SELECTIVE INHIBITORS OF PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5)

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Number 62/465,584, filed March 1 , 2017, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[0002] The disclosure is directed to PRMTS inhibitors and methods of their use.

BACKGROUND

[00031 Protein arginine methylation is a common post-translational modification that regulates numerous cellular processes, including gene transcription, mRNA splicing, DNA repair, protein cellular localization, cell fate determination, and signaling. Three types of methyl-arginine species exist: co NG monom ethyl arginine (MMA), ω NG, NG asymmetric dim ethyl arginine

(ADMA) and ω NG.N'G symmetric dimethylarginine (SDMA). The formation of methylated arginines is catalyzed by the protein arginine methyl transferases (PRMTs) family of

methyltransferases. Currently, there are nine PRMTs annotated in the human genome The majority of these enzymes are Type I enzymes (PRMT1, -2,-3,-4,-6,-8) that are capable of mono- and asymmetric dimethylation of arginine, with S-adenosylmethionine (SAM) as the methyl donor. PRMT-5, -7 and -9 are considered to be Type II enzymes that catalyze symmetric dimethylation of arginines. Each PRMT species harbors the characteristic motifs of seven beta strand

methyltransferases (Katz et al., 2003), as well as additional "double E" and "THW" sequence motifs particular to the PRMT subfamily.

[0004] PRMTS is as a general transcriptional repressor that functions with numerous transcription factors and repressor complexes, including BRG1 and hBRM, Blimp 1, and Snail. This enzyme, once recruited to a promoter, symmetrically dimethylates H3R8 and H4R3. Importantly, the H4R3 site is a major target for PRMT1 methylation (ADMA) and is generally regarded as a transcriptional activating mark. Thus, both H4R3me2s (repressive; me2s indicates SDMA modification) and H4R3me2a (active; me2a indicates ADMA modification) marks are produced in vivo. The specificity of PRMT5 for H3R8 and H4R3 can be altered by its interaction with COPR5 and this could perhaps play an important role in determining PRMT5 corepressor status.

Role of PRMTs in Cancer

[0005] Aberrant expression of PRMTs has been identified in human cancers, and PRMTs are considered to be therapeutic targets. Global analysis of hi stone modifications in prostate cancer has shown that the dimethylation of hi stone H4R3 is positively correlated with increasing grade, and these changes are predictive of clinical outcome.

[0006] PRMT5 levels have been shown to be elevated in a panel of lymphoid cancer cell lines as well as mantle cell lymphoma clinical samples. PRMT5 interacts with a number of substrates that are involved in a variety of cellular processes, including RNA processing, signal transduction, and transcriptional regulation. PRMT5 can directly modify hi stone H3 and H4, resulting in the repression of gene expression. PRMTS overexpression can stimulate cell growth and induce transformation by directly repressing tumor suppressor genes. Pal et al., Mol. Ceil. Biol. 2003, 7475; Pal et al. Mol. Ceil. Biol. 2004, 9630; Wang et al. Mol. Ceil. Biol. 2008, 6262; Chung et al. J Biol Chem 2013, 5534. In addition to its well-documented oncogenic functions in transcription and translation, the transcription factor MYC also safeguards proper pre-messenger- RNA splicing as an essential step in lymphomagenesis. Koh et al . Nature 2015, 523 7558; Hsu et al. Nature 2015 525, 384.

[0007] The discover}' of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, it has been recently discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77, MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. Cells harboring MTAP deletions possess increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP). Furthermore, MTA specifically inhibits PRMT5 enzymatic activity. Administration of either MTA or a small- molecule PRMT5 inhibitor shows a preferential impairment of cell viability for MTAP-null cancer cell lines compared to isogenic MTAP-expressing counterparts. Together, these findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration, Role of PRMT5 in Hemoglobinopathies

[0008] The developmental switch in human globin gene subtype from fetal to adult that begins at birth heralds the onset of the hemoglobinopathies, b -thala semia and sickle cell disease (SCD). The observation that increased adult globin gene expression (in the setting of hereditary persistence of fetal hemoglobin [HPFH] mutations) significantly ameliorates the clinical severity of thalassemia and SCD has prompted the search for therapeutic strategies to reverse gamma-globin gene silencing. Central to silencing of the gamma-genes is DNA methyl ation, which marks critical CpG dinucleotides flanking the gene transcriptional start site in adult bone marrow eiythroid cells. It has been shown that these marks are established as a consequence of recruitment of the DNA methyltra sferase, DNMT3A to the gamma-promoter by the protein arginine methyltransferase PRMT5. Zhao et al. Nat Struct Moi Biol. 2009 16, 304. PRMT 5 -mediated methylation of histone FI4R3 recruits DNMT3 A, coupling histone and DNA methylation in gene silencing.

[0009] PRMT5 induces the repressive histone mark, H4R3me2s, which serves as a template for direct binding of DNMT3A, and subsequent DNA methylation. Loss of PRMT 5 binding or its enzymatic activity leads to demethyiation of the CpG dinucleotides and gene activation. In addition to the H4R3me2s mark and DNA methylation, PRMT5 binding to the gamma-promoter, and its enzymatic activity are essential for assembly of a multiprotein complex on the gamma-promoter, which induces a range of coordinated repressive epigenetic marks. Disruption of this complex leads to reactivation of gamma gene expression. These studies provide the basis for developing PRMT5 inhibitors as targeted therapies for thalassemia and SCD.

SUMMARY

[0010] The disclosure is directed to compounds of Formula I, Formula II, Formula III, or

Formula IV:

or a pharmaceutically acceptable salt or solvate thereof; wherein

A is CH or N;

R ¹ is -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-C ₆ alk-C≡ H, -Co-C6alk-C≡C-Ci- Cealkyl, -Co-C6alk-C≡C-C ₃ -C6cycloalkyl, -Ci-Cealk- aryl, -Co-Cealk-heteroaryl , -Ci-Cealk-O-heteroaryl, -Ci-Cealk-S-heteroaryl, or -Ci- Ceal k-NH-heteroaryl ;

R ² is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH, -Co-Ceal k-O-Ci-Cealkyl, -Co-Cealk-NHi, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-NiCi-CealkylVCi-Cealkyl, -Co-Cealk-NH-Cs-Cecycloalkyl,

-Co-C6alk~N(Ci~C6alkyl)~C3-C6cycloalkyl, -Co-Cea k-heterocycloalkyl, heteroaryl, or -CN;

R ³ is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-CB-Ceeycloalkyl, -Co-Cealk-OH,

-Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-Mfc, -Co-Cealk-NH-Ci-Cealkyl, -Co-C ₆ alk-N(Ci- Cealky -Ci-Cealkyl, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-Cealk-NCCi-Cealky -Cs- Cecycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;

R ⁴ is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH,

-Co-Ceal k-O-Ci-Cealkyl, -Co-Cealk- Hi, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-N(Ci- Cealky -Ci-Cealkyl, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-C6alk-N(Ci-Cealkyl)-C3- Cecyeloalkyl, -Co-Cealk-heterocycloalkyl, heteroaiyl, or -CN; or R ² and R ³ , together with the atoms to which they are attached, form a

Cs-Cecyeioalkenyi ring;

or R ² and R ⁵ , together form a triple bond;

or R ^J and R ⁴ , together with the atom to which they are attached, form a Cs-Cecycloalkyl ring or a heterocycloal ky] ring;

R ⁵ is I I, halo, NFfc, or Ci-Cealkyl;

R ⁶ is H, halo, Ci-Cealkyl, -Ci-Cehaloalkyl, or -Co-C6alk-C ₃ -C6cycloalkyl,

R' is halo, -Ci-G alkyl, -C ₁ -C ₄ haloalkyl, -C3-C&cycloalkyl, -Oj-Cehaloeyeloalkyl, -C ₂ -

C4alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C ₆ alkyl, -Ci-C6alk-N(Ci- C6al kyl)R ⁸ , -Ci-Cealk-S-Ci-Cealkyl, -Ci-C6alk-S(0)-Ci-C6alkyl, -Ci-C6alk-S(0)2-Ci- Cealkyl, -CR ⁸ R ^8' CN, -N 1 1-( Ί -( Y.ai k -S-C ^' · -(Y.ai ky 1. - H-Ci-C6alk-S(0)-Ci-C6alkyl, - NH-Ci-Ceal k-S(0) ₂ -Ci-C6alky 1, -NH-Ci-Ceal k-N-Ci-CealkylfR ⁸ ), ~NHCR ⁸ R ^8' CN, - H-CN, -NHCONR ⁸ R ^8' , -NHC(S) R ⁸ R ^8' , - HC(0)OR ⁹ , -NHC(S)GR ⁹ , -NHC(O)- Ci-Cealkyl, - HC(0)-Ci-C6haloalkyl, -NH-Ci-C6alk-C(0)-C l-Cealkyl, or -N-(3-Ci- C&alkyl)imidazolidin-2-one;

R ⁸ and R ^8' are each independently H, Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl;

or R ⁸ and R ⁸ , together with the atom to which they are attached, form a Cs-Cecycloalkyl ring or a five or six membered heterocyclic ring; and

R ⁹ is -Ci-Cealkyl, or Co-Cealk-Cs-Cecycloal kyl .

f 001 1 1 Stereoisomers of the compounds of Formula I, Formula II, Formula III, or Formula IV, and the pharmaceutical salts and solvates thereof, are al so descri bed. Methods of using compounds of Formula I, Formula II, Formula III, or Formula IV are described, as well as pharmaceutical compositions including the compounds of Formula I, Formula II, Formula III, or Formula IV.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0012] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination. [0013] The term "alkyl," when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms ("C1-C12"), preferably 1 to 6 carbons atoms ("Ci-Ce"), in the group. Examples of alkyl groups include methyl (Me, C j alkyl), ethyl (Et, dalkyl), n-propyl (dalkyl), isopropyi (C ₃ alkyl), butyl (C ₄ alkyl), isobutyl (dalkyl), sec-butyl (C ₄ alkyl), tert-butyl (dalkyl), pentyl (dalkyl), isopentyl (Csalkyl), tert-pentyl (dalkyl), hexyl (dalkyl), isohexyl (dalkyl), and the like.

[0014] The term "halo" when used alone or as part of a substituent group refers to chloro, fiuoro, bromo, or iodo.

[0015] The term "haloalkyl" when used alone or as part of a substituent group refers to refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of haloalkyl groups of the disclosure include, for example, triftuorom ethyl (-CF3), chlorom ethyl (- CH2CI), and the like.

[0016| The term "cycloalkyl" when used alone or as part of a substituent group refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms ("C ₃ -C ₁₀ "), preferably from 3 to 6 carbon atoms ("C3-C6"). Examples of cycloalkyl groups include, for example, cyclopropyl (C ₃ ), cyclobutyl (C ₄ ), cyclopropylmethyl (C ₄ ), cyclopentyi (C5), cyclohexyl (d), 1- methylcyclopropyl (C ₄ ), 2-methylcyclopentyl (C ₄ ), adamantanyl (do), and the like.

[0017] The term "halocycloalkyl" when used alone or as part of a substituent group refers to a cycloalkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of cycloalkyl groups include, for example, chiorocyclopropyl (C ₃ ), fluorocyciobutyi (C ₄ ),

bromocyclopentyl (C5), iodocyclohexyl (Ce), and the like.

[0018] The term "heterocycloaikyi" when used alone or as part of a substituent group refers to any three to ten membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S. The heterocycloaikyi group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of suitable heterocycloaikyi groups include, but are not limited to, azepanyl, aziridinyi, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazoiidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like. [0019] The term "oxo-substituted-heterocycloalkyl" when used alone or as part of a substituent group refers to a heterocycloalkvl group wherein at least one of the carbon atoms in the ring is substituted with an oxo group. Examples of oxo-substituted heterocycloalkvl groups include, but are not limited to, 2-aziridinonyi, 2-azetidinonyl, pyrrolidinonyl, dioxoianonyi,

imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl, thiomorpholinonyl, oxazepanonyl, oxiranonyl, oxetanonyl, quinuclidinonyl, tetrahvdroturanonyl, tetrahydropyranonyl, piperazinonyl, and the like.

[0020] The term "alkenyl" when used alone or as part of a substituent group refers to a straight- or branched-chain group having from 2 to 12 carbon atoms ("C2-C12"), preferably 2 to 4 carbons atoms ("C2-C "), in the group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl CI 1 <; C ₂ alkenyl) allyl (-CH2- CH=CH ₂ ;

Csalkenyl), propenyl (-CH=CHCH ₃ ; Csalkenyl); isopropenyl (-C(CH ₃ )=CH ₂ ; Csalkenyl), butenyl (- C4alkenyl), iso-butenyi (- (Ί 1 C(C! } .. C ia!kenvi ), 2-butenyl (-CH2CH-CHCH3; Oa!keny! ), pentenyl

Csalkenyl), and the like.

[00211 The term "haloalkenyl" when used alone or as part of a substituent group refers to an alkenyl group wherein at least one carbon atom in the group is substituted by one or more halogen atoms. Halogen atoms include chlorine, fluorine, bromine, and iodine.

[0022] The term "cyanoalkenyl" when used alone or as part of a substituent group refers to an alkenyl group wherein at least one carbon atom in the group is substituted by one or more cyano groups.

[0023] The term "cycloalkenyl," when used alone or as part of a substituent group refers to cyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms ("C3-C10"), preferably from 3 to 6 carbon atoms ("C3-C6") and containing at least one carbon-carbon double bond. For example, cycloalkenyl groups include, but are not limited to cyclopropenyl, cyclobutenyl, and the like.

[0024] The term "aryl" when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted. Exemplary substituents include a halogen atom, a -C1-C3 alky! group, or a -C1-C3 aiky! group that is substituted with a hydroxy group, an amino group (i.e., -NH2), or an alky-substituted amino group. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of aryi groups (substituted and unsubstituted) include phenyl, naphtvl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, methyl chlorophenyl, (hydroxymethyl)chlorophenyl, (hydroxymethyl)fluorophenyl,

(hydroxymethyl)difluorophenyi, (hydroxymethyl)dichiorophenyl, (aminomethyi)chlorophenyl, (aminomethyl)fluorophenyl, (aminomethyl)difluorophenyl, (aminomethyl)di chlorophenyl,

(methylaminomethyl)chl orophenyi, (methyl aminomethy 1 )fluorophenyl,

(methylaminomethyl)difluorophenyl, (methylaminomethyl)di chlorophenyl, methyl difluorophenyl, bromophenyl, iodophenyl, chlorofluorophenyi, fluoronaphthyl, difluoronaphthyl, chloronaphthyl, bromonaphthyl, iodonaphthyl, methylphenyl, ethylphenyl, and the like.

100251 The term "heteroaryl" when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms. The heteroaryl moiety can be unsubstituted or one or more of the carbon atoms in the ring can be substituted. Exemplary substituents include a halogen atom; an amino group; a substituted amino group, including an amino group substituted with a -d-Ce cycloalkyl group or a -Ci-Ce alkyl group; or a -Ci-Cs alkyl group. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyi, imidazoiyl, purazolyl, isoxazolyi, isothiazolyl, triazolyl, thiadiazoiyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, turazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuranyi, benzothiophenyl, benzimidazolyl, benzthiazolyl, purinyl, quinoiizinyl, quinolinyi, 2- amino-3-bromoquinolin-7-yl, 2-amino-3-chloroquinolin-7-yl, 2-

((cyclopropylmethyl)amino)quinolin-7-yl, 2-(methylamino)quinolin-7-yl, 2-aminoquinolin-7-yl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.

[0026] When a range of carbon atoms is used herein, for exampl e, Ci-Ce, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, "C1-C3" includes C1-C3, C1.C2, C2-C3, Ci, C2, and C ₃ .

[0027] The term "Ci-Cealk" when used alone or as part of a substituent group refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, -CH2-, -CH(CH ₃ )-, -CH(CH3)-CH2-, and -C(CH ₃ )2-. The term "-Coalk-" refers to a bond. In some aspects, the Ci-Cealk can be substituted with one or more -OH, -Nth, or halo (e.g., -F, -CI, -Br, with -F being preferred) substituents.

[0028] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized

pharmacopoeia for use in animals, e.g., in humans.

[0029] "Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonie acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4~methylbicyclo[2.2.2]-oct-2-ene-l-carboxyiic acid, giucoheptonic acid, 3-phenylpropionie acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy-naphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium,

tetraalkyl ammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0030] A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0031] A "solvate" refers to a physical association of a compound of Formula I, Formula II, Formula III, or Formula IV with one or more solvent molecules.

100321 "Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.

[0033] "Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i .e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom ), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0034] "Compounds of the present disclosure," and equivalent expressions, are meant to embrace compounds of Formula I, Formula II, Formula III and/ or Formula IV as described herein, as well as their subgenera, which expression includes the stereoisomers of compounds of Formula I, Formula II, Formula III, and/ or Formula IVas well as the pharmaceutically acceptable salts, where the context so permits,

[0035] As used herein, the term "isotopic variant" refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance. For example, an "isotopic variant" of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( I or D), carbon- 13 ( ^! C), nitrogen- 5 ( ¹⁵ N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be H/D, any carbon may be ¹³ C, or any nitrogen may be ^l5 N, and that the presence and placement of such atoms may be determined within the skill of the art.

[0036] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers," for example, diastereomers, enantiomers, and atropisomers. The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)-or (^-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Where a chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers, are encompassed by that structure. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

100371 The disclosure is directed to compounds of Formula I, Formula II, Formula III, and Formula IV. In some aspects, the disclosure is directed to com ounds of Formula I:

[0038] In other aspects, the disclosure is directed to compounds of Formula II:

[0039] In other aspects the disclosure is directed to compounds of Formula III:

[0040] In other aspects, the disclosure is directed to compounds of Formula IV:

[0041] According to the disclosure, A in Formula I or Formula II is N or CH. In some aspects, A is N and the compoun f Formula I are of Formula IA:

[0042] In some aspects, A is N and the compounds of Formula II are of Forniu

[00431 In some aspects, A is CH and the compounds of Formula I are of Formula IB :

[0044] In other aspects, A is CH and the com ounds of Formula II are of Formula IIB:

[0045] According to the disclosure, R ¹ in Formula I, Formula II, Formula III, and Formula is -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-Cealk-C-CIl -Co-C6alk-C≡C-Ci- Cealkyl, -Co-C6alk-C≡C-Ci-C6haloalkyl, -Co-C6alk-C≡C-C ₃ -C6cycloalkyl, -Ci-Cealk-aryl, -C ₀ - Cealk-heteroaryl, -d-Cealk-O-heteroaryl, -Ci-Cealk-S-heteroaryl, or -Ci-Cealk-NH-heteroaryl.

[0046] In some aspects, R ^f i s -Co-Cealk-C i-Cealkyl, for example, -Coalk-Cialkyl, -Cialk- Cialkyl, -C ₂ alk-Cj.alkyl, -C ₃ alk-Cj.alkyl, -C ₄ alk-Cialkyl, -Csalk-Cialkyl, -Cealk-Cialkyl, -Coalk- C ₂ alkyl, -Cialk-Csalkyl, -C ₂ alk-C ₂ alkyl, -C ₃ alk-C ₂ alkyl, -C ₄ alk-C ₂ alkyl, -Csalk-C ₂ alkyl _J -Ce.alk- C alkyl, -Coalk-Csalkyl, -Cialk-Csalkyl, -Cialk-Csalkyl, -Csalk-Csalkyl, -C ialk-Oalkyl. -Csalk- Csalkyl, -Cealk-Csalkyl, -Coalk-C ₄ alkyl, -Cialk-C4alkyl, -C ₂ alk-C4alkyl, -Oai k-Oai kyk -C ₄ alk- Oaikyi, -Csalk-Cmlkyl , -C6alk-C4alkyl, -Coalk-Csalkyl, -Cialk-Csalkyl, -Cialk-Csalkyl, -Csalk- Csalkyl, -C ₄ alk-C ₅ alkyl, -Csaik-Csalkyl, -Cealk-Csalkyl, -Coalk-Cealkyl, -Cialk-Cealkyl, ~C ₂ alk~ Cealkyl, -Csalk-Cealkyl, -C ₄ alk-C6al kyl , -Csalk-Cealkyl , -Cealk-Cealkyl, methyl, ethyl, propyl , isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, -CH(OH)-Ci -Cealkyl (for example, -CH(OH)- methyl, -CH(OH)-ethyl, -CH(OH)-propyl, -CH(OH)-isopropyl, -CH(OH)-pentyl, -CH(OH)-butyl, and the like), -CH(F)-Ci-C6alkyl, -CH(NH ₂ )-Ci-C6alkyL -CH(Me)-Ci -Cealkyl, -C(Me)(OH)-Ci- Cealkyl, and the like.

[0047] In other aspects, R ¹ is -Co-Cealk-Ci-Cehaloalkyl, for example, -Coalk-Cihaloalkyl, - Cialk-Cihaloa!kyl, -C alk-Cihaloalkyl, -Csalk-Cihaloalkyl, -Gialk-dhaloalkyl, -Csalk-dhaloalkyl, - dalk-Cihaloalkyl, -Coalk-C ₂ haloalkyl, -Cialk-dhaloalkyl, -C ₂ alk-C ₂ haloalkyl, -dalk-Ohaloalkyl, - C ₄ alk-C ₂ haloalkyl, -dalk-dhaloalkyl, -C6alk-C ₂ haloalkyl, -Coalk-dhaloalkyl, -dalk-dhaloalkyl, - C ₂ alk-C ₃ haloalkyl, -C ₃ alk-C ₃ haloalkyl, -C4alk-C3haloalkyl, -Csalk-dhaloalkyl , -C6alk-C ₃ haloalkyl, - C ₀ alk-C ₄ haloalkyl, -C ₁ alk-C ₄ haloalkyl, -C2alk-C ₄ haloalkyl, -C ₃ alk-C ₄ haloalkyl, -C ₄ alk-C ₄ haloalkyl, - dalk-dhaloalkyl, -C6alk-C4haloalkyl, -Coalk-Cshaloalkyl, -dalk-Cshaloalkyl, -dalk-Cshaloalkyl, - C ₃ alk-C5haloalkyl, -dalk-dhaloalkyl, -dalk-dhaloalkyl, -dalk-dhaloalkyl, -Coalk-dhaloalkyl, - dalk-dhaloalkyl, -C ₂ alk-C6haloalkyl, -dalk-dhaloalkyl, -dalk-dhaloalkyl, -dalk-dhaloalkyl, - dalk-dhaloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, -CH(OH)-d-d haloalkyl (e.g., -CH(OH)-fluoromethyl, -CH(OH)-fluoroethyl, -CH(QH)-fluoropropyL -CH(OH)- fluoroisopropyl, -CH(OH)-fluoropentyl, -CH(OH)-fluorobutyl), -CH(F)-d-C6haloalkyl, -CH(NH ₂ )- Ci-Ce haloalkyl, -CH(Me)-Ci-C6 haloalkyl, -C(Me)(OH)-Ci-C6 haloalkyl, and the like. Thus, in some aspects, R ¹ is chloromethyl (i.e., -CH2-CI .) In some embodiments, R ¹ is -CH(OH)d- C4haloalkyl. [0048] In some aspects, R ¹ is -Co-C6alk-C≡CH, for example, -Coalk-C≡CH, -Cialk-C≡CH , -C ₂ alk-C≡CH , -C ₃ alk-C≡CH , -C ₄ alk-C≡CH , -C ₅ alk-C≡CH , -Cealk-C≡CH, ethynyl, propargyl, - CH(OH)-C≡CH, -CH(F)-C≡CH, -CH(NH ₂ )-C-CH, -CH{Me)-C O i, -C(Me)(OH)-C≡CH, and the like.

[0049] In some aspects, R ¹ is for example, -Coalk-0≡€-Ciaikyl, -Cialk-C≡C-Cialkyl, -C ₂ alk-C≡C-Cialkyl, -C ₃ alk-C≡C-Cialkyl, -C4alk-C≡C-Ciafkyf, -Csalk-C≡C- Cialkyl, -C6alk-C≡C-Cialkyl, -Coalk-C-C-C ₂ alkyl, -Cialk-C≡C-C2alkyl, -C ₂ alk-C≡ -C ₂ alkyl, - C3alk-C≡C-C ₂ alkyl, -C4alk-C≡C-C2alkyl, -C5alk-C≡C-C ₂ alkyl , -C6alk-C≡C-C?.aikyi, -Coalk-C≡C- Csalkyl, -Cialk-C≡C-C ₃ alkyl, -C -a!k-C C-OaikyL -C ₃ alk-C≡C-C ₃ alkyl, -C4alk-C≡C-C ₃ alkyl, - C5alk-C≡C-C ₃ alk 1. -Cealk-C-C-Csalkyl, -C„a!k-C C-C ia!k> L -C ialk~OC~C ₄ alkyl, -C ₂ alk-C≡C- C4aikyL -C ₃ alk-C≡C-C4alkyl, -C4alk-C≡C-C4alkyl, -C ₅ alk-C≡C-C4alkyl , -C6alk-C≡C-C4alkyl, - Coaik-C≡ -C ₅ aikyi, -Cialk-C≡C-C ₅ alkyl, -Caalk-C-C-Csalkyl, -Csalk-C-C-Csalkyl, -C ialk-C C- Csalkyl, -C ₅ alk~C≡C-C ₅ alkyl ₍ -C6alk-C≡C-Csalkyl, -Coalk-C≡C-C6alkyl, -Cialk-C≡C-C6alkyl, - C ₂ alk-C-C-C ₆ alkyl, -Csalk-C-C-Cealkyl, -Oa!k-C C-C^aikyL -Csalk-C^C-Cealkyl, -Cealk-C-C- Cealkyl, propynyl, butynyl, -CH(OH)-C≡C-Ci-C6alkyl, -<Ί Ι( Ι· ^' )-Γ C--C i -CVa!kv!. -CH(NH ₂ )-C≡C- Ci-Cealkyl, -( ^' H(Me)-C ( ^' -( ·-( .alkyL ~C(Me)(OH)~0≡ ~Ci-C ₆ alkyl, and the like. In some embodiments wherein -Co-C ₆ alk-C≡C-Ci-C ₆ alkyl is -Co-C ₆ alk-C≡C-CH ₃ , R ¹ is -CH(OH)-C≡C-CH ₃ , -CH(F)-C≡C-CH ₃ , -CH( H ₂ )-C≡C-CH ₃ , -CH(Me)-C≡C-CH ₃ , or -C(Me)(OH)-C≡C-CH ₃ . In some embodiments, R ¹ is -CH(OH)-C≡C-CH ₃ . In other embodiments, R ¹ is -CH(F)-C≡C-CH ₃ . In yet other embodiments, R ¹ is -CH(NH ₂ )-C≡C-CH ₃ . In some embodiments, R ¹ is -CH(Me)-C≡C-CH ₃ . In other embodiments, R ¹ is C! !(()[ i )(Me)-C C-C! h

[0050] In some aspects, R ¹ is -Co-Cealk-C^-d-Cehaloalkyl, for example, -Coalk-C≡C- Cihaloalkyl, -Cialk-C≡C-Cihaloalkyl, -C ₂ alk-C≡ -Cihaloalkyl, -C ₃ alk-C≡C-Cihaloalkyl, -C ₄ alk- C≡C-Cihaloalkyl, -C5alk-C≡C-Cihaloalkyl, -C&alk-C≡C-Cihaloafkyf, -Coalk-C≡C-C ₂ haloaikyi, - Cialk-C≡ -C ₂ haloalkyi, - a!k-C C-dhaioa!kv!, -C ₃ alk-C≡ -C ₂ haloalkyl, -C ₄ alk-C≡ - C?.haioalkyl, -C5alk-C≡C-C ₂ hal oalkyl, -C6alk-C≡C-C ₂ haloalkyl, -Coalk-C≡C-C ₃ haloalkyl, -Cialk- C≡C-C ₃ haioalkyl, -C ₂ alk-C≡C-C ₃ haloalkyl, -C ₃ alk-C≡C-C ₃ haloalkyl, -C4alk-C≡C-C ₃ haloalkyl, - C ₅ alk-C≡C-C ₃ haloalkyl , -Cealk-C-C-Cshaloal kyl , -Coal k-C C-Oha! oalkyl, -Cialk-C≡C- C4haioalkyl, -C2alk-C≡C-C ₄ haloalkyl, -C ₃ alk-C≡C-C4haloalkyl, -C4alk-C≡C-C4haloalkyl, -Csalk- C≡C-C ₄ hal oalkyl _s -C6alk-C≡C-C haloalkyl, -Coalk-C≡C-C5haloalkyl, -C alk-GOCshaloalkyl, - C ₂ alk-C≡C-C5haioalkyl, -C ₃ alk-C≡C-C ₅ haloalkyl, -C ₄ alk-C≡C-C5haloaikyI, -C ₅ aik-C≡C- Cshaloalkyl, -C6alk-C≡C-C5haloalkyl, -Coalk-C≡C-C&haloafkyf, -Ciaik-C≡C-C6haioalkyl, -C ₂ alk- C≡C-C ₆ haloalkyl, -C ₃ alk-C≡C-C6haloalkyl, -C4alk-C≡C-C ₆ haloalkyl, -C5alk-C≡C-C6haloalkyl, - Cealk-C^C-Cehaioalkyl, -CH(OH)-C≡C-Ci-C6haloalkyl, -CH(F)-C≡C-Ci-C6haloalkyl, -CH(NH ₂ )- C≡C-Ci-C6haloalkyl, -CH( e)-C≡C-Ci-C6haloalkyl, -C(Me)(OH)-C≡C-Ci-C6haloalkyl, and the like. In some embodiments wherein -Co-C6alk-C≡≡C-Ci-C6haloalkyl is -Co-C6alk-C≡C-CF ₃ , R ¹ is - ( ^' l i(Ol i )-( ^' C-C ·(·! ]( ⁾ ·}··(- C ^' -( -CH(NH?.)-C≡C-CF3, -CH(Me)-C≡C-CF ₃ , -C(Me)(OH)-C≡C- CPs, and the like. Thus, in some embodiments, R ¹ is -CH(OH)-C≡C-CF3.

[0051] In some aspects, R ¹ is -Co-C6alk-C≡C-C ₃ -C6cycloalkyl, for example, -Coalk-C≡C- C ₃ cycloalkyl, -Coalk-C≡C-C4cycloalkyl, -Coalk-C≡C-C5cycloalkyl, -Coalk-C≡C-C6cycloalkyl, - Cialk-C≡C-C ₃ cycloalkyl, -Cialk-C≡C-C4cycloal kyl , -Cial k-C≡C-Cs-cycloalkyl, -Cialk-C≡C- Cecycloalkyl, -C ₂ alk-C≡C-C ₃ cycloalkyl, -C2alk-C≡C-C4cycloalkyl, -C2alk-C≡C-C5cycloalkyl, - C2alk-C≡C-C6cycloalkyl, -C3alk-C≡€-C3cycloalkyl, -C ₃ alk-C≡C-C ₄ cycloalkyl, -C3alk-C≡C- Cscycloalkyl, -C ₃ alk-C≡C-C6cycloalkyl, -C ₄ alk-C≡C-C ₃ cycloalkyl, -C4alk-C≡C-C ₄ cycloalkyl, - C4alk-C-C-C ₅ cycloalkyl, -C4alk-C≡C-C6cycloalkyl, -C ₅ alk-C≡C-C ₃ cycloalkyl, -Csalk-C-C- C ₄ cycloalkyl, -C5alk-C≡C-C5cycloalkyl, -C5alk-C≡C-C&cycloalkyl, -C6alk-C≡C-C ₃ cycloalkyl, - C6alk-C≡C-C4cycloalkyl, -C6alk-C≡C-C5cycloalkyl, -Cealk-C-C-Cecycloalkyl, -CH(OH)-C≡C-C ₃ - Cecycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH( H2)-C≡C-C ₃ -C6cycloalkyl, -CH(Me)-C≡C-C3- C6cycloalkyl, or -C(Me)(OH)-C≡C-C ₃ -C6cycloalkyl. In some embodiments wherein -Co-C6alk-C≡C- Cs-Cficycloalkyl is -Co-Cealk-C^C-cyclopropyl, R ¹ is -CH(OH)-C≡C-cyclopropyl , -CH(F)-C≡C- cyclopropyl, -CH(NH2)-C≡C-cyclopropyl, -CH(Me)-C≡C-cyclopropyl, -C(Me)(OH)-C≡C- cyclopropyl, and the like. Thus, in some embodiments, R ¹ is -CH(OH)-C≡C-cyclopropyl.

[0052] In some aspects, R ¹ is -Ci-Cealk-aryl, for example, -Cialk-aryl, -C ₂ alk-aryl, -C alk- aiyl, -C salk-arvl, -Csalk-aryl, -Cealk-aryl, -CHzaryl, -CH(OH)-aryl, -C]T(F)-aryl, -CH(Nil2)-aryl, - CH(Me)-aryl, -C(Me)(OH)-aryl, -C(CF ₃ )(OH)-aryl and the like. In some embodiments wherein R ¹ is -Ci-Cealk-aryl, the -aryi is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, ~3-ffuoro-4~ chlorophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 2,4-difluorophenyl, 2-hydroxymethyl-4-chlorophenyl, 2-hydroxymethyl-5- chlorophenyl, 2-aminomethy 1 -4-chl oropheny!, 2-(methy 1 aminomethy 1 )-4-chl oropheny!, 2- hydroxymethyl-4,5-difluorophenyl, 2-aminomethyl-4,5-difluorophenyl, or 2-(methylaminomethyl)- 4,5-difluorophenyl . Thus in some embodiments, R ¹ is -CH -di fluorophenyl, -CHb-3,4- difluorophenyl, -CH2-4-chlorophenyl, -CH ₂ -3-chloro-4-fluorophenyl, -CH2-4-chloro-3 -fluorophenyl, -CH ₂ -dichlorophenyl, -CH ₂ -3,4-dichlorophenyl, -CH ₂ -3-fluoro-4-(trifluoromethyl)phenyl, or -CH ₂ - 4-chloro-3 -methylphenyl, -CH2-2,4-difluorophenyl, -CH2-2-hydroxymethyl-4-chlorophenyl, -CH?-2- hydroxymethyl-5-chlorophenyl, -CH ₂ -2-aminomethyl-4-chlorophenyl, -CFfe-2- (methylaminomethyl)-4-chlorophenyl, -CH ₂ -2-hydroxymethyl-4,5-difluorophenyl, -CH ₂ -2- aminomethyl-4,5-difluorophenyl, -CH ₂ -2-(methylaminomethyl)-4,5-difluorophenyl, -CH(OH)-4- chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4- chlorophenyl , -CH(OH)-3 -chl oro-4-fluorophenyl, -CH(OH)-3 -fluoro-4-(trifluoromethy Ijphenyl, or - CH(OH)-4-chloro-3-methylphenyl, -CH(OH)-2,4-difluorophenyl, -CH(OH)-2-hydroxymethyl-4- chl orophenyl, -CH(OH)-2-hydroxymethyl-5-chlorophenyl, -CH(OH)-2-aminomethyl-4- chlorophenyl, -CH(OH)-2-(methylaminomethyl)-4-chlorophenyl, -CH(OH)-2-hydroxyrnethyl-4,5- difluorophenyl, -CH(OH)-2-aminomethyl-4,5-difluorophenyl, -CH(OH)-2-(methylaminomethyl)-4,5- di fluorophenyl, -CH(F)-4-chloropheny 1 , -CH(F)-3 ,4-dichl orophenyl, -CH(F)-3 ,4-difluoropheny 1 , - CH(F)-3 -fluoro-4-chlorophenyl, -CH(F)-3 -chl oro-4 -flu orophenyl, -CH(F)-3 -fluoro-4- (trifluoromethyl)phenyl, -CH(F)-4-chloro-3 -methylphenyl, -CH(F)-2,4-difluorophenyl , -CH(F)-2- hydroxymethyl-4-chl orophenyl, -CH(F)-2-hydroxymethyl-5-chl orophenyl, -CH(F)-2-aminomethyl- 4-chl orophenyl, -CH(F)-2-(methylaminomethyl)-4-chlorophenyl, -CH(F)-2-hydroxymethyl-4,5- difluorophenyl, -CH(F)-2-aminomethyl-4,5-difluorophenyl, -CH(F)-2-(methylaminomethyl)-4,5- difluorophenyl, -CH(NH2)-4-chlorophenyl, -CH(NH ₂ )-3,4-dichlorophenyl, -CH(NH ₂ )-3,4- difluorophenyl, -CH(NH ₂ )-3-fluoro-4-chlorophenyl, -CH(NH ₂ )-3-chloro-4-fluorophenyl, -CH(NH ₂ )- 3 -fluoro-4-(trifluoromethyl)phenyl, or -CH(NH2)-4-chloro-3 -methylphenyl, -CH(NH ₂ )-2,4- difluorophenyl, -CH(NH ₂ )-2-hydroxymethyl-4-chl orophenyl, -CH(NH ₂ )-2-hydroxymethyl-5- chlorophenyl, -CH(NH ₂ )-2-aminomethyl-4-chlorophenyl, -CH(NH ₂ )-2-(methylaminomethyl)-4- chl orophenyl, -CH(NH ₂ )-2-hydroxymethyl-4,5-difluorophenyl, -CH(NH ₂ )-2-aminomethyl-4,5- difluorophenyl, -CH(NH ₂ )-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(Me)-4-chl orophenyl, - CH(Me)-3 ,4-dichl orophenyl , -CH(Me)-3 ,4-difluorophenyl, -CH(Me)-3 -fluoro-4-chl orophenyl, - CH(Me)-3 -chloro-4-fluorophenyl, -CH(Me)-3 -fluoro-4-(trifluoromethyl)phenyl, -CH(Me)-4-chl oro- 3 -methylphenyl, -CH(Me)-2,4-difluorophenyl, -CH(Me)-2-hydroxymethyl-4-chlorophenyl, - CH(Me)-2-hydroxymethyl-5-chlorophenyl, -CH(Me)-2-aminomethyl-4-chl orophenyl, -CH(Me)-2- (methylaminomethyl)-4-chlorophenyl, -CH(Me)-2-hydroxymethyl-4,5-difluorophenyl, -CH(Me)-2- aminomethyl-4,5-difluorophenyl, -CH(Me)-2-(methylaminomethyl)-4,5-difluorophenyl, - C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3,4-difluorophenyl, - C(Me)(OH)-3-fluoro-4-chlorophenyl, -C(Me)(OH)-3-chloro-4-fluorophenyl, -C(Me)(OH)-3-fluoro- 4-(trifluoromethyl)phenyl, -C(Me)(OH)-4-chloro-3-methylphenyl, -C(Me)(OH)-2,4-difluorophenyl, - C(Me)(OH)-2-hydroxymethyl-4-chlorophenyl, -C(Me)(OH)-2-hydroxymethyl-5-chlorophenyl, - C(Me)(OH)-2-aminomethyl-4-chlorophenyl, -C(Me)(OH)-2-(methylaminomethyl)-4-chlorophenyl, - C(Me)(OH)-2-hydroxymethyl-4,5-difluorophenyl, -C(Me)(OH)-2-aminomethyl-4,5-difluorophenyl, - C(Me)(OH)-2-(methylaminomethyl)-4,5-difluorophenyl, -C(CF ₃ )(OH)-4-chlorophenyl, - C(CF3)(OH)-3,4-dichlorophenyl, -C(CF ₃ )(OH)~3,4~difluoiOphenyl, -C(CF3)(OH)-3-fluoro-4- chlorophenyl, -C(CF3)(OFI)-3-chloro-4-fluorophenyl, -C(CF3)(OH)-3-fIuoro-4- (trifluoromethyl)phenyl, or -C(CF3)(OH)-4-chloro-3-methylphenyl, -C(CF ₃ )(OH)~2,4-difluorophenyl, -C(CF3)(OH)-2-hydroxymethyl-4-chlorophenyl, -C(CF3)(OH)-2-hydroxymethyl-5-chlorophenyl, - C(CF3)(OH)-2-aminomethyl-4-chlorophenyl, -C(CF3)(OH)-2-(methylaminomethyl)-4-chlorophenyl, -C(CF3)(OH)-2-hydroxymethyl-4,5-difluorophenyl, -C(CF3)(OH)-2-aminomethyl-4,5- difluorophenyl, -C(CF3)(OH)-2-(methylaminomethyl)-4,5-difluorophenyl.

[0053] In some aspects, R ¹ is -Co-Ceaik-heteroaryl, for example, -Coalk-heteroaryl, -Cialk- heteroaryl, -C ₂ alk-heteroaryl, -C ₃ alk-heteroaryl, -C ₄ alk-heteroaryl, -Csalk-heteroaryl, and -Cealk- heteroaiyl. In some aspects, R ¹ is 2-(2-amino-3-bromoquinolin-7-yl)ethyl, 2-(2-amino-3- chloroquinolin-7-yl)ethyl, 2-(2-((cyclopropylmethyl)amino)quinolin-7-yl)ethyl, 2-(2- (methylamino)quinolin-7-yl)ethyl, or 2-(2-aminoquinolin-7-yl)ethyl.

[0054] In some aspects, R ¹ is -Ci-Cealk-O-heteroaryl, for example, -Cialk-O-heteroaryl , - C ₂ alk-0-heteroaryl, -Csaik-Q-heteroaryl, -C ₄ alk-0-heteroaryl, -Csalk-O-heteroaryl, and -Cealk-O- heteroaryl. In some aspects, R ¹ is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl.

[0055] In some aspects, R ¹ is -Ci-Cealk-S-heteroaryl, for example, -Cialk-S-heteroaryl, - C ₂ alk-S-heteroaryl, -C3alk-S-heteroaryl, -C4alk-S-heteroaryl, -Csalk-S-heteroaryl, and -Cealk-S- heteroaryi. In some aspects, R ^! is ((2-amino-3-bromoquinolin-7-yl)thio)methyl.

