Tricyclic guanidino compounds as PRMT5 inhibitors

Abstract

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

Description

TRICYCLIC GUANIDINO COMPOUNDS AS PRMT5 INHIBITORSCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 549,381 filed February 2, 2024, the contents of which is incorporated by reference in its entirety for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDERFEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

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

[0003] NOT APPLICABLEBACKGROUND

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

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

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

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

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

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

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

[0011] In one aspect, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof. The definitions for X1, X2, X3, R4, n, ring A, ring B, R5, p, R6, and q are further described herein.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0035] NOT APPLICABLEDETAILED DESCRIPTION OF THE INVENTION

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

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

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

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

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

[0041] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0042] The term "alkyl", by itself or as part of another substituent, refers to, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. Ci-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, C4-6and C5-6. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0043] The term “alkylene” refers to a straight or branched, saturated hydrocarbon radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0044] The term “alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond and having the number of carbon atom indicated (i.e., C2-6means to two to six carbons). Alkynyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1 -pentynyl, 2-pentynyl, isopentynyl,1.3-pentadiynyl, 1,4-pentadiynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl,1.4-hexadiynyl, 1,5 -hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.

[0045] The term "cycloalkyl" refers to a non-aromatic, saturated hydrocarbon ring having the indicated number of ring atoms (e.g. , C3-6cycloalkyl). For example, “C3-10cycloalkyl”refers to a cycloalkyl group containing 3 to 10 carbon atoms as ring vertices and the term “C3-7cycloalkyl” 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 tike.

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

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

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

[0049] The term “aryl” refers to a monocyclic or bicyclic, hydrocarbon, aromatic radical. An aryl group may contain 6 to 14 carbon atoms. For example, “C6-10aryl” refers to an aryl moiety having 6 to 10 carbon atoms as ring vertices. Non-limiting examples of aryl groups include phenyl and naphthyl.

[0050] The term "heteroaryl" refers refers to a moiety comprising an aromatic monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxatinyl, quinazotinyl, cinnotinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indotizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the tike.

[0051] The term "5- or 6-membered heteroaryl” refers to a moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbonatom and containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain three heteroatoms. Exemplary groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0052] The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially unsaturated 3 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N, O, and S and the remaining ring atom being carbon. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized and one or two ring carbon atoms of the heterocyclic ring may be replaced by -C=(O) group. However, heterocycloalkyl groups are not aromatic. Non limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, , and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.

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

[0054] The term “optionally substituted” indicates that a group may be unsubstituted or substituted with one or more substituents as defined herein. The term “substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced by one of the defined substituents. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

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

[0056] The term "fused tricyclic moiety" refers to a ring system comprising three fused rings comrpsing the number of ring atoms and heteroatoms indicated, wherein each ring inthe fused system can be unsaturated, partially unsaturated, or saturated. Therefore, each ring in the fused tricyclic moiety can be aromatic or non aromatic.

[0057] As used herein, a wavy line, "w" ", that intersects a single, double or triple bond in any chemical structure depicted herein, represent the point attachment of the single, double, or triple bond to the remainder of the molecule. Additionally, a bond extending to the center of a ring (e.g., a phenyl ring) is meant to indicate attachment at any of the available ring vertices. One of skill in the art will understand that multiple substituents shown as being attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible.

[0058] The term “pharmaceutically acceptable” refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0059] As used herein, the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines, such as arginine, betaine, caffeine, choline, N,N' -dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine. When compounds of the present disclosure contain relatively basicfunctionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydriodic, or phosphorous acids, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolyl sulfonic, citric, tartaric, methanesulfonic. Also included are salts of amino acids such as arginate, and salts of organic acids like glucuronic or galactunoric acids (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0060] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0061] Certain compounds of Formula (I) possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure. When a stereochemical depiction is shown, it is meant to refer the compound in which one of the isomers is present and substantially free of the other isomer. ‘Substantially free of another isomer indicates at least an 80 / 20 ratio of the two isomers, more preferably 90 / 10, or 95 / 5 or more. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0062] Certain compounds of Formula (I) can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of Formula (I) may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0063] Certain compounds of the present disclosure can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure.

[0064] Compounds of Formula (I) or a subembodiment thereof may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. Exemplary isotopes that can be incorporated into compounds of the present disclosure, such as a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,150,170,18O,32P,33P,35S,18F,36C1,123I, and1251, respectively. Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Additionally, isotopic variants of Formula (I) or a subembodiment thereof can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. Isotopically-labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo halffife or reduced dosage requirements). In some embodiments, in compounds disclosed herein, including in Table 1 below one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as150,13N,nC, and15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. All isotopic variations of Formula (I) or a subembodiment thereof, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0065] The terms “patient” or “subject” are used interchangeably to refer to a human or a non-human animal (e.g., a mammal). Examples of patients include humans, livestock such ascows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. In one embodiment, the patient or subject is a human.

[0066] “Disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0067] “In need of treatment” as used herein refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver’s expertise.

[0068] The terms “administration”, “administer” and the like, as they apply to, for example, a subject, cell, tissue, organ, or biological fluid, refer to contact of, for example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising same, or a diagnostic agent to the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.

[0069] The terms “proliferative disorder,” “proliferative condition,” and “cell proliferation” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, prc-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, gastric, liver, pancreas, brain, and skin.

[0070] The terms “treat”, “treating”, treatment” and the like refer to a course of action (such as administering an inhibitor of PRMT5 or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a patient, or at least one of the symptoms associated with a disease, disorder, condition afflicting a patient. Thus, treatment includes inhibiting (e.g., arresting thedevelopment or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.

[0071] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a PRMT5 inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a patient’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a patient predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.

[0072] 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.

[0073] The phrase “therapeutically effective amount” as used herein means the amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive effect on any symptom, aspect, or characteristic of a disease, disorder or condition when administered to the patient. It may vary depending on the compound, the disease and its severity and the age and weight of the subject to be treated. The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the patient’s condition, and the like. By way of example, measurement of the serum level of a compound Formula (I) or a pharmaceutically acceptable salt thereof (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been used.

[0074] The term “antibody” means an immunoglobulin and is a molecule containing an antigen-binding site immunospecifically binding to an antigen. The class of the antibody of the present disclosure may be any of IgG, IgE, IgM, IgD, IgA, and IgY and is preferably IgG.The subclass of the antibody of the present disclosure may be any of IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2 and is preferably IgGl or IgG2. The antibody may be derived from any species, and preferred examples of the species can include humans, rats, mice, and rabbits. When the antibody is derived from other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody of the present disclosure may be a polyclonal antibody or a monoclonal antibody. In an embodiment, the antibody is a monoclonal antibody. The antibody of the present disclosure is capable of targeting tumor cells. In an embodiment, the antibody of the present disclosure is conjugated with an antitumor compound having antitumor activity via a linker, the antibody preferably possesses one or more of a property of recognizing a tumor cell, a property of binding to a tumor cell, a property of internalizing in a tumor cell, and a property of damaging a tumor cell. In an embodiment, the antibody is a monoclonal antibody that is reactive with a target antigen or epitope of an antigen expressed on a cancer or malignant cell. Techniques for preparing monoclonal antibodies against target antigen are known in the art. Non limiting target antigens are B7-H3, B7-H4, Trop-2, PSMA, BCMA, folate receptor, AXL, EGF receptor (ErbBl), ErbB2, ErbB3, EGFRv III, FGFR, EpCAM, HER-2, HER-3, tissue factor (TF), CD19, CD22, CD25, ILR2, ANTXR1, ROR1, 5T4, CD30, CD33, CD79b, CD74, CD138, CD56, CD70, CD166, CEACAM5, GPNMB, Claudin-18, folate receptor alpha (FRa), c-Met, Nectin-4, Mesothelin, delta-like ligand 3 (DLL3), PTK7, GPNMB, Ley, CA6, CanAng, Av integrin, SLC44A4, CEACAM5, AGS- 16, Anti-Cripto, Carbonic Anhydrase 9, Mesotheilin, TENB2, 5T4, VEGF, insulin-like growth factor (ILGF), MUC1 and TA-MUC1.COMPOUNDS

[0075] In some aspects, provided herein are compounds of Formula (I)or a pharmaceutically acceptable salt thereof, whereinX1is C(R1) or N;X2is C(R2) or N;X3is C(R3) or N;R1, R2, and R3are each independently H, C1-4alkyl, halo, or C1-4haloalkyl;n is 0, 1, 2, 3, or 4; each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl; alternatively, two R4groups when attached to the same carbon atom combine to form oxo or C3-6cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is C6-10aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R5is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)O C1-6alkyl, or -C(O)OC1-6haloalkyl; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, -C(O)OC1-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6cycloalkyl, -O-C3-6cycloalkyl, and heterocycloalkyl is independently substituted with 0, 1, or 2 R6a; each R6ais independently C1-4alkyl, halo, C1-4haloalkyl, CN, OH, or C1-4alkoxy; alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C, wherein ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R5ais independently C1-4alkyl, halo, C1-4haloalkyl, OH, or C1-4alkoxy; alternatively, two R5agroups attached to the same carbon atom combine to form oxo.

[0076] In some aspects, provided herein are compounds of Formula (I)or a pharmaceutically acceptable salt thereof, whereinX1is C(R1) or N;X2is C(R2) or N;X3is C(R3) or N;R1, R2, and R3are each independently H, C1-4alkyl, halo, or C1-4haloalkyl; n is 0, 1, 2, 3, or 4; each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl; alternatively, two R4groups when attached to the same carbon atom combine to form oxo or C3-6cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is C6-10aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each additional heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R5is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, or -C(O)OC1-6haloalkyl; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, - C(O)C1-6alkyl, -C(O)OC1-6haloalkyl, -C(O)OC1-6alkyl, -C(O)OC1-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a; each R6ais independently C1-4alkyl, halo, or C1-4haloalkyl; alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C, wherein ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, 8,S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R5ais independently C1-4alkyl, halo, or C1-4haloalkyl; alternatively, two R5agroups attached to the same carbon atom combine to form oxo.

[0077] In some aspects, provided herein are compounds of Formula (la):or a pharmaceutically acceptable salt thereof, wherein:X1is C(R') or N;X2is C(R2) or N;X3is C(R3) or N;R1, R2, and R3are each independently H, C1-4alkyl, halo, or C1-4haloalkyl; n is 0, 1, 2, 3, or 4; each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl; or two R4groups when attached to the same carbon atom combine to form oxo or C3-6cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S; ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B; and ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, or 2; q is 0, 1, or 2; each R5is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, or -C(O)OC1-6haloalkyl;each R5ais independently C1-4alkyl, halo, C1-4haloalkyl, OH, or C1-4alkoxy; alternatively, two R5agroups attached to the same carbon atom combine to form oxo; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1.6 haloalkoxy, CN, C2-6alkynyl, -O-C2 -6 alkynyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, -C(O)OC1-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6cycloalkyl, -O-C3-6cycloalkyl, and heterocycloalkyl is independently substituted with 0, 1, or 2 R6a; and each R6ais independently C1-4alkyl, halo, C1-4haloalkyl, CN, OH, or C1-4alkoxy.

[0078] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein: each R5is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, or -C(O)OC1-6haloalkyl; each R5ais independently C1-4alkyl, halo, or C1-4haloalkyl; alternatively, two R5agroups attached to the same carbon atom combine to form oxo; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, CN, -O-C3cycloalkyl, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, - C(O)OC1-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a; and each R6ais independently C1-4alkyl, halo, or C1-4haloalkyl.

[0079] Unless specifically indicated otherwise, embodiments or subembodiments related to Formula (I) are applicable to any one of Formulae (la), (Ial-1), (Ial-2), (Ia2-1), (Ia2-2), (lb), (Ibl), (II), (Da-1), and (Da-2).

[0080] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X1is N.

[0081] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X1is C(R') and R1is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0082] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X1is C(R1) and R1is H, methyl, ethyl, fluoro, chloro, or bromo.

[0083] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X1is C(R1) and R1is H, methyl, fluoro, chloro, or trifluoromethyl.

[0084] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X1is CH.

[0085] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X2is N.

[0086] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X2is C(R2) and R2is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0087] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X2is C(R2) and R2is H, methyl, ethyl, fluoro, chloro, or bromo.

[0088] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X2is C(R2) and R2is H, methyl, fluoro, chloro, or trifluoromethyl.

[0089] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X2is CH or CF. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X2is CH. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X2is CF.

[0090] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X3is N.

[0091] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X3is C(R3) andR3is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or tri fluoromethyl.

[0092] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X3is C(R3) and R3is H, methyl, ethyl, fluoro, chloro, or bromo.

[0093] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X3is C(R3) and R3is H, methyl, fluoro, chloro, or trifluoromethyl.

[0094] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X3is CH or CF. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X3is CH. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X3is CF.

[0095] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is CH; X2is C(R2) or N; and X3is C(R3).

[0096] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein X1is CH; X2is N; and X3is CH, X1is CH; X2is CH; and X3is CH or CF, or X1is CH; X2is CF; and X3is CH. In some embodiments, X1is CH; X2is N; and X3is CH. In some embodiments, X1is CH; X2is CH; and X3is CH or CF. In some embodiments, X1, X2, and X3are each CH. In some embodiments, X1is CH; X2is CH; and X3is CF. In some embodiments, X1is CH; X2is CF; and X3is CH.

[0097] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein the moietyhas the formula:, wherein X2is C(R2) orN; and R2and R3are each independently H or halo. In some embodiments, X2is N; and R3is H, X2is CH; and R3is H or F, or X2is CF; and R3is H. In some embodiments, X2is N; andR3is H. In some embodiments, X2is CH; and R3is H or F. In some embodiments, X2is CH; and R3is H. In some embodiments, X2is CH; and R3is F. In some embodiments, X2is CF; and R3is H.

[0098] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl.

[0099] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R4is independently C1-4alkyl, halo, or C1-4haloalkyl. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R4is independently C1-4alkyl or C1-4haloalkyl.

[0100] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R4is independently methyl, ethyl, fluoro, chloro, or bromo. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R4is independently methyl or -CHF2. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R4is independently methyl. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R4is independently -CHF2.

[0101] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R4is independently methyl, fluoro, or difluoromethyl.

[0102] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein n is 0, 1, 2, or 3. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein n is 0, 1, or 2. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein n is 0 or 1. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein n is 0.

[0103] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 1 ; and R4is methyl.

[0104] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein n is 1 ; and R4is -CHF2.

[0105] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein n is 2 and each R4is independently fluoro (F).

[0106] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S.

[0107] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 1 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S.

[0108] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0109] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N, O, or S. Insome embodiments, ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 5 to 6 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0110] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N, O, or S. In some embodiments, ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O. In some embodiments, ring A is heterocycloalkyl having 6 ring members with at least 1 nitrogen atom and 0 to 1 oxygen atom as ring vertices.

[0111] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0112] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl.

[0113] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

[0114] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring A is piperidinyl, substituted with 1 or 2 R5.

[0115] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring A is piperazinyl, substituted with 1 or 2 R5.

[0116] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring A is morpholinyl, substituted with 1 or 2 R5.

[0117] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring A is piperidinyl or morpholinyl, substituted with 1 or 2 R5.

[0118] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R5. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with 0, 1, or 2 R5. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperazinyl substituted with 0, 1, or 2 R5. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with 0, 1, or 2 R5.

[0119] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R5is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, or C1-4haloalkoxy.

[0120] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R5is independently C1-4alkyl, C1-4haloalkyl, or halo. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R5is C1-4alkyl.

[0121] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R5is independently C1-4alkyl, halo, OH, or C1-4alkoxy.

[0122] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R5is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0123] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R5is independently methyl, fluoro, OH, or methoxy.

[0124] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R5is independently methyl, fluoro, or methoxy.

[0125] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R5is independently methyl or fluoro.

[0126] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein each R5is independently methyl or methoxy.

[0127] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R5is independently methyl.

[0128] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, substituted with 1 or 2 R6.

[0129] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring B is phenyl or pyridyl substituted with 2 R6.

[0130] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (la)wherein, ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; q is 0, 1, or 2; andring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0131] Unless specifically indicated otherwise, embodiments or subembodiments related to Formula (la) are applicable to any one of Formulae (lai), (Ia2), (II), (Ila- 1), and (Ila-2).

[0132] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (la) or a subembodiment thereof, wherein ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O; ring B is phenyl or heteroaryl having 6 ring members with 1 to 2 nitrogen atom ring vertices; and ring C is C5-6cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

[0133] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la), or a subembodiment thereof, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl. In some embodiments, ring A is piperidinyl, piperazinyl, or morpholinyl.

[0134] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein B is phenyl or heteroaryl having 6 ring members with 1 to 2 nitrogen atom ring vertices. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring B is phenyl or pyridyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is phenyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is pyridyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is pyrazinyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is pyrimidinyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring B is pyridazinyl.

[0135] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A ispiperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R5; and each R5is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl, piperazinyl, or morpholinyl, each of which is independently substituted with 0, 1, or 2 R5; and each R5is independently methyl, fluoro, or methoxy.

[0136] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl substituted with 0 R5. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R5; and R5is methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R5; and R5is methyl, fluoro, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R5; and R5is methyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R5; and R5is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R5; and R5is OH. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R5; and R5is methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with one R5; and R5is OH.

[0137] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is morpholinyl substituted with 0 R5. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with one R5; and R5is methyl or fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is morpholinyl substituted with one R5; and R5is methyl.

[0138] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl substituted with 2 vicinal R5; and each R5is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R5; one R5is methyl; and the other R5is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R5; one R5is methyl; and the other R5is OH. Insome embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two vicinal R5; one R5is methyl; and the other R5is methoxy.

[0139] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperidinyl substituted with 2 geminal R5; and each R5is independently methyl, fluoro, OH, or methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R5; one R5is methyl; and the other R5is fluoro. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R5; one R5is methyl; and the other R5is OH. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R5; one R5is methyl; and the other R5is methoxy. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R5; and each R5is methyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring A is piperidinyl substituted with two geminal R5; and each R5is fluoro.

[0140] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is piperazinyl, substituted with 2 vicinal R5or 2 geminal R5, wherein each R5is any one of embodiments described herein.

[0141] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring A is morpholinyl substituted with 2 vicinal R5or 2 geminal R5, wherein each R5is any one of embodiments described herein.

[0142] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (Ial-1) n(Ial-1) wherein,Xais O, CH2, or CHR5; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0143] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (Ial-2)(Ial-2)wherein,Xais O, CH2, or CHR5; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0144] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is C4-7cycloalkyl substituted with 0, 1, 2, or 3 R5a.

[0145] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is C4-6cycloalkyl substituted with 0, 1, 2, or 3 R5a.

[0146] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is C5-6cycloalkyl substituted with 0, 1, or 2 R5a.

[0147] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is C6cycloalkyl substituted with 0, 1, or 2 R5a.

[0148] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is C5cycloalkyl substituted with 0, 1, or 2 R5a.

[0149] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0150] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 4 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0151] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0152] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R5a.

[0153] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is heterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0154] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C isheterocycloalkyl having 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0155] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (la) or a subembodiment thereof, wherein ring C is C5-6cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is C5-6cycloalkyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

[0156] In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is C5-6cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is C5-6cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0157] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is C5-6cycloalkyl, tetrahydrofiiranyl, tetrahydropyranyl, or oxepanyl.

[0158] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is C5-6cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0159] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl substituted with 0, 1, or 2 R5a.

[0160] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydropyranyl substituted with 0, 1, or 2 R5a. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydropyranyl substituted with 0 or 1 R5a. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compoundof Formula (I) or a subembodiment thereof, wherein ring C is tetrahydropyranyl substituted with 0 R5a

[0161] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydrofuranyl substituted with 0, 1, or 2 R5a. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydrofuranyl substituted with 0 or 1 R5a. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I) or a subembodiment thereof, wherein ring C is tetrahydrofuranyl substituted with 0 R5a.

[0162] In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl, each of which is independently substituted with 0 or 1 R5a. In some embodiments of Formula (la) or any one of the embodiments thereof, ring C is tetrahydrofuranyl substituted with 0 or 1 R5a. In some embodiments, ring C is tetrahydropyranyl substituted with 0 or 1 R5a. In some embodiments, ring C is oxepanyl substituted with 0 or 1 R5a.

[0163] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-1)(Ia2-1) wherein,Xais absent, O, CH2, or CHR5;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0164] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-1)(Ia2-1) wherein,Xais absent, O, CH2, or CHR5;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2, provided that X5aand X5bare not each absent or O.

[0165] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (Ia2-2) n(Ia2-2)wherein,Xais absent, O, CH2, or CHR5;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2, provided that X5aand X5bare not each absent or O.

[0166] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2-1), (Ia2-2), or a subembodiment thereof, wherein X1is C(R1), X2is C(R2), and X3is C(R3).

[0167] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (Ia2-1), or (Ia2-2), or a subembodiment thereof, wherein X1is C(R1), X2is N, and X3is C(R3).

[0168] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ia2-1), (Ia2-2), or a subembodiment thereof wherein Xais O, CH2, or CHR5;X5ais O or CH2, or CHR5a;X5bis O or CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0169] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ia2-1), (Ia2-2), or a subembodiment thereof wherein Xais O, CH2, or CHR5;X5ais O or CH2, or CHR5a;X5bis O or CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2 provided that X5aand X5bare not each absent or O.

[0170] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ia2-1), (Ia2-2), or a subembodiment thereof, wherein X •5:a is O, and X5bis CH2.

[0171] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ia2-1), (Ia2-2), or a subembodiment thereof, wherein X:is CH2, and X5bis O.

[0172] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ia2-1), (Ia2-2), or a subembodiment thereof, wherein X‘ is CH2, and X5bis CH2.

[0173] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ia2-1), (Ia2-2), or a subembodiment thereof wherein X5ais absent, and X5bis CH2.

[0174] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (Ia2-1), (Ia2-2), or a subembodiment thereof wherein X:is absent, and X5bis O.

