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WO2025166229A1 - Composés amidino tricycliques utilisés en tant qu'inhibiteurs de prmt5 - Google Patents

Composés amidino tricycliques utilisés en tant qu'inhibiteurs de prmt5

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Publication number
WO2025166229A1
WO2025166229A1 PCT/US2025/014121 US2025014121W WO2025166229A1 WO 2025166229 A1 WO2025166229 A1 WO 2025166229A1 US 2025014121 W US2025014121 W US 2025014121W WO 2025166229 A1 WO2025166229 A1 WO 2025166229A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
ring
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/014121
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English (en)
Inventor
Paul A. Barsanti
Melissa Fleury
Joshua P. G. TAYGERLY
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Ideaya Biosciences Inc
Original Assignee
Ideaya Biosciences Inc
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Publication of WO2025166229A1 publication Critical patent/WO2025166229A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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.
  • 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.
  • PRMT5 Protein arginine N-methyltransferase 5
  • SAM s- adenosyl methionine
  • 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.
  • PRMT5 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.
  • 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
  • MTA methylthioadenosine
  • 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.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the definitions for X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , ring A, ring B, R 7 , p, R 8 , q, and R 9 are further described herein.
  • 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.
  • 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.
  • PRMT5 protein arginine N-methyltransferase 5
  • 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.
  • 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.
  • 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.
  • 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).
  • PRMT5 protein arginine N-methyltransferase 5
  • 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.
  • 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 is provided herein.
  • 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).
  • PRMT5 protein arginine N-methyltransferase 5
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof.
  • PRMT5 protein arginine N- methyltransferase 5
  • 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.
  • PRMT5 protein arginine N-methyltransferase 5
  • a method of inhibiting protein arginine N- methyltransferase 5 (PRMT5) in vitro or in vivo 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.
  • PRMT5 protein arginine N- methyltransferase 5
  • a method of inhibiting cell profiferation in vitro or in vivo 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.
  • the methods, uses, and medicament described herein are for the treatment of human cancers.
  • 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.
  • novel intermediates as defined herein which are suitable for use in any one of the synthetic methods as set out herein.
  • [0039] Provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof for inhibition of protein arginine N-methyltransferase 5 (PRMT5), and pharmaceutical compositions comprising the same. Also provided herein are, for example, methods of treating or preventing a disease, disorder or condition, or a symptom thereof, mediated by 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.
  • PRMT5 protein arginine N-methyltransferase 5
  • 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.
  • 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.
  • 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.
  • 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 of carbons, 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.
  • alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl,
  • cycloalkyl refers to a non-aromatic, saturated hydrocarbon ring having the indicated number of ring atoms (e.g., C3-6 cycloalkyl).
  • C3-10 cycloalkyl refers to a cycloalkyl group containing 3 to 10 carbon atoms as ring vertices
  • 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.
  • halo or halogen, by itself or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • 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.
  • C1-4 haloalkyl includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • haloalkyl(OH) refers to haloalkyl, as defined above, that is further substituted with a hydroxy (OH) group.
  • alkoxy refers 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.
  • aryl refers to a monocyclic or bicyclic, hydrocarbon, aromatic radical.
  • An aryl group may contain 6 to 14 carbon atoms.
  • “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.
  • heteroaryl refers to a moiety comprising an aromatic monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • 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, p
  • 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.
  • 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.
  • heterocycloalkyl groups are not aromatic.
  • 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.
  • hydroxyalkyl refers to an alkyl, as defined above, that is substituted with one or two hydroxy.
  • 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.
  • optionally substituted indicates that a group may be unsubstituted or substituted with one or more substituents as defined herein.
  • 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.
  • 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.
  • 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.
  • a bond extending to the center of a ring e.g., a phenyl ring
  • a bond extending to the center of a ring is meant to indicate attachment at any of the available ring vertices.
  • multiple substituents shown as being attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible.
  • 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.
  • the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-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.
  • substituted amines such as arginine, betaine, caffeine, choline,
  • 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.
  • 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.
  • salts of amino acids such as arginate
  • salts of organic acids like glucuronic or galactunoric acids
  • 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.
  • 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.
  • Certain compounds of Formula (I) possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.
  • a stereochemical depiction 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%.
  • 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.
  • 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.
  • 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 include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I, and 125 1, respectively.
  • isotopic variations can provide additional utilities to those described elsewhere within this application.
  • 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.
  • 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 with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo halflife or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, n C, and 15 F 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.
  • 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.
  • the patient or subject is a human.
  • 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.
  • “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.
  • administration refers 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.
  • 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.
  • proliferative disorder refers to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • 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.
  • treat refers 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.
  • 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.
  • prevent refers 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.
  • 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.
  • 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.
  • therapeutically effective amount 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein
  • X 1 is C(R la R lb ), O, or NR 1 ;
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b ), O, or NR 3 ;
  • X 4 is C(R 4a R 4b ), O, NR 4 , S, S(O), or S(O) 2 ;
  • X 5 is C(R 5a R 5b ), O, NR 5 , S, S(O), or S(O) 2 ;
  • X 6 is C(R 6a R 6b ), O, NR 6 , S, S(O), or S(O) 2 ;
  • R 1 , R 2 , and R 3 are each independently H or Ci-4 alkyl
  • R la ,R lb , R 2a ,R 2b , R 3a , and R 3b are each independently H, Ci-4 alkyl, halo, or Ci-4 haloalkyl;
  • R 4 , R 5 , and R 6 are each independently H, Ci-4 alkyl, or Ci-4 hydroxyalkyl;
  • R 4a ,R 4b , R 5a > R 5b > R 6a , and R 6b are 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 R 7 is independently C1-6 alkyl, C1-6 haloalkyl, halo, OH, C1-6 alkoxy, C1-6 haloal
  • X 1 is C(R la R lb ), O, or NR 1 ;
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b ), O, or NR 3 ;
  • X 4 is C(R 4a R 4b ), O, NR 4 , S, S(O), or S(O) 2 ;
  • X 5 is C(R 5a R 5b ), O, NR 5 , S, S(O), or S(O) 2 ;
  • X 6 is C(R 6a R 6b ), O, NR 6 , S, S(O), or S(O) 2 ;
  • R 1 , R 2 , and R 3 are each independently H or C1-4 alkyl
  • R la ,R lb , R 2a ,R 2b , R 3a , and R 3b are each independently H, C1.4 alkyl, halo, or C1.4 haloalkyl;
  • R 4 , R 5 , and R 6 are each independently H, C1-4 alkyl, or C1-4 hydroxyalkyl;
  • R 4a , R 4b , R 5a ,R 5b , R 6a , and R 6b are 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 R 7 is independently
  • X 1 is C(R la R lb ), O, or NR 1 ;
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b ), O, or NR 3 ;
  • X 4 is C(R 4a R 4b ), 0, NR 4 , S, S(O), or S(O) 2 ;
  • X 5 is C(R 5a R 5b ), O, NR 5 , S, S(O), or S(O) 2 ;
  • X 6 is C(R 6a R 6b ), O, NR 6 , S, S(O), or S(O) 2 ;
  • R 1 , R 2 , and R 3 are each independently H or C1-4 alkyl
  • R la ,R lb , R 2a ,R 2b , R 3a , and R 3b are each independently H, C1.4 alkyl, halo, or C1.4 haloalkyl;
  • R 4 , R 5 , and R 6 are each independently H, C1-4 alkyl, or C1-4 hydroxyalkyl;
  • R 4a , R 4b , R 5a ,R 5b , R 6a , and R 6b are 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 R 7 is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalk
  • one R 7 attached to ring A and one R 8 attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R 7a , and ring A, ring B, and ring C form a fused tricyclic moiety.
  • 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, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 7 , R 7a , R 8 , and R 9 are each defined in Formula (I) and described in any one of the embodiments thereof.
  • X 1 is C(R la R lb ), O, or NR 1 ;
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b ), O, or NR 3 ;
  • X 4 is C(R 4a R 4b ), O, NR 4 , S, S(O), or S(O) 2 ;
  • X 5 is C(R 5a R 5b ), O, NR 5 , S, S(O), or S(O) 2 ;
  • X 6 is C(R 6a R 6b ), O, NR 6 , S, S(O), or S(O) 2 ;
  • R 1 , R 2 , and R 3 are each independently H or C1.4 alkyl
  • R la ,R lb , R 2a ,R 2b , R 3a , and R 3b are each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl;
  • R 4 , R 5 , and R 6 are each independently H, C1-4 alkyl, or C1-4 hydroxyalkyl;
  • R 4a , R 4b , R 5a ,R 5b , R 6a , and R 6b are 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
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (la) or a subembodiment thereof, wherein: each R 7 is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -C(O)Ci- 6 alkyl, -C(O)Ci- 6 haloalkyl, -C(O)OCi- 6 alkyl, or -C(O)OCi- 6 haloalkyl; each R 7a is independently C1.4 alkyl, halo, or C1.4 haloalkyl; alternatively, two R 7a groups attached to the same carbon atom combine to form oxo; each R 8 is independently C1-6 alkyl, C1-6 haloalkyl, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, C3- 6 cycloalkyl, -O-C3-6 cycloal
  • R 9 is H, Ci-4 alkyl, halo, or Ci-4 haloalkyl.
  • the compound is represented by Formula (Ial-1): or the pharmaceutically acceptable salt thereof, wherein X a is O, NH, N(CI-4 alkyl), CH2, or CHR 7 ; p is 0, 1, or 2; q is 0, 1, or 2; and ring C, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 7 , R 7a , R 8 , and R 9 are each defined in Formula (I) and described in any one of the embodiments thereof.
  • Formula (Ial-1) or the pharmaceutically acceptable salt thereof, wherein X a is O, NH, N(CI-4 alkyl), CH2, or CHR 7 ; p is 0, 1, or 2; q is 0, 1, or 2; and ring C, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 7 , R 7a , R 8 , and R 9 are each defined in Formula (I) and
  • the compound is represented by Formula (la 1-2): (Ial-2), or the pharmaceutically acceptable salt thereof, wherein X a is O, NH, N(CI-4 alkyl), CH2, or CHR 7 ; p is 0, 1, or 2; q is 0, 1, or 2; and ring C, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 7 , R 7a , R 8 , and R 9 are each defined in Formula (I) and described in any one of the embodiments thereof.
  • the compound is represented by Formula (Ia2-1):
  • X a is O, NH, N(CI-4 alkyl ), CH2, or CHR 7 ;
  • X 7a and X 7b are each independently absent, O, CH2, or CHR 7a , provided that X 7a and X 7b are not each O;
  • p is 0, 1, or 2;
  • q is 0, 1, or 2; and
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 7 , R 7a , R 8 , and R 9 are each defined in Formula (I) and described in any one of the embodiments thereof.
  • the compound is represented by Formula (Ia2-2): or the pharmaceutically acceptable salt thereof, wherein X a is O, NH, N(CI-4 alkyl), CH2, or CHR 7 ; X 7a and X 7b are each independently absent, O, CH2, or CHR 7a , provided that X 7a and X 7b are not each O; p is 0, 1, or 2; q is 0, 1, or 2; and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 7 , R 7a , R 8 , and R 9 are each defined in Formula (I) and described in any one of the embodiments thereof.
  • Formula (Ia2-2) or the pharmaceutically acceptable salt thereof, wherein X a is O, NH, N(CI-4 alkyl), CH2, or CHR 7 ; X 7a and X 7b are each independently absent, O, CH2, or CHR 7a , provided that X 7a and X 7b are not each
  • 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 X 1 , X 2 , and X 3 are N. In some embodiments, no more than two of X 1 , X 2 , and X 3 are O.