[0056] In some aspects, R ¹ is -C ι -Cealk- H-heteroaryl , for example, -Cialk-NH-heteroaryl, -C ₂ alk-NH-heteroaryl, -C ₃ alk- H-heteroaryl, -C4alk-NH-heteroaryl, -Csalk- H-heteroarj'l, and - C6alk- H-heteroaryl. In some aspects, R ¹ is ((2-amino-3-bromoquinolin-7-yl)amino)methyl.In some aspects, R ⁵ is H, halo, -Ci-Cealkyl, or NFb. Thus in some embodiments, R ⁵ is H. In other embodiments, R ⁵ is halo, for example F, Ci, Br, or I, with -CI being preferred. In other embodiments, R ^s is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, i sobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R ⁵ is methyl (Me). In yet other embodiments, R ⁵ is H ₂ .

100571 In compounds of the present disclosure that are compounds of Formula I or Formula II, R ^b is H, halo, -Ci-Cealkyl, -Ci-C ₆ haloalkyl, or -Co-Cealk-Cj-Cecycioalkyl,

[0058] Thus, in some embodiments, R ^b is H.

[0059] In other embodiments, R ⁶ is halo, for example F, CI, Br, or I. In some embodiments,

R ⁶ is F.

[0060] In some aspects, R ⁶ is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R ⁶ is methyl.

[0061] In some aspects, R ^b is -Ci-Cehaloalkyl, for example, -CF ₃ or -CHF ₂ .

[0062] In some aspects, R ⁶ is -Co-C6alk-C ₃ -C6cycloalkyl, for example, for example, for example -Coalk-Cjcycloalkyl, -Cialk-Cscycloalkyl, -C ₂ alk-C ₃ cycloal kyl, -C ₃ alk-C ₃ cycloalkyl, -C ₄ alk- C3cycioalkyl, -Csaik-Cscycloalkyl, -Cealk-Cscycloalkyl, -Coalk-C ₄ cycloalkyl, -Ciaik-C4cycloaikyl, - C ₂ alk-C ₄ cycloalkyl, -C ₃ alk-C4cycloalkyl, -C ₄ alk-C ₄ cycloalkyl, -Csalk-C4cycloalkyl , -Cealk- C ₄ cycloalkyl, -Coalk-Cscycloalkyl, -Cialk-Cscycloalkyl, -Czalk-Cscyeloalkyl, -Csalk-Cscycloalkyl, - C4alk-C5cycloalkyl, -Csalk-Cscycloalkyl _s -Cealk-Cscycloalkyl, -Coalk-Cecycloalkyl, -dalk- Cecycloaikyi, -C aik-Cecycloalkyl, -C ₃ alk-C6cycloalkyl, -C alk-Cecycloalkyl, -Csalk-Cecycloalkyl, and -Cealk-Cecycloalkyl. In some embodiments, R ⁶ is -Ciaik-Cscycloaikyi. Thus, in some aspects, R ⁶ is -CFfe-cyclopropyl . In other embodiments, R ⁶ is cyclopropyl .

[0063] In embodiments that are a compound of Formula I or Formula III, R ² is H, halo, -CJ - Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-C ₃ -C6cycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealky , -Co- Cealk-Mfc, -Co-Cealk- H-C i -Cealkyl, -Co-C ₆ alk-N(C i-Cealky -Ci-Cealkyi, -Co-Cealk-NH-Cs- Cecycloalkyl, -Co-Cealk-NCCi-Cealkylj-Cs-Cecycloalkyl, -Co-Cealk-heteroeycloalkyl, heteroaryl, or - CN.

[0064] In some aspects, R ² is H.

[0065] In some aspects, R ² is halo, for example, F, CI, Br, or I, with F, CI, and Br being preferred and F and CI being more preferred.

[00661 In some aspects, R ² is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, ^z is methyl.

[0067] In some aspects, R ² is -Ci-Cehaloalkyl, for example, -CF ₃ or -CHF ₂ . [0068] In some aspects, R ² is -Co-C&alk-Cs-Cecyeloalkyl, for example, -Coalk- Cscycloalkyl, -Cialk-Cscycloalkyl, -C2.alk-C3cycloalkyl, -C ₃ alk-C3cycloalkyl, -C ₄ alk-C ₃ cycloalkyl, - Csal k-Cscycloalkyl _s -Ceal k-C ₃ cycloalkyl, -Coalk-C ₄ cycloal ky] , -Gal k-C ₄ cycloalkyl, -C ₂ alk- C ₄ cycloalkyl, -C ₃ alk-C ₄ cycloalkyl, -C ₄ alk-C ₄ cycloalkyl, -Csalk-Ocycloalkyl, -C6alk-C ₄ cycloalkyl, - Coalk-C5cycloalkyl, -Gal k-Cscycloalkyl, -C ₂ alk-C ₅ cycloal ky] , -Csal k-Cscycloalkyl, -C ₄ alk- Cicycloalkyl, -Csalk-Cscycloalkyl, -C&alk-Cscycloalkyl, -Coalk-Cecycloalkyl, -Cialk-Cecycioalkyl, - C ₂ alk-C ₆ cycloalkyl, -Csalk-Cecycloalkyl, -C ₄ alk-C6cycloalkyl, -Csalk-Cecycloalkyl , -C ₆ alk- C&cycloalkyl. In some aspects wherein R ² is -Co-C6alk-C ₃ -C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ² is -Co-Cealk-G-Ceeycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OG-Gsalkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0069] In some aspects, R ² is -Co-Cealk-OH, for example, -Coalk-OH, -dalk-OH, -C ₂ alk- OII, -Csalk-OH, -C4alk-OH, -Csalk-OH, or -Cealk-OH.

[0070] In some aspects, R ² is -Co-C&alk-O-Ci-C&alkyl, for example, -Coalk-O-Cialkyl, - Cialk-O-Cialkyl, -C ₂ alk-0-Cialkyl, -Csalk-O-Cialkyl, -C4alk-0-Cialkyl, -Csalk-O-Cialkyl, -Cealk- O-Cialkyl, -Coalk-O-Galkyl, -Cialk-0-C2alkyl, -Gmlk-O-Galkyl, -C ₃ alk-0-C2alkyl, -C ₄ alk-0- C ₂ alkyl, -Csalk-0-C2alkyl, -Cealk-O-Gmlkyl, -Coalk-O-Csalkyl, -Cialk-O-Csalkyl, -C ₂ alk-0- Cjalkyl, -Cjalk-O-Galkyl, -C+alk-O-C alkyl, -Csalk-O-Csalkyl, -Ceaik-O-Galkyl, -Coalk-O- C ₄ alkyl, -Cialk-0-C4alkyl, -C ₂ alk-0-C4alkyl, -C3alk-0-C ₄ alkyl, -C4alk-0-C4alkyl, -Csalk-O- Gialkyl , -C6alk-0-C4alkyl, -Coalk-O-Csalkyl, -Cialk-O-Csalkyl, -C ₂ alk-0-C ₅ alkyl, -Csalk-O- Csalkyl, -C4alk-0-C ₅ alkyl, -Csalk-O-Csalkyl, -Cealk-O-Csalkyl, -Coalk-O-Cealkyl, -Cialk-O- Cealkyl, -Cialk-O-Cealkyl, -Galk-O-Cealkyl, -Csalk-O-Cealkyl, or -Cealk-O- Cealkyl.

[0071] In some aspects, R ² is Co-Cealk-NFb, for example, -Coalk- Ft, -Cialk-NH ₂ , -C ₂ alk- NH2, -Csalk-NIfc, ~C =a!k-M k -Csalk- fc, or CVa!k-M k

[0072] In some aspects, R ² is -Co-Cealk-NH-Ci-Cealkyl, for example, -Coalk-NH- alkyl, - Cialk-NFI-Cialkyl, -C2aik-NFI-Ciaikyi, -Csalk-NH-Cialkyl, -C ₄ aik-NH-Ciafkyf, -Csalk-NH-Cialkyl , -Cealk- H-Cialkyl, -Coalk- H-C2alkyl, -Galk-NH-Gialkyl, -C\-aik-\! l-C-aikvi. -Csalk-NH- C ₂ alkyl, -C4al k-NH-C ₂ alkyl, -Csalk-NH-Cialkyl, -Cealk-NFI-C^alkyl, -Coalk-NH-Csalkyl, -Cialk- NH-Csalkyl, -C ₂ alk-NH-C3alkyl, -Csalk-NH-Csalkyl, -C4alk-NH-C3alkyl, -Csalk-NH-Csalkyl, - Cealk-NH-C^alkyl, -Coalk-NH-C ₄ alkyl, -O al k-N H-Oal kyl, - al k-NH-C iai kyi, - al k-Xi l-C iai kvL -C4alk- H-C ₄ alkyl, -Csalk- H-C4alkyl , -C6alk- H-C4alkyl, -Coalk-NH-Csalkyl, -Cialk-NH- Csai kyl , -Cial k- H-Csalkyl, -Csal k-NH-Csalkyl, -C4al k-NH-C ₅ alkyl, -Csalk-NH-Csalkyl, -Cealk- NH-Csalkyl, -Coalk-NH-Cealkyl, -Cialk- H-Cealkyl, -Cialk- H-Cealkyl, -C :alk -N H-Cr,aikyi. - C-falk-NH-Cealky 1, -Csalk-NH-Cealkyl _t and -Cealk-NH-Cealkyl ,

[0073] In some aspects, R ² is -€VC6alk-N(Ci-C6alkyl)-C --Cealkyl, for example, -Coalk- N(Ci-C6alkyl)-Cialkyl, -Cialk-N(Ci-C6alkyl)-Cialkyl, -C2alk-N(Ci-C6alkyl)-Cialkyl, ~C u;i k-\iCV Cealky -Cialkyl, -C4alk-N(Ci-C6alkyl)-Cialkyl, -C5alk-N(Ci-C6alkyl)-Cialkyl , -Cealk- N(Ci- Cealky -Cialkyl, -Coalk- N(Ci-C6alkyl)-C ₂ alkyl, -Cialk-N(Ci-C6alkyl)-C2alkyl, -C2alk-N(Ci- Cealkyl)-C ₂ alkyl, -C3alk-N(Ci-C6alkyl)-C2alkyl, -C4alk-N(Ci-C6al ky 1)-C ₂ al kyl , -Csai k-N(Ci- C6alkyl)-C ₂ alkyl , -Coalk-N(Ci-C6alkyl)-C ₃ alkyl, -Cialk-N(Ci- Ceal kyl)-C ₃ al kyl , -C2alk-N(Ci-C6alkyl)-C ₃ alkyl, -C3alk-N(Ci-C6alkyl)-C ₃ alkyl, -Oalk-N(Ci- C-.alkvD-C uilkvl. -C ₅ alk-N(Ci-C6alkyl)-C3alkyl , -Cealk-NCCi-Cealky -Csalkyl, -Coalk-N(Ci- C6alkyl)-C ₄ alkyl, -Cialk-N(Ci-C6alkyl)-C4alkyl, -C2alk-N(Ci-C6alkyl)-C4alkyl, -C ₃ alk-N(Ci- C6alkyl)-C4alkyl, -C4alk-N(Ci-C6alkyl)-C4alkyl, -C ₅ alk-N(Ci-C ₆ alkyl)-C4alkyl , -C6alk-N(Ci- C6alkyl)-C4alkyl, -Coalk- N(Ci-C6alkyl)-C5alkyl, -Cialk-N(Ci-C6alkyl)-C ₅ alkyl, -C ₂ alk-N(Ci- Cealky -Csalkyl, -Csalk-NCCi-Cealky -Csalkyl, -C4alk-N(Ci-C6alkyl)-C ₅ alkyl, -C ₅ alk-N(Ci- (V.alkyl )- alkyl . -Cealk-NCCi-Cealky -Csalkyl, -Coalk-N(Ci-C6alkyl)-C6alkyl, -Cialk-N(Ci- Cealkyl)-Cealkyl, -C2alk-N(Ci-C6alkyl)-C6alkyl, -Csalk-NfCi-Ceal ky IVCeai kyl , -C ₄ al k-N(Ci- Cealky -Cealkyl, -Csalk-NCCi-Cealky -Cealkyl, -Cealk-NCCi-Cealky -Cealkyl and the like.

[0074] In some aspects, R ² is -Co-Cealk-NH-CB-Cecycloalkyl, for example, -Coalk-NH- C ₃ cycloalkyl, -Cialk-NH-C3cycloalkyl, -C ₂ alk-NH-C ₃ cycloalkyl, -C ₃ alk-NH-C ₃ cycloalkyl, -C4aik- NH-C3cycloalkyl, -Csalk- H-Cscycloalkyl _t -C ₆ alk-NH-C3cycloalkyl, -Coalk-NH-C4cycloalkyl, - Cialk- H-C4cycloalkyl, -C2alk-NH-C4cycloalkyl, -C3alk-NH-C ₄ cycloaikyi, -C ₄ aik-NH- C icycioa!kyL -C5alk-NH-C4cycloalkyl , -C6alk-NH-C4cycloalkyl, -Coalk-NH-Cscycloalkyl, -Cialk- NH-Cscycloalkyl, -Czalk-NH-Cscycloaikyi, -Csalk-NH-Cscycloalkyl, -C ial k-Ni !-(^cycloa!k> k - Csalk-NH-Cscycloalkyl , -Cealk-NH-Cscycloalkyl, -Coalk- H-Cecycloalkyl, -Ciaik-NH- Cecycloalkyl, -C ₂ al k-NH-C6cycloalkyl, -C ₃ alk-NH-C6cycloalkyl, -C ₄ alk-NH-C6cycloalkyl, -Csalk- NH-Cecycloaikyi, -Cealk-NH-Cecycloaikyi, and the like. In some aspects wherein R ² is -Co-Ceaik- NH-Cs-Cficycloal kyl , the cycloalkyl is unsubstituted. In other aspects wherein R ² is -Co-Cealk-NH- Cs-Cecyeioalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from d-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -Od-dalkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0075] In some aspects, R ² is -( j-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, for example, - Coalk-N(Ci -C6alkyl)-C3cycIoalkyl, -Cialk-N(d-C6alkyl)-C3cycloalkyl, -dalk- Ci-Cealkyl)- C3cycloalkyl, -C3al k-N(Ci-C6alkyl)-C3cycloalkyl, -C4alk-N(Ci-C6alkyl)-C3cycloalkyl, -Csalk-N(Ci- C6alkyl)-C3cycloalkyl , -C&alk-N(Ci-C6alkyl)-C3cycloalkyl, -Coalk-N(Ci-C6alkyl)-C4cycloalkyl, - Cialk-N(Ci-C6alkyl)-C4cycloalkyl, -C2alk-N(Ci-C6alkyl)-C4cycloalkyl, -Csalk-NCCi-Cealkyl)- C4cycl oalkyl, -C4alk-N(C i-C6alkyl)-C4cycloalkyl , -Csalk-N(C i -C6aikyI)-C4cycloaikyi , -C6aIk-N(Ci- C6alkyl)-C4cycloalkyl, -Coalk-NICi-Cealkylj-Cscycloalkyl, -Cialk-NiCi-Cealkylj-Cscycloalkyl, - C ₂ alk-N(C ₁ -C6alkyl)-C5cycloalkyl, -dalk-N(d-C6alkyl)-C5cycloalkyl, -dalk- Xd-Ceal kyl)- dcycloalkyl, -Csalk-N(C i-C6alkyl)-C ₅ cycloalkyl, -Cealk-NCCi-Ceaiky -Cscycloalkyl, -Coalk-N(Ci- dal kyl Vdcycl oalkyl, -dalk-N(d-C6alkyl)-C6cycloalkyl, -C ₂ alk-N(C ₁ -C6alkyl)-C6cycloalkyl, - C3alk-N(Ci-C6alkyl)-C6cycloalkyl, -C4alk-N(Ci-C6alkyl)-C6cycloalkyl, -dalk- Ci-Cealkyl)- Cecycloalkyl _s -C6alk-N(Ci-C6alkyl)-C6cycloalkyl, and the like. In some aspects wherein R ² is -Co- C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ² is -Co-Cealk-NiCi-Cealkylj-C -Cecycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-dalkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - Od-dalkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

100761 In some aspects, R ² is -Co-Ceal k-heterocycloalkyl, for example, -Coal k- heterocycloalkyl, -C i -Cealk-heterocycloaikyi, -C j -dalk-heterocy cl oalkyl, -C i-C alk- heterocycloal ky] , -d-dalk-heterocycl oalkyl, -d-dalk-heterocycloalkyl, or -Cial k- heterocycloalkyl. Preferred heterocvloalkyl moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and oxetanyl . In some aspects wherein R ² is -Co-Cealk-heterocycloaikyl, the heterocycloalkyl is unsubstituted. In other aspects wherein R ² is -Co-Cealk-heterocyeloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from d-dalkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -Gd-daikyi (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl ),

[0077] In some aspects, R ² is heteroaryi, for example furanyl, imidazolyi, and pyrazoiyl. In some aspects wherein R ² is heteroaryi, the heteroaryi is unsubstituted. In other aspects wherein R ² is heteroaryi, the heteroaryi is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0078] In some aspects, R ² is -CN.

[0079] In compounds of the present disclosure that are compounds of Formula I or Formula III, R ³ is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cj-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NEb, -Co-Cealk-NH-Ci-Cealkyl, -Co-C ₆ alk-N(Ci-C6alkyl)-Ci- Cealkyl, -Co-Cealk-NH-C^Cecycloalkyl, -Co-Cealk-NCCi-Cealky -Ci-Cecycloalk l, -Co-Cealk- heterocycioalkyl, heteroaryl, or -CN.

[0080] In some aspects, R ³ is H.

[00811 In some aspects, R ³ is halo, for example, F, CI, Br, or I, with F, CI , and Br being preferred and F and CI being more preferred.

[0082] In some aspects, R ³ is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl , butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

[0083] In some aspects, R ³ is -Ci-Cehaloalkyl, for example, -CF ₃ or (Ί If ·

[0084] In some aspects, R ^J is -Co-C&alk-Cs-Cecyeioalkyl, for example, -Coalk- CjCycloalkyl, -Cialk-Cscycloalkyl, -C ₂ alk-C ₃ cycloalkyl, -C ₃ alk-C ₃ cycloalkyl, -C ₄ alk-C ₃ cycloalkyl, Csalk-C3cycloalkyl _s -Cealk-Cscycloalkyl, -Coalk-C ₄ cycloalkyl, -Cialk-C4cycloalkyl, -C ₂ alk- C ₄ cycloalkyl, -C ₃ alk-C ₄ cycloalkyl, -C ₄ alk-C ₄ cycloalkyl, -Csalk-Ocycloalkyl, -Cealk-Ocycloalkyl, Coalk-C5cycloalkyl, -Cial k-Cscycloalkyl, -C ₂ alk-C5cycloal kyl , -C ₃ al k-Cscycloalkyl, -C ₄ alk- Cscycloalkyl, -Csalk-Cscycloalkyl , -Cealk-Cscycloalkyl, -Coalk-Cecycloalkyl, -Cialk-Cecycioalkyl, C ₂ al k-Cecycloalkyl, -C ₃ alk-C6cycloal kyl , -C ₄ al k-Cecycloalkyl, -Csalk-Ce.cyeloalkyl _t -Ce.alk- Cecycloaikyi. In some aspects wherein R ³ is -Co-C6alk-C3-C6cycloaikyi, the cycloalkyl is unsubstituted. In other aspects wherein R ³ is -Co-Cealk-tVCeeycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0085] In some aspects, R ³ is -Co-Cealk-OH, for example, -Coalk-OH, -Cialk-OH, -C ₂ alk- OH, -Csalk-OH, -C+alk-OH, -Csalk-OH, or -Cealk-OH.

[0086] In some aspects, R ^J is -Co-Cealk-O-Ci-Cealkyl, for example, -C ₀ alk-O-Cj.alkyl, - Cial k-O-Cialkyl, -Cialk-O-Cialkyl, -Csalk-O-Cialkyl, -C ₄ alk-0-Cialkyl, -Csalk-O-Cialkyl , -Cealk- O-Cialkyl, -Coalk-0-C ₂ alkyl, -Cialk-0-C?.alkyl, -Czalk-O-C aikyi, -C ₃ alk-0-C2alkyl, -C ₄ alk-0- Cialkyl, -Csalk-O-Cialkyl, -Cealk-O-Cialkyl, -Coalk-O-Csalkyl, -C alk-O-Csalkyl, -Cialk-O- Csalkyl, -Csalk-O-Csalkyl, -C4alk-0-C ₃ alkyl, -Csalk-O-Csalkyl, -Cealk-O-Csalkyl, -Coalk-O- C4al kyl , -Cial k-O-Csalkyl, -Cialk-O-Csalkyl, -Csal k-O-CSalkyl, -C ₄ alk-0-C4alkyl, -Csalk-O- C4alkyl _> -C6alk-0-C ₄ alkyl, -Coalk-O-Csalkyl, -Cialk-O-Csalkyl, -Cialk-O-Csalkyl, -Csalk-O- Csalkyl, -C ₄ alk-0-C ₅ alkyl, -Csalk-O-Csalkyl, -Cealk-O-Csalkyl, -Coalk-O-Cealkyl, -Cialk-O- Cealkyl, -Cialk-O-Cealkyl, -Csalk-O-Cealkyl, -C^alk-O-Cealkyl, -Csalk-O-Cealkyl, or -Cealk-O- Cealkyl.

[0087] In some aspects, R ³ is Co-Cealk-Ntk, for example, -Coalk-NHb, -Cialk-NHi, -C ₂ alk- -I2, -Csalk-NIfc, -C ;a! k-\! ! -. -C ₅ alk-NH ₂ , or (V.ai k-Xl f

100881 In some aspects, R ³ is -Co-Cealk-NH-Ci-Cealkyl, for example, -Coal k-NH-Cial kyl, - Cialk- H-Cialkyl, -C ₂ alk-NH-Cialkyl, -Csalk- H-Cialkyl, -C4alk-NH-Ciaikyi, -Csalk- H-Cialkyl, -Cealk-NH-C lalkyl, -Coalk-NH-CSalkyl, -C lalk-NI-I-CSalkyl, -CSalk-NI-I-CSalkyl, -Csalk-NH- C ₂ alkyl, -C4alk-NH-C2alkyl, -Csalk-NH-Cialkyl, -Cealk-NH-Cimlkyl, -Coalk- H-Csalkyl, -Ciaik- H-Csalkyl, -Cialk- H-Csalkyl, -Csalk-NH-Csalkyl, -C4alk-NH-Csalkyl, -Csalk-NH-Csalkyl , - Cealk-NH-Csalkyl, -Coalk-NH-C ₄ alkyl, -Cialk-NH-Cialkyl, -Czalk-NH-C^alkyl, - al k-Xi 1-C ial kvL -C4alk-NH-C4alkyl, -Csalk-NH^alkyl, -C6alk-NH-C ₄ alkyl, -Coalk-NH-Csalkyl, -Cialk-NH- Csalkyl, -C2alk-NH-Csalkyl, -Csalk-NH-Csalkyl, -C4alk-NH-Csalkyl, -Csalk-NH-Csalkyl, -Cealk- NH-Csalkyl, -Coalk-NH-Cealkyl, -Cialk-NH-Cealkyl, -Cialk- H-Cealkyl, -Csalk-NH-Cealkyl, - C ₄ alk-NH-C6alkyl, -Csaik-NH-Ceaiky 1 , and -Ceaf k-NH-Ceaf kyf ,

[0089] In some aspects, R ³ is -Co-C6alk-N(Ci-C6alkyl)-Ci-C6alkyl, for example, -Coaik- N(Ci-C6al ky])-Cialkyl, -Cialk-N(Ci-C6alkyl)-Cialkyl, -C2alk-N(Ci-C6alkyl)-Cialkyl, -Csalk-N(Ci- C-.alkvD-C ialkvl. -C4alk-N(Ci-C6alkyl)-Cialkyl, -Csalk- Ci-Cealkylj-Cialkyl , -Cealk- N(Ci- Cealky -Cialkyl, -Coalk- N(Ci-C6alkyl)-C2alkyl, -Cialk-N(Ci-C6alkyl)-C2alkyl, -C2alk-N(Ci- Cealky -Cialkyl, -Csalk-N(Ci-C6alkyl)-C2alkyl, -C4alk-N(Ci-C ₆ alkyl)-C2alkyl, -Csalk-N(Ci- C6alkyl)-C ₂ alkyl , -G.alk-\(C i-C6alkyl)-C2alkyl, -Coalk-N(Ci -Chalky Ij-Csalkyl, -Cialk-N(Ci- C&alkyl)-Csalkyl, -C2alk-N(Ci-C6alkyl)-Csalkyl, -C ₃ alk-N(Ci-C6alkyl)-Csalkyl, -C4alk-N(Ci- C-.alkvD-C uilkvl. -C5alk-N(Ci-C6alkyl)-Csalkyl , -C6alk-N(Ci-C ₆ alkylVCsalkyl, -Coalk-N(Ci- C6alkyl)-C ₄ alkyl, -Cialk-N(Ci-C6alkyl)-C4alkyl, -(ialk-NfCi-Ceal kyl)-C ₄ al kyl , -Csal k-N(Ci- C6alkyl)-C4alkyl, -C4alk-N(Ci-C6alkyl)-C4alkyl, -Csalk-N(Ci-C ₆ alkyl C4alkyl, -C6alk-N(Ci- Ceal kyl)-C ₄ al kyl , -Coalk- N(Ci-C6alkyl)-C ₅ alkyl, ~Cialk~N(Ci-C6alkyl)-Csal kyl , -C ₂ al k-N(Ci- C&alkyl)-Csalkyl, -Csalk-N(Ci-C6alkyl)-Csalkyl, -C4alk-N(Ci-C6alkyl)-C ₅ alkyl, -Csalk-N(Ci- Cealky -Csalkyl, -C6alk-N(Ci-C6alkyl)-Csalkyl, -Coalk-N(Ci-C6alkyl)-C6alkyl, -Cialk-N(Ci- Cealky -Cealkyl, -C2alk-N(Ci-C6alkyl)-C6alkyl, -C3alk-N(Ci-C6alkyl)-C6alkyl, -C .alk-Nc iY- Cealkylj-Cealkyl, -Csalk-NiCi-Cealkylj-Cealkyl _t -Cealk-NfCi-Cbalky -Cealky] and the like.

[0090] In some aspects, R ^J is -Co-Cealk- H-Cs-Cecycloalkyl, for example, -Coalk- H- Cjcycloalkyl, -Cialk-NH-Cscycloalkyl, -Cialk-NH-C cycloalkyl, -C ₃ alk-NH-C ₃ cycloalkyl, -Csalk- H-C3cycloalkyl, -Csalk-NH-Cscycloalkyl, -Ceaik-NH-Cscycioalkyl, -Coalk-NH-C4cycloalkyl, - Cialk- H-C4cycloalkyl, -Caalk-NH-C^cycloalkyl, -C ₃ alk- H-C4cycloalkyl, -C^alk-NH- C4cycloalkyl, -C5alk- H-C4cycloalkyl, -C6alk- H-C4cycloalkyl, -Coalk-NH-Cscycloalkyl, -Cialk- H-Cscycloalkyl, -C2alk-NH-C5cycloalkyl, -Csalk-NH-Cscycloalkyl, ~C lalk-Nl !- cydoalkyL - Csalk-NH-Cscycloalkyl, -Cealk-NH-Cscycloalkyl, -Coalk-N -Cecycloalkyl, -Cialk-NH- Cecycloalkyl, -C ₂ alk-NH-C6cycloalkyl, -Csalk- H-CecycloaikyL -C ₄ alk-NH-C6cycloalkyl, -Csaik- NH-Cecycloalkyl, -Cealk-NB-Cecycloalkyl, and the like. In some aspects wherein R ³ is -Co-Ce.alk- NH-Cs-Cecycloalkyl, the cycioalkyl is unsubstituted. In other aspects wherein R ³ is -Co-Cealk- H- Cs-Cecycloalkyi, the cvcloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyi, (e.g., methyl, ethyl, propyl, isopropyi, butyl), -OCi-Cealkyl (e.g., - Om ethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[0091] In some aspects, R ³ is -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloaikyi, for example, - Coalk-N(Ci-C6alkyl)-C3cycloalkyl, -Cialk-N(Ci-C ₆ alkyl)-C3cycioalkyl, -C2aik-N(Ci-C ₆ alkyl)- C3cycloalkyl, -C3al k-N(Ci-C6alkyl)-C3cycloalkyl, -C4alk-N(Ci-C6alkyl)-C3cycloalkyl, -Csalk-N(Ci- C6alkyl)-C3cycloalkyl , -C6alk-N(Ci-C6alkyl)-C3cycloalkyl, -Coalk-N(Ci-C6alkyl)-C4cycloalkyl, - Cialk-N(Ci-C6alkyl)-C4cycloalkyl, -C2alk-N(Ci-C6alkyl)-C ₄ cycloalkyl, -C ₃ alk-N(Ci-C6alkyl)- C4cycloalkyl, -C4alk-N(Ci-C6alkyl)-C4cycloalkyl, -C5alk-N(Ci-C6aikyl)-C4cycloaikyi, -C ₆ aik-N(Ci- C6alkyl)~C4cycioalkyl, -Coalk-NICi-Cealkylj-Cscycloalkyl, -Cialk-NfCi-Cealkylj-Cscycloalkyl, - C2alk-N(Ci-C6alkyl)-C5cycloalkyl, -C3alk-N(Ci-C6alkyl)-C5cycloalkyl, -C4alk-N(Ci-C ₆ alkyl)- Cscycloalkyl, -C5alk-N(Ci-C6alkyl)-C5cycloalkyl, -Cealk-NCCi-Cealky -Cscycloalkyl, -Coalk-N(Ci- C&alkyl)-C&cycloalkyl, -Cialk- (Ci-C6alkyl)-C6cycloaikyi, -C ₂ alk-N(Ci-C6alkyl)-C6cycloalkyl, - C3alk-N(Ci-C6alkyl)-C6cycloalkyl, -C4alk-N(Ci-C6alkyl)-C6cycloalkyl, -Csalk-NCCi-Cealkyl)- Cficycloalkyl _s -C6alk-N(Ci-C6alkyl)-C6cycloarkyl, and the like. In some aspects wherein R ³ is -Co- C6alk-N(Ci-C6alkyl)-C ₃ -C6cycloalkyl, the cycioalkyl is unsubstituted. In other aspects wherein W is -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloarkyl, the cycioalkyl is substituted with one, two, or three R substituents independently selected from d-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - OCi-Cealkyl (e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyi, -Obutyi), and halo (e.g., F or Ci).

[0092] In some aspects, R ³ is -Co-Cealk-heterocycloalkyl, for example, -Coalk- heterocycloalkyl, -Ci-Ceaik-heterocycloalkyl, -C i-Csalk-heterocy cioalkyl, -Ci-C ₄ alk- heterocycloalkyl, -C ₁ -C ₃ alk-heterocycloalkyl, -C ₁ -C ₂ alk-heterocycloalkyl, or -Cialk- heterocycloalkyl. Preferred heterocyioalkyl moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanvl, pyrrolidinyl, tetrahydroturanyl, tetrahydropyranyl, and oxetanvl. In some aspects wherein R ³ is -Co-Cealk-heterocycloalkyl, the heterocycloalkyl is unsubstituted. In other aspects wherein R ³ is -Co-Cealk-heterocycloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ce.alkyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyi, -Opropyl, -Oisopropyi, -Obutyi), and halo

(e.g., F or CI).

[0093] In some aspects, R ³ is heteroaryi, for example furanyl, imidazolyi, and pyrazoiyl. In some aspects wherein R ³ is heteroaryi, the heteroaryi is unsub tituted. In other aspects wherein R ³ is heteroaryi, the heteroaryi is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., - Omethyl, -Oethyi, -Opropyl, -Oisopropyi, -Obutyi), and halo (e.g., F or CI).

[0094] In some aspects, R ³ is -CN.

[00951 In compounds of the present disclosure that are compounds of Formula I or Formula III, R ⁴ is H, halo, -Ci-Cealkyl, -Ci-Cehaloaikyi, -Co-Cealk-Cs-Cecycioalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NIfc, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-NiCi-Cealky -Ci- Cealkyl, -Co-Cealk- H-Cs-Cecycloalkyl, -Co-Cealk-NCCi-Cealky -Cs-Cecycloalkyl, -Co-Cealk- heterocycloalkyl, heteroaryi, or -CN.

[0096] In some aspects, R ⁴ is H.

[0097] In some aspects, R ⁴ is halo, for example, F, CI, Br, or I, with F, CI, and Br being preferred and F and CI being more preferred.

[0098] In some aspects, R ⁴ is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

[0099] In some aspects, R ⁴ is -Ci-Cehaloaikyi, for example, -CF ₃ or -CHF?..

[00100] In some aspects, R ⁴ is -Co-Cealk-C -Cocycloalkyl, for example, -Coalk- C ₃ cycloalkyl, -Cialk-C cycloalkyl, -C ₂ alk-C ₃ cycloalkyl, -C ₃ alk-C3cycloalkyl, -C4alk-C ₃ cycloalkyl, - Cialk-C- cycloalkyl, -Cealk-O cycloalkyl, -Coalk-C4cycloalkyl, -Cialk-C4cycloalkyl, -C?.alk- C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cyc!oalkyl, -C5alk-C4cycloalkyl ₍ -C6alk~C4cycloalkyl, - Coal k-Cscycloalkyl, -Cialk-Cicycloal ky] , -C ₂ al k-Cscycloalkyl, -Csalk-Cscycloalkyl, -Ctalk- Cscycloalkyl, -Csalk-Cscycloalkyl, -Cealk-Cscycloalkyl, -Coalk-Cecycloalkyl, -Cialk-Cecycloalkyl, - Caalk-Cficycloalky] , -C ₃ al k-Cecycloalkyl, -C ₄ alk-C6cycloal ky] , -Csal k-Cecycloalkyl, -C ₆ alk- Cecycloalkyl. In some aspects wherein R ⁴ is -Co-Cealk-Cs-Cecycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ⁴ is -Co-Cealk-Cs-Cecycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or CI).

[00101] In some aspects, R ⁴ is -Co-Cealk-OH, for example, -Coalk-OH, -Cialk-OH, -C ₂ alk- OH, -Csalk-OH, -Qalk-OH, -Csalk-OH, or -Cealk-OH.

[00102] In some aspects, R ⁴ is -Co-Cealk-O-Ci-Cealkyl, for example, -Coalk-O-Cialkyl, - Cialk-O-Cialkyl, -C ₂ alk-0-Cialkyl, -Csalk-O-Cialkyl, -C ₄ alk-0-Cialkyl, -Csalk-O-Cialkyl, -Cealk- O-Cialkyl, -Coalk-0-C2alkyl, -Cialk-0-C ₂ alkyl, -C ₂ alk-0-C2alkyl, -C ₃ alk-0-C2alkyl, -C ₄ alk-0- C ₂ alkyl, -C5alk-0-C2alkyl, -C6alk-0-C2alkyl, -Coalk-O-Csalkyl, -Cialk-O-Csalkyl, -C ₂ alk-0- Csalkyl, -Csalk-O-Csalkyl, -C^alk-O-Csalkyl, -Csalk-O-Csalkyl, -Cealk-O-Csalkyl, -Coalk-O- C ₄ alkyl, -Cialk-0-C4alkyl, -C ₂ alk-0-C ₄ alkyl, -C ₃ alk-0-C4alkyl, -C4alk-0-C ₄ alkyl, -Csalk-O- C ₄ alkyl _s -C6al k-0-C ₄ aikyi, -Coalk-O-Csalkyl, -Cialk-O-Csalkyl, -C^alk-O-Csalkyl, -Csalk-O- Csalkyl, -C4alk-0-C ₅ alkyl, -Csalk-O-Csalkyl, -Cealk-O-Csalkyl, -Coalk-O-Cealkyl, -Cialk-O- Cealkyl, -C^alk-O-Cealkyl, -CBalk-O-Cealkyl, -C4al k-0-C ₆ alkyl, -Csalk-O-Cealkyl, or -Cealk-O- Cealkyl.

[00103] In some aspects, R ⁴ is -Ci-Cealk-Nft, for example, -Coalk-Ntb, -Cialk-NH ₂ , - C ₂ alk-NH2, -Csalk-NIfe, -C ₄ alk-NH2, -C ₅ aik-NH ₂ , r - ⁽ \.aik-M l.v

|Θ10 ] In some aspects, R ⁴ is -Co-Cealk-NI-I-Ci-Cealkyl, for example, -Coalk-NH-Cialkyl, - Cialk-NH-Cialkyl, -C2alk-NH-Cialkyl, -Csalk-NH-Cialkyl, -C4alk-NH-Cialkyl, -Csalk-NH-Cialkyl, -Cealk-NH-Cialkyl, -Coalk- H-C2alkyl, -Cialk- H-C2alkyl, -C2alk- H-C2alkyl, -Oak- M i- C ₂ alkyl, -O u)lk-NM-0 *lkyl, -0<alk-NM-C *lkyl , -Cealk-NH-iialkyl, -Coalk-NH-Csalkyl, -Cialk- H-Csalkyl, -Cimlk-NH-Csalkyl, -Csalk- H-Csalkyl, -C4alk- H-C ₃ alkyl, -Csalk- H-Csalkyl, - C ₆ al k-NH-Csalky 1, -Coalk- H-C4alky 1, -Cialk-NH~C ₄ alky 1, -C -aik-M !-C ialk> I,

-C4alk-NH-C4alkyl, -Csalk-NH^alkyl, -Cealk-NH-Cialkyl, -Coalk-NH-Csalkyl, -Ciaik-NH- Csalkyl, -Cialk-NH-Csalkyl, -C3alk-NH-C ₅ alkyl, -Csalk-NH-Csalkyl , -C V.al k- H-Csalkyl, -Coalk- H-Cealkyl, -Cialk- H-Cealkyl, ^•• C -al k-\! l-(Vai kvi. -Csalk- H-Cealkyl, - -Csalk-NH-Cealkyl, and -Cealk-N -Cealkyl.

1 10.1 j In some aspects, R ⁴ is -Co-C6alk-N(Ci-C6alkyl)~Ci-C6alkyl, for example, -Coalk- N(Ci-C6alkyl)-Cialkyl, -Cialk-N(Ci-C6alkyl)-Cialkyl, -(ialk-NiCi-Cealkylj-Cialkyl, -C ₃ alk-N(Ci- Cealky -Cialkyl, -C4alk-N(Ci-C6alkyl)-Cialkyl, -C5alk-N(Ci-C6alkyl)-Cialkyl, -Cealk- N(Ci- Cealky -Cialkyl, -Coalk- N(Ci-C6alkyl)-C2alkyl, -Cialk-N(Ci-C6alkyl)-C2alkyl, -C ₂ alk-N(Ci- C&alkyl)-C ₂ alkyl, -C3alk-N(Ci-C6alkyl)-C2alkyl, -C4alk-N(Ci-C6alkyl)-C2alkyl, -C5alk-N(Ci- (V.alkyD-C -alkyl , -Cealk-NCCi-Cealky -Cialkyl, -Coalk-N(Ci-C6alkyl)-C3alkyl, -Cialk-N(Ci- C6alkyl)-C ₃ alkyl, -C2alk-N(Ci-C6alkyl)-C3alkyl, -Csalk-NfCi-Ceal kyl)-C ₃ a] kyl , -C ₄ al k-N(Ci- Cealky -Csalkyl, -( ¾!k-\((VG>a!kyi )-C :aikyi . -Cealk-NCCi-Cealky -Csalkyl, -Coalk-N(Ci- Ceal kyl)-C ₄ al kyl , -Cialk-N(Ci-C6alkyl)-C4alkyl, -C2alk-N(Ci-C ₆ alkyl)-C4alkyl, -C3alk-N(Ci- C-.alkvl ^' ialkvk -C4alk-N(Ci-C6alkyl)-C4alkyl, -C ₅ alk-N(Ci-C6alkyl)-C4alkyl , -C ^' .-.alk-Xc C i - G.alkyl )-C .alkyL -Coalk- N(Ci-C6alkyl)-C ₅ alkyl, -Cialk-N(Ci-C6alkyl)-C ₅ alkyl, ~C -alk-XiC i~ Cealky -Csalkyl, -Caalk-N Ci-Cealky -Csalkyl, -C4alk-N(Ci-C6alkyl)-C5alkyl, -Csalk-N(Ci- Cealky -Csalkyl , ~G,ai k-X(i (Yaikvi )-i «! ks i, -Coalk-NiCi-Cealkylj-Cealkyl, -Cialk-N(Ci- C&alkyl)-C&alkyl, -C2alk-N(Ci-C6alkyl)-C6alkyl, -C3alk-N(Ci-C6alkyl)-C6alkyl, -C4alk-N(Ci- ( ^' .-.alkvl ) -C.-.alkvk -C ₅ dk-N(Ci-C6alkyl)-C6alkyl , -Cealk-NCCi-Cealky -Cealkyl and the like.

