CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Number 62/465,608, filed March 1, 2017, which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The disclosure is directed to PRMT5 inhibitors and methods of their use. BACKGROUND

[0003] 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: ω NG monomethylarginine (MMA), ω NG, NG asymmetric dimethylarginine

(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] PRMT5 is as a general transcriptional repressor that functions with numerous transcription factors and repressor complexes, including BRG1 and hBRM, Blimp1, 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 histone modifications in prostate cancer has shown that the dimethylation of histone 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 histone H3 and H4, resulting in the repression of gene expression. PRMT5 overexpression can stimulate cell growth and induce transformation by directly repressing tumor suppressor genes. Pal et al., Mol. Cell. Biol. 2003, 7475; Pal et al. Mol. Cell. Biol.2004, 9630; Wang et al. Mol. Cell. 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, 5237558; Hsu et al. Nature 2015525, 384.

[0007] The discovery 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-thalassemia 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 methylation, which marks critical CpG dinucleotides flanking the gene transcriptional start site in adult bone marrow erythroid cells. It has been shown that these marks are established as a consequence of recruitment of the DNA methyltransferase, DNMT3A to the gamma-promoter by the protein arginine methyltransferase PRMT5. Zhao et al. Nat Struct Mol Biol.200916, 304. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, 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 PRMT5 binding or its enzymatic activity leads to demethylation 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 CR ¹² or N; 

R ¹ is -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3-C6halocycloalkyl, C2-C6alkenyl, -C2- C ₆ haloalkenyl, -C ₀ -C ₆ alk-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C≡CH, - C0-C6alk-C≡C-C1-C6alkyl, -C0-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3- C6cycloalkyl, -C1-C6alk-aryl, -C1-C6alk-S-C1-C6alkyl, -C1-C6alk-S-C1-C6haloalkyl, - C ₁ -C ₆ alk-S-C ₃ -C ₆ cycloalkyl; -C ₁ -C ₆ alk-S-C ₃ -C ₆ halocycloalkyl, -C ₁ -C ₆ alk-O-C ₁ - C ₆ alkyl, -C ₁ -C ₆ alk-O-C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alk-S-CH ₂ -aryl, -C ₁ -C ₆ alk-C(O)NH- aryl, -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, -C0-C6alk-S(O)2aryl, -C0-C6alk-Oaryl, - C ₀ -C ₆ alk-heteroaryl, -C ₁ -C ₆ alk-O-heteroaryl, -C ₁ -C ₆ alk-S-heteroaryl, or -C ₁ -C ₆ alk- NH-heteroaryl;

R ² is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-OH, -C0-C6alk-O-C1-C6alkyl, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, -C0-C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, -C0-C6alk-heterocycloalkyl, heteroaryl, or –CN;

R ³ is H, halo, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-OH, -C ₀ -C ₆ alk-O-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-N(C ₁ - C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, -C0-C6alk-N(C1-C6alkyl)-C3- C ₆ cycloalkyl, -C ₀ -C ₆ alk-heterocycloalkyl, heteroaryl, or–CN; R ⁴ is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-OH, -C ₀ -C ₆ alk-O-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-N(C ₁ - C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ - C6cycloalkyl, -C0-C6alk-heterocycloalkyl, heteroaryl, or–CN;

or R ² and R ³ , together with the atoms to which they are attached, form a

C ₃ -C ₆ cycloalkenyl ring;

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

or R ³ and R ⁴ , together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring;

R ⁵ is H, halo, NH ₂ , or -C ₁ -C ₆ alkyl;

R ⁶ is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, or -C0-C6alk-C3-C6cycloalkyl,

R ⁷ is H, -C ₁ -C ₆ alkyl, halo, -C ₁ -C ₄ haloalkyl, -C ₃ -C ₆ cycloalkyl, -C ₃ -C ₆ halocycloalkyl, -C ₁ - C ₆ alk-O-C ₁ -C ₆ alkyl, -C ₁ -C ₆ alk-S(O)-C ₁ -C ₆ alkyl, -C ₁ -C ₆ alk-S(O) ₂ -C ₁ -C ₆ alkyl, - CR ⁸ R ^8’ CN, -NR ⁸ R ^8’ , -NHCR ⁸ R ^8’ CN, -NH-CN, -NHCONR ⁸ R ^8’ , -NHC(O)OR ⁹ , NHC(O)-C1-C6alkyl, NHC(O)-C1-C6haloalkyl, or -NH-C1-C6alk-C(O)-C1-C6alkyl; R ⁸ and R ^8’ are each independently H, C ₁ -C ₆ alkyl, or–C ₀ -C ₆ alk-OC ₁ -C ₆ alkyl;

or R ⁸ and R ^8’ , together with the atom to which they are attached, form a C3-C6cycloalkyl or C3-C6heterocycloalkyl ring; and

R ⁹ is -C ₁ -C ₆ alkyl, or C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl;

R ¹⁰ is H, halo, or -C1-C6alkyl;

R ¹¹ is H, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3- C ₆ halocycloalkyl, -C ₀ -C ₆ alk-OH, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, -C ₀ - C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-N(C ₁ - C6alkyl)-C3-C6cycloalkyl;

or R ¹¹ and R ¹ , together with the atom to which they are attached, form a C ₃ -C ₆ cycloalkyl ring or a heterocycloalkyl ring; and

R ¹² is H, halo, or -C1-C6alkyl. [0011] Stereoisomers of the compounds of Formula I, Formula II, Formula III, or Formula IV, and the pharmaceutical salts and solvates thereof, are also described. 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 (“C ₁ -C ₆ ”), in the group. Examples of alkyl groups include methyl (Me, C ₁ alkyl), ethyl (Et, C ₂ alkyl), n-propyl (C ₃ alkyl), isopropyl (C ₃ alkyl), butyl (C ₄ alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (C5alkyl), isopentyl (C5alkyl), tert-pentyl (C5alkyl), hexyl (C6alkyl), isohexyl (C6alkyl), and the like. The term“halo” when used alone or as part of a substituent group refers to chloro, fluoro, bromo, or iodo.

[0014] 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, trifluoromethyl (-CF3), chloromethyl (- CH2Cl), and the like.

[0015] 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 ), cyclopentyl (C ₅ ), cyclohexyl (C ₆ ), 1- methylcyclopropyl (C ₄ ), 2-methylcyclopentyl (C ₄ ), adamantanyl (C ₁₀ ), and the like.

[0016] 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, chlorocyclopropyl (C3), fluorocyclobutyl (C4),

bromocyclopentyl (C5), iodocyclohexyl (C6), and the like. [0017] The term“heterocycloalkyl” 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 heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.

[0018] The term“oxo-substituted-heterocycloalkyl” when used alone or as part of a substituent group refers to a heterocycloalkyl group wherein at least one of the carbon atoms in the ring is substituted with an oxo group. Examples of oxo-substituted heterocycloalkyl groups include, but are not limited to, 2-aziridinonyl, 2-azetidinonyl, pyrrolidinonyl, dioxolanonyl,

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

[0019] 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-C4”), in the group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH=CH ₂ ; C ₂ alkenyl) allyl (-CH ₂ - CH=CH ₂ ; C3alkenyl), propenyl (-CH=CHCH3; C3alkenyl); isopropenyl (-C(CH3)=CH2; C3alkenyl), butenyl (- CH=CHCH2CH3; C4alkenyl), sec-butenyl (-C(CH3)=CHCH3; C4alkenyl), iso-butenyl (- CH=C(CH ₃ ) ₂ ; C ₄ alkenyl), 2-butenyl (-CH ₂ CH=CHCH ₃ ; C ₄ alkyl), pentenyl (-CH=CHCH ₂ CH ₂ CH ₃ ; C ₅ alkenyl), and the like.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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 alkyl group, or a -C1-C3 alkyl 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 aryl groups (substituted and unsubstituted) include phenyl, naphtyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, methylchlorophenyl, (hydroxymethyl)chlorophenyl, (hydroxymethyl)fluorophenyl,

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

(methylaminomethyl)chlorophenyl, (methylaminomethyl)fluorophenyl,

(methylaminomethyl)difluorophenyl, (methylaminomethyl)dichlorophenyl, methyldifluorophenyl, bromophenyl, iodophenyl, chlorofluorophenyl, fluoronaphthyl, difluoronaphthyl, chloronaphthyl, bromonaphthyl, iodonaphthyl, methylphenyl, ethylphenyl, and the like.

[0024] 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–C ₁ -C ₆ cycloalkyl group or a–C ₁ -C ₆ alkyl group; or a -C1-C3 alkyl group. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), 5- chlorothiophen-2-yl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolinyl, 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.

[0025] When a range of carbon atoms is used herein, for example, C ₁ -C ₆ , all ranges, as well as individual numbers of carbon atoms are encompassed. For example,“C1-C3” includes C1- C3, C1-C2, C2-C3, C1, C2, and C3.

[0026] The term“C _1- C ₆ alk” 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(CH3)-, -CH(CH3)-CH2-, and -C(CH3)2-. The term“-C0alk-” refers to a bond. In some aspects, the C1-C6alk can be substituted with one or more -OH, -NH ₂ , or halo (e.g., -F, -Cl, -Br, with -F being preferred) substituents.

[0027] “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.

[0028] “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-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic 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, tetraalkylammonium, 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.

[0029] 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.

[0030] A“solvate” refers to a physical association of a compound of Formula I or Formula II with one or more solvent molecules.“Subject” includes humans. The terms“human,”“patient,” and“subject” are used interchangeably herein.

[0031] “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.

[0032] “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 IV as well as the pharmaceutically acceptable salts and solvates, where the context so permits.

[0033] 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 ( ² H or D), carbon-13 ( ¹³ C), nitrogen-15 ( 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 ² H/D, any carbon may be ¹³ C, or any nitrogen may be ¹⁵ N, and that the presence and placement of such atoms may be determined within the skill of the art.

[0034] 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 (S)-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.

[0035] The disclosure is directed to compounds of Formula I, Formula II, Formula III, or Formula IV. In some aspects, the disclosure is directed to compounds of Formula I:

[0036] In other aspects, the disclosure is directed to compounds of Formula II:

[0037] In other aspects, the disclosure is directed to compounds of Formula III:

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

[0039] According to the disclosure, A in Formula I or Formula II is N or CR ¹² . In some aspects, A is N and the compounds of Formula I are of Formula IA:

[0040] In some aspects, A is N and the compounds of Formula II are of Formula IIA:

[0041] In some aspects, A is CR ¹² and the compounds of Formula I are of Formula IB:

[0042] In other aspects, A is CR ¹² and the compounds of Formula II are of Formula IIB:

[0043] According to the disclosure, R ¹ in Formula I Formula II, Formula III, or Formula IV is -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3-C6halocycloalkyl, C2-C6alkenyl, -C2-C6haloalkenyl, - C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C≡CH, -C0-C6alk-C≡C-C1-C6alkyl, -C0- C ₆ alk-C≡C-C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C≡C-C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alk-aryl, -C ₁ -C ₆ alk-S-C ₁ - C6alkyl, -C1-C6alk-S-C1-C6haloalkyl, -C1-C6alk-S-C3-C6cycloalkyl; -C1-C6alk-S-C3- C6halocycloalkyl -C1-C6alk-O-C1-C6alkyl, -C1-C6alk-O-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, - C ₁ -C ₆ alk-C(O)NH-aryl, -C ₀ -C ₆ alk-S-aryl, -C ₀ -C ₆ alk-S(O)aryl, -C ₀ -C ₆ alk-S(O) ₂ aryl, -C ₀ -C ₆ alk- Oaryl, -C ₀ -C ₆ alk-heteroaryl, -C ₁ -C ₆ alk-O-heteroaryl, -C ₁ -C ₆ alk-S-heteroaryl, or -C ₁ -C ₆ alk-NH- heteroaryl;

[0044] In some aspects, R ¹ in Formula I , Formula II, Formula III, or Formula IV is R ¹ is - C ₀ -C ₆ alk-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C≡CH, -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ alkyl, -C ₀ - C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3-C6cycloalkyl, -C1-C6alk-aryl, -C0-C6alk-S-aryl, -C0- C6alk-S(O)aryl, -C0-C6alk-S(O)2aryl, or -C0-C6alk-Oaryl.

[0045] In other aspects, R ¹ is -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl, for example, -C ₀ alk-C ₃ cycloalkyl, -C1alk-C3cycloalkyl, -C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, -C5alk- C3cycloalkyl¸ -C6alk-C3cycloalkyl, -C0alk-C4cycloalkyl, -C1alk-C4cycloalkyl, -C2alk-C4cycloalkyl, - C ₃ alk-C ₄ cycloalkyl, -C ₄ alk-C ₄ cycloalkyl, -C ₅ alk-C ₄ cycloalkyl¸ -C ₆ alk-C ₄ cycloalkyl, -C ₀ alk- C ₅ cycloalkyl, -C ₁ alk-C ₅ cycloalkyl, -C ₂ alk-C ₅ cycloalkyl, -C ₃ alk-C ₅ cycloalkyl, -C ₄ alk-C ₅ cycloalkyl, - C5alk-C5cycloalkyl¸ -C6alk-C5cycloalkyl, -C0alk-C6cycloalkyl, -C1alk-C6cycloalkyl, -C2alk- C6cycloalkyl, -C3alk-C6cycloalkyl, -C4alk-C6cycloalkyl, -C5alk-C6cycloalkyl¸ or -C6alk- C ₆ cycloalkyl. Thus, in some aspects, R ¹ is -CH ₂ -cyclopropyl.

[0046] In some aspects, R ¹ is -C0-C6alk-C3-C6halocycloalkyl, for example, -C0alk- C3halocycloalkyl, -C1alk-C3halocycloalkyl, -C2alk-C3halocycloalkyl, -C3alk-C3halocycloalkyl, - C ₄ alk-C ₃ halocycloalkyl, -C ₅ alk-C ₃ halocycloalkyl¸ -C ₆ alk-C ₃ halocycloalkyl, -C ₀ alk-C ₄ halocycloalkyl, -C1alk-C4halocycloalkyl, -C2alk-C4halocycloalkyl, -C3alk-C4halocycloalkyl, -C4alk- C4halocycloalkyl, -C5alk-C4halocycloalkyl¸ -C6alk-C4halocycloalkyl, -C0alk-C5halocycloalkyl, - C1alk-C5halocycloalkyl, -C2alk-C5halocycloalkyl, -C3alk-C5halocycloalkyl, -C4alk-C5halocycloalkyl, -C ₅ alk-C ₅ halocycloalkyl¸ -C ₆ alk-C ₅ halocycloalkyl, -C ₀ alk-C ₆ halocycloalkyl, -C ₁ alk- C ₆ halocycloalkyl, -C ₂ alk-C ₆ halocycloalkyl, -C ₃ alk-C ₆ halocycloalkyl, -C ₄ alk-C ₆ halocycloalkyl, - C5alk-C6halocycloalkyl¸ or -C6alk-C6halocycloalkyl.

[0047] In some aspects, R ¹ is -C2-C6alkenyl, for example, vinyl, allyl, and the like.

[0048] In some aspects, R ¹ is -C ₂ -C ₆ haloalkenyl, for example, -C(F)=CHMe, -C(F)=CH ₂ , and the like.

[0049] In some aspects, R ¹ is -C0-C6alk-C1-C6alkyl, for example, -C0alk-C1alkyl, -C1alk- C ₁ alkyl, -C ₂ alk-C ₁ alkyl, -C ₃ alk-C ₁ alkyl, -C ₄ alk-C ₁ alkyl, -C ₅ alk-C ₁ alkyl¸ -C ₆ alk-C ₁ alkyl, -C ₀ alk- C ₂ alkyl, -C ₁ alk-C ₂ alkyl, -C ₂ alk-C ₂ alkyl, -C ₃ alk-C ₂ alkyl, -C ₄ alk-C ₂ alkyl, -C ₅ alk-C ₂ alkyl¸ -C ₆ alk- C2alkyl, -C0alk-C3alkyl, -C1alk-C3alkyl, -C2alk-C3alkyl, -C3alk-C3alkyl, -C4alk-C3alkyl, -C5alk- C ₃ alkyl¸ -C ₆ alk-C ₃ alkyl, -C ₀ alk-C ₄ alkyl, -C ₁ alk-C ₄ alkyl, -C ₂ alk-C ₄ alkyl, -C ₃ alk-C ₄ alkyl, -C ₄ alk- C ₄ alkyl, -C ₅ alk-C ₄ alkyl¸ -C ₆ alk-C ₄ alkyl, -C ₀ alk-C ₅ alkyl, -C ₁ alk-C ₅ alkyl, -C ₂ alk-C ₅ alkyl, -C ₃ alk- C5alkyl, -C4alk-C5alkyl, -C5alk-C5alkyl¸ -C6alk-C5alkyl, -C0alk-C6alkyl, -C1alk-C6alkyl, -C2alk- C6alkyl, -C3alk-C6alkyl, -C4alk-C6alkyl, -C5alk-C6alkyl¸ -C6alk-C6alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, -CH(OH)-C ₁ -C ₆ alkyl (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)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1-C6alkyl, -C(Me)(OH)-C1- C ₆ alkyl, and the like.

[0050] In other aspects, R ¹ is -C0-C6alk-C1-C6haloalkyl, for example, -C0alk-C1haloalkyl, - C1alk-C1haloalkyl, -C2alk-C1haloalkyl, -C3alk-C1haloalkyl, -C4alk-C1haloalkyl, -C5alk-C1haloalkyl¸ - C ₆ alk-C ₁ haloalkyl, -C ₀ alk-C ₂ haloalkyl, -C ₁ alk-C ₂ haloalkyl, -C ₂ alk-C ₂ haloalkyl, -C ₃ alk-C ₂ haloalkyl, - C ₄ alk-C ₂ haloalkyl, -C ₅ alk-C ₂ haloalkyl¸ -C ₆ alk-C ₂ haloalkyl, -C ₀ alk-C ₃ haloalkyl, -C ₁ alk-C ₃ haloalkyl, - C2alk-C3haloalkyl, -C3alk-C3haloalkyl, -C4alk-C3haloalkyl, -C5alk-C3haloalkyl¸ -C6alk-C3haloalkyl, - C ₀ alk-C ₄ haloalkyl, -C ₁ alk-C ₄ haloalkyl, -C ₂ alk-C ₄ haloalkyl, -C ₃ alk-C ₄ haloalkyl, -C ₄ alk-C ₄ haloalkyl, - C ₅ alk-C ₄ haloalkyl¸ -C ₆ alk-C ₄ haloalkyl, -C ₀ alk-C ₅ haloalkyl, -C ₁ alk-C ₅ haloalkyl, -C ₂ alk-C ₅ haloalkyl, - C3alk-C5haloalkyl, -C4alk-C5haloalkyl, -C5alk-C5haloalkyl¸ -C6alk-C5haloalkyl, -C0alk-C6haloalkyl, - C1alk-C6haloalkyl, -C2alk-C6haloalkyl, -C3alk-C6haloalkyl, -C4alk-C6haloalkyl, -C5alk-C6haloalkyl¸ - C ₆ alk-C ₆ haloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, -CH(OH)-C1-C6 haloalkyl (e.g., -CH(OH)-fluoromethyl, -CH(OH)-fluoroethyl, -CH(OH)-fluoropropyl, -CH(OH)- fluoroisopropyl, -CH(OH)-fluoropentyl, -CH(OH)-fluorobutyl), -CH(F)-C ₁ -C ₆ haloalkyl, -CH(NH ₂ )- C ₁ -C ₆ haloalkyl, -CH(Me)-C ₁ -C ₆ haloalkyl, -C(Me)(OH)-C ₁ -C ₆ haloalkyl, and the like. Thus, in some aspects, R ¹ is chloromethyl (i.e., -CH2-Cl.) In some embodiments, R ¹ is -CH(OH)C1- C4haloalkyl.

[0051] In some aspects, R ¹ is -C ₀ -C ₆ alk-C≡CH, for example, -C ₀ alk-C≡CH, -C ₁ alk-C≡CH , -C2alk-C≡CH , -C3alk-C≡CH , -C4alk-C≡CH , -C5alk-C≡CH , -C6alk-C≡CH, ethynyl, propargyl, - CH(OH)-C≡CH, -CH(F)-C≡CH, -CH(NH2)-C≡CH, -CH(Me)-C≡CH, -C(Me)(OH)-C≡CH, and the like.

[0052] In some aspects, R ¹ is -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ alkyl, for example, -C ₀ alk-C≡C-C ₁ alkyl, -C1alk-C≡C-C1alkyl, -C2alk-C≡C-C1alkyl, -C3alk-C≡C-C1alkyl, -C4alk-C≡C-C1alkyl, -C5alk-C≡C- C ₁ alkyl¸ -C ₆ alk-C≡C-C ₁ alkyl, -C ₀ alk-C≡C-C ₂ alkyl, -C ₁ alk-C≡C-C ₂ alkyl, -C ₂ alk-C≡C-C ₂ alkyl, - C ₃ alk-C≡C-C ₂ alkyl, -C ₄ alk-C≡C-C ₂ alkyl, -C ₅ alk-C≡C-C ₂ alkyl¸ -C ₆ alk-C≡C-C ₂ alkyl, -C ₀ alk-C≡C- C3alkyl, -C1alk-C≡C-C3alkyl, -C2alk-C≡C-C3alkyl, -C3alk-C≡C-C3alkyl, -C4alk-C≡C-C3alkyl, - C5alk-C≡C-C3alkyl¸ -C6alk-C≡C-C3alkyl, -C0alk-C≡C-C4alkyl, -C1alk-C≡C-C4alkyl, -C2alk-C≡C- C ₄ alkyl, -C ₃ alk-C≡C-C ₄ alkyl, -C ₄ alk-C≡C-C ₄ alkyl, -C ₅ alk-C≡C-C ₄ alkyl¸ -C ₆ alk-C≡C-C ₄ alkyl, - C0alk-C≡C-C5alkyl, -C1alk-C≡C-C5alkyl, -C2alk-C≡C-C5alkyl, -C3alk-C≡C-C5alkyl, -C4alk-C≡C- C5alkyl, -C5alk-C≡C-C5alkyl¸ -C6alk-C≡C-C5alkyl, -C0alk-C≡C-C6alkyl, -C1alk-C≡C-C6alkyl, - C ₂ alk-C≡C-C ₆ alkyl, -C ₃ alk-C≡C-C ₆ alkyl, -C ₄ alk-C≡C-C ₆ alkyl, -C ₅ alk-C≡C-C ₆ alkyl¸ -C ₆ alk-C≡C- C6alkyl, propynyl, butynyl, -CH(OH)-C≡C-C1-C6alkyl, -CH(F)-C≡C-C1-C6alkyl, -CH(NH2)-C≡C- C1-C6alkyl, -CH(Me)-C≡C-C1-C6alkyl, -C(Me)(OH)-C≡C-C1-C6alkyl, and the like. In some embodiments wherein -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ alkyl is -C ₀ -C ₆ alk-C≡C-CH ₃ , R ¹ is -CH(OH)-C≡C-CH ₃ , -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-CH ₃ . In some embodiments, R ¹ is -CH(OH)-C≡C-CH3. In other embodiments, R ¹ is -CH(F)-C≡C-CH3. 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–CH(OH)(Me)-C≡C-CH ₃ .

[0053] In some aspects, R ¹ is -C0-C6alk-C≡C-C1-C6haloalkyl, for example, -C0alk-C≡C- C1haloalkyl, -C1alk-C≡C-C1haloalkyl, -C2alk-C≡C-C1haloalkyl, -C3alk-C≡C-C1haloalkyl, -C4alk- C≡C-C ₁ haloalkyl, -C ₅ alk-C≡C-C ₁ haloalkyl¸ -C ₆ alk-C≡C-C ₁ haloalkyl, -C ₀ alk-C≡C-C ₂ haloalkyl, - C1alk-C≡C-C2haloalkyl, -C2alk-C≡C-C2haloalkyl, -C3alk-C≡C-C2haloalkyl, -C4alk-C≡C- C2haloalkyl, -C5alk-C≡C-C2haloalkyl¸ -C6alk-C≡C-C2haloalkyl, -C0alk-C≡C-C3haloalkyl, -C1alk- C≡C-C3haloalkyl, -C2alk-C≡C-C3haloalkyl, -C3alk-C≡C-C3haloalkyl, -C4alk-C≡C-C3haloalkyl, - C ₅ alk-C≡C-C ₃ haloalkyl¸ -C ₆ alk-C≡C-C ₃ haloalkyl, -C ₀ alk-C≡C-C ₄ haloalkyl, -C ₁ alk-C≡C- C ₄ haloalkyl, -C ₂ alk-C≡C-C ₄ haloalkyl, -C ₃ alk-C≡C-C ₄ haloalkyl, -C ₄ alk-C≡C-C ₄ haloalkyl, -C ₅ alk- C≡C-C4haloalkyl¸ -C6alk-C≡C-C4haloalkyl, -C0alk-C≡C-C5haloalkyl, -C1alk-C≡C-C5haloalkyl, - C2alk-C≡C-C5haloalkyl, -C3alk-C≡C-C5haloalkyl, -C4alk-C≡C-C5haloalkyl, -C5alk-C≡C- C ₅ haloalkyl¸ -C ₆ alk-C≡C-C ₅ haloalkyl, -C ₀ alk-C≡C-C ₆ haloalkyl, -C ₁ alk-C≡C-C ₆ haloalkyl, -C ₂ alk- C≡C-C6haloalkyl, -C3alk-C≡C-C6haloalkyl, -C4alk-C≡C-C6haloalkyl, -C5alk-C≡C-C6haloalkyl¸ - C6alk-C≡C-C6haloalkyl, -CH(OH)-C≡C-C1-C6haloalkyl, -CH(F)-C≡C-C1-C6haloalkyl, -CH(NH2)- C≡C-C ₁ -C ₆ haloalkyl, -CH(Me)-C≡C-C ₁ -C ₆ haloalkyl, -C(Me)(OH)-C≡C-C ₁ -C ₆ haloalkyl, and the like. In some embodiments wherein -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ haloalkyl is -C ₀ -C ₆ alk-C≡C-CF ₃ , R ¹ is - CH(OH)-C≡C-CF3, -CH(F)-C≡C-CF3, -CH(NH2)-C≡C-CF3, -CH(Me)-C≡C-CF3, -C(Me)(OH)-C≡C- CF ₃ , and the like. Thus, in some embodiments, R ¹ is -CH(OH)-C≡C-CF _3.

[0054] In some aspects, R ¹ is -C ₀ -C ₆ alk-C≡C-C ₃ -C ₆ cycloalkyl, for example, -C ₀ alk-C≡C- C3cycloalkyl, -C0alk-C≡C-C4cycloalkyl, -C0alk-C≡C-C5cycloalkyl, -C0alk-C≡C-C6cycloalkyl, - C1alk-C≡C-C3cycloalkyl, -C1alk-C≡C-C4cycloalkyl, -C1alk-C≡C-C5-cycloalkyl, -C1alk-C≡C- C ₆ cycloalkyl, -C ₂ alk-C≡C-C ₃ cycloalkyl, -C ₂ alk-C≡C-C ₄ cycloalkyl, -C ₂ alk-C≡C-C ₅ cycloalkyl, - C2alk-C≡C-C6cycloalkyl, -C3alk-C≡C-C3cycloalkyl, -C3alk-C≡C-C4cycloalkyl, -C3alk-C≡C- C5cycloalkyl, -C3alk-C≡C-C6cycloalkyl, -C4alk-C≡C-C3cycloalkyl, -C4alk-C≡C-C4cycloalkyl, - C ₄ alk-C≡C-C ₅ cycloalkyl, -C ₄ alk-C≡C-C ₆ cycloalkyl, -C ₅ alk-C≡C-C ₃ cycloalkyl, -C ₅ alk-C≡C- C4cycloalkyl, -C5alk-C≡C-C5cycloalkyl, -C5alk-C≡C-C6cycloalkyl, -C6alk-C≡C-C3cycloalkyl, - C6alk-C≡C-C4cycloalkyl, -C6alk-C≡C-C5cycloalkyl, -C6alk-C≡C-C6cycloalkyl, -CH(OH)-C≡C-C3- C ₆ cycloalkyl, -CH(F)-C≡C-C ₃ -C ₆ cycloalkyl, -CH(NH ₂ )-C≡C-C ₃ -C ₆ cycloalkyl, -CH(Me)-C≡C-C ₃ - C ₆ cycloalkyl, or -C(Me)(OH)-C≡C-C ₃ -C ₆ cycloalkyl. In some embodiments wherein -C ₀ -C ₆ alk-C≡C- C3-C6cycloalkyl is -C0-C6alk-C≡C-cyclopropyl, R ¹ is -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C- cyclopropyl, -CH(NH ₂ )-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.

[0055] In some aspects, R ¹ is -C1-C6alk-aryl, for example, -C1alk-aryl, -C2alk-aryl, -C3alk- aryl, -C4alk-aryl, -C5alk-aryl, -C6alk-aryl, -CH2aryl, -CH(OH)-aryl, -CH(F)-aryl, -CH(NH2)-aryl, - CH(Me)-aryl, -C(Me)(OH)-aryl, and the like. In some embodiments wherein R ¹ is -C ₁ -C ₆ alk-aryl, the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3- chloro-4-fluorophenyl, 2,4-difluorophenyl, 3-methyl-4-chlorophenyl, 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, 2-(methylaminomethyl)- 4,5-difluorophenyl. Thus in some embodiments, R ¹ is - CH2-difluorophenyl, -CH2-3,4-difluorophenyl, -CH2-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH2-dichlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-(2,4- difluorophenyl), -CH ₂ -(3-methyl-4-chlorophenyl), -CH ₂ -(2-hydroxymethyl-4-chlorophenyl), -CH ₂ - (2-hydroxymethyl-5-chlorophenyl), -CH2-(2-aminomethyl-4-chlorophenyl), -CH2-(2- (methylaminomethyl)-4-chlorophenyl), -CH2-(2-hydroxymethyl-4,5-difluorophenyl), -CH2-(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-chloro-4-fluorophenyl, -CH(OH)-(2,4-difluorophenyl), -CH(OH)-(3- methyl-4-chlorophenyl), -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-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)-(2,4-difluorophenyl), -CH(F)-(3-methyl-4-chlorophenyl), -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(NH2)-4-chlorophenyl, -CH(NH2)-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 )-(2,4-difluorophenyl), -CH(NH ₂ )-(3-methyl-4-chlorophenyl), - CH(NH2)-(2-hydroxymethyl-4-chlorophenyl), -CH(NH2)-(2-hydroxymethyl-5-chlorophenyl), - CH(NH ₂ )-(2-aminomethyl-4-chlorophenyl), -CH(NH ₂ )-(2-(methylaminomethyl)-4-chlorophenyl), - CH(NH ₂ )-(2-hydroxymethyl-4,5-difluorophenyl), -CH(NH ₂ )-(2-aminomethyl-4,5-difluorophenyl), - CH(NH2)-(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)-(2,4-difluorophenyl), -CH(Me)-(3-methyl-4-chlorophenyl), -CH(Me)-(2- hydroxymethyl-4-chlorophenyl), -CH(Me)-(2-hydroxymethyl-4-chlorophenyl), -CH(Me)-(2- aminomethyl-4-chlorophenyl), -CH(Me)-(2-(methylaminomethyl)-5-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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4- chlorophenyl), -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), or -C(Me)(OH)-(2-(methylaminomethyl)-4,5- difluorophenyl).

[0056] In some aspects, R ¹ is -C ₁ -C ₆ alk-S-C ₁ -C ₆ alkyl, for example -C ₁ alk-S-C ₁ alkyl, - C2alk-S-C1alkyl, -C3alk-S-C1alkyl, -C4alk-S-C1alkyl, -C5alk-S-C1alkyl¸ -C6alk-S-C1alkyl, -C1alk-S- C ₂ alkyl, -C ₂ alk-S-C ₂ alkyl, -C ₃ alk-S-C ₂ alkyl, -C ₄ alk-S-C ₂ alkyl, -C ₅ alk-S-C ₂ alkyl¸ -C ₆ alk-S-C ₂ alkyl, - C ₁ alk-S-C ₃ alkyl, -C ₂ alk-S-C ₃ alkyl, -C ₃ alk-S-C ₃ alkyl, -C ₄ alk-S-C ₃ alkyl, -C ₅ alk-S-C ₃ alkyl¸ -C ₆ alk-S- C3alkyl, -C1alk-S-C4alkyl, -C2alk-S-C4alkyl, -C3alk-S-C4alkyl, -C4alk-S-C4alkyl, -C5alk-S-C4alkyl¸ - C6alk-S-C4alkyl, -C1alk-S-C5alkyl, -C2alk-S-C5alkyl, -C3alk-S-C5alkyl, -C4alk-S-C5alkyl, -C5alk-S- C ₅ alkyl¸ -C ₆ alk-S-C ₅ alkyl, -C ₁ alk-S-C ₆ alkyl, -C ₂ alk-S-C ₆ alkyl, -C ₃ alk-S-C ₆ alkyl, -C ₄ alk-S-C ₆ alkyl, - C5alk-S-C6alkyl¸ -C6alk-S-C6alkyl, -CH2S-C2alkyl, -CH2S-C3alkyl, -CH2S-C4alkyl, -CH2S-C5alkyl, - CH2S-C6alkyl, and the like. Thus, in some aspects R ¹ is -CH2S-C1alkyl. In some aspects, R ¹ is - CH ₂ -S-CH ₃ .

[0057] In some aspects, R ¹ is -C1-C6alk-S-C1-C6haloalkyl, for example -C1alk-S- C1haloalkyl, -C2alk-S-C1haloalkyl, -C3alk-S-C1haloalkyl, -C4alk-S-C1haloalkyl, -C5alk-S- C ₁ haloalkyl¸ -C ₆ alk-S-C ₁ haloalkyl, -C ₁ alk-S-C ₂ haloalkyl, -C ₂ alk-S-C ₂ haloalkyl, -C ₃ alk-S- C ₂ haloalkyl, -C ₄ alk-S-C ₂ haloalkyl, -C ₅ alk-S-C ₂ haloalkyl¸ -C ₆ alk-S-C ₂ haloalkyl, -C ₁ alk-S- C3haloalkyl, -C2alk-S-C3haloalkyl, -C3alk-S-C3haloalkyl, -C4alk-S-C3haloalkyl, -C5alk-S- C ₃ haloalkyl¸ -C ₆ alk-S-C ₃ haloalkyl, -C ₁ alk-S-C ₄ haloalkyl, -C ₂ alk-S-C ₄ haloalkyl, -C ₃ alk-S- C ₄ haloalkyl, -C ₄ alk-S-C ₄ haloalkyl, -C ₅ alk-S-C ₄ haloalkyl¸ -C ₆ alk-S-C ₄ haloalkyl, -C ₁ alk-S- C5haloalkyl, -C2alk-S-C5haloalkyl, -C3alk-S-C5haloalkyl, -C4alk-S-C5haloalkyl, -C5alk-S- C5haloalkyl¸ -C6alk-S-C5haloalkyl, -C1alk-S-C6haloalkyl, -C2alk-S-C6haloalkyl, -C3alk-S- C ₆ haloalkyl, -C ₄ alk-S-C ₆ haloalkyl, -C ₅ alk-S-C ₆ haloalkyl¸ -C ₆ alk-S-C ₆ haloalkyl, -CH ₂ S-C ₁ haloalkyl, -CH2S-C2haloalkyl, -CH2S-C3haloalkyl, -CH2S-C4haloalkyl, -CH2S-C5haloalkyl, and -CH2S- C6haloalkyl. [0058] In some aspects, R ¹ is -C1-C6alk-S-C3-C6cycloalkyl, for example -C1alk-S- C ₃ cycloalkyl, -C ₂ alk-S-C ₃ cycloalkyl, -C ₃ alk-S-C ₃ cycloalkyl, -C ₄ alk-S-C ₃ cycloalkyl, -C ₅ alk-S- C ₃ cycloalkyl¸ -C ₆ alk-S-C ₃ cycloalkyl, -C ₁ alk-S-C ₄ cycloalkyl, -C ₂ alk-S-C ₄ cycloalkyl, -C ₃ alk-S- C4cycloalkyl, -C4alk-S-C4cycloalkyl, -C5alk-S-C4cycloalkyl¸ -C6alk-S-C4cycloalkyl, -C1alk-S- C5cycloalkyl, -C2alk-S-C5cycloalkyl, -C3alk-S-C5cycloalkyl, -C4alk-S-C5cycloalkyl, -C5alk-S- C ₅ cycloalkyl¸ -C ₆ alk-S-C ₅ cycloalkyl, -C ₁ alk-S-C ₆ cycloalkyl, -C ₂ alk-S-C ₆ cycloalkyl, -C ₃ alk-S- C6cycloalkyl, -C4alk-S-C6cycloalkyl, -C5alk-S-C6cycloalkyl¸ -C6alk-S-C6cycloalkyl, -CH2S- C3cycloalkyl, -CH2S-C4cycloalkyl, -CH2S-C5cycloalkyl, -CH2S-C6cycloalkyl, and the like.