  • subformulae e.g., (la), (Ial-1), (lal- 2), (Ia2-1), (Ia2-2), (lb), and (Ibl)
  • subembodiment thereof wherein no more than two of X 1 , X 2 , and X 3 are N. In some embodiments, no more than two of X 1 , X 2 , and X 3 are O.
  • At least one of X 1 , X 2 , and X 3 comprises a carbon atom (e.g., X 1 is C(R la R lb ), X 2 is C(R 2a R 2b ), or X 3 is C(R 3a R 3b )).
  • X 1 is C(R la R lb );
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b ).
  • X 1 is NR 1 ;
  • X 2 is C(R 2a R 2b ); and X 3 is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 1 is C(R la R lb ) or NR 1 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 1 is NR 1 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 1 is H or methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 1 is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 1 is NR 1 ; and R 1 is H. In some embodiments, X 1 is NH.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 1 is C(R la R lb ).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 1a and R lb are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R la and R lb are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R la and R lb are each H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 1 is C(R la R lb ); and R la and R lb are each H. In some embodiments, X 1 is CH2. [0100] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein R la is methyl, and R lb is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 1 is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 2 is NR 2 .
  • R 2 is H or methyl.
  • R 2 is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 2 is NR 2 ; and R 2 is H. In some embodiments, X 2 is NH.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 2 is C(R 2a R 2b ) or O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 2 is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 2 is C(R 2a R 2b ).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 2a and R 2b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 2a and R 2b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 2a and R 2b are each H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 2 is C(R 2a R 2b ); and R 2a and R 2b are each H. In some embodiments, X 2 is CH2.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 2a is methyl, and R 2b is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 3 is C(R 3a R 3b ) or NR 3 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 3 is NR 3 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 3 is H or methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 3 is C(R 3a R 3b ).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 3a and R 3b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 3a and R 3b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 3a and R 3b are each H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 3 is C(R 3a R 3b ); and R 3a and R 3b are each H. In some embodiments, X 3 is CFh.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 3a is methyl, and R 3b is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 3 is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 1 is C(R la R lb ); X 2 is C(R 2a R 2b ), O, or NR 2 ; and X 3 is C(R 3a R 3b ).
  • X 1 is CH 2 ; X 2 is O, NH, or CH 2 ; and X 3 is CH 2 .
  • 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 X 4 , X 5 , and X 6 are N. In some embodiments, no more than two of X 4 , X 5 , and X 6 are O.
  • subformulae e.g., (la), (Ial-1), (lal- 2), (Ia2-1), (Ia2-2), (lb), and (Ibl)
  • subembodiment thereof wherein no more than two of X 4 , X 5 , and X 6 are N. In some embodiments, no more than two of X 4 , X 5 , and X 6 are O.
  • At least one of X 4 , X 5 , and X 6 comprises a carbon atom (e.g., X 4 is C(R 4a R 4b ), X 5 is C(R 5a R 5b ), or X 6 is C(R 6a R 6b )).
  • X 4 is C(R 4a R 4b ); X 5 is O or NR 4 ; and X 6 is C(R 6a R 6b ).
  • X 1 is X 4 is C(R 4a R 4b ); X 5 is O; and X 6 is C(R 6a R 6b ).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 4 is C(R 4a R 4b ), O, or NR 4 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 4 is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 4 is NR 4 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 4 is H or methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 4 is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 4 is C(R 4a R 4b ).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 4a and R 4b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 4a and R 4b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 4a and R 4b are each H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 4 is C(R 4a R 4b ); and R 4a and R 4b are each H. In some embodiments, X 4 is CH2.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 4a is methyl, and R 4b is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 4 is C(R 4a R 4b ); R 4a is methyl; and R 4b is H. In some embodiments, X 4 is CH(CH3).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 5 is C(R 5a R 5b ), O, or NR 5 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 5 is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 5 is NR 5 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 5 is H or methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 5 is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 5 is C(R 5a R 5b ).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 5a and R 5b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 5a and R 5b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 5a and R 5b are each H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 5 is C(R 5a R 5b ); and R 5a and R 5b are each H. In some embodiments, X 5 is CH2.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 5a is methyl, and R 5b is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 5 is C(R 5a R 5b ); R 5a is methyl; and R 5b is H. In some embodiments, X 5 is CH(CH3).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 6 is C(R 6a R 6b ), O, or NR 6 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 6 is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 6 is NR 6 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 6 is H or methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 6 is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 6 is C(R 6a R 6b ).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 6a and R 6b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 6a and R 6b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 6a and R 6b are each H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 6 is C(R 6a R 6b ); and R 6a and R 6b are each H. In some embodiments, X 6 is CFh.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 6a is methyl, and R 6b is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 6 is C(R 6a R 6b ); R 6a is methyl; and R 6b is H. In some embodiments, X 6 is CH CHs).
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 4 is C(R 4a R 4b ); X s is O; X 6 is C(R 6a R 6b ); and R 4a , R 4b , R 6a , and R 6b are each independently H or Ci-4 alkyl.
  • X 4 is CHR 4a ; X 5 is O; X 6 is CHR 6a ; and R 4a and R 6a are each independently H or C1-4 alkyl.
  • X 4 is CHR 4a ; X 5 is O; X 6 is CH2; and R 4a is H or C1-4 alkyl. In some embodiments, X 4 is CH2 or CH(CH3); X 5 is O; and X 6 is CH2 or CH(CH3). In some embodiments, X 4 is CH2; X 5 is O; and X 6 is CH2. In some embodiments, X 4 is CH(CH 3 ); X 5 is O; and X 6 is CH 2 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X 1 is CH2; X 2 is O, NH, or CH 2 ; X 3 is CH 2 ; X 4 is CHR 4a ; X 5 is O; X 6 is CH 2 ; and R 9 is H.
  • 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.
  • 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.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 R 7 .
  • 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 R 7 .
  • 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 R 7 .
  • 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 R 7 attached to ring A and one R 8 attached to ring B, as defined herein), ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R 7 . In some embodiments, when ring C is present, ring A is piperidinyl substituted with 0, 1, or 2 R 7 . In some embodiments, when ring C is present, ring A is piperazinyl substituted with 0, 1, or 2 R 7 . In some embodiments, when ring C is present, ring A is morpholinyl substituted with 0, 1, or 2 R 7 .
  • 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 R 7 .
  • ring A is piperidinyl substituted with 0, 1, or 2 R 7 .
  • ring A is piperazinyl substituted with 0, 1, or 2 R 7 .
  • ring A is morpholinyl substituted with 0, 1, or 2 R 7 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or Ci-6 haloalkoxy.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently C1.4 alkyl, Ci-4 haloalkyl, or halo.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently Ci-4 alkyl, halo, or Ci-4 alkoxy. In some embodiments, each R 7 is independently Ci-4 alkyl, halo, OH, or Ci-4 alkoxy.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently methyl, ethyl, fluoro, chloro, bromo, methoxy, or ethoxy.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently methyl, fluoro, or methoxy.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently methyl or fluoro.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently methyl, fluoro, OH, or methoxy.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is independently methyl or methoxy.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 5 is independently methyl or methoxy.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is fluoro.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is OH.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7 is methoxy.
  • 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 R 7 attached to ring A and one R 8 attached to ring B, as defined herein), ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R 7 ; and each R 7 is independently methyl, fluoro, or methoxy.
  • 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 R 7 .
  • ring A is piperidinyl substituted with one R 7 ; and R 7 is methyl, fluoro, or methoxy.
  • R 7 is methyl.
  • ring A when ring C is present, ring A is piperidinyl substituted with one R 7 ; and R 7 is 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 R 7 ; and R 7 is methoxy.
  • 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 R 7 . 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 R 7 ; and R 7 is 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 R 7 ; and R 7 is methyl.
  • 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 .
  • 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
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or (la), or a subembodiment thereof, wherein: X 1 is C(R la R lb );
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • R 2 is H or Cu alkyl;
  • X 3 is C(R 3a R 3b );
  • X 4 is C(R 4a R 4b ); X 5 is O; X 6 is C(R 6a R 6b );
  • R la , R lb , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 6a , and R 6b are 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 R 7a ;
  • p is 0 or 1;
  • q is 1;
  • R 7 is C1-4 alkyl, halo, or C1-4 alkoxy
  • R 8 is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, or C3-6 cycloalkyl; and R 9 is H.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 R 7 ; and each R 7 is independently methyl, fluoro, OH, or methoxy.
  • ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R 7 ; and each R 7 is independently methyl, fluoro, or methoxy.
  • 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 R 7 .
  • ring A is piperidinyl substituted with one R 7 ; and R 7 is methyl, fluoro, OH, or methoxy.
  • ring A is piperidinyl substituted with one R 7 ; and R 7 is methyl, fluoro, or methoxy.
  • ring A is piperidinyl substituted with one R 7 ; and R 7 is methyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R 7 ; and R 7 is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R 7 ; and R 7 is OH. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R 7 ; and R 7 is methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R 7 ; and R 7 is OH.
  • 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 R 7 .
  • ring A is morpholinyl substituted with one R 7 ; and R 7 is methyl or fluoro.
  • ring A is morpholinyl substituted with one R 7 ; and R 7 is methyl.
  • 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 R 7 ; and each R 7 is independently methyl, fluoro, OH, or methoxy.
  • ring A is piperidinyl substituted with two vicinal R 7 ; one R 7 is methyl; and the other R 7 is fluoro.
  • ring A is piperidinyl substituted with two vicinal R 7 ; one R 7 is methyl; and the other R 7 is OH.
  • ring A is piperidinyl substituted with two vicinal R 7 ; one R 7 is methyl; and the other R 7 is methoxy.
  • 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 R 7 ; and each R 7 is independently methyl, fluoro, OH, or methoxy.
  • ring A is piperidinyl substituted with two geminal R 7 ; one R 7 is methyl; and the other R 7 is fluoro.
  • ring A is piperidinyl substituted with two geminal R 7 ; one R 7 is methyl; and the other R 7 is OH.
  • ring A is piperidinyl substituted with two geminal R 7 ; one R 7 is methyl; and the other R 7 is methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R 7 ; and each R 7 is methyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R 7 ; and each R 7 is fluoro.
  • 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 R 7 or 2 geminal R 7 , wherein each R 7 is any one of embodiments described herein.
  • 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 R 7 or 2 geminal R 7 , wherein each R 7 is any one of embodiments described herein.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, having Formula (Ial-1): wherein:
  • X a is O, NH, CH 2 , or CHR 7 ; 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 .
  • 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, X a is O, NH, CH 2 , or CHR 7 ; 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 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, having Formula (Ial-1): wherein,
  • X a is O, CH 2 , or CHR 7 ; 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 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C4-7 cycloalkyl substituted with 0, 1, 2, or 3 R 7a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C4-6 cycloalkyl substituted with 0, 1, 2, or 3 R 7a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein ring C is C5-6 cycloalkyl substituted with 0, 1 , or 2 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • ring C is C5-6 cycloalkyl substituted with 0, 1, or 2 R 7a . In some embodiments, ring C is C6 cycloalkyl substituted with 0, 1, or 2 R 7a . In some embodiments, ring C is C5 cycloalkyl substituted with 0, 1, or 2 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • ring C is heterocycloalkyl having 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R 7a .
  • 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 R 7a .
  • 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 the embodiments 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.
  • 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.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydropyranyl substituted with 0, 1, or 2 R 7a .
  • ring C is tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl, each of which is independently substituted with 0 or 1 R 7a .
