WO2018152501A1 - Selective inhibitors of protein arginine methyltransferase 5 (prmt5) - Google Patents

Selective inhibitors of protein arginine methyltransferase 5 (prmt5) Download PDF

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WO2018152501A1
WO2018152501A1 PCT/US2018/018731 US2018018731W WO2018152501A1 WO 2018152501 A1 WO2018152501 A1 WO 2018152501A1 US 2018018731 W US2018018731 W US 2018018731W WO 2018152501 A1 WO2018152501 A1 WO 2018152501A1
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alk
compound
formula
c6alk
alkyl
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PCT/US2018/018731
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French (fr)
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Juan Luengo
Raul A. LEAL
Hong Lin
Rupa SHETTY
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Prelude Therapeutics, Incorporated
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Publication of WO2018152501A1 publication Critical patent/WO2018152501A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the disclosure is directed to PRMT5 inhibitors and methods of their use.
  • 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.
  • MMA monomethylarginine
  • ADMA ⁇ NG asymmetric dimethylarginine
  • SDMA ⁇ NG,N'G symmetric dimethylarginine
  • PRMTs protein arginine methyl transferases
  • PRMTs 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.
  • SAM S-adenosylmethionine
  • 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.
  • PRMT5 is as a general transcriptional repressor that functions with numerous transcription factors and repressor complexes, including BRG1 and hBRM, Blimpl, and Snail. This enzyme, once recruited to a promoter, symmetrically dimethylates H3R8 and H4R3. Importantly, the H4R3 site is a major target for PRMTl methylation (ADMA) and is generally regarded as a transcriptional activating mark. Thus, both H4R3me2s (repressive; me2s indicates SDMA
  • H4R3me2a active; me2a indicates ADMA modification
  • H4R3me2a active; me2a indicates ADMA modification
  • PRMTs 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.
  • 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.
  • the transcription factor MYC also safeguards proper pre-messenger-RNA splicing as an essential step in lymphomagenesis. Koh et al. Nature 2015, 523 7558; Hsu et al. Nature 2015 525, 384.
  • 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.
  • A is CH or N
  • n 1 or 2;
  • 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, - C 0 -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 - C6cycloalkyl, -C1-C6alk-aryl, -C1-C6alk-S-C1-C6alkyl, -C1
  • R 2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
  • R 2a and R 2b are each independently -C 1 -C 6 alkyl, or -C 0 -C 6 alk-C 3 -C 6 cycloalkyl
  • R 3 is H, halo, -C 1 -C 6 alkyl, or NH 2 ;
  • R 4 is H, halo, -C 1 -C 6 alkyl, -C 1 -C 4 haloalkyl, -C 2 -C 6 heterocycloalkyl, oxo-substituted-C 2 - C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl.
  • R 4 is H, halo, -C 1 -C 6 alkyl, -C 1 -C 4 haloalkyl, -C 2 -C 6 heterocycloalkyl, oxo-substituted-C 2 - C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl.
  • A is CH, CR 6 or N
  • n 1 or 2;
  • R 1 is -C 0 -C 6 alk-C 3 -C 6 cycloalkyl, -C 0 -C 6 alk-C 3 -C 6 halocycloalkyl; -C 2 -C 6 alkenyl, -C 2 - 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- C 6 cycloalkyl, -C 1 -C 6 alk-aryl, -C 1 -C 6 alk-S-C 1 -C 6 alkyl
  • R 2a and R 2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
  • R 3 is H, halo, -C1-C6alkyl, or NH2;
  • R 4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C 6 heterocycloalkyl, -C 3 -C 6 cycloalkyl, or -O-C 1 -C 4 alkyl;
  • R 5 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- 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, or -C 0 -C 6 alk-N(C 1 - C 6 alkyl)-C 3 -C 6 cycloalkyl;
  • R 5 and R 1 together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring;
  • R 6 is halo or -C 1 -C 6 alkyl
  • R 6a is H, halo, or -C1-C6alkyl.
  • alkyl when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), preferably 1 to 6 carbons atoms (“Ci-Ce”), in the group.
  • alkyl groups include methyl (Me, Cialkyl), ethyl (Et, C 2 alkyl), n-propyl (C 3 alkyl), isopropyl (C 3 alkyl), butyl (C 4 alkyl), isobutyl (C 4 alkyl), sec-butyl (C 4 alkyl), tert-butyl (C 4 alkyl), pentyl (Csalkyl), isopentyl (Csalkyl), tert-pentyl (Csalkyl), hexyl (C 6 alkyl), isohexyl (C 6 alkyl), and the like.
  • halo when used alone or as part of a substituent group refers to chloro, fluoro, bromo, or iodo.
  • 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 (- CH2CI), and the like.
  • cycloalkyl 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").
  • Examples of cycloalkyl groups include, for example, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C5), cyclohexyl (C 6 ), 1-methylcyclopropyl (C 4 ), 2- methylcyclopentyl (C 4 ), adamantanyl (C10), and the like.
  • 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 halocycloalkyl groups include, for example, chlorocyclopropyl (C 3 ), fluorocyclobutyl (C 4 ), bromocyclopentyl (C5), iodocyclohexyl (C 6 ), and the like.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 (“C 3 -Cio”), preferably from 3 to 6 carbon atoms (“C 3 -C6”) and containing at least one carbon-carbon double bond.
  • cycloalkenyl groups include, but are not limited to cyclopropenyl, cyclobutenyl, and the like.
  • 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 with a halogen atom or with a - Ci-C 3 alkyl group.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • aryl groups include phenyl, naphtyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, iodophenyl, chlorofluorophenyl, fluoronaphthyl, difluoronaphthyl, chloronaphthyl, bromonaphthyl, iodonaphthyl, methylphenyl, ethylphenyl, and the like.
  • 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 with a halogen atom or with a -C1-C3 alkyl group.
  • Halogen atoms include chlorine, fluorine, bromine, and iodine.
  • heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, p
  • C1-C3 includes C1-C3, Ci- C2, C2-C3, Ci, C2, and C 3 .
  • Ci-C6alk 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)-CH 2 -, and -C(CH3)2-.
  • -Coalk- refers to a bond.
  • the Ci-C 6 alk can be substituted with one or more -OH, - H2, or halo (e.g., -F, -CI, -Br, with -F being preferred) substituents.
  • “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.
  • “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.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic
  • 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.
  • non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • 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.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • a “solvate” refers to a physical association of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII with one or more solvent molecules.
  • Subject includes humans.
  • the terms “human,” “patient,” and “subject” are used interchangeably herein.
  • 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.
  • Compounds of the present disclosure are meant to embrace compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula VIII as described herein, as well as their subgenera, which expression includes the stereoisomers of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula VIII as well as the pharmaceutically acceptable salts and solvates, where the context so permits.
  • the compounds of the present invention may also contain unnatural proportions of one, two, three, or more atomic isotopes at one or more of the atoms that constitute such
  • Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question.
  • the compounds may incorporate radioactive isotopes, such as, for example, tritium ( 3 H), iodine-125 ( 125 I), and/or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium ( 2 H), carbon-13 ( 13 C), and/or nitrogen- 15 ( 15 N).
  • radioactive isotopes such as, for example, tritium ( 3 H), iodine-125 ( 125 I), and/or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium ( 2 H), carbon-13 ( 13 C), and/or nitrogen- 15 ( 15 N).
  • isotopic variations can provide additional utilities to those described elsewhere within this application.
  • isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and/or imaging reagents,
  • isotopic variants of the compounds of the invention can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • 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:
  • a in Formula I is N or CH. In some aspects, A is N and the compounds of Formula I are of Formula IA
  • A is CH and the compounds of Formula I are of Formula IB
  • a in Formula II is N or CH.
  • A is N and the compounds of Formula II are of Formula IIA:
  • A is CH and the com ounds of Formula II are of Formula IIB:
  • n in Formula I, Formula II, Formula III, or Formula IV is 1 or 2. In some embodiments of the compounds of Formula I, Formula II, Formula III, or Formula IV, n is 1. In other embodiments, n is 2.
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C 0 -C 6 alk-C 3 -C 6 cycloalkyl, -C 0 -C 6 alk-C 3 -C 6 halocycloalkyl; -C 2 -C 6 alkenyl, -C 2 -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, -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
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C0- 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, or -C1-C6alk-aryl.
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C 6 alk-C 3 -C 6 cycloalkyl, 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-C 3 cycloalkyl, -C 5 alk-C 3 cycloalkyl ⁇ -C 6 alk-C 3 cycloalkyl, -C 0 alk- C4cycloalkyl, -C1alk-C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, - C5alk-C4cycloalkyl ⁇
  • R 1 is -CH2- cyclopropyl.
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C 6 alk-C 3 -C 6 halocycloalkyl, for example, -C 0 alk-C 3 halocycloalkyl, -C 1 alk-C 3 halocycloalkyl, -C 2 alk- C 3 halocycloalkyl, -C 3 alk-C 3 halocycloalkyl, -C 4 alk-C 3 halocycloalkyl, -C 5 alk-C 3 halocycloalkyl ⁇ - C6alk-C3halocycloalkyl, -C0alk-C4halocycloalkyl, -C1alk-C4halocycloalkyl, -C2alk-C4halocycloalkyl, -C3alk
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C 2 - C6alkenyl, for example, vinyl, allyl, and the like.
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C6alk-C1-C6alkyl, for example, -C0alk-C1alkyl, -C1alk-C1alkyl, -C2alk-C1alkyl, -C3alk-C1alkyl, - 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, - C3alk-C2alkyl, -C4alk-C2alkyl, -C5alk-C2alkyl ⁇ -C6alk-C2alkyl, -C0alk-C3alkyl, -C1alk-C3alkyl, -C1alk
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C 0 - C 6 alk-C 1 -C 6 haloalkyl, for example, -C 0 alk-C 1 haloalkyl, -C 1 alk-C 1 haloalkyl, -C 2 alk-C 1 haloalkyl, - C3alk-C1haloalkyl, -C4alk-C1haloalkyl, -C5alk-C1haloalkyl ⁇ -C6alk-C1haloalkyl, -C0alk-C2haloalkyl, - C1alk-C2haloalkyl, -C2alk-C2haloalkyl, -C3alk-C2haloalkyl, -C4alk-C2haloalkyl, -C5alk-C2haloalkyl ⁇ -
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C 0 - C 6 alk-C ⁇ CH, for example, -C 0 alk-C ⁇ CH, -C 1 alk-C ⁇ CH, -C 2 alk-C ⁇ CH, -C 3 alk-C ⁇ CH, -C 4 alk- C ⁇ CH, -C5alk-C ⁇ CH, -C6alk-C ⁇ CH, ethynyl, propargyl, -CH(OH)-C ⁇ CH, -CH(F)-C ⁇ CH, - CH(NH 2 )-C ⁇ CH, -CH(Me)-C ⁇ CH, -C(Me)(OH)-C ⁇ CH, and the like.
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C 0 - C6alk-C ⁇ C-C1-C6alkyl, for example, -C0alk-C ⁇ C-C1alkyl, -C1alk-C ⁇ C-C1alkyl, -C2alk-C ⁇ C-C1alkyl, -C3alk-C ⁇ C-C1alkyl, -C4alk-C ⁇ C-C1alkyl, -C5alk-C ⁇ C-C1alkyl ⁇ -C6alk-C ⁇ C-C1alkyl, -C0alk-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
  • 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-CH3, or -C(Me)(OH)-C ⁇ C-CH3.
  • R 1 is -CH(OH)-C ⁇ C- CH3.
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C 0 - 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-C1haloalkyl, -C5alk-C ⁇ C-C1haloalkyl ⁇ - C 6 alk-C ⁇ C-Cihaloalkyl, -Coalk-C ⁇ C-C 2 haloalkyl, -Cialk-C ⁇ C-C 2 haloalkyl, -C 2 alk-C ⁇ C- C 2 haloalkyl, -C 3 alk-C
  • R 1 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 , -C(Me)(OH)-C ⁇ C-CF 3 , and the like.
  • R 1 is -CH(OH)-C ⁇ C-CF 3 .
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -Co- C6alk-C ⁇ C-C 3 -C6cycloalkyl, for example, -Coalk-C ⁇ C-C 3 cycloalkyl, -Coalk-C ⁇ C-C 4 cycloalkyl, - Coalk-C ⁇ C-C 5 cycloalkyl, -Coalk-C ⁇ C-C 6 cycloalkyl, -Cialk-C ⁇ C-C 3 cycloalkyl, -Cialk-C ⁇ C- C 4 cycloalkyl, -Cialk-C ⁇ C-C 5 -cycloalkyl, -Cialk-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 4
  • 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.
  • R 1 is -CH(OH)-C ⁇ C-cyclopropyl.
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C 6 alk-aryl, for example, -C 1 alk-aryl, -C 2 alk-aryl, -C 3 alk-aryl, -C 4 alk-aryl, -C 5 alk-aryl, -C 6 alk-aryl, - CH(OH)-aryl, -CH(F)-aryl, -CH(NH 2 )-aryl, -CH(Me)-aryl, -C(Me)(OH)-aryl, and the like.
  • R 1 is -C1-C6alk-aryl
  • -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4- difluorophenyl, -3-fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl, or 4-chloro-3-methylphenyl.
  • R 1 is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, - CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-4-chloro-3-methylphenyl, -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)-4- chloro-3-methylphenyl, -CH(NH 2 )-4-chlorophenyl, -CH(NH 2 )-3,
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-S-C1-C6alkyl, for example -C1alk-S-C1alkyl, -C2alk-S-C1alkyl, -C3alk-S-C1alkyl, -C4alk-S- C 1 alkyl, -C 5 alk-S-C 1 alkyl ⁇ -C 6 alk-S-C 1 alkyl, -C 1 alk-S-C 2 alkyl, -C 2 alk-S-C 2 alkyl, -C 3 alk-S-C 2 alkyl, - C4alk-S-C2alkyl, -C5alk-S-C2alkyl ⁇ -C6alk-S-C2alkyl, -C1alk-S-C3alkyl, -C2alk-S-C3
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-S-C1-C6haloalkyl, for example, -C1alk-S-C1haloalkyl, -C2alk-S-C1haloalkyl, -C3alk-S- C 1 haloalkyl, -C 4 alk-S-C 1 haloalkyl, -C 5 alk-S-C 1 haloalkyl ⁇ -C 6 alk-S-C 1 haloalkyl, -C 1 alk-S- C2haloalkyl, -C2alk-S-C2haloalkyl, -C3alk-S-C2haloalkyl, -C4alk-S-C2haloalkyl, -C5alk-S- C2haloalkyl ⁇ -C6alk-S-C2haloalkyl ⁇
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C 6 alk-S-C 3 -C 6 cycloalkyl, for example, -C 1 alk-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- C4cycloalkyl, -C2alk-S-C4cycloalkyl, -C3alk-S-C4cycloalkyl, -C4alk-S-C4cycloalkyl, -C5alk-S- C 4 cycloalkyl ⁇ -C 6 alk-
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-S-C3-C6halocycloalkyl, for example -C1alk-S-C3halocycloalkyl, -C2alk-S-C3halocycloalkyl, - C 3 alk-S-C 3 halocycloalkyl, -C 4 alk-S-C 3 halocycloalkyl, -C 5 alk-S-C 3 halocycloalkyl ⁇ -C 6 alk-S- C3halocycloalkyl, -C1alk-S-C4halocycloalkyl, -C2alk-S-C4halocycloalkyl, -C3alk-S-C4halocycloalkyl, -C4alk-S-C4halocycloalkyl, -C5alk-S-C
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-OC1-C6alkyl, for example, -C1alk-O-C1alkyl, -C2alk-O-C1alkyl, -C3alk-O-C1alkyl, -C4alk-O- C 1 alkyl, -C 5 alk-O-C 1 alkyl ⁇ -C 6 alk-O-C 1 alkyl, -C 1 alk-O-C 2 alkyl, -C 2 alk-O-C 2 alkyl, -C 3 alk-O-C 2 alkyl, -C4alk-O-C2alkyl, -C5alk-O-C2alkyl ⁇ -C6alk-O-C2alkyl, -C1alk-O-C3alkyl, -C2alk-O-C3alkyl, -C2
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C 1 - C6alk-O-C3-C6cycloalkyl, for example, -C1alk-O-C3cycloalkyl, -C2alk-O-C3cycloalkyl, -C3alk-O- C3cycloalkyl, -C4alk-O-C3cycloalkyl, -C5alk-O-C3cycloalkyl ⁇ -C6alk-O-C3cycloalkyl, -C1alk-O- C 4 cycloalkyl, -C 2 alk-O-C 4 cycloalkyl, -C 3 alk-O-C 4 cycloalkyl, -C 4 alk-O-C 4 cycloalkyl, -C 5 alk-O- C 4 cycloalkyl ⁇ -C 6 alk-O-C
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C 6 alk-SCH 2 -aryl, for example -C 1 alk-SCH 2 -aryl, -C 2 alk-SCH 2 -aryl , -C 3 alk-SCH 2 -aryl, -C 4 alk-SCH 2 - aryl, -C5alk-SCH2-aryl ⁇ -C6alk-SCH2-aryl, -CH2SCH2-phenyl, -CH2SCH2-naphthyl, -CH2SCH2- fluorophenyl, -CH2SCH2-difluorophenyl, -CH2SCH2-fluoronaphthyl, -CH2SCH2-chlorophenyl, - CH 2 SCH 2 -bromophenyl, -CH 2 SCH 2 -iodophenyl, -CH 2 SCH 2 -methylphenyl, -
  • R 1 in Formula I, Formula II, Formula III, or Formula IV is -C 1 - C6alkC(O)NH-aryl, for example, -C1alk-C(O)NH-aryl, -C2alk-C(O)NH-aryl , -C3alk-C(O)NH-aryl, - C 4 alk-C(O)NH-aryl, -C 5 alk-C(O)NH-aryl ⁇ -C 6 alk-C(O)NH-aryl, -CH 2 C(O)NH-phenyl, - CH 2 C(O)NH-naphthyl, -CH 2 C(O)NH-fluorophenyl, -CH 2 C(O)NH-difluorophenyl, -CH 2 C(O)NH - fluoronaphthyl, -CH2C(O)NH-chlorophenyl, -CH2C(O)NH-chloroph
  • R 1 is -CH2C(O)NH-phenyl.
  • R 2 is H, -Ci- C 6 alkyl, or -Co-C6alk-C3-C6cycloalkyl. Thus, in some embodiments, R 2 is H.
  • R 2 is -Ci- C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 2 is methyl (i.e., -CFb, or Me).
  • R 2 is ethyl (i.e., -CH2CH3).
  • R 2 in Formula II or Formula IV is -Co-C6alk-C3-C6cycloalkyl, for example, -CoalkC3cycloalkyl, -Cialk-C3cycloalkyl, -C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, -C 4 alk- C3cycloalkyl, -Csalk-Cscycloalkyl, -C6alk-C3cycloalkyl, -Coalk-C4cycloalkyl, -Cialk-C4cycloalkyl, - C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, -C5alk-C4cycloalkyl j -C 6 alk- C4cycloalkyl, -Coalk-C3-C6cycloal
  • R 2 is -Co-C6alk-C3-C6cycloalkyl
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-C 6 alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-C 6 alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-C 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-C 6 alkyl e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl,
  • R 3 is H, halo, Ci-C 6 alkyl, or H2.
  • R 3 is H.
  • R 3 in Formula I, Formula II, Formula III, or Formula IV is halo, for example F, CI, Br, or I. In some embodiments, R 3 is F. In other embodiments, R 3 is CI.
  • R 3 in Formula I, Formula II, Formula III, or Formula IV is - Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 3 is methyl (Me).
  • R 3 is H2.
  • R 4 is H, halo, -Ci- C 6 alkyl, -Ci-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2-C6heterocycloalkyl, -C3- C 6 cycloalkyl, or -0-Ci-C4alkyl.
  • R 4 is H.
  • R 4 in Formula I or Formula II is halo, for example F, CI, Br, or I. In some embodiments, R 4 is F. [0080] In some aspects, R 4 in Formula I or Formula II is -Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R 4 is methyl.
  • R 4 in Formula I or Formula II is -Ci-C6haloalkyl, for example, -CF 3 or -CHF2.
  • R 4 in Formula I or Formula II is -C2-C6heterocycloalkyl, for example C2heterocycloalkyl, C 3 heterocycloalkyl, C 4 heterocycloalkyl, Cs heterocycloalkyl, and C 6 heterocycloalkyl, including azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.
  • R 4 is 2-oxiranyl.
  • R 4 is 1-aze
  • R 4 in Formula I or Formula II is oxo-substituted-C2- Ceheterocycloalkyl, for example, oxo-substituted-C2heterocycloalkyl, oxo-substituted- C 3 heterocycloalkyl, oxo-substituted-C4heterocycloalkyl, oxo-substituted-Csheterocycloalkyl, oxo- substituted-Ceheterocycloalkyl, including aziridinonyl, azetidinonyl, pyrrolidinonyl, dioxolanonyl, imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl, thiomorpholinonyl, oxazepanonyl, oxiranon
  • R 4 in Formula I or Formula II is -C 3 -C6cycloalkyl, for example -C 3 cycloalkyl, -C 4 cycloalkyl, -Cscycloalkyl, -Cecycloalkyl, and the like.
  • R 4 is -C 3 cycloalkyl.
  • R 4 is cyclopropyl.
  • R 4 in Formula I or Formula II is -0-Ci-C 4 alkyl, for example - O-Cialkyl, -0-C 2 alkyl, -0-C 3 alkyl, or -0-C 4 alkyl.
  • R 2a and R 2b are each, independently, -Ci-C 6 alkyl, or -Co-C6alk-C 3 -C6cycloalkyl; or R 2a and R 2b , together with the atoms to which they are attached, form a C2-C6heterocycloalkyl ring.
  • R 2b is -Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 2a is methyl.
  • R 2a is ethyl (i.e., -
  • R 2a and/or R 2b is -C 0 -C 6 alk-C 3 -C 6 cycloalkyl, 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-C 3 cycloalkyl, -C 5 alk-C 3 cycloalkyl ⁇ -C 6 alk-C 3 cycloalkyl, - C0alk-C4cycloalkyl, -C1alk-C4cycloalkyl, -C2alk-C4
  • R 2a and/or R 2b is -C 0 -C 6 alk-C 3 -C 6 cycloalkyl
  • the cycloalkyl is unsubstituted.
  • 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).
  • C1-C6alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • - OC 1 -C 6 alkyl e.g., -Omethyl, -Oethyl,
  • R 2b and R 2a together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring, for example, a 1,3-dioxolane ring or a 1,3-dioxane ring.
  • R 1 is -C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C ⁇ CH, -C0-C6alk- C ⁇ C-C1-C6alkyl, -C0-C6alk-C ⁇ C-C1-C6haloalkyl, -C0-C6alk-C ⁇ C-C3-C6cycloalkyl, or -C1-C6alk-aryl.
  • R 1 is -CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1- C6alkyl, -CH(Me)-C1-C6alkyl, -C(Me)(OH)-C1-C6alkyl, -CH(OH)-C1-C6haloalkyl, -CH(F)-C1- 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, - CH(OH)-C ⁇ CH, -CH(F)-C ⁇ CH, -CH(NH 2 )-C ⁇ CH,
  • R 1 is -CH(OH)-C ⁇ C-CH3, -CH(F)-C ⁇ C-CH3, -CH(NH2)-C ⁇ C- CH3, -CH(Me)-C ⁇ C-CH3, -C(Me)(OH)-C ⁇ C-CH3, -CH(OH)-C ⁇ C-CH3, -CH(OH)-C ⁇ C-CF3, - CH(F)-C ⁇ C-CF 3 , -CH(NH 2 )-C ⁇ C-CF 3 , -CH(Me)-C ⁇ C-CF 3 , -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)
  • the disclosure is also directed to compounds of Formula V, Formula VI, Formula VII, or Formula VIII.
  • the disclosure is directed to compounds of Formula V:
  • a in Formula V is N CH, or CR 6 .
  • s N and the compounds of Formula V are of Formula VA
  • A is CH and the compounds of Formula V are of Formula VB
  • A is CR 6 and the compounds of Formula V are of Formula VC:
  • a in Formula VI is N, CH, or CR 6 .
  • A is N and the compounds of Formula VI are of Formula VIA:
  • A is CH and the com ounds of Formula VI are of Formula VIB:
  • A is CR 6 and the compounds of Formula VI are of Formula VIC:
  • R 6 is -halo or -Ci-Calkyl.
  • R 6 is halo (e.g., -F, -CI, -Br, or - I).
  • R 6 is -F.
  • R 6 is -Cl.
  • R 6 is -C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like).
  • R 6 is methyl (i.e., -CH3, or Me).
  • n in Formula V, Formula VI, Formula VII, or Formula VIII is 1 or 2. In some embodiments of the compounds of Formula V, Formula VI, Formula VII, or Formula VIII, n is 1. In other embodiments, n is 2.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is -C 0 -C 6 alk-C 3 -C 6 cycloalkyl, -C 0 -C 6 alk-C 3 -C 6 halocycloalkyl; -C 2 -C 6 alkenyl, -C 2 - C6haloalkenyl, -C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C ⁇ CH, -C0-C6alk-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, -C 1 -C 6 alk-aryl, -C 1
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C ⁇ CH, -C0-C6alk-C ⁇ C-C1-C6alkyl, -C0- C6alk-C ⁇ C-C1-C6haloalkyl, -C0-C6alk-C ⁇ C-C3-C6cycloalkyl, -C1-C6alk-aryl, -C0-C6alk-S-aryl, -C0- C 6 alk-S(O)aryl, -C 0 -C 6 alk-S(O) 2 aryl, or -C 0 -C 6 alk-Oaryl.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C3-C6cycloalkyl, for example, -C0alk-C3cycloalkyl, -C1alk-C3cycloalkyl, -C2alk- 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-C 4 cycloalkyl, -C 3 alk-C 4 cycloalkyl, -C 4 alk- C4cycloalkyl, -C5alk-C4cycloalkyl ⁇
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C3-C6halocycloalkyl, for example, -C0alk-C3halocycloalkyl, -C1alk-C3halocycloalkyl, - C2alk-C3halocycloalkyl, -C3alk-C3halocycloalkyl, -C4alk-C3halocycloalkyl, -C5alk-C3halocycloalkyl ⁇ -C6alk-C3halocycloalkyl, -C0alk-C4halocycloalkyl, -C1alk-C4halocycloalkyl, -C2alk- C 4 halocycloalkyl, -C 3 alk-C 4 halocycloalkyl, -C 4 alk-C 4 halocycloalkyl, -C 4 al
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 2 -C 6 alkenyl, for example, vinyl, allyl, and the like.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 0 -C 6 alk-C 1 -C 6 alkyl, for example, -C 0 alk-C 1 alkyl, -C 1 alk-C 1 alkyl, -C 2 alk-C 1 alkyl, -C 3 alk-C 1 alkyl, - C4alk-C1alkyl, -C5alk-C1alkyl ⁇ -C6alk-C1alkyl, -C0alk-C2alkyl, -C1alk-C2alkyl, -C2alk-C2alkyl, - C3alk-C2alkyl, -C4alk-C2alkyl, -C5alk-C2alkyl ⁇ -C6alk-C2alkyl, -C0alk-C3alkyl, -C1alk-C
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C1-C6haloalkyl, for example, -C0alk-C1haloalkyl, -C1alk-C1haloalkyl, -C2alk-C1haloalkyl, - C 3 alk-C 1 haloalkyl, -C 4 alk-C 1 haloalkyl, -C 5 alk-C 1 haloalkyl ⁇ -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 ⁇
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C ⁇ CH, for example, -C0alk-C ⁇ CH, -C1alk-C ⁇ CH, -C2alk-C ⁇ CH, -C3alk-C ⁇ CH, -C4alk- C ⁇ CH, -C 5 alk-C ⁇ CH, -C 6 alk-C ⁇ CH, ethynyl, propargyl, -CH(OH)-C ⁇ CH, -CH(F)-C ⁇ CH, - CH(NH 2 )-C ⁇ CH, -CH(Me)-C ⁇ CH, -C(Me)(OH)-C ⁇ CH, and the like.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 0 -C 6 alk-C ⁇ C-C 1 -C 6 alkyl, for example, -C 0 alk-C ⁇ C-C 1 alkyl, -C 1 alk-C ⁇ C-C 1 alkyl, -C 2 alk-C ⁇ C- C 1 alkyl, -C 3 alk-C ⁇ C-C 1 alkyl, -C 4 alk-C ⁇ C-C 1 alkyl, -C 5 alk-C ⁇ C-C 1 alkyl ⁇ -C 6 alk-C ⁇ C-C 1 alkyl, - C0alk-C ⁇ C-C2alkyl, -C1alk-C ⁇ C-C2alkyl, -C2alk-C ⁇ C-C2alkyl, -C3alk-C ⁇ C-C2alkyl, -C4alk-C ⁇ C- C2
  • R 1 is -CH(OH)-C ⁇ C-CH3, -CH(F)-C ⁇ C-CH3, -CH(NH2)-C ⁇ C- CH 3 , -CH(Me)-C ⁇ C-CH 3 , or -C(Me)(OH)-C ⁇ C-CH 3 .
  • R 1 is -CH(OH)- C ⁇ C-CH 3.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C ⁇ C-C1-C6haloalkyl, for example, -C0alk-C ⁇ C-C1haloalkyl, -C1alk-C ⁇ C-C1haloalkyl, - C 2 alk-C ⁇ C-C 1 haloalkyl, -C 3 alk-C ⁇ C-C 1 haloalkyl, -C 4 alk-C ⁇ C-C 1 haloalkyl, -C 5 alk-C ⁇ C- C1haloalkyl ⁇ -C6alk-C ⁇ C-C1haloalkyl, -C0alk-C ⁇ C-C2haloalkyl, -C1alk-C ⁇ C-C2haloalkyl, -C2alk- C ⁇ C-C2haloalkyl, -C3alk-C ⁇ C ⁇ C
  • R 1 is -CH(OH)-C ⁇ C-CF3, -CH(F)-C ⁇ C-CF3, - CH(NH 2 )-C ⁇ C-CF 3 , -CH(Me)-C ⁇ C-CF 3 , -C(Me)(OH)-C ⁇ C-CF 3 , and the like.
  • R 1 is -CH(OH)-C ⁇ C-CF 3.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C ⁇ C-C3-C6cycloalkyl, for example, -C0alk-C ⁇ C-C3cycloalkyl, -C0alk-C ⁇ C-C4cycloalkyl, - C 0 alk-C ⁇ C-C 5 cycloalkyl, -C 0 alk-C ⁇ C-C 6 cycloalkyl, -C 1 alk-C ⁇ C-C 3 cycloalkyl, -C 1 alk-C ⁇ C- C4cycloalkyl, -C1alk-C ⁇ C-C5-cycloalkyl, -C1alk-C ⁇ C-C6cycloalkyl, -C2alk-C ⁇ C-C3cycloalkyl, - C2alk-C ⁇ C-C4cycloalkyl, -C2alk-C ⁇ C-C3cyclo
  • 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.