[0059] In some aspects, R ¹ is -C ₁ -C ₆ alk-S-C ₃ -C ₆ halocycloalkyl, for example -C ₁ alk-S- C ₃ halocycloalkyl, -C ₂ alk-S-C ₃ halocycloalkyl, -C ₃ alk-S-C ₃ halocycloalkyl, -C ₄ alk-S-C ₃ halocycloalkyl, -C5alk-S-C3halocycloalkyl¸ -C6alk-S-C3halocycloalkyl, -C1alk-S-C4halocycloalkyl, -C2alk-S- C ₄ halocycloalkyl, -C ₃ alk-S-C ₄ halocycloalkyl, -C ₄ alk-S-C ₄ halocycloalkyl, -C ₅ alk-S-C ₄ halocycloalkyl¸ -C ₆ alk-S-C ₄ halocycloalkyl, -C ₁ alk-S-C ₅ halocycloalkyl, -C ₂ alk-S-C ₅ halocycloalkyl, -C ₃ alk-S- C5halocycloalkyl, -C4alk-S-C5halocycloalkyl, -C5alk-S-C5halocycloalkyl¸ -C6alk-S-C5halocycloalkyl, -C1alk-S-C6halocycloalkyl, -C2alk-S-C6halocycloalkyl, -C3alk-S-C6halocycloalkyl, -C4alk-S- C ₆ halocycloalkyl, -C ₅ alk-S-C ₆ halocycloalkyl¸ -C ₆ alk-S-C ₆ halocycloalkyl, -CH ₂ S-C ₃ halocycloalkyl, - CH2S-C4halocycloalkyl, -CH2S-C5halocycloalkyl, -CH2S-C6halocycloalkyl, and the like.

[0060] In some aspects, R ¹ is -C1-C6alk-O-C1-C6alkyl, for example, -C1alk-O-C1alkyl, - C ₂ alk-O-C ₁ alkyl, -C ₃ alk-O-C ₁ alkyl, -C ₄ alk-O-C ₁ alkyl, -C ₅ alk-O-C ₁ alkyl¸ -C ₆ alk-O-C ₁ alkyl, -C ₁ alk- O-C2alkyl, -C2alk-O-C2alkyl, -C3alk-O-C2alkyl, -C4alk-O-C2alkyl, -C5alk-O-C2alkyl¸ -C6alk-O- C2alkyl, -C1alk-O-C3alkyl, -C2alk-O-C3alkyl, -C3alk-O-C3alkyl, -C4alk-O-C3alkyl, -C5alk-O-C3alkyl¸ -C ₆ alk-O-C ₃ alkyl, -C ₁ alk-O-C ₄ alkyl, -C ₂ alk-O-C ₄ alkyl, -C ₃ alk-O-C ₄ alkyl, -C ₄ alk-O-C ₄ alkyl, -C ₅ alk- O-C ₄ alkyl¸ -C ₆ alk-O-C ₄ alkyl, -C ₁ alk-O-C ₅ alkyl, -C ₂ alk-O-C ₅ alkyl, -C ₃ alk-O-C ₅ alkyl, -C ₄ alk-O- C5alkyl, -C5alk-O-C5alkyl¸ -C6alk-O-C5alkyl, -C1alk-O-C6alkyl, -C2alk-O-C6alkyl, -C3alk-O-C6alkyl, -C ₄ alk-O-C ₆ alkyl, -C ₅ alk-O-C ₆ alkyl¸ -C ₆ alk-O-C ₆ alkyl, -CH ₂ OC ₁ alkyl, -CH ₂ OC ₂ alkyl, - CH ₂ OC ₃ alkyl, -CH ₂ OC ₄ alkyl, -CH ₂ OC ₅ alkyl, -CH ₂ OC ₆ alkyl, and the like.

[0061] In some aspects, R ¹ is -C1-C6alk-O-C3-C6cycloalkyl, for example, -C1alk-O- C3cycloalkyl, -C2alk-O-C3cycloalkyl, -C3alk-O-C3cycloalkyl, -C4alk-O-C3cycloalkyl, -C5alk-O- C ₃ cycloalkyl¸ -C ₆ alk-O-C ₃ cycloalkyl, -C ₁ alk-O-C ₄ cycloalkyl, -C ₂ alk-O-C ₄ cycloalkyl, -C ₃ alk-O- C4cycloalkyl, -C4alk-O-C4cycloalkyl, -C5alk-O-C4cycloalkyl¸ -C6alk-O-C4cycloalkyl, -C1alk-O- C5cycloalkyl, -C2alk-O-C5cycloalkyl, -C3alk-O-C5cycloalkyl, -C4alk-O-C5cycloalkyl, -C5alk-O- C5cycloalkyl¸ -C6alk-O-C5cycloalkyl, -C1alk-O-C6cycloalkyl, -C2alk-O-C6cycloalkyl, -C3alk-O- C ₆ cycloalkyl, -C ₄ alk-O-C ₆ cycloalkyl, -C ₅ alk-O-C ₆ cycloalkyl¸ -C ₆ alk-O-C ₆ cycloalkyl, -CH ₂ O- C ₆ cycloalkyl, -CH ₂ O-C ₅ cycloalkyl, -CH ₂ O-C ₄ cycloalkyl, -CH ₂ O-C ₃ cycloalkyl, -CH ₂ O-C ₆ cycloalkyl, and the like.

[0062] In some aspects, R ¹ is -C1-C6alk-SCH2-aryl, for example -C1alk-SCH2-aryl, -C2alk- SCH ₂ -aryl , -C ₃ alk-SCH ₂ -aryl, -C ₄ alk-SCH ₂ -aryl, -C ₅ alk-SCH ₂ -aryl¸-C ₆ alk-SCH ₂ -aryl, -CH ₂ SCH ₂ - phenyl, -CH2SCH2-naphthyl, -CH2SCH2-fluorophenyl, -CH2SCH2-difluorophenyl, -CH2SCH2- fluoronaphthyl, -CH2SCH2-chlorophenyl, -CH2SCH2-bromophenyl, -CH2SCH2-iodophenyl, - CH ₂ SCH ₂ -methylphenyl, -CH ₂ SCH ₂ -4-chlorophenyl, -CH ₂ SCH ₂ -3,4-dichlorophenyl, -CH ₂ SCH ₂ -3,4- difluorophenyl, -CH ₂ SCH ₂ -3-fluoro-4-chlorophenyl, -CH ₂ SCH ₂ -3-chloro-4-fluorophenyl, and the like. Thus, in some aspects R ¹ is -CH2SCH2-phenyl. In other embodiments wherein R ¹ is–C1-C6alk- SCH ₂ -aryl, the -aryl is 2,4-difluorophenyl, 3-methyl-4-chlorophenyl, 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.

[0063] In some aspects, R ¹ is -C ₁ -C ₆ alkC(O)NH-aryl, for example, -C ₁ alk-C(O)NH-aryl, - C2alk-C(O)NH-aryl , -C3alk-C(O)NH -aryl, -C4alk-C(O)NH-aryl, -C5alk-C(O)NH-aryl¸-C6alk- C(O)NH-aryl, -CH2C(O)NH-phenyl, -CH2C(O)NH-naphthyl, -CH2C(O)NH-fluorophenyl, - CH ₂ C(O)NH-difluorophenyl, -CH ₂ C(O)NH -fluoronaphthyl, -CH ₂ C(O)NH-chlorophenyl, - CH2C(O)NH-bromophenyl, -CH2C(O)NH-iodophenyl, -CH2C(O)NH-methylphenyl, -CH2C(O)NH- 4-chlorophenyl, -CH2C(O)NH-3,4-dichlorophenyl, -CH2C(O)NH-3,4-difluorophenyl, -CH2C(O)NH- 3-fluoro-4-chlorophenyl, -CH ₂ C(O)NH-3-chloro-4-fluorophenyl and the like. Thus, in some aspects R ¹ is -CH ₂ C(O)NH-phenyl. In other embodiments wherein R ¹ is -C ₁ -C ₆ alkC(O)NH-aryl, the -aryl is 2,4-difluorophenyl, 3-methyl-4-chlorophenyl, 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.

[0064] In some aspects, R ¹ is -C0-C6alk-S-aryl, for example, -C0alk-S-aryl, -C1alk-S-aryl, - C ₂ alk-S-aryl, -C ₃ alk-S-aryl, -C ₄ alk-S-aryl, -C ₅ alk-S-aryl, -C ₆ alk-S-aryl, -S-phenyl, -S-naphthyl, -S- fluorophenyl, -S-difluorophenyl, -S-fluoronaphthyl, -S-chlorophenyl, -S-bromophenyl, -S- iodophenyl, -S-methylphenyl, and the like. In some embodiments wherein R ¹ is -C0-C6alk-S-aryl, the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3- chloro-4-fluorophenyl, 2,4-difluorophenyl, 3-methyl-4-chlorophenyl, 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. In some aspects R ¹ is -S- difluorophenyl. In some aspects R ¹ is -S-3,4-difluorophenyl. In other aspects, R ¹ is -S-chlorophenyl. In other aspects, R ¹ is -S-4-chlorophenyl. In other aspects, R ¹ is -S-chlorofluorophenyl. In other aspects, R ¹ is -S-3-chloro-4-fluorophenyl. In other aspects, R ¹ is -S-4-chloro-3-fluorophenyl. In other aspects, R ¹ is -S-dichlorophenyl. In other aspects, R ¹ is -S-3,4-dichlorophenyl. In other aspects, R ¹ is -S-2,4-difluorophenyl, -S-(3-methyl-4-chlorophenyl), -S-(2-hydroxymethyl-4- chlorophenyl), ), -S-(2-hydroxymethyl-5-chlorophenyl), -S-(2-aminomethyl-4-chlorophenyl), -S-(2- (methylaminomethyl)-4-chlorophenyl), -S-(2-hydroxymethyl-4,5-difluorophenyl), -S-(2- aminomethyl-4,5-difluorophenyl), or -S-(2-(methylaminomethyl)-4,5-difluorophenyl).

[0065] In some aspects, R ¹ is -C0-C6alk-S(O)aryl, for example, -C0alk-S(O)aryl, -C1alk- S(O)aryl, -C2alk-S(O)aryl, -C3alk-S(O)aryl, -C4alk-S(O)aryl, -C5alk-S(O)aryl, -C6alk-S(O)aryl, - S(O)-phenyl, -S(O)-naphthyl, -S(O)-fluorophenyl, -S(O)-difluorophenyl, -S(O)-fluoronaphthyl, - S(O)-chlorophenyl, -S(O)-bromophenyl, -S(O)-iodophenyl, -S(O)-methylphenyl, and the like. In some embodiments wherein R ¹ is -C0-C6alk-S(O)-aryl, the -aryl is -4-chlorophenyl, -3,4- dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, 2,4- difluorophenyl, 3-methyl-4-chlorophenyl, 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. In some aspects R ¹ is -S(O)-difluorophenyl. In some aspects R ¹ is -S(O)-3,4- difluorophenyl. In other aspects, R ¹ is -S(O)-chlorophenyl. In other aspects, R ¹ is -S(O)-4- chlorophenyl. In other aspects, R ¹ is -S(O)-chlorofluorophenyl. In other aspects, R ¹ is -S(O)-3- chloro-4-fluorophenyl. In other aspects, R ¹ is -S(O)-4-chloro-3-fluorophenyl. In other aspects, R ¹ is -S(O)-dichlorophenyl. In other aspects, R ¹ is -S(O)-3,4-dichlorophenyl. In other aspects, R ¹ is - S(O)-2,4-difluorophenyl, -S(O)-(3-methyl-4-chlorophenyl), -S(O)-(2-hydroxymethyl-4- chlorophenyl), -S(O)-(2-hydroxymethyl-5-chlorophenyl), -S(O)-(2-aminomethyl-4-chlorophenyl), - S(O)-(2-(methylaminomethyl)-4-chlorophenyl), -S(O)-(2-hydroxymethyl-4,5-difluorophenyl), -S(O)- (2-aminomethyl-4,5-difluorophenyl), or -S(O)-(2-(methylaminomethyl)-4,5-difluorophenyl). [0066] In some aspects, R ¹ is -C0-C6alk-S(O)2aryl, for example, -C0alk-S(O)2aryl, -C1alk- S(O) ₂ aryl, -C ₂ alk-S(O) ₂ aryl -C ₃ alk-S(O) ₂ aryl , -C ₄ alk-S(O) ₂ aryl, -C ₅ alk-S(O) ₂ aryl, -C ₆ alk-S(O) ₂ aryl, -S(O) ₂ -phenyl, -S(O) ₂ -naphthyl, -S(O) ₂ -fluorophenyl, -S(O) ₂ -difluorophenyl, -S(O) ₂ -fluoronaphthyl, -S(O)2-chlorophenyl, -S(O)2-bromophenyl, -S(O)2-iodophenyl, -S(O)2-methylphenyl, and the like. In some embodiments wherein R ¹ is -C0-C6alk-S(O)2-aryl, the -aryl is -4-chlorophenyl, -3,4- dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, 2,4- difluorophenyl, 3-methyl-4-chlorophenyl, 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. In some aspects R ¹ is -S(O) ₂ -difluorophenyl. In some aspects R ¹ is -S(O) ₂ -3,4- difluorophenyl. In other aspects, R ¹ is -S(O)2-chlorophenyl. In other aspects, R ¹ is -S(O)2-4- chlorophenyl. In other aspects, R ¹ is -S(O) ₂ -chlorofluorophenyl. In other aspects, R ¹ is -S(O) ₂ -3- chloro-4-fluorophenyl. In other aspects, R ¹ is -S(O) ₂ -4-chloro-3-fluorophenyl. In other aspects, R ¹ is -S(O)2-dichlorophenyl. In other aspects, R ¹ is -S(O)2-3,4-dichlorophenyl. In other aspects, R ¹ is - S(O)2-2,4-difluorophenyl, -S(O) 2-(3-methyl-4-chlorophenyl), -S(O) 2-(2-hydroxymethyl-4- chlorophenyl), -S(O) ₂ -(2-hydroxymethyl-5-chlorophenyl), -S(O) ₂ -(2-aminomethyl-4-chlorophenyl), -S(O) 2-(2-(methylaminomethyl)-4-chlorophenyl), -S(O) 2-(2-hydroxymethyl-4,5-difluorophenyl), - S(O) 2-(2-aminomethyl-4,5-difluorophenyl), or -S(O) 2-(2-(methylaminomethyl)-4,5-difluorophenyl).

[0067] In some aspects, R ¹ is -C ₀ -C ₆ alk-Oaryl, for example -C ₀ alk-Oaryl, -C ₁ alk-Oaryl, - C2alk-Oaryl -C3alk-Oaryl, -C4alk-Oaryl, -C5alk-Oaryl, -C6alk-Oaryl, -O-phenyl, -O-naphthyl, -O- fluorophenyl, -O-difluorophenyl, -O-fluoronaphthyl, -O-chlorophenyl, -O-bromophenyl, -O- iodophenyl, -O-methylphenyl, and the like. In some aspects R ¹ is -O-difluorophenyl. In some aspects R ¹ is -O-3,4-difluorophenyl. In other aspects, R ¹ is -O-chlorophenyl. In other aspects, R ¹ is - O-4-chlorophenyl. In other aspects, R ¹ is -O-chlorofluorophenyl. In other aspects, R ¹ is -O-3- chloro-4-fluorophenyl. In other aspects, R ¹ is -O-4-chloro-3-fluorophenyl. In other aspects, R ¹ is - O-dichlorophenyl. In other aspects, R ¹ is -O-3,4-dichlorophenyl. In other embodiments wherein R ¹ is -C0-C6alk-Oaryl, the -aryl is 2,4-difluorophenyl, 3-methyl-4-chlorophenyl, 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. [0068] In some aspects, R ¹ is–C0-C6alk-heteroaryl, for example,–C0alk-heteroaryl,–C1alk- heteroaryl,–C ₂ alk-heteroaryl,–C ₃ alk-heteroaryl,–C ₄ alk-heteroaryl,–C ₅ alk-heteroaryl, and–C ₆ alk- heteroaryl. 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, 2-(2-aminoquinolin-7-yl)ethyl, or 5-chlorothiophen-2- yl)(hydroxy)methyl.

[0069] In some aspects, R ¹ is -C1-C6alk-O-heteroaryl, for example, -C1alk-O-heteroaryl, - C2alk-O-heteroaryl, -C3alk-O-heteroaryl, -C4alk-O-heteroaryl, -C5alk-O-heteroaryl, and -C6alk-O- heteroaryl. In some aspects, R ¹ is ((2-amino-3-bromoquinolin-7-yl)oxy)methyl.

[0070] In some aspects, R ¹ is -C ₁ -C ₆ alk-S-heteroaryl, for example, -C ₁ alk-S-heteroaryl, - C2alk-S-heteroaryl, -C3alk-S-heteroaryl, -C4alk-S-heteroaryl, -C5alk-S-heteroaryl, and -C6alk-S- heteroaryl. In some aspects, R ¹ is ((2-amino-3-bromoquinolin-7-yl)thio)methyl.

[0071] In some aspects, R ¹ is -C ₁ -C ₆ alk-NH-heteroaryl, for example, -C ₁ alk-NH-heteroaryl, -C2alk-NH-heteroaryl, -C3alk-NH-heteroaryl, -C4alk-NH-heteroaryl, -C5alk-NH-heteroaryl, and - C6alk-NH-heteroaryl. In some aspects, R ¹ is ((2-amino-3-bromoquinolin-7-yl)amino)methyl.

[0072] In some aspects, R ⁵ is H, halo, C ₁ -C ₆ alkyl, or NH ₂ . Thus in some embodiments, R ⁵ is H. In other embodiments, R ⁵ is halo, for example F, Cl, Br, or I, with -Cl being preferred. In other embodiments, R ⁵ is -C1-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R ⁵ is methyl (Me). In yet other embodiments, R ⁵ is NH2.

[0073] In some aspects, R ¹¹ is H, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C ₀ -C ₆ alk-C ₃ -C ₆ halocycloalkyl, -C ₀ -C ₆ alk-OH, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk- N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ - C6cycloalkyl; or R ¹¹ and R ¹ , together with the atom to which they are attached, form a C3- C ₆ cycloalkyl ring or a heterocycloalkyl ring.

[0074] In some embodiments, R ¹¹ is H.

[0075] In some embodiments, R ¹¹ is -C1-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

[0076] In some embodiments, R ¹¹ is -C ₁ -C ₆ haloalkyl, for example, C ₁ haloalkyl,

C2haloalkyl, C3haloalkyl, C4haloalkyl, C5haloalkyl, or C6haloalkyl. [0077] In some aspects, R ¹¹ is -C0-C6alk-C3-C6cycloalkyl, for example -C0alk- C ₃ cycloalkyl, -C ₁ alk-C ₃ cycloalkyl, -C ₂ alk-C ₃ cycloalkyl, -C ₃ alk-C ₃ cycloalkyl, -C ₄ alk-C ₃ cycloalkyl, - C ₅ alk-C ₃ cycloalkyl¸ -C ₆ alk-C ₃ cycloalkyl, -C ₀ alk-C ₄ cycloalkyl, -C ₁ alk-C ₄ cycloalkyl, -C ₂ alk- C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, -C5alk-C4cycloalkyl¸ -C6alk-C4cycloalkyl, - C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, -C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk- C ₅ cycloalkyl, -C ₅ alk-C ₅ cycloalkyl¸ -C ₆ alk-C ₅ cycloalkyl, -C ₀ alk-C ₆ cycloalkyl, -C ₁ alk-C ₆ cycloalkyl, - C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, -C4alk-C6cycloalkyl, -C5alk-C6cycloalkyl¸ and -C6alk- C6cycloalkyl. In some embodiments, R ¹¹ is -C1alk-C3cycloalkyl. Thus, in some embodiments, R ¹¹ is -CH ₂ -cyclopropyl.

[0078] In some aspects, R ¹¹ is -C ₀ -C ₆ alk-C ₃ -C ₆ halocycloalkyl, for example -C ₀ alk- C3halocycloalkyl, -C1alk-C3halocycloalkyl, -C2alk-C3halocycloalkyl, -C3alk-C3halocycloalkyl, - C ₄ alk-C ₃ halocycloalkyl, -C ₅ alk-C ₃ halocycloalkyl¸ -C ₆ alk-C ₃ halocycloalkyl, -C ₀ alk- C ₄ halocycloalkyl, -C ₁ alk-C ₄ halocycloalkyl, -C ₂ alk-C ₄ halocycloalkyl, -C ₃ alk-C ₄ halocycloalkyl, - C4alk-C4halocycloalkyl, -C5alk-C4halocycloalkyl¸ -C6alk-C4halocycloalkyl, -C0alk- C5halocycloalkyl, -C1alk-C5halocycloalkyl, -C2alk-C5halocycloalkyl, -C3alk-C5halocycloalkyl, - C ₄ alk-C ₅ halocycloalkyl, -C ₅ alk-C ₅ halocycloalkyl¸ -C ₆ alk-C ₅ halocycloalkyl, -C ₀ alk- C6halocycloalkyl, -C1alk-C6halocycloalkyl, -C2alk-C6halocycloalkyl, -C3alk-C6halocycloalkyl, - C4alk-C6halocycloalkyl, -C5alk-C6halocycloalkyl¸ and -C6alk-C6halocycloalkyl.

[0079] In some aspects, R ¹¹ is -C ₀ -C ₆ alk-OH, for example, -C ₀ alk-OH (i.e., -OH), -C ₁ alk- OH, -C2alk-OH, -C3alk-OH, -C4alk-OH, -C5alk-OH, -C6alk-OH, and the like. In some

embodiments, R ¹¹ is -C1alk-OH. Thus, in some embodiments, R ¹¹ is hydroxymethyl (i.e., -CH2OH).

[0080] In some aspects, R ¹¹ is -C ₀ -C ₆ alk-NH ₂ , for example, -C ₀ alk-NH ₂ (i.e., -NH ₂ ), - C ₁ alk-NH ₂ , -C ₂ alk-NH ₂ , -C ₃ alk-NH ₂ , -C ₄ alk-NH ₂ , -C ₅ alk-NH ₂ , -C ₆ alk-NH ₂ , and the like. In some embodiments, R ¹¹ is -C1alk-NH2. Thus, in some embodiments, R ¹¹ is aminomethyl (i.e., -CH2NH2).

[0081] In some aspects, R ¹¹ is -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, for example, -C ₀ alk-NH-C ₁ alkyl, -C ₁ alk-NH-C ₁ alkyl, -C ₂ alk-NH-C ₁ alkyl, -C ₃ alk-NH-C ₁ alkyl, -C ₄ alk-NH-C ₁ alkyl, -C ₅ alk-NH- C1alkyl¸ -C6alk-NH-C1alkyl, -C0alk-NH-C2alkyl, -C1alk-NH-C2alkyl, -C2alk-NH-C2alkyl, -C3alk- NH-C2alkyl, -C4alk-NH-C2alkyl, -C5alk-NH-C2alkyl¸ -C6alk-NH-C2alkyl, -C0alk-NH-C3alkyl, - C ₁ alk-NH-C ₃ alkyl, -C ₂ alk-NH-C ₃ alkyl, -C ₃ alk-NH-C ₃ alkyl, -C ₄ alk-NH-C ₃ alkyl, -C ₅ alk-NH-C ₃ alkyl¸ -C6alk-NH-C3alkyl, -C0alk-NH-C4alkyl, -C1alk-NH-C4alkyl, -C2alk-NH-C4alkyl, -C3alk-NH- C4alkyl, -C4alk-NH-C4alkyl, -C5alk-NH-C4alkyl¸ -C6alk-NH-C4alkyl, -C0alk-NH-C5alkyl, -C1alk- NH-C5alkyl, -C2alk-NH-C5alkyl, -C3alk-NH-C5alkyl, -C4alk-NH-C5alkyl, -C5alk-NH-C5alkyl¸ - C ₆ alk-NH-C ₅ alkyl, -C ₀ alk-NH-C ₆ alkyl, -C ₁ alk-NH-C ₆ alkyl, -C ₂ alk-NH-C ₆ alkyl, -C ₃ alk-NH-C ₆ alkyl, -C ₄ alk-NH-C ₆ alkyl, -C ₅ alk-NH-C ₆ alkyl¸ and -C ₆ alk-NH-C ₆ alkyl.

[0082] In some aspects, R ¹¹ is -C0-C6alk-N(C1-C6alkyl)-C1-C6alkyl, for example, -C0alk- N(C1-C6alkyl)-C1alkyl, -C1alk-N(C1-C6alkyl)-C1alkyl, -C2alk-N(C1-C6alkyl)-C1alkyl, -C3alk-N(C1- C ₆ alkyl)-C ₁ alkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₁ alkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)-C ₁ alkyl¸ -C ₆ alk- N(C ₁ - C6alkyl)-C1alkyl, -C0alk- N(C1-C6alkyl)-C2alkyl, -C1alk-N(C1-C6alkyl)-C2alkyl, -C2alk-N(C1- C6alkyl)-C2alkyl, -C3alk-N(C1-C6alkyl)-C2alkyl, -C4alk-N(C1-C6alkyl)-C2alkyl, -C5alk-N(C1- C ₆ alkyl)-C ₂ alkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₂ alkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₃ alkyl, -C ₁ alk-N(C ₁ - C ₆ alkyl)-C ₃ alkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₃ alkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₃ alkyl, -C ₄ alk-N(C ₁ - C6alkyl)-C3alkyl, -C5alk-N(C1-C6alkyl)-C3alkyl¸ -C6alk-N(C1-C6alkyl)-C3alkyl, -C0alk-N(C1- C ₆ alkyl)-C ₄ alkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl, -C ₃ alk-N(C ₁ - C ₆ alkyl)-C ₄ alkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl¸ -C ₆ alk-N(C ₁ - C6alkyl)-C4alkyl, -C0alk- N(C1-C6alkyl)-C5alkyl, -C1alk-N(C1-C6alkyl)-C5alkyl, -C2alk-N(C1- C6alkyl)-C5alkyl, -C3alk-N(C1-C6alkyl)-C5alkyl, -C4alk-N(C1-C6alkyl)-C5alkyl, -C5alk-N(C1- C ₆ alkyl)-C ₅ alkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl, -C ₁ alk-N(C ₁ - C6alkyl)-C6alkyl, -C2alk-N(C1-C6alkyl)-C6alkyl, -C3alk-N(C1-C6alkyl)-C6alkyl, -C4alk-N(C1- C6alkyl)-C6alkyl, -C5alk-N(C1-C6alkyl)-C6alkyl¸ -C6alk-N(C1-C6alkyl)-C6alkyl and the like.

[0083] In some aspects, R ¹¹ is -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, for example, -C ₀ alk-NH- C3cycloalkyl, -C1alk-NH-C3cycloalkyl, -C2alk-NH-C3cycloalkyl, -C3alk-NH-C3cycloalkyl, -C4alk- NH-C3cycloalkyl, -C5alk-NH-C3cycloalkyl¸ -C6alk-NH-C3cycloalkyl, -C0alk-NH-C4cycloalkyl, - C ₁ alk-NH-C ₄ cycloalkyl, -C ₂ alk-NH-C ₄ cycloalkyl, -C ₃ alk-NH-C ₄ cycloalkyl, -C ₄ alk-NH- C ₄ cycloalkyl, -C ₅ alk-NH-C ₄ cycloalkyl¸ -C ₆ alk-NH-C ₄ cycloalkyl, -C ₀ alk-NH-C ₅ cycloalkyl, -C ₁ alk- NH-C5cycloalkyl, -C2alk-NH-C5cycloalkyl, -C3alk-NH-C5cycloalkyl, -C4alk-NH-C5cycloalkyl, - C ₅ alk-NH-C ₅ cycloalkyl¸ -C ₆ alk-NH-C ₅ cycloalkyl, -C ₀ alk-NH-C ₆ cycloalkyl, -C ₁ alk-NH- C ₆ cycloalkyl, -C ₂ alk-NH-C ₆ cycloalkyl, -C ₃ alk-NH-C ₆ cycloalkyl, -C ₄ alk-NH-C ₆ cycloalkyl, -C ₅ alk- NH-C6cycloalkyl¸ -C6alk-NH-C6cycloalkyl, and the like.

[0084] In some aspects, R ¹¹ is -C0-C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, for example, - C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₃ cycloalkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₃ cycloalkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)- C3cycloalkyl, -C3alk-N(C1-C6alkyl)-C3cycloalkyl, -C4alk-N(C1-C6alkyl)-C3cycloalkyl, -C5alk-N(C1- C6alkyl)-C3cycloalkyl ¸ -C6alk-N(C1-C6alkyl)-C3cycloalkyl, -C0alk-N(C1-C6alkyl)-C4cycloalkyl, - C1alk-N(C1-C6alkyl)-C4cycloalkyl, -C2alk-N(C1-C6alkyl)-C4cycloalkyl, -C3alk-N(C1-C6alkyl)- C ₄ cycloalkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₄ cycloalkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)-C ₄ cycloalkyl¸ -C ₆ alk-N(C ₁ - C ₆ alkyl)-C ₄ cycloalkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, - C2alk-N(C1-C6alkyl)-C5cycloalkyl, -C3alk-N(C1-C6alkyl)-C5cycloalkyl, -C4alk-N(C1-C6alkyl)- C5cycloalkyl, -C5alk-N(C1-C6alkyl)-C5cycloalkyl, -C6alk-N(C1-C6alkyl)-C5cycloalkyl, -C0alk-N(C1- C ₆ alkyl)-C ₆ cycloalkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₆ cycloalkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₆ cycloalkyl, - C3alk-N(C1-C6alkyl)-C6cycloalkyl, -C4alk-N(C1-C6alkyl)-C6cycloalkyl, -C5alk-N(C1-C6alkyl)- C6cycloalkyl¸ -C6alk-N(C1-C6alkyl)-C6cycloalkyl, and the like.

[0085] In some aspects, R ¹¹ and R ¹ , together with the atom to which they are attached, form a C ₃ -C ₆ cycloalkyl ring or a heterocycloalkyl ring.

[0086] In embodiments that are a compound of Formula I or Formula II, R ⁶ is H, halo, -C1- C ₆ alkyl, -C ₁ -C ₆ haloalkyl, or–C ₀ -C6alk-C ₃ -C ₆ cycloalkyl Thus, in some embodiments, R ⁶ is H.

[0087] In other embodiments, R ⁶ is halo, for example F, Cl, Br, or I. In some embodiments, R ⁶ is F.

[0088] In some aspects, R ⁶ is -C1-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R ⁶ is methyl.

[0089] In some aspects, R ⁶ is -C1-C6haloalkyl, for example, -CF3 or–CHF2.

[0090] In some embodiments, R ⁶ is -C0-C6alk-C3-C6cycloalkyl, for example, for example - C ₀ alk-C ₃ cycloalkyl, -C ₁ alk-C ₃ cycloalkyl, -C ₂ alk-C ₃ cycloalkyl, -C ₃ alk-C ₃ cycloalkyl, -C ₄ alk- C3cycloalkyl, -C5alk-C3cycloalkyl¸ -C6alk-C3cycloalkyl, -C0alk-C4cycloalkyl, -C1alk-C4cycloalkyl, - C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, -C5alk-C4cycloalkyl¸ -C6alk- C ₄ cycloalkyl, -C ₀ alk-C ₅ cycloalkyl, -C ₁ alk-C ₅ cycloalkyl, -C ₂ alk-C ₅ cycloalkyl, -C ₃ alk-C ₅ cycloalkyl, - C ₄ alk-C ₅ cycloalkyl, -C ₅ alk-C ₅ cycloalkyl¸ -C ₆ alk-C ₅ cycloalkyl, -C ₀ alk-C ₆ cycloalkyl, -C ₁ alk- C6cycloalkyl, -C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, -C4alk-C6cycloalkyl, -C5alk-C6cycloalkyl¸ and -C ₆ alk-C ₆ cycloalkyl. In some embodiments, R ⁶ is -C ₁ alk-C ₃ cycloalkyl. Thus, in some aspects, R ⁶ is -CH ₂ -cyclopropyl. In other embodiments, R ⁶ is cyclopropyl.

[0091] In embodiments that are a compound of Formula I or Formula II, R ¹² is H, halo (e.g., F, Cl, Br, or I), or -C1-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, t-butyl, pentyl, and the like. In some embodiments, R ¹² is methyl.

[0092] In embodiments that are a compound of Formula I or Formula III, R ² is H, halo, -C1- C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-OH, -C0-C6alk-O-C1-C6alkyl, -C0- C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0-C6alk-N(C1-C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3- C ₆ cycloalkyl, -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-heterocycloalkyl, heteroaryl, or– CN.

[0093] In some aspects, R ² is H.

[0094] In some aspects, R ² is halo, for example, F, Cl, Br, or I, with F, Cl, and Br being preferred and F and Cl being more preferred.

[0095] In some aspects, R ² is -C1-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R ² is methyl.

[0096] In some aspects, R ² is -C ₁ -C ₆ haloalkyl, for example, -CF ₃ or–CHF ₂ .

[0097] In some aspects, R ² is -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl, for example, -C ₀ alk- C3cycloalkyl, -C1alk-C3cycloalkyl, -C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, - C ₅ alk-C ₃ cycloalkyl¸ -C ₆ alk-C ₃ cycloalkyl, -C ₀ alk-C ₄ cycloalkyl, -C ₁ alk-C ₄ cycloalkyl, -C ₂ alk- C ₄ cycloalkyl, -C ₃ alk-C ₄ cycloalkyl, -C ₄ alk-C ₄ cycloalkyl, -C ₅ alk-C ₄ cycloalkyl¸ -C ₆ alk-C ₄ cycloalkyl, - C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, -C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk- C5cycloalkyl, -C5alk-C5cycloalkyl¸ -C6alk-C5cycloalkyl, -C0alk-C6cycloalkyl, -C1alk-C6cycloalkyl, - C ₂ alk-C ₆ cycloalkyl, -C ₃ alk-C ₆ cycloalkyl, -C ₄ alk-C ₆ cycloalkyl, -C ₅ alk-C ₆ cycloalkyl¸ -C ₆ alk- C6cycloalkyl. In some aspects wherein R ² is -C0-C6alk-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ² is -C0-C6alk-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC1-C6alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

[0098] In some aspects, R ² is -C ₀ -C ₆ alk-OH, for example, -C ₀ alk-OH, -C ₁ alk-OH, -C ₂ alk- OH, -C ₃ alk-OH, -C ₄ alk-OH, -C ₅ alk-OH, or -C ₆ alk-OH.

[0099] In some aspects, R ² is -C0-C6alk-O-C1-C6alkyl, for example, -C0alk-O-C1alkyl, - C ₁ alk-O-C ₁ alkyl, -C ₂ alk-O-C ₁ alkyl, -C ₃ alk-O-C ₁ alkyl, -C ₄ alk-O-C ₁ alkyl, -C ₅ alk-O-C ₁ alkyl¸ -C ₆ alk- O-C ₁ alkyl, -C ₀ alk-O-C ₂ alkyl, -C ₁ alk-O-C ₂ alkyl, -C ₂ alk-O-C ₂ alkyl, -C ₃ alk-O-C ₂ alkyl, -C ₄ alk-O- C2alkyl, -C5alk-O-C2alkyl¸ -C6alk-O-C2alkyl, -C0alk-O-C3alkyl, -C1alk-O-C3alkyl, -C2alk-O- C3alkyl, -C3alk-O-C3alkyl, -C4alk-O-C3alkyl, -C5alk-O-C3alkyl¸ -C6alk-O-C3alkyl, -C0alk-O- C ₄ alkyl, -C ₁ alk-O-C ₄ alkyl, -C ₂ alk-O-C ₄ alkyl, -C ₃ alk-O-C ₄ alkyl, -C ₄ alk-O-C ₄ alkyl, -C ₅ alk-O- C4alkyl¸ -C6alk-O-C4alkyl, -C0alk-O-C5alkyl, -C1alk-O-C5alkyl, -C2alk-O-C5alkyl, -C3alk-O- C5alkyl, -C4alk-O-C5alkyl, -C5alk-O-C5alkyl¸ -C6alk-O-C5alkyl, -C0alk-O-C6alkyl, -C1alk-O- C6alkyl, -C2alk-O-C6alkyl, -C3alk-O-C6alkyl, -C4alk-O-C6alkyl, -C5alk-O-C6alkyl¸ or -C6alk-O- C ₆ alkyl.

[00100] In some aspects, R ² is C ₀ -C ₆ alk-NH ₂ , for example, -C ₀ alk-NH ₂ , -C ₁ alk-NH ₂ , - C2alk-NH2, -C3alk-NH2, -C4alk-NH2, -C5alk-NH2, or–C6alk-NH2.