  • ring C is tetrahydrofuranyl substituted with 0 or 1 R 7a .
  • ring C is tetrahydropyranyl substituted with 0 or 1 R 7a .
  • ring C is oxepanyl substituted with 0 or 1 R 7a .
  • ring C is tetrahydropyranyl substituted with 0, 1, or 2 R 7a . In some embodiments, ring C is tetrahydropyranyl substituted with 0 or 1 R 7a . In some embodiments, ring C is tetrahydropyranyl substituted with 0 R 7a .
  • ring C is tetrahydrofuranyl substituted with 0 or 1 R 7a . In some embodiments, ring C is tetrahydrofuranyl substituted with 0 R 7a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-1): wherein,
  • X a is absent, O, CH 2 , or CHR 7 ;
  • X 7a is absent, O or CH 2 , or CHR 7a ;
  • X 7b is absent, O or CH 2 , or CHR 7a ; p is 0, 1 or 2; and q is 0, 1, or 2.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein
  • X a is O, CH 2 , or CHR 7 ;
  • X 7a is O or CH 2 , or CHR 7a ;
  • X 7b is O or CH 2 , or CHR 7a ; p is 0, 1 or 2; and q is 0, 1, or 2.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-1): wherein,
  • X a is O, NH, CH 2 , or CHR 7 ;
  • X 7a is absent, O, CH 2 , or CHR 7a ;
  • X 7b is absent, O, CH 2 , or CHR 7a ; p is 0, 1, or 2; and q is 0, 1, or 2, provided that X 7a and X 7b are not each O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-2):
  • X a is O, NH, CH 2 , or CHR 7 ;
  • X 7a is absent, O, CH 2 , or CHR 7a ;
  • X 7b is absent, O, CH 2 , or CHR 7a ; p is 0, 1, or 2; and q is 0, 1, or 2, provided that X 7a and X 7b are not each O.
  • X 7a and X 7b are not each absent.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X 7a is O; and X 7b is CH 2 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X 7a is CH 2 ; and X 71 * is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X 7a is CH 2 ; and X 7 ’’ is CH 2 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X 7a is absent; and X 76 is CH 2 .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (Ia2-1) or (Ia2-2) or a subembodiment thereof, wherein X 7a is absent; and X 711 is O.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7a is independently C1.4 alkyl, halo, or C1.4 haloalkyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7a is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 7a is independently methyl, fluoro, chloro, or trifluoromethyl
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein two R 7a groups attached to the same carbon atom combine to form oxo.
  • X 7a is O, CH2, or CHR 7a ; and X 7b is O, CH2, or CHR 7a , provided that X 7a and X 7b are not each O.
  • R 7a is C1-4 alkyl. In some embodiments, R 7a is methyl.
  • X 7a is O, and X 7b is CH2.
  • X 7a is CH2; and X 7b is O.
  • X 7a is CH2, and X 7b is CH2.
  • X 7a is O; and X 7b is CH(CH3).
  • X 7a is CH(CH3), and X 7b is O.
  • X 7a is CH 2 and X 7b is CH(CH 3 ); or X 7a is CH(CH 3 ) and X 7b is CH 2 .
  • X 7a is absent; and X 7b is O.
  • X 7a is absent; and X 7b is CH2.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, or C1-6 haloalkoxy.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is independently Ci-6 alkyl, Ci-6 haloalkyl, or halo.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is independently bromo or trifluoromethyl.
  • each R 8 is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, CN, Ci-6 alkoxy, Ci-6 haloalkoxy, or C3-6 cycloalkyl. In some embodiments, each R 8 is independently C1-6 alkyl, Ci-6 haloalkyl, halo, C1-6 haloalkoxy, or C3-6 cycloalkyl.
  • q is 1; and R 8 is 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 R 8 is Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or C 1-6 haloalkoxy.
  • q is 1 ; and R 8 is chloro, CN, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, or trifluoromethyl- O- . In some embodiments, q is 1; and R 8 is chloro, isopropyl, cyclopropyl, trifluoromethyl, or difluoromethyl-O-.
  • q is 1; and R 8 is chloro, trifluoromethyl, or difluoromethyl-O-. In some embodiments, q is 1 ; and R 8 is chloro. In some embodiments, q is 1 ; and R 8 is trifluoromethyl. In some embodiments, q is 1 ; and R 8 is difluoromethyl-O-. In some embodiments, q is 1; and R 8 is CN.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I), (la), or a subembodiment thereof, wherein each R 8 is 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.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R 8 is 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.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R 8 is chloro, trifluoromethyl, or difluoromethyl-O-.
  • 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 R 8 is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.
  • X a is O, NH, CH 2 , or CHR 7 ;
  • X 7a is O, CH 2 , or CHR 7a ;
  • X 7b is O, CH 2 , or CHR 7a ; each R 7a is independently C1-4 alkyl; each R 7 is independently F, C1-4 alkyl, or C1-4 alkoxy; and
  • R 8 is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, or C3-5 cycloalkyl, provided that X 7a and X 7b are not each O.
  • X a is O, NH, CH 2 , CHF, C(CH 3 ), or C(OCH 3 );
  • X 7a is O, CH 2 , or CH(CH 3 );
  • X 7b is O or CH 2 ;
  • R 7 is F, CH 3 , or OCH 3 ;
  • R 8 is chloro, CN, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoromethyl-O- , or trifluoromethyl-O-, provided that X 7a and X 7b are not each O.
  • X a is O, CH 2 , or CHF;
  • X 7a is O, CH 2 , or CH(CH 3 );
  • X 7b is O or CH 2 ;
  • R 7 is CH 3 ;
  • R 8 is chloro, isopropyl, cyclopropyl, trifluoromethyl, or difluoromethyl-O-, provided that X 7a and X 711 are not each O.
  • X a is CFb; X 7a is CH2; X 7b is O; and R 8 is chloro, isopropyl, cyclopropyl, trifluoromethyl, or difhioromethyl-O-
  • X a is O; X 7a is O; X 711 is CH2; and R 8 is chloro, isopropyl, cyclopropyl, trifluoromethyl, or difluoromethyl-O-.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein the moiety
  • the moiety has any one of formulae according to the Amine intermediates in
  • X 1 is C(R la R lb );
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b );
  • X 4 is C(R 4a R 4b );
  • X 5 is O;
  • X 6 is C(R 6a R 6b );
  • R 2 is H or Ci-4 alkyl;
  • R la , R lb , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 6a , and R 6b are each independently H or CM alkyl; and
  • R 9 is H.
  • the moiety or NR 2 ; and R 4a and R 6a are each independently H or C1-4 alkyl.
  • X 2 is O, NH, or CH2; R 4a is H or C1-4 alkyl; and R 6a is H.
  • X 2 is O, NH, or CH2; R 4a and R 6a are each independently H or methyl.
  • X 2 is O, NH, or CH2; and R 4a and R 6a are each H.
  • X 2 is O, NH, or CH2; R 4a is methyl; and R 6a is H. In some embodiments, X 2 is O, NH, or CH2; R 4a is H; and R 6a is methyl.
  • X2 is O, NH, or CH2; and R 4a is H or C1-4 alkyl. In some embodiments, X2 is O; and R 4a is H. In some embodiments, X2 is O; and R 4a is methyl. In some embodiments, X2 is NH; and R 4a is H. In some embodiments, X2 is NH; and R 4a is methyl. In some embodiments, X2 is CH2; and R 4a is H. In some embodiments, X2 is CH2; and R 4a is methyl.
  • R 4a is H. In some embodiments, R 4a is methyl.
  • R 4a is H or Ci-4 alkyl. In some embodiments, R 4a is H. In some embodiments, R 4a is methyl.
  • R 4a is H. In some embodiments, R 4a is methyl.
  • the moiety has one of the formulae selected from:
  • the compound is represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein: wherein:
  • X a is O, NH, NR 7 , CH 2 , CHR 7 , or C(R 7 ) 2 ;
  • X 7a is absent, 0, CH 2 , or CHR 7a ;
  • X 7b is absent, O, CH 2 , or CHR 7a , provided that X 7a and X 7b are not each absent or O; and a total number of R 7 groups is no more than 2; and p, q, ring B, X 2 , R 3a , R 4a , R 6a , R 7 , and R 8 are each defined in Formula (I) or (la), and described in any one of the embodiments thereof.
  • R 3a and R 6a are each H.
  • the compound is represented by Formula (Ila): wherein: ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl;
  • X a is O, NH, NR 7 , CH 2 , CHR 7 , or C(R 7 ) 2 ;
  • X 7a is absent, O, CH 2 , or CHR 7a ;
  • X 7b is absent, O, CH 2 , or CHR 7a , provided that X 7a and X 7b are not each absent or O; and a total number of R 7 groups is no more than 2.
  • 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.
  • ring B is phenyl.
  • ring B is pyridyl.
  • ring B is pyrazinyl.
  • ring B is pyrimidinyl.
  • ring B is pyridazinyl.
  • the compound is represented by Formula (IIa-1): wherein:
  • X a is O, NH, N(CI- 4 alkyl), CH 2 , CHR 7 , or C(R 7 ) 2 ;
  • X 7a is absent, O, CH 2 , or CHR 7a ;
  • X 7b is absent, O, CH 2 , or CHR 7a , provided that X 7a and X 7b are not each absent or O; and a total number of R 7 groups is no more than 2.
  • the compound is represented by Formula (IIa-2): wherein:
  • X a is O, NH, N(CI- 4 alkyl), CH 2 , CHR 7 , or C(R 7 ) 2 ;
  • X 7a is absent, O, CH 2 , or CHR 7a ;
  • X 7b is absent, O, CH 2 , or CHR 7a , provided that X 7a and X 7b are not each absent or O; and a total number of R 7 groups is no more than 2.
  • X 2 is O.
  • X 2 is NH.
  • X 2 is CH 2 .
  • X a is CH 2 , CHR 7 , or C(R 7 ) 2 .
  • X a is O.
  • X a is NH.
  • X a is CH 2 .
  • X a is O, NH, CH 2 , or CHR 7 ;
  • X 7a is O, CH 2 , or CHR 7a ;
  • X 7b is O, CH 2 , or CHR 7a ; and
  • p is 0 or 1.
  • X a is O, NH, or CH 2 ;
  • X 7a is O, CH 2 , or CHR 7a ;
  • X 7b is O, CH 2 , or CHR 7a ; and
  • p is 0, 1, or 2.
  • X a is C(R 7 ) 2 ;
  • X 7a is O, CH 2 , or CHR 7a ;
  • X 7b is O, CH 2 , or CHR 7a ; and
  • p is 0.
  • X 7a is O and X 7b is CH 2 ; X 7a is CH 2 and X 7b is O; X 7a is CH 2 and X 7b is CH 2 ; X 7a is O and X 7b is CH(CH 3 ); X 7a is CH(CH 3 ) and X 7b is O; X 7a is CH 2 and X 7b is CH(CH 3 ); X 7a is CH(CH 3 ) and X 7b is CH 2 ; X 7a is absent and X 7b is CH 2 ; or X 7a is absent and X 7b is O.
  • X 7a is O and X 7b is CH 2 . In some embodiments, X 7a is CH 2 and X 7b is O. In some embodiments, X 7a is CH 2 and X 711 is CH 2 . In some embodiments, X 7a is O and X is CH(CH 3 ). In some embodiments, X 7a is CH(CH 3 ) and X 7b is O. In some embodiments, X 7a is CH 2 and X 7b is CH(CH 3 ). In some embodiments, X 7a is CH(CH 3 ) and X 7b is CH 2 . In some embodiments, X 7a is absent and X 7b is CH 2 . In some embodiments, X 7a is absent and X 7b is O.
