, Xais O; X7ais O; X7bis CH2; and R8is chloro, CN, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoromethyl-O-, or trifluoromethyl-O-.

[0260] In some embodiments of the above moieties 1 to 12, Xais O, CH2, or CHF; X7ais O, CH2, or CH(CH3); X7bis O or CH2; R7is CH3; R8is chloro, isopropyl, cyclopropyl, trifluoromethyl, or difluoromethyl-O-, provided that X7aand X711are not each O. In someembodiments of moieties 1 to 4, Xais CFb; X7ais CH2; X7bis O; and R8is chloro, isopropyl, cyclopropyl, trifluoromethyl, or difhioromethyl-O- In some embodiments of moieties 1 to 4, Xais O; X7ais O; X711is CH2; and R8is chloro, isopropyl, cyclopropyl, trifluoromethyl, or difluoromethyl-O-.

[0261] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0262] In some embodiments of Formula (I), or any one of the embodiment thereof, the moietyhas any one of formulae according to the Amine intermediates inExamples, wherein the nitrogen at the ring A is attached to the remainder of the molecule.

[0263] With reference to any one of Formulae (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), or any one of the embodiments thereof, in some embodiments, X1is C(RlaRlb); X2is C(R2aR2b), O, or NR2; X3is C(R3aR3b); X4is C(R4aR4b); X5is O; X6is C(R6aR6b); R2is H or Ci-4 alkyl; Rla, Rlb, R2a, R2b, R3a, R3b, R4a, R4b, R6a, and R6bare each independently H or CM alkyl; and R9is H.

[0264] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), or any one of the embodiments thereof, in some embodiments, the moietyor NR2; and R4aand R6aare each independently H or C1-4 alkyl. In some embodiments, X2is O, NH, or CH2; R4ais H or C1-4 alkyl; and R6ais H. In some embodiments, X2is O, NH, or CH2; R4aand R6aare each independently H or methyl. In some embodiments, X2is O, NH, or CH2; and R4aand R6aare each H. In some embodiments, X2is O, NH, or CH2; R4ais methyl; and R6ais H. In some embodiments, X2is O, NH, or CH2; R4ais H; and R6ais methyl.

[0265] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), or any one of the embodiments thereof, in some embodiments, the moietyeach defined and described herein. In some embodiments, X2 is O, NH, or CH2; and R4ais H or C1-4 alkyl. In some embodiments, X2 is O; and R4ais H. In some embodiments, X2 is O; and R4ais methyl. In some embodiments, X2 is NH; and R4ais H. In some embodiments, X2 is NH; and R4ais methyl. In some embodiments, X2 is CH2; and R4ais H. In some embodiments, X2 is CH2; and R4ais methyl.

[0266] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), or any one of the embodiments thereof, in some embodiments, the moietyalkyl. In some embodiments, R4ais H. In some embodiments, R4ais methyl.

[0267] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), or any one of the embodiments thereof, in some embodiments, the moietywherein R4ais H or Ci-4 alkyl. In some embodiments, R4ais H. In some embodiments, R4ais methyl.

[0268] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), or any one of the embodiments thereof, in some embodiments, the moietyalkyl. In some embodiments, R4ais H. In some embodiments, R4ais methyl.

[0269] With reference to any one of Formulae (I), (la), (Ial-1), (Ial-2), (Ia2-1), and (Ia2-2), or any one of the embodiments thereof, in some embodiments, the moietyhas one of the formulae selected from:

[0270] In some embodiments, the compound is represented by Formula (II):or a pharmaceutically acceptable salt thereof, wherein:wherein:Xais O, NH, NR7, CH2, CHR7, or C(R7)2;X7ais absent, 0, CH2, or CHR7a;X7bis absent, O, CH2, or CHR7a, provided that X7aand X7bare not each absent or O; and a total number of R7groups is no more than 2; and p, q, ring B, X2, R3a, R4a, R6a, R7, and R8are each defined in Formula (I) or (la), and described in any one of the embodiments thereof.

[0271] Unless specifically indicated otherwise, embodiments or subembodiments related to Formula (II) are applicable to any one of Formulae (Da), (IIa-1), and (IIa-2).

[0272] In some embodiments of Formula (II), R3aand R6aare each H.

[0273] In some embodiments, the compound is represented by Formula (Ila):wherein: ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl;Xais O, NH, NR7, CH2, CHR7, or C(R7)2;X7ais absent, O, CH2, or CHR7a; andX7bis absent, O, CH2, or CHR7a, provided that X7aand X7bare not each absent or O; and a total number of R7groups is no more than 2.

[0274] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (II), (Ila), or a subembodiment thereof, wherein ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring B is phenyl. In some embodiments, ring B is pyridyl. In some embodiments, ring B is pyrazinyl. In some embodiments, ring B is pyrimidinyl. In some embodiments, ring B is pyridazinyl.

[0275] In some embodiments, the compound is represented by Formula (IIa-1):wherein:Xais O, NH, N(CI-4alkyl), CH2, CHR7, or C(R7)2;X7ais absent, O, CH2, or CHR7a; andX7bis absent, O, CH2, or CHR7a, provided that X7aand X7bare not each absent or O; and a total number of R7groups is no more than 2.

[0276] In some embodiments, the compound is represented by Formula (IIa-2):wherein:Xais O, NH, N(CI-4alkyl), CH2, CHR7, or C(R7)2;X7ais absent, O, CH2, or CHR7a; andX7bis absent, O, CH2, or CHR7a, provided that X7aand X7bare not each absent or O; and a total number of R7groups is no more than 2.

[0277] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, X2is O.

[0278] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, X2is NH.

[0279] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, X2is CH2.

[0280] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais CH2, CHR7, or C(R7)2.

[0281] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais O.

[0282] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais NH.

[0283] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais CH2.

[0284] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais O, NH, CH2, or CHR7; X7ais O, CH2, or CHR7a; X7bis O, CH2, or CHR7a; and p is 0 or 1.

[0285] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais O, NH, or CH2; X7ais O, CH2, or CHR7a; X7bis O, CH2, or CHR7a; and p is 0, 1, or 2.

[0286] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais C(R7)2; X7ais O, CH2, or CHR7a; X7bis O, CH2, or CHR7a; and p is 0.

[0287] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, X7ais O and X7bis CH2; X7ais CH2and X7bis O; X7ais CH2and X7bis CH2; X7ais O and X7bis CH(CH3); X7ais CH(CH3) and X7bis O; X7ais CH2and X7bis CH(CH3); X7ais CH(CH3) and X7bis CH2; X7ais absent and X7bis CH2; or X7ais absent and X7bis O. In some embodiments, X7ais O and X7bis CH2. In some embodiments, X7ais CH2and X7bis O. In some embodiments, X7ais CH2and X711is CH2. In some embodiments, X7ais O and X is CH(CH3). In some embodiments, X7ais CH(CH3) and X7bis O. In some embodiments, X7ais CH2and X7bis CH(CH3). In some embodiments, X7ais CH(CH3) and X7bis CH2. In some embodiments, X7ais absent and X7bis CH2. In some embodiments, X7ais absent and X7bis O.

[0288] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, each R7is independently Ci-4 alkyl, halo, OH, or Ci-4 alkoxy. In some embodiments, each R7is independently methyl, fluoro, OH, or methoxy. In some embodiments, each R7is independently methyl, fluoro, or methoxy.

[0289] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, each R8is independently C1-6 alkyl, C1-6 haloalkyl, halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, CN, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, or -O-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl and -O-C3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

[0290] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, each R8is independently chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-

[0291] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, q is 1; and R8is C1-6 alkyl, C1-6 haloalkyl, halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, CN, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, or -O-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl and -O-C3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

[0292] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, q is 1; and R8is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HOC-CH2-O-. In some embodiments, q is 1; and R8is chloro, trifluoromethyl, or difluoromethyl-O-. In some embodiments, q is 2; and each R8is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

[0293] In some embodiments of Formula (la), the moietyformula:wherein:Xais O, NH, CH2, or CHR7;X7ais O, CH2, or CHR7a;X7bis O, CH2, or CHR7a; each R7ais independently C1-4 alkyl; each R7is independently F, OH, C1-4 alkyl, or C1-4 alkoxy; andR8is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, C2alkynyl, -O-C2-4 alkynyl, C3-6 cycloalkyl, or -O-C3.6 cycloalkyl, wherein the C3-6 cycloalkyl and -O- C3-6 cycloalkyl are each independently unsubstituted or substituted with CN, provided that X7aand X7bare not each O.

[0294] In some embodiments of Formula (II), (Ila), or related Formula (IIa-1) or (IIa-2), the moietyany one of the above moieties 1 to 12.

[0295] In some embodiments of the above moieties 1 to 12, Xais O, NH, CH2, CHF, C(CH3), C(OH), or C(OCH3); X7ais O, CH2, or CH(CH3); X7bis O or CH2; R7is F, CH3, OH, or OCH3; and R8is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl,NC-cyclopropyl-, cyclopropyl-O-, HOC-, or HOC-CH2-O-, provided that X7aand X7bare not each O. In some embodiments of the above moieties 1 to 12, R8is chloro, trifluoromethyl, or difluoromethyl-O-.

[0296] In some embodiments of the above moieties 1 to 12, Xais O, CH2, or CHF; X7ais O, CH2, or CH(CHs); X7bis O or CH2; R7is CH3; and R8is chloro, trifluoromethyl, or difluoromethyl-O-, provided that X7aand X7bare not each O. In some embodiments of moieties 1 to 4, Xais CH2; X7ais CH2; X7bis O; and R8is chloro, trifluoromethyl, or difluoromethyl-O-. In some embodiments of moieties 1 to 4, Xais O; X7ais O; X7bis CH2; and R8is chloro, trifluoromethyl, or difluoromethyl-O-.

[0297] In some embodiments of Formula (la) or any one of related subformulae (II), (Ila),(IIa-1), and (IIa-2), the moietyany one of the formulae according to Amine intermediates Al, A2, A4 to A6, and A9 to Al 11 in the Examples, wherein the nitrogen at the ring A is attached to the remainder of the molecule.

[0298] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, X2is O, NH, or CH2.

[0299] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, R4ais H or C1-4 alkyl. In some embodiments, R4ais H; or R4ais methyl.

[0300] In some embodiments of Formula (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, X2 is O, NH, or CH2; and R4ais H or C1-4 alkyl. In some embodiments, X2 is O; and R4ais H. In some embodiments, X2 is O; and R4ais methyl. In some embodiments, X2 is NH; and R4ais H. In some embodiments, X2 is NH; and R4ais methyl. In some embodiments, X2 is CH2; and R4ais H. In some embodiments, X2 is CH2; and R4ais methyl.

[0301] In some embodiments of Formula (I), (la), (II), (Ila), (IIa-1), or (IIa-2), or a subembodiment thereof, wherein:

[0302] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (lb)wherein,Xais O, CH2, or CHR7; ring B is heteroaryl comprising 9 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; and q is 0, 1, 2, or 3.

[0303] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein p is 1.

[0304] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein p is 2.

[0305] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein q is 0.

[0306] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein q is 1.

[0307] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein q is 2.

[0308] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, having Formula (Ibl)

[0309] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, Ci-6 haloalkoxy, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1 , or 2 R8a.

[0310] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is independently Ci-4 alkyl, Ci-4 haloalkyl, halo, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a.

[0311] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is independently heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1 , or 2 R8a.

[0312] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 R8a.

[0313] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8is piperidinyl substituted with 0, 1, or 2 R8a.

[0314] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8ais Cu alkyl.

[0315] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8ais independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0316] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R8ais methyl.

[0317] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moiety

[0318] In some embodiments of Formula (lb) or (Ibl), or any one of the embodiments thereof, the moietyX2and R4aare each defined and described herein. In some embodiments, X2is O, NH, orCH2; and R4ais H or Ci-4 alkyl. In some embodiments, X2is O; and R4ais H. In some embodiments, X2is O; and R4ais methyl. In some embodiments, X2is NH; and R4ais H. In some embodiments, X2is NH; and R4ais methyl. In some embodiments, X2is CH2; and R4ais H. In some embodiments, X2is CH2; and R4ais methyl.

[0319] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R9is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0320] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R9is H, methyl, fluoro, chloro, or trifluoromethyl.

[0321] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R9is H.

[0322] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R9is methyl.

[0323] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R9is fluoro.

[0324] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the compound is selected from Table 1.

[0325] In some embodiments, the present disclosure provides a compound of Examples 1 to 3 and 5 to 112 in Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is selected from a compound of Examples 1 to 112, or a pharmaceutically acceptable salt thereof.

[0326] 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 readilyundergo chemical changes under physiological conditions to provide a pharmacologically 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 metabolically hydrolyzed to the carboxylic acid, the active entity. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0327] 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 “(R)” or “(S)”. When the absolute stereochemistry of one or more stereocenters in an isolated compound is not known, the following labels are indicated at the stereocenter of the displayed structure: “&” (e.g., “&1”); or “or” (e.g., “orl,” “or2,” or “or3”). Each of these labels is further described below.

[0328] The label “&” in the structures in the present disclosure refers to both chiral centers being present in the mixture. When multiple stereocenters are labelled with “&1” the relative stereochemistry between them is determined. The term “rac” in the chemical names denotes a racemic mixture.

[0329] For example, Al is a racemic mixture of two isomers, wherein the relative stereochemistry between two centers labeled with “&1” is known, as shown below:

[0330] The label “or” in the structures refers to the specific chiral center being a single undefined isomer but absolute stereochemistry was not determined. When multiplestereocenters are labelled with different labels, the relative stereochemistry between them is not determined. For example, in a compound with stereocenters labelled as “orl” and “or2”, the relative stereochemistry between the differently labelled stereocenters is not determined. When multiple stereocenters are labelled with the same label, the relative stereochemistry between the same labelled stereocenters is determined but not the absolute stereochemistry. For example, for all stereocenters labelled “orl”, the relative stereochemistry between those stereocenters labelled “orl” is determined but not the absolute stereochemistry.

[0331] For example, A2 isomer 1 is a single isomer, wherein the relative stereochemistry between two chiral centers labeled with “orl” is known, but the absolute stereochemistry is not yet determined. A2 isomer can be either the S,S-isomer or R,R-isomer.M., isomer 1

[0332] For example, A41 isomer 1 is a single isomer, wherein relative stereochemistry between two chiral centers labeled with the same “orl” is known; relative stereochemistry between chiral centers labeled with “orl” and “or2” is not known; and absolute stereochemistry of all three chiral centers is not yet determined. A41 isomer 1 can be any one of four isomers, as shown below:Isomer 1

[0333] 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

[0334] Additional compounds of Formula (I) can be prepared according to the general procedures as described in Examples 1-112 via a coupling reaction of any one of amines intermediates Al to Al 11 and any one of carboxylic acid intermediates CAI to CAI 1, wherein a combination of the amine and carboxylic acid intermediates is not used in Examples 1 to 112.PHARMACEUTICAL COMPOSITIONS

[0335] The compounds of Formula (I) or pharmaceutically acceptable salts thereof, or subembodiments thereof may be in the form of compositions suitable for administration to a subject. In general, such compositions are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.