  • R 1 is -CH(OH)-C ⁇ C-cyclopropyl.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII 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.
  • R 1 is -C1-C6alk-aryl
  • the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, or -3-chloro-4-fluorophenyl.
  • R 1 is -CH 2 -difluorophenyl, -CH 2 -3,4-difluorophenyl, -CH 2 -4-chlorophenyl, -CH 2 -3- chloro-4-fluorophenyl, -CH2-4-chloro-3-fluorophenyl, -CH2-dichlorophenyl, -CH2-3,4- dichlorophenyl, -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,
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk S-C1-C6alkyl, for example -C1alk-S-C1alkyl, -C2alk-S-C1alkyl, -C3alk-S-C1alkyl, -C4alk-S- C 1 alkyl, -C 5 alk-S-C 1 alkyl ⁇ -C 6 alk-S-C 1 alkyl, -C 1 alk-S-C 2 alkyl, -C 2 alk-S-C 2 alkyl, -C 3 alk-S-C 2 alkyl, - C4alk-S-C2alkyl, -C5alk-S-C2alkyl ⁇ -C6alk-S-C2alkyl, -C1alk-S-C3alkyl, -C2alk-S-C3alkyl, -C2
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 1 -C 6 alk-S-C 1 -C 6 haloalkyl, for example -C 1 alk-S-C 1 haloalkyl, -C 2 alk-S-C 1 haloalkyl, -C 3 alk-S- C 1 haloalkyl, -C 4 alk-S-C 1 haloalkyl, -C 5 alk-S-C 1 haloalkyl ⁇ -C 6 alk-S-C 1 haloalkyl, -C 1 alk-S- C2haloalkyl, -C2alk-S-C2haloalkyl, -C3alk-S-C2haloalkyl, -C4alk-S-C2haloalkyl, -C5alk-S- C2haloalkyl ⁇ -C6alk-S
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 1 -C 6 alk-S-C 3 -C 6 cycloalkyl, for example -C 1 alk-S-C 3 cycloalkyl, -C 2 alk-S-C 3 cycloalkyl, -C 3 alk-S- C3cycloalkyl, -C4alk-S-C3cycloalkyl, -C5alk-S-C3cycloalkyl ⁇ -C6alk-S-C3cycloalkyl, -C1alk-S- C4cycloalkyl, -C2alk-S-C4cycloalkyl, -C3alk-S-C4cycloalkyl, -C4alk-S-C4cycloalkyl, -C5alk-S-S-C 4 cycloalkyl ⁇ -C 6 alk-S-C 4 cycloalky
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk-S-C3-C6halocycloalkyl, for example -C1alk-S-C3halocycloalkyl, -C2alk-S-C3halocycloalkyl, -C 3 alk-S-C 3 halocycloalkyl, -C 4 alk-S-C 3 halocycloalkyl, -C 5 alk-S-C 3 halocycloalkyl ⁇ -C 6 alk-S- C3halocycloalkyl, -C1alk-S-C4halocycloalkyl, -C2alk-S-C4halocycloalkyl, -C3alk-S-C4halocycloalkyl, -C4alk-S-C4halocycloalkyl, -C5alk-S-C
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 1 -C 6 alk-OC 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-C 1 alkyl, -C 1 alk-O-C 2 alkyl, -C 2 alk-O-C 2 alkyl, -C 3 alk-O- C2alkyl, -C4alk-O-C2alkyl, -C5alk-O-C2alkyl ⁇ -C6alk-O-C2alkyl, -C1alk-O-C3alkyl, -C2alk-O-C
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk-O-C3-C6cycloalkyl, for example, -C1alk-O-C3cycloalkyl, -C2alk-O-C3cycloalkyl, -C3alk-O- C3cycloalkyl, -C4alk-O-C3cycloalkyl, -C5alk-O-C3cycloalkyl ⁇ -C6alk-O-C3cycloalkyl, -C1alk-O- C 4 cycloalkyl, -C 2 alk-O-C 4 cycloalkyl, -C 3 alk-O-C 4 cycloalkyl, -C 4 alk-O-C 4 cycloalkyl, -C 5 alk-O- C4cycloalkyl ⁇ -C6alk-O-C4cycl
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 1 -C 6 alk SCH 2 -aryl, for example -C 1 alk-SCH 2 -aryl, -C 2 alk-SCH 2 -aryl , -C 3 alk-SCH 2 -aryl, -C 4 alk- SCH2-aryl, -C5alk-SCH2-aryl ⁇ -C6alk-SCH2-aryl, -CH2SCH2-phenyl, -CH2SCH2-naphthyl, - CH2SCH2-fluorophenyl, -CH2SCH2-difluorophenyl, -CH2SCH2-fluoronaphthyl, -CH2SCH2- chlorophenyl, -CH 2 SCH 2 -bromophenyl, -CH 2 SCH 2 -iodophenyl, -CH 2 SCH 2 -methylphenyl, - CH2
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alkC(O)NH-aryl, for example, -C1alk-C(O)NH-aryl, -C2alk-C(O)NH-aryl , -C3alk-C(O)NH- aryl, -C 4 alk-C(O)NH-aryl, -C 5 alk-C(O)NH-aryl ⁇ -C 6 alk-C(O)NH-aryl, -CH 2 C(O)NH-phenyl, - CH 2 C(O)NH-naphthyl, -CH 2 C(O)NH-fluorophenyl, -CH 2 C(O)NH-difluorophenyl, -CH 2 C(O)NH - fluoronaphthyl, -CH2C(O)NH-chlorophenyl, -CH2C(O)(O)NH-
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 0 -C 6 alk-S-aryl, for example -C 0 alk-S-aryl, -C 1 alk-S-aryl, -C 2 alk-S-aryl, -C 3 alk-S-aryl, -C 4 alk-S- aryl, -C5alk-S-aryl , -C6alk-S-aryl, -S-phenyl, - S-naphthyl, - S-fluorophenyl, -S-difluorophenyl, -S- fluoronaphthyl, -S-chlorophenyl, -S-bromophenyl, -S-iodophenyl, -S-methylphenyl, and the like.
  • 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.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - Co-C 6 alk-S(0)aryl, for example, -Coalk-S(0)aryl, -Cialk-S(0)aryl, -C 2 alk-S(0)aryl, -C 3 alk-S(0)aryl, -C 4 alk-S(0)aryl, -C 5 alk-S(0)aryl, -C 6 alk-S(0)aryl, -S(0)-phenyl, -S(0)-naphthyl, -S(O)- fluorophenyl, -S(0)-difluorophenyl, -S(0)-fluoronaphthyl, -S(0)-chlorophenyl, -S(0)-bromophenyl, -S(0)-iodophenyl, -S(0)-methylphenyl, and the like.
  • R 1 is -S(0)-difluorophenyl. In some aspects R 1 is -S(0)-3,4-difluorophenyl. In other aspects, R 1 is -S(0)-chlorophenyl. In other aspects, R 1 is -S(0)-4-chlorophenyl. In other aspects, R 1 is -S(0)-chlorofluorophenyl. In other aspects, R 1 is -S(0)-3-chloro-4-fluorophenyl. In other aspects, R 1 is -S(0)-4-chloro-3-fluorophenyl. In other aspects, R 1 is -S(0)-dichlorophenyl. In other aspects, R 1 is -S(0)-3,4-dichlorophenyl.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - Co-C 6 alk-S(0)2aryl, for example, -Coalk-S(0) 2 aryl, -Cialk-S(0) 2 aryl, -C 2 alk-S(0) 2 aryl, -C 3 alk- S(0) 2 aryl, -C 4 alk-S(0) 2 aryl, -C 5 alk-S(0) 2 aryl , -C 6 alk-S(0) 2 aryl, -S(0) 2 -phenyl, -S(0) 2 -naphthyl, - S(0) 2 -fluorophenyl, - S(0) 2 -difluorophenyl, -S(0) 2 -fluoronaphthyl, -S(0) 2 -chlorophenyl, -S(0) 2 - bromophenyl, -S(0) 2 -iodophenyl
  • R 1 is -S(0) 2 - difluorophenyl. In some aspects R 1 is -S(0) 2 -3,4-difluorophenyl. In other aspects, R 1 is -S(0) 2 - chlorophenyl. In other aspects, R 1 is -S(0) 2 -4-chlorophenyl. In other aspects, R 1 is -S(0) 2 - chlorofluorophenyl. In other aspects, R 1 is -S(0) 2 -3-chloro-4-fluorophenyl. In other aspects, R 1 is - S(0) 2 -4-chloro-3 -fluorophenyl. In other aspects, R 1 is -S(0) 2 -dichlorophenyl. In other aspects, R 1 is -S(0) 2 -3,4-dichlorophenyl.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is - Co-C6alk-Oaryl, for example -Coalk-Oaryl, -Cialk-Oaryl, -C 2 alk-Oaryl, -C 3 alk-Oaryl, -C 4 alk-Oaryl, - C5alk-Oaryl , -Cealk-Oaryl, -O-phenyl, - O-naphthyl, - O-fluorophenyl, -O-difluorophenyl, -O- fluoronaphthyl, -O-chlorophenyl, -O-bromophenyl, -O-iodophenyl, -O-methylphenyl, and the like.
  • R 1 is -O-difluorophenyl. In some aspects R 1 is -0-3,4-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 -0-3-chloro-4-fluorophenyl. In other aspects, R 1 is -0-4- chloro-3 -fluorophenyl. In other aspects, R 1 is -O-dichlorophenyl. In other aspects, R 1 is -0-3,4- dichlorophenyl.
  • R 2 is H, -Ci-C6alkyl, or -Co-C 6 alk- C3-C6cycloalkyl.
  • R 2 is H.
  • R 2 in Formula VI or Formula VIII is -Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 2 is methyl (i.e., -CFb, or Me).
  • R 2 is ethyl (i.e., - CH2CH3).
  • R 2 in Formula VI or Formula VIII is -Co-C6alk-C3-C6cycloalkyl, for example, -Coalk C3cycloalkyl, -Cialk-C3cycloalkyl, -C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, - C4alk-C3cycloalkyl, -Csalk-Cscycloalkyl, -C6alk-C3cycloalkyl, -Coalk C4cycloalkyl, -Cialk- C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, -C5alk-C4cycloalkyl j - C6alk-C4cycloalkyl, -Coalk Cscycl
  • R 2 is -Co-C6alk-C3-C6cycloalkyl
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci- C 6 alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-C 6 alkyl (e.g., -Omethyl, -Oethyl, - Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci- C 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-C 6 alkyl e.g., -Omethyl, -Oethyl, - Opropyl, -Oisopropyl,
  • R 2a and R 2b are each, independently, -Ci-C 6 alkyl, or -Co-C6alk-C3-C6cycloalkyl; or R 2a and R 2b , together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring.
  • R 2a and/or R 2b is -Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t- butyl, pentyl, and the like.
  • R 2a is methyl.
  • R 2b is methyl.
  • R 2a is ethyl (i.e., -CH2CH3).
  • R 2b is ethyl (i.e., -CH2CH3).
  • R 2a and/or R 2b is -Co-C6alk-C3-C6cycloalkyl, for example -Coalk-C3cycloalkyl, -Cialk-C3cycloalkyl, - C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, -Csalk-Cscycloalkyl, -C 6 alk- C3cycloalkyl, -Coalk C4cycloalkyl, -Cialk-C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, - C4alk-C4cycloalkyl, -C5alk-C4cycloalkyl j -C6alk-C4cycl
  • R 2a and/or R 2b is -Co-C6alk-C 3 -C6cycloalkyl
  • the cycloalkyl is unsubstituted.
  • the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-C 6 alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-C 6 alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
  • Ci-C 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl
  • -OCi-C 6 alkyl e.g., -Omethyl, -Oethyl, -Opropyl, -
  • R 2b and R 2a together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring, for example, a 1,3-dioxolane ring or a 1,3-dioxane ring.
  • R 3 is H, halo, Ci-C 6 alkyl, or Fh.
  • R 3 is H.
  • R 3 in Formula V, Formula VI, Formula VII, or Formula VIII is halo, for example F, CI, Br, or I. In some embodiments, R 3 is F. In other embodiments, R 3 is CI.
  • R 3 in Formula V, Formula VI, Formula VII, or Formula VIII is -Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 3 is methyl (Me).
  • R 3 is Fh.
  • R 4 is H, halo, - Ci-C 6 alkyl, -Ci-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2-C6heterocycloalkyl, -C 3 - C 6 cycloalkyl, or -0-Ci-C4alkyl.
  • R 4 in Formula V or Formula VI is H.
  • R 4 in Formula V or Formula VI is halo, for example F, CI, Br, or I. In some embodiments, R 4 is -F.
  • R 4 in Formula V or Formula VI is -Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R 4 is methyl. [00153] In some aspects, R 4 in Formula V or Formula VI is -Ci-C6haloalkyl, for example, - CF 3 or -CHF2.
  • R 4 in Formula V or Formula VI is -C2-C6heterocycloalkyl, for example C2heterocycloalkyl, C 3 heterocycloalkyl, C 4 heterocycloalkyl, Cs heterocycloalkyl, and C 6 heterocycloalkyl, including azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl,
  • R 4 is 2-oxiranyl. In other embodiments, R 4 is 1-azetidinyl.
  • R 4 in Formula V or Formula VI is oxo-substituted-C2- Ceheterocycloalkyl, for example, oxo-substituted-C2heterocycloalkyl, oxo-substituted- C 3 heterocycloalkyl, oxo-substituted-C4heterocycloalkyl, oxo-substituted-Csheterocycloalkyl, oxo- substituted-Ceheterocycloalkyl, including aziridinonyl, azetidinonyl, pyrrolidinonyl, dioxolanonyl, imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl,
  • R 4 is azetidin-2-one- 1-yl.
  • R 4 in Formula V or Formula VI is -C 3 -C6cycloalkyl, for example -C 3 cycloalkyl, -C 4 cycloalkyl, -Cscycloalkyl, -Cecycloalkyl, and the like.
  • R 4 is -C 3 cycloalkyl.
  • R 4 is cyclopropyl.
  • R 4 in Formula V or Formula VI is -O-C1-C4 alkyl, for example -O-Cialkyl, -0-C 2 alkyl, -0-C 3 alkyl, or -0-C 4 alkyl.
  • R 5 is H, -Ci-C 6 alkyl, -Ci-C6haloalkyl, -Co-C6alk-C 3 -C6cycloalkyl, -Co-C6alk-C 3 -C6halocycloalkyl, -Co-C 6 alk- OH, -Co-C 6 alk- H2, -Co-Cealk-NH-Ci-Cealkyl, -Co-C6alk-N(Ci-C6alkyl)-Ci-C 6 alkyl, -Co-Cealk- H- C 3 -C6cycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C 3 -C6cycloalkyl; or R 5 and R 1 , together with the atom to which they are attached, form a C 3 -C6cycloalkyl
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is H.
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is -Ci-C 6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is -C 1 -C 6 haloalkyl, for example, C 1 haloalkyl, C 2 haloalkyl, C 3 haloalkyl, C 4 haloalkyl,
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C3-C6cycloalkyl, for example -C0alk-C3cycloalkyl, -C1alk-C3cycloalkyl, -C2alk- 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, - C0alk-C4cycloalkyl, -C1alk-C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk- C4cycloalkyl, -C5alk-C4cycloalkyl ⁇ -C6alk-
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C3-C6halocycloalkyl, for example, -C0alk-C3halocycloalkyl, -C1alk-C3halocycloalkyl, - C2alk-C3halocycloalkyl, -C3alk-C3halocycloalkyl, -C4alk-C3halocycloalkyl, -C5alk-C3halocycloalkyl ⁇ -C 6 alk-C 3 halocycloalkyl, -C 0 alk-C 4 halocycloalkyl, -C 1 alk-C 4 halocycloalkyl, -C 2 alk- C4halocycloalkyl, -C3alk-C4halocycloalkyl, -C4alk-C4halocycloalkyl, -C4
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-OH, for example, -C0alk-OH (i.e., -OH), -C1alk-OH, -C2alk-OH, -C3alk-OH, -C4alk-OH, - C 5 alk-OH, -C 6 alk-OH, and the like.
  • R 5 is -C 1 alk-OH.
  • R 5 is hydroxymethyl (i.e., -CH 2 OH).
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-NH2, for example, -C0alk-NH2 (i.e., -NH2), -C1alk-NH2, -C2alk-NH2, -C3alk-NH2, -C4alk- NH 2 , -C 5 alk-NH 2 , -C 6 alk-NH 2 , and the like.
  • R 5 is -C 1 alk-NH 2 .
  • R 5 is aminomethyl (i.e., -CH2NH2).
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII 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-C 1 alkyl ⁇ -C 6 alk-NH-C 1 alkyl, -C 0 alk-NH-C 2 alkyl, -C1alk-NH-C2alkyl, -C2alk-NH-C2alkyl, -C3alk-NH-C2alkyl, -C4alk-NH-C2alkyl, -C5alk-NH-C2alkyl ⁇ -C6al
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C 0 -C 6 alk-N(C 1 -C 6 alkyl)-C 1 -C 6 alkyl, for example, -C 0 alk-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 -C 6 alkyl)-C 1 alkyl, -C 4 alk-N(C 1 - C6alkyl)-C1alkyl, -C5alk-N(C1-C6alkyl)-C1alkyl ⁇ -C6alk- N(C1-C6alkyl)-C1alkyl, -C0alk- N(C1
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-NH-C3-C6cycloalkyl, for example, -C0alk-NH-C3cycloalkyl, -C1alk-NH-C3cycloalkyl, - C 2 alk-NH-C 3 cycloalkyl, -C 3 alk-NH-C 3 cycloalkyl, -C 4 alk-NH-C 3 cycloalkyl, -C 5 alk-NH- C3cycloalkyl ⁇ -C6alk-NH-C3cycloalkyl, -C0alk-NH-C4cycloalkyl, -C1alk-NH-C4cycloalkyl, -C2alk- NH-C4cycloalkyl, -C3alk-NH-C4cycloalkyl, -C4alk-NH-C4cycloalkyl, -C4
  • R 5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, for example, -C0alk-N(C1-C6alkyl)-C3cycloalkyl, -C1alk- N(C1-C6alkyl)-C3cycloalkyl, -C2alk-N(C1-C6alkyl)-C3cycloalkyl, -C3alk-N(C1-C6alkyl)-C3cycloalkyl, -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,
  • Formula VIII, R 5 and R 1 together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring.
  • R 6a is H, halo, or -C 1 -C 6 alkyl.
  • R 6a is H.
  • R 6a is halo (e.g., F, Cl, Br, or I).
  • R 6a is F.
  • R 6a is Cl.
  • R 6a is C1-C6alkyl, for example, ethyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like.
  • R 6a is Me (i.e., methyl).
  • R 1 is -C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C ⁇ CH, -C0- C6alk-C ⁇ C-C1-C6alkyl, -C0-C6alk-C ⁇ C-C1-C6haloalkyl, -C0-C6alk-C ⁇ C-C3-C6cycloalkyl, -C1-C6alk- 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-O-aryl.
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is -CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, - CH(Me)-C1-C6alkyl, or -C(Me)(OH)-C1-C6alkyl, -CH(OH)-C1-C6 haloalkyl, -CH(F)-C1-C6 haloalkyl, -CH(NH 2 )-C 1 -C 6 haloalkyl, -CH(Me)-C 1 -C 6 haloalkyl, or -C(Me)(OH)-C 1 -C 6 haloalkyl, -CH(OH)- C ⁇ CH, -CH(F)-C ⁇ CH, -CH(NH2)-C ⁇ CH, -
  • R 1 in Formula V, Formula VI, Formula VII, or Formula VIII is -CH(OH)-C ⁇ C-CH 3 , -CH(F)-C ⁇ C-CH 3 , -CH(NH 2 )-C ⁇ C-CH 3 , - CH(Me)-C ⁇ C-CH3, -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, -C(Me)(OH)-C ⁇ C-CF3, -CH(OH)-C ⁇ C-cyclopropyl, -CH(F)-C ⁇ C-cyclopropyl, -CH(NH 2 )-C ⁇ C-cyclopropyl, -CH(Me)-C ⁇ C-cyclopropyl, -CH(NH
  • compositions and methods of administration are provided.
  • 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.
  • the pharmaceutical compositions contain pharmaceutically acceptable salt and/or
  • diluents including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • carriers including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • 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.
  • 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.
  • 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
  • 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%, 5%,
  • 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
  • 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
  • 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
  • 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,
  • 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.
  • 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.
  • an active ingredient i.e., a compound of the disclosure
  • a pharmaceutically acceptable salt and/or coordination complex thereof include but not limited to inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions for oral administration [00192]
  • the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.
  • 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.
  • the composition further contains: (iv) an effective amount of a third agent.
  • the pharmaceutical composition may be a liquid
  • 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.
  • 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.
  • 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.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by
  • a suitable machine 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.
  • 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.
  • anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • 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
  • the carrier can take a wide variety of forms depending on the form of preparation desired for
  • 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.
  • 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.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrol
  • 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.
  • 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.
  • 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.
  • 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).
  • HLB hydrophilic-lipophilic balance
  • 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.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • 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-glycer
  • 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 phosphatidylethanolamine
  • 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 car
  • 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
  • the polyol may be glycerol, ethylene glycol, polyethylene glyco
  • 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-
  • 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;
  • 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.
  • 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.
  • 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,
  • esters such as ethyl propionate, tributylcitrate, acetyl tri ethyl citrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ⁇ -caprolactone and isomers thereof, ⁇ -valerolactone and isomers thereof, ⁇ -butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl
  • 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.
  • 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.
  • solubilizer may also be used, such as 5%>, 2%>, 1%) or even less.
  • 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.
  • 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.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • 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,
  • 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.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • 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.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • 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,
  • compositions for injection [00219]
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions for topical e.g. transdermal delivery.
  • 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.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • 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.
  • 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.
  • penetration- enhancing molecules known to those trained in the art of topical formulation.
  • 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 e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.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.
  • 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.
  • 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.
  • compositions for inhalation are provided.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. [00233] In some embodiments, a compound of the invention is administered in a single dose.
  • Such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly.
  • injection e.g., intravenous injection
  • 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.
  • 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.
  • a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • 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.
  • 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.
  • a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • IC50 refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, 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).
  • IC50 refers to the plasma concentration required for obtaining 50%> of a maximum effect in vivo.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • PRMT5 has been implicated, for example, in a variety of human cancers as well as a number of
  • Non- limiting examples of such conditions include but are not limited to
  • 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 K-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, Angio
  • B-cell leukemia B-cell lymphoma
  • Bellini duct carcinoma B-cell leukemia
  • Biliary tract cancer B-cell lymphoma
  • Bladder cancer B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer,
  • Cholangiocarcinoma 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'
  • Gastrointestinal cancer Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor,
  • 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 le
  • 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, Osteos
  • Retinoblastoma Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygeal teratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma,
  • Secondary neoplasm 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.
  • 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.
  • said method is for treating a disease selected from 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),
  • AML 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
  • MDS myelodysplastic syndrome
  • SCD sickle cell disease
  • 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.
  • 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).
  • AML acute myeloid leukemia
  • AML acute lymphocytic leukemia
  • chronic lymphocytic leukemia chronic myeloid leukemia
  • CML chronic myelogenous leukemia
  • mastocytosis chronic lymphocytic leukemia
  • CLL multiple myel
  • 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.
  • Compounds of the disclosure include, for example, the compounds identified Table A. TABLE A
  • Compounds of the disclosure also include, for example, the compounds identified Table B.
  • Step 1 Preparation of [(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d] [l,3]dioxol-6-yl]-(4-chloro-3-fluoro-phenyl)methyl] 4-phenylbenzoate (Int-1-2)
  • reaction mixture was stirred at RT over 72 h, concentrated and the residue was purified on a 4g column, which was eluted with 0-50% EA/hexane to give -80 mg of foamy white intermediate.
  • reaction solution was purified by prep-HPLC, eluted with MeCN in H 2 0 (0.1% TFA) from 5.0% to 95.0% to (2R,3S,4R,5R)-2-((R)- (4-chloro-3-fluorophenyl)(hydroxy)methyl)-5-(3-hydroxy-2,3-dihydro-7H-imidazo[l,2- c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (Ex. 35) (115.0 mg, 0.24 mmol, 28.2% yield) as a yellow solid.
  • Example 41 a white solid, was prepared similarly to that of Ex. 35 except substituting Int-1 with Int-4 in step a).
  • Example 42 a white solid, was prepared similarly to that of Ex. 22 except substitituting Int-3 with Int-4 in step a).
  • Example 56 a white solid, was prepared similarly to that of Ex. 35. LCMS
  • 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 u .
  • Chemiluminescent signal was captured with FluoChem HD2 imager (Proteinsimple) and analyzed by ImageJ.
  • Aspect 1 A compound of Formula I, Formula II, Formula III or Formula IV:
  • A is CH or N
  • n 1 or 2;
  • R 1 is -C 0 -C 6 alk-C 3 -C 6 cycloalkyl, -C 0 -C 6 alk-C 3 -C 6 halocycloalkyl, -C 2 -C 6 alkenyl, -C 2 - C6haloalkenyl, -C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C ⁇ CH, - C0-C6alk-C ⁇ C-C1-C6alkyl, -C0-C6alk-C ⁇ C-C1-C6haloalkyl, -C0-C6alk-C ⁇ C-C3- C 6 cycloalkyl, -C 1 -C 6 alk-aryl, -C 1 -C 6 alk-S-C 1 -C 6 alkyl, -C 1 -C 6 alk-S
  • R 2 is H, -C 1 -C 6 alkyl, or -C 0 -C 6 alk-C 3 -C 6 cycloalkyl;
  • R 2a and R 2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
  • R 2a and R 2b together with the atoms to which they are attached, form a C 2 - C 6 heterocycloalkyl ring;
  • R 3 is H, halo, -Ci-Cealkyl, or H 2 ;
  • R 4 is H, halo, -Ci-C 6 alkyl, -Ci-C4haloalkyl, -C 2 -C6heterocycloalkyl, oxo-substituted-C 2 - Ceheterocycloalkyl, -C3-C6cycloalkyl, or -0-Ci-C4alkyl.
  • Aspect 2 The compound of aspect 1 wherein Ri is -Co-C6alk-Ci-C6alkyl.
  • Aspect 3 The compound of aspect 2 wherein the -Co-C6alk-Ci-C6alkyl is -CH(OH)-Ci-C6alkyl, -CH(F)-Ci-C 6 alkyl, -CH( H 2 )-Ci-C 6 alkyl, -CH(Me)-Ci-C 6 alkyl, or -C(Me)(OH)-Ci-C 6 alkyl.
  • Aspect 4 The compound of aspect 1 wherein Ri is -Co-C6alk-Ci-C6haloalkyl.
  • Aspect 5 The compound of aspect 4 wherein the -Co-C6alk-Ci-C6haloalkyl is -CH(OH)-Ci-C6 haloalkyl, -CH(F)-Ci-C 6 haloalkyl, -CH( H 2 )-Ci-C 6 haloalkyl, -CH(Me)-Ci-C 6 haloalkyl, or - C(Me)(OH)-Ci-C 6 haloalkyl.
  • Aspect 6 The compound of aspect 1 wherein Ri is -Co-C6alk-C ⁇ CH.
  • Aspect 7 The compound of aspect 6 wherein the -Co-Cealk-C ⁇ CH is -CH(OH)-C ⁇ CH, -CH(F)- C ⁇ CH, -CH( H 2 )-C ⁇ CH, -CH(Me)-C ⁇ CH, or -C(Me)(OH)-C ⁇ CH.
  • Aspect 8 The compound of aspect 1 wherein Ri is -Co-C6alk-C ⁇ C-Ci-C6alkyl.
  • Aspect 9 The compound of aspect 8 wherein the -Co-C6alk-C ⁇ C-Ci-C6alkyl is -CH(OH)-C ⁇ C- Ci-Cealkyl, -CH(F)-C ⁇ C-Ci-C 6 alkyl, -CH( H 2 )-C ⁇ C-Ci-C 6 alkyl, -CH(Me)-C ⁇ C-Ci-C 6 alkyl, or - C(Me)(OH)-C ⁇ C-Ci-C 6 alkyl.
  • Aspect 10 The compound of aspect 9 wherein the -Co-C6alk-C ⁇ C-Ci-Cealkyl is -CH(OH)-C ⁇ C- CH 3 , -CH(F)-C ⁇ C-CH 3 , -CH( H 2 )-C ⁇ C-CH 3 , -CH(Me)-C ⁇ C-CH 3 , or -C(Me)(OH)-C ⁇ C-CH 3 .
  • Aspect 11 The compound of aspect 1 wherein Ri is -Co-C6alk-C ⁇ C-Ci-C6haloalkyl.
  • Aspect 12 The compound of aspect 11 wherein the -Co-C6alk-C ⁇ C-Ci-C6haloalkyl is -CH(OH)- C ⁇ C-Ci-C 6 haloalkyl, -CH(F)-C ⁇ C-Ci-C 6 haloalkyl, -CH(NH 2 )-C ⁇ C-Ci-C 6 haloalkyl, -CH(Me)-C ⁇ C- Ci-Cehaloalkyl, or -C(Me)(OH)-C ⁇ C-Ci-C 6 haloalkyl.
  • Aspect 14 The compound of aspect 1 wherein Ri is -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl.
  • Aspect 15 The compound of aspect 14 wherein the -Co-C6alk-C ⁇ C-C 3 -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 -C6cycloalkyl, - CH(Me)-C ⁇ C-C 3 -C 6 cycloalkyl, or -C(Me)(OH)-C ⁇ C-C 3 -C 6 cycloalkyl.
  • Aspect 16 The compound of aspect 15 wherein wherein the -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl is - CH(OH)-C ⁇ C-cyclopropyl, -CH(F)-C ⁇ C-cyclopropyl, -CH( H 2 )-C ⁇ C-cyclopropyl, -CH(Me)-C ⁇ C- cyclopropyl, or -C(Me)(OH)-C ⁇ C-cyclopropyl.
  • Aspect 17 The compound of aspect 1 wherein Ri is -Ci-C6alk-aryl.
  • Aspect 18 The compound of aspect 17 wherein the -Ci-C6alk-aryl is -CH(OH)-aryl, -CH(F)- aryl, -CH( H 2 )-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl.