  • each R 7 is independently Ci-4 alkyl, halo, OH, or Ci-4 alkoxy. In some embodiments, each R 7 is independently methyl, fluoro, OH, or methoxy. In some embodiments, each R 7 is independently methyl, fluoro, or methoxy.
  • each R 8 is 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.
  • R 8 is 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.
  • q is 1; and R 8 is chloro, trifluoromethyl, or difluoromethyl-O-.
  • q is 2; and each R 8 is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.
  • X a is O, NH, CH 2 , or CHR 7 ;
  • X 7a is O, CH 2 , or CHR 7a ;
  • X 7b is O, CH 2 , or CHR 7a ; each R 7a is independently C1-4 alkyl; each R 7 is independently F, OH, C1-4 alkyl, or C1-4 alkoxy; and
  • R 8 is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, C 2 alkynyl, -O-C 2 -4 alkynyl, C 3 -6 cycloalkyl, or -O-C 3 .6 cycloalkyl, wherein the C 3 -6 cycloalkyl and -O- C 3 -6 cycloalkyl are each independently unsubstituted or substituted with CN, provided that X 7a and X 7b are not each O.
  • X a is O, NH, CH2, CHF, C(CH 3 ), C(OH), or C(OCH 3 );
  • X 7a is O, CH 2 , or CH(CH 3 );
  • X 7b is O or CH 2 ;
  • R 7 is F, CH 3 , OH, or OCH 3 ;
  • R 8 is 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 X 7a and X 7b are not each O.
  • R 8 is chloro, trifluoromethyl, or difluoromethyl-O-.
  • X a is O, CH2, or CHF; X 7a is O, CH2, or CH(CHs); X 7b is O or CH2; R 7 is CH3; and R 8 is chloro, trifluoromethyl, or difluoromethyl-O-, provided that X 7a and X 7b are not each O.
  • X a is CH2; X 7a is CH2; X 7b is O; and R 8 is chloro, trifluoromethyl, or difluoromethyl-O-.
  • X a is O; X 7a is O; X 7b is CH2; and R 8 is chloro, trifluoromethyl, or difluoromethyl-O-.
  • X 2 is O, NH, or CH2.
  • R 4a is H or C1-4 alkyl. In some embodiments, R 4a is H; or R 4a is methyl.
  • X2 is O, NH, or CH2; and R 4a is H or C1-4 alkyl. In some embodiments, X2 is O; and R 4a is H. In some embodiments, X2 is O; and R 4a is methyl. In some embodiments, X2 is NH; and R 4a is H. In some embodiments, X2 is NH; and R 4a is methyl. In some embodiments, X2 is CH2; and R 4a is H. In some embodiments, X2 is CH2; and R 4a is methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, having Formula (lb) wherein,
  • X a is O, CH 2 , or CHR 7 ;
  • 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.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein p is 1.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein p is 2.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein q is 0.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein q is 1.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein q is 2.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, having Formula (Ibl)
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is 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 R 8a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is 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 R 8a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is independently heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1 , or 2 R 8a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 R 8a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8 is piperidinyl substituted with 0, 1, or 2 R 8a .
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8a is Cu alkyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8a is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R 8a is methyl.
  • 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 moiety
  • X 2 and R 4a are each defined and described herein.
  • X 2 is O, NH, or
  • X 2 is O; and R 4a is H. In some embodiments, X 2 is O; and R 4a is methyl. In some embodiments, X 2 is NH; and R 4a is H. In some embodiments, X 2 is NH; and R 4a is methyl. In some embodiments, X 2 is CH 2 ; and R 4a is H. In some embodiments, X 2 is CH 2 ; and R 4a is methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 9 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 9 is H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 9 is H.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 9 is methyl.
  • the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R 9 is fluoro.
  • 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.
  • the present disclosure provides a compound of Examples 1 to 3 and 5 to 112 in Table 1 or a pharmaceutically acceptable salt thereof.
  • a compound is selected from a compound of Examples 1 to 112, or a pharmaceutically acceptable salt thereof.
  • the present disclosure also includes prodrugs of the compound of Formula (I) or subembodiment thereof.
  • prodrug refers to compounds that readily undergo chemical changes under physiological conditions to provide a pharmacologically active parent compound.
  • 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.
  • 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.
  • a number of compounds in Table 1, below, include one or more stereocenters.
  • 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)”.
  • 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.
  • Al is a racemic mixture of two isomers, wherein the relative stereochemistry between two centers labeled with “&1” is known, as shown below:
  • the label “or” in the structures refers to the specific chiral center being a single undefined isomer but absolute stereochemistry was not determined.
  • the relative stereochemistry between them is not determined.
  • the relative stereochemistry between the differently labelled stereocenters is not determined.
  • the relative stereochemistry between the same labelled stereocenters is determined but not the absolute stereochemistry.
  • the relative stereochemistry between those stereocenters labelled “orl” is determined but not the absolute stereochemistry.
  • 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.
  • 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 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
  • 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.
  • compositions suitable for administration to a subject may be in the form of compositions suitable for administration to a subject.
  • 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.
  • 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.
  • compositions containing the active ingredient may be in a form suitable for oral use (for example as tablets, troches, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, or syrups, solutions, microbeads or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • a form suitable for oral use for example as tablets, troches, lozenges, hard or soft capsules, aqueous or oily suspensions
  • 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.
  • 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.
  • 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.
  • 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
  • lubricating agents for example magnesium stearate, stearic acid or talc.
  • 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.
  • 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, solvent
  • 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.
  • Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.
  • 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).
  • HEPES N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid)
  • MES 2-(N-Morpholino)ethanesulfonic acid
  • MES 2-(N- Morpholino)ethanesulfonic acid sodium salt
  • MOPS 3-(N-Morpholino)propanes
  • a pharmaceutical composition 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.
  • 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.
  • a single-use container e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., an EpiPen®)
  • a multi-use container e.g., a multi-use vial
  • 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.
  • implants e.g., implantable pumps
  • catheter systems e.g., slow injection pumps and devices, all of which are known in the art.
  • 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.
  • 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.
  • All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein.
  • the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment and/or prevention of all diseases or disorders provided herein.
  • the compounds and pharmaceutical compositions provided herein are for use as a medicament.
  • PRMT5 protein arginine N- methyltransferase 5
  • 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.
  • 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.
  • the patient is in recognized need of such treatment.
  • the disease or disorder is cancer.
  • 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.
  • the patient is in recognized need of such treatment.
  • the disease or disorder is cancer.
  • 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.
  • the patient is in recognized need of such treatment.
  • the present disclosure also provides a method of treating a cancer deficient in CDKN2A in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.
  • the patient is in recognized need of such treatment.
  • 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.
  • the patient is in recognized need of such treatment.
  • 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.
  • the patient is in recognized need of such treatment.
  • 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.
  • 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.
  • the proliferative disorder is cancer.
  • the patient is in recognized need of such treatment.
  • 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.
  • the patient is in recognized need of such treatment.
  • 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.
  • the patient is in recognized need of such treatment.
  • 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.
  • the present disclosure provides a method of treating a cancer in a patient, comprising: (i) determining if the cancer is MTAP null; and
  • 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.
  • 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, salivary 7 gland 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
  • 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 of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, bili
  • NSLC non-small
  • 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.
  • NLC non-small cell lung cancer
  • 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).
  • bladder cancer melanoma
  • brain cancer lung cancer, pancreatic cancer
  • breast cancer esophageal cancer
  • head and neck cancer kidney cancer
  • colon cancer colon cancer
  • DLBCL diffuse large B cell lymphoma
  • ALL acute lymphoblastic leukemia
  • MCL mantle cell lymphoma
  • 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.
  • GBM glioblastoma multiforme
  • 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
  • the cancer treated by the methods, uses, or medicaments described herein is NSLCC. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is MCL. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is DLBCL. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is ALL.
  • 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.
  • the cancer is non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.
  • 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 (DL
  • 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.
  • the disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 by said compounds.
  • the disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 by said compounds.
  • the disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 in MTAP- null cells by said compounds.
  • 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.
  • the chromosome 9p21 deletion or MTAP-null associated disease or condition is alleviated by inhibition of PRMT5 in MTAP-null cells.
  • 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.
  • 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 amel
  • 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.
  • 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, color
  • 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.
  • the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer.
  • the cancer treated by the methods, uses, or medicaments described herein is multiple myeloma (MM).
  • 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-).
  • the breast cancer can be HER2 negative.
  • the breast cancer is estrogen receptor negative, progesterone receptor negative and HER2 negative, also referred to herein as "triple negative breast cancer".
  • 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.
  • the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer.
  • the cancer treated by the methods, uses, or medicaments described herein is NSCLC (non-small cell lung carcinoma.
  • the NSCLC can be squamous NSCLC. In another embodiment, it can be adenocarcinoma.
  • cancer can be glioblastoma (GBM).
  • GBM glioblastoma
  • cancer can be mesothelioma.
  • cancer can be bladder cancer.
  • cancer can be esophageal cancer.
  • cancer can be melanoma.
  • cancer can be DLBCL, HNSCC or cholangiocarcinoma.
  • 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.
  • a cancer that lacks p53 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.
  • 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.
  • the disclosure provides a method for identifying subjects having a cancer that is sensitive to treatment with a PRMT5 inhibitor.
  • 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.
  • a subject having a p53 positive cancer is identified as a subject for treatment with a PRMT5 inhibitor.
  • the method further comprises administering to the subject a composition comprising a PRMT5 inhibitor.
  • 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.
  • the method comprises obtaining a sample from the subject; detecting the presence or absence of p53 ; and, identifying the subject as having a cancer that is not sensitive (for example, a cancer that is less sensitive than a p53 positive cancer) to treatment with a PRMT5 inhibitor if p53 is absent from the sample (e.g., if the cancer is a p53 null cancer).
  • 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.
  • 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.
  • sample 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.
  • 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.
  • angiosarcoma e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangio sarcoma
  • appendix cancer e.g., benign monoclonal gammopathy
  • biliary cancer e.g. , cholangiocarcinoma
  • bladder cancer e.g., brain cancer (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 gastrointestinal stromal tumor
  • 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!
  • ALL acute lymphocytic leukemia
  • AML acute myelocytic leukemia
  • mucosa-associated lymphoid tissue (MALT) lymphomas 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.
  • TCL peripheral T-cell lymphoma
  • CCL peripheral T-cell lymphoma
  • 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
  • MM myeloma
  • heavy chain disease e.g., alpha chain disease, gamma chain disease, mu chain disease
  • hemangioblastoma e.g., nephroblastoma a.k.a.
  • 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.
  • MDS myelodysplasia syndrome
  • MDS mesothelioma
  • MPD myeloproliferative disorder
  • PV polycythemia Vera
  • ET essential thrombocytosis
  • AMM agnogenic myeloid metaplasia
  • CML chronic myelocytic leukemia
  • CTL chronic neutrophilic leukemia
  • HES hypereosinophilic syndrome
  • neuroblastoma e.g.
  • 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.
  • SCC squamous cell carcinoma
  • KA keratoacanthoma
  • BCC basal cell carcinoma
  • 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).
  • MMH malignant fibrous histiocytoma
  • MPNST malignant peripheral nerve sheath tumor
  • chondrosarcoma chondrosarcoma
  • fibrosarcoma fibrosarcoma
  • myxosarcoma myxosarcoma
  • the cancer treated by the methods, uses, or medicaments described herein is spinal cord cancer.
  • 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).
  • active therapeutic agents e.g., chemotherapeutic agents
  • other prophylactic or therapeutic modalities e.g., radiation
  • 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.