[0336] 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.

[0337] The pharmaceutical compositions containing the active ingredient (e.g., a compound of Formula (I), a pharmaceutically acceptable salt thereof)may be in a form suitable for oral use (for example as tablets, troches, lozenges, hard or soft capsules, aqueous or oilysuspensions, emulsions, dispersible powders or granules, or syrups, solutions, microbeads or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0338] Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents. Tablets and / or capsules contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets and / or capsules. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[0339] The pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p- hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weakbases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2- 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).

[0340] 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 Equid 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.

[0341] Any drug delivery apparatus may be used to deliver the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are known in the art.

[0342] An effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0343] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0344] All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein. For example, the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment and / or preventionof all diseases or disorders provided herein. Thus, the compounds and pharmaceutical compositions provided herein are for use as a medicament.THERAPEUTIC USES AND APPLICATIONS

[0345] Provided herein are compounds that function as inhibitors of protein arginine N- methyltransferase 5 (PRMT5).

[0346] The present disclosure therefore provides a method of inhibiting PRMT5 enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0347] The present disclosure also provides a method of treating a disease or disorder in which PRMT5 activity is implicated in a patient, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer.

[0348] The present disclosure also provides a method of treating a disease or disorder treatable by inhibition of PRMT5 in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer.

[0349] The present disclosure also provides a method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0350] The present disclosure also provides a method of treating a cancer deficient in CDKN2A in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, asubembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0351] The present disclosure also provides a method of treating cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0352] The present disclosure also provides a method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0353] The present disclosure also provides a method of inhibiting cell profiferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0354] The present disclosure also provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In an embodiment, the proliferative disorder is cancer.

[0355] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0356] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In some embodiments, the patient is in recognized need of such treatment.

[0357] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the inhibition of PRMT5 enzyme activity.

[0358] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder in which PRMT5 activity is implicated.

[0359] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder treatable by inhibition of PRMT5.

[0360] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative condition. In some embodiments, the patient is in recognized need of such treatment.

[0361] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer. In some embodiments, the patient is in recognized need of such treatment.

[0362] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of PRMT5 enzyme activity.

[0363] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which PRMT5 activity is implicated.

[0364] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder treatable by inhibition of PRMT5.

[0365] In another aspect, the present disclosure provides a method of treating a cancer in a patient, comprising:(i) determining if the cancer is MTAP null; and(ii) if the cancer is MTAP null, administering to the patient a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0366] 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.

[0367] 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 nou-polyposis colorectal cancer), esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary7gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary 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, medulloblastoma and peripheral neuroectodermal tumors), Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AMI.), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, nonsmall cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma or plasmocytoma.

[0368] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is lung cancer, non-small cell lung (NSLC) cancer, bronchioloalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the vagina, carcinoma of tire vulva, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of tire adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenomas, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers.

[0369] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0370] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL) or mantle cell lymphoma (MCL).

[0371] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is gastric cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is colon cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is liver cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is glioblastoma multiforme (GBM). In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is bladder cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is esophageal cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is breast cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is NSLCC. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is MCL. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is DLBCL. In someembodiments, the cancer treated by the methods, uses, or medicaments described herein is ALL.

[0372] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma. In some embodiments, the cancer is non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.

[0373] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer ( e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, Ever, soft tissue, pleura and large intestine or sarcoma.

[0374] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is an MTA-accumulating cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is an MTAP-deficient cancer. In some embodiments, the cancer is treatable by inhibition of PRMT5.

[0375] 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 inMTAP- null cells by said compounds. Further, the present disclosure relates to the use of said compounds for the preparation of a medicament for the treatment and / or prophylaxis of a chromosome 9p21 deletion or MTAP-null associated disease and / or condition through inhibiting PRMT5 in MTAP-null cells by said compounds. In some embodiments the chromosome 9p21 deletion or MTAP-null associated disease or condition is alleviated by inhibition of PRMT5 in MTAP-null cells.

[0376] In some embodiments, provided herein is a method of treating and / or preventing a MTAP-null or chromosome 9p21 deletion associated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0377] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition includes a solid tumor in or arising from a tissue or organ, such as: • bone (e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cell tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma); • lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumors); • esophagus (e.g., Barrett's esophagus, dysplasia and adenocarcinoma); • gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus; • pancreas (e.g., serous neoplasms, including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)- associated serous cystic neoplasm, serous cystadenocarcinoma; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinarcell cystadenoma, acinar cell cystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid- pseudopapillary neoplasms (SPN), pancreatoblastoma); • gall bladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma); • neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas); • thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, papillary carcinoma, adenocarcinoma); • liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, rhabdoid tumor); • kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenasedeficient renal cell carcinoma, collecting duct carcinoma); • breast (e.g., invasive ductal carcinoma, including without limitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma; • peritoneum (e.g., mesothelioma; primary peritoneal cancer); • female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma,squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasia), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, endometrial malignant mullerian mixed tumours, gestational trophoblastic tumors (partial hydatiform mole, complete hydatiform mole, invasive hydatiform mole, placental site tumour)), vulva, vagina; • male sex organ tissues, including prostate, testis (e.g., germ cell tumors, spermatocytic seminoma), penis; • bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); • brain, (e.g., gliomas (e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, Non-Hodgkin lymphomas (NHLs), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, pituitary tumors; • eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma); • head and neck (e.g., nasopharyngeal carcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal); • thymus (e.g., thymoma); • heart (e.g., cardiac myxoma); • lung (e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma); • lymph (e.g., lymphomas, including Hodgkin’s lymphoma, nonHodgkin’s lymphoma (NHL), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associated lymphoproliferative diseases, including B cell lymphomas and T cell lymphomas (e.g., Burkitt lymphoma; large B cell lymphoma, diffuselarge B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low grade B cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK / T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma; follicular T cell lymphoma; systemic T cell lymphoma), lymphangioleiomyomatosis); • central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve glioma, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, Pituitary adenomas, cranial and paraspinal nerve tumors, stellar region tumors); neurofibroma, meningioma, peripheral nerve sheath tumors, peripheral neuroblastic tumours (including without limitation neuroblastoma, ganglion euroblastoma, ganglioneuroma), trisomy 19 ependymoma); • neuroendocrine tissues (e.g., paraganglionic system including adrenal medulla (pheochromocytomas) and extra-adrenal paraganglia ((extra-adrenal) paragangliomas); • skin (e.g., clear cell hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and • soft tissues (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, 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, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well- differentiated liposarcoma.

[0378] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition is a cancer selected from lung cancer, urothelial cancer, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cell neoplasms, head and neck cancer, bile duct cancer, esophagus cancer, glioblastoma, stomach cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, Ever cancer, renal cancer, colorectal cancer, prostate cancer, leukemia, and cervical cancer.

[0379] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition is a cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic, and bladder cancer.

[0380] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is multiple myeloma (MM). In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is breast cancer. The breast cancer can be estrogen receptor negative (ER-) or the breast cancer can be progesterone receptor negative (PR-). In further embodiments, the breast cancer can be HER2 negative. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor negative and HER2 negative, also referred to herein as "triple negative breast cancer".

[0381] 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, Phyllodes tumor, Angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapary carcinoma, mixed carcinoma, or another breast cancer, including but not limited to triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and HER and estrogen and progesterone receptor positive.

[0382] In an embodiment, the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer.

[0383] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is NSCLC (non-small cell lung carcinoma. In one embodiment, the NSCLC can be squamous NSCLC. In another embodiment, it can be adenocarcinoma.

[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.

[0384] In some aspects, one or more compounds described herein are useful for treating any PRMT5- mediated or PRMT5-responsive proliferative cell disorder, for example a cancer that is PRMT5 responsive.

[0385] In one aspect, a cancer that lacks p53 (e.g., a p53 null cancer) is less sensitive to PRMT5 inhibition than a cancer that is p5 positive. Accordingly, a cancer that is PRMT5 responsive can be a p53 positive cancer. The term "p53 positive" refers to a cancer that does not lack p53 expression and / or activity. In some embodiments, one or more compounds described herein are useful for treating a p53 positive cancer. In some aspects, a greater amount of one or more compounds described herein may be required to treat a p53 negative cancer (e.g. , a p53 null cancer) than a p53 positive cancer.

[0386] 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.

[0387] 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 thatis not sensitive (for example, a cancer that is less sensitive than a p53 positive cancer) to treatment with a PRMT5 inhibitor if p53 is absent from the sample (e.g., if the cancer is a p53 null cancer). In some embodiments, a p53 negative cancer (e.g., a p53 null cancer) is treated with a PRMT5 inhibitor, but a greater amount of PRMT5 inhibitor may be required to treat the p53 negative cancer than a p53 positive cancer. However, in some embodiments, a subject having a p53 negative cancer (e.g. , a p53 null cancer) is treated with a therapeutic agent that is not a PRMT5 inhibitor.

[0388] By "sample" is meant any biological sample derived from the subject, includes but is not limited to, cells, tissues samples, body fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), cancer cells, and cancer tissues. Detection of the presence or absence of p53 in the sample may be achieved by any suitable method for detecting p53 nucleic acid or protein, for example, nucleic acid sequencing (e.g., DNA or RNA sequencing), quantitative PCR, Western blotting, etc., or any combination of thereof.

[0389] 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; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g. , cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelio sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g. , adenocarcinoma of the esophagus, Barrett' s adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g. , stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g. , fl- cel! AML, T-cell AML), chronic myelocytic leukemia (CML) (e g. , B-cell CML, T-cellCML), and chronic lymphocytic leukemia (CLL) (e.g. , B-cell CLL, T- cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphomas (e.g. , mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., "Waldenstrom's macro globulinemia"), hairy cell leukemia (HCL), immunoblastic large cell ly mphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T- lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T- cell lymphoma (CTCL) (e.g. , mycosis fungiodes, Sezary syndrome), angioimmunoblastic T- cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis- like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g. , hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g. , systemic mastocytosis), myelodysplasia syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g. , neurofibromatosis (NF) type 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), papillary adenocarcinoma, penile cancer (e.g., Paget' s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g. , squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g. , appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST),chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).

[0390] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is spinal cord cancer.COMBINATION THERAPY

[0391] The present disclosure contemplates the use of compounds of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents frequently have different, complementary mechanisms of action. Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

[0392] 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”).

[0393] In certain embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents. In other embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless ofwhether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.

[0394] The present disclosure also contemplates the use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with at least one additional therapeutic agent as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0395] The present disclosure also provides a method of treating a disease or disorder in which PRMT5 activity is implicated in a patient, said method comprising administering to said patient (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer.

[0396] The present disclosure also provides a method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment

[0397] The present disclosure also provides a method of treating a cancer deficient in CDKN2A in a patient comprising administering to the patient (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment.

[0398] The present disclosure also provides a method of treating cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof, comprising administering to the patient (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceuticalcomposition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment.

[0399] The present disclosure provides methods for treating cancer with (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic or diagnostic agent.Additional Therapeutic Agents

[0400] The disclosure provides one or more additional therapeutic agents for use with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof and one or more pharmaceutically acceptable excipients. A wide variety of therapeutic agents with anti-cancer activity and methods of making the same are known in the art. Each of these is embraced by this disclosure. In some embodiments, the one or more additional active therapeutic agents are one, two, three, or four additional therapeutic agents. i) Chemotherapeutic Agents

[0401] In an embodiment, the additional therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents include alkylating agent, microtubule inhibitors, antimetabolites, anti-tumor antibiotics, as well as corticosteroids.

[0402] 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.

[0403] 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.

[0404] In some embodiments, the chemotherapeutic agent is a microtubule inhibitor. In an embodiment, the microtubule inhibitor is eribulin, ixabepilone, cabazitaxel, enfortumabvedotin, trastuzumab emtansine, tirbanibulin. In some embodiments microtuial inhibitors are plant alkaloids. In some embodiments, the plant alkaloid is a taxane (taxol, paclitaxel and docetaxel), a vinca alkaloid (vinblastine, vincristine, vindesine and vinorelbine), colchicine, podophyllotoxin, or abraxane (protein-bound paclitaxel). In some embodiments, the chemotherapeutic agent is paclitaxel.

[0405] 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.

[0406] 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.

[0407] In some embodiments, the chemotherapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is prednisone, methylprednisolone, or dexamethasone.

[0408] 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, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifhiridine, 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; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; 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; difhioromethylomithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In a particular embodiment, compounds of the present disclosure are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C. In a particular embodiment, the cytostatic compound is doxorubicin. Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as antiestrogens, including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as fhitamide, nilutamide, bicahitamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent.ii) Cell Cycle Checkpoint Inhibitors

[0409] In an embodiment, the additional therapeutic agent is a cell cycle checkpoint inhibitor. In some embodiments, the cell cycle checkpoint inhibitor is KU60019, AZD0156, Ceralasertib, Camonsertib, VE821, AZD7762, SRA737, Rabusertib, Prexasertib, SCH900776, or Adavosertib. In some embodiments, the cell cycle checkpoint inhibitor is KU60019. In some embodiments, the cell cycle checkpoint inhibitor is AZD0156. In some embodiments, the cell cycle checkpoint inhibitor is ceralasertib. In some embodiments, the cell cycle checkpoint inhibitor is camonsertib. In some embodiments, the cell cycle checkpoint inhibitor is VE821. In some embodiments, the cell cycle checkpoint inhibitor is AZD7762. In some embodiments, the cell cycle checkpoint inhibitor is SRA737. In some embodiments, the cell cycle checkpoint inhibitor is rabusertib. In some embodiments, the cell cycle checkpoint inhibitor is prexasertib. In some embodiments, the cell cycle checkpoint inhibitor is SCH900776. In some embodiments, the cell cycle checkpoint inhibitor is adavosertib. iii) Immune Checkpoint Inhibitors

[0410] 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.

[0411] 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, retifanlitnab, 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.

[0412] 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.

[0413] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is relatlimab.

[0414] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In some embodiments, the ipilimumab or tremelimumab

[0415] In some embodiments, the immune checkpoint inhibitor is a BTLA inhibitor.

[0416] 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).