In some aspects, R ² is -C0-C6alk-NH-C1-C6alkyl, for example, -C0alk-NH-C1alkyl, - C ₁ alk-NH-C ₁ alkyl, -C ₂ alk-NH-C ₁ alkyl, -C ₃ alk-NH-C ₁ alkyl, -C ₄ alk-NH-C ₁ alkyl, -C ₅ alk-NH-C ₁ alkyl¸ -C6alk-NH-C1alkyl, -C0alk-NH-C2alkyl, -C1alk-NH-C2alkyl, -C2alk-NH-C2alkyl, -C3alk-NH- C2alkyl, -C4alk-NH-C2alkyl, -C5alk-NH-C2alkyl¸ -C6alk-NH-C2alkyl, -C0alk-NH-C3alkyl, -C1alk- NH-C ₃ alkyl, -C ₂ alk-NH-C ₃ alkyl, -C ₃ alk-NH-C ₃ alkyl, -C ₄ alk-NH-C ₃ alkyl, -C ₅ alk-NH-C ₃ alkyl¸ - C ₆ alk-NH-C ₃ alkyl, -C ₀ alk-NH-C ₄ alkyl, -C ₁ alk-NH-C ₄ alkyl, -C ₂ alk-NH-C ₄ alkyl, -C ₃ alk-NH-C ₄ alkyl, -C4alk-NH-C4alkyl, -C5alk-NH-C4alkyl¸ -C6alk-NH-C4alkyl, -C0alk-NH-C5alkyl, -C1alk-NH- C ₅ alkyl, -C ₂ alk-NH-C ₅ alkyl, -C ₃ alk-NH-C ₅ alkyl, -C ₄ alk-NH-C ₅ alkyl, -C ₅ alk-NH-C ₅ alkyl¸ -C ₆ alk- NH-C ₅ alkyl, -C ₀ alk-NH-C ₆ alkyl, -C ₁ alk-NH-C ₆ alkyl, -C ₂ alk-NH-C ₆ alkyl, -C ₃ alk-NH-C ₆ alkyl, - C4alk-NH-C6alkyl, -C5alk-NH-C6alkyl¸ and -C6alk-NH-C6alkyl.

In some aspects, R ² is -C0-C6alk-N(C1-C6alkyl)-C1-C6alkyl, for example, -C0alk- N(C ₁ -C ₆ alkyl)-C ₁ alkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₁ alkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₁ alkyl, -C ₃ alk-N(C ₁ - C6alkyl)-C1alkyl, -C4alk-N(C1-C6alkyl)-C1alkyl, -C5alk-N(C1-C6alkyl)-C1alkyl¸ -C6alk- N(C1- C6alkyl)-C1alkyl, -C0alk- N(C1-C6alkyl)-C2alkyl, -C1alk-N(C1-C6alkyl)-C2alkyl, -C2alk-N(C1- C ₆ alkyl)-C ₂ alkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₂ alkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₂ alkyl, -C ₅ alk-N(C ₁ - C6alkyl)-C2alkyl¸ -C6alk-N(C1-C6alkyl)-C2alkyl, -C0alk-N(C1-C6alkyl)-C3alkyl, -C1alk-N(C1- C6alkyl)-C3alkyl, -C2alk-N(C1-C6alkyl)-C3alkyl, -C3alk-N(C1-C6alkyl)-C3alkyl, -C4alk-N(C1- C ₆ alkyl)-C ₃ alkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)-C ₃ alkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ alkyl, -C ₀ alk-N(C ₁ - C ₆ alkyl)-C ₄ alkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl, -C ₃ alk-N(C ₁ - C6alkyl)-C4alkyl, -C4alk-N(C1-C6alkyl)-C4alkyl, -C5alk-N(C1-C6alkyl)-C4alkyl¸ -C6alk-N(C1- C ₆ alkyl)-C ₄ alkyl, -C ₀ alk- N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₂ alk-N(C ₁ - C ₆ alkyl)-C ₅ alkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₅ alk-N(C ₁ - C6alkyl)-C5alkyl¸ -C6alk-N(C1-C6alkyl)-C5alkyl, -C0alk-N(C1-C6alkyl)-C6alkyl, -C1alk-N(C1- C6alkyl)-C6alkyl, -C2alk-N(C1-C6alkyl)-C6alkyl, -C3alk-N(C1-C6alkyl)-C6alkyl, -C4alk-N(C1- C ₆ alkyl)-C ₆ alkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl and the like.

In some aspects, R ² is -C0-C6alk-NH-C3-C6cycloalkyl, for example, -C0alk-NH- C3cycloalkyl, -C1alk-NH-C3cycloalkyl, -C2alk-NH-C3cycloalkyl, -C3alk-NH-C3cycloalkyl, -C4alk- NH-C3cycloalkyl, -C5alk-NH-C3cycloalkyl¸ -C6alk-NH-C3cycloalkyl, -C0alk-NH-C4cycloalkyl, - C ₁ alk-NH-C ₄ cycloalkyl, -C ₂ alk-NH-C ₄ cycloalkyl, -C ₃ alk-NH-C ₄ cycloalkyl, -C ₄ alk-NH- C ₄ cycloalkyl, -C ₅ alk-NH-C ₄ cycloalkyl¸ -C ₆ alk-NH-C ₄ cycloalkyl, -C ₀ alk-NH-C ₅ cycloalkyl, -C ₁ alk- NH-C5cycloalkyl, -C2alk-NH-C5cycloalkyl, -C3alk-NH-C5cycloalkyl, -C4alk-NH-C5cycloalkyl, - C5alk-NH-C5cycloalkyl¸ -C6alk-NH-C5cycloalkyl, -C0alk-NH-C6cycloalkyl, -C1alk-NH- C ₆ cycloalkyl, -C ₂ alk-NH-C ₆ cycloalkyl, -C ₃ alk-NH-C ₆ cycloalkyl, -C ₄ alk-NH-C ₆ cycloalkyl, -C ₅ alk- NH-C6cycloalkyl¸ -C6alk-NH-C6cycloalkyl, and the like. In some aspects wherein R ² is -C0-C6alk- NH-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ² is -C0-C6alk-NH- C ₃ -C ₆ cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC ₁ -C ₆ alkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ² is -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ -C ₆ cycloalkyl, for example, - C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₃ cycloalkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₃ cycloalkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)- C3cycloalkyl, -C3alk-N(C1-C6alkyl)-C3cycloalkyl, -C4alk-N(C1-C6alkyl)-C3cycloalkyl, -C5alk-N(C1- C6alkyl)-C3cycloalkyl ¸ -C6alk-N(C1-C6alkyl)-C3cycloalkyl, -C0alk-N(C1-C6alkyl)-C4cycloalkyl, - C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₄ cycloalkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₄ cycloalkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)- C4cycloalkyl, -C4alk-N(C1-C6alkyl)-C4cycloalkyl, -C5alk-N(C1-C6alkyl)-C4cycloalkyl¸ -C6alk-N(C1- C6alkyl)-C4cycloalkyl, -C0alk-N(C1-C6alkyl)-C5cycloalkyl, -C1alk-N(C1-C6alkyl)-C5cycloalkyl, - C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)- C5cycloalkyl, -C5alk-N(C1-C6alkyl)-C5cycloalkyl, -C6alk-N(C1-C6alkyl)-C5cycloalkyl, -C0alk-N(C1- C6alkyl)-C6cycloalkyl, -C1alk-N(C1-C6alkyl)-C6cycloalkyl, -C2alk-N(C1-C6alkyl)-C6cycloalkyl, - C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₆ cycloalkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₆ cycloalkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)- C ₆ cycloalkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₆ cycloalkyl, and the like. In some aspects wherein R ² is -C ₀ - C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ² is -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ -C ₆ cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - OC1-C6alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ² is -C0-C6alk-heterocycloalkyl, for example, -C0alk- heterocycloalkyl, -C ₁ -C ₆ alk-heterocycloalkyl, -C ₁ -C ₅ alk-heterocycloalkyl, -C ₁ -C ₄ alk- heterocycloalkyl, -C1-C3alk-heterocycloalkyl, -C1-C2alk-heterocycloalkyl, or -C1alk- heterocycloalkyl. Preferred heterocyloalkyl moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and oxetanyl. In some aspects wherein R ² is -C ₀ -C ₆ alk-heterocycloalkyl, the heterocycloalkyl is unsubstituted. In other aspects wherein R ² is -C ₀ -C ₆ alk-heterocycloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from C1-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC1-C6alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ² is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl. In some aspects wherein R ² is heteroaryl, the heteroaryl is unsubstituted. In other aspects wherein R ² is heteroaryl, the heteroaryl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC ₁ -C ₆ alkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ² is -CN.

In compounds of the present disclosure that are compounds of Formula I or Formula III R ³ is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-OH, - C0-C6alk-O-C1-C6alkyl, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0-C6alk-N(C1-C6alkyl)-C1- C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk- heterocycloalkyl, heteroaryl, or–CN.

In some aspects, R ³ is H.

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

In some aspects, R ³ is -C1-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

In some aspects, R ³ is -C ₁ -C ₆ haloalkyl, for example, -CF ₃ or–CHF ₂ .

In some aspects, R ³ is -C0-C6alk-C3-C6cycloalkyl, for example, -C0alk- C ₃ cycloalkyl, -C ₁ alk-C ₃ cycloalkyl, -C ₂ alk-C ₃ cycloalkyl, -C ₃ alk-C ₃ cycloalkyl, -C ₄ alk-C ₃ cycloalkyl, - C ₅ alk-C ₃ cycloalkyl¸ -C ₆ alk-C ₃ cycloalkyl, -C ₀ alk-C ₄ cycloalkyl, -C ₁ alk-C ₄ cycloalkyl, -C ₂ alk- C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, -C5alk-C4cycloalkyl¸ -C6alk-C4cycloalkyl, - C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, -C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk- C ₅ cycloalkyl, -C ₅ alk-C ₅ cycloalkyl¸ -C ₆ alk-C ₅ cycloalkyl, -C ₀ alk-C ₆ cycloalkyl, -C ₁ alk-C ₆ cycloalkyl, - C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, -C4alk-C6cycloalkyl, -C5alk-C6cycloalkyl¸ -C6alk- C6cycloalkyl. In some aspects wherein R ³ is -C0-C6alk-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ³ is -C0-C6alk-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC ₁ -C ₆ alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ³ is -C0-C6alk-OH, for example, -C0alk-OH, -C1alk-OH, -C2alk- OH, -C ₃ alk-OH, -C ₄ alk-OH, -C ₅ alk-OH, or -C ₆ alk-OH.

In some aspects, R ³ is -C0-C6alk-O-C1-C6alkyl, for example, -C0alk-O-C1alkyl, - C1alk-O-C1alkyl, -C2alk-O-C1alkyl, -C3alk-O-C1alkyl, -C4alk-O-C1alkyl, -C5alk-O-C1alkyl¸ -C6alk- O-C ₁ alkyl, -C ₀ alk-O-C ₂ alkyl, -C ₁ alk-O-C ₂ alkyl, -C ₂ alk-O-C ₂ alkyl, -C ₃ alk-O-C ₂ alkyl, -C ₄ alk-O- C ₂ alkyl, -C ₅ alk-O-C ₂ alkyl¸ -C ₆ alk-O-C ₂ alkyl, -C ₀ alk-O-C ₃ alkyl, -C ₁ alk-O-C ₃ alkyl, -C ₂ alk-O- C3alkyl, -C3alk-O-C3alkyl, -C4alk-O-C3alkyl, -C5alk-O-C3alkyl¸ -C6alk-O-C3alkyl, -C0alk-O- C ₄ alkyl, -C ₁ alk-O-C ₄ alkyl, -C ₂ alk-O-C ₄ alkyl, -C ₃ alk-O-C ₄ alkyl, -C ₄ alk-O-C ₄ alkyl, -C ₅ alk-O- C ₄ alkyl¸ -C ₆ alk-O-C ₄ alkyl, -C ₀ alk-O-C ₅ alkyl, -C ₁ alk-O-C ₅ alkyl, -C ₂ alk-O-C ₅ alkyl, -C ₃ alk-O- C5alkyl, -C4alk-O-C5alkyl, -C5alk-O-C5alkyl¸ -C6alk-O-C5alkyl, -C0alk-O-C6alkyl, -C1alk-O- C6alkyl, -C2alk-O-C6alkyl, -C3alk-O-C6alkyl, -C4alk-O-C6alkyl, -C5alk-O-C6alkyl¸ or -C6alk-O- C ₆ alkyl.

In some aspects, R ³ is C0-C6alk-NH2, for example, -C0alk-NH2, -C1alk-NH2, -C2alk- NH2, -C3alk-NH2, -C4alk-NH2, -C5alk-NH2, or–C6alk-NH2.

In some aspects, R ³ is -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, for example, -C ₀ alk-NH-C ₁ alkyl, - C1alk-NH-C1alkyl, -C2alk-NH-C1alkyl, -C3alk-NH-C1alkyl, -C4alk-NH-C1alkyl, -C5alk-NH-C1alkyl¸ -C6alk-NH-C1alkyl, -C0alk-NH-C2alkyl, -C1alk-NH-C2alkyl, -C2alk-NH-C2alkyl, -C3alk-NH- C ₂ alkyl, -C ₄ alk-NH-C ₂ alkyl, -C ₅ alk-NH-C ₂ alkyl¸ -C ₆ alk-NH-C ₂ alkyl, -C ₀ alk-NH-C ₃ alkyl, -C ₁ alk- NH-C ₃ alkyl, -C ₂ alk-NH-C ₃ alkyl, -C ₃ alk-NH-C ₃ alkyl, -C ₄ alk-NH-C ₃ alkyl, -C ₅ alk-NH-C ₃ alkyl¸ - C6alk-NH-C3alkyl, -C0alk-NH-C4alkyl, -C1alk-NH-C4alkyl, -C2alk-NH-C4alkyl, -C3alk-NH-C4alkyl, -C ₄ alk-NH-C ₄ alkyl, -C ₅ alk-NH-C ₄ alkyl¸ -C ₆ alk-NH-C ₄ alkyl, -C ₀ alk-NH-C ₅ alkyl, -C ₁ alk-NH- C ₅ alkyl, -C ₂ alk-NH-C ₅ alkyl, -C ₃ alk-NH-C ₅ alkyl, -C ₄ alk-NH-C ₅ alkyl, -C ₅ alk-NH-C ₅ alkyl¸ -C ₆ alk- NH-C5alkyl, -C0alk-NH-C6alkyl, -C1alk-NH-C6alkyl, -C2alk-NH-C6alkyl, -C3alk-NH-C6alkyl, - C4alk-NH-C6alkyl, -C5alk-NH-C6alkyl¸ and -C6alk-NH-C6alkyl.

In some aspects, R ³ is -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, for example, -C ₀ alk- N(C1-C6alkyl)-C1alkyl, -C1alk-N(C1-C6alkyl)-C1alkyl, -C2alk-N(C1-C6alkyl)-C1alkyl, -C3alk-N(C1- C6alkyl)-C1alkyl, -C4alk-N(C1-C6alkyl)-C1alkyl, -C5alk-N(C1-C6alkyl)-C1alkyl¸ -C6alk- N(C1- C6alkyl)-C1alkyl, -C0alk- N(C1-C6alkyl)-C2alkyl, -C1alk-N(C1-C6alkyl)-C2alkyl, -C2alk-N(C1- C ₆ alkyl)-C ₂ alkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₂ alkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₂ alkyl, -C ₅ alk-N(C ₁ - C ₆ alkyl)-C ₂ alkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₂ alkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₃ alkyl, -C ₁ alk-N(C ₁ - C6alkyl)-C3alkyl, -C2alk-N(C1-C6alkyl)-C3alkyl, -C3alk-N(C1-C6alkyl)-C3alkyl, -C4alk-N(C1- C6alkyl)-C3alkyl, -C5alk-N(C1-C6alkyl)-C3alkyl¸ -C6alk-N(C1-C6alkyl)-C3alkyl, -C0alk-N(C1- C ₆ alkyl)-C ₄ alkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl, -C ₃ alk-N(C ₁ - C6alkyl)-C4alkyl, -C4alk-N(C1-C6alkyl)-C4alkyl, -C5alk-N(C1-C6alkyl)-C4alkyl¸ -C6alk-N(C1- C6alkyl)-C4alkyl, -C0alk- N(C1-C6alkyl)-C5alkyl, -C1alk-N(C1-C6alkyl)-C5alkyl, -C2alk-N(C1- C ₆ alkyl)-C ₅ alkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₅ alk-N(C ₁ - C ₆ alkyl)-C ₅ alkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl, -C ₁ alk-N(C ₁ - C6alkyl)-C6alkyl, -C2alk-N(C1-C6alkyl)-C6alkyl, -C3alk-N(C1-C6alkyl)-C6alkyl, -C4alk-N(C1- C ₆ alkyl)-C ₆ alkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl and the like.

In some aspects, R ³ is -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, for example, -C ₀ alk-NH- C3cycloalkyl, -C1alk-NH-C3cycloalkyl, -C2alk-NH-C3cycloalkyl, -C3alk-NH-C3cycloalkyl, -C4alk- NH-C3cycloalkyl, -C5alk-NH-C3cycloalkyl¸ -C6alk-NH-C3cycloalkyl, -C0alk-NH-C4cycloalkyl, - C ₁ alk-NH-C ₄ cycloalkyl, -C ₂ alk-NH-C ₄ cycloalkyl, -C ₃ alk-NH-C ₄ cycloalkyl, -C ₄ alk-NH- C4cycloalkyl, -C5alk-NH-C4cycloalkyl¸ -C6alk-NH-C4cycloalkyl, -C0alk-NH-C5cycloalkyl, -C1alk- NH-C5cycloalkyl, -C2alk-NH-C5cycloalkyl, -C3alk-NH-C5cycloalkyl, -C4alk-NH-C5cycloalkyl, - C ₅ alk-NH-C ₅ cycloalkyl¸ -C ₆ alk-NH-C ₅ cycloalkyl, -C ₀ alk-NH-C ₆ cycloalkyl, -C ₁ alk-NH- C6cycloalkyl, -C2alk-NH-C6cycloalkyl, -C3alk-NH-C6cycloalkyl, -C4alk-NH-C6cycloalkyl, -C5alk- NH-C6cycloalkyl¸ -C6alk-NH-C6cycloalkyl, and the like. In some aspects wherein R ³ is -C0-C6alk- NH-C ₃ -C ₆ cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ³ is -C ₀ -C ₆ alk-NH- C ₃ -C ₆ cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C1-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC1-C6alkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ³ is -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ -C ₆ cycloalkyl, for example, - C0alk-N(C1-C6alkyl)-C3cycloalkyl, -C1alk-N(C1-C6alkyl)-C3cycloalkyl, -C2alk-N(C1-C6alkyl)- C3cycloalkyl, -C3alk-N(C1-C6alkyl)-C3cycloalkyl, -C4alk-N(C1-C6alkyl)-C3cycloalkyl, -C5alk-N(C1- C ₆ alkyl)-C ₃ cycloalkyl ¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ cycloalkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₄ cycloalkyl, - C1alk-N(C1-C6alkyl)-C4cycloalkyl, -C2alk-N(C1-C6alkyl)-C4cycloalkyl, -C3alk-N(C1-C6alkyl)- C4cycloalkyl, -C4alk-N(C1-C6alkyl)-C4cycloalkyl, -C5alk-N(C1-C6alkyl)-C4cycloalkyl¸ -C6alk-N(C1- C6alkyl)-C4cycloalkyl, -C0alk-N(C1-C6alkyl)-C5cycloalkyl, -C1alk-N(C1-C6alkyl)-C5cycloalkyl, - C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)- C ₅ cycloalkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, -C ₀ alk-N(C ₁ - C6alkyl)-C6cycloalkyl, -C1alk-N(C1-C6alkyl)-C6cycloalkyl, -C2alk-N(C1-C6alkyl)-C6cycloalkyl, - C3alk-N(C1-C6alkyl)-C6cycloalkyl, -C4alk-N(C1-C6alkyl)-C6cycloalkyl, -C5alk-N(C1-C6alkyl)- C ₆ cycloalkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₆ cycloalkyl, and the like. In some aspects wherein R ³ is -C ₀ - C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ³ is -C0-C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - OC ₁ -C ₆ alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ³ is -C0-C6alk-heterocycloalkyl, for example, -C0alk- heterocycloalkyl, -C ₁ -C ₆ alk-heterocycloalkyl, -C ₁ -C ₅ alk-heterocycloalkyl, -C ₁ -C ₄ alk- heterocycloalkyl, -C ₁ -C ₃ alk-heterocycloalkyl, -C ₁ -C ₂ alk-heterocycloalkyl, or–C ₁ alk- heterocycloalkyl. Preferred heterocyloalkyl moieties include, for example piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and oxetanyl. In some aspects wherein R ³ is -C ₀ -C ₆ alk-heterocycloalkyl, the heterocycloalkyl is unsubstituted. In other aspects wherein R ³ is -C0-C6alk-heterocycloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from C1-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC ₁ -C ₆ alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ³ is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl. In some aspects wherein R ³ is heteroaryl, the heteroaryl is unsubstituted. In other aspects wherein R ³ is heteroaryl, the heteroaryl is substituted with one, two, or three R substituents independently selected from C1-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC1-C6alkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ³ is -CN.

In compounds of the present disclosure that are compounds of Formula I or Formula III R ⁴ is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-OH, - C ₀ -C ₆ alk-O-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₁ - C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, -C0-C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, -C0-C6alk- heterocycloalkyl, heteroaryl, or–CN. In some aspects, R ⁴ is H.

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

In some aspects, R ⁴ is -C1-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

In some aspects, R ⁴ is -C ₁ -C ₆ haloalkyl, for example, -CF ₃ or–CHF ₂ .

In some aspects, R ⁴ is -C0-C6alk-C3-C6cycloalkyl, for example, -C0alk- C3cycloalkyl, -C1alk-C3cycloalkyl, -C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, - C ₅ alk-C ₃ cycloalkyl¸ -C ₆ alk-C ₃ cycloalkyl, -C ₀ alk-C ₄ cycloalkyl, -C ₁ alk-C ₄ cycloalkyl, -C ₂ alk- C ₄ cycloalkyl, -C ₃ alk-C ₄ cycloalkyl, -C ₄ alk-C ₄ cycloalkyl, -C ₅ alk-C ₄ cycloalkyl¸ -C ₆ alk-C ₄ cycloalkyl, - C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, -C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk- C ₅ cycloalkyl, -C ₅ alk-C ₅ cycloalkyl¸ -C ₆ alk-C ₅ cycloalkyl, -C ₀ alk-C ₆ cycloalkyl, -C ₁ alk-C ₆ cycloalkyl, - C ₂ alk-C ₆ cycloalkyl, -C ₃ alk-C ₆ cycloalkyl, -C ₄ alk-C ₆ cycloalkyl, -C ₅ alk-C ₆ cycloalkyl¸ -C ₆ alk- C6cycloalkyl. In some aspects wherein R ⁴ is -C0-C6alk-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ⁴ is -C0-C6alk-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC1-C6alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ⁴ is -C ₀ -C ₆ alk-OH, for example, -C ₀ alk-OH, -C ₁ alk-OH, -C ₂ alk- OH, -C3alk-OH, -C4alk-OH, -C5alk-OH, or -C6alk-OH.

In some aspects, R ⁴ is -C0-C6alk-O-C1-C6alkyl, for example, -C0alk-O-C1alkyl, - C ₁ alk-O-C ₁ alkyl, -C ₂ alk-O-C ₁ alkyl, -C ₃ alk-O-C ₁ alkyl, -C ₄ alk-O-C ₁ alkyl, -C ₅ alk-O-C ₁ alkyl¸ -C ₆ alk- O-C ₁ alkyl, -C ₀ alk-O-C ₂ alkyl, -C ₁ alk-O-C ₂ alkyl, -C ₂ alk-O-C ₂ alkyl, -C ₃ alk-O-C ₂ alkyl, -C ₄ alk-O- C2alkyl, -C5alk-O-C2alkyl¸ -C6alk-O-C2alkyl, -C0alk-O-C3alkyl, -C1alk-O-C3alkyl, -C2alk-O- C ₃ alkyl, -C ₃ alk-O-C ₃ alkyl, -C ₄ alk-O-C ₃ alkyl, -C ₅ alk-O-C ₃ alkyl¸ -C ₆ alk-O-C ₃ alkyl, -C ₀ alk-O- C ₄ alkyl, -C ₁ alk-O-C ₄ alkyl, -C ₂ alk-O-C ₄ alkyl, -C ₃ alk-O-C ₄ alkyl, -C ₄ alk-O-C ₄ alkyl, -C ₅ alk-O- C4alkyl¸ -C6alk-O-C4alkyl, -C0alk-O-C5alkyl, -C1alk-O-C5alkyl, -C2alk-O-C5alkyl, -C3alk-O- C5alkyl, -C4alk-O-C5alkyl, -C5alk-O-C5alkyl¸ -C6alk-O-C5alkyl, -C0alk-O-C6alkyl, -C1alk-O- C ₆ alkyl, -C ₂ alk-O-C ₆ alkyl, -C ₃ alk-O-C ₆ alkyl, -C ₄ alk-O-C ₆ alkyl, -C ₅ alk-O-C ₆ alkyl¸ or -C ₆ alk-O- C6alkyl. In some aspects, R ⁴ is -C1-C6alk-NH2, for example, -C0alk-NH2, -C1alk-NH2, - C ₂ alk-NH ₂ , -C ₃ alk-NH ₂ , -C ₄ alk-NH ₂ , -C ₅ alk-NH ₂ , or -C ₆ alk-NH ₂ .

In some aspects, R ⁴ is -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, for example, -C ₀ alk-NH-C ₁ alkyl, - C1alk-NH-C1alkyl, -C2alk-NH-C1alkyl, -C3alk-NH-C1alkyl, -C4alk-NH-C1alkyl, -C5alk-NH-C1alkyl¸ -C6alk-NH-C1alkyl, -C0alk-NH-C2alkyl, -C1alk-NH-C2alkyl, -C2alk-NH-C2alkyl, -C3alk-NH- C ₂ alkyl, -C ₄ alk-NH-C ₂ alkyl, -C ₅ alk-NH-C ₂ alkyl¸ -C ₆ alk-NH-C ₂ alkyl, -C ₀ alk-NH-C ₃ alkyl, -C ₁ alk- NH-C3alkyl, -C2alk-NH-C3alkyl, -C3alk-NH-C3alkyl, -C4alk-NH-C3alkyl, -C5alk-NH-C3alkyl¸ - C6alk-NH-C3alkyl, -C0alk-NH-C4alkyl, -C1alk-NH-C4alkyl, -C2alk-NH-C4alkyl, -C3alk-NH-C4alkyl, -C ₄ alk-NH-C ₄ alkyl, -C ₅ alk-NH-C ₄ alkyl¸ -C ₆ alk-NH-C ₄ alkyl, -C ₀ alk-NH-C ₅ alkyl, -C ₁ alk-NH- C ₅ alkyl, -C ₂ alk-NH-C ₅ alkyl, -C ₃ alk-NH-C ₅ alkyl, -C ₄ alk-NH-C ₅ alkyl, -C ₅ alk-NH-C ₅ alkyl¸ -C ₆ alk- NH-C5alkyl, -C0alk-NH-C6alkyl, -C1alk-NH-C6alkyl, -C2alk-NH-C6alkyl, -C3alk-NH-C6alkyl, - C ₄ alk-NH-C ₆ alkyl, -C ₅ alk-NH-C ₆ alkyl¸ and -C ₆ alk-NH-C ₆ alkyl.

In some aspects, R ⁴ is -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, for example, -C ₀ alk- N(C1-C6alkyl)-C1alkyl, -C1alk-N(C1-C6alkyl)-C1alkyl, -C2alk-N(C1-C6alkyl)-C1alkyl, -C3alk-N(C1- C6alkyl)-C1alkyl, -C4alk-N(C1-C6alkyl)-C1alkyl, -C5alk-N(C1-C6alkyl)-C1alkyl¸ -C6alk- N(C1- C ₆ alkyl)-C ₁ alkyl, -C ₀ alk- N(C ₁ -C ₆ alkyl)-C ₂ alkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₂ alkyl, -C ₂ alk-N(C ₁ - C6alkyl)-C2alkyl, -C3alk-N(C1-C6alkyl)-C2alkyl, -C4alk-N(C1-C6alkyl)-C2alkyl, -C5alk-N(C1- C6alkyl)-C2alkyl¸ -C6alk-N(C1-C6alkyl)-C2alkyl, -C0alk-N(C1-C6alkyl)-C3alkyl, -C1alk-N(C1- C ₆ alkyl)-C ₃ alkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₃ alkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₃ alkyl, -C ₄ alk-N(C ₁ - C6alkyl)-C3alkyl, -C5alk-N(C1-C6alkyl)-C3alkyl¸ -C6alk-N(C1-C6alkyl)-C3alkyl, -C0alk-N(C1- C6alkyl)-C4alkyl, -C1alk-N(C1-C6alkyl)-C4alkyl, -C2alk-N(C1-C6alkyl)-C4alkyl, -C3alk-N(C1- C ₆ alkyl)-C ₄ alkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl, -C ₅ alk-N(C ₁ -C ₆ alkyl)-C ₄ alkyl¸ -C ₆ alk-N(C ₁ - C ₆ alkyl)-C ₄ alkyl, -C ₀ alk- N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₂ alk-N(C ₁ - C6alkyl)-C5alkyl, -C3alk-N(C1-C6alkyl)-C5alkyl, -C4alk-N(C1-C6alkyl)-C5alkyl, -C5alk-N(C1- C ₆ alkyl)-C ₅ alkyl¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₅ alkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl, -C ₁ alk-N(C ₁ - C ₆ alkyl)-C ₆ alkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₆ alkyl, -C ₄ alk-N(C ₁ - C6alkyl)-C6alkyl, -C5alk-N(C1-C6alkyl)-C6alkyl¸ -C6alk-N(C1-C6alkyl)-C6alkyl and the like.

In some aspects, R ⁴ is -C0-C6alk-NH-C3-C6cycloalkyl, for example, -C0alk-NH- C ₃ cycloalkyl, -C ₁ alk-NH-C ₃ cycloalkyl, -C ₂ alk-NH-C ₃ cycloalkyl, -C ₃ alk-NH-C ₃ cycloalkyl, -C ₄ alk- NH-C3cycloalkyl, -C5alk-NH-C3cycloalkyl¸ -C6alk-NH-C3cycloalkyl, -C0alk-NH-C4cycloalkyl, - C1alk-NH-C4cycloalkyl, -C2alk-NH-C4cycloalkyl, -C3alk-NH-C4cycloalkyl, -C4alk-NH- C4cycloalkyl, -C5alk-NH-C4cycloalkyl¸ -C6alk-NH-C4cycloalkyl, -C0alk-NH-C5cycloalkyl, -C1alk- NH-C ₅ cycloalkyl, -C ₂ alk-NH-C ₅ cycloalkyl, -C ₃ alk-NH-C ₅ cycloalkyl, -C ₄ alk-NH-C ₅ cycloalkyl, - C ₅ alk-NH-C ₅ cycloalkyl¸ -C ₆ alk-NH-C ₅ cycloalkyl, -C ₀ alk-NH-C ₆ cycloalkyl, -C ₁ alk-NH- C6cycloalkyl, -C2alk-NH-C6cycloalkyl, -C3alk-NH-C6cycloalkyl, -C4alk-NH-C6cycloalkyl, -C5alk- NH-C6cycloalkyl¸ -C6alk-NH-C6cycloalkyl, and the like. In some aspects wherein R ⁴ is -C0-C6alk- NH-C ₃ -C ₆ cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ⁴ is -C ₀ -C ₆ alk-NH- C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C1-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC1-C6alkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ⁴ is -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ -C ₆ cycloalkyl, for example, - C0alk-N(C1-C6alkyl)-C3cycloalkyl, -C1alk-N(C1-C6alkyl)-C3cycloalkyl, -C2alk-N(C1-C6alkyl)- C ₃ cycloalkyl, -C ₃ alk-N(C ₁ -C ₆ alkyl)-C ₃ cycloalkyl, -C ₄ alk-N(C ₁ -C ₆ alkyl)-C ₃ cycloalkyl, -C ₅ alk-N(C ₁ - C ₆ alkyl)-C ₃ cycloalkyl ¸ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ cycloalkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₄ cycloalkyl, - C1alk-N(C1-C6alkyl)-C4cycloalkyl, -C2alk-N(C1-C6alkyl)-C4cycloalkyl, -C3alk-N(C1-C6alkyl)- C4cycloalkyl, -C4alk-N(C1-C6alkyl)-C4cycloalkyl, -C5alk-N(C1-C6alkyl)-C4cycloalkyl¸ -C6alk-N(C1- C ₆ alkyl)-C ₄ cycloalkyl, -C ₀ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₅ cycloalkyl, - C2alk-N(C1-C6alkyl)-C5cycloalkyl, -C3alk-N(C1-C6alkyl)-C5cycloalkyl, -C4alk-N(C1-C6alkyl)- C5cycloalkyl, -C5alk-N(C1-C6alkyl)-C5cycloalkyl, -C6alk-N(C1-C6alkyl)-C5cycloalkyl, -C0alk-N(C1- C ₆ alkyl)-C ₆ cycloalkyl, -C ₁ alk-N(C ₁ -C ₆ alkyl)-C ₆ cycloalkyl, -C ₂ alk-N(C ₁ -C ₆ alkyl)-C ₆ cycloalkyl, - C3alk-N(C1-C6alkyl)-C6cycloalkyl, -C4alk-N(C1-C6alkyl)-C6cycloalkyl, -C5alk-N(C1-C6alkyl)- C6cycloalkyl¸ -C6alk-N(C1-C6alkyl)-C6cycloalkyl, and the like. In some aspects wherein R ⁴ is -C0- C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ -C ₆ cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ⁴ is -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ -C ₆ cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C1-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), - OC ₁ -C ₆ alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ⁴ is -C ₀ -C ₆ alk-heterocycloalkyl, for example, -C ₀ alk- heterocycloalkyl, -C1-C6alk-heterocycloalkyl, -C1-C5alk-heterocycloalkyl, -C1-C4alk- heterocycloalkyl, -C1-C3alk-heterocycloalkyl, -C1-C2alk-heterocycloalkyl, or–C1alk- heterocycloalkyl. Preferred heterocyloalkyl moieties include, for example, piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or oxetanyl. In some aspects wherein R ⁴ is -C0-C6alk-heterocycloalkyl, the heterocycloalkyl is unsubstituted. In other aspects wherein R ⁴ is -C0-C6alk-heterocycloalkyl, the heterocycloalkyl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC ₁ -C ₆ alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ⁴ is heteroaryl, for example furanyl, imidazolyl, and pyrazolyl. In some aspects wherein R ⁴ is heteroaryl, the heteroaryl is unsubstituted. In other aspects wherein R ⁴ is heteroaryl, the heteroaryl is substituted with one, two, or three R substituents independently selected from C1-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC1-C6alkyl (e.g., - Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In some aspects, R ⁴ is -CN.

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.

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- C6cycloalkenyl ring, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

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.

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 C ₃ -C ₆ cycloalkyl ring or a heterocycloalkyl ring. In some aspects, R ³ and R ⁴ , together with the atom to which they are attached, form a C3-C6cycloalkyl ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In other aspects, R ³ and R ⁴ , together with the atom to which they are attached, form a heterocycloalkyl ring, for example, piperidinyl, piperazinyl, morpholinyl, aziridinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or oxetanyl.

In compounds of the present disclosure that are a compound of Formula II or Formula IV, R ⁷ is H, halo, -C ₁ -C ₆ alkyl, -C ₁ -C ₄ haloalkyl, -C ₃ -C ₆ cycloalkyl, -C ₃ -C ₆ halocycloalkyl, - C1-C6alk-O-C1-C6alkyl, -C1-C6alk-S(O)-C1-C6alkyl, -C1-C6alk-S(O)2-C1-C6alkyl, -CR ⁸ R ^8’ CN, - NHCR ⁸ R ^8’ CN, -NR ⁸ R ^8’ , -NH-CN, -NHCONR ⁸ R ^8’ , -NHC(O)OR ⁹ , -NHC(O)-C1-C6alkyl, or - NHC(O)-C _1- C ₆ haloalkyl.

In some embodiments, R ⁷ is H. In some embodiments, R ⁷ is halo, for example, F, Cl, Br, or I. In some embodiments, R ⁷ is -Cl.

In some embodiments, R ⁷ is -C ₁ -C ₆ alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. In some embodiments, R ⁷ is methyl.

In other embodiments, R ⁷ is -C1-C4haloalkyl, for example, -CF3 or–CHF2,– CH ₂ CH ₂ Cl, -CH ₂ CH ₂ F, or -CH ₂ CHF ₂ . In some embodiments, R ⁷ is -CH ₂ CH ₂ C. In other embodiments, R ⁷ is -CH2CH2F. In yet other embodiments, R ⁷ is -CH2CHF2.