  • such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.
  • “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”).
  • 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.
  • compounds of Formula (I) or pharmaceutically acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.
  • 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.
  • 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.
  • the patient is in recognized need of such treatment.
  • the disease or disorder is cancer.
  • 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.
  • the patient is in recognized need of such treatment
  • 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.
  • the patient is in recognized need of such treatment.
  • 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 pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent.
  • the patient is in recognized need of such treatment.
  • 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.
  • 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.
  • 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.
  • the one or more additional active therapeutic agents are one, two, three, or four additional therapeutic agents.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • Chemotherapeutic agents include alkylating agent, microtubule inhibitors, antimetabolites, anti-tumor antibiotics, as well as corticosteroids.
  • the chemotherapeutic agent is an alkylating agent.
  • the alkylating agent is altretamine, bendamustine, busulfan, improsulfan, piposulfan, procarbazine, mechlorethamine, carmustine, lomustine, semustine chlorambucil, cyclophosphamide, thiotepa, ifosfamide, dacarbazine, temozolomide, or perfosamide.
  • the alkylating agent is mechlorethamine.
  • the alkylating agent is perfosamide.
  • the alkylating agent is a platinum-based chemotherapy agent.
  • the alkylating agent is carboplatin, cisplatin, oxaliplatin, nedaplatin, saraplatin, lobaplatin, or heptaplatin.
  • the alkylating agent is carboplatin.
  • the alkylating agent is cisplatin.
  • the alkylating agent is saraplatin.
  • the chemotherapeutic agent is a microtubule inhibitor.
  • the microtubule inhibitor is eribulin, ixabepilone, cabazitaxel, enfortumab vedotin, trastuzumab emtansine, tirbanibulin.
  • microtuial inhibitors are plant alkaloids.
  • 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).
  • the chemotherapeutic agent is paclitaxel.
  • the chemotherapeutic agent is an antimetabolite.
  • 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.
  • the antimetabolite is cladribine.
  • the antimetabolite is clofarabine.
  • the antimetabolite is cytarabine.
  • the antimetabolite is gemcitabine.
  • the antimetabolite is floxuridine.
  • the chemotherapeutic agent is an antitumor antibiotics.
  • the antitumor antibiotic is bleomycin, dactinomycin, or mitomycin.
  • the antitumor antibiotic is daunorubicin, doxorubicin, doxil, epirubicin, idarubicin, mitoxantrone, valrubicin.
  • the chemotherapeutic agent is a corticosteroid.
  • the corticosteroid is prednisone, methylprednisolone, or dexamethasone.
  • 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; nitrosure
  • compounds of the present disclosure are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C.
  • a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C.
  • 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.
  • combination therapy comprises administration of a hormone or related hormonal agent.
  • the additional therapeutic agent is a cell cycle checkpoint inhibitor.
  • the cell cycle checkpoint inhibitor is KU60019, AZD0156, Ceralasertib, Camonsertib, VE821, AZD7762, SRA737, Rabusertib, Prexasertib, SCH900776, or Adavosertib.
  • the cell cycle checkpoint inhibitor is KU60019.
  • the cell cycle checkpoint inhibitor is AZD0156.
  • the cell cycle checkpoint inhibitor is ceralasertib.
  • the cell cycle checkpoint inhibitor is camonsertib.
  • 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
  • the additional therapeutic agent is an immune check point inhibitor.
  • 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.
  • the PD-1/PD-L1 inhibitor is a PD-1 inhibitor.
  • the PD-1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlitnab, or atezolizumab.
  • the PD-1 inhibitor is nivolumab.
  • the PD-1 inhibitor is pembrolizumab.
  • the PD-1 inhibitor is cemiplimab.
  • the PD-1 inhibitor is dostarlimab.
  • the PD-1 inhibitor is zimberelimab.
  • the PD-1 inhibitor is retifanlimab.
  • the PD-1 inhibitor is atezolizumab.
  • PD-1/PD-L1 inhibitor is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is avelumab, atezolizumab, or durvalumab.
  • the PD- L1 inhibitor is avelumab.
  • the PD-L1 inhibitor is atezolizumab.
  • the PD-L1 inhibitor is durvalumab.
  • the immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is relatlimab.
  • the immune checkpoint inhibitor is a CTLA-4 inhibitor.
  • the ipilimumab or tremelimumab is a CTLA-4 inhibitor.
  • the immune checkpoint inhibitor is a BTLA inhibitor.
  • the immune checkpoint inhibitor is a TIM-3 inhibitor.
  • the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367 (NCT03099109).
  • the immune checkpoint inhibitor is a TIM-3 inhibitor.
  • the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367 (NCT03099109).
  • the TIM-3 inhibitor is sabatolimab.
  • the immune checkpoint inhibitor is a TIM-3 inhibitor.
  • the TIM-3 inhibitor is TSR-022 (NCT02817633).
  • the TIM-3 inhibitor is MBG453 (NCT02608268).
  • the TIM-3 inhibitor is LY3321367 (NCT03099109).
  • the immune checkpoint inhibitor is a TIGIT inhibitor.
  • the TIGIT inhibitor is tiragohimab, domvanalimab, vibostolimab, etigilimab, M6223, or ociperlimab.
  • the TIGIT inhibitor is tiragolumab.
  • the TIGIT inhibitor is domvanalimab.
  • the TIGIT inhibitor is vibostolimab.
  • the TIGIT inhibitor is etigilimab.
  • the TIGIT inhibitor is M6223.
  • the TIGIT inhibitor is ociperlimab.
  • the additional therapeutic agent is a BCL-2 inhibitor.
  • the BCL-2 inhibitor is venetoclax, navitoclax, oblimersen, obatoclax mesylate, AT-101, subatoclax, maritoclax, gossypol, apogossypol, TW-37, UM 77, or BDA- 366.
  • Anti-CD20 therapeutic agent [0419] In some embodiments, the additional therapeutic agent is an anti-CD20 therapeutic agent.
  • the anti-CD20 therapeutic agent is rituximab, arzerra, gazyva, ibritumomab tiuxetan, obinutuzumab, ofatumumab, riabni, rituxan, ruxience, truxima, zevalin, or tositumomab.
  • the additional therapeutic agent is a hormonal therapeutic agent.
  • 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.
  • PARP Inhibitors are anastrozole, exemestand, letrozole, zoladex, lupon eligard, tamoxifen, raloxifene, goserelin, leuprorelin, fulvestrant, 4- hydroxytamoxifen, trioxifene, keoxifen
  • the additional therapeutic agent is a PARP inhibitor.
  • the PARP inhibitor is niraparib, rucaparib, olaparib, talazoparib, or veliparib. viii) MAT2A Inhibitors
  • the additional therapeutic agent is a MAT2A inhibitor.
  • the MAT2A inhibitor is AG-270, .
  • the MAT2A inhibitor is a compound disclosed in WO2020/123395, the contents of which is incorporated herein by reference for all purposes.
  • the MAT2A inhibitor is a compound disclosed in WO2018/045071, the contents of which is incorporated herein by reference for all purposes.
  • 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.
  • the MAT2A inhibitor is a compound disclosed in WO2021/1259815, WO2023/066283, WO2024/217502, W02020/139991, W02020/139992, WO2018/045071, WO2018/039972, W02019191470, W02024/002024, or WO2024/217493, the contents of which are incorporated herein by reference for all purposes.
  • the MAT2A inhibitor is ISM3412 or S095035.
  • the MAT2A inhibitor is , or, or pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor is a compound disclosed in WO2022/268180, the contents of which are incorporated herein by reference for all purposes.
  • the MAT2A inhibitor is pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is radiation therapy.
  • VEGF Inhibitors VEGF Inhibitors
  • the additional therapeutic agent is a VEGF inhibitor.
  • the VEGF inhibitor is Bevacizumab, aflibercept, ranibizumab, sorafenib, dasatinib, sunitinib, nilotinib, pazopanib, pegaptanib, axitinib, lenvatinib, ramucirumab, or regorafenib. xi) Tyrosine Kinase Inhibitors
  • the additional therapeutic agent is a tyrosine kinase inhibitor.
  • 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,
  • the additional therapeutic agent is an mTOR inhibitor.
  • the mTOR inhibitor is rapamycin, everolimus, sirolimus, temsirolimus, everolimus, or sirolimus. xiii) AKT Inhibitors
  • the additional therapeutic agent is an ATK inhibitor.
  • the ATK inhibitor is ipatasertib, mk-2206, perifosine, capivasertib, triciribine, or GSK690693. xiv)CDK Inhibitors
  • the additional therapeutic agent is a CDK inhibitor.
  • 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.
  • the CDK inhibitor is palbociclib, ribociclib, and abemaciclib. xv) PI3K Inhibitors
  • the additional therapeutic agent is a PI3K inhibitor.
  • the PI3K inhibitor is idelalisib, alpelisib, leniolisib, duvelisib, or copanlisib.
  • the additional therapeutic agent is a JAK inhibitor.
  • the JAK inhibitor is tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, filgotinib, or abrocitinib.
  • Inhibitors of Cereblon Ubiquitin Ligase
  • the additional therapeutic agent is a inhibitor of cereblon.
  • the inhibitor of cereblon is thalidomide, lenalidomide. xviii) MAPK/ERK Inhibitors
  • the additional therapeutic agent is a MAPK/ERK inhibitor.
  • 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
  • the additional therapeutic agent is a Wnt/ -catenin inhibitor.
  • the Wnt/ -catenin inhibitor is capmatinib, resibufogenin, or isoquercitrin.
  • the additional therapeutic agent is a proteosome inhibitor.
  • the proteosome inhibitor bortezomib, carfilzomib, or ixazomib. xxi)Histone Deacetylase Inhibitors
  • the additional therapeutic agent is a histone deacetylase inhibitor.
  • the histone deacetylase inhibitor vorinostat, romidepsin, panobinostat, or belinostat.
  • the additional therapeutic agent is a recombinant IL-2.
  • the recombinant IL-2 is aldesleukin. xxiii) RANKL Inhibitors
  • the additional therapeutic agent is a RANKL inhibitor.
  • the RANKL inhibitor is Denosumab or AS2676293. xxiv) B4GALNT1 Inhibitors
  • the additional therapeutic agent is a B4GALNT1 inhibitor.
  • the B4GALNT1 inhibitor is Dinutuximab. xxv ) SLAMF7 Inhibitors
  • the additional therapeutic agent is a SLAMF7 inhibitor.
  • the SLAMF7 inhibitor is elotuzumab. xxvi) IDH2/IDH1 Inhibitors
  • the additional therapeutic agent is a IDH2/IDH1 inhibitor.
  • the IDH2/IDH1 inhibitor is enasidenib, ivosidenib, AGI-6780, AG- 221, FT-2102, IDH305, GSK 321, or BAY1436032.
  • BTK Inhibitors are enasidenib, ivosidenib, AGI-6780, AG- 221, FT-2102, IDH305, GSK 321, or BAY1436032.
  • the additional therapeutic agent is a BTK inhibitor.
  • the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib. xxviii) FLT3 Inhibitors
  • the additional therapeutic agent is a FLT3 inhibitor.
  • the FLT3 inhibitor is sunitinib, midostaurin, lestaurtinib, KW-2449, crenolanib, or gilteritinib.
  • the additional therapeutic agent is a PDGFRa inhibitor.
  • the PDGFRa inhibitor is olaratumab, avapritinib, ayvakit, imatinib, ripretinib, or regorafenib.
  • the additional therapeutic agent is a smoothened inhibitor.
