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WO2025166260A1 - Composés guanidino tricycliques substitués par un amide utilisés en tant qu'inhibiteurs de prmt5 - Google Patents

Composés guanidino tricycliques substitués par un amide utilisés en tant qu'inhibiteurs de prmt5

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Publication number
WO2025166260A1
WO2025166260A1 PCT/US2025/014157 US2025014157W WO2025166260A1 WO 2025166260 A1 WO2025166260 A1 WO 2025166260A1 US 2025014157 W US2025014157 W US 2025014157W WO 2025166260 A1 WO2025166260 A1 WO 2025166260A1
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WIPO (PCT)
Prior art keywords
compound
acceptable salt
cancer
alkyl
pharmaceuticaly acceptable
Prior art date
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Pending
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PCT/US2025/014157
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English (en)
Inventor
Paul A. Barsanti
Melissa Fleury
Joshua P. G. TAYGERLY
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Ideaya Biosciences Inc
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Ideaya Biosciences Inc
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Publication of WO2025166260A1 publication Critical patent/WO2025166260A1/fr
Pending legal-status Critical Current
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • Synthetic lethality arises when a combination of deficiencies in the expression or activity of two or more genes leads to cel death, whereas a deficiency in only one of these genes does not.
  • the concept of synthetic lethality originates from studies in drosophila model systems in which a combination of mutations in two or more separate genes leads to cel death (in contrast to viability, which occurs when only one of the genes is mutated or deleted). More recently, a multitude of studies have explored maladaptive genetic changes in cancer cels that render them vulnerable to synthetic-lethality approaches. These tumor- specific genetic defects lead to the use of targeted agents that induce the death of tumor cels while sparing normal cels.
  • 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 wel as other biological functions.
  • Chromosome 9p21 encompasses, among others, CDKN2A (cyclin dependent kinase inhibitor 2A), and homozygous deletion of 9p21 genomic locus is implicated in about 15% of al cancers.
  • MTAP is located within the vicinity of the CDKN2A on chromosome 9p21 and is frequently co-deleted with CDKN2A deletion.
  • the MTAP protein (methylthioadenosine phosphorylase) is an enzyme involved in polyamine metabolism, and the deletion of MTAP results in the accumulation of 5’methylthioadenosine (MTA) in the cel.
  • MTA 5’methylthioadenosine
  • PRMT5 is competitively inhibited by MTA.
  • Cels with an MTAP deletion have increased levels of MTA, thereby partialy inhibiting PRMT5.
  • 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 cels, while leaving normal cels relatively unafected.
  • a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, or a subembodiment thereof, and one or more pharmaceuticaly acceptable excipients.
  • a method of treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient in need thereof comprising administering to the patient a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly 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 nul cancer in a patient in need thereof comprising administering to the patient a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly 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 combination thereof, comprising administering to the subject a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly 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 comprising administering to the patient a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5).
  • PRMT5 protein arginine N-methyltransferase 5
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5).
  • PRMT5 protein arginine N-methyltransferase 5
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of an MTAP nul cancer.
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or combination thereof.
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for use in the treatment of cancer.
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the production of a protein arginine N- methyltransferase 5 (PRMT5) inhibitory effect.
  • PRMT5 protein arginine N- methyltransferase 5
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for use in the production of a protein arginine N-methyltransferase 5 (PRMT5) inhibitory 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 cel with an effete amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.
  • a method of inhibiting cel proliferation in vitro or in vivo comprising contacting a cel with an effete amount of a compound of Formula (I) or a pharmaceuticaly 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 pharmaceuticaly 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.
  • Preferred, suitable, and optional features of any one particular aspect of the present invention are also prefered, suitable, and optional features of any other aspect.
  • GENERAL Provided herein are compounds of Formula (I) or a pharmaceuticaly acceptable salt thereof, or a subembodiment thereof for inhibition of protein arginine N-methyltransferase 5 (PRMT5), and pharmaceutical compositions comprising the same. Also provided herein are, for example, methods of treating or preventing a disease, disorder or condition, or a symptom thereof, mediated by inhibition of PRMT5. Further provided herein are methods treating or preventing a disease, disorder or condition, or a symptom thereof treatable by inhibition 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, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • 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 diferent atoms of the alkylene group.
  • Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.
  • 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.
  • cycloalkenyl refers to a non-aromatic, unsaturated hydrocarbon ring having the indicated number of ring atoms (e.g., C3-6 cycloalkenyl). Cycloalkenyl groups have 1, 2, or 3 one carbon-carbon double bonds. In some embodiments, cycloalkenyl groups have 1 carbon-carbon double bond. Ilustrative examples of cycloalkenyl groups include, but are not limited to, cyclopenten-3-yl, cyclohexen-4-yl and the like.
  • halo or halogen
  • alkyl refers to alkyl, as defined above, that is substituted having one or more halogen atoms, which may be the same or diferent, at one or more carbon atoms of an alkyl and includes monohaloalkyl and polyhaloalkyl.
  • C1-4 haloalkyl includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • alkoxy refers to alkyl and haloalkyl groups respectively, each as defined herein, that is atached to the remainder of the molecule via an oxygen atom, for example –O–alkyl or –O–haloalkyl.
  • aryl refers to a monocyclic or bicyclic, hydrocarbon, aromatic radical. An aryl group may contain 6 to 14 carbon atoms.
  • C6-10 aryl refers to an aryl moiety having 6 to 10 carbon atoms as ring vertices.
  • Non-limiting examples of aryl groups include phenyl and naphthyl.
  • 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 atached 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, pyrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • heterocycloalkyl or “heterocyclyl” refers to a saturated or partialy unsaturated 3 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N, O, and S and the remaining ring atom being carbon.
  • heterocycloalkyl groups are not aromatic.
  • heterocycloalkyl groups include pyrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, , and the like.
  • a heterocycloalkyl group can be atached to the remainder of the molecule through a ring carbon or a heteroatom.
  • hydroxyalkyl refers to an alkyl, as defined above, that is substituted with one or two hydroxy.
  • hydroxyC1-4 alkyl or “C1-4 hydroxyalkyl” is meant to include hydroxymethyl, 1-, or 2-hydroxyethyl, 1,2-dihydroxyethyl, hydroxypropyl, and the like.
  • optionalaly 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 atached to a member atom within a group is replaced by one of the defined substituents.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or diferent.
  • a wavy line, " ", that intersects a single, double or triple bond in any chemical structure depicted herein, represent the point atachment of the single, double, or triple bond to the remainder of the molecule.
  • a bond extending to the center of a ring is meant to indicate atachment at any of the available ring vertices.
  • a ring e.g., a phenyl ring
  • a bond extending to the center of a ring is meant to indicate atachment at any of the available ring vertices.
  • a ring e.g., a phenyl ring
  • multiple substituents shown as being atached to a ring wil occupy ring vertices that provide stable compounds and are otherwise stericaly compatible.
  • pharmaceuticalaly 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, ulceration, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceuticaly acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effectss. Such pharmaceuticaly acceptable salt may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceuticaly-acceptable inorganic bases include aluminum, ammonium, calcium, copper, feric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc.
  • Salts derived from pharmaceuticaly-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturaly-occuring amines, such as arginine, betaine, cafeine, choline, N,N’-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, the
  • 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.
  • pharmaceuticaly acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydriodic, or phosphorous acids, as wel as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic.
  • 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 alow 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 difers from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • Certain compounds of Formula (I) possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are al intended to be encompassed within the scope of the present disclosure. When a stereochemical depiction is shown, it is meant to refer the compound in which one of the isomers is present and substantialy free of the other isomer.
  • ‘Substantialy free of’ another isomer indicates at least an 80/20 ratio of the two isomers, more preferably 90/10, or 95/5 or more. In some embodiments, one of the isomers wil be present in an amount of at least 99%.
  • Certain compounds of Formula (I) can exist in unsolvated forms as wel as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of Formula (I) may exist in multiple crystaline or amorphous forms. In general, al physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • Certain compounds of the present disclosure can exist as tautomers and/or geometric isomers. Al possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure.
  • 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 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 1251, 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 eficacy during treatment.
  • Isotopicaly-labeled compounds e.g., those labeled with 3H and 14C
  • Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes can be useful for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2H) may aford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by 13C- or 14C-enriched carbon.
  • Positron emiting isotopes such as 15O, 13N, 11C, and 15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopicaly labeled compounds can generaly be prepared by folowing procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopicaly labeled reagent for a non-isotopicaly labeled reagent.
  • Al isotopic variations of Formula (I) or a subembodiment thereof, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • the terms “patient” or “subject” are used interchangeably to refer to a human or a non-human animal (e.g., a mammal).
  • disorders examples 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 generaly synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that al reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typicaly manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • “In need of treatment” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or wil benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver’s expertise.
  • the terms “administration”, “administer” and the like, as they apply to, for example, a subject, cel, tissue, organ, or biological fluid refer to contact of, for example, a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a pharmaceutical composition comprising same, or a diagnostic agent to the subject, cel, tissue, organ, or biological fluid.
  • administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cel, as wel as contact of a reagent to a fluid, where the fluid is in contact with the cel.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant celular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis.
  • Any type of cel may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, gastric, liver, pancreas, brain, and skin.
  • treat refers to a course of action (such as administering an inhibitor of PRMT5 or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition aflicting a patient, or at least one of the symptoms associated with a disease, disorder, condition aflicting a patient.
  • 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 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, generaly 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.
  • therapeuticy effete amount means the amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive 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 therapeuticaly effete 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.
  • antibody means an immunoglobulin and is a molecule containing an antigen-binding site immunospecificaly binding to an antigen.
  • the class of the antibody of the present disclosure may be any of IgG, IgE, IgM, IgD, IgA, and IgY and is preferably IgG.
  • the subclass of the antibody of the present disclosure may be any of IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2 and is preferably IgGl or IgG2.
  • the antibody may be derived from any species, and prefered examples of the species can include humans, rats, mice, and rabbits. When the antibody is derived from other than human species, it is preferably chimerized or humanized using a wel-known technique.
  • the antibody of the present disclosure may be a polyclonal antibody or a monoclonal antibody. In an embodiment, the antibody is a monoclonal antibody.
  • the antibody of the present disclosure is capable of targeting tumor cels.
  • the antibody of the present disclosure is conjugated with an antitumor compound having antitumor activity via a linker, the antibody preferably possesses one or more of a property of recognizing a tumor cel, a property of binding to a tumor cel, a property of internalizing in a tumor cel, and a property of damaging a tumor cel.
  • the antibody is a monoclonal antibody that is reactive with a target antigen or epitope of an antigen expressed on a cancer or malignant cel. Techniques for preparing monoclonal antibodies against target antigen are known in the art.
  • Non limiting target antigens are B7-H3, B7-H4, Trop-2, PSMA, BCMA, folate receptor, AXL, EGF receptor (ErbB1), ErbB2, ErbB3, EGFRvII, FGFR, EpCAM, HER-2, HER-3, tissue factor (TF), CD19, CD22, CD25, ILR2, ANTXR1, ROR1, 5T4, CD30, CD33, CD79b, CD74, CD138, CD56, CD70, CD166, CEACAM5, GPNMB, Claudin-18, folate receptor alpha (FR ⁇ ), c-Met, Nectin-4, Mesothelin, delta-like ligand 3 (DLL3), PTK7, GPNMB, Ley, CA6, CanAng, Av integrin, SLC44A4, CEACAM5, AGS-16, Anti-Cripto, Carbonic Anhydrase 9, Mesotheilin, TENB2, 5T4, VEGF, insulin-like growth factor (ILGF), M
  • X1 is C(R1) or N; each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl; alternatively, two R4 groups when atached to the same carbon atom combine to form oxo or C3-6 cycloalkyl; R7 is (i) –CH2Ar; Ar is phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein phenyl and heteroaryl are each independently substituted with 0, 1, or 2 R7a; each R7a is independently –CN, halo, C alkyl, C hal
  • X1 is C(R1) or N; each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl; alternatively, two R4 groups when atached to the same carbon atom combine to form oxo or C3-6 cycloalkyl; R7 is (i) –CH2Ar; Ar is phenyl or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein phenyl and heteroaryl are each independently substituted with 0, 1, or 2 R7a; each R7a is independently –CN, halo, C alk 7a1 7a2 7a3
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X1 is N.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X1 is C(R1) and R1 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X1 is C(R1) and R1 is H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X1 is C(R1) and R1 is H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X1 is CH.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X2 is N.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X2 is C(R2) and R2 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X2 is C(R2) and R2 is H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X2 is C(R2) and R2 is H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X2 is CH or N.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X2 is CH or CF.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X2 is CH.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X2 is CF.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X3 is N.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X3 is C(R3) and R3 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X3 is C(R3) and R3 is H, methyl, ethyl, fluoro, chloro, or bromo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X3 is C(R3) and R3 is H, methyl, fluoro, chloro, or trifluoromethyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X3 is CH or CF.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X3 is CH.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X3 is CF.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R4 is independently C1-4 alkyl, halo, or C1-4 haloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R4 is independently halo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R4 is independently fluoro.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein n is 0, 1, or 2.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein n is 0 or 1.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein n is 0 or 2.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein n is 0.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein n is 2; and each R4 is independently fluoro (F).