[0417] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor. In some embodiments, the TIGIT inhibitor is tiragohimab, 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

[0418] 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, UM 77, or BDA- 366. v) Anti-CD20 therapeutic agent

[0419] In some embodiments, the additional therapeutic agent is an anti-CD20 therapeutic agent. In some embodiments, the anti-CD20 therapeutic agent is rituximab, arzerra, gazyva, ibritumomab tiuxetan, obinutuzumab, ofatumumab, riabni, rituxan, ruxience, truxima, zevalin, or tositumomab. vi) Hormonal Therapeutic Agent

[0420] 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. vii) PARP Inhibitors

[0421] In some embodiments, the additional therapeutic agent is a PARP inhibitor. In some embodiments, the PARP inhibitor is niraparib, rucaparib, olaparib, talazoparib, or veliparib. viii) MAT2A Inhibitors

[0422] In some embodiments, the additional therapeutic agent is a MAT2A inhibitor. In some embodiments, the MAT2A inhibitor is AG-270,. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2020 / 123395, the contents of which is incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2018 / 045071, the contents of which is incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2021 / 252681, WO2021 / 252680, WO2021 / 252679, WO2021 / 252678, or WO2023 / 196985, the contents of which are incorporated herein by reference for all purposes. In some embodiments, theMAT2A inhibitor is a compound disclosed in WO2021 / 1259815, WO2023 / 066283, WO2024 / 217502, W02020 / 139991, W02020 / 139992, WO2018 / 045071, WO2018 / 039972, W02019191470, W02024 / 002024, or WO2024 / 217493, the contents of which are incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is ISM3412 or S095035. In some embodiments, the MAT2A inhibitor is, or, or pharmaceutically acceptable salt thereof.

[0423] In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2022 / 268180, the contents of which are incorporated herein by reference for all purposes.

[0424] In some embodiments, the MAT2A inhibitor ispharmaceutically acceptable salt thereof. ix) Radiotherapy

[0425] In some embodiments, the additional therapeutic agent is radiation therapy. x) VEGF Inhibitors

[0426] 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

[0427] 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. xii)mT0R Inhibitors

[0428] 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. xiii) AKT Inhibitors

[0429] 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

[0430] 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

[0431] 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

[0432] 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. xvii) Inhibitors of Cereblon (Ubiquitin Ligase)

[0433] In some embodiments, the additional therapeutic agent is a inhibitor of cereblon. In some embodiments, the inhibitor of cereblon is thalidomide, lenalidomide. xviii) MAPK / ERK Inhibitors

[0434] 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, tipifamib, lonafamib, trametinib, ulixertinib, WX-554, or cobimetinib. xix)Wnt / fi-catenin Inhibitors

[0435] In some embodiments, the additional therapeutic agent is a Wnt / -catenin inhibitor. In some embodiments, the Wnt / -catenin inhibitor is capmatinib, resibufogenin, or isoquercitrin. xx) Proteosome Inhibitors

[0436] 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

[0437] In some embodiments, the additional therapeutic agent is a histone deacetylase inhibitor. In some embodiments, the histone deacetylase inhibitor vorinostat, romidepsin, panobinostat, or belinostat. xxii) Recombinant IL-2

[0438] In some embodiments, the additional therapeutic agent is a recombinant IL-2. In some embodiments, the recombinant IL-2 is aldesleukin. xxiii) RANKL Inhibitors

[0439] In some embodiments, the additional therapeutic agent is a RANKL inhibitor. In some embodiments, the RANKL inhibitor is Denosumab or AS2676293.xxiv) B4GALNT1 Inhibitors

[0440] In some embodiments, the additional therapeutic agent is a B4GALNT1 inhibitor.In some embodiments, the B4GALNT1 inhibitor is Dinutuximab. xxv ) SLAMF7 Inhibitors

[0441] In some embodiments, the additional therapeutic agent is a SLAMF7 inhibitor. In some embodiments, the SLAMF7 inhibitor is elotuzumab. xxvi) IDH2 / IDH1 Inhibitors

[0442] 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. xxvii) BTK Inhibitors

[0443] In some embodiments, the additional therapeutic agent is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib. xxviii) FLT3 Inhibitors

[0444] 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) PDGFRa Inhibitors

[0445] In some embodiments, the additional therapeutic agent is a PDGFRa inhibitor. In some embodiments, the PDGFRa inhibitor is olaratumab, avapritinib, ayvakit, imatinib, ripretinib, or regorafenib. xxx) Smoothened (Smo) Inhibitors

[0446] 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

[0447] In some embodiments, the additional therapeutic agent is a LHRH antagonist or LHRH agonist. In some embodiments, the LHRH antagonist or LHRH agonist is goserelin, leuprorelin or buserelin. xxxii) Cell Based Therapy

[0448] In some embodiments, the additional therapeutic agent is a cell based therapy. In some embodiments, the cell based therapy is tumor-infiltrating lymphocyte (TIL) therapy; engineered t cell receptor (TCR) therapy; chimeric antigen receptor (CAR) T cell therapy; Natural Killer (NK) cell therapy; or sipuleucel-T. xxxiii) 0X40 Inhibitors

[0449] In some embodiments, the additional therapeutic agent is a 0X40 inhibitor. In some embodiments, the 0X40 inhibitor is ivuxolimab, cudarolimab, utomilumab, or INBRX- 106. xxxiv) 41BB ( CD137) Inhibitors

[0450] In some embodiments, the additional therapeutic agent is a 41BB (CD137) inhibitor. In some embodiments, the 41BB (CD137) inhibitor is urelumab. xxxv) VISTA Inhibitors

[0451] In some embodiments, the additional therapeutic agent is a VISTA inhibitor. In some embodiments, the VISTA inhibitor is hmbd-002. xxxvi) CD96 Inhibitors

[0452] In some embodiments, the additional therapeutic agent is a CD96 inhibitor. In some embodiments, the CD96 inhibitor is GSK6097608. xxxvii) TGF P Inhibitors

[0453] In some embodiments, the additional therapeutic agent is a TGF inhibitor. In some embodiments, the TGFp inhibitor is SAR-439459. xxxviii)CDI9 Inhibitors

[0454] In some embodiments, the additional therapeutic agent is a CD 19 inhibitor. In some embodiments, the CD19 inhibitor is tafasitamab, loncastuximab tesirine, or blinatumomab. xxxix) CD30 Inhibitors

[0455] 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

[0456] 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

[0457] In some embodiments, the additional therapeutic agent is a CD39 inhibitor. In some embodiments, the CD39 inhibitor is purOOl, ES002023, TTX-030, IPH5201, or SRF617. xlii) CD52 Inhibitors

[0458] In some embodiments, the additional therapeutic agent is a CD52 inhibitor. In some embodiments, the CD52 inhibitor is alemtuzumab. xliii) CD73 Inhibitors

[0459] 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

[0460] In some embodiments, the additional therapeutic agent is an A2AR inhibitor. In some embodiments, the A2AR inhibitor is istradefylline, vipadenant, CVT-6883, enprofylline, ciforadenant, imaradenant, etrumadenant, NIR178, EOS100850, CS3005, PBF- 999, or INCB 106385. xlv A BR Inhibitors

[0461] 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

[0462] In some embodiments, the additional therapeutic agent is an IDO1 or a TDO2 inhibitor. In some embodiments, the IDO1 or TDO2 inhibitor is Indoximod, Epacadostat, Navoximod, PF-06840003, BGS-5777, BMS-986205, LW106, IOM2983, RG-70099, LY- 3381916, NLG-802, or LPM-3480226. xlvii) Arginase Inhibitors

[0463] In some embodiments, the additional therapeutic agent is an arginase inhibitor. In some embodiments, the arginase inhibitor is numidargistat, pegzilarginase, or INCB001158. xlviii) B7-H3 Inhibitors

[0464] 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

[0465] 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.I) Signal transduction inhibitor (STI)

[0466] As used herein, the term “signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. Examples of signal transduction inhibitors (STIs) useful in methods described herein include, but are not limited to: (i) bcr / abl kinase inhibitors (e.g., GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) her-2 / neu receptor inhibitors (e.g., HERCEPTIN); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositol kinase inhibitors. li) Spicing inhibitor sulfonamides (SPLAMs)

[0467] In some embodiments, the additional therapeutic agent is a Spicing inhibitor sulfonamide (SPLAM).

[0468] In some embodiments, the SPLAM is indisulam or E7820.Hi) Additional Therapeutic Agents

[0469] In some embodiments, the additional therapeutic agent is a monoclonal antibody against a tumor antigen, a complex of a monoclonal antibody and toxin, a T-cell adjuvant, bone marrow transplant, or antigen presenting cells (e.g., dendritic cell therapy).

[0470] 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 antitumorcompounds and methods of making the same are known in the art. Each of these is embraced by this disclosure. In an embodiment, the antitumor compound is an additional therapeutic agent disclosed herein. In an embodiment, the antitumor compound is a chemotherapeutic agent disclosed herein.

[0471] 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, Abcmaciclib, CPI (Avelumab, Cemiplimab-rwlc, and Bevacizumab).DOSING

[0472] A compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein may be administered to a subject in an amount that is dependent upon, 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 effects associated with the agent(s) being administered.

[0473] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The “median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.Il lROUTES OF ADMINISTRATION

[0474] A compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein comprising this compound may be administered to a patient by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0475] Routes or administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., 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 intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Some embodiments of the present invention contemplate oral administration.NON-LIMITING EXEMPLARY EMBODIMENTS

[0476] The compounds of the current application can be further described by the following non-limiting embodiments: Embodiments 1 to 156; and Embodiments IB to 11 IB.

[0477] Embodiment 1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinX1is C(RlaRlb), O, or NR1;X2is C(R2aR2b), O, or NR2;X3is C(R3aR3b), O, or NR3;X4is C(R4aR4b), O, NR4, S, S(O), or S(O)2;X5is C(R5aR5b), O, NR5, S, S(O), or S(O)2;X6is C(R6aR6b), O, NR6, S, S(O), or S(O)2;R1, R2, and R3are each independently H or Ci-4 alkyl;Rla,Rlb, R2a,R2b, R3a, and R3bare each independently H, Ci-4 alkyl, halo, or Ci-4 haloalkyl;R4, R5, and R6are each independently H, C1.4 alkyl, or C1.4 hydroxyalkyl;R4a, R4b, R5a,R5b, R6a, and R6bare each independently H, C1-4 alkyl, C1-4 haloalkyl, CM hydroxyalkyl, C1-4 haloalky 1(OH); ring A is heterocycloalkyl comprising 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2; ring B is Cg-io aryl or heteroaryl comprising 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R7is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, or -C(O)OCi-6haloalkyl; each R8is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, - C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, -C(O)OCi-6haloalkyl, or heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently C1.4 alkyl, halo, or C1.4 haloalkyl; alternatively, one R7attached to ring A and one R8attached to ring B combine to form ring C comprising C4-7 cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a, and ring A, ring B, and ring C form a fused tricyclic moiety; each R7ais independently C1-4 alkyl, halo, or C1-4 haloalkyl; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; and R9is H, Ci-4 alkyl, halo, or C1-4 haloalkyl.

[0478] Embodiment 2. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein X1is C(RlaRlb) or NR1.

[0479] Embodiment 3. The compound or a pharmaceutically acceptable salt thereof of embodiment 1 or 2, wherein X1is NR1.

[0480] Embodiment 4. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 3, wherein R1is H or methyl.

[0481] Embodiment 5. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 3, wherein R1is H.

[0482] Embodiment 6. The compound or a pharmaceutically acceptable salt thereof of embodiment 1 or 2, wherein X1is C(RlaRlb).

[0483] Embodiment 7. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1, 2, and 6, wherein Rlaand Rlbare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0484] Embodiment 8. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1, 2, and 6, wherein Rlaand Rlbare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0485] Embodiment 9. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1, 2, and 6, wherein Rlaand Rlbare each H.

[0486] Embodiment 10. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1, 2, and 6, wherein Rlais methyl, and Rlbis H.

[0487] Embodiment 11. The compound or a pharmaceutically acceptable salt thereof of 1, wherein X1is O.

[0488] Embodiment 12. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11, wherein X2is C(R2aR2b) or O.

[0489] Embodiment 13. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11, wherein X2is O.

[0490] Embodiment 14. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11, wherein X2is C(R2aR2b).

[0491] Embodiment 15. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11 and 14, wherein R2aand R2bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0492] Embodiment 16. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11 and 14, wherein R2aand R2bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0493] Embodiment 17. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11 and 14, wherein R2aand R2bare each H.

[0494] Embodiment 18. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11 and 14, wherein R2ais methyl, and R2bis H.

[0495] Embodiment 19. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 18, wherein X3is C(R3aR3b) or NR3.

[0496] Embodiment 20. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19, wherein X3is NR3.

[0497] Embodiment 21. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 20, wherein R3is H or methyl.

[0498] Embodiment 22. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19, wherein X3is C(R3aR3b).

[0499] Embodiment 23. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19 and 22, wherein R3aand R3bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0500] Embodiment 24. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19 and 22, wherein R3aand R3bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0501] Embodiment 25. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19 and 22, wherein R3aand R3bare each H.

[0502] Embodiment 26. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19 and 22, wherein R3ais methyl, and R3bis H.

[0503] Embodiment 27. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 18, wherein X3is O.

[0504] Embodiment 28. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 27, wherein X4is C(R4aR4b), O, or NR4.

[0505] Embodiment 29. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 27, wherein X4is O.

[0506] Embodiment 30. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 27, wherein X4is NR4.

[0507] Embodiment 31. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 30, wherein R4is H or methyl.

[0508] Embodiment 32. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 30, wherein R4is H.

[0509] Embodiment 33. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 27, wherein X4is C(R4aR4b).

[0510] Embodiment 34. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 33, wherein R4aand R4bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0511] Embodiment 35. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 33, wherein R4aand R4bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0512] Embodiment 36. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 33, wherein R4aand R4bare each H.

[0513] Embodiment 37. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 33, wherein R4ais methyl, and R4bis H.

[0514] Embodiment 38. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 37, wherein X5is C(R5aR5b), O, or NR5.

[0515] Embodiment 39. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 37, wherein X5is O.

[0516] Embodiment 40. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 37, wherein X5is NR5.

[0517] Embodiment 41. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 40, wherein R5is H or methyl.

[0518] Embodiment 42. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 40, wherein R5is H.

[0519] Embodiment 43. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 37, wherein X5is C(R5aR5b).

[0520] Embodiment 44. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 43, wherein R5aand R5bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0521] Embodiment 45. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 43, wherein R5aand R5bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0522] Embodiment 46. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 43, wherein R5aand R5bare each H.

[0523] Embodiment 47. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 43, wherein R5ais methyl, and R5bis H.