[0175] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R5ais independently C1-4alkyl, halo, or C1-4haloalkyl.

[0176] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R5ais independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0177] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R5ais independently methyl, fluoro, chloro, or trifluoromethyl

[0178] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein two R5agroups attached to the same carbon atom combine to form oxo.

[0179] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6alkynyl, or -O-C2-6alkynyl.

[0180] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, or C1-6haloalkoxy.

[0181] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, or halo.

[0182] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently HC=C-, trifluoromethyl, chloro, bromo, HC=C-CH2-O-, difluoromethoxy, CN, or cyclopropyl.

[0183] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6isindependently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0184] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently bromo or trifluoromethyl.

[0185] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C3-6cycloalkyl and -O-C3-6cycloalkyl are each independently substituted with 0 or 1 CN.

[0186] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein each R6is independently chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-.

[0187] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R6is C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C3-6cycloalkyl and -O- C3-6cycloalkyl are each independently substituted with 0 or 1 CN.

[0188] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R6is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-,HC=C-, or HC=C-CH2-O-.

[0189] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 1; and R6is chloro, trifluoromethyl, or difluoromethyl-O-.

[0190] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein q is 2; and each R6is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

[0191] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I), (la), or a subembodiment thereof, wherein the moietyor has the formula:5

[0192] In some embodiments, the compound or the pharmaceutically acceptable salt thereof is the compound of Formula (I) (la) or a subembodiment thereof, wherein the moiety is any one of formulae:

[0193] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein the moiety oris any one of formulae:

[0194] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein the moietyhas the formula:

[0195] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), (la), or a subembodiment thereof, wherein themoietyor is any one of the formulae according to theAmine intermediates in the Examples, wherein the nitrogen at the ring A is attached to the remainder of the molecule.

[0196] In some embodiments, the compound is represented by Formula (II):or a pharmaceutically acceptable salt thereof, wherein:Xais O, NH, NR5, CH2, CHR5, or C(R5)2;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a, provided that X5aand X5bare not each absent or O; and a total number of R5groups is no more than 2; and n, p, q, ring B, Y1, X2, R3, R4, R5, R5a, and R6are each defined in Formula (I) or (la), and described in any one of the embodiments thereof.

[0197] Unless specifically indicated otherwise, embodiments or subembodiments related to Formula (II) are applicable to any one of Formulae (IIa-1) and (IIa-2).

[0198] In some embodiments of Formula (II), Y1is O.

[0199] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is the compound of Formula (II), or a subembodiment thereof, wherein ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring B is phenyl. In some embodiments, ring B is pyridyl. In some embodiments, ring B is pyrazinyl. In some embodiments, ring B is pyrimidinyl. In some embodiments, ring B is pyridazinyl.

[0200] In some embodiments, the compound is represented by Formula (IIa-1):(IIa-1),wherein:Xais O, NH, N( C1-4alkyl), CH2, CHR5, or C(R5)2;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a, provided that X5aand X5bare not each absent or O; and a total number of R5groups is no more than 2.

[0201] In some embodiments, the compound is represented by Formula (IIa-2):(IIa-2),wherein:Xais O, NH, N(C1-4alkyl), CH2, CHR5, or C(R5)2;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a, provided that X5aand X5bare not each absent or O; and a total number of R5groups is no more than 2.

[0202] In some embodiments of Formula (II), (Ila- 1), or (IIa-2), a subembodiment thereof, X2is C(R2) or N; and R2and R3are each independently H or halo.

[0203] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, X2is N and R3is H; X2is CH, and R3is H or F; or X2is CF and R3is H. In some embodiments, X2is N; and R3is H. In some embodiments, X2is CH; and R3is H. In some embodiments, X2is CH; and R3is F. In some embodiments, X2is CF; and R3is H.

[0204] In some embodiments of Formula (II), (IIa-1), or (IIa-2), a subembodiment thereof, X2is N and R3is H; and and Xais O, CH2, CHR5, or C(R5)2. In some embodiments of Formula (II), (IIa-1), or (IIa-2), a subembodiment thereof, X2is CH; R3is H or F; and Xais O, CH2, CHR5, or C(R5)2.

[0205] In some embodiments of Formula (IIa-1), a subembodiment thereof, X2is CH; R3is H or F; and Xais O, CH2, CHR5, or C(R5)2.

[0206] In some embodiments of Formula (IIa-1), a subembodiment thereof, X2is N.

[0207] In some embodiments of Formula (II), or a subembodiment thereof, each R4is independently C1-4alkyl or C1-4haloalkyl. In some embodiments, each R4is independently methyl or -CHF2. In some embodiments, each R4is methyl.

[0208] In some embodiments of Formula (II), or a subembodiment thereof, n is 0 or 1. In some embodiments of Formula (II), n is 0 or R4is absent.

[0209] In some embodiments of Formula (IIa-1) or (IIa-2), or a subembodiment thereof, R4(when present) is C1-4alkyl or C1-4haloalkyl. In some embodiments, R4(when present) is methyl or -CHF2. In some embodiments, R4(when present) is methyl. In some embodiments, R4(when present) is -CHF2.

[0210] In some embodiments of Formula (IIa-1) or (IIa-2), or a subembodiment thereof, R4is absent.

[0211] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais O, NH, CH2, or CHR5; X5ais O, CH2, or CHR5a; X5bis O, CH2, or CHR5a; and p is 0 or 1.

[0212] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais O, NH, or CH2; X5ais O, CH2, or CHR5a; X5bis O, CH2, or CHR5a; and p is 0, 1, or 2.

[0213] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, Xais C(R5)2; X5ais O, CH2, or CHR5a; X5bis O, CH2, or CHR5a; and p is 0.

[0214] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, X5ais O and X5bis CH2; X5ais CH2and X5bis O; X5ais CH2and X5bis CH2; X5ais O and X5bis CH(CH3); X5ais CH(CH3) and X5bis O; X5ais CH2and X5bis CH(CH3); X5ais CH(CH3) and X5bis CH2; X5ais absent and X5bis CH2; or X5ais absent and X5bis O. Insome embodiments, X5ais O and X5bis CH2. In some embodiments, X5ais CH2and X5bis O. In some embodiments, X5ais CH2and X5bis CH2. In some embodiments, X5ais O and X5bis CH(CH3). In some embodiments, X5ais CH(CH3) and X5bis O. In some embodiments, X5ais CH2and X5bis CH(CH3). In some embodiments, X5ais CH(CH3) and X5bis CH2. In some embodiments, X5ais absent and X5bis CH2. In some embodiments, X5ais absent and X5bis O.

[0215] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, each R5is independently C1-4alkyl, halo, OH, or C1-4alkoxy. In some embodiments, each R5is independently methyl, fluoro, OH, or methoxy. In some embodiments, each R5is independently methyl, fluoro, or methoxy.

[0216] In some embodiments of Formula (II), (Ila- 1), or (IIa-2), or a subembodiment thereof, each R6is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C3-6cycloalkyl and -O-C3-6cycloalkyl are each independently substituted with 0 or 1 CN.

[0217] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, each R6is independently chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-.

[0218] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, q is 1; and R6is C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C3-6cycloalkyl and -O-C3-6cycloalkyl are each independently substituted with 0 or 1 CN.

[0219] In some embodiments of Formula (II), (IIa-1), or (IIa-2), or a subembodiment thereof, q is 1 ; and R6is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-. In some embodiments, q is 1; and R6is chloro, trifluoromethyl, or difluoromethyl-O-. In some embodiments, q is 2; and each R6is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

[0220] Unless specifically indicated otherwise, amine moieties 1 to 12 below related to Formula (la) are applicable to any one of Formulae (I), (II), (IIa-1), and (IIa-2).

[0221] In some embodiments of Formula (la), the moietyhas the formula:wherein:Xais O, NH, CH2, or CHR5;X5ais O, CH2, or CHR5a;X5bis O, CH2, or CHR5a; each R5ais independently C1-4alkyl; each R5is independently F, OH, C1-4alkyl, or C1-4alkoxy; andR6is C1-4alkyl, C1-4haloalkyl, halo, CN, C1-4alkoxy, C1-4haloalkoxy, C2-4 alkynyl, -O-C2-4 alkynyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C3-6cycloalkyl and -O- C3-6cycloalkyl are each independently unsubstituted or substituted with CN, provided that X5aand X5bare not each O.

[0222] In some embodiments of Formula (II), or related Formula (IIa-1) or (IIa-2), the moiet is any one of the above moieties 1 to 12.

[0223] In some embodiments of the above moieties 1 to 12, Xais O, NH, CH2, CHF, C(CH3), C(OH), or C(OCH3); X5ais O, CH2, or CH(CH3); X5bis O or CH2; R5is F, CH3, OH, or OCH3; and R6is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C-, or HC=C-CH2-O-, provided that X5aand X5bare not each O. In some embodiments of moieties 1 to 12, R6is chloro, trifluoromethyl, or difluoromethyl-O-.

[0224] In some embodiments of the above moieties 1 to 12, Xais O, CHz, or CHF; X5ais O, CH2, or CH(CH3); X5bis O or CH2; R5is CH3; and R6is chloro, trifluoromethyl, or difluoromethyl-O-, provided that X5aand X5bare not each O. In some embodiments of moieties 1 to 4, Xais CH2; X5ais CH2; X5bis O; and R6is chloro, trifluoromethyl, or difluoromethyl-O-. In some embodiments of moieties 1 to 4, Xais O; X5ais O; X5bis CH2; and R6is chloro, trifluoromethyl, or difluoromethyl-O-.

[0225] In some embodiments of Formula (la) or any one of related subformulae (II), (Ila-1), and (IIa-2), the moietyis any one of the formulae according toAmine intermediates Al, A2, A4 to A6, and A9 to Al 11 in the Examples, wherein the nitrogen at the ring A is attached to the remainder of the molecule.

[0226] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (lb)(Ib) wherein,Xais O, CH2, or CHR5; ring B is C6-10aryl or heteroaryl having 9 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; and q is 0, 1, 2, or 3.

[0227] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (Ib)(Ib)wherein,Xais O, CH2, or CHR5; ring B is heteroaryl having 9 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; and q is 0, 1, 2, or 3.

[0228] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein p is 1.

[0229] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein p is 2.

[0230] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein q is 0.

[0231] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein q is 1.

[0232] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein q is 2.

[0233] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, having Formula (Ibl)(Ibl).

[0234] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a.

[0235] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently C1-4alkyl, C1-4haloalkyl, halo, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a.

[0236] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently C1-4haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a.

[0237] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a.

[0238] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 R6a.

[0239] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6is piperidinyl substituted with 0, 1, or 2 R6a.

[0240] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6ais independently C1-4alkyl.

[0241] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6ais independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0242] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein each R6ais methyl.

[0243] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein the moiety has the formula:

[0244] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein the moietyhas the formula:

[0245] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein the moiety has the formula:

[0246] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X1is CH;X2is C(R2) or N;X3is C(R3);R2and R3are each independently H or halo; n is 0, 1, 2, or 3; each R4is independently C1-6alkyl, halo, or C1-6haloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is C6-10aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 1, or 2; q is 1, or 2; each R5is independently C1-6alkyl; each R6is independently C1-6haloalkyl, halo, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6cycloalkyl and heterocycloalkyl is independently substituted with 1 R6a; each R6ais independently C1-4alkyl or CN;alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C, wherein ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0247] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein X1is CH;X2is CH, CF, or N;X3is CH or CF; n is 0, 1, 2, or 3; each R4is independently methyl, fluoro, or difluoromethyl; ring A is piperidinyl or morpholinyl; ring B is phenyl, pyridyl, or benzothiazolyl; p is 1, or 2; q is 1, or 2; each R5is independently methyl; each R6is independently trifluoromethyl, chloro, bromo, difluoromethoxy, CN, HC=C-, HC=C-CH2-O-, cyclopropyl, or piperidinyl, wherein cyclopropyl and piperidinyl are each independently substituted with 1 R6a; each R6ais independently methyl or CN; alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C, wherein ring C is cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0248] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (II) or a subembodiment thereof, wherein X2is C(R2) or N;R2and R3are each independently H or halo; n is 0, 1, 2, or 3; each R4is independently C1-6alkyl, halo, or C1-6haloalkyl;Xais O or NH;X5ais absent, O, or CH2;X5bis O or CH2, provided that X5aand X5bare not both O; ring B is phenyl or heteroaryl having 6 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S;p is 1, or 2; q is 2; each R5is independently C1-6alkyl; each R6is independently C1-6haloalkyl, halo, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, or C3-6cycloalkyl, wherein each C3-6cycloalkyl is substituted with 1 R6a; and each R6ais CN.

[0249] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (II) or a subembodiment thereof, wherein X2is CH, CF, or N;R3is H or F; n is 0, 1, 2, or 3; each R4is independently methyl, fluoro, or difluoromethyl;Xais O or NH;X5ais absent, O, or CH2;X5bis O or CH2, provided that X5aand X5bare not both O; ring B is phenyl or pyridyl; p is 1, or 2; q is 2; each R5is independently methyl; each R6is independently trifluoromethyl, chloro, bromo, difluoromethoxy, CN, HC=C-, HOC-CH2-O-, or cyclopropyl, wherein cyclopropyl is substituted with 1 R6a; and each R6ais CN.

[0250] In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein the compound is selected from Table 1. In some embodiments, the compound or the pharmaceutically acceptable salt thereof, is a compound of Formula (I) or a subembodiment thereof, wherein the compound is selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the present disclosure provides a compound of Examples 1 to 7 or a pharmaceutically acceptable salt thereof. In some embodiments, a compound is selected from a compound of Examples 1 to 51, or a pharmaceutically acceptable salt thereof.

[0252] The present disclosure also includes prodrugs of the compound of Formula (I) or subembodiment thereof. As used herein, the term “prodrug” refers to compounds that readilyundergo chemical changes under physiological conditions to provide a pharmacologically active parent compound. The term “prodrug moiety” refers to the chemical moiety of a prodrug that is released under physiological conditions to form the active parent compound. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0253] A number of compounds in Table 1, below, include one or more stereocenters.When the absolute stereochemistry of a stereocenter is known, is represented by a wedged solid ) and / or dashed ( •■ ' ) chemical bond(s) at the stereocenter without any markings or with the label of “(R)” or “(S)”. When the absolute stereochemistry of one or more stereocenters in an isolated compound is not known, the following labels are indicated at the stereocenter of the displayed structure: “&” (e.g., “&1”); or “or” (e.g., “orl”, “or2”, or “or3”). Each of these labels is further described below.

[0254] The chemical names in the present application are generated from the corresponding structures using software, for example, CHEMDRAW.

[0255] The label “&” in the structures in the present disclosure refers to both chiral centers being present in the mixture. When multiple stereocenters are labelled with “&1” the relative stereochemistry between them is determined. The term “rac” in the chemical names denotes a racemic mixture.

[0256] For example, Al is a racemic mixture of two isomers, wherein the relative stereochemistry between two centers labeled with “&1” is known, as shown below:

[0257] The label “or” in the structures refers to the specific chiral center being a single undefined isomer but absolute stereochemistry was not determined. When multiple stereocenters are labelled with different labels, the relative stereochemistry between them is not determined. For example, in a compound with stereocenters labelled as “orl” and “or2”, the relative stereochemistry between the differently labelled stereocenters is not determined. When multiple stereocenters are labelled with the same label, the relative stereochemistry between the same labelled stereocenters is determined but not the absolute stereochemistry. For example, for all stereocenters labelled “orl”, the relative stereochemistry between those stereocenters labelled “orl” is determined but not the absolute stereochemistry.

[0258] For example, A2 isomer 1 is a single isomer, wherein the relative stereochemistry between two chiral centers labeled with “orl” is known, but the absolute stereochemistry is not yet determined. A2 isomer can be either the S,S-isomer or R,R-isomer.For example, A41 isomer 1 is a single isomer, wherein relative stereochemistry between two chiral centers labeled with the same “orl” is known; relative stereochemistry between chiral centers labeled with “orl” and “or2” is not known; and absolute stereochemistry of all three chiral centers is not yet determined. A41 isomer 1 can be any one of four isomers, as shown below:

[0259] Unless otherwise indicated, Isomer 1 refers to the first eluting isomer and Isomer 2 refers to the second eluting isomer during chiral chromatographic separation. Similarly,Isomer 3 refers to a third eluting isomer, and Isomer 4 refers to a fourth eluting isomer during chiral chromatographic separation.Table 1: Exemplary Compounds

[0260] Additional compounds of Formula (I) can be prepared according to the general procedures as described in Examples 1-54 via a coupling reaction of any one of aminesintermediates A1 to A111 and any one of carboxylic acid intermediates CA1 to CA11, wherein a combination of the amine and carboxylic acid intermediates is not used in Examples 1 to 54.PHARMACEUTICAL COMPOSITIONS

[0261] The compounds of Formula (I) or pharmaceutically acceptable salts thereof, or subembodiments thereof may be in the form of compositions suitable for administration to a subject. In general, such compositions are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a subembodiment thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic methods and uses described herein.

[0262] The pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutic agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0263] The pharmaceutical compositions containing the active ingredient (e.g., a compound of Formula (I), a pharmaceutically acceptable salt thereof) may be in a form suitable for oral use (for example as tablets, troches, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, or syrups, solutions, microbeads or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0264] Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Thus, compositions intended for oral use may contain, forexample, one or more coloring, sweetening, flavoring and / or preservative agents. Tablets and / or capsules contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets and / or capsules. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

[0265] The pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p- hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2- 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).

[0266] After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, e.g., anEpiPen®)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.

[0267] Any drug delivery apparatus may be used to deliver the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are known in the art.

[0268] An effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0269] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0270] All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein. For example, the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment and / or prevention of all diseases or disorders provided herein. Thus, the compounds and pharmaceutical compositions provided herein are for use as a medicament.THERAPEUTIC USES AND APPLICATIONS

[0271] Provided herein are compounds that function as inhibitors of protein arginine N- methyltransferase 5 (PRMT5).

[0272] The present disclosure therefore provides a method of inhibiting PRMT5 enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0273] The present disclosure also provides a method of treating a disease or disorder in which PRMT5 activity is implicated in a patient, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceuticalcomposition as defined herein. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer.

[0274] The present disclosure also provides a method of treating a disease or disorder treatable by inhibition of PRMT5 in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer.

[0275] The present disclosure also provides a method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0276] The present disclosure also provides a method of treating a cancer deficient in CDKN2A in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0277] 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, or a reduced function of MTAP protein, or a combination thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0278] The present disclosure also provides a method of treating a cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In some embodiments, the patient is in recognized need of such treatment.

[0279] The present disclosure also provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0280] The present disclosure also provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein. In an embodiment, the proliferative disorder is cancer.

[0281] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0282] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In some embodiments, the patient is in recognized need of such treatment.

[0283] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the inhibition of PRMT5 enzyme activity.

[0284] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder in which PRMT5 activity is implicated.

[0285] Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder treatable by inhibition of PRMT5.

[0286] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative condition. In some embodiments, the patient is in recognized need of such treatment.

[0287] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer. In some embodiments, the patient is in recognized need of such treatment.

[0288] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of PRMT5 enzyme activity.

[0289] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in whichPRMT5 activity is implicated.

[0290] Provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder treatable by inhibition of PRMT5.

[0291] In another aspect, the present disclosure provides a method of treating a cancer in a patient, comprising:(i) determining if the cancer is MTAP null; and(ii) if the cancer is MTAP null, administering to the patient a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0292] In some embodiments, the cancers described herein are a solid tumor. In some embodiments, the solid tumor is malignant. In some embodiments, the cancers described herein are a metastatic solid tumor.

[0293] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is neuroblastoma, intestine carcinoma (such as rectum carcinoma, colon carcinoma, familial adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer), esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma,endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors), Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non- small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma or plasmocytoma.

[0294] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is lung cancer, non-small cell lung (NSLC) cancer, bronchioloalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of tire endometrium, carcinoma of the vagina, carcinoma of the vulva, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multifonne, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenomas, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers,

[0295] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0296] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL) or mantle cell lymphoma (MCL).

[0297] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is gastric cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is colon cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is liver cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is glioblastoma multiforme (GBM). In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is bladder cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is esophageal cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is breast cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is NSLCC. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is MCL. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is DLBCL. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is ALL.

[0298] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non- Hodgkin lymphoma or mesothelioma. In some embodiments, the cancer is non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.

[0299] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreaticadenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC); e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0300] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is an MTA-accumulating cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is an MTAP-deficient cancer. In some embodiments, the cancer is treatable by inhibition of PRMT5.

[0301] The disclosure further relates to the use of compounds disclosed herein for the treatment and / or prophylaxis of diseases and / or conditions through inhibiting PRMT5 by said compounds. The disclosure further relates to the use of compounds disclosed herein for the treatment and / or prophylaxis of diseases and / or conditions through inhibiting PRMT5 by said compounds. The disclosure further relates to the use of compounds disclosed herein for the treatment and / or prophylaxis of diseases and / or conditions through inhibiting PRMT5 in MTAP- null cells by said compounds. Further, the present disclosure relates to the use of said compounds for the preparation of a medicament for the treatment and / or prophylaxis of a chromosome 9p21 deletion or MTAP-null associated disease and / or condition through inhibiting PRMT5 in MTAP-null cells by said compounds. In some embodiments the chromosome 9p21 deletion or MTAP-null associated disease or condition is alleviated by inhibition of PRMT5 in MTAP-null cells.

[0302] In some embodiments, provided herein is a method of treating and / or preventing a MTAP-null or chromosome 9p21 deletion associated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein.