(0102] In some aspects, R ⁴ is -Co-Cealk-NH-Cs-Cficyeloalky], for example, -Coal k-NH- Cscycloalkyl, -Cialk-NH-Cscycloalkyl, -C ₂ alk~ H-C3cycloalkyL -Csalk-NH-Cscycloalkyl, -C ₄ aik- NH-C3cycloalkyl, -C5alk-NH-C ₃ cycloalkyl ₁ -Cealk-NH-Cscycloalkyl, -Coalk-NH-C ₄ cycloalkyl, - Cialk-NH-C4cycloalkyl, -C ₂ alk~NH-C4cycloalkyL -C3alk-NH-C4cycloalkyl, -C ₄ aik- H- C ₄ cycloalkyl, -C5alk-NH-C ₄ cycloalkyl _t -C6alk-NH-C ₄ cycloalkyl, -Coalk-NH-Cscycloalkyl, -Cialk- H-C5cycloalkyl, -C2alk-NH-C5cycloalkyl, -Csaik-NH-Cscycioalkyl, -< ^' ialk- \ ] l-C--cvc! aikyi. - Csalk-NH-Cscycloalkyl , -Cealk-NH-Cscycloalkyl, -Coalk-NH-Cecycloalkyl, -Cialk-NH- C&cycloalkyl, -C2alk-NH-C6cycloalkyi, -Csalk-NH-Cecycloalkyl, -C4alk-NH-C6cycloalkyl, -Csalk- NH-Cecycloalkyl , -Cealk- H-Cecycloalkyl, and the like. In some aspects wherein R ⁴ is -Co-Cealk- NH-C3-C ₆ cy cl oalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ⁴ is -Co-Cealk-NH- C3-C6cycioalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently- selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -Od-Cealkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyi), and halo (e.g., F or Cl). (8103) In some aspects, R ⁴ is -Co-C&alk-N(Ci-C&alkyl)-C3-C6cycloalkyl, for example, - Coalk-N(Ci-C6alkyl)-C3cycloalkyl, -Cialk-N(Ci-C ₆ alkyl)-C3cycloalkyl, -C ₂ alk-N(Ci-C6alkyl)- Cscycloalkyl, -C3alk-N(Ci-C6alkyl)-C3cycloalkyl, -C4alk-N(Ci-C6alkyl)-C3cycloalkyl, -Csalk-NiCi- Cealky -Cscycloalkyl , -Cealk-NCCi-Cealky -Cscycloalkyl, -Coaik-N(Ci-C6aikyi)-C4cycloalkyl, - Cialk-N(Ci-C6alkyl)-C4cycloalkyl, -C ₂ alk-N(C ₁ -C6alkyl)-C4cycloalkyl, -Csalk-NfCi-Cealky])- C4cycloalkyl, -C4alk-N(Ci-C6alkyl)-C4cycloalkyl, -C5alk-N(Ci-C6alkyi)-C4cycloaikyl , -C6alk-N(Ci- C6alkyl)-C ₄ cycloalkyl, -Coalk~N(Ci~C6alkyi)~C5cycloalkyl, -Cialk-N(Ci-C6alkyl)-C5cycloalkyl, - C2alk-N(Ci-C6alkyl)-C5cycloalkyl, -C3alk-N(Ci-C6alkyl)-C5cycioalkyl, -C4alk-N(Ci-C ₆ alkyl)- Cscycloalkyi, -Csalk-NCCi-Cealky -Cscycloalkyl, -Cealk-NCCi-Cealky -Cscycloalkyl, -Coalk-N(Ci- C6alkyl)-C6cycloalkyl, -Cialk-N(Ci-C6alkyl)-C6cycloalkyl, -C ₂ alk-N(C ₁ -C6alkyl)-C6cycloalkyl, - C3alk-N(Ci-C6alkyl)-C6cycloalkyl, -C4alk-N(Ci-C6alkyl)-C6cycloalkyl, -Csalk-NCCi-Cealkyl)- Cecycloalkyl, -Cbalk-NiCi-Cealkylj-Cecycloalkyl, and the like. In some aspects wherein R ⁴ is -Co- C6aik-N(Ci-C6alkyl)-C3-C6cycioalkyl, the cycloalkyl is unsubstitirted. In other aspects wherein R ⁴ is ~Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyi, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Ceaikyi, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

.104| In some aspects, R ⁴ is -Co-Cealk-heterocycloalkyl, for example, -Coalk- heterocycloalkyl, -Ci-Ceaik-heterocycloalkyl, -C i-Csalk-heterocy cioalkyl, -Ci-C4alk- heterocycloalkyl, -C ₁ -C ₃ alk-heterocycloalkyl, -C ₁ -C ₂ alk-heterocycloalkyl, or -Cialk- heterocycioalkyl. Preferred heterocyloalkyl moieties include, for example, piperidinyi, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofurany], tetrahydropyranyl, or oxetanyl. In some aspects wherein R ⁴ is -Co-Cealk-heterocycloalkyl, the heterocycloalkyl is unsubstituted. In other aspects wherein R ⁴ is -Co-Cealk-heterocycloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).

ΙΘ1Θ5] In some aspects, R ⁴ is heteroaryi, for example furanyl, imidazolyl, and pyrazoiyl. In some aspects wherein R ⁴ is heteroaryi, the heteroaryi is unsubstituted. In other aspects wherein R ⁴ is heteroaryi, the heteroaryi is substituted with one, two, or three R substituents independently- selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI). | 1 6] In some aspects, R ⁴ is -CN.

M 07] In some aspects, at least one of R ² , R ³ , and R ⁴ is H. In some aspects, R ² , R ³ , and R ⁴ are each H.

W08| In some embodiments of the disclosure wherein the compounds are of Formula I or Formula III, R ² and R ³ , together with the atoms to which they are attached, form a C3- Ceeycloalkenyl ring, for example, cyciopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

M 09] In some embodiments of the disclosure wherein the compounds are of Formula I or Formula III, R ² and R ³ together form a triple bond.

fli 1§ In some embodiments of the disclosure wherein the compounds are of Formula I or Formula III, R ³ and R ⁴ , together with the atom to which they are attached, form a Cs-Cecycloalkyl ring or a heterocvcloalkyl ring. In some aspects, R ^J and R ⁴ , together with the atom to which they are attached, form a Cs-Ce.cyeloalkyl ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexvl. In other aspects, R ³ and R ⁴ , together with the atom to which they are attached, form a heterocvcloalkyl ring, for example, piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyi, or oxetanyi.

fill I] In compounds of the present disclosure that are a compound of Formula II or Formula IV, R ⁷ is halo, -Ci-Cealkyl, -Ci-C4haloalkyl, -Cs-Cecycloaikyi, -Cs-Cehalocycloalkyi, -C2- C4alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C ₆ alkyl, -CVC ^alk-N((V( V.alkyl )R ^s . -Ci- Cealk-S-Ci-Cealkyl, -Ci-C6alk-S(0)-Ci-C6alkyl, -Ci-Cealk-S(0) ₂ -Ci-C6alkyl, -CR ⁸ R ^8' C , -NH-Ci- Cealk-S-Ci-Cealkyl, -\H-(V(Yai k-S(0)-(VG>a!kyl. -\ 1 i-C ; -( Yai k-S{ 0 ) - -C ^' i -CY.ai k !. - H-Ci- Ceal k-N-Ci-Cealky R ⁸ ), -NHCR ⁸ R ^8' CN, -NR ⁸ R ^8' , -NH-CN, -NHCONR ⁸ R ^8' , -NI-IC(S) 1 ⁸ R ^8' , - HC(0)OR ⁹ , - HC(S)OR ⁹ , HC(0)-Ci .C6aikyL HC(0)-Ci-C6haloalkyl, -NH-Ci-C6alk-C(0)-Ci- Cealkyl, or "N-(3~Ci-C6alkyl)imidazolidin-2~one.

|§112) In some embodiments, R' is halo, for example, F, CI, Br, or I. In some

embodiments, R'' is -CI.

.t J In some embodiments, R ⁷ is -Ci-Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. In some embodiments, R'' is methyl.

{in 14) In other embodiments, R ⁷ is -d-CAaloalkyl, for example, -CF3 or -CHF2, - CH2CH2CI, -CH2CH2F, or -CH2CHF2. In some embodiments, R ⁷ is -CH2CH2C. In other embodiments, R'' is -CH2CH2F, In yet other embodiments, R ⁷ is -CH2CHF2. (01 J5j In other embodiments, R ⁷ is -Cs-Cecycloalkyl, for example, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyciohexyi. In some embodiments, R ⁷ is cyclopropyl.

( ^" 0116] In other embodiments, R is -Cj-Cehalocycloalkyl, for example chlorocyclopropyl, fluorocyclobutyl, bromocyciopentyl, iodocyciohexyi, and the like.

(81 7] In some aspects, R ⁷ is -C ₂ -C ₄ alkenyl, for example vinyl {-{ ^' 1 1 { ^' I I :. C ₂ alkenyl), ally! (-CH2- CH=CH2; Csalkenyl), propenyl (-CH=CHCH ₃ ; Csalkenyl); isopropenyl (-C(CH ₃ )=CH ₂ ; C ₃ alkenyl), butenyl (-CH=CHCH ₂ CH ₃ , ( ^' ;alkenyl ), sec-butenyl (-C{Cl h) ( ! lCj h. C-salkenyl), iso- butenyl C ₄ alkenyl), 2 -butenyl ί-Π ΚΊ Ι CHO I :; C ₄ alkenyl), and the like. In some embodiments, R' is vinyl.

(01 8] In other embodiments, R ⁷ is ---Ci-Cealk-O-Ci-Cealkyl, for example, -Cialk-O- Cialkyl, -C ₂ alk-0-Cialkyl, -Csalk-O-Cialkyl, -C4alk-0-Cialkyl, -Csalk-O-Cialkyl, -Cealk-O- Cialkyl, -Cialk-O-Cialkyl, -C2alk-0-C2alkyl, -Csalk-O-C ⁱ alkyl, -C4alk-0-C ₂ alkyl, -Csalk-O- C ₂ alkyl _> -Cealk-O-Cialkyl, -Cialk-O-Csalkyl, - alk-O-Csalkyl, -Csalk-O-Csalkyl, -C4alk-0- Csalkyl, -Csalk-O-Csalkyl, -Cealk-O-Csalkyl, -Cialk-O-Cialkyl, -C2alk-0-C ₄ alkyl, -Csalk-O- C4alkyl, -C4alk-0-C ₄ alkyl, -Csalk-O-C^alkyl, -Cealk-O-C^alkyl, -Cialk-O-Csalkyl, -C ₂ alk-0- Csalkyl, -Csalk-O-Csalkyl, -C^alk-O-Csalkyl, -Csalk-O-Csalkyl, -Cealk-O-Csalkyl, -Cialk-O- C&alkyl, -Caalk-O-Ceaikyl, -Csalk-O-Cealkyl, -C ₄ alk-0-C ₆ alkyl, -Csaik-O-Cealkyi, -Ceaik-O- C-.alkvl. -CH ₂ .CH ₂ OMe, -CH ₂ OMe, -CH2CH2GCH2CH3, -CH2OCH2CH3, and the like. In some embodiments, R ⁷ is -Π ΚΊ [ >0\le

(0119] In other embodiments, R'' is ~Ci-C6alk-C(0)-Ci-C6alkyl, for example, -Cialk-C(O)- Cialkyl, -C ₂ a]k-C(0)-Cialkyl, -C ₃ alk-C(0)-Cialkyl, -C4alk-C(0)-Cialkyl, -C ₅ alk-C(0)-Cialkyl, - C.-.alk-( ^' { ⁽ ))-C ialkvl. -Cialk-C(0)-C2alkyl, -C2aik-C(0)-C ₂ alkyl, -C ₃ alk-C(0)-C ₂ alkyl, -C ₄ alk-C(0)- C ₂ alkyl, -C5alk-C(0)-C2alkyl, -C6alk-C(0)-C2alkyl, -Cialk-C(0)-C ₃ alkyl, -C2alk-C(0)-C3alkyl, - C3alk-C(0)-C3alkyl, -C4alk-C(0)-C3alkyl, -C ₅ aik-C(0)-C3aikyl , -C6alk-C(0)-C3alkyl, -Cialk-C(O)- C4alkyl, -C ₂ alk-C(0)-C4alkyl, -C ₃ alk-C(0)-C ₄ alkyl, -C ₄ alk-C(0)-C ₄ alkyl, -C ₅ alk-C(0)-C4alkyl _i - C&alk-C(0)-C4alkyl, -Cialk-C(0)-Csalkyl, -C ₂ alk-C(0)-C ₅ alkyl, -C3alk-C(0)-C ₅ alkyl, -C4alk-C(0 Csalkyl, -C ₅ alk-C(0)-C ₅ alkyl _j -C6alk-C(0)-C ₅ alkyl, -Ciaik-CiOVCealkyl, -C ₂ alk-C(0)-C6alkyl, - C3alk-C(())-Cealkyl, -C4alk-C(0)-C6alky 1, -Csalk-C(0)-C6alkyl , -C6alk-C(0)-C ₆ alkyl, - CH ₂ CH2C(0)Me, -CH ₂ C(0)Me, -CH ₂ CH2C(0)CH ₂ CH3, -Π i. iO ^' i Wl k and the like.

(0120] In other embodiments, R ⁷ is -Ci-C6ark-N(Ci-C6alkyl)R ⁸ , for example, -Cialk- N(Cialkyl)R ⁸ , -C ₂ alk-N(Cialkyl)R ⁸ , -C ₃ alk-N(Cialkyl)R ⁸ , -C4alk-N(Ciaikyi)R ⁸ , -Csalk- N(Cialkyl)R ⁸ _s -C&alk-N(Cialkyl)R ⁸ , -Cialk-N(C ₂ alkyl)R ⁸ , -C ₂ alk-N(C ₂ alkyl)R ⁸ , -C ₃ alk- N(C ₂ alkyl)R ⁸ , -C4alk-N(C ₂ alkyl)R ⁸ , · ( ^" :■ a 1 k - \ { ( ^' 2 a 1 k y 1 ) R ^K _ ~C ₆ alk~N(C ₂ alkyl)R ⁸ , -Cialk- N(C ₃ alkyl)R ⁸ , -C ₂ alk-N(C ₃ alkyl)R ⁸ , -C3alk-N(C ₃ alkyl)R ⁸ , -C4alk-N(C ₃ alkyl)R ⁸ , -Csalk- N(C ₃ alkyl)R ⁸ , -C6dk-N(C ₃ alkyl)R ⁸ , -Cialk-N(C4alkyl)R ⁸ , -C ₂ aik-N(C4alkyl)R ⁸ , -Csalk- N(C ₄ alkyl)R ⁸ , -C ₄ alk- (C4al kyl)R ⁸ , -C ¾lk-\{C ialkvl R ⁸ . -C6alk-N(C ₄ alkyl)R ⁸ , -Cialk- N(Csalkyl)R ⁸ , -C ₂ alk-N(C ₅ alkyl)R ⁸ , -C ₃ alk-N(C ₅ alkyl)R ⁸ , -C4alk-N(C ₅ alkyl)R ⁸ , -Csalk- N(C ₅ alkyl)R ⁸ _s -(V,alk-\(C a!ky! )R". -C ; a i k - N C .a i k y i ) R -C ₂ alk-N(C6alkyl)R ⁸ , -C ₃ alk- N(C ₆ alkyl)R ⁸ , -C4alk-N(C6alkyl)R ⁸ , -Csalk-N(C6alkyl)R ⁸ , -C ₆ alk~N(C6afkyf)R ⁸ , and the like. In some embodiments wherein R ⁸ is methyl, R' is -CH ₂ CH ₂ -N(CH ₃ ) ₂ .

(0121 ) In other embodiments, R ⁷ is -Ci-Cealk-S-Ci-Cealkyl, for example, -Cialk-S- Cialkyl, -C ₂ alk-S-Cialkyl, -Csalk-S-Cialkyl, -C4alk-S-Cialkyl, -Csalk-S-Cialkyl, -Cealk-S-Cialkyl, - Cialk-S-C ₂ alkyl, -C ₂ alk-S-C ₂ alkyl, -C ₃ alk-S-C ₂ alkyl, -C4alk-S-C ₂ alkyl, -Csalk-S-Qalkyl, -Cealk-S- C ₂ alkyl, -Cialk-S-C ₃ alkyl, -C ₂ alk-S-C ₃ alkyl, -Oalk-S-Oa!kvL -Oalk-S-Oalkyl. -Csalk-S-Csalkyl, - Cealk-S-Csalkyl, -Cialk-S-C4alkyl, -C ₂ alk-S-C4alkyl, -C3alk-S-C4alkyl, -C4alk-S-C4alkyl, -Csalk-S- C ₄ alkyl, -C&alk-S-C4alkyl, -Cialk-S-Csalkyl, -C ₂ alk-S-C5alkyl, -Cialk-S-Csalkyl, -C4alk-S-C5alkyl, - Csalk-S-Csalkyl, -Cealk-S-Csalkyl, -Cialk-S-Cealkyl, -Qalk-S-Cealkyl, -Csalk-S-Cealkyl, -C ₄ alk-S~ C&alkyl, -Csalk-S-Cealkyl, -Cealk-S-Cealkyl, -CH ₂ CH ₂ SMe, and the like.

|M22] In other embodiments, R' is -Ci-Cealk-SfOVCi-Cealkyl, for example, -Cialk-S(O)- Cialkyl, -C ₂ alk-S(0)-Cialkyl, -C ₃ alk-S(0)-Cialkyl, -C4alk-S(0)-Cialkyl, -C ₅ alk-S(0)-Cialkyl _s - C6alk-S(0)-Ciaikyi, -Cialk-S(0)-C ₂ alkyl, -C ₂ alk-S(0)-C ₂ alkyl, -C ₃ alk-S(0)-C ₂ alkyl, -C ₄ alk-S(0)- C ₂ alkyl, -C ₅ alk-S(0)-C ₂ alkyl _s -C6alk-S(0)-C ₂ alkyl, -Cialk-S(0)-C ₃ alkyl, -C ₂ a]k-S(0)-C ₃ alkyl, - C ₃ alk-S(0)-C ₃ alkyl, -C4alk-S(0)-C ₃ alkyl, -C ₅ alk-S(0)-C ₃ alkyl, -C6alk-S(0)-C ₃ alkyl, -Cialk-S(O)- C .alkyL -C ₂ alk-S(0)-C ₄ alkyl, -C ₃ alk-S(0)-C4alkyl, -C4alk-S(0)-C4alkyl, -C ₅ alk-S(0)-C4alkyl , - C6alk-S(0)-C4aikyi, -Cialk-S(0)-Csalkyl, -C ₂ alk-S(0)-Csalkyl, -C ₃ alk-S(0)-C ₅ alkyl, -C4alk-S(0)- Csalkyl, -C5alk-S(0)-C ₅ alkyl, -C ₆ alk-S(0)-C ₅ alkyl, -Cialk-S(0)-C6alkyl, -C ₂ alk-S(0)-C6alkyl, - C ₃ alk-S(0)-C6alkyl, -C4alk-S(0)-C6alkyl, -C5alk-S(0)-C6alkyl , -C&alk-S(0)-C6aikyl, - CH ₂ .CH ₂ S(0)Me, and the like.

(0123] In other embodiments, R ⁷ is -Ci-C6alk-S(()) ₂ -Ci-C6arkyl, for example, -Cialk- S(0) ₂ -Cialkyl, -C ₂ alk-S(0) ₂ -Cialkyl, -C ₃ alk-S(0) ₂ -Cialkyl, -C4alk-S(0) ₂ -Cialkyl, -Csalk-S(0) ₂ - Cialkyl , -C6alk-S(0) ₂ -Cialkyl, -Cialk-S(0) ₂ -C ₂ alkyl, -C ₂ alk-S(0) ₂ -C ₂ alkyl, -C ₃ alk-S(0) ₂ -C ₂ alkyl, - C4alk-S(0) ₂ -C ₂ alkyl, -C5alk-S(0) ₂ -C ₂ alkyl, -C6alk-S(0) ₂ -C ₂ alkyl, -Cialk-S(0) ₂ -C ₃ alkyl, -C ₂ alk- S(0) ₂ -C ₃ alkyl, -C ₃ alk-S(0)2-C ₃ alkyl, -C4alk-S(0)2-C ₃ alkyl, -C ₅ alk-S(0)2-C3alkyl , -C&alk-S(0) ₂ - C ₃ alkyl, -Cialk-S(0) ₂ -C4alkyl, ^•• C -ai k-SiO s -C ;alkvl. -C ₃ alk-S(0)2-C4alkyl, -C4alk-S(0)2-C4alkyl, Csal k-S(0)2-C ₄ alkyl , -C ₆ aik-S(0) ₂ -C4al ky 1, -Cial k-S(0)2-C ₅ alkyl, -C2alk-S(0)2-C ₅ alkyl, -C ₃ alk- S(0)2-C ₅ alkyl, -C4alk-S(0)2-C ₅ alkyl, -Csalk-S^-Csalkyl , -C ₆ alk-S(0)2-C ₅ alkyl, -Cialk-S(0) ₂ - Cealkyl, -C ₂ alk-S(0) ₂ -C6alkyt -C ₃ alk-S(0) ₂ -C6al kyl , -C ₄ al k-S(0) ₂ -C6alkyl, -Csalk-S(0)2-C6alkyl , C6alk-S(0)2-C6alkyl, -CH2CH ₂ S02Me, and the like.

M 24] In some embodiments, 11 is -CR ⁸ R ⁸ CN. Thus, in some embodiments wherein R and R ⁸ are both H, R is cyanomethyl (i.e., -C i K ^' X ).

l@125j In other embodiments, R' is -Nli-Ci-Cealk-S-Ci-Cealkyl, for example, ~NH-Cialk S-Cialkyl, - H-C ₂ alk-S-Cialkyl, -NH-C ₃ alk-S-Cialkyl, -NH-C ₄ alk-S-Cialkyl, -NH-Csalk-S- Cialkyl , -NH-Cealk-S-Cialkyl, - H-Cialk-S-C2alkyl, -XI l-C -aik -S-C.uiikyL -NH-C ₃ alk-S-C ₂ alkyl, H-C4alk-S-C ₂ alkyl, -NH-C ₅ alk-S~C ₂ alkyl , -NH-Ceal k-S-Cialkyl, -NH-Cialk-S-C ₃ a] kyl , - H- C ₂ alk-S-C3alkyl, -NH-Csalk-S-Csaikyi, -NH-C4alk-S-C3alkyl, -NH-Csalk-S-Csalkyl, -NH-Cealk-S- C ₃ alkyl, -NM-C ialk-S-C sal kvl, -\Ί l-(\¾il k-S-C ia! kyl , -NH-C ₃ alk-S~C4alkyl, -\ 1 l-C iai k-S-C iai kyL NH-C ₅ aik-S-C4alkyi, -NH-Cealk-S-Cialkyl, -NH-Cialk-S-Csalkyl, - i-Caalk-S-Csalkyl, -NH- Csaik-S-Csalkyl, -NH-C4alk-S-C ₅ alkyl, - H-Csalk-S-Csalkyl , - H-Cealk-S-Csalkyl, -NH-Cialk-S- C&alkyl, -NH-C2alk-S-C6alkyl, -NH-Csalk-S-Cealkyl, -NH-Ciaik-S-Ceafkyf, -NH-Csalk-S-Cealkyl , NH-Cealk-S-Cealkyl, -NH-CH ₂ CH ₂ SMe, and the like. In some embodiments, R ⁷ is -NH- Ce ₂ CH ₂ SMe.

|M26] In other embodiments, R'' is -NH-Ci-C6alk-S(0)-Ci-C6alkyl, for example, -NH- Cial k-S(0)-Cialkyl, -NH-C2alk-S(0)-Cialkyl, -NH-C ₃ alk-S(0)-Cialkyl, -NH-C4alk-S(0)-Cial kyl , NH-C ₅ alk-S(0)-Cialkyl . -NH-C6alk-S(0)-Cialkyl, ~NH-CiaIk~S(0)-C ₂ alkyl, -NH-C ₂ alk-S(0)- C -alkyL - H-C ₃ alk-S(0)-C ₂ alkyl, -NH-C4alk-S(0)-C ₂ alkyl, -NH-Csalk-S(0)-C2alkyl , -NH-Cealk- S(0)-C ₂ alkyl, -NH-Cialk-S(0)-C ₃ alkyl, -NH-C2alk-S(0)-C ₃ alkyl, - H-C ₃ alk-S(0)-C ₃ alkyl, -NH- C4alk-S(0)~C ₃ alkyl, ~Nl:i~C ₅ alk-S(0)-C ₃ alkyl _i -NH-C6alk-S(0)~C ₃ alkyl, -NH-Cialk-S(0)-C4alkyl, NH-C2alk-S(0)-C4alkyl, - H-C ₃ alk-S(0)-C4alkyl, - H-C4alk-S(0)-C4alkyl, -NH-Csalk-S(0)- C4alkyl, -NH-C6alk-S(0)-C ₄ alkyl, -NH-Cialk-S(0)-C ₅ aikyi, -NH-C ₂ alk-S(0)-C5alkyl, -NH-Csalk- S(0)-Csalky 1, -NH-C4alk-S(0)-C ₅ al kyl , - H-C5alk-S(0)-C ₅ alkyl , -NH-C6alk-S(0)-C ₅ al kyl , -NH- Cialk-S(0)-C6alkyl, -X! l-C -ai k-Si O s-C-.alkvl. -NH~C ₃ alk-S(0 C ₆ aikyL - H-C4alk-S(0)-C ₆ alkyl, \1 I- al k-S(0)-< \.a!k> i , -X ! !-( ^' .:,al k-S( ⁽ })-{ ^' .,ai k> L -Ne-CH ₂ CH ₂ S(0)Me, and the like. In some embodiments, R ⁷ is - H-CH2CH_S(0)Me. |ίΙΪ 27| In other embodiments, R ⁷ is -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, for example, -NH- Cialk-S(0) ₂ -Cialkyl, -NH-C2alk-S(0)2-Cialkyl, -NH-C ₃ alk-S(0)2-Cialkyl, -NH-C ₄ alk-S(0) ₂ - Cial kyl , - H-Csalk-S(0)2-Cialkyl , -NH-Ceal k-S(0)2-Cialkyl, -NH-C ialk-S(0)2-C ₂ alkyl, -NH- C2alk-S(0)2-C ₂ aikyi, - H-C ₃ alk-S(0)2-C2alkyl, -NH-C ₄ aik-S(Q)2-C2alkyl, - H-C ₅ alk-S(0) ₂ - C ₂ alkyl _s -NH-C6alk-S(0)2-C2alkyl, - H-Cialk-S(0) ₂ -C3aikyi, -NH-C ₂ aik-S(0)2-C3alkyl, -NH- C3alk-S(0)2-C3aikyi, -NH-C4alk-S(0)2-C ₃ alkyl, -NH-C5alk-S(0)2-C3alkyl , -NH-Cealk-S(0)2- Csalkyl, -NH-Cialk-S(0)2-C ₄ alkyl, -\I l-C ^> alk-S(0).'-C .a!ky! , -NH-C ₃ alk-S(0)2-C ₄ alkyl, -NH- C ₄ alk-S(0)2-C ₄ aikyi, -NH-C ₅ alk-S(0)2-C ₄ alkyl , -NH-C6alk-S(0)2-C4alkyl, -NH-Cialk-S(0) ₂ - Csalkyl, ~NH-C2alk-S(0)2-C ₅ alkyl, -NH-C ₃ alk-S(0)2-C5alkyl, ~NH~C ₄ aik~S(Q)2-C ₅ alkyl, -NM- C ₅ alk-S(0)2-C ₅ alkyl , -NH-C6alk-S(0)2-C5alkyl, -NH-Cialk-S(0) ₂ -C6a] kyl , -NH-C ₂ al k-S(0) ₂ - Cealkyl, -NH-C3alk-S(0)2-C ₆ alkyl, - H-C ₄ alk-S(0)2-C ₆ aikyL -NH-C5alk-S(0)2-C6alkyl , -NH- Ceal k-S(0) ₂ -C6alkyl, -NH-CH ₂ CH ₂ S(0) ₂ Me, and the like. In some embodiments, R is -NH- C! K H 'S(0) Ale.

£0128] In other embodiments, R is -X H-C i -CXai k~X(( ^' i -G.ai k ! )R ^K , for example, -NH- Cialk-N(Cialkyl)R ⁸ , -NH-C2alk-N(Cialkyl)R ⁸ , -NH-C3alk-N(Cialkyl)R ⁸ , -NH-C ₄ alk-N(Cialkyl)R ⁸ , -NH~C ₅ alk~N(Cialkyl)R ⁸ _s -NH-C6alk-N(Cialkyl)R ⁸ , -NH-Cialk-N(C2alkyl)R ⁸ , -NH-C2alk- N(C ₂ alkyl)R ^s , -NH-C3alk-N(C ₂ alkyl)R ^s , -NH-C ₄ alk-N(C ₂ alkyl)R ⁸ , -NH-Csalk-N^alky R ⁸ , -M l- C6alk-N(C ₂ alkyl)R ⁸ , -NH-Cialk-N(C ₃ alkyl)R ⁸ , -NH-C2alk-N(C3alkyl)R ⁸ , -NH-C3alk-N(C3alkyl)R ⁸ , -NH-C ₄ aik-N(C3alkyl)R ⁸ , -Xi !-(\¾i k-X(C Xai k> i )R ^x _, -NH-C6alk-N(C ₃ alkyl)R ⁸ , -NH-Cialk- N(C ₄ alkyl)R ⁸ , -NH-C ₂ alk-N(C ₄ alkyl)R ⁸ , -NH-C3alk-N(C ₄ alkyl)R ⁸ , -NH-C ₄ alk-N(C ₄ alkyl)R ⁸ , -NH- Csal k-N(C ₄ alkyl)R ⁸ , -NH-Cealk-N(C ₄ alkyl)R ⁸ , -NH-Cialk-N(C ₅ al kyl)R ⁸ , -NH-C ₂ alk-N(C ₅ al kyl)R ⁸ , -NH-C3aik-N(C ₅ aikyi)R ⁸ , -NH-C ₄ alk-N(C ₅ aikyi)R ⁸ , -NH-Csalk-NiCsaiky R ⁸ , -NH-Cealk- N(C ₅ alkyl)R ⁸ , -NH-Cialk~N(Cealkyl)R ⁸ , -NH-C2alk~N(Cealkyl)R ⁸ , -NH-Csalk-NiCealkyljR ⁸ , -X I I- C ₄ alk-N(C6alkyl)R ⁸ , -NH-Csalk-NCCealky R ⁸ , -NH-C&alk-N(C6alkyl)R ⁸ , and the like. In some embodiments wherein R ⁸ is methyl, R ⁷ is -NH-CH ₂ CH ₂ -N(CH ₃ )2.

.129| In some embodiments, R ⁷ is -NR ⁸ R ⁸ . Thus, in some embodiments wherein R ⁸ and R ^8' are both H, R ⁷ is -NH2.

|(l ί 3 | In some embodiments, R'' is -NHCR ⁸ R ⁸ CN. Thus, in some embodiments wherein R ⁸ and R ⁸ are both H, R ⁷ is -NHCH2CN.

flOiJ In some embodiments, R ⁷ i s -NH-CN. ίΙΪ32| In some embodiments, R is - HCONR ⁸ R ^8' . Thus, in some embodiments wherein R ⁸ and R ⁸ are both H, R ⁷ is -NHCO H2. In embodiments wherein R ⁸ and R ⁸ are both methyl, R ⁷ is -NHCON(CH ₃ ) ₂ . In embodiments wherein R ⁸ i s H and R ^8' is methyl, R ⁷ is -NHCO HCH3. In embodiments wherein R ⁸ and R ⁸ , together with the atom to which they are attached, form a or a five

r six membered heterocyclic rin:

[0133] In some embodiments, R ^? is - HC(S) R ⁸ R ^8' . Thus, in some embodiments wherein R ⁸ and R ⁸ are both H, ⁷ is -NHC(S)NH ₂ . In embodiments wherein R ⁸ and R ⁸ are both methyl, R' is M fC( S)N(CI f · ) ·· . In embodiments wherein R ⁸ is H and ^8' is methyl, is M fC( S)M ΙΠ k

[01.34] In some embodiments, R ⁷ i s - HC(0)OR ⁹ . Thus, in some embodiments wherein R ⁹ is methyl, R ⁷ is -NHC(0)OCH ₃ .

[9135] In some aspects, R ⁷ is -NHC(S)OR ^y . Thus, in some embodiments wherein R ⁹ is methyl, R ⁷ is -NHC(S)OCH3.

[0136] In some aspects, R ⁷ is - HC(0)-Ci-C6alkyl, for example, -NHC(0)-Cialkyl, NHC(0)-C ₂ al ky] , NHC(0)-C ₃ alkyl, NHC(0)-C ₄ alkyl, NHC(0)-C ₅ alkyl, NHC(0)-C6alkyl,

NHC(0)-methyl, NHC(0)-ethyl, and the like. In some embodiments, R ^? is -NHC(0)-m ethyl.

[0137] In other aspects, R is NHC(0)~Ci-C6haloalkyl, for example, -NHC(0)-Cihaloalkyl, NHC(0)-C ₂ haloalkyl, NHC(Q)-C ₃ haloalkyl, NHC(0)-C4haioalkyl, NHC(0)-C ₅ haloalkyl, - NITC(0)-C0haloalkyl, -NHC(0)-chloromethyl, ~NHC(0)~chloroethyl, -NHC(0)-fiuoromethyl, - NHC(0)-fluoroethyl and the like,

[M3§] In other aspects, R ⁷ is for example, -NH-Cialk- C(0)-Ci-Cealkyl, -NH-C ₂ alk-C(0)-Ci-C6alkyl, -X I I-C ^" ¾ai k-C ( < >)-< ^' i~< c.alks i, -NH-C4alk-C(0)-Ci- Cealkyl, - H-C ₅ alk-C(0)-Ci-C6alkyl, - H-C ₆ alk-C(0)-Ci-C ₆ alkyl, - H-Ci-C6alk-C(0)-Cialkyl, - NIT-Ci-C6alk-C(0)-C2alkyl, -NH-Ci-C6alk-C(0)-C ₃ alkyl, - H-Ci-C6alk-C(0)-C4alkyl, -NH-Ci- Cealk-C(0)-C5alkyl, - H-Ci-C6alk-C(0)-C6alkyl and the like. In some aspects, R ⁷ is -NH-CH2- C(0)-C¾.

).I.39| In other aspects, R ⁷ i s -N-(3-Ci-C6alkyl)iniidazolidir!-2-one, that is:

. In some embodiments, Ci-Cealkyl is methyl, ethyl, propyl, and the like. In some embodiments, Ci -Cealkyl is methyl, and R' is

| 14 ] In embodiments of the disclosure wherein the compounds are of Formula II or Formula IV, R ⁸ and R ⁸ are each independently H, Ci-Cealkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, i sobutyl, s-butyl, t-butyl, pentyl, and the like), or -Co-Cealk-OCi-Cealkyl (e.g., Coalk-OCi- Cealkyl, Ci-Cealk-OCi-Cealkyl, Ci-Csalk-OCi-Cealkyl, Ci-C4aik-QCi-Cealkyl, Ci-Csalk-OCi- Cealkyl, Ci-Cialk-OCi-Cealkyl, Cialk-OCi-Cealkyl, Co-Cealk-OCi-Csalkyl, Co-C6alk-OCi-C4alkyl, Co-Cealk-OCi-Csalkyl, or Co-Cealk-OCialkyl).

($14!] In some embodiments, R ⁸ is H or Ci-Cealkyl . In some embodiments, R ⁸ is H or Ci-Cealkyl.

[Θ142] In some embodiments, R ⁸ and R ⁸ are each H.

(0143] In other embodiments, R ⁸ and R ⁸ are each independently Ci-Cealkyl . Thus, in some embodiments R ⁸ is methyl and R ^8' is methyl.

| 1.44| In some aspects, R ⁸ is Ci-Cealkyl and R ⁸ is H. Thus, in some embodiments, R ⁸ is methyl and R ⁸ is H.

((1145] In other aspects, R ⁸ and R ⁸ are each independently -Co-Cealk-OCi -Cealkyl.

(0146] In other aspects, R ^s is -Co-Ceaik-OCi-Cealkyl and R ⁸ is H.

(1147] In embodiments of the disclosure wherein the compounds are of Formula II or Formula IV, R ⁸ and R ⁸ , together with the atom to which they are attached, form a Cs-Cecycloalkyl, for example, cyciopropyi, cyciobutyi, cyciopentyl, or cyclohexyl. In other embodiments of the disclosure wherein the compounds are of Formula II or Formula IV, R ⁸ and R ^8' , together with the atom to which they are attached, form a or a five or six membered heterocyclic ring, for example, pyrrolidine, piperidine, morpholine, piperazine, or 4-methylpiperizine.

W48| In embodiments of the disclosure wherein the compounds are of Formula II or Formula IV, R ⁹ is -Ci-Ceal ky] , or -Co-Ceal k-Cs-Cecycloalkyl . In some embodiments, R ⁹ is Ci- Cealkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyi, t-butyl, pentyi, and the like. Thus, in some embodiments, R ⁹ is methyl.

I 9| In other aspects, R ⁹ is Co-Cealk-Cs-Cecyeioalkyl, for example, -Coalk-Cscycloalkyl, -Cialk-C.3cycloalkyl, -C ₂ alk-C3cycloalkyl, -C ₃ alk-C ₃ cycloalkyl, -C ₄ alk-C ₃ cycloalkyl, -Csalk- CiCycloalkyl , -Cealk-Cjcyc!oal ky] , -Coal k-C ₄ cycloalkyl, -Cialk-C-tcycloal ky] , -C ₂ al k-C ₄ cycloalkyl, - C ₃ alk-C ₄ cycloalkyl, -C ₄ alk-C ₄ cycloalkyl, -Csalk-Ocycloalkyl, -C6alk-C ₄ cycloalkyl, -Coalk- Cscycloalkyl, -Cialk-Cicycloal ky] , -C ₂ al k-Cscycloalkyl, -Csalk-Cscycloal kyl , -C ₄ al k-C5cycloalkyl, - Csalk-Cscycloalkyl , -Cealk-Cscycloalkyl, -Coalk-Cecycloalkyl, -Cialk-Cecycloalkyl, -C ₂ alk- Cecycloalkyl, -C ₃ alk-C6cycloalkyl, -C ₄ alk-C6cycloalkyl, -Csalk-Ceeycloa!ky!, -Cealk-Ceeycloalkyl. In some aspects wherein R ² is -Co-Cealk-Cs-Cecycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ² is -Co-Cealk-Cs-Cecycloaikyi, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-Cealkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-Cealkyl (e.g., -Omethyi, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI),

eiS ] In preferred embodiments of the compounds of Formula I, Formula II, Formula III, and Formula IV, R ¹ is -CH(OH)-Ci-C ₆ al kyl , -CH(F)-Ci-C6alkyl, -CH( H ₂ )-Ci-C6al kyl , -CH(Me)- Ci-Cealkyl, -C(Me)(OH)-Ci-C ₆ alkyl, -CH(OH)-Ci-C6 haloalkyl, -CH(F)-Ci-C6 haloalkyl, - Cf [ , }-( · , -( ^' ,, haloalkyl, ~CH(Me)-Ci-C ₆ haloalkyl, -C( e)(OH)-Ci-C6 haloalkyl, -CI [( ( )! ! }- C≡CH, -CH(F)-C≡CH, -C i K N i ! ')·{ ^' ( I f , -CH(Me)-C≡CH, -C(Me)(OH)-C≡CH, -CH(OH)-C≡C- Ci-Cealkyl, -CH(F)-C≡C-Ci-C6alkyl, -C H( M !;: )-C C-iVO.ai ks i, -CH(Me)-C≡C-Ci-C6alkyl, - C(Me)(OH)-C≡C-Ci-C6alkyl, -CH(OH)-C≡C-Ci-C6haloalkyl, -CH(F)-C≡C-Ci-C6haloalkyl, - CH(NH ₂ )-C≡C-Ci-C6haloalkyl, -CH(Me)-C≡C- Ci-Cehaloalkyl, -C(Me)(OH)-C≡C-Ci-C ₆ haioalkyl, -CH(F)-C≡C-C ₃ -C6cycloalkyl, -CH(NH ₂ )-C≡C-C3-C6cycloalkyl, - CH( e)-C≡C-C ₃ -C6cycloalkyl, -C(Me)(OH)-C≡C-C ₃ -C6cycloalkyl, -CM.varyl. -CH(OH)-aryl, - CH(F)-aryl, -CH(NH ₂ )-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl. |Ιί 151 More preferred embodiments are those wherein R ¹ is -CH(OH)-C=C-CH ₃ , -CH(F)- C≡C-CH3, -CH(NH2)-C≡C-CH ₃ , -CH(Me)-C≡C-C¾, or -C(Me)(OH)-C≡C-CH ₃ , -CH(OH)-C≡C- CH ₃ , -{ ! ](()! ! )-(· C-( i \ -Π !(! ( ^' ( -{ ! _s -CH(NH2)-C≡C-CF ₃ , -CH(Me)-C≡C-CF ₃ , or - C( e)(OH)-C≡C-CF ₃ , -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH( H ₂ )-C≡C- cyclopropyl, -CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl, CH ₂ -4-fluorophenyl, - CE -phenyl, -CH ₂ -4-chl orophenyl, -CH2-3,4-dichlorophenyl, -CH ₂ -3,4-difluorophenyl, -CFfc-3- fluoro-4-chlorophenyl, -CH ₂ -3-chloro-4-fluorophenyl, -CH(OFI)-4-chl orophenyl, -CH(OH)-4- fluorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4- chlorophenyl, -CH(OH)-3-chloro-4~fluorophenyl, -CH(F)-4-chl orophenyl, ~CH(F)-4-fluorophenyl, - CH(F)-3 ,4-di chloropheny 1 , -CH(F)~3 ,4-difluorophenyl, -CH(F)-3 -fluoro-4-chloropheny 1 , -CH F)-3 - cMoro-4-fluorophenyl., -CH(NH2)-4-cMorophenyl, -CH(NH2)-4-fluorophenyl -CH(NH ₂ )-3,4- dichl orophenyl, -CH(NH ₂ )-3 ,4-difluorophenyl, -CH(NH ₂ )-3 -fluoro-4-chl orophenyl, -CH(NH ₂ )-3 - chloro-4-fluorophenyl, -CH(Me)-4-chl orophenyl, -CH(Me)-4-fluorophenyl, -CH(Me)-3 ,4- di chl orophenyl, -CH(Me)-3 ,4-difluorophenyl, -CH(Me)-3-fluoro-4-c-hl orophenyl, -CH(Me)-3- chloro-4-fluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -C(Me)(OH)- 3,4-di chl orophenyl, -C(Me)(OH)-3 ,4-difluorophenyl, -C(Me)(OH)-3-fluoro-4-chl orophenyl, or - C Me)(OH)-3-chloro-4-fluorophenyl.

fM§2] In some aspects, the disclosure is directed to compounds of Formula II or IV wherein R ^f is -Co-Cealk-heteroaryi, -Ci-Cealk-O-heteroaryl, -Ci-Cfialk-S-heteroaryl, or -Ci-Cealk- H-heteroaryl, and R ⁷ , is -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C ₆ alkyl, -Ci-C6alk-N(Ci- Ceal kyl)R ⁸ , -Ci-Ceaik-S-Ci-Cealkyl, -Ci-C6alk-S(0)-Ci-C6alkyl, -Ci-C6alk-S(0)2-Ci-C6alkyl, - CR ⁸ R ^S' C , -NH-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C ₆ alk-S(0)-Ci-C6aikyi, -NH-Ci-C ₆ alk-S(0)2-Ci- Cealkyl, - H-Ci-Cealk-N-Ci-CealkylCR ⁸ ), ~NHCR ⁸ R ^8' CN, -NI:i~CN, -NHCONR ⁸ R ^8' , - NHC(S)NR ⁸ R ^8' , -NHC(0)OR ⁹ , -NHC(S)OR ⁹ , -NHC(0)-Ci-C6alkyl, -NHC(0)-Ci-C6haloalkyl, - NH-Ci-C6alk-C(0)-Ci-C6alkyl, or -N-(3-Ci-Cealkyl)imidazolidin-2-one; and R ⁵ , R ⁶ , R ⁸ , R ^8' , and R ⁹ having any of the values described above.

|M§3] In some aspects, the disclosure is directed to compounds of formula IIB-1

wherein R ¹ is -Co-Cealk-C-C-Ci-Cealkyl, -Co-Cealk-C-C-Cs- Cecycloalkyl, or -Ci-Ceaik-aryl; R ⁷ is halo, -Ci-CAaloalkyl, -C ₃ -C6cycloalkyl, -C2-C4alkenyl, -Ci Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C6alkyl, -Ci-C6alk-N(Ci-C6alkyl)R ⁸ , -Ci-Cealk-S-Ci- C&alkyl, -NH-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, -NHCR ⁸ R ^8' CN, - NHCONR R ^8' , -NHC(S)NR ⁸ R ^8' , ~NHC(0)OR ⁹ , -NHC(S)OR ⁹ , -NHC(0)-Ci-C6alkyl, -NH-Ci- C6alk-C(())-Ci-C6alkyl, or -N-(3-Ci-C6alkyl)imidazolidin-2-one; and R ⁸ , R ^8' , and R ⁹ have any of the values described above.

| l.54| In some embodiments, the compounds of Formula IIB-1 are those wherein R ¹ is - Co-C ₆ alk-C≡C-C3-C6cycloalkyl; R ^? is halo, -Ci-Cihaloalkyl, -C3-C6cycloalkyl, -C2-C ₄ alkenyl, -Ci Cealk-O-Ci-Cealkyl, -Ci-Ceafk-CCOVCi-Cealkyl, -Ci-C6alk-N(Ci-C6alkyl)R ⁸ , -Ci-Cealk-S-Ci- Cealkyl, - H-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, -NHCR R ^8' CN, - NIiCONR¾ ^8' , -NIIC(S)NR ⁸ R ^8' , -NHC(0)OR ⁹ , -NHC(S)OR ⁹ , - HC(0)-Ci-C6alkyl, -NH-Ci- C&alk-C(0)-Ci-C6aikyi, or -N-(3-Ci-C6aikyi)imidazoiidin-2-one; and R ⁸ , R ^8' , and ⁹ have any of the values described above. In some embodiments, the compounds of Formula IIB-1 are those wherein R ^f is -Co-C6alk-C≡C-C ₃ -C6cycloal kyl , and R ⁷ is halo.

|8155] In other embodiments, the compounds of Formula IIB-1 are those wherein R ¹ is - Ci-Ce.alk-aryl, and R is halo, -Ci-Cmaloalkyl, -C ₃ -C6cycloalkyl, -C ₂ -C ₄ alkenyl, -Ci-Cealk-O-Ci- Cealkyl, -Ci-C6alk-C(0)-Ci-C ₆ alkyl, -C!-C6alk-N(Ci-C6aikyi)R ⁸ , -Ci-Cealk-S-Ci-Cealkyl, - H-C G.alk-S-( ^' i-G.alkyi. -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, -NHCR ⁸ R ^8' CN, -NHCO R ⁸ R ^8' , - NHC(S)NR ⁸ R ^8' , -NHC(0)OR ⁹ , -NHC(S)OR ⁹ , -NHC(0)-Ci-C6aikyi, - H-Ci-C6alk-C(0)-Ci- Cealkyl, or ~N~(3-Ci-C6alkyl)imidazolidin-2-one, and R ⁸ , R ^8' , and R ⁹ have any of the values described above.

|M56] Some embodiments of the compounds of Formula IIB-1 are those wherein R ¹ is - Ci-Cealk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3- fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyL 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3-methylphenyl, 2,4-difluorophenyl, ^' hydroxymethyl-4-chlorophenyl, 2-hydroxymethyl-5-chlorophenyl, 2-aminomethyl-4-chlorophenyl,

2- (methylaminomethyl)-4-chlorophenyl, 2-hydroxymethyl-4,5-difluorophenyl, 2-aminomethyl-4,5- difluorophenyl, or 2-(methylaminomethyl)-4,5-difluorophenyl; and R is halo, -C ₁ -C ₄ haloalkyl, -C ₃ - Cecycloalkyl, -C ₂ -C4alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C ₆ alkyl, -Ci-Ceaik-NfCi- Cealkyl)R ⁸ , -Ci-Cealk-S-Ci-Ceal kyl , - H-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, NHCR ^S R ^8' CN, -NHCONR ⁸ R ^8' , -NHC(S)NR ⁸ R ^8' , -NHC(0)OR ⁹ , -NHC(S)OR ⁹ , - HC(0)-Ci- Cealkyl, - H-Ci-C6alk-C(0)-Ci-C6aikyI, or -N-(3 -C i-C6aikyI)imidazoIidin-2-one; and R ⁸ , R ⁸ , and R ⁹ have any of the values described above.