  • Aspect 19 The compound of aspect 18 wherein the -Ci-C6alk-aryl is -CH(OH)-4-chlorophenyl, - CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, - CH(OH)-3-chloro-4-fluorophenyl, -CH(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( H 2 )-4- chlorophenyl, -CH( H 2 )-3,4-dichlorophenyl, -CH( H 2 )-3,
  • Aspect 20 The compound of any one of aspects 1 to 19 wherein R 3 is H.
  • Aspect 21 The compound of any one of aspects 1 to 20 wherein n is i .
  • Aspect 22 The compound of any one of aspects 1 to 20 wherein n is 2.
  • Aspect 23 The compound of any one of aspects 1 to 22 that is a compound of Formula I or Formula II.
  • Aspect 24 The compound of aspect 23 wherein A is N.
  • Aspect 25 The compound of aspect 23 wherein A is CH.
  • Aspect 26 The compound of any one of aspects 23 to 25 wherein R 4 is H.
  • Aspect 27 The compound of any one of aspects 23 to 25 wherein R 4 is halo.
  • Aspect 28 The compound of aspect 27 wherein the halo is fluoro.
  • Aspect 29 The compound of any one of aspects 23 to 25 wherein R 4 is -Ci-C6alkyl.
  • Aspect 30 The compound of aspect 29 wherein the -Ci-C6alkyl is methyl.
  • Aspect 31 The compound of any one of aspects 1 to 30 that is a compound of Formula I or Formula III.
  • Aspect 32 The compound of aspect 31 wherein R 2a is -Ci-C6alkyl.
  • Aspect 33 The compound of any one of aspects 31 or 32 wherein R 2b is -Ci-C6alkyl.
  • Aspect 34 The compound of any one of aspects 1 to 30 that is a compound of Formula II or Formula IV.
  • Aspect 35 The compound of aspect 34 wherein R 2 is H.
  • Aspect 36 The compound of aspect 34 wherein R 2 is -Ci-C6alkyl.
  • a pharmaceutical composition comprising a compound according to any one of aspects 1 to 36 and a pharmaceutically acceptable excipient.
  • Aspect 38 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 1 to 36.
  • Aspect 39 A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject comprising administering to the subject, a compound of any one of aspects 1 to 36.
  • PRMT5 protein arginine methyltransferase 5
  • Aspect 40 The method of aspect 39, 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).
  • AML acute myeloid leukemia
  • AML acute lymphocytic leukemia
  • chronic lymphocytic leukemia
  • A is CH, CR 6 or N; n is 1 or 2;
  • R 1 is -C 0 -C 6 alk-C 3 -C 6 cycloalkyl, -C 0 -C 6 alk-C 3 -C 6 halocycloalkyl; -C 2 -C 6 alkenyl, -C 2 - 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, -C
  • R 2a and R 2b are each independently -C 1 -C 6 alkyl, or -C 0 -C 6 alk-C 3 -C 6 cycloalkyl;
  • R 3 is H, halo, -C 1 -C 6 alkyl, or NH 2 ;
  • R 4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl;
  • R 5 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(C1-C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, or -C0-C6alk-N(C1- C 6 alkyl)-C 3 -C 6 cycloalkyl;
  • R 5 and R 1 together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring;
  • R 6 is halo or -C 1 -C 6 alkyl
  • R 6a is H, halo or -C 1 -C 6 alkyl.
  • Aspect 42 The compound of aspect 41 wherein R 1 is -C0-C6alk-C1-C6alkyl.
  • Aspect 43 The compound of aspect 42 wherein the -C 0 -C 6 alk-C 1 -C 6 alkyl 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, or -C(Me)(OH)-C 1 - C6alkyl.
  • Aspect 44 The compound of aspect 41 wherein R 1 is -Co-C6alk-Ci-C6haloalkyl.
  • Aspect 45 The compound of aspect 44 wherein the -Co-C6alk-Ci-C6haloalkyl is -CH(OH)-Ci- Cehaloalkyl, -CH(F)-Ci-C 6 haloalkyl, -CH(NH 2 )-Ci-C6haloalkyl, -CH(Me)-Ci-C 6 haloalkyl, or - C(Me)(OH)-Ci-C 6 haloalkyl.
  • Aspect 46 The compound of aspect 41 wherein R 1 is -Co-C6alk-C ⁇ CH.
  • Aspect 47 The compound of aspect 46 wherein the -Co-Cealk-C ⁇ CH is -CH(OH)-C ⁇ CH, - CH(F)-C ⁇ CH, -CH( H 2 )-C ⁇ CH, -CH(Me)-C ⁇ CH, or -C(Me)(OH)-C ⁇ CH.
  • Aspect 48 The compound of aspect 41 wherein R 1 is -Co-C6alk-C ⁇ C-Ci-C6alkyl.
  • Aspect 49 The compound of aspect 48 wherein the -Co-C6alk-C ⁇ C-Ci-Cealkyl is -CH(OH)- C ⁇ C-Ci-C 6 alkyl, -CH(F)-C ⁇ C-Ci-C 6 alkyl, -CH( H 2 )-C ⁇ C-Ci-C 6 alkyl, -CH(Me)-C ⁇ C-Ci-C 6 alkyl, or -C(Me)(OH)-C ⁇ C-Ci-C 6 alkyl.
  • Aspect 50 The compound of aspect 49 wherein the -Co-C6alk-C ⁇ C-Ci-C6alkyl is -CH(OH)- C ⁇ C-CH 3 , -CH(F)-C ⁇ C-CH 3 , -CH( H 2 )-C ⁇ C-CH 3 , -CH(Me)-C ⁇ C-CH 3 , or -C(Me)(OH)-C ⁇ C-CH 3 .
  • Aspect 51 The compound of aspect 41 wherein R 1 is -C0-C6alk-C ⁇ C-Cl-C6haloalkyl.
  • Aspect 52 The compound of aspect 51 wherein the -Co-C6alk-C ⁇ C-Ci-C6haloalkyl is -CH(OH)- C ⁇ C-Ci-C 6 haloalkyl, -CH(F)-C ⁇ C-Ci-C 6 haloalkyl, -CH(NH 2 )-C ⁇ C-Ci-C 6 haloalkyl, -CH(Me)-C ⁇ C- Ci-Cehaloalkyl, or -C(Me)(OH)-C ⁇ C-Ci-C 6 haloalkyl.
  • Aspect 53 The compound of aspect 52 wherein the -Co-Cealk-C ⁇ C-CF 3 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 54 The compound of aspect 41 wherein R 1 is -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl.
  • Aspect 55 The compound of aspect 54 wherein the -Co-C6alk-C ⁇ C-C 3 -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 -C6cycloalkyl, - CH(Me)-C ⁇ C-C 3 -C 6 cycloalkyl, or -C(Me)(OH)-C ⁇ C-C 3 -C 6 cycloalkyl.
  • Aspect 56 The compound of aspect 54 wherein the -Co-C6alk-C ⁇ C-C 3 -C6cycloalkyl is - CH(OH)-C ⁇ C-C 3 -C 6 cycloalkyl, -CH(F)-C ⁇ C-C 3 -C 6 cycloalkyl, -CH(NH
  • Aspect 58 The compound of aspect 57 wherein the -Ci-C6alk-aryl is -CH 2 -aryl, -CH(OH)-aryl, - CH(F)-aryl, -CH( H 2 )-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl.
  • Aspect 60 The compound of aspect 41 wherein R 1 is -Co-C6alk-S-aryl.
  • Aspect 61 The compound of aspect 60 wherein the -Co-C6alk-S-aryl is -S-4-chlorophenyl, -S- 3,4-dichlorophenyl, -S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or -S-3-chloro-4- fluorophenyl.
  • Aspect 62 The compound of aspect 41 wherein R 1 is -Co-C6alk-S(0)-aryl.
  • Aspect 63 The compound of aspect 62 wherein the -Co-C6alk-S(0)-aryl is -S(0)-4- chlorophenyl, -S(0)-3,4-dichlorophenyl, -S(0)-3,4-difluorophenyl, -S(0)-3-fluoro-4-chlorophenyl, or -S(0)-3-chloro-4-fluorophenyl.
  • Aspect 64 The compound of aspect 41 wherein R 1 is -Co-C6alk-S(0) 2 -aryl.
  • Aspect 65 The compound of aspect 64 wherein the -Co-C6alk-S(0)2-aryl is -S(0) 2 -4- chlorophenyl, -S(0) 2 -3, 4-dichlorophenyl, -S(0) 2 -3, 4-difluorophenyl, -S(0) 2 -3-fluoro-4-chlorophenyl, or -S(0) 2 -3-chloro-4-fluorophenyl.
  • Aspect 66 The compound of aspect 41 wherein R 1 is -Co-C6alk-0-aryl.
  • Aspect 67 The compound of aspect 46 wherein the -Co-C6alk-0-aryl is -O-4-chlorophenyl, -O- 3, 4-dichlorophenyl, -0-3, 4-difluorophenyl, -0-3-fluoro-4-chlorophenyl, or -0-3-chloro-4- fluorophenyl.
  • Aspect 68 The compound of any one of aspects 41 to 67 wherein n is 1.
  • Aspect 69 The compound of any one of aspects 41 to 67 wherein n is 2.
  • Aspect 70 The compound of any one of aspects 41 to 69 wherein R 3 is H.
  • Aspect 71 The compound of any one of aspects 41 to 70 wherein R 5 is H.
  • Aspect 72 The compound of any on eof aspects 41 to 71 that is a compound of Formula V or Formula VI.
  • Aspect 74 The compound of aspect 72 wherein A is CH.
  • Aspect 75 The compound of any one of aspects 72 to 74 wherein R 4 is H.
  • Aspect 76 The compound of any one of aspects 72 to 74 wherein R 4 is halo.
  • Aspect 77 The compound of aspect 76 wherein the halo is -F.
  • Aspect 78 The compound of any one of aspects 72 to 74 wherein R 4 is -Ci-C6alkyl.
  • Aspect 79 The compound of aspect 78 wherein the -Ci-C 6 alkyl is methyl.
  • Aspect 80 The compound of any one of aspects 41 to 79 that is a compound of Formula V or Formula VII.
  • Aspect 81. The compound of aspect 60 wherein R 2a is -Ci-C6alkyl.
  • Aspect 82 The compound of any one of aspects 60 to 61 wherein R is -Ci-C6alkyl.
  • Aspect 83 The compound of any one of aspects 41 to 79 that is a compound of Formula VI or
  • Aspect 84 The compound of aspect 83 wherein R 2 is H.
  • Aspect 85 The compound of aspect 83 wherein R 2 is -Ci-C6alkyl.
  • Aspect 86 The compound of any one of aspects 41 to 71 and 40 to 45 that is a compound of Formula VII or Formula VIII.
  • a pharmaceutical composition comprising a compound according to any one aspects 41 to 87 and a pharmaceutically acceptable excipient.
  • 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 41 to 87.
  • Aspect 90 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 41 to 87.
  • Aspect 91 The method of aspect 90, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon
  • 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
  • AML 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
  • hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD).
  • SCD sickle cell disease
  • A is CH or N
  • n 1 or 2;
  • R 1 is -C 0 -C 6 alk-C 3 -C 6 cycloalkyl, -C 0 -C 6 alk-C 3 -C 6 halocycloalkyl, -C 2 -C 6 alkenyl, -C 2 - 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, -C 0 - 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,
  • R 2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
  • R 2a and R 2b are each independently -C 1 -C 6 alkyl, or -C 0 -C 6 alk-C 3 -C 6 cycloalkyl;
  • R 3 is H, halo, -C 1 -C 6 alkyl, or NH 2 ; and R 4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C 6 heterocycloalkyl, -C 3 -C 6 cycloalkyl, or -O-C 1 -C 4 alkyl.
  • R 1 is -C 0 -C 6 alk-C 1 -C 6 alkyl, preferably -C 0 - C6alk-C1-C6alkyl is -CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1- C6alkyl, or -C(Me)(OH)-C1-C6alkyl.
  • Aspect 94 is -C 0 -C 6 alk-C 1 -C 6 alkyl, preferably -C 0 - C6alk-C1-C6alkyl is -CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1- C6alkyl, or -
  • R 1 is -C 0 -C 6 alk-C 1 -C 6 haloalkyl, preferably - CH(OH)-C1-C6 haloalkyl, -CH(F)-C1-C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1- C6haloalkyl, or -C(Me)(OH)-C1-C6haloalkyl.
  • Aspect 95 is -C 0 -C 6 alk-C 1 -C 6 haloalkyl, preferably - CH(OH)-C1-C6 haloalkyl, -CH(F)-C1-C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1- C6haloalkyl, or -C(Me)(OH)-C1-C6haloal
  • R 1 is -C 0 -C 6 alk-C ⁇ CH, preferably -CH(OH)- C ⁇ CH, -CH(F)-C ⁇ CH, -CH(NH 2 )-C ⁇ CH, -CH(Me)-C ⁇ CH, or -C(Me)(OH)-C ⁇ CH.
  • Aspect 96 The compound of aspect 92 wherein R 1 is -C 0 -C 6 alk-C ⁇ CH, preferably -CH(OH)- C ⁇ CH, -CH(F)-C ⁇ CH, -CH(NH 2 )-C ⁇ CH, -CH(Me)-C ⁇ CH, or -C(Me)(OH)-C ⁇ CH.
  • R1 is -C0-C6alk-C ⁇ C-C1-C6alkyl, preferably - 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 -C 6 alkyl, or -C(Me)(OH)-C ⁇ C-C 1 -C 6 alkyl, more preferably-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.
  • R1 is -C0-C6alk-C ⁇ C-C1-C6haloalkyl, preferably -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- C1-C6haloalkyl, or -C(Me)(OH)-C ⁇ C-C1-C6haloalkyl, more preferably -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 98 The compound of aspect 92 wherein R 1 is -C 0 -C 6 alk-C ⁇ C-C 3 -C 6 cycloalkyl, preferably -CH(OH)-C ⁇ C-C3-C6cycloalkyl, -CH(F)-C ⁇ C-C3-C6cycloalkyl, -CH(NH2)-C ⁇ C-C3- C6cycloalkyl, -CH(Me)-C ⁇ C-C3-C6cycloalkyl, or -C(Me)(OH)-C ⁇ C-C3-C6cycloalkyl, more preferably 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-cyclopropy
  • R1 is -C1-C6alk-aryl, preferably -CH(OH)-aryl, - CH(F)-aryl, -CH(NH 2 )-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl, more preferably -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)-4-chloro-3-methylphenyl, -CH(F)-4- chlorophenyl, -CH(F)-3,4-di chlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3,4-difluorophen
  • Aspect 100 The compound of any one of aspects 92 to 99 wherein R 3 is H.
  • Aspect 101 The compound of any one of aspects 92 to 100 wherein n is 1.
  • Aspect 102 The compound of any one of aspects 92 to 100 wherein n is 2.
  • Aspect 103 The compound of any one of aspects 92 to 102 that is a compound of Formula I or Formula II.
  • Aspect 104 The compound of aspect 103 wherein A is N.
  • Aspect 105 The compound of aspect 103 wherein A is CH.
  • Aspect 106 The compound of any one of aspects 103 to 105 wherein R 4 is H.
  • Aspect 107 The compound of any one of aspects 103 to 105 wherein R 4 is halo, preferably fluoro.
  • Aspect 108 The compound of any one of aspects 103 to 105 wherein R 4 is -Ci-C6alkyl, preferably methyl.
  • Aspect 109 The compound of any one of aspects 92 to 108 that is a compound of Formula I or Formula III.
  • Aspect 110 The compound of aspect 109 wherein R 2a is -Ci-C6alkyl.
  • Aspect 112. The compound of any one of aspects 92 to 108 that is a compound of Formula II or Formula IV.
  • Aspect 114 The compound of aspect 112 wherein R 2 is -Ci-C6alkyl.
  • Aspect 1 A compound of Formula V, Formula VI, Formula VII, or Formula VIII:
  • A is CH, CR 6 or N; n is 1 or 2;
  • R 1 is -Co-C6alk-C3-C6cycloalkyl, -Co-C6alk-C3-C6halocycloalkyl; -C2-C 6 alkenyl, -C 2 -
  • Cehaloalkenyl -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-Cealk-C ⁇ CH, -Co-
  • R 2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
  • R 2a and R 2b are each independently -C 1 -C 6 alkyl, or -C 0 -C 6 alk-C 3 -C 6 cycloalkyl;
  • R 3 is H, halo, -C 1 -C 6 alkyl, or NH 2 ;
  • R 4 is H, halo, -C 1 -C 6 alkyl, -C 1 -C 4 haloalkyl, -C 2 -C 6 heterocycloalkyl, oxo-substituted-C 2 - C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl;
  • R 5 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 - 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(C1-C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, or -C0-C6alk-N(C1-C6alkyl)-C3- C6cycloalkyl;
  • R 5 and R 1 together with the atom to which they are attached, form a C 3 -C 6 cycloalkyl ring or a heterocycloalkyl ring;
  • R 6 is halo or -C1-C6alkyl
  • R 6a is H, halo or -C 1 -C 6 alkyl.
  • Aspect 116 The compound of aspect 115 wherein R1 is -C0-C6alk-C1-C6alkyl, preferably - CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1-C6alkyl, or - C(Me)(OH)-C 1 -C 6 alkyl.
  • R1 is -C0-C6alk-C1-C6alkyl, preferably - CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1-C6alkyl, or - C(Me)(OH)-C 1 -C 6 alkyl.
  • R 1 is -C 0 -C 6 alk-C 1 -C 6 haloalkyl, preferably - CH(OH)-C1-C6haloalkyl, -CH(F)-C1-C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1- C 6 haloalkyl, or -C(Me)(OH)-C 1 -C 6 haloalkyl.
  • R 1 is -C 0 -C 6 alk-C ⁇ CH, preferably -CH(OH)- C ⁇ CH, -CH(F)-C ⁇ CH, -CH(NH2)-C ⁇ CH, -CH(Me)-C ⁇ CH, or -C(Me)(OH)-C ⁇ CH.
  • R1 is -C0-C6alk-C ⁇ C-C1-C6alkyl, preferably - 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 -C 6 alkyl, or -C(Me)(OH)-C ⁇ C-C 1 -C 6 alkyl, more preferably -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.
  • Aspect 120 The compound of aspect 115 wherein R1 is -C0-C6alk-C ⁇ C-C1-C6haloalkyl, preferably -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 - C6haloalkyl, -CH(Me)-C ⁇ C-C1-C6haloalkyl, or -C(Me)(OH)-C ⁇ C-C1-C6haloalkyl, more preferably - 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 .
  • Aspect 121 The compound of aspect 115 wherein R 1 is -C 0 -C 6 alk-C ⁇ C-C 3 -C 6 cycloalkyl, preferably -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, more preferably -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
  • R1 is -C1-C6alk-aryl, preferably -CH2-aryl, - CH(OH)-aryl, -CH(F)-aryl, -CH(NH 2 )-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl, more preferably - CH2-4-chlorophenyl, -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)-3,4- dichlorophenyl, -
  • Aspect 123 The compound of aspect 115 wherein R 1 is -Co-C6alk-S-aryl, preferably -S-4- chlorophenyl, -S-3,4-dichlorophenyl, -S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or -S-3- chloro-4-fluorophenyl .
  • Aspect 124 The compound of aspect 115 wherein R 1 is -Co-C6alk-S(0)-aryl, preferably -S(0)-4- chlorophenyl, -S(0)-3,4-dichlorophenyl, -S(0)-3,4-difluorophenyl, -S(0)-3-fluoro-4-chlorophenyl, or -S(0)-3-chloro-4-fluorophenyl.
  • Aspect 125 The compound of aspect 115 wherein R 1 is -Co-C6alk-S(0)2-aryl, preferably -S(0) 2 - 4-chlorophenyl, -S(0)2-3,4-dichlorophenyl, -S(0)2-3,4-difluorophenyl, -S(0)2-3-fluoro-4- chlorophenyl, or -S(0)2-3-chloro-4-fluorophenyl.
  • Aspect 126 The compound of aspect 115 wherein R 1 is -Co-C6alk-0-aryl, preferably -0-4- chlorophenyl, -0-3,4-dichlorophenyl, -0-3,4-difluorophenyl, -0-3-fluoro-4-chlorophenyl, or -0-3- chloro-4-fluorophenyl .
  • Aspect 127 The compound of any one of aspects 115 to 126 wherein n is 1.
  • Aspect 128 The compound of any one of aspects 115 to 126 wherein n is 2.
  • Aspect 129 The compound of any one of aspects 115 to 128 wherein R 3 is H.
  • Aspect 130 The compound of any one of aspects 115 to 128 wherein R 5 is H.
  • Aspect 131 The compound of any on eof aspects 115 to 130 that is a compound of Formula V or Formula VI.
  • Aspect 132 The compound of aspect 131 wherein A is N.
  • Aspect 133 The compound of aspect 131 wherein A is CH.
  • Aspect 134 The compound of any one of aspects 131 to 133 wherein R 4 is H.
  • Aspect 135. The compound of any one of aspects 131 to 133 wherein R 4 is halo, preferably -F.
  • Aspect 136. The compound of any one of aspects 131 to 133 wherein R 4 is -Ci-C6alkyl, preferably methyl.
  • Aspect 137 The compound of any one of aspects 115 to 130 that is a compound of Formula V or Formula VII.
  • Aspect 138 The compound of aspect 137 wherein R 2a is -Ci-C6alkyl.
  • Aspect 139 The compound of any one of aspects 137 to 138 wherein R 2b is -Ci-C6alkyl.
  • Aspect 140 The compound of any one of aspects 115 to 130 that is a compound of Formula VI or Formula VIII.
  • Aspect 141 The compound of aspect 140 wherein R 2 is H.
  • Aspect 142 The compound of aspect 140 wherein R 2 is -Ci-C6alkyl.
  • Aspect 143 The compound of any one of aspects 115 to 130 and 137 to 142 that is a compound of Formula VII or Formula VIII.
  • Aspect 144 The compound of aspect 143 wherein R 6a is H.
  • a pharmaceutical composition comprising a compound according to any one of aspects 92 to 144 and a pharmaceutically acceptable excipient.
  • 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 92 to 144.
  • PRMT5 protein arginine methyltransferase 5
  • Aspect 147 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 92 to 147.
  • Aspect 148 The method of aspect 147, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon
  • 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,
  • AML 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),
  • 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.
  • SCD sickle cell disease
  • 9P deleted cancers 9P deleted cancers
  • MTAP deleted cancers glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

Abstract

The disclosure is directed to compounds of Formula I, Formula II, Formula III, or Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII : Methods of their use in inhibiting a protein arginine methyltransferase 5 (PRMT5) enzyme and treating disease, as well as methods of their preparation are also described.

Description

SELECTIVE INHIBITORS OF PROTEIN ARGENTINE METHYLTRANSFERASE 5 (PRMT5)
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No.
62/461, 131, filed February 20, 2017, and U.S. Provisional Patent Application No. 62/461, 142, filed February 20, 2017, each of which is incorporated by reference in its entirety herein.
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, Blimpl, and Snail. This enzyme, once recruited to a promoter, symmetrically dimethylates H3R8 and H4R3. Importantly, the H4R3 site is a major target for PRMTl 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, 523 7558; Hsu et al. Nature 2015 525, 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 methyltransf erase, DNMT3 A to the gamma-promoter by the protein arginine methyltransf erase PRMT5. Zhao et al. Nat Struct Mol Biol. 2009 16, 304. PRMT5-mediated methylation of histone H4R3 recruits DNMT3 A, coupling histone and DNA methylation in gene silencing.
[0009] PRMT5 induces the repressive histone mark, H4R3me2s, which serves as a template for direct binding of DNMT3A, and subsequent DNA methylation. Loss of 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:
Figure imgf000006_0001
or a pharmaceutically acceptable salt or solvate thereof;
wherein
A is CH or N; 
n is 1 or 2;
R1 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-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3- C6cycloalkyl, -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-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, or -C1-C6alk-C(O)NH- aryl;
R2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
R2a and R2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl
or R2a and R2b, together with the atoms to which they are attached, form a C2- C6heterocycloalkyl ring;
R3 is H, halo, -C1-C6alkyl, or NH2; and
R4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl. [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.
[0012] The disclosure is also directed to compounds of Formula V, Formula VI, Formula VII, or Formula VIII:
 
Figure imgf000007_0001
or a pharmaceutically acceptable salt or solvate thereof;
wherein
A is CH, CR6 or N; 
n is 1 or 2;
R1 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-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3- C6cycloalkyl, -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-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, -C1-C6alk-C(O)NH- aryl, -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, -C0-C6alk-S(O)2aryl, -C0-C6alk-Oaryl; R2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
R2a and R2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
or R2a and R2b, together with the atom to which they are attached, form a C2- C6heterocycloalkyl ring;
R3 is H, halo, -C1-C6alkyl, or NH2;
R4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl;
R5 is H, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3- C6halocycloalkyl, -C0-C6alk-OH, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0- C6alk-N(C1-C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, or -C0-C6alk-N(C1- C6alkyl)-C3-C6cycloalkyl;
or R5 and R1, together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring;
R6 is halo or -C1-C6alkyl; and
R6a is H, halo, or -C1-C6alkyl. [0013] Stereoisomers of the compounds of Formula V, Formula VI, Formula VII, or Formula VIII, and the pharmaceutical salts and solvates thereof, are also described. Methods of using compounds of Formula V, Formula VI, Formula VII, or Formula VIII are described, as well as pharmaceutical compositions including the compounds of Formula V, Formula VI, Formula VII, or Formula VIII. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0014] 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. [0015] The term "alkyl," when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms ("C1-C12"), preferably 1 to 6 carbons atoms ("Ci-Ce"), in the group. Examples of alkyl groups include methyl (Me, Cialkyl), ethyl (Et, C2alkyl), n-propyl (C3alkyl), isopropyl (C3alkyl), butyl (C4alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (Csalkyl), isopentyl (Csalkyl), tert-pentyl (Csalkyl), hexyl (C6alkyl), isohexyl (C6alkyl), and the like.
[0016] The term "halo" when used alone or as part of a substituent group refers to chloro, fluoro, bromo, or iodo.
[0017] 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 (- CH2CI), and the like.
[0018] The term "cycloalkyl" 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"). Examples of cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4), 2- methylcyclopentyl (C4), adamantanyl (C10), and the like.
[0019] 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 halocycloalkyl groups include, for example, chlorocyclopropyl (C3), fluorocyclobutyl (C4), bromocyclopentyl (C5), iodocyclohexyl (C6), and the like.
[0020] 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. [0021] 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.
[0022] 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=CH2; C2alkenyl) allyl (-CH2- CH=CH2;
Csalkenyl), propenyl (-CH=CHCH3; C3alkenyl); isopropenyl (-C(CH3)=CH2; C3alkenyl), butenyl (- CH=CHCH2CH3; C4alkenyl), sec-butenyl (-C(CH3)=CHCH3; C4alkenyl), iso-butenyl (-CH=C(CH3)2; C4alkenyl), 2-butenyl (-CH2CH=CHCH3; C4alkyl), pentenyl (-CH=CHCH2CH2CH3; Csalkenyl), and the like.
[0023] 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.
[0024] 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.
[0025] 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-Cio"), 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.
[0026] 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 with a halogen atom or with a - Ci-C3 alkyl group. Halogen atoms include chlorine, fluorine, bromine, and iodine. Examples of aryl groups (substituted and unsubstituted) include phenyl, naphtyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, iodophenyl, chlorofluorophenyl, fluoronaphthyl, difluoronaphthyl, chloronaphthyl, bromonaphthyl, iodonaphthyl, methylphenyl, ethylphenyl, and the like.
[0027] 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 with a halogen atom or with 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), oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.
[0028] When a range of carbon atoms is used herein, for example, Ci-C6, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, "C1-C3" includes C1-C3, Ci- C2, C2-C3, Ci, C2, and C3.
[0029] The term "Ci-C6alk" 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 "-Coalk-" refers to a bond. In some aspects, the Ci-C6alk can be substituted with one or more -OH, - H2, or halo (e.g., -F, -CI, -Br, with -F being preferred) substituents.
[0030] "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.
[0031] "Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-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.
[0032] 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.
[0033] A "solvate" refers to a physical association of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, or Formula VIII with one or more solvent molecules.
[0034] "Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.
[0035] "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.
[0036] "Compounds of the present disclosure," and equivalent expressions, are meant to embrace compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula VIII as described herein, as well as their subgenera, which expression includes the stereoisomers of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, and/or Formula VIII as well as the pharmaceutically acceptable salts and solvates, where the context so permits.
[0037] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers," for example, diastereomers, enantiomers, and atropisomers. The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)-or (^-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Where a chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers, are encompassed by that structure. The methods for the
determination of stereochemistry and the separation of stereoisomers are well-known in the art.
[0038] The compounds of the present invention may also contain unnatural proportions of one, two, three, or more atomic isotopes at one or more of the atoms that constitute such
compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125I), and/or carbon-14 (14C), or non-radioactive isotopes, such as deuterium (2H), carbon-13 (13C), and/or nitrogen- 15 (15N). Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the invention can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
[0039] In some aspects, 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:
Figure imgf000014_0001
[0040] In other aspects, the disclosure is directed to compounds of Formula II
Figure imgf000014_0002
[0041] In other aspects, the disclosure is directed to compounds of Formula III:
Figure imgf000014_0003
[0042] In other aspects, the disclosure is directed to compounds of Formula IV:
Figure imgf000015_0001
[0043] According to the disclosure, A in Formula I, is N or CH. In some aspects, A is N and the compounds of Formula I are of Formula IA
Figure imgf000015_0002
In other aspects, A is CH and the compounds of Formula I are of Formula IB
Figure imgf000015_0003
[0045] According to the disclosure, A in Formula II, is N or CH. In some aspects, A is N and the compounds of Formula II are of Formula IIA:
Figure imgf000015_0004
[0046] It will be apparent that when R2 is H, compounds of Formula IIA may exist, under certain conditions, in equilibrium with a ring-opened keto form Formula IIA', shown below. Thus, compounds of Formula IIA wherein R2 is H, as disclosed herein, are meant to also encompass the structures represented by Formula IIA'.
Figure imgf000016_0001
[0047] In other aspects, A is CH and the com ounds of Formula II are of Formula IIB:
Figure imgf000016_0002
[0048] It will be apparent that when R2 is H, compounds of Formula IIB may exist, under certain conditions, in equilibrium with a ring-opened keto form Formula IIB', shown below. Thus, compounds of Formula IIB wherein R2 is H, as disclosed herein, are meant to also encompass the structures represented by Formula IIB' .
Figure imgf000016_0003
[0049] It will be apparent that when R2 is H, compounds of Formula IV may exist, under certain conditions, in equilibrium with a ring-opened keto form Formula IV, shown below. Thus, compounds of Formula IV when R2 is H, as disclosed herein, are meant to also encompass the structures represented by Formula IV’.