In other embodiments, R ⁷ is -C3-C6cycloalkyl, for example, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ⁷ is cyclopropyl.

In other embodiments, R ⁷ is -C ₃ -C ₆ halocycloalkyl, for example chlorocyclopropyl, fluorocyclobutyl, bromocyclopentyl, iodocyclohexyl, and the like.

In other embodiments, R ⁷ is–C ₁ -C ₆ alk-O-C ₁ -C ₆ alkyl, for example, -C ₁ alk-O- C ₁ alkyl, -C ₂ alk-O-C ₁ alkyl, -C ₃ alk-O-C ₁ alkyl, -C ₄ alk-O-C ₁ alkyl, -C ₅ alk-O-C ₁ alkyl¸ -C ₆ alk-O- C1alkyl, -C1alk-O-C2alkyl, -C2alk-O-C2alkyl, -C3alk-O-C2alkyl, -C4alk-O-C2alkyl, -C5alk-O- C2alkyl¸ -C6alk-O-C2alkyl, -C1alk-O-C3alkyl, -C2alk-O-C3alkyl, -C3alk-O-C3alkyl, -C4alk-O- C ₃ alkyl, -C ₅ alk-O-C ₃ alkyl¸ -C ₆ alk-O-C ₃ alkyl, -C ₁ alk-O-C ₄ alkyl, -C ₂ alk-O-C ₄ alkyl, -C ₃ alk-O- C4alkyl, -C4alk-O-C4alkyl, -C5alk-O-C4alkyl¸ -C6alk-O-C4alkyl, -C1alk-O-C5alkyl, -C2alk-O- C5alkyl, -C3alk-O-C5alkyl, -C4alk-O-C5alkyl, -C5alk-O-C5alkyl¸ -C6alk-O-C5alkyl, -C1alk-O- C ₆ alkyl, -C ₂ alk-O-C ₆ alkyl, -C ₃ alk-O-C ₆ alkyl, -C ₄ alk-O-C ₆ alkyl, -C ₅ alk-O-C ₆ alkyl¸ -C ₆ alk-O- C6alkyl, -CH2CH2OMe, -CH2OMe, -CH2CH2OCH2CH3, -CH2OCH2CH3, and the like.

In other embodiments, R ⁷ is -C1-C6alk-S(O)-C1-C6alkyl, for example, -C1alk-S(O)- C ₁ alkyl, -C ₂ alk-S(O)-C ₁ alkyl, -C ₃ alk-S(O)-C ₁ alkyl, -C ₄ alk-S(O)-C ₁ alkyl, -C ₅ alk-S(O)-C ₁ alkyl¸ - C ₆ alk-S(O)-C ₁ alkyl, -C ₁ alk-S(O)-C ₂ alkyl, -C ₂ alk-S(O)-C ₂ alkyl, -C ₃ alk-S(O)-C ₂ alkyl, -C ₄ alk-S(O)- C2alkyl, -C5alk-S(O)-C2alkyl¸ -C6alk-S(O)-C2alkyl, -C1alk-S(O)-C3alkyl, -C2alk-S(O)-C3alkyl, - C ₃ alk-S(O)-C ₃ alkyl, -C ₄ alk-S(O)-C ₃ alkyl, -C ₅ alk-S(O)-C ₃ alkyl¸ -C ₆ alk-S(O)-C ₃ alkyl, -C ₁ alk-S(O)- C ₄ alkyl, -C ₂ alk-S(O)-C ₄ alkyl, -C ₃ alk-S(O)-C ₄ alkyl, -C ₄ alk-S(O)-C ₄ alkyl, -C ₅ alk-S(O)-C ₄ alkyl¸ - C6alk-S(O)-C4alkyl, -C1alk-S(O)-C5alkyl, -C2alk-S(O)-C5alkyl, -C3alk-S(O)-C5alkyl, -C4alk-S(O)- C5alkyl, -C5alk-S(O)-C5alkyl¸ -C6alk-S(O)-C5alkyl, -C1alk-S(O)-C6alkyl, -C2alk-S(O)-C6alkyl, - C ₃ alk-S(O)-C ₆ alkyl, -C ₄ alk-S(O)-C ₆ alkyl, -C ₅ alk-S(O)-C ₆ alkyl¸ -C ₆ alk-S(O)-C ₆ alkyl, - CH2CH2S(O)Me, and the like. In other embodiments, R ⁷ is -C1-C6alk-S(O)2-C1-C6alkyl, for example, -C1alk- S(O) ₂ -C ₁ alkyl, -C ₂ alk-S(O) ₂ -C ₁ alkyl, -C ₃ alk-S(O) ₂ -C ₁ alkyl, -C ₄ alk-S(O) ₂ -C ₁ alkyl, -C ₅ alk-S(O) ₂ - C ₁ alkyl¸ -C ₆ alk-S(O) ₂ -C ₁ alkyl, -C ₁ alk-S(O) ₂ -C ₂ alkyl, -C ₂ alk-S(O) ₂ -C ₂ alkyl, -C ₃ alk-S(O) ₂ -C ₂ alkyl, - C4alk-S(O)2-C2alkyl, -C5alk-S(O)2-C2alkyl¸ -C6alk-S(O)2-C2alkyl, -C1alk-S(O)2-C3alkyl, -C2alk- S(O)2-C3alkyl, -C3alk-S(O)2-C3alkyl, -C4alk-S(O)2-C3alkyl, -C5alk-S(O)2-C3alkyl¸ -C6alk-S(O)2- C ₃ alkyl, -C ₁ alk-S(O) ₂ -C ₄ alkyl, -C ₂ alk-S(O) ₂ -C ₄ alkyl, -C ₃ alk-S(O) ₂ -C ₄ alkyl, -C ₄ alk-S(O) ₂ -C ₄ alkyl, - C5alk-S(O)2-C4alkyl¸ -C6alk-S(O)2-C4alkyl, -C1alk-S(O)2-C5alkyl, -C2alk-S(O)2-C5alkyl, -C3alk- S(O)2-C5alkyl, -C4alk-S(O)2-C5alkyl, -C5alk-S(O)2-C5alkyl¸ -C6alk-S(O)2-C5alkyl, -C1alk-S(O)2- C ₆ alkyl, -C ₂ alk-S(O) ₂ -C ₆ alkyl, -C ₃ alk-S(O) ₂ -C ₆ alkyl, -C ₄ alk-S(O) ₂ -C ₆ alkyl, -C ₅ alk-S(O) ₂ -C ₆ alkyl¸ - C ₆ alk-S(O) ₂ -C ₆ alkyl, -CH ₂ CH ₂ SO ₂ Me, and the like.

In some embodiments, R ⁷ is -CR ⁸ R ^8’ CN. Thus, in some embodiments wherein R ⁸ and R ^8’ are both H, R ⁷ is cyanomethyl (i.e., -CH ₂ CN).

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.

In some embodiments, R ⁷ is -NHCR ⁸ R ^8’ CN. Thus, in some embodiments wherein R ⁸ and R ^8’ are both H, R ⁷ is -NHCH ₂ CN.

In some embodiments, R ⁷ is -NH-CN.

In some embodiments, R ⁷ is -NHCONR ⁸ R ^8’ . Thus, in some embodiments wherein R ⁸ and R ^8’ are both H, R ⁷ is -NHCONH ₂ . In embodiments wherein R ⁸ and R ^8’ are both methyl, R ⁷ is –NHCON(CH3)2. In embodiments wherein R ⁸ is H and R ^8’ is methyl, R ⁷ is -NHCONHCH3.

In some embodiments, R ⁷ is or -NHC(O)OR ⁹ . Thus, in some embodiments wherein R ⁹ is methyl, R ⁷ is or -NHC(O)OCH ₃ .

In some aspects, R ⁷ is -NHC(O)-C _1- C ₆ alkyl, for example, -NHC(O)-C ₁ alkyl, NHC(O)-C2alkyl, NHC(O)-C3alkyl, NHC(O)-C4alkyl, NHC(O)-C5alkyl, NHC(O)-C6alkyl,

NHC(O)-methyl, NHC(O)-ethyl, and the like.

In other aspects, R ⁷ is NHC(O)-C _1- C ₆ haloalkyl, for example, -NHC(O)-C ₁ haloalkyl, NHC(O)-C2haloalkyl, NHC(O)-C3haloalkyl, NHC(O)-C4haloalkyl, NHC(O)-C5haloalkyl, - NHC(O)-C6haloalkyl, -NHC(O)-chloromethyl, -NHC(O)-chloroethyl, -NHC(O)-fluoromethyl, - NHC(O)-fluoroethyl and the like.

In other aspects, R ⁷ is -NH-C1-C6alk-C(O)-C1-C6alkyl, for example, -NH-C1alk- C(O)-C1-C6alkyl, -NH-C2alk-C(O)-C1-C6alkyl, -NH-C3alk-C(O)-C1-C6alkyl, -NH-C4alk-C(O)-C1- C6alkyl, -NH-C5alk-C(O)-C1-C6alkyl, -NH-C6alk-C(O)-C1-C6alkyl, -NH-C1-C6alk-C(O)-C1alkyl, - NH-C ₁ -C ₆ alk-C(O)-C ₂ alkyl, -NH-C ₁ -C ₆ alk-C(O)-C ₃ alkyl, -NH-C ₁ -C ₆ alk-C(O)-C ₄ alkyl, -NH-C ₁ - C ₆ alk-C(O)-C ₅ alkyl, -NH-C ₁ -C ₆ alk-C(O)-C ₆ alkyl and the like. In some aspects, R ⁷ is–NH-CH ₂ - C(O)-CH3.

In embodiments of the disclosure wherein the compounds are of Formula II or Formula IV, R ⁸ and R ^8’ are each independently H, C ₁ -C ₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like), or–C0-C6alk-OC1-C6alkyl (e.g., -C0alk-OC1- C6alkyl, -C1-C6alk-OC1-C6alkyl, -C1-C5alk-OC1-C6alkyl, -C1-C4alk-OC1-C6alkyl, -C1-C3alk-OC1- C ₆ alkyl, -C ₁ -C ₂ alk-OC ₁ -C ₆ alkyl, -C ₁ alk-OC ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-OC ₁ -C ₅ alkyl, -C ₀ -C ₆ alk-OC ₁ - C ₄ alkyl, -C ₀ -C ₆ alk-OC ₁ -C ₃ alkyl, -C ₀ -C ₆ alk-OC ₁ -C ₂ alkyl, or -C ₀ -C ₆ alk-OC ₁ alkyl).

In some embodiments, R ⁸ is H or C1-C6alkyl. In some embodiments, R ^8’ is H or C ₁ -C ₆ alkyl.

In some embodiments, R ⁸ and R ^8’ are each H.

In other embodiments, R ⁸ and R ^8’ are each independently C1-C6alkyl. Thus, in some embodiments R ⁸ is methyl and R ^8’ is methyl.

In some aspects, R ⁸ is C ₁ -C ₆ alkyl and R ^8’ is H. Thus, in some embodiments, R ⁸ is methyl and R ^8’ is H.

In other aspects, R ⁸ and R ^8’ are each independently -C0-C6alk-OC1-C6alkyl.

In other aspects, R ⁸ is–C ₀ -C ₆ alk-OC ₁ -C ₆ alkyl and R ^8’ is H.

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, may form a C3- C ₆ cycloalkyl ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

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, may form a C2- C ₆ heterocycloalkyl ring, for example, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, 4- alkylpiperidinyl, or piperidinyl.

In embodiments of the disclosure wherein the compounds are of Formula II or Formula IV, R ⁹ is -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl. In some embodiments, R ⁹ is C1- C ₆ alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R ⁹ is methyl. In other aspects, R ⁹ is -C0-C6alk-C3-C6cycloalkyl, for example, -C0alk- C ₃ cycloalkyl, -C ₁ alk-C ₃ cycloalkyl, -C ₂ alk-C ₃ cycloalkyl, -C ₃ alk-C ₃ cycloalkyl, -C ₄ alk-C ₃ cycloalkyl, - C ₅ alk-C ₃ cycloalkyl¸ -C ₆ alk-C ₃ cycloalkyl, -C ₀ alk-C ₄ cycloalkyl, -C ₁ alk-C ₄ cycloalkyl, -C ₂ alk- C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, -C5alk-C4cycloalkyl¸ -C6alk-C4cycloalkyl, - C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, -C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk- C ₅ cycloalkyl, -C ₅ alk-C ₅ cycloalkyl¸ -C ₆ alk-C ₅ cycloalkyl, -C ₀ alk-C ₆ cycloalkyl, -C ₁ alk-C ₆ cycloalkyl, - C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, -C4alk-C6cycloalkyl, -C5alk-C6cycloalkyl¸ -C6alk- C6cycloalkyl. In some aspects wherein R ² is -C0-C6alk-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R ² is -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from C ₁ -C ₆ alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OC1-C6alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, - Oisopropyl, -Obutyl), and halo (e.g., F or Cl).

In embodiments of the disclosure wherein the compounds are of Formula III or Formula IV, R ¹⁰ is H, halo, or -C1-C6alkyl. Thus in some embodiments, R ¹⁰ is H. In other embodiments, R ¹⁰ is halo, for example, F, Cl, Br, or I. Thus, in some embodimenents, R ¹⁰ is F. In other embodiments, R ¹⁰ is Cl. In yet other embodiments, R ¹⁰ is -C ₁ -C ₆ alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.

In preferred embodiments of the compounds of Formula I, Formula II, Formula III, and Formula IV R ¹ is -C ₀ -C ₆ alk-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C≡CH, -C ₀ -C ₆ alk- C≡C-C1-C6alkyl, -C0-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3-C6cycloalkyl, -C1-C6alk-aryl, - C0-C6alk-S-aryl, -C0-C6alk-S(O)-aryl, -C0-C6alk-S(O)2-aryl, or -C0-C6alk-O-aryl.

More preferred embodiments are those wherein R ¹ is -CH(OH)-C ₁ -C ₆ alkyl, - CH(F)-C ₁ -C ₆ alkyl, -CH(NH ₂ )-C ₁ -C ₆ alkyl, -CH(Me)-C ₁ -C ₆ alkyl, -C(Me)(OH)-C ₁ -C ₆ alkyl, - CH(OH)-C1-C6 haloalkyl, -CH(F)-C1-C6 haloalkyl, -CH(NH2)-C1-C6 haloalkyl, -CH(Me)-C1-C6 haloalkyl, -C(Me)(OH)-C ₁ -C ₆ haloalkyl, -CH(OH)-C≡CH, -CH(F)-C≡CH, -CH(NH ₂ )-C≡CH, - CH(Me)-C≡CH, -C(Me)(OH)-C≡CH, -CH(OH)-C≡C-C ₁ -C ₆ alkyl, -CH(F)-C≡C-C ₁ -C ₆ alkyl, - CH(NH2)-C≡C-C1-C6alkyl, -CH(Me)-C≡C-C1-C6alkyl, -C(Me)(OH)-C≡C-C1-C6alkyl, -CH(OH)- C≡C-C1-C6haloalkyl, -CH(F)-C≡C-C1-C6haloalkyl, -CH(NH2)-C≡C-C1-C6haloalkyl, -CH(Me)- C≡C- C ₁ -C ₆ haloalkyl, -C(Me)(OH)-C≡C-C ₁ -C ₆ haloalkyl, -CH(OH)-C≡C-C ₃ -C ₆ cycloalkyl, -CH(F)- C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3-C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, - C(Me)(OH)-C≡C-C3-C6cycloalkyl, -CH2-aryl, -CH(OH)-aryl, -CH(F)-aryl, -CH(NH2)-aryl, - CH(Me)-aryl, -C(Me)(OH)-aryl, -S-aryl, -S(O)-aryl, -S(O) ₂ -aryl, or -O-aryl.

Most preferred embodiments are those wherein R ¹ is -CH(OH)-C≡C-CH ₃ , -CH(F)- C≡C-CH3, -CH(NH2)-C≡C-CH3, -CH(Me)-C≡C-CH3, or -C(Me)(OH)-C≡C-CH3, -CH(OH)-C≡C- CH3, -CH(OH)-C≡C-CF3, -CH(F)-C≡C-CF3, -CH(NH2)-C≡C-CF3, -CH(Me)-C≡C-CF3, or - C(Me)(OH)-C≡C-CF ₃ , -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH ₂ )-C≡C- cyclopropyl, -CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl, CH2-4-fluorophenyl, - CH2-phenyl, -CH2-4-chlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3,4-difluorophenyl, -CH2-3- fluoro-4-chlorophenyl, -CH ₂ -3-chloro-4-fluorophenyl, -CH(OH)-4-chlorophenyl, -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-chlorophenyl, -CH(F)-4-fluorophenyl, - 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 )-4-fluorophenyl -CH(NH ₂ )-3,4- dichlorophenyl, -CH(NH2)-3,4-difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH2)-3- chloro-4-fluorophenyl, -CH(Me)-4-chlorophenyl, -CH(Me)-4-fluorophenyl, -CH(Me)-3,4- dichlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3- chloro-4-fluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -C(Me)(OH)- 3,4-dichlorophenyl, -C(Me)(OH)-3,4-difluorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, or - C(Me)(OH)-3-chloro-4-fluorophenyl, -S-4-chlorophenyl, -S-4-fluorophenyl -S-3,4-dichlorophenyl, - S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or -S-3-chloro-4-fluorophenyl, -S(O)-4- chlorophenyl, -S(O)-4-fluorophenyl, -S(O)-3,4-dichlorophenyl, -S(O)-3,4-difluorophenyl, -S(O)-3- fluoro-4-chlorophenyl, or -S(O)-3-chloro-4-fluorophenyl, -S(O) ₂ -4-chlorophenyl, -S(O) ₂ -4- fluorophenyl, -S(O) ₂ -3,4-dichlorophenyl, -S(O) ₂ -3,4-difluorophenyl, -S(O) ₂ -3-fluoro-4- chlorophenyl, or -S(O)2-3-chloro-4-fluorophenyl, -O-4-chlorophenyl, -O-4-fluorophenyl -O-3,4- dichlorophenyl, -O-3,4-difluorophenyl, -O-3-fluoro-4-chlorophenyl, or -O-3-chloro-4-fluorophenyl.

In some aspects of the disclosure, the disclosure is directed to compounds of Formula II, or IV wherein R ¹ is–C0-C6alk-heteroaryl, -C1-C6alk-O-heteroaryl, -C1-C6alk-S- heteroaryl, or -C1-C6alk-NH-heteroaryl, and R ⁷ , if present, is -C1-C6alk-O-C1-C6alkyl, -C1-C6alk- S(O)-C ₁ -C ₆ alkyl, -C ₁ -C ₆ alk-S(O) ₂ -C ₁ -C ₆ alkyl, -CR ⁸ R ^8’ CN, -NHCR ⁸ R ^8’ CN, -NH-CN, - NHCONR ⁸ R ^8’ , -NHC(O)OR ⁹ , NHC(O)-C1-C6alkyl, NHC(O)-C1-C6haloalkyl, or -NH-C1-C6alk- C(O)-C1-C6alkyl; and R ⁸ , R ^8’ , and R ⁹ having any of the values described above. In some aspects, the present disclosure is directed to compounds of Formula IIA-1

wherein R ¹ is -C ₁ -C ₆ alk-aryl, -C ₀ -C ₆ alk-S-aryl, -C ₀ -C ₆ alk-S(O)aryl, or -C ₀ -C ₆ alk-S(O) ₂ aryl; R ⁷ is - C ₁ -C ₆ alkyl, halo, -C ₁ -C ₄ haloalkyl, -C ₃ -C ₆ cycloalkyl, -C ₁ -C ₆ alk-O-C ₁ -C ₆ alkyl, -CR ⁸ R ^8’ CN, -NR ⁸ R ^8’ , -NHCR ⁸ R ^8’ CN, -NH-CN, -NHCONR ⁸ R ^8’ , -NHC(O)OR ⁹ , NHC(O)-C1-C6haloalkyl, R ⁸ and R ^8’ are each independently H or -C1-C6alkyl; and R ⁹ is C1-C6alkyl. In some embodiments, compounds of Formul IIA-1 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl, -C ₀ -C ₆ alk-S-aryl, -C ₀ -C ₆ alk-S(O)aryl, or -C ₀ - C6alk-S(O)2aryl; R ⁷ is -NR ⁸ R ^8’ , -C1-C6alkyl, -C1-C4haloalkyl, halo, -C3-C6cycloalkyl, and R ⁸ and R ^8’ are each independently H or -C1-C6alkyl.

In some preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; and R ⁷ is NH ₂ , cyclopropyl, or -Cl. In other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -C0-C6alk-S-aryl; and R ⁷ is NH2, cyclopropyl, or -Cl. In other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -C ₀ -C ₆ alk- S(O)aryl; and R ⁷ is NH ₂ , cyclopropyl, or -Cl. In yet other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -C0-C6alk-S(O)2aryl; and R ⁷ is NH2, cyclopropyl, or -Cl.

In other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; and R ⁷ is NH ₂ . In other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -C1-C6alk-aryl; and R ⁷ is cyclopropyl. In some preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -C1-C6alk-aryl; and R ⁷ is -Cl.

In other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is CH2-4-fluorophenyl, -CH2-phenyl, -CH2-4-chlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3,4- difluorophenyl, -CH2-3-fluoro-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH2-(2,4- difluorophenyl), - CH ₂ -(3-methyl-4-chlorophenyl), -CH ₂ -(2-hydroxymethyl-4-chlorophenyl), -CH ₂ - (2-aminomethyl-4-chlorophenyl), -CH ₂ -(2-(methylaminomethyl)-4-chlorophenyl), -CH ₂ -(2- hydroxymethyl-4,5-difluorophenyl), -CH2-(2-aminomethyl-4,5-difluorophenyl), -CH2-(2- (methylaminomethyl)-4,5-difluorophenyl), -CH(OH)-4-chlorophenyl, -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(OH)-(2,4-difluorophenyl), - CH(OH)-(3-methyl-4- chlorophenyl), -CH(OH)-(2-hydroxymethyl-4-chlorophenyl), - CH(OH)-(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)-4-fluorophenyl, - CH(F)-3,4-dichlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3- chloro-4-fluorophenyl, -CH(F)-(2,4-difluorophenyl), - CH(F)-(3-methyl-4-chlorophenyl), -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(NH2)-4-chlorophenyl, -CH(NH2)-4-fluorophenyl -CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4- difluorophenyl, -CH(NH ₂ )-3-fluoro-4-chlorophenyl, -CH(NH ₂ )-3-chloro-4-fluorophenyl, -CH(NH ₂ )- (2,4-difluorophenyl), - CH(NH ₂ )-(3-methyl-4-chlorophenyl), -CH(NH ₂ )-(2-hydroxymethyl-4- chlorophenyl), - CH(NH2)-(2-aminomethyl-4-chlorophenyl), -CH(NH2)-(2-(methylaminomethyl)-4- chlorophenyl), -CH(NH2)-(2-hydroxymethyl-4,5-difluorophenyl), -CH(NH2)-(2-aminomethyl-4,5- difluorophenyl), -CH(NH ₂ )-(2-(methylaminomethyl)-4,5-difluorophenyl), -CH(Me)-4- chlorophenyl, -CH(Me)-4-fluorophenyl, -CH(Me)-3,4-dichlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3-chloro-4-fluorophenyl, -CH(Me)-(2,4- difluorophenyl), - CH(Me)-(3-methyl-4-chlorophenyl), -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), -CH(Me)-(2-(methylaminomethyl)-4,5-difluorophenyl), -C(Me)(OH)-4- chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4-chlorophenyl), -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), or -C(Me)(OH)-(2-(methylaminomethyl)-4,5- difluorophenyl); R ⁷ is -NR ⁸ R ^8’ , -C ₁ -C ₆ alkyl, -C ₁ -C ₄ haloalkyl, halo, or -C ₃ -C ₆ cycloalkyl, and R ⁸ and R ^8’ are each independently H or -C1-C6alkyl. In other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -CH ₂ -phenyl,–CH ₂ -4-fluorophenyl, or–CH ₂ -4-chlorophenyl; and R ⁷ is NH ₂ , cyclopropyl, or -Cl. In some preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -CH ₂ -phenyl, –CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; and R ⁷ is NH2. In other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -CH2-phenyl,–CH2-4-fluorophenyl, or–CH2- 4-chlorophenyl; and R ⁷ is cyclopropyl. In other preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -CH2-phenyl,–CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; and R ⁷ is–Cl.

Other preferred embodiments are compounds of Formula IIA-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -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(OH)-(2,4-difluorophenyl), - CH(OH)-(3-methyl-4-chlorophenyl), -CH(OH)-(2-hydroxymethyl- 4-chlorophenyl), - CH(OH)-(2-aminomethyl-4-chlorophenyl), -CH(OH)-(2-(methylaminomethyl)-4- 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 ⁷ is NH2 or cyclopropyl, or -Cl.

In some preferred embodiments, are compounds of Formula IIA-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3,4- difluorophenyl, and R ⁷ is NH ₂ . In other preferred embodiments, are compounds of Formula IIA-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3,4- difluorophenyl, and R ⁷ is cyclopropyl. In yet other preferred embodiments, are compounds of Formula IIA-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or - CH(OH)-3,4-difluorophenyl, and R ⁷ is -Cl.

Other preferred embodiments are compounds of Formula IIA-1 are those wherein R ¹ is -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4-chlorophenyl), - 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), or -C(Me)(OH)-(2- (methylaminomethyl)-4,5-difluorophenyl), and R ⁷ is NH2 or cyclopropyl, or -Cl. In some preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -–C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or–C(Me)(OH)-3,4- difluorophenyl, and R ⁷ is NH ₂ . In other preferred embodiments, are compounds of Formula IIA-1 are those wherein R ¹ is–C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or–

C(Me)(OH)-3,4-difluorophenyl, and R ⁷ is cyclopropyl. In yet other preferred embodiments, are compounds of Formula IIA-1 are those wherein R ¹ is–C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)- 3,4-dichlorophenyl, or–C(Me)(OH)-3,4-difluorophenyl, and R ⁷ is -Cl.

Other preferred embodiments are compounds of Formula IIA-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl, -CH(F)-4-fluorophenyl, -CH(F)-3,4-dichlorophenyl, -CH(F)-3,4- difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3-chloro-4-fluorophenyl, -CH(F)-(2,4- difluorophenyl), - CH(F)-(3-methyl-4-chlorophenyl), -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(NH2)-4-chlorophenyl, -CH(NH2)-4-fluorophenyl - CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4-difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, - CH(NH ₂ )-3-chloro-4-fluorophenyl, -CH(NH ₂ )-(2,4-difluorophenyl), - CH(NH ₂ )-(3-methyl-4- chlorophenyl), -CH(NH2)-(2-hydroxymethyl-4-chlorophenyl), - CH(NH2)-(2-aminomethyl-4- chlorophenyl), -CH(NH2)-(2-(methylaminomethyl)-4-chlorophenyl), -CH(NH2)-(2-hydroxymethyl- 4,5-difluorophenyl), -CH(NH ₂ )-(2-aminomethyl-4,5-difluorophenyl), -CH(NH ₂ )-(2- (methylaminomethyl)-4,5-difluorophenyl), and R ⁷ is NH2 or cyclopropyl, or -Cl.

In some preferred embodiments, compounds of Formula IIA-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH ₂ )-4-chlorophenyl, and R ⁷ is NH ₂ . In other preferred embodiments, are compounds of Formula IIA-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or - CH(NH2)-4-chlorophenyl, and R ⁷ is cyclopropyl. In yet other preferred embodiments, are compounds of Formula IIA-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH ₂ )-4- chlorophenyl, and R ⁷ is -Cl.

In some aspects, the disclosure is directed to compounds of Formula IIA-1 wherein R ¹ is -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, or -C0-C6alk-S(O)2aryl; and R ⁷ is NH2, cyclopropyl, or– Cl. In some aspects, the disclosure is directed to compounds of Formula IIA-1 wherein R ¹ is -C ₀ - C6alk-S-aryl, -C0-C6alk-S(O)aryl, or -C0-C6alk-S(O)2aryl; and R ⁷ is NH2, cyclopropyl, or–Cl;

wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4- chlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 3-methyl-4-chlorophenyl, 2- hydroxymethyl-4-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. In some embodiments, the compounds of Formula IIA-1 are those wherein R ¹ is -C0-C6alk-S-4-chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk- S(O) ₂ -4-chlorophenyl; and R ⁷ is NH ₂ . In other embodiments, the compounds of Formula IIA-1 are those wherein R ¹ is -C0-C6alk-S-4-chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk- S(O)2-4-chlorophenyl; and R ⁷ is cyclopropyl. In yet other embodiments, the compounds of Formula IIA-1 are those wherein R ¹ is -C ₀ -C ₆ alk-S-4-chlorophenyl, -C ₀ -C ₆ alk-S(O)-4-chlorophenyl, or -C ₀ - C ₆ alk-S(O) ₂ -4-chlorophenyl; and R ⁷ is -Cl.

In some aspects, the present disclosure is directed to compounds of Formula IIB-1

wherein R ¹ is -C1-C6alk-aryl, -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, or -C0-C6alk-S(O)2aryl;

R ⁷ is -C1-C6alkyl, halo, -C1-C4haloalkyl, -C3-C6cycloalkyl, -C1-C6alk-O-C1-C6alkyl, -CR ⁸ R ^8’ CN, - NR ⁸ R ^8’ , -NHCR ⁸ R ^8’ CN, -NH-CN, -NHCONR ⁸ R ^8’ , -NHC(O)OR ⁹ , NHC(O)-C _1- C ₆ haloalkyl, R ⁸ and R ^8’ are each independently H or -C1-C6alkyl; and R ⁹ is C1-C6alkyl. In some embodiments, compounds of Formul IIB-1 are those wherein R ¹ is -C1-C6alk-aryl, -C0-C6alk-S-aryl, -C0-C6alk- S(O)aryl, or -C ₀ -C ₆ alk-S(O) ₂ aryl; R ⁷ is -NR ⁸ R ^8’ , -NHCONR ⁸ R ^8’ , -C ₁ -C ₆ alkyl, -C ₁ -C ₄ haloalkyl, halo, -C ₃ -C ₆ cycloalkyl, and R ⁸ and R ^8’ are each independently H or -C ₁ -C ₆ alkyl.

In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; and R ⁷ is NH ₂ , -NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or -Cl. In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -C ₀ -C ₆ alk-S-aryl; and R ⁷ is NH2, -NHC(O)N(CH3)2, cyclopropyl, or -Cl. In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -C0-C6alk-S(O)aryl; and R ⁷ is NH2, -NHC(O)N(CH3)2, cyclopropyl, or -Cl. In yet other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -C0-C6alk-S(O)2aryl; and R ⁷ is NH2, -NHC(O)N(CH3)2, cyclopropyl, or -Cl. In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; and R ⁷ is NH ₂ . In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; and R ⁷ is -NHC(O)N(CH ₃ ) ₂ . In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -C1-C6alk-aryl; and R ⁷ is cyclopropyl. In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -C1-C6alk-aryl; and R ⁷ is -Cl.

In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is CH2-4-fluorophenyl, -CH2-phenyl, -CH2-4-chlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3,4- difluorophenyl, -CH ₂ -3-fluoro-4-chlorophenyl, -CH ₂ -3-chloro-4-fluorophenyl, -CH ₂ -(2,4- difluorophenyl), - CH ₂ -(3-methyl-4-chlorophenyl), -CH ₂ -(2-hydroxymethyl-4-chlorophenyl), -CH ₂ - (2-aminomethyl-4-chlorophenyl), -CH2-(2-(methylaminomethyl)-4-chlorophenyl), -CH2-(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)-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(OH)-(2,4-difluorophenyl), - CH(OH)-(3-methyl-4- chlorophenyl), -CH(OH)-(2-hydroxymethyl-4-chlorophenyl), - CH(OH)-(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)-4-fluorophenyl, - CH(F)-3,4-dichlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3- chloro-4-fluorophenyl, -CH(F)-(2,4-difluorophenyl), - CH(F)-(3-methyl-4-chlorophenyl), -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 )-4-fluorophenyl -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 )- (2,4-difluorophenyl), - CH(NH2)-(3-methyl-4-chlorophenyl), -CH(NH2)-(2-hydroxymethyl-4- chlorophenyl), - CH(NH2)-(2-aminomethyl-4-chlorophenyl), -CH(NH2)-(2-(methylaminomethyl)-4- chlorophenyl), -CH(NH ₂ )-(2-hydroxymethyl-4,5-difluorophenyl), -CH(NH ₂ )-(2-aminomethyl-4,5- difluorophenyl), -CH(NH2)-(2-(methylaminomethyl)-4,5-difluorophenyl), -CH(Me)-4- chlorophenyl, -CH(Me)-4-fluorophenyl, -CH(Me)-3,4-dichlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3-chloro-4-fluorophenyl, -CH(Me)-(2,4- difluorophenyl), - CH(Me)-(3-methyl-4-chlorophenyl), -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), -CH(Me)-(2-(methylaminomethyl)-4,5-difluorophenyl), -C(Me)(OH)-4- chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4-chlorophenyl), -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), or -C(Me)(OH)-(2-(methylaminomethyl)-4,5- difluorophenyl); R ⁷ is -NR ⁸ R ^8’ , -NHCONR ⁸ R ^8’ , -C ₁ -C ₆ alkyl, -C ₁ -C ₄ haloalkyl, halo, or -C ₃ - C ₆ cycloalkyl, and R ⁸ and R ^8’ are each independently H or -C ₁ -C ₆ alkyl.

In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH2-phenyl,–CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; and R ⁷ is NH2, -NHC(O)N(CH3)2, cyclopropyl, or -Cl. In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH2-phenyl,–CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; and R ⁷ is NH2. In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH2-phenyl,–CH2-4- fluorophenyl, or–CH ₂ -4-chlorophenyl; and R ⁷ is -NHC(O)N(CH ₃ ) ₂ . In other preferred

embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH2-phenyl,–CH2-4- fluorophenyl, or–CH2-4-chlorophenyl; and R ⁷ is cyclopropyl. In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH ₂ -phenyl,–CH ₂ -4-fluorophenyl, or–CH ₂ - 4-chlorophenyl; and R ⁷ is–Cl.

Other preferred embodiments are compounds of Formula IIB-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -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(OH)-(2,4-difluorophenyl), - CH(OH)-(3-methyl-4-chlorophenyl), -CH(OH)-(2-hydroxymethyl- 4-chlorophenyl), - CH(OH)-(2-aminomethyl-4-chlorophenyl), -CH(OH)-(2-(methylaminomethyl)-4- 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 ⁷ is NH2, - NHC(O)N(CH3)2, cyclopropyl, or -Cl. In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-(3-methyl-4-chlorophenyl), - CH(OH)-(2-hydroxymethyl-4-chlorophenyl), or -CH(OH)-3,4-difluorophenyl, and R ⁷ is NH ₂ . In other preferred embodiments, are compounds of Formula IIB-1 are those wherein R ¹ is -CH(OH)-4- chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-(3-methyl-4-chlorophenyl), -CH(OH)-(2- hydroxymethyl-4-chlorophenyl), or -CH(OH)-3,4-difluorophenyl, and R ⁷ is -NHC(O)N(CH ₃ ) ₂ . In other preferred embodiments, are compounds of Formula IIB-1 are those wherein R ¹ is -CH(OH)-4- chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-(3-methyl-4-chlorophenyl), -CH(OH)-(2- hydroxymethyl-4-chlorophenyl), or -CH(OH)-3,4-difluorophenyl, and R ⁷ is cyclopropyl. In yet other preferred embodiments, are compounds of Formula IIB-1 are those wherein R ¹ is -CH(OH)-4- chlorophenyl, -CH(OH)-3,4-dichlorophenyl, -CH(OH)-(3-methyl-4-chlorophenyl), -CH(OH)-(2- hydroxymethyl-4-chlorophenyl), or -CH(OH)-3,4-difluorophenyl, and R ⁷ is -Cl.

Other preferred embodiments are compounds of Formula IIB-1 are those wherein R ¹ is -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4-chlorophenyl), - 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), or -C(Me)(OH)-(2- (methylaminomethyl)-4,5-difluorophenyl), and R ⁷ is NH2, -NHC(O)N(CH3)2, cyclopropyl, or -Cl.