6i57j Thus in some embodiments, the compounds of Formula IDS-1 are those wherein R ^l is -CH ₂ -difluorophenyl, -CH ₂ -3,4-difiuorophenyl, -CH ₂ -4-chlorophenyl, -CH -3-chloro-4- fluorophenyl, -CH?~4-chloro-3-fluorophenyl, -CFb-dichlorophenyl, -CH2-3,4-dichiorophenyl, -CH2

3- fluoro-4-(trifluoromethyl)phenyl, or -CH ₂ -4-chloro-3-methylphenyl, -CH ₂ -2,4-difluorophenyl, - CH ₂ -2-hydroxymethyl-4-chlorophenyl, -CH2-2~hydroxymethyl-5-chlorophenyl, -CFk-2- aminomethyl-4-chlorophenyl, -CFI ₂ -2-(methylaminomethyl)-4-chlorophenyl, -CFt-2- hydroxymethyl-4,5-difluorophenyl, -CH ₂ -2-aminomethyl-4,5-difluorophenyl, -CE -2- (methylaminomethyl)-4,5-difluorophenyl, -CH(OH)-4-chlorophenyl, ~CH(OH)~3,4-dichiorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)-3-chloro-4- fluorophenyl, -CH(OH)-3 -fluoro-4-(trifluoromethyl)phenyl, or -CH(OH)-4-chloro-3 -methylphenyl, -CH(OH)-2,4-difluorophenyl, -CH(OH)-2-hydroxymethyl-4-chlorophenyl, -CH(OH)-2- hydroxymethyl-5-chlorophenyl, -CH(OH)-2-aminomethyl-4-chlorophenyl, ~CH(OH)~2- (methylaminomethyl)-4-chlorophenyl , -CH(OH)-2-hydroxymethyl-4,5-difluorophenyl, -CH(OH)-2 aniinomethyi-4,5-difluorophenyl, -CH(OH)-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(F)-4- chlorophenyi, -CH(F)-3,4-dichlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4- chlorophenyl, -CH(F)-3-chloro-4-fluorophenyl, -CH(F)-3-fluoro-4-(trifluoromethyl)phenyl, -CH(F) 4~chloro~3 -methylphenyl, -CH(F)-2,4-difluorophenyl, -CH(F)-2-hydroxymethyl-4-chlorophenyl, - CH(F)-2-hydroxymethyl-5-chlorophenyl, -CH(F)-2-aminomethyl-4-chlorophenyl, -CH(F)-2- (methylaminomethyl)-4-chlorophenyl, -CH(F)-2-hydroxymethyl-4,5-difluorophenyl, -CH(F)-2- aminomethyl-4,5-difluorophenyl, -CH(F)-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(NH ₂ )-4 chlorophenvi, -CH( H ₂ )-3 ,4-diehlorophenyi, -CH(NH ₂ )-3 ,4-difiuorophenyl, -CH(NH ₂ )-3 -fluoro-4- chlorophenyl, -CH(NH ₂ )-3-chloro-4-fluorophenyl, -CH(NH ₂ )-3-fluoro-4-(trifluoromethyl)phenyl, 0 -CH(NH ₂ )-4-chloro-3-methylphenyl, -CH(NH ₂ )-2,4-difluorophenyl, -CH(NH ₂ )-2-hydroxymethyl-4 chlorophenyl, -CH(NH ₂ )-2-hydroxymethyl-5-chlorophenyl, -CH(NH ₂ )-2-aminomethyl-4- chlorophenyl, -CHCNH ₂ )-2-(methylaminomethyl)-4-chlorophenyl, -CH( H?)-2-hydroxymethyl-4,5- diiluorophenyl, -CH(NH ₂ )-2-aminomethyl-4,5-difluorophenyl, -CH(NH ₂ )-2-(methylaminomethyl)- 4, 5-dif uorophenyl, -CH(Me)-4-chlorophenyl, -CH(Me)-3 ,4-di chlorophenyl, -CH(Me)-3 ,4- difluoropheny 1 , -CH(Me)-3 -fluoro-4-chl orophenyl, -CH(Me)-3 -chloro-4-fluorophenyl, -CH(Me)-3 - fluoro-4-(trifluoromethyl)phenyl, -CH(Me)-4-chloro-3-methylphenyl, -CH(Me)-2,4-difluorophenyl, -CH(Me)-2-hydroxymethyl-4-chl orophenyl, -CH(Me)-2-hydroxymethyl-5-c-hl orophenyl, -CH(Me)- 2-aminomethyl-4-chlorophenyl, -CH(Me)-2-(methylaminomethyl)-4-chl orophenyl, -CH(Me)-2- hydroxymethyl-4,5-difluorophenyl, -CH( e)-2-aminomethyl-4,5-difluorophenyl, -CH(Me)-2- (methylaminomethyl)-4,5-difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3 ,4- di chlorophenyl, -C(Me)(OH)-3,4-difluorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, - C(Me)(OH)-3-chloro-4-fluorophenyl, -C(Me)(OH)-3-f!uoro-4-(trifluoromethyl)phenyl, - C( e)(OH)- -chloro-3-methylphenyl, -C( e)(OH)-2,4-difluorophenyl, -C(Me)(OM )-2- hydroxymethyl-4-chl orophenyl, -C(Me)(OH)-2-hydroxymethyl-5-chl orophenyl, -C(Me)(OH)-2- aminomethyl-4-chl orophenyl, -C(Me)(OH)-2-(methylaminomethyl)-4-chl orophenyl, -C(Me)(OH)- 2-hydroxymethyl-4,5-difluorophenyl, -C(Me)(OH)-2-aminomethyl-4,5-difluorophenyl, - C(Me)(OH)-2-(methyiaminomethyi)-4,5-difluorophenyl, -C(CF ₃ )(OH)-4-chlorophenyl, - C(CF3)(OH)-3,4-dichlorophenyl, -C(CF ₃ )(OH)-3,4-difluorophenyl, -C(CF ₃ )(OH)-3-fluoro-4- chloropheny 1 , -C(CF3)(OH)-3 -chloro-4-fluoropheny 1 , -C(CF ₃ )(OH)-3 -ft uoro-4- (trifluoromethyl)phenyl, or ~C(CF ₃ )(OH)-4-chloro-3~methylphenyl, -C(CF ₃ )(OH)-2,4- diiluorophenyl, -C(CF ₃ )(OH)-2-hydroxymethyl-4-chlorophenyl, -C(CF ₃ )(OH)-2-hydroxymethyl-5- chlorophenyl, -C(CF ₃ )(OH)-2-aminomethyl-4-chlorophenyl, -C(CF ₃ )(OH)-2-(methylaminomethyl)- 4-chl orophenyl, -C(CF ₃ )(OH)-2-hydroxymethyl-4,5-difluorophenyl, -C(CF ₃ )(OH)-2-aminomethyl- 4,5-difluorophenyi, -C(CF ₃ )(OFI)-2-(methylaminomethyl)-4,5-difluorophenyl; R' is halo, -Ci- C4haloalkyl, -Cs-Cecycloalkyl, -C -C iaikenyi , -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C6alkyl, -Ci-C6alk-N(Ci-C6alkyl)R ⁸ , -Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-Cealk- S(0)2-Ci-C ₆ alkyl, - HCR ⁸ R ^8' CN, -NHCO R ⁸ R ^8' , - HC(S)NR ⁸ R ^8' , -NHC(0)OR ⁹ , - HC(S)OR ⁹ , -NHC(0)-C ₁ -C6alkyl, -N -Ci-C6alk-C(())-Ci-C6alkyl, or -N-(3-Ci-C6alkyl)imidazolidin-2-one; and R ⁸ , R ⁸ , and R ⁹ have any of the values described above.

| 1.58| In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH(OH)-4-chl orophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)- 3-fIuoro-4-chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3-fluoro-4- (trifluoromethyl)phenyl, -CH(OH)-4-chloro-3-methylphenyl, -C(CF ₃ )(OH)-4-chlorophenyl; and R ⁷ i s -halo, -Ci-C haloalkyl, -Cs-Cecycloalkyl, -C ₂ -C ₄ alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Cealk- C(0)-Ci-C6alkyL -Ci-Cealk- Ci-CealkyljR ⁸ , -NH-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C6al k-S(0)2-Ci-C6aikyS, -NHCR ⁸ R ^8' CN, -NHCONR ⁸ R ^8' , -NHC(S)NR ⁸ R ^8' , -NHC(0)()R ⁹ , - NHC(S)OR ⁹ , - HC(0)-Ci-C6alkyl, -NH-Ci-C6alk-C(0)-Ci-C ₆ alkyl, or ~N-(3-Ci- C6alkyl)imidazolidin-2-one; and R ⁸ , R ^8' , and R ⁹ have any of the values described above. ,

iSf j Some particularly preferred embodiments of compounds of Formula IIB-1 are those wherein R ^l is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -( ^' ! 1(01 ! }-3.4- difluoropheny 1 , -CH( C)H)-3 -fluoro-4-chloropheny 1 , -CH(OH)-3 -chl oro-4-fluoropheny 1 , -CH(OH)-3 - fluoro-4-(trifluoromethyl)phenyl, or -CH(OH)-4-chloro-3-methylphenyl; and R ⁷ is -CI, -CH2CH2CI, cyclopropyl, vinyl, -CH2CH2-O-CH3, -Π WI KC« ⁾ )-CI h, -CI ΚΊ !. -N(C ^' 1 1 ^: ) -CH2CH2-S-CH3, - NH-CH2CH2-S-CH3, -NH-CH ₂ CH ₂ -S(0)2-CH3, - HCH2CN, -NHCO (CH ₃ )2, -NHCO H2, - HC(S)N(CH3)2, -NHC(S)NH(CH3), -NIiC(0)OCH ₃ , -NHC(S)OCH3 , -N l Ι( ^" (0)-(Ί h, -NH-CFI2-

|M60] Other particularly preferred embodiments of compounds of Formula IIB- 1 are those wherein R ^l is -CH(OH)-4-cMorophenyl, and R ⁷ is -CI, -CH2CH2CI, cyclopropyl, vinyl, -CH2CH2-O- C! h. -Ce ₂ CH2-C(0)-CH3, -CH ₂ CH ₂ -N(CH3)2, -( Ί i ·( ! h-S-C! h. -NH-CH2CH2-S-CH3, -NH- CH ₂ CH ₂ -S(0)2-CH3, -NHCH2CN, - HCON(CH ₃ ) ₂ , -NHCONH2, -NHC(S)N(CH3)2, - NIiC(S)NH(CH3), -NIiC(0)OCH ₃ , -NHC(S)OCH3 , -NHC(0)-CH ₃ , -NH-CH2-C(0)-CH ₃ ,

In some as ects, the disclosure is directed to compounds of formula ΠΑ-!

wherein R ^f is -Ci-Cealk-aryl, R ⁷ is halo, -Ci-C'Jhaloaikyi, -C ₃ -C6cycloalkyl, -Ci-Cealk-O-Ci- Cealkyl, - HCR ^S R ^8' CN, -NH-CN, -NHCONR ⁸ R ⁸ , - HC(0)OR ⁹ , -NHC(G)-C!-C ₆ alkyl, NHCfOV Ci-Cehaioalkyl, -NH-Ci-C6alk-C(0)-Ci-C6alkyl; and R ⁸ , R ^8' , and R ⁹ have any of the values described above.

|CI162] Some embodiments of the compounds of Formula IIA-1 are those wherein R ¹ is - Ci-Cealk-aryf wherein the -aryl is -4-chlorophenyl, -3 ,4-dichl orophenyl, -3,4-difluorophenyi, -3- fluoro-4-chl orophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3-methylphenyl, 2,4-difluorophenyl, 2- hydroxymethyl-4-chlorophenyl, 2-hydroxymethyl-5-chlorophenyl, 2-aminomethyl-4-chlorophenyl,

2- (methylaminomethyl)-4-chlorophenyl, 2-hydroxymethyl-4,5-difluorophenyl, 2-aminomethyi-4,5- difluorophenyl, or 2-(methylaminomethyl)-4,5-difluorophenyl; and R'' is halo, -Ci-C ₄ haloalkyl, -C ₃ - Cecycloalkyl, -Ci-Cealk-O-Ci-Ceaikyi, -NHCR ⁸ R ^8' CN, -NH-CN, -NHC()NR ⁸ R ^8' , -NHC(0)()R ⁹ , - NHC(0)-Ci-C6alkyl, HC(0)-Ci-C ₆ haloalkyl, -NH-Ci-C6alk-C(0)-Ci-C6alkyl; and R ⁸ , R ^8' , and R ⁹ have any of the values described above,

|0163] In some preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -CH(OH)-4-chl orophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, ~CH(OH)~

3 - fluoro-4-chl orophenyl , -CH(OH)-3 -chl oro-4-fluoropheny 1 , -C(Me)(OH)-4-chl orophenyl, - CH(Me)-4-chlorophenyl, or -CH(F)-4-chlorophenyl; and R ⁷ is halo, -Ci-C ₄ haloalkyl, -C ₃ - Cecycloalkyl, -Ci-Cealk-O-Ci-Cealkyl, -NHCR ⁸ R ^' CN, - H-CN, -NHCO R ⁸ R ^8' , -NHC(0)QR ⁹ , - NHC(0)-Ci-C ₆ alkyl, NHC(0)-Ci-C6haloalkyl, -NH-Ci-C6alk-C(0)-Ci-C6al kyl ; and R ⁸ , R ^8' , and R ⁹ have any of the values described above.

ICI164] In some as ects, the disclosure is directed to compounds of Formula IB-1

wherein R ¹ is -Ci-Cealk-aryl, and R ² is H or -Ci-Cealkyl. In some embodiments, the compounds of Formula IB-1 are those wherein R ¹ is -Ci-Cealk-aryl, and R ² is H. In other embodiments, the compounds of Formula IB-1 are those wherein R ¹ is -Ci-Cealk-aryl, and R ² is -Ci-Cealkyl.

|§165) Some embodiments of the compounds of Formula IB-1 are those wherein R ^! is -Ci - Cealk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro- 4-chlorophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3-methylphenyl, 2,4-difluorophenyl, 2- hydroxymethyl -4-chlorophenyl, 2-hydroxymethyl-5-chlorophenyl, 2-aminomethyl -4-chlorophenyl, 2-(methylaminomethyl)-4-chlorophenyl, 2-hydroxymethyl-4,5-difluorophenyl, 2-aminomethyl-4,5- diiluorophenyl, or 2-(methylaminomethyl)-4,5-difluorophenyl; and R ² is H or -Ci-Cealkyl,

In some embodiments, the compounds of Formula IB-1 are those wherein R ^! is - CH ₂ -difluorophenyl, -CH ₂ -3,4-difluorophenyl, -CH ₂ -4-chlorophenyl, -CH ₂ -3-c-hloro-4-fluorophenyl, -CH ₂ -4-chloro-3 -fluorophenyl, -CH ₂ -dichlorophenyl, -CH_-3,4-dichlorophenyl, -CH2-3-fluoro-4- (trifluoromethyl)phenyl, or -C¾-4-chloro-3-methylphenyl, -CH ₂ -2,4-difluorophenyl, -CHi-2- hydroxymethyl -4-chlorophenyl, -CH ₂ -2-aminomethyl -4-chlorophenyl, -CHb-2- (methylaminomethyl)-4-chlorophenyl, -CH ₂ -2-hydroxymethyl-4,5-difluorophenyl, -CH2-2- aminomethyl-4,5-difluorophenyl, -CH -2-(methylaminomethyl)-4,5-difluorophenyl, -CH(OH)-4- chlorophenyl, -CH(OH)-3,4-dichiorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4- chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3-fluoro-4-(trifluoromethyl)phenyl, or - CH(OH)-4-chloro-3-methylphenyl, -CH(OH)-2,4-difluorophenyl, -CH(OH)-2-hydroxymethyl-4- chlorophenyl, -CH(OFI)-2-aminomethyl-4-chlorophenyl, -CH(OH)-2-(methylaminomethyl)-4- chlorophenyl, -CH(OH -2-hydroxymethyl-4,5-difluorophenyl, -CH(OH)-2-aminomethyl-4,5- difluorophenyl, -CH(OH)-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(F)-4-chlorophenyl, - CH(F)-3,4-dichlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3- chloro-4-fluorophenyl, -CH(F)-3-fluoro-4-(trifluoromethyl)phenyl, -CH(F)-4-chloro-3- methylphenyl, -CH(F)-2,4-difluoropheny 1 , -CH(F)-2-hydroxymethy 1 -4-chl oropheny 1 , -CH(F)-2- aminomethyl-4-chlorophenyl, -CH(F)-2-(methylaminomethyl)-4-chlorophenyl, -CH(F)-2- hydroxymethyl-4,5-difluorophenyl, -CH(F)-2-aminomethyl-4,5-difluorophenyl, -CH(F)-2- (methylaminomethyl)-4, 5-difluorophenyl , -CH(NFI ₂ )-4-chlorophenyl, -CH(NH ₂ )-3 ,4- di chlorophenyl, -CH(NH ₂ )-3 ,4-difluorophenyl , -CH(NFi ₂ )-3 -fluoro-4-chl oropheny 1 , -CH(NH ₂ )-3 - chloro-4-fluorophenyl, -CH(NH ₂ )-3-fluoro-4-(trifluoromethyl)phenyl, or -CH(NH ₂ )-4-chloro-3- methylphenyl, -CH(NH ₂ )-2,4-difluorophenyl, -CH(NFi ₂ )-2-hydroxyniethyl-4-chlorophenyl, - CH(NH ₂ )-2-aminomethyl-4-chlorophenyl, -CH(NH2)-2-(methylaminomethyl)-4-chl oropheny), - CH(NH2)-2-hydroxymethyl-4,5-difluorophenyl, -CHCNH ₂ )-2-aminomethyl-4,5-difluorophenyl, - CH(NH ₂ )-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(Me)-4-chlorophenyl, -CH(Me)-3,4- di chlorophenyl, -CH(Me)-3 ,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3- chloro-4-fluorophenyl, -CH(Me)-3-fluoro-4-(trifluoromethyl)phenyl, -CH(Me)-4-chloro-3- methylphenyl, -CH(Me)-2,4-difluorophenyl, -CH(Me)-2-hydroxymethyl -4-chl orophenyl, -CH(Me)- 2-aminomethyl-4-chlorophenyl, -CH(Me)-2-(methylaminomethyl)-4-chlorophenyl, -CH(Me)-2- hydroxymethyl-4,5-difluorophenyl, -CH(Me)-2-aminomethyl-4,5-difluorophenyl, -CH(Me)-2- (methylaminomethyl)-4,5-difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4- dichl orophenyl, -C(Me)(OH)-3 ,4-di fluorophenyl, -C(Me)(OH)-3 -fluoro-4-chl orophenyl, - C(Me)(OH)-3-chloro-4-fluorophenyl, -C(Me)(OH)-3-fluoro-4-(trifluoromethyl)phenyl, - C(Me)(OH)-4-chloro-3-rnethylphenyl, -C(Me)(OH)-2,4-difluorophenyl, -C(Me)(OH)-2- hydroxymefhyl-4-chl orophenyl, -C(Me)(OFI)-2-aminomethyl-4-chl orophenyl , -C(Me)(OH)-2- (methylaminomethyl)-4-chl orophenyl, -C(Me)(OH)-2-hydroxymethyl-4,5-difluorophenyl, - C Me)(OH)-2-aminomethyl-4,5-difluorophenyl, -C(Me)(OH)-2-(methylaminomethyl)-4,5- difluorophenyl, -C(CF ₃ )(OH)-4-chlorophenyl, -C(CF3)(OH)-3,4-dichlorophenyL -C(CF3j(OH)-3,4- di fluorophenyl, -C(CF3)(OH)-3-fluoro-4-chl orophenyl, -C(CF ₃ )(OH)-3-chloro-4-fluorophenyl, - C(CF ₃ )(OH)-3 -fluoro-4-(trifluoromethyl)phenyl, or -C(CF ₃ )(OH)-4-cMoro-3 -methylphenyl, - C(CF3)(OH)-2,4-difluorophenyl, -C(CF3)(OH)-2-hydroxymethyl-4-chlorophenyl, -C(CF ₃ )(OH)-2- aminomethyl-4-chl orophenyl, -C(CF ₃ )(OFI)-2-(niethylaminomethyl)-4-chl orophenyl, -C(CF ₃ )(OH)- 2- hydroxymethyl-4,5-difluorophenyl, -C(CF ₃ )(OH)-2-aminomethyl-4,5-difluorophenyl, - C(CF3)(OH)-2-(methylaminomethyl)-4,5-difluorophenyl; and R ² is H or -Ci-Cealkyl.

In some preferred embodiments, compounds of Formula IB-1 are those wherein R ^f is -CH(OH)-4-cMorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-

3- fluoro-4-chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3-fluoro-4- (trifluoromethyl)phenyl, -CH(OH)-4-chloro-3-methylphenyl, -C(CF ₃ )(OH)-4-chlorophenyl; and R ² is H or -Ci-Cealkyl . In other preferred embodiments, compounds of Formula IB-1 are those wherein R ^! is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, - CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3-fluoro-4- (trifluoromethyl)phenyl, -CH(OH)-4-chloro-3 -methyl phenyl , -C(CF ₃ )(OH)-4-chlorophenyl ; and R ² is H or methyl. In yet other preferred embodiments, compounds of Formula IB-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, or -CH(OH)-3-chloro-4- fluorophenyl, and R ² is H or methyl.

£0168] In some as ects, the disclosure is directed to compounds of Formula IIIA

wherein R ¹ is -Ci-Cealk-aryl, and R ² is H or -Ci-Cealkyl. In some embodiments, the compounds of Formula IIIA are those wherein R ¹ is -Ci-Ceafk-aryl, and R ² is H. In other embodiments, the compounds of Formula IIIA are those wherein R ¹ is -Ci-Cealk-aryl, and R ² is -Ci-Cealkyl.

£0169] Some embodiments of the compounds of Formula IIIA are those wherein R ¹ is -Ci- C ₆ alk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro- 4-chlorophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3-methylphenyl, 2,4-difluorophenyl, 2- hydroxymethyl -4-chlorophenyl, 2-hydroxymethyl-5-chlorophenyl, 2-aminomethyl -4-chlorophenyl, 2-(methylaminomethyl)-4-chlorophenyl, 2-hydroxymethyl-4,5-difluorophenyl, 2-aminomethyl-4,5- difluorophenyl, or 2-(methylaminomethyl)-4,5-difluorophenyl; and R ² is H or -Ci-Cea!ky!,

|¾170| In some embodiments, the compounds of Formula IIIA are those wherein R ¹ is - CH ₂ -difluorophenyl, -CH ₂ -3,4-difluorophenyl, -CH ₂ -4-chlorophenyl, -CH ₂ -3-c-hloro-4-fluorophenyl, -CH ₂ -4-chloro-3 -fluorophenyl, -CH ₂ -dichlorophenyl, -CH2-3,4-dichiorophenyl, -CH2-3-fluoro-4- (trifluoromethyl)phenyl, or -CH ₂ -4-chloro-3-methylphenyl, -CH ₂ -2,4-difluorophenyl, -CH ₂ -2- hydroxymethyl-4-chlorophenyl, -CH ₂ -2-aminomethyl-4-chlorophenyl, -CHb-2- (methylaminomethyl)-4-chlorophenyl, -C¾-2-hydroxymethyl-4,5-difluorophenyl, -CFk-2- aminomethyl-4,5-difluorophenyl, -CH2-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(OH)-4- chlorophenyi, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4- chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3-fluoro-4-(trifluoromethyl)phenyl, or CH(OH)-4-chloro-3-methylphenyl, -CH(OH)-2,4-difluorophenyl, -CH(OH)-2-hydroxymethyl-4- chlorophenyl, -CH(OH)-2-aminomethyl-4-c-hlorophenyl, -CH(OH)-2-(methylaminomethyl)-4- chlorophenyl, -CH(OH)-2-hydroxymethyl-4,5-difluorophenyl, -CH(OH)-2-aminomethyl-4,5- difluorophenyl, -CH(OH)-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(F)-4-chlorophenyl, - CH(F)-3,4-dichlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3- chloro-4-fluorophenyl, -CH(F)-3-fluoro-4-(trifluoromethyl)phenyl, -CH(F)-4-chloro-3- methylphenyl, -CH(F)-2,4-difluorophenyl, -CH(F)-2-hydroxymethyl-4-chlorophenyl, -CI 1(F)~2- aminomethyl-4-chlorophenyl, -CH(F)-2-(methylaminomethyl)-4-chlorophenyl, -CH(F)-2- hydroxymethyl-4,5-difluorophenyl, -CH(F)-2-aminomethyl-4,5-difluorophenyl, -CH(F)-2- (methylaminomethyl)-4, 5-difluorophenyl , -CH(NFI ₂ )-4-chlorophenyl, -CH(NH ₂ )-3 ,4- dichlorophenyl,•(Ί !{\ 1 ! -)· ,4-difluorophenyl, -CH(NH ₂ )-3 -fluoro-4-chlorophenyl, -CH(NH ₂ )-3 - chloro-4-fluorophenyl, -CH(NH ₂ )-3-fluoro-4-(trifluoromethyl)phenyl, or -CH(NH ₂ )-4-chloro-3- methylphenyl, -CH(NH ₂ )-2,4-difluorophenyl, -CH(NFi ₂ )-2-hydroxymethyl-4-chlorophenyl, - CH(NH2)-2-aminomethyl-4-chlorophenyl, -CH(NH2)-2-(methylaminomethyl)-4-chlorophenyl, - CH( H?)-2-hydroxymethyl-4,5-difluorophenyl, -CHCNH ₂ )-2-aminomethyl-4,5-difluorophenyl, - CH(NH ₂ )-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(Me)-4-chlorophenyl, -CH(Me)-3,4- di chlorophenvl, -CH(Me)-3 ,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3- chloro-4-fluorophenyl, -CH(Me)-3-fluoro-4-(trifluoromethyl)phenyl, -CH(Me)-4-chloro-3- methylphenyl, -CH(Me)-2,4-difluorophenyl, -CH(Me)-2-hydroxymethyl-4-chlorophenyl, -CH(Me) 2-aminomethyl-4-chlorophenyl, -CH(Me)-2-(methylaminomethyl)-4-chlorophenyl, -CH(Me)-2- hydroxymethyl-4,5-difluorophenyl, -CH(Me)-2-aminomethyl-4,5-difluorophenyl, -CFI(Me)-2- (methylaminomethyl)-4,5-difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4- dichl orophenyl, -C(Me)(OH)-3 ,4-di fluorophenyl, -C(Me)(OH)-3 -fluoro-4-chl orophenyl, - C(Me)(OH)-3 -chloro-4-fluorophenyl , -C(Me)(OH)-3 -fluoro-4-(trifluoromethyl)phenyl, - C(Me)(OH)-4-cMoro-3-methylphenyl, -C(Me)(OH)-2,4-difluorophenyl, -C(Me)(OH)-2- hydroxymethyl-4-chlorophenyl, -C(Me)(OH)-2-aminomethyl-4-chlorophenyl, -C(Me)(OH)-2- (methylaminomethyl)-4-chlorophenyl, -C(Me)(OH)-2-hydroxymethyl-4,5-difluorophenyl, - C(Me)(OH)-2-aminomethyl-4,5-difluorophenyl, -C(Me)(OH)-2-(methylaminomethyl)-4,5- difluoropheny 1 , -C(CF ₃ )(OH)-4-chlorophenyl, -C(CF ₃ )(OH)-3 ,4-di chloropheny 1 , -C(CF ₃ )(OH)-3 ,4- difluorophenyl, -C(CF3)(OH)-3-fluoro-4-chlorophenyl, -C(CF3)(OH)-3-chloro-4-fluorophenyl, - C(CF ₃ )(OH)-3-fluoro-4-(trifluoromethyl)phenyl, or -C(CF ₃ )(OH)-4-chloro-3-methylphenyl, - C(CF ₃ )(OH)-2,4-difluorophenyl, -C(CF ₃ )(OH)-2-hydroxymethyl-4-cMorophenyl, -C(CF ₃ )(OH)-2- aminomethyl-4-chlorophenyl, -C(CF ₃ )(OH)-2-(methylaminomethyl)-4-chlorophenyl, -C(CF ₃ )(OH)-

2- hydroxymethyl-4,5-difluorophenyl, -C(CF ₃ )(OH)-2-aminomethyl-4,5-difluorophenyl, - C(CF3)(OH)-2-(methylaminomethyl)-4,5-difluorophenyl; and R ² is H or -Ci-Cealkyl.

fl!71 j In some preferred embodiments, compounds of Formula ΠΙΑ are those wherein R ¹ is -CH(OH)-4-cMorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-

3- fluoro-4-chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3-fluoro-4- (trifluoromethyl)phenyl, -CH(OH)-4-chloro-3-methylphenyl, -C(CF ₃ )(OH)-4-chlorophenyl; and R ² is H or -Ci-Cealkyl. In other preferred embodiments, compounds of Formula IIIA are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, - CH(OH)-3 -fluoro-4-cMorophenyl, -CH(OH)-3 -cMoro-4-fluorophenyl, -CH(OH)-3 -fluoro-4- (trifluoromethyl)phenyl, -CH(OH)-4-chloro-3 -methyl phenyl , -C(CF ₃ )(OH)-4-chlorophenyl ; and R ² is H or methyl.

| l.72| In some as ects, the disclosure is directed to compounds of Formula IA-1

wherein R ^f is -Co-Cealk-C-C-Ci-Cealkyl, -Co-Cealk-C-C-Cs- Cecycloalkyl, or -Ci-Cealk-aryl; and R ² is H or -Ct-Cealkyl. In some embodiments, the compounds of Formula IA-1 are those wherein R ¹ is and R ² is H or -Ci-Cealkyl. In some embodiments, the compounds of Formula IA-1 are those wherein R ¹ is -Co-C6alk-C≡C-Ci- Cehaloaikyi, and R ² is H or -Ci-Cealkyl. In some embodiments, the compounds of Formula IA-1 are those wherein R ¹ is -Co-C6alk-C≡C-C3-C6cycloalkyl, and R ² is H or -Ci-Cealkyl.

[Θ173] In some embodiments, the compounds of Formula IA-1 are those wherein R ¹ is -Ci- ( ^' •-.alk-aryl. and R ² is H. In other embodiments, the compounds of Formula IA-1 are those wherein R ¹ is -Ci-Cealk-aryl, and R ² is -Ci-Cealkyl.

|il74J In some aspects, the disclosure is directed to compounds of formula IV- A

wherein R ¹ is -Ci-Cealk-aryl, and R ⁷ is halo, -d-Ohaloalkyl, -C ₃ -C6cycloalkyl, -C ₂ -C ₄ alkenyl, -Ci- Ceal k-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C6alkyl, -Ci-Ceaik-NrCi-Cealkyl)]! ⁸ , -Ci-Cealk-S-Ci- Cealkyl, -NH-Ci-Cealk-S-Ci-Cealkyl, · N 1 1-C ; ··( V-ai k-S(() ) ( ^' i -CY.ai ky L -NHCR ^S R ^8' CN, - NHCONR ⁸ R ^8' , -NHC(S)NR ⁸ R ^8' , -NHC(0)OR ⁹ , -NHC(S)OR ⁹ , -NHC(0)-Ci-C ₆ alkyl, -NH-Ci- C6alk-C(0)-Ci-C6aikyi, or -N-(3-Ci-C6aikyi)imidazoiidin-2-one.

[0175] In other embodiments, the compounds of Formula IV- A are those wherein R ¹ is - Ci-Cealk-aryl, and R' is halo, -Ci-C4haloalkyl, -Cs-Cecycloaikyi, -C ₂ -C ₄ alkenyl, -Ci-Cealk-O-Ci- Cealkyl, -Ci-C6alk-C(0)-Ci-C ₆ alkyl, -Ci~C6aik-N(C]~C6alkyl)R ⁸ , -Ci-Cealk-S-Ci-Cealkyl, -NH-Ci- Cealk-S-Ci-Cealkyl, - H-Ci-C6alk-S(0)2-Ci-C6alkyl, - HCR ⁸ R ^' CN, -NHCONR ⁸ R ^8' , - HC(S)NR ⁸ R ^8' , - HC(0)OR ⁹ , - HC(S)OR ⁹ , - HC(0)-Ci-C6aikyi, - H-Ci-C ₆ alk-C(0)-Ci- Cealky], or -N-(3-Ci-C6al ky])imidazolidir!-2-one.

[0176] Some embodiments of the compounds of Formula IV- A are those wherein R ¹ is - Ci-Cealk-aryl wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3- fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-chloro-3- methylphenyl, 3 -fluoro-4-(trifluoromethyl)phenyl , 4-chl oro-3 -methylphenyl , 2,4-difluoropheny 1, 2- hydroxymethyl -4-chlorophenyl, 2-aminomethyl -4-chlorophenyl, 2-(methylaminomethyl)-4- chlorophenyi, 2-hydroxymethyl-4,5-difluorophenyl, 2-aminomethyl-4,5-difluorophenyl, or 2- (methylaminomethyl)-4,5-difluorophenyl; and R ⁷ is halo, -Ci-Cihaloalkyl, -C -Cecycloalkyl, -C ₂ - C4alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-C6alk-C(0)-Ci-C6alkyl, -Ci-C6alk-N(Ci-C6alkyl)R ⁸ , -Ci- Ceal k-S-Ci-Cealkyl, -NH-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C6alk-S(0)2-Ci-C6alkyl, -NI-ICR ⁸ R ^8' C ,

8 -NHCONR ⁸ R ^8' , -NHC(S)NR ⁸ R ^8' , -NHC(0)OR ⁹ , -NHC(S)OR ⁹ , -NHC(0)-Ci-C6alkyl, -NH-Ci- C6alk-C(0)-Ci-C6alkyl, or -N-(3-Ci-C6alkyl)imidazolidin-2-one.