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7 is (i) –CH2Ar.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein Ar is phenyl substituted with 0, 1, or 2 R7a.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein Ar is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S substituted with 0, 1, or 2 R7a.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl substituted with 0, 1, or 2 R7a.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein Ar is pyrolyl or pyrazolyl substituted with 0, 1, or 2 R7a.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein Ar is pyridinyl substituted with 0, 1, or 2 R7a.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, halo, C alkyl, C haloalkyl, –OR7a1, –NR7a2R7a3 7a2 7a3 1-6 1-6 , –C(O)NR R , – C(O)H, –C(O)C1-6 alkyl, or –C(O)OC1-6 alkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, halo, C1-6 alkyl, or C1-6 haloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, C1-6 alkyl, or C1-6 haloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently C1-6 haloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently –CN, methyl, or trifluoromethyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a is independently trifluoromethyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7 is independently .
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein at least one R7a is heterocycloalkyl having 4 to 6 ring members and 1 to 2 heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 halo, C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, –OC3-7 cycloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein at least one R7a is pyrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 halo, C1-6 alkyl, –C(O)H, –C(O)C1-6 alkyl, –C(O)OC1-6 alkyl, –OC3-7 cycloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7a1 is H.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a1 is C1- 4 alkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a2 is H.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7a2 is C1-4 alkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R7a3 is H.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7a3 is C1-4 alkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7 is (i) a moiety selected from (R7f) (7f m R )m .
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X4 is O.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X4 is C(R7bR7c).
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7b and R7c are each independently H, C1-4 alkyl, or halo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7b and R7c are each H.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X5 is N.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X5 is C(R7d).
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7d is H , C1-4 alkyl, or halo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7d is H.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is C1-6 alkyl, halo, C1-6 haloalkyl, –S(O)2C1-6alkyl, –S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –CN, C1-6 alkoxy, C1-6 haloalkoxy, –N(O)–OC1-6 alkyl, –C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, or pentafluorosulfanyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is C1-6 alkyl, halo, C1-6 haloalkyl, –CN, C1-6 alkoxy, or C1-6 haloalkoxy.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is H, C1-6 haloalkyl, –CN, or C1-6 haloalkoxy.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is C1-6 haloalkyl, –CN, or C1-6 haloalkoxy.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is H, trifluoromethyl, –CN, or difluoromethoxy.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is trifluoromethyl, –CN, or difluoromethoxy.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is –S(O)2C1-6alkyl, –S(O)(NH)C1-6 alkyl, –S(O)(N-C1-3 alkyl)C1-6 alkyl, –N(O)–OC1-6 alkyl, – C(O)C1-6 alkyl, –C(O)C1-6 haloalkoxy, or pentafluorosulfanyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is C3-6 cycloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heteroaryl is substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7e is pyrolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7f is C1-4 alkyl, halo, or C1-4 haloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7f is C1-4 methyl, chloro, or fluoro.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein m is 0.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R7 is a moiety selected from .
  • salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8 is C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C1-6 cycloalkyl are optionaly substituted with one or more groups, each group is independently –CN or C3-6 cycloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8 is C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C1-6 cycloalkyl are substituted with 0, 1, or 2 –CN or C3-6 cycloalkyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8 is methyl, ethyl, or cyclopropyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8 is methyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8 is –CHR8aR8b.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b are each independently H, C alk 8c 8a 8b 1-6 yl, C1-6 alkynyl, –CH2(OR), provided that R and R are not both H, and wherein C1-6 alkyl, C1-6 alkynyl are each independently substituted with 0, 1, or 2 R8a1.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8a is H or C1-6 alkyl and R8b is C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, and wherein C3-10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a1.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b are each independently H, C1-6 alkyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, and wherein heteroaryl are each independently substituted with 0,1, or 2 R8a1.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b are each independently H, C alkyl, pyrimidinyl, or pyridinyl, provided th 8a 8b 1-6 at R and R are not both H, and wherein C1-6 alkyl, pyrimidinyl, and pyridinyl are each independently substituted with 0, 1, or 2 R8a1.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b are each independently H, C alkyl, oxazolyl, thiophenyl, or thiazolyl, pr 8a 8b 1-6 ovided that R and R are not both H, and wherein C1-6 alkyl, oxazolyl, thiophenyl, and thiazolyl are each independently substituted with 0, 1, or 2 R8a1.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8a is C alkyl or C cycloalkyl; and R8b is –CH( 8c 1-6 3-10 2OR) or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein R8c is H, C1-6 alkyl, or C1-6 haloalkyl, and wherein C3-10 cycloalkyl and heteroaryl are each independently substituted with 0, 1, or 2 R8a1.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8a is methyl or cyclopropyl; and R8b is –CH2(OCH3) or pyrimidinyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8 is methyl, .
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R8a1 is independently halo, C 8d 8e 1-6 alkyl, or –C(O)NR R, –OH.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R8d and R8e is independently H or methyl.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R8a1 is independently C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, and heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein R8a and R8b and the carbon atom to which they are atached combine to form C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, C6-10 aryl, heteroaryl having 5 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl, C aryl, and heteroaryl are each independently substi 8a2 6-10 tuted with 0, 1, or 2 R .
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein each R8a2 is independently C1-6 alkyl, C1-6 alkynyl, or halo.
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X1 is CH; X2 is CH or N; X3 is CH; n is 0 or 2; each R4 is independently halo; R7 is (i) –CH2Ar; Ar is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, substituted with 1 R7a; each R7a is –CN, C1-6 alkyl, or C1-6 haloalkyl; or (i) a moiety selected from (R7f) (R7f m )m ; m is 0; R8 is –CHR8aR8b or C1-6 alkyl; and R8a and R8b are each independently C 8c 1-6 alkyl,–CH2(OR), C3-10 cycloalkyl, or heteroaryl having 5
  • the compound or the pharmaceuticaly acceptable salt thereof is the compound of Formula (I) or a subembodiment thereof, wherein X1 is CH; X2 is CH or N; X3 is CH; n is 0 or 2; each R4 is fluoro; R7 is acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the compound is selected from Table 1.
  • the present disclosure also includes prodrugs of the compound of Formula (I) or subembodiment thereof.
  • the term “prodrug” refers to compounds that readily undergo chemical changes under physiological conditions to provide a pharmacologicaly 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 metabolicaly 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. [0175]
  • 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 folowing labels are indicated at the stereocenter of the displayed structure: “&” (e.g., “&1”); or “or” (e.g., “or1”, “or2”, or “or3”). Each of these labels is further described below.
  • the chemical names in the present application are generated from the corresponding structures using software, for example, CHEMDRAW.
  • the label “&” in the structures in the present disclosure refers to both chiral centers being present in the mixture. When multiple stereocenters are labeled with “&1” the relative stereochemistry between them is determined. The term “rac” in the chemical names denotes a racemic mixture.
  • the label “or” in the structures refers to the specific chiral center being a single undefined isomer but absolute stereochemistry was not determined. When multiple stereocenters are labeled with diferent labels, the relative stereochemistry between them is not determined. For example, in a compound with stereocenters labeled as “or1” and “or2”, the relative stereochemistry between the diferently labeled stereocenters is not determined.
  • compositions suitable for administration to a subject may be pharmaceutical compositions suitable for administration to a subject.
  • compositions are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, or a subembodiment thereof, and one or more pharmaceuticaly acceptable excipients.
  • the pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, 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.
  • the pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.
  • 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.
  • the pharmaceutical 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 insuflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceuticaly elegant and palatable preparations.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Tablets and/or capsules contain the active ingredient in admixture with non-toxic pharmaceuticaly acceptable excipients which are suitable for the manufacture of tablets and/or capsules.
  • excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, corn starch, or alginic acid
  • binding agents for example starch, gelatin or acacia
  • lubricating agents for example magnesium stearate, stearic acid or talc.
  • Suitable pharmaceuticaly 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, filers, bulking agents, detergents, bufers, vehicles, diluents, and/or adjuvants.
  • a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration.
  • Neutral bufered saline or saline mixed with serum albumin are further exemplary vehicles.
  • Typical bufers include, but are not limited to, pharmaceuticaly acceptable weak acids, weak bases, or mixtures thereof.
  • the bufer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
  • Acceptable bufering agents include, for example, a Tris bufer, N-(2-Hydroxyethyl)piperazine-N'-(2- ethanesulfonic acid) (HEPES), 2-(N-Morpholino)ethanesulfonic acid (MES), 2-(N- Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), and N-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).
  • 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)prop
  • 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 liquid 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, pharmaceuticaly acceptable salts thereof, or pharmaceutical compositions described herein including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, al of which are known in the art.
  • An efective amount of a compound of Formula (I) or a pharmaceuticaly 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) wil naturaly vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to wel-known principles of medicine.
  • Al the compounds and pharmaceutical compositions provided herein can be used in al the methods provided herein.
  • the compounds and pharmaceutical compositions provided herein can be used in al the methods for treatment and/or prevention of al diseases or disorders provided herein.
  • the compounds and pharmaceutical compositions provided herein are for use as a medicament.
  • THERAPEUTIC USES AND APPLICATIONS [0190]
  • 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 cel with an effete amount of a compound of Formula (I) or a pharmaceuticaly 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 therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly 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 therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly 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 nul cancer in a patient comprising administering to the patient a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly 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 therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly 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 in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof comprising administering to the patient a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly 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 in a patient comprising administering to the patient a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment. [0198] The present disclosure also provides a method of inhibiting cel proliferation, in vitro or in vivo, said method comprising contacting a cel with an effete amount of a compound of Formula (I) or a pharmaceuticaly 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 therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.
  • the proliferative disorder is cancer.
  • Provided herein is a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in therapy.
  • the patient is in recognized need of such treatment.
  • the patient is in recognized need of such treatment.
  • the patient is in recognized need of such treatment.
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder 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 nul; and (i) if the cancer is MTAP nul, administering to the patient a therapeuticaly effective amount of a compound as disclosed herein or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein.
  • 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 non-polyposis colorectal cancer), esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medulary thyroid carcinoma, papilary thyroid carcinoma, renal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, meduloblastoma and peripheral neuroectodermal tumors), Hodgkin lymphoma, non
  • the cancer treated by the methods, uses, or medicaments described herein is lung cancer, non-smal cel lung (NSLC) cancer, bronchioloalveolar cel lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the falopian tubes, carcinoma of the endometrium, carcinoma of the vagina, carcinoma of the vulva, cancer of the smal intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cel carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer
  • the cancer treated by the methods, uses, or medicaments described herein is leukemia, glioma, melanoma, pancreatic, non-smal cel lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non- Hodgkin lymphoma or mesothelioma.
  • the cancer treated by the methods, uses, or medicaments described herein is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, difuse large B cel lymphoma (DLBCL), acute lymphoblastic leukemia (ALL) or mantle cel lymphoma (MCL).
  • the cancer treated by the methods, uses, or medicaments described herein is gastric cancer.
  • the cancer treated by the methods, uses, or medicaments described herein is colon cancer.
  • the cancer treated by the methods, uses, or medicaments described herein is liver cancer.
  • the cancer treated by the methods, uses, or medicaments described herein is glioblastoma multiforme (GBM).
  • the cancer treated by the methods, uses, or medicaments described herein is bladder cancer.
  • the cancer treated by the methods, uses, or medicaments described herein is esophageal cancer.
  • the cancer treated by the methods, uses, or medicaments described herein is breast cancer.
  • the cancer treated by the methods, uses, or medicaments described herein is NSLCC.
  • the cancer treated by the methods, uses, or medicaments described herein is MCL.