In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -–C(Me)(OH)-4-chlorophenyl, -CH(OH)-(3-methyl-4-chlorophenyl), -C(Me)(OH)-3,4- dichlorophenyl, or–C(Me)(OH)-3,4-difluorophenyl, and R ⁷ is NH ₂ . In some preferred

embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -–C(Me)(OH)-4-chlorophenyl, - CH(OH)-(3-methyl-4-chlorophenyl), -C(Me)(OH)-3,4-dichlorophenyl, or–C(Me)(OH)-3,4- difluorophenyl, and R ⁷ is -NHC(O)N(CH ₃ ) ₂ . In other preferred embodiments, are compounds of Formula IIB-1 are those wherein R ¹ is–C(Me)(OH)-4-chlorophenyl, -CH(OH)-(3-methyl-4- chlorophenyl), -C(Me)(OH)-3,4-dichlorophenyl, or–C(Me)(OH)-3,4-difluorophenyl, and R ⁷ is cyclopropyl. In yet other preferred embodiments, are compounds of Formula IIB-1 are those wherein R ¹ is–C(Me)(OH)-4-chlorophenyl, -CH(OH)-(3-methyl-4-chlorophenyl), -C(Me)(OH)-3,4- dichlorophenyl, or–C(Me)(OH)-3,4-difluorophenyl, and R ⁷ is -Cl. Other preferred embodiments are compounds of Formula IIB-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl, -CH(F)-4-fluorophenyl, -CH(F)-3,4-dichlorophenyl, -CH(F)-3,4- difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3-chloro-4-fluorophenyl, -CH(F)-(2,4- difluorophenyl), - CH(F)-(3-methyl-4-chlorophenyl), -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(NH2)-4-chlorophenyl, -CH(NH2)-4-fluorophenyl - CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4-difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, - CH(NH ₂ )-3-chloro-4-fluorophenyl, -CH(NH ₂ )-(2,4-difluorophenyl), - CH(NH ₂ )-(3-methyl-4- chlorophenyl), -CH(NH ₂ )-(2-hydroxymethyl-4-chlorophenyl), - CH(NH ₂ )-(2-aminomethyl-4- chlorophenyl), -CH(NH2)-(2-(methylaminomethyl)-4-chlorophenyl), -CH(NH2)-(2-hydroxymethyl- 4,5-difluorophenyl), -CH(NH ₂ )-(2-aminomethyl-4,5-difluorophenyl), -CH(NH ₂ )-(2- (methylaminomethyl)-4,5-difluorophenyl), and R ⁷ is NH ₂ , -NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or -Cl.

In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH2)-4-chlorophenyl, and R ⁷ is NH2. In some preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or - CH(NH2)-4-chlorophenyl, and R ⁷ is -NHC(O)N(CH3)2. In other preferred embodiments, are compounds of Formula IIB-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH2)-4- chlorophenyl, and R ⁷ is cyclopropyl. In yet other preferred embodiments, are compounds of Formula IIB-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH2)-4-chlorophenyl, and R ⁷ is -Cl.

In some aspects, the disclosure is directed to compounds of Formula IIB-1 wherein R ¹ is -C ₀ -C ₆ alk-S-aryl, -C ₀ -C ₆ alk-S(O)aryl, or -C ₀ -C ₆ alk-S(O) ₂ aryl; and R ⁷ is NH ₂ , - NHC(O)N(CH3)2, cyclopropyl, or–Cl. In some aspects, the disclosure is directed to compounds of Formula IIB-1 wherein R ¹ is -C ₀ -C ₆ alk-S-aryl, -C ₀ -C ₆ alk-S(O)aryl, or -C ₀ -C ₆ alk-S(O) ₂ aryl; and R ⁷ is NH ₂ , cyclopropyl, or–Cl; wherein the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4- difluorophenyl, -3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 3-methyl-4- chlorophenyl, 2-hydroxymethyl-4-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. In some embodiments, the compounds of Formula IIB-1 are those wherein R ¹ is -C0-C6alk-S-4-chlorophenyl, -C0-C6alk-S(O)- 4-chlorophenyl, or -C0-C6alk-S(O)2-4-chlorophenyl; and R ⁷ is NH2. In some embodiments, the compounds of Formula IIB-1 are those wherein R ¹ is -C ₀ -C ₆ alk-S-4-chlorophenyl, -C ₀ -C ₆ alk-S(O)- 4-chlorophenyl, or -C ₀ -C ₆ alk-S(O) ₂ -4-chlorophenyl; and R ⁷ is -NHC(O)N(CH ₃ ) ₂ . In other embodiments, the compounds of Formula IIB-1 are those wherein R ¹ is -C0-C6alk-S-4-chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk-S(O)2-4-chlorophenyl; and R ⁷ is cyclopropyl. In yet other embodiments, the compounds of Formula IIB-1 are those wherein R ¹ is -C ₀ -C ₆ alk-S-4- chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk-S(O)2-4-chlorophenyl; and R ⁷ is -Cl.

In some aspects, the present disclosure is directed to compounds of Formula IIB-2

wherein R ¹ is -C ₁ -C ₆ alk-aryl, -C ₀ -C ₆ alk-S-aryl, -C ₀ -C ₆ alk-S(O)aryl, or -C ₀ -C ₆ alk-S(O) ₂ aryl; R ⁷ is - NR ⁸ R ^8’ , -NHCONR ⁸ R ^8’ , -C1-C6alkyl, -C1-C4haloalkyl, halo, -C3-C6cycloalkyl, and R ⁸ and R ^8’ are each independently H or -C ₁ -C ₆ alkyl; and R ¹² is -C ₁ -C ₆ alkyl.

In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -C1-C6alk-aryl; R ⁷ is NH2, NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹² is methyl. In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -C0-C6alk-S-aryl; R ⁷ is NH ₂ , NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or–Cl; and R ¹² is methyl. In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -C0-C6alk-S(O)aryl; R ⁷ is NH2,

NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹² is methyl. In yet other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -C ₀ -C ₆ alk-S(O) ₂ aryl; R ⁷ is NH ₂ ,

NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or–Cl; and R ¹² is methyl.

In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; R ⁷ is NH _2; and and R ¹² is methyl. In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; R ⁷ is NHC(O)N(CH ₃ ) _2; and R ¹² is methyl. In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -C1-C6alk-aryl; R ⁷ is cyclopropyl; and R ¹² is methyl. In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; R ⁷ is–Cl; and R ¹² is methyl.

In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is CH2-4-fluorophenyl, -CH2-phenyl, -CH2-4-chlorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3,4- difluorophenyl, -CH2-3-fluoro-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -CH2-(2,4- difluorophenyl), - CH ₂ -(3-methyl-4-chlorophenyl), -CH ₂ -(2-hydroxymethyl-4-chlorophenyl), -CH ₂ - (2-aminomethyl-4-chlorophenyl), -CH2-(2-(methylaminomethyl)-4-chlorophenyl), -CH2-(2- hydroxymethyl-4,5-difluorophenyl), -CH2-(2-aminomethyl-4,5-difluorophenyl), -CH2-(2- (methylaminomethyl)-4,5-difluorophenyl), -CH(OH)-4-chlorophenyl, -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(OH)-(2,4-difluorophenyl), - CH(OH)-(3-methyl-4- chlorophenyl), -CH(OH)-(2-hydroxymethyl-4-chlorophenyl), - CH(OH)-(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)-4-fluorophenyl, - CH(F)-3,4-dichlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3- chloro-4-fluorophenyl, -CH(F)-(2,4-difluorophenyl), - CH(F)-(3-methyl-4-chlorophenyl), -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(NH2)-4-chlorophenyl, -CH(NH2)-4-fluorophenyl -CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4- difluorophenyl, -CH(NH ₂ )-3-fluoro-4-chlorophenyl, -CH(NH ₂ )-3-chloro-4-fluorophenyl, -CH(NH ₂ )- (2,4-difluorophenyl), - CH(NH ₂ )-(3-methyl-4-chlorophenyl), -CH(NH ₂ )-(2-hydroxymethyl-4- chlorophenyl), - CH(NH2)-(2-aminomethyl-4-chlorophenyl), -CH(NH2)-(2-(methylaminomethyl)-4- chlorophenyl), -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- chlorophenyl, -CH(Me)-4-fluorophenyl, -CH(Me)-3,4-dichlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3-chloro-4-fluorophenyl, -CH(Me)-(2,4- difluorophenyl), - CH(Me)-(3-methyl-4-chlorophenyl), -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), -CH(Me)-(2-(methylaminomethyl)-4,5-difluorophenyl), -C(Me)(OH)-4- chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4-chlorophenyl), -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), or -C(Me)(OH)-(2-(methylaminomethyl)-4,5- difluorophenyl); R ⁷ is -NR ⁸ R ^8’ , -NHCONR ⁸ R ^8’ , -C1-C6alkyl, -C1-C4haloalkyl, halo, or -C3- C ₆ cycloalkyl; R ⁸ and R ^8’ are each independently H or -C ₁ -C ₆ alkyl; and R ¹² is methyl.

In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH2-phenyl,–CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; R ⁷ is NH2, NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹² is methyl. In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH ₂ -phenyl,–CH ₂ -4-fluorophenyl, or–CH ₂ -4-chlorophenyl; R ⁷ is NH2; and R ¹² is methyl. In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH2-phenyl,–CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; R ⁷ is NHC(O)N(CH3)2; and R ¹² is methyl. In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH2-phenyl,–CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; R ⁷ is cyclopropyl; and R ¹² is methyl. In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is - CH ₂ -phenyl,–CH ₂ -4-fluorophenyl, or–CH ₂ -4-chlorophenyl; R ⁷ is -Cl; and R ¹² is methyl.

Other preferred embodiments are compounds of Formula IIB-2 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -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(OH)-(2,4-difluorophenyl), - CH(OH)-(3-methyl-4-chlorophenyl), -CH(OH)-(2-hydroxymethyl- 4-chlorophenyl), - CH(OH)-(2-aminomethyl-4-chlorophenyl), -CH(OH)-(2-(methylaminomethyl)-4- chlorophenyl), -CH(OH)-(2-hydroxymethyl-4,5-difluorophenyl), -CH(OH)-(2-aminomethyl-4,5- difluorophenyl), or -CH(OH)-(2-(methylaminomethyl)-4,5-difluorophenyl), R ⁷ is NH _{2 ,}

NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹² is methyl.

In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3,4-difluorophenyl, R ⁷ is NH2; and R ¹² is methyl. In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3,4- difluorophenyl, R ⁷ is NHC(O)N(CH3)2; and R ¹² is methyl. In other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4- dichlorophenyl, or -CH(OH)-3,4-difluorophenyl, R ⁷ is cyclopropyl; and R ¹² is methyl. In yet other preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH(OH)-4- chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3,4-difluorophenyl, R ⁷ is–Cl; and R ¹² is methyl.

Other preferred embodiments are compounds of Formula IIB-2 are those wherein R ¹ is -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4-chlorophenyl), - 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), or -C(Me)(OH)-(2- (methylaminomethyl)-4,5-difluorophenyl), R ⁷ is NH2, NHC(O)N(CH3)2,or cyclopropyl, or–Cl; and R ¹² is methyl.

In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -–C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or–C(Me)(OH)-3,4- difluorophenyl, R ⁷ is NH2; and R ¹² is methyl. In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -–C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4- dichlorophenyl, or–C(Me)(OH)-3,4-difluorophenyl, R ⁷ is NHC(O)N(CH3)2; and R ¹² is methyl. In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is–C(Me)(OH)-4- chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or–C(Me)(OH)-3,4-difluorophenyl; R ⁷ is cyclopropyl; and R ¹² is methyl. In yet other preferred embodiments, are compounds of Formula IIB-2 are those wherein R ¹ is–C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or– C(Me)(OH)-3,4-difluorophenyl, R ⁷ is–Cl; and R ¹² is methyl.

Other preferred embodiments are compounds of Formula IIB-2 are those wherein R ¹ is -CH(F)-4-chlorophenyl, -CH(F)-4-fluorophenyl, -CH(F)-3,4-dichlorophenyl, -CH(F)-3,4- difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3-chloro-4-fluorophenyl, -CH(F)-(2,4- difluorophenyl), - CH(F)-(3-methyl-4-chlorophenyl), -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(NH2)-4-chlorophenyl, -CH(NH2)-4-fluorophenyl - 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 )-(2,4-difluorophenyl), - CH(NH ₂ )-(3-methyl-4- chlorophenyl), -CH(NH2)-(2-hydroxymethyl-4-chlorophenyl), - CH(NH2)-(2-aminomethyl-4- chlorophenyl), -CH(NH2)-(2-(methylaminomethyl)-4-chlorophenyl), -CH(NH2)-(2-hydroxymethyl- 4,5-difluorophenyl), -CH(NH ₂ )-(2-aminomethyl-4,5-difluorophenyl), -CH(NH ₂ )-(2- (methylaminomethyl)-4,5-difluorophenyl); R ⁷ is NH2, NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹² is methyl.

In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH ₂ )-4-chlorophenyl, R ⁷ is NH ₂ ; and R ¹² is methyl. In some preferred embodiments, compounds of Formula IIB-2 are those wherein R ¹ is -CH(F)-4- chlorophenyl or -CH(NH ₂ )-4-chlorophenyl, R ⁷ is NHC(O)N(CH ₃ ) _2. In other preferred embodiments, are compounds of Formula IIB-2 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH ₂ )-4- chlorophenyl; R ⁷ is cyclopropyl; and R ¹² is methyl. In yet other preferred embodiments, are compounds of Formula IIB-2 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH2)-4- chlorophenyl; R ⁷ is–Cl; and R ¹² is methyl.

In some aspects, the disclosure is directed to compounds of Formula IIB-2 wherein R ¹ is -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, or -C0-C6alk-S(O)2aryl; R ⁷ is NH2, NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹² is methyl. In some aspects, the disclosure is directed to compounds of Formula IIB-2 wherein R ¹ is -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, or -C0-C6alk-S(O)2aryl; R ⁷ is NH2, cyclopropyl, or–Cl; and R ¹² is methyl; wherein the -aryl is -4-chlorophenyl, -3,4- dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, 2,4- difluorophenyl, 3-methyl-4-chlorophenyl, 2-hydroxymethyl-4-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. In some embodiments, the compounds of Formula IIB-2 are those wherein R ¹ is -C ₀ -C ₆ alk-S-4-chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk-S(O)2-4-chlorophenyl; R ⁷ is NH2; and R ¹² is methyl. In some embodiments, the compounds of Formula IIB-2 are those wherein R ¹ is -C0-C6alk-S-4- chlorophenyl, -C ₀ -C ₆ alk-S(O)-4-chlorophenyl, or -C ₀ -C ₆ alk-S(O) ₂ -4-chlorophenyl; R ⁷ is

NHC(O)N(CH3)2; and R ¹² is methyl. In other embodiments, the compounds of Formula IIB-2 are those wherein R ¹ is -C0-C6alk-S-4-chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk- S(O)2-4-chlorophenyl; R ⁷ is cyclopropyl; and R ¹² is methyl. In yet other embodiments, the compounds of Formula IIB-2 are those wherein R ¹ is -C ₀ -C ₆ alk-S-4-chlorophenyl, -C ₀ -C ₆ alk-S(O)- 4-chlorophenyl, or -C ₀ -C ₆ alk-S(O) ₂ -4-chlorophenyl; R ⁷ is–Cl; and R ¹² is methyl.

In some aspects, the present disclosure is directed to compounds of Formula IV-1

wherein R ¹ is -C ₁ -C ₆ alk-aryl, -C ₀ -C ₆ alk-S-aryl, -C ₀ -C ₆ alk-S(O)aryl, or -C ₀ -C ₆ alk-S(O) ₂ aryl; R ⁷ is - NR ⁸ R ^8’ , -NHCONR ⁸ R ^8’ , -C1-C6alkyl, -C1-C4haloalkyl, halo, -C3-C6cycloalkyl, R ⁸ and R ^8’ are each independently H or -C1-C6alkyl; and R ¹⁰ is H or -C1-C6alkyl.

[0001] In other aspects, the disclosure is directed to compounds of Formula IV-1 wherein R ¹ is -C1-C6alk-aryl; R ⁷ is -NR ⁸ R ^8’ , -NHCONR ⁸ R ^8’ , -C1-C6alkyl, -C1-C4haloalkyl, halo, -C3- C6cycloalkyl; R ⁸ and R ^8’ are each independently H or -C1-C6alkyl; and R ¹⁰ is H or -C1-C6alkyl.

In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; R ⁷ is NH ₂ , NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or–Cl; and R ¹⁰ is H. In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -C0-C6alk-S-aryl; R ⁷ is NH2, NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or–Cl; and R ¹⁰ is H. In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -C ₀ -C ₆ alk-S(O)aryl; R ⁷ is NH ₂ , NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or–Cl; and R ¹⁰ is H. In yet other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -C0-C6alk-S(O)2aryl; R ⁷ is NH2, NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹⁰ is H.

In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -C1-C6alk-aryl; R ⁷ is NH2; and R ¹⁰ is H. In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -C ⁰

1-C6alk-aryl; R ⁷ is NHC(O)N(CH3)2; and R ¹ is H. In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -C ₁ -C ₆ alk-aryl; R ⁷ is

cyclopropyl; and R ¹⁰ is H. In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -C1-C6alk-aryl; R ⁷ is–Cl; and R ¹⁰ is H. In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is CH ₂ -4-fluorophenyl, -CH ₂ -phenyl, -CH ₂ -4-chlorophenyl, -CH ₂ -3,4-dichlorophenyl, -CH ₂ -3,4- difluorophenyl, -CH ₂ -3-fluoro-4-chlorophenyl, -CH ₂ -3-chloro-4-fluorophenyl, -CH ₂ -(2,4- difluorophenyl), - CH2-(3-methyl-4-chlorophenyl), -CH2-(2-hydroxymethyl-4-chlorophenyl), -CH2- (2-aminomethyl-4-chlorophenyl), -CH2-(2-(methylaminomethyl)-4-chlorophenyl), -CH2-(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)-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(OH)-(2,4-difluorophenyl), - CH(OH)-(3-methyl-4- chlorophenyl), -CH(OH)-(2-hydroxymethyl-4-chlorophenyl), - CH(OH)-(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)-4-fluorophenyl, - CH(F)-3,4-dichlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3- chloro-4-fluorophenyl, -CH(F)-(2,4-difluorophenyl), - CH(F)-(3-methyl-4-chlorophenyl), -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 )-4-fluorophenyl -CH(NH ₂ )-3,4-dichlorophenyl, -CH(NH ₂ )-3,4- difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH2)-3-chloro-4-fluorophenyl, -CH(NH2)- (2,4-difluorophenyl), - CH(NH2)-(3-methyl-4-chlorophenyl), -CH(NH2)-(2-hydroxymethyl-4- chlorophenyl), - CH(NH ₂ )-(2-aminomethyl-4-chlorophenyl), -CH(NH ₂ )-(2-(methylaminomethyl)-4- chlorophenyl), -CH(NH ₂ )-(2-hydroxymethyl-4,5-difluorophenyl), -CH(NH ₂ )-(2-aminomethyl-4,5- difluorophenyl), -CH(NH2)-(2-(methylaminomethyl)-4,5-difluorophenyl), -CH(Me)-4- chlorophenyl, -CH(Me)-4-fluorophenyl, -CH(Me)-3,4-dichlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3-chloro-4-fluorophenyl, -CH(Me)-(2,4- difluorophenyl), - CH(Me)-(3-methyl-4-chlorophenyl), -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), -CH(Me)-(2-(methylaminomethyl)-4,5-difluorophenyl), -C(Me)(OH)-4- chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4-chlorophenyl), -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), or -C(Me)(OH)-(2-(methylaminomethyl)-4,5- difluorophenyl); R ⁷ is -NR ⁸ R ^8’ , -NHCONR ⁸ R ^8’ , -C ₁ -C ₆ alkyl, -C ₁ -C ₄ haloalkyl, halo, or -C ₃ - C6cycloalkyl; R ⁸ and R ^8’ are each independently H or -C1-C6alkyl; and R ¹⁰ is H.

In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH ₂ -phenyl,–CH ₂ -4-fluorophenyl, or–CH ₂ -4-chlorophenyl; R ⁷ is NH ₂ , NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or–Cl; and R ¹⁰ is H. In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH2-phenyl,–CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; R ⁷ is NH2; and R ¹⁰ is H. n some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH ₂ - phenyl,–CH ₂ -4-fluorophenyl, or–CH ₂ -4-chlorophenyl; R ⁷ is NHC(O)N(CH ₃ ) _2; and R ¹⁰ is H. In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH2-phenyl,– CH2-4-fluorophenyl, or–CH2-4-chlorophenyl; R ⁷ is cyclopropyl; and R ¹⁰ is H. In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH ₂ -phenyl,–CH ₂ -4- fluorophenyl, or–CH2-4-chlorophenyl; R ⁷ is -Cl; and R ¹⁰ is H.

Other preferred embodiments are compounds of Formula IV-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -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(OH)-(2,4-difluorophenyl), - CH(OH)-(3-methyl-4-chlorophenyl), -CH(OH)-(2-hydroxymethyl- 4-chlorophenyl), - CH(OH)-(2-aminomethyl-4-chlorophenyl), -CH(OH)-(2-(methylaminomethyl)-4- chlorophenyl), -CH(OH)-(2-hydroxymethyl-4,5-difluorophenyl), -CH(OH)-(2-aminomethyl-4,5- difluorophenyl), or -CH(OH)-(2-(methylaminomethyl)-4,5-difluorophenyl), R ⁷ is NH2,

NHC(O)N(CH ₃ ) ₂ , cyclopropyl, or–Cl; and R ¹⁰ is H.

In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3,4-difluorophenyl, R ⁷ is NH2; and R ¹⁰ is H. In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3,4-difluorophenyl, R ⁷ is NHC(O)N(CH3)2; and R ¹⁰ is H. In other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or -CH(OH)-3,4- difluorophenyl, R ⁷ is cyclopropyl; and R ¹⁰ is H. In yet other preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, or - CH(OH)-3,4-difluorophenyl, R ⁷ is–Cl; and R ¹⁰ is H.

Other preferred embodiments are compounds of Formula IV-1 are those wherein R ¹ is -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-4-fluorophenyl, -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)-(2,4-difluorophenyl), - C(Me)(OH)-(3-methyl-4-chlorophenyl), - 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), or -C(Me)(OH)-(2- (methylaminomethyl)-4,5-difluorophenyl), R ⁷ is NH2, NHC(O)N(CH3)2,or cyclopropyl, or–Cl; and R ¹⁰ is H.

In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -–C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or–C(Me)(OH)-3,4- difluorophenyl, R ⁷ is NH2; and R ¹⁰ is H. In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -–C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or– C(Me)(OH)-3,4-difluorophenyl, R ⁷ is NHC(O)N(CH3)2; and R ¹⁰ is H. In other preferred embodiments, compounds of Formula IIB-1 are those wherein R ¹ is–C(Me)(OH)-4-chlorophenyl, - C(Me)(OH)-3,4-dichlorophenyl, or–C(Me)(OH)-3,4-difluorophenyl; R ⁷ is cyclopropyl; and R ¹⁰ is H. In yet other preferred embodiments, are compounds of Formula IV-1 are those wherein R ¹ is– C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, or–C(Me)(OH)-3,4-difluorophenyl, R ⁷ is–Cl; and R ¹⁰ is H.

Other preferred embodiments are compounds of Formula IV-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl, -CH(F)-4-fluorophenyl, -CH(F)-3,4-dichlorophenyl, -CH(F)-3,4- difluorophenyl, -CH(F)-3-fluoro-4-chlorophenyl, -CH(F)-3-chloro-4-fluorophenyl, -CH(F)-(2,4- difluorophenyl), - CH(F)-(3-methyl-4-chlorophenyl), -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 )-4-fluorophenyl - CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4-difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, - CH(NH2)-3-chloro-4-fluorophenyl, -CH(NH2)-(2,4-difluorophenyl), - CH(NH2)-(3-methyl-4- chlorophenyl), -CH(NH2)-(2-hydroxymethyl-4-chlorophenyl), - CH(NH2)-(2-aminomethyl-4- chlorophenyl), -CH(NH ₂ )-(2-(methylaminomethyl)-4-chlorophenyl), -CH(NH ₂ )-(2-hydroxymethyl- 4,5-difluorophenyl), -CH(NH ₂ )-(2-aminomethyl-4,5-difluorophenyl), -CH(NH ₂ )-(2- (methylaminomethyl)-4,5-difluorophenyl); R ⁷ is NH2, NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹⁰ is H.

In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH2)-4-chlorophenyl, R ⁷ is NH2; and R ¹⁰ is H. In some preferred embodiments, compounds of Formula IV-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or - CH(NH ₂ )-4-chlorophenyl, R ⁷ is NHC(O)N(CH ₃ ) ₂ ; and R ¹⁰ is H. In other preferred embodiments, are compounds of Formula IV-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH ₂ )-4- chlorophenyl; R ⁷ is cyclopropyl; and R ¹⁰ is H. In yet other preferred embodiments, are compounds of Formula IV-1 are those wherein R ¹ is -CH(F)-4-chlorophenyl or -CH(NH ₂ )-4-chlorophenyl; R ⁷ is –Cl; and R ¹⁰ is H.

In some aspects, the disclosure is directed to compounds of Formula IV-1 wherein R ¹ is -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, or -C0-C6alk-S(O)2aryl; R ⁷ is NH2, NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹⁰ is H. In some aspects, the disclosure is directed to compounds of Formula IV-1 wherein R ¹ is -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, or -C0-C6alk-S(O)2aryl; R ⁷ is NH2, NHC(O)N(CH3)2, cyclopropyl, or–Cl; and R ¹⁰ is H; wherein the -aryl is -4-chlorophenyl, -3,4- dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, 2,4- difluorophenyl, 3-methyl-4-chlorophenyl, 2-hydroxymethyl-4-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. In some embodiments, the compounds of Formula IV-1 are those wherein R ¹ is -C ₀ -C ₆ alk-S-4-chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk-S(O)2-4-chlorophenyl; R ⁷ is NH2; and R ¹⁰ is H. In some embodiments, the compounds of Formula IV-1 are those wherein R ¹ is -C ₀ -C ₆ alk-S-4- chlorophenyl, -C ₀ -C ₆ alk-S(O)-4-chlorophenyl, or -C ₀ -C ₆ alk-S(O) ₂ -4-chlorophenyl; R ⁷ is

NHC(O)N(CH3)2; and R ¹⁰ is H. In other embodiments, the compounds of Formula IV-1 are those wherein R ¹ is -C0-C6alk-S-4-chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk-S(O)2-4- chlorophenyl; R ⁷ is cyclopropyl; and R ¹⁰ is H. In yet other embodiments, the compounds of Formula IV-1 are those wherein R ¹ is -C0-C6alk-S-4-chlorophenyl, -C0-C6alk-S(O)-4-chlorophenyl, or -C0-C6alk-S(O)2-4-chlorophenyl; R ⁷ is–Cl; and R ¹⁰ is H. References to Formula I, Formula II, Formula III, or Formula IV herein include all subgenera described herein, including, for example, IIA-1, IIB-1, IIB-2, and IV-1.

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

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.

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

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.

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.

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.

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%, 11.50%, 11.25% 11%, 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.

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.

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 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

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 g, 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 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 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 g, 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.

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 exemplary 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.

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.

Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same. Pharmaceutical compositions for oral administration.

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.

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.

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 non- aqueous 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 all 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.

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.

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

disintegrating 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.

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 pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

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. 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, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

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 oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn 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.

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.

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.

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.

A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic 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.

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.

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.

Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, 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.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine,

lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2- lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters 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 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; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene- polyoxypropylene 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.

Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, 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, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 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.

Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated 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; polyoxyethylated 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.

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.

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, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose 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-alkylcaprolactam,

dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N- hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

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 solubilizers 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.

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

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, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, 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, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic 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.

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, alginic 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, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic 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. Pharmaceutical compositions for injection.

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.

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, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

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, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

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.

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.

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.

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.

Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, 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.

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.

The construction and use of transdermal patches for the delivery 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.

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.

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 Drug 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 Hill, 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.

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.

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.

In some embodiments, a compound of the invention is administered in a single dose.

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.

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.

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.

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.

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 wall 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, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO- PLLA); polydimethylsiloxane, 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 intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.

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.

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.

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.

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 be 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.

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

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.

As used herein, the term "IC ₅₀ " 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, cell 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.

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 nM 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 nM or less, 550 nM or less, 600 nM 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 μΜ or less, 1.8 μΜ or less, 1.9 μΜ or less, 2 μΜ or less, 5 μΜ or less, 10 μΜ or less, 15 μΜ or less, 20 μΜ or less, 25 μΜ or less, 30 μΜ or less, 40 μΜ or less, 50 μΜ, 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).

In some embodiments, the PRMT5 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 above) than its IC50 value against one, two, or three other PRMTs.

In some embodiments, the PRMT5 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 μΜ, 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.

The subject methods are useful for treating a disease condition associated with PRMT5. Any disease condition that results directly or indirectly from an abnormal activity or expression level of PRMT5 can be an intended disease condition.

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

hemoglobinopathies.

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-cell lymphoma, 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,

Endodermal 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, Gonadoblastoma, 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), Hemangioblastoma, 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, Lymphoepithelioma, 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, Oligoastrocytoma, 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 cell 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 Cell 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,

Supratentorial 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 prolymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell 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.

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.

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.

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-thalassemia and sickle cell disease (SCD).

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.

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

Compounds of the disclosure include, for example, the compounds identified in Table A. TABLE A          

          Synthesis of Intermediates

Synthesis of Int-1

Int-1.7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a-te trahydro-3aH- cyclopenta[d][1,3]dioxol-4-yl]-5-bromo-4-chloro-pyrrolo[2,3- d]pyrimidine (Int-1) To (3aR,4S,6R,6aS)-2,2,6-trimethyl-4,5,6,6a-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-4-ol; ethylene(Int-1-2) (J. Org. Chem., 2004, vol.69, 3993 - 3996 ) (1.09g, 5.43 mmol) in 25 mL of anhydrous THF under an atmosphere of nitrogen at 0 °C was added the triphenylphosphane (2871.8 mg, 10.95 mmol) and isopropyl (NE)-N-isopropoxycarbonylimin Carbamate (2.0 mL, 10.1 mmol) dropwise. The reaction mixture was stirred for 30 mins and to this was added the 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Int-1-1) (1816 mg, 7.81 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 12 h, followed by heating at 50 °C for additional 8 h. The reaction mixture was concentrated under vacuum and the crude mixture was purified by silica gel chromatography using a 80 g Agela silica gel column and gradient of 0-50% EtOAc in hexane over 40 mins to give 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-5-bro mo-4-chloro-pyrrolo[2,3-d]pyrimidine (Int-1) (1.7 g, 4.3 mmol, 78.6% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.35 (s, 1H), 5.94 (ddd, J = 17.2, 10.3, 6.9 Hz, 1H), 5.24– 5.09 (m, 1H), 5.03 (ddd, J = 11.9, 7.0, 5.2 Hz, 1H), 4.92 (dd, J = 7.4, 5.2 Hz, 1H), 4.62– 4.52 (m, 1H), 2.82 (dq, J = 13.0, 6.6 Hz, 1H), 2.47 (dt, J = 13.2, 6.7 Hz, 1H), 2.40– 2.22 (m, 1H), 1.58 (s, 3H), 1.31 (s, 3H). Synthesis of Int-2a and Int-2b

Int-2a isomer 1 Int-2b isomer 2

Stepe 1: Synthesis of (3aS,4R,6S,6aR)-4-(5-bromo-4-chloro-pyrrolo[2,3-d]pyrimidin- 7-yl)-2,2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxole-6 -carbaldehyde (Int-2-1)

To 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a-tetrahydro- 3aH- cyclopenta[d][1,3]dioxol-4-yl]-5-bromo-4-chloro-pyrrolo[2,3- d]pyrimidine (Int-1, 1.01g, 2.52 mmol) dissolved in MeOH (40 mL) and H ₂ O (20 mL), and sodium;periodate (2156.7mg, 10.1 mmol) was added. After the mixture was cooled to 0 °C, osmium tetraoxide, REAGENTPLUS (14.7mg, 0.06 mmol) was added. The reaction was stirred at the same temperature for 1 h and then at room temperature for 2 h. The white solid that resulted was removed by filtration and the filtrate removed at ambient temperature. Methylene chloride (200 mL) was added to the residue and the organic solution washed with H2O (30 mL) and brine (30 mL) and dried (MgSO4). The crude was purified by silica gel chromatography using 0-30% EtOAc in hexane to give (3aS,4R,6S,6aR)-4-(5- bromo-4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4, 5,6,6a-tetrahydro-3aH- cyclopenta[d][1,3]dioxole-6-carbaldehyde (Int-2-1) (300 mg, 0.75 mmol, 29.7% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 9.87 (d, J = 0.7 Hz, 1H), 8.59 (s, 1H), 7.29 (s, 1H), 5.19 (dd, J = 6.5, 4.4 Hz, 1H), 5.13– 4.89 (m, 2H), 3.26– 3.05 (m, 1H), 2.76– 2.47 (m, 2H), 1.58 (s, 3H), 1.31 (s, 3H).