  • the smoothened inhibitor is sonidegib, itraconazole, or glasdegib. xxxi ) LHRH antagonists or LHRH agonists
  • the additional therapeutic agent is a LHRH antagonist or LHRH agonist.
  • the LHRH antagonist or LHRH agonist is goserelin, leuprorelin or buserelin.
  • the additional therapeutic agent is a cell based therapy.
  • 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.
  • TIL tumor-infiltrating lymphocyte
  • TCR engineered t cell receptor
  • CAR chimeric antigen receptor
  • NK Natural Killer
  • the additional therapeutic agent is a 0X40 inhibitor.
  • the 0X40 inhibitor is ivuxolimab, cudarolimab, utomilumab, or INBRX- 106. xxxiv) 41BB ( CD137) Inhibitors
  • the additional therapeutic agent is a 41BB (CD137) inhibitor.
  • the 41BB (CD137) inhibitor is urelumab. xxxv) VISTA Inhibitors
  • the additional therapeutic agent is a VISTA inhibitor.
  • the VISTA inhibitor is hmbd-002. xxxvi) CD96 Inhibitors
  • the additional therapeutic agent is a CD96 inhibitor.
  • the CD96 inhibitor is GSK6097608.
  • the additional therapeutic agent is a TGF inhibitor.
  • the TGFp inhibitor is SAR-439459. xxxviii)CDI9 Inhibitors
  • the additional therapeutic agent is a CD 19 inhibitor.
  • the CD19 inhibitor is tafasitamab, loncastuximab tesirine, or blinatumomab. xxxix) CD30 Inhibitors
  • the additional therapeutic agent is a CD30 inhibitor.
  • 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
  • the additional therapeutic agent is a CD39 inhibitor.
  • the CD39 inhibitor is purOOl, ES002023, TTX-030, IPH5201, or SRF617. xlii) CD52 Inhibitors
  • the additional therapeutic agent is a CD52 inhibitor.
  • the CD52 inhibitor is alemtuzumab. xliii) CD73 Inhibitors
  • the additional therapeutic agent is a CD73 inhibitor.
  • 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.
  • A2AR Inhibitors 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.
  • the additional therapeutic agent is an A2AR inhibitor.
  • the A2AR inhibitor is istradefylline, vipadenant, CVT-6883, enprofylline, ciforadenant, imaradenant, etrumadenant, NIR178, EOS100850, CS3005, PBF- 999, or INCB 106385.
  • the additional therapeutic agent is an A2BR inhibitor.
  • the A2BR inhibitor is pbf-1129, QAF805, LAS101057 AB928, ISAM140, or TT-4. xlvi) IDO1 & TDO2 Inhibitors
  • the additional therapeutic agent is an IDO1 or a TDO2 inhibitor.
  • 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.
  • 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
  • the additional therapeutic agent is a B7-H3 inhibitor.
  • the B7-H3 inhibitor is enoblituzumab, I-Omburtamab, DS-7300, or MGC018. xlix) B7-H4 Inhibitors
  • the additional therapeutic agent is a B7-H4 inhibitor.
  • the B7-H4 inhibitor is mt-1660, FPA150, or AZD8205.
  • 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)
  • the additional therapeutic agent is a Spicing inhibitor sulfonamide (SPLAM).
  • SPLAM Spicing inhibitor sulfonamide
  • the SPLAM is indisulam or E7820.
  • 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).
  • the additional therapeutic agent is a an antibody drug conjugate (ADC) comprising one or more antitumor compound conjugated to an antibody via a linker.
  • ADC antibody drug conjugate
  • the antibody is a bispecific antibody.
  • the antibody is a monospecific antibody.
  • a number of ADCs comprising antitumor compounds and methods of making the same are known in the art. Each of these is embraced by this disclosure.
  • the antitumor compound is an additional therapeutic agent disclosed herein.
  • the antitumor compound is a chemotherapeutic agent disclosed herein.
  • 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).
  • 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.
  • An effective dose 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.
  • 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.
  • 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.
  • 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).
  • 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, sub
  • Embodiments 1 to 156 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.
  • Embodiment 1 A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein
  • X 1 is C(R la R lb ), O, or NR 1 ;
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b ), O, or NR 3 ;
  • X 4 is C(R 4a R 4b ), O, NR 4 , S, S(O), or S(O) 2 ;
  • X 5 is C(R 5a R 5b ), O, NR 5 , S, S(O), or S(O) 2 ;
  • X 6 is C(R 6a R 6b ), O, NR 6 , S, S(O), or S(O) 2 ;
  • R 1 , R 2 , and R 3 are each independently H or Ci-4 alkyl;
  • R la ,R lb , R 2a ,R 2b , R 3a , and R 3b are each independently H, Ci-4 alkyl, halo, or Ci-4 haloalkyl;
  • R 4 , R 5 , and R 6 are each independently H, C1.4 alkyl, or C1.4 hydroxyalkyl;
  • R 4a , R 4b , R 5a ,R 5b , R 6a , and R 6b are 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 R 7 is independently C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloal
  • Embodiment 2 The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein X 1 is C(R la R lb ) or NR 1 .
  • Embodiment 3 The compound or a pharmaceutically acceptable salt thereof of embodiment 1 or 2, wherein X 1 is NR 1 .
  • Embodiment 4. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 3, wherein R 1 is H or methyl.
  • Embodiment 5 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 3, wherein R 1 is H.
  • Embodiment 6 The compound or a pharmaceutically acceptable salt thereof of embodiment 1 or 2, wherein X 1 is C(R la R lb ).
  • Embodiment 7 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1, 2, and 6, wherein R la and R lb are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 8 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1, 2, and 6, wherein R la and R lb are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 9 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1, 2, and 6, wherein R la and R lb are each H.
  • Embodiment 10 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1, 2, and 6, wherein R la is methyl, and R lb is H.
  • Embodiment 11 The compound or a pharmaceutically acceptable salt thereof of 1, wherein X 1 is O.
  • Embodiment 12 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11, wherein X 2 is C(R 2a R 2b ) or O.
  • Embodiment 13 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11, wherein X 2 is O.
  • Embodiment 14 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11, wherein X 2 is C(R 2a R 2b ).
  • Embodiment 15 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11 and 14, wherein R 2a and R 2b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 16 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11 and 14, wherein R 2a and R 2b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 17 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11 and 14, wherein R 2a and R 2b are each H.
  • Embodiment 18 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 11 and 14, wherein R 2a is methyl, and R 2b is H.
  • Embodiment 19 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 18, wherein X 3 is C(R 3a R 3b ) or NR 3 .
  • Embodiment 20 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19, wherein X 3 is NR 3 .
  • Embodiment 21 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 20, wherein R 3 is H or methyl.
  • Embodiment 22 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19, wherein X 3 is C(R 3a R 3b ).
  • Embodiment 23 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19 and 22, wherein R 3a and R 3b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 24 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19 and 22, wherein R 3a and R 3b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 25 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19 and 22, wherein R 3a and R 3b are each H.
  • Embodiment 26 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 19 and 22, wherein R 3a is methyl, and R 3b is H.
  • Embodiment 27 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 18, wherein X 3 is O.
  • Embodiment 28 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 27, wherein X 4 is C(R 4a R 4b ), O, or NR 4 .
  • Embodiment 29 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 27, wherein X 4 is O.
  • Embodiment 30 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 27, wherein X 4 is NR 4 .
  • Embodiment 31 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 30, wherein R 4 is H or methyl.
  • Embodiment 32 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 30, wherein R 4 is H.
  • Embodiment 33 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 27, wherein X 4 is C(R 4a R 4b ).
  • Embodiment 34 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 33, wherein R 4a and R 4b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 35 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 33, wherein R 4a and R 4b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 36 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 33, wherein R 4a and R 4b are each H.
  • Embodiment 37 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 28 and 33, wherein R 4a is methyl, and R 4b is H.
  • Embodiment 38 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 37, wherein X 5 is C(R 5a R 5b ), O, or NR 5 .
  • Embodiment 39 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 37, wherein X 5 is O.
  • Embodiment 40 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 37, wherein X 5 is NR 5 .
  • Embodiment 41 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 40, wherein R 5 is H or methyl.
  • Embodiment 42 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 40, wherein R 5 is H.
  • Embodiment 43 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 37, wherein X 5 is C(R 5a R 5b ).
  • Embodiment 44 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 43, wherein R 5a and R 5b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 45 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 43, wherein R 5a and R 5b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 46 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 43, wherein R 5a and R 5b are each H.
  • Embodiment 47 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 38 and 43, wherein R 5a is methyl, and R 5b is H.
  • Embodiment 48 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 47, wherein X 6 is C(R 6a R 6b ), O, NR 6 .
  • Embodiment 49 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 47, wherein X 6 is O.
  • Embodiment 50 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 47, wherein X 6 is NR 6 .
  • Embodiment 51 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 50, wherein R 6 is H or methyl.
  • Embodiment 52 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 50, wherein R 6 is H.
  • Embodiment 53 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 47, wherein X 6 is C(R 6a R 6b ).
  • Embodiment 54 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 53, wherein R 6a and R 6b are each independently H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 55 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 53, wherein R 6a and R 6b are each independently H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 56 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 53, wherein R 6a and R 6b are each H.
  • Embodiment 57 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 48 and 53, wherein R 6a is methyl, and R 6b is H.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 R 7 .
  • 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 R 7 .
  • Embodiment 64 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 63, wherein R 7 is Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or Ci-6 haloalkoxy.
  • Embodiment 65 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 63, wherein R 7 is Ci-4 alkyl, Ci-4 haloalkyl, or halo.
  • Embodiment 66 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 63, wherein R 7 is methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • Embodiment 67 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 63, wherein R 7 is methyl.
  • 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 .
  • 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
  • X a is O, CH 2 , or CHR 7 ; 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 .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • Embodiment 82 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, having Formula (Ia2-1): wherein,
  • X a is absent, O, CH 2 , or CHR 7 ;
  • X 7a is absent, O or CH 2 , or CHR 7a ;
  • X 7b is absent, O or CH 2 , or CHR 7a ; p is 0, 1 or 2; and q is 0, 1, or 2.
  • Embodiment 83 The compound or a pharmaceutically acceptable salt thereof of embodiment 82, wherein
  • X a is O, CH 2 , or CHR 7 ;
  • X 7a is O or CH 2 , or CHR 7a ;
  • X 7b is O or CH 2 , or CHR 7a ; p is 0, 1 or 2; and q is 0, 1, or 2.
  • Embodiment 84 The compound or a pharmaceutically acceptable salt thereof of embodiment 82 or 83, wherein X 7a is O, and X 7b is CH2.
  • Embodiment 85 The compound or a pharmaceutically acceptable salt thereof of embodiment 82 or 83, wherein X 7a is CH2, and X 7b is O.
  • Embodiment 86 The compound or a pharmaceutically acceptable salt thereof of embodiment 82 or 83, wherein X 7a is CH2, and X 7b is CH2.
  • Embodiment 87 The compound or a pharmaceutically acceptable salt thereof of embodiment 82, wherein X 7a is absent, and X 7b is CH2.
  • Embodiment 88 The compound or a pharmaceutically acceptable salt thereof of embodiment 82, wherein X 7a is absent, and X 7b is O.
  • Embodiment 89 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 88, wherein R 7a is C1-4 alkyl, halo, or C1-4 haloalkyl.
  • Embodiment 90 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 88, wherein R 7a is methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • Embodiment 91 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 88, wherein R 7a is methyl, fluoro, chloro, or trifluoromethyl
  • Embodiment 92 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 88, wherein two R 7a groups attached to the same carbon atom combine to form oxo.