  • the cancer treated by the methods, uses, or medicaments described herein is DLBCL.
  • 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-smal cel lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non- Hodgkin lymphoma or mesothelioma.
  • the cancer is non-smal cel 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 cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC); e.g., lung s
  • NSCLC non-smal cel lung
  • 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. [0220] The disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 by said compounds. The disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 by said compounds.
  • the disclosure further relates to the use of compounds disclosed herein for the treatment and/or prophylaxis of diseases and/or conditions through inhibiting PRMT5 in MTAP- nul cels by said compounds. Further, the present disclosure relates to the use of said compounds for the preparation of a medicament for the treatment and/or prophylaxis of a chromosome 9p21 deletion or MTAP-nul associated disease and/or condition through inhibiting PRMT5 in MTAP-nul cels by said compounds. In some embodiments the chromosome 9p21 deletion or MTAP-nul associated disease or condition is aleviated by inhibition of PRMT5 in MTAP-nul cels.
  • a method of treating and/or preventing a MTAP-nul or chromosome 9p21 deletion associated disease or condition in a patient in need thereof comprising administering to the patient a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.
  • the chromosome 9p21 deletion or MTAP-nul associated disease or condition includes a solid tumor in or arising from a tissue or organ, such as: • bone (e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dediferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cel tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma); • lips and oral cavity (e.g., odontogenic
  • the chromosome 9p21 deletion or MTAP-nul associated disease or condition is a cancer selected from lung cancer, urothelial cancer, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cel neoplasms, head and neck cancer, bile duct cancer, esophagus cancer, glioblastoma, stomach cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, liver cancer, renal cancer, colorectal cancer, prostate cancer, leukemia, and cervical cancer.
  • lung cancer urothelial cancer, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cel neoplasms, head and neck cancer, bile duct cancer, esophagus cancer, glioblastoma, stomach cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, liver cancer, renal cancer, colorectal cancer, prostate cancer
  • the chromosome 9p21 deletion or MTAP-nul associated disease or condition is a cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic, and bladder cancer.
  • 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 refered 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, Phylodes tumor, Angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medulary carcinoma, mucinous carcinoma, papilary 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, and HER and estrogen and progesterone receptor
  • 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-smal cel 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 cel disorder, for example a cancer that is PRMT5 responsive.
  • a cancer that lacks p53 e.g., a p53 nul cancer
  • 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 nul 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. In some embodiments, the method comprises obtaining a sample from the subject; detecting the presence or absence of p53; and, identifying the subject as having a cancer that is sensitive to treatment with a PRMT5 inhibitor if p53 is present in the sample.
  • 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 nul cancer).
  • a p53 negative cancer e.g., a p53 nul cancer
  • PRMT5 inhibitor may be required to treat the p53 negative cancer than a p53 positive cancer.
  • a subject having a p53 negative cancer is treated with a therapeutic agent that is not a PRMT5 inhibitor.
  • a therapeutic agent that is not a PRMT5 inhibitor.
  • sample any biological sample derived from the subject, includes but is not limited to, cels, tissues samples, body fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), cancer cels, and cancer tissues.
  • Detection of the presence or absence of p53 in the sample may be achieved by any suitable method for detecting p53 nucleic acid or protein, for example, nucleic acid sequencing (e.g., DNA or RNA sequencing), quantitative PCR, Western bloting, etc., or any combination of thereof.
  • nucleic acid sequencing e.g., DNA or RNA sequencing
  • quantitative PCR e.g., quantitative PCR
  • Western bloting e.g., Western bloting, 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; meduloblastoma
  • bronchus cancer carcinoid tumor, cervical cancer (e.g. , cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelio sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g.
  • adenocarcinoma of the esophagus Baret' s adenocarinoma
  • Ewing sarcoma eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gal bladder cancer, gastric cancer (e.g.
  • stomach adenocarcinoma gastrointestinal stromal tumor
  • GIST gastrointestinal stromal tumor
  • head and neck cancer e.g., head and neck squamous cel carcinoma
  • oral cancer e.g., oral squamous cel carcinoma (OSCC)
  • throat cancer e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer
  • hematopoietic cancers e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cel ALL, T-cel ALL), acute myelocytic leukemia (AML) (e.g. , fl- cel!
  • ALL acute lymphocytic leukemia
  • AML acute myelocytic leukemia
  • mucosa-associated lymphoid tissue (MALT) lymphomas mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cel lymphoma, splenic marginal zone B-cel lymphoma), primary mediastinal B-cel lymphoma, Burkit lymphoma, lymphoplasmacytic lymphoma (e.g., "Waldenstrom's macro globulinemia"), hairy cel leukemia (HCL), immunoblastic large cel ly mphoma, precursor B -1ymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cel NHL such as precursor T- 1ymphoblastic lymphoma/leukemia, peripheral T-cel lymphoma (PTCL) (e.g., cutaneous T- cel lymphoma (CTCL) (e.g.
  • TCL peripheral T-cel lymphoma
  • mycosis fungiodes Sezary syndrome
  • angioimmunoblastic T- cel lymphoma extranodal natural kiler T-cel lymphoma, enteropathy type T-cel lymphoma, subcutaneous panniculitis-1ike T-cel lymphoma, anaplastic large cel lymphoma
  • 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, smal cel lung cancer (SCLC), non-smal cel 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
  • CNL 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
  • papilary adenocarcinoma penile cancer (e.g., Paget' s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g. , squamous cel carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cel carcinoma (BCC), smal bowel cancer (e.g.
  • SCC squamous cel carcinoma
  • KA keratoacanthoma
  • BCC basal cel carcinoma
  • smal 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., papilary carcinoma of the thyroid, papilary thyroid carcinoma (PTC), medulary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).
  • 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.
  • COMBINATION THERAPY [0236]
  • the present disclosure contemplates the use of compounds of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation).
  • active therapeutic agents e.g., chemotherapeutic agents
  • other prophylactic or therapeutic modalities e.g., radiation
  • the various active agents frequently have diferent, complementary mechanisms of action.
  • Such combination therapy may be especialy advantageous by alowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents.
  • 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 pharmaceuticaly acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered or applied sequentialy, e.g., where one agent is administered prior to one or more other agents.
  • compounds of Formula (I) or pharmaceuticaly acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentialy or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.
  • the present disclosure also contemplates the use of the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with at least one additional therapeutic agent as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.
  • the present disclosure also provides a method of treating a disease or disorder in which PRMT5 activity is implicated in a patient, said method comprising administering to said patient (a) a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent.
  • 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 nul cancer in a patient comprising administering to the patient a therapeuticaly effete amount of (a) a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent.
  • 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 therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent.
  • the patient is in recognized need of such treatment.
  • the present disclosure also provides a method of treating a cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, an absence of the MTAP gene, an absence of MTAP protein, a reduced level of MTAP protein, a reduced function of MTAP protein, or a combination thereof comprising administering to the patient (a) a therapeuticaly effete amount of a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent.
  • the patient is in recognized need of such treatment.
  • the present disclosure provides methods for treating a cancer with (a) a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic or diagnostic agent.
  • Additional Therapeutic Agents [0245] The disclosure provides one or more additional therapeutic agents for use with a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof and one or more pharmaceuticaly acceptable excipients. A wide variety of therapeutic agents with anti-cancer activity and methods of making the same are known in the art. Each of these is embraced by this disclosure. In some embodiments, the one or more additional active therapeutic agents are one, two, three, or four additional therapeutic agents.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • Chemotherapeutic agents include alkylating agent, microtubule inhibitors, antimetabolites, anti-tumor antibiotics, as wel 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. In some embodiments, the alkylating agent is carboplatin. In some embodiments, the alkylating agent is cisplatin. In some embodiments, the alkylating agent is saraplatin. [0249] In some embodiments, 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, podophylotoxin, 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. In an embodiment, the antimetabolite is cytarabine. In an embodiment, the antimetabolite is gemcitabine. In an embodiment, the antimetabolite is floxuridine.
  • the chemotherapeutic agent is an antitumor antibiotics. In some embodiments, the antitumor antibiotic is bleomycin, dactinomycin, or mitomycin. In some embodiments, the antitumor antibiotic is daunorubicin, doxorubicin, doxil, epirubicin, idarubicin, mitoxantrone, valrubicin.
  • 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, chlornaphazine, cholophosphamide, estramustine, ifosf
  • 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 anti- estrogens, including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and pharmaceuticaly acceptable salts, acids or derivatives of any of the above.
  • combination therapy comprises administration of a hormone or related hormonal agent.
  • the additional therapeutic agent is a cel cycle checkpoint inhibitor.
  • the cel cycle checkpoint inhibitor is KU60019, AZD0156, Ceralasertib, Camonsertib, VE821, AZD7762, SRA737, Rabusertib, Prexasertib, SCH900776, or Adavosertib.
  • the cel cycle checkpoint inhibitor is KU60019.
  • the cel cycle checkpoint inhibitor is AZD0156.
  • the cel cycle checkpoint inhibitor is ceralasertib.
  • the cel cycle checkpoint inhibitor is camonsertib.
  • the cel cycle checkpoint inhibitor is VE821. In some embodiments, the cel cycle checkpoint inhibitor is AZD7762. In some embodiments, the cel cycle checkpoint inhibitor is SRA737. In some embodiments, the cel cycle checkpoint inhibitor is rabusertib. In some embodiments, the cel cycle checkpoint inhibitor is prexasertib. In some embodiments, the cel cycle checkpoint inhibitor is SCH900776. In some embodiments, the cel cycle checkpoint inhibitor is adavosertib. ii) Immune Checkpoint Inhibitors [0255] In an embodiment, 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, retifanlimab, or atezolizumab.
  • the PD-1 inhibitor is nivolumab.
  • the PD-1 inhibitor is pembrolizumab.
  • the PD-1 inhibitor is cemiplimab. In an embodiment, the PD-1 inhibitor is dostarlimab. In an embodiment, the PD-1 inhibitor is zimberelimab. In an embodiment, the PD-1 inhibitor is retifanlimab. In an embodiment, the PD-1 inhibitor is atezolizumab. [0257] In an embodiment PD-1/PD-L1 inhibitor is a PD-L1 inhibitor. In an embodiment, the PD-L1 inhibitor is avelumab, atezolizumab, or durvalumab. In an embodiment, the PD- L1 inhibitor is avelumab. In an embodiment, the PD-L1 inhibitor is atezolizumab.
  • the PD-L1 inhibitor is durvalumab.
  • the immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is relatlimab. [0259] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In some embodiments, the ipilimumab or tremelimumab [0260] In some embodiments, the immune checkpoint inhibitor is a BTLA inhibitor. [0261] In some embodiments, 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). In some embodiments, the TIM-3 inhibitor is MBG453 (NCT02608268). In some embodiments, the TIM-3 inhibitor is LY3321367 (NCT03099109).
  • the immune checkpoint inhibitor is a TIGIT inhibitor. In some embodiments, the TIGIT inhibitor is tiragolumab, domvanalimab, vibostolimab, etigilimab, M6223, or ociperlimab. In some embodiments, the TIGIT inhibitor is tiragolumab. In some embodiments, the TIGIT inhibitor is domvanalimab.
  • the TIGIT inhibitor is vibostolimab. In some embodiments, the TIGIT inhibitor is etigilimab. In some embodiments, the TIGIT inhibitor is M6223. In some embodiments, the TIGIT inhibitor is ociperlimab. iv) BCL-2 Inhibitors [0263] In some embodiments, the additional therapeutic agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoclax, navitoclax, oblimersen, obatoclax mesylate, AT-101, subatoclax, maritoclax, gossypol, apogossypol, TW-37, UMI-77, or BDA- 366.
  • the additional therapeutic agent is an anti-CD20 therapeutic agent.
  • the anti-CD20 therapeutic agent is rituximab, arzera, 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.
  • the additional therapeutic agent is a PARP inhibitor.
  • the PARP inhibitor is niraparib, rucaparib, olaparib, talazoparib, or veliparib.
  • MAT2A Inhibitors [0267]
  • the additional therapeutic agent is a MAT2A inhibitor.
  • the MAT2A inhibitor is AG- or some embodiments, the MAT2A inhibitor is a compound disclosed contents of which is incorporated herein by reference for al purposes.
  • the MAT2A inhibitor is a compound disclosed in WO2018/045071, the contents of which is incorporated herein by reference for al 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 al purposes.