).t77| Thus in some embodiments, the compounds of Formula IV- A are those wherein R is -CHb-difluorophenyl, -CH?~3,4~difluorophenyl, -CH?-4-chlorophenyl, -CH ₂ -3-chloro-4- fl uorophenyl , -CH ₂ -4-chl oro-3 -fluorophenyl , -CFb-di chloropheny 1 , -CH ₂ -3 ,4-dichlorophenyl, -CH ₂ 3-fluoro-4-(trifluoromethyl)phenyl, or -CH ₂ -4-chloro-3-methylphenyl, -CH2-2,4-difluorophenyl, - C¾-2-hydroxymethyl-4-chlorophenyl, -CH ₂ -2-aminomethyl-4-chlorophenyl, -Clh-2- (methylaminomethyl)-4-chlorophenyl, -CH ₂ -2-hydroxymethyl-4,5-difluorophenyl, -CH ₂ -2- aminomethyl-4,5-difluorophenyl, -CFI ₂ -2-(methylaminomethyl)-4,5-difluorophenyl, -CFI(OFI)-4- chlorophenyl, -CH(OH)-3 ,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4- chlorophenyl, -CH(OH)-3 -chloro-4-fluorophenyl, -CH(OH)~3 -fluoro-4-(trifluoromethyl)phenyl, or CH(OH)-4-chl oro-3 -methyl phenyl, -CH(OH)-2,4-difluorophenyl, -CH(OH)-2-hydroxymethyl-4- chlorophenyl, -CH(OH)-2-aminomethyl-4-chlorophenyl, -CH(OH)-2-(methylaminomethyl)-4- chlorophenyl, -CH(OFI)-2-hydroxymethyl-4,5-difluorophenyl, -CH(OH)-2-aminomethyl-4,5- difluorophenyl, -CH(OH)-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(F)-4-chlorophenyl, - CH(F)-3 ,4-dichlorophenyl, -CH(F)-3 ,4-difluoropheny 1, -CH(F)-3 -fluoro-4-chlorophenyl, -CH(F)-3 ^■ chloro-4-fluorophenyl, -CH(F)-3-fluoro-4-(trifluoromethyl)phenyl, -CH(F)-4-chl oro-3 - methylphenyl, -CH(F)-2,4-difluorophenyl, -CH(F)-2-hydroxymethyl-4-chlorophenyl, -CH(F)-2- aminomethyl-4-chlorophenyl, -CH(F)-2-(methylaminomethyl)-4-chlorophenyl, -CH(F)-2- hydroxymethyl-4,5-difluorophenyl, -CH(F)-2-aminomethyl-4,5-difluorophenyl, -CH(F)-2- (methylaminomethyl)-4,5-difluorophenyl, -CH{NH ₂ )-4-chlorophenyl, -CH(NH ₂ )-3 ,4- dichlorophenyl, -CH( H ₂ )-3,4-difluorophenyL -CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH ₂ )-3- chloro-4-fluorophenyl, -CH(NH ₂ )-3-fluoro-4-(trifluoromethyl)phenyl, or -CH(NH ₂ )-4-chloro-3- methylphenyl, -CH(NH ₂ )-2,4-difluorophenyl, -CH(NH ₂ )-2-hydroxymethyl-4-chl orophenyi, - CH(NH2)-2~aminomethyl~4-chlorophenyl, -CH(NH ₂ )-2-(methylaminomethyl)-4-chl orophenyi, - CH(NH2)-2-hydroxymethyl-4,5-difluorophenyl, -CH(NFI ₂ )-2-aminomethyl-4,5-difluorophenyl, - CH( H?)-2-(methylaminomethyl)-4,5-difluorophenyl, -CH(Me)-4-chlorophenyl, -CH(Me)-3 ,4- dichlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3- chloro-4-fluorophenyl, -CH(Me)-3 -fluoro-4-(trifluoromethyl)phenyl, -CH(Me)-4-chl oro-3 - methylphenyl, -CH(Me)-2,4-difluorophenyl, -CH(Me)-2-hydroxymethyl-4-chl orophenyi, -CH(Me) 2-aminomethyl-4-chlorophenyl, -CH(Me)-2-(methylaminomethyl)-4-chl orophenyi, -CH(Me)-2- hydroxymethyl-4,5-difluorophenyl, -CH(Me)-2-aminomethyl-4,5-difluorophenyl, -CH(Me)-2- (methylaminomethyl)-4,5-difluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3 ,4- di chl orophenyl, -C(Me)(OH)-3 ,4-di fluorophenyl, -C(Me)(OH)-3 -fluoro-4-chl orophenyl, - C(Me)(OH)-3-chloro-4-fluorophenyl, -C(Me)(OH)-3-fluoro-4-(trifluoromethyl)phenyl, - C(Me)(OH)-4-chloro-3-methylphenyl, -C(Me)(OH)-2,4-difluorophenyl, -C(Me)(OH)-2- hydroxymethyl-4-chl orophenyl, -C(Me)(OH)-2-aminomethyl-4-chl orophenyl, -C(Me)(OH -2- (methylaminomethyl)-4-chl orophenyl, -C(Me)(OH)-2-hydroxymethyl-4,5-difluorophenyl, - C Me)(OH)-2-aminomethyl-4,5-difluorophenyl, -C(Me)(OH)-2-(methylaminomethyl)-4,5- difluorophenyl, -C(CF3)(OH)-4-chlorophenyl, -C(CF ₃ )(OH)-3,4-dichlorophenyl, -C(CF3)(OH)-3,4- di fluorophenyl, -C(CF ₃ )(OH)-3-fluoro-4-chl orophenyl, -C(CF ₃ )(OH)-3-chloro-4-fluorophenyl, - C(CF3)(OH)-3-fluoro-4-(trifluoromethyl)phenyl, or -C(CF ₃ )(OH)-4-cMoro-3 -methylphenyl, - C(CF3)(OH)-2,4-difluorophenyl, -C(CF ₃ )(OH)-2-hydroxymethyl-4-chlorophenyl, -C(CF ₃ )(OH)-2- aminomethyl-4-chlorophenyl, -C(CF ₃ )(OH)-2-(methylaminomethyl)-4-chlorophenyl, -C(CF ₃ )(OH)-

2- hydroxymethyl-4,5-difluorophenyl, -C(CF ₃ )(OFI)-2-aminomethyl-4,5-difluorophenyl, - C(CF ₃ )(OH)-2-(methylaminomethyl)-4,5-difluorophenyl; and R ^; is halo, -Ci-C4haloaikyi, -C ₃ - Cecycloalkyl, -C ₂ -C ₄ alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-C ₆ alk-C(0)-Ci-C6alkyl, -Ci-C ₆ alk-N(Ci- C&alkyl)R ⁸ , -Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C ₆ alk-S(0)2-Ci-C6alkyl, - NHCR ⁸ R ^8' C , -NHCONR ⁸ R ^8' , - HC(S) R ⁸ R ^8' , - HC(0)OR ⁹ , -NHC(S)OR ⁹ , -NHC(0)-Ci- Cealkyl, -NH-Ci-C6al k-C(0)-Ci-C6alkyl, o -N-(3-Ci-C6alkyl)irr!idazolidin-2-one.

0178] In some preferred embodiments, compounds of Formula IV- A are those wherein R ¹ is -CH(OH)-4-chl orophenyl, -CH(OH)-3,4-dichlorophenyl , -CH(OH)-3,4-difluorophenyl, -CH(OH)-

3- fluoro-4-chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3-fluoro-4- (trifluoromethy Ijphenyl, -CH(OH)-4-chloro-3 -methylphenyl, -C(CF ₃ )(OH)-4-chl orophenyl ; and R ' is -halo, -C --C4haloalkyl, -Cs-Cecycloaikyi, -C ₂ -C ₄ alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Cealk- C(0)-Ci-C6alkyl, -Ci-C6alk-N(Ci-C6alkyl)R ⁸ , -Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-Cealk-S-Ci-Cealkyl, -NH-Ci-C ₆ alk-S(0)2-Ci-C6alkyi, -NHCR^ ^' CN, -NHCONR ⁸ R ^8' , -NHC(S)NR ⁸ R ^8' , - HC(0)OR ⁹ , - HC(S)OR ⁹ , - HC(0)-Ci-C6alkyl, -NH-C]-C6alk-C(0)-Ci-C ₆ alkyl, or -N-(3-Ci- C6alkyl)imidazolidin-2-one.

{ ^' 8179] Some particularly preferred embodiments of the compounds of Formula IV- A are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichl orophenyl, -CH(OH)-3,4- difluorophenyl, -CH(OH)-3-fluoro-4-chl orophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-3- fluoro-4-(trifluoromethyl)phenyl, or -CH(OH)-4-chloro-3-methylphenyl; and R ⁷ is -CI, -CH2CH2CI, cyclopropyl, vinyl, -CH2CH2-O-CH3, ~CH ₂ CH ₂ -C(0)-CH3, -Π W! I '-NCC! Ι ψ, -CH2CH2-S-CH3, - H-CH2CH2-S-CH3, -NH-CH ₂ CH2-S(0)2-CH3, -NHCH2CN, -X! ! ⁽ 0\{( ! ! ^; ) ^■ . - HCONH2, - HC(S)N(CH3)2, - HC(S)NH(CH3), -NHC(0)OCH ₃ , -NHC(S)OCH3 , - \ ! ί( ^" (())·( ^" ί h. - H-CH2-

|U 8 ] Other particularly preferred embodiments of the compounds of Formula IV- A are those wherein R ¹ is -CH(OH)-4-chlorophenyl, and R ⁷ is -CI, -CH2CH2CI, cyclopropyl, vinyl, - CH2CH2-O-CH3, -CH ₂ CH ₂ -C(0)-CH3, -CH ₂ CH2-N(CH ₃ ) ₂ , -CH2CH2-S-CH3, -NH-CH2CH2-S-CH3, -NH-CH2Ce2-S(())2-CH3, -NHCH2CN, -NHCON(CH ₃ ) ₂ , -NHCO H2, -NHC(S)N(CH ₃ )2, - HC(S)NH(C¾), - HC(0)OCH3, -M !C ( S )OCl h , -NHC(0)-CH ₃ , -NH-CH2-C(0)-CH ₃ ,

In some aspects, the disclosure is directed to compounds of formula IIB

wherein R ^f is -Ci-Cealk-aryl wherein the aryl is (hydroxymethyl)chlorophenyl,

(hydroxymethyl)fluorophenyl, (hydroxymethyl)difluorophenyl, (hydroxymethyl)dichlorophenyl, (aminomethyl)chlorophenyl, (aminomethyl)fluorophenyl, (aminomethyl)difluorophenyl,

(aminomethyl)dichlorophenyl, (methylaminomethyl)chlorophenyl,

(methylaminomethyl)fluorophenyl, (methylaminomethyl)difluorophenyl,

(methylaminomethyl)dichlorophenyl; and R is -NR ⁸ R ⁸ or -Ci-Cealkyl; and R ⁸ and R ⁸ are independently H or Ci-Cealkyl.

I82| In some embodiments, the compounds of Formula ΠΒ-2 are those wherein R ¹ is - CH(OH)-2-hydroxymethyl-4-c-hlorophenyl, -CH(OH)-2-hydroxymethyl-5-chlorophenyl, -CH(OH)- 2-aminomethyl-4-chlorophenyl, -CH(OH)-2-(methylaminomethyl)-4-chlorophenyl, -CH(OH)-2- (methylaminomethyl)-5-chlorophenyl, -CH(OH)-2-hydroxymethyl-4,5-difluorophenyl, -CH(OH)-2- aminomethyl-4,5-difluorophenyl, -CH(OH)-2-(methylaminomethyl)-4,5-difluorophenyl , and R ' is NH ₂ or methyl.

|CI183] Preferred embodiments of the compounds of Formula IIB-2 are those wherein R ¹ is -CH(OH)-2-hydroxymethyl-4-chlorophenyl, -CH(OFf)-2-hydroxymethyl-5-chlorophenyl, -CH(OH)- 2-hydroxymethyl-4,5-difluorophenyl, -CH(OH)-2-aminomethyl-4,5-difluorophenyl, -CH(OH)-2- (methylaminomethyl)-4,5-difluorophenyl; and R ⁷ is NH ₂ or methyl.

|0184] References to Formula I, Formula II, Formula III, or Formula IV herein include all subgenera described herein, including, for example, IA-1, EB-1, IIA-1, IIB-1, IIB-2, IIIA, and IV- 1.

|ll8Sj Stereoisomers of compounds of Formula I, Formula II, Formula III, or Formula IV are also contemplated and encompassed by the disclosure.

01 6 Pharmaceutically acceptable salts and solvates of the compounds of Formula I, Formula II, Formula III, or Formula IV are also within the scope of the disclosure.

101.87] Isotopic variants of the compounds of Formula I, Formula II, Formula III, or Formula IV are also contemplated and encompassed by the present disclosure.

Pharmaceutical compositions and methods of administration 0188 _. 1 The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

W89| The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

|li90| In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0,9%, 0,8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0,2%, 0, 1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0,002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0,0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w/w, w/v or v/v.

.191| In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18,75%, 18.50%, 18.25% 18%, 17,75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16,25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 1 1 .50%, 11 ,25% 1 1%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4,25%, 4%, 3.75%, 3,50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25% , 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0, 1 %, 0,09%, 0.08%, 0.07%, 0,06%, 0.05%, 0.04%, 0.03%, 0,02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w/w, w/v, or v/v.

{ ^' 8192] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001 % to approximately 40%, approximately 0.01 % to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0,3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/ ^' v.

(0193 j In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0,02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2,5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately !%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

.l.94| In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 _, 3.5 g, 3.0 g, 2.5 g, 2,0 g, 1 .5 g, 1.0 g, 0,95 g, 0.9 g, 0.85 g, 0,8 g, 0,75 g, 0.7 g, 0,65 g, 0.6 g, 0.55 g 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0,01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0,004 g, 0,003 g, 0,002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 (or a number in the range defined by and including any two numbers above).

|W95) In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 0.03 g, 0,035 g, 0,04 g, 0.045 g, 0.05 g, 0.055 g, 0,06 g, 0,065 g, 0,07 g, 0.075 g, 0.08 g, 0,085 g, 0.09 g, 0.095 g, 0.1 g, , 0.15 g, 0.2 g, , 0.25 g, 0.3 g, , 0.35 g, 0.4 g, , 0.45 g, 0.5 g, 0.55 g, 0.6 g, , 0.65 g, 0.7 g, 0,75 g, 0,8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1 .5 g, 2 g, 2,5, 3 g, 3 ,5, 4 g, 4,5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above).

In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1- 3 g-

|M97| The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplar}' dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. fll j A pharmaceutical composition of the invention typically contains an active ingredient (i.e., a compound of the disclosure) of the present invention or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

.199| Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same.

Pharmaceutical compositions for oral administration.

620 ] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.

{82QJ ] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention, optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

{ ^' 8202] In some embodiments, the pharmaceutical composition may be a liquid

pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or nonaqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but ail methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

{8203) This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

{ΙΙ2Θ4) An active ingredient can be combined in an intimate admixture with a

pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and

disi tegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

ICI205) Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrol idone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

|O206] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

|β207] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form

pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar- agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacriiin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[0208] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oi l, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryi sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

|β209] When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

{Θ2Ϊ 0) The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0211] Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0212] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophi lic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hvdrophobicitv of non-ionic amphophi lic compounds is the hy drophili c-lipophili c balance (" HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

[Θ213] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i .e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

|l2i4| Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins, lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts, sodium docusate, acyl lactylates, mono- and di- acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[Θ215] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, iysoiecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts, sodium docusate, acylactylates; mono- and di- acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[02.16] Ionic surfactants may be the ionized forms of lecithin, Iysoiecithin,

phosphatidylcholine, phosphatidyl ethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidyl serine, lysophosphatidyl choline, lysophosphatidylethanolamine,

lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, iactylic esters of fatty acids, stearoyl-2- lactylate, stearoyl lactyiate, succinylated monoglycerides, niono/diacetyiated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, iaurate, myri state, palmitate, oieate, ricinoieate, iinoleate, iinolenate, stearate, iauiyl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof. {ίίΐί 7] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alky! ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids raonoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterifi cation products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; poiyoxy ethylene sterols, derivatives, and analogues thereof, polyoxyethylated vitamins and derivatives thereof; polyoxy ethyl ene- poiyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

2I.S] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 iaurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oieate, PEG- 15 oieate, PEG-20 oieate, PEG-20 dioieate, PEG-32 oieate, PEG-200 oieate, PEG-400 oieate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioieate, PEG-20 glyceryl laurate, PEG-30 glyceryl iaurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oieate, PEG-30 glyceryl oieate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG- 35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyeeryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oieate, PEG-80 sorbitan laurate, poiysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers. ίΙ219| Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetyiated glycerol fatty acid esters; lower alcohol fatty acids esters;

propylene glycol fatty acid esters, sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxvethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil- soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

|122§j In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[8221] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitoi, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methyicelluiose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkyicaprolactam,

dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl tri ethyl citrate, acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caproiactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubiiizers known in the art, such as dimethyl acetamide, dimethyl isosorhide, N-methyl pyrrolidones, monooctanoin, di ethylene glycol monoethyl ether, and water.

)222| Mixtures of solubiiizers may also be used. Examples include, but not limited to, triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N- hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcel lulose, hy droxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubiiizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

18223] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily- determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubiiizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.

16224] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, am - foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

16 25] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethyl amine, ethanol amine, eth yl en edi amine, triethanoiamine, triethyiamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, aiginic acid, alkanesultonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfomc acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

j 02261 Suitable acids are pharmaceutically acceptable organic or inorganic acids.

Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, aiginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfomc acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toiuenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical compositions for injection.

|CI227] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

| ^' Θ228] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

| 229| Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chJo obutanol, phenol, sorbic acid, thimerosal, and the like.

{Θ230] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Pharmaceutical compositions for topical (e.g. transdermal) delivery.

23 i] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

|0232] Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

}0233j The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation. |0234] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanoi), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl my ri state and sodium lauryl sulfate), pyrrol idones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

|i235| Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.

I&236] The construction and use of transdermal patches for the deliver}' of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001 ,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Pharmaceutical compositions for inhalation.

}023?j Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

Other pharmaceutical compositions.

|023S] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Dnig Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed,, Basic and Clinical Pharmacology, Ninth Edition, McGraw Hili, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill , 2001 , Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

||239| Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

{Θ240) The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.

{824J ] In some embodiments, a compound of the invention is administered in a single dose.

jl242j Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition.

I&243J In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

fl244] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

|124Sj An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant,

jl24?V| The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wail which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent.

Polymeric matrices suitable for such use, include, for example, laetone-based polyesters or copolyesters such as polyiactide, poiycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO- PLLA); poiydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip/ spin coating, spray coating, dip-coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravasculariy from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via adventiai application of formulations of the invention may also be performed to decrease restenosis.

fl24?J A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5451233; U.S. Pat. No. 5040548, U.S. Pat. No. 5061273; U.S. Pat. No. 5496346; U.S. Pat. No. 5292331; U.S. Pat. No. 5674278; U.S. Pat. No. 3657744; U.S. Pat. No. 4739762; U.S. Pat. No. 5195984, U.S. Pat. No. 5292331 ; U.S. Pat. No. 5674278, U.S. Pat. No. 5879382; U.S. Pat. No. 6344053.

|CI248] The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.

[8249] When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly.

j¾250] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The

pharmaceutical composition may he in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

|i2Sl| Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

Methods of Use

252J The method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention. The therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

|0253] As used herein, the term "IC50" refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, ceil receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50). EC50 refers to the plasma concentration required for obtaining 50%> of a maximum effect in vivo.

2S4] In some embodiments, the subject methods utilize a PRMT5 inhibitor with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro assay. In some embodiments, the PRMT5 inhibitor inhibits PRMT5 a with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM. or less, 40 nM or less. 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 n : or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 ίΛ4 or less, 550 nM or less, 600 n : or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM: or less, 850 nM or less, 900 nM: or less, 950 nM or less, 1 μΜ or less, 1.1 μΜ or less, 1.2 μΜ or less, 1.3 μΜ or less, 1.4 μΜ or less, 1.5 μΜ or less, 1.6 μΜ or less, 1.7 uM or less, 1.8 μΜ or less, .9 μ.Μ or less, 2 μΜ or less, 5 μΜ or less, 0 μΜ or less, 15 μΜ or less, 20 μΜ or less, 25 μΜ or less, 30 μΜ or less, 40 μΜ or less, 50 uM, 60 μΜ, 70 μΜ, 80 μΜ, 90 μΜ, 100 μΜ, 200 μΜ, 300 μΜ, 400 μΜ, or 500 μΜ, or less, (or a number in the range defined by and including any two numbers above).

| 255| In some embodiments, the PRMTS inhibitor selectively inhibits PRMT5 a with an IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in the range defined by and including any two numbers abovejthan its IC50 value against one, two, or three other PRMTs.

2S6] In some embodiments, the PRMTS inhibitor selectively inhibits PRMT5 a with an IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM:, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 μΜ, 1.1 μΜ, 1 .2 μΜ, 1 ,3 μΜ, 1.4 μΜ, 1.5 μΜ, 1.6 μΜ, 1 .7 μΜ, 1.8 μ\1, 1.9 μΜ, 2 μΜ, 5 μΜ, 10 μΜ, 15 μΜ, 20 μΜ, 25 μΜ, 30 μΜ, 40 μΜ, 50 μΜ, 60 μΜ, 70 μΜ, 80 μΜ, 90 μΜ, 100 μΜ 200 μΜ, 300 μΜ, 400 μΜ, or 500 μΜ (or in the range defined by and including any two numbers above), and said IC50 value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, or 1000 times less (or a number in the range defined by and including any two numbers above) than its IC50 value against one, two or three other PRMTs.

[Θ257] The subject methods are useful for treating a disease condition associated with PRMTS. Any disease condition that results directly or indirectly from an abnormal activity or expression level of PRMT5 can be an intended disease condition. |i2S ] Different disease conditions associated with PRMT5 have been reported. PRMT5 has been implicated, for example, in a variety of human cancers as well as a number of

hemogl obi nopathi es .

259j Non- limiting examples of such conditions include but are not limited to

Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblasts leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute myelogenous leukemia, Acute promyelocytic leukemia, Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma. Adenoma, Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell leukemia, B-ceil iymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of Unknown Primary Site, Carcinosarcoma, Castleman's Disease, Central Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma, Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease, Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma,

Endodermai sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy -associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epidermoid cancer, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget's disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer, Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer, Gastric lymphoma. Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Germ cell tumor, Germinoma, Gestational choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadobiastoma, Granulosa cell tumor, Hairy Cell Leukemia, Head and Neck Cancer, Head and neck cancer, Heart cancer, Hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), Hemangiobiastoma, Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocytic leukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigo maligna melanoma, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma, Lymphoepitheiioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia, Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma, Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia. Mastocytosis, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma, Medulloblastoma,

Medulloepithelioma, Melanoma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplasia Disease, Myelodysplasia Syndromes, Myeloid leukemia.

Myeloid sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Ocular oncology, Oiigoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer.

Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget' s disease of the breast, Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroid cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Perivascular epithelioid ceil tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor of Intermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitary adenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonary blastoma, Polyembryoma, Precursor T- lymphoblastic lymphoma, Primary central nervous system lymphoma, Primary effusion lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer, Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell carcinoma. Respiratory Tract Carcinoma Involving the NUT Gene onChromosome 15,

Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygeal teratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma,

Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor, Small cell carcinoma, Small Ceil Lung Cancer, Small cell lymphoma, Small intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma,

Supratentoriai Primitive Neuroectodermal Tumor, Surface epithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell proiymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Ceil Cancer of Renal Pelvis and Ureter, Transitional ceil carcinoma, Urachal cancer, Urethral cancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, Wilms' tumor, or any combination thereof.

| ^' Θ260] In some embodiments, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and

scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer. | 261 ] In other embodiments, said method is for treating a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer,

|§262] In other embodiments, said method is for treating a disease selected from leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML),

mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b -thai as semi a and sickle cell disease (SCD).

|β263] In yet other embodiments, said method is for treating a disease selected from CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma,

ICI264] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single

enantiomers/diastereomers may be obtained by methods known to those skilled in the art,

| 265| Compounds of the disclosure can be prepared, for example, by reference to the following schemes.

-75 - Scheme 2

-77- Scheme 4

|§266) Compounds of the disclosure include, for example, the compounds identified in Table A,

Ex.

Structure ame No,

2 431.833 N-(l-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)acryiamide

3 0 445.86 N-{l-{(2R,3R,4S,5R)-5-{(R)-{4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)methacrylamide

Hd H ¾ _H

4 454.264 2-chloro-N-(l-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)acetamide

5 437.81240 N-(l-((2R,3R,4S,5R)-5-((R)-(4- 3 chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)-2-fluoroacetamide

6 435.821 methyl (l-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)carbamate Ex.

Structure ame No,

7 0 434.837 l-(l-((2R,3R,4S,5R)-5-((R)-(4-

HNAN-' chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)-3-methylurea

Hd H - _5h

8 420.81 l-(l-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)urea

9 448.864 3-(l-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)-l,l-dimethylurea

10 402.795 N-(l-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)cyanamide

Hd ^" H 5 _H

11 N 416.822 2-((l-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4-

H ^

dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)amino)acetonitrile

Hd H - _&H Ex.

Structure ame

No,

17 402.835 (2R,3S,4 ,5R)-2-(( )-(4- chlorophenyl)(hydroxy)methyl)-5-(4-cyclopropyl-lH- pyrazolo[3,4-d]pyrimidin-l-yl)tetrahydrofuran-3,4-diol

18 459.887 N-(l-((2R,3R,4S _i 5S)-5-((R)-l-(4-chlorophenyl)-l- hydroxyethy!)-3,4-dihydroxytetrahydrofuran-2-yl)-lH- pyrazolo[3,4-d]pyrimidin-4-yl)methacrylamide

19 447.85140 N-(l-((2R,3R,4S,5S)-5-((R)-(4- 3 chlorophenyl)fluoromethyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)methacrylamide

20 395.24 (2R,3R,4S,5R)-2-(4-chloro-lH-pyrazolo[3,4- d]pyrimidin-l-yl)-5-((R)-l-(4- chlorophenyl)ethyl)tetrahydrofuran-3,4-diol

21 395.24 (2R,3R^S,5R)-2-(4-chloro-lH-pyrazolo[3,4- d]pyrimidin-l-yl)-5-((S)-l-(4- chlorophenyl)ethyl)tetrahydrofuran-3,4-diol

' ^H &H Ex.

Structure ame

No,

22 0 373.369 N-(l-((2 ,3R,4S,5 )-3,4-dihydroxy-5-((R)-l- hydroxybut-2-yn-l-yl)tetrahydrofuran-2-yl)-l H- pyrazoio[3,4-d]pyrirnidin-4-yi)methacryiamide

23 0 399.407 N-(l-((2R,3R,4S,5R)-5-((R)-3-cyclopropyl-l- hydroxyprop-2-yn-l-yl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)methacrylamide

24 427.34021 N-(l-((2R,3R,4S _i 5R)-3,4-dihydroxy-5-((R)-4,4,4- trifluoro-l-hydroxybut-2-yn-l-yl)tetrahydrofuran-2- yl)-lH-pyrazolo[3,4-d]pyrimidin-4-yl)methacrylamide

25 447.39880 N-(l-((2R,3R,4S,5R)-5-((R)-(3,4- 6 difluorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)methacrylamide

26 463.85040 N-(l-((2R R,4S,5R)-5-((R)-(3-chloro-4- 3 fluorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)methacrylamide Ex.

Structure ame

No,

27 0 463.85040 N-(l-((2 ,3R,4S,5 )-5-((R)-(4-chloro-3- 3 fluorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)methacrylamide

HCJ H ¾ _H

28 480.302 N-(l-((2R,3R,4S,5R)-5-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yl)methacrylamide

Hd H ¾ _H

29 396.224 (2R _i 3R,4S,5R)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((R)-(4-

' >· pi chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4- diol

HO H - _&H

30 0 430.84 N-(7-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)acrylamide

31 444.87 N-(7-((2R,3R,4S,5R)-5-((lR)-(4-chlorocyclohex-l-en-l- yi)(hydroxy)methyl)-3,4-dihydroxytetrahydro†uran-2- yi)-7H-pyrro!o[2,3-djpyrimidin-4-y!)methacry!amide

Ex.

Structure ame

No,

47 0 446.86340 N-(7-((2R,3R,4S,5S)-5-((R)-(4- 3 chlorophenyl)fluoromethyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)methacrylamide

F H OH

48 442.9 N-(7-((2R,3R,4S,5R)-5-((R)-l-(4-chlorophenyl)ethyl)- 3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)methacrylamide

49 442.9 N-(7-((2R,3R,4S _i 5R)-5-((S)-l-(4-chlorophenyl)ethyl)-

3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)methacrylamide

50 ρ 372.381 N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-((R)-l- hydroxybut-2-yn-l-yl)tetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)methacrylamide

HO H ¾ _H

51 0 398.419 N-(7-((2R,3R,4S,5R)-5-((R)-3-cyclopropyl-l- hydroxyprop-2-yn-l-yl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)methacrylamide

HO H - _&H

Ex.

Structure ame No,

60 454.264 2-chloro-N-(9-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6- yi)acetarnide

61 437.81240 N-(9-((2R,3R,4S,5R)-5-((R)-(4- 3 chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)-2- fluoroacetamide

62 435.821 methyl (9-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6- y!)carbamate

63 434.837 l-(9-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)-3- methylurea

Ex.

Structure ame

No,

68 408.81440 (2R,3S,4 ,5R)-2-(( )-(4- 3 ch!oropheny!)(hydroxy)rnethy!)-5-(6-{2-fkjoroethy!)- 9H-purin-9-yl)tetrahydrofuran-3,4-diol

69 426.80480 (2R,3S,4R,5R)-2-((R)-(4- 6 chlorophenyl)(hydroxy)methyl)-5-(6-(2,2- difluoroethyl)-9H-purin-9-yl)tetrahydrofuran-3,4-diol

70 425.266 (2R,3R,4S,5R)-2-(6-(2-chloroethyl)-9H-purin-9-yl)-5- ((R)-(4- chlorophenyl)(hydroxy)methyl)tetrahydrofuran-3,4- diol

71 420.85 (2R,3S,4R,5R)-2-((R)-(4- chlorophenyl)(hydroxy)methyl)-5-(6-(2- methoxyethyl)-9H-purin-9-yl)tetrahydrofuran-3,4-diol

Ex.

Structure ame

No,

76 443.888 N-(9-((2 ,3R,4S,5 )-5-((R)-l-(4-chlorophenyl)ethyl)- 3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-6- yi)methacryiamide

77 443.888 N-(9-((2R,3R,4S,5R)-5-((S)-l-(4-chlorophenyl)ethyl)-

3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-6- yl)methacrylamide

78 373.369 N-(9-((2R,3R,4S,5R)-3,4-dihydroxy-5-((R)-l- hydroxybut-2-yn-l-yl)tetrahydrofuran-2-yl)-9H-purin-

6-yi)methacrylamide

79 399.407 N-(9-((2R,3R,4S,5R)-5-((R)-3-cyclopropyl-l- hydroxyprop-2-yn-l-yl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6- yl)methacrylamide

Ex.

Structure ame

No,

SO 427.34021 N-(9-((2 ,3R,4S,5 )-3,4-dihydroxy-5-((R)-4,4,4- trifluoro-l-hydroxybut-2-yn-l-yl)tetrahydrofuran-2- yi)-9H-purin-6-yl)methacry!amide

81 447.39880 N-(9-((2R,3R,4S,5R)-5-((R)-(3,4- 6 difluorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6-

-W yl)methacr lamide

^N ^ ^N HiO't y OHt

82 463,85040 N-(9-((2R,3R,4S,5R)-5-((R)-(3-chloro-4- 3 fluorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6- yl)methacrylamide

83 463.85040 N-(9-((2R _/ 3R,4S,5R)-5-((R)-(4-chloro-3- 3 fluorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6- yl)methacrylamide

Ex.

Structure ame

No,

84 480.302 N-(9-((2R,3R,4S,5R)-5-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-6- yi)methacryiamide

85 o _N -¼, _HO 556.42 3-(7-((2R,3R,4S,5R)-5-(2-(2-amino-3-bromoquinolin-7- yl)ethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)-l,l-dimethylurea

86 5? HO 553.42 N-(7-((2R,3R,4S,5R)-5-(2-(2-amino-3-bromoquinolin-7- yl)ethyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)methacrylamide

87 434.40 l-((7-((2R,3R,4S,5R)-5-((R)-(3,4- difluorophenyl)(hydroxy)methyl)-3,4-

-pro:, dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)propan-2-one

88 HO ^H 9 418.83 N-(7-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)acetamide

0 Ex.

Structure ame

o,

95 435.92 (2R,3S,4 ,5R)-2-(( )-(4- chlorophenyl)(hydroxy)methyl)-5-(4-(2- (methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol

96 419.86 (2R,3S,4R,5R)-2-((R)-(4- chlorophenyl)(hydroxy)methyl)-5-(4-(2- methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrabydrofuran-3,4-diol

97 450.9 O-methyl (7-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)carbamothioate

98 464.22 (2R,3R,4S)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)-5-((R)-l-(4-chlorophenyl)-2,2,2-trifluoro-l- hydroxyethyl)tetrahydrofuran-3,4-diol

99 465.86 3-(7-((2R,3R,4S,5R)-5-((R)-(4-chloro-3- fluorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-l,l-dimethylurea

Ex.

Structure ame No,

106 482.32 3-(7-((2R,3R,4S,5R)-5-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-l,l-dimethylurea

0

107 487.94 N-(7-((2R _/ 3R,4S,5R)-5-((R)-(4-chloro-3- methylphenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrrolidine-l-carboxamide

108 461.9 3-(7-((2R,3R,4S,5R)-5-((R)-(4-chloro-3- methylphenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-l,l-dimethylurea

109 524.35 N-(7-((2R,3R,4S,5R)-5-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)morpholine-4-carboxamide

110 523.37 N-(7-((2R,3R,4S,5R)-5-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-l-carboxamide

0 503.94 N-(7-((2R,3R,4S)-5-((R)-(4-chloro-3- methylphenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)morpholine-4-carboxamide

6 Ex.

Structure ame

No,

112 0 488.92 N-(7-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)piperazine-l-carboxamide

113 537.4 N-(7-((2R,3R,4S,5R)-5-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-4-rnethy!piperazine-l-carboxamide

114 494.33 l-(7-((2R,3R,4S,5R)-5-((R)-(3,4- dichlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3-methylimidazolidin-2-one

1 1 5 HO ^0H p 451.879 (2S,3S,4R,5R)-2-((R)-l-(4-chloro-3-fluorophenyl)-l- hydroxyethyl)-5-(4-(2-methoxyethyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol

116 468.331 (2S _i 3S,4R,5R)-2-((R)-l-(3,4-dichlorophenyl)-l- hydroxyethyl)-5-(4-(2-methoxyethyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol

117 485.436 (2S,3S,4R,5R)-2-((R)-l-(3-fluoro-4- (trifluoromethyl)phenyl)-l-hydroxyethyl)-5-(4-(2- methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol Ex.

Structure ame

No,

118 MO > OH _F 435.428 (2S,3S,4R,5 )-2-((R)-l-(3,4-difluorophenyl)-l-

^Η0! -< ρ hydroxyethyl)-5-(4-(2-methoxyethyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol

119 HO ^H 9 406.82 (2R,3R _/ 4S,5R)-2-(4-amino-7H-pyrrolo[2 _/ 3-d]pyrimidin- 7-yl)-5-((R)-(4-chloro-2-

{hydroxymethy!)phenyl)(hydroxy)methyl)tetrahydrofu ran-3,4-diol

H ₂

120 HO ^H 9 p 408.36 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-

^Η ° ^Μ ·< 0¾ 7-yl)-5-((R)-(4,5-difluoro-2-

(hydroxymethyl)phenyl)(hydroxy)methyl)tetrahydrofu ran-3,4-diol

NH ₂

121 HO ^hi 9 406.82 (2R,3R,4S,5R)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((R)-(5-chloro-2-

(hydroxymethyl)phenyl)(hydroxy)methyl)tetrahydrofu ran-3,4-diol

H ₂

122 HQ VF'H p 422.39 (2R _i 3R,4S,5S)-2-(4-amino-7H-pyrrolo[2 _/ 3-d]pyrimidiri- 7-yl)-5-((R)-l-(4,5-difluoro-2-(hydroxymethyl)phenyl)- l-hydroxyethyl)tetrahydrofuran-3,4-diol

NH ₂

123 421 .4 (2S _i 3S,4R,5R)-2-((R)-l-(4,5-difluoro-2-

(hydroxymethyl)phenyl)-l-hydroxyethyl)-5-(4-methyl-

H,

7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4- dio!

HO ^0H Ex.

Structure ame

No,

124 421.4 (2R,3 ,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)-5-((R)-l-(2-(aminomethyl)-4,5-difluorophenyl)-l- hydroxyethyl)tetrahydrofuran-3,4-diol

NH ₂

125 420.42 (2S,3S,4R,5R)-2-((R)-l-(2-(aminomethyl)-4,5- difluorophenyl)-l-hydroxyethyl)-5-(4-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3 _/ 4-diol

126 434.44 (2S,3S,4R,5R)-2-((R)-l-(4,5-difluoro-2- ((methylamino)methyl)phenyl)-l-hydroxyethyl)-5-(4- methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol

Synthesis of Int-1

Int-1 -1 int-1 -2 Int-1 )267| To a solution of Int-1-1 (730 mg, 1.94 mmol, reported in US2016/244475 Al) and imidazole (1.98 g, 29.1 mmol) in DMF (15 mL) was added ethylchlorosilane (2.93 g, 19.4 mmol). The reaction mixture was stirred for 18 h at 25 °C. LCMS showed the reaction was completed. The solution was poured into water (150 mL), extracted with EA (50 mL><3). The combined organic layers were washed with brine, dried over anhydrous a2S0 . The solvent was concentrated under reduced pressure to give the caide product, which was purified by silica gel column chromatography (eluted with EtO Ac/petroleum ether = 1 : 10 to 1 : 1) to give Int-1-2 (1.2 g, 86%) as a yellow oil. LCMS | M · I I I 719.5, 721 .5; [M+Na] 741 ,5, 743.4. ¾ NMR (400 MHz, DMSO-a¾): δ 8.35 (s, 1 H), 7.20 (m, 4 H), 7.07 (d, 1 H), 6.40 (d, 1 H), 5.98 (d, 1 H), 5.43 (s, 1 H), 5.27 (dd, IH), 5.13 (d, 1H), 4.43 (d, I H), 3.95 (d, IH), 0,90-0,96 (m, 18H), 0.72 (t, 9H), 0,51 -0,59 (m, 12H), 0.27-0.37 (m, 3H), 0.15-0.25 (m, 3H).

|§268) To a solution of Int-1-2 (600 mg, 0.835 mmol) in pyridine (12 mL) was added phenyl chloroformate (1.3 g, 8,35 mmol). The reaction mixture was heated to 70 °C and stirred for 2 h. LCMS showed the reaction was completed. The solution was poured into water (100 mL), extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ S0 ₄ . The solvent was concentrated under reduced pressure to give crude lnt-1 (800 mg) which was used in the next step without further purification. This intermediate could not be detected by LCMS. Synthesis of (R)-((2S,3S,4R,5R)-5- (6-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-

Step 1. Preparation of (lR)-(4-chlorophenyl)((2S,3S,4R)-3,4,5-trihydroxytetrahydrof uran-2- yl)methyl[l,l'- biphenyl]-4-carboxylate (Int-2-2)

|(I26 | To a mixture of (S)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l ,3]dioxol-6-yl]-(4-chlorophenyl)methanol (Int-2-1) (41. g, 130 mmol) andPPhj (51.3g, 195 mmol) in Toluene (600 mL) was added 4-Biphenylcarboxylic acid (38.7g, 195 mmol), then reaction mixture was stirred for 0.5 h, then DIAD (38.5mL, 195mmol) was added to the reaction mixture and continue stirred for 2 h. TCL showed the reaction was completed. The reaction mixture was concentrated and the crude the product was purified by silica gel column (PE:EA = 2: 1) and concentrated to give [(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-(4-chlorophenyl)methy l] 4-phenylbenzoate (Int-2-2) (40 g, 80.8 mmol, 62.0% yield) as a yellow solid.

Step 2. Preparation of Int-2-3

(8270] [(S)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl--3a,4,6,6a etrahydrofuro[3,4- d][l,3]dioxol-6-yl]-(4-chlorophenyl)methyl] 4-phenylbenzoate (40. g, 80.81 mmol) was added to a raiscible liquids of TFA (400. mL, 5402.6 mmol) and Water (400 mL), then the reaction mixture was stirred at rt for 72h. TCL(PE:EA = 1 : 1, Rf = 0.3) showed the reaction was completed. The reaction mixture was concentrated under vacuum and the crude product was purified by silica gel column (PE:EA = 10: 1 to 1 :2) and concentrated to give [(S)-(4-chlorophenyl)-[(2S,3S,4R)-3,4,5- trihydroxytetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-2-3) (21 g, 47.6 mmol, 58.9% yield) as a white solid.