[0524] Embodiment 48. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 47, wherein X6is C(R6aR6b), O, NR6.

[0525] Embodiment 49. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 47, wherein X6is O.

[0526] Embodiment 50. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 47, wherein X6is NR6.

[0527] Embodiment 51. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 50, wherein R6is H or methyl.

[0528] Embodiment 52. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 50, wherein R6is H.

[0529] Embodiment 53. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 47, wherein X6is C(R6aR6b).

[0530] Embodiment 54. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 53, wherein R6aand R6bare each independently H, methyl, ethyl, fluoro, chloro, or bromo.

[0531] Embodiment 55. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 53, wherein R6aand R6bare each independently H, methyl, fluoro, chloro, or trifluoromethyl.

[0532] Embodiment 56. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 53, wherein R6aand R6bare each H.

[0533] Embodiment 57. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 53, wherein R6ais methyl, and R6bis H.

[0534] Embodiment 58. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein ring A is heterocycloalkyl comprising 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0535] Embodiment 59. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein ring A is heterocycloalkyl comprising 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 1 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0536] Embodiment 60. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0537] Embodiment 61. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

[0538] Embodiment 62. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein ring A is piperidinyl, substituted with 1 or 2 R7.

[0539] Embodiment 63. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein ring A is morpholinyl, substituted with 1 or 2 R7.

[0540] Embodiment 64. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 63, wherein R7is Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or Ci-6 haloalkoxy.

[0541] Embodiment 65. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 63, wherein R7is Ci-4 alkyl, Ci-4 haloalkyl, or halo.

[0542] Embodiment 66. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 63, wherein R7is methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0543] Embodiment 67. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 63, wherein R7is methyl.

[0544] Embodiment 68. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, having Formula (la)wherein, ring B is phenyl or heteroaryl comprising 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; q is 0, 1, or 2; and ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and comprises C4-7 cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0545] Embodiment 69. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, having Formula (Ial-1):wherein,Xais O, CH2, or CHR7; p is 0 or 1;q is 0, 1, or 2; and ring C is C4-7 cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0546] Embodiment 70. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is C4-7 cycloalkyl substituted with 0, 1, 2, or 3 R7a.

[0547] Embodiment 71. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is C4-6 cycloalkyl substituted with 0, 1, 2, or 3 R7a.

[0548] Embodiment 72. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is C5-6 cycloalkyl substituted with 0, 1, or 2 R7a.

[0549] Embodiment 73. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is C6 cycloalkyl substituted with 0, 1, or 2 R7a.

[0550] Embodiment 74. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is C5 cycloalkyl substituted with 0, 1, or 2 R7a.

[0551] Embodiment 75. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0552] Embodiment 76. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is heterocycloalkyl comprising 4 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0553] Embodiment 77. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is heterocycloalkyl comprising 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0554] Embodiment 78. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is heterocycloalkyl comprising 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a.

[0555] Embodiment 79. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is heterocycloalkyl comprising 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0556] Embodiment 80. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is heterocycloalkyl comprising 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a.

[0557] Embodiment 81. The compound or a pharmaceutically acceptable salt thereof of embodiments 68 or 69, wherein ring C is tetrahydropyranyl substituted with 0, 1, or 2 R7a.

[0558] Embodiment 82. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, having Formula (Ia2-1):wherein,Xais absent, O, CH2, or CHR7;X7ais absent, O or CH2, or CHR7a;X7bis absent, O or CH2, or CHR7a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0559] Embodiment 83. The compound or a pharmaceutically acceptable salt thereof of embodiment 82, whereinXais O, CH2, or CHR7;X7ais O or CH2, or CHR7a;X7bis O or CH2, or CHR7a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0560] Embodiment 84. The compound or a pharmaceutically acceptable salt thereof of embodiment 82 or 83, wherein X7ais O, and X7bis CH2.

[0561] Embodiment 85. The compound or a pharmaceutically acceptable salt thereof of embodiment 82 or 83, wherein X7ais CH2, and X7bis O.

[0562] Embodiment 86. The compound or a pharmaceutically acceptable salt thereof of embodiment 82 or 83, wherein X7ais CH2, and X7bis CH2.

[0563] Embodiment 87. The compound or a pharmaceutically acceptable salt thereof of embodiment 82, wherein X7ais absent, and X7bis CH2.

[0564] Embodiment 88. The compound or a pharmaceutically acceptable salt thereof of embodiment 82, wherein X7ais absent, and X7bis O.

[0565] Embodiment 89. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 88, wherein R7ais C1-4 alkyl, halo, or C1-4 haloalkyl.

[0566] Embodiment 90. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 88, wherein R7ais methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0567] Embodiment 91. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 88, wherein R7ais methyl, fluoro, chloro, or trifluoromethyl

[0568] Embodiment 92. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 88, wherein two R7agroups attached to the same carbon atom combine to form oxo.

[0569] Embodiment 93. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 92, wherein each R8is independently C1-6 alkyl, Ci-6 haloalkyl, halo, C1-6 alkoxy, or C1-6 haloalkoxy.

[0570] Embodiment 94. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 92, wherein each R8is independently C1-6 alkyl, C1-6 haloalkyl, or halo.

[0571] Embodiment 95. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 92, wherein each R8is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0572] Embodiment 96. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 92, wherein each R8is independently bromo or trifluoromethyl.

[0573] Embodiment 97. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, wherein the moietyhas the formula:

[0574] Embodiment 98. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, having Formula (lb)wherein,Xais O, CH2, or CHR7; ring B is heteroaryl comprising 9 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; and q is 0, 1, 2, or 3.

[0575] Embodiment 99. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 98, wherein p is 1.

[0576] Embodiment 100. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 98, wherein p is 2.

[0577] Embodiment 101. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 100, wherein q is 0.

[0578] Embodiment 102. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 100, wherein q is 1 .

[0579] Embodiment 103. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 100, wherein q is 2.

[0580] Embodiment 104. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, having Formula (Ibl)

[0581] Embodiment 105. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, Ci-6 haloalkoxy, or heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a.

[0582] Embodiment 106. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R8is independently Ci-4 alkyl, Ci-4 haloalkyl, halo, or heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a.

[0583] Embodiment 107. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R8is independently heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a.

[0584] Embodiment 108. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R8is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 R8a.

[0585] Embodiment 109. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R8is piperidinyl substituted with 0, 1, or 2 R8a.

[0586] Embodiment 110. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 109, wherein each R8ais C1-4 alkyl.

[0587] Embodiment 111. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 109, wherein each R8ais independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0588] Embodiment 112. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, and 98 to 109, wherein each R8ais methyl.

[0589] Embodiment 113. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, wherein the moiety

[0590] Embodiment 114. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R9is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0591] Embodiment 115. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R9is H, methyl, fluoro, chloro, or trifluoromethyl.

[0592] Embodiment 116. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R9is H.

[0593] Embodiment 117. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R9is methyl.

[0594] Embodiment 118. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R9is fluoro.

[0595] Embodiment 119. The compound or a pharmaceutically acceptable salt thereof of any embodiment 1, wherein the compound is selected from Examples 1 to 8.

[0596] Embodiment 120. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, and a pharmaceutically acceptable excipient.

[0597] Embodiment 121. A method for treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120.

[0598] Embodiment 122. The method of embodiment 121, wherein the disease is cancer.

[0599] Embodiment 123. A method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120.

[0600] Embodiment 124. 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 patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120.

[0601] Embodiment 125. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120.

[0602] Embodiment 126. The method of any one of embodiments 122 to 125, wherein the cancer is an MTAP-deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0603] Embodiment 127. The method of embodiment 122 or 126, wherein the cancer is deficient in CDKN2A.

[0604] Embodiment 128. The method of any one of embodiments 122 to 127, wherein the cancer is a solid tumor.

[0605] Embodiment 129. The method of embodiment 128, wherein the solid tumor is malignant.

[0606] Embodiment 130. The method of any one of embodiments 122 to 129, wherein the patient is in recognized need of such treatment.

[0607] Embodiment 131. The method of any one of embodiments 122 to 130, wherein the cancer is selected from the group consisting of biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer ( e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0608] Embodiment 132. The method of any one of embodiments 122 to 130, wherein the cancer is selected from the group consisting of leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma,osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma.

[0609] Embodiment 133. The method of any one of embodiments 122 to 130, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

[0610] Embodiment 134. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120, for use in therapy.

[0611] Embodiment 135. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120, for use in the treatment cancer.

[0612] Embodiment 136. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 135, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0613] Embodiment 137. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 135 or 136, wherein said cancer is deficient in CDKN2A.

[0614] Embodiment 138. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 135 to 137, wherein said cancer is an MTAP null cancer.

[0615] Embodiment 139. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 135 to 137, 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.

[0616] Embodiment 140. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 135 to 139, wherein said cancer is a solid tumor.

[0617] Embodiment 141. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 140, wherein the solid tumor is malignant.

[0618] Embodiment 142. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 135 to 141, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, Ever, soft tissue, pleura and large intestine or sarcoma.

[0619] Embodiment 143. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 135 to 141, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0620] Embodiment 144. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120, in the manufacture of a medicament for use in therapy.

[0621] Embodiment 145. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120, in the manufacture of a medicament for use in the treatment of cancer.

[0622] Embodiment 146. The use of embodiment 145, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0623] Embodiment 147. The use of embodiment 145 or 146, wherein said cancer is deficient in CDKN2A.

[0624] Embodiment 148. The use of any one of embodiments 145 to 147, wherein said cancer is an MTAP null cancer.

[0625] Embodiment 149. The use of any one of embodiments 145 to 147, 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.

[0626] Embodiment 150. The use of any one of embodiments 145 to 149, wherein said cancer is a solid tumor.

[0627] Embodiment 151. The use of embodiment 150, wherein said solid tumor is malignant.

[0628] Embodiment 152. The use of any one of embodiments 145 to 151, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer ( e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0629] Embodiment 153. The use of any one of embodiments 145 to 151, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0630] Embodiment 154. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120.

[0631] Embodiment 155. A method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120.

[0632] Embodiment 156. A method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired with an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1 to 119, or a pharmaceutical composition of embodiment 120.

[0633] Embodiment IB. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinX1is C(RlaRlb), O, or NR1;X2is C(R2aR2b), O, or NR2;X3is C(R3aR3b), O, or NR3;X4is C(R4aR4b), O, NR4, S, S(O), or S(O)2;X5is C(R5aR5b), O, NR5, S, S(O), or S(O)2;X6is C(R6aR6b), O, NR6, S, S(O), or S(O)2;R1, R2, and R3are each independently H or Ci-4 alkyl;Rla,Rlb, R2a,R2b, R3a, and R3bare each independently H, Ci-4 alkyl, halo, or Ci-4 haloalkyl;R4, R5, and R6are each independently H, C1.4 alkyl, or C1.4 hydroxyalkyl;R4a,R4b, R5ajR5b;R6a;and R6bare each independently H, C1-4 alkyl, C1-4 haloalkyl, CM hydroxyalkyl, or C1-4 haloalkyl(OH); ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is Ce-io aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3;q is 0, 1, 2, or 3; each R7is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, Ci-6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, or -C(O)OCi-6haloalkyl; each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, C3- 6 cycloalkyl, -O-C3-6 cycloalkyl, -C(O)Ci-6 alkyl, -C(O)Ci-6 haloalkyl, -C(O)OCi-6 alkyl, -C(O)OCi-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently C1-4 alkyl, halo, or C1-4 haloalkyl; alternatively, one R7attached to ring A and one R8attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a, and ring A, ring B, and ring C form a fused tricyclic moiety; each R7ais independently C1-4 alkyl, halo, or C1-4 haloalkyl; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; and R9is H, C1-4 alkyl, halo, or Ci^ haloalkyl.

[0634] Embodiment 2B. The compound or a pharmaceutically acceptable salt thereof of embodiment IB, wherein one R7attached to ring A and one R8attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R7a, and ring A, ring B, and ring C form a fused tricyclic moiety.

[0635] Embodiment 3B. The compound or a pharmaceutically acceptable salt thereof of embodiment IB or 2B, wherein X1is C(RlaRlb).

[0636] Embodiment 4B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 3B, wherein X1is CH2.

[0637] Embodiment 5B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X2is NR2.

[0638] Embodiment 6B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 5B, wherein X2is NH.

[0639] Embodiment 7B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X2is O.

[0640] Embodiment 8B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X2is C(R2aR2b).

[0641] Embodiment 9B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 8B, wherein X2is CH2.

[0642] Embodiment 10B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 9B, wherein X3is C(R3aR3b).

[0643] Embodiment 11B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 10B, wherein X3is CH2.

[0644] Embodiment 12B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 11B, wherein X4is C(R4aR4b), O, or NR4.

[0645] Embodiment 13B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 12B, wherein X4is C(R4aR4b).

[0646] Embodiment 14B. The compound or a pharmaceutically acceptable salt thereof of embodiment 13B, wherein R4aand R4bare each H.

[0647] Embodiment 15B. The compound or a pharmaceutically acceptable salt thereof of embodiment 13B, wherein R4ais methyl, and R4bis H.

[0648] Embodiment 16B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 15B, wherein X5is C(R5aR5b), O, or NR5.

[0649] Embodiment 17B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 16B, wherein X5is O.

[0650] Embodiment 18B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 17B, wherein X6is C(R6aR6b), O, or NR6.

[0651] Embodiment 19B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 18B, wherein X6is C(R6aR6b).

[0652] Embodiment 20B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 19B, wherein R6aand R6bare each H.

[0653] Embodiment 21B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 18B, wherein R6ais methyl; and R6bis H.

[0654] Embodiment 22B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 21B, wherein ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is N, O, or S.

[0655] Embodiment 23B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 21B, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0656] Embodiment 24B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 21B, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

[0657] Embodiment 25B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 21B, wherein ring A is piperidinyl, substituted with 0, 1, or 2 R7.

[0658] Embodiment 26B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 21B, wherein ring A is piperazinyl, substituted with 0, 1, or 2 R7.

[0659] Embodiment 27B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 21B, wherein ring A is morpholinyl, substituted with 0, 1, or 2 R7.

[0660] Embodiment 28B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R7is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or Ci-6 haloalkoxy.

[0661] Embodiment 29B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R7is independently CH alkyl, halo, or Ci-4 alkoxy.

[0662] Embodiment 30B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R7is independently methyl, fluoro, or methoxy.

[0663] Embodiment 31B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R7is independently methyl or fluoro.