Step 2: Synthesis of ((3aR,4R,6R,6aS)-6-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimi din-7-yl)- 2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)(4-c hlorophenyl)methanol (Int-2a isomer 1 and Int-2b isomer 2)

To (3aS,4R,6S,6aR)-4-(5-bromo-4-chloro-pyrrolo[2,3-d]pyrimidin- 7-yl)-2,2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxole-6 -carbaldehyde (Int-2-1, 100.mg, 0.2500 mmol) in 10 mL of anhydrous THF under an atmosphere of nitrogen at -76 °C was added Bromo(4-chlorophenyl)magnesium (0.5mL, 0.5000 mmol) dropwise and stirred for 1h. The reaction was slowly warmed to 0 °C and stirred for an additional 1h, quenched by addition of saturated ammonium chloride and stirred for 10 mins. The reaction was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography using 0-50% EtOAc in hexane to give ((3aR,4R,6R,6aS)-6-(5-bromo-4- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahyd ro-4H-cyclopenta[d][1,3]dioxol-4- yl)(4-chlorophenyl)methanol (Int-2b isomer 2) (40 mg, 0.076 mmol, 30% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 7.40 (s, 1H), 7.30 (d, J = 2.5 Hz, 4H), 5.10 (d, J = 3.7 Hz, 1H), 4.98 (dtd, J = 11.3, 5.0, 2.5 Hz, 1H), 4.89– 4.84 (m, 2H), 2.63– 2.51 (m, 1H), 2.36 (dt, J = 13.2, 11.3 Hz, 1H), 2.19– 2.08 (m, 1H), 1.57 (s, 3H), 1.31 (s, 3H). The less polar isomer (Int-2a isomer 1) (30 mg, 0.059 mmol, 23% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 7.31 (s, 5H), 5.00 (dd, J = 7.3, 5.9 Hz, 1H), 4.92– 4.80 (m, 2H), 4.69 (d, J = 8.3 Hz, 1H), 2.53 (dtd, J = 12.3, 7.5, 5.0 Hz, 1H), 2.20 (dt, J = 13.1, 12.0 Hz, 1H), 2.12– 1.97 (m, 2H), 1.59 (s, 3H), 1.32 (s, 3H). Synthesis of Int-3

Step1: Synthesis of compound Int-3-2

To a suspension of copper(I) Bromide-Dimethyl Sulfide (56.7 mg, 0.28 mmol) in THF (20.0 mL) at -78 °C was added benzylchloromagnesium (1.4 M in THF, 5.2 mL, 7.3 mmol) dropwise. After the addition, the mixture was stirred at -78 °C for 10 min. To this solution was added a solution of (3aR,6aR)-3a,6a-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxo l-4-one (Int-3- 1) (500.0 mg, 3.24 mmol), chlorotrimethylsilane (0.8 mL, 6.58 mmol) and HMPA (1.5 mL, 8.34 mmol) in THF (20 mL) dropwise. The reaction was completed after 3 h at -78 °C under N2. The reaction mixture was quenched by brine (5 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give a crude product which was purified by silica gel chromatography eluted with EtOAc/petroleum ether = 1:50 to 1:20 to afford Int-3-2 (670.0 mg, 55.1%) as a colorless oil. ¹ H NMR(400 MHz, CDCl3) δ 6.90-7.20 (m, 5H), 4.52-4.86 (m, 1H), 4.13-4.37 (m, 1H), 2.70-2.73 (m, 1H), 2.53-2.59 (m, 1H), 2.30-2.37 (m, 1H), 1.23-1.35 (m, 2H), 1.10 (s, 3H), 1.05 (s, 3H). Step 2: Synthesis of compound Int-3-3

To a solution of Int-3-2 (660.0 mg, 1.88 mmol) in THF (15 mL) was added LiAlH ₄ (128.1 mg, 3.38 mmol) at 0 °C. The reaction mixture was stirred at 0 °C. After 3h, the reaction was completed (monitored by LC-MS). The reaction was quenched with water (5.0 mL) and NaOH aqueous solution (15%, 5.00 mL). The mixture was stirred for 30 min and filtered. The filtrate was concentrated in vacuum to give a crude product which was purified by silica gel chromatography eluted with EtOAc/petroleum ether = 1:20 to 1:10 to afford Int-3-3 (330.0 mg, 0.66 mmol) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10-7.39 (m, 5H), 4.59-4.61 (m, 1H), 4.45-4.55 (m, 1H), 4.39-4.41(m, 1H), 4.09-4.19 (m, 2H), 2.80-2.42 (m, 2H), 2.01-2.09 (m, 1H), 1.67-1.78 (m, 2H), 1.58 (s, 3H), 1.43 (s, 3H). Step 3: Synthesis of compound Int-3

To a solution of Int-3-3 (165.0 mg, 0.66 mmol, 1.0 eq) in DCM (15.0 mL) was added trifluoromethane-sulfonic anhydride (281.2 mg, 1.0 mmol) and pyridine (1.0 mL) at 25 °C. The reaction mixture was stirred at 25 °C. After 30 min, the reaction was completed (monitored by LC-MS). The reaction mixture was diluted with DCM (100.0 mL) and washed with brine. The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuum to give a crude product, which was purified by silica gel chromatography eluted with EtOAc/petroleum ether = 1:20 to afford Int-3 (220.0 mg, 0.29 mmol, 43.5%) as a colorless oil. ¹ H NMR(400 MHz, CDCl3) δ 7.14- 7.36 (m, 5H), 4.91-5.02 (m, 1H), 4.59-4.65 (m, 2H), 4.43-4.44 (m, 1H), 4.13-4.15 (m, 1H),2.70-2.78 (m,1H), 2.01-2.27 (m, 1H), 1.84-1.88 (m, 1H), 1.57 (s, 3H), 1.43 (s, 3H). Synthesis of Int-4 Step 1: Synthesis of compound Int-4-1

To a suspension of copper(I) Bromide-Dimethyl Sulfide (21 mg, 0.10 mmol) in THF (8.0 mL) at -78 °C was added (4-chlorobenzyl)magnesium bromide (0.5 M in THF, 3.0 mL,1.5 mmol) dropwise. The mixture was stirred at -78 °C for 10 min before a solution of (3aR,6aR)-3a,6a- di

hydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (Int-3-1) (154 mg, 1.0 mmol), chlorotrime thylsilane (0.25 mL, 2.0 mmol) and HMPA (0.46 mL, 2.6 mmol) in THF (2.0 mL) was added dropwise. The reaction mixture was stirred at -78 °C under N2. After 3 h the reaction was warmed to rt gradually. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and diluted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give a crude product, which was purified by silica gel chromatography eluted with EtOAc/petroleum ether = 1:20 to 1:10 to afford Int-4-1 (246 mg, 0.87 mmol, 87.00%) as a colorless oil. Step 2:Synthesis of compound Int-4-2

To a suspension of LiAlH ₄ (50 mg, 1.3 mmol) in THF (5.0mL) was added a solution of Int-4-1 (246 mg, 0.87 mmol, 1.00 eq) in THF (1mL) dropwise at 0 °C, then stirred overnight. After the reaction was completed, it was quenched with water (5.0 mL) and NaOH aqueous solution (15%, 5.0 mL). The reaction mixture was stirred for 30 min and filtered. The filtrate was concentrated in vacuum to give a crude product, which was purified by silica gel chromatography eluted with EtOAc/petroleum ether = 1:10 to 1:6 to afford Int-4-2 (90 mg, 0.32 mmol, 37%) as a colorless oil. Step 3:Synthesis of compound Int-4

To a solution of Int-4-2 (90.00 mg, 0.32 mmol) in DCM (15.00 mL) was added trifluoromethane

-sulfonic anhydride (135.00 mg, 0.48 mmmol) and pyridine (0.30mL) at 25 °C. The reaction mixture was stirred at 25 °C. After 30 min the reaction was completed (monitored by TLC). The reaction mixture was diluted with DCM (100 mL), which was washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a crude product which was purified by silica gel chromatography eluted with EtOAc/petroleum ether = 1:10 to afford Int-4 (70.00 mg, 0.17 mmol, 52.80%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.30 (m, 2H), 7.08-7.10 (m, 1H), 5.00-5.04 (m, 1H), 4.64-4.66 (m, 1H), 4.38-4.40 (m, 1H), 2.70-2.74 (m, 1H), 2.46-2.54 (m, 2H), 2.24-2.31 (m, 1H), 1.79-1.85 (m,1H), 1.55 (s, 3H), 1.52 (s, 3H). ¹⁹ F NMR (400 MHz, CDCl3) δ -75.18. Synthesis of Int-5 Step 1: Synthesis of compound Int-5-1

To a suspension of copper(I) Bromide-Dimethyl Sulfide (80 mg) in THF (10 mL) at -78 °C was added 4-fluorobenzylmagnesium chloride solution (0.33 M in THF, 24 mL, 8 mmol). The mixture was stirred for 10 min before a solution of Int-3-1 (616 mg, 4 mmol), TMSCl (1 mL, 8.1 mmol) and HMPA (1.8 mL, 10.3 mmol) in THF (5 mL) was added. The mixture was stirred at - 75 °C for 3 h, and then warmed to 0 °C. Sat.aq.NH4Cl (10 mL) was added to quench the reaction. After stirred for 10 min, the mixture was extracted with ethyl acetate (25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc = 3:1 to afford Int-5-1 (480 mg, 1.82 mmol, 45%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.98-7.35 (m, 4H), 4.56-4.67 (m, 1H), 4.15-4.16 (m, 1H), 2.69-2.67 (m, 3H), 2.46- 2.52 (m, 1H), 2.04-2.08 (m, 1H), 1.49 (s, 3H), 1.36 (s, 3H). Step 2: Synthesis of compound Int-5-2

To a solution of Int-5-1 (480 mg, 1.82 mmol) in anhydrous THF (10 mL) at 0 °C was added LiAlH4 (100 mg, 2.63 mmol). The mixture was stirred at 0 °C for 1 h. TLC showed Int- 5-1 was consumed. Water (0.5 mL) was added to quench the reaction. MgSO4 was added, and then the mixture was stirred for 10 min. After standing for 1 h, the mixture was filtered. The filtrate was concentrated in vacuo to afford Int-5-2 (450 mg, 1.69 mmol, 93%) as a colorless oil, which was carried over to the next step without further purification. Step 3: Synthesis of compound Int-5

To a solution of Int-5-2 (450 mg, 1.69 mmol) and pyridine (270 mg, 3.4 mmol) in DCM (10 mL) at 0 °C was added Tf ₂ O (620 mg, 2.2 mmol). The mixture was stirred at 0 °C for 1 h, quenched with aq. NaHCO3 (15 mL). The water layer was extracted with DCM (25 mL). The combined organic layers were washed with water, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, purified by silica gel chromatography eluted with petroleum ether: EtOAc = 5:1 to afford Int-5 (210 mg, 0.53 mmol, 31%) as a colorless oil. ¹ H NMR (400 MHz, CDCl3) δ 6.93-7.03 (m, 4H), 4.69-4.73 (m, 2H), 4.63-4.66 (m, 1H), 4.39-4.40 (m, 3H), 3.49-3.50 (m, 1H), 2.47-2.73 (m, 2H), 2.23-2.28 (m, 1H), 1.36 (s, 3H), 1.32 (s, 3H). Synthesis of Int-6

Step 1: Synthesis of compound Int-6-1

To a solution of compound Int-1-2 (2.5 g, 13.6 mmol, prepared according to J. Org. Chem., 2004, vol.69, 3993 - 3996 ) in DCM (10 mL) was added the imidazole (1.85 g, 27.1 mmol) and TBDPSCl (5.6 g, 20 mmol), then the mixture was stirred at 25 °C for 2h. TLC (PE: EtOAc=10:1) showed the starting materials was consumed completed and a new spot was detected. The reaction was concentrated to dryness and the residue was diluted with EtOAc (100 ml), which was washed with water (50 ml×2) and brine (40 ml). The combined organic layers were dried over Na ₂ SO ₄ before concentration to dryness. The residue was purified by flash column chromatography (PE: EtOAc = 40:1 to 20:1) to afford Int-6-1 (5.6 g, 13.25 mmol, 97.6 %) as a colorless oil. ¹ H NMR (400 MHz, CDCl3): δ 7.76-7.71(m, 4 H) , 7.43-7.35(m, 6 H), 5.57-5.49(m, 1 H), 4.83 (d, 1 H), 4.74 (d, 1 H), 4.27-4.21 (m, 2 H), 4.04-3.99 (m, 1 H), 2.56 (t, 1 H) , 2.08-2.00 ( m, 1 H), 1.59-1.52 (m, 1H), 1.59 (s, 3 H), 1.30 (s, 3 H), 1.07(s, 9 H).

Step 2: Synthesis of compound Int-6-2

To a solution of compound Int-6-1 (5.6 g, 13 mmol) in THF (100 mL) and H2O (50 mL) was added NMO (2.3 g, 20 mmol) and K ₂ OsO ₄ ·2H ₂ O (488 mg, 1.33 mmol), then the reaction was stirred at 25 °C overnight. TLC (PE: EtOAc=1:1) showed the starting materials was consumed completely and a new spot was detected. EtOAc (20 mL) was added to the mixture and the organic layer was washed with saturated Na ₂ SO ₃ solution (2 mL) and brine (10 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated in vacuo to afford a residue. The residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc = 3:1 to 1:1 to afford Int-6-2 (4.6 g, 9.44 mmol, 71.25%) as a colorless oil. LCMS [M+23] 479.2; ¹ H NMR (400 MHz, CDCl3): δ 7.76-7.71 (m, 4 H), 7.44-7.35 (m, 6 H), 4.28-4.11 (m, 3H), 3.50-3.33 (m, 3H), 2.10-2.04 (m, 1 H), 1.94-1.88 (m, 1 H), 1.58-1.52 (m, 1H), 1.54 (s, 3 H), 1.31 (s, 3 H), 1.08 (s, 9 H).

Step 3: Synthesis of compound Int-6-3

To a solution of compound Int-6-2 (4.6 g, 10. mmol) in THF (50 mL) and water (25 mL) was added NaIO4 (6.46 g, 30.2 mmol), then the mixture was stirred at 25 °C for 2 h. TLC (PE:EtOAc=3:1) showed the starting materials was consumed and a new spot was detected. The mixture was poured into EtOAc (100 ml) and the organic layer was washed with water (50 ml×2) and brine (50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude Int-6-3 (4.0 g, 9.42 mmol, 93.52%) as a colorless oil, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.47(s, 1 H), 7.74-7.68(m, 4 H), 7.45-7.34(m, 6 H), 4.70 (d, 1 H), ,4.18-4.13(m, 1 H), 3.81-3.76(m, 3H), 2.77 (d, 1 H), 3.50-3.33 (m, 3H), 2.16-2.04 (m, 1 H), 1.92-1.88 (m, 1 H), 1.53 (s, 3 H), 1.30 (s, 3 H), 1.07 (s, 9 H).

Step 4: Synthesis of compound Int-6-4

To a solution of compound Int-6-3 (4.0 g, 9.42 mmol) in dry THF (20 mL) was added Bromo (4-chlorophenyl)magnesium (1M in THF, 47.1 mL, 47.1 mmol), then the reaction was stirred at 25 °C for 1 h. TLC (PE:EtOAc=3:1) showed the starting material was consumed completely and a new spot was detected. H2O (1 ml) was added to the reaction mixture to quench the reaction and the mixture was diluted with EtOAc (50 ml), washed with H ₂ O (40 ml×2) and brine (30 ml×2). The organic layer was separated and dried over Na ₂ SO ₄ before concentration to dryness. The residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc = 5:1 to 3:1 to afford Int-6-4 (3.5 g, 6.52 mmol, 69.17%) as a white solid. ¹ H NMR (400 MHz, CDCl3): δ 7.75-7.68 (m, 4 H), 7.46-7.30 (m, 6 H), 7.24-6.97 (m, 4 H), 4.63-4.55 (m, 1 H), 4.38-4.03(m, 3 H), 2.25-2.23 (m, 1H), 1.83-1.75 (m, 2H), 1.54 (s, 3 H, two peaks from epimers), 1.31 (s, 3 H, two peaks from epimers), 1.03 (s, 9 H, two peaks from epimers).

Step 5: Synthesis of compound Int-6-5

To a solution of compound Int-6-4 (3.5 g, 6.52 mmol) in toluene (100 mL) was added PPh3 (2.56 g, 9.77 mmol), 4-phenylbenzoic acid (1.94 g, 9.77 mmol), DIAD (1.98 g, 9.77 mmol) at 0 °C, then the mixture was stirred at 20 °C for 2 h. TLC (PE:EtOAc=10:1) showed the starting materials was consumed completely and a new spot was detected. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc = 30:1 to 20:1 to afford Int-6-5 (4.60 g, 6.41 mmol, 98.4%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.25-7.01 (m, 23 H), 5.85-5.37 (m, 1 H), 4.45-4.27 (m, 2 H), 4.14-4.09 (m, 1 H), 2.54-2.49 (m, 1 H), 2.04-1.97 (m, 1H), 1.67-1.63 (m, 1H), 1.56 (s, 3 H, two peaks from epimers), 1.28 (s, 3 H, two peaks from epimers), 1.04 (s, 9 H, two peaks from epimers). Step 6: Synthesis of compound Int-6-6

To a solution of compound Int-6-5 (4.60 g, 6.41 mmol) in THF (20 mL) was added tetrabutylammonium fluoride (1 M in THF, 32 mL, 32 mmol), then the mixture was stirred at 25 °C overnight. TLC (PE:EtOAc=3:1) showed the starting materials was almost consumed completely. The solution was concentrated in vacuo and purified by silica gel chromatography eluted with petroleum ether: EtOAc =10:1 to 5:1 to afford Int-6-6 (1.60 g, 3.34 mmol, 52.1%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13-7.26 (m, 13 H), 6.11-5.73 (m, 1 H), 4.63-4.46 (m, 2 H), 4.29- 4.11 (m, 1 H), 2.78-2.75 (m, 1 H), 2.50-2.39 (m, 1H), 2.04-1.91(m, 1H), 1.53 (s, 3 H, two peaks from epimers), 1.33 (s, 3 H, two peaks from epimers).

Step 7: Synthesis of compound Int-6

To a solution of compound Int-6-6 (1.60 g, 3.34 mmol) in DCM (20 mL) was added the pyridine (1.4 mL, 16.7 mmol), then Tf2O (1.41 g, 5.01 mmol) was added slowly to the mixture and stirred at rt for 2 h. TLC (PE:EtOAc=10:1) showed the starting materials was consumed and a new spot was detected. The mixture was purified by silica gel chromatography eluted with petroleum ether: EtOAc =20:1 to 10:1 to give the desired product Int-6 (1.80 g, 2.95 mmol, 88.2%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.13-7.28 (m, 13 H), 6.16-5.82 (m, 1 H), 5.34-5.07 (m, 1 H), 4.72-4.54 (m, 2 H), 2.84-2.82 (m, 1 H), 2.34-2.12 (m, 2H), 1.53 (s, 3 H, two peaks from epimers), 1.31 (s, 3 H, two peaks from epimers).

Synthesis of 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfanyl-2,2-dimethyl-4 ,5,6,6a-tetrahydro- 3aH-cyclopenta[d][1,3]dioxol-6-yl]-4-chloro-pyrrolo[2,3-d]py rimidine (Int-7)

S _{tep 1. Preparation of Int-7-2}

To lithium;alumanuide (25.4mg, 0.67 mmol) in 5 mL of anhydrous THF at 0 oC was added the (3aR,6S,6aS)-6-(4-chlorophenyl)sulfanyl-2,2-dimethyl-3a,5,6, 6a- tetrahydrocyclopenta[d][1,3]dioxol-4-one (Int-7-1, prepared as described in Tetrahedron 65 (2009) 8007-8013) (100.mg, 0.33 mmol) dissolved in 5 mL of anhydrous THF and stirred for 1 h at 0 °C. The reaction was quenched by dropwise addition of saturated ammonium chloride, extracted with ethyl acetate. The organic layer was seperated, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatographyusing 0-30% EtOac in hexane to give (3aS,4S,6S,6aS)-4-(4-chlorophenyl)sulfanyl-2,2-dimethyl-4,5, 6,6a-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-6-ol (100 mg, 0.332 mmol, 99.3% yield). ¹ H NMR (400 MHz,

Chloroform-d) δ 7.28 (s, 4H), 4.60 (t, J = 5.4 Hz, 1H), 4.46 (d, J = 5.6 Hz, 1H), 4.31 (tt, J = 10.0, 5.5 Hz, 1H), 3.62– 3.54 (m, 1H), 2.35 (d, J = 9.6 Hz, 1H), 2.14 (ddd, J = 13.4, 10.1, 6.6 Hz, 1H), 2.08– 1.99 (m, 1H), 1.50 (s, 3H), 1.32 (s, 3H).

Step 2. Preparation of Int-7

To (3aR,4R,6S,6aR)-4-(4-chlorophenyl)sulfanyl-2,2-dimethyl-4,5, 6,6a-tetrahydro- 3aH-cyclopenta[d][1,3]dioxol-6-ol (Int-7-2) (0.08g, 0.27 mmol)in 10 mL of anhydrous THF under an atmosphere of nitrogen at 0 °C was added the triphenylphosphane (140.71mg, 0.54 mmol) and isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (0.1mL, 0.49 mmol) dropwise. The reaction mixture was stirred for 30 mins and to this was added the 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (58.79mg, 0.38 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. The reaction mixture was concentrated and the crude purified by silica gel chromatography using 0-30% EtOAc in hexane to 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfanyl- 2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxo l-6-yl]-4-chloro-pyrrolo[2,3- d]pyrimidine (Int-7) (0.07 g, 0.16 mmol, 60% yield) which was contaminated with some pyrrolopyrimidine side product. ¹ H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 7.40– 7.36 (m, 2H), 7.33 (d, J = 3.6 Hz, 1H), 7.31– 7.27 (m, 2H), 5.13– 4.93 (m, 2H), 4.75 (dd, J = 6.1, 4.6 Hz, 1H), 3.66 (ddd, J = 10.2, 7.1, 4.6 Hz, 1H), 2.81 (dt, J = 13.7, 6.8 Hz, 1H), 2.52– 2.34 (m, 1H), 1.63 (s, 3H), 1.59 (s, 3H). Synthesis of Int-8

S _{tep 1. Synthesis of [(3aR,4S,6R, 6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a-tetrahydro-3aH-} cyclopenta[d][1,3]dioxol-4-yl] trifluorometh-anesulfonate (Int-8-1)

To a mixture of (3aS,4S,6R,6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a-tetrahydro-3aH - cyclopenta[d][1, 3]dioxol-4-ol (Int-1-2) (2000.00 mg, 10.86 mmol, prepared according to J. Org. Chem., 2004, vol.69, 3993 - 3996) in DCM (20 mL) was added the pyridine (4293.55 mg, 54.28 mmol), then Tf ₂ O (4594.04 mg, 16.28 mmol) in DCM (10.00 mL) was added slowly to the mixture at 0 °C and the reaction was stirred for 0.5 hour at rt. TLC (PE: EA=10: 1) showed the start materials was consumed completely and a new spot was on TLC. The mixture was washed with NH ₄ Cl solution and the organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 22: 1) to give the desired product [(3aR,4S,6R, 6aR)- 2,2-dimethyl-6-vinyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1 ,3]dioxol-4-yl] trifluorometh- anesulfonate (Int-8-1) (2.89 g, 9.14 mmol, 84.17% yield) and used directly in the next step. Step 2. Synthesis of 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a-tetrahydro- 3aH- cyclopenta[d][1,3]dioxol-4-yl]-4-chloro-pyrrolo[2,3-d]pyrimi dine (Int-8-2)

To a solution of (4-chloropyrrolo[2,3-d]pyrimidin-7-yl)potassium (2166.92 mg, 11.31 mmol) in DMF (22.5 mL) was added [(3aR,4S,6R,6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl] trifluoromethanesulfonate (Int-8-1) (2.98 g, 9.42 mmol) in DMF (7.5 mL) dropwise at 0℃. Then the mixture was stirred at 25℃ for 16 hrs. LCMS showed Int-8-2 is the major product in the reaction mixture. The mixture was diluted by EA (300.00 mL), washed with H ₂ O (30.00 mL×5) and NaCl aqueous solution (50.00 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column (PE: EA=15: 1) to give the desired product 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4-chl oro-pyrrolo[2,3-d]pyrimidine (Int-8-2) (2.00 g, 6.13 mmol, 65.09% yield) as white solid. LCMS [M+H]: 320.1. Step 3. Synthesis of (3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2 -dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxole-6-carbalde hyde (Int-8)

To a mixture of 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a-tetrahydro- 3aH- cyclopenta [d][1,3]dioxol-4-yl]-4-chloro-pyrrolo[2,3-d] pyrimidine (Int-8-2) (1.6 g, 5.00 mmol) in acetone (25.0 mL), methanol (25.0 mL), water (25.0 mL) was added K ₂ OsO ₄ ·2H ₂ O (184.3 mg, 0.5 mmol) and NaIO ₄ (2140.3 mg, 10.01 mmol), then the mixture was stirred at 20℃ for 18 hrs. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in THF/H ₂ O (75.00 mL, v: v = 2: 1) and the NaIO ₄ (2140.0 mg) was added. The mixture was stirred at 25℃ for 1h. LCMS showed 39% Int-8 was in the mixture. The mixture was filtered and the aqueous phase was extracted with EA (50.0 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude (3aS,4R,6S,6aR)-4-(4- chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-te trahydro-3aH- cyclopenta[d][1,3]dioxole-6-carbaldehyde (Int-8) (2000 mg, 2.75 mmol, 55.06% yield, purity ~44%) was obtained. LCMS [M+H]: 322.1.

Examples Example 31. (1R,2S,3R,5S)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5 - benzylcyclo entane-12-diol 31

Int-3 ^{31a Ex. 31}

Step 1: Synthesis of 1-((3aS,4R,6S,6aR)-6-benzyl-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 -amine (31a)

To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (30.0 mg, 0.22 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 13.3 mg, 0.33 mmol) at 0 °C. After 30 min Int-3 (101.3 mg, 0.27 mmol) was added to the stirred reaction mixture. After 2 h, the reaction was completed and the mixture was diluted with DCM (100 mL), washed with brine (30 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a crude product, which was purified by silica gel chromatography eluted with petroleum ether: EtOAc =20:1 to DCM : MeOH = 20 :1 to afford 31a (60.0 mg, 0.10 mmol, 43.6%) as a colorless oil. LCMS [M+1] 366.2; ¹ H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.90 (s, 1H), 7.05-7.19 (m, 5H), 5.39-5.43 (m, 2H), 5.11-5.25 (m, 2H), 3.17-3.19 (m,1H), 2.48-2.62 (m, 1H), 2.20-2.23 (m, 1H), 2.04-2.07 (m, 1H), 1.59 (s, 3H), 1.32 (s, 3H)

Step 2: Synthesis of (1R,2S,3R,5S)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5 - benzylcyclopentane-1,2-diol (31)

To a solution of 31a (60.0 mg, 0.16 mmol) in water (1.0 mL) and MeCN (1.0 mL) was added TFA (1.0 mL). The reaction mixture was stirred at 40 °C. After 2 h, the reaction was completed and the mixture was adjusted to pH = 7.0 with Na2CO3 (aq.) and filtered, concentrated in vacuum to give a crude product which was purified by prep-HPLC (eluting with H ₂ O/CH ₃ CN (0.5 % NH ₄ HCO ₃ ) from 80:10 to 10: 90) to afford 31 (10.6 mg, 0.03 mmol, 19.8%) as a white solid. LCMS [M+1] 326.1;

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 (s,1H), 8.11 (s,1H), 7.66 (br, 2H), 7.17-7.27 (m, 5H), 4.93- 4.96 (m, 1H), 4.83 (s,1H), 4.70 (s,1H), 4.26 (s,1H), 3.77 (s,1H), 2.92-2.97 (m, 1H), 2.50-2.62 (m, 1H), 2.22-2.23 (m, 1H), 2.04-2.07 (m, 1H), 1.55-1.58 (m, 1H). ¹ H NMR (400 MHz, DMSO- d6+D2O) δ 8.12 (d, 2H, J = 3.2), 7.17-7.27 (m, 5H), 4.94-4.96 (m, 1H), 4.26 (s,1H), 3.76 (s,1H), 2.91-2.96 (m, 1H), 2.51-2.62 (m, 1H), 2.20-2.22 (m, 1H), 2.04-2.07 (m, 1H), 1.54-1.57 (m, 1H). Example 32. (1R,2S,3R,5S)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5 -(4- fluorobenz l c clo entane-12-diol 32

Step 1: Synthesis of 1-((3aS,4R,6S,6aR)-6-(4-fluorobenzyl)-2,2-dimethyltetrahydro -4H- cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 -amine (32a)

To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.3 mmol) in DMF (5 mL) at 0 °C was added NaH (60% in mineral oil, 20 mg, 0.5 mmol). The mixture was stirred at 0 °C for 0.5 h. Then Int-5 (100 mg, 0.25 mmol) was added. The mixture was warmed to 20 °C and stirred for 2 h. After quenched by water, the mixture was extracted with ethyl acetate (25 mL). The organic layer was washed with brine (25 mL), dried over MgSO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to afford 32a (75 mg, 0.19 mmol, 78%) as a colorless oil. LCMS [M+1] 384.2.

Step 2: Synthesis of (1R,2S,3R,5S)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5 -(4- fluorobenzyl)cyclopentane-1,2-diol (32)

To a solution of 32a (55 mg, 0.14 mmol) in MeCN (1 mL) and water (2 mL) was added TFA (1 mL, 13.4 mmol). The reaction mixture was stirred at 0 °C for 3 h. LCMS showed the reaction was completed. The reaction mixture was adjusted to pH = 7.0 with NaHCO ₃ (aq) and extracted with ethyl acetate (25 mL). The organic layer was washed with brine (25 mL), dried over MgSO4 and filtered. The filtrate was concentrated in vacuum to give crude 32. The crude 32 was purified by prep-HPLC, eluting with H ₂ O/CH ₃ CN (0.5 % NH ₄ HCO ₃ ) from 80:20 to 70:30 to obtained 32 (15.5 mg, 0.045 mmol, 31.4%) as a white solid. LCMS [M+1] 344.1. ¹ H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.10 (s, 1H), 7.54-7.75 (brs, 2H), 7.23-7.26 (m, 2H), 7.06-7.11 (m, 2H), 4.95 (m, 1H), 4.83 (d, J = 6.0 Hz, 1H), 4.69 (d, J = 5.2 Hz, 1H), 4.24 (q, J = 15.2, 5.6 Hz, 1H), 3.75 (q, J = 15.2, 5.4 Hz, 1H), 2.90-2.94 (m, 1H), 2.55-2.62 (m, 1H), 2.17-2.27 (m, 1H), 2.01-2.09 (m, 1H), 1.51-1.59 (m, 1H). ¹ H NMR(400 MHz , DMSO-d6+D2O) δ 8.14 (s, 1H), 8.13 (s, 1H), 7.23-7.27 (m, 2H), 7.05-7.11 (m, 2H), 4.95 (m, 1H), 4.25 (t, J = 6.0 Hz, 1H), 3.76 (t, J = 5.4 Hz, 1H), 2.90-2.95 (m, 1H), 2.55-2.62 (m, 1H), 2.17-2.27 (m, 1H), 2.01-2.08 (m, 1H), 1.51-1.58 (m, 1H). Example 33. (1R,2S,3R,5S)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5 -(4- chlorobenzyl)cyclopentane-1,2-diol (33)

Int-4 33a Ex.33 Step 1: Synthesis of 1-((3aS,4R,6S,6aR)-6-(4-chlorobenzyl)-2,2-dimethyltetrahydro -4H- cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4 -amine (33a)

To a solution of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (21 mg, 0.15 mmol) in DMF (2 mL) was added NaH (60% in mineral oil, 9.00 mg, 0.22 mmol) at 0 °C. Int-4 (63.00 mg, 0.15mmol) was added to the reaction mixture after 30 min. After 2 h, the reaction was completed (monitored by LC-MS). The reaction mixture was diluted with DCM (100 mL) and washed with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuum to give a crude 33a (70.00 mg) as a colorless oil, which was used in the next step without further purification.

Step 2: Synthesis of (1R,2S,3R,5S)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5 -(4- chlorobenzyl)cyclopentane-1,2-diol (33)

To a solution of crude 33a (70.00 mg) in water (2.00 mL) was added TFA (1.50 mL). The reaction mixture was stirred at 25 °C for 30 min and the reaction was completed

(monitored by LC-MS). The reaction mixture was adjusted to pH = 7.0 with Na ₂ CO ₃ (solid) and filtered. The filtrate was concentrated in vacuum to give a crude product which was purified by prep-HPLC (eluting with H2O/CH3CN (0.5 % NH4HCO3) from 80:10 to 10: 90) to afford 33 (16 mg, 0.04 mmol, 26%) as a white solid. LCMS [M+1] 360.1; ¹ H NMR (400 MHz, DMSO-d6) δ 8.12-8.14 (m, 2H), 7.32-7.34 (m,2H),7.24-7.26 (m, 2H), 4.92-4.98 (m,1H), 4.22-4.25 (m,1H), 3.74- 3.76 (m,1H), 2.90-2.95 (m,1H), 2.58-2.64 (m, 1H), 2.18-2.24 (m,1H), 2.03-2.10 (m, 1H), 1.51-1.59 (m, 1H). ¹ H NMR (400 MHz, DMSO-d6+D2O) δ 8.12-8.14 (m, 2H), 7.32-7.34 (m,2H),7.24-7.26 (m, 2H), 4.92-4.98 (m,1H), 4.22-4.25 (m,1H), 3.74-3.76 (m,1H), 2.90-2.95 (m,1H), 2.58-2.64 (m, 1H), 2.18-2.24 (m,1H), 2.03-2.10 (m, 1H), 1.51-1.59 (m, 1H). Example 39. (1R,2S,3R,5R)-3-(4-amino-5-bromo-pyrrolo[2,3-d]pyrimidin-7-y l)-5-vinyl- c clo entane-12-diol 39

Int-2b isomer 2 39a Ex. 39 Step 1: Synthesis of [(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2 -dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-(4-ch lorophenyl)methanol (39a) To [(3aS,4R,6R,6aR)-4-(5-bromo-4-chloro-pyrrolo[2,3-d]pyrimidin -7-yl)-2,2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-(4-chlorophenyl)methanol (Int-2b isomer 2) (170 mg, 0.33 mmol)in 2 mL of methanol was added the AMMONIA, CA.7N

SOLUTION IN METHANOL (2.8 mL, 19.8 mmol) heated at 80 °C for 16 h, cooled, and concentrated to give 165 mg of the crude [(3aS,4R,6R,6aR)-4-(4-amino-5-bromo-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclo penta[d][1,3]dioxol-6-yl]-(4- chlorophenyl)methanol, which was carried over to the next step without further purification.

To [(3aS,4R,6R,6aR)-4-(4-amino-5-bromo-pyrrolo[2,3-d]pyrimidin- 7-yl)-2,2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-(4-chlorophenyl)methanol (165.mg, 0.32 mmol) in 10 mL of anhydrous THF under an atmosphere of nitrogen at -76 °C was added n-butyllithium (0.81mL, 1.3 mmol, 1.6 M) and stirred for 30 mins. The reaction mixture was quenched with saturated ammonium chloride, warmed to room temperature, extracted with DCM. The DCM layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography on a 12 g Agela column, eluted with 0-10% MeOH in DCM to give [(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2 -dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-(4-ch lorophenyl)methanol (39a) (49 mg, 0.12 mmol, 36% yield) Step 2: Synthesis of (1R,2S,3R,5R)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4- chlorophenyl)-hydroxy-methyl]cyclopentane-1,2-diol (39) To [(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-2,2 -dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-(4-ch lorophenyl)methanol (41a) (45.mg, 0.1100 mmol) in 2 mL of methanol was added 2 mL of 1N HCl and stirred at room temperature for 2 h. The LC indicated complete cleavage of the acetal, the reaction was concentrated under vacuum. The crude was re-dissolved back in 2 mL of methanol and 2 mL of water and treated with Amberlite IRA 67/65 resin and stirred for an hour. The mixture was filtered and concentrated. The crude was purified by silica gel chromatography using 0-15% MeOH in DCM to give (1R,2S,3R,5R)-3-(4- aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4-chlorophenyl)-hydro xy-methyl]cyclopentane-1,2-diol (39) (20 mg, 0.053 mmol, 49% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.46– 7.30 (m, 4H), 7.19 (d, J = 3.6 Hz, 1H), 6.96 (s, 2H), 6.53 (d, J = 3.5 Hz, 1H), 5.63 (d, J = 4.5 Hz, 1H), 4.89– 4.74 (m, 2H), 4.57 (dd, J = 6.8, 4.5 Hz, 1H), 4.51 (d, J = 3.8 Hz, 1H), 3.92 (s, 1H), 2.26– 2.15 (m, 1H), 2.00– 1.85 (m, 1H), 1.56-1.49 (m, 1H). Example 57 isomer 1 and isomer 2. (1S,2R,3R,5R)-3-((4-chlorophenyl)(hydroxy)methyl)-5-(4- cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2 -diol (isomer 1 and isomer 2)

57-1 57-2-A 57-2-B

Ex. 57 isomer 1 Ex. 57 isomer 2

Step 1: Synthesis of compounds 57-2-A and 57-2-B To the solution of compound 57-1 (100 mg, 0.629 mmol, reported in

US2009/286783 A1) in DMF (5 mL) was added NaH (38 mg, 0.943 mmol, 60% in mineral oil) and the mixture was stirred for 1 h at 0 °C under N ₂ . Then Int-6 (383 mg, 0.629 mmol) in DMF (2 mL) was added. The mixture was stirred for 3 h at 25 °C. After the reaction was completed, the mixture was cooled to 0 °C and diluted with water (10mL). The mixture was extracted by EtOAc (5mL×3) and the organic layers were combined and washed with brine, dried and concentrated to afford a residue. The residue was purified by silica gel chromatography eluted with petroleum ether: EtOAc = 1:1 to give 57-2-A (54 mg, 0.12 mmol, 19 %) and 57-2-B (42 mg, 0.095 mmol, 15 %) as white solids. LCMS [M+H] 440.2, 442.2;

Step 2: Synthesis of Ex.57 isomer 1 and Ex.57 isomer 2

The solution of 57-2-A (53 mg, 0.12 mmol) in TFA (3 mL) and H2O (6 mL) was stirred for 12 h at 25 °C. After the reaction was completed, LCMS showed the starting material was consumed completely and desired product was the major peak. The solution was adjusted to PH = 7- 8 by NaHCO3 (solid) and the mixture was filtered. The filtrate was purified by prep-HPLC

(H2O/CH3CN (0.1% NH4HCO3) from 90:10 to 5:95) to give Ex.57 ismoer 1 (23 mg, 44.4%) as a white solid. LCMS [M+H] 400.1; ¹ H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.65 (d, J = 3.6 Hz, 1H), 7.37 (s, 4H), 6.84 (d, , J = 3.6 Hz, 1H), 5.59 (d, J = 4.8 Hz, 1H), 4.96-4.78 (m, 3H), 4.67 (m, 1H), 4.24 (m, 1H), 3.89 (m, 1H), 2.25-2.18 (m, 1H), 1.88-1.74 (m, 2H), 1.23-1.12 (m, 2H), 1.10- 1.07 (m, 2H); cyclopropyl CH is likely underneath DMSO peak at 2.50 ppm.

The solution of 57-2-B (40 mg, 0.095 mmol) in TFA (3 mL) and H2O (6 mL) was stirred for 12 h at 25 °C. After the reaction was completed, LCMS showed the starting material was consumed completely and desired product was the major peak. The solution was adjusted to PH = 7- 8 by NaHCO ₃ (solid) and the mixture was filtered. The filtrate was purified by prep-HPLC

(H2O/CH3CN (0.1% NH4HCO3) from 90:10 to 5:95) to give Ex.57 isomer 2 (5 mg, 13.9%) as a white solid. LCMS [M+H] 400.1, 402.1; ¹ H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1 H), 7.62 (d, J = 3.6 Hz, 1 H), 7.43-7.37 (m, 4 H), 6.81 (d, J = 3.6 Hz, 1 H), 5.59 (d, J = 4.8 Hz, 1 H), 5.00-4.93 (m, 1 H), 4.80 (d, J = 6.8 Hz, 1 H), 4.60-4.56 (m, 2 H), 4.34-4.29 (m, 1H), 3.96 (s, 1H), 2.27-2.22 (m, 1H), 2.01-1.94 (m, 1H), 1.62-1.54 (m, 1H), 1.17-1.16 (m, 2H), 1.12-1.10 (m, 2H); cyclopropyl CH is likely underneath DMSO peak at 2.50 ppm. Example 69. (1R,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- benzylcyclopentane-1,2-diol (69)

Step 1: Synthesis of 7-((3aS,4R,6S,6aR)-6-benzyl-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- amine (69a)

To a solution of 7H-pyrrolo[2,3-d]pyrimidin-4-amine (100.0 mg, 0.75 mmol) in DMF (5.0 mL) was added NaH (60% in mineral oil, 45.0 mg, 1.13 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min under N2. Int-3 (283.6 mg, 0.75 mmol) was added to the mixture and the reaction mixture was stirred at 0 °C. After 2 h, the reaction was completed

(monitored by LC-MS). The mixture was diluted with EtOAc (100.0 mL) and washed with brine (50 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a crude product which was purified by silica gel chromatography eluted with petroleum ether: EtOAc =4:1 to DCM : MeOH = 20 :1 to afford 69a (170.0 mg, 0.29 mmol, 26.0%) as a brown solid. LCMS [M+1] 365.2; ¹ H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.16-7.30 (m, 7H), 6.33-6.44 (m,1H), 4.90-5.04 (m, 2H), 4.51-4.57 (m, 1H), 4.11-4.13 (m, 1H), 3.14-3.19 (m, 1H), 2.61-2.68 (m, 1H), 2.11-2.22 (m, 1H), 1.98-2.04 (m, 1H), ), 1.58 (s, 3H), 1.54 (s, 3H).