[0303] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition includes a solid tumor in or arising from a tissue or organ, such as: • bone (e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiatedchondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cell tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma); • lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumors); • esophagus (e.g., Barrett's esophagus, dysplasia and adenocarcinoma); • gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus; • pancreas (e.g., serous neoplasms, including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)- associated serous cystic neoplasm, serous cystadenocarcinoma; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cell cystadenoma, acinar cell cystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid- pseudopapillary neoplasms (SPN), pancreatoblastoma); • gall bladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma); • neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas); • thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, papillary carcinoma, adenocarcinoma); • liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma,York sac tumor, carcinosarcoma, rhabdoid tumor); • kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase- deficient renal cell carcinoma, collecting duct carcinoma); • breast (e.g., invasive ductal carcinoma, including without limitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma; • peritoneum (e.g., mesothelioma; primary peritoneal cancer); • female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasia), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, endometrial malignant mullerian mixed tumours, gestational trophoblastic tumors (partial hydatiform mole, complete hydatiform mole, invasive hydatiform mole, placental site tumour)), vulva, vagina; • male sex organ tissues, including prostate, testis (e.g., germ cell tumors, spermatocytic seminoma), penis; • bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); • brain, (e.g., gliomas (e.g., astrocytomas, including non-infiltrating, low-grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, Non-Hodgkin lymphomas (NHLs), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, pituitary tumors; • eye(e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma); • head and neck (e.g., nasopharyngeal carcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal); • thymus (e.g., thymoma); • heart (e.g., cardiac myxoma); • lung (e.g., small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma); • lymph (e.g., lymphomas, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (NHL), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associated lymphoproliferative diseases, including B cell lymphomas and T cell lymphomas (e.g., Burkitt lymphoma; large B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low grade B cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK / T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma; follicular T cell lymphoma; systemic T cell lymphoma), lymphangioleiomyomatosis); • central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve glioma, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal- glial tumors, pineal region tumors, embryonal tumors, medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, Pituitary adenomas, cranial and paraspinal nerve tumors, stellar region tumors); neurofibroma, meningioma, peripheral nerve sheath tumors, peripheral neuroblastic tumours (including without limitation neuroblastoma,ganglioneuroblastoma, ganglioneuroma), trisomy 19 ependymoma); • neuroendocrine tissues (e.g., paraganglionic system including adrenal medulla (pheochromocytomas) and extraadrenal paraganglia ((extra-adrenal) paragangliomas); • skin (e.g., clear cell hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and • soft tissues (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's tumors / primitive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma / malignant lipomatous tumors, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft parts, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well- differentiated liposarcoma.

[0304] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition is a cancer selected from lung cancer, urothelial cancer, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cell neoplasms, head and neck cancer, bile duct cancer, esophagus cancer, glioblastoma, stomach cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, liver cancer, renal cancer, colorectal cancer, prostate cancer, leukemia, and cervical cancer.

[0305] In some embodiments, the chromosome 9p21 deletion or MTAP-null associated disease or condition is a cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic, and bladder cancer.

[0306] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer. In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is multiple myeloma (MM). In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is breast cancer. The breast cancer can be estrogen receptor negative (ER-) or the breast cancercan be progesterone receptor negative (PR-). In further embodiments, the breast cancer can be HER2 negative. In some embodiments, the breast cancer is estrogen receptor negative, progesterone receptor negative and HER2 negative, also referred to herein as "triple negative breast cancer".

[0307] In further aspects, a breast cancer can be a lobular carcinoma in situ (LCIS), a ductal carcinoma in situ (DOS), an invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumor, Angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapary carcinoma, mixed carcinoma, or another breast cancer, including but not limited to triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and HER and estrogen and progesterone receptor positive.

[0308] In an embodiment, the cancer treated by the methods, uses, or medicaments described herein is pancreatic cancer.

[0309] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is NSCLC (non-small cell lung carcinoma. In one embodiment, the NSCLC can be squamous NSCLC. In another embodiment, it can be adenocarcinoma. In a further aspect, cancer can be glioblastoma (GBM). In a further aspect, cancer can be mesothelioma. In one aspect, cancer can be bladder cancer. In another aspect, cancer can be esophageal cancer. In a further aspect, cancer can be melanoma. In one aspect, cancer can be DLBCL, HNSCC or cholangiocarcinoma.

[0310] In some aspects, one or more compounds described herein are useful for treating any PRMT5- mediated or PRMT5-responsive proliferative cell disorder, for example a cancer that is PRMT5 responsive.

[0311] In one aspect, a cancer that lacks p53 (e.g., a p53 null cancer) is less sensitive to PRMT5 inhibition than a cancer that is p53 positive. Accordingly, a cancer that is PRMT5 responsive can be a p53 positive cancer. The term "p53 positive" refers to a cancer that does not lack p53 expression and / or activity. In some embodiments, one or more compounds described herein are useful for treating a p53 positive cancer. In some aspects, a greater amount of one or more compounds described herein may be required to treat a p53 negative cancer (e.g. , a p53 null cancer) than a p53 positive cancer.

[0312] In some aspects, the disclosure provides a method for identifying subjects having a cancer that is sensitive to treatment with a PRMT5 inhibitor. In some embodiments, the method comprises obtaining a sample from the subject; detecting the presence or absence of p53; and, identifying the subject as having a cancer that is sensitive to treatment with a PRMT5 inhibitor if p53 is present in the sample. Accordingly, in some embodiments, a subject having a p53 positive cancer is identified as a subject for treatment with a PRMT5 inhibitor. In some embodiments, the method further comprises administering to the subject a composition comprising a PRMT5 inhibitor.

[0313] In some embodiments, the disclosure relates to a method for identifying subjects having a cancer that is insensitive (or that has low sensitivity) to treatment with a PRMT5 inhibitor. In some embodiments, the method comprises obtaining a sample from the subject; detecting the presence or absence of p53 ; and, identifying the subject as having a cancer that is not sensitive (for example, a cancer that is less sensitive than a p53 positive cancer) to treatment with a PRMT5 inhibitor if p53 is absent from the sample (e.g., if the cancer is a p53 null cancer). In some embodiments, a p53 negative cancer (e.g., a p53 null cancer) is treated with a PRMT5 inhibitor, but a greater amount of PRMT5 inhibitor may be required to treat the p53 negative cancer than a p53 positive cancer. However, in some embodiments, a subject having a p53 negative cancer (e.g. , a p53 null cancer) is treated with a therapeutic agent that is not a PRMT5 inhibitor.

[0314] By "sample" is meant any biological sample derived from the subject, includes but is not limited to, cells, tissues samples, body fluids (including, but not limited to, mucus, blood, plasma, serum, urine, saliva, and semen), cancer cells, and cancer tissues. Detection of the presence or absence of p53 in the sample may be achieved by any suitable method for detecting p53 nucleic acid or protein, for example, nucleic acid sequencing (e.g., DNA or RNA sequencing), quantitative PCR, Western blotting, etc., or any combination of thereof.

[0315] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangio sarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g. , cholangiocarcinoma), bladder cancer, brain cancer (e.g., meningioma; glioma, e.g. , astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g. , cervical adenocarcinoma), choriocarcinoma, chordoma,craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelio sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g. , adenocarcinoma of the esophagus, Barrett' s adenocarinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g. , stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g. , fl- cel! AML, T-cell AML), chronic myelocytic leukemia (CML) (e g. , B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g. , B-cell CLL, T- cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphomas (e.g. , mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., "Waldenstrom's macro globulinemia"), hairy cell leukemia (HCL), immunoblastic large cell ly mphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T- lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T- cell lymphoma (CTCL) (e.g. , mycosis fungiodes, Sezary syndrome), angioimmunoblastic T- cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis- like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g. , hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g. , systemic mastocytosis), myelodysplasia syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis,chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g. , neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g. , cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer (e.g., Paget' s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g. , squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g. , appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).

[0316] In some embodiments, the cancer treated by the methods, uses, or medicaments described herein is spinal cord cancer.COMBINATION THERAPY

[0317] The present disclosure contemplates the use of compounds of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents frequently have different, complementary mechanisms of action. Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

[0318] As used herein, “combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g.,as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a “co-formulation”).

[0319] In certain embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents. In other embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, subembodiments thereof, or pharmaceutical compositions as defined herein are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.

[0320] The present disclosure also contemplates the use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein in combination with at least one additional therapeutic agent as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0321] The present disclosure also provides a method of treating a disease or disorder in which PRMT5 activity is implicated in a patient, said method comprising administering to said patient (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment. In an embodiment, the disease or disorder is cancer.

[0322] The present disclosure also provides a method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment

[0323] The present disclosure also provides a method of treating a cancer deficient inCDKN2A in a patient comprising administering to the patient (a) a therapeutically effectiveamount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment.

[0324] 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, areduced function of MTAP protein, or a combination thereof comprising administering to the patient (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic agent. In some embodiments, the patient is in recognized need of such treatment.

[0325] The present disclosure provides methods for treating a cancer with (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein and (b) at least one additional therapeutic or diagnostic agent.Additional Therapeutic Agents

[0326] The disclosure provides one or more additional therapeutic agents for use with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof and one or more pharmaceutically acceptable excipients. A wide variety of therapeutic agents with anti-cancer activity and methods of making the same are known in the art. Each of these is embraced by this disclosure. In some embodiments, the one or more additional active therapeutic agents are one, two, three, or four additional therapeutic agents. i) Chemotherapeutic Agents

[0327] In an embodiment, the additional therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents include alkylating agent, microtubule inhibitors, antimetabolites, anti-tumor antibiotics, as well as corticosteroids.

[0328] In some embodiments, the chemotherapeutic agent is an alkylating agent. In some embodiments, the alkylating agent is altretamine, bendamustine, busulfan, improsulfan, piposulfan, procarbazine, mechlorethamine, carmustine, lomustine, semustine chlorambucil,cyclophosphamide, thiotepa, ifosfamide, dacarbazine, temozolomide, or perfosamide. In some embodiments, the alkylating agent is mechlorethamine. In some embodiments, the alkylating agent is perfosamide.

[0329] In an embodiment, the alkylating agent is a platinum-based chemotherapy agent. In some embodiments, the alkylating agent is carboplatin, cisplatin, oxaliplatin, nedaplatin, saraplatin, lobaplatin, or heptaplatin. In some embodiments, the alkylating agent is carboplatin. In some embodiments, the alkylating agent is cisplatin. In some embodiments, the alkylating agent is saraplatin.

[0330] In some embodiments, the chemotherapeutic agent is a microtubule inhibitor. In an embodiment, the microtubule inhibitor is eribulin, ixabepilone, cabazitaxel, enfortumab vedotin, trastuzumab emtansine, tirbanibulin. In some embodiments microtuial inhibitors are plant alkaloids. In some embodiments, the plant alkaloid is a taxane (taxol, paclitaxel and docetaxel), a vinca alkaloid (vinblastine, vincristine, vindesine and vinorelbine), colchicine, podophyllotoxin, or abraxane (protein-bound paclitaxel). In some embodiments, the chemotherapeutic agent is paclitaxel.

[0331] In some embodiments, the chemotherapeutic agent is an antimetabolite. In an embodiment, the antimetabolite is 5 -fluorouracil (5-FU), capecitabine, floxuridine, cytarabine, 5 -fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, cytosine arabinoside, 5-azacytidine, gemcitabine, clofarabine, mercaptopurine, thioguanine, azathioprine, pentostatin, erythrohydroxynonyladenine, fludarabine, cladribine decitabine, Azacitidine, vidaza, or methotrexate. In an embodiment, the antimetabolite is cladribine. In an embodiment, the antimetabolite is clofarabine. In an embodiment, the antimetabolite is cytarabine. In an embodiment, the antimetabolite is gemcitabine. In an embodiment, the antimetabolite is floxuridine.

[0332] In some embodiments, the chemotherapeutic agent is an antitumor antibiotics. In some embodiments, the antitumor antibiotic is bleomycin, dactinomycin, or mitomycin. In some embodiments, the antitumor antibiotic is daunorubicin, doxorubicin, doxil, epirubicin, idarubicin, mitoxantrone, valrubicin.

[0333] In some embodiments, the chemotherapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is prednisone, methylprednisolone, or dexamethasone.

[0334] Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fhidarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylomithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. In a particular embodiment, compounds of the present disclosure are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C. In a particular embodiment, the cytostatic compound is doxorubicin. Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormonal action on tumors such as antiestrogens, including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogens such as fhitamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises administration of a hormone or related hormonal agent. ii) Cell Cycle Checkpoint Inhibitors

[0335] In an embodiment, the additional therapeutic agent is a cell cycle checkpoint inhibitor. In some embodiments, the cell cycle checkpoint inhibitor is KU60019, AZD0156, Ceralasertib, Camonsertib, VE821, AZD7762, SRA737, Rabusertib, Prexasertib, SCH900776, or Adavosertib. In some embodiments, the cell cycle checkpoint inhibitor is KU60019. In some embodiments, the cell cycle checkpoint inhibitor is AZD0156. In some embodiments, the cell cycle checkpoint inhibitor is ceralasertib. In some embodiments, the cell cycle checkpoint inhibitor is camonsertib. In some embodiments, the cell cycle checkpoint inhibitor is VE821. In some embodiments, the cell cycle checkpoint inhibitor is AZD7762. In some embodiments, the cell cycle checkpoint inhibitor is SRA737. In some embodiments, the cell cycle checkpoint inhibitor is rabusertib. In some embodiments, the cell cycle checkpoint inhibitor is prexasertib. In some embodiments, the cell cycle checkpoint inhibitor is SCH900776. In some embodiments, the cell cycle checkpoint inhibitor is adavosertib.Hi) Immune Checkpoint Inhibitors

[0336] In an embodiment, the additional therapeutic agent is an immune check point inhibitor. In some embodiments, the immune checkpoint inhibitor is a PD-1 / PD-L1 inhibitor, a LAG-3 inhibitor, a CTLA-4 inhibitor, a BTLA inhibitor, a TIM-3 inhibitor, or a TIGIT inhibitor.

[0337] In an embodiment, the PD-1 / PD-L1 inhibitor is a PD-1 inhibitor. In an embodiment, the PD-1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, or atezolizumab. In an embodiment, the PD-1 inhibitor is nivolumab. In an embodiment, the PD-1 inhibitor is pembrolizumab. In an embodiment, the PD-1 inhibitor is cemiplimab. In an embodiment, the PD-1 inhibitor is dostarlimab. In an embodiment, the PD-1 inhibitor is zimberelimab. In an embodiment, the PD-1 inhibitor is retifanlimab. In an embodiment, the PD-1 inhibitor is atezolizumab.

[0338] In an embodiment PD-1 / PD-L1 inhibitor is a PD-L1 inhibitor. In an embodiment, the PD-L1 inhibitor is avelumab, atezolizumab, or durvalumab. In an embodiment, the PD-L1 inhibitor is avelumab. In an embodiment, the PD-L1 inhibitor is atezolizumab. In an embodiment, the PD-L1 inhibitor is durvalumab.

[0339] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is relatlimab.

[0340] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In some embodiments, the ipilimumab or tremelimumab

[0341] In some embodiments, the immune checkpoint inhibitor is a BTLA inhibitor.

[0342] In some embodiments, the immune checkpoint inhibitor is a TIM- 3 inhibitor. In some embodiments, the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367 (NCT03099109). In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM- 3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367 (NCT03099109). In some embodiments, the TIM- 3 inhibitor is sabatolimab. In some embodiments, the immune checkpoint inhibitor is a TIM- 3 inhibitor. In some embodiments, the TIM-3 inhibitor is TSR-022 (NCT02817633). In some embodiments, the TIM-3 inhibitor is MBG453 (NCT02608268). In some embodiments, the TIM-3 inhibitor is LY3321367 (NCT03099109).

[0343] In some embodiments, the immune checkpoint inhibitor is a TTGIT inhibitor. In some embodiments, the TTGIT inhibitor is tiragolumab, domvanalimab, vibostolimab, etigilimab, M6223, or ociperlimab. In some embodiments, the TIGIT inhibitor is tiragolumab. In some embodiments, the TIGIT inhibitor is domvanalimab. In some embodiments, the TTGIT inhibitor is vibostolimab. In some embodiments, the TIGITinhibitor is etigilimab. In some embodiments, the TIGIT inhibitor is M6223. In some embodiments, the TIGIT inhibitor is ociperlimab. iv) BCL-2 Inhibitors

[0344] In some embodiments, the additional therapeutic agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoclax, navitoclax, oblimersen, obatoclax mesylate, AT-101, subatoclax, maritoclax, gossypol, apogossypol, TW-37, UMI-77, or BDA- 366. v) Anti-CD20 therapeutic agent

[0345] In some embodiments, the additional therapeutic agent is an anti-CD20 therapeutic agent. In some embodiments, the anti-CD20 therapeutic agent is rituximab, arzerra, gazyva, ibritumomab tiuxetan, obinutuzumab, ofatumumab, riabni, rituxan, ruxience, truxima, zevalin, or tositumomab. vi) Hormonal Therapeutic Agent

[0346] In some embodiments, the additional therapeutic agent is a hormonal therapeutic agent. In some embodiments, the hormonal therapeutic agent is anastrozole, exemestand, letrozole, zoladex, lupon eligard, tamoxifen, raloxifene, goserelin, leuprorelin, fulvestrant, 4- hydroxytamoxifen, trioxifene, keoxifene, onapristone, toremifene; fhitamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, or goserelin. vii)PARP Inhibitors

[0347] In some embodiments, the additional therapeutic agent is a PARP inhibitor. In some embodiments, the PARP inhibitor is niraparib, rucaparib, olaparib, talazoparib, or veliparib. viii) MAT2A Inhibitors

[0348] In some embodiments, the additional therapeutic agent is a MAT2A inhibitor. In some embodiments, the MAT2A inhibitor is AG-270In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2020 / 123395, the contents of which is incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2018 / 045071, the contents of which is incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2021 / 252681, WO2021 / 252680, WO2021 / 252679, WO2021 / 252678, or WO2023 / 196985, the contents of which are incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2021 / 1259815, WO2023 / 066283, WO2024 / 217502, W02020 / 139991, W02020 / 139992, WO2018 / 045071, WO2018 / 039972, W02019191470, W02024 / 002024, or WO2024 / 217493, the contents of which are incorporated herein by reference for all purposes. In some embodiments, the MAT2A inhibitor is ISM3412 or S095035. In some embodiments, the MAT2A inhibitor is, or pharmaceutically acceptable salt thereof.

[0349] In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2022 / 268180, the contents of which are incorporated herein by reference for all purposes.

[0350] In some embodiments, the MAT2A inhibitor isor pharmaceutically acceptable salt thereof. ix) Radiotherapy

[0351] In some embodiments, the additional therapeutic agent is radiation therapy. x) VEGF Inhibitors

[0352] In some embodiments, the additional therapeutic agent is a VEGF inhibitor. In some embodiments, the VEGF inhibitor is Bevacizumab, aflibercept, ranibizumab, sorafenib, dasatinib, sunitinib, nilotinib, pazopanib, pegaptanib, axitinib, lenvatinib, ramucirumab, or regorafenib. xi) Tyrosine Kinase Inhibitors

[0353] In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is afatinib, cetuximab, imatinib, trastuzumab, gefitinib, dacomitinib, osimertinib, neratinib, ahnonertinib, brigatinib, icotinib, olmutinib, sorafenib, dasatinib, bosutinib, ponatinib, asciminib, sunitinib, erlotinib, nilotinib, lapatinib, tucatinib, pyrotinib, panitumumab, nimotuzumab, necitumumab, mobocertinib, vandetanib, lenvatinib, pazopanib, mubritinib, fostamatinib, calquence, pertuzumab, acalabrutinib, alectinib, cabozantinib, ceritinib, capmatinib, or crizotinib. xii)mT0R Inhibitors

[0354] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is rapamycin, everolimus, sirolimus, temsirolimus, everolimus, or sirolimus. xiii) AKT Inhibitors

[0355] In some embodiments, the additional therapeutic agent is an ATK inhibitor. In some embodiments, the ATK inhibitor is ipatasertib, mk-2206, perifosine, capivasertib, triciribine, or GSK690693. xiv)CDK Inhibitors

[0356] In some embodiments, the additional therapeutic agent is a CDK inhibitor. In some embodiments, the CDK inhibitor is flavopiridol, roscovitine, RO-3306, dinaciclib, milciclib, palbociclib, ribociclib, abemaciclib, BS-181, DRB, meriolin 3, variolin b, meridianin e, nortopsentins, AZD5438, roniciclib, SNS-032, sorafenib, K03861, THZ531, THZ1, E9, SY- 1365, or seliciclib. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, and abemaciclib. xv) PI3K Inhibitors

[0357] In some embodiments, the additional therapeutic agent is a PI3K inhibitor. In some embodiments, the PI3K inhibitor is idelalisib, alpelisib, leniolisib, duvelisib, or copanlisib. xvi)JAK Inhibitors

[0358] In some embodiments, the additional therapeutic agent is a JAK inhibitor. In some embodiments, the JAK inhibitor is tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, filgotinib, or abrocitinib. xvii) Inhibitors of Cereblon (Ubiquitin Ligase)

[0359] In some embodiments, the additional therapeutic agent is a inhibitor of cereblon. In some embodiments, the inhibitor of cereblon is thalidomide, lenalidomide. xviii ) MAPK / ERK Inhibitors

[0360] In some embodiments, the additional therapeutic agent is a MAPK / ERK inhibitor. In some embodiments, the MAPK / ERK inhibitor is vemurafenib, dabrafenib, octreotide, pasireotide, SB590885, GDC0879, LGX818, AZ628, RAF709, binimetinib, L-778, MK2206, pimasertib, rafametinib, salirasib, selumetinib, SML-8-731, tipifamib, lonafamib, trametinib, ulixertinib, WX-554, or cobimetinib. xix)Wnt / β~catenin Inhibitors

[0361] In some embodiments, the additional therapeutic agent is a Wnt / β-catenin inhibitor.In some embodiments, the Wnt / |3-catenin inhibitor is capmatinib, resibufogenin, or isoquercitrin. xx) Proteosome Inhibitors

[0362] In some embodiments, the additional therapeutic agent is a proteosome inhibitor. In some embodiments, the proteosome inhibitor bortezomib, carfilzomib, or ixazomib.xxi)Histone Deacetylase Inhibitors