  • the MAT2A inhibitor is a compound disclosed in WO2021/1259815, WO2023/066283, WO2024/217502, WO2020/139991, WO2020/139992, WO2018/045071, WO2018/039972, WO2019191470, WO2024/002024, or WO2024/217493, the contents of which are incorporated herein by reference for al purposes.
  • the MAT2A inhibitor is ISM3412 or S095035. In some embodiments, the MAT2A inhibitor is , pharmaceuticaly acceptable salt thereof. MAT2A inhibitor is a compound disclosed in WO2022/268180, the contents of which are incorporated herein by reference for al purposes. [0269] In some embodiments, the MAT2A inhibitor is pharmaceuticaly acceptable salt thereof. ix) Radiotherapy [0270] In some embodiments, the additional therapeutic agent is radiation therapy. x) VEGF Inhibitors [0271] In some embodiments, 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.
  • 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, pazopanib, mubritinib, fostamatinib, calquence, pertu
  • the additional therapeutic agent is an mTOR inhibitor.
  • the mTOR inhibitor is rapamycin, everolimus, sirolimus, temsirolimus, everolimus, or sirolimus.
  • AKT Inhibitors [0274]
  • the additional therapeutic agent is an ATK inhibitor.
  • the ATK inhibitor is ipatasertib, mk-2206, perifosine, capivasertib, triciribine, or GSK690693.
  • xiv)CDK Inhibitors [0275] In some embodiments, 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.
  • the additional therapeutic agent is a PI3K inhibitor.
  • the PI3K inhibitor is idelalisib, alpelisib, leniolisib, duvelisib, or copanlisib.
  • xvi)JAK Inhibitors [0277]
  • the additional therapeutic agent is a JAK inhibitor.
  • the JAK inhibitor is tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, filgotinib, or abrocitinib.
  • the additional therapeutic agent is a inhibitor of cereblon.
  • the inhibitor of cereblon is thalidomide, lenalidomide.
  • MAPK/ERK Inhibitors [0279] In some embodiments, 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, tipifarnib, lonafarnib, trametinib, ulixertinib, WX-554, or cobimetinib.
  • the additional therapeutic agent is a Wnt/ ⁇ -catenin inhibitor.
  • the Wnt/ ⁇ -catenin inhibitor is capmatinib, resibufogenin, or isoquercitrin.
  • Proteosome Inhibitors [0281] In some embodiments, the additional therapeutic agent is a proteosome inhibitor. In some embodiments, the proteosome inhibitor bortezomib, carfilzomib, or ixazomib.
  • 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.
  • RANKL Inhibitors [0284]
  • the additional therapeutic agent is a RANKL inhibitor.
  • the RANKL inhibitor is Denosumab or AS2676293.
  • B4GALNT1 Inhibitors [0285] In some embodiments, the additional therapeutic agent is a B4GALNT1 inhibitor.
  • the B4GALNT1 inhibitor is Dinutuximab.
  • SLAMF7 Inhibitors [0286]
  • the additional therapeutic agent is a SLAMF7 inhibitor.
  • the SLAMF7 inhibitor is elotuzumab.
  • IDH2/IDH1 Inhibitors [0287]
  • 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.
  • the additional therapeutic agent is a BTK inhibitor.
  • the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib.
  • FLT3 Inhibitors [0289] In some embodiments, the additional therapeutic agent is a FLT3 inhibitor. In some embodiments, the FLT3 inhibitor is sunitinib, midostaurin, lestaurtinib, KW-2449, crenolanib, or gilteritinib.
  • PDGFR ⁇ Inhibitors [0290] In some embodiments, the additional therapeutic agent is a PDGFR ⁇ inhibitor.
  • the PDGFR ⁇ inhibitor is olaratumab, avapritinib, ayvakit, imatinib, ripretinib, or regorafenib.
  • xxx) Smoothened (Smo) Inhibitors [0291]
  • the additional therapeutic agent is a smoothened inhibitor.
  • the smoothened inhibitor is sonidegib, itraconazole, or glasdegib.
  • xxxi) LHRH antagonists or LHRH agonists [0292]
  • the additional therapeutic agent is a LHRH antagonist or LHRH agonist.
  • the LHRH antagonist or LHRH agonist is goserelin, leuprorelin or buserelin.
  • Cel Based Therapy the additional therapeutic agent is a cel based therapy.
  • the cel based therapy is tumor-infiltrating lymphocyte (TIL) therapy; engineered t cel receptor (TCR) therapy; chimeric antigen receptor (CAR) T cel therapy; Natural Kiler (NK) cel therapy; or sipuleucel-T.
  • TIL tumor-infiltrating lymphocyte
  • TCR engineered t cel receptor
  • CAR chimeric antigen receptor
  • NK Natural Kiler
  • sipuleucel-T xxxii) OX40 Inhibitors
  • the additional therapeutic agent is a OX40 inhibitor.
  • the OX40 inhibitor is ivuxolimab, cudarolimab, utomilumab, or INBRX- 106.
  • 41BB (CD137) Inhibitors [0295]
  • the additional therapeutic agent is a 41BB (CD137) inhibitor.
  • the 41BB (CD137) inhibitor is urelumab.
  • xxxv) VISTA Inhibitors [0296]
  • the additional therapeutic agent is a VISTA inhibitor.
  • the VISTA inhibitor is hmbd-002.
  • CD96 Inhibitors [0297]
  • the additional therapeutic agent is a CD96 inhibitor.
  • the CD96 inhibitor is GSK6097608.
  • TGF ⁇ Inhibitors [0298] In some embodiments, the additional therapeutic agent is a TGF ⁇ inhibitor. In some embodiments, the TGF ⁇ inhibitor is SAR-439459.
  • xxxvii) CD19 Inhibitors [0299] In some embodiments, the additional therapeutic agent is a CD19 inhibitor. In some embodiments, the CD19 inhibitor is tafasitamab, loncastuximab tesirine, or blinatumomab.
  • CD30 Inhibitors [0300] In some embodiments, the additional therapeutic agent is a CD30 inhibitor.
  • the CD30 inhibitor is brentuximab, vedotin, SGN-30, or MDX-060.
  • CD38 Inhibitors [0301] 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 [0302] In some embodiments, the additional therapeutic agent is a CD39 inhibitor. In some embodiments, the CD39 inhibitor is pur001, ES002023, TTX-030, IPH5201, or SRF617.
  • the additional therapeutic agent is a CD52 inhibitor.
  • the CD52 inhibitor is alemtuzumab.
  • xlii) CD73 Inhibitors In some embodiments, 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.
  • the additional therapeutic agent is an A2AR inhibitor.
  • the A2AR inhibitor is istradefyline, vipadenant, CVT-6883, enprofyline, ciforadenant, imaradenant, etrumadenant, NIR178, EOS100850, CS3005, PBF- 999, or INCB106385.
  • the additional therapeutic agent is an A2BR inhibitor.
  • the A2BR inhibitor is pbf-1129, QAF805, LAS101057 AB928, ISAM140, or TT-4.
  • 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 In some embodiments, the additional therapeutic agent is an arginase inhibitor.
  • the arginase inhibitor is numidargistat, pegzilarginase, or INCB001158.
  • B7-H3 Inhibitors [0309]
  • 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.
  • STI Signal Transduction Inhibitor
  • the term “signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway.
  • Examples of signal transduction inhibitors (STIs) useful in methods described herein include, but are not limited to: (i) bcr/abl kinase inhibitors (e.g., GLEEVEC); (i) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (ii) her-2/neu receptor inhibitors (e.g., HERCEPTIN); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cel cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositol kinase inhibitors.
  • GLEEVEC epidermal growth factor
  • EGF epidermal growth factor
  • HERCEPTIN her-2/neu receptor
  • the additional therapeutic agent is a Spicing inhibitor sulfonamide (SPLAM).
  • SPLAM is indisulam or E7820.
  • Additional Therapeutic Agents is a monoclonal antibody against a tumor antigen, a complex of a monoclonal antibody and toxin, a T-cel adjuvant, bone marow transplant, or antigen presenting cels (e.g., dendritic cel therapy).
  • 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, Abemaciclib, CPI (Avelumab, Cemiplimab-rwlc, and Bevacizumab).
  • a compound of Formula (I) or a pharmaceuticaly acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof.
  • the dosing regimen may also take into consideration the existence, nature, and extent of any adverse effectss associated with the agent(s) being administered.
  • An effete 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 al relevant factors.
  • the effete amount is more than the calculated ED50, in other situations the effete amount is less than the calculated ED50, and in stil other situations the effete amount is the same as the calculated ED50.
  • a compound of Formula (I) or a pharmaceuticaly 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 systemicaly/peripheraly or topicaly (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 insuflation therapy using e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal,
  • a compound of Formula (I): (I) or a pharmaceuticaly X1 is C(R1) or N; X2 is C(R2) or N; X3 is C(R3) or N; R1, R2, and R3 are each independently H, C1-4 alkyl, halo, or C1-4 haloalkyl; n is 0, 1, 2, 3, or 4; each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl; alternatively, two R4 groups when atached to the same carbon atom combine to form oxo or C3-6 cycloalkyl; R7 is (i) –CH2Ar; Ar is phenyl or heteroaryl having 5
  • Embodiment 2 The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, or a pharmaceuticaly acceptable salt thereof, wherein X1 is N.
  • Embodiment 3. The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, or a pharmaceuticaly acceptable salt thereof, wherein X1 is C(R1) and R1 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • Embodiment 4 The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, or a pharmaceuticaly acceptable salt thereof, wherein X1 is C(R1) and R1 is H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 5 The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, or a pharmaceuticaly acceptable salt thereof, wherein X1 is C(R1) and R1 is H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 6. The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, or a pharmaceuticaly acceptable salt thereof, wherein X1 is CH.
  • Embodiment 7. The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 6, or a pharmaceuticaly acceptable salt thereof, wherein X2 is N.
  • Embodiment 9 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 6, or a pharmaceuticaly acceptable salt thereof, wherein X2 is C(R2) and R2 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • Embodiment 9 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 6, or a pharmaceuticaly acceptable salt thereof, wherein X2 is C(R2) and R2 is H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 11 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 6, or a pharmaceuticaly acceptable salt thereof, wherein X2 is C(R2) and R2 is H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 11 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 6, or a pharmaceuticaly acceptable salt thereof, wherein X2 is CH or CF.
  • Embodiment 12 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 6, or a pharmaceuticaly acceptable salt thereof, wherein X2 is CH.
  • Embodiment 13 Embodiment 13.
  • Embodiment 14 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein X3 is N.
  • Embodiment 15 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein X3 is C(R3) and R3 is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • Embodiment 16 Embodiment 16.
  • Embodiment 17 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein X3 is C(R3) and R3 is H, methyl, ethyl, fluoro, chloro, or bromo.
  • Embodiment 17 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein X3 is C(R3) and R3 is H, methyl, fluoro, chloro, or trifluoromethyl.
  • Embodiment 18 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein X3 is CH or CF.
  • Embodiment 19 Embodiment 19.
  • Embodiment 20 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein X3 is CH.
  • Embodiment 20 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein X3 is CF.
  • Embodiment 21 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 20, or a pharmaceuticaly acceptable salt thereof, wherein each R4 is independently C1-6 alkyl, halo, C1-6 haloalkyl, C1-6 hydroxyalkyl, or C3-6 cycloalkyl.
  • Embodiment 22 Embodiment 22.
  • Embodiment 23 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 22, or a pharmaceuticaly acceptable salt thereof, wherein n is 0, 1, or 2.
  • Embodiment 24 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 22, or a pharmaceuticaly acceptable salt thereof, wherein n is 0 or 1.
  • Embodiment 25 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 20, or a pharmaceuticaly acceptable salt thereof, wherein n is 0 or 1.
  • Embodiment 26 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 22, or a pharmaceuticaly acceptable salt thereof, wherein n is 0.
  • Embodiment 26 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 22, or a pharmaceuticaly acceptable salt thereof, wherein n is 2 and each R4 is independently F.
  • Embodiment 27 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26, or a pharmaceuticaly acceptable salt thereof, wherein R7 is (i) –CH2Ar.
  • Embodiment 28 Embodiment 28.
  • Embodiment 29 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 27, or a pharmaceuticaly acceptable salt thereof, wherein Ar is phenyl substituted with 0, 1, or 2 R7a.
  • Embodiment 29 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 27, or a pharmaceuticaly acceptable salt thereof, wherein Ar is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S substituted with 0, 1, or 2 R7a.