Step 3. Preparation of (R)~((2S,3S,4R,5R)-5~ (6-chloro-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)(4-chlorophenyl)methyl [Ι,Ι'-biphenyl] -4-carboxylate (Int-2) Θ271] [00455] To a mixture of 6-Chloropurine (1.6 g, 10.6 mmol) in THF (40.0 mL) was added pyridine (0.8 mL, 10.6 mmol ), tributyl phosphine (5.2 mL, 21.1 mmol) and DIAD (4.6 mL, 23.2 mmol). The mixture was cooled with ice-bath and [(R)-(4-chlorophenyl)-[(2S,3S,4R)- 3,4,5-trihydroxy tetrahydrofuran-2-yl]methyl]4-phenylbenzoate (Int-2-3) (5.0 g, 10.6 mmol) in THF (30,0 mL) was added. The mixture was stirred at 25 °C for 2h. The solvent was removed and the residue was purified by reversed phase combi-flash eiuting with CH3CN/H20 (neutral condition) from 30/70 to 70/30 to give [(R)-(4-chlorophenyl)-[(2S,3S,4R,5R)-5-(6-chloropurin-9-yl)- 3,4- dihydroxy-tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (2.6 g, 4.22 mmol, 40.0 % yield) as yellow solid. I CMS: no MS signal. 1H NMR (400 M Hz, DMSQ~d6): δ 8.75 (s, 1 H), 8.54 (s, I 1 1 ).. 8.20 (d, J = 4.4 Hz, 2 H), 7.87 (d, J = 4.4 Hz, 2 H), 7.77 (d, J = 4.0 Hz, 2 H), 7.50-7.55 (m, 2 H), 7.43-7.47 (m, 3 1 1 ).. 7.29 (d, J = 4,0 Hz, 2 I f ), 6.25 (d, J = 5.2 Hz, 1 H), 6,04 (d, J = 5.6 Hz, 1 H), 5.69 (d, J = 6,0 Hz, 1 H), 5.57 (d, J = 5.2 Hz, 1 H), 4.91-4.96 (m, 1 H), 4.47-4.50 (m, 1 H), 4.41-4.44 (m, 1 H). IH NMR (400 M Hz, DMSO-d6+D20): δ 8.67 (s, 1 H), 8.51 (s, 1 H), 8.11 (d, J = 4.4 Hz, 2 H), 7.86 (d, J = 8.4 Hz, 2 H), 7.77 (d, J = 7.6 Hz, 2 H), 7,52-7,56 (m, 2 H), 7,43-7,49 (m, 3 H), 7.27 (d, J = 8.4 Hz, 2 H), 6.23 (d, J = 4.4 Hz, 1 H), 6.04 (d, J = 5.2 Hz, 1 H), 4.96 (t, J = 4.8 Hz, 1 H), 4,54 (t J = 4.8 Hz, 1 H), 4.51 (t, J = 4,8 Hz, I I f ),

[0272] To a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.85g, 5.56 mmol) in dry THF (150 mL) was added pyridine (0.45mL, 5.56 mmol), Then Tributylphosphane (2.78mL, 11.11 mmol) and DIAD (2.3mL, 11.67 mmol) was added at 30 °C, [(R)-(4-chlorophenyl)-[(2S,3S,4R)- 3,4,5-trihydroxytetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-2-3) (2,5g, 5,56 mmol) in dry THF was added at once. The reaction mixture was stirred at 30 °C for 1 h. I. CMS showed the reaction was completed. The reaction mixture was concentrated and purified by reversed-phase combi-flash (neutral condition) eiuting with H ₂ 0:CH ₃ CN from 90: 10 to 5:95 to give ] ( }-{4- chlorophenyl)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3-d]pyrimi din-7-yl)-3,4-dihydroxy

tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-3) (2, 1 g, 2.91 mmol, 52.4% yield) as a yellow solid. Examples

Example 29. (2 ,3S,4 ,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-(4-chloropyrr olo[2,3- d]pyrimidin-7- l tetrah drofuran-3 4-diol 29

29-1 Ex. 29

|1273| A 50 niL RBF and septum containing (R)-[(3aR,4R,6R,6aR)-4-(4- chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-t etrahydrofxiro[3,4-d][l,3]dio

(4-chlorophenyl)methanol (29-1, Ref, PC! Int. Appl., 2016178870) (455. mg, 1.04 mmol,) was charged with a RT mixture of 2,2,2-trifluoroacetic acid (2.5mL, 32.45 mmol) and water (2.5 niL), sonicated for 10 s, blanketed with Ar, and stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to remove the water and most of the I FA. The reaction was then diluted in MeOH (20 mL), and quenched with Amberlyst I A -67 until a neutral pH was obtained. The mixture was then filtered through a cotton plug, rinsed with additional MeOH and DCM, and concentrated under reduced pressure to light brown foam. The cmde product was purified by FCC (40g Si02, 3->4% MeOH in DCM, wet-loaded in DCM) to yield (2R,3S,4R,5R)-2-[(R)-(4- chlorophenyl)-hydroxy-methyl]-5-(4-cM

(29) (128 mg, 0.31 mmol, 30.0% yield) as a white powder. Rf .26 (3% MeOH in DCM). LCMS (ESI) m/z calcd for | \ F l ! i C17H16CI2N3O4: 396.051. Found: 396.0. ¾ MR (400 MHz, DMSO- ίίό) δ 8,67 (s, IH), 8,02 (d, J= 3.8 Hz, IH), 7,44 - 7,32 (m, 4H), 6.79 (d, J ------- 3.7 Hz, 1H), 6.19 (d, J

= 7.7 Hz, IH), 6.02 (d, J= 4.1 Hz, IH), 5.39 (s, IH), 5.21 (d, J= 4.0 Hz, IH), 4.80 (t, J= 4.1 Hz, IH), 4,58 (s, IH), 4, 12 (t, J ------ 3.3 Hz, IH), 4.00 (dd, J ------ 5,3, 1.3 Hz, IH). ¾ NMR of (400 MHz,

DMSO-t/r- DO) δ 8.66 - 8.60 (m, IH), 7.96 - 7.87 (m, IH), 7.42 - 7.29 (m, 41 1 ), 6.76 (t, J 3. 1 Hz, IH), 6.15 (dd, J= 7.6, 3.5 Hz, IH), 4.76 (t, J= 3.9 Hz, IH), 4.55 (t, J= 6.5 Hz, IH), 4.11 (d, J = 5.1 Hz, I H), 4.01 (dd, ,/ 5. 1 , 1 .1 Hz, I H), Example 30. (lS,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- ((4'

ehloropheiiyI)thio)cycIopentane~l,2~diol (30)

30a Ex. 30

a) Synthesis of compound 30a 0274] To a solution of 7-[(2R,3R,4R,5R)-5-[(R)-(4-chlorophenyl)-triethylsilyloxy- methyl]-3,4-bis (triethylsilyloxy)tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimid in-4-amine (Int-1-2) (1.4 g, .95 mmol) and TEA ( 1.08 mL, 7.78 mmol) in DCM (15 mL) was added acryiyl chloride (0.47 mL, 5.84 mmol) at 0 °C and stirred for 0,5 h. TLC (PE:EA = 5: 1 f 0.7) showed the reaction was complete. The solution was poured into water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous a2S0 . The solvent was concentrated under reduced pressure to give crude product which was purified by silica gel column chromatography (PE:EA = 50: 1 to PE:EA = 10: 1) to give N-[7-[(2R,3R,4R,5R)-5-[(R)-(4-chlorophenyl)- triethylsilyloxy-methyl]-3,4-bis(triethylsilyloxy) tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4- yl]-N-prop-2-enoyl-prop-2-enamide (30a) (0.996 g, 1.2 mmol, 61.85% yield) as oil. ¾ NMR (400 MHz, D\!S( ): δ 8,87 (s, 1 H), 7.37 (d, ,/ 3.6 Hz, 1 H), 7,24-7,28 (m, 4 H), 6.51 -6,56 (m, 2 H), 6.35-6.42 (m, 3 H), 6.18 (d, J = 8.0 Hz, 1 H), 5.77-5.80 (m, 1 H), 5.04 (d, J = 6.4 Hz, 1 H), 4.97- 4.99 (m, 1 H), 4.42 (d, J= 4.4 Hz, 1 H), 4.02 ( ύ, .ί 6,4 Hz, 1 H), 0.90-0.95 (m, 18 I f }.. 0.70 (t, J 8.0 Hz, 9 H), 0.48-0.58 (m, 12 H), 0.24-0.34 (m, 3 H), 0.11-0.20 (m, 3 H).

b) Synthesis of N-[7-[(2R,3R,4S,5R)-5-[(R)-(4-chlorophenyl)-hydroxy-methyl]- 3,4-dihydroxy^ tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]prop-2-ena mide (Ex. 30)

102751 To a solution of N-[7-[(2R,3R,4R,5R)-5-[(R)-(4-chlorophenyl)-triethylsilyloxy - methyl]-3,4-bis (triethylsilyloxy)tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimid in-4-yl]-N-prop-2- enoyl-prop-2-enamide (30a) (1 g, 1.2 mmol) in methanol (8 mL) was added HC1 (12M, 2 mL, 24 mmol) and stirred at 25 °C for 18 hrs. LCMS (ZFL001-39-R1) showed the reaction was complete. The solvent was concentrated under reduced pressure and the residue was dissolved in methanol (10 ffiL) and water (10 n L), then Amberlite IRA-67(4 g) was added and stirred at 25 ^C' C for 1 h.

Filtered, the solvent was concentrated under reduced pressure and the residue was purified by si lica gel column chromatography (DCM:MeOH = 50: 1 to DCM:MeOH = 30: 1) to give impure product (200 nig, HPLC:93%). The impure product was purified by prep-HPLC (0.1 % ΝΗ3Ή2Ο) eluting with ! 1 >():( ^' ! h( N from 85 : 5 to 5 :95 to give N-[7-[(2R,3R,4S,5R)-5-[(R)-(4-chlorophenyl)- hydroxy-methyl]-3,4-dihydroxy- tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]prop-2-ena mide (Ex. 30) (67 mg, 0.15 mmoi, 12.83% yield) as white solid. ^! H MR (400 MHz, DMSO-£¾) δ 1 1.00 (s, I I I ). 8.54 (s, 1 H), 7.71 (d, J = 4,0 Hz, I 1 1 ).. 7.35-7.43 (m, 4 H), 6.89 (d, ./ 4.0 Hz, 1 H), 6.69- 6.76 (m, 1 H), 6.37-6.42 (m, 1 H), 6, 19 (d, ,/ 8.0 Hz, 1 H), 6.07 (d, ./ 4.4 Hz, 1 ! ! }. 5 ,86-5 ,89 (m, 1 H), 5.30 (d, J = 6.8 Hz, 1 H), 5.1 1 (d, J = 4.0 Hz, 1 H), 4.78-4.80 (m, 1 H), 4.54-4.59 (m, 1 H), 4. 10 (m, 1 H), 3.99 (d, 4,8 Hz, 1 H). ¾ NMR (400 MHz, DMSO-iftrHDiO) δ 8.55 (s, 1 H), 7.67 (d, J = 3.6 Hz, 1 H), 7.36-7.43 (m, 4 H), 6.88 (d, J = 4.0 Hz, 1 H), 6.67-6.74 (m, 1 H), 6.39-6.43 (m, 1 H), 6. 19 ( ύ, .ί 8.0 Hz, 1 H), 5 ,89-5 ,92 (m, 1 H), 4,78-4,80 (m, 1 H), 4,55-4,59 (m, 1 H), 4, 12 (d, J = 4.8 Hz, 1 H), 4.02 (d, J= 4.4 Hz, 1 H).

Example 36. l-(7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)- 3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)urea (36)

lnt-1 3S-1 Ex, 36

|0276| To a solution of Lit- 1 (300 mg, crude) in THF (10 mL) was added NH3/CH3OH (5 mL) and the mixture was stirred for 18 h at 25 °C. LCMS showed the reaction was completed, and the solvent was concentrated under reduced pressure to give crude 36-1 (200 mg) which was used in the next step without further purification. LCMS [M+H] 762.5, 764.5. Step 2: Synthesis of compound 36

|1277] To a solution of 36-1 (200 mg, crude) in THF (5 mL) was added TBAF (1M in THF, 1 .3 mL) and the mixture was stirred for Ih at 25 °C, LCMS showed the reaction was completed. The solvent was concentrated under reduced pressure, and the residue was purified by prep-TLC (DCM; MeOH = 8: 1) and prep-HPLC (eiuted with HiO/CH CN/O. l H TFA) from 85: 15 to 5:95) to give compound 36 (14.6 mg) as a white solid. LCMS [M+H] 420.3, 422.3. Ή NMR (400 MHz, DMSO-6/6 ^' ): δ 10.0 (s, IH), 8.43 (s, IH), 7.64 (d, J = 2,4 Hz, 1FI), 7.41 (d, J = 8,4 Hz, 21 1 ), 7.36 (d, J= 8.4 Hz, 2H), 7.10 (d, J= 3.6 Hz, IH), 6.10 (d, J= 7.2 Hz, IH), 4.78 (d, J= 4.8 Hz, IH), 4.56 (dd, 5.2 I !/, 7.6 Hz, IH), 4,09 (d, J= 4.4 Hz, IH), 3.99 (d, J = 4,4 Hz, H i).

Example 37. 3-(7-((2R,3R,4S,5R)-5-(( )-(4-chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-l,l-dimethylurea (37)

i.nt-1 37-1 Ex. 37

Step 1 : Synthesis of compound 37-1

|(I278) To a solution of Int-1 (400 mg, crude) in THF (5 mL) was added dimethylamine

(33% in water, 2 mL) and the mixture was stirred for 18 h at 25 °C. LCMS showed the reaction was completed. The reaction mixture was extracted with EtOAc (5 mi. 3 ), and the combined organic layers were dried over anhydrous Na ₂ S0 ₄ . The solvent was removed under reduced pressure to give crude 37-1 (240 mg) which was used in the next step without further purification. LCMS [M+H] 790.6, 792.5.

Step 2: Synthesis of compound 37

j¾279] To a solution of 37-1 (240 mg, crude) in THF ^' (5 mL) was added TBAF (1M in THF, 1.5 mL) and the mixture was stirred for 1 h at 25 °C. LCMS showed the reaction was completed. The solvent was removed under reduced pressure, and the residue was purified by prep- TLC (DCM: MeOH = 8: 1) and prep-HPLC (eiuted with HzO/CHsCN/O. P/o TFA from 85: 15 to 5:95) to give 37 (15.2 mg) as a white solid. LCMS [M+H] 448,3, 450.3, ^l B NMR (400 Mi l/,

- I l l - DM$Q-d6) δ 8.46 (s, IH), 7.69 (d, J = 3.6 Hz, IH), 7.40 (q, 41 1 X 6.80 (d, J= 3.2 Hz, 1H), 6. 14 (d, J = 8.0 Hz, IH), 4.79 (d, J= 4.8 Hz, IH), 4.55 (dd, J= 5.2 Hz, 7.6 Hz, IH), 4.10 (d, J= 4.8 Hz, IH), 4.0 (d, ./ 4.8 Hz, I H), 3.02 (s, 6H).

Example 87. l-((7-((2R,3R,4S,5R)-5-((R)-(3,4-difluorophenyl)(hydroxy)met hyl)-3,4- dihydroxytetrahydrofera!i~2-yI)-7H~pyrroIo[2 ~d]pyrimidiM~4-yI)amiMo)propaii-2~oii^ (87)

87a 87b Ex. 87 a) Preparation of (2R,3 S,4R,5R)-2-[(R)-(3,4-difluorophenyl)-hydroxy-methyl]-5-[4-[( 2-methyl- l,3-dioxolan-2-yl)methylamino]pyrrolo[2,3-d]pyrimidin-7-yl]t etrahydrofuran-3,4-diol (87b) 6280] A 2 mL microwave vial containing (2R,3R,4S,5R)-2-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-5-[(R)-(3,4-difluorophenyl)-hydroxy-rnethy l]tetrahydrofuran-3,4-diol (50. mg, 0.13 mmol), l-(2-Methyl-l,3-dioxolan-2-yl)methanamine (87a, prepared similar to that of Ex. 29) (55, mg, 0.47 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.05mL, 0.29 mmol) was charged with 1-Propanol (1 mL) and sparged with Ar for 2 min The vial was then heated in a microwave reactor at 110 °C for 2 h 20 min. The reaction mixture (clear solution) was concentrated under reduced pressure and purified by FCC (12 g Si02, 0->6% MeOH in DCM, wet-loaded in eluent) to yiekj (2R,3S,4R,5R)~2-[(R)~(3,4~difluoro^

yl)methylamino]pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofur an-3,4-diol (87b) (57 mg, 0.12 mmol, 95% yield) as a thick oil. R f 0.58 (2: 1 Hexanes:EtOAc); LCMS M i l 479.2. b) Preparation of l-[[7-[(2R,3R,4S,5R)-5-[(R)-(3,4-difluorophenyl)-hydroxy-met hyl]-3,4- dihydroxy-tetrahydrofuran-2-yl]pyn-olo[2,3-d]pyrimidin-4-yl] amino]propan-2-one (Ex. 87)

10281 ] A 20 mL vial containing (2R,3 S,4R,5R)-2-[(R)-(3,4-difluorophenyl)-hydroxy- methyl]-5-[4-[(2-methyl-l,3-dioxolan-2-yl)methylamino]pyrrol o[2,3-d]pyrimidi

yl]tetrahydrofuran-3,4-diol (87b) (55. mg, 0.11 mmol) was charged with a RT solution of 2,2,2- trifluoroacetic acid;TFA (0.5mL, 6.49 mmol) in Water (0.50 mL), then was purged with Ar for 3 min. The reaction was stirred at RT for 1 d. Reaction complete by HPLC analysis. The reaction mixture was charged with a small amount of DMSO, loaded onto a 30 g CI 8 column, and purified by FCC (0->35% MeCN in H20). Fractions containing pure product by HPLC were combined and coevaporated twice under reduced pressure with 1 N HC1 (aq) and MeCN. The sample was then coevaporated thrice under reducded pressure with MeCN and water and heat (up to 50 °C) to yield

1- [[7-[(2R,3R,4S,5R)-5-[(R)-(3,4-difluorophenyl)-hydroxy-methy l]-3,4-dihydroxy-tetrahydrofuran-

2- yl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]propan-2-one hydrochloride (43.4 mg, 0.089 mmol, 78% yield) as a shiny, pale yellow powder. A portion of the HC1 salt product was dissolved in MeOH, neutralized with Amberlite IRA-67 resin, and filtered. The filtrate was concentrated under reduced pressure and heat (50 °C) to yield l-[[7-[(2R,3R,4S,5R)-5-[(R)-(3,4-difluorophenyl)-hydroxy- methyl]-3,4-dihydroxy-tetrahydrofuran-2-y^ (Ex. 87) (12.5 mg, 0.02786 mmol, 24.231% yield) as a white powder. 'H MR (400 MHz, DMSO-d6) δ 8.10 (s, 1 1 1 ).. 7.98 (s, !H), 7,48 - 7.32 (m, 3H), 7.30 - 7,21 (m, 1 1 1 ), 6.66 (dd, J= 13,2, 3.7 Hz, 2H), 5.94 (d, J 7.8 Hz, 1H), 5.26 (d, J 7.1 Hz, 1 1 1 ), 5.06 (d, J 4.0 Hz, 1H), 4.81 (t, .1 4.1 Hz, 1H), 4.61 (id, J= 7.4, 4.9 Hz, 1H), 4.28 (d, J 5.8 Hz, 2H), 4.06 - 3.97 (m, 2H), 2, 13 (s, 3H). LCMS M+H ⁺ Found:435.2

Ex. 89

j 2821 To a solution of 6-chloro-9H-purine (92.7 mg, 0.60 mmol) in MeCN (20,0 mL) was added BSA (244.1 mg, 1.2 mmol) at 25 °C. After stirring for 20 min, (3R,4R,5R)-5-((R)-(([l, 1 '- biphenyl]-4-carbonyl)oxy)(4-chlorophenyl)methyl)tetrahydrofu ran-2,3,4-triyl triacetate (89a) (340,2 mg, 0.60 mmol) and TMSOTf (399.6 mg, 1.8 mmol) were added to the reaction mixture. The reaction mixture was stirred 85 °C for 2 hrs. LCMS showed the reaction was complete. The reaction mixture was combined with MCI 0997-070-1 and concentrated in vacuum to give crude product which was purified by silica gel column (DCM: MeOH = 125: 1) to afford (2R,3R,4R,5R)-2-((R)- (([ 1 , 1 ^! -biphenyl]~4-carbonyl)oxy)(4~chlorophenyl)methyl)-5-(6 ~chloro-9H~purin~9-- yl)tetrahydrofuran-3,4-diyl diacetate (89b) (711.0 mg, crude) as white solid. It was used in the next step directly.

b) Synthesis of compound 89c

{8283] To a solution of (2R,3R,4R,5R)-2-((R)-(([l , l'-biphenyl]-4-carbonyl)oxy)(4- chlorophenyl)methyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrofur an-3,4-diyl diacetate (406.0 mg, 0.61 mmol) in EtOH (15.0 mL) was added 2-aminoacetonitrile hydrochloride (89b) (284,0 mg, 3.10 mmol) and TEA (620 mg, 6.14 mmol). The reaction mixture was stirred at 80 °C for 18 hrs under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuum to give crude product which was purified by silica gel column (DCM: eOH = 1 50: 1 to DCM: MeOH = 100: 1) to afford ((2R,3R,4R,5R)-2-((R)-(([l , l'-biphenyl]-4-carbonyl)-oxy)(4- chlorophenyl)methyl)-5-(6-cyanamido-9H-purin-9-yl)tetrahydro furan-3,4-diyl diacetate (89c) (102.0 mg, 25.0% yield) as white solid. LCMS [M+H]:681.3.

e) Synthesis of 2-[[9-[(2S,3R,4S,5R)-5-[(R)-(4-chlorophenyl)-hydroxy-methyl] -3,4-dihydroxy- tetrahydrofuran-2-yl]purin-6-yl]amino]acetonitrile (Ex, 89)

|t284] To a solution of [(R)-(4-chlorophenyl)-[(2R,3R,4R,5S)-3,4-diacetoxy-5-[6- (cyanomethylamino)-purin-9-yl]tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (89c) (102.0 mg, 0.13 mmol) in methanol (2 mL) was added K2CO3 (91.1 mg, 0.66 mmol), then the mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was purified by prep-HPLC (0.1% ΝΗ3Ή2Ο, CH3CN/H2O: from 20% to 50% _s ) to give 2-[[9- [(2S,3R,4S,5R)-5-[(R)-(4-chlorophenyl)-hydroxy-methyl]-3,4-d ihydroxy-tetrahydrofuran-2- yl]purin-6-yl]amino]acetonitrile (Ex, 89) (3.2 mg, 0.0075 mmol, 5.7% yield) as white solid. LCMS [M+H]: 417.0. ¾ NMR (400 MHz, DMSO-t¾): δ 8.47(s, 1H), 8.42 (s, IH ), 7.44-7.34 (m, 4H), 5.92 (d, 7.6 Hz, I I I ). 4,82 (d, 4.8 Hz, i l l), 4,78-4,76 (m, I H), 4.50 (s, 2H), 4.11 (d, 5.2 Hz, IH), 4.07 (d, J= 4.8 Hz, IH). Ipurin-

a) Synthesis of compound 90a

ft285] To a solution of [(4-chlorophenyl)-[(2R,3R,4R,5S)-3,4-diacetoxy-5-(6-chloropu rin- 9- yl)tetrahydrofuran-2-yl]methyl]4-phenylbenzoate (89b) (100.0 mg, 0.15 mmol) in Toluene (6.0 mL) and Water (1.0 mL) was added cyclopropylboronic acid (54.2 mg, 0.60 mrnoi), K3PQ4 (128.4 mg, 0.60 mmol), Tricyciohexyi phosphine (127.2 mg, 0.50 mmol) and Pd(OAc)?. (37.3 mg, 0.2 mmol). The reaction mixture was stirred at 100 °C for 2 h under N2. TLC (PE : EA = 5 : 1, Rf = 0.4) showed the starting material consumed. The reaction mixture was diluted with water (100.0 mL) and extracted with EA (50.0 mL X 3). The organic layers were washed with brine (100.0 mL X 3), dried over a ₂ S0 ₄ and concentrated in vacuum to give crude product which was purified by silica chromatography column (PE: EA = 10 : 1 to 2 : 1) to give [(4-chlorophenyl)-[(2R,3R,4R,5S)-3,4 - diacetoxy-5-(6-cyclopropylpurin-9-yl)tetrahydrofuran-2-yl]me thyl]4-phenylbenzoate (90a) (15.0 mg, 0.02 mmol, 14.9 % yield). b) Synthesis of give (2R,3S,4R,5R)-2 -[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-(6- cycl opropylpurin-9-yl)tetrahy drofuran-3 ,4-diol (Ex, 90)

IQ286J To a solution of [(R)-(4-chlorophenyl)-[(2R,3R,4R,5R)-3,4-diacetoxy-5-(6- cyclopropylpurin-9- yl)tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (90a) (1 1.0 mg, 0.02 mmol) in Methanol (2.0 mL) was added K2CO3 (11.4 mg, 0.10 mmol), then the mixture was stirred at 20 °C for 2 h. LCMS showed the reaction was completed. The mixture was filtered and the filtrate was purified by prep-HPLC, eluted with CH3CN in H2O (0.1% \1 hOI 1 ) from 30.0% to 60.0% to give

(2R,3S,4R,5R)-2 -[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-(6-cyclopropylpurin -9- yl)tetrahydrofuran-3,4-diol (Ex. 90) (5.1 mg, 0.01 mmol, 76.9 % yield) as a white solid, LCMS [M+HJ: 403.1. ¾ NMR (400 MHz, DMSO-ί ό): δ 8.73 (s, 1 H), 8.72 (s, M i ), 7.41-7.33 (m, 4 H), 6.19 (s, 1 H), 5.98 (d, J= 7.6 Hz,l H), 5.36 (s, 2 H), 4.86 (d, J = 5.2 Hz, l H), 4.81-4.78 (m, 1 H), 4. 16 (d, 4,4 Hz, l H), 4.05 (d, ./ 4,8 Hz, l H), 2.73-2.68 (m, l H), 1 ,30-1 ,22 (m, 4 I i ). Ή MR (400 MHz, DMSO-^+D ₂ 0): δ 8.71 (s, 1 H), 8.63 (s, 1 H ), 7.41-7.33 (m, 4 H), 6.00 (d, J = 6.8 Hz, 1 1 1 ). 4.87 (d, ./ 4,4 Hz, 1 ! ! }. 4,82-4,79 (m, 1 H),4.21 (d, ,/ 3,6 Hz, 1 H), 4, 13 (m, 1 H), 2,74- 2.71 (m, 1 H), 1.37-1.24 (m, 4 H).

Example 9L (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methylJ-5-[4-( 2- methylsulfanylethylamino) pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (Ex. 91)

91 a Ex, 91 a) Synthesis of compound 91a

{8287] To a solution of [(4-chlorophenyl)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl) -3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (100.0 mg, 0.17 mmol) in ethanol (2.0 raL) was added 2-methylsulfanylethanamine hydrochloride (109.8 mg, 0.86 mmol) and DIPEA (0.2 mL, 1.03 mmol). The mixture was stirred at 80 °C for 24 hrs. LCMS indicated the reaction was complete (one major peak in LCMS), The mixture was used directly in the next step without further purification. LCMS [ M I f ] : 63 1 .1.

b) Synthesis of (2R,3 S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-(2- methylsulfanylethylamino) pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (Ex. 91)

|¾288| To the reaction mixture of the last step (containing [(R)-(4-chlorophenyl)- [(2S,3S,4R,5R) -3,4-dihydroxy-5-[4-(2-methylsulfanylethylamino)pyrrolo[2,3- d]pyrirnidin-7- yl]tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate), hydrazine hydrate (2,0 mL, 41 , 15 mmol) was added. The mixture was stirred at 25 °C for 1 h. LCMS indicated the reaction was completed. The mixture was purified by reversed phase combi-flash eluting with CH3CN/H2O (neutral condition) from 5/95 to 50/50 to give (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-( 2- methylsulfanylethylamino) pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (Ex. 91) (35.0 mg, 0.07 mmol, 7,23 % yield) as off-white solid, LCMS | \ i I I I: 451.1. ^f H NMR (400 M Hz, DMSO-i¾): δ 8.14 (s, 1 H), 7.77-7.80 (m, 1 H), 7.36-7.45 (m, 4 H), 7.34 (d, J= 3.6 Hz, 1 H), 6.65 (d, J = 3,6 Hz, 1 H), 6.61 (d, ./ 3.6 Hz, 1 H), 5.92 (d, ./ 8.0 Hz, 1 ! ! }. 5,20 (d, J= 6.8 Hz, 1 H), 5.01 (d, J= 4.0 Hz, 1 H), 4.81 (t, J= 4.0 Hz, 1 H), 4.60-4.65 (m, 1 H), 4.00-4.03 (m, 2 H), 3.64-3.68 (m, 2 I I ). 2.72 (t, J = 7,2 Hz, 2 I f }.. 2.12 (s, 3 H). ^! ! 1 NMR (400 M Hz, DMSO-</rt · D.-O ); δ 8. 14 (s, I H), 7.37-7.45 (m, 4 H), 7.32 (d, J= 3.6 Hz, 1 H), 6.62 (d, J= 3.6 Hz, 1 H), 5.92 (d, J= 7.6 Hz, 1 H), 4.81 (d, J= 4.0 Hz, 1 H), 4.60-4.65 (m, 1 H), 4.00-4.03 (m, 2 H), 3.65-3.69 (m, 2 H), 2.72 (t, ./ 6.8 Hz, 2 H), 2, 1 1 (s, 3 H).

Example 92. (2R,3R,4S,5R)-2-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-5-[(l R)-3-cyclopropyl-l- hydroxy-prop-2-ynyl]tetrahydrofuran-3,4-diol (Ex. 92)

a) l-[(3aR _^ 4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2-diniethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-3-cyclopropyl-prop-2- yn-l-one (92a)

f§289] Butyllithium (0.6mL, 0.96 mmol ) was added dropwise to a solution of

Ethynylcyclopropane (0.1 mL, 1. 15 mmol) in dry THF (4 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 30 min. A solution of (3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7- yl)-N-methoxy-N,2,2-trimethyl-3a,4,6,6a-tetrahydrofliro[3,4- d][l,3]dioxole-6-carboxamide

(245. mg, 0.64 mmol) in THF was added dropwise at -78 °C and the resulting mixture was warmed up to RT and stirred for 30 min. TLC showed a small less polar (3 : 1 hexane/EA) peak and most starting material. The reaction mixture was poured onto a mixture of ice cold EtOAc and sat. aq. NH4CI. The organic layer was separated, dried and concentrated and the residue was purified on a 12 g column, eluted with 10-50% EA/hexane to give l-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4

prop-2-yn-l-one (92a) (213 mg, 0.549 mmol, 85.8% yield) as a light yellow foamy solid. b) (lR)-l-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7 -yl)-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3 ,4-d] [ 1 ,3 ]dioxol-6-yl]-3 -cyclopropyl-prop-2-yn- 1 -ol (92b)

| ^" Θ290] Diisobutylalumanylium;hydride (l . lmL, 1 . 1 mmol) (1 M in toluene) was added dropwise to a solution of l-[(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)- 2,2- dimethy 1 -3 a,4,6,6a-tetrahy drofuro[3 ,4-d] [ 1 ,3 ]di oxol-6-yl]-3 -cycl opropyl-prop-2-yn- 1 -one (213.rag, 0.55 mmol) in dry Toluene (3 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 2 hr. TLC showed the reaction was completed (3 : 1 hexane EA). less polar spot was less, about 1 :2 or 1 :3 ratio. This is the opposite selectivity when compared to substituted phenyl tail work up: add 0.04 mL water, 0.04 mL 15% NaOH, 0. 1 mL water. The resulting mixture was stirred for 30 min at RT, not solid was formed. Dry MgS0 ₄ was added, filtered and rinsed with EtOAc. The combined filtrates were concentrated and the residue was purified on a 12 g column, which was eiuted with 0- 100% EA/hexane to give 27 mg of (lR)-l -[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrof\Jro[3, -d][l,3]dioxol-6-yl]-3-cyclopropyl-prop-2-yn-l-ol (92b), and fractions mixed with the S isomer.

c) Preparation of (2R,3R,4S,5R)-2-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-5-[(l R)-3- cyclopropyl- 1 -hydroxy-prop-2-ynyl]tetrahydrofuran-3,4-diol (Ex. 92)

|1291| HQ (O. lmL, 1.2 mmol ) (aq. IN) was added to a solution of ( I R)-l- [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][ l ,3]dioxol-6-yl]-3-cyclopropyl-prop-2-yn-l-ol (92b) (22. mg, 0.06 mmol) in Methanol (0.50 mL), and the resulting mixture was stirred at RT for 1 hr. TLC showed most st.m. was consumed (10: 1 DCM MeOH, Rf -0.4). The reaction was cooled to 0 °C, cone. aq. NH ₄ OH was added dropwise until pH ~8. The reaction mixture was concentrated to give white solid, which was tritriated with EtOAc, filtered. The filtrates was concentrated and the residue was purified on a 4 g column, which was eiuted with 0-100% EA/hexane to give (2R,3R,4S,5R)-2-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-5-[(lR)-3-cyclopropyl-l-hydroxy-prop-2-yny l]tetrahydrofuran-3,4-diol (Ex. 92) (10 mg, 0.026 mmol, 46% yield) as a white solid. ¾ NMR (400 MHz, DMSO-iii+DiO); δ 8.65 (s, 1 1 1 ). 7.87 (d, J=3 Hz, I B), 6.78 (d, J 3 Hz, 1H), 6.21 (d, J=8 Hz, 1H), 4.43 (m, 1H), 4.34 (m, 1 1 1 ). 4.15 (m, 1 1 1 ), 3.90 (m, i l l ). 1.30 (m, 1 H), 0.77 (m, 2H), 0.56 (m, 2H); LCMS \ i ! ! 350.1. Example 93. (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methylJ-5-[4-( 2- methylsulfonylethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrah ydrofuran-3,4-diol (Ex. 93)

[Θ292] To a solution of (2R,3 S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-(2- methylsulfanyl ethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4- diol (Ex. 91) (15.0 nig, 0.03 mmol) in DCM (2.0 mL) was added m-CPBA (13.79 mg, 0.08 mmol). The mixture was stirred at 25 °C for 30 min. LCMS indicated the reaction was completed. The mixture was purified by reversed phase combi-flash during with CH3CN H2O (neutral condition) from 15/85 to 85/15 to give (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-( 2- methylsulfonylethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrah ydrofuran-3,4-diol (Ex. 93) (7.0 mg, 0.01 mmol, 42.32 % yield) as white solid. LCMS [M+H] : 407.3, ¾ NMR (400 M Hz, DMSO-tM): δ 8.20 (s, 1 H), 7.88-7.91 (m, 1 H), 7.34-7.44 (m, 5 H), 6.62 (d, J= 3.2 Hz, 1 H), 6.56 (d, J = 3.2 Hz, 1 i !), 5.95 (d, ,/ 8.0 Hz, 1 H), 5,22 (d, ./ 6.8 Hz, 1 H), 5.04 (s, l H), 4.80-4.82 (m, 1 H), 4.59-4.64 (m, 1 H), 4.00-4.03 (m, 2 H), 3.85-3.90 (m, 2 H), 3.45 (t, J 6.8 Hz, 2 H), 3.03 (s, 3 H). ^! H MR (400 M Hz, DMSO-ii6 ^' +D ₂ 0 ): 6 8.20 (s, 1 H), 7,38-7,45 (m, 4 H), 7.35 (d, J = 3 ,6 Hz, I I f },. 6.61 (d, J= 3.6 Hz, 1 H), 5.94 (d, J= 8.0 Hz, 1 H), 4.81 (d, J= 4.0 Hz, 1 H), 4.59-4.63 (m, 1 H), 4.02-4.06 (m, 2 I I ). 3.90-3.92 (m, 2 H), 3.46 (t, J = 6,8 Hz, 2 H), 3.03 (s, 3 H).

Example 94. (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-[ 2- dimethylamino)ethyl]pyrrolo[2,3-d]pyrimidi -7-yl]tetrahydrofuran-3,4-diol (Ex. 94)

a) Synthesis of compoesid 94a

[6293] To a solution of [(R)-(4-chlorophenyl)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-3) (1.0 g, 1.73 mmol) in 1,4-dioxane (20.0 mL) and water (2.0 niL)was added 4,4,5, 5-tetramethyl-2-vinyl-l, 3,2- dioxaborolane (534.4 mg, 3.47 mmol) and sodium carbonate (367.8 mg, 3.47 mmol) and 1,Γ~ Bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (141 ,6 mg. 0.17 mmoi) at 25 °C. The reaction mixture was stirred at 85 °C for 12 hrs under N ₂ . After the reaction was complete, the reaction mixture was cooled to room temperature and filtered, concentrated in vacuum to give crude product which was purified by silica gel column

chromatogram to afford [(R)-(4-chlorophenyl)-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(4- vinylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl]methy l] 4-phenylbenzoate (94a) (277,0 mg, 0.35 mmoi, 20.4% yield) as white solid. LCMS [ X! I l l: 568.0.

b) b) Synthesis of (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-[ 2- (dimethylamino)ethyl]pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydro furan-3,4-diol (Ex. 94)

11294] To a solution of [(R)-(4-chlorophenyl)-[(2S,3 S,4R,5R)-3,4-dihydroxy-5-(4- vinylpyrrolo[2,3-d]-pyrimidin-7-yl)tetrahydrofuran-2-yl]meth yl] 4-phenylbenzoate (94a) (165.7 mg, 0.21 mmoi) in DMF (5.0 mL) and was added sodium thiomethoxide (155.9 mg, 2. 1 1 mmoi) at 25 °C, The reaction mixture was stirred at 55 °C for 12 hrs under N?, The reaction mixture was cooled to room temperature and filtered, concentrated in vacuum to give the crude product which was purified by prep-HPLC (eiuting with H2O/CH3CN (0.1% ΝΗ4Ή2Ο) from 80:20 to 5:95) to obtain (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-m

d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (Ex, 94, likely formed due to decomposition of DMF to dimethylamine) (6,0 mg, 0.01 mmoi, 6.2% yield) as white solid. LCMS M+H] : 433. 1. Ή NMR (400 MHz, DMSO-£¾) δ 8.69 (s, 1H), 7.79 (d, J= 3.6 Hz, 1H), 7.35-7.44 (m, 4H), 6.83 (d, J= 3.6 Hz, 1H), 6.16 (d, ./ 7.6 Hz, 1 1 1 ), 6.11 (d, J 4.4 Hz, 1 1 1 ).. 5.29 (d, J= 7.2 Hz, IH), 5.11 (d, J= 4 Hz, IH), 4.82-4.79 (t, J= 9.2 Hz , 1H), 4.60 (d, J= 5.2 Hz, IH), 4.12-4.10 (t, J= 8.4 HZ, IH), 4.01 (d, J= 4.8 Hz , 1H), 4.12-4.10 (t, J = 14.4 Hz, 2 H), 4.12-4.10 (t, J= 14.8 Hz, 2H), 2.19 (s, 6H). ¾ NMR (400 MHz, DMSO-i¾+D ₂ 0) δ 8.67 (s, IH), 7.75(d, J= 3.6 Hz, IH), 7,34-7,42 (m, 4H), 6.81 (d, J = 3.6 Hz, IH), 6.14 (d, J = 8 Hz, IH), 4.78 (d, J = 4.8 Hz, IH), 4.60-4.57 (m, IH), 4.09 (d, J = 5.2 Hz, IH), 4,01 (d, ./ 4.8 Hz , 1 H), 3.13-3.10 (t, J = 14.8 Hz, 2 H), 2.74-2.70 (t, J= 14.8 Hz, 2 H), 2.18 (s, 6 H).

Example 95. (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-( 2- ethyIsi8lfasiylethyl)pyrroIo[2 ₅ 3-d]pyrim5dm-7-yI]ietrahydrofuraii~3,4-dioI (Ex. 95)

10295] To a solution of [(R)-(4~chiorophenyl)-[(2S,3 S,4R,5R)-3,4~dihydroxy-5~(4- vinylpyrrolo[2,3-d]-pyrimidin-7-yl)tetrahydrofuran-2-yl]meth yl] 4-phenylbenzoate (94a) (41 ,4 mg, 0.05 mmoi) in NMP (5.0 mL) was added sodium thiomethoxide (23.4 mg, 0.32 mmoi) at 25 ^C 'C. The reaction mixture was stirred at 65 °C for 12 hrs under N2. The reaction mixture was cooled to room temperature and filtered, concentrated to give crude product which was purified by prep-HPLC (eluting with H ₂ 0:CH3CN (0.1%TFA) from 80: 10 to 5 :95) to afford 2R,3 S,4R,5R)-2-[(R)-(4- chlorophenyl)-hydroxy-methyl]-5-[4-(2-ethylsulfanylethyl)pyr rolo[2,3-d]pyrimidin-7- yl]tetrahydrofuran-3,4-diol (Ex. 95) (TFA salt, 2.0 mg, 0.0032 mmol, 6.0% yield) as a white solid. LCMS [M+H] : 436,0. ¾ NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1 H), 7,86 (d, J - 4.0 Hz, 1 H), 7.35-7.43 (m, 4 H), 6.91 (d, J = 3.6 Hz, 1 H), 6.18 (d, J = 7.6 Hz, 1 H), 4.81 (d, J = 4.8 Hz, 1 S i ). 4.58-4.62 (m, 1 1 1 ), 4.12 (d, J = 4.8 Hz, I I f ), 4.01 (d, J = 4.8 Hz, 1 H), 3.31 (t, J - 3 ,6 Hz, 1 H), 2.98 (t, J = 3.8 Hz, 1 S i ). 2.12 (s, 3 H ). 1 H NMR (400 MHz, DMSO-d6+D ₂ 0) δ 8.81 (s, 1 H), 7.87 (d, J = 4.0 Hz, 1 H), 7,34-7,41 (rn, 4 H), 6,96 (d, J = 3.6 Hz, 1 H), 6, 18 (d, J - 7,6 Hz, 1 H), 4,79 (d, J = 4.8 S ix. 1 H), 4.56-4.60 ( rn. 1 S i ), 4.1 1 (d, J - 4,8 Hz, 1 H), 4.02 (d, J = 4,8 Hz, I H), 3.33 (t, J 3.6 Hz, 1 H), 2.97 (t, J = 3.8 Hz, 1 H), 2.09 (s, 3 H ).

Example 96. 2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-(2 - methoxyethyl)pyrrolo-[2,3-d]pyrimidin-7-ylJtetrahydrofuran-3 ,4-diol (Ex. 96)

1 296] To a solution of HC1 (3M, 10.0 mL, 30 mmol) in methanol (10 mL) was added [(R)-(4-chlorophenyl)-[(2S,3 S,4R,5R)-3,4-dihydroxy-5-(4-vinylpyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (94a) (230.0 mg, 0.40 mmol) at 25 °C. The reaction mixture was stirred at 75 °C for 12 hrs under N ₂ . After the reaction was complete, the reaction mixture was cooled to room temperature and was added hydrazine hydrate (2.0 mL, 41.15 mmol) and stirred for 0.5 h. The reaction mixture was purified by prep-HPLC (eluting with

HzOiCHsCN (0. TON S i -i !,-<) } from 90: 10 to 5 :95) to give 2R,3 S,4R,5R)-2-[(R)-(4-chlorophenyl)- hydroxy-methyl]-5-[4-(2-methoxyethy (Ex. 96) (23.6 mg, 0.0530 mmol, 13.1 % yield) as a white solid. LCMS [M+Hj: 420.1 , ¾ NMR (400 MHz, DMSO-i¾) δ 8.67 (s, 1 H), 7.79 (d, J = 3.6 Hz, 1 H), 7.43-7.35 (m, 4 H), 6.83 (d, J = 3.6 Hz, 1 H), 6.16 (d, ./ 7.6 Hz, 1 H), 6,09 (d, J= 4 Hz, 1 I S ), 5.29 (d, ./ 6,8 Hz, 1 H ), 5.10 (d, ./ 4,0 Hz, 1 H), 4.82-4.79 (m, 1 H), 4.63-4.57 (m, 1 H), 4. 13-4. 10 (m, 1 H), 4.01 (d, ./ 5.2 Hz, 1 S i ). 3.84- 3.81 (m, 2 I ! }, 3.24-3. 19 (m, 5H), ¾ NMR (400 MHz, I)MS()-c.'¾ · 0 :0) 6 8.64 (s, 1 I S ), 7.66 (d, J 3.6 Hz, 1 H), 7.38-7.31 (m, 4 H), 6.78 (d, ./ 4 Hz, 1 H), 6.09 (d, 7.6 Hz, 1 H), 4.76 (d, ../ 4.8 Hz, 1 H), 4,59-4,56 (m, 1 H ), 4. 1 1 -4. 10 n,. 2 H), 3.80-3.76 (m, 2 H), 3.21-3. 17 (m, 5 H). Example 97. O-methyl N-[7-[(2R,3R,4S,5R)-5-[(R)-(4-chlorophenyl)-hydroxy-methylJ- 3,4-di- hydroxy-tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]ca rbamothioate (Ex. 97)

S

HN J

HO— < °

HO Ci

97a Ex, 97

a) Synthesis of compound 97a 0297] To a solution of 7-[(2S,3R,4R,5R)-5-[(R)-(4-chlorophenyl)-triethylsilyloxy- methyl]-3,4-bis(triethylsilyloxy)tetrahydrofuran-2-yl]pyrrol o[2,3-d]pyrimidin-4-amine (Int-1-2)

(50,0 mg, 0.07 mmol) was stirred in chloroform (3.0 mL) and water (1 ,0 mL), Na ₂ C0 ₃ (36.82 mg, 0,35 mmol) was added followed by drop wise addition of thiocarbonyl dichlonde (0,02 mL, 0,21 mmol). The reaction mixture was stirred at r.t. for 4 hrs, then diluted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuum. To this chloroform solution of crude isothiocyanate was added methanol (3.0 mL) and the mixture was heated 65 °C in a sealed tube for 2 hrs. The reaction mixture was concentrated in vacuum to give crude product which was used in the next step directly. b) Synthesis of O-methyl N-[7-[(2R,3R,4S,5R)-5-[(R)-(4-chlorophenyl)-hydroxy-methyl]- 3,4- di-hydroxy-tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl ]carbamothioate (Ex, 97)

|1298] To a solution of O-methyl N-[7-[(2R,3R,4R,5R)-5-[(R)-(4-chlorophenyl)- triethylsilyloxy-methyl]-3,4-bis(triethylsilyloxy)tetrahydro furan-2-yl]pyrrolo[2,3-d]pyrimidin-4- yljcarbamothioate (97a) (50.0 mg, 0.06 mmol) in DMSO (3.0 mL) and methanol (0.04 mL) was added CsF (47.85 mg, 0.3 mmol). The reaction mixture was stirred at 25 °C for 4 hrs. After the reaction was complete, the mixture was concentrated in vacuum and the residue was purified by Prep-HPLC (0, 1% NH H W), 10-40% MeCN/H ₂ 0) to give O-methyl \-i 7-| (2 _; 3R _: 4S^ )-5-i (R)- (4-chlorophenyl)-hydroxy-methyl]-3,4-di-hydroxy-tetrahydrofu ran-2-yl]pyrrolo[2,3-d]pyrimidin-4- yljcarbamothioate (Ex. 97) (4.0 mg, 0.008 mmol, 12.7% yield) as yellow solid. LCMS [M+tl]: 451.3. ¾ NMR (400 MHz, CDsQD-tW): δ 9.30 (s, 1 H), 7.42-7.33 (m, 5 H), 6.92 ( d, J= 3.2 Hz, 1 H ), 6.37 ( d, J= 3.6 Hz, 1 H ), 5.91 ( d, J = 6.8 Hz, 1 H ), 4.84 ( m, 1 H), 4.32 (t, J = 6.0 Hz, 1 H), 4. 17 ( , 1 H), 4.09 ( m, 4 H).