[0363] In some embodiments, the additional therapeutic agent is a histone deacetylase inhibitor. In some embodiments, the histone deacetylase inhibitor vorinostat, romidepsin, panobinostat, or belinostat. xxii) Recombinant IL-2

[0364] In some embodiments, the additional therapeutic agent is a recombinant IL-2. In some embodiments, the recombinant IL-2 is aldesleukin. xxiii ) RANKL Inhibitors

[0365] In some embodiments, the additional therapeutic agent is a RANKL inhibitor. In some embodiments, the RANKL inhibitor is Denosumab or AS2676293. xxiv) B4GALNT1 Inhibitors

[0366] In some embodiments, the additional therapeutic agent is a B4GALNT1 inhibitor.In some embodiments, the B4GALNT1 inhibitor is Dinutuximab. xxv) SLAMF7 Inhibitors

[0367] In some embodiments, the additional therapeutic agent is a SLAMF7 inhibitor. In some embodiments, the SLAMF7 inhibitor is elotuzumab. xxvi) IDH2 / IDH1 Inhibitors

[0368] In some embodiments, the additional therapeutic agent is a IDH2 / IDH1 inhibitor. In some embodiments, the IDH2 / IDH1 inhibitor is enasidenib, ivosidenib, AGI-6780, AG- 221, FT-2102, IDH305, GSK 321, or BAY1436032. xxvii) BTK Inhibitors

[0369] In some embodiments, the additional therapeutic agent is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib. xxviii) FLT3 Inhibitors

[0370] In some embodiments, the additional therapeutic agent is a FLT3 inhibitor. In some embodiments, the FLT3 inhibitor is sunitinib, midostaurin, lestaurtinib, KW-2449, crenolanib, or gilteritinib. xxix) PDGFRa Inhibitors

[0371] In some embodiments, the additional therapeutic agent is a PDGFRa inhibitor. In some embodiments, the PDGFRa inhibitor is olaratumab, avapritinib, ayvakit, imatinib, ripretinib, or regorafenib. xxx) Smoothened ( Smo ) Inhibitors

[0372] In some embodiments, the additional therapeutic agent is a smoothened inhibitor.In some embodiments, the smoothened inhibitor is sonidegib, itraconazole, or glasdegib. xxxi ) LHRH antagonists or LHRH agonists

[0373] In some embodiments, the additional therapeutic agent is a LHRH antagonist or LHRH agonist. In some embodiments, the LHRH antagonist or LHRH agonist is goserelin, leuprorelin or buserelin. xxxii) Cell Based Therapy

[0374] In some embodiments, the additional therapeutic agent is a cell based therapy. In some embodiments, the cell based therapy is tumor-infiltrating lymphocyte (TIL) therapy; engineered t cell receptor (TCR) therapy; chimeric antigen receptor (CAR) T cell therapy; Natural Killer (NK) cell therapy; or sipuleucel-T. xxxiii) 0X40 Inhibitors

[0375] In some embodiments, the additional therapeutic agent is a 0X40 inhibitor. In some embodiments, the 0X40 inhibitor is ivuxolimab, cudarolimab, utomilumab, or INBRX- 106. xxxiv ) 41 BB ( CD! 37) Inhibitors

[0376] In some embodiments, the additional therapeutic agent is a 41BB (CD137) inhibitor. In some embodiments, the 41BB (CD137) inhibitor is urelumab. xxxv ) VISTA Inhibitors

[0377] In some embodiments, the additional therapeutic agent is a VISTA inhibitor. In some embodiments, the VISTA inhibitor is hmbd-002. xxxvi) CD96 Inhibitors

[0378] In some embodiments, the additional therapeutic agent is a CD96 inhibitor. In some embodiments, the CD96 inhibitor is GSK6097608. xxxvii) TGF β Inhibitors

[0379] In some embodiments, the additional therapeutic agent is a TGF / 3 inhibitor. In some embodiments, the TGF / 3 inhibitor is SAR-439459. xxxviii ) GDI 9 Inhibitors

[0380] In some embodiments, the additional therapeutic agent is a CD 19 inhibitor. In some embodiments, the CD 19 inhibitor is tafasitamab, loncastuximab tesirine, or blinatumomab. xxxix) CD30 Inhibitors

[0381] In some embodiments, the additional therapeutic agent is a CD30 inhibitor. In some embodiments, the CD30 inhibitor is brentuximab, vedotin, SGN-30, or MDX-060. xl) CD38 Inhibitors

[0382] 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

[0383] In some embodiments, the additional therapeutic agent is a CD39 inhibitor. In some embodiments, the CD39 inhibitor is purOOl, ES002023, TTX-030, IPH5201, or SRF617. xlii) CD52 Inhibitors

[0384] In some embodiments, the additional therapeutic agent is a CD52 inhibitor. In some embodiments, the CD52 inhibitor is alemtuzumab. xliii) CD73 Inhibitors

[0385] In some embodiments, the additional therapeutic agent is a CD73 inhibitor. In some embodiments, the CD73 inhibitor is oleclumab, PSB-12379, OP-5244, AB-680, CD73-IN-3, MethADP triammonium, dalutrafusp alfa, BK50164, mupadolimab, uliledlimab, MRS4620, BMS-986179, NZV930, AK119, SYM024, INCA00186, or ORIC-533. xliv) A2AR Inhibitors

[0386] In some embodiments, the additional therapeutic agent is an A2AR inhibitor. In some embodiments, the A2AR inhibitor is istradefylline, vipadenant, CVT-6883, cnprofylline, ciforadenant, imaradenant, etrumadenant, NIR178, EOS100850, CS3005, PBF- 999, or INCB 106385. xlv)A2BR Inhibitors

[0387] In some embodiments, the additional therapeutic agent is an A2BR inhibitor. In some embodiments, the A2BR inhibitor is pbf-1129, QAF805, LAS101057 AB928, ISAM 140, or TT-4. xlvi) IDO1 & TDO2 Inhibitors

[0388] In some embodiments, the additional therapeutic agent is an IDO1 or a TDO2 inhibitor. In some embodiments, the IDO1 or TDO2 inhibitor is Indoximod, Epacadostat, Navoximod, PF-06840003, BGS-5777, BMS-986205, LW106, IOM2983, RG-70099, LY- 3381916, NLG-802, or LPM-3480226. xlvii) Arginase Inhibitors

[0389] In some embodiments, the additional therapeutic agent is an arginase inhibitor. In some embodiments, the arginase inhibitor is numidargistat, pegzilarginase, or INCB001158. xlviii) B7-H3 Inhibitors

[0390] In some embodiments, the additional therapeutic agent is a B7-H3 inhibitor. In some embodiments, the B7-H3 inhibitor is enoblituzumab, I-Omburtamab, DS-7300, or MGC018. xlix) B7-H4 Inhibitors

[0391] In some embodiments, the additional therapeutic agent is a B7-H4 inhibitor. In some embodiments, the B7-H4 inhibitor is mt- 1660, FPA150, or AZD8205.I) Signal Transduction Inhibitor (STI)

[0392] As used herein, the term “signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signaling pathway. Examples of signal transduction inhibitors (STIs) useful in methods described herein include, but are not limited to: (i) bcr / abl kinase inhibitors (e.g., GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) her-2 / neu receptor inhibitors (e.g., HERCEPTIN); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositol kinase inhibitors. li ) Spicing Inhibitor Sulfonamides ( SPLAMs )

[0393] In some embodiments, the additional therapeutic agent is a Spicing inhibitor sulfonamide (SPLAM).

[0394] In some embodiments, the SPLAM is indisulam or E7820. lit) Additional Therapeutic Agents

[0395] In some embodiments, the additional therapeutic agent is a monoclonal antibody against a tumor antigen, a complex of a monoclonal antibody and toxin, a T-cell adjuvant, bone marrow transplant, or antigen presenting cells (e.g., dendritic cell therapy).

[0396] In some embodiments, the additional therapeutic agent is a an antibody drug conjugate (ADC) comprising one or more antitumor compound conjugated to an antibody via a linker. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody is a monospecific antibody. A number of ADCs comprising antitumor compounds and methods of making the same are known in the art. Each of these is embraced by this disclosure. In an embodiment, the antitumor compound is an additional therapeutic agent disclosed herein. In an embodiment, the antitumor compound is a chemotherapeutic agent disclosed herein.

[0397] In some embodiments, the additional therapeutic agent is Temozolomide, Pemetrexed, Pegylated liposomal doxorubicin (Doxil), Eribulin (Halaven), Ixabepilone (Ixempra), Protein-bound paclitaxel (Abraxane), Oxaliplatin, Irinotecan, Venatoclax (bcl2 inhibitor), 5-azacytadine, Anti-CD20 therapeutics, such as Rituxan and obinutuzumab, Hormonal agents (anastrozole, exemestand, letrozole, zoladex, lupon eligard), CDK4 / 6 inhibitors, Palbociclib, Abemaciclib, CPI (Avelumab, Cemiplimab-rwlc, and Bevacizumab).DOSING

[0398] A compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered.

[0399] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The “median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeuticresponse or desired effect in 50% of the population to which it is administered. Although the ED50is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.ROUTES OF ADMINISTRATION

[0400] A compound of Formula (I) or a pharmaceutically acceptable salt thereof, a subembodiment thereof, or a pharmaceutical composition as defined herein comprising this compound may be administered to a patient by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0401] Routes or administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Some embodiments of the present invention contemplate oral administration.NON-LIMITING EXEMPLARY EMBODIMENTS

[0402] The compounds of the current application can be further described by the following non-limiting exemplary embodiments:

[0403] Embodiment 1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinX1is C(R') or N;X2is C(R2) or N;X3is C(R3) or N;R1, R2, and R3are each independently H, C1-4alkyl, halo, or C1-4haloalkyl; n is 0, 1, 2, 3, or 4; each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl; alternatively, two R4groups when attached to the same carbon atom combine to form oxo or C3-6cycloalkyl; ring A is heterocycloalkyl comprising 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2; ring B is C6-10aryl or heteroaryl comprising 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R5is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, or -C(O)OC1-6haloalkyl; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, - C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, -C(O)OC1-6haloalkyl, or heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a;R6ais C1-4alkyl, halo, or C1-4haloalkyl; alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C comprising C4-7cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R5ais independently C1-4alkyl, halo, or C1-4haloalkyl; alternatively, two R5agroups attached to the same carbon atom combine to form oxo.

[0404] Embodiment 2. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein X1is N.

[0405] Embodiment 3. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein X1is C(R' ) and R1is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0406] Embodiment 4. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein X1is C(R1) and R1is H, methyl, ethyl, fluoro, chloro, or bromo.

[0407] Embodiment 5. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein X1is C(R1) and R1is H, methyl, fluoro, chloro, or trifluoromethyl.

[0408] Embodiment 6. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein X1is CH.

[0409] Embodiment 7. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 6, wherein X2is N.

[0410] Embodiment 8. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 6, wherein X2is C(R2) and R2is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0411] Embodiment 9. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 6, wherein X2is C(R2) and R2is H, methyl, ethyl, fluoro, chloro, or bromo.

[0412] Embodiment 10. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 6, wherein X2is C(R2) and R2is H, methyl, fluoro, chloro, or trifluoromethyl.

[0413] Embodiment 11. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 6, wherein X2is CH or CF.

[0414] Embodiment 12. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 6, wherein X2is CH.

[0415] Embodiment 13. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 6, wherein X2is CF.

[0416] Embodiment 14. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 13, wherein X3is N.

[0417] Embodiment 15. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 13, wherein X3is C(R3) and R3is H, methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0418] Embodiment 16. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 13, wherein X3is C(R3) and R3is H, methyl, ethyl, fluoro, chloro, or bromo.

[0419] Embodiment 17. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 13, wherein X3is C(R3) and R3is H, methyl, fluoro, chloro, or trifluoromethyl.

[0420] Embodiment 18. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 13, wherein X3is CH or CF.

[0421] Embodiment 19. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 13, wherein X3is CH.

[0422] Embodiment 20. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 13, wherein X3is CF.

[0423] Embodiment 21. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 20, wherein each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl.

[0424] Embodiment 22. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 20, wherein each R4is independently C1-4alkyl, halo, or C1-4haloalkyl.

[0425] Embodiment 23. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 22, wherein n is 0, 1, or 2.

[0426] Embodiment 2244.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 22, wherein n is 0 or 1.

[0427] Embodiment 2255.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 22, wherein n is 0.

[0428] Embodiment 26. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 22, wherein n is 2 and each R4is independently F.

[0429] Embodiment 2277.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 26, wherein ring A is heterocycloalkyl comprising 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0430] Embodiment 28. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 26, wherein ring A is heterocycloalkyl comprising 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 1 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0431] Embodiment 2299.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 26, wherein ring A is pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyL

[0432] Embodiment 3300.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 26, wherein ring A is piperidinyl, piperazinyl, or morpholinyL

[0433] Embodiment 31. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 30, wherein ring A is piperidinyl, substituted with 1 or 2 R5.

[0434] Embodiment 32. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 30, wherein ring A is morpholinyL substituted with 1 or 2 R5.

[0435] Embodiment 33. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 32, wherein R5is C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, or C1-6haloalkoxy.

[0436] Embodiment 34. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 32, wherein R5is C1-4alkyl, C1-4haloalkyl, or halo.

[0437] Embodiment 35. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 32, wherein R5is methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0438] Embodiment 36. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 32, wherein R5is methyl.

[0439] Embodiment 3377.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36, having Formula (la)(la)wherein, ring B is phenyl or heteroaryl comprising 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; q is 0, 1, or 2; and ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and comprises C4-7cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0440] Embodiment 3388.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36, having Formula (Ial-1)(Ial-1) wherein,Xais O, CH2, or CHR5; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7cycloalkyl or heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0441] Embodiment 39. The compound of embodiments 37 or 38, wherein ring C is C4-7cycloalkyl substituted with 0, 1, 2, or 3 R5a.

[0442] Embodiment 40. The compound of embodiments 37 or 38, wherein ring C is C4-6 cycloalkyl substituted with 0, 1, 2, or 3 R5a.

[0443] Embodiment 41. The compound of embodiments 37 or 38, wherein ring C is C5-6cycloalkyl substituted with 0, 1, or 2 R5a.

[0444] Embodiment 42. The compound of embodiments 37 or 38, wherein ring C is Ce cycloalkyl substituted with 0, 1, or 2 R5a.

[0445] Embodiment 43. The compound of embodiments 37 or 38, wherein ring C is C5 cycloalkyl substituted with 0, 1, or 2 R5a.

[0446] Embodiment 44. The compound of embodiments 37 or 38, wherein ring C is heterocycloalkyl comprising 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0447] Embodiment 4455.. The compound of embodiments 37 or 38, wherein ring C is heterocycloalkyl comprising 4 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0448] Embodiment 4466.. The compound of embodiments 37 or 38, wherein ring C is heterocycloalkyl comprising 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0449] Embodiment 4477.. The compound of embodiments 37 or 38, wherein ring C is heterocycloalkyl comprising 5 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, or 2 R5a.

[0450] Embodiment 4488.. The compound of embodiments 37 or 38, wherein ring C is heterocycloalkyl comprising 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0451] Embodiment 49. The compound of embodiments 37 or 38, wherein ring C is heterocycloalkyl comprising 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0452] Embodiment 50. The compound of embodiments 37 or 38, wherein ring C is tetrahydropyranyl substituted with 0, 1, or 2 R5a.

[0453] Embodiment 51. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36, having Formula (Ia2-1)(Ia2-1)wherein,Xais absent, O, CH2, or CHR5;X5ais absent, O or CH2, or CHR5a;X5bis absent, O or CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2.

[0454] Embodiment 52. The compound or a pharmaceutically acceptable salt thereof of embodiment 51, wherein Xais O, CH2, or CHR5; X5ais O or CH2, or CHR5a; X5bis O or CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1 , or 2.

[0455] Embodiment 53. The compound or a pharmaceutically acceptable salt thereof of embodiment 51 or 52, wherein X5ais O, and X5bis CH2.

[0456] Embodiment 54. The compound or a pharmaceutically acceptable salt thereof of embodiment 51 or 52, wherein X5ais CH2, and X5bis O.

[0457] Embodiment 55. The compound or a pharmaceutically acceptable salt thereof of embodiment 51 or 52, wherein X5ais CH2, and X5bis CH2.

[0458] Embodiment 56. The compound or a pharmaceutically acceptable salt thereof of embodiment 51, wherein X5ais absent, and X5bis CH2.

[0459] Embodiment 57. The compound or a pharmaceutically acceptable salt thereof of embodiment 51, wherein X5ais absent, and X5bis O.

[0460] Embodiment 58. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein R5ais C1-4alkyl, halo, or C1-4haloalkyl.

[0461] Embodiment 59. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein R5ais methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0462] Embodiment 60. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein R5ais methyl, fluoro, chloro, or trifluoromethyl

[0463] Embodiment 61. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 57, wherein two R5agroups attached to the same carbon atom combine to form oxo.

[0464] Embodiment 62. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 61, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, or C1-6haloalkoxy.

[0465] Embodiment 63. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 61, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, or halo.

[0466] Embodiment 64. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 61, wherein each R6is independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0467] Embodiment 65. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 61, wherein each R6is independently bromo or trifluoromethyl.

[0468] Embodiment 66. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36, wherein the moiety has the formula:

[0469] Embodiment 6677.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36, having Formula (Ib)(Ib)wherein,Xais O, CH2, or CHR5; ring B is heteroaryl comprising 9 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; and q is 0, 1, 2, or 3.

[0470] Embodiment 6688.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, wherein p is 1.

[0471] Embodiment 69. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 67, wherein p is 2.

[0472] Embodiment 7700.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 69, wherein q is 0.

[0473] Embodiment 71. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 69, wherein q is 1.

[0474] Embodiment 7722.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 69, wherein q is 2.

[0475] Embodiment 7733.. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36, having Formula (Ibl)(Ibl).

[0476] Embodiment 74. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36 and 67 to 73, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, or heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a.

[0477] Embodiment 75. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36 and 67 to 73, wherein each R6is independently C1-4alkyl, C1-4haloalkyl, halo, or heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a.

[0478] Embodiment 76. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36 and 67 to 73, wherein each R6is independently heterocycloalkyl comprising 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a.

[0479] Embodiment 77. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36 and 67 to 73, wherein each R6is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl substituted with 0, 1, or 2 R6a.

[0480] Embodiment 78. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36 and 67 to 73, wherein each R6is piperidinyl substituted with 0, 1, or 2 R6a.

[0481] Embodiment 79. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36 and 67 to 78, wherein each R6ais C1-4alkyl.

[0482] Embodiment 80. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36 and 67 to 78, wherein each R6ais independently methyl, ethyl, fluoro, chloro, bromo, fluoromethyl, difluoromethyl, or trifluoromethyl.

[0483] Embodiment 81. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36, and 67 to 78, wherein each R6ais methyl.

[0484] Embodiment 82. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 36 and 67 to 81, wherein the moietyhas the formula:

[0485] Embodiment 8833.. The compound or a pharmaceutically acceptable salt thereof of embodiment 1, wherein the compound is selected from Table 1.

[0486] Embodiment 84. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, and a pharmaceutically acceptable excipient.

[0487] Embodiment 8855.. A method for treating a disease treatable by inhibition of protein arginine N-methyltransferase 5 (PRMT5) in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84.

[0488] Embodiment 86. The method of embodiment 85, wherein the disease is cancer.

[0489] Embodiment 8877.. A method of treating an MTAP null cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84.

[0490] Embodiment 88. A method for treating a cancer in a patient, wherein the cancer is characterized by a reduction or absence of MTAP gene expression, the absence of the MTAP gene, absence of MTAP protein, reduced level of MTAP protein, or reduced function of MTAP protein, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84.

[0491] Embodiment 8899.. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84.

[0492] Embodiment 90. The method of any one of embodiments 86 to 89, wherein the cancer is an MTAP-deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0493] Embodiment 91. The method of embodiment 86 or 90, wherein the cancer is deficient in CDKN2A.

[0494] Embodiment 92. The method of any one of embodiments 86 to 91, wherein the cancer is a solid tumor.

[0495] Embodiment 93. The method of embodiment 92, wherein the solid tumor is malignant.

[0496] Embodiment 9944.. The method of any one of embodiments 86 to 93, wherein the patient is in recognized need of such treatment.

[0497] Embodiment 95. The method of any one of embodiments 86 to 94, wherein the cancer is selected from the group consisting of biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, Ever, soft tissue, pleura and large intestine or sarcoma.

[0498] Embodiment 9966.. The method of any one of embodiments 86 to 94, wherein the cancer is selected from the group consisting of leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma.

[0499] Embodiment 9977.. The method of any one of embodiments 86 to 94, wherein the cancer is selected from the group consisting of non-small cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

[0500] Embodiment 9988.. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84, for use in therapy.

[0501] Embodiment 99. A compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84, for use in the treatment cancer.

[0502] Embodiment 100. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 99, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0503] Embodiment 101. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 99 or 100, wherein said cancer is deficient in CDKN2A.

[0504] Embodiment 102. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 99 to 101, wherein said cancer is an MTAP null cancer.

[0505] Embodiment 103. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 99 to 101, 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.

[0506] Embodiment 104. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 99 to 103, wherein said cancer is a solid tumor.

[0507] Embodiment 105. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 104, wherein the solid tumor is malignant.

[0508] Embodiment 106. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 99 to 105, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer ( e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladder urothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0509] Embodiment 107. The compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of embodiments 99 to 105, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma or mesothelioma.

[0510] Embodiment 108. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84, in the manufacture of a medicament for use in therapy.

[0511] Embodiment 109. Use of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 39, in the manufacture of a medicament for use in the treatment of cancer.

[0512] Embodiment 110. The use of embodiment 109, wherein said cancer is an MTAP- deficient cancer, MTA-accumulating cancer, or a combination thereof.

[0513] Embodiment 111. The use of embodiment 109 or 110, wherein said cancer is deficient in CDKN2A.