  • Embodiment 30 Embodiment 30.
  • Embodiment 31 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 27, or a pharmaceuticaly acceptable salt thereof, wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl substituted with 0, 1, or 2 R7a.
  • Embodiment 31 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 27, or a pharmaceuticaly acceptable salt thereof, wherein Ar is pyrolyl or pyrazolyl substituted with 0, 1, or 2 R7a.
  • Embodiment 32 Embodiment 32.
  • Embodiment 39 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, 37, and 38, or a pharmaceuticaly acceptable salt thereof, wherein each R7a2 is H.
  • Embodiment 40 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, 37, and 38, or a pharmaceuticaly acceptable salt thereof, wherein R7a2 is C1-4 alkyl.
  • Embodiment 41 Embodiment 41.
  • Embodiment 42 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33 and 37 to 40, or a pharmaceuticaly acceptable salt thereof, wherein each R7a3 is H.
  • Embodiment 42 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33 and 37 to 40, or a pharmaceuticaly acceptable salt thereof, wherein R7a3 is C1-4 alkyl.
  • Embodiment 43 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26, or a pharmaceuticaly acceptable salt thereof, wherein R7 is (i) a moiety selected from (R7f) (7f m R )m . of embodiment 43, or a pharmaceuticaly acceptable salt thereof, wherein R7 is (R7f)m .
  • Embodiment 45 The compound or a pharmaceuticaly acceptable salt thereof of embodiment 43, or a pharmaceuticaly acceptable salt thereof, wherein R7 is 7).
  • Embodiment 46 T ceuticaly acceptable salt thereof of embodiment 43, or a pharmaceuticaly acceptable salt thereof, wherein R7 is (R7f)m R7e .
  • Embodiment 47 acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 46, or a pharmaceuticaly acceptable salt thereof, wherein X4 is O.
  • Embodiment 48 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 46, or a pharmaceuticaly acceptable salt thereof, wherein X4 is C(R7bR7c).
  • Embodiment 49 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 48, or a pharmaceuticaly acceptable salt thereof, wherein R7b and R7c are each independently H, C1-4 alkyl, or halo.
  • Embodiment 50 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 48, or a pharmaceuticaly acceptable salt thereof, wherein R7b and R7c are each H.
  • Embodiment 51 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 50, or a pharmaceuticaly acceptable salt thereof, wherein X5 is N.
  • Embodiment 52 Embodiment 52.
  • Embodiment 53 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 52, or a pharmaceuticaly acceptable salt thereof, wherein X5 is C(R7d).
  • Embodiment 53 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 52, or a pharmaceuticaly acceptable salt thereof, wherein R7d is H , C1-4 alkyl, or halo.
  • Embodiment 54 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 52, or a pharmaceuticaly acceptable salt thereof, wherein R7d is H.
  • Embodiment 55 Embodiment 55.
  • Embodiment 60 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 54, or a pharmaceuticaly acceptable salt thereof, wherein R7e is C3-6 cycloalkyl.
  • Embodiment 59 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 54, or a pharmaceuticaly acceptable salt thereof, wherein R7e is heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heteroaryl is substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo.
  • Embodiment 61 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 60, or a pharmaceuticaly acceptable salt thereof, wherein R7f is C1-4 alkyl, halo, or C1-4 haloalkyl.
  • Embodiment 62 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 54, or a pharmaceuticaly acceptable salt thereof, wherein R7e is pyrolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl substituted with 0, 1, or 2 C1-4 alkyl, C1-4 haloalkyl, or halo.
  • Embodiment 62 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 60, or a pharmaceuticaly acceptable salt thereof, wherein R7f is C1-4 alkyl, halo, or C1-4 haloalkyl.
  • Embodiment 64 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 26 and 43 to 60, or a pharmaceuticaly acceptable salt thereof, wherein R7f is C1-4 methyl, chloro, or fluoro.
  • Embodiment 63 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 62, or a pharmaceuticaly acceptable salt thereof, wherein R8 is C1-6 alkyl, or C3-6 cycloalkyl, wherein C1-6 alkyl and C1-6 cycloalkyl are optionaly substituted with one or more groups, each group is independently –CN or C3-6 cycloalkyl.
  • Embodiment 65 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 62, or a pharmaceuticaly acceptable salt thereof, wherein R8 is –CHR8aR8b.
  • Embodiment 66 Embodiment 66.
  • R8a is H or C1-6 alkyl and R8b is C3-10 cycloalkyl, C3-10 cycloalkenyl, heterocycloalkyl having 4 to 10 ring members and 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, phenyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, and wherein C3-10 cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are each independently substituted with 0, 1, or 2 R8a1.
  • Embodiment 68 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 65, or a pharmaceuticaly acceptable salt thereof, wherein R8a and R8b are each independently H, C1-6 alkyl, or heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, provided that R8a and R8b are not both H, and wherein heteroaryl are each independently substituted with 0, 1, or 2 R8a1.
  • Embodiment 69 Embodiment 69.
  • Embodiment 72 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 71, or a pharmaceuticaly acceptable salt thereof, wherein each R8d and R8e is independently H or methyl.
  • Embodiment 73 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 70, or a pharmaceuticaly acceptable salt thereof, wherein each R8a1 is independently halo, C alk 8d 8e 1-6 yl, or –C(O)NR R, –OH.
  • Embodiment 72 The compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 71, or a pharmaceuticaly acceptable salt thereof, wherein each R8d and R8e is independently H or methyl.
  • Embodiment 73 Embodiment 73.
  • each R8a1 is independently C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, and heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S.
  • each R8a1 is independently C4-6 cycloalkyl, C4-6 cycloalkenyl, heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is N, and heteroaryl having 5 to 6 ring members and 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S.
  • Embodiment 75 The compound or a pharmaceuticaly acceptable salt thereof of embodiment 74, or a pharmaceuticaly acceptable salt thereof, wherein each R8a2 is independently C1-6 alkyl, C1-6 alkynyl, or halo.
  • Embodiment 76 The compound or a pharmaceuticaly acceptable salt thereof of embodiment 1, wherein the compound is selected from Table 1.
  • Embodiment 77 A pharmaceutical composition comprising a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, and a pharmaceuticaly acceptable excipient.
  • Embodiment 78 A pharmaceutical composition comprising a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, and a pharmaceuticaly acceptable excipient.
  • a method for treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient comprising administering to the patient a therapeuticaly effete amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77.
  • PRMT5 protein arginine N-methyltransferase 5
  • Embodiment 80 A method of treating an MTAP nul cancer in a patient comprising administering to the patient a therapeuticaly effete amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77.
  • Embodiment 81 Embodiment 81.
  • a method for treating a cancer in a patient comprising administering to the subject a therapeuticaly effete amount of a compound or pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77.
  • Embodiment 82 A method of treating cancer in a patient comprising administering to the patient a therapeuticaly effete amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77.
  • Embodiment 83 Embodiment 83.
  • Embodiment 84 The method of embodiment 79 or 83, wherein the cancer is deficient in CDKN2A.
  • Embodiment 85 The method of any one of embodiments 79 to 84, wherein the cancer is a solid tumor.
  • Embodiment 86 The method of embodiment 85, wherein the solid tumor is malignant.
  • Embodiment 87 The method of any one of embodiments 79 to 86, wherein the patient is in recognized need of such treatment.
  • Embodiment 88 Embodiment 88.
  • the cancer is selected from the group consisting of biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undiferentiated pleiomorphic sarcoma, lymphoma (e.g., difuse large B-cel lymph
  • Embodiment 89 The method of any one of embodiments 79 to 87, wherein the cancer is selected from the group consisting of leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-smal cel lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma.
  • Embodiment 90 Embodiment 90.
  • Embodiment 91 A compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77, for use in therapy.
  • Embodiment 92 A compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77, for use in the treatment cancer.
  • Embodiment 93 A compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77, for use in the treatment cancer.
  • Embodiment 94 The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of embodiment 92 or 93, wherein said cancer is deficient in CDKN2A.
  • Embodiment 95 The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 92 to 94, wherein said cancer is an MTAP nul cancer.
  • Embodiment 96 The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 92 to 94, wherein said cancer is an MTAP nul cancer.
  • Embodiment 97 The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 92 to 96, wherein said cancer is a solid tumor.
  • Embodiment 98 The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of embodiment 97, wherein the solid tumor is malignant.
  • Embodiment 99 Embodiment 99.
  • any one of embodiments 92 to 98 wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undiferentiated pleiomorphic sarcoma, lymphoma (e.g., difuse
  • NSCLC non-smal cel lung cancer
  • Embodiment 100 The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition of any one of embodiments 92 to 98, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-smal cel lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma or mesothelioma.
  • Embodiment 101 Embodiment 101.
  • Embodiment 102 Use of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77, in the manufacture of a medicament for use in therapy.
  • Embodiment 102 Use of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77, in the manufacture of a medicament for use in the treatment of cancer.
  • Embodiment 103 The use of embodiment 102, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.
  • Embodiment 104 The use of embodiment 102 or 103, wherein said cancer is deficient in CDKN2A.
  • Embodiment 105 The use of any one of embodiments 102 to 104, wherein said cancer is an MTAP nul cancer.
  • Embodiment 106 The use of any one of embodiments 102 to 104, wherein said cancer is characterized by a reduction or absence of MTAP gene expression, the absence of the MTAP gene, absence of MTAP protein, reduced level of MTAP protein, or reduced function of MTAP protein.
  • Embodiment 107 The use of any one of embodiments 102 to 106, wherein said cancer is a solid tumor.
  • Embodiment 108 The use of embodiment 107, wherein said solid tumor is malignant.
  • Embodiment 109 The use of embodiment 107, wherein said solid tumor is malignant.
  • any one of embodiments 102 to 108 wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cel carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, galbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-smal cel lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undiferentiated pleiomorphic sarcoma, lymphoma (e.g., difuse large B-cel lymphoma (DLBCL)
  • Embodiment 110 The use of any one of embodiments 102 to 108, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-smal cel lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non- Hodgkin lymphoma or mesothelioma.
  • Embodiment 111 Embodiment 111.
  • a method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient comprising administering to said patient an effete amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77.
  • PRMT5 protein arginine N-methyltransferase 5
  • Embodiment 112. A method of inhibiting cel proliferation, in vitro or in vivo, said method comprising contacting a cel with an effete amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77.
  • Embodiment 113 Embodiment 113.
  • a method for inhibiting PRMT5 activity in a cel comprising contacting the cel in which inhibition of PRMT5 activity is desired with an efective amount of a compound or pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 76, or a pharmaceutical composition of embodiment 77.
  • EXAMPLES [0435] The folowing examples are put forth so as to provide those of ordinary skil in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the experiments below were performed or that they are al of the experiments that may be performed.
  • Step 2 1:1 mixture of tert-butyl (S)-2-(2-amino-3-fluoro-5- (methoxycarbonyl)phenyl)pyrolidine-1-carboxylate and tert-butyl (R)-2-(2-amino-3-fluoro- 5-(methoxycarbonyl)phenyl)pyrolidine-1-carboxylate O
  • Pd/C 50% active on carbon
  • Step 3 1:1 mixture of methyl (S)-4-amino-3-fluoro-5-(pyrolidin-2-yl)benzoate and methyl (R)-4-amino-3-fluoro-5-(pyrolidin-2-yl)benzoate [0438] A 1:1 (methoxycarbonyl)phenyl)pyrolidine-1-carboxylate and tert-butyl (R)-2-(2-amino-3-fluoro- 5-(methoxycarbonyl)phenyl)pyrolidine-1-carboxylate (4.20 g, 12.41 mmol) and TFA (35 mL) in DCM (75 mL) was stired at room temperature for 4 h.
  • Step 4 1:1 mixture of methyl (S)-5-amino-7-fluoro-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylate and (R)-5-amino-7-fluoro-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylate
  • a benzoate and methyl (R)-4- g, and BrCN (2.40 g, 22.66 mmol) in 1,4-dioxane (60 mL) was stired at 80 °C for 7 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc.
  • Step 5 1:1 mixture of (S)-5-amino-7-fluoro-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline- 9-carboxylic acid and (R)-5-amino-7-fluoro-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9- carboxylic acid [0440] To [1,2- c]quinazoline-9-carboxylate and (R)-5-amino-7-fluoro-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylate (1.00 g, 3.79 mmol) in THF (10 mL) and H2O (5 mL) was added LiOH (272 mg, 11.39 mmol) in portions at room temperature.