Step 2: Synthesis of (1R,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- benzylcyclopentane-1,2-diol (69)

To a solution of 73a (160.0 mg, 0.44 mmol) in MeCN (1.0 mL) and water (2.0 mL) was added TFA (1.0 mL, 13.51 mmol). The reaction mixture was stirred at 30 °C. After 18 h, the reaction was completed (monitored by LC-MS). The reaction mixture was adjusted to pH = 7.0 with Na ₂ CO ₃ (aq.) and filtered, concentrated in vacuum to give a crude product which was purified by prep-HPLC, eluting with H2O/CH3CN (0.5 % NH4HCO3) from 80:20 to 70:30 to obtained 69 (30.0 mg, 0.092 mmol, 20.9%) as a white solid. LCMS [M+1] 325.2; ¹ H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.16-7.30 (m, 6H), 6.91 (s, 2H), 6.53 (d, J = 8.8 Hz, 1H), 6.04 (s,1H), 4.74-4.81 (m, 1H), 4.26-4.30 (m, 1H), 3.75-3.78 (m, 1H), 2.87-3.07 (m, 1H), 2.61-2.68 (m, 1H), 2.06-2.20 (m, 1H), 1.98-2.04 (m, 1H), ), 1.45-1.53 (m, 1H). ¹ H NMR (400 MHz, DMSO-d6+D2O) δ 7.96 (s, 1H), 7.15-7.26 (m, 6H), 6.54 (d, J = 3.6 Hz, 1H), 4.73-4.75 (m, 1H), 4.26-4.30 (m, 1H), 3.75-3.78 (m, 1H), 2.89-32.90 (m, 1H), 2.51-2.681 (m, 1H), 2.18-2.19 (m, 1H), 2.00-2.03 (m, 1H), 1.39-1.41 (m, 1H). Example 70. (1R,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (4- fluorobenzyl)cyclopentane-1,2-diol (70)

Example 70 was prepared using the same method described in Example 73 except for substituting Int-3 with Int-5. LCMS [M+1] 343.2; ¹ H NMR (400 MHz, DMSO-d6+D2O) δ 8.02 (s, 1H), 7.27 (dd, J = 8.4, 5.6 Hz, 1H), 7.23 (d, J = 3.6 Hz, 1H), 7.10 (dd, J = 9.2, 8.8 Hz, 1H), 6.56 (d, J = 3.6 Hz, 1H), 4.78 (ddd, J = 10.0, 8.4, 8.0 Hz, 1H), 4.26 (dd, J = 8.0, 5.6 Hz, 1H), 3.75 (dd, J = 5.2, 5.2 Hz, 1H), 2.93 (dd, J = 13.6, 6.4 Hz, 1H), 2.63 (dd, J = 13.6, 9.2 Hz, 1H), 2.16 (m, 1H). 2.03 (ddd, J = 12,8, 8.4, 8.0 Hz, 1H), 1.47 (ddd, J = 12.8, 10.0, 10.0 Hz, 1H). Example 72. (1S,2S,3R,5S)-3-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- ((4- chloro hen l thio c clo entane-12-diol 72

Int-7 ^{72a Ex. 72} a) Preparation of 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfanyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]pyrrolo[2,3-d]p yrimidin-4-amine (72a) To 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfanyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-4-chloro-pyrro lo[2,3-d]pyrimidine (70.mg, 0.16 mmol) in Methanol (2 mL) was added AMMONIA, CA.7N SOLUTION IN METHANOL (0.23mL, 1.6 mmol) and the reaction heated at 80 ^o C for 16 h. The reaction was concentrated under vacuum and the crude was purified by silica gel chromatography using a 4 g Agela column with a gradient of 0-10% Methanol in DCM to give 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfanyl-2,2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]pyrrolo[2,3-d]pyrimidin-4-amine (72a) (50 mg, 0.11993 mmol, 74.757% yield). b) Preparation of (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(4- chlorophenyl)sulfanyl-cyclopentane-1,2-diol (Ex.72) To 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfanyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]pyrrolo[2,3-d]p yrimidin-4-amine (72a) (20.mg, 0.05 mmol) in Methanol (1 mL) was added 1 mL of 1N HCl and stirred at room temperature for 4 h. The reaction mixture was concentrated under vacuum and the residue was re-dissolved in 1:1 Methanol :water. It was neutralized by stirring with Amberlite® IRA-67 for 30 mins. The mixture was filtered, the filtrate concentrated. The crude was purified by preparative TLC on silica gel plate using 10:1:0.1 DCM:MeOH:NH4OH to give (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5- (4-chlorophenyl)sulfanyl-cyclopentane-1,2-diol (Ex.72) (6 mg, 0.015 mmol, 31% yield). ¹ H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.38– 7.31 (m, 2H), 7.27 (d, J = 3.7 Hz, 1H), 6.67 (d, J = 3.7 Hz, 1H), 5.07 (q, J = 8.9 Hz, 1H), 4.53 (dd, J = 8.6, 5.1 Hz, 1H), 4.05 (dd, J = 5.1, 3.1 Hz, 1H), 3.64 (ddd, J = 9.8, 7.3, 3.0 Hz, 1H), 2.85 (dt, J = 14.0, 8.7 Hz, 1H), 1.85 (ddd, J = 14.0, 9.4, 7.1 Hz, 1H). Examples 73 and 73A. (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(4- chlorophenyl)sulfinyl-cyclopentane-1,2-diol (Ex.73) and (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3- d]pyrimidin-7-yl)-5-(4-chlorophenyl)sulfinyl-cyclopentane-1, 2-diol (Ex. 73A)

Ex.73 Ex.73A a) Preparation of Intermediates 73Aa and 73a

To 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfanyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]pyrrolo[2,3-d]p yrimidin-4-amine (72a) (101.6mg, 0.24 mmol) in 10 mL of DCM was added the m-CPBA (60.08mg, 0.27 mmol) and stirred at room temperature for 3 h. The reaction mixture was diluted with additional 10 mL of DCM, washed with saturated NaHCO ³ , dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography using 0-50% EtOAc in hexane to give 7-[(3aS,4S,6R,6aS)-4-(4- chlorophenyl)sulfinyl-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-c yclopenta[d][1,3]dioxol-6- yl]pyrrolo[2,3-d]pyrimidin-4-amine (73Aa, isomer 1) (20 mg, 0.046 mmol, 19% yield) and 7- [(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfinyl-2,2-dimethyl-4,5 ,6,6a-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-6-yl]pyrrolo[2,3-d]pyrimidin-4-amin e (73a, isomer 2) (8 mg, 0.02 mmol, 8% yield).

b) Preparation of (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(4- chlorophenyl)sulfinyl-cyclopentane-1,2-diol (Ex.73) To 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfinyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]pyrrolo[2,3-d]p yrimidin-4-amine (73a) (8.mg, 0.02 mmol) in 1 mL of methanol was added 1 mL of 1N HCl and stirred at room tempertaure for 1 h. the reaction was concentrated, the crude was redissolved in 1:1 MeOH:H ₂ O and treated with Amberlite IRA -67, stirring for 30 mins. The reaction mixture was filtered, concentrated and the crude purified by silica gel chromatography on a 4 g Agela column using 0-10% MeOH in DCM to give

(1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-( 4-chlorophenyl)sulfinyl-cyclopentane- 1,2-diol (Ex.73) (2 mg, 0.005 mmol, 27.5% yield). ¹ H NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.79– 7.73 (m, 2H), 7.67– 7.61 (m, 2H), 7.29 (d, J = 3.7 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 5.05 (q, J = 9.2 Hz, 1H), 4.34– 4.17 (m, 2H), 3.4 (m, 1H), 2.63 (dt, J = 8.9, 13.8 Hz, 1H), 2.24– 2.08 (m, 1H).

c) Preparation of (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(4- chlorophenyl)sulfinyl-cyclopentane-1,2-diol (Ex.73A) To 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfinyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]pyrrolo[2,3-d]p yrimidin-4-amine (73Aa) (18.53mg, 0.04 mmol) in 1 mL of methanol was added 1 mL of 1N HCl and stirred at room tempertaure for 1 h. the reaction was concentrated, the crude was redissolved in 1:1 MeOH:H ₂ O and treated with Amberlite IRA -67, stirring for 30 mins. The reaction mixture was filtered, concentrated and the crude purified by silica gel chromatography on a 4 g Agela column using 0-10% MeOH in DCM to give (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(4-c hlorophenyl)sulfinyl- cyclopentane-1,2-diol (Ex.73A) (6 mg, 0.015 mmol, 36% yield). ¹ H NMR (400 MHz, Methanol- d4) δ 8.01 (s, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 3.7 Hz, 1H), 6.60 (d, J = 3.7 Hz, 1H), 4.62 (s, 2H), 4.48 (t, J = 4.8 Hz, 1H), 4.18 (dd, J = 5.3, 7.5 Hz, 1H), 2.11 (dt, J = 8.7, 14.0 Hz, 1H), 1.95 (dt, J = 8.8, 14.0 Hz, 1H). Example 74 (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(4- chloro hen l sulfon l-c clo entane-12-diol Ex.74

Int-7 74a Ex. 74

a) Preparation of 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfonyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-4-chloro-pyrro lo[2,3-d]pyrimidine (74a) To 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfanyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-4-chloro-pyrro lo[2,3-d]pyrimidine (Int-7)

(36.63mg, 0.08 mmol) in 2 mL of DCM was added the m-CPBA (41.39mg, 0.18 mmol) and stirred at room temperature for 3 h. The reaction mixture was diluted with additional 10 mL of DCM, washed with saturated NaHCO3, dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography using 0-30% EtOAc in hexane to give 7-[(3aS,4S,6R,6aS)-4- (4-chlorophenyl)sulfonyl-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H-cyclopenta[d][1,3]dioxol-6-yl]-4- chloro-pyrrolo[2,3-d]pyrimidine (74a) (26 mg, 0.056 mmol, 66% yield). ¹ H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.37 (t, J = 3.9 Hz, 1H), 6.71 (d, J = 3.7 Hz, 1H), 5.22 (dd, J = 7.0, 5.4 Hz, 1H), 5.17– 4.96 (m, 2H), 3.74 (ddd, J = 12.3, 7.2, 5.3 Hz, 1H), 2.88 (dt, J = 13.3, 11.7 Hz, 1H), 2.65 (dt, J = 13.8, 7.2 Hz, 1H), 1.80 (s, 2H), 1.54 (s, 3H), 1.31 (s, 3H).

b) Preparation of (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(4- chlorophenyl)sulfonyl-cyclopentane-1,2-diol (Ex.74) To 7-[(3aS,4S,6R,6aS)-4-(4-chlorophenyl)sulfonyl-2,2-dimethyl-4 ,5,6,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-4-chloro-pyrro lo[2,3-d]pyrimidine (74a) (29 mg, 0.06 mmol) in 2 mL of methanol was added the AMMONIA, CA.7N SOLUTION IN METHANOL (0.99mL, 6.94 mmol) and heated at 90 ^o C for 18 h. The reaction mixture was concentrated under vacuum and redissolved in 1 mL of methanol to which was added a few drops of conc. HCl. The reaction was stirred at room temperature for 2 h, concentrated under vacuum. The crude was dissolved back in 1 mL of methanol and 1 mL of water, treated with Amberlite IRA-67, stirred for 30 mins, filtered and concentrated. The crude was purified by preparative silica gel TLC using 10:1:0.5 DCM:MeOH:NH4OH to give (1S,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5- (4-chlorophenyl)sulfonyl-cyclopentane-1,2-diol (Ex.74) (2.5 mg, 0.0058 mmol, 9.2% yield). ¹ H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 3.7 Hz, 1H), 6.62 (d, J = 3.7 Hz, 1H), 4.39 (d, J = 5.9 Hz, 1H), 3.95 (br s, 1H), 3.79 (d, J = 7.6 Hz, 1H), 2.66– 2.44 (m, 1H), 2.32 (q, J = 11.5, 10.0 Hz, 1H); missed one proton, likely underneath DHO peak.

Example 114. (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4- chlorophenyl)- fluoro -methyl] cyclopentane-1,2-diol (Ex.114, a mixture of diastereomers)

114d Ex.114

a) Synthesis of compound 114a To a solution of [(3aR,4S,6R,6aR)-4-[tert-butyl(diphenyl)silyl]oxy-2,2-dimeth yl- 4,5,6,6a-tetra hydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]-(4-chlorophenyl)met hanol (Int-6-4) (500.0 mg, 0.93 mmol) in DCM (15.0 mL) was added DAST (0.4 mL, 2.79 mmol) at 0℃, then the mixture was stirred at 20℃ for 1 h. TLC (PE:EA = 10:1) showed the starting materials was consumed completely. LCMS showed a main peak but no mass signal. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE:EA = 30:1 to 20:1) to give

[(3aR,4S,6S,6aR)-6-[(4-chlorophenyl)-fluoro-methyl]-2,2-d imethyl-4,5,6,6a-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-4-yl]oxy-tert-butyl-diphenyl-silane (114a) (510.0 mg, crude, 23.1% purity, 0.22 mmol, 23.50 % yield) as colorless oil, which was used directly in the next step. LCMS, no MS signal.

b) Synthesis of compound 114b To a solution of [(3aR,4S,6S,6aR)-6-[(4-chlorophenyl)-fluoro-methyl]-2,2- dimethyl-4,5,6,6a-tetra hydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy-tert-butyl-diphe nyl-silane (114a) (547.6 mg, 1.02 mmol) in THF (20.0 mL), tetrabutylammonium fluoride (5.1 mL, 5.08 mmol) was added, the mixture was stirred at 25℃ for 16 hrs. TLC (PE:EA = 3:1) showed the starting materials was almost consumed. The solution was concentrated and the residue was purified by silica gel column chromatography (PE:EA = 10:1 to 5:1) to give (3aS,4S,6S,6aR)-6-[(4- chlorophenyl)-fluoro -methyl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][ 1,3]dioxol-4-ol (114b) (240.0 mg, 0.71 mmol, 70.00 % yield) as colorless oil. LCMS, no MS signal.

c) Synthesis of compound 114c To a solution of (3aS,4S,6S,6aR)-6-[(4-chlorophenyl)-fluoro-methyl]-2,2-dimet hyl- 4,5,6,6a-tetra hydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (114b) (240.0 mg, 0.80 mmol) in DCM (5.0 mL), pyridine (189.4 mg, 2.39 mmol) was added, then Tf2O (450.3 mg, 1.6 mmol) was added, the mixture was stirred at 20℃ for 1h. TLC (PE:EA = 10:1, Rf = 0.3-0.4) showed the desired product formed and the starting materials was consumed completely. The mixture was quenched by H2O (0.2 mL), extracted with EA (30.0 mL×3). The combined organic layers were washed with brine (10.0 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-TLC (PE:EA = 10:1) to give [(3aR,4S,6S,6aR)-6-[(4-chlorophenyl)-fluoro-methyl]-2,2-dime thyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl] trifluoromethanesulfonate (114c) (90.0 mg, 0.21 mmol, 26.1 % yield) as light colorless oil. LCMS, no MS signal.

d) Synthesis of compound 114d To a solution of 7H-pyrrolo[2,3-d]pyrimidin-4-amine (50.8 mg, 0.38 mmol) in DMF (2.0 mL) at 0℃ was added NaH (60 % in mineral oil, 16.7 mg, 0.42 mmol). The mixture was stirred at 0℃ for 10 min, then [(3aR,4S,6S,6aR)-6-[(4-chlorophenyl)-fluoro-methyl]-2,2-dime thyl- 4,5,6,6a-tetra hydro-3aH-cyclopenta[d][1,3]dioxol-4-yl] trifluoromethanesulfonate (114c) (82.0 mg, 0.19 mmol) in DMF (1.0 mL) was added. The mixture was stirred at room temperature for 2 hrs. LCMS showed the desired mass was detected, and TLC (PE/EA=10/1) stained with

phosphomolybdic acid hydrate showed no compound 114c remained. Water (5.0 mL) was added to quench the reaction, and the resulting mixture was extracted with EA (10.0 mL×3). The combined organic layers were washed with brine (10.0 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated. LCMS showed two isomers detected in 254 nm. The residue was purified by prep-TLC eluted with DCM/MeOH = 10/1 to give the desired product (mixture of two isomers) 7-[(3aS,4R,6S,6aR) -6- [(4-chlorophenyl)-fluoro-methyl]-2,2-dimethyl-4,5,6,6a-tetra hydro-3aH-cyclopenta[d][1,3]dioxol-4- yl]pyrrolo[2,3-d]pyrimidin-4-amine (114d) (65.0 mg, 0.16 mmol, 83.00 % yield) as yellow oil. LCMS [M+H]: 417.1. e) Synthesis of (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4- chlorophenyl)-fluoro -methyl] cyclopentane-1,2-diol (Ex.114) To a mixture of trifluoroacetic acid (0.3 mL, 4.06 mmol) in water (3.0 mL) was added 7-[(3aS,4R,6S,6aR)-6-[(4-chlorophenyl)-fluoro-methyl]-2,2-di methyl-4,5,6,6a-tetrahydro- 3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4- amine (114d) (50.0 mg, 0.12 mmol). The mixture was stirred at 30℃ for 1 h. LCMS indicated the reaction was almost completed. The mixture was adjusted to pH≈ 7 with saturated NaHCO3 aqueous solution. The resulting mixture was purified by prep-HPLC eluting with CH3CN/H2O (0.1 % NH4HCO3 containing) from 20/80 to 80/20 to give (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(4- chlorophenyl)-fluoro -methyl] cyclopentane-1,2-diol (Ex.114, a mixture of diastereomers) (7.4 mg, 0.02 mmol, 16 % yield) (two isomers, the ratio is about 1/1.3 by HPLC, 214 nm) as white solid. LCMS [M+H]: 377.2. ¹ H NMR (400 MHz, DMSO-d6): δ 8.01-8.02 (m, 1H), 7.41-7.48 (m, 4 H), 7.20-7.23 (m, 1 H), 6.91-6.92 (m, 2 H), 6.51-6.56 (m, 1 H), 5.53-5.82 (m, 1 H), 4.94-4.97 (m, 1 H), 4.78-4.86 (m, 2 H), 4.19-4.38 (m, 1H), 3.82-4.04 (m, 1 H), 1.38-2.05 (m, 3 H). ¹ H NMR (400 MHz, DMSO-d6+D2O): δ 8.01-8.03 (m, 1H), 7.42-7.49 (m, 4 H), 7.23-7.26 (m, 1 H), 6.56-6.60 (m, 1 H), 5.52-5.83 (m, 1 H), 4.82-4.89 (m, 1 H), 4.05-4.37 (m, 2 H), 1.38-2.07 (m, 3 H). ¹⁹ F NMR (376 MHz, DMSO-d6): δ -170.48 (s, 1.27 F), - 180.07 (s, 1 F). Example 117. (1S,2R,3R,5R)-3-((S)-amino(4-chlorophenyl)methyl)-5-(4-chlor o-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (Ex.117)

1 ^17a 117b ^117c Ex.117 a) Preparation of compound 117b

DIAD (0.12mL, 0.63 mmol) was added to a solution of (R)-[(3aS,4R,6R,6aR)-4-(4- chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-te trahydro-3aH- cyclopenta[d][1,3]dioxol-6-yl]-(4-chlorophenyl)methanol (117a, prepared similar to that of Int-2) (183.mg, 0.42 mmol), Phthalimide (75.9 mg, 0.51 mmol), and Triphenylphosphine (133 mg, 0.51 mmol) in dry THF (4 mL). The resulting mixture was stirred at RT overnight, concentrated and purified on a 20 g columne which was eluted with 0-50% EA/hexane. The less polar spot (TLC 3:1 hexane:EA, Rf 0.4) was isolated to show the right mass, 2-[(S)-[(3aS,4R,6R,6aR)-4-(4- chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-te trahydro-3aH- cyclopenta[d][1,3]dioxol-6-yl]-(4-chlorophenyl)methyl]isoind oline-1,3-dione (117b) (240 mg, 0.425 mmol, 101.1% yield), this white solid contained phthalamide due to poor solubility.

b) Preparation of compound 117c

Hydrazine (0.85mL, 0.85 mmol) (1M in THF) was added to a solution of 2-[(S)- [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2-dimethyl-4,5,6,6a-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-6-yl]-(4-chlorophenyl)methyl]isoind oline-1,3-dione (117b) (240.mg, 0.43 mmol) in Ethanol (4 mL) and the resulting mixture was stirred at RT overnight., concentrated and the residue was purified a 12 g column, which was eluted with 0-10% MeOH/DCM to give (S)- [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2-dimethyl-4,5,6,6a-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-6-yl]-(4-chlorophenyl)methanamine (117c) (100 mg, 0.231 mmol, 54.2% yield) as a white foamy solid. TLC DCM:MeOH 10:1 Rf 0.4.

c) Preparation of (1S,2R,3R,5R)-3-((S)-amino(4-chlorophenyl)methyl)-5-(4-chlor o-7H- pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (Ex.117) A mixture of (S)-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl )-2,2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-(4-chlorophenyl)methanamine (117c) (20.mg, 0.05 mmol) and 1:1 TFA/H2O (0.5 mL) was stirred at RT for 1 hr, concentrated and redissolved in MeOH, cooled to 0 C, neutralized with conc. NH4OH to pH ~8, concentrated under vacuum. The residue was purified on a 4 g column, which was eluted with 0-15% MeOH/DCM to give (1S,2R,3R,5R)-3-[(S)-amino-(4-chlorophenyl)methyl]-5-(4-chlo ropyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1,2-diol (Ex.117) (12 mg, 0.02746 mmol, 59.501% yield) as a white solid. LCMS showed correct M+H 393/395/397 (major fragment peaks are 376/378/380, M+H-NH ₃ ); ¹ HNMR (400 MHz, MeOH-d4): δ 8.54 (s, 1H), 7.61 (d, J=3.6 Hz, 1H), 7.45-7.43 (m, 4H), 6.67 (d, J=3.6 Hz, 1H), 4.97 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 4.15 (d, J=9.6 Hz, 1H), 2.49 (m, 1H), 1.90 (m, 1H), 1.72 (m, 1H). Example 124A. (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1S )-1-(3,4- dichlorophenyl)-1-hydroxy-ethyl]cyclopentane-1,2-diol (Ex. 124A)

124Ad 124A a) Preparation of Compound 124a To a solution of (3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2 - dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxole-6 -carbaldehyde (Int-8) (700.mg, 0.71 mmol) in THF (10 mL) was added bromo-(3,4-dichlorophenyl)magnesium (4.26mL, 2.13 mmol) at 0 °C, the solution stirred at 0 °C 1h. LC-MS showed the reaction was completed. EA (60mL) was added to quench the reaction, followed by H ₂ O (30mL). The organic layer was separated, washed with H ₂ O (30mL) and NaCl aqueous (30mL), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum, the residue purified by column (PE:EA=5:1 - PE:EA=3:1) to give [(3aS,4R,6R,6aR)-4-(4- chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-te trahydro-3aH- cyclopenta[d][1,3]dioxol-6-yl]-(3,4-dichlorophenyl)methanol (124a, a mixture of diastereomers) (450 mg, 0.67199 mmol, 94.7% yield). LCMS [M+H]: 468.1.

b) Preparation of compound 124b

To a solution of [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-(3,4-dichlorophenyl)methanol (124a) (450.0 mg, 0.96 mmol) in DCM (10.0 mL) was added Dess-Martin periodinane (1221.5 mg, 2.88 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The reaction mixture was added NaHCO ₃ aqueous (30.0 mL) and extracted with DCM (50.0 mL X 3). The organic layers were dried over Na2SO4, filtered, concentrated in vacuum to give crude product which was purified by silica chromatography column (PE : EA = 8 : 1) to give

[(3aS,4R,6S,6aR)-4 -(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6 a-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-6-yl]-(3,4-dichlorophenyl)methanone (124b) (370.0 mg, 0.79 mmol, 82.6% yield) as a white solid. LCMS [M+H]: 466.1.

c) Preparation of Compound 124Bc and 124Ac To a solution of [(3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-(3,4-dichlorophenyl)methanone (124b) (370.0 mg, 0.79 mmol) in THF (7.0 mL) was added bromo(methyl)magnesium (0.79 mL, 3.0 N in THF, 2.38 mmol) at 0 °C. The reaction mixture was stirred at 25 °C 30 mins. TLC showed the reaction was completed. The reaction was quenched with NH4Cl aqueous (10.0 mL) and extracted with EA (30.0 mL X 3 ). The organic layers were dried over Na2SO4, filtered, concentrated in vacuum to give crude product which was purified by silica chromatography column (PE : EA = 7 : 1 to PE : EA = 5 : 1) to give (1S)-1-[(3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7 -yl)-2,2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-1-(3,4-dichlorophenyl)ethanol (124Ac, more polar) (100.0 mg, 0.21 mmol, 26.1 % yield) and (1R)-1-[(3aS,4R,6S, 6aR)-4-(4- chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a -tetrahydro-3aH- cyclopenta[d][1,3]dioxol-6-yl]-1-(3,4-dichlorophenyl)ethanol (124Bc, less polar) (80.0 mg, 0.17 mmol, 20.9 % yield). LCMS [M+H]: 482.1.

d) Synthesis of compound 124Ad To a solution of (1S)-1-[(3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7 - yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]d ioxol-6-yl]-1-(3,4- dichlorophenyl)ethanol (124Ac) (100.0 mg, 0.21 mmol) in 1,4-Dioxane (3.00 mL) was added ammonia hydrate (3.0 mL, 0.62 mmol). The mixture was sealed and stirred at 120 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated and added EA (100.0 mL). The reaction mixture was washed with brine (60.0 mL), dried over Na ₂ SO ₄ , concentrated in vacuum to give crude product (1S)-1 -[(3aS,4R,6S,6aR)-4-(4-aminopyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH -cyclopenta[d][1,3]dioxol-6-yl]-1-(3,4- dichlorophenyl)ethanol (124Ad) (100.0 mg, 0.14 mmol, 67.7 % yield) LCMS [M+H]: 463.1. e) Synthesis of (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1S )-1-(3,4- dichlorophenyl)-1-hydroxy-ethyl]cyclopentane-1,2-diol (Ex.124A) To a solution of (1S)-1-[(3aS,4R,6S,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7- yl)- 2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxo l-6-yl]-1-(3,4-dichlorophenyl)ethanol (100.0 mg, 0.14 mmol) in Water (2.0 mL) was added TFA (1.3 mL, 16.87 mmol). The reaction mixture was stirred at 30 °C for 0.5 h. LCMS showed the reaction was completed. The mixture was purified by prep-HPLC, eluted with CH3CN in H2O (0.1 % NH4OH) from 5.0% to 95.0% to give (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1S )-1-(3,4-dichlorophenyl)-1-hydroxy- ethyl]cyclopentane-1,2-diol (Ex.124A) (35.0 mg, 0.08 mmol, 58.8% yield) as a white solid. LCMS [M+H]: 423.2. ¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.06 (s, 1 H), 7.74-7.75 (m, 1 H), 7.58-7.60 (m, 1 H), 7.48-7.50 (m, 1 H), 7.26-7.27 (m, 1 H), 6.62-6.63 (m, 1 H), 4.83-4.90 (m, 1 H), 4.03-4.07 (m, 1 H), 3.49-3.50 (m, 1 H), 2.33-2.45 (m, 1 H), 2.16-2.24 (m, 1 H), 1.86-1.94 (m, 1 H), 1.36 (s, 3 H). Example 124B. (1R,2S,3R,5S)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(1R )-1-(3,4- dichlorophenyl)-1-hydroxy-ethyl]cyclopentane-1,2-diol (124B) Example 124B, a white solid, was prepared similar to that of Ex. 124A. LCMS [M+H]: 423.2. ¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.07 (s, 1 H), 7.63-7.64 (m, 1 H), 7.52-7.54 (m, 1 H), 7.38-7.40 (m, 1 H), 7.26-7.27 (m, 1 H), 6.62-6.63 (m, 1 H), 4.70-4.77 (m, 1 H), 4.08-4.14 (m, 2 H), 2.32-2.41 (m, 1 H), 1.55 (s, 3 H), 1.45-1.51 (m, 1 H), 1.35-1.40 (m, 1 H).

Example 128.3-[7-[(1R,2S,3R,4R)-4-[(S)-(3,4-dichlorophenyl)-hydroxy- methyl]-2,3- dihydroxy-cyclopentyl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dime thyl-urea (128)

128a 128b 128c Ex.128 a) Synthesis of compound 128a To a solution of (S)-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl )- 2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxo l-6-yl]-(3,4-dichlorophenyl)methanol (124a, R isomer) (400.0 mg, 0.85 mmol) in DMF (5.0 mL) was added imidazole (174.3 mg, 2.56 mmol) and Chloro(triethyl)silane (257.2 mg, 1.71 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h. TLC showed the reaction completed (PE : EA = 5 : 1). The mixture was added EA (50.0 mL), washed with H2O (20.0 mL X 3) and brine (30.0 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated in vacuum to give crude product which was purified by silica chromatography column (PE : EA = 10 : 1 to PE : EA = 5 : 1) to give 7-[(3aS,4R,6S,6aR)-6-[(S)-(3,4- dichlorophenyl)-triethylsilyloxy-methyl] -2,2-dimethyl-4,5,6,6a-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]pyrimidin-4-amin e (128a) (390.0 mg, 0.35 mmol, 40.8 % yield).

b) Synthesis of compound 128b To a solution of [(S)-[(3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-y l)- 2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxo l-6-yl]-(3,4- dichlorophenyl)methoxy]-triethyl-silane (128a) (390.0 mg, 0.67 mmol) in 1,4-Dioxane (5.0 mL) was added 1,1-dimethylurea (117.9 mg, 1.34 mmol), Xantphos (58.1 mg, 0.10 mmol) and Pd2(dba)3 (24.5 mg, 0.03 mmol). The mixture was stirred at 80 °C 16 h under N ₂ . LCMS showed the reaction was completed. The mixture was filtered and concentrated in vacuum to give crude product which was purified by silica chromatography column (PE : EA = 10 : 1 to PE : EA = 5 : 1) to give 3-[7- [(3aS,4R,6S,6aR)-6-[(S)-(3,4 -dichlorophenyl)-triethylsilyloxy-methyl]-2,2-dimethyl-4,5,6 ,6a- tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrolo[2,3-d]p yrimidin-4-yl]-1,1-dimethyl-urea (128b) (240.0 mg, 0.37 mmol, 55.9 % yield). LCMS [M+H]: 634.3.

c) Synthesis of compound 128c To a solution of 3-[7-[(3aS,4R,6S,6aR)-6-[(S)-(3,4-dichlorophenyl)- triethylsilyloxy-methyl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3a H-cyclopenta[d][1,3]dioxol-4- yl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dimethyl-urea (128b) (240.0 mg, 0.38 mmol) in THF (5.0 mL) was added TBAF (197.7 mg, 0.76 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was completed. The mixture was added EA (50.0 mL), washed with H2O (20.00 mL X 3) and brine (30.0 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated in vacuum to give crude product which was purified by silica chromatography column (PE : EA = 5 : 1 to PE : EA = 2 : 1) to give 3-[7-[(3aS,4R,6R,6aR)-6-[(S)-(3,4-dichlorophenyl)-hydroxy-me thyl]-2,2-dimethyl- 4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]pyrrol o[2,3-d]pyrimidin-4-yl]-1,1-dimethyl- urea (128c) (180.0 mg, 0.35 mmol, 91.5 % yield). LCMS [M+H]: 520.2.

d) Synthesis of 3-[7-[(1R,2S,3R,4R)-4-[(S)-(3,4-dichlorophenyl)-hydroxy-meth yl]-2,3- dihydroxy-cyclopentyl]pyrrolo[2,3-d]pyrimidin-4-yl]-1,1-dime thyl-urea (Ex.128) To a solution of 3-[7-[(3aS,4R,6R,6aR)-6-[(S)-(3,4-dichlorophenyl)-hydroxy- methyl]-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1 ,3]dioxol-4-yl]pyrrolo[2,3- d]pyrimidin-4-yl]-1,1-dimethyl-urea (128c) (180.0 mg, 0.35 mmol) in Water (3.0 mL) was added TFA (2.0 mL, 25.96 mmol). The reaction mixture was stirred at 30 °C for 0.5 h. LCMS showed the reaction was completed. The mixture was purified by prep-HPLC, eluted with CH3CN in H2O (0.1 % NH4OH) from 5.0% to 95.0% to give 3-[7-[(1R,2S,3R,4R)-4-[(S)-(3,4-dichlorophenyl)-hydroxy- methyl]-2,3-dihydroxy-cyclopentyl]pyrrolo[2,3-d]pyrimidin-4- yl]-1,1-dimethyl-urea (Ex.128) (51.0 mg, 0.10 mmol, 29.9 % yield) as a white solid. LCMS [M+H]: 480.2; ¹ H NMR (400 MHz, DMSO- d6+D2O): δ 8.35 (s, 1 H), 7.58-7.63 (m, 2 H), 7.38-7.43 (m, 2 H), 6.55-6.56 (m, 1 H), 4.93-5.00 (m, 1 H), 4.60-4.62 (m, 1 H), 4.22-4.26 (m, 1 H), 3.90-3.92 (m, 1 H), 2.98 (s, 6 H), 2.23-2.28 (m, 1 H), 1.99-2.06 (m, 1 H), 1.55-1.63 (m, 1 H). Example 129A. (1R,2S,3R,5R)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(S) -[4-chloro-2- (hydroxymethyl)phenyl]-hydroxy-methyl]cyclopentane-1,2-diol (Ex.129A)

129Ab 129Ac Ex.129 a) Synthesis of compound 129a To a solution of (2-bromo-5-chloro-phenyl)methoxy-tert-butyl-dimethyl-silane (1826.0 mg, 5.44 mmol) in THF (20.0 mL) was added butyllithium (2.8 mL, 5.44 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h. Then, (3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclo penta[d][1,3]dioxole-6-carbaldehyde (Int-8) (1750.0 mg, 5.44 mmol) in THF was added to the mixture. The reaction mixture was stirred at -78 °C for 1 h. LCMS showed the reaction was completed. The reaction was quenched with H2O (30.0 mL) and extracted with EA (60.0 mL). The organic layers were dried over Na2SO4, filtered, and concentrated in vacuum to give crude product which was purified by silica chromatography column (PE : EA = 3 : 1) to give [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-[2-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-chloro-phenyl]methanol (129a, a mixture of diastereomers) (360.0 mg, 0.62 mmol, 11.4 % yield). LCMS [M+H]: 578.2. b) Synthesis of compound 129Ab and 129Bb To a solution of [(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2, 2- dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6- yl]-[2-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-chloro-phenyl]methanol (129a) (360.0 mg, 0.62 mmol) in THF (5.00 mL) was added TBAF (0.62 mL, 1.0 N in THF， 0.62 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed the reaction was completed. The mixture was added EA (50.0 mL), washed with H2O (20.0 mL X 3) and brine (30.0 mL). The organic layer was dried over Na2SO4, concentrated in vacuum to give crude product was purified by prep-TLC (PE: EA = 3: 1) to give (S)-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo -[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro- 3aH-cyclopenta[d][1,3]dioxol-6-yl]-[4-chloro-2-(hydroxymethy l)phenyl]methanol (129Ab, more polar) (42.0 mg, 0.09 mmol, 14.5 % yield) and (R)-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclo penta[d][1,3]dioxol-6-yl]-[4-chloro-2- (hydroxymethyl)phenyl]methanol (129Bb, less polar) (55.0 mg, 0.12 mmol, 19.0 % yield). LCMS [M+H]: 464.1. c) Synthesis of compound 129Ac To a solution of (S)-[(3aS,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl )- 2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxo l-6-yl]-[4-chloro-2- (hydroxymethyl)phenyl]methanol (129Ab) (40.0 mg, 0.09 mmol) in 1,4-Dioxane (3.0 mL) was added ammonia hydrate (3.0 mL, 0.26 mmol). The mixture was sealed and stirred at 120 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated and added EA (100.0 mL). The reaction mixture was washed with brine (60.0 mL), dried over Na ₂ SO ₄ ,

concentrated in vacuum to crude product (S)-[(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin- 7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3 ]dioxol-6-yl]-[4-chloro-2- (hydroxymethyl)phenyl]methanol (129Ac) (40.0 mg, 0.07 mmol, 78.3% yield). LCMS [M+H]: 445.4.

d) Synthesis of (1R,2S,3R,5R)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(S) -[4-chloro-2- (hydroxymethyl)phenyl]-hydroxy-methyl]cyclopentane-1,2-diol (Ex.129A) To a solution of (S)-[(3aS,4R,6R,6aR)-4-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl) - 2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxo l-6-yl]-[4-chloro-2- (hydroxymethyl)phenyl]methanol (129Ac) (30.0 mg, 0.07 mmol) in Water (2.0 mL) was added TFA (1.0 mL, 12.98 mmol). The reaction was stirred at 30 °C for 0.5 h. LCMS showed the reaction was completed. The mixture was purified by prep-HPLC, eluted with CH3CN in H2O (0.1 % NH4OH) from 5.0% to 95.0% to give (1R,2S,3R,5R)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(S) -[4- chloro-2-(hydroxymethyl)phenyl]-hydroxy-methyl]cyclopentane- 1,2-diol (Ex.129A) (1.5 mg, 0.003 mmol, 5.4 % yield) as a white solid. LCMS [M+H]: 405.1. ¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O): δ 8.01 (s, 1 H), 7.46-7.48 (m, 1 H), 7.41-7.42 (m, 1 H), 7.28-7.30 (m, 1 H), 7.20-7.21 (m, 1 H), 6.52- 6.53 (m, 1 H), 4.79-4.86 (m, 1 H), 4.68-4.70 (m, 1 H), 4.64 (s, 2 H), 4.29-4.33 (m, 1 H), 4.00-4.02 (m, 1 H), 2.23-2.27 (m, 1 H), 1.93-2.01 (m, 1 H), 1.46-1.54 (m, 1 H). Example 129B. (1R,2S,3R,5R)-3-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R) -[4-chloro-2- (hydroxymethyl)phenyl]-hydroxy-methyl]cyclopentane-1,2-diol (129B) Example 129B, as a white solid, was prepared similar to that of Ex.129A. LCMS [M+H]: 405.1. ¹ H NMR (400 MHz, DMSO-d6+D2O): δ 8.01 (s, 1 H), 7.43-7.44 (m, 2 H), 7.24-7.27 (m, 2 H), 6.56-6.57 (m, 1 H), 4.96-4.97 (m, 1 H), 4.73-4.80 (m, 1 H), 4.54-4.66 (m, 2 H), 4.16-4.19 (m, 1 H), 3.89-3.87 (m, 1 H), 2.10-2.13 (m, 1 H), 1.73-1.85 (m, 2 H). Table 2. Examples made similar to the above mentioned methods with spectra data

Biochemical Assay Protocol Compounds were solubilized and 3-fold diluted in 100% DMSO. These diluted compounds were further diluted in the assay buffer (50 mM Tris-HCl, pH 8.5, 50 mM NaCl, 5 mM MgCl2, 0.01% Brij35, 1 mM DTT, 1% DMSO) for 10-dose IC50 mode at a concentration 10-fold greater than the desired assay concentration. Standard reactions were performed in a total volume of 50 μl in assay buffer, with histone H2A (5 µM final) as substrate. To this 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 μM. Following a 60 minutes incubation at 30 °C, the reaction was stopped by adding 100 μL of 20% TCA. Each reaction was spotted onto filter plate (MultiScreen FB Filter 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 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 (Corning 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 mL 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 1 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 (Corning, Catalog #: 25-053-CI), neutralized with 1 mL 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 1 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:

Abcam, 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 #: NA934-1ML; 1:5,000) for 2 hours at RT, followed by 5 x 5 min washes with TBST, and incubation with ECL substrates (Bio-Rad, Catalog #: 1705061, 1705062). Chemiluminescent signal was captured with Fluochem HD2 imager (Proteinsimple) and analyzed by ImageJ.