[0514] Embodiment 112. The use of any one of embodiments 109 to 111, wherein said cancer is an MTAP null cancer.

[0515] Embodiment 113. The use of any one of embodiments 109 to 111, 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.

[0516] Embodiment 114. The use of any one of embodiments 109 to 113, wherein said cancer is a solid tumor.

[0517] Embodiment 115. The use of embodiment 114, wherein said solid tumor is malignant.

[0518] Embodiment 116. The use of any one of embodiments 109 to 115, wherein said cancer is biliary tract cancer, glioblastoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), colon cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), gastric cancer, bladder cancer (e.g., bladderurothelial carcinoma, gallbladder cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, lung cancer (e.g., non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma)), astrocytoma, undifferentiated pleiomorphic sarcoma, lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma), stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

[0519] Embodiment 117. The use of any one of embodiments 109 to 115, wherein said cancer is leukemia, esophageal cancer, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma or mesothelioma.

[0520] Embodiment 118. A method of inhibiting protein arginine N-methyltransferase 5 (PRMT5) in vivo in a patient, said method comprising administering to said patient an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84.

[0521] Embodiment 119. A method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84.

[0522] Embodiment 120. A method for inhibiting PRMT5 activity in a cell, comprising contacting the cell in which inhibition of PRMT5 activity is desired with an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1 to 83, or a pharmaceutical composition of embodiment 84.

[0523] The compounds of the current application can also be described by the following additional non-limiting exemplary embodiments:

[0524] Embodiment 1A. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinX1is C(R1) or N;X2is C(R2) or N;X3is C(R3) or N;R1, R2, and R3are each independently H, C1-4alkyl, halo, or C1-4haloalkyl; n is 0, 1, 2, 3, or 4; each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl; alternatively, two R4groups when attached to the same carbon atom combine to form oxo or C3-6cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or )2; S(O ring B is C6-10aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R5is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, or -C(O)OC1-6haloalkyl; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, -O-C3-6cycloalkyl, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, -C(O)OC1-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6cycloalkyl, -O-C3-6cycloalkyl, and heterocycloalkyl is independently substituted with 0, 1, or 2 R6a; each R6ais independently C1-4alkyl, halo, C1-4haloalkyl, CN, OH, or C1-4alkoxy; alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C, wherein ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R5ais independently C1-4alkyl, halo, C1-4haloalkyl, OH, or C1-4alkoxy; alternatively, two R5agroups attached to the same carbon atom combine to form oxo.

[0525] Embodiment 2A. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, whereinX1is C(R') or N;X2is C(R2) or N;X3is C(R3) or N;R1, R2, and R3are each independently H, C1-4alkyl, halo, or C1-4haloalkyl; n is 0, 1, 2, 3, or 4; each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl; alternatively, two R4groups when attached to the same carbon atom combine to form oxo or C3-6cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is C6-10aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; each R5is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, or -C(O)OC1-6haloalkyl; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, - C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, -C(O)OC1-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices,wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a; each R6ais independently C1-4alkyl, halo, or C1-4haloalkyl; alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C, wherein ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a, and ring A, ring B, and ring C form a fused tricyclic moiety; and each R5ais independently C1-4alkyl, halo, or C1-4haloalkyl; alternatively, two R5agroups attached to the same carbon atom combine to form oxo.

[0526] Embodiment 3A. The compound or a pharmaceutically acceptable salt thereof of embodiment 1A or 2A, wherein X1is C(R'); and R1is H, methyl, fluoro, chloro, or trifluoromethyl.

[0527] Embodiment 4A. The compound or a pharmaceutically acceptable salt thereof of embodiment 1A or 2A, wherein X1is CH.

[0528] Embodiment 5A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 4A, wherein X2is N.

[0529] Embodiment 6A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 4A, wherein X2is C(R2); and R2is H, methyl, fluoro, chloro, or trifluoromethyl.

[0530] Embodiment 7A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 4A, wherein X2is CH or CF.

[0531] Embodiment 8A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 7A, wherein X3is C(R3); and R3is H, methyl, fluoro, chloro, or trifluoromethyl.

[0532] Embodiment 9A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 7A, wherein X3is CH or CF.

[0533] Embodiment 10A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 9A, wherein each R4is independently C1-4alkyl, halo, or C1-4haloalkyl.

[0534] Embodiment 11A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 10A, wherein each R4is independently methyl, fluoro, or difluoromethyl.

[0535] Embodiment 12A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 11A, wherein n is 0, 1, 2, or 3.

[0536] Embodiment 13A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 11A, wherein n is 2; and each R4is independently fluoro.

[0537] Embodiment 14A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 13A, wherein ring A is heterocycloalkyl having 4 to 6 ring members with at least 1 nitrogen atom ring vertex, and 0 to 1 additional heteroatoms as ring vertices, wherein each heteroatom is independently N, O, or S.

[0538] Embodiment ISA. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 14A, wherein ring A is piperidinyl or morpholinyl, substituted with 1 or 2 R5.

[0539] Embodiment 16. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to ISA, wherein each R5is independently C1-4alkyl, C1-4haloalkyl, or halo.

[0540] Embodiment 17A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 16A, wherein each R5is independently methyl.

[0541] Embodiment 18A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A, wherein ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, substituted with 1 or 2 R6.

[0542] Embodiment 19A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 18A, wherein ring B is phenyl or pyridyl substituted with 2 R6.

[0543] Embodiment 20A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 19A, having Formula (la)wherein, ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; q is 0, 1, or 2; and ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B, and comprises C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0544] Embodiment 21 A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A, having Formula (Ial-1)wherein,Xais O, CH2, or CHR5; p is 0 or 1 ; q is 0, 1, or 2; and ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0545] Embodiment 22A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A, having Formula (Ial-2)wherein,Xais O, CH2, or CHR5; p is 0 or 1; q is 0, 1, or 2; and ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0546] Embodiment 23A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 20A to 22A, wherein ring C is C5-6cycloalkyl substituted with 0, 1, or 2 R5a.

[0547] Embodiment 24A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 20A to 22A, wherein ring C is heterocycloalkyl having 5 to 6 ring members with 1 to 2 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, S(O), or S(O)2, wherein ring C is substituted with 0, 1, 2, or 3 R5a.

[0548] Embodiment 25A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 20A to 22A, wherein ring C is cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl substituted with 0, 1, or 2 R5a.

[0549] Embodiment 26A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 20A to 22A, wherein ring C is tetrahydropyranyl substituted with 0, l, or 2 R5a.

[0550] Embodiment 27A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A, having Formula (Ia2-1)wherein,Xais absent, O, CH2, or CHR5;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2, provided that X5aand X5bare not each absent or O.

[0551] Embodiment 28A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A, having Formula (Ia2-2) wherein,Xais absent, O, CH2, or CHR5;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2, provided that X5aand X5bare not each absent or O.

[0552] Embodiment 29A. The compound or a pharmaceutically acceptable salt thereof of embodiment 27A or 28A, wherein Xais O, CH2, or CHR5;X5ais O, CH2, or CHR5a;X5bis O, CH2, or CHR5a; p is 0, 1 or 2; and q is 0, 1, or 2, provided that X5aand X5bare not each O.

[0553] Embodiment 30A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 27A to 29A, wherein X5ais O, and X5bis CH2.

[0554] Embodiment 31A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 27A to 29A, wherein X5ais CH2, and X5bis O.

[0555] Embodiment 32A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 27A to 29A, wherein X5ais CH2, and X5bis CH2.

[0556] Embodiment 33A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 27A to 29A, wherein X5ais absent, and X5bis CH2.

[0557] Embodiment 34A. The compound or a pharmaceutically acceptable salt thereof of embodiment 27 A to 29A, wherein X5ais absent, and X5bis O.

[0558] Embodiment 35A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 34A, wherein each R5ais independently methyl, fluoro, chloro, or trifluoromethyl

[0559] Embodiment 36A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 35A, wherein each R6is independently C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, halo, C1-6alkoxy, C2-6alkynyloxy, C1-6haloalkoxy, or CN.

[0560] Embodiment 37A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 35A, wherein each R6is independently HC=C - trifluoromethyl, chloro, bromo, HC=C-CH2-O— , diflUOromethoxy, CN, or cyclopropyl.

[0561] Embodiment 38A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 20A, wherein the moietyhas the formula:

[0562] Embodiment 39A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 18A, having Formula (lb)wherein,Xais O, CH2, or CHR5; ring B is C6-10aryl or heteroaryl having 9 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1 or 2; and q is 0, 1, 2, or 3.

[0563] Embodiment 40A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 39A, wherein p is 1.

[0564] Embodiment 41 A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 40A, wherein q is 2.

[0565] Embodiment 42A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A, having Formula (lb 1)

[0566] Embodiment 43A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A and 39A to 42A, wherein each R6is independently C1-4haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a.

[0567] Embodiment 44A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A and 39A to 42A, wherein each R6is piperidinyl substituted with 0, 1, or 2 R6a.

[0568] Embodiment 45A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 17A, and 39A to 44A, wherein each R6ais methyl.

[0569] Embodiment 46A. The compound or a pharmaceutically acceptable salt thereof of( any one of embodiments 1A to 17A and 39A to 45A, wherein the moietyhas the formula:

[0570] Embodiment 47 A. The compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 46A, wherein the moiety has theformula:

[0571] Embodiment 48A. The compound or a pharmaceutically acceptable salt thereof of embodiment 1A, whereinX1is CH;X2is C(R2) or N;X3is C(R3);R2and R3are each independently H or halo; n is 0, 1, 2, or 3; each R4is independently C1-6alkyl, halo, or C1-6haloalkyl;ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, S, S(O), or S(O)2; ring B is C6-10aryl or heteroaryl having 5 to 10 ring members with 1 to 4 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 1, or 2; q is 1, or 2; each R5is independently C1-6alkyl; each R6is independently C1-6haloalkyl, halo, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6cycloalkyl and heterocycloalkyl is independently substituted with 1 R6a; each R6ais independently C1-4alkyl or CN; alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C, wherein ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, S, S(O), or S(O)2.

[0572] Embodiment 49A. The compound or a pharmaceutically acceptable salt thereof of embodiment 1A, whereinX1is CH;X2is CH, CF, or N;X3is CH or CF; n is 0, 1, 2, or 3; each R4is independently methyl, fluoro, or difluoromethyl; ring A is piperidinyl or morpholinyl; ring B is phenyl, pyridyl, or benzothiazolyl; p is 1, or 2; q is 1, or 2; each R5is independently methyl; each R6is independently trifluoromethyl, chloro, bromo, difluoromethoxy, CN, HC=C-HC=C-CH2-O-;cyclopropyl, or piperidinyl, wherein cyclopropyl and piperidinyl are each independently substituted with 1 R6a;each R6ais independently methyl or CN; alternatively, one R5attached to ring A and one R6attached to ring B combine to form ring C, wherein ring C is cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0573] Embodiment 50A. The compound or a pharmaceutically acceptable salt thereof of embodiment 1A, wherein the compound is selected from Table 1.

[0574] Embodiment 51A. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A to 50A, and a pharmaceutically acceptable excipient.

[0575] Embodiment 52A. A method or use as described herein of a compound of any one of embodiments 1A to 50A, or a pharmaceutical composition of embodiment 51A.EXAMPLES

[0576] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the experiments below were performed or that they are all of the experiments that may be performed. It is to be understood that exemplary descriptions written in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate data and the like of a nature described therein. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental errors and deviations should be accounted for.List of Selected Abbreviations:MeOH - methanolMeCN - acetonitrilePdCh(dppf)-DCM adduct - palladium chloride- 1 ,1 -ferrocenediyl-bis(diphenylphosphino)- dichloromethane adductK2CO3- potassium carbonateAPhos Pd G3 - palladium G3-(4-(N,N -Dimethylamino)phenyl)di-tert-butylphosphine, [4- (Di-tert-butylphosphino)-7V,7V-dimethylaniline-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate dppf Pd G3 - methanesulfonato l,l-ferrocenediyl-bis(diphenylphosphino) (2'-amino-l,l - biphenyl-2-yl) palladium(II)DI H2O - deionized water(4,4'-dtbbpy)NiC12 - [4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride[Ir(dtbbpy)(ppy)2]PF6 - [4,4'-Bisl,l-dimethylethyl)-2,2'-bipyridine-N1, N1']bis[2-(2- pyridinyl-7V)phenyl-C]iridium(III) hexafluorophosphateAminosupersilane - N-(Adamantan-l-yl)-1 , 1,1, 3,3, 3-hexamethyl-2-(trimethylsilyl)trisilan-2- amineDPPF Pd G3 - Methanesulfonato l,l-ferrocenediyl-bis(diphenylphosphino) (2 '-amino- 1,1'- biphenyl-2-yl) palladium(II)Na2CO3- sodium carbonateAcCN - acetonitrileTsOH - p-Toluenesulfonic acid i-PrOH - isopropanolTHF - tetrahydrofuranDMF - N,N -dimethylformamideDCM -dichloromethaneTFA - trifluoroacetic acidNaH - sodium hydrideTIPSOTf - Triisopropylsilyl trifluoromethanesulfonateNH4CI - ammonium chlorideEtOAC - ethyl acetateDBU - 1,8-diazabicyclo(5.4.0)undec-7-eneSynthesis ExamplesCarboxylic Acid (CA) intermediate synthesisIntermediate CAI: 1:1 mixture of (S)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acid and (R)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acidStep 1: tert-butyl 5-(2-amino-3-fluoro-5-(methoxycarbonyl)phenyl)-2,3-dihydro-lH-pyrrole-1 -carboxylate

[0577] A mixture of methyl 4-amino-3-bromo-5-fluorobenzoate (5.00 g, 20.15 mmol),Palladium acetate (452 mg, 2.01 mmol), PPh3(1.05 g, 4.03 mmol), tert-butyl 2,3-dihydro-l H-pyrrole- 1 -carboxylate (3.73 g, 22.2 mmol) and K2CO3(8.35 g, 60.47 mmol) in 1,4-dioxane (50 mL) was stirred at 90 °C for 16 h under nitrogen atmosphere. The resulting mixture was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with 0-20% EtOAc in petroleum ether to afford tert-butyl 2-[2-amino-3-fluoro-5-(methoxycarbonyl)phenyl]-2,5-dihydropyrrole-l- carboxylate (4.90 g, 41%) as a brown solid. MS ESI calculated for C17H21FN2O4 [M+H]+, 337.15; found, 337.10.Step 2: 1:1 mixture of tert-butyl (S)-2-(2-amino-3-fluoro-5-(methoxycarbonyl)phenyl)pyrrolidine-l -carboxylate and tert-butyl (R)-2-(2-amino-3-fluoro-5-(methoxycarbonyl)phenyl)pyrrolidine-l-carboxylate

[0578] To a solution of tert-butyl 2-[2-amino-3-fluoro-5-(methoxycarbonyl)phenyl]-2,5- dihydropyrrole-1 -carboxylate (4.90 g, 14.56 mmol) in MeOH (50 mL) was added Pd / C (10% active on carbon, 500 mg). The mixture was hydrogenated at room temperature for 16 h under hydrogen atmosphere with a hydrogen balloon. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford a 1: 1 mixture of tert-butyl (S)-2-(2-amino-3-fluoro-5-(methoxycarbonyl)phenyl)pyrrolidine-l- carboxylate and tert-butyl (R)-2-(2-amino-3-fluoro-5-(methoxycarbonyl)phenyl)pyrrolidine- 1 -carboxylate (4.20 g, crude) as a light yellow solid. MS ESI calculated for C17H23FN2O4 [M+H]+, 339.16; found, 339.10.Step 3: 1:1 mixture of methyl (S)-4-amino-3-fluoro-5-(pyrrolidin-2-yl)benzoate and methyl (R)-4-amino-3-fluoro-5-(pyrrolidin-2-yl)benzoate

[0579] A 1:1 mixture of tert-butyl (S)-2-(2-amino-3-fluoro-5-(methoxycarbonyl)phenyl)pyrrolidine-l -carboxylate and tert-butyl (R)-2-(2-amino-3-fluoro-5-(methoxycarbonyl)phenyl)pyrrolidine-l-carboxylate (4.20 g, 12.41 mmol) and TEA (35 mL) in DCM (75 mL) was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure to afford 1 : 1 mixture of methyl (S)-4-amino-3-fluoro-5- (pyrrolidin-2-yl)benzoate and methyl (R)-4-amino-3-fluoro-5-(pyrrolidin-2-yl)benzoate (3.50 g, crude) as a brown solid. MS ESI calculated for C12H15FN2O2 [M+H]+, 239.11; found, 239.20.Step 4: 1:1 mixture of methyl (S)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c] quinazoline-9-carboxylate and (R)-5-amino-7 -fluoro- 1 ,2,3, 1 Ob-tetrahydropyrrolo [1,2- c] quinazoline-9-carboxylate

[0580] A 1 : 1 mixture of methyl (S)-4-amino-3-fluoro-5-(pyrrolidin-2-yl)benzoate and methyl (R)-4-amino-3-fluoro-5-(pyrrolidin-2-yl)benzoate (5.40 g, 22.66 mmol) and BrCN (2.40 g, 22.66 mmol) in 1,4-dioxane (60 mL) was stirred at 80 °C for 7 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc. The precipitated solids were collected by filtration and washed with EtOAc to afford 1:1 mixture of methyl (S)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c] quinazoline-9-carboxylate and (R)-5-amino-7 -fluoro- 1 ,2,3, 1 Ob-tetrahydropyrrolo [1,2- c]quinazoline-9-carboxylate (2.50 g, 42%) as a grey solid. MS ESI calculated for C13H14FN3O2 [M+H]+, 264.11; found, 264.05.1H NMR (400 MHz, DMSO-d6) δ 7.40 - 7.32 (m, 1H), 7.32 (s, 1H), 6.53 (s, 2H), 4.56 (dd, J = 10.0, 5.6 Hz, 1H), 3.77 (s, 3H), 3.50 - 3.42 (m, 2H), 2.60 - 2.55 (m, 1H), 2.09 - 1.88 (m, 2H), 1.85 - 1.72 (m, 1H).Step 5: 1:1 mixture of (S)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline- 9-carboxylic acid and (R)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9- carboxylic acid

[0581] To 1:1 mixture of methyl (S)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylate and (R)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,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. The reaction mixture was stirred at 50 °C for 16 h. The mixture was acidified to pH 5 with HC1 (2 N). The precipitated solids were collected by filtration and washed with H2O, then dried over vacuum to afford 1:1 mixture of (S)-5-amino-7-fluoro- 1 ,2,3, 10b-tetrahydropyrrolo[l ,2-c]quinazoline-9-carboxylic acid and (R)-5-amino-7-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid (500 mg, crude) as a yellow solid. MS ESI calculated for C12H12FN3O2[M+H]+, 250.09; found, 250.20.1H NMR (400 MHz, DC1) δ 7.28 (d, J= 10.4 Hz, 1H), 7.20 (s, 1H), 4.41 (dd, J = 10.4, 5.6 Hz, 1H), 3.36 - 3.24 (m, 2H), 2.40 - 2.36 (m, 1H), 1.85 - 1.81 (m, 2H), 1.59 - 1.52 (m, 1H).Intermediate CA2: 1:1 mixture of (S)-5-amino-l, 2,3, 10b-tetrahydropyrrolo[l, 2- c]quinazoline-9-carboxylic acid and (R)-5-amino-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acidStep 1: methyl 3-bromo-4-nitrobenzoate

[0582] To a stirred mixture of 3-bromo-4-nitrobenzoic acid (3.0 g, 12.19 mmol) in DMF (30 mL) were added Mel (2.60 g, 18.29 mmol) and K2CO3(3.37 g, 24.39 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-30% EtOAc in petroleum ether to afford methyl 3-bromo-4-nitrobenzoate (2.86 g, 89%) as a pink solid. MS ESIcalculated for (C8H6BrNO4) [M+H]+, 259.94.1H NMR (300 MHz, DMSO-d6) δ 8.35 - 8.29 (m, 1H), 8.19 - 8.09 (m, 2H), 3.92 (s, 3H).Step 2: tert-butyl 5-(5-(methoxycarbonyl)-2-nitrophenyl)-2,3-dihydro-lH-pyrrole-l- carboxylate

[0583] A degassed mixture of methyl 3-bromo-4-nitrobenzoate (2.00 g, 7.69 mmol), tert- butyl 2,3-dihydropyrrole-l-carboxylate (1.82 g, 10.77 mmol), 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 stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered through paper, and concentrated under vacuum. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford tert-butyl 2-[5-(methoxycarbonyl)-2-nitrophenyl]-2,5-dihydropyrrole-l- carboxylate (960 mg, 25%) as a yellow oil. MS ESI calculated for (C17H20N2O6) [M-56]+, 293.13; found, 292.95.Step 3: 1:1 mixture of tert-butyl (S)-2-(2-amino-5-(methoxycarbonyl)phenyl)pyrrolidine-l- carboxylate and tert-butyl (R)-2-(2-amino-5-(methoxycarbonyl)phenyl)pyrrolidine-l- carboxylate

[0584] To a solution of tert-butyl 2-[5-(methoxycarbonyl)-2-nitrophenyl]-2,5- dihydropyrrole-1 -carboxylate (780 mg, 2.24 mmol) in EtOH (10 mL) was added PtO2(102 mg, 0.45 mmol) at 20 °C under nitrogen atmosphere. The reaction mixture was degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at 20 °C for 2 h under hydrogen with a balloon (1 atm.). The mixture was filtered through a Celite pad. The filtrate was collected and concentrated under vacuum to afford 1:1 mixture of tert-butyl (S)-2-(2-amino-5- (methoxycarbonyl)phenyl)pyrrolidine-l -carboxylate and tert-butyl (R)-2-(2-amino-5-(methoxy carbonyl)phenyl)pyrrolidine-l -carboxylate (690 mg, crude) as a yellow solid. MS ESI calculated for (C17H24N2O4) [M+H]+, 321.17; found, 321.10.Step 4: 1:1 mixture of methyl (S)-4-amino-3-(pyrrolidin-2-yl)benzoate and methyl (R)-4- amino-3-(pyrrolidin-2-yl)benzoate