[0664] Embodiment 32B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, having Formula (la):wherein: ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, or 2; q is 0, 1, or 2; and ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0665] Embodiment 33B. The compound or a pharmaceutically acceptable salt thereof of embodiment 32B, wherein:X1is C(RlaRlb);X2is C(R2aR2b), O, or NR2;X3is C(R3aR3b);X4is C(R4aR4b);Xsis O;X6is C(R6aR6b);R2is H or C1-4 alkyl;Rla, Rlb, R2a, R2b, R3a, and R3bare each independently H or C1-4 alkyl;R4a, R4b, R6a, and R6bare each independently H or C1-4 alkyl; ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is N or O;ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; ring C is C5-7 cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a, p is 0 or 1; q is 1;R7is C1-4 alkyl, halo, or C1-4 alkoxy,;R8is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, or C3-6 cycloalkyl; each R7ais independently C1-4 alkyl or halo; andR9is H.

[0666] Embodiment 34B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, having Formula (Ial-1):wherein:Xais O, NH, CH2, or CHR7; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0667] Embodiment 35B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, having Formula (Ial-2):wherein,Xais O, NH, CH2, or CHR7; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0668] Embodiment 36B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 35B, wherein ring C is C5-6 cycloalkyl substituted with 0, 1, or 2 R7a.

[0669] Embodiment 37B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 36B, wherein ring C is Ce cycloalkyl substituted with 0, 1, or 2 R7a.

[0670] Embodiment 38B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 36B, wherein ring C is C5 cycloalkyl substituted with 0, 1, or 2 R7a.

[0671] Embodiment 39B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 35B, wherein ring C is heterocycloalkyl having 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a.

[0672] Embodiment 40B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 35B and 39B, wherein ring C is heterocycloalkyl having 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a.

[0673] Embodiment 41B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 35B and 39B, wherein ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R7a.

[0674] Embodiment 42B. The compound or a pharmaceutically acceptable salt thereof of embodiment 40B, wherein ring C is tetrahydrofuranyl substituted with 0 R7a.

[0675] Embodiment 43B. The compound or a pharmaceutically acceptable salt thereof of embodiment 41B, wherein ring C is tetrahydropyranyl substituted with 0 or 1 R7a.

[0676] Embodiment 44B. The compound or a pharmaceutically acceptable salt thereof of embodiment 41B, wherein ring C is tetrahydropyranyl substituted with 0 R7a.

[0677] Embodiment 45B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, having Formula (Ia2-1):wherein,Xais O, NH, CH2, or CHR7;X7ais absent, O, CH2, or CHR7a;X7bis absent, O, CH2, or CHR7a; p is 0, 1, or 2; and q is 0, 1, or 2, provided that X7aand X7bare not each absent or O.

[0678] Embodiment 46B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, having Formula (Ia2-2):wherein,Xais O, NH, CH2, or CHR7;X7ais absent, O, CH2, or CHR7a;X7bis absent, O, CH2, or CHR7a; p is 0, 1, or 2; and q is 0, 1, or 2, provided that X7aand X7bare not each absent or O.

[0679] Embodiment 47B. The compound or a pharmaceutically acceptable salt thereof of embodiment 45B or 46B, whereinXais O, CH2, or CHR7;X7ais O, CH2, or CHR7a; andX7bis O, CH2, or CHR7a.

[0680] Embodiment 48B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X7ais O; and X7bis CH2.

[0681] Embodiment 49B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X7ais CH2; and X715is O.

[0682] Embodiment SOB. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X7ais CH2; and X711is CH2.

[0683] Embodiment SIB. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X7ais O; and X7bis CH(CHa).

[0684] Embodiment 52B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X7ais CH(CHs); and X7bis O.[068S] Embodiment 53B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X7ais CH2and X^ is CH(CH3); or X7ais CH(CH3) and X7bis CH2.

[0686] Embodiment 54B. The compound or a pharmaceutically acceptable salt thereof of embodiment 45B or 46B, wherein X7ais absent; and X7bis CH2.

[0687] Embodiment 55B. The compound or a pharmaceutically acceptable salt thereof of embodiment 45B or 46B, wherein X7ais absent; and X7bis O.

[0688] Embodiment 56B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 55B, wherein each R8is independently C1-6 alkyl, C1-6 haloalkyl, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, or C3-6 cycloalkyl.

[0689] Embodiment 57B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 56B, wherein q is 1; and R8is C1-6 alkyl, Ci-6 haloalkyl, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, or C3-6 cycloalkyl.

[0690] Embodiment 58B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 57B, wherein q is 1; and R8is chloro, CN, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, or trifluoromethyl-O-.

[0691] Embodiment 59B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 58B, wherein q is 1; and R8is chloro, trifluoromethyl, or difluoromethyl-O-.

[0692] Embodiment 60B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 59B, wherein q is 1; and R8is chloro.

[0693] Embodiment 61B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 59B, wherein q is 1; and R8is trifluoromethyl.

[0694] Embodiment 62B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 59B, wherein q is 1; and R8is difluoromethyl-O-.

[0695] Embodiment 63B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, wherein the moietyhas the formula:wherein:Xais O, NH, CH2, or CHR7;X7ais O, CH2, or CHR7a;X7bis O, CH2, or CHR7a; each R7ais independently C1-4 alkyl; each R7is independently F, C1.4 alkyl, or C1.4 alkoxy; andR8is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, or C3-5 cycloalkyl, provided that X7aand X7bare not each O.

[0696] Embodiment 64B. The compound or a pharmaceutically acceptable salt thereof of embodiment 63B, wherein Xais O, NH, CH2, CHF, C(CH3), or C(OCH3); X7ais O, CH2, or CH(CH3); X7bis O or CH2; R7is F, CH3, or OCH3; R8is chloro, CN, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoromethyl-O-, or trifluoromethyl-O-, provided that X7aand X78are not each O.

[0697] Embodiment 65B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 64B, wherein R9is H.

[0698] Embodiment 66B. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 65B, wherein:wherein X2 is O, NH, or CH2; and R4ais H or C1-4 alkyl.

[0699] Embodiment 67B. The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is O; and R4ais H.

[0700] Embodiment 68B. The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is O; and R4ais methyl.

[0701] Embodiment 69B. The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is NH; and R4ais H.

[0702] Embodiment 70B. The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is NH; and R4ais methyl.

[0703] Embodiment 71B. The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is CH2; and R4ais H.

[0704] Embodiment 72B. The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is CH2; and R4ais methyl.

[0705] Embodiment 73B. The compound or a pharmaceutically acceptable salt thereof of embodiment IB, represented by any one of the structures of Examples 1 to 3 and 5 to 42 in Table 1.

[0706] Embodiment 74B. A compound or a pharmaceutically acceptable salt thereof, represented by any one of the structures of Examples 1 to 44.

[0707] Embodiment 75B. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, and a pharmaceutically acceptable excipient.

[0708] Embodiment 76B. A method for treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptablesalt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75.

[0709] Embodiment 77B. The method of embodiment 76B, wherein the disease is cancer.

[0710] Embodiment 78B. A method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B.

[0711] Embodiment 79B. A method for treating cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B.

[0712] Embodiment 80B. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B.

[0713] Embodiment 81B. The method of any one of embodiments 77B to 80B, wherein the cancer is a MTA-accumulating cancer.

[0714] Embodiment 82B. The method of embodiment 77B or 81B, wherein the cancer is deficient in CDKN2A.

[0715] Embodiment 83B. The method of any one of embodiments 77B to 82B, wherein the cancer is a solid tumor.

[0716] Embodiment 84B. The method of embodiment 83B, wherein the solid tumor is malignant.

[0717] Embodiment 85B. The method of any one of embodiments 76B to 84B, wherein the patient is in recognized need of such treatment.

[0718] Embodiment 86B. The method of any one of embodiments 77B to 85B, wherein the cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nervesheath tumors (MPNST), colon cancer, esophageal cancer ( e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer e.g., non-small cell lung cancer (NSCLC); e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, Ever, soft tissue, pleura and large intestine, or sarcoma.

[0719] Embodiment 87B. The method of any one of embodiments 77B to 85B, wherein the cancer is selected from the group consisting of leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, and mesothelioma.

[0720] Embodiment 88B. The method of any one of embodiments 77B to 85B, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

[0721] Embodiment 89B. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B, for use in therapy.

[0722] Embodiment 90B. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B, for use in the treatment of cancer.

[0723] Embodiment 91B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to embodiment 90B, wherein said cancer is an MTAP null cancer.

[0724] Embodiment 92B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to embodiment 90B, wherein said 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, or a reduced function of MTAP protein, or a combination thereof.

[0725] Embodiment 93B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 90B to 92B, wherein said cancer is MTA-accumulating cancer.

[0726] Embodiment 94B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 90B to 93B, wherein said cancer is deficient in CDKN2A.

[0727] Embodiment 95B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 90B to 94B, wherein said cancer is a solid tumor.

[0728] Embodiment 96B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to embodiment 95B, wherein the solid tumor is malignant.

[0729] Embodiment 97B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, for use according to any one of embodiments 90B to 96B, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer ( e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, fiver, soft tissue, pleura and large intestine or sarcoma.

[0730] Embodiment 98B. The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition for use according to any one of embodiments 90B to 96B, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non- small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer,myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma or mesothelioma.

[0731] Embodiment 99B. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B, in the manufacture of a medicament for use therapy.

[0732] Embodiment 100B. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B, in the manufacture of a medicament for the treatment of cancer.

[0733] Embodiment 101B. The use of embodiment 100B, wherein said cancer is an MTAP null cancer.

[0734] Embodiment 102B. The use of embodiment 100B, wherein said cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof.

[0735] Embodiment 103B. The use of any one embodiments 100B to 102B, wherein said cancer is MTA-accumulating cancer,.

[0736] Embodiment 104. The use of any one of embodiments 100B to 103B, wherein said cancer is deficient in CDKN2A.

[0737] Embodiment 105B. The use of any one of embodiments 100B to 102B, wherein said cancer is a solid tumor.

[0738] Embodiment 106B. The use of embodiment 105B, wherein said solid tumor is malignant.

[0739] Embodiment 107B. The use of any one of embodiments 100B to 106B, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer ( e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC); e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia,head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0740] Embodiment 108B. The use of any one of embodiments 100B to 106B, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0741] Embodiment 109B. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B.

[0742] Embodiment HOB. A method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75B.

[0743] Embodiment 111B. A method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired with an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment75B.EXAMPLES

[0744] The following examples are put forth so as to provide those of ordinary skill 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 all of the experiments that may be performed. It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate data and the like of a nature described therein. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for.List of Selected Abbreviations:MeOH - methanolMeCN - acetonitrilePdCh(dppf)-DCM adduct - palladium chloride- 1,1 -ferrocenediyl-bis(diphenylphosphino)- dichloromethane adductK2CO3 - potassium carbonateAPhos Pd G3 - palladium G3-(4-(A, A-Dimethylamino)phenyl)di-terr-butylphosphine, [4- (Di-terZ-butylphosphino)-7V,A-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate dppf Pd G3 - methanesulfonato l,l-ferrocenediyl-bis(diphenylphosphino) (2'-amino-l,l'- biphenyl-2-yl) palladium(II)DI H2O - deionized water(4,4'-dtbbpy)NiC12 - [4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride[Ir(dtbbpy)(ppy)2]PFe - [4,4'-Bi5(l,l-dimethylethyl)-2,2'-bipyridine-Al,Al']bis[2-(2- pyridinyl-7V)phenyl-C]iridium(III) hexafluorophosphateAminosupersilane - 7V-( Adamantan- 1 -yl)- 1,1,1 ,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2- amineDPPF Pd G3 - Methanesulfonato l,l-ferrocenediyl-bis(diphenylphosphino) (2'-amino-l,l'- biphenyl-2-yl) palladium(II)Na2COs - sodium carbonateAcCN - acetonitrileTsOH - p-Toluenesulfonic acid i-PrOH - isopropanolTHF - tetrahydrofuranDMF - 7V,7V-dimethylformanrideDCM -dichloromethaneTFA - trifluoroacetic acidNaH - sodium hydrideTIPSOTf - Triisopropylsilyl trifluoromethanesulfonateNH4CI - ammonium chlorideEtOAC - ethyl acetateDBU - l,8-diazabicyclo(5.4.0)undec-7-eneSynthesis Examples Carboxylic Acid (CA) intermediate synthesisIntermediate CAI: 1:1 mixture of (R)-4-amino-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline- 8-carboxylic acid and (S)-4-amino-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline-8-carboxylic acidCA1Step 1: 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate

[0745] To a stirred solution of 4-oxooxolane-3-carbonitrile (9.0 g, 81.00 mmol) and DIEA (16.93 mL, 97.21 mmol) in DCM (180 mL) was added triflic anhydride (13.68 mL, 4.50 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 40 min. The reaction mixture was quenched by water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-cyano-2,5- dihydrofuran-3-yl trifluoromethanesulfonate (14.25 g, crude) as a brown oil. 'H NMR (400 MHz, DMSO-J6) 8 4.87 (s, 4H).Step 2: Methyl 4-amino-l,3-dihydrofuro[3,4-c]quinoline-8-carboxylate

[0746] To a solution of 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (14.25 g, 58.60 mmol) and methyl 4-amino-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (12.99 g, 46.88 mmol) in dioxane (280 mL) and H2O (28 mL) were added K2CO3 (24.30 g, 175.81 mmol) and Pd(dppf)Ch-CH2C12 (4.77 g, 5.86 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and H2O (50 mL) and stirred at room temperature for 30 min. The precipitated solids were collected by filtration and washed with ethyl acetate (50 mL) and 2% MeOH in DCM (50 mL) to afford methyl 4-amino-lH,3H-furo[3,4-c]quinoline-8-carboxylate (8.11 g, 54%) as a brown solid. MS ESI calculated for C13H12N2O3 [M+H]+, 245.08; found, 244.95. 'H NMR (300 MHz, DMSO-d6) 5 9.17 (s, 2H), 8.33 - 8.25 (m, 2H), 7.84 (d, J = 8.7 Hz, 1H), 5.52 (t, J = 3.6 Hz, 2H), 5.11 (t, J = 3.6 Hz, 2H), 3.91 (s, 3H).Step 3: 1 :1 mixture of methyl (R)-4-amino-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline-8- carboxylate and methyl (S)-4-amino-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline-8- carboxylate