  • reaction mixture was stired at 50 °C for 16 h.
  • the mixture was acidified to pH 5 with HCl (2 N).
  • the precipitated solids were colected by filtration and washed with H2O, then dried over vacuum to aford 1:1 mixture of (S)-5-amino-7-fluoro-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9-carboxylic acid and (R)-5-amino-7-fluoro-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9-carboxylic acid (500 mg, crude) as a yelow solid.
  • Step 2 tert-butyl 5-(5-(methoxycarbonyl)-2-nitrophenyl)-2,3-dihydro-1H-pyrole-1- carboxylate O N
  • a degassed mixture (2.00 g, 7.69 mmol), tert- butyl 2,3-dihydropyrole-1- , K2CO3 (3.19 g, 23.07 mmol), PPh3 (0.40 g, 1.54 mmol) and Pd(OAc)2 (0.17 g, 0.77 mmol) in DMF (20 mL) was stired at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate.
  • Step 3 1:1 mixture of tert-butyl (S)-2-(2-amino-5-(methoxycarbonyl)phenyl)pyrolidine-1- carboxylate and tert-butyl (R)-2-(2-amino-5-(methoxycarbonyl)phenyl)pyrolidine-1- carboxylate [0443] To a -2,5- dihydropyrole-1-carboxylate (780 mg, 2.24 mmol) in EtOH (10 mL) was added PtO2 (102 mg, 0.45 mmol) at 20 oC under nitrogen atmosphere. The reaction mixture was degassed via vacuum evacuation, then backfiled with hydrogen, and this process was repeated three times.
  • Step 4 1:1 mixture of methyl (S)-4-amino-3-(pyrrolidin-2-yl)benzoate and methyl (R)-4- amino-3-(pyrolidin-2-yl)benzoate [0444] To a 1 (methoxycarbonyl)phenyl)pyrolidine-1-carboxylate and tert-butyl (R)-2-(2-amino-5- (methoxycarbonyl)phenyl)pyrolidine-1-carboxylate (690 mg, 2.15 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at 25 °C for 2 h.
  • Step 5 1:1 mixture of methyl (S)-5-amino-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9- carboxylate and methyl (R)-5-amino-1,2,3,10b-tetrahydropyrrolo[1,2-c]quinazoline-9- carboxylate [0445] A and methyl (R)-4- amino-3-(pyrolidin-2-yl)benzoate (1 g, 4.54 mmol) and BrCN (481 mg, 4.54 mmol) in dioxane (10 mL) was stired at 80 °C for 2 h. The solvents were removed under vacuum and purified directly.
  • Step 6 1:1 mixture of (S)-5-amino-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9- carboxylic acid and (R)-5-amino-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9-carboxylic acid [0446] A 1:1 lo[1,2- c]quinazoline-9-carboxylate and methyl (R)-5-amino-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylate (235 mg, 0.96 mmol) in THF (2 mL) and H2O (2 mL) was added LiOH (69 mg, 2.87 mmol) at 25 °C.
  • Step 2 1:1 mixture of tert-butyl (S)-2-(2-(tert-butoxycarbonyl)-l2-azaneyl)-5- (methoxycarbonyl)phenyl)-4,4-difluoropyrrolidine-1-carboxylate and tert-butyl (R)-2-(2- (tert-butoxycarbonyl)-l2-azaneyl)-5-(methoxycarbonyl)phenyl)-4,4-difluoropyrolidine-1- carboxylate [0448] To a -3-iodobenzoate (11.00 g, 29.16 mmol), 1-(tert-butoxycarbonyl)-4,4-difluoropyrolidine-2-carboxylic acid (10.99 g, 43.75 mmol), IR[DF(CF3)PPY]2(DTBPY)PF6 (327 mg, 0.29 mmol), NICKEL(I) CHLORIDE ETHYLENE GLYCOL DIMETHYL ETHER
  • Step 4 1:1 mixture of methyl (S)-5-amino-2,2-difluoro-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylate and methyl (R)-5-amino-2,2-difluoro-1,2,3,10b- tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylate [0450]
  • a [1,2- c]quinazoline-9-carboxylate and methyl (R)-5-amino-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylate 650 mg, 2.54 mmol
  • BrCN 269 mg, 3.51 mmol
  • Step 5 1:1 mixture of (S)-5-amino-2,2-difluoro-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylic acid and (R)-5-amino-2,2-difluoro-1,2,3,10b- tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylic acid [0451] A tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylate and methyl (R)-5-amino-2,2-difluoro- 1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9-carboxylate (300 mg, 1.07 mmol) in THF (3 mL) and water (3 mL) was added LiOH (102 mg, 4.27 mmol) at room temperature.
  • Step-2 [0453] To 2-sulfinamide (16.50 g, 53.89 mmol) and alyl bromide (9.78 g, 80.83 mmol) in THF (170 mL) was added In powder (9.28 g, 80.83 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stired at 60 oC for 16 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure.
  • Step-3 [0454] To a stired mixture of (R)-N-(S)-1-(2-bromo-4-fluorophenyl)but-3-en-1-yl)-2- methylpropane-2-sulfinamide (10.00 g, 28.71 mmol) in DCM (100 mL) was added mCPBA (14.91 g, 86.43 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stired at room temperature for 16 h. The reaction was quenched by the addition of Na2S2O3 (aq.) at room temperature. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4.
  • Step-4 - oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide and N-(S)-1-(2-bromo-4-fluorophenyl)- 2-(S)-oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (5.00 g, 13.15 mmol) and K2CO3 (5.45 g, 39.45 mmol) in DMF (50 mL) was added KI (2.18 g, 13.15 mmol) at room temperature under nitrogen atmosphere.
  • the resulting mixture was stired at 100 °C overnight. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-5 [045 1-(tert- butylsulfonyl)pyrolidin-3-ol and (3R,5S)-5-(2-bromo-4-fluorophenyl)-1-(tert- butylsulfonyl)pyrolidin-3-ol (5.00 g, 13.15 mmol) in DCM (50 mL) was added DMP (11.15 g, 26.30 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stired at room temperature for 16 h.
  • Step-7 [0458] -4,4- mmol) in dioxane (10 mL) were added Cs2CO3 (1.46 g, 4.49 mmol), XantPhos (130 mg, 0.23 mmol) and Pd2(dba)3 (206 mg, 0.23 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stired at 100 °C overnight. The resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-8 [0459] 2-yl)-5- fluorophenyl)-1,1-diphenylmethanimine (1.25 g, 2.50 mmol) in MeOH (20 mL) was added HCl (conc.) (4 mL). The mixture was stired at room temperature for 2 h . The mixture was basified with saturated NaHCO3 (aq.) to pH 8. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-10 [0461] To 2-yl)-5-fluoro- 4-iodoaniline (550 mg, 1.19 mmol) in DCM (20 mL) was added trifluoromethanesulfonic acid (0.6 mL). The mixture was stired at room temperature for 2 h under nitrogen atmosphere. The mixture was quenched by water and basified with NaOH to pH 8. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4.
  • Step-11 A solution of (S)-2-(4,4-difluoropyrolidin-2-yl)-5-fluoro-4-iodoaniline (400 mg, 1.17 mmol) and BrCN (124 mg, 1.17 mmol) in dioxane (5 mL) was stired at 80 °C under nitrogen atmosphere for 2 h. The precipitated solids were colected by filtration and washed with 1,4-dioxane, then dried under vacuum to aford (S)-2,2,8-trifluoro-9-iodo-1,2,3,10b- tetrahydropyrrolo[1,2-c]quinazolin-5-amine (370 mg, crude) as a white solid.
  • Step-13 [0464] tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylate (100 mg, 0.33 mmol) in THF (2 mL) and H2O (1 mL) was added LiOH (16 mg, 0.67 mmol) at room temperature . The resulting mixture was stired at room temperature for 16 h. The resulting mixture was concentrated under vacuum to aford (S)-5-amino-2,2,8-trifluoro-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylic acid (CA4) (120 mg, crude) as a yelow solid.
  • CA4 aford (S)-5-amino-2,2,8-trifluoro-1,2,3,10b-tetrahydropyrolo[1,2- c]quinazoline-9-carboxylic acid
  • Step-2 [0466] To 2- sulfinamide (30.00 g, 97.98 mmol) and 3-bromoprop-1-ene (8.89 g, 73.48 mmol) in THF (230 mL) was added In powder (8.44 g, 73.48 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stired at 60 °C for 16 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-3 -2- methylpropane-2-sulfinamide (21.45 g, 61.59 mmol) in DCM (528 mL) was added m-CPBA (31.88 g, 184.77 mmol) in portions at 0 °C. The resulting mixture was stired at room temperature for 16 h. The reaction was quenched with Na2S2O3 (sat.) at room temperature. The aqueous layers were extracted with DCM and washed with NaHCO3 (sat.). The organic layers was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-4 - oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide and N-(R)-1-(2-bromo-4-fluorophenyl)- 2-(R)-oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (18.45 g, 48.52 mmol) in DMF (180 mL) were added K2CO3 (20.12 g, 145.55 mmol) and KI (8.05 g, 48.52 mmol) at room temperature under nitrogen atmosphere.
  • the resulting mixture was stired at 100 °C for 16 h.
  • the resulting mixture was diluted with water and extracted with EtOAc.
  • the combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-5 [0469] -1- (tert-butylsulfonyl)pyrolidin-3-ol and (3R,5R)-5-(2-bromo-4-fluorophenyl)-1-(tert- butylsulfonyl)pyrolidin-3-ol (9.63 g, 25.32 mmol) in DCM (500 mL) was added DMP (21.48 g, 50.65 mmol) in portions at 0 °C. The resulting mixture was stired at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure.
  • Step-6 O F F [0470] To a butylsulfonyl)pyrolidin-3-one in DCM (160 mL) was added DAST (9.84 g, 61.07 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stired at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure.
  • Step-7 [0471] To a -4,4- difluoropyrolidine (1.85 g, 4.62 mmol) and diphenylmethanimine (1.01 g, 5.55 mmol) in dioxane (25 mL) were added Cs2CO3 (3.01 g, 9.24 mmol), Pd2(dba)3 (0.42 g, 0.46 mmol) and XantPhos (0.27 g, 0.46 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stired at 100 °C for 16 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4.
  • Step-8 [0472] To a 2- yl)-5-fluorophenyl)-1,1-diphenylmethanimine (3.88 g, 7.75 mmol) in MeOH (40 mL) were added HCl (2 N, 8 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stired at room temperature for 2 h. The resulting mixture was diluted with water. The mixture was basified with saturated NaHCO3 (aq.) to PH 8. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-10 [0474] To a 2-yl)-5- fluoro-4-iodoaniline (2.29 g, 4.95 mmol) in DCM (100 mL) was added TfOH (2 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stired at room temperature for 2 h. The mixture was basified with NaOH (2N) to PH 8. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-12 [0476] To a [1,2- c]quinazolin-5-amine (700 mg, 1.91 mmol) in MeOH (15 mL) was added TEA (960 mg, 9.54 mmol) and Pd(dppf)Cl2 (140 mg, 0.19 mmol). The mixture was stired at 80 °C for 16 h under CO atmosphere (20 atm.). The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-13 [0477] To a 0b- tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylate (210 mg, 0.70 mmol) in H2O (1 mL), THF (2 mL) and MeOH (2 mL) was added LiOH (59 mg, 2.45 mmol) at room temperature. The resulting mixture was stired at room temperature for 16 h. The organic solvent was removed under reduced pressure. The remained aqueous solution was acidified by HCl (conc.).
  • Step-3 - mmol) in MeOH (90 mL) and H2O (90 mL) was added Selectfluor (91.30 g, 257.86 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stired at 80 °C for 16 h. The mixture was cooled down to room temperature. The mixture was basified with saturated NaHCO3 (aq.) to pH 7. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4.
  • Step-5 - difluoropyrolidin-2-yl)benzoaten and methyl (R)-4-bromo-3-(3,3-difluoropyrolidin-2- yl)benzoate (2.40 g, 7.49 mmol) and TEA (2.28 g, 22.49 mmol) in DCM (24 mL) was added Boc2O (2.13 g, 9.74 mmol) at room temperature. The resulting mixture was stired at room temperature for 2 h.