[0585] To a 1:1 mixture solution of tert-butyl (S)-2-(2-amino-5-(methoxycarbonyl)phenyl)pyrrolidine-l -carboxylate and tert-butyl (R)-2-(2-amino-5- (methoxycarbonyl)phenyl)pyrrolidine-l -carboxylate (690 mg, 2.15 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at 25 °C for 2 h. The solvents were removed under vacuum to afford a 1:1 mixture of methyl (S)-4-amino-3-(pyrrolidin-2-yl)benzoate and methyl (R)-4- amino-3-(pyrrolidin-2-yl)benzoate (1.0 g, crude) as a brown oil. MS ESI calculated for (C12H16N2O2) [M+H]+, 221.12; found, 221.05.Step 5: 1:1 mixture of methyl (S)-5-amino-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9- carboxylate and methyl (R)-5-amino-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9- carboxylate

[0586] A 1:1 mixture of methyl (S)-4-amino-3-(pyrrolidin-2-yl)benzoate and methyl (R)-4- amino-3-(pyrrolidin-2-yl)benzoate (1 g, 4.54 mmol) and BrCN (481 mg, 4.54 mmol) in dioxane (10 mL) was stirred at 80 °C for 2 h. The solvents were removed under vacuum and purified directly. The resulting residue was purified by normal phase flash chromatography with 0-60% ethyl acetate in petroleum ether to afford 1 : 1 mixture of methyl (S)-5-amino- l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate and methyl (R)-5-amino- 1,2,3, 10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate (520 mg, 37%) as a yellow solid. MS ESI calculated for (C13H15N3O2) [M+H]+, 246.11; found, 246.05.1H NMR (300 MHz, DMSO-d6) δ 8.01 (s, 2H), 7.90 (dd, J= 8.4, 1.8 Hz, 1H), 7.74 (t, J= 1.5 Hz, 1H), 7.14 (d, J= 8.4 Hz, 1H), 4.80 (dd, J= 10.2, 5.4 Hz, 1H), 3.84 (s, 3H), 3.74 - 3.43 (m, 2H), 2.90 - 2.67 (m, 1H), 2.18 - 1.99 (m, 2H), 1.98 - 1.73 (m, 1H).Step 6: 1:1 mixture of (S)-5-amino-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9- carboxylic acid and (R)-5-amino-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid

[0587] A 1 : 1 mixture of methyl (S)-5-amino- 1 ,2,3 , 1 Ob-tetrahydropyrrolo [1,2- c]quinazoline-9-carboxylate and methyl (R)-5-amino-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylate (235 mg, 0.96 mmol) in THE (2 mL) and H2O (2 mL) was added LiOH (69 mg, 2.87 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 16 h. The solvents were removed under vacuum to afford 1:1 mixture of (S)-5-amino-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid and (R)-5-amino- 1,2, 3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid (280 mg, crude) as a yellow solid. MS ESI calculated for (C12H13N3O2) [M+H]+, 232.10; found, 232.05.1H NMR (400 MHz, DMSO-d6) δ 7.58 (dd, J = 8.0, 2.0 Hz, 1H), 7.48 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.87 (s, 2H), 4.46 (dd, J = 10.0, 5.6 Hz, 1H), 2.51 - 2.43 (m, 3H), 2.03 - 1.86 (m, 2H), 1.83 - 1.63 (m, 1H).Intermediate CA3: 1:1 mixture of (S)-5-amino-2,2-difluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid and (R)-5-amino-2,2-difluoro- 1 ,2,3 , 1 Ob-tetrahydropyrrolo[ 1 ,2-c]quinazoline-9-carboxylic acidCA3Step 1 : methyl 4-((tert-butoxycarbonyl)amino)-3-iodobenzoate

[0588] To a stirred solution of methyl 4-amino-3-iodobenzoate (20.00 g, 72.19 mmol) andDMAP (882 mg, 7.22 mmol) in DCM (200 mL) were added TEA (14.61 g, 144.37 mmol)and BOC2O (15.75 g, 72.19 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) which applied to 330 g silica gel column and eluted with 0-25% ethyl acetate in petroleum ether within 30 min to afford methyl 4-((tert-butoxycarbonyl)amino)-3-iodobenzoate (11.50 g, 40%) as a white solid. MS (ESI) calculated for (C13H16INO4) [M-l]", 376.01; found, 376.15.1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.40 - 8.26 (m, 1H), 7.97 - 7.89 (m, 1H), 7.68 (dd, J = 7.2, 4.8 Hz, 1H), 3.84 (s, 3H), 1.48 (d, J= 2.4 Hz, 9H).Step 2: 1:1 mixture of tert-butyl (S)-2-(2-((tert-butoxycarbonyl)-12-azaneyl)-5- (methoxycarbonyl)phenyl)-4,4-difluoropyrrolidine-l -carboxylate and tert-butyl (R)-2-(2- ((tert-butoxycarbonyl)-12-azaneyl)-5-(methoxycarbonyl)phenyl)-4,4-difluoropyrrolidine-l- carboxylate

[0589] To a degassed mixture of methyl 4-[(tert-butoxycarbonyl)amino]-3-iodobenzoate (11.00 g, 29.16 mmol), l-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (10.99 g, 43.75 mmol), IR[DF(CF3)PPY]2(DTBPY)PF6(327 mg, 0.29 mmol), NICKEL(II) CHLORIDE ETHYLENE GLYCOL DIMETHYL ETHER COMPLEX (641 mg, 2.92 mmol), dtbbpy (1.17 g, 4.38 mmol) and Cs2CO3(28.51 g, 87.49 mmol) in DMF (220 mL) was stirred at 25 °C for 16 h under blue light. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in DMF (20 mL) which was applied to a 330 g C18 column and purified by Combi Flash (Biotage Isolera Prime), eluted with 5-65% acetonitrile in water within 30 min to afford 1 : 1 mixture of tert-butyl (S)-2-(2-((tert-butoxycarbonyl)-12-azaneyl)- 5-(methoxycarbonyl)phenyl)-4,4-difluoropyrrolidine-l -carboxylate and tert-butyl (R)-2-(2- ((tert-butoxycarbonyl)-12-azaneyl)-5-(methoxycarbonyl)phenyl)-4,4-difluoropyrrolidine-l- carboxylate (1.65 g, 11%) as a yellow oil. MS (ESI) calculated for (C22H30F2N2O6) [M-l]", 455.21; found, 455.15.Step 3: 1:1 mixture of methyl (R)-4-amino-3-(4,4-difluoropyrrolidin-2-yl)benzoate and methyl (R)-4-amino-3-(4,4-difluoropyrrolidin-2-yl)benzoate

[0590] To a 1:1 mixture of tert-butyl (S)-2-(2-((tert-butoxycarbonyl)-12-azaneyl)-5- (methoxycarbonyl)phenyl)-4,4-difluoropyrrolidine-l -carboxylate and tert-butyl (R)-2-(2- ((tert-butoxycarbonyl)-12-azaneyl)-5-(methoxycarbonyl)phenyl)-4,4-difluoropyrrolidine-l- carboxylate (1.65 g, 3.62 mmol) in DCM (15 mL) was added TFA (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum to afford 1 : 1 mixture of methyl (R)-4-amino-3-(4,4- difluoropyrrolidin-2-yl)benzoate and methyl (R)-4-amino-3-(4,4-difluoropyrrolidin-2- yl)benzoate (650 mg, crude) as a brown oil. MS (ESI) calculated for (C12H14F2N2O2) [M+H]+, 257.10; found, 257.05.Step 4: 1:1 mixture of methyl (S)-5-amino-2,2-difluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylate and methyl (R)-5-amino-2,2-difluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate

[0591] A solution of 1:1 mixture methyl (S)-5-amino-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylate and methyl (R)-5-amino-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylate (650 mg, 2.54 mmol) and BrCN (269 mg, 3.51 mmol) in dioxane (10 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting residue was dissolved in DCM (2 mL) and purified by Combi Flash (Biotage Isolera Prime) which applied to a 80 g silica gel column that was eluted with 0~l 1% methanol in dichloromethane within 30 min to afford 1:1 mixture of methyl (S)-5-amino-2,2-difluoro-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9- carboxylate and methyl (R)-5-amino-2,2-difluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylate (300 mg, 39%) as a brown solid. MS (ESI) calculated for(C13H13F2N3O2) [M+H]+, 282.10; found, 282.25.1H NMR (300 MHz, DMSO-d6) 5 8.69 (s, 2H), 8.01 - 7.92 (m, 1H), 7.77 (t, J= 1.8 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 5.22 (dd, J = 11.4, 6.0 Hz, 1H), 4.25 - 4.00 (m, 2H), 3.85 (s, 3H), 3.46 - 3.32 (m, 1H), 2.92 - 2.59 (m, 1H).Step 5: 1:1 mixture of (S)-5-amino-2,2-difluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acid and (R)-5-amino-2,2-difluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid

[0592] A solution of 1 : 1 mixture of methyl (S)-5-amino-2,2-difluoro- 1 ,2,3, 10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate and methyl (R)-5-amino-2,2-difluoro- l,2,3,10b-tetrahydropyrrolo[l,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. The resulting mixture was stirred at 30 °C for 16 h. The resulting mixture was concentrated under vacuum to afford 1:1 mixture of (S)-5-amino-2,2-difluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acid and (R)-5-amino-2,2-difluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid (400 mg, crude) as a brown solid. MS (ESI) calculated for (C12H11F2N3O2) [M+H]+, 268.08; found, 268.05.1H NMR (300 MHz, DMSO-d6) δ 7.61 (dd, J = 8.2, 1.8 Hz, 1H), 7.48 - 7.39 (m, 1H), 6.58 (d, J= 8.2 Hz, 1H), 6.02 (s, 2H), 4.79 (dd, J= 10.2, 6.0 Hz, 1H), 4.16 - 3.90 (m, 1H), 3.86 - 3.66 (m, 1H), 3.14 - 2.94 (m, 1H), 2.50 - 2.24 (m, 1H).Intermediate CA4: (S)-5-amino-2,2,8-trifluoro- 1 ,2,3, 1 Ob-tetrahydropyrrolo[ 1 ,2- c]quinazoline-9-carboxylic acidStep-1:

[0593] To a stirred solution of 2-bromo-4-fluorobenzaldehyde (15.00 g, 73.89 mmol) and (R)-2-methylpropane-2-sulfinamide (9.85 g, 81.28 mmol) in THF (100 mL) was added Ti(OEt)4(30 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. To the above mixture was added 300 mL ethyl acetate, 200 mL brine and eelatom at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford (R,E)-N-(2-bromo-4- fluorobenzylidene)-2-methylpropane-2-sulfinamide (16.20 g, crude) as a brown oil. MS ESI calculated for C11H13BrFNOS [M+H]+, 305.99, 307.99; found, 305.90, 307.90.Step-2:

[0594] To a stirred solution of (R,E)-N-(2-bromo-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (16.50 g, 53.89 mmol) and allyl 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 stirred at 60 °C for 16 h.The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-70% ethyl acetate in petroleum ether to afford (R)-N-((S)-l-(2-bromo-4-fluorophenyl)but-3-en-l-yl)-2-methylpropane-2-sulfinamide (10.50 g, 52%) as a yellow oil. MS ESI calculated for C14H19BrFNOS [M+H]+, 348.04,350.04; found, 348.05,350.05.Step-3:

[0595] To a stirred mixture of (R)-N-((S)-l-(2-bromo-4-fluorophenyl)but-3-en-l-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 stirred 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. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-60% ethyl acetate in petroleum ether to afford a 1:1 mixture of N-((S)-l-(2-bromo-4-fluorophenyl)-2-((R)- 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 (4.2 g, 33%) as a white solid. MS ESI calculated for C14H19BrFNO3S [M+H]+, 380.03, 382.03; found, 380.10, 382.10.Step-4:

[0596] To a stirred solution of 1:1 mixture of N-((S)-l-(2-bromo-4-fluorophenyl)-2-((R)- 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 stirred 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. The residue was purified by silica gel column chromatography, eluted with 0-70% ethyl acetate in petroleum ether to afford a 1:1 mixture of (3S,5S)-5-(2-bromo-4-fluorophenyl)-l-(tert- butylsulfonyl)pyrrolidin-3-ol and (3R,5S)-5-(2-bromo-4-fluorophenyl)- 1 -(tert- butylsulfonyl)pyrrolidin-3-ol (3.80 g, 68%) as a yellow oil. MS ESI calculated for C14H19BrFNO3S [M+H]+, 380.03, 382.03; found, 380.10, 382.10.Step-5:

[0597] To a stirred solution of 1:1 mixture of (3S,5S)-5-(2-bromo-4-fluorophenyl)-l-(tert- butylsulfonyl)pyrrolidin-3-ol and (3R,5S)-5-(2-bromo-4-fluorophenyl)- 1 -(tert- butylsulfonyl)pyrrolidin-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 stirred at room temperature for 16 h. The reaction was quenched by the addition of Na2S2O3(sat.) and NaHCO3(sat.). The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-60% ethyl acetate in petroleum ether to afford (S)-5-(2-bromo-4-fluorophenyl)-l-(tert-butylsulfonyl)pyrrolidin-3-one (3.50 g, 65%) as a yellow oil. MS ESI calculated for C14H17BrFNO3S [M+H]+, 378.01, 380.01; found, 378.15, 380.15.Step-6:

[0598] To a stirred solution of (S)-5-(2-bromo-4-fluorophenyl)-l-(tert- butylsulfonyl)pyrrolidin-3-one (5.00 g, 13.22 mmol2) in DCM (50 mL) was added DAST (6.39 g, 39.65 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of NaHCO3(sat.). The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford (S)-2-(2- bromo-4-fluorophenyl)-l-(tert-butylsulfonyl)-4,4-difluoropyrrolidine (1.00 g, 14%) as a brown solid. MS ESI calculated for C14H17BrFNO2S [M+H]+, 400.01, 402.01; found, 400.10, 402.10.Step-7:

[0599] To a stirred solution of (S)-2-(2-bromo-4-fluorophenyl)-l-(tert-butylsulfonyl)-4,4- difluoropyrrolidine (900 mg, 2.25 mmol) and diphenylmethanimine (489 mg, 2.70 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 stirred 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. The residue was purified by silica gel column chromatography, eluted with 0-30% ethyl acetate in petroleum ether to afford (S)-N-(2-(l- (tert-butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)-5-fluorophenyl)- 1 , 1 -diphenylmethanimine (1.02 g, 72%) as a yellow oil. MS ESI calculated for C27H27F3N2O2S [M+H]+, 501.17; found, 501.25.Step-8:

[0600] To a solution of (S)-N-(2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)-5- fluorophenyl)- 1,1 -diphenylmethanimine (1.25 g, 2.50 mmol) in MeOH (20 mL) was added HC1 (cone.) (4 mL). The mixture was stirred 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. The residue was purified by silica gel column chromatography, eluted with 0-25% ethyl acetate in petroleum ether to afford (S)-2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)-5-fluoroaniline (0.50 g, 55%) as a white solid. MS ESI calculated for C14H19F3N2O2S [M+H]+, 337.11; found, 337.05.Step-9:

[0601] To a solution of (S)-2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)-5- fluoroaniline (450 mg, 1.34 mmol) in DMF (6 mL) was added NIS (301 mg, 1.34 mmol). The mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% ethyl acetate in petroleum ether to afford (S)-2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)- 5-fluoro-4-iodoaniline (550 mg, 89%) as a white solid. MS ESI calculated for C14H18F3IN2O2S [M+H]+, 463.01; found, 463.05.Step- 10:

[0602] To a solution of (S)-2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-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 stirred 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. After filtration, the filtrate was concentrated under reduced pressure to afford (S)-2-(4,4-difluoropyrrolidin-2-yl)-5-fluoro-4- iodoaniline (401 mg, crude) as a yellow solid. MS ESI calculated for C10H10F3IN2[M+H]+, 342.98; found, 342.90.Step-11:

[0603] A solution of (S)-2-(4,4-difluoropyrrolidin-2-yl)-5-fluoro-4-iodoaniline (400 mg, 1.17 mmol) and BrCN (124 mg, 1.17 mmol) in dioxane (5 mL) was stirred at 80 °C under nitrogen atmosphere for 2 h. The precipitated solids were collected by filtration and washed with 1,4-dioxane, then dried under vacuum to afford (S)-2,2,8-trifluoro-9-iodo-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazolin-5-amine (370 mg, crude) as a white solid. MS ESI calculated for C11H9F3IN3[M+H]+, 367.98; found, 367.95.Step- 12:

[0604] To a stirred solution of (S)-2,2,8-trifluoro-9-iodo-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazolin-5-amine (350 mg, 0.95 mmol) and Et3N (482 mg, 4.77 mmol) in MeOH (5 mL) were added Pd(dppf) CI2(70 mg, 0.10 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under CO (20 atm.). The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combi Flash with a 40 g Cl 8 column, eluted with 10-60% acetonitrile in water (10 mM NH4HCO3) to afford methyl (S)-5-amino-2,2,8-trifluoro- l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate (150 mg, 53%) as a white solid. MS ESI calculated for C13H12F3N3O2[M+l]+, 300.09; found, 300.05.Step- 13:

[0605] To a solution of methyl (S)-5-amino-2,2,8-trifluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate (100 mg, 0.33 mmol) in THE (2 mL) and H2O (1 mL) was added LiOH (16 mg, 0.67 mmol) at room temperature . The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum to afford (S)-5-amino-2,2,8-trifluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acid (CA4) (120 mg, crude) as a yellow solid. MS ESI calculatedfor C12H10F3N3O2[M+H]+, 286.07; found, 286.15.1H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J= 8.4 Hz, 1H), 6.27 - 6.14 (m, 1H), 4.82 - 4.65(m, 1H), 4.08 - 3.88 (m, 1H), 3.83 - 3.65 (m, 1H), 3.10 - 2.93 (m, 1H), 2.49 - 2.31 (m, 1H).Intermediate CAS: (R)-5-amino-2,2,8-trifluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acidStep-1:

[0606] To a mixture of 2-bromo-4-fluorobenzaldehyde (20.00 g, 98.52 mmol) and (S)-2- methylpropane-2-sulfinamide (13.13 g, 108.37 mmol) in THF (64 mL) was added Ti(OEt)4 (44 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction was quenched with a mixture of EtOAc and brine at room temperature. The heterogeneous mixture was filtered through a pad of celite, and washed with EtOAc. The organic layer was washed with brine and dried with Na2SO4, After filtration, the filtrate was concentrated under vacuum. This resulted in (S,E)-N-(2-bromo-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (7.00 g, 88%) as a brown oil. MS ESI calculated for C11H13BrFNOS [M+H]+, 305.99, 307.99; found, 306.00, 308.00.Step-2:

[0607] To a stirred mixture of (S,E)-N-(2-bromo-4-fluorobenzylidene)-2-methylpropane-2- sulfinamide (30.00 g, 97.98 mmol) and 3-bromoprop-l-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 stirred 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. The residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in PE to afford (S)-N-((R)-l-(2-bromo-4-fluorophenyl)but-3-en-l-yl)-2-methylpropane-2- sulfinamide (10.00 g, 58%) as a yellow oil. MS ESI calculated for C14H19BrFNOS [M+H]+, 348.04, 350.04; found, 348.05, 350.05.Step-3:

[0608] To a stirred mixture of (S)-N-((R)-l-(2-bromo-4-fluorophenyl)but-3-en-l-yl)-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 stirred 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. The residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in PE to afford a 1:1 mixture of N-((R)-l-(2-bromo-4-fluorophenyl)-2-((S)- oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide and N-((R)-l-(2-bromo-4-fluorophenyl)- 2-((R)-oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (18.45 g, 74%) as a colorless oil. MS ESI calculated for C14H19BrFNO3S [rM+H]+, 380.03, 382.03; found, 379.95, 381.95.Step-4:

[0609] To a stirred mixture of a 1 : 1 mixture of N-((R)-l-(2-bromo-4-fluorophenyl)-2-((S)- oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide and N-((R)-l-(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 stirred 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. The residue was purified by silica gel column chromatography, eluted with 0-60% EtOAc in PE to afford a 1:1 mixture of (3S,5R)- 5-(2-bromo-4-fluorophenyl)- 1 -(tert-butylsulfonyl)pyrrolidin-3-ol and (3R,5R)-5-(2-bromo-4- fluorophenyl)-l-(tert-butylsulfonyl)pyrrolidin-3-ol (14.63 g, 76%) as a yellow oil. MS ESI calculated for C14H19BrFNO3S [M+H]+, 380.03, 382.03; found, 379.95, 381.95.Step-5:

[0610] To a stirred mixture of a 1:1 mixture of (3S,5R)-5-(2-bromo-4-fluorophenyl)-l- (tert-butylsulfonyl)pyrrolidin-3-ol and (3R,5R)-5-(2-bromo-4-fluorophenyl)- 1 -(tert- butylsulfonyl)pyrrolidin-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 stirred at room temperature for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-60% EtOAc in PE to afford (R)-5-(2-bromo-4-fluorophenyl)-l-(tert- butylsulfonyl)pyrrolidin-3-one (7.77 g, 68%) as a yellow oil. MS ESI calculated for C14H17BrFNO3S [rM+H]+, 378.01, 380.01; found, 377.90, 379.90.Step-6:

[0611] To a stirred mixture of (R)-5-(2-bromo-4-fluorophenyl)-l-(tert- butylsulfonyl)pyrrolidin-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 stirred at room temperature for 16h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% EtOAc in PE to afford (R)-2-(2- bromo-4-fluorophenyl)-l-(tert-butylsulfonyl)-4,4-difluoropyrrolidine (3.80 g, 42%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.75 (t, J = 7.6 Hz, 1H), 7.59 (dd, J = 8.6, 2.6 Hz, 1H), 7.37 - 7.32 (m, 1H), δ 5.52 (t, J = 8.0 Hz, 1H), 4.16 - 4.10 (m, 2H), 3.08 - 2.97 (m, 1H), 2.39 (br, 1H), 1.16 (s, 9H).Step-7:

[0612] To a stirred mixture of (R)-2-(2-bromo-4-fluorophenyl)-l-(tert-butylsulfonyl)-4,4- difluoropyrrolidine (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 stirred 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. The residue was purified by silica gel column chromatography, eluted with 0-40% EtOAc in PE to afford (R)-N-(2-(l -(tert-butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)-5-fluorophenyl)- 1,1- diphenylmethanimine (2.50 g, 97%) as a yellow oil. MS ESI calculated for C27H27F3N2O2S [M+H]+, 501.17; found, 501.25.Step-8:

[0613] To a stirred solution of (R)-N-(2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-2- yl)-5-fluorophenyl)-l,l-diphenylmethanimine (3.88 g, 7.75 mmol) in MeOH (40 mL) were added HC1 (2 N, 8 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was dilutedwith 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 Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0 - 40% EtOAc in PE to afford (R)-2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)-5- fluoroaniline (1.95 g, 74%) as a white solid. MS ESI calculated for [M+H]+, 337.11; found, 337.05.Step-9:

[0614] To a stirred solution of (R)-2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)-5- fluoroaniline in DMF (100 mL) was added NIS (1.36 g, 6.05 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 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. The residue was purified by silica gel column chromatography, eluted with 0 - 30% EtOAc in PE to afford (R)-2-(l-(tert- butylsulfonyl)-4,4-difluoropyrrolidin-2-yl)-5-fluoro-4-iodoaniline (2.29 g, 74%) as a yellow oil. MS ESI calculated for C14H18F3IN2O2S [M+H]+, 463.01; found, 462.90.Step-10:Y

[0615] To a stirred solution of (R)-2-(l-(tert-butylsulfonyl)-4,4-difluoropyrrolidin-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 stirred at room temperature for 2 h. The mixture was basified with NaOH (2N) to PH 8. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in a 5:1 mixture of (R)-2-(4,4-difluoropyrrolidin-2-yl)-5-fluoro-4-iodoaniline and (S)-2-(4,4-difluoropyrrolidin-2-yl)-5-fluoro-4-iodoaniline (1.75 g, 96%) as a yellow solid. MS ESI calculated for C10H10F3IN2 [M+H]+, 342.98; found, 342.85.Step-11:

[0616] To a stirred mixture of (R)-2-(4,4-difluoropyrrolidin-2-yl)-5-fluoro-4-iodoaniline (1.75 g, 5.11 mmol) in dioxane (87 mL) was added BrCN (0.54 g, 5.11 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The precipitated solids were collected by filtration and washed with 1,4-dioxane. The resulting solid was dried under vacuum to afford (R)-2,2,8-trifluoro-9-iodo-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazolin-5-amine (1.03 g, 52%) as a white solid. MS ESI calculated for C11H9F3IN3, 367.98; found, 367.95.Step-12:

[0617] To a solution of (R)-2,2,8-trifluoro-9-iodo-l,2,3,10b-tetrahydropyrrolo[l,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)Ch (140 mg, 0.19 mmol). The mixture was stirred 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. The residue was purified by reverse phase flash column chromatography with 10% to 50% MeCN in water (10 mmol / L NH4HCO3) to afford methyl (R)-5-amino-2,2,8-trifluoro- 1 ,2,3 , 1 Ob-tetrahydropyrrolo[ 1 ,2-c] quinazoline-9-carboxylate (210 mg, 30%) as a yellow solid. MS ESI calculated for C13H12F3N3O2 [M+H]+, 300.09; found, 300.00.Step- 13:CAS

[0618] To a stirred mixture of methyl (R)-5-amino-2,2,8-trifluoro-l,2,3,10b- tetrahydropyrrolo[l,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 stirred at room temperature for 16 h. The organic solvent was removed under reduced pressure. The remained aqueous solution was acidified by HC1 (cone.). The solids were collected and dried under vacuum to afford (R)-5-amino-2,2,8-trifluoro- 1,2,3, 10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid hydrochloride (CA5) (130 mg, 58%) as a white solid. MS ESI calculated for C12H10F3N3O2 [M+H]+, 286.07; found 285.95.1H NMR (400 MHz, DMSCO-d6) 1 δ3.24 (s, 1H), 12.12 (s, 1H), 8.60 (s, 2H), 7.69 (d, .7 = 7.2 Hz, 1H), 7.00 (d, J= 11.4 Hz, 1H), 5.15 (dd, J = 11.2, 6.0 Hz, 1H), 4.33 - 3.93 (m, 2H), 3.40 - 3.19 (m, 1H), 2.84 - 2.61 (m, 1H). Absolute stereochemistry was determined by single crystal X-ray crystallography of Example 12, prepared using CA5.Intermediate CA6: 1:1 mixture of (R)-5-amino- 1,1 -difluoro- 1,2, 3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid and (S)-5-amino-l,l-difluoro- 1 ,2,3 , 1 Ob-tetrahydropyrrolo[ 1 ,2-c]quinazoline-9-carboxy lie acid

[0619] To a stirred solution of methyl 4-bromo-3-iodobenzoate (20.00 g, 58.66 mmol) in THE (200 mL) was added i-PrMgCl (2M in THE) (31 mL, 62 mmol) at -15 °C under nitrogen atmosphere. After stirring at -15 °C for 1 h, a solution of tert-butyl 2-oxopyrrolidine-l- carboxylate (11.95 g, 64.52 mmol) in THE (20 mL) was added dropwise over 2 min at -10 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-40% EtOAc in PE to afford methyl 4-bromo-3-(4-((tert- butoxycarbonyl)amino)butanoyl)benzoate (13.2 g, 84%) as a white solid. MS ESI calculated for C17H22BrNO5[M+H]+, 400.07, 402.07; found, 400.10, 402.10.Step-2:

[0620] To a stirred solution of methyl 4-bromo-3-(4-((tert- butoxycarbonyl)amino)butanoyl)benzoate (13.20 g, 32.97 mmol) DCM (132 mL) was added TEA (44 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under vacuum. The residue was basified with saturated NaHCO3(aq.) to pH 7. The resulting mixture was extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford methyl 3-(4-aminobutanoyl)-4- bromobenzoate (8.6 g, crude) as a yellow solid. MS ESI calculated ford6) δ Br CN12OH317Br [M+H]+, 300.02, 402.02; found, 400.05, 402.05.Step-3:

[0621] To a stirred solution of methyl 3-(4-aminobutanoyl)-4-bromobenzoate (8.6 g, 28.65 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 stirred at 80 °C for16 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. After filtration, the filtrate was concentrated under vacuum to afford methyl 4-bromo-3-(4,4- difluoro-3,4-dihydro-2H-pyrrol-5-yl)benzoate (7.18 g, crude) as a yellow oil. MS ESI calculated for C12H10BrF2NO2[M+H]+, 318.00, 320.00; found, 318.05, 320.05.Step-4:

[0622] To a stirred solution of methyl 4-bromo-3-(4,4-difluoro-3,4-dihydro-2H-pyrrol-5- yl)benzoate (7.18 g, 22.57 mmol) and AcOH (0.14 g, 2.25 mmol) in MeOH (72 mL) was added NaBH3CN (3.55 g, 56.42 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was basified with saturated NaHCO3(aq.). 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 vacuum. The residue was purified by silica gel column chromatography, eluted with 0-40% EtOAc in PE to afford a 1:1 mixture of methyl (S)-4-bromo-3-(3,3-difluoropyrrolidin-2-yl)benzoaten and methyl (R)-4-bromo-3-(3,3-difluoropyrrolidin-2-yl)benzoate (2.4 g, 21%) as a yellow oil. MS ESI calculated for C12H12BrF2NO2[M+H]+, 320.00, 322.00; found, 320.05, 322.05.Step-5:

[0623] To a stirred solution of 1: 1 mixture of methyl (S)-4-bromo-3-(3,3- difluoropyrrolidin-2-yl)benzoaten and methyl (R)-4-bromo-3-(3,3-difluoropyrrolidin-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 stirred at room temperature for 2 h. The mixture was concentrated under vacuum to afford a 1:1 mixture of tert-butyl (S)-2-(2-bromo-5-(methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine-l -carboxylateand tert-butyl (R)-2-(2-bromo-5-(methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine- 1- carboxylate (3.67 g, crude) as a yellow oil. MS ESI calculated for Ci?H2oBrF2N04 [M+H]+, 420.05, 422.05; found, 420.05, 422.05.Step-6:

[0624] To a stirred solution of 1: 1 mixture of tert-butyl (S)-2-(2-bromo-5- (methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine-l -carboxylate and tert-butyl (R)-2-(2- bromo-5-(methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine-l-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 stirred at 100 °C for 2 h. The reaction was quenched by water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-30% EtOAc in PE to afford a 1:1 mixture of tert-butyl (S)-2-(2-((tert-butoxycarbonyl)amino)-5- (m ethoxy carbonyl)phenyl)-3, 3-di fluoropyrrolidine- 1 -carboxylate and tert-butyl (R)-2-(2- ((tert-butoxycarbonyl)amino)-5-(methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine-l- carboxylate (3 g, 57%) as a yellow oil. MS ESI calculated for C22H30F2N2O6 [M+H]+, 457.21, 459.21; found, 457.30, 459.30.Step-7:

[0625] To a mixture of 1:1 mixture of tert-butyl (S)-2-(2-((tert-butoxycarbonyl)amino)-5- (methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine-l -carboxylate and tert-butyl (R)-2-(2- ((tert-butoxycarbonyl)amino)-5-(methoxycarbonyl)phenyl)-3,3-difluoropyrrolidine-l- carboxylate (3.00 g, 6.57 mmol) in DCM (30 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 2 h.The resulting mixture was concentrated under vacuum to afford a 1:1 mixture of methyl (S)-4-amino-3-(3,3-difluoropyrrolidin-2-yl)benzoate andmethyl (R)-4-amino-3-(3,3-difluoropyrrolidin-2-yl)benzoate (5.2 g, crude) as a yellow oil.MS ESI calculated for C12H14F2N2O2 [M+H]+, 257.10; found, 257.10.Step-8:

[0626] To a stirred solution of methyl 4-amino-3-(3,3-difluoropyrrolidin-2-yl)benzoate (2.10 g, 8.19 mmol) in dioxane (21 mL) was added BrCN (0.87 g, 8.19 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The precipitated solids were collected by filtration and washed with dioxane (2 mL). The solid was dried under vacuum to afford a 1:1 mixture of methyl (R)-5-amino-l,l-difluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylate and methyl (S)-5-amino-l,l-difluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate (1.34 g, 57%) as a white solid. MS ESI calculated for C13H13F2N3O2 [M+H]+, 282.10; found, 282.05.Step-9:

[0627] To a stirred solution of 1:1 mixture of methyl (R)-5-amino-l,l-difluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate and methyl (S)-5-amino-l,l-difluoro- 1,2,3, 10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate (1.34 g, 4.76 mmol) in THF (6 mL) and H2O (2 mL) and MeOH (6 mL) was added LiOH (0.68 g, 28.58 mmol) at room temperature. The resulting mixture was stirred at room temperature for 32 h. The resulting mixture was concentrated under vacuum to afford a 1:1 mixture of (R)-5-amino-l,l-difluoro- 1 ,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid and (S)-5-amino-l,l- difluoro-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid (CA6) (2 g, crude) as a white solid. MS ESI calculated for C13H13F2N3O2 [M+H]+, 268.08; found, 268.05.1H NMR (400 MHz, DMSO-d6) δ 7.72 - 7.55 (m, 2H), 6.59 (d, J = 8.0 Hz, 1H), 4.94 - 4.84 (m, 1H), 3.77 - 3.64 (m, 1H), 3.63 - 3.51 (m, 1H), 2.48 - 2.30 (m, 2H).Intermediate CA7 isomer 1: rel-(R)-5-amino-8-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acid isomer 1Intermediate CA7 isomer 2: rel-(R)-5-amino-8-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylic acid isomer 2Step-1:

[0628] To a stirred solution of methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-2- fluorobenzoate (10 g, 28.72 mmol) and tert-butyl 2,3-dihydro-lH-pyrrole-l -carboxylate (5.35 g, 31.59 mmol) in 1,4-dioxane (100 mL) were added Pd(OAc)2 (0.64 g, 2.87 mmol), PPh3(1.51 g, 5.74 mmol) and K2CO3(11.91 g, 86.16 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 100 °C for 16 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash column chromatography with 5-50% MeCN in Water (10 mmol / L NH4HCO3) to afford a 1:1 mixture of tert-butyl (S)-2-(2- ((tert-butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)-2,5-dihydro-lH-pyrrole- 1 -carboxylate and tert-butyl (R)-2-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5- (methoxycarbonyl)phenyl)-2,5-dihydro-lH-pyrrole-l-carboxylate (3.2 g, 25%) as a yellow oil. MS ESI calculated for C22H29FN2O6[M+H]+, 437.20; found, 437.15.Step-2:

[0629] To a solution of 1 : 1 mixture of tert-butyl (S)-2-(2-((tert-butoxycarbonyl)amino)-4- fluoro-5-(methoxycarbonyl)phenyl)-2,5-dihydro-lH-pyrrole-l-carboxylate and tert-butyl (R)- 2-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)-2,5-dihydro-lH- pyrrole-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 balloon. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford a 1:2 mixture of tert-butyl (R)-2-(2-((tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)pyrrolidine- 1 -carboxylate and tert-butyl (S)-2-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5 -(methoxy carbonyl)phenyl)pyrrolidine-l -carboxylate (2.7 g, crude) as a yellow oil. MS ESI calculated for C22H31FN2O6 [M+H]+, 439.22; found, 439.20.Step-3: X

[0630] To a stirred solution of a 1:2 mixture of tert-butyl (R)-2-(2-((tert- butoxycarbonyl)amino)-4-fluoro-5-(methoxycarbonyl)phenyl)pyrrolidine-l-carboxylate and tert-butyl (S)-2-(2-((tert-butoxycarbonyl)amino)-4-fluoro-5 - (methoxycarbonyl)phenyl)pyrrolidine-l -carboxylate (2.70 g, 6.16 mmol) in DCM (15 mL) was added TFA (15 mL). The resulting mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to afford a 1 :2 mixture of methyl (R)-4-amino-2-fluoro- 5-(pyrrolidin-2-yl)benzoate and methyl (S)-4-amino-2-fluoro-5-(pyrrolidin-2-yl)benzoate (3.4 g, crude) as a yellow oil. MS ESI calculated for C12H15FN2O2 [M+H]+, 239.11; found, 239.05.Step-4:

[0631] To a stirred solution of a 1:2 mixture of methyl (R)-4-amino-2-fluoro-5-(pyrrolidin- 2-yl)benzoate and methyl (S)-4-amino-2-fluoro-5-(pyrrolidin-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 stirred at 80 °C for 4 h. The precipitated solids were collected by filtration and washed with EtOAc. The solids were dried under vacuum to afford a 1:2 mixture of methyl (R)-5-amino-8-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate and methyl (S)-5-amino-8-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline- 9-carboxylate (1.2 g, crude) as a white solid. MS ESI calculated for C13H14FN3O2 [M+H]+, 264.11; found, 264.05Step-5:

[0632] The 1:2 mixture of methyl (R)-5-amino-8-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2- c]quinazoline-9-carboxylate and methyl (S)-5-amino-8-fluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate (1.20 g) was separated by Prep-Chiral SFC with the following conditions: [Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: ETOH : ACN=2:1 (0.1% 2M NH3-MeOH); Flow rate: 100 mL / min; Gradient: isocratic 50% B; Back Pressure (bar): 100; Wave Length: 220 nm; RT1 (min): 6.2; RT2 (min): 8.5; Sample Solvent: MEOH; Injection Volume: 4.5 mL] to afford rel-methyl (R)-5 -amino-8-fluoro- 1 ,2,3 , 1 Ob-tetrahydropyrrolo[ 1 ,2-c] quinazoline-9- carboxylate, isomer 1 (190 mg, 17%) as a white solid with retention time at 6.2 min. MS ESI calculated for C13H14FN3O2 [M+H]+, 264.11; found, 264.05.

[0633] The chiral separation also afford rel-methyl (R)-5-amino-8-fluoro-l,2,3,10b- tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylate, isomer 2 (350 mg, 31%) as a white solid with retention time at 8.5 min. MS ESI calculated for C13H14FN3O2 [M+H]+, 264.11; found, 264.05.Step-6:

[0634] To a stirred solution of rel-methyl (R)-5-amino-8-fluoro-l,2,3,10b- tetrahydropyrrolo[l,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 stirred at 50 °C for 3 h. The mixture was acidified with HC1 (2N) to pH 3. The resulting mixture was concentrated under reduced pressure to afford rel-(R)-5-amino- 8-fluoro-l,2,3,10b-tetrahydropyrrolo[l,2-c]quinazoline-9-carboxylic acid isomer 1 (CA7 isomer 1) (300 mg, crude) as a white solid. MS ESI calculated for C12H12FN3O2 [M+H]+, 250.09; found, 250.05.1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 2H), 7.64 (d, J = 7.2 Hz, 1H), 6.90 (d, J= 11.2 Hz, 1H), 4.73 (dd, J= 10.6, 5.6 Hz, 1H), 3.74 - 3.69 (m, 1H), 3.58 - 3.51 (m, 1H), 2.76 - 2.70 (m, 1H), 2.11 - 2.02 (m, 2H), 1.91 - 1.81 (m, 1H).Step-7:isomer 2 CA7 isomer 2

[0635] To a stirred solution of rel-methyl (R)-5-amino-8-fluoro-l,2,3,10b- tetrahydropyrrolo[l,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 stirred at 50 °C for 3 h. The mixture was acidified with HC1 (2N) to pH 3. The resulting mixture was concentrated under reduced pressure to afford rel-(R)-5-amino- 8-fluoro- 1 ,2,3 , 1 Ob-tetrahydropyrrolo [ 1 ,2-c] quinazoline-9-carboxylic acid hydrochloride isomer 2 (CA7 isomer 2) (500 mg, crude) as a white solid. MS ESI calculated for C12H12FN3O2 [M+l]+, 250.09; found, 250.05.rH NMR (400 MHz, DMSO-<Z6) 8 13.20 (hr, 1H), 11.83 (br, 1H), 8.29 (s, 2H), 7.65 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 11.6 Hz, 1H), 4.73 (dd, J= 10.4, 5.6 Hz, 1H), 3.76 - 3.71 (m, 1H), 3.60 - 3.50 (m, 1H), 2.76 - 2.70 (m, 1H), 2.13 - 1.99 (m, 2H), 1.91 - 1.76 (m, 1H).Intermediate CAS: 1:1 mixture of (S)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid and (R)-6-amino-9,9- difluoro-8 ,9, 10, 1 Oa-tetrahydropyrido [4, 3-e] pyrrolo [ 1 ,2-c]pyrimidine-2-carboxylic acidStep-1:F

[0636] A solution of methyl methyl 5-amino-4-bromopicolinate (1 g, 4.33 mmol), (S)-l- (tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (supplier: Bide Pharmatech Co., Ltd. CAS# 203866-15-3) (1.63 g, 6.49 mmol), IREDF(CF3)PPY]2(DTBPY)PF6(97 mg, 0.087 mmol), Nickel(II) chloride ethylene glycol dimethyl ether complex (95 mg, 0.43 mmol), dtbbpy (174 mg, 0.65 mmol) and CS2CO3(4.23 g, 12.98 mmol) in DMF (20 mL) was stirred at 25 °C for 2 days under nitrogen atmosphere under blue light (450 nm). 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. The resulting residue was purified by Combi Flash (Biotage Isolera Prime) which applied to a 80 g silica gel column that was eluted with 0-90% ethyl acetate in petroleum ether to afford a 1: 1 mixture of methyl (S)-5-amino-4-(l-(tert- butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)picolinate and methyl (R)-5-amino-4-(l-(tert- butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)picolinate (950 mg, 61%) as a yellow solid. MS ESI calculated for C16H21F2N3O4 [M+H]+, 358.15; found, 358.05. NMR (400 MHz, DMSO-d6) 8 8.02 (s, 1H), 7.59 (s, 1H), 6.15 (s, 2H), 5.07 - 5.04 (m, 1H), 4.14 - 3.85 (m, 2H), 3.77 (s, 3H), 3.12 - 2.87 (m, 1H), 2.25 - 2.09 (m, 1H), 1.42 - 1.10 (m, 9H).Step-2:

[0637] To a stirred solution of 1:1 mixture of methyl (S)-5-amino-4-(l-(tert- butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)picolinate and methyl (R)-5-amino-4-(l-(tert- butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)picolinate (500 mg, 1.40 mmol) in DCM (6 mL) was added trifluoroacetic acid (2 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under vacuum to afford a 1:1 mixture of methyl (S)-5-amino-4-(4,4-difluoropyrrolidin-2-yl)picolinate and methyl (R)-5-amino-4-(4,4- difluoropyrrolidin-2-yl)picolinate (500 mg, crude) as a brown oil. MS ESI calculated for C11H13F2N3O2[M+H]+, 258.10; found, 258.10.Step-3:

[0638] To a stirred solution of 1:1 mixture of methyl (S)-5-amino-4-(4,4- difluoropyrrolidin-2-yl)picolinate and methyl (R)-5-amino-4-(4,4-difluoropyrrolidin-2- yl)picolinate (500 mg, 1.94 mmol) in 1,4-dioxane (6 mL) was added carbononitridic bromide (206 mg, 1.94 mmol) at 25 °C. The resulting mixture was stirred at 80 °C for 1 h. The precipitated solids were collected by filtration and washed with DCM. The filter cake was collected and dried under vacuum to afford a 1:1 mixture of methyl (S)-6-amino-9,9-difluoro- 8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylate and methyl (R)-6- amino-9,9-difluoro-8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2- carboxylate (350 mg, crude) as a grey solid. MS ESI calculated for C12H12F2N4O2 [M+H]+, 283.09; found, 283.10.Step-4:

[0639] To a stirred solution of 1:1 mixture of methyl (S)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylate and methyl (R)-6-amino-9,9- difluoro-8,9, 10, 10a-tetrahydropyrido[4,3-e]pyrrolo[l ,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 °C. The resulting mixture was stirred at 25 °C for 1 h. The mixture was acidifiedto pH 5~6 with HC1 (aq.). The precipitated solids were collected by filtration and washed with acetonitrile. The filter cake was collected and dried under vacuum to afford a 1:1 mixture of (S)-6-amino-9,9-difluoro-8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[l,2- c]pyrinudine-2-carboxylic acid and (R)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid (200 mg, crude) as a brown solid. MS ESI calculated for C11H10F2N4O2 [M+H]+, 269.07; found, 269.10. *H NMR (400 MHz, Methanol-d4) δ 12.07 (s, 1H), 8.88 - 8.48 (m, 2H), 8.43 (s, 1H), 7.91 (s, 1H), 5.34- 5.22 (m, 1H), 4.25 - 4.04 (m, 2H), 3.48 - 3.32 (m, 1H), 2.86 - 2.63 (m, 1H).Intermediate CAS isomer 1: rel-(R)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid isomer 1Step-1:

[0640] The 1:1 mixture of methyl (S)-5-amino-4-(l-(tert-butoxycarbonyl)-4,4- difluoropyrrolidin-2-yl)picolinate and methyl (R)-5-amino-4-(l-(tert-butoxycarbonyl)-4,4- difluoropyrrolidin-2-yl)picolinate (4.5 g) was separated by prep-chiral SFC with the following conditions: [Column: CHIRAL AD-SZ, 3*10 cm, 3 pm; Mobile Phase A: CO2, Mobile Phase B: IPA (0.5% 2M NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 40% B; Wave Length: 220 nm; RTl(min): 1.04; RT2(min): 1.25; Sample Solvent: MeOH] to afford rel-methyl (R)-5-amino-4-(l-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)picolinate, isomerl (1.90 g, 42%) as a brown oil with retention time at 1.04 minute and rel- methyl (R)-5-amino-4-(l-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)picolinate, isomer2 (1.60 g, 36%) as a brown oil. with retention time at 1.25 minute.