[0747] To a solution of methyl 4-amino-lH,3H-furo[3,4-c]quinoline-8-carboxylate (8.11 g, 33.20 mmol) and TEA (20.16 g, 199.22 mmol) in DMF (80 mL) was added AC2O (13.56 g, 132.81 mmol) at room temperature. The resulting solution was stirred at 90 °C for 5 h. The reaction mixture was diluted by water and EtOAc. The precipitated solids were collected by filtration and washed with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The precipitated solids were dissolved in TFA (100 mL), then PtO2 (4.28 g, 18.86 mmol) was added to the above mixture. The resulting solution was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was concentrated under vacuum. The residue was basified with NaHCOs (aq.) to pH 8 and extracted with DCM. The combined organic layers were filtered, the filter cake was washed with DCM / MeOH (1:1, v / v). The filtrate was collected and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography with 0 ~ 80% EtOAc in petroleum ether and further purified by reverse phase flash column chromatography with 5 ~ 20% MeCN in water (0.1% TFA) to afford 1:1 mixture of methyl (R)-4-amino- 1,3, 6,7,8, 9-hexahydrofuro[3,4-c]quinoline-8- carboxylate and methyl (S)-4-amino- 1,3, 6,7,8, 9-hexahydrofuro[3,4-c]quinoline-8- carboxylate (3.78 g, 39%) as a white solid. MS ESI calculated for C15H18N2O4 [M+H]+, 291.13; found, 291.20. 'H NMR (400 MHz, DMSO-d6) 6 10.33 (s, 1H), 5.03 - 4.92 (m, 2H), 4.90 - 4.84 (m, 2H), 3.66 (s, 3H), 2.92 - 2.66 (m, 5H), 2.24 - 2.13 (m, 1H), 2.02 (s, 3H), 1.93 - 1.78 (m, 1H).Step 4: 1:1 mixture of (R)-4-amino-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline-8-carboxylic acid and (S)-4-amino-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline-8-carboxylic acidCA1

[0748] To a 1:1 mixture of methyl (R)-4-amino- 1,3, 6,7,8, 9-hexahydrofuro[3,4-c]quinoline- 8-carboxylate and methyl (S)-4-amino- 1,3, 6,7,8, 9-hexahydrofuro[3,4-c]quinoline-8- carboxylate (1.8 g, 6.20 mmol) in dioxane (10 mL) and H2O (10 mL) was added NaOH (496 mg, 12.40 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The organic solvent was concentrated under vacuum. Then the mixture was acidified with HC1 (aq. IN) to pH 5. The precipitated solids were collected by filtration and washed with water, then dried under vacuum to afford 1:1 mixture of (R)-4-amino-l,3,6,7,8,9- hexahydrofuro[3,4-c]quinoline-8-carboxylic acid and (S)-4-amino-l,3,6,7,8,9- hexahydrofuro[3,4-c]quinoline-8-carboxylic acid (1.4 g, 77%) as a white solid. MS ESI calculated for C12H14N2O3 [M+H]+, 235.10; found, 235.05. 'H NMR (400 MHz, DMSO-6) 8 13.77 (s, 1H), 7.83 (s, 2H), 5.15 - 5.01 (m, 2H), 4.98 - 4.92 (m, 2H), 2.91 - 2.77 (m, 2H), 2.76 - 2.53 (m, 3H), 2.20 - 2.11 (m, 1H), 1.84 - 1.72 (m, 1H).Intermediate CAI isomer 1: (S)-4-amino-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline-8- carboxylic acid isomer 1Isomer 1Intermediate CAI isomer 2: (R)-4-amino- 1,3, 6,7,8, 9-hexahydrofuro[3, 4-c]quinolinc-8- carboxylic acid isomer 2

[0749] 1 :1 mixture of methyl (S)-4-acetamido-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline- 8-carboxylate and methyl (R)-4-acetamido- 1,3, 6,7,8, 9-hexahydrofuro[3,4-c]quinoline-8- carboxylate (25.0 g, 80% purity) was separated by Prep-chiral HPLC with the following conditions: [Column: CHIRAL ART Cellulose-SC, 7*25 cm, 10 pm; Mobile Phase A: Hex (0.1% DEA)-HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 200 mL / min; Gradient: 40% B to 40% B in 20 min; Wave Length: 220 nm; RTl(min): 13.84; RT2(min): 18.96; Sample Solvent: MeOH: DCM=1: 1— HPLC] to afford methyl (S)-4-acetamido- l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline-8-carboxylate (10.4 g) as a white solid with retention time at 13.84 minute. MS ESI calculated for C15H18N2O4 [M+H]+, 291.13; found, 291.10. 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 10.33 (s, 1H), 5.06 - 4.84 (m, 4H), 3.66 (s, 3H), 2.93 - 2.66 (m, 5H), 2.24 - 2.11 (m, 1H), 2.02 (s, 3H), 1.93 - 1.79 (m, 1H).

[0750] The chiral separation also afforded methyl (R)-4-acetamido-l,3,6,7,8,9- hexahydrofuro[3,4-c]quinoline-8-carboxylate (9.0 g) as a white solid with retention time at 18.96 minute. MS ESI calculated for C15H18N2O4 [M+H]+, 291.13; found, 291.10. 'H NMR (400 MHz, DMSO-d6) 5 (ppm) 10.33 (s, 1H), 5.06 - 4.84 (m, 4H), 3.66 (s, 3H), 2.93 - 2.66 (m, 5H), 2.24 - 2.11 (m, 1H), 2.02 (s, 3H), 1.93 - 1.79 (m, 1H).Isomer 1

[0751] A mixture of methyl (S)-4-acetamido-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinoline-8- carboxylate (5.0 g, 17.22 mmol) and HC1 (cone.) (40 mL) was stirred at 100 °C for 2 h. Thereaction mixture was concentrated under vacuum to afford (S)-4-amino-l,3,6,7,8,9- hexahydrofuro[3,4-c]quinoline-8-carboxylic acid hydrochloride isomer 1 (CAI isomer 1) (4.8 g, crude) as light yellow solid. MS ESI calculated for C12H14N2O3 [M+H]+, 235.10; found, 234.95. 'H NMR (400 MHz, DMSO-6) 8 (ppm) 14.13 (s, 1H), 12.52 (br, 1H), 7.79 (s, 2H), 5.14 - 5.00 (m, 2H), 4.98 - 4.95 (m, 2H), 2.94 - 2.78 (m, 2H), 2.77 - 2.64 (m, 2H), 2.63 - 2.53 (m, 1H), 2.19 - 2.10 (m, 1H), 1.85 - 1.71 (m, 1H).Step-3:

[0752] A mixture of methyl (R)-4-acetamido-l,3,6,7,8,9-hexahydrofuro[3,4-c]quinofine-8- carboxylate (5.0 g, 17.22 mmol) and HC1 (cone.) (50 mL) was stirred at 100 °C for 2.5 h. The reaction mixture was concentrated under vacuum to afford (R)-4-amino-l,3,6,7,8,9- hexahydrofuro[3,4-c]quinoline-8-carboxylic acid hydrochloride isomer 2 (CAI isomer 2) (4.7 g, crude) as a light yellow solid. MS ESI calculated for C12H14N2O3 [M+H]+, 235.10; found, 235.00. 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 14.18 (s, 1H), 12.53 (brs, 1H), 7.81 (s, 2H), 5.14 - 5.00 (m, 2H), 4.99 - 4.94 (m, 2H), 2.88 - 2.78 (m, 2H), 2.76 - 2.64 (m, 2H), 2.63 - 2.54 (m, 1H), 2.22 - 2.09 (m, 1H), 1.84 - 1.72 (m, 1H). The absolute stereochemistry was confirmed by single crystal X-ray crystallography of Example 8, prepared using CAI isomer 2.Intermediate CA2: 1:1 mixture of (R)-2-(tert-butylamino)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridine-6-carboxylic acid and (S)-2-(tert-butylamino)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridine-6-carboxylic acidCA2Step 1: 3-(bromomethyl)-2-chloropyridine

[0753] To a solution of 2-chloro-3-methylpyridine (25.00 g, 196.35 mmol) and N- bromosuccinimide (38.44 g, 215.99 mmol) in carbon tetrachloride (500 mL) was added Benzoyl peroxide (2.52 g, 9.82 mmol) at room temperature. The resulting solution was stirred at 80 °C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-25% ethyl acetate in petroleum ether to afford 3-(bromomethyl)-2-chloropyridine (21 g, 52%) as a light yellow solid. MS ESI calculated for C6H5BrClN [M+H]+, 205.93, 207.93; found, 205.85, 207.85. 'H NMR (400 MHz, DMSO-d6) 6 8.39 (dd, J = 4.8, 2.0 Hz, 1H), 8.08 (dd, J = 7.6, 2.0 Hz, 1H), 7.49 - 7.44 (m, 1H), 4.74 (s, 2H).Step 2: ethyl 2-((2-chloropyridin-3-yl)methyl)pent-4-enoate

[0754] To a solution of ethyl pent-4-enoate (26.12 g, 203.86 mmol) in tetrahydrofuran (300 mL) was added LDA (102.5 mL, 205.00 mmol, 2M in tetrahydrofuran) dropwise at -78 °C under nitrogen atmosphere. Then a solution of 3-(bromomethyl)-2-chloropyridine (21.0 g, 102.43 mmol) in tetrahydrofuran (120 mL) was added to the above mixture dropwise at - 78 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution at room temperature 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 - 13% ethyl acetate in petroleinn ether to afford ethyl 2-[(2-chloropyridin-3-yl)methyl]pent-4-enoate (12.8 g, 49%) as a brown oil. MS ESI calculated for C13H16CINO2 [M+H]+, 254.09; found, 254.15. 'H NMR (400 MHz, DMSO-rfc) 8 8.29 (dd, J = 4.8, 2.0 Hz, 1H), 7.74 (dd, J = 7.6, 2.0 Hz, 1H), 7.40 - 7.35 (m, 1H), 5.83 - 5.72 (m, 1H), 5.14 - 5.01 (m, 2H), 3.97 (q, J = 7.2 Hz, 2H), 2.93 - 2.82 (m, 3H), 2.43 - 2.23 (m, 2H), 1.04 (t, J = 7.2 Hz, 3HStep 3: ethyl 2-((2-vinylpyridin-3-yl)methyl)pent-4-enoate

[0755] A mixture of ethyl 2-[(2-chloropyridin-3-yl)methyl]pent-4-enoate (12.8 g, 50.43 mmol), ethenyltrifluoro-A,-4-borane potassium (10.14 g, 75.67 mmol), (2- dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl)[2-(2'-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate (4.22 g, 5.04 mmol) and sodium carbonate (16.04 g, 151.34 mmol) in dioxane (218 mL) and water (24 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase flash column chromatography with 5 ~ 45% acetonitrile in water (0.1% formic acid) and further purified by flash column chromatography with 0 - 25% ethyl acetate in petroleum ether to afford ethyl 2-[(2-ethenylpyridin-3-yl)methyl]pent-4-enoate (8.00 g, 64%) as a yellow oil. MS ESI calculated for C15H19NO2 [M+H]+, 246.14; found, 246.20.Step 4: ethyl 6,7-dihydro-5H-cyclohepta[b]pyridine-6-carboxylate

[0756] A mixture of ethyl 2-[(2-ethenylpyridin-3-yl)methyl]pent-4-enoate (8.00 g, 32.65 mmol) and [l,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro{ [2-(propan-2- yloxy)phenyl]methylidene} ruthenium (6.13 g, 9.79 mmol) in dichloromethane (200 mL) was stirred at 40 °C for 4 h under nitrogen atmosphere. The reaction mixture was concentrated under vacuum. The residue was purified by flash column chromatography with 0 - 50% ethyl acetate in petroleum ether to afford ethyl 5H,6H,7H-cyclohepta[b]pyridine-6-carboxylate (3.65 g, 51%) as a brown oil. MS ESI calculated for C13H15NO2 [M+H]+, 218.11; found, 218.05. 'H NMR (400 MHz, DMSO-d6) 8 8.39 (d, J = 4.8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H),7.18 - 7.12 (m, 1H), 6.57 (d, 7= 12.8, 1H), 6.17 - 6.11 (m, 1H), 4.02 (q, J = 7.2 Hz, 2H), 3.10 - 2.88 (m, 3H), 2.64 - 2.58 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H).Step 5: ethyl 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6-carboxylate

[0757] To a solution of ethyl 5H,6H,7H-cyclohepta[b]pyridine-6-carboxylate (3.00 g, 13.81 mmol) in ethanol (30 mL) was added Pd / C (294 mg, 10% active on carbon) at room temperature. The mixture was stirred at room temperature for 16 h under hydrogen atmosphere (1 atm.). The resulting mixture was filtered, the filter cake was washed with ethanol. The filtrate was collected and concentrated under reduced pressure to afford ethyl 5H,6H,7H,8H,9H-cyclohepta[b]pyridine-6-carboxylate (2.3 g, 72%) as a brown oil. MS ESI calculated for C13H17NO2 [M+H]+, 220.13; found, 220.05. 'H NMR (400 MHz, Chloroform- d) 8 8.34 (d, J = 4.8 Hz, 1H), 7.47 (d, J = 7.6, 1H), 7.10 - 7.06 (m, 1H), 4.20 - 4.12 (m, 2H), 3.17 - 2.96 (m, 4H), 2.57 - 2.46 (m, 1H), 2.25 - 2.20 (m, 1H), 2.10 - 1.93 (m, 2H), 1.67 - 1.53 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H).Step 6: 6-(ethoxycarbonyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 1-oxide

[0758] To a stirred solution of ethyl 5H,6H,7H,8H,9H-cyclohepta[b]pyridine-6-carboxylate (2.30 g, 10.48 mmol) in dichloromethane (23 mL) was added 3-chloroperoxybenzoic acid (2.71 g, 15.73 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. 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% methanol in dichloromethane to afford 6-(ethoxycarbonyl)-5H,6H,7H,8H,9H-cyclohepta[b]pyridin-l-ium- 1-olate (1.4 g, 56%) as a brown solid. MS ESI calculated for C13H17NO3 [M+H]+, 236.12; found, 236.10.Step 7: ethyl 2-(tert-butylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6-carboxylate

[0759] To a stirred solution of 6-(ethoxycarbonyl)-5H,6H,7H,8H,9H-cyclohepta[b]pyridin- 1-ium-l-olate (1.40 g, 5.95 mmol) and (4-methylbenzene)sulfonyl 4-methylbenzene-l- sulfonate (4.86 g, 14.88 mmol) in tetrahydrofuran (40 mL) was added 2-methylpropan-2- amine (1.96 g, 26.77 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. Then (4-methylbenzene)sulfonyl 4-methylbenzene-l-sulfonate (4.86 g, 14.88 mmol) and 2-methylpropan-2-amine (1.96 g, 26.77 mmol) were sequentially added to the above mixture. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with 5% ~ 75% acetonitrile in water (10 mmol / L ammonium bicarbonate) to afford ethyl 2-(tert-butylamino)-5H,6H,7H,8H,9H- cyclohepta[b]pyridine-6-carboxylate (430 mg, 17%) as a brown oil. MS ESI calculated for C17H26N2O2 [M+H]+, 291.20; found, 291.25. 'H NMR (400 MHz, DMSO-d6) 87.06 (d, J = 8.0 Hz, 1H), 6.20 (d, J= 8.0 Hz, 1H), 5.78 (s, 1H), 4.04 (q, J = 7.2 Hz, 2H), 2.83 - 2.65 (m, 4H), 2.45 - 2.27 (m, 1H), 2.11 - 1.97 (m, 1H), 1.90 - 1.75 (m, 2H), 1.52 - 1.38 (m, 1H), 1.36 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H).Step 8: 1:1 mixture of (R)-2-(tert-butylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine- 6-carboxylic acid and (S)-2-(tert-butylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6- carboxylic acid