Figure imgf000017_0001
[0050] According to the disclosure, n in Formula I, Formula II, Formula III, or Formula IV is 1 or 2. In some embodiments of the compounds of Formula I, Formula II, Formula III, or Formula IV, n is 1. In other embodiments, n is 2.
[0051] According to the disclosure, R1 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- C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3-C6cycloalkyl, -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-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, or - C1-C6alk-C(O)NH-aryl.
[0052] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C≡CH, -C0-C6alk-C≡C-C1-C6alkyl, -C0- C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3-C6cycloalkyl, or -C1-C6alk-aryl.
[0053] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C6alk-C3-C6cycloalkyl, for example, -C0alk-C3cycloalkyl, -C1alk-C3cycloalkyl, -C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, -C5alk-C3cycloalkyl¸ -C6alk-C3cycloalkyl, -C0alk- C4cycloalkyl, -C1alk-C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, - C5alk-C4cycloalkyl¸ -C6alk-C4cycloalkyl, -C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, -C2alk- C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk-C5cycloalkyl, -C5alk-C5cycloalkyl¸ -C6alk-C5cycloalkyl, - C0alk-C6cycloalkyl, -C1alk-C6cycloalkyl, -C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, -C4alk- C6cycloalkyl, -C5alk-C6cycloalkyl¸ or -C6alk-C6cycloalkyl. Thus, in some aspects, R1 is -CH2- cyclopropyl. [0054] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C6alk-C3-C6halocycloalkyl, for example, -C0alk-C3halocycloalkyl, -C1alk-C3halocycloalkyl, -C2alk- C3halocycloalkyl, -C3alk-C3halocycloalkyl, -C4alk-C3halocycloalkyl, -C5alk-C3halocycloalkyl¸ - C6alk-C3halocycloalkyl, -C0alk-C4halocycloalkyl, -C1alk-C4halocycloalkyl, -C2alk-C4halocycloalkyl, -C3alk-C4halocycloalkyl, -C4alk-C4halocycloalkyl, -C5alk-C4halocycloalkyl¸ -C6alk- C4halocycloalkyl, -C0alk-C5halocycloalkyl, -C1alk-C5halocycloalkyl, -C2alk-C5halocycloalkyl, - C3alk-C5halocycloalkyl, -C4alk-C5halocycloalkyl, -C5alk-C5halocycloalkyl¸ -C6alk-C5halocycloalkyl, -C0alk-C6halocycloalkyl, -C1alk-C6halocycloalkyl, -C2alk-C6halocycloalkyl, -C3alk- C6halocycloalkyl, -C4alk-C6halocycloalkyl, -C5alk-C6halocycloalkyl¸ and -C6alk-C6halocycloalkyl.
[0055] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C2- C6alkenyl, for example, vinyl, allyl, and the like.
[0056] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C2- C6haloalkenyl, for example, -C(F)=CHMe, -C(F)=CH2, and the like.
[0057] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C6alk-C1-C6alkyl, for example, -C0alk-C1alkyl, -C1alk-C1alkyl, -C2alk-C1alkyl, -C3alk-C1alkyl, - C4alk-C1alkyl, -C5alk-C1alkyl¸ -C6alk-C1alkyl, -C0alk-C2alkyl, -C1alk-C2alkyl, -C2alk-C2alkyl, - C3alk-C2alkyl, -C4alk-C2alkyl, -C5alk-C2alkyl¸ -C6alk-C2alkyl, -C0alk-C3alkyl, -C1alk-C3alkyl, - C2alk-C3alkyl, -C3alk-C3alkyl, -C4alk-C3alkyl, -C5alk-C3alkyl¸ -C6alk-C3alkyl, -C0alk-C4alkyl, - C1alk-C4alkyl, -C2alk-C4alkyl, -C3alk-C4alkyl, -C4alk-C4alkyl, -C5alk-C4alkyl¸ -C6alk-C4alkyl, - C0alk-C5alkyl, -C1alk-C5alkyl, -C2alk-C5alkyl, -C3alk-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)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1-C6alkyl, - C(Me)(OH)-C1-C6alkyl, and the like.
[0058] In other aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C6alk-C1-C6haloalkyl, for example, -C0alk-C1haloalkyl, -C1alk-C1haloalkyl, -C2alk-C1haloalkyl, - C3alk-C1haloalkyl, -C4alk-C1haloalkyl, -C5alk-C1haloalkyl¸ -C6alk-C1haloalkyl, -C0alk-C2haloalkyl, - C1alk-C2haloalkyl, -C2alk-C2haloalkyl, -C3alk-C2haloalkyl, -C4alk-C2haloalkyl, -C5alk-C2haloalkyl¸ - C6alk-C2haloalkyl, -C0alk-C3haloalkyl, -C1alk-C3haloalkyl, -C2alk-C3haloalkyl, -C3alk-C3haloalkyl, - C4alk-C3haloalkyl, -C5alk-C3haloalkyl¸ -C6alk-C3haloalkyl, -C0alk-C4haloalkyl, -C1alk-C4haloalkyl, - C2alk-C4haloalkyl, -C3alk-C4haloalkyl, -C4alk-C4haloalkyl, -C5alk-C4haloalkyl¸ -C6alk-C4haloalkyl, - C0alk-C5haloalkyl, -C1alk-C5haloalkyl, -C2alk-C5haloalkyl, -C3alk-C5haloalkyl, -C4alk-C5haloalkyl, - C5alk-C5haloalkyl¸ -C6alk-C5haloalkyl, -C0alk-C6haloalkyl, -C1alk-C6haloalkyl, -C2alk-C6haloalkyl, - C3alk-C6haloalkyl, -C4alk-C6haloalkyl, -C5alk-C6haloalkyl¸ -C6alk-C6haloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, -CH(OH)-C1-C6haloalkyl, -CH(F)-C1- C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1-C6haloalkyl, -C(Me)(OH)-C1-C6haloalkyl, and the like.
[0059] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C6alk-C≡CH, for example, -C0alk-C≡CH, -C1alk-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.
[0060] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C0- C6alk-C≡C-C1-C6alkyl, for example, -C0alk-C≡C-C1alkyl, -C1alk-C≡C-C1alkyl, -C2alk-C≡C-C1alkyl, -C3alk-C≡C-C1alkyl, -C4alk-C≡C-C1alkyl, -C5alk-C≡C-C1alkyl¸ -C6alk-C≡C-C1alkyl, -C0alk-C≡C- C2alkyl, -C1alk-C≡C-C2alkyl, -C2alk-C≡C-C2alkyl, -C3alk-C≡C-C2alkyl, -C4alk-C≡C-C2alkyl, - C5alk-C≡C-C2alkyl¸ -C6alk-C≡C-C2alkyl, -C0alk-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-C4alkyl, -C3alk-C≡C-C4alkyl, -C4alk-C≡C- C4alkyl, -C5alk-C≡C-C4alkyl¸ -C6alk-C≡C-C4alkyl, -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, -C2alk-C≡C-C6alkyl, -C3alk-C≡C-C6alkyl, - C4alk-C≡C-C6alkyl, -C5alk-C≡C-C6alkyl¸ -C6alk-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 -C0-C6alk-C≡C-C1- C6alkyl is -C0-C6alk-C≡C-CH3, R1 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-CH3. Thus, in some embodiments, R1 is -CH(OH)-C≡C- CH3.
[0061] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV 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-C1haloalkyl, -C5alk-C≡C-C1haloalkyl¸ - C6alk-C≡C-Cihaloalkyl, -Coalk-C≡C-C2haloalkyl, -Cialk-C≡C-C2haloalkyl, -C2alk-C≡C- C2haloalkyl, -C3alk-C≡C-C2haloalkyl, -C4alk-C≡C-C2haloalkyl, -C5alk-C≡C-C2haloalkylj -Cealk- C≡C-C2haloalkyl, -Coalk-C≡C-C3haloalkyl, -Cialk-C≡C-C3haloalkyl, -C2alk-C≡C-C3haloalkyl, - C3alk-C≡C-C3haloalkyl, -C4alk-C≡C-C3haloalkyl, -C5alk-C≡C-C3haloalkylj -Cealk-C≡C- C3haloalkyl, -Coalk-C≡C-C4haloalkyl, -Cialk-C≡C-C4haloalkyl, -C2alk-C≡C-C4haloalkyl, -C3alk- C≡C-C4haloalkyl, -C4alk-C≡C-C4haloalkyl, -C5alk-C≡C-C4haloalkylj -C6alk-C≡C-C4haloalkyl, - Coalk-C≡C-C5haloalkyl, -Cialk-C≡C-C5haloalkyl, -C2alk-C≡C-C5haloalkyl, -C3alk-C≡C- Cshaloalkyl, -C4alk-C≡C-C5haloalkyl, -C5alk-C≡C-C5haloalkylj -C6alk-C≡C-C5haloalkyl, -Coalk- C≡C-C6haloalkyl, -Cialk-C≡C-C6haloalkyl, -C2alk-C≡C-C6haloalkyl, -C3alk-C≡C-C6haloalkyl, - C4alk-C≡C-C6haloalkyl, -C5alk-C≡C-C6haloalkylj -C6alk-C≡C-C6haloalkyl, -CH(OH)-C≡C-Ci- Cehaloalkyl, -CH(F)-C≡C-Ci-C6haloalkyl, -CH(NH2)-C≡C-Ci-C6haloalkyl, -CH(Me)-C≡C-Ci- Cehaloalkyl, -C(Me)(OH)-C≡C-Ci-C6haloalkyl, and the like. In some embodiments wherein -Co- C6alk-C≡C-Ci-C6haloalkyl is -Co-Cealk-C≡C-CF3, R1 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-CF3, and the like. Thus, in some embodiments, R1 is -CH(OH)-C≡C-CF3.
[0062] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -Co- C6alk-C≡C-C3-C6cycloalkyl, for example, -Coalk-C≡C-C3cycloalkyl, -Coalk-C≡C-C4cycloalkyl, - Coalk-C≡C-C5cycloalkyl, -Coalk-C≡C-C6cycloalkyl, -Cialk-C≡C-C3cycloalkyl, -Cialk-C≡C- C4cycloalkyl, -Cialk-C≡C-C5-cycloalkyl, -Cialk-C≡C-C6cycloalkyl, -C2alk-C≡C-C3cycloalkyl, - C2alk-C≡C-C4cycloalkyl, -C2alk-C≡C-C5cycloalkyl, -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, -C4alk-C≡C-C5cycloalkyl, -C4alk-C≡C- Cecycloalkyl, -C5alk-C≡C-C3cycloalkyl, -C5alk-C≡C-C4cycloalkyl, -C5alk-C≡C-C5cycloalkyl, - C5alk-C≡C-C6cycloalkyl, -C6alk-C≡C-C3cycloalkyl, -C6alk-C≡C-C4cycloalkyl, -Cealk-C≡C- Cscycloalkyl, -C6alk-C≡C-C6cycloalkyl, -CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3- Cecycloalkyl, -CH(NH2)-C≡C-C3-C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)- C≡C-C3-C6cycloalkyl. In some embodiments wherein -Co-C6alk-C≡C-C3-C6cycloalkyl is -Co-C6alk- C≡C-cyclopropyl, R1 is -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C- cyclopropyl, -CH(Me)-C≡C-cyclopropyl, -C(Me)(OH)-C≡C-cyclopropyl, and the like. Thus, in some embodiments, R1 is -CH(OH)-C≡C-cyclopropyl. [0063] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-aryl, for example, -C1alk-aryl, -C2alk-aryl, -C3alk-aryl, -C4alk-aryl, -C5alk-aryl, -C6alk-aryl, - CH(OH)-aryl, -CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-aryl, -C(Me)(OH)-aryl, and the like. In some embodiments wherein R1 is -C1-C6alk-aryl, -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4- difluorophenyl, -3-fluoro-4-chlorophenyl, -3-chloro-4-fluorophenyl, or 4-chloro-3-methylphenyl. Thus in some embodiments, R1 is -CH(OH)-4-chlorophenyl, -CH(OH)-3,4-dichlorophenyl, - CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, -CH(OH)-3-chloro-4-fluorophenyl, -CH(OH)-4-chloro-3-methylphenyl, -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)-4- chloro-3-methylphenyl, -CH(NH2)-4-chlorophenyl, -CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4- difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH2)-3-chloro-4-fluorophenyl, -CH(NH2)- 4-chloro-3-methylphenyl, -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)-4- chloro-3-methylphenyl, -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, or–C(Me)(OH)-4-chloro-3-methylphenyl.
[0064] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-S-C1-C6alkyl, for example -C1alk-S-C1alkyl, -C2alk-S-C1alkyl, -C3alk-S-C1alkyl, -C4alk-S- C1alkyl, -C5alk-S-C1alkyl¸ -C6alk-S-C1alkyl, -C1alk-S-C2alkyl, -C2alk-S-C2alkyl, -C3alk-S-C2alkyl, - C4alk-S-C2alkyl, -C5alk-S-C2alkyl¸ -C6alk-S-C2alkyl, -C1alk-S-C3alkyl, -C2alk-S-C3alkyl, -C3alk-S- C3alkyl, -C4alk-S-C3alkyl, -C5alk-S-C3alkyl¸ -C6alk-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-C5alkyl¸ -C6alk-S-C5alkyl, -C1alk-S-C6alkyl, - C2alk-S-C6alkyl, -C3alk-S-C6alkyl, -C4alk-S-C6alkyl, -C5alk-S-C6alkyl¸ -C6alk-S-C6alkyl, -CH2S- C2alkyl, -CH2S-C3alkyl, -CH2S-C4alkyl, -CH2S-C5alkyl, -CH2S-C6alkyl, and the like. Thus, in some aspects R1 is -CH2S-C1alkyl. In some aspects, R1 is -CH2-S-CH3.
[0065] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-S-C1-C6haloalkyl, for example, -C1alk-S-C1haloalkyl, -C2alk-S-C1haloalkyl, -C3alk-S- C1haloalkyl, -C4alk-S-C1haloalkyl, -C5alk-S-C1haloalkyl¸ -C6alk-S-C1haloalkyl, -C1alk-S- C2haloalkyl, -C2alk-S-C2haloalkyl, -C3alk-S-C2haloalkyl, -C4alk-S-C2haloalkyl, -C5alk-S- C2haloalkyl¸ -C6alk-S-C2haloalkyl, -C1alk-S-C3haloalkyl, -C2alk-S-C3haloalkyl, -C3alk-S- C3haloalkyl, -C4alk-S-C3haloalkyl, -C5alk-S-C3haloalkyl¸ -C6alk-S-C3haloalkyl, -C1alk-S- C4haloalkyl, -C2alk-S-C4haloalkyl, -C3alk-S-C4haloalkyl, -C4alk-S-C4haloalkyl, -C5alk-S- C4haloalkyl¸ -C6alk-S-C4haloalkyl, -C1alk-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-C6haloalkyl, -C4alk-S-C6haloalkyl, -C5alk-S- C6haloalkyl¸ -C6alk-S-C6haloalkyl, -CH2S-C1haloalkyl, -CH2S-C2haloalkyl, -CH2S-C3haloalkyl, - CH2S-C4haloalkyl, -CH2S-C5haloalkyl, and -CH2S-C6haloalkyl.
[0066] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-S-C3-C6cycloalkyl, for example, -C1alk-S-C3cycloalkyl, -C2alk-S-C3cycloalkyl, -C3alk-S- C3cycloalkyl, -C4alk-S-C3cycloalkyl, -C5alk-S-C3cycloalkyl¸ -C6alk-S-C3cycloalkyl, -C1alk-S- C4cycloalkyl, -C2alk-S-C4cycloalkyl, -C3alk-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-C5cycloalkyl¸ -C6alk-S-C5cycloalkyl, -C1alk-S- C6cycloalkyl, -C2alk-S-C6cycloalkyl, -C3alk-S-C6cycloalkyl, -C4alk-S-C6cycloalkyl, -C5alk-S- C6cycloalkyl¸ -C6alk-S-C6cycloalkyl, -CH2S-C3cycloalkyl, -CH2S-C4cycloalkyl, -CH2S- C5cycloalkyl, -CH2S-C6cycloalkyl, and the like.
[0067] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-S-C3-C6halocycloalkyl, for example -C1alk-S-C3halocycloalkyl, -C2alk-S-C3halocycloalkyl, - C3alk-S-C3halocycloalkyl, -C4alk-S-C3halocycloalkyl, -C5alk-S-C3halocycloalkyl¸ -C6alk-S- C3halocycloalkyl, -C1alk-S-C4halocycloalkyl, -C2alk-S-C4halocycloalkyl, -C3alk-S-C4halocycloalkyl, -C4alk-S-C4halocycloalkyl, -C5alk-S-C4halocycloalkyl¸ -C6alk-S-C4halocycloalkyl, -C1alk-S- C5halocycloalkyl, -C2alk-S-C5halocycloalkyl, -C3alk-S-C5halocycloalkyl, -C4alk-S-C5halocycloalkyl, -C5alk-S-C5halocycloalkyl¸ -C6alk-S-C5halocycloalkyl, -C1alk-S-C6halocycloalkyl, -C2alk-S- C6halocycloalkyl, -C3alk-S-C6halocycloalkyl, -C4alk-S-C6halocycloalkyl, -C5alk-S-C6halocycloalkyl¸ -C6alk-S-C6halocycloalkyl, -CH2S-C3halocycloalkyl, -CH2S-C4halocycloalkyl, -CH2S- C5halocycloalkyl, -CH2S-C6halocycloalkyl, and the like.
[0068] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-OC1-C6alkyl, for example, -C1alk-O-C1alkyl, -C2alk-O-C1alkyl, -C3alk-O-C1alkyl, -C4alk-O- C1alkyl, -C5alk-O-C1alkyl¸ -C6alk-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-C3alkyl, -C5alk-O-C3alkyl¸ -C6alk-O-C3alkyl, -C1alk-O-C4alkyl, -C2alk-O- C4alkyl, -C3alk-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-C6alkyl, -C2alk-O-C6alkyl, -C3alk-O-C6alkyl, -C4alk-O-C6alkyl, -C5alk-O-C6alkyl¸ -C6alk-O- C6alkyl, -CH2OC1alkyl, -CH2OC2alkyl, -CH2OC3alkyl, -CH2OC4alkyl, -CH2OC5alkyl, - CH2OC6alkyl, and the like.
[0069] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-O-C3-C6cycloalkyl, for example, -C1alk-O-C3cycloalkyl, -C2alk-O-C3cycloalkyl, -C3alk-O- C3cycloalkyl, -C4alk-O-C3cycloalkyl, -C5alk-O-C3cycloalkyl¸ -C6alk-O-C3cycloalkyl, -C1alk-O- C4cycloalkyl, -C2alk-O-C4cycloalkyl, -C3alk-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-C6cycloalkyl, -C4alk-O-C6cycloalkyl, -C5alk-O- C6cycloalkyl¸ -C6alk-O-C6cycloalkyl, -CH2O-C6cycloalkyl, -CH2O-C5cycloalkyl, -CH2O- C4cycloalkyl, -CH2O-C3cycloalkyl, -CH2O-C6cycloalkyl, and the like.
[0070] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alk-SCH2-aryl, for example -C1alk-SCH2-aryl, -C2alk-SCH2-aryl , -C3alk-SCH2-aryl, -C4alk-SCH2- aryl, -C5alk-SCH2-aryl¸-C6alk-SCH2-aryl, -CH2SCH2-phenyl, -CH2SCH2-naphthyl, -CH2SCH2- fluorophenyl, -CH2SCH2-difluorophenyl, -CH2SCH2-fluoronaphthyl, -CH2SCH2-chlorophenyl, - CH2SCH2-bromophenyl, -CH2SCH2-iodophenyl, -CH2SCH2-methylphenyl, -CH2SCH2-4- chlorophenyl, -CH2SCH2-3,4-dichlorophenyl, -CH2SCH2-3,4-difluorophenyl, -CH2SCH2-3-fluoro-4- chlorophenyl, -CH2SCH2-3-chloro-4-fluorophenyl, and the like. Thus, in some aspects R1 is - CH2SCH2-phenyl.
[0071] In some aspects, R1 in Formula I, Formula II, Formula III, or Formula IV is -C1- C6alkC(O)NH-aryl, for example, -C1alk-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, -CH2C(O)NH-difluorophenyl, -CH2C(O)NH - fluoronaphthyl, -CH2C(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, -CH2C(O)NH-3-chloro-4- fluorophenyl and the like. Thus, in some aspects R1 is -CH2C(O)NH-phenyl. [0072] In embodiments of the compounds of Formula II or Formula IV, R2 is H, -Ci- C6alkyl, or -Co-C6alk-C3-C6cycloalkyl. Thus, in some embodiments, R2 is H.
[0073] In other embodiments of the compounds of Formula II or Formula IV, R2 is -Ci- C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R2 is methyl (i.e., -CFb, or Me). In other embodiments, R2 is ethyl (i.e., -CH2CH3).
[0074] In some aspects, R2 in Formula II or Formula IV is -Co-C6alk-C3-C6cycloalkyl, for example, -CoalkC3cycloalkyl, -Cialk-C3cycloalkyl, -C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk- C3cycloalkyl, -Csalk-Cscycloalkyl, -C6alk-C3cycloalkyl, -Coalk-C4cycloalkyl, -Cialk-C4cycloalkyl, - C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, -C5alk-C4cycloalkylj -C6alk- C4cycloalkyl, -Coalk-Cscycloalkyl, -Cialk-Cscycloalkyl, -C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, - C4alk-C5cycloalkyl, -Csalk-Cscycloalkyl, -Cealk-Cscycloalkyl, -Coalk-C6cycloalkyl, -Cialk- C6cycloalkyl, -C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, -C4alk-C6cycloalkyl, -Csalk-Cecycloalkyl, or -C6alk-C6cycloalkyl. In some aspects wherein R2 is -Co-C6alk-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R2 is -Co-C6alk-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-C6alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
[0075] In embodiments of the compounds of Formula I, Formula II, Formula III, or Formula IV, R3 is H, halo, Ci-C6alkyl, or H2. Thus in some embodiments, R3 is H.
[0076] In some embodiments, R3 in Formula I, Formula II, Formula III, or Formula IV is halo, for example F, CI, Br, or I. In some embodiments, R3 is F. In other embodiments, R3 is CI.
[0077] In other embodiments, R3 in Formula I, Formula II, Formula III, or Formula IV is - Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R3 is methyl (Me). In yet other embodiments, R3 is H2.
[0078] In embodiments that are a compound of Formula I or Formula II, R4 is H, halo, -Ci- C6alkyl, -Ci-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2-C6heterocycloalkyl, -C3- C6cycloalkyl, or -0-Ci-C4alkyl. Thus, in some embodiments, R4 is H.
[0079] In other embodiments, R4 in Formula I or Formula II is halo, for example F, CI, Br, or I. In some embodiments, R4 is F. [0080] In some aspects, R4 in Formula I or Formula II is -Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R4 is methyl.
[0081] In some aspects, R4 in Formula I or Formula II is -Ci-C6haloalkyl, for example, -CF3 or -CHF2.
[0082] In some embodiments, R4 in Formula I or Formula II is -C2-C6heterocycloalkyl, for example C2heterocycloalkyl, C3heterocycloalkyl, C4 heterocycloalkyl, Cs heterocycloalkyl, and C6 heterocycloalkyl, including azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like. Thus, in some embodiments, R4 is 2-oxiranyl. In other embodiments, R4 is 1-azetidinyl.
[0083] In some embodiments, R4 in Formula I or Formula II is oxo-substituted-C2- Ceheterocycloalkyl, for example, oxo-substituted-C2heterocycloalkyl, oxo-substituted- C3heterocycloalkyl, oxo-substituted-C4heterocycloalkyl, oxo-substituted-Csheterocycloalkyl, oxo- substituted-Ceheterocycloalkyl, including aziridinonyl, azetidinonyl, pyrrolidinonyl, dioxolanonyl, imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl, thiomorpholinonyl, oxazepanonyl, oxiranonyl, oxetanonyl, quinuclidinonyl, tetrahydrofuranonyl, tetrahydropyranonyl, piperazinonyl, and the like. Thus, in some embodiments, R4 is azetidin-2-one- 1-yl.
[0084] In some embodiments, R4 in Formula I or Formula II is -C3-C6cycloalkyl, for example -C3cycloalkyl, -C4cycloalkyl, -Cscycloalkyl, -Cecycloalkyl, and the like. In some embodiments, R4 is -C3cycloalkyl. Thus, in some embodiments, R4 is cyclopropyl.
[0085] In some embodiments, R4 in Formula I or Formula II is -0-Ci-C4alkyl, for example - O-Cialkyl, -0-C2alkyl, -0-C3alkyl, or -0-C4alkyl.
[0086] In embodiments that are a compound of Formula I or Formula III, R2a and R2b are each, independently, -Ci-C6alkyl, or -Co-C6alk-C3-C6cycloalkyl; or R2a and R2b, together with the atoms to which they are attached, form a C2-C6heterocycloalkyl ring.
[0087] In some embodiments that are a compound of Formula I or Formula III, R2a and/or
R2b is -Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R2a is methyl. In other embodiments, R2a is ethyl (i.e., -
CH2CH3). In some embodiments, R2b is methyl. In other embodiments, R2b is ethyl (i.e., -CH2CH3). [0088] In some embodiments that are a compound of Formula I or Formula III, R2a and/or R2b is -C0-C6alk-C3-C6cycloalkyl, for example, -C0alk-C3cycloalkyl, -C1alk-C3cycloalkyl, -C2alk- C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, -C5alk-C3cycloalkyl¸ -C6alk-C3cycloalkyl, - C0alk-C4cycloalkyl, -C1alk-C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk- C4cycloalkyl, -C5alk-C4cycloalkyl¸ -C6alk-C4cycloalkyl, -C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, - C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk-C5cycloalkyl, -C5alk-C5cycloalkyl¸ -C6alk- C5cycloalkyl, -C0alk-C6cycloalkyl, -C1alk-C6cycloalkyl, -C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, - C4alk-C6cycloalkyl, -C5alk-C6cycloalkyl¸ or -C6alk-C6cycloalkyl. In some aspects wherein R2a and/or R2b is -C0-C6alk-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R2a and/or R2b is -C0-C6alk-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).
[0089] In other embodiments that are a compound of Formula I or Formula III, R2b and R2a, together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring, for example, a 1,3-dioxolane ring or a 1,3-dioxane ring.
[0090] In preferred embodiments of the compounds of Formula I, Formula II, Formula III, or Formula IV, R1 is -C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C≡CH, -C0-C6alk- C≡C-C1-C6alkyl, -C0-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3-C6cycloalkyl, or -C1-C6alk-aryl.
[0091] More preferred embodiments of the compounds of Formula I, Formula II, Formula III, or Formula IV are those wherein R1 is -CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1- C6alkyl, -CH(Me)-C1-C6alkyl, -C(Me)(OH)-C1-C6alkyl, -CH(OH)-C1-C6haloalkyl, -CH(F)-C1- C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1-C6haloalkyl, -C(Me)(OH)-C1-C6haloalkyl, - CH(OH)-C≡CH, -CH(F)-C≡CH, -CH(NH2)-C≡CH, -CH(Me)-C≡CH, -C(Me)(OH)-C≡CH, - 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, -CH(OH)-C≡C-C1-C6haloalkyl, -CH(F)-C≡C-C1- C6haloalkyl, -CH(NH2)-C≡C-C1-C6haloalkyl, -CH(Me)-C≡C-C1-C6haloalkyl, -C(Me)(OH)-C≡C-C1- C6haloalkyl, -CH(OH)-C≡C-C3-C6cycloalkyl, -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, -CH(OH)-aryl, - CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl.
[0092] Most preferred embodiments of the compounds of Formula I, Formula II, Formula III, or Formula IV are those wherein R1 is -CH(OH)-C≡C-CH3, -CH(F)-C≡C-CH3, -CH(NH2)-C≡C- CH3, -CH(Me)-C≡C-CH3, -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, -C(Me)(OH)-C≡C-CF3, -CH(OH)-C≡C- cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C-cyclopropyl, -CH(Me)-C≡C-cyclopropyl, - C(Me)(OH)-C≡C-cyclopropyl, -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)-4-chloro-3-methylphenyl, -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)-4-chloro- 3-methylphenyl, -CH(NH2)-4-chlorophenyl, -CH(NH2)-3,4-dichlorophenyl, -CH(NH2)-3,4- difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH2)-3-chloro-4-fluorophenyl, -CH(NH2)- 4-chloro-3-methylphenyl, -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)-4- chloro-3-methylphenyl, -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, or -C(Me)(OH)-4-chloro-3-methylphenyl.
[0093] Some aspects of the disclosure are directed to compounds of Formula IC or IIIC:
Figure imgf000027_0001
[0094] Some aspects of the disclosure are directed to compounds of Formula IIC or IVC:
Figure imgf000028_0001
[0095] Some aspects of the disclosure are directed to compounds of Formula IID or IVD:
Figure imgf000028_0002
[0096] Stereoisomers of compounds of Formula I, Formula II, Formula III, or Formula IV are also contemplated.
[0097] 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.
[0098] The disclosure is also directed to compounds of Formula V, Formula VI, Formula VII, or Formula VIII. In some aspects, the disclosure is directed to compounds of Formula V:
Figure imgf000028_0003
[0099] In other aspects, the disclosure is directed to compounds of Formula VI
Figure imgf000029_0001
[00100] In other aspects, the disclosure is directed to compounds of Formula VII:
Figure imgf000029_0002
[00101] In other aspects, the disclosure is directed to compounds of Formula VIII:
Figure imgf000029_0003
[00102] According to the disclosure, A in Formula V, is N CH, or CR6. In some aspects, s N and the compounds of Formula V are of Formula VA
Figure imgf000029_0004
[00103] In other aspects, A is CH and the compounds of Formula V are of Formula VB
Figure imgf000030_0001
[00104] In other aspects, A is CR6 and the compounds of Formula V are of Formula VC:
Figure imgf000030_0002
[00105] According to the disclosure, A in Formula VI, is N, CH, or CR6. In some aspects, A is N and the compounds of Formula VI are of Formula VIA:
Figure imgf000030_0003
[00106] It will be apparent that when R2 is H, compounds of Formula VIA may exist, under certain conditions, in equilibrium with a ring-opened keto form Formula VIA', shown below. Thus, compounds of Formula VIA wherein R2 is H, as disclosed herein, are meant to also encompass the structures represented by Formula VIA'.
Figure imgf000031_0001
[00107] In other aspects, A is CH and the com ounds of Formula VI are of Formula VIB:
Figure imgf000031_0002
[00108] It will be apparent that when R2 is H, compounds of Formula VIB may exist, under certain conditions, in equilibrium with a ring-opened keto form Formula VIB', shown below. Thus, compounds of Formula VIB wherein R2 is H, as disclosed herein, are meant to also encompass the structures represented by Formula VIB' .