  • Step-6 (methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine-1-carboxylate and tert-butyl (R)-2-(2- bromo-5-(methoxycarbonyl)phenyl)-3,3-difluoropyrolidine-1-carboxylate (3.67 g, 8.73 mmol) and BocNH2 (1.23 g, 10.48 mmol) in dioxane (37 mL) were added Cs2CO3 (8.54 g, 26.19 mmol) and XPhos Pd G3 (0.74 g, 0.87 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stired at 100 °C for 2 h.
  • Step-7 - -5- (methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine-1-carboxylate and tert-butyl (R)-2-(2- (tert-butoxycarbonyl)amino)-5-(methoxycarbonyl)phenyl)-3,3-difluoropyrolidine-1- carboxylate (3.00 g, 6.57 mmol) in DCM (30 mL) was added TFA (10 mL).
  • Step-2 O O O O Boc 4- fluoro-5-(methoxycarbonyl)phenyl)-2,5-dihydro-1H-pyrole-1-carboxylate and tert-butyl (R)- 2-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)-2,5-dihydro-1H- pyrole-1-carboxylate (3.10 g, 7.10 mmol) in methanol (60 mL) was added Pd/C (10%, 0.08 g).
  • the mixture was hydrogenated at room temperature for 16 h under hydrogen atmosphere using a hydrogen baloon.
  • the reaction mixture was filtered through a Celite pad.
  • the filtrate was concentrated under reduced pressure to aford a 1:2 mixture of tert-butyl (R)-2-(2-(tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)pyrolidine-1-carboxylate and tert-butyl (S)-2-(2-(tert-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)pyrolidine-1-carboxylate (2.7 g, crude) as a yelow oil.
  • Step-3 butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)pyrolidine-1-carboxylate and tert-butyl (S)-2-(2-(tert-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)pyrolidine-1-carboxylate (2.70 g, 6.16 mmol) in DCM (15 mL) was added TFA (15 mL). The resulting mixture was stired at 25 °C for 1 h.
  • Step-4 2-yl)benzoate and methyl (S)-4-amino-2-fluoro-5-(pyrolidin-2-yl)benzoate (3.30 g, 13.85 mmol) in 1,4-dioxane (33 mL) was added BrCN (2.93 g, 27.70 mmol) in portions at room temperature. The mixture was stired at 80 °C for 4 h. The precipitated solids were colected by filtration and washed with EtOAc.
  • Step-6 [0493] tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylate isomer 1 (190 mg, 0.72 mmol) in THF (2 mL) and H2O (1 mL) was added LiOH (69 mg, 2.89 mmol) at room temperature. The resulting mixture was stired at 50 °C for 3 h. The mixture was acidified with HCl (2N) to pH 3.
  • Step-7 [0494] tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylate isomer 2 (350 mg, 1.33 mmol) in THF (4 mL) and H2O (2 mL) was added LiOH (127 mg, 5.31 mmol) at room temperature. The resulting mixture was stired at 50 °C for 3 h. The mixture was acidified with HCl (2N) to pH 3.
  • Step-2 F F F F F F F F F F F F F F F F F F F butoxycarbonyl)-4,4-difluoropyrolidin-2-yl)picolinate and methyl (R)-5-amino-4-(1-(tert- butoxycarbonyl)-4,4-difluoropyrolidin-2-yl)picolinate (500 mg, 1.40 mmol) in DCM (6 mL) was added trifluoroacetic acid (2 mL) at 25 oC. The resulting mixture was stired at 25 oC for 1 h.
  • Step-4 tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylate and methyl (R)-6-amino-9,9- difluoro-8,9,10,10a-tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylate (350 mg, 1.24 mmol) in methanol (2 mL), THF (4 mL) and H2O (2 mL) was added LiOH (89 mg, 3.72 mmol) at 25 oC.
  • Step-2 [0502] -4,4- difluoropyrolidin-2-yl)picolinate isomer 1 (2 g, 5.60 mmol) in DCM (20 mL) was added trifluoroacetic acid (10 mL) at 25 oC. The resulting mixture was stired at 25 oC for 1 h. The resulting mixture was concentrated under vacuum to aford rel-methyl (R)-5-amino-4-(4,4- difluoropyrolidin-2-yl)picolinate isomer 1 (2.5 g, crude) as a brown oil. MS ESI calculated for CH FNO [M+H+ 11 132 3 2 ], 258.10; found, 258.10.
  • Step-3 [0503] To a 2- yl)picolinate isomer 1 (2.0 g, 7.78 mmol) in 1,4-dioxane (20 mL) was added carbononitridic bromide (824 mg, 7.78 mmol) at 25 oC. The resulting mixture was stired at 80 °C for 1 h. The precipitated solids were colected by filtration and washed with DCM.
  • Step-4 [0504] To a stired solution of rel-methyl (R)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylate isomer 1 (1.40 g, 4.96 mmol) in methanol (4 mL), THF (8 mL) and H2O (4 mL) was added LiOH (356 mg, 14.88 mmol) at 25 oC. The resulting mixture was stired at 25 oC for 1 h. The mixture was acidified with HCl (aq.) to pH 5 ⁇ 6.
  • the precipitated solids were colected by filtration and washed with acetonitrile.
  • the solids were colected and dried under vacuum to aford rel-(R)-6-amino-9,9- difluoro-8,9,10,10a-tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylic acid isomer 1 (1.14 g, 85%) as a brown solid.
  • Step-3 [0507] To tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylate isomer 2 (1.2 g, 4.25 mmol) in THF (8 mL) and methanol (4 mL) was added a solution of LiOH (0.31 g, 12.75 mmol) in H2O (4 mL) at room temperature. The resulting mixture was stired at room temperature for 1 h. The mixture was acidified with HCl (aq.) to pH 5-6. The precipitated solids were colected by filtration and washed with acetonitrile.
  • Step-2 (21.50 g, 122.76 mmol) and DMAP (3.00 g, 24.55 mmol) in DCM (1.2 L) was added DIEA (47.60 g, 368.29 mmol) at room temperature. To the above mixture was added a solution of Boc2O (214.34 g, 982.10 mmol) in DCM (400 mL) dropwise at 0 °C. The resulting mixture was stired at room temperature for 1 h. The reaction was quenched with water and extracted with CH2Cl2.
  • Step-3 F F F O O F - dicarboxylate (29.50 g, 107.18 mmol) in EtOH (600 mL) was added Pd/C (15 g, 10% active on carbon) at room temperature. The mixture was placed under hydrogen atmosphere with a baloon (1 atm.). The reaction mixture degassed via vacuum evacuation, then backfiled with hydrogen, and this process was repeated three times. The reaction mixture was stired at room temperature for 1 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH.
  • Step-4 dicarboxylate (27.40 g, 98.11mmol) in THF (300 mL), methanol (100 mL) and H2O (150 mL) was added LiOH (7.05 g, 294.32 mmol) at room temperature. The resulting mixture was stired at room temperature for 3 h. The resulting mixture was concentrated under vacuum. The residue was acidified with 1 M HCl (aq.) to pH ⁇ 2. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4.
  • Step-5 a - - (difluoromethyl)pyrolidine-2-carboxylic acid and (2R,5S)-1-(tert-butoxycarbonyl)-5- (difluoromethyl)pyrolidine-2-carboxylic acid (7.50 g, 28.27 mmol) and methyl 5-amino-4- bromopicolinate (4.57 g, 19.79 mmol) in DMF (150 mL) were added Ir[dF(CF3)ppy]2(dtbpy)PF6 (635 mg, 0.57 mmol), dichloronickel;1,2-dimethoxyethane (621 mg, 2.83 mmol), Dtbpy (1.14 g, 4.24 mmol) and N,N,N',N'-tetramethylguanidine (9.77 g, 84.82 mmol) at room temperature under nitrogen atmosphere.
  • Step-7 (difluoromethyl)pyrolidin-2-yl)picolinate isomer 1 and rel-methyl 5-amino-4-(2R,5S)-5- (difluoromethyl)pyrolidin-2-yl)picolinate isomer 2 and rel-methyl 5-amino-4-(2R,5R)-5- (difluoromethyl)pyrolidin-2-yl)picolinate isomer 3 and rel-methyl 5-amino-4-(2R,5R)-5- (difluoromethyl)pyrolidin-2-yl)picolinate isomer 4 (8.60 g, 31.70 mmol) in methanol (90 mL) was added carbononitridic bromide (6.72 g, 63.41 mmol) at room temperature.
  • the resulting mixture was stired at 80 °C for 3 h.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by trituration with MTBE.
  • the crude product was acidified with saturated NaHCO3 (aq.).to pH ⁇ 8 and extracted with EtOAc.
  • the combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-8 [0518] yl)- 8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[1,2-c]pyrimidine-2-carboxylate, isomer 1 (120 mg, 0.41 mmol) in THF (2 mL) and H2O (0.5 mL) was added LiOH (30 mg, 1.22 mmol) at room temperature. The resulting mixture was stired at room temperature for 16 h.
  • Step-9 [0519] - - 8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[1,2-c]pyrimidine-2-carboxylate, isomer 2 (550 mg, 1.86 mmol) in THF (6 mL) and H2O (1.5 mL) was added LiOH (134 mg, 5.57 mmol) at room temperature. The resulting mixture was stired at room temperature for 16 h.
  • Step-10 [0520] hyl)- 8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[1,2-c]pyrimidine-2-carboxylate, isomer 3 (118 mg, 0.40 mmol) in THF (2 mL) and H2O (0.5 mL) was added LiOH (29 mg, 1.20 mmol) at room temperature. The resulting mixture was stired at room temperature for 16 h.
  • Step-11 [0521] - - 8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[1,2-c]pyrimidine-2-carboxylate, isomer 4 (500 mg, 1.69 mmol) in THF (6 mL) and H2O (1.5 mL) was added LiOH (122 mg, 5.07mmol) at room temperature. The resulting mixture was stired at room temperature for 16 h.
  • Step-3 [0524] To a stired solution of 2,3-dibenzyl 1-(tert-butyl) (5S)-5-methyl-4-oxopyrolidine- 1,2,3-tricarboxylate (33 g, 70.58 mmol) in isopropanol (100 mL) and THF (100 mL) were added Pd/C (1.5 g, 14.11 mmol) and Paladium hydroxide (5% on carbon, anhydrous) (2.0 g, 14.11 mmol) at room temperature. The resulting mixture was stired at room temperature for 16 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with THF (100 mL).
  • Pd/C 1.5 g, 14.11 mmol
  • Paladium hydroxide 5% on carbon, anhydrous
  • Step-5 [0526] To 1,2- dicarboxylate (1 g, 3.88 mmol) and SiO2 (50 mg, 0.83 mmol) in DCE (2.7 mL), then toluene (2.58 g, 27.98 mmol) and H2O (7.00 mg, 0.38 mmol) was added. This was folowed by the addition of 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-l4-sulfanamine (2.58 g, 11.66 mmol) dropwise at room temperature. The resulting mixture was stired at 70 °C for 12 h.
  • Step-7 methylpyrolidine-2-carboxylic acid (3.5 g, 13.19 mmol) and methyl 5-amino-4- bromopicolinate (2.0 g, 8.79 mmol) in DMF (80 mL) were added Ir[dF(CF3)ppy]2(dtbpy)PF6 (197 mg, 0.17 mmol), Nickel(I) chloride ethylene glycol dimethyl ether complex (19 mg, 0.88 mmol), Dtbbpy (354 mg, 1.32 mmol) and N,N,N',N'-tetramethylguanidine (3.0 g, 26.39 mmol) at room temperature. The resulting mixture was stired for 16 h at room temperature under Blue LED (450 nm).
  • Step-10 [0538] A mixture of rel-methyl (8R,10aS)-6-amino-9,9-difluoro-8-methyl-8,9,10,10a- tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylate isomer 1 (50 mg, 0.17 mmol) and LiOH (12 mg, 0.50 mmol) in methanol (0.8 mL) and H2O (0.2 mL) was stired for 2 h at room temperature.
  • Step-11 [0539] A mixture of rel-methyl (8R,10aS)-6-amino-9,9-difluoro-8-methyl-8,9,10,10a- tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylate isomer 2 (50 mg, 0.17 mmol) and LiOH (12 mg, 0.50 mmol) in methanol (0.8 mL) and H2O (0.2 mL) was stired at room temperature for 2 h.