[0760] To a solution of ethyl 2-(tert-butylamino)-5H,6H,7H,8H,9H-cyclohepta[b]pyridine- 6-carboxylate (400 mg, 1.37 mmol) in tetrahydrofuran (2 mL), water (2 mL) and methanol (2 mL) was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum to afford lithium 1:1 mixture of (R)-2-(tert-butylamino)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridine-6-carboxylic acid and (S)-2-(tert-butylamino)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridine-6-carboxylic acid (510 mg, crude) as a yellow solid. MS ESI calculated for C15H22N2O2 [M+H]+, 263.17; found, 263.20. 'H NMR (400 MHz, DMSO-d6) 6 7.01 (d, J = 8.0 Hz, 1H), 6.18 (d, J = 8.0 Hz, 1H), 5.59 (s, 1H), 2.79 - 2.54 (m, 4H), 2.17 - 2.09 (m, 1H), 1.90 - 1.81 (m, 1H), 1.79 - 1.70 (m, 1H), 1.69 - 1.55 (m, 1H), 1.36 (s, 9H), 1.30 - 1.17 (m, 1H).Intermediate CA3: 1:1 mixture of (S)-4-((tert-butoxycarbonyl)amino)-3,6,8,9-tetrahydro- lH-furo[3,4-d]pyrano[3,4-b]pyridine-8-carboxylic acid and (R)-4-((tert- butoxycarbonyl)amino)-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridine-8-carboxylic acidStep-1:

[0761] To a stirred solution of 3-(prop-2-yn-l-yloxy)prop-l-yne (40.0 g, 425.02 mmol) in DCM (500 mL) were added NBS (188.36 g, 1058.30 mmol) and AgNO3(168.22 g, 990.29 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. Then the crude product was diluted with diethyl ether. Then the solids were filtered off, the filter cake was washed with diethyl ether. The filtrate was concentrated under reduced pressure to afford l-bromo-3-((3-bromoprop-2-yn-l- yl)oxy)prop-l-yne (116 g, 97%) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) 84.28 (s, 4H).Step-2:

[0762] To a stirred mixture of l-bromo-3-((3-bromoprop-2-yn-l-yl)oxy)prop-l-yne (100.0 g, 388.96 mmol) and ethyl carbonocyanidate (78.68 g, 793.94 mmol) in DCE (1 L) was added Cp*RuCl(cod) (7.54 g, 19.84 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-30% EtOAc in petroleum ether to afford ethyl 4,7-dibromo-l,3-dihydrofuro[3,4-c]pyridine-6- carboxylate (52.3 g, 37%) as a yellow solid. MS ESI calculated for CioHgBnNCh [M+H]+, 349.89; found, 349.75. ’H NMR (400 MHz, DMSO-J6) 8 (ppm) 5.25 - 5.08 (m, 4H), 4.40 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H).Step-3:

[0763] To a solution of ethyl 4,7-dibromo-l,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (50.0 g, 143.16 mmol) in N-methyl-2-pyrrolidone (500 mL) were added (4- methoxyphenyl)methanamine (29.46 g, 217.74 mmol) at room temperature. The solution was stirred at 120 °C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-40% EtOAc in petroleum ether to afford ethyl 7-bromo-4-((4-methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridine-6- carboxylate (38 g, 65%) as a yellow oil. MS ESI calculated for CisHi9BrN2O4 [M+H]+, 407.05; found, 406.95. 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 7.32 - 7.23 (m, 3H), 6.90 - 6.82 (m, 2H), 5.01 - 4.94 (m, 4H), 4.43 (d, J = 5.6 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).Step-4:

[0764] To a solution of ethyl 7-bromo-4-((4-methoxybenzyl)amino)-l,3-dihydrofuro[3,4- c]pyridine-6-carboxylate (36 g, 88.39 mmol) and allyltributylstannane (58.54 g, 176.79 mmol) in DMF (360 mL) was added Pd(PPh3)4 (5.11 g, 4.42 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-40% EtOAc in petroleum ether to afford ethyl 7-allyl-4-((4-methoxybenzyl)amino)-l,3- dihydrofuro[3,4-c]pyridine-6-carboxylate (27 g, 82%) as a yellow solid. MS ESI calculated for C21H24N2O4 [M+H]+, 369.17; found, 369.35.Step-5:

[0765] To a stirred mixture of ethyl 7-allyl-4-((4-methoxybenzyl)amino)-l,3- dihydrofuro[3,4-c]pyridine-6-carboxylate (27.0 g, 73.28 mmol) in THF (270 mL), t-BuOH (54 mL) and water (54 mL) were added NMO (10.29 g, 87.94 mmol) and OsO4 (0.93 g, 3.71 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of sodium hyposulfite (sat.) at room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-100% EtOAc in petroleum ether to afford a 1 : 1 mixture of ethyl (R)- 7-(2,3-dihydroxypropyl)-4-((4-methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridine-6- carboxylate and ethyl (S)-7-(2,3-dihydroxypropyl)-4-((4-methoxybenzyl)amino)-l,3- dihydrofuro[3,4-c]pyridine-6-carboxylate (24.2 g, 82%) as an off-white solid. MS ESI calculated for C21H26N2O6 [M+H]+, 403.18; found, 403.30. 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 7.36 - 7.28 (m, 2H), 6.88 - 6.83 (m, 2H), 6.80 (t, J = 6.0 Hz, 1H), 5.12 - 4.95 (m, 2H),4.94 - 4.85 (m, 2H), 4.57 - 4.50 (m, 2H), 4.44 (d, 7= 5.6 Hz, 2H), 4.26 (q, 7= 7.2 Hz, 2H), 3.72 (s, 3H), 3.57 - 3.48 (m, 1H), 3.30 - 3.21 (m, 2H), 2.81 - 2.75 (m, 1H), 2.40 - 2.33 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H).Step-6:

[0766] To a stirred mixture of a 1:1 mixture of ethyl (R)-7-(2,3-dihydroxypropyl)-4-((4- methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridine-6-carboxylate and ethyl (S)-7-(2,3- dihydroxypropyl)-4-((4-methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (14.0 g, 34.78 mmol) and lH-imidazole (3.55 g, 52.18 mmol) in DCM (150 mL) was added tert-butylchlorodiphenylsilane (9.56 g, 34.78 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0 - 50% EtOAc in petroleum ether to afford a 1:1 mixture of ethyl (R)- 7-(3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropyl)-4-((4-methoxybenzyl)amino)-l,3- dihydrofuro[3,4-c]pyridine-6-carboxylate and ethyl (S)-7-(3-((tert-butyldiphenylsilyl)oxy)-2- hydroxypropyl)-4-((4-methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (18.8 g, 84%) as a yellow oil. MS ESI calculated for C37H44N2O6S1 [M+H]+, 641.30; found, 641.45. ’H NMR (400 MHz, DMSO-d6) 8 (ppm) 7.69 - 7.58 (m, 4H), 7.52 - 7.38 (m, 6H), 7.38 - 7.30 (m, 2H), 6.90 - 6.76 (m, 3H), 5.12 - 4.83 (m, 4H), 4.73 (d, J = 5.2 Hz, 1H), 4.44 (d, J = 6.0 Hz, 2H), 4.22 (q, J = 6.8 Hz, 2H), 3.75 - 3.65 (m, 4H), 3.60 - 3.43 (m, 2H), 2.95 - 2.88 (m, 1H), 2.47 - 2.39 (m, 1H), 1.26 (t, J = 6.8 Hz, 3H), 1.00 (s, 9H).Step-7:

[0767] To a stirred solution of a 1:1 mixture of ethyl (R)-7-(3-((tert- butyldiphenylsilyl)oxy)-2-hydroxypropyl)-4-((4-methoxybenzyl)amino)-l,3-dihydrofuro[3,4- c]pyridine-6-carboxylate and ethyl (S)-7-(3-((tert-butyldiphenylsilyl)oxy)-2-hydroxypropyl)- 4-((4-methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (18.8 g, 29.33mmol) in THF (100 mL) and EtOH (100 mL) were added CaCh (6.51g, 58.67 mmol) and NaBH4 (3.32 g, 88.01 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction mixture was diluted with water at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-50% EtOAc in petroleum ether to afford a 1:1 mixture of (R)-l-((tert-butyldiphenylsilyl)oxy)-3-(6- (hydroxymethyl)-4-((4-methoxybenzyl)amino)- 1 ,3-dihydrofuro [3 ,4-c]pyridin-7 -yl)propan-2- ol and (S)- l-((tert-butyldiphenylsilyl)oxy)-3-(6-(hydroxymethyl)-4-((4- methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridin-7-yl)propan-2-ol (14 g, 79%) as a colorless oil. MS ESI calculated for Css^i zOsSi [M+H]+, 599.29; found, 599.20.Step-8:

[0768] To a stirred solution of a 1:1 mixture of (R)-l-((tert-butyldiphenylsilyl)oxy)-3-(6- (hydroxymethyl)-4-((4-methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridin-7-yl)propan-2- ol and (S)- l-((tert-butyldiphenylsilyl)oxy)-3-(6-(hydroxymethyl)-4-((4- methoxybenzyl)amino)-l,3-dihydrofuro[3,4-c]pyridin-7-yl)propan-2-ol (15.1 g, 25.21 mmol) in THF (50 mL) and toluene (100 mL) was added 2-(tributyl-A,5- phosphaneylidene)acetonitrile (CAS No. 157141-27-0) (12.17 g, 50.43 mmol) at room temperature under nitrogen atmosphere. The solution was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with 0-29% ethyl acetate in petroleum ether to afford a 1:1 mixture of (S)-8-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(4-methoxybenzyl)-3,6,8,9-tetrahydro-lH- furo[3,4-d]pyrano[3,4-b]pyridin-4-amine and (R)-8-(((tert-butyldiphenylsilyl)oxy)methyl)-N- (4-methoxybenzyl)-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin-4-amine (9.2 g, 62%) as a yellow semi-solid. MS ESI calculated for CssFLo zCLSi [M+H]+, 581.28; found, 581.15.Step-9:

[0769] A 1:1 mixture of (S)-8-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(4- methoxybenzyl)-3,6,8,9-tetrahydro- lH-furo[3,4-d]pyrano[3,4-b]pyridin-4-amine and (R)-8- (((tert-butyldiphenylsilyl)oxy)methyl)-N -(4-methoxybenzyl)-3,6,8 ,9-tetrahydro- 1 H-furo [3 ,4- d]pyrano[3,4-b]pyridin-4-amine (4.7 g, 8.09 mmol) in TFA (50 mL) and trifluoromethanesulfonic acid (0.47 mL, 6.71 mmol) was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in MeOH (40 mL), then K2CO3 (4.47 g, 32.36 mmol) was added. The resulting mixture was stirred at 65 °C for 3 h. Then the reaction mixture was concentrated under vacuum. The residue was purified by flash column chromatography with 0-20% MeOH in DCM to afford a 1:1 mixture of (S)-(4-amino-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin-8- yl)methanol and (R)-(4-amino-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin-8- yl)methanol (940 mg, 42%) as a yellow solid. MS ESI calculated for C11H14N2O3 [M+H]+, 223.10; found, 223.05. 'H NMR (400 MHz, DMSO-6) 5 (ppm) 5.78 (s, 2H), 4.96 - 4.81 (m, 4H), 4.79 (t, J = 5.6 Hz, 1H), 4.50 (s, 2H), 3.71 - 3.61 (m, 1H), 3.57 - 3.42 (m, 2H), 2.39 (d, J = 7.2 Hz, 2H).

[0770] To a solution of a 1:1 mixture of (S)-(4-amino-3,6,8,9-tetrahydro-lH-furo[3,4- d]pyrano[3,4-b]pyridin-8-yl)methanol and (R)-(4-amino-3,6,8,9-tetrahydro-lH-furo[3,4- d]pyrano[3,4-b]pyridin-8-yl)methanol (940 mg, 4.23 mmol) and BOC2O (3.69 g, 16.92 mmol) in THF (10 mL) were added DMAP (155 mg, 1.27 mmol) and TEA (2.57 g, 25.38 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase flash column chromatography with 10% ~ 90% MeCN in water (10 mmol / L NH4HCO3) to afford a 1:1 mixture of tert-butyl (S)-(tert-butoxycarbonyl)(8-(((tert-butoxycarbonyl)oxy)methyl)- 3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin-4-yl)carbamate and tert-butyl (R)- (tert-butoxycarbonyl)(8-(((tert-butoxycarbonyl)oxy)methyl)-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin-4-yl)carbamate (1.2 g, 46%) as a yellow solid. MS ESI calculated for C26H38N2O9 [M+H]+, 523.26; found, 523.45.Step-11:

[0771] To a stirred solution of a 1 :1 mixture of tert-butyl (S)-(tert-butoxycarbonyl)(8- (((tert-butoxycarbonyl)oxy)methyl)-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin- 4-yl)carbamate and tert-butyl (R)-(tert-butoxycarbonyl)(8-(((tert- butoxycarbonyl)oxy)methyl)-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin-4- yl)carbamate (1.2 g, 2.29 mmol) in MeOH (48 mL) was added NaOH (14.4 mL, 25% aqueous solution) at room temperature. The mixture was stirred at room temperature for 1 h. The organic solvent was concentrated under reduced pressure. The residue was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaiSCk. After filtration, the filtrate was concentrated under reduced pressure to afford a 1:1 mixture of tert-butyl (S)-(8-(hydroxymethyl)-3,6,8,9-tetrahydro-lH- furo[3,4-d]pyrano[3,4-b]pyridin-4-yl)carbamate and tert-butyl (R)-(8-(hydroxymethyl)- 3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin-4-yl)carbamate (740 mg, crude) as a colorless oil. MS ESI calculated for C16H22N2O5 [M+H]+, 323.15; found, 323.20. 'H NMR (400 MHz, DMSO-de) 5 (ppm) 9.54 (s, 1H), 5.06 - 4.83 (m, 5H), 4.70 - 4.60 (m, 2H), 3.77 - 3.69 (m, 1H), 3.59 - 3.48 (m, 2H), 2.60 - 2.53 (m, 2H), 1.44 (s, 9H).Step- 12:CA3