Figure imgf000031_0003
[00109] In other aspects, A is CR6 and the compounds of Formula VI are of Formula VIC:
Figure imgf000032_0001
[00110] It will be apparent that when R2 is H, compounds of Formula VIC may exist, under certain conditions, in equilibrium with a ring-opened keto form Formula VIC, shown below. Thus, compounds of Formula VIC wherein R2 is H, as disclosed herein, are meant to also encompass the structures represented b Formula VIC .
Figure imgf000032_0002
[00111] It will be apparent that when R2 is H, compounds of Formula VIII may exist, under certain conditions, in equilibrium with a ring-opened keto form Formula VIIF, shown below. Thus, compounds of Formula VIII when R2 is H, as disclosed herein, are meant to also encompass the structures represented by Formula VIIF .
Figure imgf000032_0003
[00112] In some aspects of Formula V or Formula VI, R6 is -halo or -Ci-Calkyl. Thus in some embodiments of the compound of Formula V or Formula VI, R6 is halo (e.g., -F, -CI, -Br, or - I). Thus, in some embodiments of the compound of Formula V or Formula VI, R6 is -F. In other embodiments of the compound of Formula V or Formula VI, R6 is -Cl.
[00113] In other aspects of Formula V or Formula VI, R6 is -C1-C6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like). Thus in some embodiments of Formula V or Formula VI, R6 is methyl (i.e., -CH3, or Me).
[00114] According to the disclosure, n in Formula V, Formula VI, Formula VII, or Formula VIII is 1 or 2. In some embodiments of the compounds of Formula V, Formula VI, Formula VII, or Formula VIII, n is 1. In other embodiments, n is 2.
[00115] According to the disclosure, R1 in Formula V, Formula VI, Formula VII, or Formula VIII 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-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3-C6cycloalkyl, -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-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, -C1- C6alk-C(O)NH-aryl, -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, -C0-C6alk-S(O)2aryl, or -C0-C6alk-Oaryl.
[00116] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C≡CH, -C0-C6alk-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)2aryl, or -C0-C6alk-Oaryl.
[00117] In other aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C3-C6cycloalkyl, for example, -C0alk-C3cycloalkyl, -C1alk-C3cycloalkyl, -C2alk- C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, -C5alk-C3cycloalkyl¸ -C6alk-C3cycloalkyl, - C0alk-C4cycloalkyl, -C1alk-C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk- C4cycloalkyl, -C5alk-C4cycloalkyl¸ -C6alk-C4cycloalkyl, -C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, - C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk-C5cycloalkyl, -C5alk-C5cycloalkyl¸ -C6alk- C5cycloalkyl, -C0alk-C6cycloalkyl, -C1alk-C6cycloalkyl, -C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, - C4alk-C6cycloalkyl, -C5alk-C6cycloalkyl¸ or -C6alk-C6cycloalkyl. Thus, in some aspects, R1 is -CH2- cyclopropyl.
[00118] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C3-C6halocycloalkyl, for example, -C0alk-C3halocycloalkyl, -C1alk-C3halocycloalkyl, - C2alk-C3halocycloalkyl, -C3alk-C3halocycloalkyl, -C4alk-C3halocycloalkyl, -C5alk-C3halocycloalkyl¸ -C6alk-C3halocycloalkyl, -C0alk-C4halocycloalkyl, -C1alk-C4halocycloalkyl, -C2alk- C4halocycloalkyl, -C3alk-C4halocycloalkyl, -C4alk-C4halocycloalkyl, -C5alk-C4halocycloalkyl¸ - C6alk-C4halocycloalkyl, -C0alk-C5halocycloalkyl, -C1alk-C5halocycloalkyl, -C2alk-C5halocycloalkyl, -C3alk-C5halocycloalkyl, -C4alk-C5halocycloalkyl, -C5alk-C5halocycloalkyl¸ -C6alk- C5halocycloalkyl, -C0alk-C6halocycloalkyl, -C1alk-C6halocycloalkyl, -C2alk-C6halocycloalkyl, - C3alk-C6halocycloalkyl, -C4alk-C6halocycloalkyl, -C5alk-C6halocycloalkyl¸ or -C6alk- C6halocycloalkyl.
[00119] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C2-C6alkenyl, for example, vinyl, allyl, and the like.
[00120] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C2-C6haloalkenyl, for example, -C(F)=CHMe, -C(F)=CH2, and the like.
[00121] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C1-C6alkyl, for example, -C0alk-C1alkyl, -C1alk-C1alkyl, -C2alk-C1alkyl, -C3alk-C1alkyl, - C4alk-C1alkyl, -C5alk-C1alkyl¸ -C6alk-C1alkyl, -C0alk-C2alkyl, -C1alk-C2alkyl, -C2alk-C2alkyl, - C3alk-C2alkyl, -C4alk-C2alkyl, -C5alk-C2alkyl¸ -C6alk-C2alkyl, -C0alk-C3alkyl, -C1alk-C3alkyl, - C2alk-C3alkyl, -C3alk-C3alkyl, -C4alk-C3alkyl, -C5alk-C3alkyl¸ -C6alk-C3alkyl, -C0alk-C4alkyl, - C1alk-C4alkyl, -C2alk-C4alkyl, -C3alk-C4alkyl, -C4alk-C4alkyl, -C5alk-C4alkyl¸ -C6alk-C4alkyl, - C0alk-C5alkyl, -C1alk-C5alkyl, -C2alk-C5alkyl, -C3alk-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)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1-C6alkyl, - C(Me)(OH)-C1-C6alkyl, and the like.
[00122] In other aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C1-C6haloalkyl, for example, -C0alk-C1haloalkyl, -C1alk-C1haloalkyl, -C2alk-C1haloalkyl, - C3alk-C1haloalkyl, -C4alk-C1haloalkyl, -C5alk-C1haloalkyl¸ -C6alk-C1haloalkyl, -C0alk-C2haloalkyl, - C1alk-C2haloalkyl, -C2alk-C2haloalkyl, -C3alk-C2haloalkyl, -C4alk-C2haloalkyl, -C5alk-C2haloalkyl¸ - C6alk-C2haloalkyl, -C0alk C3haloalkyl, -C1alk-C3haloalkyl, -C2alk-C3haloalkyl, -C3alk-C3haloalkyl, - C4alk-C3haloalkyl, -C5alk-C3haloalkyl¸ -C6alk-C3haloalkyl, -C0alk-C4haloalkyl, -C1alk-C4haloalkyl, - C2alk-C4haloalkyl, -C3alk-C4haloalkyl, -C4alk-C4haloalkyl, -C5alk-C4haloalkyl¸ -C6alk-C4haloalkyl, - C0alk-C5haloalkyl, -C1alk-C5haloalkyl, -C2alk-C5haloalkyl, -C3alk-C5haloalkyl, -C4alk-C5haloalkyl, - C5alk-C5haloalkyl¸ -C6alk-C5haloalkyl, -C0alk C6haloalkyl, -C1alk-C6haloalkyl, -C2alk-C6haloalkyl, - C3alk-C6haloalkyl, -C4alk-C6haloalkyl, -C5alk-C6haloalkyl¸ -C6alk-C6haloalkyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoropentyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, chloropentyl, bromomethyl, bromoethyl, bromopropyl, bromobutyl, bromopentyl, iodomethyl, iodoethyl, iodopropyl, iodobutyl, iodopentyl, -CH(OH)-C1-C6haloalkyl, -CH(F)-C1- C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1-C6haloalkyl, -C(Me)(OH)-C1-C6haloalkyl, and the like.
[00123] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C≡CH, for example, -C0alk-C≡CH, -C1alk-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.
[00124] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C≡C-C1-C6alkyl, for example, -C0alk-C≡C-C1alkyl, -C1alk-C≡C-C1alkyl, -C2alk-C≡C- C1alkyl, -C3alk-C≡C-C1alkyl, -C4alk-C≡C-C1alkyl, -C5alk-C≡C-C1alkyl¸ -C6alk-C≡C-C1alkyl, - C0alk-C≡C-C2alkyl, -C1alk-C≡C-C2alkyl, -C2alk-C≡C-C2alkyl, -C3alk-C≡C-C2alkyl, -C4alk-C≡C- C2alkyl, -C5alk-C≡C-C2alkyl¸ -C6alk-C≡C-C2alkyl, -C0alk-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-C4alkyl, -C3alk-C≡C-C4alkyl, - C4alk-C≡C-C4alkyl, -C5alk-C≡C-C4alkyl¸ -C6alk-C≡C-C4alkyl, -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, -C2alk-C≡C-C6alkyl, -C3alk-C≡C- C6alkyl, -C4alk-C≡C-C6alkyl, -C5alk-C≡C-C6alkyl¸ -C6alk-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 -C0-C6alk-C≡C- C1-C6alkyl is -C0-C6alk-C≡C-CH3, R1 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-CH3. Thus, in some embodiments, R1 is -CH(OH)- C≡C-CH3.
[00125] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII 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-C1haloalkyl, -C5alk-C≡C- C1haloalkyl¸ -C6alk-C≡C-C1haloalkyl, -C0alk-C≡C-C2haloalkyl, -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, -C5alk-C≡C-C3haloalkyl¸ -C6alk- C≡C-C3haloalkyl, -C0alk-C≡C-C4haloalkyl, -C1alk-C≡C-C4haloalkyl, -C2alk-C≡C-C4haloalkyl, - C3alk-C≡C-C4haloalkyl, -C4alk-C≡C-C4haloalkyl, -C5alk-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-C5haloalkyl¸ -C6alk-C≡C-C5haloalkyl, - C0alk-C≡C-C6haloalkyl, -C1alk-C≡C-C6haloalkyl, -C2alk-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-C1-C6haloalkyl, -CH(Me)-C≡C- C1-C6haloalkyl, -C(Me)(OH)-C≡C-C1-C6 haloalkyl, and the like. In some embodiments wherein -C0- C6alk-C≡C-C1-C6haloalkyl is -C0-C6alk-C≡C-CF3, R1 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-CF3, and the like. Thus, in some embodiments, R1 is -CH(OH)-C≡C-CF3.
[00126] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C≡C-C3-C6cycloalkyl, for example, -C0alk-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-C6cycloalkyl, -C2alk-C≡C-C3cycloalkyl, - C2alk-C≡C-C4cycloalkyl, -C2alk-C≡C-C5cycloalkyl, -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, -C4alk-C≡C-C5cycloalkyl, -C4alk-C≡C- C6cycloalkyl, -C5alk-C≡C-C3cycloalkyl, -C5alk-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-C6cycloalkyl, -CH(F)-C≡C-C3- C6cycloalkyl, -CH(NH2)-C≡C-C3-C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)- C≡C-C3-C6cycloalkyl. In some embodiments wherein -C0-C6alk-C≡C-C3-C6cycloalkyl is -C0-C6alk- C≡C-cyclopropyl, R1 is -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C- cyclopropyl, -CH(Me)-C≡C-cyclopropyl, -C(Me)(OH)-C≡C-cyclopropyl, and the like. Thus, in some embodiments, R1 is -CH(OH)-C≡C-cyclopropyl.
[00127] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII 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 R1 is -C1-C6alk-aryl, the -aryl is -4-chlorophenyl, -3,4-dichlorophenyl, -3,4-difluorophenyl, -3-fluoro-4-chlorophenyl, or -3-chloro-4-fluorophenyl. Thus in some embodiments, R1 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, -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(NH2)-4-chlorophenyl, -CH(NH2)-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)-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.
[00128] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk S-C1-C6alkyl, for example -C1alk-S-C1alkyl, -C2alk-S-C1alkyl, -C3alk-S-C1alkyl, -C4alk-S- C1alkyl, -C5alk-S-C1alkyl¸ -C6alk-S-C1alkyl, -C1alk-S-C2alkyl, -C2alk-S-C2alkyl, -C3alk-S-C2alkyl, - C4alk-S-C2alkyl, -C5alk-S-C2alkyl¸ -C6alk-S-C2alkyl, -C1alk-S-C3alkyl, -C2alk-S-C3alkyl, -C3alk-S- C3alkyl, -C4alk-S-C3alkyl, -C5alk-S-C3alkyl¸ -C6alk-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-C5alkyl¸ -C6alk-S-C5alkyl, -C1alk-S-C6alkyl, - C2alk-S-C6alkyl, -C3alk-S-C6alkyl, -C4alk-S-C6alkyl, -C5alk-S-C6alkyl¸ -C6alk-S-C6alkyl, -CH2S- C2alkyl, -CH2S-C3alkyl, -CH2S-C4alkyl, -CH2S-C5alkyl, -CH2S-C6alkyl, and the like. Thus, in some aspects R1 is -CH2S-C1alkyl. In some aspects, R1 is -CH2-S-CH3.
[00129] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk-S-C1-C6haloalkyl, for example -C1alk-S-C1haloalkyl, -C2alk-S-C1haloalkyl, -C3alk-S- C1haloalkyl, -C4alk-S-C1haloalkyl, -C5alk-S-C1haloalkyl¸ -C6alk-S-C1haloalkyl, -C1alk-S- C2haloalkyl, -C2alk-S-C2haloalkyl, -C3alk-S-C2haloalkyl, -C4alk-S-C2haloalkyl, -C5alk-S- C2haloalkyl¸ -C6alk-S-C2haloalkyl, -C1alk-S-C3haloalkyl, -C2alk-S-C3haloalkyl, -C3alk-S- C3haloalkyl, -C4alk-S-C3haloalkyl, -C5alk-S-C3haloalkyl¸ -C6alk-S-C3haloalkyl, -C1alk-S- C4haloalkyl, -C2alk-S-C4haloalkyl, -C3alk-S-C4haloalkyl, -C4alk-S-C4haloalkyl, -C5alk-S- C4haloalkyl¸ -C6alk-S-C4haloalkyl, -C1alk-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-C6haloalkyl, -C4alk-S-C6haloalkyl, -C5alk-S- C6haloalkyl¸ -C6alk-S-C6haloalkyl, -CH2S-C1haloalkyl, -CH2S-C2haloalkyl, -CH2S-C3haloalkyl, - CH2S-C4haloalkyl, -CH2S-C5haloalkyl, and -CH2S-C6haloalkyl.
[00130] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk-S-C3-C6cycloalkyl, for example -C1alk-S-C3cycloalkyl, -C2alk-S-C3cycloalkyl, -C3alk-S- C3cycloalkyl, -C4alk-S-C3cycloalkyl, -C5alk-S-C3cycloalkyl¸ -C6alk-S-C3cycloalkyl, -C1alk-S- C4cycloalkyl, -C2alk-S-C4cycloalkyl, -C3alk-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-C5cycloalkyl¸ -C6alk-S-C5cycloalkyl, -C1alk-S- C6cycloalkyl, -C2alk-S-C6cycloalkyl, -C3alk-S-C6cycloalkyl, -C4alk-S-C6cycloalkyl, -C5alk-S- C6cycloalkyl¸ -C6alk-S-C6cycloalkyl, -CH2S- C3cycloalkyl, -CH2S-C4cycloalkyl, -CH2S- C5cycloalkyl, -CH2S-C6cycloalkyl, and the like.
[00131] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk-S-C3-C6halocycloalkyl, for example -C1alk-S-C3halocycloalkyl, -C2alk-S-C3halocycloalkyl, -C3alk-S-C3halocycloalkyl, -C4alk-S-C3halocycloalkyl, -C5alk-S-C3halocycloalkyl¸ -C6alk-S- C3halocycloalkyl, -C1alk-S-C4halocycloalkyl, -C2alk-S-C4halocycloalkyl, -C3alk-S-C4halocycloalkyl, -C4alk-S-C4halocycloalkyl, -C5alk-S-C4halocycloalkyl¸ -C6alk-S-C4halocycloalkyl, -C1alk-S- C5halocycloalkyl, -C2alk-S-C5halocycloalkyl, -C3alk-S-C5halocycloalkyl, -C4alk-S-C5halocycloalkyl, -C5alk-S-C5halocycloalkyl¸ -C6alk-S-C5halocycloalkyl, -C1alk-S-C6halocycloalkyl, -C2alk-S- C6halocycloalkyl, -C3alk-S-C6halocycloalkyl, -C4alk-S-C6halocycloalkyl, -C5alk-S-C6halocycloalkyl¸ -C6alk-S-C6halocycloalkyl, -CH2S-C3halocycloalkyl, -CH2S-C4halocycloalkyl, -CH2S- C5halocycloalkyl, -CH2S-C6halocycloalkyl, and the like.
[00132] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk-OC1-C6alkyl, for example, -C1alk-O-C1alkyl, -C2alk-O-C1alkyl, -C3alk-O-C1alkyl, -C4alk- O-C1alkyl, -C5alk-O-C1alkyl¸ -C6alk-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-C3alkyl, -C5alk-O-C3alkyl¸ -C6alk-O-C3alkyl, -C1alk-O-C4alkyl, -C2alk- O-C4alkyl, -C3alk-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-C6alkyl, -C2alk-O-C6alkyl, -C3alk-O-C6alkyl, -C4alk-O-C6alkyl, -C5alk-O-C6alkyl¸ -C6alk- O-C6alkyl, -CH2OC1alkyl, -CH2OC2alkyl, -CH2OC3alkyl, -CH2OC4alkyl, -CH2OC5alkyl, - CH2OC6alkyl, and the like.
[00133] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk-O-C3-C6cycloalkyl, for example, -C1alk-O-C3cycloalkyl, -C2alk-O-C3cycloalkyl, -C3alk-O- C3cycloalkyl, -C4alk-O-C3cycloalkyl, -C5alk-O-C3cycloalkyl¸ -C6alk-O-C3cycloalkyl, -C1alk-O- C4cycloalkyl, -C2alk-O-C4cycloalkyl, -C3alk-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-C6cycloalkyl, -C4alk-O-C6cycloalkyl, -C5alk-O- C6cycloalkyl¸ -C6alk-O-C6cycloalkyl, -CH2O-C6cycloalkyl, -CH2O-C5cycloalkyl, -CH2O- C4cycloalkyl, -CH2O-C3cycloalkyl, -CH2O-C6cycloalkyl, and the like.
[00134] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alk SCH2-aryl, for example -C1alk-SCH2-aryl, -C2alk-SCH2-aryl , -C3alk-SCH2-aryl, -C4alk- SCH2-aryl, -C5alk-SCH2-aryl¸-C6alk-SCH2-aryl, -CH2SCH2-phenyl, -CH2SCH2-naphthyl, - CH2SCH2-fluorophenyl, -CH2SCH2-difluorophenyl, -CH2SCH2-fluoronaphthyl, -CH2SCH2- chlorophenyl, -CH2SCH2-bromophenyl, -CH2SCH2-iodophenyl, -CH2SCH2-methylphenyl, - CH2SCH2-4-chlorophenyl, -CH2SCH2-3,4-dichlorophenyl, -CH2SCH2-3,4-difluorophenyl, - CH2SCH2-3-fluoro-4-chlorophenyl, -CH2SCH2-3-chloro-4-fluorophenyl, and the like. Thus, in some aspects R1 is -CH2SCH2-phenyl.
[00135] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C1-C6alkC(O)NH-aryl, for example, -C1alk-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, -CH2C(O)NH-difluorophenyl, -CH2C(O)NH - fluoronaphthyl, -CH2C(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, -CH2C(O)NH-3-chloro-4- fluorophenyl and the like. Thus, in some aspects R1 is -CH2C(O)NH-phenyl.
[00136] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-S-aryl, for example -C0alk-S-aryl, -C1alk-S-aryl, -C2alk-S-aryl, -C3alk-S-aryl, -C4alk-S- aryl, -C5alk-S-aryl , -C6alk-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 aspects R1 is -S-difluorophenyl. In some aspects R1 is -S-3,4-difluorophenyl. In other aspects, R1 is -S-chlorophenyl. In other aspects, R1 is -S-4-chlorophenyl. In other aspects, R1 is -S- chlorofluorophenyl. In other aspects, R1 is -S-3-chloro-4-fluorophenyl. In other aspects, R1 is -S-4- chloro-3 -fluorophenyl. In other aspects, R1 is -S-dichlorophenyl. In other aspects, R1 is -S-3,4- dichlorophenyl.
[00137] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - Co-C6alk-S(0)aryl, for example, -Coalk-S(0)aryl, -Cialk-S(0)aryl, -C2alk-S(0)aryl, -C3alk-S(0)aryl, -C4alk-S(0)aryl, -C5alk-S(0)aryl, -C6alk-S(0)aryl, -S(0)-phenyl, -S(0)-naphthyl, -S(O)- fluorophenyl, -S(0)-difluorophenyl, -S(0)-fluoronaphthyl, -S(0)-chlorophenyl, -S(0)-bromophenyl, -S(0)-iodophenyl, -S(0)-methylphenyl, and the like. In some aspects R1 is -S(0)-difluorophenyl. In some aspects R1 is -S(0)-3,4-difluorophenyl. In other aspects, R1 is -S(0)-chlorophenyl. In other aspects, R1 is -S(0)-4-chlorophenyl. In other aspects, R1 is -S(0)-chlorofluorophenyl. In other aspects, R1 is -S(0)-3-chloro-4-fluorophenyl. In other aspects, R1 is -S(0)-4-chloro-3-fluorophenyl. In other aspects, R1 is -S(0)-dichlorophenyl. In other aspects, R1 is -S(0)-3,4-dichlorophenyl.
[00138] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - Co-C6alk-S(0)2aryl, for example, -Coalk-S(0)2aryl, -Cialk-S(0)2aryl, -C2alk-S(0)2aryl, -C3alk- S(0)2aryl, -C4alk-S(0)2aryl, -C5alk-S(0)2aryl , -C6alk-S(0)2aryl, -S(0)2-phenyl, -S(0)2-naphthyl, - S(0)2-fluorophenyl, - S(0)2-difluorophenyl, -S(0)2-fluoronaphthyl, -S(0)2-chlorophenyl, -S(0)2- bromophenyl, -S(0)2-iodophenyl, -S(0)2-methylphenyl, and the like. In some aspects R1 is -S(0)2- difluorophenyl. In some aspects R1 is -S(0)2-3,4-difluorophenyl. In other aspects, R1 is -S(0)2- chlorophenyl. In other aspects, R1 is -S(0)2-4-chlorophenyl. In other aspects, R1 is -S(0)2- chlorofluorophenyl. In other aspects, R1 is -S(0)2-3-chloro-4-fluorophenyl. In other aspects, R1 is - S(0)2-4-chloro-3 -fluorophenyl. In other aspects, R1 is -S(0)2-dichlorophenyl. In other aspects, R1 is -S(0)2-3,4-dichlorophenyl.
[00139] In some aspects, R1 in Formula V, Formula VI, Formula VII, or Formula VIII is - Co-C6alk-Oaryl, for example -Coalk-Oaryl, -Cialk-Oaryl, -C2alk-Oaryl, -C3alk-Oaryl, -C4alk-Oaryl, - C5alk-Oaryl , -Cealk-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 R1 is -O-difluorophenyl. In some aspects R1 is -0-3,4-difluorophenyl. In other aspects, R1 is -O-chlorophenyl. In other aspects, R1 is -O-4-chlorophenyl. In other aspects, R1 is -O- chlorofluorophenyl. In other aspects, R1 is -0-3-chloro-4-fluorophenyl. In other aspects, R1 is -0-4- chloro-3 -fluorophenyl. In other aspects, R1 is -O-dichlorophenyl. In other aspects, R1 is -0-3,4- dichlorophenyl.
[00140] In some aspects of Formula VI or Formula VIII, R2 is H, -Ci-C6alkyl, or -Co-C6alk- C3-C6cycloalkyl. Thus, in some embodiments, R2 is H.
[00141] In some embodiments, R2 in Formula VI or Formula VIII is -Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R2 is methyl (i.e., -CFb, or Me). In other embodiments, R2 is ethyl (i.e., - CH2CH3).
[00142] In some aspects, R2 in Formula VI or Formula VIII is -Co-C6alk-C3-C6cycloalkyl, for example, -Coalk C3cycloalkyl, -Cialk-C3cycloalkyl, -C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, - C4alk-C3cycloalkyl, -Csalk-Cscycloalkyl, -C6alk-C3cycloalkyl, -Coalk C4cycloalkyl, -Cialk- C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk-C4cycloalkyl, -C5alk-C4cycloalkylj - C6alk-C4cycloalkyl, -Coalk Cscycloalkyl, -Cialk-Cscycloalkyl, -C2alk-C5cycloalkyl, -C3alk- Cscycloalkyl, -C4alk-C5cycloalkyl, -Csalk-Cscycloalkyl, -Cealk-Cscycloalkyl, -Coalk-Cecycloalkyl, - Cialk-C6cycloalkyl, -C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, -C4alk-C6cycloalkyl, -Csalk- Cecycloalkyl, and -C6alk-C6cycloalkyl. In some aspects wherein R2 is -Co-C6alk-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R2 is -Co-C6alk-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci- C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-C6alkyl (e.g., -Omethyl, -Oethyl, - Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
[00143] In some aspects of Formula V or Formula VII, R2a and R2b are each, independently, -Ci-C6alkyl, or -Co-C6alk-C3-C6cycloalkyl; or R2a and R2b, together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring.
[00144] In other embodiments that are a compound of Formula V or Formula VII, R2a and/or R2b is -Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t- butyl, pentyl, and the like. In some embodiments, R2a is methyl. In some embodiments, R2b is methyl. In other embodiments, R2a is ethyl (i.e., -CH2CH3). In other embodiments, R2b is ethyl (i.e., -CH2CH3).
[00145] In some embodiments that are a compound of Formula V or Formula VII, R2a and/or R2b is -Co-C6alk-C3-C6cycloalkyl, for example -Coalk-C3cycloalkyl, -Cialk-C3cycloalkyl, - C2alk-C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, -Csalk-Cscycloalkyl, -C6alk- C3cycloalkyl, -Coalk C4cycloalkyl, -Cialk-C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, - C4alk-C4cycloalkyl, -C5alk-C4cycloalkylj -C6alk-C4cycloalkyl, -Coalk-Cscycloalkyl, -Cialk- Cscycloalkyl, -C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk-C5cycloalkyl, -Csalk-Cscycloalkyl, - Cealk-Cscycloalkyl, -Coalk-C6cycloalkyl, -Cialk-C6cycloalkyl, -C2alk-C6cycloalkyl, -C3alk- C6cycloalkyl, -C4alk-C6cycloalkyl, -Csalk-Cecycloalkyl, and -C6alk-C6cycloalkyl. In some aspects wherein R2a and/or R2b is -Co-C6alk-C3-C6cycloalkyl, the cycloalkyl is unsubstituted. In other aspects wherein R2a and/or R2b is -Co-C6alk-C3-C6cycloalkyl, the cycloalkyl is substituted with one, two, or three R substituents independently selected from Ci-C6alkyl, (e.g., methyl, ethyl, propyl, isopropyl, butyl), -OCi-C6alkyl (e.g., -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Obutyl), and halo (e.g., F or CI).
[00146] In other embodiments that are a compound of Formula V or Formula VII, R2b and R2a, together with the atom to which they are attached, form a C2-C6heterocycloalkyl ring, for example, a 1,3-dioxolane ring or a 1,3-dioxane ring.
[00147] According to the disclosure, in compounds of Formula V, Formula VI, Formula VII, or Formula VIII, R3 is H, halo, Ci-C6alkyl, or Fh. Thus in some embodiments, R3 is H.
[00148] In some embodiments, R3 in Formula V, Formula VI, Formula VII, or Formula VIII is halo, for example F, CI, Br, or I. In some embodiments, R3 is F. In other embodiments, R3 is CI.
[00149] In other embodiments, R3 in Formula V, Formula VI, Formula VII, or Formula VIII is -Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R3 is methyl (Me). In yet other embodiments, R3 is Fh.
[00150] In embodiments that are a compound of Formula V or Formula VI, R4 is H, halo, - Ci-C6alkyl, -Ci-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2-C6heterocycloalkyl, -C3- C6cycloalkyl, or -0-Ci-C4alkyl. Thus, in some embodiments, R4 in Formula V or Formula VI is H.
[00151] In other embodiments, R4 in Formula V or Formula VI is halo, for example F, CI, Br, or I. In some embodiments, R4 is -F.
[00152] In some aspects, R4 in Formula V or Formula VI is -Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. In some embodiments, R4 is methyl. [00153] In some aspects, R4 in Formula V or Formula VI is -Ci-C6haloalkyl, for example, - CF3 or -CHF2.
[00154] In some embodiments, R4 in Formula V or Formula VI is -C2-C6heterocycloalkyl, for example C2heterocycloalkyl, C3heterocycloalkyl, C4 heterocycloalkyl, Cs heterocycloalkyl, and C6 heterocycloalkyl, including azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl,
imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl,
thiomo holinyl, oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like. Thus, in some embodiments, R4 is 2-oxiranyl. In other embodiments, R4 is 1-azetidinyl.
[00155] In some embodiments, R4 in Formula V or Formula VI is oxo-substituted-C2- Ceheterocycloalkyl, for example, oxo-substituted-C2heterocycloalkyl, oxo-substituted- C3heterocycloalkyl, oxo-substituted-C4heterocycloalkyl, oxo-substituted-Csheterocycloalkyl, oxo- substituted-Ceheterocycloalkyl, including aziridinonyl, azetidinonyl, pyrrolidinonyl, dioxolanonyl, imidazolidinonyl, pyrazolidinonyl, piperazinonyl, piperidinonyl, dioxanonyl, dithianonyl,
thiomorpholinonyl, oxazepanonyl, oxiranonyl, oxetanonyl, quinuclidinonyl, tetrahydrofuranonyl, tetrahydropyranonyl, piperazinonyl, and the like. Thus, in some embodiments, R4 is azetidin-2-one- 1-yl.
[00156] In some embodiments, R4 in Formula V or Formula VI is -C3-C6cycloalkyl, for example -C3cycloalkyl, -C4cycloalkyl, -Cscycloalkyl, -Cecycloalkyl, and the like. In some embodiments, R4 is -C3cycloalkyl. Thus, in some embodiments, R4 is cyclopropyl.
[00157] In some embodiments, R4 in Formula V or Formula VI is -O-C1-C4 alkyl, for example -O-Cialkyl, -0-C2alkyl, -0-C3alkyl, or -0-C4alkyl.
[00158] In some aspects of Formula V, Formula VI, Formula VII, or Formula VIII, R5 is H, -Ci-C6alkyl, -Ci-C6haloalkyl, -Co-C6alk-C3-C6cycloalkyl, -Co-C6alk-C3-C6halocycloalkyl, -Co-C6alk- OH, -Co-C6alk- H2, -Co-Cealk-NH-Ci-Cealkyl, -Co-C6alk-N(Ci-C6alkyl)-Ci-C6alkyl, -Co-Cealk- H- C3-C6cycloalkyl, -Co-C6alk-N(Ci-C6alkyl)-C3-C6cycloalkyl; or R5 and R1, together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring.