  • Embodiment 93 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 92, wherein each R 8 is independently C1-6 alkyl, Ci-6 haloalkyl, halo, C1-6 alkoxy, or C1-6 haloalkoxy.
  • Embodiment 94 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 92, wherein each R 8 is independently C1-6 alkyl, C1-6 haloalkyl, or halo.
  • Embodiment 95 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 92, wherein each R 8 is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • Embodiment 96 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 92, wherein each R 8 is independently bromo or trifluoromethyl.
  • Embodiment 97 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, wherein the moiety has the formula:
  • Embodiment 98 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, having Formula (lb) wherein,
  • X a is O, CH 2 , or CHR 7 ;
  • 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.
  • Embodiment 99 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 98, wherein p is 1.
  • Embodiment 100 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 98, wherein p is 2.
  • Embodiment 101 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 100, wherein q is 0.
  • Embodiment 102 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 100, wherein q is 1 .
  • Embodiment 103 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 100, wherein q is 2.
  • Embodiment 104 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, having Formula (Ibl)
  • Embodiment 105 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R 8 is 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 R 8a .
  • each R 8 is 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 R 8a .
  • Embodiment 106 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R 8 is 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 R 8a .
  • Embodiment 107 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R 8 is independently heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R 8a .
  • Embodiment 108 Embodiment 108.
  • each R 8 is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 R 8a .
  • Embodiment 109 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 104, wherein each R 8 is piperidinyl substituted with 0, 1, or 2 R 8a .
  • Embodiment 110 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 109, wherein each R 8a is C1-4 alkyl.
  • Embodiment 111 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67 and 98 to 109, wherein each R 8a is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • Embodiment 112 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, and 98 to 109, wherein each R 8a is methyl.
  • Embodiment 113 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, wherein the moiety
  • Embodiment 114 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R 9 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • Embodiment 115 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R 9 is H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 116 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R 9 is H.
  • Embodiment 117 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R 9 is methyl.
  • Embodiment 118 The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 113, wherein R 9 is fluoro.
  • Embodiment 119 The compound or a pharmaceutically acceptable salt thereof of any embodiment 1, wherein the compound is selected from Examples 1 to 8.
  • 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.
  • 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.
  • PRMT5 protein arginine N-methyltransferase 5
  • Embodiment 122 The method of embodiment 121, wherein the disease is cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • Embodiment 127 The method of embodiment 122 or 126, wherein the cancer is deficient in CDKN2A.
  • Embodiment 128 The method of any one of embodiments 122 to 127, wherein the cancer is a solid tumor.
  • Embodiment 129 The method of embodiment 128, wherein the solid tumor is malignant.
  • Embodiment 130 The method of any one of embodiments 122 to 129, wherein the patient is in recognized need of such treatment.
  • 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.,
  • NSCLC
  • 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.
  • 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 lymphom
  • 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.
  • non-small cell lung cancer squamous and adenocarcinoma
  • urothelial cancer bladedder and upper urinary tract
  • esophageal cancer esophageal cancer
  • gastric cancer gastric cancer
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Embodiment 141 The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 140, wherein the solid tumor is malignant.
  • 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
  • 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.
  • 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.
  • 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.
  • Embodiment 146 The use of embodiment 145, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.
  • Embodiment 147 The use of embodiment 145 or 146, wherein said cancer is deficient in CDKN2A.
  • Embodiment 148 The use of any one of embodiments 145 to 147, wherein said cancer is an MTAP null cancer.
  • 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.
  • Embodiment 150 The use of any one of embodiments 145 to 149, wherein said cancer is a solid tumor.
  • Embodiment 151 The use of embodiment 150, wherein said solid tumor is malignant.
  • 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 lymph
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Embodiment IB A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b ), O, or NR 3 ;
  • X 4 is C(R 4a R 4b ), O, NR 4 , S, S(O), or S(O) 2 ;
  • X 5 is C(R 5a R 5b ), O, NR 5 , S, S(O), or S(O) 2 ;
  • X 6 is C(R 6a R 6b ), O, NR 6 , S, S(O), or S(O) 2 ;
  • R 1 , R 2 , and R 3 are each independently H or Ci-4 alkyl
  • R la ,R lb , R 2a ,R 2b , R 3a , and R 3b are each independently H, Ci-4 alkyl, halo, or Ci-4 haloalkyl;
  • R 4 , R 5 , and R 6 are each independently H, C1.4 alkyl, or C1.4 hydroxyalkyl;
  • R 4a ,R 4b , R 5a j R 5b ; R 6a ; and R 6b are 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 R 7 is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, Ci-6 haloalkoxy,
  • Embodiment 2B The compound or a pharmaceutically acceptable salt thereof of embodiment IB, wherein one R 7 attached to ring A and one R 8 attached to ring B combine to form ring C, wherein ring C is C4-7 cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O) 2 , wherein ring C is substituted with 0, 1, 2, or 3 R 7a , and ring A, ring B, and ring C form a fused tricyclic moiety.
  • Embodiment 3B The compound or a pharmaceutically acceptable salt thereof of embodiment IB or 2B, wherein X 1 is C(R la R lb ).
  • Embodiment 4B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 3B, wherein X 1 is CH 2 .
  • Embodiment 5B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X 2 is NR 2 .
  • Embodiment 6B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 5B, wherein X 2 is NH.
  • Embodiment 7B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X 2 is O.
  • Embodiment 8B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B, wherein X 2 is C(R 2a R 2b ).
  • Embodiment 9B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 4B and 8B, wherein X 2 is CH2.
  • Embodiment 10B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 9B, wherein X 3 is C(R 3a R 3b ).
  • Embodiment 11B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 10B, wherein X 3 is CH2.
  • Embodiment 12B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 11B, wherein X 4 is C(R 4a R 4b ), O, or NR 4 .
  • Embodiment 13B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 12B, wherein X 4 is C(R 4a R 4b ).
  • Embodiment 14B The compound or a pharmaceutically acceptable salt thereof of embodiment 13B, wherein R 4a and R 4b are each H.
  • Embodiment 15B The compound or a pharmaceutically acceptable salt thereof of embodiment 13B, wherein R 4a is methyl, and R 4b is H.
  • Embodiment 16B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 15B, wherein X 5 is C(R 5a R 5b ), O, or NR 5 .
  • Embodiment 17B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 16B, wherein X 5 is O.
  • Embodiment 18B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 17B, wherein X 6 is C(R 6a R 6b ), O, or NR 6 .
  • Embodiment 19B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 18B, wherein X 6 is C(R 6a R 6b ).
  • Embodiment 20B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 19B, wherein R 6a and R 6b are each H.
  • Embodiment 21B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 18B, wherein R 6a is methyl; and R 6b is H.
  • 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.
  • 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.
  • 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.
  • 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 R 7 .
  • 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 R 7 .
  • 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 R 7 .
  • Embodiment 28B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R 7 is independently Ci-6 alkyl, Ci-6 haloalkyl, halo, Ci-6 alkoxy, or Ci-6 haloalkoxy.
  • Embodiment 29B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R 7 is independently CH alkyl, halo, or Ci-4 alkoxy.
  • Embodiment 30B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R 7 is independently methyl, fluoro, or methoxy.
  • Embodiment 31B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 27B, wherein each R 7 is independently methyl or fluoro.
  • 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 .
  • 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
  • Embodiment 33B The compound or a pharmaceutically acceptable salt thereof of embodiment 32B, wherein:
  • X 1 is C(R la R lb );
  • X 2 is C(R 2a R 2b ), O, or NR 2 ;
  • X 3 is C(R 3a R 3b );
  • X 4 is C(R 4a R 4b );
  • X s is O
  • X 6 is C(R 6a R 6b );
  • R 2 is H or C1-4 alkyl
  • R la , R lb , R 2a , R 2b , R 3a , and R 3b are each independently H or C1-4 alkyl;
  • R 4a , R 4b , R 6a , and R 6b are 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 R 7a , p is 0 or 1; q is 1;
  • R 7 is C1-4 alkyl, halo, or C1-4 alkoxy,
  • R 8 is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, or C3-6 cycloalkyl; each R 7a is independently C1-4 alkyl or halo; and
  • R 9 is H.
  • Embodiment 34B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, having Formula (Ial-1): wherein:
  • X a is O, NH, CH 2 , or CHR 7 ; 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.
  • X a is O, NH, CH 2 , or CHR 7 ; 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 .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 R 7a .
  • 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 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R 7a .
  • 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 R 7a .
  • Embodiment 42B The compound or a pharmaceutically acceptable salt thereof of embodiment 40B, wherein ring C is tetrahydrofuranyl substituted with 0 R 7a .
  • Embodiment 43B The compound or a pharmaceutically acceptable salt thereof of embodiment 41B, wherein ring C is tetrahydropyranyl substituted with 0 or 1 R 7a .
  • Embodiment 44B The compound or a pharmaceutically acceptable salt thereof of embodiment 41B, wherein ring C is tetrahydropyranyl substituted with 0 R 7a .
  • Embodiment 45B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, having Formula (Ia2-1): wherein,
  • X a is O, NH, CH 2 , or CHR 7 ;
  • X 7a is absent, O, CH 2 , or CHR 7a ;
  • X 7b is absent, O, CH 2 , or CHR 7a ; p is 0, 1, or 2; and q is 0, 1, or 2, provided that X 7a and X 7b are not each absent or O.
  • Embodiment 46B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, having Formula (Ia2-2):
  • X a is O, NH, CH 2 , or CHR 7 ;
  • X 7a is absent, O, CH 2 , or CHR 7a ;
  • X 7b is absent, O, CH 2 , or CHR 7a ; p is 0, 1, or 2; and q is 0, 1, or 2, provided that X 7a and X 7b are not each absent or O.
  • Embodiment 47B The compound or a pharmaceutically acceptable salt thereof of embodiment 45B or 46B, wherein
  • X a is O, CH 2 , or CHR 7 ;
  • X 7a is O, CH 2 , or CHR 7a ;
  • X 7b is O, CH 2 , or CHR 7a .
  • Embodiment 48B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X 7a is O; and X 7b is CH 2 .
  • Embodiment 49B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X 7a is CH 2 ; and X 715 is O.
  • Embodiment SOB The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X 7a is CH 2 ; and X 711 is CH 2 .
  • Embodiment SIB The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X 7a is O; and X 7b is CH(CHa).
  • Embodiment 52B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X 7a is CH(CHs); and X 7b is O.
  • Embodiment 53B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 45B to 47B, wherein X 7a is CH 2 and X ⁇ is CH(CH3); or X 7a is CH(CH 3 ) and X 7b is CH 2 .
  • Embodiment 54B The compound or a pharmaceutically acceptable salt thereof of embodiment 45B or 46B, wherein X 7a is absent; and X 7b is CH2.
  • Embodiment 55B The compound or a pharmaceutically acceptable salt thereof of embodiment 45B or 46B, wherein X 7a is absent; and X 7b is O.
  • Embodiment 56B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 55B, wherein each R 8 is independently C1-6 alkyl, C1-6 haloalkyl, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, or C3-6 cycloalkyl.
  • Embodiment 57B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 56B, wherein q is 1; and R 8 is C1-6 alkyl, Ci-6 haloalkyl, halo, CN, C1-6 alkoxy, C1-6 haloalkoxy, or C3-6 cycloalkyl.
  • Embodiment 58B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 57B, wherein q is 1; and R 8 is chloro, CN, isopropyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, or trifluoromethyl-O-.
  • Embodiment 59B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 58B, wherein q is 1; and R 8 is chloro, trifluoromethyl, or difluoromethyl-O-.