Example 98. (2 ,3R,4S,SS)-2-(4-ehloro-7H-pyrrolo[2,3-d]pyrimidisi-7-yI)-5-{ { )-l-{4- ch!oropheeyI)-2 ₅ 2,2~irifl oro~l~hydroxyethyS)tetra ydroferai¾-3,4-diol (98)

a) Preparation of compound 98a

299| To a solution of ((3aS,4S,6R,6aR)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl )- 2,2-dimethyltetrahydrofuro[3,4-d][l ,3]dioxol-4-yl)(4-chlorophenyl)methanone (50 mg, 115 umol, I eq.) in THF (2 mL) was added CsF (87.5 nig, 576 umol, 21.2 uL, 5 eq.), TMSCFs (32.7 mg, 230 umol, 2 eq.). The mixture was stirred at -20 °C for 3 hr. LC-MS showed the reaction was completed and one main peak with desired MS was detected. The reaction was quenched by H2O (4 mL), and extracted with EtOAc (4 mL*3), and the organic phase was concentrated in vacuo. The residue was purified by prep-TLC (S1O2, Petroleum ether: Ethyl acetate = 5: 1). Compound 98a (10 mg, crude) was obtained as a white solid. The more polar product was the other diastereomer. ^l H NMR

(400MHz, CHLOROFORM-d) δ - 8,63 (s, IH), 8,07 (s, IH), 7.65 - 7,53 (m, 2H), 7.36 (d, j 8.3 Hz, 2H), 7.26 - 7.20 (m, IH), 6.57 (d, .1=3.5 Hz, IH), 5.78 (d, j=5.0 Hz, IH), 5.09 - 4.90 (m, 2H), 4.48 (br d, j 6.4 Hz, IH), 1.48 (s, 3H), 1.09 - 1 ,04 (m, 3H); I ( ^" MS: (M I S ): 503.9, 505,9; TLC

(Petroleum ether: Ethyl acetate = 5: 1) Rf = 0.43.

b) Preparation of (2R,3R,4S,5S)-2-(4-cMoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- ((R)-l-(4- chloropheny 1 )-2,2,2-trifluoro- 1 -hydroxy ethyl)tetrahydrofuran-3 ,4-di ol (98)

| ^' 0300j A solution of compound 98a (10 mg, 19,8 umol, 1 eq.) in TFA (0,98 mL) and H2O (0.02 mL), the mixture was stirred at 25 °C for 1 hr. LC-MS showed compound 98a was consumed completely and one main peak with desired MS was detected. The mixture was concentrated in vacuo at 25 °C. The residue was purified by prep-HPLC. Ex. 98 (7 mg, 15 umol, 73% yield, 96% purity) was obtained as a colorless oil. ¾ NMR (400MHz, DMSO-d6) δ = 8.76 (s, 1 1 1 ).. 8.06 (d, j=3.8 Hz, IH), 7.87 (s, IH), 7.70 (d, j 8.7 Hz, 2H), 7.58 (d, j 8.7 Hz, 21 1 ), 6.82 (d, .1=3.8 Hz, IH), 6.15 (d, j 8 1 Hz, 1 1 1), 4.71 (s, IH), 4.53 (dd, j 5,4, 8.0 Hz, IH), 3 ,65 (br d, .1 5.4 Hz, IH); ' I f MR (400MHz, DMSO-d6 + D20) δ = 8.72 (s, IH), 8.00 (d, J=3.5 Hz, H), 7.71 - 7.63 (m, 2H), 7.54 (d, J=8.8 Hz, 2H), 6.79 (d, J=3.9 Hz, 1H), 6.10 (d, J=8.3 Hz, IH), 4.68 (s, IH), 4.50 (dd, J=5.3, 7.9 Hz, I H), 3.61 (d, .) 5.3 Hz, H), LCMS: (M+H+): 464,0; HPLC purity: 97,96%,

Example 101. (2R,3S,4R,5R)-2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methy l)-5-(4-(2- ch!oroethyI)-7H-pyrrolo[2^-d]pyrimidin~7~y!)teirahydrofuraii ~3,4~dioI (101)

10301 J To a solution of (2R,3 S,4R,5R)-2-[(R)-(4-chloro-3-fluoro-phenyl)-hydroxy- methyl]-5-(4-vinylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofur an-3,4-diol (Ex, 102) (27 rng) in HCl/dioxane (1 ml) was stirred at 25 °C for 30 min. LCMS showed the desired product. The reaction mixture was purified directly by reversed phase Chem-flash eluting with CH3CN/H2O (neutral condition) from 5/95 to 95/5 to give the solution of the desired product which was lyphilized to give (2R,3R,4S,5R)-2-[4-(2-cMoroethyl)pyrrolo[2,3-d]pyrimidin-7-y l]-5-[(R)-(4- chloro-3-fluoro-phenyl)-hydroxy-methyl]tetrahydrofuran-3,4-d iol (Ex. 101) (1 .38 mg, 0.003 mmol , 4.6% yield) as a white solid. This compound is not stable under strong acidic conditions, and elimination occurs to give the vinyl starting material (Ex. 102). ¾ NMR (400 M Hz, DMSO-d6): δ 8.75 (s, 1 H), 7.84 (d, J = 3.6 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 7.39 (dd, Jl = 10.8 Hz, Jl = 1.2 Hz, 1 H), 7,27 (d, J = 8,0 Hz, I 1 1 ).. 6.87 (d, J = 3 ,6 Hz, I I f }.. 6.17-6.19 (m, 2 I f ), 5.30 (d, J = 7.2 Hz, 1 S i ). 5.14 (d, J = 4.0 Hz, 1 H), 4.82 (t, J = 4.8 Hz, 1 H), 4.56-4.62 (m, 1 H), 4.11-4.16 (m, 3 H), 4.01 (d, J = 5.2 Hz, 1 H), 3.48 (t, J = 6.4 Hz, 2 H). ¾ NMR (400 M Hz, DMSO-d6 + D20 ): δ 8.75 (s, 1 i s), 7,81 (d, J = 3.6 Hz, 1 H), 7,51 (t, J = 8.0 Hz, 1 H), 7.38 (d, J = 10.4 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 6.86 (d, J = 3.6 Hz, 1 H), 6.18 (d, J = 7.6 Hz, 1 H), 4.82 (t, J = 5.2 Hz, 1 H), 4.58-4.61 (m, 1 H), 4, 12-4, 16 ins, 3 H), 4,03 (d, J = 5,2 Hz, 1 H), 3.48 (t, J = 6.4 Hz, 2 H). ^{i 9} F NMR (376 M Hz, DMSO-d6): δ -116.89 (s, I F).

Example 102. (2R,3S,4R,5R)-2-[(R)-(4-chloro-3-fluoro-phenyl)-hydroxy-meth yl]-5-(4- vinylpyrrolo[2,3-dlpyrimidin-7-yl)tetrahydrofuran-3,4-diol (Ex. 102)

102a Ex. 102 a) Synthesis of compound (0302] A mixture of [(R)-(4-chloro-3-fluoro-phenyl)-[(2S,3S,4R,5R)-5-(4- chloropyrrolo[2,3 -d]pyrimidin -7-yl)-3 ,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (prepared similar to that of Int-3) (500.0 mg, 0.84 mmol), pinacol vinylboronate (1295.5 mg, 8.41 mmol), l, -bis(diphenylphosphino)ferrocene-palladium(n) dichloride dichloromethane complex (68.7 mg, 0.08 mmol), potassium phosphate (535.7 mg, 2.52 mmol), 1,4-dioxane (30.0 mL) and water (5.0 mL, 277.47 mmol) was degassed with N2. The mixture was stirred at 90 °C for 16 hrs. LCMS (SYZ002-5-R1) showed the desired product was detected. The mixture was concentrated and the residue was purified by reversed phase combi-flash eluting with CH3CN/H2O (neutral condition) from 10/90 to 90/10 to give [(R)-(4-chloro-3-fluoro-phenyl)-[(2S,3S,4R,5R)-3,4-dihydroxy -5-(4- vinylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl]methy l]4-phenylbenzoate (160.0 mg, 0.27 mmol, 32.46 % yield) as white solid. LCMS [M+H]: 586.2.

b) Synthesis of (2R,3 S,4R5R)-2-[(R)-(4-chloro-3-fluoro-phenyl)-hydroxy-methyl]-5- (4- vinylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (Ex. 102)

|Θ303| To a suspension of [(R)-(4-chloro-3-fluoro-phenyl)-[(2S,3S,4R,5R)-3,4-dihydroxy - 5-(4-vinylpyrrolo [2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (160,0 mg, 0.26 mmol) in 1-butanol (6.0 mL), potassium carbonate (35.7 mg, 0.26 mmol) was added. The mixture was stirred at 1 10 °C for 1 h, LCMS showed the reaction was completed. The mixture was filtered and the filtrate was purified by reversed phase combi-flash eluting with CH3CN/H2Q

(neutral condition) from 5/95 to 95/5 to give the solution of the desired product which was lyophilized to give (2R,3 S,4R,5R)-2-[(R)-(4-chloro-3-fiuoro-phenyl)-hydroxy-methyl]-5 -(4- vinylpyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (Ex. 102) (62,3 mg, 0.15 mmol, 56.53 % yield) as a white solid. LCMS [M+H] : 406.1. ^l H NMR (400 M Hz, DMSO-rfd): δ 8.76 (s, 1 H), 7.90 (d, J = 4.0 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 7.39 (dd, Jj = 10.8 Hz, Ji = 1.2 Hz, 1 H), 7.19-7.28 (m, 2 H), 6.98 (d, 4,0 Hz, 1 H), 6,64 (dd, Ji = 17.2 Hz, J ₂ = 2,4 Hz, 1 H), 6.17-6.19 (m, 2 H), 5.82 (dd, J= 10.8 Hz, 1.2 Hz, 1 H), 5.30 (d, J= 7.2 Hz, 1 H), 5.14 (d, J= 4.0 Hz, 1 H), 4.83 (t, J = 4.8 Hz, 1 H), 4.57-4,62 (m, 1 H), 4, 12 (i, 4,4 Hz, 1 H), 4,01 (d, ./ 4.8 Hz, I H). ¾ NMR. (400 : HZ, ΌΜ&Ο-άό+ΏιΟ ): δ 8.76 (s, 1 H), 7.85 (d, J= 4.0 Hz, 1 H), 7.51 (t, J= 8.0 Hz, 1 H), 7.38 (dd, J = 10.4 Hz, 1 ,6 Hz, I 1 1 ).. 7.19-7.28 (m, 2 1 1 ).. 6.97 (d, J= 3.6 Hz, 1 H), 6.64 (dd, J == 13 ,6 Hz, 1.2 Hz, 1 i f ), 6.18 (d, 7.6 Hz, 1 H), 5.84 (dd, Ji = 10.8 Hz, Ji == 1 .6 Hz, 1 H), 4,83 (d, ./ 5.2 Hz, 1 H), 4.60 (m, 1 H), 4.13 (d, J= 5.2 Hz, 1 H), 4.04 (dd, J = 5.2 Hz, 1.6 Hz, 1 H). ¹⁹ F NMR (376 M Hz, DMSO-<¾): δ -1 16.90 (s, I F). Example 103. l-(7-((2R,3R,4S,5R)-5-((R)-(4-chloro-3-fluorophenyl)(hydroxy )methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylthiourea (103)

a) Synthesis of compound 103b 0304] To a solution of7-[(2R,3R,4R,5R)-5-[(R)-(4-chloro-3-fluoro-phenyl)- triethylsilyloxy-methyl]-3,4-bis(triethylsilyloxy)tetrahydro furan-2-yl]pyrrolo[2,3-d]pyri amine (103a, prepared similarly to that of In t- 1-2) (780. nig, 1.06 mmol) in Chloroform (9 ml.) and water (3 mL), Sodium carbonate (560.44mg, 5.29 mmol) was added, and then Thiophosgene (364.78mg, 3.17 mmol) was added by dropwise. The reaction mixtrure was stirred at 25 °C for 4 hrs. DCM (20 mL) was added. The organic layer was seperated, dried over Na2S04, filtered and concentrated to give a brown oil which was used directly for the next step.

b) Synthesis of compound 103c

To a solution of[(R)-(4-chloro-3-fluoro-phenyl)-[(2R,3R,4R,5R)-5-(4- isothiocyanatopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-bis(tri^

yl]methoxy]-triethyl-silane (103b) (623.7mg, 0.80 mmol) in Chloroform (4 mL), Methyl amine in THF (3.mL, 0.80 mmol) was added. The mixture was sealed and stirred at 65 °C for 2 hrs. The reaction mixture was used directly for the next step.

c) Synthesis of . l-(7-((2R,3R,4S,5R)-5-((R)-(4-chloro-3-fluorophenyl)(hydroxy )methyl)- 3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidi n-4-yl)-3- methylthiourea (103)

10305] To a solution of l-[7-[(2R,3R,4R,5R)-5-[(R)-(4-chloro-3-fluoro-phenyl)- triethylsilyIoxy-methyl]~3,4 ^ 3-methyl-thiourea (103c) (650. mg, 0.64 mmol) (from the crude reaction mixture of SYZ002-13-1) in DMSO (5 mL) and Methanol (Q.OSniL, 1.23 mmol), Caesium fluoride (487.17mg, 3.21 mmol) was added. The mixture was stirred at 25 °C for 4 h. TLC showed 103c (PE/EA == 5/1 , Rf = 0,4) had been consumed completely. LCMS showed the desired product was detected. The mixture was filtered and the fi ltrate was purified by reversed phase Chem-fiash eluting with eluting with

CH3CN/H2Q from 5/95 to 95/5 to give the crude product (35 mg, purity 91 %), which was sent to Prep-HPLC to take the further purification (eluting with CH3CN/H20 from 5/95 to 95/5) to give 1 - [7-[(2R _^ 3R,4S,5R)-5-[(R)-(4-chloro-3-fluoro-phenyl)-hydroxy-me thyl]-3,4-dihydroxy- tetrahydrofuran-2-yl]pynOlo[2,3-d]pyrimidin-4-yl]-3-methyl-t hiourea (Ex. 103) (17.8 mg, 0.037 mmol, 5,71 % yield) (yield over three steps) (purity 96.3 %) as a white solid. ¾ NMR (400 M Hz, DMSO-d6): δ 12.01 (d, J = 4.0 Hz, 1 H), 10.88 (s, 1 H), 8.46 (s, 1 H), 7.70 (d, J = 3.2 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 10.8 Hz, 1 H), 7,3 (d, J = 3 ,2 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 6.12-6.16 (m, 2 H), 5.29 (d, J = 6.4 Hz, 1 H), 5.13 (d, J = 3.6 Hz, 1 H), 4.81 (brs, 1 H), 4.52-4.58 (m, 1 H), 4. 1 1 (brs, I I I ), 4.00 (d, J = 4.8 Hz, 1 H), 3.15 (d, J = 4.0 Hz, 3 H). ¾ NMR (400 M Hz, DM:SO-d6 + D20 ): δ 8.47 (s, 1 H), 7.68 (d, J = 3.6 Hz, 1 S i ). 7.51 (t, J = 8.0 Hz, 1 H), 7.38 (dd, J = 10.8, 1.6 Hz, 1 H), 7,25-7,29 (m, 2 H), 6, 13 (d, J - 7.6 Hz, 1 H), 4,78 (d, J = 4,8 Hz, I 1 1 ).. 4.54-4.57 (m, 1 H), 4.1 1 (d, J = 4.8 Hz, 1 H), 4.01 (d, J = 4.8 Hz, 1 H), 3.15 (s, 3 H). ^{i 9} F NMR (376 M Hz, DMSO-d6): 5 -1 16.89 (s, I F).

Example 104. 4-(7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)- 3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)butan-2-o (104)

a) Synthesis of compound 104a

|§306) To a solution of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine (2784.4 mg, 11.36 mmol) in dry THF (30.0 mL) was added pyridine (0,92 mL, 1 1.34 mmol), DIAD (4,7 mL, 23.82 mmol), tributylphosphane (5.7 mL, 22.68 mmol) and [(R)-(4-chlorophenyl)-[(2S,3S,4R)-3,4,5- trihydroxytetrahydrofuran -2-yl] methyl] 4-phenylbenzoate (Int-2-3) (5000.0 mg, 11.34 mmol) under N ₂ . The reaction mixture was stirred at 30 °C for 1 h under N ₂ . LCMS showed the reaction was completed. The mixture was purified by silica chromatography column (DCM : CH OH = 100 : 1 to 60 : 1) to give [(R)-(4-chlorophenyl)-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(4-iodo pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (104a) (2.0 g, 2.99 mmol, 26.4% yield). LCMS [M+H] : 668.2.

b) Synthesis of compound 104b

10307] To a solution of [(R)-(4-chlorophenyl)-[(2S,3 S,4R,5R)-3,4-dihydroxy-5-(4- iodopynOlo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (104a) (2.0 g, 2.99 mmol) in DMF (25.0 mL) was added 2,2-Dimethoxypropane (11.1 mL, 90.4 mmol) and Amberlyst 15 ion-exchange resin (2.0 g). The mixture was stirred at 55 °C 2 h. LCMS showed the reaction was completed. The reaction mixture was filtered, washed with EA (20.00 mL), added H2O (10.00 mL) and EA (50.00 mL) to the filtrate. The organic phase was washed with H2O (10.0 mL X 3), dried over Na ₂ S0 ₄ , filtered, concentrated in vacuum to give crude product which was purified by silica chromatography column (PE : EA = 8 : 1) to give [(R)-[(3aR,4R,6R,6aR)-4-(4- iodopyrrolo[2,3-d]pyrimidin-7-yl)-2,2 -dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]- (4-chlorophenyl)methyl]4-phenylbenzoate (104b) (1.0 g, 1.42 mmol, 47.2% yield). LCMS [M+H]: 708,0.

c) Synthesis of compound 104c

11308] To a solution of [(R)-[(3aR,4R,6R,6aR)-4-(4-iodopyrrolo[2,3-d]pyrimidin-7-yl) - 2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6-yl ]-(4-chlorophenyl)methyl] 4- phenylbenzoate (104b) (35.0 mg, 0.05 mmol) in DMF (2.00 mL) was added but-3-yn-2-ol (0.06 mL, 0.20 mmol), triethylamine (25.0 mg, 0.25 mmol), dichloropalladium triphenylphosphane (3.5 mg, 0.01 mmol), and iodocopper (1.9 mg, 0.01 mmol). The mixture was stirred at 25 °C for 2 h under N ₂ . LCMS showed the reaction was completed. The reaction mixture was concentrated to give crude product which was purified by pre-TLC (PE : EA = 6 : 1 ) to give (l R)-(4- chlorophenyl)((3aR,4R,6R,6aR)-6-(4 -(3-hydroxybut -l-yn-l-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-

rag, 0.03 nmiol, 47,2% yield). LCMS [M+H] : 650.2,

d) Synthesis of compound 104d i m\ To a solution of [(R)-[(3aR,4R,6R,6aR)-4-[4-(3-hydroxybut-l-ynyl)pyrrolo[2,3- d]pyrimidin-7-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][l ,3]dioxol-6-yl]-(4- chlorophenyl)methyl]4-phenylbenzoate (104c) (1060.0 nig, 1.63 mmol) in DCM (20.0 mL) was added Dess-Martin periodinane (1383.1 mg, 3 ,26 mmol). The mixture was stirred at 30 °C 16 h. LCMS showed the reaction was completed. The reaction mixture was added NaHCCb aqueous (30.00 mL), extracted with DCM (30.00 mL X 3). The organic layers were washed with brine (50.0 mL), dried over Na2S0 ₄ , concentrated in vacuum to give crude product which was purified silica chromatography column (PE : EA = 5 : 1) to give [(R)-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-[4-(3- oxobut-l-ynyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrah ydrofuro[3,4-d][l ,3]dioxol-6-yl]-(4- chlorophenyi)methyl] 4-phenylbenzoate (690.0 mg, 1.06 mmol, 65.3 % yield). LCMS [M+H]:

648.2,

e) Synthesis of compound 104e im ] To a solution of [(R)-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-[4-(3-oxobut-l- ynyl)pyrrolo[2,3-d]pyramidin-7-yl]-3a,4,6,6a-tetrahydrofuro[ 3,4-d][l ,3]dioxol-6-yl]-(4- chlorophenyi)methyl] 4-phenylbenzoate (104d) (290.0 mg, 0.45 mmol) in ethanoi (10.0 mL) was added palladium on carbon (29.0 mg ). The mixture was stirred at 30 °C for 2 h. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in vacuum to give crude product which was used for the next step directly. LCMS [M+H]: 652.3.

f) Synthesis of compound 104f

113111 To a solution of [(R)-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-[4-(3-oxobutyl)pyrrolo[ 2,3- d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol -6-yl]-(4-chlorophenyl)methyl] 4- phenylbenzoate (104e) (290.0 mg, 0.45 mmol) in methanol (5.0 mL) was added K2CQ3 (122.7 mg, 0.89 mmol). The mixture was stirred at 30 °C 2 h. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in vacuum to give crude product which was purified by silica chromatography column (PE : EA = 3 : 1) to give 4-[7-[(3aR,4R,6R,6aR)-6-[(R)-(4- chlorophenyl) -hydroxy-methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d ][l ,3]dioxol-4- yl]pyrrolo[2,3-d]pyrimidin-4-yl]butan-2-one (104f) (120.0 mg, 0.25 mmol, 57.2 % yield). LCMS [M+H]: 472.2.

g) Synthesis of 4-[7-[(2R,3 ,4S,5 )-5-[(R)-(4-chlorophenyl)-hydroxy-methyl]-3,4-dihydroxy- tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]butan-2-on e (Ex. 104)

[0312] To a solution of 4-[7-[(3aR,4R,6R,6aR)-6-[(R)-(4-chlorophenyl)-hydroxy-methyl ]- 2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l ,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-yl]butan-^ one (Ex. 104) (120.0 mg, 0.25 mmol) in Water (2.0 niL) was added TFA (1.7 niL, 22.33 mmol). The reaction mixture was stirred at 30 °C for 0.5 h. LCNTS showed the reaction was completed. The mixture was purified by prep-HPLC, eluted with CH ₃ CN in H ₂ 0 (0.1 % TFA) from 5.0% to 95.0% to give 4-[7-[(2R,3R,4S,5R)-5-[(R)-(4-c oro

tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]butan-2 -one (Ex. 104) (25.0 mg, 0.06 mmol, 22.4% yield) as a white solid. LCMS [M+H]: 432.2, ¾ NMR (400 MHz, DM S(W- · [).:()): δ 8,66 (s. 1 1 1 ), 7.75-7.76 (d, ,/ 3.6 Hz, 1 H), 7.36-7.43 (m, 4 H), 6.81 -6.82 (d, .1 3,6 Hz, 1 ! ! }. 6, 14-6, 16 (d, J = 8.0 Hz, 1 H), 4.79-4.80 (d, J= 4.8 Hz, 1 H), 4.58-4.61(m, 1 H), 4.1 1-4.12 (d, J= 5.2 Hz, 1 i s), 4,02-4,03 (d, ./ 4.0 Hz, 1H), 3, 18-3.22(m, 2 H), 3.01-3.05(m, 2 H), 2.16(s, 3 Ft).

Example 114. l-(7-((2Et,3R,4S,5R)-5-((R)-(3,4-dichlorophenyl)(hydroxy)met hyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-3-methylimidazolidin- (1

114b

a) Synthesis of compound 114b jS313j A mixture of [(R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-y l)-2,2- dimethyl- 3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-(3,4-dichlo rophenyl)methyl]4- phenyibenzoate (114a, prepared similar to that of Int-3) (200.0 mg, 0.30 mmol), 1 - methylimidazolidin-2-one (61.5 mg, 0.60 mmol), Potassium carbonate (106.2 mg, 0.80 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (35.6 mg, 0.10 mmol) and ™S(D:IBENZYLIDENEACETONE)DIPALLAD1IJM(0) (28.1 mg, 0.03 mmol) in 1,4-Dioxane (8.0 mL) was degassed with N ₂ . The mixture was stirred at 80 °C for 16 h. LCMS showed the reaction was completed. This batch was combined with another reaction (100,0 mg, 0.15 mmol)). The mixture was filtered and extracted with EA (100.0 mL X 3). The organic layers were concentrated to give crude product which was purified by silica chromatography (PE ; EA = ^;: 5 : 1 to 1 : 1) to give [( )-[(3aR,4R,6R,6aR)-2,2-dimethyl-4-[4-(3-methyl-2-oxo-imidazo lidin-l - yl)pyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3, 4-d][l,3]dioxol-6-yl]-(3,4- dichlorophenyl)methyl]4-phenylbenzoate (114b) (280.0 mg, 0.39 mmol, 86.7%) as a white solid. LCMS [M-i-H] : 714,3 , b) Synthesis of compound 114c ί 31 1 To a solution of [(R) (3aR,4R,6R,6aR)-2,2H!imethyl-4-[4-(3-methyl-2-oxo- imidazolidin-1 - yl)pyrrolo[2,3-d]pyrimidin-7-yl]-3a,4,6,6a-tetrahydrofuro[3, 4-d][l,3]dioxol-6-yl]- (3,4-dichlorophenyl)methyl] 4-phenylbenzoate (114b) (270.0 mg, 0. 1 mmol) in 1-Butanol (4.0 mL), Potassium carbonate ( 156.7 mg, 1.1 mmol) was added. The mixture was stirred at 60 °C for 2 h. LCMS showed the reaction was completed. The mixture was filtered and washed with EA (50.0 mL). The filtrate was concentrated to give crude product which was purified by reversed-phase combi-flash, eluted with CEbCN in H2O (neutral condition) from 5.0% to 95.0% to give l-[7- [(3aR,4R,6R,6aR) -6-[(R)-(3,4-dichlorophenyl)-hydroxy-methyl]-2,2-dim

tetrahydrofuro[3,4-d][ l ,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-yl]-3-methyl-imidaz olidin-2-one

(114c) (180.0 mg, 0.30 mmol, 89.1 % yield) as a white solid. LCMS [M+Ffj : 534. 1.

c) Sy thesis of l-[7-[(2R,3R,4S,5R)-5-[(R)-(3,4-dichlorophenyl)-hydroxy-meth yl]-3,4- dihydroxy-tetrahydrofuran-2-yi]pyrro^

hydrochloride (Ex. 114)

(0315] A mixture of l-[7-[(3aR,4R,6R,6aR)-6-[(R)-(3,4-dichlorophenyl)-hydroxy-me thyl]- 2,2-dimethyl- 3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-4-yl]pyrrolo[2,3- d]pyrimidin-4-yl]-3- methyl-imidazolidin-2-one (160,0 mg, 0.31 mmol) in TFA (1.6 mL, 21.51 mmol) and Water (2,4 mL, 133.20 mmol) was stirred at 25 °C for 2 h. LCMS showed the reaction was completed. The mixture was concentrated and purified by prep-HPLC, eluted with CFLCN in H2O (0. 1 % TFA) from 5.0% to 95.0% to give the solution of the desired product which was added HCl aq. (4.0 mL, 2 N) and lyophilized to give l-[7-[(2R,3R,4S,5R)-5-[(R)-(3,4-dichlorophenyl)-hydroxy-m dihydroxy-tetrahydrofuran-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl] -3-methyl-imidazoli

hydrochloride (Ex. 114) (115.0 mg, 0.21 mmol, 72, 1 % yield) as a white solid. LCMS [M+H]:

494.3. ¾ NMR (400 M Hz, DMSO-fife): δ 8.58 (s, 1 H), 7.85 (d, J = 3.6 Hz, 1 H), 7.63 (d, J= 1.6 Hz, 1 H), 7,57 (d, J= 8.4 Hz, 1 H), 7.38-7.41 (m, 1 H), 7.17 (d, ,/ 4.0 Hz, 1 H), 6,20 (d, ./ 7.6 Hz, 1 H), 4.82 (d, J= 5.6 Hz, 1 H), 4.52-4.56 (m, 1 H), 4.21-4.25 (m, 2 H), 4.12 (d, J= 5.2 Hz, 1 H), 4.01 (d, J = 5,2 Hz, 1 H), 3.61-3.65 (m, 2 H), 2,90 (s, 3 I I ). Ή NMR (400 M Hz, DM S(W- · [ ^" ).:() ): δ 8.60 (s, 1 H), 7.83 (d, J= 4.0 Hz, 1 H), 7.60 (d, J= 1.6 Hz, 1 H), 7.57 (d, J= 8.4 Hz, 1 H), 7.37- 7.40 (m, 1 I I ). 7.15 (d, J= 4.0 Hz, 1 H), 6.21 (ύ, .ί 7,6 Hz, 1 H), 4,81 (d, J= 5.2 Hz, 1 H), 4.53- 4.56 (m, 1 1 1 },, 4.26-4.31 (m, 2 H), 4, 14 (d, 5.2 Hz, 1 H), 4.06 (d, ./ 5,2 Hz, 1 H), 3 ,65-3 ,69 (m, 2 H), 2.91 (s, 3 H).

Example 119. (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R) -[4-chloro-2- (hydroxymethyl)phenyl]-hydroxy-methyl]tetrahydrofuran-3,4-di oI (Ex. 119)

119c 119d Ex, 119

a) Synthesis of compound 119a

|i3 ^' I6] To a solution of (2-bromo-5-chloro-phenyl)methoxy-tert-butyl-dimethyl-silane

(4.3g, 12.8 mmol) in THF (50 mL) under an atmosphere of nitrogen at -78 °C was added

butyllithium (0.59g, 9.14 mmol), and the resultant solution was stirred for 10 min. A solution of the

(3aR,4R,6S,6aS)-4-(4-chloropyirolo[2,3-d]pyrimidin-7-yl)- N-methoxy-N,2,2-trimethyl-3a,4,6 tetrahydrofuro[3,4-d][l ,3]dioxole-6-carboxamide (1.4g, 3.66 mmol) in THF (50 mL) was then added dropwise, and the mixture was stirred at -78 °C for 30 min. The reaction was monitored by

LCMS, which showed the desired mass. Saturated NH ₄ C1 solution (50 mL) was added, and the aqueous mixture was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (40 mL) and dried over NauSO, and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (100-200 mesh size) using petroleum ether/EtOAc (20: 1-10: 1) as eiuent to give [(3aR,4R,6S,6aS)- 4-cWoropyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyl-3a,4,6,6a-tetraty^

butyl(dimethyl)silyl]oxymethyl]-4-chloro-phenyl]methanone (119a) (1.3 g, 2.25 mmol, 61.4% yield) as a pale yellow oil. LCMS M l ! 578.2/580.2, b) Synthesis of compound 119b

10317] To a solution of [(3aR,4R,6S,6aS)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2- dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l _^

4-chloro-phenyl]methanone (119a) (500. mg, 0.86 mmol) in Toluene (20 mL) under an atmosphere of nitrogen at -78 °C was added diisobutylalumane (245.82mg, 1.73 mmol), the reaction mixture was stirred at -78 °C for 0.5 h. The reaction was monitored by TLC (PE EA = 3/1, Rf = 0.3), it was showed the starting material consumed. The reaction mixture was washed with water (10 mL) and saturated NaCl (10 mL). The resulting organic layer was dried over anhydrous Na ₂ S0 ₄ and the solvent was removed in vacuo to give (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7- yl)-2,2-dimethyl~3a,4,6,6a-tetrahydrofuro[3,4~d][L3]dioxol-6 -yl] 2-[[tert~

butyl(dimethyl)silyl]oxymethyl]-4-chloro-phenyl]methanol (119b) (490 mg, 0.844 mmol, 97,7% yield) as a pale yellow solid.

c) Synthesis of compound 119c

{0318] To a solution of (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl )- 2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6-yl ]-[2-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-chloro-phenyl]methanol (119b) (490. mg, 0.84 mmol) in DMSO (10 mL) and Methanol (0.10 mL) at 25 °C was added CsF (384.6mg, 2.53 mmol), the reaction mixture was stirred at 25 °C for 0.5 h. The reaction was monitored by TLC (PE/EA = 3/1, Rf = 0.5), which showed the starting material was consumed. The reaction mixture was washed with water (10 mL) and saturated NaCl (10 mL). The resulting organic layer was dried over anhydrous Na2S04 and the solvent was removed in vacuo to give (R)-[(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][l,3]dioxol-6-yl]-[4-chloro-2- (hydroxymethyl)phenyl]methanol (119c) (300 mg, 0.643 mmol, 76.2% yield) as a pale yellow solid. d) Synthesis of compound 119d

18319) A solution of (R)-[(3aR,4R,6R,6aR)-4-(4-cWoropyrrolo[2,3-d]pyrimidin-7-yl) -2,2- dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-[4 -chloro-2-

(hydroxymethyl)phenyl]methanol (119c) (50. mg, 0.1 1 mmol) in 1,4-Dioxane (5 niL) and X! l ; ^» l f <() (5.mL, 130 mmol) was stirred at 120 °C for 16 hours. The reaction was monitored by LCMS, which showed the desired mass. The solvent was removed in vacuo and the residue was purified by reversed phase Chem-flash eluting (neutral condition, H2O/ACN=80/20-5/95) to give (R)- [(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2 -dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-[4-chloro-2-(hydroxym ethyl)phenyl]methanol (119d) (45 nig, 0.10 mmol, 93.9% yield) as pale yellow solid. LCMS M ! 1 447.2.

e) Synthesis of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R) -[4-chloro-2- (hydroxymethyl)phenyl]-hydroxy-methyl]tetrahydrofuran-3,4-di ol (Ex. 119)

|132f I A solution of (R)-[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl) -2,2- dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-[4 -chloro-2-

(hydroxymethyl)phenyl]methanol (45. mg, 0.10 mmol) in TFA (3.mL, 40.39 mmol) and Water (3 mL) was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS, which showed the desired mass. The solvent was removed in vacuo, then the crude product was purified by prep- HPLC (eluting with H2();CH3CN (0.1 % NH3.H20) from 90: 10 to 5:95 ) to obtain (2R,3R,4S,5R.)~ 2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-[4-chloro-2-( hydroxymethyl)phenyl]-hydroxy- methyl]tetrahydrofuran-3,4-diol (Ex. 119) (15.18 mg, 0,0371 mmol, 36.9% yield) as a white solid, ¾ NMR (400 M Hz, DMSO-d6): δ 8.06 (s, 1 H), 7.55-7.58 (m, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.31-7.36 (m, 2 H), 7.21 (s, 2.0 H), 6,61-6,62 (m, 2 H), 5.89-5.91 (m, 1 H), 5.30-5.33 (m, 1 H), 5.21-5.22 (d, J = 7.2 Hz, 1 H), 4.99-5.00 (d, J = 4.0 Hz, 1 H), 4.93 (m, 1 H), 4.58-4.67 (m, 2 H), 4.47-4.48 (m, I 1 1 ).. 4.13-4.16 (m,l H), 3.98-3.99 (m, 1 H). Ή NMR (400 M Hz, DMSO-ii(> · D.-.O): δ 8.06 (s, 1 H), 7.56-7.58 (m, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.33-7.36 (m, 2 H), 6.62-6.63 (d, j 3.6 Hz, 1 H), 5.90-5.92 (d, J = 7.6 Hz, 1 H), 4.93-4.94 (d, J = 3.6 Hz, 1 H), 4.58-4.68 (m, 2 H), 4.44- 4.47 (m, 1 H), 4.15-4.16 (d, J = 7.2 Hz, 1 H), 3.99-4.00 (d, J = 3.2 Hz, 1 H).

032.1 j Table 2. Examples made similar to the above mentioned methods with spectra data: Synthesis

Ex.# Structures similar Spectra Data

to Ex.#

4.0 Hz, 1 H), 4.79-4.82 (m, 1 H), 4.52-4.58 (m, 1 H), 4.07-4.10 (m, 1 H), 3.99 (d, J = 5.2 Hz, 1 H), 2.99 (s, 6 H). Ή NMR (400 M Hz, DMSO-d6+D20 ): δ 8.40 (s, 1 H), 7.60 (d, J = 1.2 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.52 (d, J = 3.2 Hz, 1 H), 7.39 (dd, Jl = 8.4 Hz, J 2 - 1.2 Hz, 1 H), 6,61 (d, J = 3 ,6 Hz, I H), 6.10 (d, J = 7.6 Hz, 1 H), 4.81 (d, J = 4.8 Hz, 1 H), 4.55-4.59 (m, 1 H), 4.1 1 (d, J = 5.2 Hz, 1 H), 4.02 (d, J = 4.8 Hz, 1 H), 3.00 (s, 6 H). [ .C MS: M i l 482.1/484.0

107 HCl salt; ¹ H MR (400 M Hz, M SO-t/rt): δ

8.65 (s, 1 i ! ), 7.92-7.93 (d, J 4.0 Hz, 1 H), 7.37-7.40 (m, 2 H), 7.33-7.35 (m, 1 H), 7.23- 7.25 (m, 1 H), 6.20-6.21 (d, .1 = 7.6 Hz, 1 H), 4.75-4.76 (d, J 4.8 Hz, 1 H), 4.51 -4.54 (m, 1 H), 4. 13-4. 14 (d, J = 4.8 Hz, 1 H), 4.03- 4.04 (d, ./ 4,8 Hz, 1 H), 3.67 (m, 4 H), 2.30 (s, 3 H), 1.92 (m, 4 H). ¾ NMR (400 M Hz, DMSO-iM+DiO ): δ 8.65 (s, 1 H), 7.89-7.90 (d, ./ 3 ,6 Hz, 1 H), 7.33-7.36 (m, 2 H), 7.29-7.30 (d, J = 3.6 Hz, 1 H), 7.23-7.25 (m, 1 H), 6.20-6.22 (d, J= 3.6 Hz, 1 H), 4.75- 4.76 (d, J == 4,8 Hz, I I f ), 4.51-4.55 (m, I I f }.. 4.14-4.16 (d, J= 5.2 Hz, 1 H), 4.06-4.08 (d, ,/ 4.8 Hz, 1 I s ), 3 ,67 (m, 4 H), 2,30 (s, 3 H),

37 1.93 (m, 4 I f ), LCMS: M+H ⁺ 488, 1

108 HCl salt, ^l H NMR (400 M Hz, OMSO~d6): δ

8.54 (s, 1 H), 7.77-7.78 (d, J = 3.6 Hz, 1 H), 7.33-7.37 (m, 2 H), 7.23-7.25 (m, 1 H , 7.06 (s, I H), 6.15-6.17 (d, J 7.6 Hz, 1 H), 4.75- 4.76 (d, J= 5.2 Hz, 1 H), 4.52-4.55 (m, 1 H), 4.1 1 -4.12 (d, ./ 4,4 Hz, 1 H), 4.02-4.03 (d, J= 4.8 Hz, 1 H), 3.06 (s, 6 H), 2.30 (s, 3 H).