[00159] In some embodiments, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is H.
[00160] In some embodiments, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is -Ci-C6alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. [00161] In some embodiments, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is -C1-C6haloalkyl, for example, C1haloalkyl, C2haloalkyl, C3haloalkyl, C4haloalkyl,
C5haloalkyl, or C6haloalkyl.
[00162] In some aspects, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C3-C6cycloalkyl, for example -C0alk-C3cycloalkyl, -C1alk-C3cycloalkyl, -C2alk- C3cycloalkyl, -C3alk-C3cycloalkyl, -C4alk-C3cycloalkyl, -C5alk-C3cycloalkyl¸ -C6alk-C3cycloalkyl, - C0alk-C4cycloalkyl, -C1alk-C4cycloalkyl, -C2alk-C4cycloalkyl, -C3alk-C4cycloalkyl, -C4alk- C4cycloalkyl, -C5alk-C4cycloalkyl¸ -C6alk-C4cycloalkyl, -C0alk-C5cycloalkyl, -C1alk-C5cycloalkyl, - C2alk-C5cycloalkyl, -C3alk-C5cycloalkyl, -C4alk-C5cycloalkyl, -C5alk-C5cycloalkyl¸ -C6alk- C5cycloalkyl, -C0alk-C6cycloalkyl, -C1alk-C6cycloalkyl, -C2alk-C6cycloalkyl, -C3alk-C6cycloalkyl, - C4alk-C6cycloalkyl, -C5alk-C6cycloalkyl¸ -C6alk-C6cycloalkyl, and the like. In some embodiments, R5 is C1alk-C3cycloalkyl. Thus, in some embodiments, R5 is -CH2-cyclopropyl.
[00163] In some aspects, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-C3-C6halocycloalkyl, for example, -C0alk-C3halocycloalkyl, -C1alk-C3halocycloalkyl, - C2alk-C3halocycloalkyl, -C3alk-C3halocycloalkyl, -C4alk-C3halocycloalkyl, -C5alk-C3halocycloalkyl¸ -C6alk-C3halocycloalkyl, -C0alk-C4halocycloalkyl, -C1alk-C4halocycloalkyl, -C2alk- C4halocycloalkyl, -C3alk-C4halocycloalkyl, -C4alk-C4halocycloalkyl, -C5alk-C4halocycloalkyl¸ - C6alk-C4halocycloalkyl, -C0alk-C5halocycloalkyl, -C1alk-C5halocycloalkyl, -C2alk-C5halocycloalkyl, -C3alk-C5halocycloalkyl, -C4alk-C5halocycloalkyl, -C5alk-C5halocycloalkyl¸ -C6alk- C5halocycloalkyl, -C0alk-C6halocycloalkyl, -C1alk-C6halocycloalkyl, -C2alk-C6halocycloalkyl, - C3alk-C6halocycloalkyl, -C4alk-C6halocycloalkyl, -C5alk-C6halocycloalkyl¸ and -C6alk- C6halocycloalkyl, and the like.
[00164] In some aspects, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-OH, for example, -C0alk-OH (i.e., -OH), -C1alk-OH, -C2alk-OH, -C3alk-OH, -C4alk-OH, - C5alk-OH, -C6alk-OH, and the like. In some embodiments, R5 is -C1alk-OH. Thus, in some embodiments, R5 is hydroxymethyl (i.e., -CH2OH).
[00165] In some aspects, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-NH2, for example, -C0alk-NH2 (i.e., -NH2), -C1alk-NH2, -C2alk-NH2, -C3alk-NH2, -C4alk- NH2, -C5alk-NH2, -C6alk-NH2, and the like. In some embodiments, R5 is -C1alk-NH2. Thus, in some embodiments, R5 is aminomethyl (i.e., -CH2NH2). [00166] In some aspects, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-NH-C1-C6alkyl, for example, -C0alk-NH-C1alkyl, -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-C2alkyl, -C4alk-NH-C2alkyl, -C5alk-NH-C2alkyl¸ -C6alk-NH-C2alkyl, -C0alk-NH-C3alkyl, -C1alk-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, -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¸ -C6alk-NH-C5alkyl, -C0alk-NH-C6alkyl, -C1alk-NH-C6alkyl, -C2alk-NH-C6alkyl, -C3alk-NH-C6alkyl, -C4alk-NH-C6alkyl, -C5alk-NH-C6alkyl¸ -C6alk-NH-C6alkyl and the like.
[00167] In some aspects, R5 in Formula V, Formula VI, Formula VII, or Formula VIII 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-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-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-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-C6alkyl)-C4alkyl, -C1alk-N(C1- C6alkyl)-C4alkyl, -C2alk-N(C1-C6alkyl)-C4alkyl, -C3alk-N(C1-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-C6alkyl)-C5alkyl, -C3alk-N(C1- C6alkyl)-C5alkyl, -C4alk-N(C1-C6alkyl)-C5alkyl, -C5alk-N(C1-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-C6alkyl)-C6alkyl, -C5alk-N(C1- C6alkyl)-C6alkyl¸ and -C6alk-N(C1-C6alkyl)-C6alkyl and the like.
[00168] In some aspects, R5 in Formula V, Formula VI, Formula VII, or Formula VIII 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, -C1alk-NH-C4cycloalkyl, -C2alk- NH-C4cycloalkyl, -C3alk-NH-C4cycloalkyl, -C4alk-NH-C4cycloalkyl, -C5alk-NH-C4cycloalkyl¸ - C6alk-NH-C4cycloalkyl, -C0alk-NH-C5cycloalkyl, -C1alk-NH-C5cycloalkyl, -C2alk-NH-C5cycloalkyl, -C3alk-NH-C5cycloalkyl, -C4alk-NH-C5cycloalkyl, -C5alk-NH-C5cycloalkyl¸ -C6alk-NH- C5cycloalkyl, -C0alk-NH-C6cycloalkyl, -C1alk-NH-C6cycloalkyl, -C2alk-NH-C6cycloalkyl, -C3alk- NH-C6cycloalkyl, -C4alk-NH-C6cycloalkyl, -C5alk-NH-C6cycloalkyl¸ -C6alk-NH-C6cycloalkyl and the like.
[00169] In some aspects, R5 in Formula V, Formula VI, Formula VII, or Formula VIII is - C0-C6alk-N(C1-C6alkyl)-C3-C6cycloalkyl, 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-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)-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, -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-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)-C6cycloalkyl¸ -C6alk-N(C1-C6alkyl)-C6cycloalkyl, and the like.
[00170] In some aspects of compounds of Formula V, Formula VI, Formula VII, or
Formula VIII, R5 and R1, together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring.
[00171] In embodiments of the disclosure that are compounds of Formula VII or Formula VIII, R6a is H, halo, or -C1-C6alkyl. Thus in some embodiments of the compounds of Formula VII or Formula VIII, R6a is H. In other embodiments of the compound of Formula VII or Formula VIII, R6a is halo (e.g., F, Cl, Br, or I). In some embodiments of the compound of Formula VII or Formula VIII, R6a is F. In other embodiments of the compound of Formula VII or Formula VIII, R6a is Cl. In some embodiments of the compounds of Formula VII or Formula VIII, R6a is C1-C6alkyl, for example, ethyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, and the like. Thus, in some embodiments, R6a is Me (i.e., methyl).
[00172] In preferred embodiments of the compounds of Formula V, Formula VI, Formula VII, or Formula VIII, R1 is -C0-C6alk-C1-C6alkyl, -C0-C6alk-C1-C6haloalkyl, -C0-C6alk-C≡CH, -C0- C6alk-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.
[00173] More preferred embodiments are those wherein R1 in Formula V, Formula VI, Formula VII, or Formula VIII is -CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, - CH(Me)-C1-C6alkyl, or -C(Me)(OH)-C1-C6alkyl, -CH(OH)-C1-C6 haloalkyl, -CH(F)-C1-C6 haloalkyl, -CH(NH2)-C1-C6 haloalkyl, -CH(Me)-C1-C6 haloalkyl, or -C(Me)(OH)-C1-C6 haloalkyl, -CH(OH)- C≡CH, -CH(F)-C≡CH, -CH(NH2)-C≡CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH, -CH(OH)-C≡C- C1-C6alkyl, -CH(F)-C≡C-C1-C6alkyl, -CH(NH2)-C≡C-C1-C6alkyl, -CH(Me)-C≡C-C1-C6alkyl, or - 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- C1-C6haloalkyl, or -C(Me)(OH)-C≡C-C1- C6haloalkyl, -CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3- C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, or -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.
[00174] Most preferred embodiments are those wherein R1 in Formula V, Formula VI, Formula VII, or Formula VIII is -CH(OH)-C≡C-CH3, -CH(F)-C≡C-CH3, -CH(NH2)-C≡C-CH3, - CH(Me)-C≡C-CH3, -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, -C(Me)(OH)-C≡C-CF3, -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C-cyclopropyl, -CH(Me)-C≡C-cyclopropyl, -C(Me)(OH)- C≡C-cyclopropyl, -CH2-4-chlorophenyl, -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(NH2)-4- chlorophenyl, -CH(NH2)-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)-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, -C(Me)(OH)-3-chloro-4-fluorophenyl, -S-4- chlorophenyl, -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)-3,4-dichlorophenyl, -S(O)-3,4-difluorophenyl, - S(0)-3-fluoro-4-chlorophenyl, or -S(0)-3-chloro-4-fluorophenyl, -S(0)2-4-chlorophenyl, -S(0)2-3,4- dichlorophenyl, -S(0)2-3,4-difluorophenyl, -S(0)2-3-fluoro-4-chlorophenyl, or -S(0)2-3-chloro-4- fluorophenyl, -O-4-chlorophenyl, -0-3,4-dichlorophenyl, -0-3,4-difluorophenyl, -0-3-fluoro-4- chlorophenyl, or -0-3-chloro-4-fluorophenyl.
[00175] Some aspects of the disclosure are directed to compounds of Formula VD and
VIID:
Figure imgf000048_0001
[00176] Some aspects of the disclosure are directed to compounds of Formula VID and VIIID:
Figure imgf000048_0002
[00177] Some aspects of the disclosure are directed to compounds of Formula VIE and VIIIE:
Figure imgf000048_0003
[00178] Stereoisomers of compounds of Formula V, Formula VI, Formula VII, or Formula VIII are also contemplated.
[00179] Pharmaceutically acceptable salts and solvates of the compounds of Formula V, Formula VI, Formula VII, or Formula VIII are also within the scope of the disclosure.
Pharmaceutical compositions and methods of administration
[00180] 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.
[00181] 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.
[00182] 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.
[00183] 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.
[00184] 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.
[00185] 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.
[00186] 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).
[00187] 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).
[00188] 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-
[00189] 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.
[00190] 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.
[00191] Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same.
Pharmaceutical compositions for oral administration. [00192] 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.
[00193] 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.
[00194] 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.
[00195] 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.
[00196] 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.
[00197] 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.
[00198] 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.
[00199] 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.
[00200] 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.
[00201] 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.
[00202] 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. [00203] 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.
[00204] 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.
[00205] 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.
[00206] 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.
[00207] 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. [00208] 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.
[00209] 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.
[00210] 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 di oleate, 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, polyglyceiyl-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.
[00211] 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.
[00212] 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.
[00213] 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 tri ethyl citrate, 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.
[00214] 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.
[00215] 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.
[00216] 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.
[00217] 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)aminom ethane (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.
[00218] 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. [00219] 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.
[00220] 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.
[00221] 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.
[00222] 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.
[00223] 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.
[00224] 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.
[00225] 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.
[00226] 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.
[00227] 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.
[00228] 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.
[00229] 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.
[00230] 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.
[00231] 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.
[00232] 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. [00233] In some embodiments, a compound of the invention is administered in a single dose.
[00234] 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.
[00235] 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.
[00236] 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.
[00237] 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.
[00238] 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.
[00239] 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. [00240] 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.
[00241] 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.
[00242] 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.
[00243] 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
[00244] 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. [00245] As used herein, the term "IC50" refers to the half maximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, 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.
[00246] 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).
[00247] 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.
[00248] 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.
[00249] 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.
[00250] 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.
[00251] 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 K-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, Bronchi oloalveolar 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.
[00252] 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.
[00253] In some embodiments, said method is for treating a disease selected from 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).
[00254] 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.
[00255] 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).
[00256] 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.
[00257] 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.
[00258] Compounds of the disclosure can be prepared, for example, by reference to the following schemes.
Figure imgf000071_0001
Figure imgf000072_0002
Figure imgf000072_0001
Scheme 3
Figure imgf000073_0001
Scheme 4
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Scheme 2-B
Figure imgf000077_0001
Scheme 3-B
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
[00259] Compounds of the disclosure include, for example, the compounds identified Table A. TABLE A
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0002
[00260] Compounds of the disclosure also include, for example, the compounds identified Table B.
TABLE B
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0002
Experimental Procedures
Synthesis of Intermediates
Synthesis of Int-1
Figure imgf000106_0001
Step 1. Preparation of [(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d] [l,3]dioxol-6-yl]-(4-chloro-3-fluoro-phenyl)methyl] 4-phenylbenzoate (Int-1-2)
[00261] (S)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][l,3]dioxol-6-yl]-(4-chloro-3-fluoro-phenyl)methanol (Int-1-1) (30.g, 90.16 mmol), Ph3P (35.47g, 135.2 mmol) and 4-Biphenylcarboxylic acid (26.81g, 135.24 mmol) was added to Toluene (600 mL), then the reaction mixture was stirred for 0.5h, then DIAD (27.35g, 135.2 mmol) was added to the mixture at 0 °C, then the reaction mixture was stirred at rt for 2h. TLC showed the reaction was completed.
[00262] The reaction mixture was concentrated and the crude product was purified by silica gel column (PE:EA = 10: 1) to give [(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-(4-chloro-3-fluoro-phenyl)methyl] 4-phenylbenzoate (Int-1-2) (13.5 g, 26.3 mmol, 29.2% yield) as a yellow oil.
Step 2. Preparation of [(R)-(3,4-dichlorophenyl)-[(2S,3S,4R)-3,4,5- trihydroxytetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-1-3)
[00263] [(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][l,3]dioxol-6-yl]-(4-chloro-3-fluoro-phenyl)methyl] 4-phenylbenzoate (Int-1-2) (13.56g, 26.44 mmol) was added to a miscible liquids of TFA (130. mL, 1755.8 mmol) and Water (130 mL), then the reaction mixture was stirred at rt for 72h. TLC (PE : EA = 1 : 1, Rf = 0.2) showed the reaction was completed. The crude product was purifited by silica gel column (PE:EA =20: 1 to 1 :2) and concentrated to give [(S)-(4-chloro-3-fluoro-phenyl)-[(2S,3 S,4R)-3,4,5-trihydroxytetrahydrofuran-2- yljmethyl] 4-phenylbenzoate (Int-1-3) (6.2 g, 13.5 mmol, 51.1% yield) as a white solid.
Step 3. Preparation of [(R)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo [2,3-d]pyrimidin-7-yl)-3,4- dihydroxy-tetrahydrofuran-2-yl]-(3,4-dichlorophenyl)methyl]4-phenylbenzoate (Int-1)
To a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (l .g, 6.51 mmol) and Pyridine (0.53mL, 6.51 mmol) in dry THF (50 mL) was added tributylphosphine (3.25mL, 13.02 mmol) and DIAL) (2.56mL, 13.02 mmol) at 0 °C under N2. Then [(R)-(4-chloro-3-fluoro-phenyl)-[(2S,3S,4R,5S)- 3,4,5-trihydroxytetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-1-3) (2.99g, 6.51 mmol) in dry THF (30 mL) was added in one portion. The reaction mixture was stirred at rt overnight. LCMS showed the reaction was completed. The solution was purified by Prep-ELPLC (0.1% TFA) eluting with H20:CH3CN from 85: 15 to 30:70 to give[(R)-(4-chloro-3-fluoro-phenyl)-[(2S,3S,4R,5R)-5- (4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4- phenylbenzoate (Int-1) (1.9 g, 2.45 mmol, 37.7% yield) as pale yellow solid. LCMS [M+H]:
594.1/596.1. Synthesis of Int-
Figure imgf000108_0001
[00264] To a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (3.35 g, 21.39 mmol) and pyridine (1.73 mL, 21.39 mmol) in dry THF (50 mL) was added tributylphosphane (10.68 mL, 42.77 mmol) and DIAD (8.84 mL, 44.91 mmol) at 30 °C. Then [(R)-(3,4-dichlorophenyl)-[(2S,3S,4R)- 3,4,5- trihydroxytetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-2-1) (10.7 g, 21.39 mmol) in dry THF (100 mL) was added. The reaction mixture was stirred at 30 °C for 1 h. LCMS showed the reaction was completed. The solution was purified by reversed-phase combi-flash (neutral condition) eluting with H20:CH3CN from 90: 10 to 5:95 to give [(R)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo [2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]-(3,4-dichlorophenyl)methyl]4- phenylbenzoate (Int-2) (10.4 g, 13.11 mmol, 61.30% yield) as pale yellow solid. LCMS
[M+H]:612.2.
Synthesis of [(R)-(4-chlorophenyl)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)- 3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-3)
Figure imgf000108_0002
Step 1. Synthesis of [(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d] [l,3]dioxol-6-yl]-(4-chlorophenyl)methyl] 4-phenylbenzoate (Int-3-2)
[00265] To a solution of (S)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-(4-chlorophenyl)methanol (Int-3-1) (28.4g, 90.23 mmol) in Toluene (300 mL) was added 4-phenylbenzoic acid (27. g, 136.21 mmol), and triphenylphosphine (35.67g, 135.99 mmol) at 0 °C. The reaction mixture was stirred at 0 °C. (E)-diisopropyl diazene- 1,2-dicarboxylate (27.5g, 136 mmol) was added dropwise at 0 °C, stirred for 30 min at the same temperature and continued for 2h at 25 °C. The reaction mixture was filtered, and the filtrates were concentrated under reduced pressure. The crude product was purified by silica chromatography (PE: EA = 50: 1) to give [(R)-[(3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4- d][l,3]dioxol-6-yl]-(4-chlorophenyl)methyl] 4-phenylbenzoate (Int-3-2) (40 g, 80.815 mmol, 89.6% yield) as a whilte solid.
Step 2. [(R)-(4-chlorophenyl)-[(2S,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl]methyl] 4- phenylbenzoate (Int-3-3)
[00266] A solution of [(R)-[(3aR,6R,6aR)-4-methoxy-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-(4-chlorophenyl)methyl] 4-phenylbenzoate (Int-3-2) (40. g,
73.54 mmol) in 2,2,2-trifluoroacetic acid (2.L, 25960 mmol) and Water (1 L) was stirred at 25 °C for 30 hrs. LCMS showed the reaction was complete. The solution was neutralized with NaOH aqueous solution to pH 7-8, extrated with EA 3 times, the combined organic layers were washed with brine, dried over anhydrous Na2S04. The solvent was removed under reduced pressure to give crude product, which was purified by silica gel column chromatography (PE:EA=10: 1 to PE:EA=1 : 1) to give [(R)-(4-chlorophenyl)-[(2S,3 S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl]methyl] 4- phenylbenzoate (Int-3-3) (29 g, 61 mmol, 83% yield) as a white solid. 1H NMR (400 M Hz, DMSO- d6): δ 8.13 (d, J= 8.4 Hz, 2 H), 7.85 (d, J= 8.0 Hz, 2 H), 7.75 (d, J= 7.6 Hz, 2 H), 7.54-7.41 (m, 7 H), 6.40 (d, J = 4.4 Hz, 1 H), 6.01-5.97 (m, 1 H), 4.98-4.81 (m, 3 H), 4.17-4.10 (m, 2 H), 3.67 (d, J = 3.6 Hz, 1 H).
Step 3. Synthesis of [(R)-(4-chlorophenyl)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3-d]pyrimidin- 7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-3)
[00267] To a solution of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (809.88mg, 5.27 mmol) in dry THF (40 mL) was added pyridine (0.43mL, 5.27 mmol), Then Tributylphosphane (2.63mL,
10.55 mmol) and DIAD (2.18mL, 11.07 mmol) was added at 30 °C, [(R)-(4-chlorophenyl)-
[(2S,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-3-3) (2.5g, 5.27 mmol) was added at once. The reaction mixture was stirred at 30 °C for 2h. LCMS showed the reaction was completed. The reaction mixture was concentreated and the crude product was purified by Prep-HPLC eluting with H20:CH3CN from 85: 15 to 5:95 to give [(R)-(4-chlorophenyl)- [(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2- yljmethyl] 4-phenylbenzoate (Int-3) (875 mg, 1.518 mmol, 28.78% yield) as a pale yellow solid. LCMS M+H+: 576.2/578.2
Synthesis of (R)-((2S,3S,4R,5R)-5- (6-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)(4-chlorophenyl)methyl [Ι,Ι'-biphenyl] -4-carboxylate (Int-4)
Figure imgf000110_0001
[00268] To a mixture of 6-Chloropurine (1.6 g, 10.6 mmol) in THF (40.0 mL) was added pyridine (0.8 mL, 10.6 mmol), tributyl phosphine (5.2 mL, 21.1 mmol) and DIAL) (4.6 mL, 23.2 mmol). The mixture was cooled with ice-bath and [(R)-(4-chlorophenyl)-[(2S,3S,4R)-3,4,5- trihydroxy tetrahydrofuran-2-yl]methyl]4-phenylbenzoate (Int-3-3) (5.0 g, 10.6 mmol) in THF (30.0 mL) was added. The mixture was stirred at 25 °C for 2h. The solvent was removed and the residue was purified by reversed phase combi-flash eluting with CH3CN/H2O (neutral condition) from 30/70 to 70/30 to give [(R)-(4-chlorophenyl)-[(2S,3S,4R,5R)-5-(6-chloropurin-9-yl)-3,4-dihydroxy- tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-4) (2.6 g, 4.22 mmol, 40.0 % yield) as yellow solid. LCMS: no MS signal. 1H MR (400 M Hz, OMSO-d6): δ 8.75 (s, 1 H), 8.54 (s, 1 H), 8.20 (d, J= 4.4 Hz, 2 H), 7.87 (d, J= 4.4 Hz, 2 H), 7.77 (d, J= 4.0 Hz, 2 H), 7.50-7.55 (m, 2 H), 7.43-7.47 (m, 3 H), 7.29 (d, J= 4.0 Hz, 2 H), 6.25 (d, J= 5.2 Hz, 1 H), 6.04 (d, J= 5.6 Hz, 1 H), 5.69 (d, J = 6.0 Hz, 1 H), 5.57 (d, J= 5.2 Hz, 1 H), 4.91-4.96 (m, 1 H), 4.47-4.50 (m, 1 H), 4.41-4.44 (m, 1 H). ¾ MR (400 M Hz, DMSO-^+D20): δ 8.67 (s, 1 H), 8.51 (s, 1 H), 8.11 (d, J= 4.4 Hz, 2 H), 7.86 (d, J= 8.4 Hz, 2 H), 7.77 (d, J= 7.6 Hz, 2 H), 7.52-7.56 (m, 2 H), 7.43-7.49 (m, 3 H), 7.27 (d, J = 8.4 Hz, 2 H), 6.23 (d, J= 4.4 Hz, 1 H), 6.04 (d, J= 5.2 Hz, 1 H), 4.96 (t, J= 4.8 Hz, 1 H), 4.54 (t, J = 4.8 Hz, 1 H), 4.51 (t, J= 4.8 Hz, 1 H). Example 19. (2R,3 S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(3-methoxy-2,3-dihydro- 7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (19)
Figure imgf000111_0001
[00269] 2,2-Dimethoxyethanamine (O. lmL, 0.92 mmol) was added to a mixture of (R)- [(3aR,4R,6R,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a- tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]-(4-chlorophenyl)methanol (Ref. PCT Int. Appl., 2016178870) (80.mg, 0.1800 mmol) in IPA (1 mL), sealed and heated at 100 °C for 2 hr. TLC showed a more polar product and small amount of unreacted starting material.
[00270] The reaction mixture was stirred at RT over 72 h, concentrated and the residue was purified on a 4g column, which was eluted with 0-50% EA/hexane to give -80 mg of foamy white intermediate.
[00271] Hydrolysis of the intermediate was carried out in trifluoracetic acid (0.5mL, 0.18 mmol) and Water (0.05 mL) at 0 °C. After 2 hr, TLC showed the completion of the reaction (9: 1 DCM/MeOH) and formation of a clean polar spot. The reaction mixture was concentrated, taken into MeOH, cooled to 0 °C, and neutralized with concentrated Η4ΟΗ to pH 9. The resulting mixture was concentrated and purified on a 4g column, which was eluted with 0-14% MeOH/DCM to give a TFA salt of (2R,3 S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-(3-methoxy-2,3- dihydroimidazo[l,2-c]pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (19) (66 mg, 66% yield), as a white solid. LCMS [M+H]+ 433.0/435.0; 19F MR -75 ppm; ¾ NMR (400 MHz, DMSO- de + OiO) (mixture of diastereomers) δ 8.89/8.88 (s, 1H), 7.84/7.83 (s, 1H), 7.42-7.36 (m, 4H), 6.88- 6.86 (m, 1H), 6.30-6.27 (m, 1H), 6.16-6.13 (m, 1H), 4.77 (d, J= 5.3 Hz, 1H), 4.51-4.46 (m, 1H), 4.17-4.11 (m, J= 12.2, 2H), 4.05 - 3.96 (m, 2H), 3.46/3.45 (s, 3H).
Example 21 (2R,3 S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(3-hydroxy-2,3-dihydro- 7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (21)
Figure imgf000112_0001
[00272] A mixture of (2R,3 S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-(3- methoxy-2,3-dihydroimidazo[l,2-c]pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (19)
(45.mg, 0.082 mmol) and IN HCl (0.5mL, 0.50 mmol) was heated at 100 °C for 2 h. LCMS showed completion of hydrolysis of 19. The reaction mixture was concentrated under vacuum to give an HCl salt of (2R,3 S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(3-hydroxy-2,3-dihydro-7H- imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (21) (39 mg, 0.08 mmol, 100% yield) as a white solid. LCMS [M+H]+ 419.1/421.5. ¾ NMR (400 MHz, DMSO- de + ΌιΟ) (mixture of diastereomers) δ 8.73/8.72 (s, 1H), 7.86-7.84 (m, 1H), 7.43-7.36 (m, 4H), 6.90-6.89 (m, 1H), 6.48 - 6.41 (m, 1H), 6.16-6.13 (m, 1H), 4.78 (d, J= 5.3 Hz, 1H), 4.51-4.46 (m, 1H), 4.23-4.18 (m, 1H), 4.11 (d, J= 4.9 Hz, 1H), 4.01 (dd, J= 5.3, 1.7 Hz, 1H), 3.82-3.78 (m, 1H)
Example 22. (2R,3 S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(4-hydroxy-3,4- dihydropyrimido[l,2-c]pyrrolo[3,2-e]pyrimidin-8(2H)-yl)tetrahydrofuran-3,4-diol (22)
Figure imgf000112_0002
a) Synthesis of Compounds 22a
[00273] To a solution of [(R)-(4-chlorophenyl)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (Int-3) (400. mg, 0.69 mmol) in Ethanol (2 mL), 3,3-diethoxypropan-l-amine (2.mL, 12.36 mmol) was added. The mixture was stirred at 80 °C for 4 h. LCMS indicated the reaction was completed and formation of the mixture of 22a. The mixture of crude products was used directly for the next step. b) Synthesis of (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4-(3,3- diethoxypropylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (22b)
[00274] To the reaction mixture of compound 22a ( both [(R)-(4-chlorophenyl)- [(2S,3S,4R,5R)-5-[4-(3,3-diethoxypropylamino)pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy- tetrahydrofuran-2-yl]methyl] 4-phenylbenzoate (4.mL, 0.16 mmol) and (2R,3S,4R,5R)-2-[(R)-(4- chlorophenyl)-hydroxy-methyl]-5-[4-(3,3-diethoxypropylamino)pyrrolo[2,3-d]pyrimidin-7- yl]tetrahydrofuran-3,4-diol (4.mL, 0.53 mmol) was contained), hydrazine hydrate (2.mL, 41.15 mmol) was added. The mixture was stirred at 25 °C for 4 h. The mixture was purified by reverse phase Chem-flash eluting with CH3CN/H2O from 10/90 to 90/10 to give (2R,3S,4R,5R)-2-[(R)-(4- chlorophenyl)-hydroxy-methyl]-5-[4-(3,3-diethoxypropylamino)pyrrolo[2,3-d]pyrimidin-7- yl]tetrahydrofuran-3,4-diol (22b) (297 mg, 0.557 mmol, 85.2% yield) (total yield over two steps) as a yellow solid. LCMS M+H+: 507.1 c) Synthesis of (2R,3S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(4-hydroxy-3,4- dihydropyrimido[l,2-c]pyrrolo[3,2-e]pyrimidin-8(2H)-yl)tetrahydrofuran-3,4-diol hydrochloride (22)
[00275] To a solution of (2R,3 S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-[4- (3,3-diethoxypropylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (22b) (250. mg, 0.47 mmol) in THF (1 mL), 1 M HC1 (2 ml) was added. The mixture was stirred at 105 °C for 1 h. LCMS indicated the reaction has been completed. The mixture was combined with another reaction and purified by Prep-HPLC eluting with by Prep-HPLC eluting with CH3CN/H2O (0.1% TFA contained) from 5/95 to 95/5 to give (2R,3S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(4- hydroxy-3,4-dihydropyrimido[l,2-c]pyrrolo[3,2-e]pyrimidin-8(2H)-yl)tetrahydrofuran-3,4-diol hydrochloride (22) (100 mg, 0.212 mmol, 45.2% yield) as a white solid. ¾ MR (1 : 1 mixture of two isomers) (400 M Hz, DMSO-d6): δ 10.45 (s, 1 H), 8.48 (s, 1 H), 7.89 (s, 1 H), 7.76 (t, J= 3.2 Hz, 1 H), 7.36-7.42 (m, 4 H), 6.99 (d, J= 3.2 Hz, 1 H), 6.05-6.09 (m, 2 H), 5.97 (s, 1 H), 5.38 (s, 1 H), 5.24 (s, 1 H), 4.77 (d, J= 4.0 Hz, 1 H), 4.47-4.48 (m, 1 H), 4.12 (s, 1 H), 4.00 (s, 1 H), 3.57-3.63 (m, 2 H), 2.22-2.26 (m, 1 H), 2.14-2.16 (m, 1 H). ¾ MR (400 M Hz, DMSO-d6 + D20): δ 8.42 (s, 1 H), 7.69-7.71 (m, 1 H), 7.36-7.42 (m, 4 H), 6.95 (d, J= 2.8 Hz, 1 H), 6.09 (dd, Ji = 7.6 Hz, 1H, two peaks from 2 isomers), 6.03 (s, 1 H), 4.76 (d, J= 5.2 Hz, 1 H), 4.47-4.52 (m, 1 H), 4.15 (d, J= 4.8 Hz, 1 H), 4.04 (d, J= 5.6 Hz, 1 H), 3.60-3.64 (m, 2 H), 2.25-2.29 (m, 1 H), 2.10-2.19 (m, 1 H).