To determine enzyme inhibition IC ₅₀ 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 cells (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. Cells 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. IC ₅₀ values were calculated using Graphpad Prism. Cell proliferation assay to determine IC ₅₀ on Granta-519 cells

Granta-519 cells were maintained in PRMI 1640 (Corning Cellgro, Catalog #: 10- 040-CV) medium supplemented with 10% v/v FBS (GE Healthcare, Catalog #: SH30910.03).

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 1 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 ^L 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 0.5x10 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.

One day 3, 10 ^L of Cell Counting Kit-8 (CCK-8, Jojindo, CK04-13) solution was added to a new 96 well plate. Cells incubated with drugs for 3 days were resuspended by pipetting up and down, and 100 ^L of cells were transferred to 96 well plate containing CCK-8 reagent to measure viable cells. Plates were incubated in CO2 incubator for 2 hours and OD450 values were measured with a microplate reader (iMark microplate reader, Bio-Rad).

For re-plating, compound working stocks were diluted at 1:50 with fresh medium and 10 ^L of diluted drugs were added to a new 96 well plate. Cells from Day 3 plate (50 ul) were added to 96 well plate containing fresh drug and additional 150 ^L 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.

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 IC50 values on day 10. Table 3. Biochemical and cellular potency (in Granta-519 cell line)

FaSSIF solubility Compounds were first dispersed in freshly prepared FaSSIF (http://biorelevant.com/site_media/upload/documents/How_to_m ake_FaSSIF_FeSSIF_and_FaSSGF.pdf ) buffer in 1 mg/mL respectively, and the standard samples were prepared by preparing 1 mg/mL of test compounds in DMSO. The compounds were then sufficient mixed by vortex mixer for 30 sec, and agitated at 25 °C using 300 rpm form 4 hour in thermo mixer. After incubation, the prepared samples were centrifuged at 10000 rpm for 10 min to remove the undissolved solid, the resulting supernatants were applied to HPLC. The actual concentrations of the compounds were evaluated by measuring the peak area, and the solubility (S) of compounds was calculated according to following equation:

S=Csmp=C std*(A smp/Astd) * (Vstd/Vsmp) Where C is the sample concentration in µg/mL, A is the peak area, and V is the injection volume. Warfarin (10-25 µg/mL), Atovaquone (<2 µg/mL) and Nimesulide (100-200 µg/mL) are positive controls in this experiment. Example 120 was measured to have a FaSSIF solubility of 45 µg/mL. In vivo pharmacokinetic properties of Example 120. In a rat (SD, male, non-fasted) non-crossover PK study, Example 120 was dosed at 1 mg/kg (DMA: 20%HPBCD=5:95, solution) via i.v. administration (N=3) and 1 mg/kg (0.5% Na CMC + 0.5%Tween80, solution) via oral gauge (p.o.) (N=3). It showed average T1/2 of 2.1 hr, Vss of 3.96 L/kg, plasma clearance of 27 mL/min/kg in the i.v. group; it showed average dose normalized AUC _0-inf of 287 ng*h*kg/mL/mg and 46% of oral bioavailability in the p.o. group. In vivo pharmacodynamic effect and tumor growth inhibition of Example 120 in Granta-519 mouse xenograft model. Granta-519 cells was maintained in DMEM medium supplemented with 10% fetal bovine serum and 2 mM L-Glutamine at 37 ºC in an atmosphere of 5% CO ₂ in air. Cells in exponential growth phase were harvested and 1x10 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 ^TM 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 120 or vehicle (0.5% Na CMC + 0.5% Tween80, suspension) were administered orally (QD or BID for Example 120, QD for vehicle) at a dose of 60 mg/kg (QD) or 30 mg/kg (BID) for 18 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.

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.

Following this protocol, Example 120 showed an average of 33% (N=5) tumor growth inhibition at 60 mg/kg with body weight gain of 3%; and an average of 71% (N = 5) tumor growth inhibition at 30 mg/kg with body weight loss of 4%. It also showed 98% inhibition of sDMA in tumor samples in 60 mg/kg QD dosing group and no detectable of sDMA in tumor samples in 30 mg/kg BID dosing group.

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 CR ¹² or N; 

R ¹ is -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3-C6halocycloalkyl, C2-C6alkenyl, -C2- C6haloalkenyl, -C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C≡CH, -C0- C ₆ alk-C≡C-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C≡C-C ₃ -C ₆ cycloalkyl, -C1-C6alk-aryl, -C1-C6alk-S-C1-C6alkyl, -C1-C6alk-S-C1-C6haloalkyl, -C1-C6alk-S-C3- C6cycloalkyl; -C1-C6alk-S-C3-C6halocycloalkyl -C1-C6alk-O-C1-C6alkyl, -C1-C6alk-O- C ₃ -C ₆ cycloalkyl, --C ₁ -C ₆ alk-S-CH ₂ -aryl, -C ₁ -C ₆ alk-C(O)NH-aryl, -C ₀ -C ₆ alk-S-aryl, -C ₀ - C ₆ alk-S(O)aryl, -C ₀ -C ₆ alk-S(O) ₂ aryl, or -C ₀ -C ₆ alk-Oaryl;

R ² is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-OH, -C ₀ -C ₆ alk-O-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl,

-C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl,

-C0-C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, -C0-C6alk-heterocycloalkyl, heteroaryl, or– CN;

R ³ is H, halo, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-OH, -C0-C6alk-O-C1-C6alkyl, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0-C6alk-N(C1- C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, -C0-C6alk-N(C1-C6alkyl)-C3- C ₆ cycloalkyl, -C ₀ -C ₆ alk-heterocycloalkyl, heteroaryl, or–CN;

R ⁴ is H, halo, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-OH, -C0-C6alk-O-C1-C6alkyl, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0-C6alk-N(C1- C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, -C0-C6alk-N(C1-C6alkyl)-C3- C ₆ cycloalkyl, -C ₀ -C ₆ alk-heterocycloalkyl, heteroaryl, or–CN;

or R ² and R ³ , together with the atoms to which they are attached, form a

C3-C6cycloalkenyl ring;

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

or R ³ and R ⁴ , together with the atom to which they are attached, form a C ₃ -C ₆ cycloalkyl ring or a heterocycloalkyl ring;

R ⁵ is H, halo, NH ₂ , or C ₁ -C ₆ alkyl;

R ⁶ is H, halo, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ haloalkyl, or -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl,

R ⁷ is H, -C1-C6alkyl, halo, -C1-C4haloalkyl, -C3-C6cycloalkyl, -C3-C6halocycloalkyl, -C1- C6alk-O-C1-C6alkyl, -C1-C6alk-S(O)-C1-C6alkyl, -C1-C6alk-S(O)2-C1-C6alkyl, - CR ⁸ R ^8’ CN, -NR ⁸ R ^8’ , -NHCR ⁸ R ^8’ CN, -NH-CN, -NHCONR ⁸ R ^8’ , -NHC(O)OR ⁹ , - NHC(O)-C1-C6alkyl, or -NHC(O)-C1-C6haloalkyl;

R ⁸ and R ^8’ are each independently H, C1-C6alkyl, or–C0-C6alk-OC1-C6alkyl;

or R ⁸ and R ^8’ , together with the atom to which they are attached, form a C ₃ -C ₆ cycloalkyl or a C3-C6heterocycloalkyl ring; and

R ⁹ is -C1-C6alkyl, or C0-C6alk-C3-C6cycloalkyl;

R ¹⁰ is H, halo, or C ₁ -C ₆ alkyl; and

R ¹¹ is H, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-C ₃ - C6halocycloalkyl, -C0-C6alk-OH, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0-C6alk- N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ - C ₆ cycloalkyl;

or R ¹¹ and R ¹ , together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring; and

R ¹² is H, halo, or -C ₁ -C ₆ alkyl.

Aspect 2. The compound of claim 1 wherein R ¹ is -C1-C6alk-aryl. Aspect 3. The compound of claim 2 wherein the -C1-C6alk-aryl is -CH2-aryl, -CH(OH)-aryl, - CH(F)-aryl, -CH(NH ₂ )-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl.

Aspect 4. The compound of claim 3 wherein the -C ₁ -C ₆ alk-aryl is -CH ₂ -phenyl, -CH ₂ -4- chlorophenyl, -CH2-4-fluorophenyl, -CH2-3,4-dichlorophenyl, -CH2-3,4-difluorophenyl, - CH2-3-fluoro-4-chlorophenyl, -CH2-3-chloro-4-fluorophenyl, -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(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(NH ₂ )-3,4-difluorophenyl, -CH(NH ₂ )-3-fluoro-4-chlorophenyl, -CH(NH ₂ )-3-chloro-4- fluorophenyl, -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, - C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4-dichlorophenyl, -C(Me)(OH)-3,4- difluorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, or -C(Me)(OH)-3-chloro-4- fluorophenyl.

Aspect 5. The compound of claim 1 wherein R ₁ is -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ alkyl. Aspect 6. The compound of claim 5 wherein the -C0-C6alk-C≡C-C1-C6alkyl is -CH(OH)-C≡C- C1-C6alkyl, -CH(F)-C≡C-C1-C6alkyl, -CH(NH2)-C≡C-C1-C6alkyl, -CH(Me)-C≡C-C1- C ₆ alkyl, or -C(Me)(OH)-C≡C-C ₁ -C ₆ alkyl. Aspect 7. The compound of claim 6 wherein the -C0-C6alk-C≡C-C1-C6alkyl is -CH(OH)-C≡C- CH3, -CH(F)-C≡C-CH3, -CH(NH2)-C≡C-CH3, -CH(Me)-C≡C-CH3, or -C(Me)(OH)-C≡C- CH ₃ . Aspect 8. The compound of claim 1 wherein R ₁ is -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ haloalkyl. Aspect 9. The compound of claim 8 wherein the -C0-C6alk-C≡C-C1-C6haloalkyl is -CH(OH)- C≡C-C ₁ -C ₆ haloalkyl, -CH(F)-C≡C-C ₁ -C ₆ haloalkyl, -CH(NH ₂ )-C≡C-C ₁ -C ₆ haloalkyl, - CH(Me)-C≡C-C ₁ -C ₆ haloalkyl, or -C(Me)(OH)-C≡C-C ₁ -C ₆ haloalkyl. Aspect 10. The compound of claim 9 wherein the -C0-C6alk-C≡C-C1-C6haloalkyl is -CH(OH)- C≡C-CF ₃ , -CH(F)-C≡C-CF ₃ , -CH(NH ₂ )-C≡C-CF ₃ , -CH(Me)-C≡C-CF ₃ , or -C(Me)(OH)- C≡C-CF ₃ . Aspect 11. The compound of claim 1 wherein R1 is -C0-C6alk-C≡C-C3-C6cycloalkyl. Aspect 12. The compound of claim 11 wherein the -C0-C6alk-C≡C-C3-C6cycloalkyl is -CH(OH)- C≡C-C ₃ -C ₆ cycloalkyl, -CH(F)-C≡C-C ₃ -C ₆ cycloalkyl, -CH(NH ₂ )-C≡C-C ₃ -C ₆ cycloalkyl, - CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)-C≡C-C3-C6cycloalkyl. Aspect 13. The compound of claim 12 wherein the -C0-C6alk-C≡C-C3-C6cycloalkyl is -CH(OH)- C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH ₂ )-C≡C-cyclopropyl, -CH(Me)-C≡C- cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl. Aspect 14. The compound of claim 1 wherein R ¹ is -C0-C6alk-S-aryl. Aspect 15. The compound of claim 14 wherein the -C ₀ -C ₆ alk-S-aryl is -S-4-chlorophenyl, -S-4- fluorophenyl, -S-3,4-dichlorophenyl, -S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or - S-3-chloro-4-fluorophenyl. Aspect 16. The compound of claim 1 wherein R ¹ is -C0-C6alk-S(O)-aryl. Aspect 17. The compound of claim 16 wherein the -C ₀ -C ₆ alk-S(O)-aryl is -S(O)-4-chlorophenyl, -S(O)-4-fluorophenyl, -S(O)-3,4-dichlorophenyl, -S(O)-3,4-difluorophenyl, -S(O)-3-fluoro- 4-chlorophenyl, or -S(O)-3-chloro-4-fluorophenyl. Aspect 18. The compound of claim 1 wherein R ¹ is -C ₀ -C ₆ alk-S(O) ₂ -aryl. Aspect 19. The compound of claim 18 wherein the -C0-C6alk-S(O)2-aryl is -S(O)2-4- chlorophenyl, -S(O)2-4-fluorophenyl -S(O)2-3,4-dichlorophenyl, -S(O)2-3,4-difluorophenyl, - S(O) ₂ -3-fluoro-4-chlorophenyl, or -S(O) ₂ -3-chloro-4-fluorophenyl. Aspect 20. The compound of claim 1 wherein R ¹ is -C ₀ -C ₆ alk-O-aryl. Aspect 21. The compound of claim 20 wherein the -C0-C6alk-O-aryl is -O-4-chlorophenyl, -O-4- fluorophenyl, -O-3,4-dichlorophenyl, -O-3,4-difluorophenyl, -O-3-fluoro-4-chlorophenyl, or -O-3-chloro-4-fluorophenyl. Aspect 22. The compound of any one of claims 1 to 21 wherein R ⁵ is H. Aspect 23. The compound of any one of claims 1 to 22 wherein R ¹¹ is H. Aspect 24. The compound of any one of claims 1 to 23 that is a compound of Formula I or

Formula II. Aspect 25. The compound of claim 24 wherein A is CR ¹² . Aspect 26. The compound of claim 25 wherein R ¹² is H. Aspect 27. The compound of claim 25 wherein R ¹² is -C ₁ -C ₆ alkyl. Aspect 28. The compound of claim 27 wherein the -C1-C6alkyl is methyl. Aspect 29. The compound of claim 24 wherein A is N. Aspect 30. The compound of any one of claims 24 to 29 wherein R ⁶ is H. Aspect 31. The compound of any one of claims 24 to 29 wherein R ⁶ is halo. Aspect 32. The compound of any one of claims 1 to 31 that is a compound of Formula I or

Formula III. Aspect 33. The compound of claim 32 wherein R ² is H. Aspect 34. The compound of claim 32 wherein R ² is -C1-C6alkyl. Aspect 35. The compound of any one of claims 32 to 34 wherein R ³ is H. Aspect 36..The compound of any one of claims 32 to 35 wherein R ⁴ is H. Aspect 37. The compound of any one of claims 1 to 31 that is a compound of Formula II or Formula IV. Aspect 38. The compound of claim 37 wherein R ⁷ is halo. Aspect 39. The compound of claim 37 wherein R ⁷ is -C ₁ -C ₄ haloalkyl. Aspect 40. The compound of claim 39 wherein -C ₁ -C ₄ haloalkyl is–CH ₂ CH ₂ Cl, -CH ₂ CH ₂ F, or– CH2CHF2. Aspect 41. The compound of claim 37 wherein R ⁷ is -C3-C6cycloalkyl. Aspect 42. The compound of claim 41 wherein the -C ₃ -C ₆ cycloalkyl is cyclopropyl. Aspect 43. The compound of claim 37 wherein R ⁷ is -C1-C6alk-O-C1-C6alkyl. Aspect 44. , The compound of claim 37 wherein R ⁷ is -C1-C6alk-S(O)-C1-C6alkyl. Aspect 45. The compound of claim 37 wherein R ⁷ is -C ₁ -C ₆ alk-S(O) ₂ -C ₁ -C ₆ alkyl. Aspect 46. The compound of claim 37 wherein R ⁷ is -NH-CN. Aspect 47. The compound of claim 37 wherein R ⁷ is -CR ⁸ R ^8’ CN. Aspect 48. The compound of claim 37 wherein R ⁷ is NHCR ⁸ R ^8’ CN. Aspect 49. The compound of claim 37 wherein R ⁷ is -NHCONR ⁸ R ^8’ . Aspect 50. The compound of claim 37 wherein R ⁷ is -NHR ⁸ R ^8’ . Aspect 51. The compound of any one of claims 47 to 50 wherein R ⁸ and R ^8’ are each,

independently, H or -C ₁ -C ₆ alkyl. Aspect 52. The compound of claim 37 wherein R ⁷ is -NHC(O)-C1-C6alkyl. Aspect 53. The compound of claim 37 wherein R ⁷ is -NHC(O)-C1-C6haloalkyl. Aspect 54. The compound of claim 37 wherein R ⁷ is -NHC(O)OR ⁹ . Aspect 55. The compound of claim 54 wherein R ⁹ is -C1-C6alkyl. Aspect 56. The compound of any one of any one of claims 1 to 23 or 32 to 55 wherein R ¹⁰ is H. Aspect 57. The compound of any one of any one of claims 1 to 23 or 32 to 55 wherein R ¹⁰ is - C ₁ -C ₆ alkyl. Aspect 58. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable excipient. Aspect 59. 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 claims 1 to 57. Aspect 60. 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 claims 1 to 57. Aspect 61. The method of claim 60, 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 62. A compound of Formula I, Formula II, Formula III, or Formula IV:

or a pharmaceutically acceptable salt or solvate thereof;

wherein

A is CR ¹² or N; 

R ¹ is -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3-C6halocycloalkyl, C2-C6alkenyl, -C2- C ₆ haloalkenyl, -C ₀ -C ₆ alk-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C≡CH, - C0-C6alk-C≡C-C1-C6alkyl, -C0-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3- C6cycloalkyl, -C1-C6alk-aryl, -C1-C6alk-S-C1-C6alkyl, -C1-C6alk-S-C1-C6haloalkyl, - C ₁ -C ₆ alk-S-C ₃ -C ₆ cycloalkyl; -C ₁ -C ₆ alk-S-C ₃ -C ₆ halocycloalkyl -C ₁ -C ₆ alk-O-C ₁ - C ₆ alkyl, -C ₁ -C ₆ alk-O-C ₃ -C ₆ cycloalkyl, --C ₁ -C ₆ alk-S-CH ₂ -aryl, -C ₁ -C ₆ alk-C(O)NH- aryl, -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, -C0-C6alk-S(O)2aryl, -C0-C6alk-Oaryl, - C ₀ -C ₆ alk-heteroaryl, -C ₁ -C ₆ alk-O-heteroaryl, -C ₁ -C ₆ alk-S-heteroaryl, or -C ₁ -C ₆ alk- NH-heteroaryl;

R ² is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-OH, -C0-C6alk-O-C1-C6alkyl, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl,

-C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl,

-C0-C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, -C0-C6alk-heterocycloalkyl, heteroaryl, or –CN;

R ³ is H, halo, -C ₁ -C ₆ alkyl, -C ₁ -C ₆ haloalkyl, -C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-OH, -C ₀ -C ₆ alk-O-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-N(C ₁ - C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, -C0-C6alk-N(C1-C6alkyl)-C3- C ₆ cycloalkyl, -C ₀ -C ₆ alk-heterocycloalkyl, heteroaryl, or–CN; R ⁴ is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-OH, -C ₀ -C ₆ alk-O-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-N(C ₁ - C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₃ - C6cycloalkyl, -C0-C6alk-heterocycloalkyl, heteroaryl, or–CN;

or R ² and R ³ , together with the atoms to which they are attached, form a

C ₃ -C ₆ cycloalkenyl ring;

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

or R ³ and R ⁴ , together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring;

R ⁵ is H, halo, NH ₂ , or C ₁ -C ₆ alkyl;

R ⁶ is H, halo, -C1-C6alkyl, -C1-C6haloalkyl, or -C0-C6alk-C3-C6cycloalkyl,

R ⁷ is H, -C ₁ -C ₆ alkyl, halo, -C ₁ -C ₄ haloalkyl, -C ₃ -C ₆ cycloalkyl, -C ₃ -C ₆ halocycloalkyl, -C ₁ - C ₆ alk-O-C ₁ -C ₆ alkyl, -C ₁ -C ₆ alk-S(O)-C ₁ -C ₆ alkyl, -C ₁ -C ₆ alk-S(O) ₂ -C ₁ -C ₆ alkyl, - CR ⁸ R ^8’ CN, -NR ⁸ R ^8’ , -NHCR ⁸ R ^8’ CN, -NH-CN, -NHCONR ⁸ R ^8’ , -NHC(O)OR ⁹ , - NHC(O)-C1-C6alkyl, -NHC(O)-C1-C6haloalkyl, or -NH-C1-C6alk-C(O)-C1-C6alkyl; R ⁸ and R ^8’ are each independently H, C ₁ -C ₆ alkyl, or–C ₀ -C ₆ alk-OC ₁ -C ₆ alkyl;

or R ⁸ and R ^8’ , together with the atom to which they are attached, form a C3-C6cycloalkyl or a C3-C6heterocycloalkyl ring; and

R ⁹ is -C ₁ -C ₆ alkyl, or C ₀ -C ₆ alk-C ₃ -C ₆ cycloalkyl;

R ¹⁰ is H, halo, or C1-C6alkyl; and

R ¹¹ is H, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3- C ₆ halocycloalkyl, -C ₀ -C ₆ alk-OH, -C ₀ -C ₆ alk-NH ₂ , -C ₀ -C ₆ alk-NH-C ₁ -C ₆ alkyl, -C ₀ - C ₆ alk-N(C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkyl, -C ₀ -C ₆ alk-NH-C ₃ -C ₆ cycloalkyl, -C ₀ -C ₆ alk-N(C ₁ - C6alkyl)-C3-C6cycloalkyl;

or R ¹¹ and R ¹ , together with the atom to which they are attached, form a C ₃ -C ₆ cycloalkyl ring or a heterocycloalkyl ring; and

R ¹² is H, halo, or -C1-C6alkyl.

Aspect 63. The compound of aspect 62 wherein R ¹ is -C1-C6alk-aryl.

Aspect 64. The compound of aspect 63 wherein the -C ₁ -C ₆ alk-aryl is -CH ₂ -aryl, -CH(OH)-aryl, - CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl. Aspect 65. The compound of aspect 64 wherein the -C1-C6alk-aryl is -CH2-phenyl, -CH2-4- chlorophenyl, -CH ₂ -4-fluorophenyl, -CH ₂ -3,4-dichlorophenyl, -CH ₂ -3,4-difluorophenyl, - CH ₂ -3-fluoro-4-chlorophenyl, -CH ₂ -3-chloro-4-fluorophenyl, -CH ₂ -(2,4-difluorophenyl), - CH2-(3-methyl-4-chlorophenyl), -CH2-(2-hydroxymethyl-4-chlorophenyl), -CH2-(2- aminomethyl-4-chlorophenyl), -CH2-(2-(methylaminomethyl)-4-chlorophenyl), -CH2-(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-chloro-4-fluorophenyl, -CH(OH)-(2,4-difluorophenyl), -CH(OH)-(3-methyl-4- chlorophenyl), -CH(OH)-(2-hydroxymethyl-4-chlorophenyl), -CH(OH)-(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)-(2,4-difluorophenyl), -CH(F)-(3-methyl-4-chlorophenyl), - 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(NH2)-3,4-difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, - CH(NH2)-3-chloro-4-fluorophenyl, -CH(NH2)-(2,4-difluorophenyl), -CH(NH2)-(3-methyl-4- chlorophenyl), -CH(NH ₂ )-(2-hydroxymethyl-4-chlorophenyl), -CH(NH ₂ )-(2-aminomethyl-4- chlorophenyl), -CH(NH ₂ )-(2-(methylaminomethyl)-4-chlorophenyl), -CH(NH ₂ )-(2- hydroxymethyl-4,5-difluorophenyl), -CH(NH2)-(2-aminomethyl-4,5-difluorophenyl), - CH(NH ₂ )-(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)-(2,4-difluorophenyl), -CH(Me)- (3-methyl-4-chlorophenyl), -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), -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)- (2,4-difluorophenyl), -C(Me)(OH)-(3-methyl-4-chlorophenyl), -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), or–C(Me)(OH)-(2- (methylaminomethyl)-4,5-difluorophenyl).

Aspect 66. The compound of aspect 62 wherein R1 is -C0-C6alk-C≡C-C1-C6alkyl. Aspect 67. The compound of aspect 66 wherein the -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ alkyl is -CH(OH)- C≡C-C ₁ -C ₆ alkyl, -CH(F)-C≡C-C ₁ -C ₆ alkyl, -CH(NH ₂ )-C≡C-C ₁ -C ₆ alkyl, -CH(Me)-C≡C-C ₁ - C6alkyl, or -C(Me)(OH)-C≡C-C1-C6alkyl. Aspect 68. The compound of aspect 67 wherein the -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ alkyl is -CH(OH)- C≡C-CH ₃ , -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-CH3. Aspect 69. The compound of aspect 62 wherein R1 is -C0-C6alk-C≡C-C1-C6haloalkyl. Aspect 70. The compound of aspect 69 wherein the -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ haloalkyl is -CH(OH)- C≡C-C1-C6haloalkyl, -CH(F)-C≡C-C1-C6haloalkyl, -CH(NH2)-C≡C-C1-C6haloalkyl, - CH(Me)-C≡C-C1-C6haloalkyl, or -C(Me)(OH)-C≡C-C1-C6haloalkyl. Aspect 71. The compound of aspect 70 wherein the -C ₀ -C ₆ alk-C≡C-C ₁ -C ₆ haloalkyl is -CH(OH)- C≡C-CF3, -CH(F)-C≡C-CF3, -CH(NH2)-C≡C-CF3, -CH(Me)-C≡C-CF3, or -C(Me)(OH)- C≡C-CF3. Aspect 72. The compound of aspect 62 wherein R ₁ is -C ₀ -C ₆ alk-C≡C-C ₃ -C ₆ cycloalkyl. Aspect 73. The compound of aspect 72 wherein the -C ₀ -C ₆ alk-C≡C-C ₃ -C ₆ cycloalkyl is - CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3- C ₆ cycloalkyl, -CH(Me)-C≡C-C ₃ -C ₆ cycloalkyl, or -C(Me)(OH)-C≡C-C ₃ -C ₆ cycloalkyl. Aspect 74. The compound of aspect 73 wherein the -C0-C6alk-C≡C-C3-C6cycloalkyl is - CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH ₂ )-C≡C-cyclopropyl, - CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl. Aspect 75. The compound of aspect 62 wherein R ¹ is -C0-C6alk-S-aryl. Aspect 76. The compound of aspect 75 wherein the -C0-C6alk-S-aryl is -S-4-chlorophenyl, -S-4- fluorophenyl, -S-3,4-dichlorophenyl, -S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or - S-3-chloro-4-fluorophenyl. Aspect 77. The compound of aspect 62 wherein R ¹ is -C0-C6alk-S(O)-aryl. Aspect 78. The compound of aspect 77 wherein the -C ₀ -C ₆ alk-S(O)-aryl is -S(O)-4- chlorophenyl, -S(O)-4-fluorophenyl, -S(O)-3,4-dichlorophenyl, -S(O)-3,4-difluorophenyl, - S(O)-3-fluoro-4-chlorophenyl, or -S(O)-3-chloro-4-fluorophenyl. Aspect 79. The compound of aspect 62 wherein R ¹ is -C ₀ -C ₆ alk-S(O) ₂ -aryl. Aspect 80. The compound of aspect 79 wherein the -C ₀ -C ₆ alk-S(O) ₂ -aryl is -S(O) ₂ -4- chlorophenyl, -S(O)2-4-fluorophenyl -S(O)2-3,4-dichlorophenyl, -S(O)2-3,4-difluorophenyl, - S(O)2-3-fluoro-4-chlorophenyl, or -S(O)2-3-chloro-4-fluorophenyl. Aspect 81. The compound of aspect 62 wherein R ¹ is -C ₀ -C ₆ alk-O-aryl. Aspect 82. The compound of aspect 81 wherein the -C0-C6alk-O-aryl is -O-4-chlorophenyl, -O- 4-fluorophenyl, -O-3,4-dichlorophenyl, -O-3,4-difluorophenyl, -O-3-fluoro-4-chlorophenyl, or -O-3-chloro-4-fluorophenyl. Aspect 83. The compound of aspect 62, wherein R ¹ is–C0-C6alk-heteroaryl, -C1-C6alk-O- heteroaryl, -C1-C6alk-S-heteroaryl, or -C1-C6alk-NH-heteroaryl. Aspect 84. The compound of aspect 83 wherein the–C ₀ -C ₆ alk-heteroaryl is 2-(2-amino-3- bromoquinolin-7-yl)ethyl, 2-(2-amino-3-chloroquinolin-7-yl)ethyl, or 5-chlorothiophen-2- yl)(hydroxy)methyl. Aspect 85. The compound of any one of aspects 62 to 84 wherein R ⁵ is H. Aspect 86. The compound of any one of aspects 62 to 85 wherein R ¹¹ is H. Aspect 87. The compound of any one of aspects 62 to 86 that is a compound of Formula I or Formula II. Aspect 88. The compound of aspect 87 wherein A is CR ¹² . Aspect 89. The compound of aspect 88 wherein R ¹² is H. Aspect 90. The compound of aspect 88 wherein R ¹² is -C ₁ -C ₆ alkyl. Aspect 91. The compound of aspect 90 wherein the -C1-C6alkyl is methyl. Aspect 92. The compound of aspect 87 wherein A is N. Aspect 93. The compound of any one of aspects 87 to 92 wherein R ⁶ is H. Aspect 94. The compound of any one of aspects 87 to 92 wherein R ⁶ is halo. Aspect 95. The compound of any one of aspects 62 to 94 that is a compound of Formula I or Formula III. Aspect 96. The compound of aspect 95 wherein R ² is H. Aspect 97. The compound of aspect 95 wherein R ² is -C1-C6alkyl. Aspect 98. The compound of any one of aspects 95 to 97 wherein R ³ is H. Aspect 99..The compound of any one of aspects 95 to 98 wherein R ⁴ is H. Aspect 100. The compound of any one of aspects 62 to 94 that is a compound of Formula II or Formula IV. Aspect 101. The compound of aspect 100 wherein R ⁷ is halo. Aspect 102. The compound of aspect 100 wherein R ⁷ is -C1-C4haloalkyl. Aspect 103. The compound of aspect 102 wherein -C1-C4haloalkyl is–CH2CH2Cl, - CH ₂ CH ₂ F, or–CH ₂ CHF ₂ . Aspect 104. The compound of aspect 100 wherein R ⁷ is -C ₃ -C ₆ cycloalkyl. Aspect 105. The compound of aspect 104 wherein the -C3-C6cycloalkyl is cyclopropyl. Aspect 106. The compound of aspect 100 wherein R ⁷ is -C1-C6alk-O-C1-C6alkyl. Aspect 107. , The compound of aspect 100 wherein R ⁷ is -C ₁ -C ₆ alk-S(O)-C ₁ -C ₆ alkyl. Aspect 108. The compound of aspect 100 wherein R ⁷ is -C1-C6alk-S(O)2-C1-C6alkyl. Aspect 109. The compound of aspect 100 wherein R ⁷ is -NH-CN. Aspect 110. The compound of aspect 100 wherein R ⁷ is -CR ⁸ R ^8’ CN. Aspect 111. The compound of aspect 100 wherein R ⁷ is NHCR ⁸ R ^8’ CN. Aspect 112. The compound of aspect 100 wherein R ⁷ is -NHCONR ⁸ R ^8’ . Aspect 113. The compound of aspect 100 wherein R ⁷ is -NR ⁸ R ^8’ . Aspect 114. The compound of any one of aspects 110 to 113 wherein R ⁸ and R ^8’ are each, independently, H or -C1-C6alkyl. Aspect 115. The compound of aspect 100 wherein R ⁷ is -NHC(O)-C1-C6alkyl. Aspect 116. The compound of aspect 100 wherein R ⁷ is -NHC(O)-C _1- C ₆ haloalkyl. Aspect 117. The compound of aspect 100 wherein R ⁷ is -NHC(O)OR ⁹ . Aspect 118. The compound of aspect 117 wherein R ⁹ is -C1-C6alkyl. Aspect 119. The compound of aspect 100 wherein R ⁷ is -NH-C ₁ -C ₆ alk-C(O)-C ₁ -C ₆ alkyl. Aspect 120. The compound of any one of any one of aspects 62 to 84 or 93 to 119 wherein R ¹⁰ is H. Aspect 121. The compound of any one of any one of aspects 62 to 86 or 95 to 119 wherein R ¹⁰ is -C ₁ -C ₆ alkyl. Aspect 122. A pharmaceutical composition comprising a compound according to any one of the preceding aspects and a pharmaceutically acceptable excipient. Aspect 123. 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 62 to 121. Aspect 124. 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 62 to 121. Aspect 125. The method of aspect 124, 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), CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers;

glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.