1 NMR (400 M Hz, DMSO-£¾+D ₂ 0 ): δ 8.53 (s, 1 H), 7.75-7.76 (d, J == 3 ,6 Hz, 1 I f ), 7.32-7.34 (m, 2 H), 7.21-7.23 (m, 1 H), 7.02- 7.03 (d, ./ 3 ,6 Hz, 1 H), 6.14-6.16 (d, ,/ 7.2 Hz, 1 H), 4,73-4,74 (d, J= 4.8 Hz, 1 H), 4.50-4.54 (m, 1 H), 4.10-4.1 1 (d, .7 = 4.8 Hz, 1 H), 4.02-4.04 (d, J == 4,8 Hz, 1 H), 3.04 (s,

37 6 H), 2.28 (s, 3 H). LCMS: M+H ⁺ 462.1 Synthesis

Ex.# Structures similar Spectra Data

to Ex.#

109 HCl salt; Ί Ι NMR (400 M Hz, DMSO-d6): δ

8.54 (s, 1 H), 7.82 (d, J = 3.2 Hz, 1 H), 7.62 (d, J = 1.6 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.37-7.40 (m, 1 H), 7.07 (s, 1 H), 6, 17 (d, J = 7.6 Hz, 1 H), 4.81 (d, J = 5.6 Hz, 1 H), 4.51-4.55 (m, 1 H), 4.12 (d, J = 4.8 Hz, 1 H), 4.01 (d, J = 4.4 Hz, 1 H), 3.65-3.66 (m, 4 H), 3.50-3.60 (m, 4 H). ^! H NMR (400 M Hz, DMSO-d6+D20 ): δ 8.54 (s, 1 H), 7.75 (d, J - 4,0 Hz, 1 H), 7,59 (d, J = 1 ,2 Hz, I H), 7.57 (d, J = 8.4 Hz, 1 H), 7.37-7.40 (m, 1 H),

AXA ^,0H 6.98 (d, J = 3.6 Hz, 1 H), 6.16 (d, J = 7.2 Hz,

^U OH °» 1 H), 4.81 (d, J = 4.8 Hz, 1 H), 4.53-4.57 (m,

1 H), 4.14 (d, J = 4.8 Hz, 1 H), 4.06 (d, J = 4.8 Hz, 1 H), 3 ,66-3 ,70 (m, 4 1 1 ). 3 ,54-3 ,60

37 (ni, 4 H). LCMS: M+H ⁺ 524.1/526.1

110 0 2 HCl salt; ¾ NMR (400 MHz, DMSO-d6)

5 9.35 (br, 2 H), 8.55 (s, 1 H), 7.83 (s, 1 H), 7.56-7.82 (m, 2 H), 7.39-7.40 (m, 1 H), 7.15 (m, 1 H), 6.17 (d, J = 7.6 Hz, 1 H), 4.81 (d, J = 6.0 Hz, 1 l i ). 4.52-4.55 (m, 1 1 1 ). 4.12 (d, J

OH = 4.8 Hz, 1 H), 4.00 (d, J = 5.6 Hz, 1 H),

3.83 (s, 4 H), 3.19 (s, 4 H). ^! H NMR (400 MHz, DMSO-d6+D ₂ 0) δ 8,55 (s, 1 H), 7.79 (d, J = 3.6 Hz, 1 H), 7.56-7.61 (m, 2 H), 7.38-7.40 (m, 1 H), 7.02 (s, 1 H), 6.16 (d, J = 7.6 Hz, 1 1 1 ), 4.80 (d, J == 5.2 Hz, 1 H), 4.52- 4.55 (m, 1 H), 4.12-4.14 (m, 1 H), 4.02-4.04 (m, 1 H), 3.79-3.82 (m, 4 H), 3.20-3.22 (m, 4

37 1 1 ). LCMS: M l ! 523. 1/525.2

111 0 HCl salt; ¾ NMR (400 M Hz, DMSO~d6): δ

8.54 (s, 1 H), 7.78-7.79 (d, J = 3.6 Hz, 1 H), 7.33-7.39 ( πΊ , 2 H), 7.23-7.26 (m, 1 H), 7.10- 7.13 (m, 1 H), 6.15-6.17 (d, J = 7.6 Hz, 1 H), 4.75-4.76 (d, J = 4.8 Hz, 1 H), 4.52-4.55 (m,

6H ^6H 1 H), 4. 1 1 -4. 12 (d, J == 4.0 Hz, 1 H), 4.01- 4.03 (d, J = 4.8 Hz, IH), 3.66 (s, 4 H), 3.59 (s, 4 H), 2.30 (s, 3 H). Ί ί NMR (400 M Hz, DMSO~d6+D ₂ 0 ): δ 8.55 (s, 1 H), 7.76-7.77 (d, J = 3.6 Hz, 1 H), 7.32-7.34 (m, 2 H), 7.21-7.23 (m, 1 H), 7.02-7.03 (d, J = 3.6 Hz, 1 H), 6. 14-6. 16 (d, J == 7.6 Hz, 1 H), 4.73-

37 4.74 (d, J = 5.2 Hz, 1 H), 4.50-4.53 (m, 1 H), Synthesis

Ex.# Structures similar Spectra Data

to Ex.#

,/ 7.6 Hz, 1 I s ), 4,94 (s, 1 H), 4.56-4.60 (m, 2 H), 4.43 (d, ./ 14.0 Hz, 1 H), 4.19 (d, ./ 4.8 Hz, 1 H), 4.02 (s, 1 H). ⁱ⁹ FNMR (377 M Hz, DMSO-<¾) : δ -141.51 (d, ./ 23.00 Hz, 1 F), - 141.90 (d, J = 21.8 Hz, 1 F); LCMS:

M i l 409.2.

119 ^! H MR (400 M Hz, DMSO-i/6): δ 8.05 (s,

I I I ). 7.54 (s, 1 H), 7.41 (d, J = 8,0 Hz , 1 H), 7.30-7.34 (m, 2 H), 7.14 (br, 2 H), 6.73 (br, 1 ! ! }. 6,60 (d, J------ 3.6 Hz, 1 H), 5.91 (d, J = 8.0

NH ₂ Hz, 1 I I ). 5.20-5.26 (m, 2 H), 5 ,00 (d, J = 4.0

Hz, 2 H), 4.56-4.69 (m, 2 H), 4.41 -4.46 (m, 1 H), 4.13 (t, 3.6 Hz, 1 I I ). 4.02 (d, J = 3.2 Hz, 1 H). ¾ NMR (400 M Hz, DMSO- d6+DiQ ) : δ 8.05 (s, 1 H), 7.54 (s, 1 H), 7.41 (d, J = 8,4 Hz , 1 H), 7.31-7.34 (m, 2 H),

6.61 (d, J= 3.2 Hz, 1 H), 5.91 (d, J = 7.6 Hz, 1 H), 5.00 (d, 3.2 FIz, 1 H), 4.64-4.67 (m, I ] [ }.. 4.57 (d, ./ 13.6 Fiz, 1 H), 4.44 (d, J ------

13.6 Hz, 1 H), 4.14 (d, J = 5.2 Hz, 1 H), 4.03

121 (d, J = 3 ,2 Hz, 1 H), LCMS: M i ! 407.0.

(0322] Compounds were soiubilized and 3-fold diluted in 100% DMSO. These diluted compounds were further diluted in the assay buffer (50 niM Tris-HCl, pH 8.5, 50 niM NaCl, 5 niM MgCh, 0.01% Brij35, 1 mM DTT, 1% DMSO) for 10-dose ICso mode at a concentration 10-fold greater than the desired assay concentration. Standard reactions were performed in a total volume of 50 μΐ in assay buffer, with hi stone FI2A (5 μΜ final) as substrate. To thi s was added the

PRMT5/MEP50 complex diluted to provide a final assay concentration of 5 nM and the compounds were allowed to preincubate for 15 to 20 minutes at room temperature. The reaction was initiated by- adding S-[3 H-methyl]-adenosyl-L-methionine (PerkinElmer) to final concentration of 1 μΜ.

Following a 60 minutes incubation at 30 °C, the reaction was stopped by adding 100 μΕ of 20% TCA. Each reaction was spotted onto filter plate (MultiScreen FB Fi lter Plate, Millipore), and washed 5 times with PBS buffer, Scintillation fluid was added to the filter plate and read in a scintillation counter. IC50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software

Cellular Assay Protocol

Cell treatment and Western Blotting for detecting Symmetric Di-Methyl Arginine (sDMA) and Histone H3R8 Dimethyl Symmetric (H3R8me2s) marks

|1323] Initial compounds screening in A549 cells: Compounds were dissolved in DMSO to make 10 mM stock and further diluted to 0.1, and 1 mM. A549 cells were maintained in PRMI 1640 (Coming Cellgro, Catalog #: 10-040-CV) medium supplemented with 10% v/v FBS (GE Healthcare, Catalog #: SH30910.03). One day before experiment, 1.25 x 10 ⁵ cells were seeded in 6 well plate in 3 niL medium and incubated overnight. The next day, medium was changed and 3 uL of compound solution was added (1 : 1,000 dilution, 0.1 and I uM final concentration; DMSO concentration: 0. 1 %), and incubated for 3 days. Cells incubated with DMSO was used as a vehicle control. Cells were washed once with PBS, trypsinized in 150 uL 0.25% Trypsin (Coming, Catalog #: 25-053-CI), neutralized with 1 raL complete medium, transferred to micr°Centrifuge tubes and collected. Cell pellet was then resuspended in 15 uL PBS, lysed in 4% SDS, and homogenized by ^¬ passing through homogenizer column (Omega Biotek, Catalog #: HCR003). Total protein concentrations were determined by BCA assay (ThermoFisher Scientific, Catalog #: 23225). Lysates were mixed with 5x Laemmli buffer and boiled for 5 min. Forty ug of total protein was separated on SDS-PAGE gels (Bio-Rad, catalog #: 4568083, 4568043), transferred to PVDF membrane, bl°Cked with 5% dry milk (Bio-Rad, Catalog #: 1706404) in TBS with 0.1% v/v Tween 20 (TBST) for 3 hour at room temperature (RT), and incubated with primary antibodies (sDMA: Cell signaling, Catalog #: 13222, 1 :3,000; H3R8me2s: Epigentek, Catalog #: A-3706-100, 1 :2,000, β-Actin:

Abeam, Catalog #: ab8227, 1 : 10,000) in 5% dry milk in TBST at 4 °C for overnight. The next day, membranes were washed with TBST, 5 x 5 min, and incubated with HRP conjugated seconded antibody (GE Healthcare; Catalog #: NA934-1 ML; 1 :5,000) for 2 hours at RT, followed by 5 5 min washes with TBST, and incubation with ECL substrates (Bio-Rad, Catalog #: 1705061, 1705062). Chemiluminescent signal was captured with Fluochem HD2 imager (Protemsimple) and analyzed by Image J. (0324] To determine enzyme inhibition ICso values using Western Blot analysis, Granta cells were seeded at density of 5 x 10 ⁵ cells/mL in 3 mL medium (PRMI +10% v/v FBS). Nine-point 3-fold serial dilutions of compound were added to cell s (3 ul, 1 : 1,000 dilution, DMSO concentration was 0.1%; final top concentration was 10 or 1 uM, depending on compounds potency) and incubated for 3 days. Cells incubated with DMSO was used as a vehicle control. Cel ls were harvested and subjected to western blot analysis as described above. SmD3me2s and H3R8me2s bands were quantified by ImageJ. Signals were normalized to β-Actin and DMSO control. ICso values were calculated using Graphpad Prism.

\932S\ Example 29 exhibited a PRMT5/MEP50 ICso (nM) of 1.4 (N = 2); and 87% inhib. sDMA inhibition @ 0 μΜ in A549.

Cell proliferation assay to determine ICso on Granta-5 ^' 19 cells

[0326] Granta-5 ^' 19 cells were maintained in PRMI 1640 (Corning Cellgro, Catalog #: 10- 040-CV) medium supplemented with 10% v/v FBS (GE Healthcare, Catalog #: SI 130910.03 ).

Compounds were dissolved in DMSO to make 10 mM stocks and stored at -20 °C. Nine-point, 3- fold serial dilutions were made with DMSO with top concentration at I mM (working stocks).

On day of experiment, compound working stocks were further diluted at 1 :50 with fresh medium in 96 well plate, and 10 uL of diluted drugs were added to a new 96 well plate for proliferation assay. Cells growing at exponential phase were spun down at 1500 rpm for 4 min and resuspend in fresh medium to reach a density of O.SxlO ⁶ cells/ml. 200 ul of cells were added to 96 well plate containing diluted drugs and incubated for 3 days, DMSO was used a vehicle control.

327J One day 3, 10 ,uL of Cell Counting Kit-8 (CCK-8, Jojindo, CK04-13) solution was added to a new 96 well plate. Ceils incubated with drugs for 3 days were resuspended by pipetting up and down, and 100 Ε of cells were transferred to 96 well plate containing CCK-8 reagent to measure viable cells. Plates were incubated in CO:? incubator for 2 hours and OD450 values were measured with a microplate reader (iMark microplate reader, Bio-Rad).

[0328] For re-plating, compound working stocks were diluted at 1 :50 with fresh medium and 10 uL of diluted drags were added to a new 96 well plate. Cells from Day 3 plate (50 ul) were added to 96 well plate containing fresh drag and additional 150 ih of fresh medium was added to reach 200 ul volume. Plate was returned to CO2 incubator and incubated for 3 more days. Viable cells measurement and re-plating were repeated on day 6, and the final viable cells measurement was taken on day 10. (0329] Percentage of viable cells, relative to DMSO vehicle control, were calculated and plotted in Graphpad Prism ([Inhibitor] vs. normalized response - Variable slope) to determine proliferation ICso values on day 10.

Table 3 Biochemical and cellular potency (in Granta-519 cell line)

101 0.0072 I

102 0.0057 1

103 1.484 1

104 0.059 1 2 1

105 0.0248 1 0.65 1

106 0.035 1 0.113 1 0.07 ¹

107 0.21 1

108 0,0193 1 0.0068 1

109 0,071 1 0.021 1

110 0,0231 1 0.0104 1 0.012 1

11 1 0,061 1 0.0708 I 0.1 15 1

112 0.0411 1

113 0,0252 1

114 0.312 1

119 0.121 0.037 1 0.163 1

In vivo pharmacokinetic properties of Example 99.

(8330] In a mouse (CD-I , male, non-fasted) non-crossover PK study, Example 99 was dosed at 1 mg/kg (DMA: 20%HPBCD=5:95, solution) via i.v. administration (N=3) and 10 mg/kg (0.5% Na CMC + 0.5%Tween80, suspension) via oral gauge (p.o.) (N=3). It showed average T1/2 of 0.75 hr, Vss of 0.21 L/kg, plasma clearance of 12.8 mL/min/kg in the i.v. group; it showed average dose normalized AUCO-M of 489 ng*h*kg mL/mg and 37% of oral bioavailability in the p.o. group.

ICS331 Granta-519 ceils was maintained in DMEM medium supplemented with 10% fetal bovine serum and 2 mM L-Glutamine at 37 °C in an atmosphere of 5% CO2 in air. Cells in exponential growth phase were harvested and Ixl O ⁷ cells in 0.1 mL of PBS with Matrigel (1 : 1) were injected subcutaneously at the right lower flank region of each mouse for tumor development. The treatments were started when the mean tumor size reaches approximately 300-400mm ³ . Mice were assigned into groups using StudyDirector ^IM software (Studylog Systems, Inc. CA, USA) and one optimal randomization design (generated by either Matched distribution or Stratified method) that shows minimal group to group variation in tumor volume was selected for group allocation. Example 99 or vehicle (0.5% Na CMC + 0.5% TweenSO, suspension) were administered orally (QD for Example 99, QD for vehicle) at a dose of 10 mg/kg (QD) for 27 days. Body weights and tumor size were measured every 3 to 4 days after randomization. Animals were euthanized 4 hours after last dosing, and blood and tumor samples were collected for analysis.

|0 3 j To measure sDMA levels in tumor samples, tumors from each mouse were weighted and homogenized in RIPA buffer supplemented with protease inhibitor (cOmplete™, EDTA-free Protease Inhibitor Cocktail, Roche). Lysate were centrifuged at 14,000 rpm for 30 min at 4 °C to remove debris. Total protein concentrations of lysate were determined by BCA assay (ThermoFisher Scientific, Catalog #: 23225). Equal amount of total proteins from each tumor were separated on SDS-PAGE gel, and sDMA levels were determined by WB as described previously.

[0333] Following this protocol, Example 99 showed an average of 51% (N=5) tumor growth inhibition (compared to the control group on day 18 of dosing, when the control group was terminated) at 10 mg/kg with body weight loss of 6% at termination on day 28 when reduced tumor sizes were observed.

[0334] The disclosure is directed to the following aspects:

Aspect 1. A compound of Formula I, Formula II, Formula III, or Formula IV:

or a pharmaceutically acceptable salt or solvate thereof;

wherein A is CH or N;

R ¹ is -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-Cealk-C≡CH, -Co-C ₆ alk-C≡C- Ci-Cealkyl, -Co-C6alk-C≡C-C ₁ -C6haloalkyl, -Co-C6alk-C≡C-C ₃ -C6cycloalkyl, or -Ci- Cealk-aryl,

R ² is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cj-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NIfc, -Co-Cealk-NH-Ci-Cealkyl,

-Co-Cealk-NCCi-Cealky -Ci-Cealkyl, -Co-Cealk-NH-Cs-Cecycloalkyl,

-Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Co-Cealk-heterocycioalkyl, heteroaryl, or - CN;

R ³ is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cj-Cecycloalkyl, -Co-Cealk-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk- Hi, -Co-Cealk-NH-Ci-Cealkyl, -Co-C ₆ alk-N(Ci- Cealkyl)-Ci-C ₆ alkyl, -C ₀ -Cealk-NH-C ₃ -Cecycloalkyl, ₀ -Cealk-N(Ci-Cealkyl)-C ₃ - Cecycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;

R is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalky , -Co-Cealk-OH,

-Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NHi, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-N(Ci-

Cealky -Ci-Cealkyl, -Co-Cealk-NH-Cs-Cecycloalkyl, -Co-C6alk-N(Ci-Cealkyl)-C3-

Cecycloaikyi, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;

or R ^z and R ³ , together with the atoms to which they are attached, form a

Ci-Cecycloalkenyl ring,

or R ² and R ³ , together form a triple bond;

or R ⁵ and R ⁴ , together with the atom to which they are attached, form a C ₃ -C6cycloalkyl ring or a heterocycloalkyl ring;

R ⁵ is H, halo, NH ₂ , or -Ci-Cealkyl;

R ⁶ is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, or -Co-Cealk-C ₃ -Cecycloalkyl,

R ⁷ is halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Cj-Cecyeloalkyl, -CVCehaloeyeloalkyl, ~Ci- Cealk-O-Ci-Cealkyl, -Ci-C6alk-S(0)-Ci-C6alkyl, -Ci-C6alk-S(0)2-Ci-C6alkyl, - CR ⁸ R ^S' CN, NHCR ⁸ R ^8' CN, -NH-CN, -NHCONR ⁸ R ^8' , -NHC(0)OR ⁹ , -NHC(0)-Ci- Cealkyl, or -NHC(0)-Ci-Cehaloalkyl;

R ⁸ and R ^8' are each independently H, -CJ -Cealkyl, or -Co-Cealk-OCi -Cealkyl;

or R ⁸ and R ^8' , together with the atom to which they are attached, form a Cs-Cecycloalkyl ring; and R ⁹ is -Ci-Cealkyl, or Co-C6aik-C3-C&cycfoalkyl.

Aspect 2. The compound of aspect 1 wherein R ¹ is -Ci-Cealk-aryl.

Aspect 3 , The compound of aspect 2 wherein the -Ci-Cealk-aryl is -CEb-aryl, -CH(OH)-aryl, - CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-ar l, or -C(Me)(OH)-aryl .

Aspect 4. The compound of aspect 3 wherein the -Ci-Gsaik-aryl is -CFb-phenyl, - i -4- chlorophenyl, -CH ₂ -4-fluorophenyl, -CH_-3,4-dichlorophenyl, -CH ₂ -3,4-difluorophenyl, - CH ₂ -3-fluoro-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH(OH)-4-chlorophenyl, - CH(OI-I)-3 ,4-dichlorophenyl, -CI [(()! ! }- ,4-difluorophenyl , -CH(OH)-3 -fluoro-4- chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(F)-4-chlorophenyl, -CH(F)-3,4- dichlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3- chloro-4-fluorophenyl ., -CH(NH ₂ )-4-chlorophenyl , -CH(NH ₂ )-3,4-dichlorophenyl , - CH(NH2)-3 ,4-difluorophenyl, -CH(NH ₂ )-3 -fluoro-4-chlorophenyl, -CH( H ₂ )-3 -chloro-4- fluorophenyl, -CH(Me)-4-chloropheny ] , -CH(Me)~3 ,4-dichl orophenyl, -CH(Me)-3 ,4- difluorophenyl, -CH(Me)-3 -fluoro-4-chl orophenyl, -CH(Me)-3 -chloro-4-fluorophenyl, - C(Me)(0]T)~4-chlorophenyl, -C(Me)(OH)-3 ,4-dichlorophenyl, ~C(Me)(OH)~3 ,4- difluorophenyl, -C(Me)(OH)-3-fluoro-4-chl orophenyl, or -C(Me)(OH)-3-chloro-4- fluorophenyl.

Aspect 5, The compound of aspect 1 wherein Ri i

Aspect 6, The compound of aspect 5 wherein the -CH(OH)-C≡C Ci-Cealkyl, -CH(F)-C≡C-C l-Cealky 1, -CH(NH2)-C≡C-Ci-C6alkyl, -CH(Me)-C≡C-C i- Cealkyl, or -C(Me)(OH)-C≡C-Ci-C6alkyl.

Aspect 7. The compound of aspect 6 wherein the is -CH(OH)-0≡C Clh, -CH(F)-C≡C-CH ₃ , -CH(NH ₂ )-C≡C-CH ₃ , -CH(Me)-C≡C-CH ₃ , or -C(Me)(OH)-C≡C-

Aspect 8. The compound of aspect 1 wherein Rj is -C ₀ -C6alk-C≡C-Ci-C6haloalkyl.

Aspect 9. The compound of aspect 8 wherein the -Co-C6alk-C≡C-Ci-C6haloalkyl is -CH(OH)- C≡ -Ci-C ₆ haloalkyl, -CH(F)-C≡C-Ci-C6haloalkyl, -CH(NH2)-C≡C-Ci-C6haloalkyl, - CH(Me)-C≡C-Ci-C6haloalkyl, or -C(Me)(OH)-C≡C-Ci-C&haloaikyi . Aspect 10. The compound of aspect 9 wherein the is -CH(OH)- C≡C-CF ₃ , -CH(F)-C≡C-CF ₃ , -CH(NH2)-C≡C-CF ₃ , -CH(Me)-C≡C-CF ₃ , or -C(Me)(OM )- C≡C-CF ₃ .

Aspect 1 1. The compound of aspect 1 wherein Ri is -Co-C6al k-C≡C-C ₃ -C6cycloalkyl .

Aspect 12, The compound of aspect 1 1 wherein the -Co-C6alk-C≡C-C ₃ -C6cycloalkyl is - CH(OH)-C≡C-C ₃ -C6cycloalkyl, -CH(F)-C≡C-C ₃ -C6cycloalkyl, -Π K M i ^< )-C C--CV Cecycloalkyl, -CM( \ !e)-C C- -CYcycioal kyL or -C(Me)(OH)-C≡C-C ₃ -C6<^cloalkyl.

Aspect 13. The compound of aspect 12 wherein the -Co-C6alk-C≡C-C ₃ -C6cycloalkyl is ~

CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -Π Ιί Μ Ι ' C-cyc! propyi, - CH(Me)-C≡C-cyclopropyl, or -C( e)(OH)-C≡C-cyclopropyl.

Aspect 14. The compound of any one of aspects 1 to 13 wherein R ³ is H.

Aspect 15. The compound of any one of aspects 1 to 14 that is a compound of Formula I or Formula II.

Aspect 16. The compound of aspect 15 wherein A is CH.

Aspect 17. The compound of aspect 15 wherein A is N.

Aspect 18. The compound of any one of aspects 15 to 17 wherein R ⁶ is H.

Aspect 19. The compound of any one of aspects 1 to 18 that is a compound of Formula I or Formula III.

Aspect 20, The compound of aspect 19 wherein R ² i s H. Aspect 21 , The compound of aspect 19 wherein R ² i s -Ci-Cealkyl. Aspect 22, The compound of any one of aspects 19 to 21 wherein R ³ is H. Aspect 23 , .The compound of any one of aspects 19 to 22 wherein R ⁴ is H. Aspect 24. The compound of any one of aspects 1 to 18 that is a compound of Formula II or Formula IV.

Aspect 25. The compound of aspect 24 wherein R' is halo.

Aspect 26. The compound of aspect 24 wherein R' is -Ci-C ₄ haloalkyl.

Aspect 27. The compound of aspect 26 wherein the -d-CAaloalkyl is --CH2CH2CI, -CH2CH2F,

Aspect 28. The compound of aspect 24 wherein R'' is -Cs-Cecycloalkyl.

Aspect 29. The compound of aspect 28 wherein the -Cs-Cecycloalkyl is cyclopropyl.

Aspect 30. The compound of aspect 24 wherein R ⁷ is -C 1 -Cealk-O-C 1 -Cealky 1.

Aspect 31. , The compound of aspect 24 wherein R' is -Ci-Ceaik-SfOVCi-Cealkyl.

Aspect 32. The compound of aspect 24 wherein R ⁷ is -Ci-Cealk-SfOVCi-Ceaikyi.

Aspect 33. The compound of aspect 24 wherein R' is -NH-CN.

Aspect 34. The compound of aspect 24 wherein R ⁷ is -CR ⁸ R ^8' CN.

Aspect 35. The compound of aspect 24 wherein R' is NHCR ⁸ R ⁸ CN.

Aspect 36. The compound of aspect 24 wherein R' is - HCONR ⁸ R ⁸ .

Aspect 37. The compound of aspect 24 wherein R' is - HR ⁸ R ⁸ .

Aspect 38. The compound of any one of aspects 34 to 37 wherein R ⁸ and R ^8' are each,

independently, H or -Ci-Cealkyl.

Aspect 39. The compound of aspect 24 wherein R' is NHC(0)-Ci-C6alkyl.

Aspect 40. The compound of aspect 24 wherein R' is NHC(0)-Ci-C6haloalkyl.

Aspect 41. The compound of aspect 24 wherein R ⁷ is -NHC(0)OR ⁹ . Aspect 42. The compound of aspect 42 wherein R is -Ci-Ceaikyl.

Aspect 43. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 42 and a pharmaceutically acceptable excipient.

Aspect 44. A method of inhibiting a protein arginine methyltransterase 5 (PRMT5) enzyme, comprising: contacting the PRMT5 enzyme with an effective amount of a compound of any one of any one of aspects 1 to 42.

Aspect 45. A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject comprising administering to the subject, a compound of any one of aspects 1 to

42.

Aspect 46. The method of aspect 45, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, or hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).

Aspect 47. A compound of Formula I, Formula II, Formula III, or Formula IV:

IV or a pharmaceutically acceptable salt or solvate thereof;

wherein

A is CH o N;

R ^l is -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaioalkyl, -Co-Ceaik-C≡CH, -Co-C ₆ alk-C≡C-Ci- Ceal ky] , -Co-Cfialk-C-C-Ci-Cehaloalkyl, -Co-Cealk-C^C-C -Cecycloalkyl, -Ci-Cealk- aryl, -Co-Ceaik-heteroaryl, -Ci-Cealk-O-heteroaryi, -Ci-Cealk-S-heteroaryl, or -Ci- Cealk-NH-heteroaryl .

R ² is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Ceaik-OH, -Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NHi, -Co-Cealk- H-Ci-Cealkyl,

-Co-C6alk- (Ci-C6alkyl)-Ci-C6alkyl, -Co-Cealk-NH-Cs-Cecycloalkyl,

-Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl, -Co-Cealk-heterocycloaikyi, heteroaryl, or -CN;

R ³ is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH,

-Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-NHa, -Co-Cealk- H-Ci-Cealkyl, -Co-C ₆ alk-N(Ci- Cealky -Ci-Cealkyl, -Co-Cealk- H-Cs-Cecycloalkyl, -Co-C6aik-N(Ci-Ceaikyi)-C3- Cecycloalkyl, -Co-Cealk-heterocycloalkyl, heteroaryl, or -CN;

R ⁴ is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, -Co-Cealk-Cs-Cecycloalkyl, -Co-Cealk-OH,

-Co-Cealk-O-Ci-Cealkyl, -Co-Cealk-Mt, -Co-Cealk-NH-Ci-Cealkyl, -Co-Cealk-N(Ci- Ceal kyl VCi-Cealkyl, -Co-Cealk-NH-Cs-Cecycloalkyl,

Cecycloalkyl, -Co-Cealk-heterocycloaikyi, heteroaryl, or -CN;

or R ² and R ⁵ , together with the atoms to which they are attached, form a

Cs-Cecycioalkenyi ring;

or R ² and R ³ , together form a triple bond;

or R ^J and R ⁴ , together with the atom to which they are attached, form a C3-C6cycioalkyl ring or a heterocycloalkyl ring,

R ⁵ is H, halo, NH ₂ , or -Ci-Cealkyl;

R ⁶ is H, halo, -Ci-Cealkyl, -Ci-Cehaloalkyl, or -Co-Cealk-Cs-Cecycloaikyl,

R ⁷ i s halo, -Ci-Cealkyl, -Ci-C-Aaloalkyl, -Cs-Cecycloal kyl , -Cs-Cehalocycloalkyl, -C ₂ -

C4alkenyl, -Ci-Cealk-O-Ci-Cealkyl, -Ci-Cealk-C(0)-Ci-Cealkyl, -Ci -Cealk-NiCi- Cealkyl)R ⁸ , -Ci-Cealk-S-Ci-Ceal kyl , -Ci~Cealk~S(0)-Ci-C ₆ alkyl, -Ci~Cealk-S(0) ₂ -Ci- Cealkyl, -CR ⁸ R ^8' CN, -NH-Ci-Cealk-S-Ci-Ceaikyi, -NH-Ci-€ k-S(0)-Ci-Cealkyl, - NH-Ci-C6dk-S(0)2-Ci-C ₆ alkyi, -NH-Ci-C ₆ alk-N-Ci-C6alkyl(R ⁸ ), -NHCR R ^8" CN, - NH-CN, - HCO R ⁸ R ^8' , - HC(S)NR ⁸ R ^8' , - HC(0)OR ⁹ , HC(S)OR ⁹ , -NHC(O)- Ci-Cealkyl, -NHC(0)-Ci-C6haloalkyl, -NH-Ci-C6alk-C(0)-Ci-C6alkyl, or -N-(3-Ci- C6alkyl)imidazolidin-2-one;

R ⁸ and R ^8' are each independently H, -Ci-Cealkyl, or -Co-Cealk-OCi-Cealkyl;

or R ⁸ and R ⁸ , together with the atom to which they are attached, form a Cs-Cecycloalkyl ring or a five or six membered heterocyclic ring, and

R ⁹ is -Ci-Ceafkyf, or Co-Ceaik-Cn-Cecycloalkyl.

Aspect 48. The compound of aspect 47 wherein R ¹ is -Ci-Cealk-aryl.

Aspect 49. The compound of aspect 48 wherein the -Ci-Cealk-aryl is -CEb-aryl, -CH(OH)-aryl, - CH(F)-aryl, -01 hj-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl.

Aspect 50. The compound of aspect 49 wherein the -Ci-Cea!k-aryi is -CH ₂ -phenyl, -CH ₂ -4- chlorophenyl, -CH2-4-fluorophenyl, -CH ₂ -3 ,4-dichl orophenyl, -CH ₂ -3,4-dif!uorophenyl, - CH ₂ -3-fluoro-4-chl orophenyl, -CH ₂ -3-chloro-4-fluorophenyl, -CH(OH)-4-chlorophenyl, - CH(OH)~3 ,4-dichl orophenyl, -CH(OH)-3 ,4-difluorophenyl, -CH(OH)-3 -fluoro-4- chl orophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(F)-4-chl orophenyl, -CH(F)-3,4- di chl orophenyl , -CH(F)-3 ,4-difluorophenyl, -CH(F)-3 -fluoro-4-chl orophenyl , -CH(F)-3 - chloro-4-fiuorophenyl., -CH(NH ₂ )-4-chlorophenyl, -CH(NH ₂ )-3,4-dichlorophenyl, - CH( H ₂ )-3,4-difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH2)-3-chloro-4- fluorophenyl, -CH(Me)-4-chlorophenyl, -CH(Me)-3,4-dichlorophenyl, -CH(Me)-3 ,4- difluorophenyl, -CH(Me)-3 -fluoro-4-chl orophenyl, -CH(Me)-3 -chloro-4-fluorophenyl, - C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3,4- di fluorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, or -C(Me)(OFi)-3-chloro-4- fluorophenyl .

Aspect 51 . The compound of aspect 47 wherein Ri i

Aspect 52, The compound of aspect 51 wherein the -CH(OH)- C≡C-Ci-C ₆ alkyl, -CH(F)-C≡C-Ci-C6alkyl, -CH(NH2)-C≡C-Ci-C6alkyl, -CH(Me)-C≡C-Ci- Cealkyl, or -C(Me)(OH)-C≡C-Ci-C6alkyl . Aspect 53. The compound of aspect 52 wherein the -Co-C6alk-C=C-C ₁ -C6alkyl is -CH(OH)- C C -C l k -CH(F)-C≡C-C¾, -CH(NH2)-C≡C-C¾, -CH(Me)-C≡C-C¾, or -C(Me)(OH)- C≡C-CH ₃ .

Aspect 54, The compound of aspect 47 wherein Ri is -Co-Cealk-C^C-Ci-Ce.haloalkyl.

Aspect 55, The compound of aspect 54 wherein the is -CH(OH)- C≡C-Ci-C6haloalkyl, -CH(F)-C≡C-Ci-C6haloalkyl, -CH(NH2)-C≡C-Ci-C6haloalkyl, - CH(Me)-C≡C-Ci-C6haloalkyl, or -C(Me)(OH)-C≡C-Ci-C6haloalkyl.

Aspect 56. The compound of aspect 55 wherein the is -CH(OH)- C≡C-CF ₃ , -CH(F)-C≡C-CF ₃ , -CH(NH2)-C≡C-CF ₃ , -CH(Me)-C≡C-CF ₃ , or -C(Me)(OH)- C≡C-CF ₃ .

Aspect 57. The compound of aspect 47 wherein Ri is -Co-C6alk-C≡C-C3-C6cycloalkyl.

Aspect 58. The compound of aspect 57 wherein the -Co-C6alk-C≡C-C ₃ -C6cycloalkyl is - CH(OH)-C≡C-C ₃ -C6cycloalkyl, -CH(F)-C≡C-C ₃ -C6cycloalkyl, -CH(NH ₂ )-C≡C-C ₃ - Cecycloalkyl, -CH(Me)-C≡C-C ₃ -C6cycloalkyl, or -C(Me)(OH)-C≡C-C ₃ -C6cycloalky 1.

Aspect 59. The compound of aspect 58 wherein the -Co-C6alk-C≡C-C ₃ -C6cycloalkyl is - CH(OH)-C≡C-cyclopropyl, ~CH(F)-C=C-cyclopropyl, -CH(NH2)-C≡ -cyclopropyl, - CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl.

Aspect 60. The compound of aspect 47 wherein R ¹ is -Ci-Cealk-heteroar '!, -Ci-Cealk-O- heteroaryl, -Ci-Cealk-S-heteroaryl, or -Ci-Cealk-NH-heteroaryl.

Aspect 61. The compound of aspect 60 wherein the -Ci-Cealk-heteroaryl is 2-(2-amino-3- bromoquinoli n-7-yl)ethy 1 or 2-(2-ami no-3 -chloroquinolin-7-yl)ethyl .

Aspect 62, The compound of any one of aspects 47 to 61 wherein R ³ is H.

Aspect 63. The compound of any one of aspects 47 to 62 that is a compound of Formula I or Formula II

Aspect 64. The compound of aspect 63 wherein A is CH. Aspect 65. The compound of aspect 63 wherein A is N.

Aspect 66. The compound of any one of aspects 63 to 65 wherein R ⁶ is H.

Aspect 67. The compound of any one of aspects 47 to 66 that is a compound of Formula I or Formula III

Aspect 68. The compound of aspect 67 wherein R ² is H.

Aspect 69. The compound of aspect 67 wherein R ² is -Ci-Cealkyl.

Aspect 70. The compound of any one of aspects 67 to 69 wherein R ³ is H.

Aspect 71. .The compound of any one of aspects 67 to 70 wherein R ⁴ is H.

Aspect 72. The compound of any one of aspects 47 to 66 that is a compound of Formula II or Formula IV.

Aspect 73. The compound of aspect 72 wherein R' is halo.

Aspect 74. The compound of aspect 72 wherein R' is -Ci-C ₄ haloalkyl.

Aspect 75. The compound of aspect 74 wherein the -Ci-CAaloalkyl is -CH2CH2CI, -CH2CH2F,

Aspect 76. The compound of aspect 72 wherein R'' is -Cs-Cecycloalkyl.

Aspect 77. The compound of aspect 76 wherein the -Cs-Cecycloalkyl is cyclopropyl.

Aspect 78. The compound of aspect 72, wherein R ^; is -C ₂ -C ₄ alkenyl, preferably vinyl.

Aspect 79. The compound of aspect 72 wherein R' is -Ci-C6aik-C(0)-Ci-C6alkyl, preferably - (Ί Ί !. < ^' « ⁾ ) ^{( '} I k

Aspect 80, The compound of aspect 72 wherein R ⁷ is -Ci-Cealk-NfCi-CbalkyljR ⁸ , preferably - CH2CH ₂ (CH ₃ )2. Aspect 81. The compound of aspect 72 wherein R' is -C ι -Cealk-S-C i-Cealkyl, preferably - CH2CH2.-S-CH3.The compound of aspect 26 wherein R ⁷ is -C i-Cealk-O-C 1 -Cealkyl .

Aspect 82. , The compound of aspect 72 wherein R' is -Ci-Ceaik-SfOVCi-Cealkyl.

Aspect 83. The compound of aspect 72 wherein R ⁷ is -Ci-Ccalk-SiOVCi-Ceaikyi.

Aspect 84. The compound of aspect 72 wherein R' is - H-CN.

Aspect 85. The compound of aspect 72 wherein R' is -CR ^S R ^S CN, preferably -NHCH2CN.

Aspect 86. The compound of aspect 72 wherein R' is -NH-Ci-Ceafk-S-C i-Cealkyl, preferably -

Aspect 87. The compound of aspect 72 wherein R ⁷ is -NH-C i-C6alk-S(0)-Ci-C6alkyl, preferably

Aspect 88, The compound of aspect 72 wherein R ⁷ is -NH-Ci~C6alk~S(())2-Ci-(¾arkyl,

preferably ·ΝΠ·(Ί ! -( ! b -S{())-CI h .

Aspect 89. The compound of aspect 72 wherein R ^? is -NTT-Ci-Ceaik-N-Ci-Cealky^R ⁸ ).

Aspect 90. The compound of aspect 72 wherein R ⁷ is NHCR ⁸ R ^8' CN.

Aspect 91. The compound of aspect 72 wherein R ^? is -NHCONR ⁸ R ^8' , preferably -

Aspect 92. The compound of aspect 72 wherein R ⁷ is -NHC(S)NR ⁸ R ^8' , preferably - NHC(S)N(CH3)2, or -M l( ^' (S )M Aspect 93. The compound of aspect 72 wherein R ' is -NR R ^8' .

Aspect 94. The compound of any one of aspects 80, 85, or 89 to 93 wherein R ⁸ and R ⁸ are each, independently, H or -Ci-Cealkyl.

Aspect 95. The compound of aspect 72 wherein R' is NHC(0)-Ci-C6aikyi, preferably -NHC(O)- CH ₃ .

Aspect 96. The compound of aspect 72 wherein R ⁷ is NHC(0)-C ι-Cehaloalky 1. Aspect 97. The compound of aspect 72 wherein R ⁷ is - HC(0)OR ⁹ . Aspect 98. The compound of aspect 72 wherein R ⁷ is NHC(S)OR ⁹ ..

Aspect 99. The compound of any one of aspects 97-98 wherein R ^y is -Ci-Cealkyl, preferably methyl.

Aspect 100. The compound of aspect 72 wherein R ⁷ is -NH-Ci-C6al k-C(0)-Ci-C6alkyl., preferably -ΧΠ-<Ή --( ^' {<})-( ^' ! k

As ompound of aspect 72 wherein R' is -N-(3-Ci-C6alkyl)imidazolidin-2-

one,

Aspect 102. A compound of Formula IIB-2

wherein R ¹ is -Ci-Cealk-aryl, wherein the aryi is (hydroxymethyl)chlorophenyl,

(hydroxymethyi)fluorophenyi, (hydroxymethyl)difluorophenyl,

(hydroxymethyl)dichlorophenyl, (aminomethyl)chlorophenyl, (aminomethyl )fluorophenyl, (aminomethyl)difluorophenyl, (aminomethyl)dichlorophenyl,

(methylaminomethyl)chlorophenyl, (methylaminomethyl)fluorophenyl,

(methylaminomethyl)difluorophenyl, or (methylaminomethyl)dichlorophenyl; R ⁷ is -NR ⁸ R ⁸ or -( ! -C ^' ..alk ; and R ^s and R ⁸ are independently H or Ci-Cealkyl.

Aspect 103. The compound of aspect 102, wherein R ¹ is -CH(OH)-2-hydroxymethyl-4- chlorophenyl, -CH(OH)-2-hydroxymethyl-5-c-hlorophenyl, -CH(OH)-2-aminomethyl-4- chlorophenyl, -CH(OH)-2-(methylaminomethyl)-4-chlorophenyl, -CH(OH)-2- (methylaminomethyl)-5-chlorophenyl, -CH(OH)-2-hydroxymethyl-4,5-difluorophenyl, - CH(OH -2-aminomethyl-4,5-difluorophenyl, or -CH(OH)-2-(methylaminomethyl)-4,5- difluorophenyl; and R' is NH ₂ or methyl.

Aspect 104. The compound of aspect 102, wherein R ¹ is -CH(OH)-2-hydroxymethyl-4- chlorophenyl, -CH(OH)-2-hydroxymethyl-5-chlorophenyl, -CH(OH)-2-hydroxymethyl-4,5- difluorophenyl, -CH(OH)-2-aminomethyl-4,5-difluorophenyl, or -CH(OH)-2- (methylaminomethyl)-4,5-difluorophenyl; and R ' is NH2 or methyl.

Aspect 105. A pharmaceutical composition comprising a compound according to any one of aspects 47 to 104 and a pharmaceutically acceptable excipient.

Aspect 106. A method of inhibiting a protein arginine methyltransferase 5 (PRMT5)

enzyme, comprising: contacting the PRMT5 enzyme with an effective amount of a compound of any one of any one of aspects 47 to 104.

Aspect 107. A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject comprising administering to the subject, a compound of any one of aspects 47 to 104.

Aspect 108. The method of aspect 107, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), CD 2A deleted cancers; 9P deleted cancers; MTAP deleted cancers, glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.