Example 35. (2R,3S,4R,5R)-2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)-5-(3-hydroxy-2,3- dihydro-7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (35)
Figure imgf000114_0001
a) Synthesis of [(R)-(4-chloro-3-fluoro-phenyl)-[(2S,3S,4R,5R)-5-[4-(2,2- dimethoxyethylamino) pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yljmethyl] 4-phenylbenzoate (35a)
[00276] To a solution of [(R)-(4-chloro-3-fluoro-phenyl)-[(2S,3S,4R,5R)-5-(4- chloropyrrolo[2,3-d] pyrimidin-7-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl]4-phenylbenzoate (Int-1) (500.0 mg, 0.84 mmol) in Ethanol (4.0 mL) was added 2,2-Dimethoxyethanamine (1.77 g, 16.82 mmol). The reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was used for the next step directly. LCMS [M+H]: 663.2.
b) Synthesis of (2R,3S,4R,5R)-2-[(R)-(4-chloro-3-fluoro-phenyl)-hydroxy-methyl]-5-[4-(2,2- dimethoxyethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (35b)
[00277] To a solution of [(R)-(4-chloro-3-fluoro-phenyl)-[(2S,3S,4R,5R)-5-[4-(2,2- dimethoxyethylamino) pyrrolo[2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4- phenylbenzoate (35a) (557.0 mg, 0.84 mmol) in Ethanol (4.0 mL) was added Hydrazine hydrate (4.0 mL, 82.3 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction solution was poured into water (15.0 mL), extracted with EA (20.0 mL X 3). The organic layers were washed with brine (20.0 mL X 3), dried over Na2SC"4, concentrated in vacuum to give crude product (520.0 mg) which was used for the next step directly. LCMS [M+H]: 483.2.
c) Synthesis of (2R,3 S,4R,5R)-2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)-5-(3- hydroxy-2,3-dihydro-7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4- diol hydrochloride (Ex. 35)
[00278] To a solution of Hydrochloric acid (0.5 mL, 16.64 mmol) in Water (5.5 mL) was added (2R,3S,4R,5R)-2-[(R)-(4-chloro-3-fluoro-phenyl)-hydroxy-methyl]-5-[4-(2,2- dimethoxyethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (35b) (405.6 mg, 0.84 mmol). The reaction mixture was stirred at 110 °C for 4 h. The reaction solution was purified by prep-HPLC, eluted with MeCN in H20 (0.1% TFA) from 5.0% to 95.0% to (2R,3S,4R,5R)-2-((R)- (4-chloro-3-fluorophenyl)(hydroxy)methyl)-5-(3-hydroxy-2,3-dihydro-7H-imidazo[l,2- c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (Ex. 35) (115.0 mg, 0.24 mmol, 28.2% yield) as a yellow solid. LCMS [M+H]: 437.1. 1H MR: (DMSO-de, 400 MHz): δ 10.87 (s, 1 H), 8.71 (s, 1 H), 8.18 (brs, 1 H), 7.87 (s, 1 H), 7.53 (t, 1 H), 7.40 (d, J= 10.8 Hz, 1 H), 7.27 (d, J= 8.4 Hz, 1 H), 6.87 (d, J= 2.8 Hz, 1 H), 6.46 (s, 1 H), 6.11-6.16 (m, 2 H), 5.41 (br s, 1 H), 5.25 (br s, 1 H), 4.81 (d, J= 4.8 Hz, 1 H), 4.47 (d, J= 6.0 Hz, 1 H), 4.19-4.24(m, 1 H), 4.12 (d, J = 4.0 Hz, 1 H), 4.02 (d, J= 5.2 Hz, 1 H), 3.8 (d, J= 12.4 Hz, 1 H). ¾ MR: (DMSO-i¾+D20, 400 MHz): δ 8.70 (s, 1 H), 7.86 (s, 1 H), 7.53 (t, 1 H), 7.40 (d, J= 10.4 Hz, 1 H), 7.27 (d, J= 8.0 Hz, 1 H), 6.87 (d, J= 3.2 Hz, 1 H), 6.45-6.46 (m, 1 H), 6.14-6.17 (m, 1 H), 4.81 (d, J= 5.2 Hz, 1 H), 4.46- 4.50 (m, 1 H), 4.19-4.24(m, 1 H), 4.11 (d, J= 4.8 Hz, 1 H), 4.03 (d, J= 5.2 Hz, 1 H), 3.44-3.82 (m, 1 H). 19F MR: (DMSO-^6, 377 MHz): δ -116.84 (s, 1 F).
Example 36. (2R,3S,4R,5R)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-5-(3-hydroxy-2,3- dihydro-7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (36)
Figure imgf000116_0001
a) Synthesis of [(R)-(3,4-dichlorophenyl)-[(2S,3S,4R,5R)-5-[4-(2,2- dimethoxyethylamino)pyrrolo[2,3-d] -pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2- yljmethyl] 4-phenylbenzoate (36a)
[00279] To a solution of [(R)-[(2S,3S,4R,5R)-5-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxy- tetrahydrofuran-2-yl]-(3,4-dichlorophenyl)methyl] 4-phenylbenzoate (Int-2) (500.0 mg, 0.82 mmol) in Ethanol (8.0 mL) was added 2,2-dimethoxyethylamine (1721.2 mg, 16.37 mmol. The mixture was stirred at 90 °C for 2 h. LCMS showed the reaction was completed. The mixture was concentrated to give [(R)-(3,4-dichlorophenyl)-[(2S,3S,4R,5R)-5-[4-(2,2- dimethoxyethylamino)pyrrolo[2,3-d] -pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4- phenylbenzoate (36a) (750.0 mg, 0.56 mmol, 68.8 % yield) as a yellow solid which was used for the next step directly. LCMS [M+H]: 679.2. b) Synthesis of (2R,3S,4R,5R)-2-[(R)-(3,4-dichlorophenyl)-hydroxy-methyl] -5-[4-(2,2- dimethoxyethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (36b)
[00280] To a solution of [(R)-(3,4-dichlorophenyl)-[(2S,3S,4R,5R)-5-[4-(2,2- dimethoxyethylamino)pyrrolo [2,3-d]pyrimidin-7-yl]-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl] 4- phenylbenzoate (36a) (750.0 mg, 0.56 mmol) in 1-Butanol (5.0 mL) was added Potassium carbonate (233.4 mg, 1.69 mmol). The mixture was stirred at 60 °C for 4 h. LCMS showed the desired mass was detected. The mixture was concentrated and purified by reversed-phase combi-flash, eluted with CftCN in H20 (neutral condition) from 5.0% to 95.0% to give (2R,3S,4R,5R)-2-[(R)-(3,4- dichlorophenyl)-hydroxy-methyl] -5-[4-(2,2-dimethoxyethylamino)pyrrolo[2,3-d]pyrimidin-7- yl]tetrahydrofuran-3,4-diol (36b) (255.0 mg, 0.51 mmol, 90.7 % yield) as a white solid. LCMS
[M+H]: 499.0. c) Synthesis of (2R,3 S,4R,5R)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-5-(3-hydroxy-2,3- dihydro-7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol
hydrochloride (Ex. 36)
[00281] A mixture of (2R,3S,4R,5R)-2-[(R)-(3,4-dichlorophenyl)-hydroxy-methyl]-5-[4- (2,2-dimethoxyethy lamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (36b) (285.0 mg, 0.57 mmol) in HCl (4.0 mL, 4.00 mmol) was heated and stirred at 105 °C for 4 h. LCMS showed the reaction was completed. The mixture was purified by prep-HPLC, eluted with CH3CN in H2O (0.1 % TFA) from 5.0% to 95.0% to give the preparation solution which was added HCl (IN aq, 3.0 mL) and lyophilized to afford (2R,3S,4R,5R)-2-((R)-(3,4-dichlorophenyl)(hydroxy)methyl)-5-(3- hydroxy-2,3-dihydro-7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (Ex. 36) (117.1 mg, 0.24 mmol, 41.6 % yield) as a white solid. LCMS [M+H]: 453.2. ¾ NMR (400 M Hz, OMSO-de): δ 11.16 (s, 1 H), 8.80 (d, J= 5.2 Hz, 1 H), 8.32 (s, 1 H), 7.85-7.88 (m, 1 H), 7.62 (s, 1 H), 7.57 (d, J= 8.0 Hz, 1 H), 7.39 (d, J= 8.4 Hz, 1 H), 6.95 (s, 1 H), 6.45-6.47 (m, 1 H), 6.12-6.16 (m, 1 H), 4.82 (d, J= 5.6 Hz, 1 H), 4.46-4.51 (m, 1 H), 4.17-4.23 (m, 1 H), 4.12 (d, J= 4.8 Hz, 1 H), 4.00-4.02 (m, 1 H), 3.78-3.82 (m, 1 H). ¾ NMR (400 M Hz, DMSO-^+D20 ): δ 8.68 (s, 1 H), 7.79-7.81 (m, 1 H), 7.56-7.61 (m, 2 H), 7.39 (d, J= 8.0 Hz, 1 H), 6.90 (s, 1 H), 6.47 (d, J= 7.2 Hz, 1 H), 6.14-6.16 (m, 1 H), 4.81 (d, J= 5.2 Hz, 1 H), 4.48-4.52 (m, 1 H), 4.21-4.26 (m, 1 H), 4.15 (d, J = 4.4 Hz, 1 H), 4.05 (s, 1 H), 3.80 (m, 1 H, under DHO in DMSO-d).
Example 37. (2R,3 S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(4-((2,2- dimethoxyethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (37)
Figure imgf000118_0001
a) (2R,3S,4R,5R)-2 (R) 4-chlorophenyl)-hydroxy-methyl]-5-(4-chloropyrrolo[2,3-d]pyrimidin-7- yl)tetrahydrofuran-3,4-diol (37a)
[00282] A 50 mL RBF and septum containing (R)-[(3aR,4R,6R,6aR)-4-(4- chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6-yl]- (4-chlorophenyl)methanol (455. mg, 1.04 mmol,) was charged with a RT mixture of 2,2,2- trifluoroacetic acid (2.5mL, 32.45 mmol) and Water (2.5 mL), sonicated for 10 s, blanketed with Ar, and stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to remove the water and most of the TFA. The reaction was then diluted in MeOH (20 mL), and quenched with Amberlyst IRA-67 until a neutral pH was obtained. The mixture was then filtered through a cotton plug, rinsed with additional MeOH and DCM, and concentrated under reduced pressure to light brown foam. The crude product was purified by FCC (40g Si02, 3->4% MeOH in DCM, wet-loaded in DCM) to yield (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-(4-chloropyrrolo[2,3- d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (37a) (128 mg, 0.31 mmol, 30.0% yield) as a white powder. Rf = .26 (3% MeOH in DCM). LCMS (ESI) m/z calcd for [M+H]+ C17H16CI2N3O4: 396.051. Found: 396.0. ¾ NMR (400 MHz, DMSO-d) δ 8.67 (s, 1H), 8.02 (d, J= 3.8 Hz, 1H), 7.44 - 7.32 (m, 4H), 6.79 (d, J= 3.7 Hz, 1H), 6.19 (d, J= 7.7 Hz, 1H), 6.02 (d, J= 4.1 Hz, 1H), 5.39 (s, 1H), 5.21 (d, J= 4.0 Hz, 1H), 4.80 (t, J = 4.1 Hz, 1H), 4.58 (s, 1H), 4.12 (t, J= 3.3 Hz, 1H), 4.00 (dd, J = 5.3, 1.3 Hz, 1H). ¾ NMR of (400 MHz, OMSO-de+OiO) δ 8.66 - 8.60 (m, 1H), 7.96 - 7.87 (m, 1H), 7.42 - 7.29 (m, 4H), 6.76 (t, J= 3.1 Hz, 1H), 6.15 (dd, J= 7.6, 3.5 Hz, 1H), 4.76 (t, J= 3.9 Hz, 1H), 4.55 (t, J= 6.5 Hz, 1H), 4.11 (d, J= 5.1 Hz, 1H), 4.01 (dd, J= 5.1, 1.1 Hz, 1H).
b) (2R,3S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(4-((2,2-dimethoxyethyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (37) [00283] A 4 mL vial containing a mixture of (2R,3 S,4R,5R)-2-[(R)-(4-chlorophenyl)- hydroxy-methyl]-5-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (37a) (21. mg, 0.050 mmol) and 2,2-Dimethoxyethanamine (0.03mL, 0.28 mmol) in 1,4-Dioxane (0.4 mL) and IPA (0.1 mL) was blanketed with Ar, sealed, and heated at 100 °C for 10 h. TLC showed some SM remained. The mixture was concentrated under reduced pressure and purified by FCC (4g S1O2, 3- >5% MeOH in DCM, wet-loaded in DCM+eluent). Fractions containing product were concentrated under reduced pressure and heat (50 °C) to yield (2R,3S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy- methyl]-5-[4-(2,2-dimethoxyethylamino)pyrrolo[2,3-d]pyrimidin-7-yl]tetrahydrofuran-3,4-diol (18.1 mg, 0.038 mmol, 72% yield) as a white powder. LCMS (ESI) m/z calcd for [M+H]+ C21H26CIN4O6: 465.154. Found: 465.0. Rf = 0.5 (10% MeOH in DCM). ¾ MR (400 MHz, DMSO-i¾) δ 8.15 (s, 1H), 7.75 (t, J= 6.0 Hz, 1H), 7.47 - 7.36 (m, 4H), 7.35 (d, J= 3.7 Hz, 1H), 6.68 (d, J= 3.6 Hz, 1H), 6.64 (d, J= 3.3 Hz, 1H), 5.92 (d, J= 7.9 Hz, 1H), 5.23 (d, J= 6.3 Hz, 1H), 5.04 (d, J= 3.7 Hz, 1H), 4.81 (t, J= 3.6 Hz, 1H), 4.62 (q, J= 6.1 Hz, 1H), 4.58 (t, J= 5.4 Hz, 1H), 4.04 - 3.97 (m, 2H), 3.58 (t, J= 5.7 Hz, 2H), 3.30 (s, 6H).
Example 38 2-((7-((2R,3R,4S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)acetaldehyde (38)
Figure imgf000119_0001
[00284] An HC1 salt of (2R,3 S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(3- hydroxy-2,3-dihydro-7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol (21) (19 mg, 0.043 mmol,) was dissolved in a mixture of 0.3 mL of MeOH and 1 mL of H2O, pH -4-5, Amberlite IRA-67 free base was added until pH ~8. The resulting mixture was stirred at RT for 30 min, filtered through a cotton ball in a pipette, concentrated to give 2-((7-((2R,3R,4S,5R)-5-((R)-(4- chlorophenyl)(hydroxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrim yl)amino)acetaldehyde (38) (11 mg, 0.026 mmol, 62% yield) as a white solid. LCMS [M+H]+ 419.0/421.0; ¾ NMR (400 MHz, DMSO- de + ΌιΟ) δ 9.59 (s, 1H), 8.09 (s, 1H), 7.42-7.35 (m, 5H), 6.64 (s, 1H), 5.93-5.87 (m, 1H), 4.79 (d, J= 4.2 Hz, 1H), 4.58 (t, J= 6.3 Hz, 1H), 4.25 (m, 1H), 4.02- 4.00 (m, 3H).
Example 41 (2R,3 S,4R,5R)-2-[(R)-(4-chlorophenyl)-hydroxy-methyl]-5-(7-hydroxy-7,8- dihydroimidazo[2, l-f]purin-3-yl)tetrahydrofuran-3,4-diol hydrochloride (41)
[00285] Example 41, a white solid, was prepared similarly to that of Ex. 35 except substituting Int-1 with Int-4 in step a). ¾ NMR (400 MHz, DMSO-de) δ 11.43 (s, 1H), 8.89 (s, 1H), 8.81(d, J = 2.4 Hz, 1 H), 8.24 (s, 1H), 7.35-7.41 (m, 4H), 6.5 (s, 1H), 5.98 (d, J = 6.4 Hz, 1H), 5.56 (s, 1H), 5.32 (s, 1H), 4.82 (d, J = 5.2 Hz, 1H), 4.63-4.69 (m, 1H), 4.22-4.26 (m, 1H), 4.18 (s, 1H), 4.07 (d, J = 4.4 Hz, 1H), 3.80-3.84 (m, 1H). ¾ NMR (400 MHz, DMSO-de+D20) δ 8.85 (s, 1H), 8.76 (d, J = 3.2 Hz, 1H), 7.34-7.44 (m, 4H), 6.49-6.52 (m, 1H), 5.99 (dd, J = 2.4 Hz , J = 6.8 Ηζ,ΙΗ), 4.82 (d, J = 5.2 Hz, 1H), 4.63-4.69 (m, 1H), 4.23-4.28 (m, 1H), 4.17-4.19 (m, 1H). 4.09 (d, J = 4.8 Hz, 1H), 3.81-3.85 (m, 1H). LCMS M+H+: 420.3/422.3
Example 42. (2R,3 S,4R,5R)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)-5-(7-hydroxy-8,9- dihydropyrimido[2, l-i]purin-3(7H)-yl)tetrahydrofuran-3,4-diol (42)
[00286] Example 42, a white solid, was prepared similarly to that of Ex. 22 except substitituting Int-3 with Int-4 in step a). ¾ NMR (400 M Hz, DMSO-d6): δ 10.81 (s, 1 H), 8.73 (d, J = 4.8 Hz, 1 H), 8.67 (s, 1 H), 7.97 (s, 1 H), 7.34-7.41 (m, 4 H), 6.10 (s, 1 H), 5.99 (s, 1 H), 5.93 (d, J = 7.2 Hz, 1 H), 5.55 (brs, 1 H), 5.32 (brs, 1 H), 4.81 (d, J= 4.4 Hz, 1 H), 4.66 (s, 1 H), 4.17 (d, J = 4.0 Hz, 1 H), 4.06 (d, J= 5.6 Hz, 1 H), 3.57-3.61 (m, 2 H), 2.24-2.27 (m, 1 H), 2.13-2.19 (m, 1 H). ¾ NMR (400 M Hz, DMSO-d6 + D20): δ 8.65 (d, J= 4.4 Hz, 1 H), 8.61 (s, 1 H), 7.33-7.42 (m, 4 H), 6.09 (s, 1 H), 5.93 (dd, Ji = 7.2 Hz, J2 = 2.8 Hz, 1 H), 4.18 (dd, J= 4.8 Hz, 1.2 Hz, 1 H), 4.09 (dd, J= 5.2 Hz, 1.6 Hz, 1 H), 3.58-3.66 (m, 2 H), 2.27-2.30 (m, 1 H), 2.16-2.20 (m, 1 H). LCMS M+H+: 434.1/436.1 Example 56. (2R,3 S,4R,5R)-2-((R)-(4-chloro-3-methylphenyl)(hydroxy)methyl)-5-(3-hydroxy-2,3- dihydro-7H-imidazo[l,2-c]pyrrolo[3,2-e]pyrimidin-7-yl)tetrahydrofuran-3,4-diol hydrochloride (56)
[00287] Example 56, a white solid, was prepared similarly to that of Ex. 35. LCMS
[M+H]: 433.3. ¾ NMR (DMSO-de, 400 MHz): δ 10.78 (s, 1H), 8.71 (s, 1H), 8.09 (d, J= 5.6 Hz, 1 H), 7.85 (s, 1 H), 7.34-7.37 (m, 2 H), 7.22-7.24 (m, 1 H), 6.86 (s, 1 H), 6.45 (s, 1 H), 6.15 (d, J= 7.2 Hz, 1 H), 5.95 (s, 1 H), 5.39 (s, 1 H), 5.23 (s, 1 H), 4.76 (s, 1 H), 4.49 (s, 1 H), 4.19-4.23 (m, 1 H), 4.11 (s, 1 H), 4.03 (s, 1 H), 3.80 (d, J= 12 Hz, 1 H), 2.30 (s, 3 H). ¾ MR (DMSO-i¾+D20, 400 MHz): δ 8.70 (s, 1 H), 7.84 (s, 1 H), 7.34-7.37 (m, 2 H), 7.23-7.24 (m, 1 H), 6.87 (s, 1 H), 6.46 (s, 1H), 6.14 (d, J= 7.2 Hz, 1 H), 4.75 (s, 1 H), 4.48 (s, 1 H), 4.19-4.24 (m, 1 H), 4.11 (s, 1H), 4.03 (s, 1 H), 3.81 (d, J= 12 Hz, 1 H), 2.30 (s, 3 H).
Biochemical Assay Protocol
[00288] 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 ICso mode at a concentration 10-fold greater than the desired assay concentration. Standard reactions were performed in a total volume of 50 μΐ in assay buffer, with histone H2A (5 μΜ 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 u .
Following a 60 minutes incubation at 30 °C, the reaction was stopped by adding 100 μΐ^ of 20% TCA. Each reaction was spotted onto filter plate (Multi Screen 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. ICso 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
[00289] 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 105 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 microcentrifuge 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, blocked 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: Abeam, Catalog #: ab8227, 1 : 10,000) in 5% dry milk in TBST at 4 °C for overnight. The next day, membranes were washed with TBST, 5 x 5 min, and incubated with HRP conjugated seconded antibody (GE
Healthcare; Catalog #: NA934-1ML; 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.
[00290] To determine enzyme inhibition ICso values using Western Blot analysis, Granta cells were seeded at density of 5 x 105 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. ICso values were calculated using Graphpad Prism.
Table 2 Biochemical and cellular potency (in Granta cell line)
Figure imgf000123_0001
[00291] The disclosure encompasses the following aspects:
Aspect 1: A compound of Formula I, Formula II, Formula III or Formula IV:
Figure imgf000124_0001
or a pharmaceutically acceptable salt or solvate thereof;
wherein
A is CH or N; 
n is 1 or 2;
R1 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-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3- C6cycloalkyl, -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-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, or -C1-C6alk-C(O)NH- aryl;
R2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
R2a and R2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
or R2a and R2b, together with the atoms to which they are attached, form a C2- C6heterocycloalkyl ring; R3 is H, halo, -Ci-Cealkyl, or H2; and
R4 is H, halo, -Ci-C6alkyl, -Ci-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- Ceheterocycloalkyl, -C3-C6cycloalkyl, or -0-Ci-C4alkyl.
Aspect 2: The compound of aspect 1 wherein Ri is -Co-C6alk-Ci-C6alkyl.
Aspect 3 : The compound of aspect 2 wherein the -Co-C6alk-Ci-C6alkyl is -CH(OH)-Ci-C6alkyl, -CH(F)-Ci-C6alkyl, -CH( H2)-Ci-C6alkyl, -CH(Me)-Ci-C6alkyl, or -C(Me)(OH)-Ci-C6alkyl.
Aspect 4: The compound of aspect 1 wherein Ri is -Co-C6alk-Ci-C6haloalkyl.
Aspect 5: The compound of aspect 4 wherein the -Co-C6alk-Ci-C6haloalkyl is -CH(OH)-Ci-C6 haloalkyl, -CH(F)-Ci-C6haloalkyl, -CH( H2)-Ci-C6haloalkyl, -CH(Me)-Ci-C6haloalkyl, or - C(Me)(OH)-Ci-C6haloalkyl.
Aspect 6: The compound of aspect 1 wherein Ri is -Co-C6alk-C≡CH.
Aspect 7: The compound of aspect 6 wherein the -Co-Cealk-C≡CH is -CH(OH)-C≡CH, -CH(F)- C≡CH, -CH( H2)-C≡CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH.
Aspect 8: The compound of aspect 1 wherein Ri is -Co-C6alk-C≡C-Ci-C6alkyl.
Aspect 9: The compound of aspect 8 wherein the -Co-C6alk-C≡C-Ci-C6alkyl is -CH(OH)-C≡C- Ci-Cealkyl, -CH(F)-C≡C-Ci-C6alkyl, -CH( H2)-C≡C-Ci-C6alkyl, -CH(Me)-C≡C-Ci-C6alkyl, or - C(Me)(OH)-C≡C-Ci-C6alkyl.
Aspect 10: The compound of aspect 9 wherein the -Co-C6alk-C≡C-Ci-Cealkyl is -CH(OH)-C≡C- CH3, -CH(F)-C≡C-CH3, -CH( H2)-C≡C-CH3, -CH(Me)-C≡C-CH3, or -C(Me)(OH)-C≡C-CH3.
Aspect 11 : The compound of aspect 1 wherein Ri is -Co-C6alk-C≡C-Ci-C6haloalkyl.
Aspect 12: The compound of aspect 11 wherein the -Co-C6alk-C≡C-Ci-C6haloalkyl is -CH(OH)- C≡C-Ci-C6haloalkyl, -CH(F)-C≡C-Ci-C6haloalkyl, -CH(NH2)-C≡C-Ci-C6haloalkyl, -CH(Me)-C≡C- Ci-Cehaloalkyl, or -C(Me)(OH)-C≡C-Ci-C6haloalkyl. Aspect 13 : The compound of aspect 12 wherein wherein the -Co-C6alk-C=C-Ci-C6haloalkyl is - CH(OH)-C≡C-CF3, -CH(F)-C≡C-CF3, -CH( H2)-C≡C-CF3, -CH(Me)-C≡C-CF3, or -C(Me)(OH)- C≡C-CF3.
Aspect 14: The compound of aspect 1 wherein Ri is -Co-C6alk-C≡C-C3-C6cycloalkyl.
Aspect 15: The compound of aspect 14 wherein the -Co-C6alk-C≡C-C3-C6cycloalkyl is - CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3-C6cycloalkyl, - CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)-C≡C-C3-C6cycloalkyl.
Aspect 16: The compound of aspect 15 wherein wherein the -Co-C6alk-C≡C-C3-C6cycloalkyl is - CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH( H2)-C≡C-cyclopropyl, -CH(Me)-C≡C- cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl.
Aspect 17: The compound of aspect 1 wherein Ri is -Ci-C6alk-aryl.
Aspect 18: The compound of aspect 17 wherein the -Ci-C6alk-aryl is -CH(OH)-aryl, -CH(F)- aryl, -CH( H2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl.
Aspect 19: The compound of aspect 18 wherein the -Ci-C6alk-aryl is -CH(OH)-4-chlorophenyl, - CH(OH)-3,4-dichlorophenyl, -CH(OH)-3,4-difluorophenyl, -CH(OH)-3-fluoro-4-chlorophenyl, - CH(OH)-3-chloro-4-fluorophenyl, -CH(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( H2)-4- chlorophenyl, -CH( H2)-3,4-dichlorophenyl, -CH( H2)-3,4-difluorophenyl, -CH( H2)-3-fluoro-4- chlorophenyl, -CH( H2)-3-chloro-4-fluorophenyl, -CH(Me)-4-chlorophenyl, -CH(Me)-3,4- di chlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-fluoro-4-chlorophenyl, -CH(Me)-3-chloro- 4-fluorophenyl, -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 20: The compound of any one of aspects 1 to 19 wherein R3 is H.
Aspect 21 : The compound of any one of aspects 1 to 20 wherein n is i .
Aspect 22: The compound of any one of aspects 1 to 20 wherein n is 2. Aspect 23 : The compound of any one of aspects 1 to 22 that is a compound of Formula I or Formula II.
Aspect 24: The compound of aspect 23 wherein A is N.
Aspect 25: The compound of aspect 23 wherein A is CH.
Aspect 26: The compound of any one of aspects 23 to 25 wherein R4 is H.
Aspect 27: The compound of any one of aspects 23 to 25 wherein R4 is halo.
Aspect 28: The compound of aspect 27 wherein the halo is fluoro.
Aspect 29: The compound of any one of aspects 23 to 25 wherein R4 is -Ci-C6alkyl.
Aspect 30: The compound of aspect 29 wherein the -Ci-C6alkyl is methyl.
Aspect 31 : The compound of any one of aspects 1 to 30 that is a compound of Formula I or Formula III.
Aspect 32: The compound of aspect 31 wherein R2a is -Ci-C6alkyl.
Aspect 33 : The compound of any one of aspects 31 or 32 wherein R2b is -Ci-C6alkyl.
Aspect 34: The compound of any one of aspects 1 to 30 that is a compound of Formula II or Formula IV.
Aspect 35: The compound of aspect 34 wherein R2 is H.
Aspect 36: The compound of aspect 34 wherein R2 is -Ci-C6alkyl.
Aspect 37: A pharmaceutical composition comprising a compound according to any one of aspects 1 to 36 and a pharmaceutically acceptable excipient.
Aspect 38: 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 1 to 36. Aspect 39: A method of treating a disease or disorder associated with aberrant PRMT5 activity in a subject comprising administering to the subject, a compound of any one of aspects 1 to 36.
Aspect 40: The method of aspect 39, 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 41. A compound of Formula V, Formula VI, Formula VII, or Formula VIII:
Figure imgf000128_0001
Figure imgf000128_0002
or a pharmaceutically acceptable salt or solvate thereof; wherein
A is CH, CR6 or N; n is 1 or 2;
R1 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-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3- C6cycloalkyl, -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-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, -C1-C6alk-C(O)NH- aryl, -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, -C0-C6alk-S(O)2aryl, or -C0-C6alk-Oaryl; R2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
R2a and R2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
or R2a and R2b, together with the atom to which they are attached, form a C2- C6heterocycloalkyl ring;
R3 is H, halo, -C1-C6alkyl, or NH2;
R4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl;
R5 is H, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3- C6halocycloalkyl, -C0-C6alk-OH, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0- C6alk-N(C1-C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, or -C0-C6alk-N(C1- C6alkyl)-C3-C6cycloalkyl;
or R5 and R1, together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring;
R6 is halo or -C1-C6alkyl; and
R6a is H, halo or -C1-C6alkyl.
Aspect 42. The compound of aspect 41 wherein R1 is -C0-C6alk-C1-C6alkyl. Aspect 43. The compound of aspect 42 wherein the -C0-C6alk-C1-C6alkyl is -CH(OH)-C1- C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1-C6alkyl, or -C(Me)(OH)-C1- C6alkyl. Aspect 44. The compound of aspect 41 wherein R1 is -Co-C6alk-Ci-C6haloalkyl.
Aspect 45. The compound of aspect 44 wherein the -Co-C6alk-Ci-C6haloalkyl is -CH(OH)-Ci- Cehaloalkyl, -CH(F)-Ci-C6haloalkyl, -CH(NH2)-Ci-C6haloalkyl, -CH(Me)-Ci-C6haloalkyl, or - C(Me)(OH)-Ci-C6haloalkyl.