[0772] To a stirred a 1:1 mixture of tert-butyl (S)-(8-(hydroxymethyl)-3,6,8,9-tetrahydro- lH-furo[3,4-d]pyrano[3,4-b]pyridin-4-yl)carbamate and tert-butyl (R)-(8-(hydroxymethyl)- 3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridin-4-yl)carbamate (350 mg, 1.08 mmol) in ACN (4 mL) and H2O (2 mL) were added TEMPO (68 mg, 0.43 mmol) and BAIB (420 mg, 1.30 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was purified directly by reverse phase flash column chromatography with 0-25% MeCN in water (10 mmol / L NH4HCO3) to afford a 1:1 mixture of (S)-4-((tert- butoxycarbonyl)amino)-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridine-8-carboxylic acid and (R)-4-((tert-butoxycarbonyl)amino)-3,6,8,9-tetrahydro- lH-furo[3,4-d]pyrano[3,4- b]pyridine-8-carboxylic acid (CA3) (75 mg, 20%) as an off-white solid. MS ESI calculated for C16H20N2O6 [M+H]+, 337.13; found, 337.05. 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 9.52 (s, 1H), 5.08 - 4.87 (m, 4H), 4.85 - 4.50 (m, 2H), 4.02 - 3.97 (m, 1H), 2.93 - 2.63 (m, 2H), 1.44 (s, 9H).Intermediate CA3 isomer 1: rel-(R)-4-((tert-butoxycarbonyl)amino)-3,6,8,9-tetrahydro-lH- furo[3,4-d]pyrano[3,4-b]pyridine-8-carboxylic acid, isomer 1:Intermediate CA3 isomer 2: rel-(R)-4-((tert-butoxycarbonyl)amino)-3,6,8,9-tetrahydro-lH- furo[3,4-d]pyrano[3,4-b]pyridine-8-carboxylic acid, isomer 2:CA3 isomer 2

[0773] Intermediate CA3 (810 mg) was separated by Prep-chiral HPLC with the following conditions: [Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.1% TFA)— HPLC, Mobile Phase B: MeOH: DCM=1: 1— HPLC; Flow rate: 20 mL / min; Gradient (B%): 50% B to 50% B in 11 min; Wave Length: 220 / 254 nm; RTl(min): 5.41; RT2(min): 9.63;Sample Solvent: MeOH: DCM=1: 1— HPLC] to afford rel-(R)-4-((tert- butoxycarbonyl)amino)-3,6,8,9-tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridine-8-carboxylic acid isomer 1 (CA3 isomer 1) (381 mg) as a white solid with retention time at 5.41 minute. MS ESI calculated for Ci6H2oN206[M+H]+, 337.13; found, 337.05 'H NMR (400 MHz, DMSO-J6) 8 (ppm) 9.61 (s, 1H), 5.10 - 4.83 (m, 4H), 4.80 - 4.68 (m, 2H), 4.45 - 4.42 (m, 1H), 2.88 - 2.60 (m, 2H), 1.44 (s, 9H). Absolute stereochemistry was not determined.

[0774] The chiral separation also afforded rel-(R)-4-((tert-butoxycarbonyl)amino)-3, 6,8,9- tetrahydro-lH-furo[3,4-d]pyrano[3,4-b]pyridine-8-carboxylic acid isomer 2 (CA3 isomer 2) (365 mg) as a white solid with retention time at 9.63 minute. MS ESI calculated for CI6H2ON206[M+H]+, 337.13; found, 337.05. 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 9.62 (s, 1H), 5.08 - 4.80 (m, 4H), 4.80 - 4.68 (m, 2H), 4.45 - 4.42 (m, 1H), 2.90 - 2.68 (m, 2H), 1.44 (s, 9H).

[0775] Absolute stereochemistry of CA3 isomer 1 was determined based on single crystal X-ray crystallography of Example 33 prepared using CA3 isomer 1. Accordingly, CA3 isomer 1 (S-configuration) and CA3 isomer 2 (R-configuration) are each represented by the respective structures:Isomer 1an(| Isomer 2Intermediate CA4: 1:1 mixture of (S)-4-amino-7-(tert-butoxycarbonyl)-l,3,6,7,8,9- hexahydrofuro[3,4-c][l,7]naphthyridine-8-carboxylic acid and (R)-4-amino-7-(tert- butoxy carbonyl)-! ,3,6,7,8,9-hexahydrofuro[3,4-c] [l,7]naphthyridine-8-carboxylic acidCA4Step-1:

[0776] To a stirred solution of 4-oxotetrahydrofuran-3-carbonitrile (25.0 g, 225.02 mmol) and DIEA (34.9 g, 270.02 mmol) in DCM (500 mL) were added (trifhioromethane)sulfonyl trifluoromethanesulfonate (63.4 g, 225.02 mmol) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The mixture was diluted with ethyl acetate and washed with NaHCCh (sat.). The organic layer was dried over anhydrous Na2SO4, filtered and concnetrated under vacuum. The residue was purified by flash column chromatography with 0-60% ethyl acetate in petroleum ether to afford 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (40.0 g, 73%) as a brown oil. MS ESI calculated for C6H4F3NO4S [M+l]+, 243.98; found, 244.20.Step-2:

[0777] A mixture of methyl 5-aminopyridine-2-carboxylate (25.00 g, 164.31 mmol) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (31.54 g, 246.46 mmol) in anhydrous THF (200 mL) was stirred at 50 °C for 1 h under nitrogen atmosphere. The reaction mixture was cooled to 25 °C and then added to a mixture of Bis(pinacolato)diboron (20.86 g, 82.15...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (la) :or a pharmaceutically acceptable salt thereof, whereinX1is C(RlaRlb), O, or NR1;X2is C(R2aR2b), O, or NR2;X3is C(R3aR3b), O, or NR3;X4is C(R4aR4b), O, NR4, S, S(O), or S(O)2;X5is C(R5aR5b), O, NR5, S, S(O), or S(O)2;X6is C(R6aR6b), O, NR6, S, S(O), or S(O)2;R1, R2, and R3are each independently H or Ci-4 alkyl;Rla,Rlb, R2a,R2b, R3a, and R3bare each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl;R4, R5, and R6are each independently H, C1.4 alkyl, or C1.4 hydroxyalkyl;R4a, R4b, R5a,R5b, R6a, and R6bare each independently H, C1.4 alkyl, C1-4 haloalkyl, Cu hydroxyalkyl, or C1-4 haloalkyl(OH); ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S; ring B isphenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B; and ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, or 2; q is 0, 1, or 2; each R7is independently C1-6 alkyl, Ci-6 haloalkyl, halo, OH, C1-6 alkoxy, C1.6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, or -C(O)OCi6haloalkyl;each R7ais independently Ci-4 alkyl, halo, C1-4 haloalkyl, OH, or Ci-4 alkoxy; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, OH, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, - C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, -C(O)OCi-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6 cycloalkyl, -O-C3-6 cycloalkyl, and heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently C1-4 alkyl, halo, C1-4 haloalkyl, CN, OH, or C1-4 alkoxy; and R9is H, C1-4 alkyl, halo, or C1-4 haloalkyl.

2. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein: each R7is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, Ci-6 haloalkoxy, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)OCi-6alkyl, or -C(O)OCi-6haloalkyl; each R7ais independently C1-4 alkyl, halo, or C1-4 haloalkyl; alternatively, two R7agroups attached to the same carbon atom combine to form oxo; each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, C3- 6 cycloalkyl, -O-C3-6 cycloalkyl, -C(O)Ci-6 alkyl, -C(O)Ci-6 haloalkyl, -C(O)OCi-6 alkyl, -C(O)OCi-6 haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R8a; each R8ais independently C1-4 alkyl, halo, or C1-4 haloalkyl; and R9is H, Ci-4 alkyl, halo, or CM haloalkyl.

3. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2, wherein X1is CH2; X2is O, NH, or CH2; X3is CH2; X4is CHR4a; X5is O; X6is CH2; and R9is H.

4. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein X2is O.

5. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein X2is NH.

6. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein X2is CH2.

7. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 6, wherein ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein each additional heteroatom is independently N or O; ring B is phenyl or heteroaryl having 6 ring members with 1 to 2 nitrogen atom ring vertices; and ring C is C5-6 cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

8. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl.

9. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 8, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

10. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 9, wherein ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

11. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 10, wherein ring C is C5-6 cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl.

12. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 11, wherein ring C is C5-6 cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl.

13. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 12, having Formula (Ila):wherein: ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl;Xais O, NH, NR7, CH2, CHR7, or C(R7)2;X7ais absent, O, CH2, or CHR7a; andX7bis absent, O, CH2, or CHR7a, provided that X7aand X7bare not each absent or O; and a total number of R7groups is no more than 2.

14. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 13, wherein ring B is phenyl or pyridyl.

15. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 14, having Formula (Ila- 1):wherein:Xais O, NH, N(CI-4alkyl), CH2, CHR7, or C(R7)2;X7ais absent, O, CH2, or CHR7a; andX7bis absent, O, CH2, or CHR7a, provided that X7aand X7bare not each absent or O; and a total number of R7groups is no more than 2.

16. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 14, having Formula (IIa-2):wherein:Xais O, NH, N(CI-4alkyl), CH2, CHR7, or C(R7)2;X7ais absent, O, CH2, or CHR7a; andX7bis absent, O, CH2, or CHR7a, provided that X7aand X7bare not each absent or O; and a total number of R7groups is no more than 2.

17. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 16, wherein R4ais H or CM alkyl.

18. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 17, wherein R4ais H; or R4ais methyl.

19. The compound or a pharmaceutically acceptable salt thereof of any one of claims 13 to 18, wherein Xais CH2, CHR7, or C(R7)2.

20. The compound or a pharmaceutically acceptable salt thereof of any one of claims 13 to 18, wherein:Xais O, NH, CH2, or CHR7;X7ais O, CH2, or CHR7a;X7bis O, CH2, or CHR7a; and p is 0 or 1.

21. The compound or a pharmaceutically acceptable salt thereof of any one of claims 13 to 18, wherein:Xais O, NH, or CH2;X7ais O, CH2, or CHR7a;X7bis O, CH2, or CHR7a; and p is 0, 1, or 2.

22. The compound or a pharmaceutically acceptable salt thereof of any one of claims 13 to 18, wherein:Xais C(R7)2;X7ais O, CH2, or CHR7a;X7bis O, CH2, or CHR7a; and p is 0.

23. The compound or a pharmaceutically acceptable salt thereof of any one of claims 13 to 22, wherein:X7ais absent and X7bis CH2; orX7ais absent and X7bis O.

24. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 23, wherein each R7is independently Ci-4 alkyl, halo, OH, or Ci-4 alkoxy.

25. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 24, wherein each R7is independently methyl, fluoro, OH, or methoxy.

26. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 25, wherein each R7is independently methyl, fluoro, or methoxy.

27. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 26, wherein each R8is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, CN, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, or -O-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl and -O-C3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

28. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 27, wherein q is 1; and R8is Ci-6 alkyl, Ci-6 haloalkyl, halo, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, CN, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6 cycloalkyl, or -O-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl and -O-C3-6 cycloalkyl are each independently substituted with 0 or 1 CN.

29. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 28, wherein q is 1; and R8is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C- CH2-O-.

30. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 29, wherein q is 1; and R8is chloro, trifluoromethyl, or difluoromethyl-O-.

31. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 27, wherein q is 2; and each R8is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

32. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 3 to 31, wherein the moietywherein:Xais O, NH, CH2, or CHR7;X7ais O, CH2, or CHR7a;X7bis O, CH2, or CHR7a; each R7ais independently Ci-4 alkyl; each R7is independently F, OH, Ci-4 alkyl, or Ci-4 alkoxy; andR8is Ci-4 alkyl, Ci-4 haloalkyl, halo, CN, Ci-4 alkoxy, C haloalkoxy, C2-4 alkynyl, - O-C2-4 alkynyl, C3-6 cycloalkyl, or -O-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl and -O- C3-6 cycloalkyl are each independently unsubstituted or substituted with CN, provided that X7aand X7bare not each O.

33. The compound or a pharmaceutically acceptable salt thereof of claim 32, wherein Xais O, NH, CH2, CHF, C(CH3), C(OH), or C(OCH3); X7ais O, CH2, or CH(CH3); X7bis O or CH2; R7is F, CH3, OH, or OCH3; and R8is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl- O- , trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-, provided that X7aand X711are not each O.

34. The compound or a pharmaceutically acceptable salt thereof of claim32 or 34, wherein R8is chloro, trifluoromethyl, or difluoromethyl-O-.

35. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 34, whereinX2is O and R4ais H;X2is NH and R4ais H;X2is NH and R4ais methyl;X2is CH2and R4ais H; orX2is CH2and R4ais methyl.

36. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 35, wherein:

37. The compound or a pharmaceutically acceptable salt thereof of claim1, represented by any one of the structures of Examples 1 to 3 and 5 to 112 in Table 1.

38. A compound or a pharmaceutically acceptable salt thereof, represented by any one of the structures of Examples 1 to 112.

39. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 38, and a pharmaceutically acceptable excipient.

40. A method for treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 38, or a pharmaceutical composition of claim 39.

41. The method of claim 40, wherein the disease is cancer.

42. A method of treating an MTAP null cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 38, or a pharmaceutical composition of claim 39.

43. A method for treating cancer in a patient in need thereof, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 38, or a pharmaceutical composition of claim 39.

44. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 38, or a pharmaceutical composition of claim 39.

45. The method of any one of claims 41 to 44, wherein the cancer is a MTA-accumulating cancer.

46. The method of claim 41 or 45, wherein the cancer is deficient in CDKN2A.

47. The method of any one of claims 41 to 46, wherein the cancer is a solid tumor.

48. The method of claim 47, wherein the solid tumor is malignant.

49. The method of any one of claims 41 to 48, wherein the cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer e.g., non-small cell lung cancer (NSCLC); e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine, or sarcoma.

50. The method of any one of claims 41 to 48, wherein the cancer is selected from the group consisting of leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, and mesothelioma.

51. The method of any one of claims 41 to 48, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

52. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 38, or a pharmaceutical composition of claim 39.

53. A method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 38, or a pharmaceutical composition of claim 39.

54. A method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired with an effective amount of acompound or pharmaceutically acceptable salt thereof of any one of claims 1 to 38, or a pharmaceutical composition of claim 39.

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