[0641] rel-methyl (R)-5-amino-4-(l -(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2- yl)picolinate, isomerl: MS ESI calculated for C16H21F2N3O4 [M+H]+, 358.15; found, 358.10.

[0642] rel-methyl (R)-5-amino-4-( 1 -(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2- yl)picolinate, isomer2: MS ESI calculated for C16H21F2N3O4[M+H]+, 358.15; found, 358.10.Step-2:

[0643] To a stirred solution of rel-methyl (R)-5-amino-4-(l-(tert-butoxycarbonyl)-4,4- difluoropyrrolidin-2-yl)picolinate isomer 1 (2 g, 5.60 mmol) in DCM (20 mL) was added trifluoroacetic acid (10 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under vacuum to afford rel-methyl (R)-5-amino-4-(4,4- difluoropyrrolidin-2-yl)picolinate isomer 1 (2.5 g, crude) as a brown oil. MS ESI calculated for C11H13F2N3O2[M+H]+, 258.10; found, 258.10.Step-3:

[0644] To a stirred solution of rel-methyl (R)-5-amino-4-(4,4-difluoropyrrolidin-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 °C. The resulting mixture was stirred at 80 °C for 1 h. The precipitated solids were collected by filtration and washed with DCM. The solids were dried under vacuum to afford rel-methyl (R)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylate isomer 1 (1.4 g, 63%) as a grey solid. MS ESI calculated for C12H12F2N4O2[M+H]+, 283.09; found, 283.10.Step-4:

[0645] To a stirred solution of rel-methyl (R)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylate isomer 1 (1.40 g, 4.96 mmol) in methanol (4 mL), THE (8 mL) and H2O (4 mL) was added LiOH (356 mg, 14.88 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The mixture was acidified with HCI (aq.) to pH 5-6. The precipitated solids were collected by filtration and washed with acetonitrile. The solids were collected and dried under vacuum to afford rel-(R)-6-amino-9,9- difluoro-8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid isomer 1 (1.14 g, 85%) as a brown solid. MS ESI calculated for C11H10F2N4O2 [M+H]+, 269.07; found, 269.10.1H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 8.73 (br, 2H), 8.43 (s, 1H), 7.90 (s, 1H), 5.28 (dd, J= 11.4, 6.2 Hz, 1H), 4.26 - 4.02 (m, 2H), 3.51 - 3.26 (m, 1H), 2.94 - 2.64 (m, 1H).Intermediate CAS isomer 2: rel-(R)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid isomer 2Step-1:

[0646] To a stirred solution of rel-methyl (R)-5-amino-4-(l-(tert-butoxycarbonyl)-4,4- difluoropyrrolidin-2-yl)picolinate isomer 2 (1.6 g, 4.47 mmol) in DCM (18 mL) was addedtrifluoroacetic acid (6 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1.5 h. The mixture was concentrated under vacuum to afford rel-methyl (R)-5-amino-4-(4,4- difluoropyrrolidin-2-yl)picolinate isomer 2 (2.4 g, crude) as a brown oil. MS ESI calculated for C11H13F2N3O2 [M+H]+, 258.10; found, 258.10.Step-2:

[0647] A mixture of rel-methyl (R)-5-amino-4-(4,4-difluoropyrrolidin-2-yl)picolinate isomer 2 (2.4 g, 9.33 mmol) and carbononitridic bromide (0.99 g, 9.33 mmol) in 1,4-dioxane (30 mL) was stirred at 80 °C for 2 h. The precipitated solids were collected by filtration and washed with DCM. The solids were dried under vacuum to afford rel-methyl (R)-6-amino- 9,9-difluoro-8,9,10,10a-tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylate isomer 2 (1.2 g, 94% over 2 steps) as a yellow solid. MS ESI calculated for C12H12F2N4O2 [M+H]+, 283.09; found, 283.10.Step-3:

[0648] To a stirred solution of rel-methyl (R)-6-amino-9,9-difluoro-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylate isomer 2 (1.2 g, 4.25 mmol) in THE (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 stirred at room temperature for 1 h. The mixture was acidified with HC1 (aq.) to pH 5-6. The precipitated solids were collected by filtration and washed with acetonitrile. The solids were dried under vacuum to afford rel-(R)-6-amino-9,9-difluoro-8,9,10,10a-tetrahydropyrido[4,3- e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid isomer 2 (CA8 isomer 2) (950 mg, 83%) as a brown solid. MS ESI calculated for C11H10F2N4O2 [M+H]+, 269.07; found, 269.10.1H NMR(400 MHz, DMSO) 8 12.09 (s, 1H), 8.73 (br, 2H), 8.43 (s, 1H), 7.90 (s, 1H), 5.28 (dd, J = 11.4, 6.2 Hz, 1H), 4.26 - 4.02 (m, 2H), 3.51 - 3.26 (m, 1H), 2.94 - 2.64 (m, 1H).Intermediate CA9 isomer 1: rel-(8R,10aR)-6-amino-8-(difluoromethyl)-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid isomer 1Intermediate CA9 isomer 2: rel-(8R,10aR)-6-amino-8-(difluoromethyl)-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid isomer 2Intermediate CA9 isomer 3: rel-(8R,10aR)-6-amino-8-(difluoromethyl)-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid isomer 3Intermediate CA9 isomer 4: rel-(8R,10aR)-6-amino-8-(difluoromethyl)-8,9,10,10a- tetrahydropyrido[4,3-e]pyrrolo[l,2-c]pyrimidine-2-carboxylic acid isomer 4Step-1:

[0649] To a stirred solution of methyl 5 -formyl- lH-pyrrole-2-carboxylate (21 g, 137.13 mmol) in 1 ,2-dichlorobenzene (210 mL) was added BAST (91.02 g, 411.40 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The reaction was quenched with sodium bicarbonate (sat.) at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash column chromatography which applied to 330 g silica gel column and eluted with 0-30% ethyl acetate in petroleum ether to afford methyl 5- (difluoromethyl)-lH-pyrrole-2-carboxylate (21.5 g, 89% yield) as a white solid. MS ESI calculated for C7H7F2NO2[M+H]+, 176.04; found, 176.05.Step-2:

[0650] To a stirred solution of methyl 5-(difluoromethyl)-lH-pyrrole-2-carboxylate (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 stirred at room temperature for 1 h. The reaction was quenched with water and extracted with CH2CI2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase flash chromatography which applied to 330 g silica gel column and eluted with 0-12% ethyl acetate in petroleum ether to afford 1 -(tert-butyl) 2-methyl 5- (difluoromethyl)-lH-pyrrole-l,2-dicarboxylate (29.5 g, 87% yield) as a light yellow oil. MS ESI calculated for C12H15F2NO4 [M+H]+, 276.10; found, 276.05.Step-3:

[0651] To a solution of 1 -(tert-butyl) 2-methyl 5-(difluoromethyl)-lH-pyrrole-l,2- 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 balloon (1 atm.). The reaction mixture degassed via vacuum evacuation, then backfilled with hydrogen, and this process was repeated three times. The reaction mixture was stirred at room temperature for 1 h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to afford a 1 :1 mixture of 1 -(tert-butyl) 2-methyl (2S,5R)-5-(difluoromethyl)pyrrolidine-l,2- dicarboxylate and l-(tert-butyl) 2-methyl (2R,5S)-5-(difluoromethyl)pyrrolidine-l,2- dicarboxylate (crude, 27.4 g) as a fight yellow oil. MS ESI calculated for C12H19F2NO4 [M+H]+, 280.13; found, 280.05.Step-4:

[0652] To a stirred solution of 1 -(tert-butyl) 2-methyl 5-(difluoromethyl)pyrrolidine-l,2- dicarboxylate (27.40 g, 98.1 Immol) 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 stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum. The residue was acidified with 1 M HC1 (aq.) to pH - 2. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford a 1:1 mixture of (2S,5R)-l-(tert-butoxycarbonyl)-5-(difluoromethyl)pyrrolidine-2-carboxylic acid and (2R,5S)-l-(tert-butoxycarbonyl)-5-(difluoromethyl)pyrrolidine-2-carboxylic acid (crude, 25.6 g) as a yellow oil. MS ESI calculated for C11H17F2NO4 [M+H]+, 266.11; found, 266.00.Step-5:

[0653] To a stirred solution of 1:1 mixture of (2S,5R)-l-(tert-butoxycarbonyl)-5- (difluoromethyl)pyrrolidine-2-carboxylic acid and (2R,5S)-l-(tert-butoxycarbonyl)-5- (difluoromethyl)pyrrolidine-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-dimethoxy ethane (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. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere with Blue LEDs (450 nm). The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by normal phase flash chromatography which applied to 120 g silica gel column and eluted with 0-10% methanol in dichloromethane to afford 1: 1:2:2 mixture of rel-methyl 5-amino-4-((2R,5S)-l- (tert-butoxycarbonyl)-5-(difluoromethyl)pyrrolidin-2-yl)picolinate isomer 1 and rel-methyl 5- amino-4-((2R,5S)-l-(tert-butoxycarbonyl)-5-(difluoromethyl)pyrrolidin-2-yl)picolinate isomer 2 and rel-methyl 5-amino-4-((2R,5R)-l-(tert-butoxycarbonyl)-5- (difluoromethyl)pyrrolidin-2-yl)picolinate isomer 3 and rel-methyl 5-amino-4-((2R,5R)-l- (tert-butoxycarbonyl)-5-(difluoromethyl)pyrrolidin-2-yl)picolinate isomer 4 (2.2 g, 21% yield) as a yellow solid.. MS ESI calculated for C17H23F2N3O4 [M+H]+, 372.17; found, 372.25.Step-6:

[0654] A solution of 1:1:2:2 mixture of rel-methyl 5-amino-4-((2R,5S)-l-(tert- butoxycarbonyl)-5-(difluoromethyl)pyrrolidin-2-yl)picolinate isomer 1 and rel-methyl 5- amino-4-((2R,5S)-l-(tert-butoxycarbonyl)-5-(difluoromethyl)pyrrolidin-2-yl)picolinate isomer 2 and rel-methyl 5-amino-4-((2R,5R)-l-(tert-butoxycarbonyl)-5- (difluoromethyl)pyrrolidin-...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (la):or a pharmaceutically acceptable salt thereof, whereinX1is C(R’) or N;X2is C(R2) or N;X3is C(R3) or N;R1, R2, and R3are each independently H, C1-4alkyl, halo, or C1-4haloalkyl; n is 0, 1, 2, 3, or 4; each R4is independently C1-6alkyl, halo, C1-6haloalkyl, C1-6hydroxyalkyl, or C3-6cycloalkyl; or two R4groups when attached to the same carbon atom combine to form oxo or C3-6cycloalkyl; ring A is heterocycloalkyl having 4 to 7 ring members with at least 1 nitrogen atom ring vertex, and 0 to 2 additional heteroatoms as ring vertices, wherein each additional heteroatom is independently N, O, or S; ring B is phenyl or heteroaryl having 5 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; ring C is fused to (a) two adjacent ring vertices of ring A and (b) two adjacent ring vertices of ring B; and ring C is C4-7cycloalkyl or heterocycloalkyl having 4 to 7 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S; p is 0, 1, or 2; q is 0, 1, or 2; each R5is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, or -C(O)OC1-6haloalkyl; each R5ais independently C1-4alkyl, halo, C1-4haloalkyl, OH, or C1-4alkoxy; alternatively, two R5agroups attached to the same carbon atom combine to form oxo; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-4haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, -O-C3-6cycloalkyl,-C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, -C(O)OC1-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein each of the C3-6cycloalkyl, -O-C3-6cycloalkyl, and heterocycloalkyl is independently substituted with 0, 1, or 2 R6a; and each R6ais independently C1-4alkyl, halo, C1-4haloalkyl, CN, OH, or C1-4alkoxy;2. The compound or a pharmaceutically acceptable salt thereof of claim1, wherein: each R5is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, or -C(O)OC1-6haloalkyl; each R5ais independently C1-4alkyl, halo, or C1-4haloalkyl; alternatively, two R5agroups attached to the same carbon atom combine to form oxo; each R6is independently C1-6alkyl, C1-6haloalkyl, halo, C1-6alkoxy, C1-6haloalkoxy, CN, -O-C3 cycloalkyl, -C(O)C1-6alkyl, -C(O)C1-6haloalkyl, -C(O)OC1-6alkyl, - C(O)OC1-6haloalkyl, or heterocycloalkyl having 4 to 6 ring members with 1 to 3 heteroatom ring vertices, wherein each heteroatom is independently N, O, or S, and wherein the heterocycloalkyl is substituted with 0, 1, or 2 R6a; and each R6ais independently C1-4alkyl, halo, or C1-4haloalkyl.

3. The compound or a pharmaceutically acceptable salt thereof of claim 1 or 2, wherein X1is CH; X2is C(R2) or N; and X3is C(R3).

4. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein ring A is heterocycloalkyl having 5 to 7 ring members with at least 1 nitrogen atom and 0 to 1 additional heteroatom as ring vertices, wherein the additional heteroatom is N or O; ring B is phenyl or heteroaryl having 6 ring members with 1 to 2 nitrogen atom ring vertices; and ring C is C5-6cycloalkyl or heterocycloalkyl having 5 to 7 ring members with 1 heteroatom ring vertex, wherein the heteroatom is N or O.

5. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 4, wherein ring A is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl.

6. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 5, wherein ring A is piperidinyl, piperazinyl, or morpholinyl.

7. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 6, wherein ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

8. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 7, wherein ring C is C5-6cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, or oxepanyl.

9. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 8, wherein ring C is C5-6cycloalkyl, tetrahydrofuranyl, or tetrahydropyranyl.

10. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 9, having Formula (II):wherein: ring B is phenyl, pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl;Xais O, NH, NR5, CH2, CHR5, or C(R5)2;X5ais absent, O, CH2, or CHR5a;X5bis absent, O, CH2, or CHR5a, provided that X5aand X5bare not each absent or O; and a total number of R5groups is no more than 2.

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

12. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 11, having Formula (Ila- 1):wherein:Xais O, NH, N(C1-4alkyl), CH2, CHR5, or C(R5)2;X5ais absent, O, CH2, or CHR5a; andX5bis absent, O, CH2, or CHR5a, provided that X5aand X5bare not each absent or O; and a total number of R5groups is no more than 2.

13. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 11, having Formula (IIa-2):wherein:Xais O, NH, N(C1-4alkyl), CH2, CHR5, or C(R5)2;X5ais absent, O, CH2, or CHR5a; andX5bis absent, O, CH2, or CHR5a, provided that X5aand X5bare not each absent or O; and a total number of R5groups is no more than 2.

14. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 13, wherein X2is C(R2) or N; and R2and R3are each independently H or halo.

15. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 11, whereinX1is CH; X2is N; and X3is CH,X1is CH; X2is CH; and X3is CH or CF, orX1is CH; X2is CF; and X3is CH.

16. The compound or a pharmaceutically acceptable salt thereof of any one of claims 10 to 14, whereinX2is N; and R3is H,X2is CH; and R3is H or F, orX2is CF; and R3is H.

17. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 16, wherein each R4is independently C1-4alkyl or C1-4haloalkyl.

18. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 17, wherein each R4is independently methyl or -CHF2.

19. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 18, wherein each R4is methyl.

20. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 9, wherein n is 0 or 1.

21. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 20, wherein n is 0 or R4is absent.

22. The compound or a pharmaceutically acceptable salt thereof of any one of claims 10 to 21, wherein:Xais O, NH, CH2, or CHR5;X5ais O, CH2, or CHRSa;X5bis O, CH2, or CHR5a; and p is 0 or 1.

23. The compound or a pharmaceutically acceptable salt thereof of any one of claims 10 to 21, wherein:Xais O, NH, or CH2;X5ais O, CH2, or CHR5a;X5bis O, CH2, or CHR5a; and p is 0, 1, or 2.

24. The compound or a pharmaceutically acceptable salt thereof of any one of claims 10 to 21, wherein:Xais C(R5)2;X5ais O, CH2, or CHR5a;X5bis O, CH2, or CHR5a; and p is 0.

25. The compound or a pharmaceutically acceptable salt thereof of any one of claims 10 to 22, wherein:X5ais O and X5bis CH2;X5ais CH2and X5bis O;X5ais CH2and X5bis CH2;X5ais O and X5bis CH(CH3);X5ais CH(CH3) and X5bis O;X5ais CH2and X5bis CH(CH3);X5ais CH(CH3) and X5bis CH2;X5ais absent and X5bis CH2; orX5ais absent and X5bis O.

26. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 25, wherein each R5is independently C1-4alkyl, halo, OH, or C1-4alkoxy.

27. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 26, wherein each R5is independently methyl, fluoro, OH, or methoxy.

28. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 27, wherein each R5is independently methyl, fluoro, or methoxy.

29. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 28, wherein each R6is independently C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6 alkynyl, -O-C2-6 alkynyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C3-6cycloalkyl and -O-C3-6cycloalkyl are each independently substituted with 0 or 1 CN.

30. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 29, wherein q is 1; and R6is C1-6alkyl, C1-6haloalkyl, halo, OH, C1-6alkoxy, C1-6haloalkoxy, CN, C2-6alkynyl, -O-C2-6alkynyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C3-6cycloalkyl and -O-C3-6cycloalkyl are each independently substituted with 0 or 1 CN.

31. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30, wherein q is 1; and R6is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl-O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, HC=C , or HC=C-CH2-O-.

32. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 31, wherein q is 1; and R6is chloro, trifluoromethyl, or difluoromethyl-O-33. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 29, wherein q is 2; and each R6is independently fluoro, chloro, methoxy, trifluoromethyl, or difluoromethyl-O-.

34. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 and 33, wherein the moietyhas the formula:X5wherein:Xais O, NH, CH2, or CHR5;X5ais O, CH2, or CHR5a;X5bis O, CH2, or CHR5a; each R5ais independently C1-4alkyl; each R5is independently F, OH, C1-4alkyl, or C1-4alkoxy; andR6is C1-4alkyl, C1-4haloalkyl, halo, CN, C1-4alkoxy, C1-4haloalkoxy, C2-4alkynyl, - O-C2-4 alkynyl, C3-e cycloalkyl, or -O-C3.e cycloalkyl, wherein the C3-e cycloalkyl and -O- C3-e cycloalkyl are each independently unsubstituted or substituted with CN, provided that X5aand X5bare not each O.

35. The compound or a pharmaceutically acceptable salt thereof of claim34, wherein Xais O, NH, CH2, CHF, C(CH3), C(OH), or C(OCH3); X5ais O, CH2, or CH(CH3); X5bis O or CH2; R5is F, CH3, OH, or OCH3; and R6is chloro, CN, isopropyl, methoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethyl-O-, difluoromethyl- O-, trifluoromethyl-O-, cyclopropyl, NC-cyclopropyl-, cyclopropyl-O-, CH=CH- or CH=CH-CH2-O-, provided that X5aand X5bare not each O.

36. The compound or a pharmaceutically acceptable salt thereof of claim34 or 35, wherein R6is chloro, trifluoromethyl, or difluoromethyl-O-.

37. The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 36, wherein the moietyhas the formula:0 FO o o 4-FN’N N' NN NH211N NH2F F N NH2N NH2oVFTl N F NN NH238. The compound or a pharmaceutically acceptable salt thereof of claim1, wherein the compound is selected from Table 1.

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

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

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

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

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

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

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

46. The method of claim 41 or 45, wherein the cancer is deficient inCDKN2A.

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

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

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

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

51. The method of any one of claims 41 to 48, wherein the cancer is nonsmall cell lung cancer (squamous and adenocarcinoma), urothelial cancer (bladder and upper urinary tract), esophageal cancer, or gastric cancer.

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

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

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

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