  • Embodiment 60B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 59B, wherein q is 1; and R 8 is chloro.
  • Embodiment 61B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 59B, wherein q is 1; and R 8 is trifluoromethyl.
  • Embodiment 62B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 59B, wherein q is 1; and R 8 is difluoromethyl-O-.
  • Embodiment 63B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 31B, wherein the moiety has the formula: wherein:
  • X a is O, NH, CH 2 , or CHR 7 ;
  • X 7a is O, CH 2 , or CHR 7a ;
  • X 7b is O, CH 2 , or CHR 7a ; each R 7a is independently C1-4 alkyl; each R 7 is independently F, C1.4 alkyl, or C1.4 alkoxy; and
  • R 8 is C1-4 alkyl, C1-4 haloalkyl, halo, CN, C1-4 alkoxy, C1-4 haloalkoxy, or C3-5 cycloalkyl, provided that X 7a and X 7b are not each O.
  • Embodiment 64B The compound or a pharmaceutically acceptable salt thereof of embodiment 63B, wherein X a is O, NH, CH 2 , CHF, C(CH 3 ), or C(OCH 3 ); X 7a is O, CH 2 , or CH(CH 3 ); X 7b is O or CH 2 ; R 7 is F, CH 3 , or OCH 3 ; R 8 is chloro, CN, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, difluoromethyl-O-, or trifluoromethyl-O-, provided that X 7a and X 78 are not each O.
  • Embodiment 65B The compound or a pharmaceutically acceptable salt thereof of any one of embodiments IB to 64B, wherein R 9 is H.
  • 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 R 4a is H or C1-4 alkyl.
  • Embodiment 67B The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is O; and R 4a is H.
  • Embodiment 68B The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is O; and R 4a is methyl.
  • Embodiment 69B The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is NH; and R 4a is H.
  • Embodiment 70B The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is NH; and R 4a is methyl.
  • Embodiment 71B The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is CH2; and R 4a is H.
  • Embodiment 72B The compound or a pharmaceutically acceptable salt thereof of embodiment 66B, wherein X2 is CH2; and R 4a is methyl.
  • 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.
  • Embodiment 74B A compound or a pharmaceutically acceptable salt thereof, represented by any one of the structures of Examples 1 to 44.
  • 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.
  • 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 acceptable salt thereof of any one of embodiments IB to 74B, or a pharmaceutical composition of embodiment 75.
  • PRMT5 protein arginine N-methyltransferase 5
  • Embodiment 77B The method of embodiment 76B, wherein the disease is cancer.
  • 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.
  • 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.
  • 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.
  • Embodiment 81B The method of any one of embodiments 77B to 80B, wherein the cancer is a MTA-accumulating cancer.
  • Embodiment 82B The method of embodiment 77B or 81B, wherein the cancer is deficient in CDKN2A.
  • Embodiment 83B The method of any one of embodiments 77B to 82B, wherein the cancer is a solid tumor.
  • Embodiment 84B The method of embodiment 83B, wherein the solid tumor is malignant.
  • Embodiment 85B The method of any one of embodiments 76B to 84B, wherein the patient is in recognized need of such treatment.
  • Embodiment 86B The method of any one of embodiments 77B to 85B, 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-
  • 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.
  • 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-Hodg
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, or a reduced function of MTAP protein, or a combination thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 sarcom
  • 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.
  • 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-Hodg
  • 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.
  • 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.
  • Embodiment 101B The use of embodiment 100B, wherein said cancer is an MTAP null cancer.
  • 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.
  • Embodiment 103B The use of any one embodiments 100B to 102B, wherein said cancer is MTA-accumulating cancer,.
  • Embodiment 104 The use of any one of embodiments 100B to 103B, wherein said cancer is deficient in CDKN2A.
  • Embodiment 105B The use of any one of embodiments 100B to 102B, wherein said cancer is a solid tumor.
  • Embodiment 106B The use of embodiment 105B, wherein said solid tumor is malignant.
  • 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-
  • 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.
  • PRMT5 protein arginine N-methyltransferase 5
  • 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.
  • 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.
  • TIPSOTf Triisopropylsilyl trifluoromethanesulfonate
  • 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
  • Step 2 ethyl 2-((2-chloropyridin-3-yl)methyl)pent-4-enoate
  • Step 4 ethyl 6,7-dihydro-5H-cyclohepta[b]pyridine-6-carboxylate
  • Step 5 ethyl 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6-carboxylate
  • Step 7 ethyl 2-(tert-butylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6-carboxylate
  • 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 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.
  • sodium hyposulfite sat.
  • 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.

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Abstract

L'invention concerne des composés de formule (I) ou un sel pharmaceutiquement acceptable de ceux-ci. Les composés selon l'invention sont des inhibiteurs de la protéine arginine N-méthyltransférase 5 (PRMT5) utiles. L'invention concerne également des compositions pharmaceutiques comprenant de tels composés et des procédés de fabrication de tels composés. L'invention concerne également d'autres utilisations et avantages présentés par lesdits composés.
PCT/US2025/014121 2024-02-02 2025-01-31 Composés amidino tricycliques utilisés en tant qu'inhibiteurs de prmt5 Pending WO2025166229A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448388B2 (en) 2023-04-21 2025-10-21 Gilead Sciences, Inc. PRMT5 inhibitors and uses thereof

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039972A1 (fr) 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires
WO2018045071A1 (fr) 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires
WO2019191470A1 (fr) 2018-03-30 2019-10-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et leurs méthodes d'utilisation pour le traitement du cancer
WO2020123395A1 (fr) 2018-12-10 2020-06-18 Ideaya Biosciences, Inc. Dérivés de 2-oxoquinazoline utilisés en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a
WO2020139992A1 (fr) 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Inhibiteurs aza-hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
WO2020139991A1 (fr) 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Inhibiteurs aza-hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
WO2021125981A1 (fr) 2019-12-19 2021-06-24 Abodo Wood Limited Procédé d'amélioration de la durabilité et de la tenue aux intempéries de bois d'œuvre par des couches techniques
WO2021252681A1 (fr) 2020-06-10 2021-12-16 Ideaya Biosciences, Inc. Dérivés de quinolinone en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a
WO2021252678A1 (fr) 2020-06-10 2021-12-16 Ideaya Biosciences, Inc. Dérivés de 2-oxoquinazoline substitués par un alkylène hétéroaryle utilisés en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a
WO2021252680A1 (fr) 2020-06-10 2021-12-16 Ideaya Biosciences, Inc. Dérivés de 4-arylquinazoline en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a
WO2021252679A1 (fr) 2020-06-10 2021-12-16 Ideaya Biosciences, Inc. Dérivés de 2-aminoquinazolinone comme inhibiteurs de la méthionine adénosyltransférase 2a
WO2022132914A1 (fr) * 2020-12-16 2022-06-23 Amgen Inc. Inhibiteurs de prmts
WO2022169948A1 (fr) * 2021-02-04 2022-08-11 Amgen Inc. Inhibiteurs de prmt5 tricycliques-amido-bicycliques
WO2022268180A1 (fr) 2021-06-23 2022-12-29 石药集团中奇制药技术（石家庄）有限公司 Composé hétérocyclique aromatique à six chaînons contenant de la pyrimidine et de l'azote et son utilisation
WO2023066283A1 (fr) 2021-10-20 2023-04-27 Insilico Medicine Ip Limited Inhibiteurs de la méthionine adénosyltransférase 2a (mat2a) et leurs utilisations
WO2023196985A1 (fr) 2022-04-08 2023-10-12 Ideaya Biosciences, Inc. Inhibiteurs de méthionine adénosyltransférase 2a
WO2024002024A1 (fr) 2022-06-27 2024-01-04 石药集团中奇制药技术（石家庄）有限公司 Composés tricycliques et leurs utilisations
WO2024220917A1 (fr) * 2023-04-21 2024-10-24 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations
WO2024217493A1 (fr) 2023-04-19 2024-10-24 Insilico Medicine Ip Limited Inhibiteur de méthionine adénosyltransférase 2a (mat2a) cristallin et ses utilisations
WO2024217502A1 (fr) 2023-04-19 2024-10-24 Insilico Medicine Ip Limited Combinaisons d'inhibiteurs de méthionine adénosyltransférase 2a (mat2a) et leurs utilisations

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039972A1 (fr) 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires
WO2018045071A1 (fr) 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires
WO2019191470A1 (fr) 2018-03-30 2019-10-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et leurs méthodes d'utilisation pour le traitement du cancer
WO2020123395A1 (fr) 2018-12-10 2020-06-18 Ideaya Biosciences, Inc. Dérivés de 2-oxoquinazoline utilisés en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a
WO2020139992A1 (fr) 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Inhibiteurs aza-hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
WO2020139991A1 (fr) 2018-12-27 2020-07-02 Agios Pharmaceuticals, Inc. Inhibiteurs aza-hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
WO2021125981A1 (fr) 2019-12-19 2021-06-24 Abodo Wood Limited Procédé d'amélioration de la durabilité et de la tenue aux intempéries de bois d'œuvre par des couches techniques
WO2021252679A1 (fr) 2020-06-10 2021-12-16 Ideaya Biosciences, Inc. Dérivés de 2-aminoquinazolinone comme inhibiteurs de la méthionine adénosyltransférase 2a
WO2021252678A1 (fr) 2020-06-10 2021-12-16 Ideaya Biosciences, Inc. Dérivés de 2-oxoquinazoline substitués par un alkylène hétéroaryle utilisés en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a
WO2021252680A1 (fr) 2020-06-10 2021-12-16 Ideaya Biosciences, Inc. Dérivés de 4-arylquinazoline en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a
WO2021252681A1 (fr) 2020-06-10 2021-12-16 Ideaya Biosciences, Inc. Dérivés de quinolinone en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a
WO2022132914A1 (fr) * 2020-12-16 2022-06-23 Amgen Inc. Inhibiteurs de prmts
WO2022169948A1 (fr) * 2021-02-04 2022-08-11 Amgen Inc. Inhibiteurs de prmt5 tricycliques-amido-bicycliques
WO2022268180A1 (fr) 2021-06-23 2022-12-29 石药集团中奇制药技术（石家庄）有限公司 Composé hétérocyclique aromatique à six chaînons contenant de la pyrimidine et de l'azote et son utilisation
WO2023066283A1 (fr) 2021-10-20 2023-04-27 Insilico Medicine Ip Limited Inhibiteurs de la méthionine adénosyltransférase 2a (mat2a) et leurs utilisations
WO2023196985A1 (fr) 2022-04-08 2023-10-12 Ideaya Biosciences, Inc. Inhibiteurs de méthionine adénosyltransférase 2a
WO2024002024A1 (fr) 2022-06-27 2024-01-04 石药集团中奇制药技术（石家庄）有限公司 Composés tricycliques et leurs utilisations
WO2024217493A1 (fr) 2023-04-19 2024-10-24 Insilico Medicine Ip Limited Inhibiteur de méthionine adénosyltransférase 2a (mat2a) cristallin et ses utilisations
WO2024217502A1 (fr) 2023-04-19 2024-10-24 Insilico Medicine Ip Limited Combinaisons d'inhibiteurs de méthionine adénosyltransférase 2a (mat2a) et leurs utilisations
WO2024220917A1 (fr) * 2023-04-21 2024-10-24 Gilead Sciences, Inc. Inhibiteurs de prmt5 et leurs utilisations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BERGE, S.M. ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
no. 174953-30-1

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448388B2 (en) 2023-04-21 2025-10-21 Gilead Sciences, Inc. PRMT5 inhibitors and uses thereof

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