Aspect 46. The compound of aspect 41 wherein R1 is -Co-C6alk-C≡CH.
Aspect 47. The compound of aspect 46 wherein the -Co-Cealk-C≡CH is -CH(OH)-C≡CH, - CH(F)-C≡CH, -CH( H2)-C≡CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH.
Aspect 48. The compound of aspect 41 wherein R1 is -Co-C6alk-C≡C-Ci-C6alkyl.
Aspect 49. The compound of aspect 48 wherein the -Co-C6alk-C≡C-Ci-Cealkyl is -CH(OH)- C≡C-Ci-C6alkyl, -CH(F)-C≡C-Ci-C6alkyl, -CH( H2)-C≡C-Ci-C6alkyl, -CH(Me)-C≡C-Ci-C6alkyl, or -C(Me)(OH)-C≡C-Ci-C6alkyl.
Aspect 50. The compound of aspect 49 wherein the -Co-C6alk-C≡C-Ci-C6alkyl is -CH(OH)- C≡C-CH3, -CH(F)-C≡C-CH3, -CH( H2)-C≡C-CH3, -CH(Me)-C≡C-CH3, or -C(Me)(OH)-C≡C-CH3.
Aspect 51. The compound of aspect 41 wherein R1 is -C0-C6alk-C≡C-Cl-C6haloalkyl.
Aspect 52. The compound of aspect 51 wherein the -Co-C6alk-C≡C-Ci-C6haloalkyl is -CH(OH)- C≡C-Ci-C6haloalkyl, -CH(F)-C≡C-Ci-C6haloalkyl, -CH(NH2)-C≡C-Ci-C6haloalkyl, -CH(Me)-C≡C- Ci-Cehaloalkyl, or -C(Me)(OH)-C≡C-Ci-C6haloalkyl.
Aspect 53. The compound of aspect 52 wherein the -Co-Cealk-C≡C-CF3 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 54. The compound of aspect 41 wherein R1 is -Co-C6alk-C≡C-C3-C6cycloalkyl.
Aspect 55. The compound of aspect 54 wherein the -Co-C6alk-C≡C-C3-C6cycloalkyl is - CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3-C6cycloalkyl, - CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)-C≡C-C3-C6cycloalkyl. Aspect 56. The compound of aspect 55 wherein the -Co-C6alk-C=C-C3-C6cycloalkyl is - CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH( H2)-C≡C-cyclopropyl, -CH(Me)-C≡C- cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl.
Aspect 57. The compound of aspect 41 wherein R1 is -Ci-C6alk-aryl.
Aspect 58. The compound of aspect 57 wherein the -Ci-C6alk-aryl is -CH2-aryl, -CH(OH)-aryl, - CH(F)-aryl, -CH( H2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl.
Aspect 59. The compound of aspect 58 wherein the -Ci-C6alk-aryl is -CH2-4-chlorophenyl, - CH2-3,4-di chlorophenyl, -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( H2)-4-chlorophenyl, -CH( H2)-3,4-dichlorophenyl, -CH( H2)-3,4- difluorophenyl, -CH( H2)-3-fluoro-4-chlorophenyl, -CH( H2)-3-chloro-4-fluorophenyl, -CH(Me)- 4-chlorophenyl, -CH(Me)-3,4-di chlorophenyl, -CH(Me)-3,4-difluorophenyl, -CH(Me)-3-fluoro-4- chlorophenyl, -CH(Me)-3-chloro-4-fluorophenyl, -C(Me)(OH)-4-chlorophenyl, -C(Me)(OH)-3,4- di chlorophenyl, -C(Me)(OH)-3,4-difluorophenyl, -C(Me)(OH)-3-fluoro-4-chlorophenyl, or - C(Me)(OH)-3-chloro-4-fluorophenyl.
Aspect 60. The compound of aspect 41 wherein R1 is -Co-C6alk-S-aryl.
Aspect 61. The compound of aspect 60 wherein the -Co-C6alk-S-aryl is -S-4-chlorophenyl, -S- 3,4-dichlorophenyl, -S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or -S-3-chloro-4- fluorophenyl.
Aspect 62. The compound of aspect 41 wherein R1 is -Co-C6alk-S(0)-aryl.
Aspect 63. The compound of aspect 62 wherein the -Co-C6alk-S(0)-aryl is -S(0)-4- chlorophenyl, -S(0)-3,4-dichlorophenyl, -S(0)-3,4-difluorophenyl, -S(0)-3-fluoro-4-chlorophenyl, or -S(0)-3-chloro-4-fluorophenyl.
Aspect 64. The compound of aspect 41 wherein R1 is -Co-C6alk-S(0)2-aryl. Aspect 65. The compound of aspect 64 wherein the -Co-C6alk-S(0)2-aryl is -S(0)2-4- chlorophenyl, -S(0)2-3, 4-dichlorophenyl, -S(0)2-3, 4-difluorophenyl, -S(0)2-3-fluoro-4-chlorophenyl, or -S(0)2-3-chloro-4-fluorophenyl.
Aspect 66. The compound of aspect 41 wherein R1 is -Co-C6alk-0-aryl.
Aspect 67. The compound of aspect 46 wherein the -Co-C6alk-0-aryl is -O-4-chlorophenyl, -O- 3, 4-dichlorophenyl, -0-3, 4-difluorophenyl, -0-3-fluoro-4-chlorophenyl, or -0-3-chloro-4- fluorophenyl.
Aspect 68. The compound of any one of aspects 41 to 67 wherein n is 1.
Aspect 69. The compound of any one of aspects 41 to 67 wherein n is 2.
Aspect 70. The compound of any one of aspects 41 to 69 wherein R3 is H.
Aspect 71. The compound of any one of aspects 41 to 70 wherein R5 is H.
Aspect 72. The compound of any on eof aspects 41 to 71 that is a compound of Formula V or Formula VI.
Aspect 73. The compound of aspect 72 wherein A is N.
Aspect 74. The compound of aspect 72 wherein A is CH.
Aspect 75. The compound of any one of aspects 72 to 74 wherein R4 is H.
Aspect 76. The compound of any one of aspects 72 to 74 wherein R4 is halo.
Aspect 77. The compound of aspect 76 wherein the halo is -F.
Aspect 78. The compound of any one of aspects 72 to 74 wherein R4 is -Ci-C6alkyl.
Aspect 79. The compound of aspect 78 wherein the -Ci-C6alkyl is methyl.
Aspect 80. The compound of any one of aspects 41 to 79 that is a compound of Formula V or Formula VII. Aspect 81. The compound of aspect 60 wherein R2a is -Ci-C6alkyl.
Aspect 82. The compound of any one of aspects 60 to 61 wherein R is -Ci-C6alkyl.
Aspect 83. The compound of any one of aspects 41 to 79 that is a compound of Formula VI or
Formula VIII.
Aspect 84. The compound of aspect 83 wherein R2 is H.
Aspect 85. The compound of aspect 83 wherein R2 is -Ci-C6alkyl.
Aspect 86. The compound of any one of aspects 41 to 71 and 40 to 45 that is a compound of Formula VII or Formula VIII.
Aspect 87. The compound of aspect 86 wherein R6a is H.
Aspect 88. A pharmaceutical composition comprising a compound according to any one aspects 41 to 87 and a pharmaceutically acceptable excipient.
Aspect 89. 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 41 to 87.
Aspect 90. 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 41 to 87.
Aspect 91. The method of aspect 90, 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 92. A compound of Formula I, Formula II, Formula III, or Formula IV:
Figure imgf000134_0001
or a pharmaceutically acceptable salt or solvate thereof;
wherein
A is CH or N; 
n is 1 or 2;
R1 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-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3-C6cycloalkyl, - 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-C3- C6cycloalkyl, -C1-C6alk-S-CH2-aryl, or -C1-C6alk-C(O)NH-aryl;
R2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
R2a and R2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
or R2a and R2b, together with the atoms to which they are attached, form a C2- C6heterocycloalkyl ring;
R3 is H, halo, -C1-C6alkyl, or NH2; and R4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl. Aspect 93. The compound of aspect 92 wherein R1 is -C0-C6alk-C1-C6alkyl, preferably -C0- C6alk-C1-C6alkyl is -CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1- C6alkyl, or -C(Me)(OH)-C1-C6alkyl. Aspect 94. The compound of aspect 92 wherein R1 is -C0-C6alk-C1-C6haloalkyl, preferably - CH(OH)-C1-C6 haloalkyl, -CH(F)-C1-C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1- C6haloalkyl, or -C(Me)(OH)-C1-C6haloalkyl. Aspect 95. The compound of aspect 92 wherein R1 is -C0-C6alk-C≡CH, preferably -CH(OH)- C≡CH, -CH(F)-C≡CH, -CH(NH2)-C≡CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH. Aspect 96. The compound of aspect 92 wherein R1 is -C0-C6alk-C≡C-C1-C6alkyl, preferably - CH(OH)-C≡C-C1-C6alkyl, -CH(F)-C≡C-C1-C6alkyl, -CH(NH2)-C≡C-C1-C6alkyl, -CH(Me)-C≡C- C1-C6alkyl, or -C(Me)(OH)-C≡C-C1-C6alkyl, more preferably-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-CH3. Aspect 97. The compound of aspect 92 wherein R1 is -C0-C6alk-C≡C-C1-C6haloalkyl, preferably -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, more preferably -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 98. The compound of aspect 92 wherein R1 is -C0-C6alk-C≡C-C3-C6cycloalkyl, preferably -CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3- C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)-C≡C-C3-C6cycloalkyl, more preferably CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C-cyclopropyl, - CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl. Aspect 99. The compound of aspect 93 wherein R1 is -C1-C6alk-aryl, preferably -CH(OH)-aryl, - CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl, more preferably -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)-4-chloro-3-methylphenyl, -CH(F)-4- chlorophenyl, -CH(F)-3,4-di chlorophenyl, -CH(F)-3,4-difluorophenyl, -CH(F)-3-fluoro-4- chlorophenyl, -CH(F)-3-chloro-4-fluorophenyl, -CH(F)-4-chloro-3-methylphenyl, -CH( H2)-4- chlorophenyl, -CH( H2)-3,4-dichlorophenyl, -CH(NH2)-3,4-difluorophenyl, -CH( H2)-3-fluoro-4- chlorophenyl, -CH( H2)-3-chloro-4-fluorophenyl, -CH( H2)-4-chloro-3-methylphenyl, -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)-4-chloro-3-methylphenyl, -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, or -C(Me)(OH)-4-chloro-3- methylphenyl.
Aspect 100. The compound of any one of aspects 92 to 99 wherein R3 is H.
Aspect 101. The compound of any one of aspects 92 to 100 wherein n is 1.
Aspect 102. The compound of any one of aspects 92 to 100 wherein n is 2.
Aspect 103. The compound of any one of aspects 92 to 102 that is a compound of Formula I or Formula II.
Aspect 104. The compound of aspect 103 wherein A is N.
Aspect 105. The compound of aspect 103 wherein A is CH.
Aspect 106. The compound of any one of aspects 103 to 105 wherein R4 is H.
Aspect 107. The compound of any one of aspects 103 to 105 wherein R4 is halo, preferably fluoro.
Aspect 108. The compound of any one of aspects 103 to 105 wherein R4 is -Ci-C6alkyl, preferably methyl.
Aspect 109. The compound of any one of aspects 92 to 108 that is a compound of Formula I or Formula III.
Aspect 110. The compound of aspect 109 wherein R2a is -Ci-C6alkyl. Aspect 111. The compound of any one of aspects 108 or 109 wherein R2b is -Ci-C6alkyl.
Aspect 112. The compound of any one of aspects 92 to 108 that is a compound of Formula II or Formula IV.
Aspect 113. The compound of aspect 112 wherein R2 is H.
Aspect 114. The compound of aspect 112 wherein R2 is -Ci-C6alkyl.
Aspect 1 15. A compound of Formula V, Formula VI, Formula VII, or Formula VIII:
Figure imgf000137_0001
or a pharmaceutically acceptable salt or solvate thereof; wherein
A is CH, CR6 or N; n is 1 or 2;
R1 is -Co-C6alk-C3-C6cycloalkyl, -Co-C6alk-C3-C6halocycloalkyl; -C2-C6alkenyl, -C2-
Cehaloalkenyl, -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-Cealk-C≡CH, -Co-
C6alk-C≡C-Ci-C6alkyl, -Co-C6alk-C≡C-Ci-C6haloalkyl, -Co-C6alk-C≡C-C3-C6cycloalkyl, - 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-C3- C6cycloalkyl, -C1-C6alk-S-CH2-aryl, -C1-C6alk-C(O)NH-aryl, -C0-C6alk-S-aryl, -C0-C6alk- S(O)aryl, -C0-C6alk-S(O)2aryl, or -C0-C6alk-Oaryl;
R2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
R2a and R2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
or R2a and R2b, together with the atom to which they are attached, form a C2- C6heterocycloalkyl ring;
R3 is H, halo, -C1-C6alkyl, or NH2;
R4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl;
R5 is H, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3- C6halocycloalkyl, -C0-C6alk-OH, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0-C6alk- N(C1-C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, or -C0-C6alk-N(C1-C6alkyl)-C3- C6cycloalkyl;
or R5 and R1, together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring;
R6 is halo or -C1-C6alkyl; and
R6a is H, halo or -C1-C6alkyl.
Aspect 116. The compound of aspect 115 wherein R1 is -C0-C6alk-C1-C6alkyl, preferably - CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1-C6alkyl, or - C(Me)(OH)-C1-C6alkyl. Aspect 117. The compound of aspect 115 wherein R1 is -C0-C6alk-C1-C6haloalkyl, preferably - CH(OH)-C1-C6haloalkyl, -CH(F)-C1-C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1- C6haloalkyl, or -C(Me)(OH)-C1-C6haloalkyl. Aspect 118. The compound of aspect 115 wherein R1 is -C0-C6alk-C≡CH, preferably -CH(OH)- C≡CH, -CH(F)-C≡CH, -CH(NH2)-C≡CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH. Aspect 119. The compound of aspect 115 wherein R1 is -C0-C6alk-C≡C-C1-C6alkyl, preferably - CH(OH)-C≡C-C1-C6alkyl, -CH(F)-C≡C-C1-C6alkyl, -CH(NH2)-C≡C-C1-C6alkyl, -CH(Me)-C≡C- C1-C6alkyl, or -C(Me)(OH)-C≡C-C1-C6alkyl, more preferably -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-CH3. Aspect 120. The compound of aspect 115 wherein R1 is -C0-C6alk-C≡C-C1-C6haloalkyl, preferably -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, more preferably - 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 121. The compound of aspect 115 wherein R1 is -C0-C6alk-C≡C-C3-C6cycloalkyl, preferably -CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3- C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)-C≡C-C3-C6cycloalkyl, more preferably -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C-cyclopropyl, - CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl. Aspect 122. The compound of aspect 115 wherein R1 is -C1-C6alk-aryl, preferably -CH2-aryl, - CH(OH)-aryl, -CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl, more preferably - CH2-4-chlorophenyl, -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(NH2)-4- chlorophenyl, -CH(NH2)-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)-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 123. The compound of aspect 115 wherein R1 is -Co-C6alk-S-aryl, preferably -S-4- chlorophenyl, -S-3,4-dichlorophenyl, -S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or -S-3- chloro-4-fluorophenyl .
Aspect 124. The compound of aspect 115 wherein R1 is -Co-C6alk-S(0)-aryl, preferably -S(0)-4- chlorophenyl, -S(0)-3,4-dichlorophenyl, -S(0)-3,4-difluorophenyl, -S(0)-3-fluoro-4-chlorophenyl, or -S(0)-3-chloro-4-fluorophenyl.
Aspect 125. The compound of aspect 115 wherein R1 is -Co-C6alk-S(0)2-aryl, preferably -S(0)2- 4-chlorophenyl, -S(0)2-3,4-dichlorophenyl, -S(0)2-3,4-difluorophenyl, -S(0)2-3-fluoro-4- chlorophenyl, or -S(0)2-3-chloro-4-fluorophenyl.
Aspect 126. The compound of aspect 115 wherein R1 is -Co-C6alk-0-aryl, preferably -0-4- chlorophenyl, -0-3,4-dichlorophenyl, -0-3,4-difluorophenyl, -0-3-fluoro-4-chlorophenyl, or -0-3- chloro-4-fluorophenyl .
Aspect 127. The compound of any one of aspects 115 to 126 wherein n is 1.
Aspect 128. The compound of any one of aspects 115 to 126 wherein n is 2.
Aspect 129. The compound of any one of aspects 115 to 128 wherein R3 is H.
Aspect 130. The compound of any one of aspects 115 to 128 wherein R5 is H.
Aspect 131. The compound of any on eof aspects 115 to 130 that is a compound of Formula V or Formula VI.
Aspect 132. The compound of aspect 131 wherein A is N.
Aspect 133. The compound of aspect 131 wherein A is CH.
Aspect 134. The compound of any one of aspects 131 to 133 wherein R4 is H.
Aspect 135. The compound of any one of aspects 131 to 133 wherein R4 is halo, preferably -F. Aspect 136. The compound of any one of aspects 131 to 133 wherein R4 is -Ci-C6alkyl, preferably methyl.
Aspect 137. The compound of any one of aspects 115 to 130 that is a compound of Formula V or Formula VII.
Aspect 138. The compound of aspect 137 wherein R2a is -Ci-C6alkyl.
Aspect 139. The compound of any one of aspects 137 to 138 wherein R2b is -Ci-C6alkyl.
Aspect 140. The compound of any one of aspects 115 to 130 that is a compound of Formula VI or Formula VIII.
Aspect 141. The compound of aspect 140 wherein R2 is H.
Aspect 142. The compound of aspect 140 wherein R2 is -Ci-C6alkyl.
Aspect 143. The compound of any one of aspects 115 to 130 and 137 to 142 that is a compound of Formula VII or Formula VIII.
Aspect 144. The compound of aspect 143 wherein R6a is H.
Aspect 145. A pharmaceutical composition comprising a compound according to any one of aspects 92 to 144 and a pharmaceutically acceptable excipient.
Aspect 146. 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 92 to 144.
Aspect 147. 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 92 to 147.
Aspect 148. The method of aspect 147, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon
cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer,
hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.

Claims

What is claimed:
1. A compound of Formula I, Formula II, Formula III, or Formula IV:
Figure imgf000143_0001
or a pharmaceutically acceptable salt or solvate thereof;
wherein
A is CH or N; 
n is 1 or 2;
R1 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-C6alk-C≡C-C1-C6haloalkyl, -C0-C6alk-C≡C-C3- C6cycloalkyl, -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-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, or -C1-C6alk-C(O)NH- aryl;
R2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
R2a and R2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl;
or R2a and R2b, together with the atoms to which they are attached, form a C2- C6heterocycloalkyl ring; R3 is H, halo, -C1-C6alkyl, or NH2; and
R4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl.
2. The compound of claim 1 wherein R1 is -C0-C6alk-C1-C6alkyl, preferably -C0-C6alk-C1- C6alkyl is -CH(OH)-C1-C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1- C6alkyl, or -C(Me)(OH)-C1-C6alkyl.
3. The compound of claim 1 wherein R1 is -C0-C6alk-C1-C6haloalkyl, preferably -CH(OH)-C1- C6 haloalkyl, -CH(F)-C1-C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1-C6haloalkyl, or -C(Me)(OH)-C1-C6haloalkyl.
4. The compound of claim 1 wherein R1 is -C0-C6alk-C≡CH, preferably -CH(OH)-C≡CH, - CH(F)-C≡CH, -CH(NH2)-C≡CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH.
5. The compound of claim 1 wherein R1 is -C0-C6alk-C≡C-C1-C6alkyl, preferably -CH(OH)- C≡C-C1-C6alkyl, -CH(F)-C≡C-C1-C6alkyl, -CH(NH2)-C≡C-C1-C6alkyl, -CH(Me)-C≡C-C1- C6alkyl, or -C(Me)(OH)-C≡C-C1-C6alkyl, more preferably-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-CH3.
6. The compound of claim 1 wherein R1 is -C0-C6alk-C≡C-C1-C6haloalkyl, preferably - 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, more preferably -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.
7. The compound of claim 1 wherein R1 is -C0-C6alk-C≡C-C3-C6cycloalkyl, preferably - CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3- C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)-C≡C-C3-C6cycloalkyl, more preferably CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C- cyclopropyl, -CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl.
8. The compound of claim 1 wherein R1 is -C1-C6alk-aryl, preferably -CH(OH)-aryl, -CH(F)- aryl, -CH(NH2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl, more preferably -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)-4-chloro-3- methylphenyl, -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)- 4-chloro-3-methylphenyl, -CH(NH2)-4-chlorophenyl, -CH(NH2)-3,4-dichlorophenyl, - CH(NH2)-3,4-difluorophenyl, -CH(NH2)-3-fluoro-4-chlorophenyl, -CH(NH2)-3-chloro-4- fluorophenyl, -CH(NH2)-4-chloro-3-methylphenyl, -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)-4-chloro-3-methylphenyl, -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, or -C(Me)(OH)-4-chloro-3- methylphenyl.
9. The compound of any one of claims 1 to 8 wherein R3 is H.
10. The compound of any one of claims 1 to 9 wherein n is 1.
11. The compound of any one of claims 1 to 9 wherein n is 2.
12. The compound of any one of claims 1 to 11 that is a compound of Formula I or Formula II.
13. The compound of claim 12 wherein A is N.
14. The compound of claim 12 wherein A is CH.
15. The compound of any one of claims 12 to 14 wherein R4 is H.
16. The compound of any one of claims 12 to 14 wherein R4 is halo, preferably fluoro.
17. The compound of any one of claims 12 to 14 wherein R4 is -C1-C6alkyl, preferably methyl.
18. The compound of any one of claims 1 to 17 that is a compound of Formula I or Formula III.
19. The compound of claim 18 wherein R2a is -C1-C6alkyl.
20. The compound of any one of claims 17 or 18 wherein R2b is -C1-C6alkyl.
21. The compound of any one of claims 1 to 17 that is a compound of Formula II or Formula IV.
22. The compound of claim 21 wherein R2 is H.
23. The compound of claim 21 wherein R2 is -Ci-C6alkyl.
24. A compound of Formula V, Formula VI, Formula VII, or Formula VIII:
Figure imgf000146_0001
or a pharmaceutically acceptable salt or solvate thereof; wherein
A is CH, CR6 or N; n is 1 or 2;
R1 is -Co-C6alk-C3-C6cycloalkyl, -Co-C6alk-C3-C6halocycloalkyl; -C2-C6alkenyl, -C2-
Cehaloalkenyl, -Co-Cealk-Ci-Cealkyl, -Co-Cealk-Ci-Cehaloalkyl, -Co-Cealk-C≡CH, - Co-C6alk-C≡C-Ci-C6alkyl, -Co-C6alk-C≡C-Ci-C6haloalkyl, -Co-Cealk-C≡C-C3- Cecycloalkyl, -Ci-Cealk-aryl, -Ci-Cealk-S-Ci-Cealkyl, -Ci-Cealk-S-Ci-Cehaloalkyl, - Ci-C6alk-S-C3-C6cycloalkyl, -Ci-C6alk-S-C3-C6halocycloalkyl, -Ci-Cealk-O-Ci- C6alkyl, -C1-C6alk-O-C3-C6cycloalkyl, -C1-C6alk-S-CH2-aryl, -C1-C6alk-C(O)NH- aryl, -C0-C6alk-S-aryl, -C0-C6alk-S(O)aryl, -C0-C6alk-S(O)2aryl, or -C0-C6alk-Oaryl; R2 is H, -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl; R2a and R2b are each independently -C1-C6alkyl, or -C0-C6alk-C3-C6cycloalkyl; or R2a and R2b, together with the atom to which they are attached, form a C2- C6heterocycloalkyl ring; R3 is H, halo, -C1-C6alkyl, or NH2; R4 is H, halo, -C1-C6alkyl, -C1-C4haloalkyl, -C2-C6heterocycloalkyl, oxo-substituted-C2- C6heterocycloalkyl, -C3-C6cycloalkyl, or -O-C1-C4alkyl; R5 is H, -C1-C6alkyl, -C1-C6haloalkyl, -C0-C6alk-C3-C6cycloalkyl, -C0-C6alk-C3- C6halocycloalkyl, -C0-C6alk-OH, -C0-C6alk-NH2, -C0-C6alk-NH-C1-C6alkyl, -C0- C6alk-N(C1-C6alkyl)-C1-C6alkyl, -C0-C6alk-NH-C3-C6cycloalkyl, or -C0-C6alk-N(C1- C6alkyl)-C3-C6cycloalkyl; or R5 and R1, together with the atom to which they are attached, form a C3-C6cycloalkyl ring or a heterocycloalkyl ring; R6 is halo or -C1-C6alkyl; and R6a is H, halo or -C1-C6alkyl.
25. The compound of claim 24 wherein R1 is -C0-C6alk-C1-C6alkyl, preferably -CH(OH)-C1- C6alkyl, -CH(F)-C1-C6alkyl, -CH(NH2)-C1-C6alkyl, -CH(Me)-C1-C6alkyl, or -C(Me)(OH)- C1-C6alkyl.
26. The compound of claim 24 wherein R1 is -C0-C6alk-C1-C6haloalkyl, preferably -CH(OH)-C1- C6haloalkyl, -CH(F)-C1-C6haloalkyl, -CH(NH2)-C1-C6haloalkyl, -CH(Me)-C1-C6haloalkyl, or -C(Me)(OH)-C1-C6haloalkyl.
27. The compound of claim 24 wherein R1 is -C0-C6alk-C≡CH, preferably -CH(OH)-C≡CH, - CH(F)-C≡CH, -CH(NH2)-C≡CH, -CH(Me)-C≡CH, or -C(Me)(OH)-C≡CH.
28. The compound of claim 24 wherein R1 is -C0-C6alk-C≡C-C1-C6alkyl, preferably -CH(OH)- C≡C-C1-C6alkyl, -CH(F)-C≡C-C1-C6alkyl, -CH(NH2)-C≡C-C1-C6alkyl, -CH(Me)-C≡C-C1- C6alkyl, or -C(Me)(OH)-C≡C-C1-C6alkyl, more preferably -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-CH3.
29. The compound of claim 24 wherein R1 is -C0-C6alk-C≡C-C1-C6haloalkyl, preferably - 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, more preferably -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.
30. The compound of claim 24 wherein R1 is -C0-C6alk-C≡C-C3-C6cycloalkyl, preferably - CH(OH)-C≡C-C3-C6cycloalkyl, -CH(F)-C≡C-C3-C6cycloalkyl, -CH(NH2)-C≡C-C3- C6cycloalkyl, -CH(Me)-C≡C-C3-C6cycloalkyl, or -C(Me)(OH)-C≡C-C3-C6cycloalkyl, more preferably -CH(OH)-C≡C-cyclopropyl, -CH(F)-C≡C-cyclopropyl, -CH(NH2)-C≡C- cyclopropyl, -CH(Me)-C≡C-cyclopropyl, or -C(Me)(OH)-C≡C-cyclopropyl.
31. The compound of claim 24 wherein R1 is -C1-C6alk-aryl, preferably -CH2-aryl, -CH(OH)- aryl, -CH(F)-aryl, -CH(NH2)-aryl, -CH(Me)-aryl, or -C(Me)(OH)-aryl, more preferably - CH2-4-chlorophenyl, -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(NH2)-4-chlorophenyl, -CH(NH2)-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)-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.
32. The compound of claim 24 wherein R1 is -Co-C6alk-S-aryl, preferably -S-4-chlorophenyl, -S- 3, 4-di chlorophenyl, -S-3,4-difluorophenyl, -S-3-fluoro-4-chlorophenyl, or -S-3-chloro-4- fluorophenyl.
33. The compound of claim 24 wherein R1 is -Co-C6alk-S(0)-aryl, preferably -S(0)-4- chlorophenyl, -S(0)-3,4-dichlorophenyl, -S(0)-3,4-difluorophenyl, -S(0)-3-fluoro-4- chlorophenyl, or -S(0)-3-chloro-4-fluorophenyl.
34. The compound of claim 24 wherein R1 is -Co-C6alk-S(0)2-aryl, preferably -S(0)2-4- chlorophenyl, -S(0)2-3,4-dichlorophenyl, -S(0)2-3,4-difluorophenyl, -S(0)2-3-fluoro-4- chlorophenyl, or -S(0)2-3-chloro-4-fluorophenyl.
35. The compound of claim 24 wherein R1 is -Co-C6alk-0-aryl, preferably -O-4-chlorophenyl, - 0-3, 4-di chlorophenyl, -0-3,4-difluorophenyl, -0-3-fluoro-4-chlorophenyl, or -0-3-chloro-4- fluorophenyl.
36. The compound of any one of claims 24 to 35 wherein n is 1.
37. The compound of any one of claims 24 to 35 wherein n is 2.
38. The compound of any one of claims 24 to 37 wherein R3 is H.
39. The compound of any one of claims 24 to 37 wherein R5 is H.
40. The compound of any on eof claims 24 to 39 that is a compound of Formula V or Formula VI.
41. The compound of claim 40 wherein A is N.
42. The compound of claim 40 wherein A is CH.
43. The compound of any one of claims 40 to 42 wherein R4 is H.
44. The compound of any one of claims 40 to 42 wherein R4 is halo, preferably -F.
45. The compound of any one of claims 40 to 42 wherein R4 is -Ci-C6alkyl, preferably methyl.
46. The compound of any one of claims 24 to 39 that is a compound of Formula V or Formula VII.
47. The compound of claim 46 wherein R2a is -Ci-C6alkyl.
48. The compound of any one of claims 46 to 47 wherein R2b is -Ci-C6alkyl.
49. The compound of any one of claims 24 to 39 that is a compound of Formula VI or Formula VIII.
50. The compound of claim 49 wherein R2 is H.
51. The compound of claim 49 wherein R2 is -Ci-C6alkyl.
52. The compound of any one of claims 24 to 39 and 46 to 51 that is a compound of Formula VII or Formula VIII.
53. The compound of claim 52 wherein R6a is H.
54. A pharmaceutical composition comprising a compound according to any one of the
preceding claims and a pharmaceutically acceptable excipient.
55. A method of inhibiting a protein arginine methyltransf erase 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 53.
56. 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 56.
57. The method of claim 56, wherein the disease or disorder associated with aberrant PRMT5 activity is breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, cervical cancer, leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), epidermoid cancer, hemoglobinopathies such as b-thalassemia and sickle cell disease (SCD), CDKN2A deleted cancers; 9P deleted cancers; MTAP deleted cancers; glioblastoma, NSCLC, head and neck cancer, bladder cancer, or hepatocellular carcinoma.
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