  • Step-12 [0540] A mixture of rel-methyl (8R,10aS)-6-amino-9,9-difluoro-8-methyl-8,9,10,10a- tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylate isomer 3 (70 mg, 0.23 mmol) and LiOH (17 mg, 0.71 mmol) in methanol (0.8 mL) and H2O (0.2 mL) was stired at room temperature for 2 h.
  • Step-13 [0541] A mixture of rel-methyl (8R,10aS)-6-amino-9,9-difluoro-8-methyl-8,9,10,10a- tetrahydropyrido[4,3-e]pyrolo[1,2-c]pyrimidine-2-carboxylate isomer 4 (80 mg, 0.14 mmol) and LiOH (17 mg, 0.71 mmol) in methanol (0.8 mL) and H2O (0.2 mL) was stired for 2 h at room temperature.
  • Step-2 nitrobenzoate (8.80 g, 28.17 mmol) in THF (100 mL) were added 2- (trimethylsilyl)methyl)alyl acetate (8.40 g, 45.08 mmol) and Pd(PPh3)4 (3.26 g, 2.82 mmol) at 25 oC. The resulting mixture was stired at room temperature for 16 h under nitrogen atmosphere. The solvents were removed under vacuum and purified directly.
  • Step-3 methylenepyrolidin-2-yl)-4-nitrobenzoate and methyl 3-(S)-1-((R)-tert-butylsulfinyl)-4- methylenepyrolidin-2-yl)-4-nitrobenzoate (4.40 g, 12.01 mmol) in MeCN (10 mL) were added RuCl3.H2O (0.08 g, 0.36 mmol), NaIO4 (10.27 g, 48.03 mmol), CCl4 (10 mL) and H2O (30 mL) at 25 oC. The resulting solution was stired at 25 oC for 16 h. The reaction mixture was diluted by the addition of water and extracted with dichloromethane.
  • the resulting solution was stired at 25 oC for 16 h.
  • the reaction mixture was quenched by the addition of NaHCO (s o 3 at.) at 0C.
  • the mixture was extracted with DCM.
  • the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
  • Step-5 difluoropyrolidin-2-yl)-4-nitrobenzoate and methyl (S)-3-(1-(tert-butylsulfonyl)-4,4- difluoropyrolidin-2-yl)-4-nitrobenzoate (2.30 g, 5.66 mmol) in DCM (30 mL) were added anisole (6.12 g, 56.60 mmol) and TfOH (2.54 g, 16.98 mmol) at 0 oC. The resulting solution was stired at 25 oC for 1 h. The solvents were removed under vacuum.
  • Step-7 - yl)benzoate (1.50 g, 5.85 mmol) in dioxane (15 mL) was added BrCN (0.62 g, 5.85 mmol) at 25 oC. The resulting solution was stired at 80 oC for 1 h. The solvents were removed under vacuum.
  • Step-8 c]quinazoline-9-carboxylate and methyl (S)-5-amino-2,2-difluoro-1,2,3,10b- tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylate (2.0 g, 7.11 mmol) was separated by prep- chiral SFC with the folowing conditions: [Column: Lux 5um Celulose-43*25 cm, 5 ⁇ m; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 100 mL/min; Gradient (B%): isocratic 40% B; RT1(min): 9; RT2(min): 11; Sample Solvent: MeOH; Injection Volume: 1 mL; Number Of Runs: 80] to aford methyl (R)-5-amino-2,2- difluoro-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9-car
  • Step-9 [0551] tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylate (980 mg, 3.48 mmol) in THF (5 mL) and HO (5 mL) was added LiOH (334 mg, 1 o 2 3.94 mmol) at 25C. The resulting solution was stired at 25 oC for 16 h. The solvents were removed under vacuum to aford (R)-5-amino- 2,2-difluoro-1,2,3,10b-tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylic acid (CA11) (1.7 g, crude) as a light yelow solid.
  • CA11 -5-amino- 2,2-difluoro-1,2,3,10b-tetrahydropyrrolo[1,2-c]quinazoline-9-carboxylic acid
  • Step 3 (R)-1-cyclopropyl-2-methoxyethan-1-amine [0561] To a stired mixture of tert-butyl N-[(1R)-1-cyclopropyl-2-methoxyethyl]carbamate (13.80 g, 64.10 mmol) in MeOH (70 mL) was added HCl (gas in ethyl acetate, 4M) (70 mL, 301.27 mmol) at room temperature. The mixture was stired at room temperature for 16 h.
  • HCl gas in ethyl acetate, 4M
  • Step 4 (R)-1-cyclopropyl-2-methoxy-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1- amine A1 [0562] To a stired mixture 2-methoxyethanamine (5.00 g, 43.41 mmol) and 5-(trifluoromethyl)pyridine-2-carbaldehyde (6.08 g, 34.73 mmol) in MeOH (50 mL) was added TEA (6.59 g, 65.12 mmol) at room temperature. The resulting mixture was stired at room temperature for 1 h. Then NaBH4 (3.61 g, 95.51 mmol) was added to the above mixture at 0 °C.
  • the resulting solution was stired at 25 oC for 1 h.
  • the reaction mixture was quenched by water and extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper, and concentrated under vacuum.
  • Step-2 [0570] To a mmol) in THF (200 mL) and H2O (100 mL) were added OsO4 (1.59 g, 6.24 mmol) and NaIO4 (26.70 g, 124.84 mmol) at 0 °C. The mixture was stired at room temperature for 16 h. The reaction mixture was quenched by the addition of NaHCO3 aqueous solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • Step 3 N NH2 N (R) HCl [0571] A , AcOK (3.80 g, 33.83 mmol) and (R)-1-(pyrimidin-2-yl)ethan-1-amine hydrochloride ((supplier: PharmaBlock Inc. CAS# 2387560-79-2) (4.5 g, 28.19 mmol) in MeOH (40 mL) was stired at room temperature for 3 h. To the above mixture was added NaBH3CN (5.31 g, 84.57 mmol) at room temperature. The resulting mixture was stired at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was diluted by NaHCO3 aqueous solution and extracted with DCM.
  • the resulting mixture was purified by prep-HPLC with the folowing conditions: [Column: Xselect CSH C18 OBD Column 30 *150 mm 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 3% B to 30% B in 10 min; Wave Length: 254/220 nm; RT1(min): 7.9] to aford (R*)- 5-amino-N-((R)-1-cyclopropyl-2-methoxyethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)- 1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9-carboxamide formate (2.8 mg, 1%) as a white solid.
  • Example 3 (R*)-5-amino-N-(S)-7-cyanoisochroman-4-yl)-2,2-difluoro-N-methyl- 1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9-carboxamide [0574] Exam mple 1, wherein intermediate CA2 is changed for CA3 and intermediate A1 is changed for A3.
  • Example 4 1:1:1:1 mixture of (R*)-5-amino-2,2-difluoro-N-methyl-N-(R)-2- (trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-1,2,3,10b- tetrahydropyrrolo[1,2-c]quinazoline-9-carboxamide intermediate CA2 is changed for CA3 and intermediate A1 is changed for A4.
  • Example 5 1:1:1:1 mixture of (R*)-5-amino-2,2-difluoro-N-methyl-N-(R)-2- (trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-1,2,3,10b- tetrahydropyrrolo[1,2-c]quinazoline-9-carboxamide [0576]
  • Example 5 is synthesized using same procedure as used in Example 1, wherein intermediate CA2 is changed for CA3 and intermediate A1 is changed for A5.
  • Example 6 1:1 mixture of (R*)-5-amino-2,2-difluoro-N-((R)-1-(pyrimidin-2-yl)ethyl)-N- (5-(trifluoromethyl)pyridin-2-yl)methyl)-1,2,3,10b-tetrahydropyrolo[1,2-c]quinazoline-9- carboxamide [0577] Exam mple 1, wherein intermediate CA2 is changed for CA3 and intermediate A1 is changed for A6.
  • Example 7 1:1 mixture of (R*)-6-amino-9,9-difluoro-N-methyl-N-((S)-1,2,3,4- tetrahydronaphthalen-1-yl)-8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[1,2-c]pyrimidine- 2-carboxamide and (R*)-6-amino-9,9-difluoro-N-methyl-N-((R)-1,2,3,4- tetrahydronaphthalen-1-yl)-8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[1,2-c]pyrimidine- 2-carboxamide [0578] To a stired solution of A7 (supplier: Beijing Feilongrui Trading Co., Ltd.
  • PRMT5 Biochemical Assay [0580] The PRMT5 biochemical assay was conducted in 384-wel, assay-ready compound plates (PerkinElmer, Inc.; catalog number 6007290) with a final enzymatic reaction volume of 16 ⁇ L; plates were prepared a priori, starting at 10 ⁇ M with 10 concentration points in a 3- fold serial dilution series for test compounds. The controls were defined as Low Control and High Control; Low Control contained al reagents aside from PRMT5 protein, and the High Control contained al reagents plus PRMT5.
  • the enzymatic reaction was caried out at a final concentration of PRMT5 (in complex with MEP50, Proteros, GmbH; catalog number PR-0376) of 1.2 nM (equal to the PRMT5 monomer concentration), in a reaction mixture bufer and incubated for 60 minutes at 37 °C, in the presence and absence of 100 nM MTA (EMD Milipore, Inc.; catalog number 260585); the mixture consisted of 2 ⁇ M S-adenosyl-methionine (Promega, Inc.; catalog number V7601), 2.3 ⁇ M ful-length histone H2A (New England Biolabs, Inc.; catalog number M2502) in assay bufer; assay bufer consisted of 50 mM Tris-HCl (pH 8) (ThermoFisher Scientific, Inc.; catalog number AM9856), 50 mM NaCl (ThermoFisher Scientific, Inc.; catalog number AM9759), 1 mM TCEP
  • the reaction was subjected to a detection procedure utilizing the MTase-GloTM Methyltransferase Assay (Promega, Inc.; catalog number V7601).
  • MTase-GloTM Methyltransferase Assay Promega, Inc.; catalog number V7601.
  • 4 uL of 5X MTase-GloTM Reagent (Promega, Inc.; catalog number V7601), diluted from the original 10X stock with assay bufer, was added to added to the enzymatic reaction mixture and incubated for 30 minutes at room temperature.
  • Second, 20 uL of 2X MTase-GloTM Detection Solution (Promega, Inc.; catalog number V7601) was added, and the mixture was incubated for 30 minutes at room temperature.
  • Percent inhibition for each concentration of test compound was determined by calculating the ratio between the test compound, low control, and high control signals; the resulting data was fited and the IC50 was estimated using Levenberg-Marquardt algorithm.
  • the IC50 of a representative compound in Table 1 above is disclosed in Table 2 below, where 2.3 ⁇ M ful-length histone H2A (New England Biolabs, Inc.; catalog number M2502) was used: A ⁇ 0.1 ⁇ M Table 2: PRMT5 Biochemical Assay Results Ex # PRMT5 Biochemical Assay (+MTA) ( ⁇ M)
  • Table 2A PRMT5 Biochemical Assay Results Ex # PRMT5 Biochemical ) Biological Example els [0584] The cel viability was determined by doing cel nuclear counts; cel nuclei were labeled with a fluorescent protein kit using the manufacturer’s protocol (Sartorius).
  • HCT116 MTAP-/- were cultured in DMEM/F12 with GlutaMAX (Gibco) supplemented with 10% Fetal Bovine Serum (FBS, Gibco) and 2ug/mL puromycin (Gibco).
  • Cels were seeded in 384-wel plates, at a density of 166 cels/wel in 50 ⁇ L of cel culture media without puromycin. Cel plates were incubated overnight at 37°C with 5% CO2. After the overnight incubation, cels were imaged in a confocal microscope with nuclear count capabilities for the pre-treatment data set.
  • Cels were treated starting at a 20 ⁇ M in 9-points and 4-fold serial dilutions for test compounds; the negative control was DMSO. Al compounds and the negative control had a final DMSO concentration of 0.2%. Cels were incubated for 5 days at 37°C with 5% CO2. On day 5, cels were imaged, and nuclei were counted for the post-treatment data set. [0587] Percent inhibition for each concentration of test compound was determined by calculating the ratio between the post-treatment and pre-treatment nuclei count, and negative control; the resulting data was fited and the EC50 was estimated using the Levenberg- Marquardt algorithm.

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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 des utilités et des avantages supplémentaires.
PCT/US2025/014157 2024-02-02 2025-01-31 Composés guanidino tricycliques substitués par un amide utilisés en tant qu'inhibiteurs de prmt5 Pending WO2025166260A1 (fr)

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Cited By (1)

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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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